ISSN 0482-5004
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
MARCH/APRILt7PMVNFt/VNCFS
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www.reumatologia.com.br
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
Bimonthly Edition (Publicação Bimestral)
Editors (Editores)
Coeditors (Coeditores)
Max Victor Carioca Freitas
Eloísa Silva Dutra de Oliveira Bonfá
Mittermayer Barreto Santiago
Roberto Ezequiel Heymann
Hilton Seda
Paulo Louzada-Junior
Universidade Federal do Ceará, Fotaleza, CE, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil
Pontifícia Universidade Católica do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
João Carlos Tavares Brenol
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Ricardo Fuller
Simone Appenzeller
Universidade Estadual de Campinas, Campinas, SP, Brazil
Editorial Board (Conselho Editorial)
Acir Rachid
Geraldo da Rocha Castelar Pinheiro
Maurício Levy Neto
Universidade Federal do Paraná, Curitiba, PR, Brazil
Universidade do Estado do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
Gilberto Santos Novaes
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Alexandre Wagner S Souza
Natalino H. Yoshinari
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Pontifícia Universidade Católica de São Paulo,
São Paulo, SP, Brazil
Ari Stiel Radu
Isídio Calich
Nílzio Antônio da Silva
Adil Muhib Samara
Milton Helfenstein Jr.
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Carlos Alberto von Muhlen
Ivânio Alves Pereira
Percival Degrava Sampaio-Barros
Faculdade de Medicina da Pontifícia Universidade
Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
Universidade Federal de Santa Catarina,
Florianópolis, SC, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Claudia Goldenstein-Schainberg
Jamil Natour
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Rio Grande do Sul,
Porto Alegre, RS, Brazil
Cláudio Arnaldo Len
João Francisco Marques Neto
Rina Dalva P. N. Giorgi
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Clóvis Artur Almeida da Silva
Universidade de São Paulo, São Paulo, SP, Brazil
Cristiano Augusto de Freitas Zerbini
Hospital Heliópolis, São Paulo, SP, Brazil
Daniel Feldman Polak
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Durval Kraychete
Escola Bahiana de Medicina e Universidade
Federal da Bahia, Salvador, BA, Brazil
Eduardo de Souza Meireles
Universidade de São Paulo, São Paulo, SP, Brazil
Eduardo Ferreira Borba Neto
Universidade Estadual de Campinas, Campinas, SP, Brazil
José Goldenberg
Universidade Federal de São Paulo, São Paulo, SP, Brazil
José Roberto Provenza
Universidade Estadual de Campinas, Campinas, SP, Brazil
Jozélio Freire de Carvalho
Universidade Federal de Goiás, Goiânia, GO, Brazil
Ricardo M. Xavier
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
Roger A. Levy
Universidade Estadual do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Rosa Maria Rodrigues Pereira
Universidade de São Paulo, São Paulo, SP, Brazil
Centro Médico Aliança, Salvador, BA, Brazil
Rozana Mesquita Ciconelli
Lais V. Lage
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Samuel Katsuyki Shinjo
Lilian Tereza Lavras Costallat
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
Sebastião Cézar Radominski
Luís Eduardo Coelho Andrade
Universidade Federal do Paraná, Curitiba, PR, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Sheila Knupp de Oliveira
Emília Inoue Sato
Luiz Fernando de Souza Passos
Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Amazonas, Manaus, AM, Brazil
Fernanda Rodrigues de Lima
Marcelo de Medeiros Pinheiro
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Fernando Queiroz da Cunha
Maria Odete E. Hilário
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Francisco Airton Castro Rocha
Marta Maria das Chagas Medeiros
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Simone Appenzeller
Universidade de Campinas, Campinas, SP, Brazil
Vera Lúcia Szejnfeld
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Wiliam H. Chahade
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
International Editorial Board (Conselho Editorial Internacional)
Ariel Masetto
Juan Manuel Anaya
Munther Khamashta
Université de Sherbrooke, Sherbrooke, Canada
Corporación de Investigaciones Biológicas, Medellín, Colômbia
St. Thomas´ Hospital, London, UK
Arthur Kavanaugh
Luis Javier Jara
H Ralph Schumacher Jr
University of California, San Diego, USA
Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
University of Pennsylvania, Philadelphia, USA
Bernardo Pons Estel
Mario Cardiel
Ricardo Cervera Segura
Universidad Nacional de Rosario, Rosario, Argentina
Instituto Nacional de la Nutrición "Salvador Zubiran",
Morrelia, Mexico
Hospital Clinic, Barcelona, Spain
Hospital Monte Sinai, Cuenca, Equador
Mario Garcia-Carrasco
Chapel Allerton Hospital, Leeds, UK
Ernest Choy
Facultad de Medicina, BUAP, Puebla, Mexico
Claudio Galarza Maldonado
King's College, London, UK
Mário Viana de Queiroz
Jordi Antón López
Universidade Clássica de Lisboa, Lisboa, Portugal
Hospital Sant Joan de Déu, Barcelona, Spain
Marvin Fritzler
José Antonio Melo Gomes
University of Calgary, Calgary, Canada
Instituto Português de Reumatologia, Lisboa, Portugal
Richard J Wakefield
Thomas Dörner
Charite Hospital, Berlin, Germany
Yehuda Shoenfeld
Chaim Sheba Medical Center, Tel Aviv University,
Tel Hashomer, Israel
BSR Office (Secretaria SBR)
Rogério Quintiliano Amaral
Av. Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94
CEP 01402-000
São Paulo, SP
Fone/fax: 55 (11) 3289-7165
E-mail: [email protected]; [email protected]
website: www.reumatologia.com.br
Brazilian Journal of Rheumatology is listed in Web of Science, MEDLINE,
LILACS, SciELO, Scopus and Index Copernicus databases. BJR is affiliated to the
International Committee of Medical Journal Editors.
A Revista Brasileira de Reumatologia é indexada nas bases de dados Web of
Science, MEDLINE, LILACS, SciELO, Scopus e Index Copernicus. A RBR é filiada
ao International Committee of Medical Journal Editors.
Brazilian Journal of Rheumatology (BJR) is an official publication of the Brazilian
Society of Rheumatology (BSR) in partnership with Elsevier Editora Ltda. and is
dedicated to the medical community in Brazil and Latin America.
Edited by Brazilian Society of Rheumatology.
Published by Elsevier Editora Ltda. © 2013.
Tradução | Translation: Stela Maris Costalonga | American Journal Experts
All rights reserved and protected by law 9.610 - 19/02/98. No part of this publication
may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording or any information storage and
retrieval system, without permission in writing from BSR and the Publisher.
BJR receives finnancial support from Fundos Remanescentes da Sociedade
Brasileira de Reumatologia.
A Revista Brasileira de Reumatologia (RBR) é uma publicação oficial da Sociedade
Brasileira de Reumatologia (SBR) em conjunto com Elsevier Editora Ltda., distribuída
exclusivamente à classe médica do Brasil e da América Latina.
Editada por Sociedade Brasileira de Reumatologia.
Publicada por Elsevier Editora Ltda. © 2013.
Todos os direitos reservados e protegidos pela lei 9.610 - 19/02/98. Nenhuma parte desta
publicação poderá ser reproduzida, sem autorização prévia, por escrito, da Elsevier
Editora Ltda. e da SBR, sejam quais forem os meios empregados: eletrônicos, mecânicos,
fotográficos, gravação ou quaisquer outros.
A RBR recebe auxílio financeiro de Fundos Remanescentes da Sociedade Brasileira de
Reumatologia.
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Content dedicated to the medical community. Material de distribuição exclusiva à classe médica.
INSTRUCTIONS TO AUTHORS
The Brazilian Journal of Rheumatology (BJR), an official organ of Sociedade
Brasileira de Reumatologia (Brazilian Society of Rheumatology), was founded
in 1957 and is published bimonthly. The journal publishes original articles,
review articles, brief communications, case reports and letters to the editors.
To submit a manuscript, please access the site http://ees.elsevier.com/bjr.
Format of the manuscript
The manuscript can be submitted in Portuguese or English, double spaced,
with 2.5 cm margins. Unconventional abbreviations, medical jargon and
telegraphic style should not be used in the text. Citation of drugs and
pharmaceutical products must be done using pharmacological nomenclature,
without any mention to commercial names.
Manuscript structure
Manuscript*, Title Page*, Cover Letter, and Author Agreement* must be
submitted in separate files. Tables and Figures should be numbered as cited
in the text and sent in separate files with corresponding titles and legends.
(*required files)
Title page
The title page should contain: a) the full title; b) the full name of the authors
and their most important academic degree; c) the department and institution
where the study was originated; d) the full address and e-mail of the
corresponding author; e) conflict of interest and relevant financial agencies;
f) a running title with no more than 60 characters.
Author Agreement
It is the document where the authors declare that the manuscript is original, in
addition to approve the manuscript object of the submission, the authorship
and the order of authors listed. It must be signed by all authors. Below is
presented an example.
Dear Editor,
We, the undersigned, declare that this manuscript is original, has not been
published before and is not currently being considered for publication elsewhere.
We would like to draw the attention of the Editor to the following publications
of one or more of us that refer to aspects of the manuscript presently being
submitted.
We confirm that the manuscript has been read and approved by all named
authors and that there are no other persons who satisfied the criteria for
authorship but are not listed. We further confirm that the order of authors
listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the
Editorial process. He/she is responsible for communicating with the other
authors about progress, submissions of revisions and final approval of proofs.
(Signature of all authors)
Original article
The original article should contain: the title page, the abstract page with
keywords, introduction, material and methods or patients and methods, results
and discussion, acknowledgements, references, tables, figures and figure
legends. Original articles should not exceed 5,000 words including references
and excluding the title page, abstract, tables and legends. It is allowed up to
six figures or tables and 50 references.
Abstract page
The abstract page should contain: a) objective, methods, results and
conclusions, with no more than 250 words; b) three to five keywords.
Introduction
As the aim of this section is to define the purpose and the reasons for the
accomplishment of the work, we do not recommend a large literature review.
Patients and methods or Material and methods
This section should include enough information that allows the reproduction of
the work and, when it is relevant, the approval by the institutional Committee
of Ethics. The methods employed in the statistical analysis should always
be quoted.
Results
They should be clear and concise. Tables and graphics should not duplicate
information.
Discussion
It should be concise, interpreting the results in the context of the present literature.
Please do not exceed the limit of half the number of pages of the complete work.
Acknowledgments
Only to people who contributed; i.e., with techniques, discussion and sending
patients. Financial help should be referred in the title page.
References
They should be quoted in the text in Arabic numerals, superscript, with no brackets.
Numbering should be sequencial, according to the quotation order in the text.
Please quote all the authors in works with until six authors; after six authors,
quote the first six followed by the expression et al. Reference Manager or Endnote
programs are strongly recommended for use adopting the Vancouver style.
Examples for reference citation are presented below. Authors should consult
NLM’s Citing Medicine for additional information on the reference formats.
Printed article
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Reference retrieved from electronic address
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink. com.w10069.dotlib.com.
br/content/l05j4j3332041225/fulltext.pdf. [Accessed in February 24, 2008].
Book
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical
microbiology. 4th ed. St. Louis: Mosby; 2002.
Tables and figures
Each Table or Figure should be numbered with Arabic numerals and sent in
an individual file (.jpg, .tif, .png, .xls, .doc) with minimum of 300 dpi. Titles
and legends should be in the same Table/Figure file to wich they refer. Tables
and Figures should include enough information so the reader can understand
them without going to the text.
Photomicrographies should include the appropriated scale.
Review article
Reviews, preferentially systematic, may be submitted to BJR. They should
cover deeply any interesting theme for the rheumatologist. They do not present
a standard structure, neither introduction or conclusion. Please send abstracts
without subdivisions with three to five keywords. Review articles should not
exceed 6,000 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to five figures or tables and 70 references.
Case report
Must have six authors at most. They should include an abstract and keywords,
without subdivisions. The text, however, should present the following sections:
introduction, which should be concise; case report, containing the description and
the evolution of the clinical case, laboratory exams, illustrations and tables (that
substitute the sections material and methods and results); and discussion. It should
not exceed 1,500 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to two figures or tables and 15 references.
Brief communication
It covers a point or a specific detail. It should present an abstract with no
more than 250 words and three to five keywords. The text does not include
subdivisions, and should not exceed 2,500 words including references and
excluding the title page, abstract, tables and legends. It is allowed up to three
figures or tables and 25 references.
Rules for applying the appropriate tense in scientific writing
Context or section
Appropriate verb tense
Abstract
Past tense
Introduction
Most present tense (established facts,
previous published data)
Methods, materials used,
and results
Past tense
Discussion/Conclusion
Mixture of past and present, sometimes
future tense
Attribution
Past tense
Ex.: Andrade et al. reported that...
Description of Tables and
Figures
Present tense
Established knowledge,
previous results etc.
Present tense
General rules to obtain a good scientific writing:
1. Use active voice.
2. Setences must be short, clear and objective.
3. Units of measurement are abbreviated when use with numerical values
(e.g., 1 mg), but are not abbreviated if used without numerical values.
Systeme International d'Únites (SI units) must be used. Remember to
leave a space between the number and unit (e.g., 10 mg/dL), except for
the percentage mark that follows the number without space (e.g., 70%).
The plural form of units of measurement is the same as the singular form
(e.g., 1 mL, 10 mL; 1 h, 10 h). Spell out numbers at the beginning of a
sentence.
4. Define abbreviations the first time they appear. Avoid abbreviations in
tittles and abstracts.
5. Do not use contractions (e.g., doesn't, can't etc.).
Recommended book: Rogers SM. Mastering scientific and medical writing:
a self-help guide. Berlin: Springer; 2007.
Legal and ethical considerations
According to the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals (International Committee of Medical Journal Editors –
February 2006).
Conflict of interest
Public trust in the peer review process and the credibility of published
articles depend in part on how well conflict of interest is handled during
writing, peer review, and editorial decision making. Conflict of interest
exists when an author (or the author’s institution), reviewer, or editor has
financial or personal relationships that inappropriately influence (bias) his
or her actions (such relationships are also known as dual commitments,
competing interests, or competing loyalties). These relationships vary
from those with negligible potential to those with great potential to
influence judgment, and not all relationships represent true conflict of
interest. The potential for conflict of interest can exist whether or not
an individual believes that the relationship affects his or her scientific
judgment. Financial relationships (such as employment, consultancies,
stock ownership, honoraria, paid expert testimony) are the most easily
identifiable conflicts of interest and the most likely to undermine the
credibility of the journal, the authors, and of science itself. However,
conflicts can occur for other reasons, such as personal relationships,
academic competition, and intellectual passion.
Informed consent
Patients have a right to privacy, that should not be infringed without
informed consent. Identifying information, including patients’ names,
initials, or hospital numbers, should not be published in written descriptions,
photographs, and pedigrees unless the information is essential for scientific
purposes and the patient (or parent or guardian) gives written informed
consent for publication. Informed consent for this purpose requires that a
patient who is identifiable be shown the manuscript to be published. Authors
should identify Individuals who provide writing assistance and disclose the
funding source for this assistance. Identifying details should be omitted if
they are not essential.
Complete anonymity is difficult to achieve. However, an informed consent
should be obtained if there is any doubt. For example, masking the eye
region in photographs of patients is inadequate protection of anonymity. If
identifying characteristics are altered to protect anonymity, such as in genetic
pedigrees, authors should provide assurance that alterations do not distort
scientific meaning and editors should so note. When informed consent has
been obtained it should be indicated in the published article.
Ethical treatment
When reporting experiments on human subjects, authors should indicate
whether the procedures followed were in accordance with the ethical
standards of the responsible committee on human experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as
revised in 2000. If doubt exists whether the research was conducted in
accordance with the Helsinki Declaration, the authors must explain the
rationale for their approach, and demonstrate that the institutional review
body explicitly approved the doubtful aspects of the study. When reporting
experiments on animals, authors should be asked to indicate whether the
institutional and national guide for the care and use of laboratory animals
was followed.
Clinical trials registry
Clinical trials must be registered according to WHO recommendation at www.
who.int/ictrp/en/. The definition of clinical trial include preliminary trials
(phase I): any study with prospective recruiting of subjects to undergo any
health-related intervention (drugs, surgical procedures, equipment, behavioral
therapies, food regimen, changes in health care) to evaluate the effects on
clinical outcomes (any biomedical or health-related parameter, including
pharmacokinetics measurements and adverse reactions).
The BJR has the right not to publish trials not complying with these and
other legal and ethical standards determined by international guidelines.
Financing and support
The authors should also inform if they received financing or support
from institutions like CNPq, CAPES, SBR Remaining Funds, Graduated
Institutions, Laboratories etc.
INSTRUÇÕES PARA OS AUTORES
A Revista Brasileira de Reumatologia (RBR), órgão oficial da Sociedade Brasileira de Reumatologia, foi fundada em 1957 e é publicada bimestralmente.
A revista publica artigos originais, artigos de revisão, comunicações breves,
relatos de casos e cartas aos editores.
Resultados
Devem ser claros e concisos. Tabelas e gráficos não devem duplicar informações.
Discussão
O manuscrito deve ser submetido online através do site http://ees.elsevier.com/bjr.
Deve ser concisa, interpretando os resultados no contexto da literatura atual. É
conveniente não ultrapassar a metade do número de páginas do trabalho completo.
Apresentação do manuscrito
Agradecimentos
O manuscrito pode ser submetido em português ou inglês, em espaço
duplo, com margens de 2,5 cm. No texto não devem ser empregadas
abreviaturas não convencionais, gírias (jargões) médicas ou redação tipo
telegráfica. A citação de medicamentos e produtos farmacêuticos deve
ser feita utilizando-se apenas a nomenclatura farmacológica, sem menção
do nome comercial.
Estrutura do manuscrito
Manuscript*, Title Page*, Cover Letter e Author Agreement* devem ser
enviados em arquivos individuais. Tabelas e figuras devem ser numeradas
conforme citadas no texto e enviadas em arquivos separados, com títulos e
legendas correspondentes. (*arquivos obrigatórios)
Página do título
Deve conter: a) título do artigo; b) nome completo dos autores e sua titulação
mais importante; c) departamento(s) e instituição(ões) onde se originou o trabalho; d) nome, endereço completo e e-mail válido do autor responsável para
correspondência; e) conflito de interesse e agências financiadoras relevantes;
f) título resumido com no máximo 60 caracteres.
Author Agreement
É o documento no qual os autores declaram a originalidade do manuscrito,
além de aprovarem o artigo objeto da submissão, a autoria e a ordem da lista
de autores. Deve ser assinado por todos os autores. A seguir é apresentado
um modelo.
Caro Editor,
Os autores, abaixo assinados, declaram que este manuscrito é original,
não foi publicado antes e não se encontra submetido para qualquer outra
publicação.
Gostaríamos de pedir a atenção do Editor para a presente publicação de nós
autores, referente a aspectos do presente manuscrito submetido.
Confirmamos que o manuscrito foi lido e aprovado por todos os autores
signatários e que não há nenhum outro autor a fazer parte senão os listados.
Confirmamos também que a ordem dos autores listada no manuscrito foi
aprovada por todos.
Entendemos que o Autor para Correspondência será o único contato para o
processo editorial. Ele será o único responsável pela comunicação com os
demais autores acerca do progresso da submissão, da revisão do manuscrito
e de sua aprovação final.
(Assinatura de todos os autores)
Artigo Original
Deve conter: página do título, página de resumo com palavras-chave, introdução, material e métodos ou pacientes e métodos, resultados e discussão,
agradecimentos, referências, tabelas, figuras e legendas das figuras. Não
deve exceder 5.000 palavras, incluindo-se as referências e excluindo-se a
página do título, resumo, tabelas e legendas. Pode exibir até seis figuras ou
tabelas e até 50 referências.
Apenas às pessoas que contribuíram, por exemplo, com técnicas, discussão e
envio de pacientes. Auxílio financeiro deve ser referido na página do título.
Referências
Devem ser citadas no texto em algarismos arábicos, sobrescritos e depois da
pontuação, sem parênteses ou colchetes. A numeração deve ser sequencial,
de acordo com a ordem de citação no texto. Nas referências com mais de
seis autores, devem ser citados os seis primeiros, seguidos pela expressão
et al. Sugere-se a utilização dos programas Reference Manager ou Endnote,
seguindo-se o estilo Vancouver. Exemplos de referência para diferentes
formatos são apresentados a seguir. Os autores devem consultar o NLM’s
Citing Medicine para mais informações sobre os formatos das referências.
Artigo de revista
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Artigo extraído de endereço eletrônico
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink.com.w10069.dotlib.com.br/
content/l05j4j3332041225/fulltext. pdf. [Accessed in February 24, 2008].
Livro
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.
Tabelas e Figuras
Cada tabela ou figura deverá ser numerada em algarismo arábico e enviada
em arquivo separado (.jpg, .tif, .png, .xls, .doc) com 300 dpi no mínimo.
Título e legenda devem estar no mesmo arquivo da figura ou tabela a que se
referem. Tabelas e ilustrações devem ser autoexplicativas, com informações
suficientes para sua compreensão sem que se tenha de recorrer ao trabalho.
Fotomicrografias devem incluir a escala apropriada.
Artigo de Revisão
Revisões, preferencialmente sistemáticas, podem ser submetidas à RBR,
devendo abordar com profundidade um tema de interesse para o reumatologista. Não apresentam estruturação padronizada, prescindindo de introdução
ou discussão. Devem apresentar resumo sem subdivisões, com três a cinco
palavras-chave, e não devem exceder 6.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Podem
exibir até cinco figuras ou tabelas e até 70 referências.
Relato de Caso
Introdução
Deve incluir resumo e palavras-chave, sem necessidade de subdivisões. O texto,
porém, apresenta as seguintes seções: introdução, que deve ser concisa; relato de
caso, contendo a descrição e a evolução do quadro clínico, exames laboratoriais,
ilustrações e tabelas (que substituem as seções material e métodos e resultados);
e discussão. Deve conter no máximo seis autores, e não deve exceder 1.500
palavras, incluindo-se as referências e excluindo-se a página do título, resumo,
tabelas e legendas. Pode exibir até duas figuras ou tabelas e até 15 referências.
A finalidade dessa seção é definir o propósito e as razões para a realização
do trabalho. Não se recomenda extensa revisão da literatura.
Comunicação breve
Página de resumo
Deve conter: a) objetivo, métodos, resultados e conclusões, não excedendo
250 palavras; b) três a cinco palavras-chave.
Pacientes e métodos ou Material e métodos
Deve incluir informações suficientes que permitam a reprodução do trabalho e,
quando pertinente, a aprovação pelo Comitê de Ética institucional. Os métodos
empregados na análise estatística devem sempre ser citados.
Aborda um ponto ou detalhe específico de um tema. Deve incluir resumo
com no máximo 250 palavras, e três a cinco palavras-chave. O texto não
necessita subdivisões, deve ter até 2.500 palavras incluindo-se as referências
e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até
três figuras ou tabelas e até 25 referências.
Regras para aplicar tempos verbais apropriados de acordo com
o contexto ou seção
Contexto ou seção
Resumo
Introdução
Métodos, materiais e
resultados
Discussão/Conclusão
Atribuições
Descrição de Tabelas e Figuras
Conhecimento estabelecido e
resultados prévios
Tempo verbal apropriado
Passado
Presente, quando se referir a fatos estabelecidos e conhecimento prévio
Passado
Combinado de passado (quando se referir a resultados obtidos no trabalho) e
presente (quando se referir a fatos estabelecidos e conhecimento prévio); às
vezes pode ser utilizado o futuro (especialmente quando se referir a perspectivas de trabalhos a serem realizados)
Passado
Ex.: Andrade et al. relataram...
Presente
Presente
Regras gerais para se obter uma boa escrita em um artigo científico:
1. Prefira a voz ativa.
2. As sentenças devem ser curtas, claras e objetivas.
3. A unidade de medida deve ser abreviada quando empregada com
valores numéricos (p. ex., 1 mg), mas escrita por extenso quando
separada de valor numérico. Utilize o Sistema Internacional de
Unidades (SI units) para definir as unidades de medida. Lembre-se
de deixar um espaço entre o número e a unidade (p. ex., 10 mg/dL),
exceto quando for porcentagem, que deve estar junto (p. ex., 70%).
O plural das unidades de medida é a mesma forma do singular (p.
ex., 1 mL, 10 mL; 1 h, 10 h). Quando iniciarem a frase, os números
devem estar por extenso, e não em algarismo arábico.
4. Defina a abreviação na primeira vez que aparecer no texto principal.
Após a definição, use sempre a abreviação em vez da forma por extenso.
Evite o uso de abreviações no título e no resumo.
5. Ao escrever em inglês, não utilize contrações (p. ex., prefira does not em
vez de doesn't).
Livro recomendado: Rogers SM. Mastering scientific and medical writing: a
self-help guide. Berlin: Springer; 2007.
Considerações éticas e legais
A RBR segue as normas do Uniform Requirements for Manuscripts (URM)
Submitted to Biomedical Journals desenvolvidas pelo The International
Committee of Medical Journal Editors (ICMJE) – fevereiro de 2006.
Conflito de interesse
A confiança pública no processo de revisão por pares e a credibilidade
dos artigos publicados dependem, em parte, de como o conflito de
interesse é administrado durante a redação, a revisão por pares e a
decisão editorial. O conflito de interesse existe quando um autor (ou
instituição do autor), revisor ou editor tem relações financeiras ou
pessoais que influenciem de forma inadequada (viés) suas ações (tais
relações são também conhecidas como duplo compromisso, interesses
conflitantes ou fidelidades conflitantes). Essas relações variam entre
aquelas com potencial insignificante até as com grande potencial
para influenciar o julgamento, e nem todas as relações representam
verdadeiro conflito de interesse. O potencial conflito de interesse pode
existir dependendo se o indivíduo acredita ou não que a relação afete
seu julgamento científico. Relações financeiras (tais como emprego, consultorias, posse de ações, testemunho de especialista pago) são os conflitos
de interesse mais facilmente identificáveis e os mais suscetíveis de minar a
credibilidade da revista, dos autores e da própria ciência. No entanto, podem
ocorrer conflitos por outras razões, tais como relações pessoais, competição
acadêmica e paixão intelectual.
Consentimento informado
Os pacientes têm o direito à privacidade, que não deve ser infringida
sem o consentimento informado. A identificação de informações,
incluindo os nomes dos pacientes, iniciais ou números no hospital,
não devem ser publicadas em descrições, fotografias e genealogias, a
menos que a informação seja essencial para os propósitos científicos
e o paciente (ou responsável) dê o consentimento livre e esclarecido
para a publicação.
O consentimento informado para este propósito requer que o manuscrito
a ser publicado seja mostrado ao paciente. Os autores devem identificar
os indivíduos que prestam assistência a escrever e divulgar a fonte de
financiamento para essa assistência. Detalhes identificadores devem ser
omitidos se não são essenciais.
O anonimato completo é difícil de se conseguir; no entanto, no caso
de qualquer dúvida, o consentimento deve ser obtido. Por exemplo,
mascarar a região ocular em fotografias de pacientes é uma proteção
de anonimato inadequada. Se as características de identificação são
alteradas para proteger o anonimato, como na linhagem genética, os
autores devem garantir que as alterações não distorçam o significado
científico. Quando o consentimento informado foi obtido, ele deve ser
indicado no artigo publicado.
Princípios éticos
Ao relatar experimentos em seres humanos, os autores devem indicar
se os procedimentos seguidos estiveram de acordo com os padrões
éticos do comitê responsável por experimentação humana (institucional e nacional) e com a Declaração de Helsinki de 1975, revisado em
2000. Se houver dúvida se a pesquisa foi realizada em conformidade
com a Declaração de Helsinki, os autores devem explicar a razão
para sua abordagem e demonstrar que o corpo de revisão institucional
aprovou explicitamente os aspectos duvidosos do estudo. Ao relatar
experimentos com animais, os autores devem indicar se as orientações
institucionais e nacionais para o cuidado e a utilização de animais de
laboratório foram seguidas.
Registro de ensaios clínicos
Os ensaios clínicos devem ser registrados segundo recomendação da
OMS em www.who.int/ictrp/en/. A definição de ensaios clínicos incluem ensaios preliminares (fase I): um estudo prospectivo com o
recrutamento de indivíduos submetidos a qualquer intervenção relacionada à saúde (medicamentos, procedimentos cirúrgicos, aparelhos,
terapias comportamentais, regime alimentar, mudanças nos cuidados
de saúde) para avaliar os efeitos em desfechos clínicos (qualquer
parâmetro biomédico e de saúde, inclusive medidas farmacocinéticas
e reações adversas).
A RBR tem o direito de não publicar trabalhos que não cumpram estas
e outras normas legais e éticas explicitadas nas diretrizes internacionais.
Financiamento e apoio
Os autores devem, também, informar se receberam financiamento ou apoio
de instituições como CNPq, CAPES, Fundos Remanescentes da SBR,
instituições universitárias, laboratórios etc.
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Founded on July 15, 1948 (Fundada em 15 de julho de 1948)
Executive Board of Directors for the 2012–2014 Biennium
Diretoria Executiva para o Biênio 2012–2014
President (Presidente)
Walber Pinto Vieira, CE
General secretary (Secretário geral)
Francisco José Fernandes Vieira, CE
1st secretary (1º secretário)
Lauredo Ventura Bandeira, SP
2nd secretary (2ª secretária)
Rosa Maria Rodrigues Pereira, SP
Treasurer (Tesoureiro)
José Eyorand Castelo B. Andrade, CE
Vice-treasurer (Vice-tesoureiro)
José Roberto Provenza, SP
Scientific director (Diretor científico)
Mittermayer Barreto Santiago, BA
Elected president (Presidente eleito)
Cesar Emile Baaklini, SP
Rheumatology Aid Fund to
Rheumatology Research and Teaching
Conselho do Fundo de Auxílio a
Pesquisa e Ensino em Reumatologia
Acir Rachid, PR
Adil Muhib Samara, SP
Antônio Carlos Ximenes, GO
Caio Moreira, MG
Cesar Emile Baaklini, SP
Emília Inoue Sato, SP
Fernando de Souza Cavalcanti, PE
Fernando Neubarth, RS
Geraldo da Rocha Castelar Pinheiro, RJ
Geraldo Gomes de Freitas, PE
Hilton Seda, RJ
Iêda Maria Magalhães Laurindo, SP
João Carlos Tavares Brenol, RS
João Francisco Marques Neto, SP
Nílzio Antônio da Silva, GO
Sebastião Cezar Radominski, PR
Walber Pinto Vieira, CE
Wiliam Habib Chahade, SP
Members (Membros)
Ana Cristina de Medeiros Ribeiro, SP
Claiton Viegas Brenol, RS
Eduardo de Souza Meirelles, SP
Jussara de Almeida L. Kochen, SP
Rafael Mendonça da Silva Chakr, RS
Epidemiology Commission
Comissão de Epidemiologia
Specialist Title Commission
Comissão de Título de Especialista
Coordinator (Coordenadora)
Emília Inoue Sato, SP
Members (Membros)
Fernanda Rodrigues Lima, SP
Gilda Aparecida Ferreira, MG
Ines Guimarães Silveira, RS
José Tupinambá Souza Vasconcelos, PI
Marcelo de Medeiros Pinheiro, SP
Mauro Goldfarb, RJ
Nafice Costa Araujo, SP
Rafael Navarrete, GO
Valeria Valim Cristo, ES
Wilton Silva dos Santos, DF
Editorial Council (Conselho Editorial)
Kaline Medeiros Costa Pereira, SP
Edgard Torres dos Reis Neto, SP
Editors (Editores)
Tânia Carolina Monteiro de Castro, SP
Frederico Augusto Gurgel Pinheiro, SP
Collaborator (Colaborador)
Plínio José do Amaral, SP
Brazilian Journal of Rheumatology
Revista Brasileira de Reumatologia
Editors (Editores)
Max Victor Carioca Freitas, CE
Roberto Ezequiel Heymann, SP
Eloísa Silva Dutra de Oliveira Bonfá, SP
Hilton Seda, RJ
João Carlos Tavares Brenol, RS
Mittermayer Barreto Santiago, BA
Paulo Louzada-Junior, SP
Ricardo Fuller, SP
Simone Appenzeller, SP
Representante junto ao Ministério da Saúde
Ana Patrícia de Paula, DF
Mário Soares Ferreira, DF
Representantes junto à AMB
Eduardo de Souza Meirelles, SP
Gustavo de Paiva Costa, DF
Morton Aaron Scheinberg, SP
BSR Bulletin (Boletim SBR)
Coeditors (Coeditores)
Representatives of Ministry of Health
Representatives of AMB
Comissão de Comunicação Social
Comissão de Economia da Saúde
Mirhelen Mendes de Abreu, SP
Representantes junto à PANLAR
Adil Muhib Samara, SP
Antonio Carlos Ximenes, GO
Fernando Neubarth, RS
Maria Amazile Ferreira Toscano, SC
Media Commission
Health Economy Commission
Coordinator (Coordenadora)
Representatives of PANLAR
Maria Teresa R. A. Terreri, SP
Tania Caroline Castro, SP
Teresa Cristina Robazzi, BA
Coordinator (Coordenadora)
Eutilia Andrade Medeiros Freire, PB
Members (Membros)
Alessandra Souza Braz C. Andrade, PB
Bernardo Matos da Cunha, DF
Camila Cruz Leijoto, RJ
Carlos Augusto F. de Andrade, RJ
Jussara de Almeida L. Kochen, SP
Mirhelen Mendes de Abreu, SP
Pediatric Rheumatology Commission
BSR Website (Site SBR)
Coordinators (Coordenadores)
Marcelo Cruz Rezende, MS
Maria Roseli Monteiro Callado, CE
Ethics and Discipline Commission
Comissão de Ética e Disciplina
Coordinator (Coordenador)
José Marques Filho, SP
Members (Membros)
Adriana Maria Kakehasi, MG
Antonio Carlos Althoff, SC
Henrique Josef, SP
João Elias Moura Jr., SC
José Geraldo Araújo Paiva, CE
José Roberto Pereira Santos, ES
Comissão de Reumatologia Pediátrica
Coordinator (Coordenador)
Cláudio Arnaldo Len, SP
Members (Membros)
Adriana Maluf Elias Sallum, SP
Ana Paula Vecchi, GO
Andre de Souza Cavalcanti, PE
Blanca Elene Rios Gomes Bica, RJ
Carlos Nobre Rabelo Jr., CE
Claudia Saad Magalhães, SP
Clovis Artur Almeida da Silva, SP
Cynthia Torres Franca da Silva, RJ
Luciana Brandão Paim Marques, CE
Marcia Bandeira, PR
Teaching and Medical
Education Commission
Comissão de Ensino e Educação Médica
Coordinator (Coordenador)
Francisco Airton Castro da Rocha, CE
Members (Membros)
Cesar Emile Baaklini, SP
Charles Lubianca Kohem, RS
Claudia Diniz Lopes Marques, PE
Elaine Lira Medeiros de Bezerra, RN
Elisa Martins das N. de Albuquerque, RJ
Jozélia Rego, GO
Marcelo Pimenta, GO
Maria José Pereira Vilar, RN
Ricardo Machado Xavier, RS
Congresses, Journeys, and
Events Commission
Comissão de Congressos, Jornadas e Eventos
Coordinators (Coordenadores)
Fernando Neubarth, RS
Georges Basile Christopoulos, AL
José Roberto Provenza, SP
Commission of Relations
with Groups of Patients
Members (Membros)
Members (Membros)
Antônio Carlos dos Santos Novaes, SP
Claudia Diniz Lopes Marques, PE
Elda Matilde Hirose Pastor, SP
Francisco Saraiva da Silva Júnior, CE
Hilton Seda, RJ
José Caetano Macieira, SE
Reno Martins Coelho, RJ
Ricardo Fuller, SP
Ari Stiel Radu Halpern, SP
Carlos Appel da Silva, RS
Jamil Natour, SP
Jose Gerardo de Araújo Paiva, CE
Luíza Helena Coutinho Ribeiro, SP
Maria Amazile Ferreira Toscano, SC
Renê Donizeti Ribeiro de Oliveira, SP
Silvio Figueira Antonio, SP
Vasculopathies Commission
Osteomethabolic Diseases and
Osteoporisis Commission
Comissão de Vasculopatias Coordinator (Coordenador)
Comissão de Doenças
Osteometabólicas e Osteoporose
Comissão de Relações com
Grupos de Pacientes
Roger Abramino Levy, RJ
Members (Membros)
Sebastião Cezar Radominski, PR
Coordinators (Coordenadores)
Members (Membros)
Ana Maria Camargo Gallo, SC
Ana Paula Espinula Gianordoli, ES
Eduardo de Souza Meirelles, SP
Luis Piva Junior, DF
Valderílio Feijó Azevedo, PR
Wanda Heloisa Rodrigues Ferreira, RJ
Adriana Danowski, RJ
Adriana Maria Kakehasi, MG
Alexandre Wagner S. de Souza, SP
Ana Beatriz S. Bacchiega de Freitas, RJ
Andreas Funke, PR
Carlos Ewerton Maia Rodrigues, CE
Danieli Castro Oliveira de Andrade, SP
Isabella Vargas de Souza Lima, BA
Jozélia Rego, GO
Manuella Lima Gomes Ochtrop, RJ
Occupational Rheumatology Commission
Image Commission
Spondiloarthropathies Commission
Comissão de Reumatologia Ocupacional
Comissão de Imagem Comissão de Espondiloartropatias
Coordinator (Coordenador)
Coordinator (Ccoordenador)
Coordinator (Coordenador)
Helenice Alves Teixeira Gonçalves, DF
Members (Membros)
Milton Helfenstein Junior, SP
Members (Membros)
Anna Beatriz Assad Maia, DF
Antônio Techy, PR
César Augusto Fávaro Siena, SP
Marco Aurélio Goldenfum, RS
BiobadaBrasil Comission
Comissão do BiobadaBrasil
Coordinator (Coordenador)
Aline Ranzolin, PE
André Luiz Shinji Hayata, SP
Ines Guimarães da Silveira, RS
Mirhelen Mendes de Abreu, SP
Paulo Louzada-Junior, SP
Roberto Ranza, MG
Valéria Cristo Valim, ES
Rheumatoid Arthritis Commission
Célio Roberto Gonçalves, SP
Members (Membros)
RBE Coordinator (Coordenador RBE)
Andrea B. Vannucci Lomonte, SP
Cristiane Kayser Veiga da Silva, SP
Iêda Maria Magalhães Laurindo, SP
Inês Guimarães Silveira, RS
Jamil Natour, SP
Karine Rodrigues da Luz, SP
Laura Maria C. Mendonça, RJ
Simone Appenzeller, SP
Verônica Silva Vilela, RJ
Procedures Commission
Comissão de Procedimentos
Coordinator (Ccoordenador)
Jamil Natour, SP
Members (Membros)
Geraldo da Rocha Castelar Pinheiro, RJ
Luiza Helena Coutinho Ribeiro, SP
Monique Sayuri Konai, SP
Rita Nely Vilar Furtado, SP
Comissão de Artrite Reumatoide
Lupus Commission
Coordinator (Coordenadora)
Comissão de Lúpus
Licia Maria Henrique da Mota , DF
Members (Membros)
Bóris Afonso Cruz, MG
Claiton Viegas Brenol, RS
Geraldo da Rocha Castelar Pinheiro, RJ
Ieda Maria Magalhães Laurindo, SP
Jozélio Freire de Carvalho, BA
Manoel Barros Bertolo, SP
Max Victor Carioca Freitas, CE
Nilzio Antônio da Silva, GO
Paulo Louzada-Junior, SP
Rina Dalva Neubarth Giorgi, SP
Rodrigo Aires Corrêa Lima, DF
Ana Patricia de Paula, DF
Caio Moreira, MG
Charlles Heldan de Moura Castro, SP
Cristiano Augusto de F. Zerbini, SP
Elaine de Azevedo, SP
Laura Maria C. de Mendonça, RJ
Mailze Campos Bezerra, CE
Marco Antonio Rocha Loures, PR
Vera Lúcia Szejnfeld, SP
José Alexandre Mendonça, SP
David Cezar Titton, PR
Members (Membros)
Coordinator (Coordenador)
Coordinator (Coordenador)
Evandro Mendes Klumb, RJ
Members (Membros)
Cristina Costa Duarte Lanna, MG
Eduardo Ferreira Borba Neto, SP
Eloisa Silva Dutra de Oliveira Bonfá, SP
Emília Inoue Sato, SP
Francinne Machado Ribeiro, RJ
João Carlos Tavares Brenol, RS
Lilian Tereza Lavras Costallat, SP
Luiz Carlos Latorre, SP
Maria de Fátima Lobato da Cunha, PA
Odirlei Andre Monticielo, RS
Percival Degrava Sampaio Barros, SP
Members (Membros)
Antonio Carlos Ximenes, GO
Eduardo de Souza Meirelles, SP
Gustavo Gomes Rezende, MG
Ivânio Alves Pereira, SC
Marcelo Medeiros Pinheiro, SP
Mauro Waldemar Keisermann, RS
Thelma Larocca Skare, PR
Walber Pinto Vieira, CE
Washington Alves Bianchi, RJ
Psoriatic Arthritis Subcommission
(Sub-Comissão de Artrite Psoriásica)
Claudia Goldenstein-Schainberg, SP
Roberto Ranza, MG
Rubens Bonfiglioli, SP
Sueli Coelho da Silva Carneiro, RJ
Valderilio Feijó Azevedo, PR
Pain, Fibromyalgia and Other Painful
Syndromes of the Soft Parts Commission
Comissão de Dor, Fibromialgia e Outras
Síndromes Dolorosas de Partes Moles
Coordinator (Coordenador)
Marcelo Cruz Rezende, MS
Members (Membros)
Aline Ranzolin, PE
Daniel Feldman Pollak, SP
Eduardo dos Santos Paiva, PR
José Eduardo Martinez, SP
José Roberto Provenza, SP
Marcos Aurélio Freitas Machado, SP
Nilton Salles Rosa Neto, SP
Rafael Mendonça da Silva Chakr, RS
Roberto Ezequiel Heymann, SP
Documentation and Historical
Registry Commission
Osteoarthrosis Commission
Spinal Commission
Comissão de Osteoartrose
Comissão de Coluna Vertebral
Comissão de Documentação e
Registro Histórico
Coordinator (Coordenador)
Coordinator (Coordenador)
Coordinator (Coordenador)
Ibsen Bellini Coimbra, SP
Marcos Renato de Assis, SP
Joaquim Jaguaribe Nava Ribeiro, RJ
Members (Membros)
Célio Roberto Gonçalves, SP
Henrique Josef, SP
José Eduardo Gonçalves, CE
José Knoplich, SP
José Marques Filho, SP
Lauredo Ventura Bandeira, SP
Lipe Goldenstein, BA
Plínio José Amaral, SP
Systemic Sclerosis Commission
Comissão de Esclerose Sistêmica
Coordinator (Coordenador)
Percival Degrava Sampaio-Barros, SP
Members (Membros)
Adriana Fontes Zimmermann, SC
Carolina de Souza Muller, PR
Cláudia Tereza Lobato Borges, MA
Cristiane Kayser Veiga da Silva, SP
Eutília Andrade Medeiros Freire, PB
Giselle Baptista Maretti, RJ
João Francisco Marques Neto, SP
Maria Cecília Fonseca Salgado, RJ
Maria de Fátima Lobato da Cunha Sauma, PA
Mário Newton Leitão de Azevedo, RJ
Sheila Marcia de A. Fontenele, CE
Sjögren Syndrome Commission
(Comissão de Síndrome de Sjögren)
Coordinator (Coordenadora)
Valéria Valim Cristo, ES
Members (Membros)
Érica Vieira Serrano, ES
Leandro Augusto Tanure, MG
Sandra Gofinet Pasoto, SP
Sandra Lucia Euzébio Ribeiro, AM
Virginia Fernandes Moça Trevisani, SP
Professional Defense Commission
Endemic and Infectious
Diseases Commission
(Comissão de Doenças
Endêmicas e Infecciosas)
Coordinators (Coordenadores)
Izaias Pereira da Costa, MS
Sandra Lucia Euzébio Ribeiro, AM
Members (Membros)
Ana Carolina de Oliveira S. Montandon, GO
Helena Lucia A. Pereira, AM
Luiz Sergio Guedes Barbosa, MT
Mauro Furtado Cavalcanti, PI
Natalino Hajime Yoshinari, SP
Rejane Maria R. de Abreu, CE
Roberta de Almeida Pernambuco, SP
Assisted Therapy Immunobiological
Centers Commission
(Comissão de Centros de Terapia
Imunobiológica Assistida)
Coordinator (Coordenador)
Reno Martins Coelho, RJ
Members (Membros)
Adrian Nogueira Bueno, MG
Ana Teresa Amoedo Medrado, BA
Antonio Carlos Scafutto, MG
Claudio Goldenstein Schainberg, SP
Eliezer Rushansky, PE
Evelin D. Goldenberg M. M. da Costa, SP
José Eyorand Castelo B Andrade, CE
José Roberto Silva Miranda, SP
Manoel Barros Bertolo, SP
Rafael de Oliveira Fraga, MG
Ricardo Jorge de Percia Name, RJ
Vander Fernandes, MT
Supervisory Board (Conselho Fiscal)
Fernando Neubarth, RS
Iêda Maria Magalhães Laurindo, SP
Geraldo da Rocha Castelar Pinheiro, RJ
(Comissão de Defesa Profissional)
Coordinators (Coordenadores)
BSR – Regionals
Francisco Deoclécio D. Rocha, RN
Vander Fernandes, MT
Regionais – SBR
Members (Membros)
Sociedade Alagoana de Reumatologia
Dra. Inês Cristina de Mello
Francisco Alves Bezerra Neto, RN
Matheus Staufackar Carlos, RN
Inês Cristina de Mello Lima, AL
Mauro Furtado Cavalcante, PI
Gout Commission
(Comissão de Gota)
Coordinator (Coordenador)
Rheumatology Society of Alagoas
Rheumatology Society of Amazonas
Rheumatology Society of Ceará
Sociedade Cearense de Reumatologia
Dr. José Eyorand Castelo Branco de Andrade
Rheumatology Society of Goiânia
Sociedade Goiana de Reumatologia
Dra. Ana Carolina Oliveira e Silva Montandon
Rheumatology Society of Maranhão
Sociedade Maranhense de Reumatologia
Dra. Raquel Moraes da Rocha Nogueira
Rheumatology Society Mato Grosso
Associação Mato-Grossense de Reumatologia
Dr. Vander Fernandes
Rheumatology Society of Minas Gerais
Sociedade Mineira de Reumatologia
Dr. Rafael de Oliveira Fraga
Rheumatology Society of São Paulo
Sociedade Paulista de Reumatologia
Dr. Paulo Louzada-Junior
Rheumatology Society of Pará
Sociedade Paraense de Reumatologia
Dr. Otávio Augusto Gomes da Paz
Rheumatology Society of Paraíba
Sociedade Paraibana de Reumatologia
Dra. Danielle Christinne Soares Egypto de Brito
Rheumatology Society of Paraná
Sociedade Paranaense de Reumatologia
Dr. Eduardo Santos Paiva
Rheumatology Society of Pernambuco
Sociedade Pernambucana de Reumatologia
Dra. Lílian David de Azevedo Valadares
Rheumatology Society of Piauí
Sociedade Piauiense de Reumatologia
Dra. Aline do Socorro Miranda Ribeiro
Rheumatology Society of Espírito Santo
Sociedade de Reumatologia do Espírito Santo
Dr. José Roberto Pereira Santos
Rheumatology Society of Mato Grosso do Sul
Sociedade de Reumatologia
do Mato Grosso do Sul
Dr. Marcelo Cruz Rezende
Rheumatology Society of Rio de Janeiro
Sociedade de Reumatologia do Rio de Janeiro
Dr. Evandro Mendes Klumb
Sociedade Amazonense de Reumatologia
Dra. Maria do Socorro A. de Souza
Rheumatology Society of
Rio Grande do Norte
Rheumatology Society of Bahia
Sociedade de Reumatologia
do Rio Grande do Norte
Dr. Francisco Deoclécio Damasceno Rocha
Sociedade Baiana de Reumatologia
Dr. Mittermayer Barreto Santiago
Rheumatology Society of Rio Grande do Sul
Geraldo da Rocha Castelar Pinheiro, RJ
Rheumatology Society of Brasília
Members (Membros)
Sociedade de Reumatologia de Brasília
Dr. Cleandro Pires de Albuquerque
Sociedade de Reumatologia
do Rio Grande do Sul
Dr. Marco Aurélio Goldenfum
Rheumatology Society of Santa Catarina
Rheumatology Society of Sergipe
Sociedade Catarinense de Reumatologia
Dr. Gláucio Ricardo Werner de Castro
Sociedade Sergipana de Reumatologia
Dra. Regina Adalva de Lucena Couto Ocea
Adil Muhib Samara, SP
Antonio José Lopes Ferrari, SP
Ana Beatriz Vargas dos Santos, RJ
Hellen Mary da Silveira de Carvalho, DF
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Avenida Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 – CEP: 01402-000 – São Paulo, SP, Brasil
Phone/Fax:
55 11 3289-7165
E-mail:
[email protected], [email protected]
Website:
www.reumatologia.com.br
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Volume 53. Number 2. March/April 2013
Volume 53. Número 2. Março/Abril 2013
CONTENTS | SUMÁRIO
Editorial | Editorial
Alexander and the Guidelines – the importance of strategy and the guidelines for the
diagnosis and medicamentous treatment of rheumatoid arthritis
Alexandre e as Diretrizes – a importância da estratégia e as Diretrizes para diagnóstico e
tratamento medicamentoso da artrite reumatoide
Licia Maria Henrique da Mota, Geraldo da Rocha Castelar Pinheiro .................................................
137
Antiphospholipid syndrome
Síndrome do anticorpo antifosfolipídeo
Adriana Danowski, Roger A. Levy .....................................................................................................
139
Guidelines | Documentos de Diretrizes
Guidelines for the diagnosis of rheumatoid arthritis
Diretrizes para o diagnóstico da artrite reumatoide
Sociedade Brasileira de Reumatologia, Sociedade Brasileira de Pneumologia e Tisiologia,
Colégio Brasileiro de Radiologia .........................................................................................................
141
Guidelines for the drug treatment of rheumatoid arthritis
Diretrizes para o tratamento da artrite reumatoide
Sociedade Brasileira de Reumatologia ................................................................................................
158
Guidelines for the treatment of antiphospholipid syndrome
Diretrizes para o tratamento da síndrome do anticorpo antifosfolipídeo
Adriana Danowski, Jozelia Rego, Adriana M. Kakehasi, Andreas Funke, Jozelio Freire de Carvalho,
Isabella V. S. Lima, Alexandre Wagner Silva de Souza, Roger A. Levy ...............................................
184
Original Articles | Artigos Originais
Resistance training versus weight-bearing aquatic exercise: a cross-sectional
analysis of bone mineral density in postmenopausal women
Treinamento de força versus hidroginástica: uma análise transversal comparativa da densidade
mineral óssea em mulheres na pós-menopausa
Sandor Balsamo, Licia Maria Henrique da Mota, Frederico dos Santos de Santana,
Dahan da Cunha Nascimento, Lídia Mara Aguiar Bezerra, Denise Osti Coscrato Balsamo,
João Lindolfo Cunha Borges, Ana Patrícia de Paula, Martim Bottaro .................................................
193
Lack of association between interleukin-18 polymorphisms and rheumatoid arthritis
Ausência de associação entre os polimorfismos do gene interleucina-18 e artrite reumatoide
Ticiana Della Justina Farias, Luisa Matos do Canto, Mayara Delagnelo Medeiros,
Aline Fernanda Rodrigues Sereia, Lia Kubelka Fernandes de Carlos Back, Filipe Martins de Mello,
Adriana Fontes Zimmermann, Ivânio Alves Pereira, Yara Costa Netto Muniz, Andrea Rita Marrero,
Ilíada Rainha de Souza.......................................................................................................................
199
Review Articles | Artigos de Revisão
What a rheumatologist needs to know about yellow fever vaccine
O que o reumatologista deve saber sobre a vacina contra febre amarela
Ana Cristina Vanderley Oliveira, Licia Maria Henrique da Mota, Leopoldo Luís dos Santos-Neto,
Pedro Luiz Tauil ..................................................................................................................................
206
Update on the treatment of calcinosis in dermatomyositis
Atualização na terapêutica da calcinose em dermatomiosite
Samuel Katsuyuki Shinjo, Fernando Henrique Carlos de Souza ........................................................
211
Case Reports | Relatos de Caso
Chondrolysis of the hip in an adolescent: clinical and radiological outcomes
Condrólise de quadril em uma adolescente: evolução clínica e radiológica
Ana Paula Sakamoto, Larissa Lucati Ramos, Artur da Rocha Corrêa Fernandes, Maria Teresa Terreri
215
Mesenteric vasculitis in a juvenile systemic lupus erythematosus patient
Vasculite mesentérica em paciente com lúpus eritematoso sistêmico juvenil
Adão F. Albuquerque-Netto, Erica G. Cavalcante, Adriana M. E. Sallum, Nádia E. Aikawa,
Uenis Tannuri, Clovis Artur Almeida da Silva ...................................................................................
219
Erratum | Errata
The quality of life of patients with lúpus erythematosus influences cardiovascular
capacity in 6-minute walk test
Qualidade de vida de pacientes com lúpus eritematoso influencia a capacidade cardiovascular
em teste de caminhada de 6 minutos
[Rev Bras Reumatol 2013;53(1):75-87]
Sandor Balsamo, Dahan da Cunha Nascimento, Ramires Alsamir Tibana,
Frederico Santos de Santana, Licia Maria Henrique da Mota, Leopoldo Luiz dos Santos-Neto..........
223
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REVISTA BRASILEIRA DE
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Editorial
Alexander and the Guidelines – the importance of strategy
and the guidelines for the diagnosis and medicamentous
treatment of rheumatoid arthritis
Alexander and the Guidelines – the importance of strategy
and the guidelines for the diagnosis and medicamentous
treatment of rheumatoid arthritis
Alexander III, who would enter History as “the Great”,
son of Philip II and Olympias, was born in Pella, the capital of the Ancient Greek Kingdom of Macedon, in the year
356 b.C. When he died, at the age of 33 years, somewhere in
Babylon, he had conquered all the world then known – and
had the following titles King of Macedon, King of Greece,
Lord of Asia, Shahanshah of Persia, Pharaoh of Egypt and
Hegemon of the Hellenic League. As his greatest legacy, Alexander had fused the Greek culture to the Eastern culture,
forming the base of the later called Hellenistic Civilization,
which influenced profoundly several aspects of the current
Western culture.1
But why are we writing about Alexander, the Great, in a
scientific editorial on the guidelines for rheumatoid arthritis
(RA)? Because Alexander was, more than a great conqueror,
a brilliant strategist, maybe the greatest in entire History.
The word ‘strategy’ comes from the ancient Greek (stratos,
“army”, and ago, “leadership” or “command”), and designated the military commander at the time of Athenian democracy. Currently, the term ‘strategy’ can be understood as a
way to plan the future, integrated in the decision making
process and based on a formalized procedure that articulates results. Using the figure of a great strategist to illustrate the elaboration and publication of guidelines is part of
the strategy of the Brazilian Society of Rheumatology (SBR)
to spread and implant knowledge based on scientific evidence for the diagnosis and treatment of RA in Brazil.
Rheumatoid arthritis is a chronic systemic disease, usually progressive, that affects 0.5%–1% of the world population, characterized by inflammatory involvement of the
synovial membrane, mainly in peripheral joints. The daily
fight of rheumatologists against that disease comprises
treating the pain and preventing or delaying both structural
joint damage and functional and labor disability, in addition
to preventing early mortality of the patients. Success in this
battle depends mainly on the adoption of proper strategies,
including early diagnosis and adequate treatment as soon
as possible in the RA natural history.
The SBR, through its Rheumatoid Arthritis Committee,
has elaborated over the past two years four consensual documents guiding the diagnosis and treatment of RA in Brazil,
including peculiarities such as management of comorbidities and vaccination of patients immunosuppressed by the
disease and its treatment.2–5
Consensus documents are educational instruments,
rather than normative guidelines, that allow their authors
to add information originating from experience and experts’
opinion to scientific evidence. If, as a publication, the consensus loses in grade of recommendation and level of evidence, it gains as an educational tool to prize the experience
of those who deal with daily practice difficulties in managing the disease.6,7
The Guidelines Project of the Brazilian Medical Association (AMB) and the Federal Board of Medicine (CFM), was
aimed at producing diagnostic, therapeutic and, when applicable, preventive guidance, based on scientific evidence,
conciliating information of the medical area to standardize
management that helps physician’s reasoning and decision
making. The documents present the grade of recommendation and level of scientific evidence published, preserving
in its elaboration the autonomy of the authors, medical experts, of the texts.8
Thus, that was the strategy of the Rheumatoid Arthritis
Committee when elaborating both documents presented in
this issue of the Revista Brasileira de Reumatologia – the Guidelines for the Diagnosis of RA9 and the Guidelines for the Medicamentous Treatment of RA.10 The elaboration of the texts
carefully followed the recommendations of the AMB and the
CFM, the result being evidence-based responses to the following questions: Are the new 2010 ACR/EULAR classification criteria for RA superior to the 1987 classification criteria
of the early phase of disease? Are genetic markers (search
for HLA-DRB1 alleles – shared epitope and PTPN22 genes)
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useful to characterize patients with poorer prognosis of RA?
Is it feasible to treat the disease to achieve remission? Does
the use of corticosteroids in the early phase of disease improve the patient’s prognosis?
Although the personality and some actions of Alexander
the Great might be questioned, studying how he managed
his armies and his actions to conquer Persia and Asia, including the historical battles of Gaugamela, Issus, Granicus
and Hydaspes, leads us to conclude that there is a close relationship between the success achieved by Alexander and
the proper use of the entire management process, formally
conceived and used to a specific purpose, i.e., the implementation of strategies.11 We hope that, by reading and applying the strategies proposed by the guidelines currently
published, rheumatologists, and, to a lesser extent, their patients, can be as victorious in their fight against RA as was
the magnificent strategist Alexander in his many battles.
“And it happened afterwards that Alexander, the son of Philip
the Macedonian, who first reigned in Greece having come
from the land of Kittim, struck Darius the king of the Persians
and the Medes. He appointed many battles, and took hold of
all the fortifications and he executed the kings of the earth.
And he passed through even to the ends of the earth. And
he received the spoils of many nations. And the earth was
silenced in his sight.”
Maccabees 1, 1-3
Licia Maria Henrique da Mota
Medical School, Universidade de Brasília (UnB),
Brasília, DF, Brazil
Brazilian Society of Rheumatology Rheumatoid
Arthritis Committee
E-mail: [email protected]
Geraldo da Rocha Castelar Pinheiro
Discipline of Rheumatology, Universidade do Estado do
Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
REFERENCES
1. Bose P. Alexander the Great’s Art of Strategy. Crows Nest,
N.S.W: Allen & Unwin; 2003.
2. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Fronza LS,
Bertolo MB, et al. 2011 Consensus of the Brazilian Society
of Rheumatology for diagnosis and earlyassessment of
rheumatoid arthritis. Rev Bras Reumatol. 2011;51(3):199219.
3. da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza
LS, Bertolo MB, et al.; Brazilian Society of Rheumatology.
2012 Brazilian Society of Rheumatology Consensus for
the treatment of rheumatoid arthritis. Rev Bras Reumatol.
2012;52(2):152-74.
4. Pereira IA, Mota LM, Cruz BA, Brenol CV, Fronza LS, Bertolo
MB, et al.; Brazilian Society of Rheumatology. 2012 Brazilian
Society of Rheumatology Consensus on the management
of comorbidities in patients with rheumatoid arthritis. Rev
Bras Reumatol. 2012;52(4):474-95.
5. Brenol CV, Mota LCH, Cruz BA, Pileggi GS, Pereira IA,
Rezende LS, et al. Consenso 2012 da Sociedade Brasileira
de Reumatologia sobre vacinação em pacientes com artrite
reumatoide. Rev Bras Reumatol. 2013;53(1):4-23.
6. da Mota LM. Considerations about the 2011 consensus
of the Brazilian Society of Rheumatology for diagnosis
and early assessment of rheumatoid arthritis. Rev Bras
Reumatol. 2011;51(3):197-8.
7. Mota LM. On mosaics and consensus: Gaudí, Brazil and
rheumatoid arthritis. Rev Bras Reumatol. 2012;52(2):133-4.
8. Projeto Diretrizes. [Accessed on: 22 fevereiro 2013]
Available from: http://www.projetodiretrizes.org.br.
9. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza
LS, Bertolo MB, et al., Sociedade Brasileira de Reumatologia,
Sociedade Brasileira de Pneumologia e Tisiologia, Colégio
Brasileiro de Radiologia. Diretrizes para o diagnóstico da
artrite reumatoide. Rev Bras Reumatol. 2013;53(2):141-57.
10. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza
LS, Bertolo MB, et al., Sociedade Brasileira de Reumatologia.
Diretrizes para o tratamento da artrite reumatoide. Rev
Bras Reumatol. 2013;53(2):158-83.
11. Rodrigues RC. Alexandre, “o Grande”, e a informação para o
planejamento estratégico. Inf Soc. 2007;17(2):74-85.
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Editorial
Antiphospholipid syndrome
The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis, gestational morbidity and presence of elevated and
persistently positive levels of antiphospholipid antibodies.1
The treatment of APS is controversial, especially because
of the absence of good quality clinical studies. In the primary prevention of thrombosis, clinical studies report different
results.2,3 The association of risk factors with thrombotic
events and the type and number of positive antiphospholipid antibodies are current concepts and should be considered in the therapeutic decision, be it medicamentous or a
change in lifestyle.
Full anticoagulation for undetermined time is indicated
for secondary prevention, but the therapeutic target is still
discussed. Although retrospective studies have suggested a
lower number of recurrences with an elevated international
normalized ratio (INR), prospective studies do not corroborate such findings.4,5 However, the inclusion of patients with
arterial thrombosis in those protocols was small, making the
definitive conclusion about the target INR in APS difficult.
The obstetric questions have also generated discussion:
teratogenicity associated with warfarin6 and the dosing of
heparin in patients with vascular APS have little scientific
evidence.7
International efforts aimed at designing and conducting
good quality prospective studies for patients with antiphospholipid antibodies, such as the creation of a multicenter
data bank, have been observed.8 Thus, new perspectives arise and, in the near future, we will have answers based on
better evidence regarding the treatment of APS, including
the use of hydroxychloroquine for primary prevention, the
use of new anticoagulants, and biologic therapy.
In face of the need to improve understanding and treatment, and to establish recommendations for rheumatologists and other specialists about the management of APS,
the Committee of Vasculopathies and APS of the Brazilian
Society of Rheumatology (SBR), with the support of the Brazilian Medical Association (AMB), publishes this guideline,
elaborated from nine relevant and controversial clinical
questions related to the treatment of APS, based on the best
scientific evidence available.
Once finished this first publication, our committee proceeds to the objectives established for the next two years:
elaboration and publication of guidelines for the diagnosis
of APS and elaboration and publication of guidelines and
manuals for patients with Granulomatosis with Polyangiitis and Takayasu’s Artheritis. In addition, the committee has
been working along with AMB to include the following tests
in the table of procedures: IgM/IgG anti-beta 2-glycoprotein
I test; IgA anticardiolipin test; antiproteinase 3 test; and antimyeloperoxidase test.
Adriana Danowski
Hospital Federal dos Servidores do Estado (HFSE),
Rio de Janeiro, RJ, Brazil
E-mail: [email protected]
Roger A. Levy
Universidade do Estado do Rio de Janeiro (UERJ),
Rio de Janeiro, RJ, Brazil
REFERENCES
1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL,
Cervera R, et al. International consensus statement on an
update to the classification for definite antiphospholipid
syndrome (APS). J Thromb Haemost. 2006;4:295-306.
2. Tarr T, Lakos G, Bhattoa HP, Shoenfeld Y, Szegedi G, Kiss E.
Analysis of risk factors for the development of thrombotic
complications in antiphospholipid antibody positive lupus
patients. Lupus. 2007;16:39-45.
3. Erkan D, Harrison MJ, Levy RA, Peterson M, Petri M,
Sammaritano L, et al. Aspirin for primary thrombosis
prevention in the antiphospholipid syndrome: a randomized,
double-blind, placebo-controlled trial in asymptomatic
antiphospholipid antibodypositive individuals. Arthritis
Rheum. 2007;56:2382-91.
4. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F,
Musial J, et al. A randomized clinical trial of high-intensity
warfarin vs. conventional antithrombotic therapy for the
prevention of recurrent thrombosis in patients with the
antiphospholipid syndrome (WAPS). J Thromb Haemost.
2005;3:848-53.
5. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J,
Douketis J, et al. A comparison of two intensities of warfarin
for the prevention of recurrent thrombosis in patients with
the antiphospholipid antibody syndrome. N Engl J Med.
2003;349:1133-8.
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6. Levy RA, Jesús GR, Jesús NR. Obstetric antiphospholipid
syndrome: still a challenge. Lupus. 2010;19:457-9.
7. Hunt BJ, Gattens M, Khamashta M, Nelson-Piercy C, Almeida
A. Thromboprophylaxis with unmonitored intermediate-dose
low molecular weight heparin in pregnancies with a previous
arterial or venous thrombotic event. Blood Coagul Fibrinolysis.
2003;14:735-9.
8. APS ACTION – AntiPhospholipid Syndrome Alliance For Clinical
Trials and InternatiOnal Networking. D Erkan, MD Lockshin on
behalf of APS ACTION members. Lupus. 2012;21:695-8.
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Guidelines
Guidelines for the diagnosis of rheumatoid arthritis
Diretrizes para o diagnóstico da artrite reumatoide
Sociedade Brasileira de Reumatologia, Sociedade Brasileira de Pneumologia e Tisiologia,
Colégio Brasileiro de Radiologia (Brazilian Society of Rheumatology, Brazilian Society of
Pneumology and Tuberculosis, Brazilian College of Radiology)
Projeto Diretrizes da Associação Médica Brasileira, São Paulo, SP, Brazil
Participants
Licia Maria Henrique da Mota*, Bóris Afonso Cruz,
Claiton Viegas Brenol, Ivânio Alves Pereira,
Lucila Stange Rezende-Fronza, Manoel Barros Bertolo,
Max Vitor Carioca Freitas, Nilzio Antônio da Silva,
Paulo Louzada-Junior, Rina Dalva Neubarth Giorgio,
Rodrigo Aires Corrêa Lima, Ronaldo Adib Kairalla,
Alexandre de Melo Kawassaki,
Wanderley Marques Bernardo,
Geraldo da Rocha Castelar Pinheiro
Final elaboration
D: Opinion that is not substantiated by critical evaluation,
based on consensus, physiological studies or animal
models.
Objective
To formulate guidelines for the management of rheumatoid
arthritis (RA) in Brazil, with a focus on diagnosis. The aim of
the present document is to summarise the current position of
the Brazilian Society of Rheumatology on this topic to orient
Brazilian doctors, particularly rheumatologists, to RA diagnosis
in our country.
12 April 2012
Description of the evidence collection method
A review of the scientific literature was performed with the Medline database. The search for evidence was based on actual clinical scenarios and used the following Medical Subject Headings
(MeSH) terms: Arthritis, Rheumatoid, Diagnosis (Delayed Diagnosis OR Delay OR Early Rheumatoid Arthritis OR VERA), Prognosis, Criteria (American College of Rheumatology/European
League Against Rheumatism OR ACR/EULAR OR classification),
Comparative Study, Smoking (OR tobacco use disorder), Rheumatoid Factor, Anti-cyclic Citrullinated Peptide (or anti-CCP),
HLA-DRB1 OR PTPN22 OR EPITOPE, extra-articular OR extraarticular OR systemic OR ExRA, Disease Progression, Radiography
OR X RAY, ULTRASONOGRAPHY, and MAGNETIC RESONANCE
Grades of recommendation and strength of evidence
A: Most consistent experimental and observational studies.
B: Less consistent experimental and observational studies.
C: Case reports (uncontrolled studies).
Introduction
Rheumatoid arthritis (RA) is a chronic, progressive, and systemic inflammatory disease that preferentially affects the synovial
membranes of joints and eventually leads to bone and cartilage destruction1(D). RA affects 0.5%–1% of the adult population worldwide; the disease targets patients from every ethnic
background2(D) and predominately affects females (2- or 3-fold
more often than males). Although RA can occur at any age, it
is more frequent among individuals in the fourth to sixth decades of life3(D).
A Brazilian multicentre study conducted with samples
from the various macro-regions found a prevalence of up
to 1% in Brazil’s adult population4(B), which corresponds to
1,300,000 people.
As a chronic disease that causes irreversible joint damage,
RA exacts high costs from both the patients and society at
large 5(B) 6,7(D).
* Corresponding author.
E-mail: [email protected] (L.M.H Mota)
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In recent years, significant advances have been achieved
in understanding the physiopathogenesis, diagnostic methods, and therapeutic management of RA. Among these advances, the recently attributed significance of the early disease
stages or so-called early RA (first 12 months with RA symptoms) stands out as an acknowledged “window of therapeutic
opportunity”8(B)9,10(D). However, despite all advances, the currently available (clinical, laboratory, and radiological) diagnostic and prognostic indicators are of limited value to early diagnoses and individual prognoses11(B).
The demographic and clinical features of RA vary as a function of the affected population12(B). Most available data correspond to populations in Europe and the United States13,14(D). Few
studies have been conducted on the Brazilian population15,16(B).
RA affects mostly individuals within the economically productive age range, and the disease eventually imposes significant limitations on their functional ability that result in the
loss of work abilities. For these reasons, the indirect costs associated with RA must be included in pharmacoeconomic
studies17(B).
In Brazil and industrialised countries, the costs associated
with RA are high18(B). The impact of the expenses associated
with RA is more remarkable in developing countries in which
the financial resources allocated to healthcare are less robust.
This situation points to the relevance of studies adapted to
Brazilian conditions that assess the costs and allocation of resources for the diagnosis and treatment of RA19(B).
RA diagnosis is based on clinical findings and complementary diagnostic tests. No single laboratory, imaging, or histopathological test alone can confirm a diagnosis.
Several illnesses that present with arthritis must be considered in the differential diagnosis of RA20-22(D), as described
in Table 1.
Diagnosis is easier when RA presents with the well-known
pattern and the full range of typical symptoms. Diagnosis
might be difficult in the early stages of disease because the
characteristic serologic and radiological alterations are often
absent23(D).
The clinical manifestations of RA can be classified as articular and extra-articular. As RA is a systemic disease, general
symptoms such as fever, asthenia, fatigue, myalgia, and weight
loss can appear before or concomitantly with the onset of the
articular manifestations24(D).
The characteristic features of arthritis in RA are as
follows24(D):
a) Polyarticular affection: usually involving more than four
joints. Nevertheless, RA might begin and eventually remain as mono- or oligoarthritis.
b) Hand and wrist arthritis: affections of the wrist, metacarpophalangeal (MCP), and proximal interphalangeal (PIP)
joints are frequent from the very early disease stages. The
distal interphalangeal (DIP) joints are seldom affected, a
feature that distinguishes RA from other conditions such
as osteoarthritis and psoriatic arthritis.
c) Symmetric arthritis: symmetric affection of joints is a
common finding, although not mandatorily absolute in
cases of the PIP, MCP, and metatarsophalangeal (MTP)
joints.
d) Cumulative or additive arthritis: arthritis usually exhibits
a cumulative pattern (progressive affection of new joints
concomitant to inflammation of the previously affected
ones).
e) Morning stiffness: prolonged stiffness that appears in the
morning, which is accompanied by a sensation of swelling,
is near-universal feature of synovial inflammation. Unlike
the short-lasting (5–10 minutes, as a rule) variety observed
in osteoarthritis, in inflammatory diseases, stiffness tends
to last for more than 1 hour. This phenomenon is associated with immobility that occurs concomitantly to the
state of sleep or rest, rather than to a particular time of the
day. The duration of stiffness tends to correlate with the
degree of inflammation and is an important parameter in
follow-up evaluations25(B)26(C).
Extra-articular manifestations
Although the articular manifestations are the most characteristic, other organs and systems can also be affected by
RA. The most common extra-articular manifestations of
Table 1 – Differential diagnoses of arthritis.
Classes of diseases
Infections
Articular manifestations
Although the articular manifestations of RA might be reversible in the early stages, persistent and uncontrolled synovitis
leads to bone and cartilage destruction and irreversible tendon
and ligament injuries.
The basic factor behind RA articular manifestations is synovial inflammation (synovitis), which can affect any diarthrodial
joint in the body.
The clinical complaints include pain, swelling, and motion
limitations of the affected joints. A physical examination will
disclose the presence of pain, increased joint volume, intraarticular effusion, heat, and eventual redness. Those findings might not be evident in deep joints such as the hips and
shoulders24(D).
Spondyloarthritis
Systemic rheumatic
diseases
Microcrystalline
arthritis
Endocrine diseases
Neoplastic diseases
Others
Diseases
Viral (e.g. dengue, human
immunodeficiency virus – HIV,
parvovirus, cytomegalovirus, hepatitis),
bacterial (e.g. N. gonorrhoeae, S. aureus),
microbacterial, fungal, and others
Reactive arthritis (Chlamydia, Salmonella,
Shigella, Yersinia), ankylosing spondylitis,
psoriatic arthritis, enteropathic arthritis
Systemic lupus erythematosus,
polymyositis/dermatomyositis, systemic
sclerosis, Sjögren’s syndrome, Behçet’s
disease, rheumatic polymyalgia, systemic
vasculitis, and others
Gout, calcium pyrophosphate deposition
disease, and others
Hypothyroidism, hyperthyroidism
Metastatic neoplastic disease, lymphoma,
paraneoplastic syndromes, and others
Osteoarthritis, haemochromatosis,
amyloidosis, sarcoidosis, serum sickness
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RA include skin, eye, pleuropulmonary, heart, blood, neurological, and osteo-metabolic conditions. These occur more
often in patients with severe and polyarticular disease,
positive serology for the rheumatoid factor (RF) or cyclic
citrullinated peptide antibodies (anti-CCP), and rheumatoid
nodules27(B)28(D).
Brazilian studies confirmed that the initial manifestations
of RA include polyarticular affection with persistent synovitis
in the hands, long-lasting morning stiffness, a large number
of painful and swollen joints, and fatigue15,16(B).
1. Is diagnosis of RA within the first 12 months
of symptoms (early RA) associated with better
radiological and functional prognosis, compared
to later diagnosis?
The modern differentiation of RA from other joint diseases
dates from 1907. As no pathognomonic traits allow a distinction among the various types of arthritis in their early stages,
the exact moment at which RA begins to progress as a separate entity from other articular illnesses is unknown12(B).
The definition of early RA is important from both the theoretical and practical perspectives, although the terms “early” and “RA” might be addressed independently, particularly
because the criteria applied to these classifications are based
on established RA13(D).
Although controversial, early RA might be defined as the
initial stage of disease or a “window of therapeutic opportunity” in which adequate therapy might modify the disease
progression; the prognosis in this stage is better than that of
later stages14(D).
The required symptom duration for the definition of early
RA varies widely in the specialised literature. Historically, any
RA of a duration less than five years has been characterised
as “early”15(B). However, together with the notion of a “window of opportunity”, the original length of early RA needed
to be restricted. Starting in the early 90’s, early RA was consistently defined as the presence of symptoms for less than
24 months, with the main emphasis on the first 12 months of
clinical manifestations16(B).
The current indications are to assess patients with articular symptoms as soon as possible and to limit the early
stage of RA to the first weeks or months of symptoms (as a
rule, less than 12 months). In particular, the first 12 weeks
are a critical period known as “very early” RA (VERA), while
patients with more than 12 weeks but fewer than 12 months
of articular symptoms are classified as so-called “late early
RA” (LERA)17(B).
The proportion of rheumatologists with opportunities to
assess patients within the first six weeks of symptoms increased from 9% in 1997 to 17% in 2003; however, not every
case is liable to such early assessment18(B).
Even while admitting imprecisions in the definition of
early RA, several authors have suggested that a substantial
proportion of the cases with short-lasting (less than eight
weeks) inflammatory arthritis exhibit spontaneous resolution, while only the few patients with persistent clinical
manifestations progress into proper RA19(B)20-22(D). Thus, the
143
establishment of clinical, serologic, or genetic markers that
can identify patients who will progress to RA at the earliest
stages and consequently will need appropriate treatments to
reduce the odds of developing persistent disease and articular damage is of paramount importance.
The average time for the first visit of RA patients with a
rheumatologist is 17 months, and 19 months usually elapse
before the first administration of disease-modifying antirheumatic drugs (DMARDs). Factors such as education, the
number of swollen joints, age, and occupation are associated
with such delays29(B).
Arthritis is characterised by articular swelling that is associated with pain or stiffness. Cases that involve more
than one articulation should be referred to a rheumatologist, ideally within the first six weeks following the onset of
symptoms30(D).
For cases in which articular swelling was present only during the first year of disease, the risk of articular erosion was
reduced by five years (NNT: 4), compared to those patients
with joint swelling throughout the follow-up period31(B).
RA diagnosis within the first three months of VERA was
predictive of clinical (American College of Rheumatology –
ACR) and radiological (Sharp score) remission32(B).
The early identification of some factors allows clinicians
to predict whether the RA lesions will exhibit radiological
progression in the following 12 months. These factors include the Sharp score and modified Total Sharp Score (mTSS),
the presence of autoantibodies such as RF and anti-CCP, and
increased acute-phase reactants such as an erythrocyte sedimentation rate (ESR) greater than 28 mm and an average Creactive protein (CRP) level of 10 mg/L33(B).
The higher the erosion score at the onset of treatment, the
worse the 10-year radiological prognosis (Sharp score)34(B).
Early (within the first year) calculations of the Sharp, erosion, and reduced joint space scores permitted predictions
of the radiological progression of RA patients who were followed-up for three years35(B).
In spite of the early (three to six months from the beginning of symptoms) administration of DMARD treatment,
63.6% of the patients exhibited erosion three years later due
to constitutional factors such as the presence of autoantibodies (e.g. RF or anti-CCP) and the length of disease activity
(CRP, joint swelling, and response to treatment)36(B).
The duration of RA interferes with the functional prognosis, which is measured by means of the Health Assessment
Questionnaire (HAQ) and is independent of the baseline
values37(B).
When DMARD treatment was initiated within the first
year of disease (average symptom duration, six months), the
radiological progression (Ratingen score) was reduced at the
5-year follow-up38(B).
In patients with symptom durations less than 12 weeks
who were treated for RA, the radiological progression (Sharpvan der Heijde score, SHS) was reduced after six years of follow-up. Sustained DMARD-induced remission was 8% higher
(NNT: 13) in patients with symptom durations less than 12
weeks39(B).
DMARD treatment of RA patients within the first year
of disease induced better functional (Keitel Functional Test
– KFT) and clinical (joint swelling) progression at a 10-year
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follow-up, compared to those who were treated one to five
years after disease onset40(B).
Recommendation
Diagnosis of RA with a symptom duration of less than 12
months (early RA) is of paramount importance because early
diagnosis exerts beneficial effects on radiological and functional prognoses compared to later diagnosis.
2. Are the new 2010 ACR/European league against
rheumatism (EULAR) classification criteria for RA
superior to the 1987 classification criteria for the
early disease stage?
RA classifications were essentially based on the criteria formulated by the ACR in 198741(B), which are described in Table
2. However, those criteria did not perform well in early RA
cases42(B). The ACR classification criteria for RA were based on
individuals with long-standing disease and, until then, were
considered to be the standard for the selection of patients
for clinical studies. These criteria exhibit 91%–94% sensitivity
and 89% specificity for established RA. However, some of the
items, such as radiological changes (erosions) and rheumatoid
nodules, do not occur often in early RA. Thus, such criteria are
suboptimal for the identification of individuals with early RA
(40%–90% sensitivity, and 50%–90% specificity)43(B).
Table 2 – 1987 American College of Rheumatology
classification criteria for rheumatoid arthritis.
Criteria
Definition
1.Morning stiffness
Morning stiffness lasting at least 1 hour
before maximal improvement
2.Arthritis of 3 or more
At least three joint areas simultaneously
joint areas
affected and observed by a physician.
The possible areas include the right or
left PIP, MCP, wrist, elbow, knee, ankle,
and MTP joints.
3.Arthritis of hand joints Arthritis in wrist, MCP, or PIP joint
4.Symmetric arthritis
Simultaneous involvement of the same
joint areas on both sides of the body.
5.Rheumatoid nodules
Subcutaneous nodules over bony
prominences, extensor surfaces, or in
juxta-articular regions as observed by
a physician
6.Serum rheumatoid
Demonstration of abnormal amounts of
factor
serum rheumatoid factor.
7.Radiographic changes Radiographic changes typical
of rheumatoid arthritis on
posteroanterior hand and wrist
radiographs showing juxta-articular
bone thinning or erosions
For classification purposes, a patient shall be said to have rheumatoid
arthritis if he/she has satisfied at least four or these seven criteria.
Criteria 1 through 4 must have been present for at least six weeks.
Modified from: Arnett FC, Edworthy SM, Bloch DA, McShane DJ,
Fries JF, Cooper NS et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum. 1988;31:315-24.
As a result, new RA classification criteria were needed, with
a special focus on the early disease stages14(D).
The new ACR/EULAR classification criteria can be applied
to any patient, provided that two basic requirements are met
as follows:
1) Evidence of active clinical synovitis in at least one joint at
the time of examination.
2) Synovitis cannot be better explained by another disease.
The new criteria (Table 3) are based on a score system that
is calculated by direct addition. The clinical manifestations are
grouped into the following four domains: joint involvement,
serology, duration of symptoms, and acute-phase reactants. In
questionable cases, the number of involved joints can be calculated by the use of imaging methods such as ultrasound (US)
and magnetic resonance (MRI). A score > 6 is needed to classify
a patient as having definite RA44(B). These criteria can be applied both prospectively and retrospectively, provided that the
data were properly recorded.
It is worth observing that whenever a patient exhibits typical erosions upon radiological examination and a clinical history compatible with RA (albeit non-documented), RA diagnosis can be directly established in a manner independent of the
applicability of the classification criteria14(D).
The new 2010 criteria were not developed for the purpose
of diagnosis but rather of classification. The criteria basically
serve to select homogeneous populations for studies.
Clinical RA diagnoses are extremely complex and includes
multiple features that are hard to reconcile with a single scoring system14(D). Eventually, the formal criteria might serve to
guide clinical diagnoses.
Several features of the new criteria must be subjected to
careful analysis before they can be universally accepted. In particular, the criteria must be validated in different populations,
including Brazilian early RA cohorts.
In patients who use methotrexate and those with persistent
RA, the discriminatory powers of the 2010 ACR/EULAR criteria
were 76% and 87%, respectively, when the score was at least 6,
and 63% and 46%, respectively, when it was < 645(B).
Assuming the need for methotrexate, a diagnostic gold
standard, during the first year of follow-up, the 2010 ACR/EULAR criteria were able to diagnose 86% of the cases for which
the score was at least 6 and 49% when it was < 645, compared
to 87% and 41%, respectively, when the 1987 ACR criteria were
used46(B).
A comparison of the 2010 ACR/EULAR (score of at least 6)
and 1987 ACR (score > 4) criteria relative to the diagnosis of patients with a disease duration of less than 12 months showed
positive predictive values of 70.7% and 65.3%, respectively, and
negative predictive values of 76.1% and 79.1%, respectively47(B).
The discriminatory powers of the 2010 ACR/EULAR and 1987
ACR criteria during an 18-month follow-up period were compared and are shown in Table 4.
The application of the 2010 ACR/EULAR criteria at disease
onset detected more patients who required DMARD treatment
than did the 1987 ACR criteria; the values were 62% and 38%,
respectively, and more particularly with regard to the use of
methotrexate during the 18-month follow-up, the values were
68% versus 42%, respectively. However, the 2010 ACR/EULAR
criteria were associated with a higher rate of false-positive
cases (8% versus 2% for the 1987 ACR criteria)48(B).
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Table 3 – 2010 ACR/EULAR classification criteria for rheumatoid arthritis.
Target population (Who should be tested?) Patients who meet the following criteria:
1) Have at least 1 joint with definite clinical synovitis (swelling)*
2) Present with synovitis that is not better explained by another disease
*Differential diagnoses might include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If the relevant
differential diagnoses to consider are unclear, an expert rheumatologist should be consulted.
Joint involvement (0–5)
Serology (0–3)
1 large joint
0
2–10 large joints
1
1–3 small joints (large
joints are not taking
into account)
4–10 small joints (large
joints are not taking
into account )
> 10 joints (at least 1
small joint)
2
Negative RF AND negative
ACPA
Low-positive RF OR lowpositive ACPA
High-positive RF OR highpositive ACPA
Duration of symptoms (0–1)
0
< 6 weeks
0
2
≥ 6 weeks
1
Acute-phase reactants (0–1)
Normal CRP AND normal
ERS
Abnormal CRP OR
abnormal ERS
0
1
3
3
5
A score ≥ 6 is needed for the classification of a patient with definite RA. “Joint involvement” refers to any swollen or tender joint on
examination, which might be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first
metatarsophalangeal joints are excluded from assessment. “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal
joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. “Large joints” refers to the shoulders,
elbows, knees, and ankles. In the category “> 10 joints” at least one of the involved joints must be a small joint; the other joints can include
any combination of large and additional small joints, as well as joints that are not specifically listed elsewhere (e.g., temporomandibular,
acromioclavicular, sternoclavicular).
In “Serology”, negative refers to IU values of the rheumatoid factor or anti-citrullinated protein antibody that are less than equal to the upper
limit of normal (ULN) for the laboratory and assay, low-positive refers to IU values that are higher than the ULN, but ≤ 3 times the ULN for the
laboratory and assay, and high-positive refers to IU values that are ≥ 3 times the ULN for the laboratory and assay.
“Duration of symptoms” refers to patient self-reports of the duration of signs or symptoms of joint synovitis that are clinically involved at the
time of assessment.
“Acute-phase reactants” (erythrocyte sedimentation rate, and C-reactive protein) are considered to be normal/abnormal according to the local
laboratory standards.
Modified from: Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd. 2010 rheumatoid arthritis classification criteria: an
American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010; 69(9):1580-8.
Table 4 – Positive and negative predictive values from the 1987 ACR and 2010 ACR/EULAR criteria for patients with
rheumatoid arthritis who are using disease-modifying anti-rheumatic drugs at the onset of disease and 18 months later.
Measurement
Cohort onset
2010 ACR/EULAR
+ predictive value
- predictive value
75%
66%
18 months later
1987 ACR
85%
59%
In cases for which the 1987 ACR criteria had been used to
define RA (without radiological aid), the 2010 ACR/EULAR criteria were diagnostic of disease in 59% of the cases (positive
predictive value), and ruled out the diagnosis in 93% (negative
predictive value). The rate of false-positive results for the 2010
ACR/EULAR criteria was 17%. If RA was considered a chronic
disease (five years of follow-up), the discriminatory power of
the 2010 ACR/EULAR criteria fell to 68% when the score was at
least 6 and to 61% when the score was < 6. Nevertheless, the
1987 ACR criteria identified 11.3% fewer cases as RA than did
the 2010 ACR/EULAR criteria49(B).
Recommendation
The 2010 CR/EULAR criteria identify more patients with
early RA than do the 1987 ACR criteria. However, the rate of
2010 ACR/EULAR
73%
69%
1987 ACR
81%
79%
false-positive cases is higher with the newer criteria. When
follow-up criteria such as use of DMARDs or disease persistence are used, the discriminatory powers of the 2010 CR/
EULAR and the 1987 ACR criteria are similar.
3. Is smoking associated with a poorer prognosis
for articular disease in RA patients?
Smoking was found to increase the risk of non-response
(ACR50) by 18.3% [number needed to harm (NNH): 6] in patients with early RA (24 weeks of symptom duration)50(B).
According to the EULAR criteria, RA patients who were
smokers were less likely to achieve a good response at three
months of treatment, compared to the non-smokers (NNH: 11).
The patients who continued to smoke exhibited lower odds
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of good treatment responses during a 5-year follow up period.
That difference in good treatment responses was somewhat
higher in patients who were treated with anti-tumour necrosis
factor (TNF) (14%; NNH: 7)51(B).
Smokers tend to exhibit more extra-articular manifestations of RA (pleuritic, pericarditis, interstitial lung disease,
neuropathy, glomerulonephritis, vasculitis), compared to nonsmokers, as well as higher average Disease Activity Score (DAS28), and Health Assessment Questionnaire (HAQ) values 52(B).
Smoking increased the use of DMARDs in RA patients and
reduced their clinical responses (ACR50) by 16% (NNH: 6), particularly in smokers of more than 20 packages/year53(B).
The radiological progression of RA was similar in smokers
and non-smokers after three years, which did not agree with
the poorer clinical responses exhibited by the former54(B).
RA patients who were smokers exhibited greater disease activity (joint pain and swelling) when compared to non-smokers
after 24 months of treatment. The pain scores [(on a visual analogue scale – VAS) were also higher among the smokers. However, radiological progression did not differ between smokers
and non-smokers55(B).
Disease activity (measured as joint swelling, pain, and DAS28) was greater in patients with an average symptom duration
of seven months who were smokers when compared to nonsmokers after a 5-year follow-up56(B).
Recommendation
Smoking increases the disease activity of RA and reduces clinical and functional responses over time. However, there is no
sufficient evidence regarding its influence on radiological disease progression.
4. Is measurement of the rheumatoid factor
a reliable test for diagnosis and prognostic
stratification in RA?
RF is an antibody that targets the Fc fragment of IgG57(D). RF
is classically associated with RA, is found in the serum of approximately 70% of RA patients, and is significantly correlated
with a poorer prognosis. High RF levels are associated with
aggressive disease, the presence of rheumatoid nodules, and
extra-articular manifestations58(D).
The diagnostic value of RF alone is limited because 30%–
50% of patients might be seronegative during the early stage of
RA57(D). In addition to its low sensitivity, its specificity is limited. Individuals without RA might test positive for RF, and its
prevalence increases with age59(B). Patients with other medical
conditions, both rheumatologic and not, might also test positive for RF44,60(B). Therefore, negative RF serology does not rule
out a diagnosis of RA, whereas the interpretation of positive
results must be carefully checked against the clinical findings.
Brazilian data (incident early RA cohort) indicate a RF prevalence of approximately 50% in patients 61(B).
RF-positive patients with RA exhibited a 17% increase of
mortality (NNH: 6) and cardiovascular mortality (NNH: 6) after
20 years of follow-up62(A).
The mortality of RA patients with RF-positive serology did
not differ from that of seronegative patients after 14 years of
follow-up. However, when the results were analysed according
to the number of expected events in the population, the mortality, and more specifically the cardiovascular mortality, was
elevated in the RF-positive patients 63(B).
A 10-year follow-up study of RA patients, in which 24% of
the cases tested positive for RF of the IgM and IgA isotypes,
found that radiological progression was associated with and
could be predicted by the serological findings (e.g. IgM or
IgA)64(B).
In a population of RA patients, 51% of whom were RF-positive, the presence of RF was predictive of radiological progression in 69% of the cases, whereas its absence ruled out progression in 83%.
RF was predictive of radiological progression (Larsen score)
in RA patients after 5 years of follow-up65(B).
RF was predictive of radiological progression (Sharp or Larsen scores)35,66(B) and the need for biological therapy67(B) in RA
patients after three years of follow-up.
The risk of radiological progression was 24.3% (NNH: 4) higher among RF-positive patients versus RF-negative patients68(A).
With a pre-test RA probability rate of 35%, positive RF (IgM,
IgA, and IgG isotypes), measured by ELISA, increased the diagnostic probability rate to 94%, while negative serology ruled out
RA with an 85% certainty rate69(B).
In a population of patients with a 35% probability rate of
RA, RF (IgM, IgA, and IgG isotypes) increased the post-test probability to 96%70(B).
Recommendation
RF measurement contributes estimations of prognosis for RA
patients, particularly with regard to radiological progression
and mortality. Positive RF serology, particularly in populations
with a pre-test probability rate of 35%, increased the diagnostic probability to 94%–96%, whereas negative RF serology
ruled RA out with a post-test probability of 85%.
5. Is anti-CCP investigation superior to
rheumatoid factor investigation for RA diagnosis?
Recently, several anti-citrullinated protein antibodies (ACPA)
were shown to behave as important diagnostic tools for
RA; these had a similar sensitivity and superior specificity
to RF, in addition to their possible participation in disease
physiopathogenesis71(B). Their possible roles as markers of RA
activity are controversial72(B).
Cyclic citrullinated peptide antibodies
Among the investigated antibodies that target filaggrin-citrulline system antigens, anti-CCP exhibits the widest clinical applicability, with 70%–75% sensitivity and approximately 95% specificity. Anti-CCP analyses are particularly useful
for patients with early RA and negative RF serology73(B).
Anti-CCP measurements are also valid in investigations
of undifferentiated arthritis. These antibodies are detected very early in the course of RA, and thus might be used
as markers for progression and disease prognosis41-43,7478
(B)21,79(D).
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Other antibodies
Other antibodies are also used to investigate RA. The aim is
to develop methods with sensitivities and specificities satisfactory for early disease diagnosis, as well as more reliable markers for activity and prognosis. These antibodies
include anti-mutated citrullinated vimentin (anti-MCV)8082
(B), anti-keratin (AKA), anti-perinuclear factor (APF)83(B),
anti-filaggrin84(B), anti-citrullinated fibrinogen (ACF)85(B), antiprotein A2 of the heterogeneous nuclear ribonucleoprotein
complex (anti-RA33)83(B), anti-interleukin 1 (anti-IL1)86(B),
anti-1-α-enolase87(B), and anti-advanced glycation end-product (AGE)88(B). The specificities of these antibodies are generally satisfactory for RA diagnosis, but their sensitivities is
generally lower than that of anti-CCP.
The 2010 ACR/EULAR criteria14(D) include only RF and ACPA
under the heading “autoantibodies”, and the values of these
antibodies are described as negative, low, or high titres. As
the values of both RF and anti-CCP are expressed as international units (IU), the results are rated negative when they are
equal to or higher than the upper limit of normal (ULN) in the
corresponding laboratory; low-positive when they are higher
than the ULN, but equal to or lower than 3 times the ULN; and
high-positive when they are higher than three times the ULN.
Positive anti-CCP correlated with the MRI swelling and erosion score at a 4-year follow-up, whereas negative anti-CCP
correlated with the synovitis score89(B).
Anti-CCP was superior to RF for predictions of the progression of undifferentiated arthritis into RA (diagnostic certainties of 93% and 68%, respectively). The former also permitted
better estimates of the severity of disease at a 7-year followup90(B).
The risk of positive anti-CCP serology in patients with active RA is 23% higher than that of patients in the period before
disease. The anti-CCP alterations did not change after seven
years of follow-up91(B).
With regard to the use of anti-CCP (second generation,
anti-CCP2) and data from 15 recent RA cohorts, it was concluded that a single positive result permits a diagnosis of RA
(likelihood ratio, LR+ 12.7), but that a single negative result
does not rule out RA (LR− 0.45). Upon comparing RF and antiCCP2, we found that their sensitivities are similar (56% and
58%, respectively), but the specificity of anti-CCP2 is superior
(96% versus 86% for RF). The sensitivity and specificity of antiCCP2 are higher than those of anti-CCP1. The combination of
positive RF and anti-CCP2 only slightly increases the diagnostic certainty, compared to anti-CCP2 alone (LR+ 27 versus 22,
respectively). An analysis of global evidence allows us to estimate the sensitivity of anti-CPP2 a 67%, and the specificity as
96%. Assuming a prevalence of 42% in RA patients according
to the 1987 ACR criteria, positive anti-CCP2 serology increases
the diagnostic certainty to 90%, and negative serology rules
out RA with a certainty of 75%92(B).
Recommendation
The sensitivity of anti-CCP is similar to that of RF, but the specificity of the former is superior, especially in the early disease
stages. Anti-CCP evaluations are recommended in patients
with a clinical suspicion of RA and negative RF test serology.
147
6. Are genetic markers (evaluations of HLA-DRB1
shared epitope alleles and PTPN22 genes) useful
for characterisations of RA patients with poorer
prognosis?
Although countless genetic markers have been described in association with RA, only the HLA-DRB1 shared epitope (SE) 10The
presence of SE (HLA-DRB1) in RA patients did not correlate with
radiological disease progression105,107(B). However, according to
some data, SE alleles and anti-CCP antibody levels might be associated with the severity of joint damage (erosion and radiological damage score) in RA patients108(B). The HLA SE had no
predictive value relative to radiological RA progression109(B).
The frequency of HLA-DRB1 alleles with SE was found to be
high in Latin American RA patients110(B).
The presence of SE alleles (DRB1) might be predictive of mortality, including cardiovascular mortality, in RA patients with
RA111,112(B).
An association was found between the DRB1 genotype
and RF-positive RA patients with a 3.0%–3.7% (NNH: 30) risk
increase113(B).
Recommendation
The PTPN22 gene polymorphism is associated with RA. Although it is not predictive of specific therapeutic responses
to biological therapy, it is predictive of remission when associated with anti-CCP. Alone or in combination with HLADRB1 (SE), the PTPN22 polymorphism permits estimations of
radiological progression or disease activity. The HLA-DRB1 allele seems to play a more important role in the prediction of
poor prognosis relative to the progression, activity, severity,
and mortality of RA.
7. Does the occurrence of extra-articular
manifestations denote a more aggressive disease
progression?
Although articular manifestations are the most characteristic,
RA can also affect other organs and systems. The most frequent extra-articular manifestations include skin, eye, pleuropulmonary, heart, blood, neurological, and osteo-metabolic
conditions. These occur more often in patients with severe
and polyarticular disease, positive RF or anti-CCP serology, and
rheumatoid nodules27(B)28(D).
The incidence of extra-articular manifestations in RA is
47.5%, which includes cardiovascular, blood, eye, and lung affections. Such manifestations are associated with a greater
likelihood of the use of biological agents114(B).
Clinically significant lung interstitial disease occurs in 10%
of RA patients115(B). Patient mortality depends on the type of
lung affection and is greater when the affection is diffuse116(B).
Pulmonary fibrosis-related mortality is approximately 6%115(B).
The average survival of patients with interstitial pneumonia is
3.2 years, and thus is generally lower compared to that of other
varieties of interstitial disease (6.6 years)116(B). In RA patients
with lung interstitial disease, anti-TNF drugs must be used
cautiously due to the risk of increased mortality117(B).
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The mortality rate of RA patients with lung interstitial disease is 7%, and the average survival duration after diagnosis
is three years. In spite of the association between interstitial
lung disease and RA activity, the latter was only denoted by
increased ESR in that study118(B).
The presence of kidney dysfunction in RA patients is not associated with the activity, progression, dysfunction, or severity
of the disease119(B).
RA patients with extra-articular manifestations exhibit a
20% increase in the risk of cardiovascular events (including
acute myocardial infarction, angina, coronary disease, and
stroke) (NNH: 5)120(B).
The survival of patients with extra-articular manifestations
of RA (18% of cases) is lower than that of patients with exclusive articular manifestations, and the relative risk of death in
the former increases by 27% after seven years of follow-up.
Similar to the extra-articular manifestations, comorbidities
also increase mortality, particularly cardiovascular conditions
because these cause 31% of patient deaths. Increased mortality correlates with greater disease activity (RF), worse function
(HAQ), and increased radiological progression121(B).
In RA patients with extra-articular manifestations, the
scores that assess disease activity, such as DAS28 and HAQ,
and the Larsen radiological score tend to be poorer, thus denoting a greater disease severity. Only 4.1% of such patients
achieved remission122(B).
After 15 years of follow-up, mortality increased only in the
patients with extra-articular manifestations (relative risk increase: 51%), compared to those without such conditions; pericarditis was the most significant of the manifestations123(B).
The mortality rate of RA patients with extra-articular manifestations (7.9% prevalence) was one death per 4.3 patients per
year, whereas the rate of patients without articular manifestations was one death per 11.4 patients per year124(B).
The risk of severe gastrointestinal diseases is elevated in RA
patients with extra-articular manifestations (4.6% prevalence).
In such patients, the disease intensity (ACR criteria) and the
signs of radiological progression are also greater125(B).
Recommendation
RA progression is more severe in patients with extra-articular
manifestations. These patients have more intense disease activity with reduced functional capacities, responses to treatment (less occurrence of remission), and life expectancies,
compared to those with exclusive articular manifestations.
8. Is conventional radiography an appropriate test
for RA diagnosis?
Conventional radiography is the most widely used imaging
method for assessments of structural joint damage in RA. In
addition to its diagnostic utility, conventional radiography
plays an important role in the monitoring of disease progression, provided that it is performed at regular intervals126(D).
The initial radiographic signs include increased amounts
of soft tissues and juxta-articular osteopenia. More characteristic signs of RA, such as reduced joint space and bone erosion, appear later in the disease course.
The presence of bone erosion during the early stages of
RA represents a risk factor for the development of persistent
arthritis127(B). This factor is associated with functional limitation and thus with poorer prognosis128(B).
When erosions are identified by radiography (15% prevalence), the diagnostic probability increases to 100%. However,
as negative findings do not reduce the probability (18%), they
do not rule out a RA diagnosis129(B).
In patients with strong clinical suspicion of RA but negative RF serology and radiography, the presence of anti-CCP
antibodies and erosions on MRI are highly specific for RA
diagnosis130(B).
In RA patients, the sensitivity of MRI for the detection
of erosions is greater than that of conventional radiography. Conventional radiography detected 89% of erosions
in the MCP joint bones and 15.8% in the wrist bones; these
were lower than the MRI detection rates of 100% and 69%,
respectively131(B).
The diagnostic accuracy of conventional radiography in
the detection of wrist bone erosions in RA patients was 63%,
whereas the accuracy of MRI was 77%132(B).
The diagnostic sensitivity of radiography for the detection
of MCP joint bone erosions in RA patients was 14%, compared
to 66% with MRI133(B).
In RA patients who were followed-up for two years, radiography identified damage progression in 40% of the cases
(total Larsen score) and 15% of the MCP joint bones (Larsen
score). The accuracy of plain radiography in the identification
of damage progression was similar to that of MRI134(B).
Detection of erosions by means of the E score in RA patients was lower on radiographic assessment (13.1 ± 8.3) than
on MRI (28.8 ± 10.0)135(B).
In a population of RA patients with joint erosions (95%
prevalence), radiography identified 59% of the cases, compared to 95% by MRI136(B).
Radiography of the hands of RA patients identified 50%
fewer erosions than MRI, although the identification of radiological progression was similar with both methods137(B).
In a population of RA patients with a 43% prevalence of
erosions, radiography increased the diagnostic probability to
80% for cases with positive findings, and ruled out a diagnosis
in 85% for those with negative findings. After a 3-year followup period, the identification of erosions on radiography decreased to 81% and 60%, respectively138(B).
In a population of patients with arthritis, 36% of whom
were diagnosed with RA, diagnostic radiography increased
the probability of RA to 50%, but when the results were negative, the probability decreased to 33%139(B).
Radiographic assessment of RA patients only slightly increased the probability of distinguishing between RF seropositive and seronegative cases. In a population with a 59% prevalence of RF seropositive cases, positive radiographic findings
(destruction) increased the probability to 66%, and a lack of
radiographic findings decreased it to 47%140(B).
Recommendation
Conventional radiography must be used in diagnostic and
prognostic assessments of RA. When needed and available, US
and MRI should also be used.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
9. Is ultrasound superior to conventional
radiography in the diagnosis and establishment
of prognosis of RA?
The sensitivity of musculoskeletal US and MRI for the detection of structural damage was superior to that of conventional radiography141(D).
US is useful for early detection, as well as the monitoring of inflammatory activity and signs of joint destruction
when performed by an operator with significant experience
in musculoskeletal diseases135(B).
Compared to MRI, the cost of US is lower, and it is not
contraindicated for patients with metallic implants or claustrophobia. Additionally, US permits dynamic assessments of
the joints and bilateral comparisons, as well as evaluations
of other anatomical structures134(B)141,143(D).
The use of power and colour Doppler might provide complementary information and thus contribute to characterisations of inflammatory activity144(D).
Positive and negative US findings, when used to identify
joint inflammation in RA patients, permits definite diagnoses in 79% and 55% of the cases, respectively. These results
are similar those of radiography (Sharp score) when it exhibits positive findings (74%), but superior when the radiographic findings are negative (38%)145(B).
Using MRI as the gold-standard (as in the present study),
US was superior to radiography in the detection of bone erosions in patients with recent RA, whereby the LR+ values
were 31 and 20, respectively. Based on a lesion prevalence of
50%, in cases with positive findings, the diagnostic probabilities of US and radiography increase to 99% and 97%, respectively. Therefore, the utility of both methods is similar135(B).
Relative to the detection of erosions in RA patients, when
US exhibits positive findings, it achieves a diagnostic certainty of 82% and for negative findings, a certainty rate of 61%,
compared to 95% and 55%, respectively, for radiography146(B).
The sensitivity and specificity of US in the detection of
inflammatory signs and interphalangeal joint destruction
in RA patients were 59% and 98%, respectively, compared
to 42% and 99% for radiography, respectively. The diagnostic
certainties relative to US and conventional radiography were
97% and 98%, respectively, when those results were positive
and 71% and 63%, respectively, when they were negative147(B).
The sensitivity and specificity of US in the detection of
MCP joint erosions in the of RA patients were 79% and 97%,
respectively, compared to 32% and 98% for conventional radiography, respectively. The diagnostic certainties relative to
US and conventional radiography were 96% and 94%, respectively, when those results were positive and 82% and 46%,
respectively, when they were negative148(B).
The sensitivity and specificity of US in the detection of
glenohumeral joint erosions in RA patients were 74% and
75%, respectively, compared to 67% and 100% for radiography, respectively. The diagnostic certainties relative to US
and conventional radiography were 75% and 100%, respectively, when those results were positive and 74% and 75%,
respectively, when they were negative149(B).
The diagnostic accuracy of US in the identification of erosions in RA patients was 84% and was thus superior to that
149
of radiography (73%). However, when only the tests with
positive findings were considered for analysis, the LR of
US was lower (5 versus 13), which indicates less diagnostic
certainty150(B).
In patients with early RA, US found erosions that were
not identified by radiography in 19.3% of the cases, but
failed to diagnose 8.8% of the cases that were identified
by radiography. The combination of both methods permitted the diagnosis of 45.6% of the lesions in that patient
population151(B).
In patients with early RA, US correlated with disease activity (DAS28) and functional capacity (HAQ) scores at 12
months of follow-up152(B).
In patients with early RA, US increased the detection of
erosions in 42.0% of the cases at the time of diagnosis and
after 9 months of follow-up, compared to radiography153(B).
The detection of joint lesions in RA patients was greater
with US versus radiography; specifically, US detection was
5% greater at the time of diagnosis, and 23% greater after
seven years of follow-up154(B). However, in another study,
radiography identified a larger number of erosions in RA
patients, compared to US (37% and 30%, respectively). After
six months, the rates were 48% and 41%, respectively155(B).
After accounting for the number of humeral erosions
(greater tuberosity, anteromedial, and posterolateral) in RA
patients, the diagnostic certainties of US and radiography
were 90% and 40%, respectively, when the findings were
positive and 96% and 39%, respectively, when the findings
were negative152(B).
Recommendation
US might contribute to the diagnosis of joint erosions in RA
patients, as well to the monitoring of disease progression.
10. Is magnetic resonance superior to
conventional radiography and ultrasound for the
diagnosis and establishment of prognosis of RA?
MRI is the most sensitive method with which to detect the
changes associated with the early stages of RA. It permits
the assessment of structural alterations of the soft tissues,
bone, and cartilage, in addition to erosions at an earlier
stage than conventional radiography138(B).
In addition to the features identified by conventional
radiography, MRI is further able to detect bone swelling,
which was shown to be a predictor of bone erosion135(B).
In Brazil, factors such as the high cost and lack of standardisation limit the use of MRI in clinical practice.
The results of MRI relative to RA diagnosis vary widely
as a function of the applied criteria and the investigated
population. Thus, the sensitivity varies from 20% to 100%,
and the specificity from 0% to 100%136,156-158(B). Additionally,
the results of MRI relative to RA progression vary widely,
with a sensitivity range from 18% to 100% and a specificity range from 6% to 97%156,159-161(B). Furthermore, the use
of MRI in the management of patients with recent RA does
not seem to be cost-effective when compared to standard
diagnostic and prognostic assessments162(B).
150
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
In RA patients, MRI (Outcome Measures in Rheumatology
– OMERACT - definition) permits the diagnosis of erosions
(hands or wrists) with 35%–90% sensitivity and 35%–90%
specificity, bone swelling (hands, wrists, or MCP joints) with
32.5%–65% sensitivity and 82.5%–100% specificity, and synovitis (hands or wrists) with 40-80% sensitivity and 57.7%–92.5%
specificity163(B).
Compared to MRI, when the findings were positive, conventional radiography could diagnose MCP and PIP joint erosions with certainty in 98%–100% of the cases, and US in 86%–
7% of the cases. When the findings were negative, the rates
were 84% and 93%, respectively 135,155(B).
The diagnostic accuracy of Doppler US for the identification of joint inflammation in RA patients was 75%, compared
to MRI164(B).
Using computed tomography (CT) as the gold-standard for
the diagnosis of erosions in the wrists of RA patients, when
the findings were positive, MRI accurately diagnosed 90% of
the cases, compared to conventional radiography138,154(B).
Using high-field MRI as the gold-standard for the diagnosis
of erosions in the wrists and MCP joints of RA patients, when
the findings were positive, limb MRI accurately diagnosed 88%
to 93% of the cases, compared to conventional radiography
(94%–98%) and US (82%)165,166(B).
A combination of MRI synovitis, swelling, and erosion
scores permitted the identification of RA patient responses to
TNF-α inhibitor treatment at a 12-month follow-up167(B).
As a method for long-term functional assessments in RA
patients, MRI identified improvements only in 29% of the
cases, compared to the functional status (assessed by doctors
and patients)168(B).
MRI (bone swelling) and US (inflammation) exhibited similar abilities to identify the progression of erosion in RA patients (using the Rheumatoid Arthritis MRI Scoring System
– RAMRIS – as the gold standard) over a 12-month follow-up
period152(B).
The progression of erosion was identified by MRI (OMERACT) in 23% of patients with RA over a 5-year period, compared
with 40% by conventional radiography (Larsen score)140(B).
Recommendation
MRI is the most sensitive method with which to detect the
changes associated with the early stages of RA. It permits the
assessment of structural alterations of the soft tissues, bone,
and cartilage, in addition to erosions at an earlier stage than
conventional radiography. In Brazil, factors such as the high
cost and lack of standardisation have limited the use of MRI
in clinical practice.
Table 5 summarises the advantages and disadvantages of
the imaging methods used to assess RA patients.
Conclusion
The present guidelines were elaborated by the Commission
of Rheumatoid Arthritis of the Brazilian Society of Rheumatology to formulate recommendations for the diagnosis and
initial assessment of RA in Brazil. Due to the country’s territorial extension and the diversity of its macro-regions, local differences relative to differential diagnoses and access to some
(laboratory or imaging) technologies might occur.
RA diagnosis is of paramount importance, especially in the
earliest stages.
Lack of diagnosis means a lack of appropriate treatment
and, consequently, an increased risk of the development of
persistent inflammation and progressive joint damage. Rheumatologists must be included as early as possible in assessments of patients with arthritis due to their wider experience
and familiarity with the possible differential diagnoses and
investigational approaches.
Despite the recent publication of guidelines for the diagnosis of RA, a revision of this subject that accounts for particular
Brazilian features is relevant.
Therefore, the establishment of recommendations for RA
ultimately seeks to define and provide a solid basis for Brazilian rheumatologists with data from controlled trials to promote a homogeneous approach to diagnosis within the Brazilian socioeconomic context.
Table 5 – Advantages and disadvantages of the imaging methods used to assess patients with rheumatoid arthritis.
Methods
Advantages
Conventional radiography
- Low cost
- Easy access
Ultrasound
- Intermediate cost
- No ionising radiation
- Allows assessing several joints
- Guides diagnostic and therapeutic
interventions
- Early detection of cartilage and bone structural
damage
- Detection of inflammatory activity by means
of power Doppler
- High sensitivity
- No ionising radiation
- Complementation using contrast agents
- Early detection of bone swelling, cartilage and
bone structural damage
Magnetic resonance
Disadvantages
- Two-dimensional representation of 3-D lesions
- Exposure to ionising radiation
- Low sensitivity for early bone damage
- Operator-dependent test
- Poor sensitivity to detect changes in deep joints (hips)
- High cost
- Limited equipment availability
- Long testing time
- Limited to one joint per exam (e.g., knee, hand)
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
Because the knowledge relative to RA increases rapidly,
the corresponding recommendations should be updated on a
periodic and regular basis.
Conflicts of interest
Mota LMH: Participated in clinical and/or experimental studies sponsored by Roche and Mantecorp; was given personal or
institutional grants by Abbott, AstraZeneca, MSD, Roche, and
Pfizer; and was a guest lecturer at meetings and other activities
sponsored by Abbott, MSD, Novartis, Roche, and Wyeth.
Cruz BA: Participated in clinical and/or experimental studies sponsored by Roche; was given personal or institutional
grants by Abbott, Bristol-Myers Squibb, Mantecorp, MSD, Novartis, Roche, Wyeth, and Pfizer; and was a guest lecturer at
meetings and other activities sponsored by Abbott, MSD, Mantecorp, Novartis, Roche, and Wyeth.
Brenol CV: Participated in clinical and/or experimental
studies sponsored by Bristol-Myers Squibb, Pfizer, Roche, and
Wyeth; was given personal or institutional grants by Abbott,
Bristol-Myers Squibb, Mantecorp, MSD, Roche, and Wyeth; and
was a guest lecturer at meetings and other activities sponsored
by Abbott and Roche.
Pereira IA: Participated in clinical and/or experimental studies sponsored by Roche; was given personal or institutional
grants by Abbott, MSD, Roche, BMS, Jansen, and Pfizer; was a
guest lecturer at meetings and other activities sponsored by
Abbott, MSD, BMS, Pfizer, Roche, and Janssen; is a member of
the consultant or executive boards of pharmaceutical companies or the normative committees of scientific studies sponsored by Abbott, BMS, Janssen, Roche, Pfizer, and MSD.
Rezende-Fronza LS: Participated in clinical and/or experimental studies sponsored by Bristol-Myers Squibb, Pfizer, and
Roche; and wrote scientific papers for journals sponsored by
Pfizer.
Bertolo MB: Was a guest lecturer at meetings and other activities sponsored by Abbott, Pfizer, and Sanofi Aventis.
Freitas MVC: Was given personal or institutional grants by
Abbott, MSD, Pfizer, Roche, and Wyeth; was a guest lecturer at
meetings and other activities sponsored by Abbott, MSD, Pfizer,
Roche, and Wyeth; is a member of the consultant or executive
boards of pharmaceutical companies or the normative committees of scientific studies sponsored by AstraZeneca, MSD,
and Wyeth; and wrote scientific papers for journals sponsored
by Abbott, AstraZeneca, Bristol-Myers Squibb, and Wyeth.
Silva NA: Participated in clinical and/or experimental studies sponsored by Bristol-Myers Squibb and Roche; was given
personal or institutional grants by Abbott, MSD, Pfizer, Roche,
and Wyeth; and was a guest lecturer at meetings and other activities sponsored by Janssen, Mantecorp, MSD, and Roche.
Louzada-Junior P: Participated in clinical and/or experimental studies sponsored by Merck and Roche; was given personal
or institutional grants by Abbott; and was a guest lecturer at
meetings and other activities sponsored by Bristol-MeyersSquibb, Pfizer, and Roche.
Giorgi RD: Was given personal or institutional grants by
Bristol-Myers Squibb and Roche; and was a guest lecturer at
meetings and other activities sponsored by Bristol-Myers
Squibb and Roche.
151
Lima RAC: Participated in clinical and/or experimental studies sponsored by Mantecorp and Roche; was given personal or
institutional grants by Acteion, Lilly, and Pfizer; and was a guest
lecturer at meetings and other activities sponsored by Acteion,
Lilly, and Pfizer.
Pinheiro GRC: Was given personal or institutional grants by
Janssen and Roche.
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Funck-Brentano T, Etchepare F, Joulin SJ, Gandjbakch F,
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R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Guidelines
Guidelines for the drug treatment of rheumatoid arthritis
Diretrizes para o tratamento da artrite reumatoide
Sociedade Brasileira de Reumatologia (Brazilian Society of Rheumatology)
Projeto Diretrizes da Associação Médica Brasileira, São Paulo, SP, Brazil
Participants
Objective
Licia Maria Henrique da Mota*, Bóris Afonso Cruz,
Claiton Viegas Brenol, Ivânio Alves Pereira,
Lucila Stange Rezende-Fronza, Manoel Barros Bertolo,
Max Vitor Carioca Freitas, Nilzio Antônio da Silva,
Paulo Louzada-Junior, Rina Dalva Neubarth Giorgio,
Rodrigo Aires Corrêa Lima, Wanderley Marques Bernardo,
Geraldo da Rocha Castelar Pinheiro
These guidelines aim to provide recommendations for the
treatment of rheumatoid arthritis in Brazil. Although North
American and European guidelines for the treatment of rheumatoid arthritis have been recently published, it is important
to review the subject with regard to specific aspects of Brazilian reality. Thus, the ultimate purpose of the establishment of
consensus guidelines for the treatment of rheumatoid arthritis
in Brazil is to provide an orientation and foundation for Brazilian rheumatologists with evidence from scientific studies and
the experience of a committee of experts on the subject. Thus,
therapeutic approaches to rheumatoid arthritis within the Brazilian socioeconomic context will be standardized, while physician autonomy will be maintained with regard to the indication/selection of available treatment options.
As knowledge in this scientific field progresses rapidly, we
suggest biannual updates to these guidelines.
Final elaboration
12 April, 2012
Description of evidence collection method
A literature review of the scientific articles referenced in
these guidelines was conducted with the MEDLINE database. The evidence search was based on real clinical scenarios, and the following keywords (MeSH terms) were used:
Arthritis, Rheumatoid, Therapy (early OR late OR later OR
time factors OR delay), Prognosis, Remission, Steroids, AntiInflammatory Agents, Non-Steroidal, NSAIDs, Diclofenac,
Ibuprofen, Indomethacin, Piroxicam, COX-2, Celecoxib, Etoricoxib, Disease-modifying antirheumatic drug OR DMARD,
Methotrexate, Gold sodium, Leflunomide, Sulfasalazine,
Hydroxychloroquine, Tumor Necrosis Factor-alpha, Adalimumab, Certolizumab, Etanercept, Infliximab, Golimumab,
Rituximab, Tocilizumab and Abatacept.
Grade of recommendation and strength of evidence
A: Most consistent experimental and observational
studies.
B: Less consistent experimental and observational studies.
C: Case reports (uncontrolled studies).
D: Opinion that is not substantiated by critical evaluation,
based on consensus, physiological studies or animal
models.
Introduction
Rheumatoid arthritis (RA) is a systemic and inflammatory autoimmune disease that is characterized by the preferential impairment of the synovial membranes of peripheral joints. The
RA prevalence varies between 0.5% and 1% of the population,
and RA affects predominantly women and adults in the 30- to
50-year age group1,2(B).
The generally symmetrical involvement of small and large
joints is the main feature of RA, and involvement of the hands
and feet is common. The chronic and destructive nature of the
disease can lead to significant functional limitations, including
the loss of ability to work and an impaired quality of life, unless
a diagnosis is made at an early stage of the disease and treatment leads to clinical improvements3(B). In addition to the irreversible deformity and functional limitations, patients with
* Corresponding author.
E-mail: [email protected] (L.M.H Mota)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
advanced-stage RA might have lower survival rates, a finding
that highlights the severity of this disease4(B) 5(D).
RA-related costs are high as the result of both direct (spending on various medications, such as expensive biologic drugs,
and medical and hospital expenses) and indirect (loss of personal productivity, absenteeism, payment of disability pensions and a total loss of working capacity) factors6(B).
In the last two decades, there have been significant advances in an understanding of RA physiopathology, accompanied by the development of new therapeutic categories and
the implementation of different treatment strategies, patient
monitoring and intensive intervention and disease control at
early symptomatic stages7(D). The initial period of the disease,
particularly the first 12 months, is known as early RA5(D) and is
considered to be a window of therapeutic opportunity, a time
during which rapid and effective pharmaceutical intervention
can change the long-term disease course. These interventions
result in better disease control and the possibility of sustained
RA remission7,8(D).
Treatment of RA
RA treatment includes patient and family education, drug therapy, physiotherapy, psychosocial support, occupational therapy
and surgical approaches. Drug therapies that will be addressed
in this document include non-steroidal anti-inflammatory
drugs (NSAIDs), corticosteroids, biologic and synthetic diseasemodifying anti-rheumatic drugs (DMARDs) and immunosuppressive drugs.
DMARDs should be indicated for all patients once a diagnosis of RA9(B) has been established. The use of DMARDs can
be considered for patients with undifferentiated arthritis and
positive test levels for RA predictive biomarkers such as anticyclic citrullinated peptides (anti-CCPs) and/or rheumatoid factors (RFs)10(B).
Table 111-44(A) 45-64(B) 65-80(D) summarizes the DMARDs that are
most frequently used in Brazil along with their presentations,
doses and monitoring considerations.
1. Is disease treatment with the intent to achieve
remission a feasible goal?
Once a diagnosis of RA has been established, an initial disease
assessment is important and should include the adequate
monitoring of disease activity by assessing not only articular
but also extra-articular manifestations and the presence of comorbidities.
Some of the parameters that have been found to correlate
with RA activity include patient visual pain scales, patient and
physician-reported disease activity, the number of tender and
swollen joints, instruments for functional capacity assessments (e.g., the Health Assessment Questionnaire – HAQ), inflammatory markers (e.g., erythrocyte sedimentation rate – ESR
and/or C-reactive protein – CRP), fatigue, duration of morning
stiffness, radiography of the hands, wrists and feet and quality of life indices (e.g., the Short Form – SF-36)81-83(A) 84(B) 85,86(C).
Composite indices of disease activity (CIDAs) have been created and validated with these parameters. The main indices
159
are the one based on 28 joint count (Disease Activity Score 28
– DAS-28), the simplified disease activity index (SDAI) and the
clinical disease activity index (CDAI). These indices use a more
simplified count of 28 joints (bilateral proximal interphalangeal, metacarpophalangeal (MCP), wrist, elbow, shoulder and
knee joints) and determine a numerical value for RA activity.
Tables 2, 3 and 4 detail the calculations and uses for these indices87-95(A) 96(B).
There are good correlations between the CIDAs (CDAI, SDAI
and DAS-28), and any of these indices can be used alone. Patients who are in remission or have low disease activity according to any index also have reduced radiographic progression
and improved functional outcomes. Therefore, the aim should
always be to keep the patient in clinical remission or, if this
outcome is not possible, in a state of low disease activity87(A).
The use of methotrexate (MTX), especially in combination with other DMARDs (gold, chloroquine or sulfasalazine),
led to clinical remission in 14.0%97(B), 33.3%98(A), 38.0%3(B) and
95%99(A) of adult patients with active RA of a duration ranging
between four months and five years (mostly between one and
two years), according to the American College of Rheumatology (ACR) criteria. The best results were observed in the first 6
months after treatment. According to DAS-28 criteria, the remission rate at 24 months is 76%100(B).
A combination of MTX and infliximab led to remission in
70% (ACR criteria)101(A) and 21.3% (SDAI criteria)102(A) of patients
with RA of a duration less than 36 months who were evaluated
between 54 weeks and 24 months. Similarly, MTX and etanercept combinations have achieved remission rates in a period
of 12 to 36 months in 37% (DAS-44 ≤ 1.6)103(A), 50% (DAS-28 ≤
2.6)43,45,104(A) and 50% (DAS-28 ≤ 3.2) of patients105(A).
Remission, as measured by the DAS-28 ≤ 2.6 parameter, was
achieved in 43% to 45% of patients with active RA (12 months)
within four to nine years with a combination of adalimumab
and MTX28,106(A). The remission rate, as measured by SDAI
criteria, was 15% at 24 months107(B). The rates of early (in the
first 12 months) remission in these patients, according to different criteria, were 47.7%, 50.8% and 32.3% for EULAR (European League against Rheumatism; DAS-28), ACR70 and DAS-28,
respectively108(B).
Responses to recent RA treatments (less than 24 months of
illness) with combinations of DMARDs (MTX, gold, chloroquine
or sulfasalazine) have also been measured according to several
criteria or parameters during remission periods ranging from
2–11 years; the different criteria included ACR (14%–48%)109-113(B),
DAS ≤ 2.4 (39%–43%)114,115(B) and DAS-28 ≤ 2.6 (23%–51%)116,117(B).
Recommendation
RA patient remission, as measured by any of the objective
parameters of disease activity (DAS, DAS-28, SDAI and CDAI),
should be considered as central objective of patient treatment.
2. Does the early initiation of RA treatment offer
benefits over a later initiation with respect to
clinical and radiographic prognosis?
In patients who began treatment with non-biologic DMARDs,
the remission rate at 12 months, defined as a CDAI score <
160
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Table 1 – Disease-modifying antirheumatic drugs used for treating rheumatoid arthritis in Brazil.
Drug
Presentation
Dose
Clinical response and monitoring
Synthetic disease-modifying antirheumatic drugs
Methotrexate
Tablets: 2.5 mg
Solution for injection:
50 mg/2 mL
10–30 mg/week
(orally, IM or SC)
Sulfasalazine
Tablets: 500 mg
1–3 g/day (orally)
Leflunomide
Tablets: 20 mg
20 mg/day or alternate days
(orally)
Hydroxychloroquine
sulfate
Chloroquine
disphophate
Tablets: 400 mg
Up to 6 mg/kg/day (orally)
Tablets or capsules:
150 mg or 250 mg
Up to 4 mg/kg/day (orally)
Gold salts
(aurothioglucose
or sodium
aurothiomalate)
Solution for injection:
50 mg/0.5 mL
50 mg/week, deeply IM,
usually initiating with 25
mg/week. After control,
fortnightly and monthly
doses. The cumulative dose
should not exceed 3 g
Reduces signs and symptoms of disease activity,
improves the functional status, and reduces
the radiographic disease progression. Currently
considered the standard drug for treating RA.
Monitoring: blood count, creatinine and liver
enzymes every 4–12 weeks.
Reduces signs and symptoms of disease activity,
improves the functional status, and reduces the
radiographic disease progression. Monitoring: blood
count and liver enzymes every 8–12 weeks. Can be
associated with MTX and other DMARDs.
Reduces signs and symptoms of disease activity,
improves the functional status, and reduces the
radiographic disease progression. Monitoring:
blood count, creatinine and liver enzymes every
4–12 weeks. Can be associated with MTX and other
DMARDs.
Antimalarials are currently considered less potent
drugs, and should be used at initial cases of RA
or undifferentiated arthritis, with low erosive
potential. Can be associated with MTX and other
DMARDs. Monitoring: initial ophthalmologic exam
and annually after five years (or annually since
the beginning, in the presence of risk factors for
maculopathy or retinopathy).
Effective in controlling symptoms and reducing
the radiographic disease progression, rarely used
in Brazil, due to their adverse effects and low
availability. Monitoring: monthly; blood count, liver
enzymes, and urinalysis.
Biologic disease-modyfing antirheumatic drugs
Tumor necrosis
factor blockers
Effective in controlling symptoms and reducing
the radiographic disease progression. Should be
preferably prescribed after failure of two schedules
with synthetic DMARDs (one of which should
include the combination with synthetic DMARDs,
with MTX preferably as the anchor drug), associated
with MTX or other synthetic DMARD. Monitoring:
investigation of latent TB before starting treatment
(clinical history, chest radiography, PPD and/or
IGRA), blood count, liver enzymes every 4–12 weeks.
Careful monitoring of the occurrence of infection,
particularly during the first year of use.
Adalimumab
Certolizumab
Prefilled syringes: 40 mg
Prefilled syringes: 200 mg
Etanercept
Infliximab
25-mg and 50-mg vials or 50mg prefilled syringes
Vials: 100 mg
Golimumab
Prefilled pen: 50 mg
40 mg SC every 15 days
400 mg SC every two weeks, in
weeks 0, 2 and 4, and, then,
200 mg every two weeks, or
400 mg every four weeks
50 mg/week
3–5 mg/kg/dose IV infusion
in weeks 0, 2 and 6, followed
by the same dose every 6–8
weeks
50 mg SC monthly
(continued on next page)
161
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
Table 1 – Disease-modifying antirheumatic drugs used for treating rheumatoid arthritis in Brazil. (continued)
Drug
Presentation
Dose
Clinical response and monitoring
Biologic DMARDs
Costimulation
modulator
Abatacept
250-mg vials
B lymphocyte
depletion agent
Rituximab
500-mg vials
IL-6 receptor blocker
Tocilizumab
80-mg or 200-mg vials
IV infusion of 500 mg in
Reduces signs and symptoms of disease activity
patients weighing less than
and the radiographic disease progression . Can be
60 kg, of 750 mg in patients
prescribed after failure of synthetic DMARDs or
weighing 60-100 kg, and of
failure of and/or intolerance to biologic DMARDs.
1,000 mg in patients over 100 It is preferentially used in association with MTX or
kg, every four weeks
other synthetic DMARDs.
Monitoring: blood count and liver enzymes every
4–8 weeks. Occurrence of infection should be
monitored.
500 mg to 1 g IV on days 0 and Effective in reducing signs and symptoms of RA
14 (1–2 g/cycle)
and the radiographic disease progression. Can be
prescribed after failure of and/or intolerance to
anti-TNF or other biologic DMARDs. It should not be
prescribed after failure of synthetic DMARDs, except
for exceptional situations. The presence of RF and/
or anti-CCP predicts better therapeutic response
to rituximab. It should be preferably prescribed in
association with MTX or other synthetic DMARD.
The cycles can be repeated at minimum intervals of
six months, according to disease evolution.
Monitoring: blood count and liver enzymes every 4–12
weeks. Occurrence of infection should be assessed.
8 mg/kg/dose on IV infusion
Effective in reducing signs and symptoms of RA
every four weeks
and the radiographic disease progression. Can be
prescribed after failure of synthetic DMARDs or
failure of and/or intolerance to anti-TNF or other
biologic DMARDs. Preferential use in association
with MTX or other synthetic DMARDs, although it
can be used as monotherapy.
Monitoring: blood count, liver enzymes, and lipid
profile at every infusion.
Immunosuppressive drugs
Considered less effective in controlling signs and
symptoms of RA and reducing radiographic disease
progression. They are inferior options compared
with DMARDs. They are mainly indicated to treat
extra-articular manifestations and vasculitis.
Azathioprine
Tablets: 50 mg
1–3 mg/kg/day, orally
Cyclophosphamide
Tablets: 50 mg
200-mg or 1,000-mg vials
2–2.5 mg/kg/day, orally, or
monthly pulse therapy with
750 mg to 1 g/m2 of body
surface, IV, every four weeks
Cyclosporine
Tablets: 50 and 100 mg
3–5.0 mg/kg/day, orally
Monitoring: blood count and liver enzymes every 4–8
weeks.
Reserved for patients with severe extra-articular
manifestations.
Monitoring: blood count, liver enzymes, and
urinalysis (due to the risk of hemorrhagic cystitis)
every four weeks.
Blood pressure and renal function every 2–4 weeks.
RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drug; IGRA, interferon gamma release assays; IM, intramuscular; IV,
intravenous; MTX, methotrexate; PPD, tuberculin skin test; RTX, rituximab; SC, subcutaneous.
2.8, was 21.3% in those with a disease duration of five years
or less, compared to 19.6% in patients with a disease duration
between 6–10 years and 13.5% in those with a disease duration of at least 11 years. Therefore, there is a 1.7% (number
needed to treat – NNT: 60) and 7.8% (NNT: 13) greater chance
of response (remission) when synthetic non-biologic DMARD
treatment is initiated within the first five years of the disease,
compared with 6–10 years or after 11 years of the disease,
respectively51(B).
In patients who received anti-TNF biologic DMARD treatment, the benefit of early treatment in the first five years of
the disease was 4.6% (NNT: 22) or 9.5% (NNT: 10) compared
with treatment after 6–10 years or more than 11 years,
respectively51(B). The percentage of patients who achieved
sustained remission remained higher in patients who were
treated in the first five years of disease throughout the course
of treatment.
In patients who were diagnosed with RA within the first
five years since the onset of symptoms, the use of synthetic
DMARDs (MTX, leflunomide, sulfasalazine, chloroquine/hydroxychloroquine, intravenous (IV) gold sodium, cyclosporine)
within the first year of symptoms led to reduced radiographic
disease progression (measured by joint damage according to
the Ratingen score) than for patients whose treatment started
after symptoms had occurred for one to five years. Patients
with for years of symptoms had a 0.31% greater chance of
162
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Table 2 – Calculation and total value of composite indices of disease activity (CIDAs).
Elements
SDAI
Swollen joint count
Painful joint count
Acute phase reactants
Overall assessment of health
(patient)
Global assessment of disease
(patient)
Global assessment of disease
(evaluator)
Total index
(Change in rate)
CDAI
DAS-28 (4 variables)
(0-28) Simple sum
(0-28) Simple sum
CRP (0.1–10 mg/dL)
(0-28) Simple sum
(0-28) Simple sum
-
(0-10 cm)
(0-10 cm)
Square root of the simple sum
Square root of the simple sum
ESR 2-100 mm
or CRP 0.1-10 mg/dL logarithmic
transformation
0-100 mm
(0-10 cm)
(0-10 cm)
-
Simple sum
(0.1-86)
Simple sum
(0–76)
Number requires entry into the
calculator (0.49-9.07)
SDAI, simplified disease activity index; CDAI, clinical disease activity index; DAS-28, disease activity index (28 joints); CRP, C-reactive protein;
ESR, erythrocyte sedimentation rate. Ranges of 2-100 mm/h for ESR and 0.1-10 mg/dL for CRP are assumed.
Table 3 – Cutoffs for composite indices according to RA
activity.
Index
SDAI
CDAI
DAS-28
State of disease
activity
Remission
Low
Moderate
High
Remission
Low
Moderate
High
Remission
Low
Moderate
High
Cutoffs
≤5
> 5 and ≤ 20
> 20 and ≤ 40
> 40
≤ 2.8
≤ 10
> 10 and ≤ 22
> 22
≤≤ 2.6
> 2.6 and ≤ 3.2
> 3.2 and ≤ 5.1
> 5.1
SDAI, simplified disease activity index; CDAI, clinical disease
activity index; DAS-28, disease activity index (28 joints).
Modified from Aletaha D, Smolen JS. The Simplified Disease
Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI):
A review of their usefulness and validity in rheumatoid arthritis.
Clin Exp Rheumatol 2005; 23(39):S100–8.
joint damage progression per year than patients who were
treated after less than one year of symptoms118(B).
Early administration of DMARD treatment (less than nine
months from symptom onset) produced a 33% relative reduction in radiographic disease progression during the following
three years119(B).
It was also found that for patients whose treatment began with 3 g/day of sulfasalazine or more than 15 mg/week
of MTX in the first three months after symptom onset, the
following results were observed in comparison to patients
whose treatment began after 12 months: a 40% increase in
the number of patients with responses within 32 months (as
measured by DAS-28 < 3.2; NNT: 2); a 4-fold reduction in joint
damage progression (measured by the Larsen radiographic
score) and a 35% increase (NNT: 3) in the number of patients
who achieved 50% and 70% ICR120(B).
However, in patients with symptom durations of less than
24 months, no differences in the ACR (20 or 50) or DAS-44 <
1.6 response rates were found between patients who began
non-biologic DMARD therapy after less than five months of
Table 4 – Responses according to variations in the
Composite Indices of Disease Activity points.
Index
Response
EULAR-DAS2887,88(A)
SDAI response90
(A)
CDAI response90
(A)
Response Type
Good: down > 1.2 points and patients achieve
DAS-28 with low activity (≤ 3.2).
Moderate: down 1.2 points on DAS-28; down
between 0.6 and 1.2 points with a decline in
disease activity from high to moderate activity
or moderate to low activity.
Good: down 17 points.
Moderate: down 7 points.
BGood: down 14 points.
Moderate: down 6 points.
SDAI, simplified disease activity index; CDAI, clinical disease
activity index, DAS-28; disease activity index (28 joints).
Modification of: Aletaha D, Funovits J, Wards MM, Smolen JS,
Kvie TK. Perception of improvement in patients with rheumatoid
arthritis varies with disease activity levels at baseline. Arthritis
Rheum. 2009;61:313–20.
symptoms and those who started treatment after more than
five months 121(B).
If four months after symptom onset is set as the cutoff
for delayed or retarded treatment with 1.0 g of sulfasalazine
(monotherapy) or 500 mg of sulfasalazine twice per day, 7.5
mg of methotrexate per week, 300 mg of hydroxychloroquine
and 5 mg of prednisone per day (combination therapy), the
disease remission rate in response to earlier treatment (< 4
months) is 24% greater (NNT: 4) in patients who underwent
monotherapy, despite the similar time course for those who
underwent combination therapy110(B).
In patients with early RA who were treated for two years
with DMARDs (MTX, combined or not with adalimumab), the
additional time to achieve remission (SDAI) in the first year of
treatment was accompanied by an increase in joint damage
progression, as evaluated by imaging, in the second year107(B).
Recommendation
Treatment introduction for patients with early RA should
be early (in the first few months after symptom onset) to
increase the clinical response rate (NNT: 2–4) and reduce
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
radiological joint damage progression in the early years of
treatment.
3. Does corticosteroid use in early-stage disease
improve patient outcomes?
Improvements in inflammation and pain are the bestknown and expected effects of corticosteroids in RA. However, some studies have indicated that corticosteroids,
when combined with DMARDs, can modify the course of
the disease14(A) 66(D).
Most studies on the use of corticosteroids in RA treatment suggest the use of prednisone or prednisolone at low
doses (≤ 15 mg/day). There are no comparative studies that
have preferentially indicated higher doses at the beginning
of treatment14(A) 66(D).
Because corticosteroids have many side effects, their
usage should be kept to a minimum. If corticosteroid use
for three or more months is foreseen, calcium and vitamin
D supplements should be taken. The use of antiresorptive
drugs such as bisphosphonates could be considered in patients with risk factors as determined by fractures or bone
densitometry results50(B).
Gastric protection via proton pump inhibitors is recommended for patients who concomitantly use corticosteroids and NSAIDs67(D).
The use of intra-articular corticosteroids can be considered at any treatment stage during which the disease remains active in a small number of joints67(D). In patients
with early RA (less than 12 months of symptoms) and involvement of the MCP joints, the use of MTX in combination with intra-articular methylprednisolone infiltration
can reduce bone loss in the inflamed joints122(B).
Prednisone (12.5 mg/day for two weeks and 6.25 mg/day
for 12 months), when combined with MTX (15 mg/month),
led to an increase of 43.4% (NNT: 2) in the 6-month remission rate (according to DAS) in patients with early RA (less
than 12 months of disease)115(B).
In patients with early-stage arthritis (less than 16 weeks
of symptoms), the use of an intramuscular glucocorticoid
(single injection of 120 mg methylprednisolone) offered no
benefit with respect to symptom remission or RA development at 52 weeks123(B).
The use of 1–4 mg of prednisone per day for 24 weeks reduced the risk of loss of treatment adherence due to a lack
of efficacy by 31% (NNT: 3) in RA patients124(A).
In RA patients, combined treatment with MTX (15 mg
weekly) and prednisone (60 mg per day with gradual reduction) for 24 months reduced radiological progression and
improved functional responses (HAQ) but increased the
number of patients with a loss of treatment adherence by
7% (number needed to harm – NNH: 14)125(A).
The combination of MTX (15 mg/week) and prednisone
(60 mg/day) led to an increase in the 24-month remission
rate (DAS ≤ 2.4) of 18% (NNT: 6), increases in clinical responses (ICR) and functional capacity (HAQ), and reductions in radiographic progression in RA patients, compared
to treatment without prednisone56(B) 126(A). However, de-
163
spite the lack of increased adverse events, patients reported greater intolerance to this combination127(B).
The combination of DMARDs and prednisolone (7.5 mg/
day) over 24 months reduced radiological joint damage
progression (Sharp score) and increased disease remission
(DAS-28) by 22.7% (NNT: 4), with few adverse events in patients with early RA (less than 12 months of symptoms)128(A).
The use of budesonide (9 mg/day) or prednisone (7.5 mg/
day) in RA patients (less than 12 months of disease) for 12
weeks caused improvements in disease activity (number of
involved joints) and function (HAQ)129(B).
There was no increased clinical benefit from the use of
prednisone at 10 mg/day for 24 months in patients with
early-stage RA. However, there is evidence for reduced radiographic joint damage progression, and no increases in
the rates of bone fractures have been reported130,131(A).
The combination of prednisolone (initial dose of 30 mg/
day and maintenance of 4.5 mg/day) and DMARDs only
caused a reduction in radiographic injury progression
(Larsen score) at 12 months in patients with early RA132(B).
Recommendation
The use of corticosteroids, particularly daily prednisone, in
combination with drugs that modify the disease course, especially MTX, for 12 to 24 months offers radiological and clinical benefits to patients with early RA. Because corticosteroids
have many side effects, their usage should be kept to a minimum, and their dose should be the smallest possible.
4. Does the prescription of anti-inflammatory
drugs alter the disease prognosis with regard to
clinical and radiographic progression?
NSAIDs are useful because they decrease inflammation and
pain, especially early in the disease, as DMARDs are not immediately effective. NSAIDs can also be used when disease
activity is not completely controlled and when disease flareups occur47(B)65(D).
Patients who were diagnosed with RA within the past
12 months and who initially received NSAID treatment (12
months) alone or, if necessary, with DMARDs, had worse
clinical responses within five years than those who initially
received DMARDs (gold sodium, chloroquine, MTX or sulfasalazine), as measured by ESR (in mm/hour), mean pain
score (visual analogue scale – VAS-100 mm), articular score
(Thompson articular index of edema and joint pain, 0–534),
general well-being (VAS-100 mm), duration of morning stiffness (maximum, 720 minutes), grip strength (kPa; measured
with a vigorimeter), and functional disability (HAQ) (0–3)133(B).
Of the patients who used NSAIDs for the first 14 months (on
average), 86% discontinued the treatment due to ineffectiveness and were subsequently treated with DMARDs for an average of 42 months. Patients who remained on NSAIDs for
five years had worse clinical and radiological progressions in
comparison to those who discontinued treatment133(B).
Furthermore, adult patients who had RA for at least six
months and had previous clinical responses to NSAIDs had
varying lower discontinuance rates due to ineffectiveness
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of 12%–20% and 10%–50% after 12-week treatments with 90
mg/day of etoricoxib or 500 mg of naproxen twice daily, respectively. However, there were measurable benefits for patients who remained on the treatment, according to the patient global assessment scores (PGA), Investigator of Global
Assessment of Disease Activity scores and the number of
joints with edema134,135(A).
Patients who had been diagnosed with RA in the previous
12 months were treated with either 1.2 g/day of sulfasalazine or 100 mg/day of diclofenac; 11% and 20%, respectively,
did not complete the 12-month treatment course due to
ineffectiveness. The number of radiographic erosions was
significantly higher in patients treated with diclofenac. Furthermore, with regard to the disease activity scores (ESR and
DAS), swollen joints, patient global assessments and HAQ,
the patients treated with sulfasalazine had 65% to 82% better responses than those treated with NSAIDs136(B).
Despite a discontinuation rate of 15%, the use of diclofenac for active RA treatment produced significant responses
at 12 weeks according to the ACR20 criteria, patient global
assessments, VAS for pain, functional HAQ scores and joint
swelling. CRP and ESR outcomes did not show significant
benefits137(A).
RA patients (duration of more than three months) who
used different doses of celecoxib (100 mg, 200 mg or 400 mg)
or a dose of naproxen (500 mg twice daily) showed functional (HAQ) and quality of life (SF-36) improvements at 12 weeks
according to the ACR20 and also the number of involved
joints, VAS for pain, HAQ and PGA, with no differences in
response between these medications. However, naproxen
produced adverse gastrointestinal events in a number of
patients138,139(A).
Patients with RA for at least six months who used 200 mg
of celecoxib or 75 mg of diclofenac twice daily for 24 weeks
were found to have reduced edema, joint stiffness and PGA
score indices with no differences between the treatments.
However, adverse gastrointestinal events were significantly
more frequent in patients treated with diclofenac140(A).
There are indications that the combination of NSAIDs
and DMARDs is a favorable prognostic factor for RA
remission141(B). The chosen NSAID should be personalized,
as there is no known superiority of any drug in this class.
Greater control, replacement, suspension, shorter usage
time and lower dose should be considered if there are any
medical conditions that might be aggravated by NSAIDs
such as previous NSAID hypersensitivity, hypertension,
heart failure, renal failure, gastrointestinal disease, arterial
failure, liver disease or clotting disorders48(B).
For patients with a history of gastrointestinal disease, the
selective cyclooxygenase 2 (COXIB) inhibitors present a lower risk than other NSAIDs49(B). For those with a higher risk
of cardiovascular disease, anti-inflammatory drugs should
generally be used with caution13(A).
Recommendation
The use of NSAIDs alone as an early treatment in patients
with active RA produces a worse clinical response in the first
24 months than combined treatment with DMARDs and also
suffers from a high rate of treatment discontinuation due to
inefficacy. The rate of adverse gastrointestinal events associated with treatment discontinuation, the short treatment
response evaluation time, as well as the worse radiological
clinical prognosis means that RA treatment with NSAIDs
alone is not recommended. Apparently, the use of NSAIDs
in combination with DMARDs during early-stage disease is a
favorable prognostic factor for RA remission.
5. Should methotrexate be the first treatment
option?
MTX is an immunomodulatory agent that acts by inhibiting
the synthesis of DNA, RNA, thymidylate and proteins. In RA,
the anti-inflammatory effects of MTX appear to be at least
partly related to the modulation of adenosine metabolism
and to possible effects on tumor necrosis factor (TNF) activity. The immunosuppressive and toxic effects of MTX are
due to the inhibition of dihydrofolate reductase, an enzyme
involved in folic acid metabolism that prevents the reduction of dihydrofolate to active tetrahydrofolate. The time to
maximum concentration is 1–5 hours orally (OR) and 30–60
minutes intramuscularly (IM) or subcutaneously (SC). After
administration, 40% - 90% is eliminated renally in an unaltered form68(D). MTX is currently considered the standard
drug for RA treatment69(D). Its abilities to reduce the signs
and symptoms of RA activity and improve patient functionality have been demonstrated15(A). Additionally, MTX reduces the progression of radiographic lesions.
An initial dose of 10–15 mg/week MTX, administered
orally or parenterally (IM or SC), is recommended. If disease
improvement or control is not observed in response to the
initial dose, the dose should be gradually increased every 2–4
weeks to a final dose of 20–30 mg/week, preferably within
the first 12 weeks. Parenteral presentation may be indicated
in patients with gastrointestinal intolerances or inadequate
responses to the oral form70(D).
The adverse events most frequently reported in response
to MTX are anemia, neutropenia, nausea and vomiting, mucositis, and elevated liver enzyme levels. Less frequent manifestations include interstitial pneumonia. It is contraindicated in patients with renal failure, liver disease, alcoholism,
bone marrow suppression and in women of childbearing
potential who are not using contraception. Pregnancy and
breastfeeding are formally contraindicated in MTX-treated
patients. MTX should be used with caution in patients with
mild lung disease and avoided in patients with moderate or
severe pulmonary disorders70(D).
It has been suggested that MTX administration should be
combined with folic acid at doses of 5–10 mg/week, given
24–48 hours after MTX, to minimize adverse events70(D).
Recommendation
The efficacy of MTX for the treatment of active and early RA
is well established. MTX is currently considered the standard
drug for RA treatment. Its abilities to reduce the signs and
symptoms of RA activity and improve patient functionality
have been demonstrated. MTX also reduces the progression
of radiographic lesions.
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6. Are other DMARDs such as leflunomide,
sulfasalazine and gold sodium equivalent to
MTX in terms of safety and efficacy for disease
treatment?
Leflunomide
Leflunomide is an immunomodulatory agent that inhibits the
enzyme dihydroorotate dehydrogenase, which is involved in
pyrimidine synthesis, and thus presents with antiproliferative activity. It is absorbed via the gastrointestinal tract, and
biotransformation most likely occurs in the liver and gastrointestinal wall, where leflunomide is mainly transformed into
M1, the active metabolite responsible for all leflunomide-associated actions. The time to maximum concentration (peak) of
M1 is 6-12 hours, and elimination is renal and intestinal71(D).
Leflunomide improves disease activity and patient quality
of life and reduces radiographic progression18(A) 53(B).
Leflunomide is prescribed at a dose of 20 mg/day (OR)18(A)
53
(B) 71(D), although a dose of 20 mg on alternate days may be
used.
Adverse events in response to leflunomide include nausea,
vomiting, abdominal pain and diarrhea, abnormal liver enzyme levels, rash and hypertension71(D). It is contraindicated
in women of childbearing potential who are not using contraception, as well as in patients with renal and hepatic disease.
Pregnancy and breastfeeding are formally contraindicated in
leflunomide-treated patients, and its suspension is recommended for two years before a possible pregnancy. In cases
of complications, especially in pregnancy, leflunomide can be
eliminated by the administration of cholestyramine, given in
8-g doses three times daily for 11 days71(D).
A comparison between MTX (25 mg/day) and leflunomide
(20 mg/day) combined with prednisone, given for 24 weeks,
showed no difference in clinical response in patients with RA
for more than 2.4 years as measured by DAS-28142(B).
In a systematic review of randomized controlled trials
(RCTs) that studied the use of leflunomide in patients with
active RA, it was concluded that there was no difference in
clinical outcomes compared to MTX143(A) .
In patients with active RA, the use of leflunomide (20 mg/
day) for four months showed no differences in clinical (ICR
and VAS) or functional (HAQ) responses compared with MTX
(15 mg/week) but showed better results according to MR imaging criteria144(A). However, this comparison was performed
with submaximal doses of MTX.
There was no difference between leflunomide (20 mg/day)
and MTX (15 mg/week) with respect to clinical response (ICR)
in RA patients after a 24-month treatment, but functional responses (HAQ) were higher in response to leflunomide145(A).
In a 24-month RA treatment with leflunomide (20 mg/
day) or MTX (15 mg/week), the results were similar for the
two forms of treatment with regard to ICR, joint swelling,
overall evaluations and radiological responses146(A). The functional response (HAQ) was also similar for the two forms of
treatment146(A).
Leflunomide treatment (20 mg/day) in patients with active
RA produced similar effects to MTX (15 mg/week) with regard
to radiological disease progression147(B).
165
The clinical (ICR) and radiological responses in patients
with RA for more than 6 months were similar when the patients were treated for 52 weeks with leflunomide (20 mg/day)
or MTX (7.5 mg/week)148(A). However, the functional results in
some components of the HAQ and SF-36 were better in the
leflunomide-treated patients149(A). Again, we must emphasize
that the dose of methotrexate used in this study was lower
than the doses typically used for RA treatment.
Patients with active RA showed a greater tolerance to MTX
treatment (15 mg/week) than to leflunomide treatment (20
mg/day), but the clinical and radiological efficacies over 12
months were similar150,151(A) 152(B).
Sulfasalazine
Sulfasalazine belongs to the group of salicylates and sulfonamides. It is produced by intestinal bacteria from sulfapyridine and 5-aminosalicylic acid. Sulfapyridine has multiple
immunomodulatory effects, including the inhibition of prostaglandin production, various neutrophilic and lymphocytic
functions and chemotaxis. It also inhibits folate-dependent
enzymes. The peak serum concentration of sulfasalazine is
approximately 1.5–6 hours, and it has an elimination half-life
of 5–10 hours. The drug is metabolized in the gastrointestinal tract (via the intestinal flora), and its excretion is renal
(75%–91%)16(A).
Sulfasalazine is considered to be more effective than a
placebo with regard to disease activity reduction, pain control and global clinical assessments. Its clinical efficacy
and interference with radiographic progression have been
confirmed16(A).
Sulfasalazine is usually prescribed at a dose of 1-3 g/day
(OR)16,17(A).
Side effects include gastrointestinal intolerance (anorexia,
nausea, vomiting), rash, elevated liver enzyme levels, oral ulcers and myelosuppression (leukopenia with neutropenia).
Hypersensitivity pneumonitis, neurological manifestations
and changes in male fertility are rarely observed. Most effects
are benign and reversible with drug withdrawal17(A).
Salicylates or any components of the sulfasalazine formula are contraindicated in patients with known sulfonamide
hypersensitivity and individuals with porphyria16,17(A).
There was no difference in the clinical responses (DAS ≤ 2.4)
of RA patients who received MTX monotherapy (15 mg/week)
or sulfasalazine (40 mg/kg/day), although the combination of
the two forms of treatment produced better outcomes at 18
months14(A).
In patients with RA for less than 12 months, sulfasalazine
treatment (2 g/day) produced similar results (DAS, EULAR and
ACR) as MTX treatment (15 mg/week) over 52 weeks; however
the combined therapies appeared to increase the treatment
benefits, according to DAS measurements66(D).
Gold sodium
Gold sodium, specifically in injectable forms (aurothioglucose
and aurothiomalate), is able to reduce both the constitutional
and articular symptoms and slow the radiographic evolution
of RA22(A). It can be used alone or in combination with other
agents23(A).
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The usual dose of gold sodium is 50 mg/week; the treatment is usually initiated at 25 mg/week, and it is possible to
increase the application interval to biweekly and monthly
doses after the symptoms are controlled. The cumulative
dose should not exceed 3 g22,23(A).
Its toxicity profile includes myelotoxicity (particularly
thrombocytopenia), oral ulcers, skin reactions (exfoliative
dermatitis), nephropathy (possibly including involving proteinuria) and interstitial lung disease22,23(A).
Although it has been recommended in recent international reports66(D), gold sodium is currently used very rarely
in Brazil due to its adverse effects and the difficulty of drug
acquisition in this area.
A comparison between MTX (15 mg/week) and gold sodium (50 mg/week) for the treatment of RA patients (duration > 4 months) demonstrated improved clinical outcomes
(swelling and stiffness) in the first year for patients treated
with gold sodium but similar outcomes in the third year of
follow up. There was greater toxicity in the first and third
year (increased risk of 38%; NNH: 3)98,153(A) and similar results
with regard to radiological progression in one154(A) and three
years22(A).
Gold sodium (50 mg/week) has a similar treatment efficacy
(clinical and functional) as MTX (20 mg/week) for RA patients
but also has an increase in toxicity of 24% (NNH: 4 )154(A).
Recommendation
Leflunomide, sulfasalazine and gold sodium appear to have
similar efficacies to that of MTX for the treatment of active
RA; however, there is a greater risk of intolerance and toxicity
and discontinuation with these drugs relative to MTX.
7. Are antimalarial drugs effective in RA
treatment?
Antimalarials have been used in RA treatment for more than
50 years. These drugs are safe and effective, especially for
early and mild forms of RA. The action mechanism is still
unclear, although it appears to involve multiple factors, including anti-inflammatory activity (stabilization of lysosomal
membranes, inhibition of lysosomal enzymes and chemotaxis and polymorphonuclear phagocytosis) and interference in
prostaglandin production, among others19,20(A).
The two available forms are chloroquine diphosphate and
hydroxychloroquine sulfate; the latter is preferred due to its
better safety profile, especially with regard to ophthalmologic
factors. The maximum daily doses of chloroquine phosphate
and hydroxychloroquine sulfate are 4 mg/kg/day and 6 mg/
kg/day orally, respectively, depending on the ideal weight of
the patient. The onset of action is slow and requires three to
four months to achieve peak efficiency in approximately 50%
of patients.
The side effects are diverse and include gastrointestinal
intolerance (nausea, vomiting, abdominal pain), skin hyperpigmentation, headache, dizziness, myopathy and retinopathy. The latter is infrequent, but regular ophthalmologic monitoring is indicated (baseline and annually after five years, or
annually from the outset in patients with risk factors such
as those with renal or hepatic impairment or maculopathy,
those who are elderly or those with a cumulative dose greater
than 1,000 g of hydroxychloroquine sulfate or 460 g of chloroquine diphosphate)72(D).
Hydroxychloroquine was more effective than a placebo in reducing the analyzed clinical and laboratory parameters (ESR), although in isolation it did not alter radiographic progression19-21(A). Similar results were observed
with chloroquine, which is less expensive. These drugs are
contraindicated in patients with retinal and visual field
abnormalities21(A)72(D).
Although these drugs are traditionally used in Brazil, often
in combination with other DMARDs, antimalarials are currently considered less potent drugs and should only be used
in early cases of RA or undifferentiated arthritis with a low
erosion potential.
Several therapeutic regimen studies have included hydroxychloroquine; however, these studies did not permit a
specific and individualized analysis of the effects of hydroxychloroquine in early-stage RA treatment.
In RA patients who did not respond to NSAID use, hydroxychloroquine treatment (200-400 mg/day) for 12 weeks led to
reduced swelling, stiffness and joint pain (20%, 23% and 26%,
respectively) and increased clinical responses (ICR)(ACR20) of
20% (NNT: 5). There was no increase in adverse events155(A).
Hydroxychloroquine treatment (7 mg/kg/day) in RA patients (disease duration less than 24 months) for 36 weeks
reduced joint involvement and pain and improved functional
responses20(A). A follow-up after 36 months showed better
outcomes for these patients than for those who were treated
later (after nine months)156(B).
There were no differences in treatment responses and
numbers of adverse events between three different doses of
hydroxychloroquine (400 mg/day, 800 mg/day or 1.2 g/day)
during a 24-week period in patients with early-stage RA157(B).
Patients (more than six months of RA) who were previously
treated with a combination of MTX (15 mg/week) and hydroxychloroquine (400 mg/day) for 24 weeks have benefited from a
12-week maintenance regimen of hydroxychloroquine158(B).
In early-stage RA patients, hydroxychloroquine treatment
(400 mg/day for 24 weeks) reduced joint involvement by 10%
(NNT: 10) and pain by 19% (NNT: 5), while overall patient and
physician evaluations improved by 16% (NNT: 6) and 12%
(NNT: 8), respectively. There was an increase in adverse events
in 13% of patients (NNT: 8)19(A).
The combination of MTX (15 mg/week) and hydroxychloroquine (200 mg/day) for six months for the treatment of early-stage RA patients increased clinical responses and reduced
pain and joint impairment when compared with hydroxychloroquine treatment alone159(B).
The addition of hydroxychloroquine (400 mg/day) to the
treatment regimens of patients with partial responses to gold
sodium (six months) added no benefits with respect to pain
and joint involvement160(B).
Recommendation
The treatment of early-stage RA with hydroxychloroquine
at doses of 200–400 mg/day provides benefits related to pain,
joint involvement and clinical responses, although the evi-
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dence for these benefits is weak, whether due to improper
measures used to demonstrate the benefits, the reduced size
of the benefits or weak supporting evidence. Although these
drugs are traditionally used in Brazil, often in combination
with other DMARDs, antimalarials are currently considered
less potent drugs and should be used in early cases of RA or
undifferentiated arthritis with low erosion potential.
Biologic DMARDs
One of the most important advances in RA therapy has been
the development of biologic DMARDs. While these medications effectively control RA, studies are needed to determine
their long-term safety. The following biologic DMARDs are
approved by the National Agency for Sanitary Surveillance
(Agência Nacional de Vigilância Sanitária (ANVISA)) for use
in Brazil:
• TNF blockers: adalimumab, certolizumab, etanercept, infliximab and golimumab;
• B lymphocyte depletion: rituximab;
• Costimulatory blocker: abatacept;
• Interleukin-6 (IL-6) receptor blocker: tocilizumab.
These drugs are indicated for patients with persistent disease activity despite treatment with at least two synthetic
DMARD regimens (at least one in combination with DMARDs).
Biologic agents must be combined with a DMARD, preferably
MTX. However, one biologic DMARD may be prescribed earlier
in the course of RA treatment, especially in cases of disease
with signs of poor prognosis (a high number of involved joints,
radiographic erosions in early-stage disease, high rheumatoid
factor and/or anti-CCP levels); this exception is described below.
Social, educational and demographic characteristics of
different macro-regions of Brazil, including difficulties in
the administration of SC medications for certain patients
and their families, as well as the absence of infusion centers
for the administration of IV medications in certain places,
may determine the choice of biologic DMARDs. Public or
private drug dispensing and infusion centers should inform
patients and families about the appropriate conditions for
each medication or send them directly to the infusion sites
to avoid losses in treatment efficacy. It is recommended
that these drugs be used as indicated and monitored by a
rheumatologist78(D).
Biologic DMARDs should not be combined due to the potential risk of serious infection.
8. Is the introduction of biologic therapy
with anti-TNF drugs such as adalimumab,
certolizumab, etanercept, infliximab and
golimumab effective and safe for RA patients?
Currently, the most commonly used biologic DMARDs are
TNF blockers. TNF is a potent inflammatory cytokine that is
expressed in large amounts in the serum and synovial fluid
of RA patients. TNF promotes the release of other cytokines,
particularly IL-1, IL-6 and IL-8, and stimulates protease pro-
167
duction. TNF inhibition has been shown to be an effective and
rapid method of controlling disease activity79(D).
In terms of effectiveness, no evidence suggests the superiority of any of the 5 anti-TNF agents approved in Brazil for
RA treatment55,56 (B).
Anti-TNFs should be used in combination with MTX or other
DMARDs because the combined use of these drugs is safe and
effective and provides rapid control of disease activity, compared to anti-TNF monotherapy. In patients who have contraindications to the use of synthetic DMARDs, anti-TNF may eventually be prescribed as a monotherapy77(D) 26-31,43,44(A) 45,57,58(B).
Adalimumab
Adalimumab is a human monoclonal anti-TNF antibody prescribed for SC use at a biweekly dose of 40 mg28,33-37,45(A). A
52-week follow-up of RA patients who were treated with MTX
and adalimumab (40 mg or 20 mg biweekly) showed increased
clinical responses (ACR50) of 32% (NNT: 3) and 28.2% (NNT:
4), respectively, with combination therapy compared to MTX
monotherapy. There was also a reduction in radiographic progression and functional improvement (HAQ) with the combination therapy, with no increase in adverse events161(A) 162(B).
Treatment of RA patients with a combination of biweekly
40 mg adalimumab and MTX (20 mg weekly) increased clinical responses (ACR50) by 21% (NNT: 5) and 16% (NNT: 6) compared to adalimumab and MTX monotherapies, respectively.
There was also a reduction in radiographic progression, as
well as an increase in clinical remission (DAS-28 ≤ 2.6) of 20%
(NNT: 5) and of 22% (NNT: 5) compared to adalimumab and
MTX monotherapy, respectively57(B).
The clinical response (ACR50) obtained with biweekly 40
mg adalimumab for 24 weeks in RA treatment concomitantly
with the use of synthetic DMARDs increased clinical responses (ACR50) by 17.6% (NNT: 6) and did not increase the risk of
adverse events or serious adverse events34(A).
The combination of adalimumab in doses of 20 mg, 40 mg
or 80 mg and MTX (15 mg/week) for 24 weeks produced increases in clinical response (ACR50) of 23.8% (NNT: 4), 47.1%
(NNT: 2) and 30.4% (NNT: 3), respectively, compared to MTX
monotherapy, with no difference in adverse events163(A).
Certolizumab
Certolizumab pegol is a Fab fragment of a humanized, highaffinity anti-TNF antibody linked to two polyethylene glycol
molecules. It is prescribed for SC use at a biweekly dose of 400
mg during weeks 0, 2 and 4 and at a dose of 200 mg every two
weeks or 400 mg every four weeks thereafter30,31,37(A).
Certolizumab treatment at 200 mg or 400 mg biweekly for
52 weeks, combined with MTX (15 mg/week), increased clinical responses (ACR50) by 29.5% (NNT: 3), reduced the progression of radiological lesions and increased functional responses (HAQ) when compared to MTX monotherapy. There was a
35% increase in serious adverse events (NNH: 3) with both certolizumab regimens. There were no differences in response or
adverse events between the certolizumab doses164(A). There
was also evidence of a positive impact on patient quality
of life 30(A). According to RAPID3 criteria, there was an increase in remission of 32% (NNT: 3) in patients treated with
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certolizumab165(B), and clinical responses were also higher
than the hybrid ICR score166(B).
Etanercept
Etanercept is a fusion protein composed of the TNF soluble receptor that binds more strongly to the Fc region than to the IgG.
This therapy is prescribed at a weekly dose of 50 mg SC36(A)
43,45,59
(B).
At a 52-week follow-up of RA patients, it was concluded that
a combined treatment of etanercept (50 mg/week) and MTX
(15 mg/week) increased remission by 22.5% (NNT: 5) and reduced radiographic lesion progression when compared to MTX
monotherapy105(A). This effect was maintained after 24 months
of follow-up45(B).
The use of etanercept (50 mg/week) for 24 weeks in patients
with active RA, with or without sulfasalazine (2–3 g/day), demonstrated superior clinical responses (ACR50) of 32% to 38%
(NNT: 3); however there was a 19.6% increase in the number
of infections (NNH: 5), as well as infusion reactions167(A). At a
24-month follow-up, there was less treatment discontinuation
due to lack of efficacy in patients undergoing etanercept treatment (NNT: 2), and the benefits were permanently sustained.
There was, however, an increase in infectious adverse events
and adverse events from local application168(B).
An ACR-N analysis of the clinical responses of RA patients
after 24 weeks of treatment with etanercept (50 mg/week) combined with MTX (15 mg/week) showed a 6.1% increase (NNT:
17)169(A). After 52 weeks, remission remained evident in 18.2%
(NNT: 6) and 12.4% (NNT: 8) of patients who received etanercept alone or combined with MTX, respectively170(B). Additionally, after 52 weeks, there was a reduction in radiological lesion
progression in these patients171(B).
Of the RA patients who were treated with etanercept (50
mg/week), 51% showed a clinical response (ACR50) after three
years, and this response was maintained after five years. There
was a reduction in disease activity (DAS < 2.4) in 44% of the
patients. However, 44% of the patients experienced episodes
of infection, which can induce cancer and treatment-related
death172,173(C).
After a 12-month treatment, the use of 50 mg etanercept per
week conferred greater benefits to RA patients than a dose of
20 mg/week. When compared with MTX (15 mg/week), the clinical responses (ACR50) was similar, although there were greater radiological lesion progression and more adverse events in
MTX-treated patients174(A). These results were maintained at a
24-month follow-up, and the functional responses (HAQ) were
better in 18% (NNT: 6) of the etanercept-treated patients59(B).
In patients with inadequate responses to a combination of
MTX (15 mg/week) and etanercept (50 mg/week), an increased
dose of etanercept (100 mg/week) did not improve the patient
clinical responses175(A).
Infliximab
Infliximab is a monoclonal mouse-human chimeric anti-TNF
antibody that is prescribed at an initial dose of 3 mg/kg, given
IV, followed by the same dose (3 mg/kg) in the second and
sixth weeks and every eight weeks thereafter76(D). In patients
with insufficient responses, the dose can be increased to 5
mg/kg by infusion, or the dose interval can be reduced. Larger
doses add little therapeutic benefit and increase the risk of infectious complications; thus, this approach should be avoided
in RA treatment27,58(B) 36,38,44(A).
In RA patients who are nonresponsive to MTX (15 mg/week),
when combined with infliximab (3 mg/kg initially at weeks 0,
2 and 6 and every 8 weeks thereafter), there were increases in
clinical response according to the EULAR and ACR50 criteria
of 14% (NNT: 7) and 10% (NNT: 10), respectively, compared to
a combination of sulfasalazine and hydroxychloroquine58(B).
Treatment of RA patients with a combination of infliximab
(3 mg/kg or 10 mg/kg at weeks 0, 2 and 6, and every 8 weeks
thereafter) and MTX (15 mg/week) for 22 weeks increased
clinical responses by 22.4% (NNT: 5) and 25.7% (NNT: 4) and
remission (DAS-28 < 2.6) by 17.0% (NNT: 6) and 18.0 % (NNT:
6), respectively. There was no difference in response between
the two infliximab dose regimens. There was no difference in
adverse events related to infliximab treatment, regardless of
the dose176(A).
Treatment of RA patients with a combination of 3 mg/kg
or 6 mg/kg infliximab (initially at weeks 0, 2 and 6, and every
8 weeks thereafter) and MTX (15 mg/week) for 54 weeks increased ACR-N clinical responses by 12.5% (NNT: 8) and 20.3%
(NNT: 5), respectively, ACR50 clinical responses by 13.5% (NNT:
7) and 18.3% (NNT: 6), reduced the progression of radiological
damage (Sharp score) and increased functional responses by
6.2% (NNT: 16) and 16.0% (NNT: 6), respectively. No difference
in efficacy was observed between the two treatment regimens. There were increases in the rates of serious adverse
events of 3.5% (NNH: 30) and 2.9% (NNH: 33) with the doses of
3 mg/kg and 6 mg/kg, respectively177(A).
Golimumab
Golimumab is a human monoclonal anti-TNF antibody that is
administered at a dose of 50 mg/month SC44,60(B).
Treatment of RA patients with a combination of MTX (15
mg/week) and golimumab (50 mg every 4 weeks) for 24 weeks
increased remission rates (ACR50) by 10.9% (NNT: 10) and 13.9%
(NNT: 7) (DAS-28 ≤ 2.6) compared to MTX monotherapy. There
were no increases in adverse events for this combination over
monotherapy44(B). The radiological response (Sharp score) was
also higher in response to golimumab (50 mg) plus MTX178(B).
In RA patients, a 14-week treatment with a combination
of MTX (15 mg/week) and golimumab (50 mg or 100 mg every four weeks) yielded increases of 25.0% (NNT: 4) and 19.4%
(NNT: 5), respectively, in clinical responses and of 14.2% (NNT:
7) and 16.5% (NNT: 6), respectively, in remission (DAS-28).
However, there was an increase in adverse events and serious
adverse events with the 100 mg dose of golimumab compared
to the 50 mg dose179(A). After a 52-week follow-up, there were
no differences with respect to monotherapy, although the
clinical response and remission rates were maintained43(B).
After a 24-week treatment with a combination of golimumab (2 mg/kg or 4 mg/kg) and MTX, the proportion of patients who achieved clinical responses (ACR50) increased by
9.3% (NNT: 10) and 17.7% (NNT: 6), respectively, compared to
MTX monotherapy. Remission (DAS-29 ≤ 2.6) over the same
period was greater only with a golimumab dose of 4 mg/kg.
There were no differences in adverse events and serious ad-
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
verse events between the combination of MTX and golimumab and MTX monotherapy180(A).
RA treatment with a combination of MTX and golimumab
(50 mg or 100 mg every two or four weeks for 16 weeks) resulted in similarly increased clinical response rates (ACR50)
and remission rates (DAS-28 ≤ 2.6) with all regimens; the only
treatment regimen that showed no benefit compared to MTX
monotherapy was a 50-mg dose every four weeks. There were
no differences in adverse events between the various forms
of treatment181(A).
Adverse events and contraindications of TNF blockers
Adverse events include infusion reactions to IV drugs (fever,
chills, chest pain, blood pressure fluctuation, dyspnea, rash
and/or hives) and manifestations at SC drug injection sites
(erythema, itching, local pain and/or hives). These drugs increase the risk of infections, especially in the first year of use
(including serious infections and those caused by intracellular
pathogens such as tuberculosis bacillus, listeria, histoplasma,
atypical mycobacteria, legionella) cardiac dysfunction, demyelinating diseases, autoimmune phenomena (autoantibody
production), cutaneous vasculitis, interstitial lung disease
and a possible increased risk of lymphoma37,39(A) 61,62(B).
Human anti-chimeric antibodies (HACA) can occur in response to all drugs in this class, but their effects on treatment
efficacy are uncertain63,64(B).
Anti-TNF drugs are contraindicated in women who are
pregnant or breastfeeding; in patients with class III and IV
congestive heart failure, according to the New York Heart Association classification; in patients with infection; or in those
who have a high risk of infection development (chronic ulcers
of the lower limbs, septic arthritis in the past 12 months), recurrent pulmonary infections, multiple sclerosis, or current
or previous cancer diagnoses (less than five years). Patients
should be carefully monitored for the possible emergence
of signs of infection, which should be treated promptly and
immediately39(A) 61,62(B).
Recommendation
RA patients can be treated with anti-TNF biologic DMARDs,
including adalimumab (40 mg SC every two weeks), certolizumab (400 mg SC every two weeks at weeks 0, 2 and 4 and 200
mg every two weeks thereafter or 400 mg every four weeks, or
monthly), etarnecept (50 mg SC every two weeks), golimumab
(50 SC every four weeks or monthly), or infliximab (3 mg/kg IV
at weeks 0, 2 and 6 and every 8 weeks thereafter). All anti-TNF
biologic DMARDs should be preferentially prescribed in combination with MTX (15 mg weekly) or another synthetic DMARD
to achieve clinical, radiological and functional benefits and
remission. There may be an increased risk of serious adverse
events and local reactions to treatment administration.
9. Is rituximab a safe and effective alternative
treatment for RA patients?
Rituximab is a chimeric monoclonal antibody directed against
CD20+ lymphocytes. It is indicated for patients with moderate
169
to severe active RA who failed to respond to anti-TNF agents.
Rituximab is administered at a dose of 1,000 mg in two IV
infusions at 14-day intervals. Each infusion is preceded by a
dose of 100 mg of IV methylprednisolone 60 minutes before
the rituximab, as well as 1 g of paracetamol and antihistamine to decrease the severity and frequency of infusion reactions81-83(A) 86(C).
Given the severity of the condition, it should be noted that
reports have linked the occurrence of progressive multifocal
leukoencephalopathy to rituximab use182(C).
Rituximab is preferentially used in combination with MTX
and can be prescribed in combination with other DMARDs.
It is important to stress that there might be a delay of 3–4
months before the onset of symptomatic improvement81-83(A).
Rituximab induces better therapeutic responses in individuals who are seropositive for RF and/or anti-CCP84(B).
Should the disease reactivate, individuals with good treatment responses can be subjected to new courses of rituximab
at intervals of no less than six months81-83(A) 86(C).
The most frequent adverse events are infusion reactions,
which occur in 35% of patients during the first infusion and
approximately 10% during the second infusion. Infectious
complications may occur, as well as interstitial pneumonia,
neutropenia and thrombocytopenia81-83(A) 86(C).
In RA patients, treatment with rituximab (two IV 500 g doses at 15 day intervals) combined with MTX (10–25 mg/week)
and etanercept (50 mg/week) or adalimumab (40 mg every
15 days) for 24 weeks did not cause an increase in adverse
events, including serious adverse events, relative to the placebo combined with MTX. There were increased risks of 22%
(NNH: 5) for infusion reactions and of 15% (NNH: 7) for grade
three infections. There were no differences in the clinical response (ACR50) or remission rates (DAS-28 < 2.6)183(A).
Treatment of RA patients (disease duration of 8 weeks to
4 years) over 52 weeks with 1 g or 2 g of rituximab combined
with MTX increased clinical responses (ACR50) by 17% and
23%, respectively, and remission rates (DAS-28 ≤ 2.6) by 20%
and 23%, respectively. There were also increases in functional response (HAQ), and there were no increases in adverse
events184(A).
Treatment of RA patients whose conditions were nonresponsive to MTX treatment with 1 g or 2 g rituximab increased the clinical response rate (ACR50) by 17% (NNT: 6)
after 24 weeks. There was no increase in adverse events82(A).
A comparison of 1-g, 1-g escalated to 2-g after 24 weeks
and 2-g rituximab doses for the treatment of RA patients (with
inadequate responses to MTX) after 48 weeks demonstrated
similar clinical responses between the treatments (ACR50), a
higher EULAR clinical response to the 2-g dose, compared to
the 1-g dose and a higher remission rate (DAS-28 < 2.6) with
the 1-g dose, compared to the escalated dose. There were no
differences in adverse events185(A).
The treatment of anti-TNF-α and MTX-nonresponsive RA
patients with 1 g rituximab led to reduced radiological disease progression, decreased pain (FACIT-F) and improved
functional responses (HAQ) and quality of life (SF-36) after 24
weeks83,186(A). The clinical responses (ACR50 and EULAR) increased by 22% (NNT: 5) and 43% (NNT: 2), respectively81(A).
Treatment of RF-positive RA patients with a combination
of rituximab and MTX for 24 weeks resulted in increased clin-
170
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
ical response rates that (ACR50) ranged from 10%–20%, compared to monotherapy. A greater number of patients did not
require additional treatment for 48 months, due to the positive effects on functional capacity (NNT: 4)187(A).
In patients who were nonresponsive to synthetic DMARD
treatment, the use of 1 g or 2 g rituximab for 24 weeks increased the proportion of patients with clinical responses
(ACR50 or EULAR) by 20% and reduced disease activity (DAS28)188(A).
The combination of rituximab (1 g) and MTX (10 mg/week)
for the treatment of RA patients produced better results after
24 weeks than monotherapy with either of these drugs, increased the clinical response rates (ACR50) by 10%–30%, and
increased clinical responses (EULAR) and rates of disease remission (DAS-28). There were no differences in the numbers
of adverse events189(A).
Recommendation
In RA patients with inadequate responses to MTX or other
synthetic DMARDs and anti-TNF, the use of rituximab (1-g
and 2-g doses), primarily in combination with MTX, improved
clinical, radiological and functional progress while increasing
the risk of adverse events.
10. Is tocilizumab proven for use in RA treatment?
Tocilizumab is a humanized monoclonal antibody that binds
to the IL-6 receptor, thus inhibiting the biological effects of IL6. It can be used alone or in combination with MTX or other
DMARDs. The incidence of infections and serious infections
with tocilizumab is equivalent to that of other biologic agents. It
is prescribed at a dose of 8 mg/kg IV every four weeks87,88(A) 96(B).
Tocilizumab can cause dose-dependent adverse events
such as neutropenia, thrombocytopenia and elevated transaminase levels. There may even be elevated levels of total
and low-density lipoprotein (LDL) cholesterol, as well as an
increased risk of infections87,88(A) 96(B). Tocilizumab should be
avoided in patients who have a greater risk of bowel perforation and those with diverticular disease of the colon89(A).
RA patients with inadequate responses to MTX have
shown positive results in response to tocilizumab (4 mg/kg or
8 mg/kg every four weeks for 52 weeks) with respect to clinical response (ACR70), remission (DAS < 2.6), and functional
(HAQ) and radiological (Sharp score) responses. Radiological
disease progression was reduced by 74% and 70%, respectively, compared to MTX monotherapy. There were significant
functional improvements of 15.4% (NNT: 6) and 9.9% (NNT:
10), respectively, and a functional response of > 0.3 units was
maintained. The clinical response rates were 6.0% (NNT: 16)
and 3.5% (NNT: 30), respectively. Disease remission rates were
39.3% (NNT: 2) and 22.3% (NNT: 5), respectively. There was a
2% incidence of neoplasias in patients who received tocilizumab, a 2.5% incidence of severe anaphylactic reactions (4
mg/kg), and a 5% increase in the risk of severe adverse events
(NNH: 20)190(A).
In RA patients between six months and five years, the administration of 8 mg/kg tocilizumab every four weeks for 52
weeks led to a reduction in radiographic disease progression
of 15% (NNT: 7) compared to synthetic DMARDs, and this effect was greater in patients at a high risk for progression191(A).
The clinical efficacy (ACR50) was 51% (NNT: 2). The remission
rate was 56% higher (NNT: 2), and the functional response
rate improved by 28% (NNT: 4). There was an increase of 5%
in the occurrence of serious adverse events in response to tocilizumab (NNH: 20) and 2% and 7% increases in cancer incidence and infusion reaction rates, respectively. There were no
differences in mild to moderate adverse events between the
two forms of treatment191(A).
A comparison between 8 mg/kg tocilizumab, given every
four weeks, and 15 mg/week MTX for a 24-week treatment
of RA patients provided results in favor of tocilizumab. Tocilizumab was found to increase the clinical response rate
(ACR50) by 10.6% (NNT: 9) and the remission rate (DAS-28 < 2.6)
by 21.5% (NNT: 5). The most common adverse reactions were
infections, although no difference was observed between the
two forms of treatment. There was an increase of 3.8% in the
infusion reaction rate with tocilizumab (NNH: 30)96(A).
In RA patients (more than six months), treatment with
8 mg/kg tocilizumab every four weeks in combination with
DMARDs (MTX, chloroquine, gold sodium, sulfasalazine, azathioprine or leflunomide) produced an increased clinical response rate (ACR50) of 29% (NNT: 3), an increase in remission
(DAS-28 < 2.6) and a functional response rate of (HAQ) of 26%
after 24 weeks (NNT: 4) compared to monotherapy with these
drugs. There was an increase of 11.7% in the risk of adverse
events (NNH: 9)192(A).
RA patients with inadequate responses to MTX showed
positive results after treatment with tocilizumab (4 mg/kg or 8
mg/kg every four weeks for 24 weeks) with respect to clinical
response (ACR50), remission (DAS < 2.6), and functional (HAQ)
response. There were significant functional improvements
with both doses. The clinical response rates were 20.0% (NNT:
5) and 33% (NNT: 3), respectively. Disease remission rates were
12.2% (NNT: 8) and 26.2% (NNT: 4), respectively. There were no
differences in the various adverse events, of which infection
was the most frequent193(A).
Recommendation
Tocilizumab treatment of RA patients, especially those with
inadequate responses to MTX, when combined with MTX or
synthetic DMARDs or as a monotherapy, produces effective
clinical, functional, radiological and remission responses. Tocilizumab is also effective in patients who are nonresponsive
to anti-TNFs. There may be an increased risk of adverse events.
11. Is abatacept a treatment option for patients
with RA, considering its safety and efficacy
profile?
Abatacept is a CTLA-4-IgG fusion protein that acts as an inhibitor of T lymphocyte costimulation. It is indicated for patients
with active RA who have experienced DMARD or anti-TNF
agent treatment failure. Abatacept can be used in combination with DMARDs or as a monotherapy. Abatacept should be
administered as an IV infusion over a 30-minute period and
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
should be administered at a dose of 500 mg to patients with
a body weight less than 60 kg, 750 mg to patients between
60–100 kg and 1,000 mg to patients greater than 100 kg. The
next dose should be administered 2 to 4 weeks after the initial dose and every four weeks thereafter40-42(A). Abatacept
is associated with a greater risk of infectious complications
than a placebo, similarly to other biologic DMARDs. Infusion reactions to abatacept are uncommon and are mainly
hypersensitivity reactions that manifest as a rash or bronchospasms. Abatacept is contraindicated in patients with
symptoms of chronic obstructive pulmonary disease (COPD)
due to its exacerbation of dyspnea and the increased risk of
infections40(A) 85(C).
Abatacept treatment (10 mg/kg every four weeks) produces benefits (ACR50) in 30% of patients with RA of an average 8.5-year duration. According to ACR50, for every three
patients treated, one experiences no increase in adverse
events194(A).
RA patients (of at least a 12-month duration) who were
nonresponsive to MTX yielded increases in clinical response
rates of 12.1% (NNT: 9), 9.9% (NNT: 10) and 9.1% (NNT: 11) according to the EULAR, DAS-28 and ACR50 criteria, respectively, after treatment with 500–1000 mg abatacept every 30 days
for 12 months. The functional improvement rate (HAQ) was
20.6% (NNT: 5). There was no increase in adverse events195(A).
In RA patients who were nonresponsive to anti-TNF-α,
treatment with 500-1000 mg abatacept for six months led
to a clinical response rate of 16.5% (NNT: 6; ACR50 criteria)
and a functional response rate of 24.0% (NNT: 4). There was
no increase in adverse events196(A). At 24 months, there were
improvements of 32.3% and 20.3% in the clinical response
(ACR50) and remission rates (DAS-28), respectively. The functional response rate was 47.9% 197(B).
After a year of treatment with 500–1,000 mg abatacept, RA
patients who were nonresponsive to MTX had a clinical improvement rate (ACR50) of 30.1% (NNT: 3). Physical function
improved by 24.7% (NNT: 4), with no difference in the rate of
adverse events198(A). After 24 months of treatment, the patients had a clinical improvement rate (ACR50) of 55.6% and
a remission rate (DAS-28) of 30.9%199(B).
Recommendation
In RA patients who are nonresponsive to MTX or anti-TNF
therapy, the use of abatacept at doses between 500–1,000 mg
led to increased clinical responses (ACR50), remission (DAS28) and functional responses (HAQ) over 6–12 months, and
these rates were maintained over a 24-month period. However, there may be an increased risk of adverse events.
12. Are there indications that some biologic
treatment regimens are superior to others in the
treatment of RA patients?
Treatment of RA patients with a combination of MTX (15 mg/
week) and golimumab (50 mg every four weeks) for 24 weeks
yielded increases (ACR50) of 10.9% (NNT: 10) and 13.9% (NNT:
7) in the remission rate (DAS-28 ≤ 2.6) compared to MTX
monotherapy44(A).
171
A 52-week follow-up of RA patients who were treated with
MTX and adalimumab (40 mg every other week) showed an
increase (ACR50) of 32% (NNT: 3) in the clinical response rate
compared with MTX monotherapy162(A). A decrease in radiographic progression and an increase in clinical remission
(DAS-28 ≤ 2.6) of 23% (NNT: 5) were observed in comparison to
MTX monotherapy74(D).
At a 52-week follow-up of RA patients, it was concluded that
treatment with etanercept (50 mg/week) in combination with
MTX (15 mg/week) increased the remission rate (DAS-28) by
22.5% (NNT: 5) compared to MTX monotherapy. Additionally,
the clinical response rate (ACR50) was 22% higher (NNT: 5)105(A).
Treatment of RA patients with 3 mg/kg infliximab (initially
at weeks 0, 2 and 6 and every eight weeks thereafter) in combination with MTX (15 mg/week) for 22 weeks increased the
clinical response rate (ACR50) by 22.4% (NNT: 5) and the disease remission rate (DAS-28 < 2.6) by 17.0% (NNT: 6)176(A).
Treatment with 200 mg or 400 mg of certolizumab (every
two weeks for 52 weeks) in combination with MTX (15 mg/
week) increased the clinical response rate (ACR50) by 29.5%
(NNT: 3), compared to MTX monotherapy. The remission rate
(DAS-28) was 16% (NNT: 6). There was an increase of 35% in
the rate of serious adverse events (NNH: 3)164(A) 165(B).
Treatment of RA patients (disease duration between eight
weeks and four years) for 52 weeks with rituximab (1.0 g IV
infusion at intervals of 15 days) in combination with MTX
increased the clinical response rate (ACR50) by 17% (NNT: 6)
and the remission rate (DAS-28 ≤ 2.6) by 20% (NNT: 5)184(A). RA
patients with inadequate responses to MTX who were treated
with tocilizumab (8 mg/kg every four weeks for 24 weeks) in
combination with MTX showed positive results with respect
to clinical response (ACR50) and remission (DAS ≤ 2.6). There
were significant functional improvements at both doses. The
clinical response rate was 33% (NNT: 3). The remission rate
was 26.2% (NNT: 4). There were no differences in the various
adverse events, of which infection was the most frequent193(A).
Patients with RA (duration of at least 12 months) who were
nonresponsive to MTX had 9.9% (DAS-28; NNT: 10) and 9.1%
(ACR50; NNT: 11) increases in the clinical response rate after
treatment with 500-1000 mg of abatacept every 30 days for 12
months195(A).
Table 5 summarizes the ACR50 and DAS-28 measures,
which are expressed as the estimated benefits with the NNT.
Recommendation
The various treatment regimens that use biologic DMARDs in
combination with MTX in RA patients present similar results
compared to MTX monotherapy, using ACR50 and DAS-28 as
parameters with minor variations in the NNT (3–11 for ACR50
and 4–10 for DAS-28). There are no direct comparisons that
enable an accurate estimate of the differences in benefits between the various biologics.
Strategies for RA treatment in Brazil
DMARD treatment should be initiated immediately after diagnosis. The treatment should be adjusted as needed after
frequent clinical evaluations within a period of 30–90 days.
172
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
Treatment strategies based on specific goals produce better clinical outcomes and functional capacities as well as lower structural radiographic damage, compared to conventional
treatments94(A). The goal is remission or at least low disease
activity; this outcome can be evaluated by composite indices
of disease activity (CIDAs) while taking into consideration the
role of treatment responses in reducing CIDA values, as established in the 2011 Consensus of the SBR for the Diagnosis and
Initial Assessment of Rheumatoid Arthritis5(D).
First line – synthetic drugs that alter the course of the disease
MTX should be the first choice for DMARD treatment95(A)
66,200
(D). In cases with contraindications, sulfasalazine201(A)
or leflunomide143(A) can be used as a first option202(B).
Antimalarial
drugs
(chloroquine
diphosphate
and
hydroxychloroquine)203(B) might be indicated only for patients
with mild disease or undifferentiated arthritis with low erosion potential. In exceptional cases, such as patients with hypersensitivity to other DMARDs or those with viral hepatitis,
gold sodium can be used.
MTX should preferentially be prescribed as a monotherapy
during early treatment128(A).
In the absence of an objectified clinical response (remission or lower disease activity) to the maximum tolerated
MTX dose or in the presence of adverse events, it is recommended that MTX be exchanged for another DMARD monotherapy or DMARD combinations. The most frequently used
combinations are MTX with chloroquine, sulfasalazine, a
combination of these three drugs15(A) and MTX combined
with leflunomide204(A). Therapy progression should be rapid,
with monthly patient evaluations during the first 6 months of
treatment, and the doses and schedules should be adjusted
as required. A maximum of six months should be allowed to
define an absence of response to the first-line treatment66(D).
Low doses of corticosteroids (up to 15 mg/day of prednisone or equivalent) and anti-inflammatories may be used at
the beginning of the treatment regimen, although caution
and usage for the shortest time possible are recommended to
minimize the occurrence of adverse events66(D).
Second line – biologic disease-modifying drugs
Immunobiological RA treatment is indicated for patients who
persist with moderate to high disease activity (according to
Table 5 – ACR50 and DAS-28 measures expressed as the
estimated benefit using Number Needed to Treat (NNT).
Biologic
Golimumab
Adalimumab
Etanercept
Infliximab
Certolizumab
Rituximab
Tocilizumab
Abatacept
Dose
50 mg
40 mg
50 mg
3 mg/kg
200 mg
1,000 mg
8 mg/kg
500–1,000 mg
Time
24 weeks
52 weeks
52 weeks
22 weeks
52 weeks
52 weeks
24 weeks
52 weeks
CIDAs) despite treatment with at least two of the regimens
proposed for the first line of treatment. In Brazil, anti-TNF
drugs are the first choice of biologic therapy after the failure
of synthetic DMARD regimens. This approach is justified by
the most comprehensive post-marketing experience, as well
as the increased volume of safety information from clinical
studies, registries and national205(B) and international66(D)
recommendations. However, other drugs such as abatacept
and tocilizumab may be prescribed at the discretion of the
attending physician after a failure with synthetic DMARDs,
given the publication of randomized controlled trials that
support this indication40,88(A). Rituximab should be avoided as
a first-line biologic66(D) except in specific cases (e.g., patients
with contraindications to other biologics, preferably those
who are positive for RF and/or anti-CCP or those who present
with a diagnosis associated with lymphoma).
In exceptional situations, biologic DMARDs may be indicated after a failure of the first regimen of synthetic DMARDs
in patients with associated poor prognostic factors, including
very high disease activity, a high number of painful/inflamed
joints, high RF and/or anti-CCP levels and the early occurrence of radiographic erosions66(D). Poor prognosis factors are
better detailed in the 2011 Consensus of the SBR Diagnosis
and Initial Assessment of Rheumatoid Arthritis5(D).
The use of biologic drugs as a first-line RA treatment is
not indicated in Brazil because there is no evidence of costeffectiveness in this country.
Third line – failure or intolerance to modifying drugs in the
course of biological disease
In clinical scenarios where there is no response to the initial
biologic treatment, a progression to loss of response, or major
adverse events, one biologic agent may be exchanged for another. The biologics that have presented benefits in randomized clinical trials in patients for whom anti-TNF treatment
failed are abatacept, rituximab and tocilizumab206(B). Patients
for whom the first anti-TNF agent failed have also derived
benefits from the use of a second drug from the same class,
including adalimumab, certolizumab, etanercept, golimumab
or infliximab, in prospective observational studies and randomized controlled double-blind trials (golimumab), but uncertainties persist about the magnitude of the therapeutic effects and the cost-effectiveness of this strategy207(B).
The choice of the employed treatment sequence remains
at the discretion of the physician, depending on the particularities of each case. A minimum of three months and a maximum of six months of clinical evaluation are recommended
before proceeding to a change in regimen (switching between
biologic DMARDs).
NNT
ACR50
DAS-28
10
3
5
5
3
6
3
11
7
5
5
6
6
5
4
10
Withdrawal of medications and eventual suspension of therapy
There are no data that allow us to define the RA treatment duration, and currently the medication to which the patient has
an adequate response should be maintained for an indefinite
period at the physician’s discretion. In cases of complete (remission) and sustained (more than 6–12 months) responses,
a gradual and careful withdrawal can be attempted according
to the following sequence: first NSAIDs, then corticosteroids
173
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
and biologic DMARDs, while maintaining the use of synthetic
DMARDs208(B). In exceptional situations, if remission is maintained, the physician may very cautiously attempt to withdraw synthetic DMARDs66(D). Sustained drug-free remission
is uncommon, especially in patients with biomarkers such as
anti-CCP and/or RF.
Fig. 1 summarizes RA drug treatment in Brazil as a flowchart, as proposed by the RA SBR Commission.
Treatment monitoring
In patients with active early-stage disease and symptoms of a
12-month duration or less, intensive monitoring with monthly
visits is recommended with rapid medication progression when
necessary209(B) 210(D). The treatment regimens and their possible
adverse events have been discussed in previous sections.
At each visit, physicians should evaluate the efficacy and
safety of the therapeutic interventions while considering patient comorbidities and preferentially targeting remission or
the lowest disease activity possible, as well as an improved
functional status and quality of life. In patients with established disease, especially in those with controlled disease,
visits can occur every three months108,109,209(B) 210(D).
Table 6 summarizes in schematic form the monitoring frequencies for the main parameters considered appropriate for
evaluations of a patient undergoing RA treatment.
Conflicts of interest
Mota LMH participated in clinical and/or experimental studies sponsored by the companies Roche and Mantecorp; received personal or institutional assistance from the companies Abbott, AstraZeneca, Merck, Pfizer and Roche; and was
a speaker at events or activities sponsored by the companies
Abbott, MSD, Novartis, Roche and Wyeth.
Cruz BA participated in clinical and/or experimental studies sponsored by Roche; received personal or institutional assistance from the companies Abbott, Bristol-Myers Squibb,
Mantecorp, MSD, Novartis, Roche, Wyeth and Pfizer; and was
a speaker at events or activities sponsored by the companies
Abbott, MSD, Mantecorp, Novartis, Roche and Wyeth.
Brenol CV participated in clinical and/or experimental studies sponsored by the companies Bristol-Myers Squibb, Pfizer,
Roche and Wyeth; received personal or institutional assistance
from the companies Abbott, Bristol-Myers Squibb, Mantecorp,
At all phases:
Monotherapy
(preferably MTX)
Q
Failure ĂŌĞƌ 3 months
Prednisone up to 15 mg/day
or equivalent (for the
ƐŚŽƌƚĞƐƚƟŵĞ possible)
ŝŶƚƌĂĂƌƟĐƵlar
ĐorƟĐoid
and/or NSAIDs and
painkillers
First line
Q
ParƟĂůresponse to MTX
IntoleranĐe to MTX
Failure ĂŌĞƌ 3 months
CombinaƟon of
ƐLJŶƚŚĞƟĐDZDs
džĐŚĂŶŐĞďĞƚǁĞĞŶ
ƐLJŶƚŚĞƟĐDZƐ
^ĞĐond line
Failure aŌer 3 months
SyntheƟĐMARD
(preferably MTX)
+
BioloŐŝĐDZ
(anƟ-TNF ĂƐĮrst ĐŚŽŝĐĞor ABAT or TOCI)
Third line
Failure aŌer 3-6 months
Failure of or intolerĂŶĐĞ to bioůŽŐŝĐ DMARD:
To maintain ƐLJŶƚŚĞƟĐDZD (preferably MTX)
and ĐŚĂŶŐĞ biologiĐ DMARD to another ĂŶƟ-TNF
or ABAT or RTX or TOCI
Failure aŌer 3-6 months
ĐƟǀĞĚŝƐĞĂƐĞ͗
Consider CIDA aiming at remission
or at least lower disease ĂĐƟǀŝƚLJ
Fig. 1 – RA drug treatment flowchart for Brazil, as proposed by the RA SBR Commission.
ABAT, abatacept; CIDA, compound indices of disease activity; DMARD, diseasemodifying antirheumatic drug; MTX,
methotrexate; NSAIDs, nonsteroidal anti-infl ammatory drugs; RTX, rituximab; TOCI, tocilizumab.
X
Evaluation and education regarding emergency situations*****
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CIDA, compound indices of disease activity (SDAI – simple disease activity index; CDAI – clinical disease activity index; DAS28 – disease activity score - 28 joints); +, for CIDA goals, see the 2011 BSR
Consensus for diagnosis and early assessment of RA; mHAQ, modified health assessment questionnaire; HAQ-DI, health assessment questionnaire - disability index; ESR, erythrocyte sedimentation rate;
CRP, C-reactive protein; PPD, tuberculin skin test; IGRA, interferon gamma release assays.
* Extra-articular manifestations: rheumatoid nodules, interstitial lung disease, serositis, ocular inflammation, and vasculitides.
**Comorbidities: arterial hypertension, cardiovascular ischemia, diabetes mellitus, atherosclerosis, low bone mass, depression, fibromyalgia, etc.
***Laboratory exams: blood count, liver function, lipid profile, and renal function; depending on the comorbidities, consider additional exams.
****Medication for RA: consider the efficacy and safety issues of each medication detailed throughout the text.
*****Urgencies on RA: scleromalacia perforans, myelopathies, multiple mononeuritis and vasculitis, pregnant patients on teratogenic drugs.
X
Serologies (hepatitis B and
hepatitis C at the beginning
of the investigation, HIV in
selected situations)
X
Gestational counseling
Evaluation of infections (clinical assessment and occasional
complementary exams)
X
Coordination of the multidisciplinary team
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(minimum reduction desired: 0.22
points)
X
(if negative at the first assessment,
they can be repeated in the two initial
years)
Annual assessment
Conventional radiography (hands and wrists, feet and ankles,
other joints affected)
Joint resonance or ultrasound (in doubt regarding the synovitis)
Assessment of extra-articular manifestations *
Assessment of comorbidities**
Inflammatory activity tests (ESR and CRP)
Laboratory assessment***
Vaccination assessment
Specific medicamentous treatment for RA****
Medicamentous treatment of comorbidities
PPD (or IGRA) and chest radiography (if a biologic DMARD,
specially anti-TNF, is prescribed)
Occupational therapy
Rehabilitation
Evaluation of orthotic indication
Evaluation of surgical indication
X
X
X
Assessment every
three months
(established RA)
X
X
X
X
Extra
consultations
RF/anti-CCP
X
X
Monthly
assessment
(early RA)
X
X
X
Initial assessment
Education of patients and families
CIDA+
mHAQ or HAQ-DI (0–3 points)
Parameter
Table 6 – Monitoring the treatment of rheumatoid arthritis (continued).
174
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
MSD, Roche and Wyeth; and was a speaker at events or activities sponsored by the companies Abbott and Roche.
Rezende-Fronza LS participated in clinical and/or experimental studies sponsored by the companies Bristol-Myers
Squibb, Pfizer, and Roche; and elaborated scientific papers in
journals sponsored by Pfizer.
Bertolo MB was a speaker at events or activities sponsored
by the companies Abbott, Pfizer and Sanofi Aventis.
Freitas MVC received personal or institutional assistance
from the companies Abbott, MSD, Pfizer, Roche and Wyeth; was
a speaker at events or activities sponsored by the companies
Abbott, MSD, Pfizer, Roche Wyeth; is an advisory board member
or director of pharmaceutical industry or advisory committees
of scientific studies sponsored by the companies AstraZeneca,
MSD and Wyeth; and elaborated scientific papers in journals
sponsored by the companies Abbott, AstraZeneca, Bristol-Myers Squibb, Wyeth.
Silva NA participated in clinical and/or experimental studies sponsored by the companies Bristol-Myers Squibb and
Roche; received personal or institutional assistance from the
companies Abbott, MSD, Roche and Wyeth; and was a speaker
at events or activities sponsored by the companies Janssen,
Mantecorp, MSD and Roche.
Louzada-Junior P participated in clinical and/or experimental studies sponsored by the companies Merck and Roche; received personal or institutional assistance from Abbott; and
was a speaker at events or activities sponsored by the companies Bristol-Meyers Squibb, Pfizer and Roche.
Giorgi RD received personal or institutional assistance from
the companies Bristol-Myers Squibb and Roche; was a speaker
at events or activities sponsored by the companies Bristol-Myers Squibb and Roche; and was a speaker at events or activities
sponsored by the companies Bristol-Myers Squibb and Roche.
Lima RAC participated in clinical and/or experimental studies sponsored by the companies Mantecorp and Roche; received personal or institutional assistance from the companies
Acteion, Lilly and Pfizer; and was a speaker at events or activities sponsored by the companies Acteion, Lilly and Pfizer.
Pinheiro GRC received personal or institutional assistance
from the companies Janssen and Roche.
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R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Guidelines
Guidelines for the treatment of antiphospholipid syndrome
Adriana Danowskia,*, Jozelia Regob, Adriana M. Kakehasic, Andreas Funked,
Jozelio Freire de Carvalhoe, Isabella V. S. Limaf, Alexandre Wagner Silva de Souzag,
Roger A. Levyh
a
Hospital Federal dos Servidores do Estado (HFSE), Rio de Janeiro, RJ, Brazil
Medical School, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil
c
Locomotor Department, Medical School, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
d
Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil
e
Centro Médico Aliança, Salvador, BA, Brazil
f
Universidade Federal da Bahia (UFBA), Salvador, BA, Brazil
g
Discipline of Rheumatology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/Unifesp), São Paulo, SP, Brazil
h
Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
b
article info
abstract
Article history:
The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized
Received on 11 December 2012
by arterial and venous thrombosis, gestational morbidity and presence of elevated and
Accepted on 13 December 2012
persistently positive serum titers of antiphospholipid antibodies. The treatment of APS is
still controversial, because any therapeutic decision potentially faces the risk of an insuf-
Keywords:
ficient or excessive antithrombotic coverage associated with anticoagulation and its major
Antiphospholipid syndrome
adverse effects. This guideline was elaborated from nine relevant clinical questions related
Treatment
to the treatment of APS by the Committee of Vasculopathies of the Brazilian Society of
Pregnancy
Rheumatology. Thus, this study aimed at establishing a guideline that included the most
Anticoagulation
relevant and controversial questions in APS treatment, based on the best scientific evi-
Thrombosis
dence available. The questions were structured by use of the PICO (patient, intervention or
indicator, comparison and outcome) process, enabling the generation of search strategies
for evidence in the major primary scientific databases (MEDLINE/PubMed, Embase, Lilacs,
Scielo, Cochrane Library, Premedline via OVID). A manual search for evidence and theses
was also conducted (BDTD and IBICT). The evidence retrieved was selected based on critical assessment by using discriminatory instruments (scores) according to the category of
the therapeutic question (JADAD scale for randomized clinical trials and Newcastle-Ottawa
scale for non-randomized studies). After defining the potential studies to support the recommendations, they were selected according to level of evidence and grade of recommendation, according to the Oxford classification.
© 2013 Elsevier Editora Ltda. All rights reserved.
* Corresponding author.
E-mail: [email protected] (A. Danowski)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
185
Diretrizes para o tratamento da síndrome do anticorpo antifosfolipídeo
resumo
Palavras-chave:
A síndrome do anticorpo antifosfolipídeo (SAF) é uma doença sistêmica autoimune carac-
Síndrome do anticorpo antifosfo-
terizada por trombose arterial e venosa, morbidade gestacional e presença de níveis séricos
lipídeo
de anticorpos antifosfolipídeos elevados e persistentemente positivos. O tratamento da SAF
Tratamento
ainda é sujeito a controvérsias, já que qualquer decisão terapêutica potencialmente irá con-
Gestação
frontar-se com o risco de uma cobertura antitrombótica insuficiente ou com o risco excessivo
Anticoagulação
associado à anticoagulação e seus principais efeitos adversos. Esta diretriz foi elaborada a
Trombose
partir de nove questões clínicas relevantes e relacionadas ao tratamento da SAF pela Comissão de Vasculopatias da Sociedade Brasileira de Reumatologia. O objetivo deste trabalho foi
criar uma diretriz que incluísse as questões mais relevantes e controversas no tratamento da
SAF, com base na melhor evidência científica disponível. As questões foram estruturadas por
meio do P.I.C.O. (paciente, intervenção ou indicador, comparação e outcome/desfecho), o que
possibilitou a geração de estratégias de busca da evidência nas principais bases primárias de
informação científica (MEDLINE/Pubmed, Embase, Lilacs/ Scielo, Cochrane Library, Premedline via OVID). Também realizou-se busca manual da evidência e de teses (BDTD e IBICT). A
evidência recuperada foi selecionada a partir da avaliação crítica, utilizando instrumentos
(escores) discriminatórios de acordo com a categoria da questão terapêutica (JADAD para ensaios clínicos randomizados e New Castle Ottawa Scale para estudos não randomizados). Após
definir os estudos potenciais para sustento das recomendações, eles foram selecionados pela
força da evidência e pelo grau de recomendação, segundo a classificação de Oxford.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis, gestational morbidity and presence of elevated and persistently positive serum titers of antiphospholipid antibodies.
It is currently recognized as the most frequent cause of acquired thrombophilia associated with venous and arterial
thrombosis.
The current classification meant for inclusion in clinical
research protocols, but often used in daily practice to establish the diagnosis of APS1(D) and indicate a treatment, was
reviewed in 2006 and includes clinical and laboratory criteria.
Clinical criteria
• Vascular thrombosis: one or more episodes of arterial or
venous thrombosis or thrombosis of small vessels of any
organ or tissue, confirmed on Doppler or histopathology,
vasculitis excluded;
• Gestational morbidity:
- One or more deaths of a morphologically normal fetus
after the 10th gestational week, confirmed on ultrasound
or by examining the fetus;
- One or more premature births of a morphologically
normal fetus before the 34th gestational week due to
eclampsia, preeclampsia or causes of placental insufficiency;
- Three or more spontaneous abortions before the 10th
gestational week, with neither maternal hormonal nor
anatomical abnormalities, paternal and maternal chromosomal causes excluded.
Laboratory criteria
• Presence of lupus anticoagulant antibody (LA) in the plasma
on two or more occasions at a minimum 12-week interval,
detected according to the recommendations of the International Society on Thrombosis and Hemostasis (ISTH);
• Moderate (> 40) to high (> 80) titers of IgG or IgM anticardiolipin antibodies (ACL) on two or more occasions at a minimum
12-week interval, detected by using standard ELISA test;
• IgG or IgM anti-beta 2-GPI antibodies in the plasma on two or
more occasions at a minimum 12-week interval, detected by
using standard ELISA test.
The presence of arterial or venous thrombosis or thrombosis of small vessels is the major characteristic of the disease
and the major cause of death in those patients. The disease
can affect vessels of any caliber and from any place. The most
frequently reported events are deep venous thrombosis, pulmonary embolism, and encephalic vascular accident (EVA).
Untreated patients with APS have been reported to be at high
risk for recurrence (B).2
The treatment of APS is still controversial, because any
therapeutic decision potentially faces the risk of an insufficient
or excessive antithrombotic coverage associated with anticoagulation and its major adverse effects. Currently, the indication of lifelong oral anticoagulation in cases of arterial, venous
or microcirculatory thrombosis is consensual, but its intensity
and possibility of interruption are still discussed. The new anticoagulants (rivaroxaban and dabigatran), indicated to prevent
EVA and systemic embolism in patients with non-valvular atrial
fibrillation after hip or knee arthroplasty, are still being studied
in patients with APS, and the short- and medium-term study
results are awaited. New anticoagulants that do not require
186
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
monitoring and bearing a lower risk of bleeding are certainly of
interest. Once confirmed their efficacy and safety, they will have
a solid place in the arsenal of APS treatment. However, the current objective of the research in the area is to improve the therapeutic management of APS, aiming at acting on the pathogenic
process triggered by antiphospholipid antibodies. The candidates are as follows: agents potentially used in primary prophylaxis, such as hydroxychloroquine and clopidogrel; agents used
in more severe situations, such as intravenous gamma globulin
and rituximab; and others more recently introduced that can reduce antibody production, such as tocilizumab and belimumab.
The management of individuals with antiphospholipid antibodies and no previous thrombotic events, such as primary
thromboprophylaxis, is still a matter of concern and debate.
Thus, this study aimed at establishing a guideline that included
the most relevant and controversial questions in APS treatment,
based on the best scientific evidence available.
Material and methods
This guideline was elaborated from nine relevant clinical questions related to the treatment of APS by the Committee of Vasculopathies of the Brazilian Society of Rheumatology. The questions were structured by use of the PICO (patient, intervention
or indicator, comparison and outcome) process, enabling the
generation of search strategies (Appendix 1) for evidence in the
major primary scientific databases (MEDLINE/PubMed, Embase,
Lilacs, Scielo, Cochrane Library, Premedline via OVID). A manual
search for evidence and theses was also conducted (BDTD and
IBICT). The evidence retrieved was selected based on critical assessment by using discriminatory instruments (scores) according to the category of the therapeutic question (JADAD scale
for randomized clinical trials and Newcastle-Ottawa scale for
non-randomized studies). After defining the potential studies to
support the recommendations, they were selected according to
level of evidence and grade of recommendation, based on the
Oxford classification.
Grade of recommendation and level of evidence:
A: data derived from more consistent experimental and observational studies.
B: data derived from less consistent experimental and observational studies.
C: case reports (uncontrolled studies).
D: expert opinion without explicit critical appraisal, or based on
consensus, physiological studies or animal models.
Results
1. Do asymptomatic individuals positive for
antiphospholipid antibodies (moderate or high
IgG or IgM LA+ or ACL or anti-beta 2-GP) and
with no history of thrombosis benefit from
anticoagulation? And from antiplatelet agents?
Adult patients with antiphospholipid antibodies on a mean
36-month follow-up and undergoing continuous thromboprophylaxis (aspirin) show no difference in the risk of thromboem-
bolic events. However, patients undergoing thromboprophylaxis and at risky situations (surgery/immobilization, pregnancy/
puerperal period) show a 31% reduction in the risk of thrombotic events (NNT:3) (B).3
The primary prevention of thrombosis in patients positive
for antiphospholipid antibodies either with low doses of aspirin
(75 mg/day) or with aspirin associated with warfarin shows 5%
of thrombotic events for both forms of prophylaxis, and, in one
to five years, there is an incidence of 4.9 events per 100 patientyears in both groups (B).4 A 5% reduction in the risk of thrombotic events (NNT:20) is observed in patients with antiphospholipid antibodies on primary prevention with aspirin and/or
coumarins (B).5
Thrombosis prophylaxis (low dose of aspirin, long-term
warfarin or heparin) in patients with antiphospholipid antibodies (medium/high titers of ACL) and arterial hypertension can
reduce the risk of events by 51.2% (NNT:2) (B).6 In populations
positive for antiphospholipid antibody, the prophylactic use of
aspirin can reduce the risk of thrombotic events in 17% of the
cases over 120 months (NNT:6) (B).7
However, there is evidence of no difference between using
aspirin or not to prevent thrombotic events in those patients; in
addition, there is even a 6% increase in the risk of thrombotic
events (NNH:16) in patients on aspirin (B).8
The benefit of thromboprophylaxis (primary prevention) is
controversial in patients with antiphospholipid antibodies and
no clinical symptoms (B).9
In pregnant women with consecutive spontaneous abortions, with neither antiphospholipid antibodies nor any apparent cause, the use of aspirin or enoxaparin does not reduce the
risk of new events (A).10
Recommendation
Because of the controversial results of thromboprophylaxis (primary prevention) in patients positive for antiphospholipid antibodies, the continuous administration of aspirin and/or coumarins cannot be recommended to those patients, their use being
reserved to situations with an elevated risk of thrombosis.
2. Is anticoagulation for undetermined time
indicated to patients positive for antiphospholipid
antibodies and with a history of venous
thrombosis? What should the target INR be?
In patients with a history of venous thrombosis and moderate
to high titers of ACL and/or LA, anticoagulation with a target
range for INR of 2.0 to 3.0 reduces the risk of recurrence similarly to anticoagulation with a target range for INR of 3.0 to 4.0,
as compared to no anticoagulation (B).2
In patients with antiphospholipid antibodies, the use of
moderate intensity anticoagulation with warfarin (target range
for INR of 2.0 to 3.0) as compared to no treatment reduces the
risk of venous thrombosis by 80% to 90% (B).9
Intensive regimens of anticoagulation (INR between 3.5 and
4.5) as compared to conventional regimens (INR between 2.0
and 3.0) for the treatment of patients with APS reduce the risk
of thrombosis recurrence at similar rates, but intensive anticoagulation increases the risk of mild bleeding (B).11,12
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
187
In the treatment of patients with APS and a history of venous thrombosis with warfarin, the following target ranges
for INR yielded similar recurrence indices: INR between 3.0
and 4.0, 7.1%; and INR between 2.0 and 3.0, 2.2% (A).13 The
recurrence risk of thrombosis in patients with APS and no
treatment for one year is 29%. Anticoagulation with warfarin
(INR between 2.0 and 3.0) reduces the risk by 19% (NNT:5), and
when the goal is an INR > 3.0, either associated or not with
aspirin, the risk is reduced by 27.5% (NNT:4). After six months
of treatment cessation, the risk is increased by 100% (NNH:1)
(B).14 In patients with a history of venous or arterial thrombosis and positive for antiphospholipid antibody, treatment
with warfarin (INR between 2.0 and 2.9) and aspirin (75 mg/
day) leads to a 21% increase in the risk of recurrence within
24 months as compared to warfarin (INR > 2.9) and aspirin
(75 mg/day) (B).15
Patients positive for antiphospholipid antibodies and previous venous thrombosis, when treated with anticoagulation,
have an increase in the likelihood of thrombosis-free survival
of 50% and 78% within two and eight years, respectively (B).16
The thromboprophylaxis of patients with APS and previous
venous thrombosis recommends maintaining long-term anticoagulation with oral anticoagulants, aiming at an INR between 2.0 and 3.0 (B).17
There is a 56% reduction in the risk of recurrence of arterial events in anticoagulated patients with antiphospholipid
antibody as compared to untreated ones. Patients on highintensity warfarin (INR > 3.0) either with or without aspirin
have a 90% probability of not experiencing a new thrombotic
event within five years (B).14
Regarding the thromboprophylaxis of arterial events in
patients with antiphospholipid antibodies, treatment with
warfarin (INR > 2.9) and aspirin (75 mg/day) reduces the risk
of events by 50% as compared to aspirin alone at the same
dosage. The recurrence risk of thrombotic events does not differ between warfarin with an INR greater than or lower than
2.9 (B).15
Triple-positive APS patients (with three positive antiphospholipid tests) have a high recurrence rate, more frequently
arterial. Warfarin with a target INR between 2.0 and 3.0 is
more effective than low-dose aspirin or no therapy; however,
in patients on warfarin (target INR between 2.0 and 3.0) for six
years, the recurrence rate is 30% (B).17
Over a five-year treatment with oral anticoagulants, patients with APS have an 11% reduction in the recurrence risk
of arterial events as compared to untreated patients (B).19
Recommendation
The treatment of patients with antiphospholipid antibody and
history of arterial thrombosis should be long and performed
with warfarin (INR between 2.0 and 3.0 or INR > 3.0) either associated or not with antiplatelet agents. The prospective studies that found no difference between high-intensity warfarin
and standard INR included a small group of patients with arterial thrombosis, hindering, thus, definitive conclusions. The
authors suggest long-term anticoagulation with high-intensity
warfarin.
Patients with APS and previous venous thrombosis should remain on anticoagulants for undetermined time, aiming at an
INR between 2.0 and 3.0.
3. Is anticoagulation for undetermined time
indicated for patients with APS and previous
arterial thrombosis? Which should the target INR
be?
The recurrence rate of thrombotic events in patients with
APS and previous arterial thrombosis is greater in untreated
patients and lower in those on warfarin and INR between 3.0
and 4.0, as compared to low-intensity warfarin (INR between
2.0 and 3.0) or aspirin alone. Patients with arterial events are at
a greater risk of recurrence than those with venous events (B).2
Warfarin and aspirin seem to be equivalent in preventing
thromboembolic complications in patients with their first ischemic EVA and positive for antiphospholipid antibodies. The use
of warfarin (INR 1.4–2.8) or aspirin (325 mg/day) does not differ
regarding the risk for cerebral arterial thrombotic events (recurrence) (A).18
The number of arterial events (transient cerebral ischemia,
EVA or death due to EVA) occurring in patients with antiphospholipid antibodies and history of arterial thrombotic events
during thromboprophylaxis with high-intensity warfarin (INR
between 3.5 and 4.5) or standard warfarin (INR between 2.0 and
3.0) is similar (B).11
The risk of recurrence of thrombotic events in patients with
antiphospholipid antibody and history of arterial thrombosis
in a three-year follow-up on warfarin (target INR between 3.1
and 4.0) or aspirin (target INR between 2.0 and 3.0) is 21.4% and
7.6%, respectively (A).12
Recommendation
4. Is anticoagulation for undetermined time
indicated for patients with APS who have only
obstetric events? And antiplatelet therapy?
In patients with obstetric APS on aspirin (75,100 mg/day)
having used low-weight heparin during pregnancy and six
weeks after delivery, the number of thrombotic events in 36
months can be 3.3/100 patient-years. The determinant factor
for events, independently of anticoagulation or antiplatelet
therapy, is the presence of at least two antibodies, when the
rate of events is 4.6/100 patient-years (C).20
The five-year incidence of thrombotic events in pregnant
patients with obstetric manifestations of APS can be 2.5%, being even reported in one patient on aspirin. Approximately
7.4% of the patients on anticoagulants can have hemorrhagic
manifestations (B).21
Treating women with APS and obstetric manifestations by
using low-dose aspirin reduces the risk of thrombotic event
by 49% over an eight-year follow-up (B).22
The nine-year follow-up of patients with obstetric APS
(obstetric events) treated with low-dose aspirin (100 mg/day),
as compared to patients with no antiphospholipid antibody,
shows an increased risk for pulmonary embolism of 31%, for
deep venous thrombosis of 103%, and for EVA of 13% (B).23
188
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
Recommendation
Patients diagnosed with APS and exclusive presence of obstetric events should undergo long-term thromboprophylaxis with
low-dose aspirin, aiming at reducing thrombotic events, especially the arterial ones.
5. Should a primipara positive for antiphospholipid
antibodies with no history of thrombosis undergo
any intervention?
In female patients positive for antiphospholipid antibodies,
considered at low-risk due to the lack of associated morbidities (none or one spontaneous abortion or no previous
thrombosis), low-dose aspirin reduces the risk of neither
events nor complications (B).24
The risk of venous thromboembolism in pregnant patients positive for antiphospholipid antibody and with no
history of thrombotic events is similar to that of pregnant
patients with no antiphospholipid antibody (B).25,26 The risk
of thrombotic events in patients with antiphospholipid antibodies and history of obstetric events is 19% in 12 months,
but the risk of patients with antiphospholipid antibody and
no history of obstetric events is 0% (zero) (B);27 thus, pharmacological treatment (thromboprophylaxis) is not justified in
those patients (B).28
Recommendation
Patients with antiphospholipid antibodies and no history of
thrombotic events should not receive pharmacological treatment during pregnancy.
6. Is oral anticoagulation indicated for pregnant
women (between 14 and 35 weeks) with APS and
previous thrombosis? Which should the target
INR be?
Oral anticoagulants are recommended during pregnancy (16th
to 36th week), or even for six weeks after delivery (D),29 to patients with antiphospholipid antibody and history of thrombosis, mainly arterial thrombosis, based on extrapolation of the
use of oral anticoagulants in similar, but not pregnant, patients
and on the fact of the lower teratogenic risk of those medications at that phase of pregnancy (D).30
Events can recur in 20% of patients with APS, even when on
oral anticoagulants (80% with INR between 2.0 and 3.0, and 20%
with INR > 3.0) (B).21 The use of oral anticoagulants (INR between
2.0 and 3.0) in 80% of patients with APS reduces the recurrence
risk of thromboembolism within five years by 22% (NNT:5) (B).19
However, their specific use in pregnant women has not been
properly studied.
Recommendation
Pregnant patients with APS and history of thromboembolic
events should not receive oral anticoagulants, because their
use in that population has not been properly studied.
7. Is heparin indicated to pregnant women with
APS and previous thrombosis? Which dosing
should be used for unfractionated and low
molecular weight heparin?
Treating pregnant women with APS and history of thromboembolic events (venous or arterial) with dalteparin (5,000 IU/day,
subcutaneously, once a day, increasing to twice a day between
the 16th and 20th gestational week) can cause a 100% reduction in thrombotic events over a 35-week follow-up (B).31
In pregnant women with APS and history of thromboembolic events, treatment with full dose low molecular weight
heparin associated with aspirin during pregnancy and for six
weeks after delivery can reduce the recurrence risk of thrombotic events by 100% (NNT:1) (B).32
Comparing the use of low molecular weight heparin (enoxaparin, 1 mg/kg/day) associated with 100 mg of aspirin and warfarin (INR between 2 and 2.5) from the 14th to the 34th gestational week to patients with APS and one previous thrombotic
episode shows a 28.9% increase in the risk of thrombosis in
those receiving warfarin (NNH: 4) (B).33
Pregnant patients with APS and previous episodes of thrombosis have a high recurrence rate of thrombosis, and the antithrombotic treatment should be maintained during pregnancy
and post-partum. The standard regimen combines low-dose
aspirin and heparin (unfractionated or low molecular weight).
Warfarin, except between the 6th and 12th week, might be an
alternative to heparin, and should be reinitiated after delivery
(D).34
Recommendation
The use of low molecular weight heparin subcutaneously
(dalteparin, 5,000 IU/day or enoxaparins, 1 mg/kg/day, doubling
one or the other after the 16th week) associated with aspirin
(100 mg/day) during pregnancy and after delivery reduces the
occurrence of maternal thrombosis and fetal loss. Warfarin is
the option after the 13th gestational week. Despite the lack
of good quality scientific evidence, the authors recommend,
based on case series, case reports and personal experience,
that pregnant patients with APS and previous thrombosis
maintain full dose and nonprophylactic low molecular weight
heparin associated with aspirin during pregnancy due to the
high risk of new thromboembolic events in that period.
8. Is there any difference in the management of
pregnant women with history of late fetal loss or
early abortions? Are there advantages in using
aspirin?
Pregnant patients with APS and history of either early abortions or late fetal loss can be managed with low-dose aspirin
and low molecular weight heparin.
However, under the same treatment, the outcomes of patients with history of early abortions as compared to those of
patients with history of late fetal loss differ, a higher number
of premature deliveries and small for gestational age newborns
being observed in patients with history of late fetal loss (B).35
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Comparison of low molecular weight heparin and aspirin in isolation for the treatment of pregnant women with
APS and history of repeated abortions shows a 14% increase
(NNT:7) in fetal survival and in newborn weight in patients
medicated with heparin (B).36
The use of aspirin to treat pregnant patients with APS and
repeated abortions has no benefits regarding prenatal complications (for example, premature delivery) and neonatal outcomes (for example, weight) (B).37
Neonatal and obstetric outcomes occur at similar numbers
in pregnant patients with antiphospholipid antibody and history of repeated abortions treated with aspirin and low molecular weight heparin as compared to those treated only
with aspirin (A).38,39 However, when aspirin is associated with
unfractionated heparin, a 29% increase (NNT:3) in newborn
survival is observed (A).40
Recommendation
Pregnant patients with antiphospholipid antibody and history
of early or late abortions should be treated with heparin (unfractionated or low molecular weight) and aspirin.
9. Is the association of other medications
(corticosteroid, immune globulin, rituximab)
with anticoagulants in the catastrophic
antiphospholipid syndrome (CAPS)
advantageous?
Considering the presence or absence of one single treatment,
improvement occurs in 63.1% of the episodes of CAPS treated
with anticoagulants versus 22.2% of episodes not treated with
anticoagulants (NNT:2). In addition, there is no difference in
improvement between presence and absence of individual
treatment with other agents, such as corticosteroids, plasmapheresis, immune globulin or antiplatelet agents. The individual use of corticosteroids produces the poorest recovery (B).41,42
When treatments are associated, the most common combination is anticoagulants and corticosteroids, followed by anticoagulants, corticosteroids, plasmapheresis and/or immune
globulin. The recovery rate showed no difference between the
several combinations, and no difference between combining
with anticoagulants or not (B).41,42
189
Acknowledgements
The authors thank Dr. Wanderley Marques Bernardo, from the
Brazilian Medical Association, for his valuable collaboration
in this project.
Appendix 1: Search strategies and words used in
the search for the clinical questions.
PICO 1
Do asymptomatic individuals positive for antiphospholipid
antibodies (moderate or high IgG or IgM LA+ or ACL or antibeta 2-GP) and with no history of thrombosis benefit from
anticoagulation? And from antiplatelet agents?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome
OR Anti-Phospholipid Syndrome OR Antibodies,
Antiphospholipid) AND (Platelet Aggregation Inhibitors OR Anticoagulants OR Coumarins OR Heparin or Aspirin) AND (randomized controlled trial[Publication Type] OR
(randomized[Title/Abstract] AND controlled[Title/Abstract]
AND trial[Title/Abstract]) OR random*[Title/Abstract] OR
random allocation[MeSH Terms])
PICO 2
Is anticoagulation for undetermined time indicated to patients positive for antiphospholipid antibodies and with
a history of venous thrombosis? What should the target
INR be?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome
OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND (Anticoagulants OR Coumarins OR Heparin) AND Embolism and Thrombosis AND ((clinical[Title/
Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH
Terms] OR clinical trial[Publication Type] OR random*[Title/
Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)
PICO 3
Recommendation
There are no good quality studies confirming the benefit of
the association of other medications with anticoagulants in
the treatment of patients with CAPS. Despite the limited good
quality scientific evidence, the authors recommend, based on
case series, case reports and personal experience, the association of corticosteroid, plasmapheresis and/or rituximab with
anticoagulant therapy, because of the high mortality of that
condition.
Conflicts of interest
The authors declare no conflicts of interest.
Is anticoagulation for undetermined time indicated for patients with APS and previous arterial thrombosis? Which
should the target INR be?
(Antiphospholipid Syndrome OR Anti-Phospholipid
Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies,
Antiphospholipid ) AND (Anticoagulants OR Coumarins OR
Heparin OR INR) AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract] AND
trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/ Abstract] OR
random allocation[MeSH Terms] OR therapeutic use[MeSH
Subheading] OR Comparative study OR Epidemiologic
methods)
190
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
PICO 4
Is anticoagulation for undetermined time indicated for
patients with APS who have only obstetric events? And antiplatelet therapy?
Pregnancy Complications AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND
(Platelet Aggregation Inhibitors OR Anticoagulants OR Coumarins OR Heparin OR Aspirin) AND ((clinical[Title/Abstract]
AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR
clinical trial[Publication Type] OR random*[Title/ Abstract] OR
random allocation[MeSH Terms] OR therapeutic use[MeSH
Subheading] OR Comparative study OR Epidemiologic methods)
OR therapeutic use[MeSH Subheading] OR Comparative study
OR Epidemiologic methods)
PICO 8
Is there any difference in the management of pregnant women with history of late fetal loss or early abortions? Are there
advantages in using aspirin?
Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND heparin AND ((clinical[Title/
Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH
Terms] OR clinical trial[Publication Type] OR random*[Title/
Abstract] OR random allocation[MeSH Terms] OR therapeutic
use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)
PICO 5
PICO 9
Should a primipara positive for antiphospholipid antibodies
with no history of thrombosis undergo any intervention?
Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND ((clinical[Title/Abstract] AND
trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical
trial[Publication Type] OR random*[Title/Abstract] OR random
allocation[MeSH Terms] OR therapeutic use[MeSH Subheading])
PICO 6
Is oral anticoagulation indicated for pregnant women (between 14 and 35 weeks) with APS and previous thrombosis?
Which should the target INR be?
Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND (Embolism and Thrombosis
OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract]
AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR
clinical trial[Publication Type] OR random*[Title/Abstract] OR
random allocation[MeSH Terms]
OR therapeutic use[MeSH Subheading] OR Comparative
study OR Epidemiologic methods)
PICO 7
Is heparin indicated to pregnant women with APS and previous thrombosis? Which dosing should be used for unfractionated and low molecular weight heparin?
Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid
Antibody Syndrome OR Anti-Phospholipid Syndrome OR
Antibodies, Antiphospholipid) AND heparin AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND
((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR
random*[Title/Abstract] OR random allocation[MeSH Terms]
Is the association of other medications (corticosteroid, immune globulin, rituximab) with anticoagulants in the catastrophic antiphospholipid syndrome (CAPS) advantageous?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR
Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND Catastrophic AND ((clinical[Title/Abstract] AND
trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical
trial[Publication Type] OR random*[Title/Abstract] OR random
allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Resistance training versus weight-bearing aquatic exercise:
a cross-sectional analysis of bone mineral density in
postmenopausal women
Sandor Balsamoa,b,c,*, Licia Maria Henrique da Motaa, Frederico Santos de Santana a,b,c,
Dahan da Cunha Nascimentoc,d, Lídia Mara Aguiar Bezerrae, Denise Osti Coscrato Balsamoc,
João Lindolfo Cunha Borgesf, Ana Patrícia de Paulag, Martim Bottaroe
a
Postgraduate Program in Medical Sciences, Medical School, Universidade de Brasília (UnB), Brasília, DF, Brazil
Department of Physical Education, Centro Universitário Euro-Americano (UNIEURO), Brasília, DF, Brazil
c
Research group of strength training and Health (GEPEEFS), Brasília, DF, Brazil
d
Postgraduate Program in Physical Education, School of Physical Education, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil
e
School of Physical Education, Universidade de Brasília (UnB), Brasília, DF, Brazil
f
Department of Medicine, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil
g
Postgraduate Program in Sciences for Health, Health Sciences Teaching and Research Foundation, Secretary of State of Health (FEPECS/
SESDF), Ministry of Health, Brasilia, DF, Brazil
b
article info
abstract
Article history:
Introduction: Many studies have shown that resistance training has a positive effect on bone
Received on 7 January 2012
mineral density (BMD). However, few studies have compared the BMD of individuals undergo-
Accepted on 13 December 2012
ing resistance training and those training aquatic weight-bearing exercises.
Objective: To compare, in a cross-sectional study, the BMD of postmenopausal women undergo-
Keywords:
ing resistance training and postmenopausal women training aquatic weight-bearing exercises.
Strength training
Methods: The sample comprised 63 women divided into the following three groups: resistance
Aquatic weight-bearing exercises
training (STRENGTH: n = 15; 51.4 ± 2.7 years); aquatic weight-bearing exercises (WATER: n =
Bone density
22; 54.5 ± 3.3 years); and non-trained controls (CONTROL: n = 26; 52.0 ± 3.3 years). All volun-
Postmenopause
teers were on hormone replacement therapy for at least one year. The STRENGTH and WATER
groups were training for at least one year prior to study beginning (mean years of training –
STRENGTH: 4.5 ± 2.0; WATER: 4.2 ± 2.2).
Results: The STRENGTH group had higher BMD of total body, femoral neck, lumbar spine L2L4 as compared with the CONTROL group (all P < 0.05). The WATER group had higher BMD of
total body, total hip, lumbar spine L2-L4 as compared with the CONTROL group (all P < 0.05).
However, no difference was observed between the STRENGTH and WATER groups regarding
the sites assessed.
Conclusions: Those findings suggest that not only the resistance training, but also aquatic
weight-bearing exercises might be a non-pharmacological strategy to prevent BMD loss in
postmenopausal women.
© 2013 Elsevier Editora Ltda. All rights reserved.
* Corresponding author.
E-mail: [email protected] (S. Balsamo)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
194
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 3 – 1 9 8
Treinamento de força versus hidroginástica: uma análise transversal
comparativa da densidade mineral óssea em mulheres na pós-menopausa
resumo
Palavras-chave:
Introdução: Há um grande número de estudos mostrando que o treinamento de força tem
Treinamento de força
um efeito positivo sobre a densidade mineral óssea (DMO). Porém, existem poucos estudos
Hidroginástica
comparando a DMO entre praticantes de hidroginástica e treinamento de força.
Densidade óssea
Objetivo: Comparar, em uma análise transversal, a DMO de mulheres praticantes de treina-
Pós-menopausa
mento de força com mulheres praticantes de hidroginástica, na pós-menopausa.
Métodos: A amostra foi composta de 63 mulheres, divididas em três grupos: treinamento de
força (FORÇA: n = 15; 51,4 ± 2,7 anos), hidroginástica (HIDRO: n = 22; 54,5 ± 3,3 anos) e controles não treinadas (CONTROLE: n = 26; 52,0 ± 3,3 anos). Todas as voluntárias estavam em
terapia de reposição hormonal há no mínimo um ano. Os grupos FORÇA e HIDRO treinavam
há pelo menos um ano antes do início do estudo (média de anos de treinamento – FORÇA:
4,5 ± 2,0; HIDRO: 4,2 ± 2,2).
Resultados: O grupo FORÇA apresentou maior DMO de corpo total, colo femoral e coluna
lombar L2-L4 quando comparado ao grupo-controle (todos P < 0,05). O grupo HIDRO apresentou maior DMO no corpo total, quadril total e coluna lombar L2-L4 quando comparado
ao grupo-controle (todos P < 0,05). Entretanto, não foram observadas diferenças entre os
grupos FORÇA e HIDRO em nenhum dos sítios avaliados.
Conclusões: Estes achados sugerem que não apenas o treinamento de força, mas também a
hidroginástica podem ser estratégias não farmacológicas para prevenção da perda de DMO
em mulheres na pós-menopausa.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
There is growing evidence that exercise contributes to the prevention and treatment of osteoporosis due to the osteogenic
effect of mechanical stimulus on bone tissue.1-3 It has been
suggested that activities that require heavy loading with few
repetitions, resulting in high strain rates, may be optimal for
increasing bone mineral density (BMD).4 Cross-sectional studies have shown that resistance-trained individuals showed
more BMD than inactive5,6. Some experts recommendations,7
prospective8 or meta-analysis9 studies have shown increases
or maintenance of BMD on those individuals.
On the other hand, water weight bearing exercises has been
associated with improve in neuromuscular and functional fitness10 and cardiometabolic health,11 and also is highly recommended for old people with disability, because of security.10,12
Although, in the last 20 years, only a few studies have investigated BMD and water weight bearing exercises.13-16 Nevertheless, the literature is not clear whether there is an association
between water weight bearing exercises and BMD. Most studies have yielded conflicting results ranging from worsening14
to improve bone health.15 Additionally, to date, no studies have
compared, in a cross-sectional analysis, BMD in postmenopausal women resistance-trained versus postmenopausal
women who are practicing aquatic weight bearing exercise,
which is a novel approach.
The purpose of this study was to compare BMD in postmenopausal women resistance-trained with postmenopausal
women aquatic-trained with weight bearing exercises, and
both with untrained controls. It was hypothesized that postmenopausal women aquatic-trained with weight bearing ex-
ercises would have similar BMD as postmenopausal women
resistance-trained, and they would have higher BMD than untrained controls.
Materials and methods
Subjects
The research project was approved by the Research Ethics Committee of the Universidade Católica de Brasília (UCB) according
to the institutional policies and the Declaration of Helsinki.17
All the participants were from Brasília and were recruited by
means of electronic mail and leaflets and posters distributed
in the city of Brasília. During the study, a single blinded rheumatologist analyzed the medical records and conducted the
structured interviews with 95 women. The volunteers were
composed by three groups: resistance-trained (STRENGTH),
aquatic-trained with weight bearing exercises (WATER) and
untrained controls (CONTROL).
Inclusion criteria
All participants should be: a) at the minimum of one year in
menopause; b) in exclusive estrogen hormone replacement
therapy (HRT); c) into the STRENGTH and WATER groups required that the subject had been training at least one year
before the study; d) into the CONTROL group the participants
should not be engaged in regular physical activities programs
for at least six months prior to the study. We used a questionnaire consisting of three questions to identify type of exercise, its regularity, frequency, intensity, and duration: 1) What
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 3 – 1 9 8
type of exercise do you practice regularly during one week?;
2) How often do you do this exercise during one week?; and 3)
Which is the average duration in minutes of a single session
of physical exercises?
Exclusion criteria
All the participants with the following characteristics were
excluded: a) using drugs or treatment that affects bone metabolism, except for calcium supplementation and HRT; b)
smoking; c) with the body mass index (BMI) < 18 kg/m2 and
> 30 kg/m2 (obesity); d) have any disease that affects the bone
metabolism or strength (hypothyroidism/fibromyalgia/rheumatoid arthritis).
The resistance-trained and aquatic-trained with weight
bearing exercises group
The STRENGTH group had traditional resistance training at
least three nonconsecutive days per week with supervision
with a physical education teacher, each session lasting approximately 60 minutes, and the program consisted in a zone
of 10 to 15 repetitions each exercise (included leg press, knee
extension, knee flexion, seated bench press, seated row/lat pull
down, biceps curls and core exercise). The WATER group had
classes through at least three nonconsecutive days per week
(one hour each session) with a physical education teacher
certified by the Aquatic Exercise Association (AEA). The goal
was to reach a heart rate of 60%–80% of maximum during the
session, being exercised the major muscle groups with movements of pushing and pulling, jumping and displacements.
We could not control exactly how many training sessions the
trained groups (STRENGTH/WATER) did in last year(s).
Procedures
Participants eligible for the study attended to the laboratory
at the same time (8 am to 12 pm). Participants had to attend
the following procedures prior to the laboratory visits: avoid
practicing intense activities, caffeine use or alcohol derivatives 24 hours before the test, and have their last meal (including water) at least two hours before the test. All the tests
were evaluated by a single blinded examiner.
Anthropometric measurements
For height, weight, BMI, individuals were asked to remove
shoes and any weight that might interfere in the measurements. For measuring the height, the individual should be
barefoot with heels and trunk against the wall, head in the
Frankfurt plane. The subject’s body weight in minimal clothing was measured to the nearest 100 g with a precision scale
weight (Filizola ID-1500, Brazil), and height was measured to
the nearest 5 mm with a wall-mounted stadiometer (Sanny
Standard ES 2030, Brazil).
Bone densitometry
The BMD of the total body, lumbar spine L2-L4, femur neck,
total hip and forearm – 33% radius, ultradistal radius, and
195
total radius were measured using a dual-energy X-ray absorptiometry (DPX-L; Lunar Radiation Corporation, Madison,
Wisconsin, U.S.A) and the scan were analyzed using software
version 3.6. Before the tests, the devices were calibrated according to manufacturers recommendations and the same
examiner performed all examinations.
Statistical analysis
Values are presented as mean and standard error. We used a
model analysis of covariance (ANCOVA) by a factor, with the
measure of BMD as the dependent variable and measures of
age, total muscle mass, fat mass and body fat percentage as
covariates. The Bonferroni correction was used to adjust the
pre-specified comparisons and it was considered, in the analysis, a significance level of 5%. Coefficient of variation (CV)
was used to calculate within-participant variation (CV% =
[SD/mean] x 100). To identify the differences among groups of
the percentage of voluntaries with osteoporosis, osteopenia
and normal scores, according ISCD (2005), the Kruskal-Wallis
test was applied using the Mann-Whitney test with Bonferroni correction, considering in this test a significance level of
P < 0.012. Data were analyzed using SAS for Windows.
Results
Sample: Sixty-three healthy postmenopausal women were
eligible for the study [32 excluded: hypothyroidism (n = 4);
fibromyalgia (n = 3); BMI < 18 kg/m2 (n = 3) and > 30 kg/m2
(n = 14); smoking (n = 4); drugs or treatment that affects bone
metabolism (n = 4). Fifteen in the STRENGTH group, 22 in the
WATER group and 26 in the CONTROL group. Ninety percent
of the STRENGTH and WATER group had been training regularly in the past year of the study in Young Men Christian Associations (YMCA).
Main characteristics of the three groups (STRENGTH; WATER;
CONTROL) are presented in Table 1. There were no significant
differences between groups for BMI, HRT (the dose of estrogen
varied, e.g., 0.3–2.5 mg in all groups), and years of menopause.
And the training time (years) of STRENGTH and WATER groups
were not different (P > 0.05). However, the WATER group was
older then the STRENGTH and CONTROL groups.
The results of dependent variable BMD in the STRENGTH
group was significantly higher compared to the CONTROL in
total body (5.73%), in the sites lumbar spine, L2-L4 (16.40%)
and femoral neck (8.73%), all P < 0.05. However no significant
difference was found in the other sites (total hip, total radius,
ultra-distal radius and 33% radius). The WATER group also
showed a significantly higher BMD compared to CONTROL
group in total body (6.50%) and in the sites lumbar spine, L2L4 (17.69%) and total hip (9.52%), all P < 0.05. However no significant difference was found in the other sites (femoral neck,
total radius, ultra-distal radius and 33% radius) (Table 2).
The groups STRENGTH and WATER did not differ regarding
the total body BMD and also in all the tested sites (lumbar
spine L2-L4; femoral neck; total hip; total radius; ultra-distal
radius; 33% radius) (P > 0.05) (Table 2).
The number of participants with osteopenia in lumbar
spine L2-L4 (T-score of BMD) was higher in the CONTROL
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Table 1 – Characteristics of resistance-trained group
(STRENGTH), aquatic-trained weight bearing exercises
group (WATER) and untrained controls group (CONTROL)
(mean ± SD).
Variables
STRENGTH
(n = 15)
WATER
(n = 22)
CONTROL
(n = 26)
Age (years)
BMI (kg/m2)
Menopause time
(years)
HRT (years)
Training time (years)
51.4 ± 2.7
24.0 ± 2.7
3.3 ± 2.6
54.5 ± 3.3*
24.7 ± 2.7
5.1 ± 2.5
52.0 ± 3.4
24.0 ± 3.4
3.5 ± 2.8
3.0 ± 1.7
4.5 ± 2.0
3.8 ± 2.5
4.2 ± 2.2
4.0 ± 2.8
—
*P < 0.05 significantly higher than STRENGTH group and CONTROL
group.
BMI, body mass index; HRT, hormone replacement therapy; SD,
standard deviation.
group compared with the STRENGTH group (P < 0.05). For other
variables, no significant difference was detected (all P > 0.05).
More details of the percentage of voluntaries with osteoporosis, osteopenia and normal are presented in the Table 3.
Discussion
This study aimed to compare the DMO of postmenopausal women for at least one year, training for a period of at
least one year, and in use of HRT therapy. We compare a
STRENGTH group that were resistance-trained with WATER group that were weight-bearing-exercise-trained, and
both with untrained controls. It was hypothesized that
postmenopausal women aquatic-trained with weight bearing exercises would have similar BMD as postmenopausal
women resistance-trained, and they would have higher BMD
than untrained controls. Our hypotheses were confirmed
data from no significant difference between WATER group
and STRENGTH group in total body BMD and in any of the
evaluated sites. Also the present study confirms the initial
hypothesis that, compared to CONTROL group, WATER presented a higher BMD in lumbar spine L2-L4, total hip sites
and in total body. Furthermore, the STRENGTH group presented higher BMD in lumbar spine L2-L4, femoral neck and
total body compared with CONTROL group. Additionally the
CONTROL group presented significant higher percentage of
participants with osteopenia in lumbar spine L2-L4 T-score
compared with the STRENGTH group.
The present study methodology exclusion criteria provide minimal bias and/or potential confounders aspects that
could influence in the results of BMD, such as with all participants, were all postmenopausal, and physical characteristics such BMI, body composition, weight, height and clinical conditions, were all similar with HRT. Also, no participant
was smoker or had concurrent disease that affects BMD. In
addition the STRENGTH and the WATER group were for at
least one year trained prior to the study. In addition our new
approach revealed that those postmenopausal women who
practiced aquatic weight-bearing exercises had similar BMD
to that of women who did resistance-trained. The current
study is unique in that it is not an intervention study. This is
a relevant information because in a cross sectional analysis
we can compare different sports and modalities. Moreover,
osteogenic responses are associated with specific and intensity loading,4,8 but not with low intensity and/or short time
of intervention.8 Previous studies with WATER exercise had
investigated short time of intervention to bone modulation15
with low intensity14 and with osteopenic women;14 rather, we
compare the total body BMD and BMD in different sites in
postmenopausal women STRENGTH group with postmenopausal women WATER group, and both with a CONTROL
group which was evaluated to data.
Table 2 – Bone mineral density values for resistance-trained group (STRENGTH), aquatic-trained with weight bearing
exercises group (WATER) and untrained controls group (CONTROL).
BMD site (g/cm2)
Total body
CV%
Lumbar spine-L2-L4
CV%
Femoral neck
CV%
Total hip
CV%
Total radius
CV%
Ultra-distal radius
CV%
33% radius
CV%
P+
Groups*
STRENGTH
(n = 15)
WATER
(n = 22)
CONTROL
(n = 26)
STRENGTH vs.
CONTROL
WATER vs.
CONTROL
STRENGTH
vs. WATER
1.221 ± 0.022
6.2
1.283 ± 0.169
12.6
1.020 ± 0.142
13.2
1.046 ± 0.119
11.1
0.550 ± 0.032
7.7
0.385 ± 0.038
13.9
0.693 ± 0.045
8.0
1.232 ± 0.012
4.0
1.294 ± 0.112
8.6
0.982 ± 0.075
7.6
1.049 ± 0.089
8.5
0.550 ± 0.025
5.5
0.368 ± 0.026
8.3
0.692 ± 0.029
4.9
1.153 ± 0.014
5.7
1.07 ± 0.03
9.5
0.934 ± 0.023
8.1
0.947 ± 0.085
13.5
0.518 ± 0.038
10.5
0.345 ± 0.034
13.3
0.653 ± 0.049
10.6
0.0163*
0.0019*
1.0000
0.0001*
< 0.0001*
1.0000
0.0374*
0.4725
0.6273
0.1172
0.0276*
1.0000
0.9856
0.2460
1.0000
0.0821
0.1384
1.0000
0.8371
0.2403
1.0000
Values are mean plus or minus ± standard error. + P for comparisons between groups were calculated using ANCOVA (with age, total muscle
mass, fat mass and percentage body fat as covariates). Correction of Bonferroni was used to adjust the pre-specified comparisons.
* P < 0.05 compared to CONTROL.
CV%, coefficient of variation percentage (CV% = [SD/O mean] x 100).
197
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Table 3 – Percentage of voluntaries with osteoporosis, osteopenia and normal scores according to ISCD, 2005.
International Society for Clinical Densitometry. The ISCDs official positions (updated 2005). Washington: ISCD, 2005.
Variable (T-score)
T score: lumbar spine L2-L4
T score: femur neck
T score: total hip
T score: ultra-distal radius
T score: 33% radius
T score: total radius
STRENGTH, n(%)
WATER, n(%)
CONTROL, n(%)
15 (100)
0 (0)
0 (0)
14 (95)
1 (5)
0 (0)
14 (95)
1 (5)
0 (0)
13 (87)
2 (13)
0 (0)
13 (87)
2 (13)
0 (0)
13 (87)
2(13)
0 (0)
21 (95)
1 (5)
0 (0)
22 (100)
0 (0)
0 (0)
22 (100)
0 (0)
0 (0)
17 (77)
5 (23)
0 (0)
20 (91)
2 (9)
0 (0)
21 (95)
1 (5)
0 (0)
14 (54)
9 (35)*
3 (11)
21 (81)
4 (15)
1 (4)
19 (73)
6 (23)
1 (4)
14 (54)
7 (27)
5 (19)
15 (58)
10 (38)
1 (4)
19 (73)
6 (23)
1 (4)
Normal
Osteopenia
Osteoporosis
Normal
Osteopenia
Osteoporosis
Normal
Osteopenia
Osteoporosis
Normal
Osteopenia
Osteoporosis
Normal
Osteopenia
Osteoporosis
Normal
Osteopenia
Osteoporosis
*CONTROL group had significantly higher perceptual of participants with osteopenia compared with the STRENGTH group.
Some prospective studies had similar results when
STRENGTH group was compared with CONTROL group in
the total body BMD18 and in the sites total hip sites,7 femoral neck8 and also Kelley et al.9 meta-analysis in the spine
L2-L4. Most of these studies involved high intensity protocols, what explains the efficiency of the stimulus on bone
progenitor cells. It is possible that, in the present study, no
significant difference was found between STRENGTH group
and WATER group because both methods of training were
sufficient positive to stimulate the BMD. Moreover, in radius
sites our results were different of meta-analysis of Kelley et
al.,9 although, similar of Bassey et al.19 It seems that this site
requires a more intense stimulus to improve osteogenic responses.4
This is the first study to report that the WATER group
had a higher total body BMD compared with the CONTROL
group. Also, presented higher BMD in spine and total hip
when compared with the CONTROL group. Our results are
in agreement with those by Tsukahara et al.16 and Rotstein
et al,.15 who demonstrated that the water group also had
similar BMD in spine and total hip compared to the controls.
Furthermore, Littrell and Snow (a published conference
communication abstract) reported that in a short time study
(six months) of aquatic training only preserved BMD in postmenopausal women in all sites, showing that this type of
training was useful to maintain bone mass while BMD in the
CONTROL group decreased.20
The results of this study agree with the experimental
study of Bravo et al.,14 which showed no significant difference in femoral neck BMD of osteopenic women after one
year of an aquatic physical activity similar to WATER. Additionally, Rotstein et al.15 found no significant difference
in femoral neck BMD after only seven months of training in
healthy postmenopausal women. It is important to remember that DXA provides a static measurement of BMD and,
therefore, does not reflects metabolic activity. To this effect,
Ay and Yurtkur13,21 studied bone anabolic (IGF-1 and calcitonin) and catabolic (parathormone, PTH) hormone activity
and analyzed BMD using an ultrasound test in postmenopausal women after an aquatic training program. The results
showed increased levels of calcitonin and IGF-1, improvement of the ultrasonography values and decrease of PTH in
the experimental group while the opposite happened to the
CONTROL group. Thus, it can be stated that aquatic training
affects bone metabolism positively.
This is the primary study to analyze forearm radius on
the WATER group compared with the CONTROL-group.
These results suggest that this strategy of exercise provides
little stimulus to the forearm region and perhaps wrist flexion, extension and hand grip exercises are not effective to
improve BMD in these sites.
Regarding the BMD in all evaluated sites, there were no
significant differences between STRENGTH group and WATER group. Recently, Tolomio et al.12 did not present significant differences in femoral neck among postmenopausal
women with osteoporosis. The experimental protocol consisted of combined land and water exercise program. With
resistance training and water weight bearing exercises,
were performed combined in two sessions per week, for 11
months.
Most studies associate BMD with resistance exercise due
to its specific and localized effect on body mass.4,5 However,
in the present study, in spite of being significantly older than
the STRENGTH group (three years), the evaluated sites did
not present higher values in STRENGTH group in comparison to WATER group.
The present study has limitations. Its design was not
experimental since researchers do not allocated the participants in groups. Participants had chosen to exercise
(STRENGTH/WATER) or not and then were observed by the
investigators. The intervention was not pre-defined by the
researchers. Consider to include in limitations/pitfalls section the effect of previous physical activities, especially during the bone mass acquisition period (up to reach peak bone
mass). In conclusion, the findings reported herein provide
novel evidence that weight-bearing water exercise produces
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R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 3 – 1 9 8
a strain stimulus for muscle development and provides continuous limb movement against water resistance. These results
have important practical implications, suggesting that not only
resistance training, but also weight-bearing water exercises
could be a nonpharmacological strategy for prevention of BMD
loss in postmenopausal women. This information is also important for professionals involved with healthcare and physical exercise, as water exercise is very popular in health centers
and tends to pose little risk, but further research is required to
provide supporting evidence for this exercise modality.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES
1. Chodzko-Zajko WJ, Proctor DN,
Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ, et
al. American College of Sports Medicine position stand.
Exercise and physical activity for older adults. Med Sci
Sports Exerc. 2009;41(7):1510-30.
2. Pereira RM, Carvalho JF,
Paula AP, Zerbini C, Domiciano DS, Gonçalves H, et
al. Guidelines for the prevention and treatment of
glucocorticoid-induced osteoporosis. Rev Bras Reumatol.
2012;52(4):580-93.
3. Gualano B, Pinto AL, Perondi MB,
Roschel H, Sallum AM, Hayashi AP, et al. Therapeutic effects
of exercise training in patients with pediatric rheumatic
diseases. Rev Bras Reumatol. 2011;51(5):490-6.
4. Kerr D, Morton A, Dick I, Prince R. Exercise effects on bone
mass in postmenopausal women are site-specific and loaddependent. J Bone Miner Res. 1996;11(2):218-25.
5. Dinc H, Savci G, Demirci A, Sadikoglu MY, Tuncel E,
Yavuz H. Quantitative computed tomography for
measuring bone mineral density in athletes. Calcif Tissue
Int. 1996;58(6):398-401.
6. Karlsson MK, Johnell O, Obrant KJ. Bone mineral density in
weight lifters. Calcif Tissue Int. 1993;52(3):212-15.
7. Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King
AC, et al. Physical activity and public health in older adults:
recommendation from the American College of Sports
Medicine and the American Heart Association. Circulation.
2007;116(9):1094-105.
8. Vincent KR, Braith RW. Resistance exercise and bone turnover
in elderly men and women. Med Sci Sports Exerc. 2002;34(1):1723.
9. Kelley GA, Kelley KS, Tran ZV. Resistance training and bone
mineral density in women: a meta-analysis of controlled trials.
Am J Phys Med Rehabil. 2001;80(1):65-77.
10. Tsourlou T, Benik A, Dipla K, Zafeiridis A, Kellis S. The effects
of a twenty-four-week aquatic training program on muscular
strength performance in healthy elderly women. J Strength
Cond Res. 2006;20(4):811-18.
11. Meredith-Jones K, Waters D, Legge M, Jones L. Upright waterbased exercise to improve cardiovascular and metabolic health:
a qualitative review. Complement Ther Med. 2011;19(2):93-103.
12. Tolomio S, Lalli A, Travain G, Zaccaria M. Effects of a combined
weight-bearing and non-weight-bearing (warm water) exercise
program on bone mass and quality in postmenopausal women
with low bone-mineral density. Clin Ter. 2009;160(2):105-9.
13. Ay A, Yurtkuran M. Evaluation of hormonal response and
ultrasonic changes in the heel bone by aquatic exercise in
sedentary postmenopausal women. Am J Phys Med Rehabil.
2003;82(12):942-9.
14. Bravo G, Gauthier P, Roy PM, Payette H, Gaulin P. A weightbearing, water-based exercise program for osteopenic women:
its impact on bone, functional fitness, and well-being. Arch
Phys Med Rehabil. 1997;78(12):1375-80.
15. Rotstein A, Harush M, Vaisman N. The effect of a water exercise
program on bone density of postmenopausal women. J Sports
Med Phys Fitness. 2008;48(3):352-59.
16. Tsukahara N, Toda A, Goto J, Ezawa I. Cross-sectional and
longitudinal studies on the effect of water exercise in
controlling bone loss in Japanese postmenopausal women. J
Nutr Sci Vitaminol (Tokyo). 1994;40(1):37-47.
17. Gandevia B, Tovell A. Declaration of Helsinki. Med J Aust.
1964;2:320-1.
18. Notelovitz M, Martin D, Tesar R, Khan FY, Probart C, Fields C, et al. Estrogen therapy and variable-resistance weight training
increase bone mineral in surgically menopausal women. J Bone
Miner Res. 1991;6(6):583-90.
19. Bassey EJ, Ramsdale SJ. Weight-bearing exercise and ground
reaction forces: a 12-month randomized controlled trial of
effects on bone mineral density in healthy postmenopausal
women. Bone. 1995;16(4):469-76.
20. Littrell TR, Snow CM. Bone Density and Physical Function in
Postmenopausal Women after a 12-month Water Exercise
Intervention. Abstract conference of Med Sci Sports Exerc.
2004;5:289-90.
21. Ay A, Yurtkuran M. Influence of aquatic and weightbearing exercises on quantitative ultrasound variables
in postmenopausal women. Am J Phys Med Rehabil.
2005;84(1):52-61.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 9 – 2 0 5
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Lack of association between interleukin-18 polymorphisms
and rheumatoid arthritis
Ticiana Della Justina Fariasa,&, Luisa Matos do Cantoa,&, Mayara Delagnelo Medeirosa,
Aline Fernanda Rodrigues Sereiaa, Lia Kubelka Fernandes de Carlos Backa,
Filipe Martins de Mellob, Adriana Fontes Zimmermannc, Ivânio Alves Pereirac,
Yara Costa Netto Muniza, Andrea Rita Marreroa, Ilíada Rainha de Souzaa,*
a
Laboratory of genetic polymorphisms, Universidade Federal de Santa Catarina (LAPOGE/UFSC), Florianópolis, SC, Brazil
Hospital das Clínicas, Medical School, Universidade do Estado de São Paulo (HC-FMUSP), São Paulo, SP, Brazil
c
Rheumatology Service, Hospital Universitário, Universidade Federal de Santa Catarina (HU-UFSC), Florianópolis, SC, Brazil
b
article info
abstract
Article history:
Objective: To assess the association of the polymorphisms of the interleukin-18 (IL-18) gene
Received on 2nd February 2012
with rheumatoid arthritis (RA) and with risk factors for cardiovascular diseases (CVD).
Accepted on 13 December 2012
Methods: This sample comprised 97 patients with RA and 151 healthy controls. In the patients, risk factors for CVD were analyzed, such as cholesterol levels, arterial hypertension,
Keywords:
smoking habit, C-reactive protein (CRP) level, and rheumatoid factor. DNA was extracted
Interleukin-18
and the single nucleotide polymorphisms (SNP) at the -607C/A and -137G/C positions of
Rheumatoid arthritis
the IL-18 gene were assessed in both groups. The Hardy-Weinberg equilibrium (HWE) was
Cardiovascular diseases
calculated and the odds ratio (OR) test performed, considering a 95% CI and P < 0.05.
Gene polymorphism
Results: The frequencies of the -607A allele in patients with RA and in controls were 0.443
Brazil
and 0.424, respectively, and of the -137C allele, 0.304 and 0.291, respectively. The genotype
frequencies were in HWE, except for controls in the -137 locus (P = 0.006). Association of
the polymorphisms of the IL-18 gene was found with neither RA nor risk factors for CVD,
including cholesterol level and CRP (P > 0.05). In addition, more smokers were found among
patients with RA as compared with controls (OR = 1.691; P = 0.088), and the CRP levels were
slightly higher in patients who smoked than in patients who did not (OR = 2.673; P = 0.061).
Conclusions: In this sample of patients with RA in the South of Brazil, association of the
polymorphisms of the IL-18 gene was observed with neither RA nor risk factors for CVD.
© 2013 Elsevier Editora Ltda. All rights reserved.
&
Both authors contributed equally to this manuscript.
* Corresponding author.
E-mail: [email protected] (I. R. de Souza)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
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Ausência de associação entre os polimorfismos do gene interleucina-18
e artrite reumatoide
resumo
Palavras-chave:
Objetivo: Analisar a associação dos polimorfismos do gene interleucina-18 (IL-18) com
Interleucina-18
artrite reumatoide (AR) e com fatores de risco de doenças cardiovasculares (DCV).
Artrite reumatoide
Métodos: A amostra foi constituída por 97 pacientes com AR e 151 controles saudáveis. Nos
Doenças cardiovasculares
primeiros, foram analisados fatores de risco de DCV, tais como níveis do colesterol, hi-
Polimorfismo genético
pertensão arterial, tabagismo e fator reumatoide, bem como o nível da proteína C-reativa
Brasil
(CRP). O DNA foi extraído e foram analisados os polimorfismos de nucleotídeo único (SNP)
nas posições -607C/A e -137G/C do gene IL-18 em ambos os grupos. O equilíbrio de Hardy-Weinberg (EHW) e o odds ratio (OR) foram realizados, considerando IC 95% e P < 0,05.
Resultados: As frequências do alelo -607A nos pacientes com AR e nos controles foram de
0,443 e 0,424 e do alelo -137C foram de 0,304 e 0,291, respectivamente. As frequências do
genótipo estavam em EHW, exceto em controles no locus -137 (P = 0,006). Não foi encontrada associação dos polimorfismos do gene IL-18 com AR, nem com fatores de risco de
DCV, incluindo o nível do colesterol e de CRP (P > 0,05). Além disso, observaram-se mais
indivíduos fumantes entre pacientes com AR em comparação aos controles (OR = 1,691;
P = 0,088), e os níveis de CRP eram ligeiramente mais elevados em pacientes fumantes
quando comparados aos de pacientes não fumantes (OR = 2,673; P = 0,061).
Conclusões: Ao analisar uma amostra de pacientes com AR no sul do Brasil, não foi encontrada associação dos polimorfismos do gene IL-18 com AR, nem com os fatores de risco
de DCV.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease
characterized by chronic inflammation, leading to joint destruction and systemic complications which increase morbidity and mortality.1,2 This disease affects 0.5%–1% of the
general population worldwide, with a higher incidence in
women than in men.3 Although the incidence and clinical
manifestations of RA have been shown to vary in many different geographical regions, in Latin America, especially in
Brazil, this information is scarce.4,5 Therefore, it is very important to enlighten RA pathogenesis in heterogeneous population such as in Brazil.
The RA has a complex and unclear etiology, but in genetically susceptible individuals, specific environmental
factors can potentially activate pathogenic immune reactions, including autoantibody formation and autoreactivity
response.1-3,6 The onset of RA can be indicated by the development of antibodies against citrullinated protein antigens
(ACPA) and rheumatoid factor (RF) related to the self-tolerance loss.7 Recently, it has been recognized two RA subsets
based on presence or absence of ACPA. Patients with ACPA
positive have more extra-articular manifestations, smoking
habit, and worse prognosis.2 The main cause of mortality in
RA patients is cardiovascular diseases (CVD). Once the risk of
CVD in RA patients is 50% higher when compared with the
general population, it is believed that other risk factors are
present in RA disease.8,9 Thus, the pathogenesis of accelerated cardiovascular damage is caused by traditional cardiovascular risk factors in combination to disease-related inflammatory and autoimmune mechanisms.10,11
Inflammation has an important role in atherosclerotic
lesion and RA patients have a higher prevalence of atherosclerosis.12 In immune-mediated diseases such as RA, the
accelerated and early atherosclerotic vascular damage may
partially be explained by humoral and cellular autoimmune
response against antigens expressed on the endothelium.8,13
Cytokines are also implicated in many immune processes
associated with the pathogenesis of RA, especially in maintaining the active chronic inflammatory response. Because
cytokines are involved in immune-regulatory and tissuedestructive events, it is likely that they would influence the
severity of RA manifestations.7 Interleukin-18 (IL-18), a proinflammatory cytokine produced in RA by several synovium
cells such as macrophages, chondrocytes and osteoblasts,
induces signaling pathways common to other IL-1 family
members, such as activation of nuclear factor-κB (NF-κB) and
interferon-γ expression.7,14–16
Administration of IL-18 to mice caused development of
erosive, inflammatory arthritis, suggesting that this cytokine
can play a pro-inflammatory role in vivo.14 Furthermore, IL-18
mRNA and its protein were detected in RA synovial tissues in
higher levels than in osteoarthritic controls.14 The structure,
levels and regulation of IL-18 can be due to genetic differences on IL-18 gene expression.16
The chronic inflammatory condition seen in RA increase
the levels and expression of C-reactive protein (CRP), tumor
necrosis factor alpha (TNFα), interleukins-1, -6, and also -18,
which are relevant as CVD risk factors.11,13,19 IL-18 is considered pro-atherogenic, presumably as a mediator of vascular
inflammation itself, leading to augmentation and vulnerability of atherosclerotic plaque and finally, to its rupture.18
Human adipocytes are also capable of producing IL-18, con-
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tributing to systemic IL-18 concentrations and development
of the increased risk of diabetes and CVD that are associated
with obesity and insulin resistance states.19
Plasma IL-18 concentration has shown to be increased
in post myocardial infarction patients and was associated
with coronary atherosclerosis.20 Indeed, variations in the IL18 gene were associated with raised IL-18 serum concentrations and higher cardiovascular mortality among coronary
artery disease (CAD) patients.21 Other studies showed that
IL-18 gene polymorphisms are involved in the development
of ischemic stroke,22 myocardial infarction (MI),23 and higher
cardiovascular mortality risk.24 Moreover, IL-18 serum levels
were associated with traditional risk factors such as LDL- and
HDL-cholesterol abnormal values, obesity, insulin resistance
and cell dysfunction.20
Even though the endogenous production of IL-18 is affected by multiple factors, individual differences could also be
determined by genetic polymorphisms, potentially affecting
the balance between Th1 and Th2 cytokine responses. This
mechanism could be responsible for an increased resistance
to microbial infections, but also for a higher susceptibility to
autoimmune disorders in individuals carrying more active
IL-18 alleles.15
The IL-18 gene is regulated by its promoter region polymorphisms, which variability could lead to differences in
transcription factor binding. Two single nucleotide polymorphisms (SNPs) in the promoter region at -607C/A and
-137G/C position have been studied, and those changes disrupts a potential binding site of the cAMP-responsive element binding (CREB) protein and the H4TF-1 nuclear factor,
respectively.15,25
In RA patients, the higher frequency of -607A allele and/
or higher frequency of -137C allele are related to deficiency in
gene transcription; that would be beneficial for the individual, protecting against the development of RA. Accordingly,
one study demonstrates that the -607AA genotype is associated with lower prevalence of RA in a Chinese population.25
On the other hand, the homozygous for C at position -607
and G at position -137 promote higher levels of IL-18 mRNA
compared to the other genotypes, and the resulting elevated
levels of the pro-inflammatory IL-18 protein mediate many
acute and chronic inflammatory processes.15,25
The aim of this study was to analyze the influence of the
IL-18 polymorphisms on RA pathogenesis, as well as in CVD
risk factors (dyslipidemia, blood pressure, smoking).
Methods
Ninety seven RA patients diagnosed according to 1987 ACR
classification criteria, from the outpatient clinic of the Rheumatology Division at the University Hospital of the Federal
University of Santa Catarina, Florianópolis, Brazil, were enrolled. Control group was composed by 151 healthy volunteers without personal or family history of autoimmune diseases. The study was approved by the local Ethics Committee
(CEP/UFSC – case number 172/06). All participants gave their
written informed consent. Familial and epidemiologic data
were collected using structured questionnaires. Clinical data
were obtained from medical records.
As traditional CVD risk factors, we considered: high total (> 200 mg/dL) and LDL (> 100 mg/dL) cholesterol levels,
systemic arterial hypertension (systolic arterial pressure (AP)
≥ 140 mmHg and/or dyastolic AP ≥ 90 mmHg), current smoking habit, RF positivity (> 20 IU/mL), and levels of CRP above
the reference value (> 5mg/L).
Peripheral blood samples were collected for DNA extraction.26 The SNP -607C/A (rs1946518) of IL-18 gene was detected
by the polymerase chain reaction restriction fragment length
polymorphism (PCR-RFLP) technique, amplifying a 301 base
pair (bp) segment covering the polymorphic site by using the
primers sequences on Table 1.27 To detect the polymorphism,
the PCR products were followed by MseI restriction enzyme
(BioLabs Inc., New England) digestion, at 37°C for 12 hours,
then subjected to electrophoresis in a 3% agarose gel and
stained with ethidium bromide (1%). The digested PCR products were identified as CC homozygous individuals when cut
into 199 and 73bp fragments, and as AA homozygous individuals when cut into 101, 98 and 73 bp fragments. Thus, the
CA heterozygous individuals were identified when showing
the expected fragments: 199, 101, 98 and 73 bp (Fig. 1a).
The SNP -137G/C (rs187238) of the same gene was detected by sequence specific PCR (PCR-SSP) method, according to
Takada et al. (2002).27 In this method were used a common
reverse primer (R) and two sequence-specific forwards primers, specific F1 for C allele and specific F2 for G allele, amplifying a product of 261 bp (Table 1). As an internal positive
amplification control, a control forward primer (F) was used
to amplify a 446 bp fragment which covers the polymorphic
site (Table 1) (Fig. 1b). For confirmation of typing, we used
negative and positive controls for each genotype in all experiments in both SNP detection methods.
The frequencies of alleles and genotypes in RA patients
and controls of both SNPs -607 and -137 was performed
by direct counting. To verify the genotype distribution, the
Hardy-Weinberg Equilibrium (HWE) test was calculated using GENEPOP software.28 Since both SNPs are located in the
same gene, we have verified if they were inherited together
due to linkage disequilibrium (LD) using GENEPOP software.
Once both SNPs are linked, they can be considered as one
haplotype, and frequency of its combination was calculated
by PHASE software.29
The odds ratio (OR) with 95% confidence interval was obtained for association analysis30 of the polymorphisms (alleles, genotypes and haplotypes). The analysis was performed
Table 1 – Primers sequences used to amplify the -607
and -137 single polymorphisms nucleotide (SNP) in
promoter site of interleukin (IL)-18 gene by polymerase
chain reaction (PCR).
Position
-607
-137
Allele C
Allele G
Primers sequences*
F: 5-CTTTGCTATCATTCCAGGAA-3
R: 5-TAACCTCATTCAGGACTTCC-3
control F: 5-CCAATAGGACTGATTATTCCGCA-3
control R: 5-AGGAGGGCAAAATGCACTGG-3
specific F1: 5-CCCCAACTTTTACGGAAGAAAAG-3
specific F2: 5-CCCCAACTTTTACGGAAGAAAAC-3
*F, forward primer; R, reverse primer.
G and C denote alleles.
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Fig. 1 – Genotyping for the IL-18 position -607 (a) and -137 (b) polymorphisms. (a) Genotyping SNP -607 C/A locus in IL-18
gene by PCR-RFLP technique, whose PCR products were followed by MseI (Biolabs, New England) digestion at 37°C for 12
hours, then subjected to electrophoresis 3% agarose gel and stained with ethidium bromide (1%).27 (b) Genotyping SNP -137
G/C locus in IL-18 gene by PCR-SSP technique, whose PCR products are allele specific, subjected to electrophoresis 1.5%
agarose gel and stained with ethidium bromide (1%).27 In the picture, each lane represents an individual. In (1) the PCR
products were amplified with specific primer to G allele (arrow). In (2) the PCR products were amplified with specific primer
to C allele (arrowhead). The fragment that was amplified by specific primers had 261 bp, while an intern control is present
in both assays and amplified a fragment with 446 bp. Thus, if both bands are present in the gel it means that the specific
allele is present (e.g. lane 2 represents the genotype GC).
L, 50bp ladder; 1, PCR product (301bp) without digestion; samples 2 and 4 were genotype as CA (199bp. 101bp. 98bp and 73bp);
sample 3 was genotyped as AA (101bp. 98bp and 73bp) and sample 5 was considered as CC genotype (199 bp and 73 bp).
separately for clinical and epidemiological data as well as for
RA susceptibility and further confirmed using the HDS EpiMax Calculator.31 The -607A and -137G alleles were considered
as risk alleles to RA susceptibility. A P value below 0.05 was
considered significant.
Results
Women were 88.66% of the RA patients and 96.40% of the controls (P > 0.05). Mean age was 54.63 (± 12.48) in patients and
48.00 (± 15.56) years old in controls (P > 0.05). Although in RA
and controls the predominant ethnicity was Euro-Brazilian,
frequency of Afro-Brazilians and Amerindian-Brazilians was
higher in RA patients than in controls (P = 0.027) (Table 2).
The allele, genotype and haplotypes frequencies of IL-18
gene polymorphisms were estimated in case and controls.
The allele frequencies were showed in Table 3. The genotype
frequencies distribution for both SNPs were in HWE in RA patients and controls, except for the genotype frequencies for
-137 SNP in controls (P = 0.006) (Table 4). Furthermore, because
we found that the polymorphisms -607 and -137 were in linkage disequilibrium in RA patients and controls (P < 0.001),
both SNPs were analyzed as haplotypes (Table 5). We showed
that the allele, genotype and haplotype frequencies of IL-18
gene were similar in RA patients and controls, and the IL-18
polymorphisms were not associated with the development of
RA (P > 0.05).
Among the prevalence of CVD risk factors in RA patients, it
was observed the presence of hypercholesterolemia (54.95%),
arterial hypertension (56.99%), smoking habit (41.76%), positive
RF (66.27%), and high CRP levels (52.38%) (Table 2). High cholesterol levels and arterial hypertension were not associated
with IL-18 gene polymorphisms. Also, we observed that smok-
ing habit in RA patients have a tendency to be associated with
levels of positive RF (OR = 2.199; 0.739–6.677 95 CI%; P = 0.182),
and CRP high levels (OR = 2.673; 0.961–7.546 95% CI; P = 0.061).
The frequency of smokers was higher among RA patients than
in controls (OR = 1.691; 0.930–3.079 95% CI; P = 0.088), however
not statistically significant. Furthermore, neither RF nor smoking was associated with -607 or -137 polymorphisms. Discussion
This is an important study that analyses for the first time in
a Brazilian population the genetic features of the pro-inflammatory cytokine IL-18, and its role in RA. This cytokine can
be involved in the characteristic inflammatory condition that
causes so many injuries in RA patients.
The genotype frequencies of both -607 and -137 SNPs found
in the present study resemble to other case-control studies
including Caucasian RA patients, such as Polish,32 and Spanish.33 On the other hand, the genotype frequencies found in
Asian studies differ from ours.25,34 Thus, the similarity to the
European population regarding genotype frequencies could
be explained by the high prevalence of Euro-descendants in
our sample, since many immigrants from Europe were settled
in Southern Brazil.35
A Chinese study found that the AA genotype of -607 SNP
confers protection against RA development.25 However, this
study showed no association between both -607 and -137
SNPs of IL-18 gene and susceptibility for RA development. In
the same way, a recent meta-analysis on autoimmune diseases36 concluded that these polymorphisms were not related
to RA development, similar to other studies done in Poland,32
Spain,33 and China.34 The latter study also showed that -607
SNP did not change IL-18 serum levels.34
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Table 2 – Clinical and epidemiological characterization of rheumatoid arthritis patients and controls from Southern
Brazil.
Patients, n (%)
Total, n *
Controls, n (%)
Total, n *
86 (88.65)
54.63 (± 12.48)
69 (75.82)
20 (21.98)
2 (2.20)
38 (41.76)
97
97
91
91
91
91
146 (96.40)
48.00 (± 15.56)
121 (88.32)
15 (10.94)
1 (7.29)
39 (29.77)
151
151
137
137
137
131
50 (54.95)
53 (56.99)
55 (66.27)
44 (52.38)
91
93
83
84
MD
MD
MD
MD
Epidemiological data
Female
Mean age
Euro-Brazilian
Afro-Brazilian
Amerindian-Brazilian
Smoking habit
Clinical data
Hypercholesterolemia
Arterial hypertension
Positive RF
High CRP levels
MD, missing data.
* The n value differs because of data availability.
Table 3 – Allele frequencies of promoter IL-18 polymorphisms (-607C/A and -137G/C) in rheumatoid arthritis patients
and controls.
SNP-607
Allele A
SNP-137
Allele C
RA patients, n = 97(%)
Controls, n = 151(%)
OR (95% CI)
P
43 (44.3)
64 (42.4)
1.064 (0.732–1.547)
0.80
30 (30.4)
44 (29.1)
1.063 (0.703–1.606)
0.84
IL-18,interleukin-18; RA, rheumatoid arthritis; OR, odds ratio; CI, confidence interval.
P < 0.05 was considered significant.
Table 4 – Genotypes frequencies of promoter IL-18 polymorphisms (-607C/A and -137G/C) in rheumatoid arthritis
patients and controls.
-607 Genotypes
CC
CA
AA
(CA+AA) versus CC
HWE
-137 Genotypes
GG
GC
CC
(GC+CC) versus GG
HWE
RA patients n = 97 (%)
Controls n = 151 (%)
OR (95% CI)
P
31 (32)
46 (47)
20 (21)
—
48 (32)
78 (52)
25 (16)
—
—
χ2 = 0.502
1.0 (Ref.)
0.914 (0.497-1.681)
1.164 (0.522-2.593)
0.947 (0.550-1.729)
—
—
—
0.86
0.83
1.00
0.83
0.33
70 (46)
74 (49)
7 (5)
—
—
χ2 = 5.264
1.0 (Ref.)
0.946 (0.540-1.658)
1.556 (0.452-5.365)
0.999 (0.580-1.720)
—
—
—
0.94
0.62
1.00
0.34
0.006
χ2 = 0.149
—
45 (46)
45 (46)
7 (8)
—
χ2 = 0.599
—
IL-18,interleukin-18; RA, rheumatoid arthritis; OR, odds ratio; χ2, chi-square value; CI, confidence interval.
P < 0.05 was considered significant.
The -607CC and -137GG genotypes were considered as reference (OR = 1.0).
Although RA is a disease of complex etiology, it is believed
to be caused by the combination of genetic susceptibility and
several environmental factors such as infections and lifestyle
characteristics, the exact contribution of each of these factors
for RA development in distinct populations are not well understood and need further investigation.3,37
We demonstrated that the IL-18 SNPs were in linkage disequilibrium in RA patients, as it was ever previously shown
by other studies.25,32,33 Also, we found no association of haplotypes with RA susceptibility, in agreement to results from
Spanish34 and Chinese studies.25 Nevertheless, a study from
Poland found a significant decreased number of subjects
with AC/AC and AG/AG diplotypes among RA patients as
compared with controls, suggesting these diplotypes are related to RA development.32 The polymorphisms in the IL-18
promoter gene affect its activity, but this effect depends on
204
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 9 – 2 0 5
Table 5 – Haplotypes frequencies of promoter IL-18 polymorphisms (-607C/A and -137G/C) in rheumatoid arthritis
patients and controls.
Haplotype (-607/-137)
C/G
C/C
A/G
A/C
RA patients 2n = 194(%)
Controls 2n = 302 (%)
OR (95% CI)
P
103 (53)
5 (3)
32 (16)
54 (28)
159 (53)
15 (5)
55 (18)
73 (24)
1.018 (0.698–1.485)
0.512 (0.160–1.534)
0.898 (0.541–1.260)
1.228 (0.798–1.888)
0.99
0.28
0.75
0.38
IL-18,interleukin-18; RA, rheumatoid arthritis; OR, odds ratio; CI, confidence interval.
P < 0.05 was considered significant.
cell types and local cytokine environment. Thus, the interaction between genotype and cellular environment remains to
be evaluated.15
Although dyslipidemia is a controversial factor of CVD in
RA, studies showed that low levels of HDL-cholesterol are common and could contribute for increased CV morbidity in these
patients.8,17,38,39 Dyslipidemia has been associated with high levels of IL-18.20 However, our study showed that high levels of total cholesterol were not associated with the presence of the IL18 SNPs analyzed, which was found by other studies as well.24,40
Arterial hypertension is common among RA patients, but
the cause of this increased prevalence compared with controls is unclear. There are multiple factors that influence blood
pressure, such as obesity, physical inactivity, specific genetic
polymorphisms, and some antirheumatic medications.8,37 Arterial hypertension is associated with increased IL-18 serum
levels,20 and the expression of mRNA of this cytokine in atherosclerotic tissue samples was augmented when the -137GC
polymorphisms and arterial hypertension were both present.41
Furthermore, a study about metabolic risk factors for CVD
found that -137GC genotype confers increased risk of arterial
hypertension development to African women when compared
with -137GG subjects.41 In our study, however, arterial hypertension was not associated with IL-18 polymorphisms, as also
demonstrated by Szeto et al.24
Smoking is a known risk factor for development of RA, and
smokers with RA appear to have higher RF titers and worse
prognosis in terms of disability, radiographic damage, and
treatment response.38 We found no association between smoking habit and the IL-18 polymorphisms, nor between smoking
habit and RF in RA patients (OR = 2.2; P > 0.05), which differs
from data of a recent meta-analysis.38 In the same way, the
presence of RF was not associated with the polymorphisms of
IL-18 gene, as showed by other studies in RA.15,33 High levels of
CRP were more frequent in RA patients who smoke, but this association was not statistically significant (OR = 2.67; P = 0.061).
CRP levels were not associated with IL-18 gene polymorphisms,
similarly to the results of another study.24
Although other studies have demonstrated that expression
of IL-18 gene is higher in RA patients and that this cytokine
might be relevant in the pathogenesis of the disease, we found
that the polymorphisms -607 and -137 of IL-18 gene do not play
a major role in RA susceptibility in our population. In addition,
these polymorphisms are not associated with CVD risk factors
in our RA patients.
IL-18 exhibits pleiotropic activities in RA, with a wide variety of effects that are influenced by the overall cytokine
network. Future studies considering novel genetic markers
within IL-18 or other genes involved in the cytokine network
should be performed to evaluate their relevance in the context of RA and other inflammatory diseases.
Financial support
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento Pessoal de
Ensino Superior (CAPES) and Fundação de Amparo à Pesquisa
e Inovação do Estado de Santa Catarina (FAPESC).
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação
de Aperfeiçoamento Pessoal de Ensino Superior (CAPES) and
Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC). The authors wish to thank the patients
and volunteers for their cooperation, and the colleagues that
helped in this work.
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B, Drozdzik M, Herczynska M. Interleukin-18 promoter
polymorphism in patients with rheumatoid arthritis. Tissue
Antigens. 2006;67(5):415-8.
Rueda B, González-Gay MA, Mataran L, López-Nevot MA,
Martín J. Interleukin-18-promoter polymorphisms are
not relevant in rheumatoid arthritis. Tissue Antigens.
2005;65(6):544-8.
Ying B, Shi Y, Pan X, Song X, Huang Z, Niu Q, et al. Association
of polymorphisms in the human IL-10 and IL-18 genes with
rheumatoid arthritis. Mol Biol Rep. 2011;38(1):379-58.
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Study of Brazilian Populations. Detroit: Wayne State University
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Pan HF, Leng RX, Ye DQ. Lack of association of interleukin-18
gene promoter -607 A/C polymorphism with susceptibility
to autoimmune diseases: a meta-analysis. Lupus.
2011;20(9):945-51.
Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS,
Bertolo MB, et al. 2012 Brazilian Society of Rheumatology
Consensus for the treatment of rheumatoid arthritis. Rev Bras
Reumatol. 2012;52(2):152-74.
Boyer JF, Gourraud PA, Cantagrel A, Davignon JL, Constantin A.
Traditional cardiovascular risk factors in rheumatoid arthritis:
A meta-analysis. Jt, Bone Spine. 2011;78(2):179-83.
Torigoe, DY, Laurindo, IMM. Artrite Reumatoide e Doenças
Cardiovasculares. Rev Bras Reumatol. 2006;46(1):60-6.
Evans J, Collins M, Jennings C, van der Merwe L, Söderström I,
Olsson T, et al. The association of interleukin-18 genotype and
serum levels with metabolic risk factors for cardiovascular
disease. Eur J Endocrinol. 2007;157(5):633-40.
Hernesniemi JA, Anttila K, Nieminen T, Kähönen M, Mononen
N, Nikus K, et al. IL-18 gene polymorphism, cardiovascular
mortality and coronary artery disease. Eur J Clin Invest.
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R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Review article
What a rheumatologist needs to know about yellow fever vaccine
Ana Cristina Vanderley Oliveiraa, Licia Maria Henrique da Motaa,b,*,
Leopoldo Luiz dos Santos-Netob, Pedro Luiz Tauilc
a
Medical Sciences Program, Medical School, Universidade de Brasília (FMUnB), Brasília, DF, Brazil
Department of Internal Medicine, Hospital das Forças Armadas, Brasília, DF, Brazil
c
Tropical Medicine Program, Medical School, Universidade de Brasília (FMUnB), Brasília, DF, Brazil
b
article info
abstract
Article history:
Patients with rheumatic diseases are more susceptible to infection, due to the underlying
Received 2nd December 2011
disease itself or to its treatment. The rheumatologist should prevent infections in those
Accepted 13 December 2012
patients, vaccination being one preventive measure to be adopted. Yellow fever is one of
such infectious diseases that can be avoided. The yellow fever vaccine is safe and effective
Keywords:
for the general population, but, being an attenuated live virus vaccine, it should be avoided
Yellow fever
whenever possible in rheumatic patients on immunosuppressive drugs. Considering that
Yellow fever vaccine
yellow fever is endemic in a large area of Brazil, and that vaccination against that disease
Rheumatic diseases
is indicated for those living in such area or travelling there, rheumatologists need to know
Immunosuppressive agents
that disease, as well as the indications for the yellow fever vaccine and contraindications
to it. Our paper was aimed at highlighting the major aspects rheumatologists need to
know about the yellow fever vaccine to decide about its indication or contraindication in
specific situations.
© 2013 Elsevier Editora Ltda. All rights reserved.
O que o reumatologista deve saber sobre a vacina contra febre amarela
resumo
Palavras-chave:
Os pacientes portadores de doenças reumáticas são mais suscetíveis à infecção, quer seja
Febre amarela
pela própria doença de base ou pelo tratamento empregado. É papel do reumatologista pre-
Vacina contra febre amarela
venir as infecções nesse grupo de pacientes e, dentre as estratégias empregadas, encontra-
Doenças reumáticas
-se a vacinação. No grupo das doenças infecciosas que podem ser prevenidas está a febre
Agentes imunossupressores
amarela. Sua vacina é segura e eficaz na população em geral, mas, assim como as vacinas
contendo organismos vivos atenuados, deve ser evitada sempre que possível em portadores de doenças reumáticas em uso de medicamentos imunossupressores. Sendo a febre
amarela endêmica em grande parte do Brasil, e estando a vacinação contra essa doença
indicada para a população residente em extensa parte do território nacional (além dos viajantes para essas regiões), torna-se essencial que o reumatologista tenha conhecimento da
doença, das indicações e contraindicações da vacina contra a febre amarela. Nosso artigo
tem o objetivo de destacar os principais aspectos que o reumatologista precisa conhecer
* Corresponding author.
E-mail: [email protected] (L.M.H. Mota)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
207
sobre a vacina contra a febre amarela, para decidir por sua indicação ou contraindicação
após avaliação do risco-benefício em situações específicas.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
The treatment of rheumatic diseases has improved over the
years.1 The prescription of immunosuppressive drugs, usually
early or even aggressive, is aimed at reducing and eventually
eliminating disease activity.2 That immune system manipulation inherent to therapy in association with the autoimmune disease dysfunction can increase the risk for infections
in that group of patients.2,3 The risk for severe infections in
that population is two times greater than that in the general
population.1
Vaccination is one of the most effective measures to prevent infectious diseases.2,4 However, the vaccination of rheumatic patients on immunosuppressive therapy requires some
special considerations. Its efficacy can be jeopardized due to
the immune system changes characteristic of those patients.4
In addition, there is the risk of disease activation following
immunization.4,5
Vaccines containing attenuated live organisms should be
avoided whenever possible in rheumatic patients on immunosuppressive drugs.2,4 These vaccines represent an increased
risk to patients who cannot fight infections; in addition, vaccines can lead to manifestations similar to those of primary
disease.2 The yellow fever vaccine is one of such vaccines.2,4
Yellow fever is endemic in a large area of Brazil, the yellow
fever vaccine being indicated for the population living in that
area and for travelers to that area; therefore, rheumatologists
need to know that disease, as well as the indications for the
yellow fever vaccine and contraindications to it. Our paper
was aimed at highlighting the major aspects rheumatologists
need to know about the yellow fever vaccine to decide about
its indication or contraindication in specific situations.
Yellow fever
Yellow fever is an infectious, hemorrhagic, febrile, viral disease, which is noncontagious (it is not transmitted through
contact) and endemic in regions of the Africa and South
America, being caused by a single-stranded RNA virus.6 In
Brazil, since 2009, the Ministry of Health, based on epizootics
occurring in 2008 and 2009, divided the regions according to
their potential of yellow fever transmission into areas with
recommendation for vaccination, previously called endemic
and of transition, and areas without recommendation for vaccination, previously called disease-free areas. The areas with
recommendation for vaccination are as follows: the North
and West-Central Brazilian regions; the states of Maranhão
and Minas Gerais; and part of the states of São Paulo, Piauí,
Bahia, Paraná, Rio Grande do Sul and Santa Catarina.7,8 The
disease is transmitted by the bite of hematophagous mosquitoes of the Culicidae family, especially of the Aedes and Hae-
magogus genera.6 Its transmission comprises two cycles: the
urban and the sylvatic.6 In Brazil, the last urban cases were
identified in 1942. Since then, the disease cases reported have
been of sylvatic transmission.6
Susceptibility to yellow fever is general and neither a
race nor an age group more or less susceptible to the virus
is known.6 The most affected individuals are young males,
because of greater exposure.6 The mean incubation period
ranges from 3–6 days.6
The clinical findings vary from lack of symptoms or shortduration mild fever to a severe and fulminant infection.6,9 In
moderate and severe forms, the following can occur: kidney
and liver failures; heart disorders; hemorrhage; and shock.9
The overall fatality rate ranges from 5%–10%.6 Only 10% of the
cases are estimated to be severe forms, associated with high
fatality rate, ranging from 40%–60% of the cases.6 According to
the Ministry of Health, the mean fatality rate is 52.8%, ranging
from 23%–100%.7
Yellow fever cannot be eradicated because it is a zoonosis.10 Disease outbreaks occur every 5 to 7 years.7 There is
no specific treatment for the disease.6 Regarding the general
measures to be taken, the fight against the Aedes aegypiti
mosquito is one of the major aspects to consider in combating the urban form. Appropriate garbage collection and
water supply, use of larvicides, health education provided by
government institutions, and population awareness to reduce transmission should prevent water stagnation, such as
in flowerpots, gutters or untreated swimming pools. Regarding the urban form, wild areas should be avoided in regions
with recommendation for vaccination if no immunization
was performed in the period from 10 days and 10 years from
the trip.6–8,10 The yellow fever vaccine is the major way to prevent that disease.6
Yellow fever vaccine
The yellow fever 17D vaccine has been available in Brazil
since 1937.10,11 Over 500 million doses have been used worldwide.12 It is considered to be one of the most effective and
safe vaccines in the world.12 It provides protection for at
least 10 years, and even lifelong protection.6,13 Within 30 days
from vaccination, more than 90% of the individuals develop
antibodies against yellow fever.9 About 98%–100% of the individuals vaccinated become immunized.13,14 Nevertheless,
the World Health Organization recommends a booster shot
every 10 years.13
Vaccination should be performed from the age of 9 months
in areas with recommendation for vaccination according to
the Ministry of Health. In situations of epidemic or outbreak,
it should be performed from the age of 6 months.7
The original 17D strain has been developed from 176 passages of the wild Asabi strain in murine and gallinaceous
tissues.13 The vaccines currently used derive from two sub-
208
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
strains, 17DD and 17D204,11,13 which are obtained from 287–
289 and from 235–240 passages, respectively.13 The passages
are aimed at attenuating the virulence of the virus.11 In Brazil,
the vaccine used is the 17DD, produced in Biomanguinhos, an
agency of the Fundação Oswaldo Cruz.6
After immunization, low viremia is detected in half of the
individuals vaccinated.13 There is rapid induction of humoral
response and immunoglobulin M (IgM) can be detected in 7 to
10 days.13 Neutralizing antibody titers as low as 1:10 are sufficient to provide protection.13
The 17D strain is a potent inducer of CD4+ and CD8+ cytotoxic T responses.13 The innate immune system is also involved, because the 17D strain replicates minimally in dendritic cells, and can lead to their apoptosis.13 The toll-like
receptors (TLR) 2, 3, 7, 8 and 9 are stimulated and the IFNα/β/γ, TNF-α and IL-1β levels increase.13,15
Adverse effects
Although safe, the 17DD vaccine still has adverse effects, usually well tolerated. The following effects are considered mild
and usually occur between 2 and 11 days after vaccination:
local pain; inflammation; mild headache; myalgia; back pain;
and transient elevation in transaminases.13,16
Anaphylaxis secondary to yellow fever vaccine is another
relevant effect that occurs at the frequency of 0.9 to 1.8 per
100,000 doses, being attributed to allergy to egg or vaccinerelated gelatin allergy.12,16,17
The most relevant serious adverse effects (SAEs) are the
yellow fever vaccine-associated neurotropic disease (YELAND) and the yellow fever vaccine-associated viscerotropic
disease (YEL-AVD).6,13,18 According to data of the Information
System of the National Immunization Program of the Brazilian Ministry of Health, 1994 adverse effects were reported
from 2000 to 2008, when 101,564,083 doses of the 17DD vaccine were administered.17 The SAEs occurred more frequently
after the administration of the first dose than after revaccination. There were 0.023 cases of anaphylactic shock, 9 cases
of hypersensitivity, and 0.84 episodes of YEL-AND for every
1,000,000 doses. Twenty-six cases of viscerotropic disease
were identified. During that period, there was an increase in
publications on SAEs in Brazil.17
Yellow fever vaccine-associated neurotropic disease (YEL-AND)
The incidence of YEL-AND worldwide is estimated to be between 0.4 and 9.9 for every 100,000 doses.12 It is more frequent
under the age of 6 months, whose incidence varies from 0.5 to
4 cases for every 1,000 vaccines.19 The occurrence of YEL-AND
decreased after suspending vaccination to that age group.20
YEL-AND might manifest as encephalitis, meningitis, neuropathy, myelitis or Guillain-Barré syndrome.12,16,19 Its clinical
findings are typically mild, with complete recovery.19
Yellow fever vaccine-associated viscerotropic disease (YEL-AVD)
In 2001, the first cases of YEL-AVD were reported,18,21,22 although a retrospective analysis indicates its occurrence in
the 1970s.13 In Brazil, the expected frequency is 0.006 to 1.32
cases per 100,000 doses.13 The risk of YEL-AVD increases with
age. The risk for patients aged 60 to 69 years is 4.2 per 100,000
doses, and it might reach 12.6 per 100,000 doses in those over
the age of 75 years.16
It is a severe condition, whose expected fatality rate is
about 60%.13 On average, the symptoms begin four days after
vaccination, the findings being identical to those of the infection by the wild virus.6,23
Studies on YEL-AVD are scarce, because of the small number of cases.13 Most cases reported, except for the outbreak in
Ica, Peru, have been related to different vaccine lots.13,23 Thomas et al.,24 in a systematic review, have estimated between 11.1
and 15.6 SAEs per million doses administered.
The gene sequencing obtained from individuals with YELAVD is identical to that of corresponding vaccine strains.12,23
This suggests that YEL-AVD is more related to host conditions, who cannot control vaccine replication, than to mutations of the vaccine virus.12
Considering those findings, some risk factors for SAEs have
already been identified: advanced age (over 60 years); male
gender; thymectomy; and use of immunosuppressive drugs.13
Yellow fever vaccine and rheumatic patients
Chronic rheumatic patients on immunosuppressive drugs are
more often exposed to infection, and, thus, their immunization has been increasingly studied and recommended.1,4
However, according to current recommendations, the yellow fever vaccine should be avoided or even contraindicated
to that group of patients, because it is an attenuated live virus vaccine with risk for uncontrolled vaccine viral replication.4,13,25,26 The European League Against Rheumatism (EULAR)
recommends that live virus vaccines should be avoided and
their risk should be weighed.4 According to the British Pediatric Rheumatology Group, live virus vaccines are contraindicated to all patients on cytotoxic drugs.27 However, the Brazilian
Immunization Consensus for Children and Adolescents With
Rheumatic Diseases recommends that children and adolescents with rheumatic diseases on immunosuppressive agents
should not receive live virus vaccines, referring specifically
to yellow fever.26 Da Luz states that the vaccine should not
be administered to immunocompromised patients, because
of their high risk of encephalitis.3 Hayes has contraindicated
vaccination to those patients and encouraged the creation of
new vaccines.12 However, there is no specific recommendation regarding rheumatic patients at risky areas, temporarily
or not, and who are susceptible to the disease. Still regarding
rheumatic patients, cases of YEL-AVD have been reported in
patients with systemic lupus erythematosus and rheumatic
polymyalgia.17,22,23 Thus, analysis of the risk of infection and
possible SAEs associated with vaccine in that population is
required.
The immunosuppression degree should be assessed and
varies according to the disease, the immunosuppressive drugs
used, their dose and use duration.26 The disease influences
the intensity of immunodeficiency because it also defines
the dose and duration of treatment.28 There is no consensus
about the minimum dose that causes clinical immunosuppression, and there is little evidence about the immunodeficiency caused by cytotoxic drugs at doses used for rheumatic
diseases.27 Regarding corticosteroids, the use of prednisone at
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
equivalent doses of 10 mg/day has not been associated with
an increase in infection.28 Prednisone doses at equivalent doses of 2 mg/kg/day for more than one week or 1 mg/kg/day for
more than one month are contraindication to live virus vaccines in those patients.27 The British Pediatric Rheumatology
Group admits immunization with live virus in patients with
juvenile idiopathic arthritis who are not on immunosuppressive drugs,27 indicating that immunosuppression can be more
related to therapy than to the underlying disease.
Another factor to be considered is the seroconversion capacity of those patients, which is inversely proportional to
their immunosuppression degree.25 Regarding the immune
response of rheumatic patients, a study has assessed 17 patients with rheumatoid arthritis on biologics, who received
the yellow fever vaccine. Their pre- and post-vaccine IgG and
IgM titers were measured by using a method with sensitivity
and specificity similar to those of the plaque reduction assay
to determine neutralizing antibody titers (gold standard to assess protective immune response). Comparing the antibody
titers of patients and controls, a tendency towards a reduced
response in the group studied was observed, although a statistical analysis could not be performed because of the small
number of patients.29
The only study about the adverse effects in that population has assessed 70 patients with several rheumatic diseases, with a mean age of 46 years, who inadvertently received
the yellow fever vaccine. Of those patients, 16 (22.5%) reported
minor adverse effects, which is in accordance with that expected for the healthy population.30
It is worth noting that, in general, vaccines can be related
to the development of autoimmune diseases. Viral molecular structures can induce the immune activation of cells of
the innate defense system and lead to self-sustained chronic
inflammation.31 The time interval between vaccination and
the occurrence of autoimmunity can vary from days to years,
making its identification difficult.5 There have been reports of
cases in which the yellow fever vaccine has triggered autoimmune diseases, such as multiple sclerosis, transverse myelitis and Kawasaki disease.32–34 Cases of autoimmune hepatitis
and of multiple evanescent white dot syndrome have been
reported in association with hepatitis A vaccination.35,36 Infections and immunizations can also promote immunomodulation, leading to a reduction in the exacerbated inflammatory
activity.31 Regulatory T cells activated in that process can be
investigated in the control of inflammation and autoimmunity.31 Similarly to that which happens with allergic diseases,
the “hygiene hypothesis” suggests that the relative absence
of infections would account for the increasing incidence of
autoimmune diseases.31
209
So what to do with patients living in endemic areas, close
to the wilderness or who are exposed during work?
There are no other studies assessing the response to yellow
fever vaccination or its adverse effects in rheumatic patients
on immunosuppressive drugs. Due to ethical reasons, that vaccine cannot be administered to those patients for scientific
research purposes. In addition, conclusive results can only be
yielded after assessing a large number of patients, because adverse effects seem to be rare, even in that population. To assess the cost-benefit ratio, the risk of contracting the infection
should be compared with the risk of contracting the disease.25
The immunosuppressive dose used is fundamental to
support the physician’s decision. According to the American Academy of Pediatrics, prednisone at equivalent doses
of 2 mg/kg/day or 20 mg/day or greater doses contraindicate
vaccination with live virus vaccines (Varicella Zoster).38 The
Brazilian Immunization Consensus for Children and Adolescents With Rheumatic Diseases of the Brazilian Society of
Rheumatology, when considering the yellow fever vaccine,
states that rheumatic patients should not receive live virus
vaccines, a type of vaccine that is usually contraindicated in
immunosuppressed individuals.26
In specific cases, a window of opportunity can exist before
starting the immunosuppressive drugs, when the live virus
vaccines can be administered.27 According to the British Society of Rheumatology, vaccination should occur two weeks
before beginning the treatment.27 According to that same
group, at least three months should be waited for immunization with those vaccines.27 Specialists advocate the risk/benefit analysis for patients on corticosteroids and/or cytotoxic
drugs. The EULAR specialists state that those vaccines should
be avoided, but the risks and benefits should be considered.
It is up to the assistant physician to instruct patients about
the areas with recommendation for vaccination, epidemics
and outbreaks, as well as to assess the individualized risk of
infection and the immunosuppression degree of each patient
so that the yellow fever vaccine can be properly indicated.
Financial support
The author Ana Cristina Vanderley Oliveira has a CAPES-CNPq grant.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES
Final considerations
The current recommendation is that patients on immunosuppressive drugs should not be vaccinated against yellow
fever.2,4 The vaccine with the inactivated virus is being developed and has shown good protective immune response in
murines.37 However, the occurrence of periodical outbreaks
enables the appearance of new cases before the vaccine is
available for the population.
1. Glück T, Müller-Ladner U. Vaccination in patients with
chronic rheumatic or autoimmune diseases. Clin Infect Dis.
2008;46(9):1459-65.
2. Kavanaugh A. Infection prophylaxis in antirheumatic
therapy: emphasis on vaccination. Curr Opin Rheumatol.
2009;21(4):419-24.
3. da Luz KR, de Souza DCC, Ciconelli RM. Vacinação em
Pacientes Imunossuprimidos e com Doenças Reumatológicas
Autoimunes. Revis Bras Reumatol. 2007;47(2):106-13.
210
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
4. van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF,
Dougados M, et al. EULAR recommendations for vaccination
in adult patients with autoimmune inflammatory rheumatic
diseases. Ann Rheum Dis. 2011;70(3):414-22.
5. Dell’Era L, Esposito S, Corona F, Principi N. Vaccination
of children and adolescents with rheumatic diseases.
Rheumatology (Oxford). 2011;50(8):1358-65.
6. Vasconcelos PF. Yellow Fever. Rev Soc Bras Med Trop.
2003;36(2):275-93.
7. Ministério da Saúde. Doenças infecciosas e parasitárias: guia de
bolso. 8 ed. Brasília: Ministério da Saúde; 2010.
8. Ministério da Saúde. 2008 [cited 2011 3 de fevereiro]; Available
from: http://portal.saude.gov.br/portal/arquivos/pdf/nota_fa.pdf.
9. Vellozzi C, Mitchell T, Miller E, Casey CG, Eidex RB, Hayes EB.
Yellow fever vaccine-associated viscerotropic disease (YEL-AVD)
and corticosteroid therapy: eleven United States cases, 19962004. Am J Trop Med Hyg. 2006;75(2):333-6.
10. Tauil PL. Critical aspects of yellow fever control in Brazil. Rev
Saude Publica. 2010;44(3):555-8.
11. Frierson JG. The yellow fever vaccine: a history. Yale J Biol Med.
2010;83(2):77-85.
12. Hayes EB. Is it time for a new yellow fever vaccine? Vaccine.
2010;28(51):8073-6.
13. Barrett AD, Teuwen DE. Yellow fever vaccine – how does it work
and why do rare cases of serious adverse events take place?
Curr Opin Immunol. 2009;21(3):308-13.
14. Monath TP, Cetron MS, McCarthy K, Nichols R, Archambault
WT, Weld L, et al. Yellow fever 17D vaccine safety and
immunogenicity in the elderly. Hum Vaccin. 2005;1(5):207-14.
15. Neves PC, Matos DC, Marcovistz R, Galler R. TLR expression
and NK cell activation after human yellow fever vaccination.
Vaccine. 2009;27(41):5543-9.
16. Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF,
Marano N, et al. Adverse event reports following yellow fever
vaccination. Vaccine. 2008;26(48):6077-82.
17. Martins RM, Maia MLS, Santos EM, Cruz RLS, Santos PG,
Carvalho SMD, et al. Yellow Fever Vaccine Post-marketing
Surveillance in Brazil. Procedia in Vaccinology. 2010;2:178-83.
18. Vasconcelos PF, Luna EJ, Galler R, Silva LJ, Coimbra TL, Barros
VL, et al. Serious adverse events associated with yellow
fever 17DD vaccine in Brazil: a report of two cases. Lancet.
2001;358(9276):91-7.
19. Fernandes GC, Camacho LA, Sa Carvalho M, Batista M, de
Almeida SM. Neurological adverse events temporally associated
to mass vaccination against yellow fever in Juiz de Fora, Brazil,
1999-2005. Vaccine. 2007;25(16):3124-8.
20. McMahon AW, Eidex RB, Marfin AA, Russell M, Sejvar JJ, Markoff
L, et al. Neurologic disease associated with 17D-204 yellow fever
vaccination: a report of 15 cases. Vaccine. 2007;25(10):1727-34.
21. Chan RC, Penney DJ, Little D, Carter IW, Roberts JA, Rawlinson
WD. Hepatitis and death following vaccination with 17D-204
yellow fever vaccine. Lancet. 2001;358(9276):121-2.
22. Martin M, Tsai TF, Cropp B, Chang GJ, Holmes DA, Tseng J, et
al. Fever and multisystem organ failure associated with 17D204 yellow fever vaccination: a report of four cases. Lancet.
2001;358(9276):98-104.
23. Whittembury A, Ramirez G, Hernández H, Ropero AM,
Waterman S, Ticona M, et al. Viscerotropic disease
following yellow fever vaccination in Peru. Vaccine.
2009;27(43):5974-81.
24. Thomas RE, Lorenzetti DL, Spragins W, Jackson D,
Williamson T. Active and passive surveillance of yellow
fever vaccine 17D or 17DD-associated serious adverse
events: systematic review. Vaccine. 2011;29(28):4544-55.
25. Bruyand M, Receveur MC, Pistone T, Verdière CH, Thiebaut R,
Malvy D. Yellow fever vaccination in non-immunocompetent
patients. Med Mal Infect. 2008;38(10):524-32.
26. Silva CAA, Terreri MTRA, Barbosa CMPL, Hilário MOE, Pileggi
GCS, Ferriani VPL, et al. Consenso de imunização para
crianças e adolescentes com doenças reumatológicas. Rev
Bras Reumatol. 2009;49(5):562-89.
27. Davies K, Woo P. Immunization in rheumatic diseases
of childhood: an audit of the clinical practice of British
Paediatric Rheumatology Group members and a review of
the evidence. Rheumatology (Oxford). 2002;41(8):937-41.
28. Cutolo M, Seriolo B, Pizzorni C, Secchi ME, Soldano S,
Paolino S, et al. Use of glucocorticoids and risk of infections.
Autoimmun Rev. 2008;8(2):153-5.
29. Scheinberg M, Guedes-Barbosa LS, Mangueira C, Rosseto
EA, Mota L, Oliveira AC, et al. Yellow fever revaccination
during infliximab therapy. Arthritis Care Res (Hoboken).
2010;62(6):896-8.
30. Mota LM, Oliveira AC, Lima RA, Santos-Neto LL, Tauil
PL. Vaccination against yellow fever among patients on
immunosuppressors with diagnoses of rheumatic diseases.
Rev Soc Bras Med Trop. 2009;42(1):23-7.
31. Cooke A, Ferraccioli GF, Herrmann M, Romani L, Schulze C,
Zampieri S, et al. Induction and protection of autoimmune
rheumatic diseases. The role of infections. Clin Exp
Rheumatol. 2008;26(1 Suppl 48):S1-7.
32. Schmöeller D, Keiserman MW, Staub HL, Velho FP, de Fatima
Grohe M. Yellow fever vaccination and Kawasaki disease.
Pediatr Infect Dis J. 2009;28(11):1037-8.
33. Gout O. Vaccinations and multiple sclerosis. Neurol Sci.
2001;22(2):151-4.
34. Chaves M, Riccio P, Patrucco L, Rojas JI, Cristiano E.
Longitudinal myelitis associated with yellow fever
vaccination. J Neurovirol. 2009;15(4):348-50.
35. Stangos A, Zaninetti M, Petropoulos I, Baglivo E, Pournaras
C. Multiple evanescent white dot syndrome following
simultaneous hepatitis-A and yellow fever vaccination. Ocul
Immunol Inflamm. 2006;14(5):301-4.
36. Perumalswami P, Peng L, Odin JA. Vaccination as a
triggering event for autoimmune hepatitis. Semin Liver Dis.
2009;29(3):331-4.
37. Monath TP, Lee CK, Julander JG, Brown A, Beasley DW, Watts
DM, et al. Inactivated yellow fever 17D vaccine: development
and nonclinical safety, immunogenicity and protective
activity. Vaccine. 2010;28(22):3827-40.
38. American Academy of Pediatrics. Committee of Infectious
Diseases. Red Book. 28.ed. Elk Groove Village, IL; 2009. p.
72–86.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 1 – 2 1 4
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Review article
Update on the treatment of calcinosis in dermatomyositis
Samuel Katsuyuki Shinjo*, Fernando Henrique Carlos de Souza
Service of Rheumatology, Hospital das Clínicas, Medical School, Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil
article info
abstract
Article history:
Calcinosis is a connective tissue disorder classified into the following four types: metastat-
Received 2nd February 2012
ic; idiopathic; iatrogenic and dystrophic. Dystrophic calcinosis can occur, for example, in
Accepted 13 December 2012
dermatomyositis, mainly in juvenile dermatomyositis, and is characterized by an abnormal
deposition of calcium salts in affected skin, subcutaneous tissues, and muscles or tendons,
Keywords:
with normal serum levels of calcium and phosphate. The treatment of calcinosis in der-
Review
matomyositis remains a challenge, with few descriptions in the literature of low scientific
Calcinosis
evidence. So far, no therapy has proved to be highly effective in the combat and resolution
Dermatomyositis
of that comorbidity. The present study discusses the concept of calcinosis, particularly in
Therapy
dermatomyositis, as well as its treatment described in the literature.
© 2013 Elsevier Editora Ltda. All rights reserved.
Atualização na terapêutica da calcinose em dermatomiosite
informações
resumo
Palavras-chave:
Calcinose é uma afecção do tecido conjuntivo classificada em quatro tipos: metastática,
Revisão
idiopática, iatrogênica e distrófica. Esta última é o que acontece, por exemplo, em derma-
Calcinose
tomiosite, principalmente na forma juvenil, e é caracterizada por uma deposição anormal
Dermatomiosite
de sais de cálcio em pele afetada, tecidos subcutâneos, músculos ou tendões, sendo os
Terapêutica
níveis séricos de cálcio e fósforo normais. O tratamento da calcinose em dermatomiosite
continua sendo um desafio, havendo poucas descrições na literatura, de pouca evidência
científica. Não se apresenta, até o momento, nenhuma terapia altamente eficaz no combate
e resolução dessa comorbidade. No presente trabalho, abordamos o conceito de calcinose,
particularmente em dermatomiosite, assim como o seu tratamento descrito na literatura.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Concept of calcinosis
Calcinosis is a connective tissue disorder classified into the
four following types: metastatic; idiopathic; iatrogenic and
dystrophic.1,2 Metastatic calcinosis refers to the deposition
of calcium salts in normal tissues, with increased serum
levels of calcium and/or phosphate, whose product is ≥ 70.1,2
Idiopathic calcification occurs in normal tissues, with normal serum levels of calcium and phosphate.1,2 Iatrogenic
calcinosis includes the hypersensitivity reaction, which
usually begins with livedo reticularis rapidly progressing to
* Corresponding author.
E-mail: [email protected] (S.K. Shinjo)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
212
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 1 – 2 1 4
the formation of skin ulcers and necrosis; it is more commonly reported in patients with chronic renal failure on hemodialysis.1 Dystrophic calcinosis is the abnormal deposition of calcium salts in affected skin, subcutaneous tissue,
and muscles or tendons, with normal serum levels of calcium and phosphate.2,3 Dystrophic calcinosis can occur, for
example, in dermatomyositis (DM).
Calcinosis in dermatomyositis
In patients with DM, calcinosis is much more frequent in the
pediatric age group, being present in 10%–70% of the cases.4–9 In adults, it is reported in about 20% of the patients,10,11
and can precede the diagnosis of DM or even appear years
after that. Usually, calcinosis appears between the first and
third years of the disease.6
In DM, calcinosis can present as follows: (a) hard nodules or plaques in subcutaneous or periarticular regions;
(b) tumors; (c) deposits in the intermuscular fascia, leading to mobility limitation of the affected muscles; (d) severe
dystrophic calcification similar to an exoskeleton; and (e)
mixed form.4 Calcinosis can have a negative impact on the
patients’ quality of life, causing weakness, functional disability, joint contractures, muscle atrophy, skin ulcers, and,
consequently, local pains and secondary infections.
Pathogenesis and risk factors
The etiopathogenesis of calcinosis in DM is unknown. Based
on case reports, calcinosis is believed to result from the intracellular accumulation of calcium secondary to a change
in cell membrane. It can be triggered by trauma and/or
chronic inflammation,12,14–31 such as in cases nonresponsive
to corticotherapy, in the presence of generalized cutaneous
vasculitis, important muscle weakness, and persistent elevation in muscle enzymes.4–6,13–15
The hypothesis of inflammation at the calcinosis site is
plausible, because several authors have shown the presence
of cells and pro-inflammatory cytokines, such as IL-116 and
TNF-alpha,17 and a variety of proteins related to mineralization, such as osteopontin, osteonectin, bone sialoprotein
and hydroxyapatite,18 at the calcinosis site.17 It has also been
associated with the presence of antibodies against the 140
kDa protein19 and with TNF-alpha-308A polymorphism.16
Fisler et al.20 have studied 35 cases and reported an association between calcinosis and a delay in the diagnosis
and/or beginning of treatment, increased muscle enzymes,
and prolonged disease duration. Similarly, Pachman et al.13
have observed calcinosis and a delay in disease diagnosis.
However, Sallum et al.6 have reported the association of the
development of calcified nodules, systemic involvement of
the myopathy and aggressive use of medicaments. Bowyer
et al.4 have shown that inadequate initial therapy plays an
important role in the development of calcinosis. In addition, as previously mentioned, calcinosis is less frequent in
adults with DM, raising the possibility that age-dependent
factors could influence the risk of developing ectopic calcifications.21
Treatment of calcinosis in dermatomyositis
The present study systematically review the treatments reported for calcinosis in DM. A literature search was conducted in
the MEDLINE database by using the following terms: calcinosis
and dermatomyositis.
Except for 14 cases reported as having spontaneous resolution,1–4,9,22–24 calcinosis in DM tends to increase with disease
progression. An early and aggressive therapeutic intervention
against DM activity has been suggested to possibly reduce the
musculocutaneous sequelae of the disease, including calcinosis itself.20
However, so far, no consensus has been achieved about the
effective treatment for calcinosis in DM, and the data available in the literature are based only on reports and/or case
series, particularly in juvenile DM. The use of the following
medications has been mentioned: bisphosphonates; probenecid; warfarin; aluminum hydroxide; colchicine; diltiazem;
and infliximab.
Ambler et al.25 have reported the case of an 8-year-old child
with chronic juvenile DM, whose calcinosis was completely resolved after using alendronate (10 mg/day) for 12 months. The
patient had previously received diltiazem (15 mg, 2x/day) and
probenecid (500 mg, 2x/day), with no resolution of the calcinosis. Similarly, Mukamel et al.26 have reported an improvement
in calcinosis in a 6-year-old patient with juvenile DM by introducing alendronate (10 mg/day) for 12 months.
Mori et al.27 have reported the use of etidronate (800 mg/
day) in a 26-year-old patient with DM, who, in addition to calcinosis, had osteoporosis. Those authors have reported the
regression of calcinosis three months after beginning drug
therapy. In addition, a significant improvement was observed
in densitometric values after a three-year follow-up. Nevertheless, Metzger et al.28 have assessed the effect of etidronate
in three patients with DM and calcinosis for 12 months, no
satisfactory effect being observed.
The use of pamidronate has also been described.29,30 Three
patients with juvenile DM received pamidronate at the dosage of 1 mg/kg/day for three consecutive days, repeated every
month. A satisfactory response was observed in all cases, including one complete resolution of the calcinosis.
Based on the principle that probenecid might reduce the local inflammatory process, it has been used, but the results are
controversial.8,9,31–33
Fuchs et al.34 have described a case of juvenile DM with calcinosis in the prepatellar region, accompanied by inflammation
and localized cutaneous ulcer. An improvement in the cutaneous lesions was observed two months after using colchicine at
the dosage of 1 mg/day.
Based on the theory of having an inhibitory effect on the calcium channels of the cell membrane, diltiazem has proved to
be, mainly in cases of juvenile DM, a therapeutic alternative.35–39
Its dosages have varied from 30–180 mg/day, and that drug was
introduced to patients whose treatments with bisphosphonate and aluminum hydroxide did not succeed. All cases described35–39 showed an excellent response in follow-ups ranging
from 6–10 months.
Miyamae et al.40 have assessed the beneficial effect of thalidomide in one 14-year-old female patient with juvenile DM
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 1 – 2 1 4
for ten years, who had previously undergone pulse therapy
with methylprednisolone, cyclophosphamide, cyclosporine,
azathioprine, probenecid, magnesium hydroxide, aluminum
hydroxide, in addition to infliximab (suspended due to adverse
effects) and etanercept for disease activity and calcinosis progression. Later, at the age of 12 years, thalidomide was introduced (1.3 mg/kg/day, orally, in the first month, and, then, 2 mg/
kg/day), the response being satisfactory.
Older descriptions have evidenced good results with aluminum hydroxide for patients with juvenile DM, no adverse effects being reported.41–44 Nakagawa et al.42 have reported a case
with an almost complete resolution of calcinosis after eight
months of treatment.
Vitamin K plays an important role in calcium binding with
bones and tissues.23 Based on this concept, Berger et al.45 and
Matsuoka et al.46 have used low doses of warfarin to patients
with juvenile DM and nodular calcinosis. Those authors have
reported a reduction in the size of the lesions after using warfarin for three years.
Regression of cutaneous calcinosis following intralesional
infiltration of corticosteroid has been described by Al-Mayouf et
al.47 in a 10.5-year-old patient, preceded by use of methotrexate
and corticosteroid for disease activity. For the calcinosis located
in one of the elbows, colchicine and pamidronate infusion every three months (total of five doses) were unsuccessfully used.
Corticosteroid infiltration using the barbotage technique was
performed, with consequent regression of the calcinosis.
Surgical procedures have been reserved to extensive areas
of calcification,48,49 with incision and local drainage, and have
shown satisfactory results.
In the era of biological therapy, infliximabe has been used at
the dosage of 3 mg/kg (same schedule for rheumatoid arthritis)
to treat five patients with juvenile DM refractory to previously
proposed treatments; all cases had a positive response, with
calcinosis regression in periods ranging from 8–30 months after beginning treatment.50 Arabshahi et al.51 have reported the
use of abatacept (10 mg/kg, monthly, after fortnightly application in the first month) and sodium thiosulfate (topic, initially
at 3%, and, then, at 10%, fortnightly) to a 14-year-old patient
with juvenile DM for three years, refractory to corticosteroid,
tacrolimus and intravenous human immunoglobulin, who had
progressive calcinosis and ulcerated cutaneous lesions. The
therapy instituted determined a reduction in musculocutaneous inflammation and calcinosis regression.
In conclusion, the treatment of calcinosis in both adult
and juvenile DM remains a challenge, with few descriptions in
the literature of low scientific evidence. So far, no therapy has
proved to be highly effective in the combat and resolution of
that comorbidity.
Conflicts of interest
The authors declare no conflicts of interest.
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of juvenile dermatomyositis: a study of composition and
treatment. J Pediatr. 2001;138(5):763–6.
27. Mori H, Okada Y, Yamaoka K, Saito K, Tanaka Y. Marked
improvement of calcinosis in adult dermatomyositis with
etidronate therapy. J Bone Miner Metab. 2012;30(1):114–8.
28. Metzger AL, Singer FR, Bluestone R, Pearson CM. Failure of
disodium etidronate in calcinosis due to dermatomyositis
and scleroderma. N Engl J Med. 1974;291(24):1294–6.
29. Marco Puche A, Calvo Penades I, Lopez Montesinos B.
Effectiveness of the treatment with intravenous pamidronate
in calcinosis in juvenile dermatomyositis. Clin Exp
Rheumatol. 2010;28(1):135–40.
30. Slimani S, Abdessemed A, Haddouche A, Ladjouze-Rezig A.
Complete resolution of universal calcinosis in a patient with
juvenile dermatomyositis using pamidronate. Jt, Bone Spine.
2010;77(1):70–2.
31. Skuterud E, Sydnes OA, Haavik TK. 1981 Calcinosis
in dermatomyositis treated with probenecid. Scand J
Rheumatol. 1981;10(2):92–4.
32. Ansell BM. Treatment of dermatomyositis. Arthritis Rheum.
1977;20:341.
33. Ansell BM. Management of polymyositis and
dermatomyositis. Clin Rheum Dis. 1984;10(1):205–13.
34. Fuchs D, Fruchter L, Fishel B, Holtzman M, Yaron M.
Colchicine suppression of local inflammation due to
calcinosis in dermatomyositis and progressive systemic
sclerosis. Clin Rheumatol. 1986;5(4):527–30.
35. Downey EC, Woolley MM, Hanson V. Required surgical therapy
in the pediatric patient with dermatomyositis. Arch Surg.
1988;123(9):1117–20.
36. Ichiki Y, Akiyama T, Shimozawa N, Suzuki Y, Kondo N,
Kitajima Y. An extremely severe case of cutaneous calcinosis
with juvenile dermatomyositis, and successful treatment
with diltiazem. Br J Dermatol. 2001;144(4):894–7.
37. Jiang X, Yi Q, Liu D, Wang S, Li L. A case of juvenile
dermatomyositis with severe calcinosis and successful
treatment with prednisone and diltiazem Int J Dermatol.
2011;50(1):74–7.
38. Oliveri MB, Palermo R, Mautalen C, Hübscher O. Regression
of calcinosis during diltiazem treatment in juvenile
dermatomyositis. J Rheumatol. 1996;23(12):2152–5.
39. Vinen CS, Patel S, Bruckner FE. Regression of calcinosis
associated with adult dermatomyositis following diltiazem
therapy. Rheumatology (Oxford). 2000;39(3):333–4.
40. Miyamae T, Sano F, Ozawa R, Imagawa T, Inayama Y, Yokota S.
Efficacy of thalidomide in a girl with inflammatory calcinosis,
a severe complication of juvenile dermatomyositis. Pediatr
Rheumatol Online J. 2010;8(1):6.
41. Aihara Y, Mori M, Ibe M, Kuriyama T, Takahashi Y, Shimizu
C, et al. A case of juvenile dermatomyositis with calcinosis
universalis-remarkable improvement with aluminum
hydroxide therapy. Ryumachi. 1994;34(5):879–84.
42. Nakagawa T, Takaiwa T. Calcinosis cutis in juvenile
dermatomyositis responsive to aluminum hydroxide
treatment. J Dermatol. 1993;20(9):558–60.
43. Wang WJ, Lo WL, Wong CK. Calcinosis cutis in juvenile
dermatomyositis: remarkable response to aluminum
hydroxide therapy. Arch Dermatol. 1988;124(11):1721–2.
44. Nassim JR, Connolly CK. Treatment of calcinosis
universalis with aluminium hydroxide. Arch Dis Child.
1970;45(239):118–21.
45. Berger RG, Featherstone GL, Raasch RH, McCartney WH,
Hadler NM. Treatment of calcinosis universalis with low-dose
warfarin. Am J Med. 1998;83(1):72–6.
46. Matsuoka Y, Miyajima S, Okada N. A case of calcinosis
universalis successfully treated with low-dose warfarin. J
Dermatol. 1998;25(11):716–20.
47. Al-Mayouf SM, Alsonbul A, Alismail K. Localized calcinosis
in juvenile dermatomyositis: successful treatment with
intralesional corticosteroids injection. Int J Rheumatic Dis.
2010;13(3):e26–e28.
48. Jashin J, Bradie J, Metz MD. Calcinosis Cutis of Juvenile
Dermatomyositis Treated with Incision and Drainage
Dermatol Surg. 2008;34(4):575–7.
49. Vitale A, Delia G, La Torre F, Calcagno G, D Alcontres FS.
Massive gluteal calcinosis in a 10-year-old girl with juvenile
dermatomyositis: successful surgical management. Plast
Reconstr Surg. 2009;124(6):456e–8e.
50. Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ, Pilkington
CA. Effectiveness of infliximab in the treatment of refractory
juvenile dermatomyositis with calcinosis. Rheumatology
(Oxford). 2008;47(6):877–80.
51. Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept
and sodium thiosulfate for treatment of recalcitrant juvenile
dermatomyositis complicated by ulceration and calcinosis. J
Pediatr. 2012;160(3):520–2.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 5 – 2 1 8
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Case report
Chondrolysis of the hip in an adolescent: clinical and
radiological outcomes
Ana Paula Sakamotoa, Larissa Lucati Ramosb, Artur da Rocha Corrêa Fernandesc,
Maria Teresa Terreria,*
a
Pediatric Rheumatology Sector, Department of Pediatrics, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil
Department of Pediatrics, Santa Casa de Misericórdia de São Paulo (SCMSP), São Paulo, SP, Brazil
c
Imaging Diagnosis Department, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil
b
article info
abstract
Article history:
Idiopathic chondrolysis of the hip is a rare condition of unknown etiology characterized by
Received 26 April 2011
progressive destruction of the hyaline cartilage that covers the femoral head and acetabu-
Accepted 13 December 2012
lum. Idiopathic chondrolysis of the hip has an insidious beginning and affects more often
female adolescents. Patients report severe hip pain, mobility limitation, and even claudi-
Keywords:
cation. This study aimed at reporting one case of that rare disease: an 11-year-old female
Hip
adolescent with chondrolysis, followed up for three years. Inflammatory activity tests were
Adolescent
normal. Imaging tests (radiography, ultrasonography and magnetic resonance) were essen-
Child
tial for the diagnosis. The treatment was based on pain control and preservation of the
Idiopathic chondrolysis of the hip
joint mobility, and included low-impact physical activity, non-steroidal anti-inflammatory
drugs, and disease-modifying antirheumatic drugs, with good response after 12 months of
treatment. Surgery was not necessary.
© 2013 Elsevier Editora Ltda. All rights reserved.
Condrólise de quadril em uma adolescente: evolução clínica e radiológica
resumo
Palavras-chave:
A condrólise idiopática de quadril é uma condição rara, caracterizada por destruição pro-
Quadril
gressiva da cartilagem articular da cabeça do fêmur e do acetábulo, sem etiologia conheci-
Adolescente
da. A CIQ tem início insidioso e acomete com maior frequência meninas na adolescência.
Criança
Os pacientes apresentam dor intensa em quadril, restrição de movimentação e até claudi-
Condrólise idiopática de quadril
cação. O objetivo do trabalho foi demonstrar um caso dessa doença rara: uma adolescente
de 11 anos de idade, com condrólise, em acompanhamento por três anos. As provas de
atividade inflamatória eram normais. Os exames de imagem (radiografia, ultrassonografia
e ressonância magnética) foram essenciais para o diagnóstico. O tratamento baseou-se no
controle da dor e preservação da mobilidade articular, incluindo atividades físicas de baixo
impacto, anti-inflamatórios não hormonais e droga modificadora de doença, com boa resposta após um ano de tratamento. Intervenção cirúrgica não foi necessária.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
* Corresponding author.
E-mail: [email protected] (M. T. Terreri)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
216
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 5 – 2 1 8
Introduction
Idiopathic chondrolysis of the hip (ICH) is a rare condition
of unknown etiology characterized by narrowing of the joint
space caused by the progressive destruction of the hyaline
cartilage that covers the femoral head and acetabulum.1
In the literature, the description of ICH in the pediatric age
group is rare, being mostly restricted to case reports.2–6 Chondrolysis can occur as an apparently idiopathic event or be secondary to other hip pathologies.7
The most common causes of secondary chondrolysis are
as follows: prolonged immobilization; neoplasias; Legg-CalvéPerthes disease (avascular necrosis of the femoral head); trauma; septic arthritis; juvenile idiopathic arthritis (JIA); Stickler
syndrome; and slipped upper femoral epiphysis.
Idiopathic chondrolysis of the hip most frequently affects
female adolescents (80%) of Asian or African ethnicity, and is
more commonly monoarticular (60% affects the right side).3,8
Bilateral ICH occurs in 5% of the cases.3,8 It is clinically characterized by severe pain in the hip, knee or the entire lower
limb, mobility limitation, and claudication. Shortening of the
limb might result.
The differential diagnosis of ICH is difficult to be made,
mainly with JIA. However, ICH lacks systemic symptoms and
has normal laboratory findings (hematological, microbiological, immunological, and acute phase markers).7 In addition, the
sole involvement of the hip joint is not frequent in JIA.
In juvenile ICH, the radiological images are useful to exclude secondary causes.3 Magnetic resonance imaging plays an
important role in the diagnosis and follow-up of that disease.8,9
Some authors have speculated on a genetic and hormonal
(girls) etiology, but such hypotheses have not yet been confirmed.10,11 Morrissy et al.12 have suggested that ICH, similarly
to slipped upper femoral epiphysis, could represent a seronegative type of immune response, because its joint space
narrowing is similar to that of JIA.12 Other authors have demonstrated that antibodies and immune complexes in the
synovial fluid could play an important role in the development of chondrolysis.13–16 Thus, although the treatment is still
Fig. 1 – Initial frontal radiography of the pelvis (Lauenstein,
frog view). Osteopenia of the left hip and mild joint space
narrowing can be seen.
debated and literature evidence lacks, non-steroidal antiinflammatory drugs and disease-modifying antirheumatic
drugs are used. The use of biologics, such as anti-TNF-alpha
agents, has been limited to a case report.10
In severe cases, when there is no response to clinical treatment, cutaneous traction can be used, in addition to surgery.
The major indications of those procedures are improvement of
pain and of the hip range of motion, and correction of the deformity.10 The surgical treatment includes capsulectomy with
or without psoas and/or adductor tenotomy, hip arthrodesis
and arthroplasty, but the results are not promising.11,17 Physical
therapy is an important measure in the treatment. According
to the literature, remission occurs in 54% of the cases.9
Because of the scarcity of reports on ICH in the pediatric
age group, we describe the case of an 11-year-old female adolescent.
Case report
The patient is an 11-year-old white female, complaining of pain
in the left hip and claudication after physical exercise for one
month and a half. She denied infections and/or trauma. She
used a non-steroidal anti-inflammatory drug for one month
with no improvement. She also denied involvement of other
joints. The osteoarticular exam revealed pain and limitation to
external and internal rotation of the left hip joint and limping gait. Her laboratory tests showed normal complete blood
count, erythrocyte sedimentation rate of 10 mm in the first
hour, normal C-reactive protein, and a negative antinuclear
antibody result. The diagnostic hypothesis of chronic arthritis
of the left hip was suggested. Naproxen (500 mg/day – 12 mg/
kg/day) was introduced and slit lamp examination performed,
resulting normal. The tuberculin skin test was negative.
The hip radiography (postero-anterior and Lauenstein
views) showed mild joint space narrowing and mild osteopenia to the left (Fig. 1). Ultrasonography of the hip showed
synovial thickening and joint effusion to the left. On scintigraphy, increased enhancement of the left hip was observed.
Magnetic resonance imaging showed joint effusion in the left
hip, a small area of 8 mm of hyposignal in T1 and hypersignal
in T2 compatible with subchondral edema related to inflammatory process, with no cartilaginous lesion (Fig. 2).
The diagnostic hypotheses were as follows: JIA; avascular necrosis; and chondrolysis. There was no response to
naproxen, which was replaced with indomethacin (50 mg/
day – 1.2 mg/kg/day). After one month with no improvement,
oral methotrexate (15 mg/week – 0.25 mg/kg/week) was introduced. Indomethacin was maintained, and motor physical
therapy and swimming were initiated.
After five months, the patient returned to consultation
with persistent pain, and reported not using methotrexate for
two months. The physical therapy and swimming were maintained. Her physical exam was unaltered. Three months after
reintroducing methotrexate, the patient returned to consultation reporting pain on physical exertion and claudication after that. The methotrexate dose was increased to 20 mg, once
a week, subcutaneously (0.4 mg/kg/week), the physical therapy and swimming were maintained, and new tests requested.
Six months after reintroducing methotrexate, the patient was
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 5 – 2 1 8
217
Fig. 2 – Initial magnetic resonance imaging of the left hip. Coronal plane, T1- and T2-weighed fast spin-echo sequence
showing moderate joint effusion and a small area with hyposignal in T1 and hypersignal in T2 (arrow), compatible with
subchondral edema.
asymptomatic, with no claudication. On physical exam, mild
limitation of her left hip mobility was observed.
Twelve months later and 24 months of disease progression, the patient, on regular use of methotrexate, remained
asymptomatic with no limitation of her left hip mobility. Her
hip ultrasonography was normal. Her left hip magnetic resonance imaging showed mild lateral subchondral thinning,
with no edema, and small effusion to the left in T2, showing
an improvement as compared with the previous exam. Slow
and progressive reduction in the methotrexate dose was initiated. After three months, the patient returned to consultation, with no complaints and denying claudication; her physical exam showed no changes. After four more months with
no complaints, methotrexate was suspended. The patient is
well. After a 12-month follow-up with no medication, her left
hip magnetic resonance imaging showed a small amount of
synovial fluid and subchondral and coxofemoral thinning in
the posterosuperior portion of her hip (burden area), in addition to mild subchondral edema.
Discussion
We report the case of a female adolescent with chondrolysis,
whose initial complaint was chronic pain in the left hip with
claudication. She reported no history of trauma, and had limitation of her hip mobility and normal laboratory tests. After
receiving methotrexate and undergoing physical therapy, she
improved. Her disease is currently under remission with no
medication.
According to the literature, ICH usually manifests as hip
pain and/or radiated pain to the knees.2 The diagnosis is clinical
and radiographic.1 Our patient had monoarticular involvement
of the hip, as frequently described in the literature.6 In addition, hers is the most frequently reported joint impairment in a
female adolescent.3 Functional limitation and limb shortening
might lead to claudication, if the diagnosis and treatment are
delayed, which was not the case of our patient.4,12
The patient’s radiological findings were joint space narrowing and osteopenia. The following radiographic changes
of ICH are described in the literature: joint space narrowing;
acetabular protrusion; subchondral cysts; joint erosion; premature closure of the growth plate; and lateral increase of the
femoral head.3,6,8,9,12
The patient’s ultrasonography of the hip showed synovial
thickening and joint effusion. The magnetic resonance imaging findings of ICH included early subchondral edema, joint
effusion and bone marrow edema; on the progression, focal
loss of the cartilage, muscle mass loss and acetabular and
femoral remodeling occur.7–9
The diagnosis of ICH is difficult, requiring the exclusion
of inflammatory diseases that progress with monoarthritis.4,8 The most important differential diagnosis is with JIA,
the most frequent chronic arthritis of childhood. However,
JIA is hardly ever restricted to the hip, usually affecting other
joints.18 In addition, the patient had neither laboratory test
changes (acute phase markers or presence of autoantibodies)
nor extra-articular manifestations, such as iridocyclitis. In JIA,
the magnetic resonance imaging shows hypervascular synovial thickening (synovial enhancement), reflecting intense inflammatory activity.8 Avascular necrosis of the femoral head,
epiphysiolysis and neoplasia were excluded based on imaging
tests. Trauma as a cause of chondrolysis was also ruled out
because of the long duration of the symptoms and progression of the findings. Infectious causes, such as tuberculosis,
should also be excluded.
Van der Hoeven et al.4 have reported the presence of antinuclear antibodies, immune complex deposition and immune
disorders in some patients, physiopathological factors of ICH
similar to those of JIA. That fact can justify the treatment with
drugs usually used to treat JIA, although the literature lacks
evidence of good response.
The treatment is based on controlling the progression of
the disease and its symptoms, for whose relief non-steroidal
anti-inflammatory drugs are recommended. Disease-modifying antirheumatic drugs, such as methotrexate, are used in
218
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 5 – 2 1 8
the absence of response to anti-inflammatory drugs, as was
the case of our patient.10 Physical therapy and low-impact
physical activities are additional measures that should be
associated to drug treatment. Despite the poor adhesion to
treatment initially, our patient had a good response in the
nine months following methotrexate reintroduction. Increasing the methotrexate dose was necessary to achieve that good
response. There was complete reversion of the findings, similarly to that reported in other studies.2,10 We believe that the
early diagnosis and treatment, and the rapid institution of
physical therapy were important factors for success.
In addition, the favorable clinical and radiological outcomes prevented the need for surgery. In a case series of 14
adolescents with chondrolysis, about 70% required surgery.19
Of the 14 adolescents assessed, 4 (28%) had a poor outcome.19
Idiopathic chondrolysis of the hip should be considered in
the differential diagnosis of the monoarticular involvement
of the hip. Sequelae, such as an expressive reduction in the
joint cartilage or changes in limb size, can be prevented with
early treatment.3
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES
1. Bruschini S. Ortopedia Pediátrica. 2.ed. São Paulo: Atheneu; 1998.
2. François J, Mulier M. Idiopathic chondrolysis of the hip: a case
report. Acta Orthop Belg. 2007;73(5):653–7.
3. Hughes AW. Idiopathic chondrolysis of the hip: a case
report and review of the literature. Ann Rheum Dis.
1985;44(44):268–72.
4. Van der Hoeven H, Keessen W, Kuis W. Idiopathic
chondrolysis of the hip - a distinct clinical entity? Acta
Orthop Scand. 1989;60(6):661–3.
5. Rachinsky I, Boguslavsky L, Cohen E, Hertzanu Y, Lantsberg S.
Bilateral idiopathic chondrolysis of the hip: a case report. Clin
Nucl Med. 2000;25(12):1007–9.
6. Mounach A, Nouijai A, Ghozlani I, Ghazi M, Bezza A, Achemlal
L, et al. Idiopathic chondrolysis of the hip – case report. Jt,
Bone Spine 2007;74(6):656–8.
7. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of
Pediatric Rheumatology. 6.ed. Philadelphia: Elsevier; 2011.
8. Johnson K, Haigh SF, Ehtisham S, Ryder C, Gardner-Medwin J.
Childhood idiopathic chondrolysis of the hip: MRI features.
Pediatr Radiol. 2003;33(3):194–9.
9. Laor T, Crawford AH. Idiopathic chondrolysis of the
hip in children: early MRI findings. Am J Roentgenol.
2009;192(2):526–33.
10. Appleyard DV, Schiller JR, Eberson CP, Ehrlich MG. Idiopathic
chondrolysis treated with etanercept. Orthopedics.
2009;32(3):214–7.
11. Korula RJ, Jebaraj I, David KS. Idiopathic chondrolysis of the
hip: medium to long-term results. ANZ J Surg. 2005;75(9):750–3.
12. Morrissy RT, Steele RW, Gerdes MH. Localized immune
complexes and slipped upper femoral epiphysis. J Bone Joint
Surg Br. 1983;65(5):574–9.
13. Eisenstein A, Rothschild S. Biochemical abnormalities
in patients with slipped capital femoral epiphysis and
chondrolysis. J Bone Joint Surg Am. 1976;58(4):459–67.
14. Herman JH, Herzig EB, Crissman JD, Dennis MV, Hess EV.
Idiopathic chondrolysis – an immunopathological study. J
Rheumatol. 1980;7(5):694–705.
15. Joseph B, Pydisetty RK, Chondrolysis and the stiff hip in
Perthes´disease: an immunological study. J Pediatr Orthop.
1996;16(1):15–9.
16. Yoshioka Y, Shichikawa K. Autoimmunity and chondrolysis of
the hip. A report of two cases. Int Orthop. 1987;11(3):289–93.
17. Abril JC, Ferrer A, Castillo F, Ferrer-Torrelles M. An
intraarticular hip process with chondrolysis simulating
Perthes disease: a report of five cases. J Pediatr Orthop.
2000;20(6):729–35.
18. Houghton KM. Review for the generalist: evaluation of
pediatric hip pain. Pediatr Rheumatol Online J. 2009;7:10–9.
19. Bilski P, Snela S. Difficulties in treating chondrolysis and
avascular necrosis of the hip in adolescent patients. Ortop
Traumatol Rehabil. 2006;8(1):34–40.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 9 – 2 2 2
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Case report
Mesenteric vasculitis in a juvenile systemic lupus
erythematosus patient
Adão F. Albuquerque-Nettoa, Erica G. Cavalcanteb, Adriana M. E. Sallumc,
Nádia E. Aikawab, Uenis Tannurid, Clovis Artur Almeida da Silvab,*
a
Faculdade de Ciências Médicas e da Saúde, Pontifícia Universidade Católica de São Paulo (FCMS-PUC-SP), São Paulo, SP, Brazil
Pediatric Rheumatology Unit, Department of Clinical Medicine, Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina,
Universidade de São Paulo (ICr-HC-FMUSP), São Paulo, SP, Brazil
c
Department of Pediatrics, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
d
Pediatric Surgery Unit, Department of Surgery, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
b
article info
abstract
Article history:
Lupus mesenteric vasculitis (LMV) is a rare cause of acute abdominal pain. Few cases of
Received on 16 May 2011
LMV have been reported in adults, children and adolescents. However, to our knowledge,
Accepted on 13 December 2012
the prevalence of that severe vasculitis in a pediatric population with lupus is yet to be
studied. This study reviewed data from 28 consecutive years and included 5,508 patients
Keywords:
being followed up at the hospital of the Faculdade de Medicina of the Univesidade de São
Vasculitis
Paulo (FMUSP). We identified 279 (5.1%) patients meeting the American College of Rheuma-
Adolescent
tology classification criteria for the diagnosis of systemic lupus erythematosus (SLE), one
Cutaneous lupus erythematosus
of whom (0.4%) had LMV. That male patient was diagnosed with SLE at the age of 11 years.
At the age of 13 years, he was hospitalized with diffuse and acute abdominal pain, nausea,
bilious vomiting, abdominal distension, rebound tenderness, and abdominal muscle guarding. The patient underwent laparotomy immediately, and segmentary intestinal ischemia
with intestinal wall edema and adhesions were identified. Partial small bowel resection
with lysis of the adhesions was performed, as were pulses of intravenous methylprednisolone. The histopathologic analysis evidenced mesenteric arteritis. After 13 days, the diffuse
and intense abdominal pain recurred, and the patient underwent a new laparotomy, during which adhesive small bowel obstruction with intestinal gangrene was identified. New
intestinal resection was performed, and the patient received pulses of intravenous methylprednisolone and infusion of immunoglobulin. Thus, LMV is a rare and severe abdominal
manifestation of the pediatric population with lupus, and can be the only manifestation of
disease activity. In addition, this study stresses the importance of the early diagnosis and
immediate treatment.
© 2013 Elsevier Editora Ltda. All rights reserved.
* Corresponding author.
E-mail: [email protected] (C.A.A. da Silva)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.
220
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 9 – 2 2 2
Vasculite mesentérica em paciente com lúpus eritematoso sistêmico juvenil
resumo
Palavras-chave:
A vasculite mesentérica lúpica (VML) é uma rara causa de dor abdominal aguda. Há poucos
Vasculite
relatos de caso demonstrando VML em adultos e, particularmente, em crianças e adoles-
Adolescente
centes. No entanto, para o nosso conhecimento, a prevalência dessa grave vasculite em uma
Lúpus eritematoso cutâneo
população pediátrica com lúpus ainda não foi estudada. Portanto, dados de 28 anos consecutivos foram revisados e incluídos 5.508 pacientes em seguimento no Hospital da Faculdade de Medicina da Univesidade de São Paulo (FMUSP). Identificamos 279 (5,1%) casos que
preencheram critérios de classificação diagnóstica do American College of Rheumatology
para lúpus eritematoso sistêmico (LES) e um (0,4%) desses apresentou VML. Este paciente
recebeu diagnóstico de LES aos 11 anos de idade. Aos 13 anos foi hospitalizado com dor
abdominal difusa e aguda, náuseas, vômitos biliosos, distensão e rigidez abdominal, com
descompressão brusca positiva. O paciente foi prontamente submetido à laparotomia exploradora, identificando isquemia intestinal segmentar, com edema de parede intestinal e
aderências. Foi realizada ressecção parcial de intestino delgado, com lise das aderências e
pulsoterapia com metilprednisolona. A análise histopatológica identificou arterite de vasos
mesentéricos. Após 13 dias, apresentou recorrência de dor abdominal difusa intensa, sendo
novamente submetido à laparotomia exploradora, identificando obstrução em intestino
delgado por aderências, com gangrena intestinal. Nova ressecção intestinal foi realizada,
além de pulsoterapia com metilprednisolona e infusão de imunoglobulina. Portanto, VML é
uma rara e grave manifestação abdominal na população com lúpus pediátrico, e pode ser a
única manifestação de atividade da doença. Além disso, este estudo reforça a importância
do diagnóstico precoce e do tratamento imediato.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Case report
Systemic lupus erythematosus (SLE) may affect multiple organs and systems, such as gastrointestinal involvement.1,2
Digestive tract manifestations in SLE patients are generally
caused by treatment related to adverse events, infections,3
and disease activity.2,4
Of note, lupus mesenteric vasculitis (LMV) is a cause of
acute abdominal pain, associated with nausea, vomiting,
diarrhea in SLE patients usually with disease activity.4 The
diagnosis of LMV requires the evaluation of bowel wall and
the abdominal vasculature by image examination,4 such as
abdominal ultrasound,3,5,6 computer tomography scan,3,7,8
magnetic resonance image,6 digital arteriography,8 and/or
particularly histopathological findings.4
A few case reports have demonstrated LMV in adult
SLE7,8,10 and particularly in juvenile SLE (JSLE) patients.5,6,9,10
However, to our knowledge, the prevalence of this severe
vasculitis in paediatric lupus population has not been
studied.
Therefore, from January 1983 to December 2010, 5,508 patients were followed-up at the Paediatric Rheumatology Unit
of the Instituto da Criança, Hospital das Clínicas, Faculdade
de Medicina, Universidade de São Paulo (ICr-HC-FMUSP) and
279 (5%) of them were acquainted to the American College
of Rheumatology (ACR)11 classification criteria for SLE. Only
one (0.4%) of our JSLE patients had LMV, confirmed by the
description of histopathological findings and required intestinal resections. This study was approved by the Local Ethics
Committee of FMUSP.
An 11-year old boy was diagnosed with JSLE based on malar rash, arthritis, pericarditis, psychosis, lymphopenia, and
thrombocytopenia, and positivity of the following autoantibodies: antinuclear antibodies (ANA) 1:1280 (speckled pattern), anti-Sm, and anti-double stranded DNA (anti-dsDNA)
antibodies. At that moment, the SLE Disease Activity Index
2000 (SLEDAI-2K)12 was 19 and he received three pulses of
intravenous methylprednisolone, intravenous cyclophosphamide (500–1,000 mg/m2/month for 24 months) and prednisone (2.0 mg/kg/day), with progressive dose decrease to
7.5 mg/day. At the age of 13, he was hospitalized due to an
acute diffuse abdominal pain, nausea and bilious vomiting.
On physical examination, he had abdominal distension, rebound tenderness and abdominal muscle guarding, compatible with acute surgical abdomen. At that moment, he was
under 7.5 mg/day of prednisone and abdominal ultra-sound
examination showed mild ascites, diffuse distension and
bowel-wall thickening. Laboratory tests showed hemoglobin
13.5 g/L, hematocrit 40%, white blood cell count 5,400/mm3
(72% neutrophils, 21% lymphocytes, 4% eosinophils and 3%
monocyte), platelets 265,000/mm3, proteinuria (0.02 g/24h),
urinalysis – leukocytes 500 high-power field, and erythrocytes 250 high-power field, urea 19 mg/dL (normal range 10–
42), creatinine 0.5 mg/dL (normal range 0.5–0.9), C3 0.86 mg/
dL (normal range 0.5–1.8), C4 0.13 mg/dL (normal range 0.1–
0.4), and amylases 46 U/L (normal < 106 U/L). The erythrocyte
sedimentation rate was 42 mm in the first hour. Immunological tests revealed negative for anti-dsDNA, lupus anticoagu-
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 9 – 2 2 2
lant, and IgG and IgM anticardiolipin antibodies. The patient
immediately underwent a laparotomy and segmental edema
with adhesions and small bowel infarctions were identified. Partial small bowel resection (4 cm vs. 2.5 cm) was performed with lysis of adhesions. The histopathology showed
submucosa edema with a diffuse inflammatory infiltrate of
mononuclear cells, and mesenteric vessels arteritis. At that
moment, his SLEDAI-2K12 was 8 and he received three pulses
of intravenous methylprednisolone. After four days, he was
transferred to out-patient clinic of FMUSP receiving 10 mg/
day of prednisone. Thirteen days later, he had recurrence
of severe and diffuse abdominal pain and distension, with
bilious vomiting and acute diarrhea. A plain radiography of
the abdomen showed diffuse bowel distension with air-fluid
level compatible to partial intestinal occlusion. The patient
was promptly submitted to a new laparotomy which identified adhesive small bowel obstruction with intestinal gangrene. Remarkably, resections of 12 cm vs. 6.5 cm of small
bowel and 12 cm vs. 7 cm of caecum, lysis of adhesions and
terminal ileostomy were also performed. At that moment,
he received three pulses of intravenous methylprednisolone
and a single infusion of intravenous immunoglobulin (2 g/
kg/day), followed by 10 mg/day of prednisone, with rapid recovery and improvement of his gastrointestinal symptoms.
At 13.5 years, loop ileostomy closure was carried out and the
SLEDAI-2K12 was 0. The Systemic Lupus International Collaborating Clinics of the American College of Rheumatology
– Damage Index (SLICC/ACR-DI)13 was 2 and he was receiving prednisone 5 mg/day. No complications after intestinal
resections were observed.
Discussion
We described a case of LMV followed at the tertiary Paediatric University Hospital that evidenced the rare occurrence of
this severe vasculitis as a cause of permanent disease damage. Moreover, this complication required multiple intestinal
resections without late bowel complications.
LMV in adult patients has been reported from 0.2% to
9.7%,3,4,8 with very few cases described in paediatric lupus
population.5,6,10,14 This complication is a life-threatening abdominal manifestation characterized by bowel ischemia, with
high mortality rates up to 50%.3,4,8 Usually, the abdominal pain
triggered by LMV shows a diffuse pattern and is generally
associated with nausea, vomiting, diarrhea, abdominal distension, rebound tenderness and abdominal muscle guarding,3,4,6–8 as observed in this case . In addition, the occurrence
of acute abdomen that required intestinal resections was
rarely reported in lupus adolescent population,14 as also evidenced herein.
The signs and symptoms of LMV are non-specific, and radiological investigations3,4,6,8 or pathological findings3,4,6 are
necessary to confirm the diagnosis. Abdominal ultrasonography can demonstrate small intestinal edema and thickening
of the bowel-wall.3 In fact, the patient’s ultrasound revealed
mild ascites, diffuse distension and bowel-wall thickening.
Remarkably, the LMV histopathology evidences sub-mucosal
edema, diffuse inflammatory infiltrate of mononuclear cells,
and both small vessel arteritis and venulitis.4
221
Generally lupus patients with mesenteric vasculitis have
active disease with high SLEDAI scores,4,7,8 associated with
nephritis,6,7,8 neuropsychiatric involvement,6 and/or hematological abnormalities.7 The presence of LMV with low disease activity was rarely described.6 The pathogenesis of LMV
is unknown, but it is suggested that it involves a vasculitis
with immune-complex deposition and/or intestinal vessels
thrombosis3 leading to mesenteric ischemia.3,4 Autoantibodies, such as antiphospholipid and anti-endothelial cell antibodies, may also contribute in the immunopathogenesis of
this complication.3,4
Of note, LMV requires prompt diagnose and appropriate
treatment with corticosteroids,15 particularly intravenous infusion of methylprednisolone, and immunosuppressive therapy
in non-responsive cases.3,4,6–8 The patient was previously treated with intravenous cyclophosphamide, therefore, we used intravenous immunoglobulin associated with corticosteroid.
Furthermore, as utilized in this present case, early surgical
treatment should be indicated in JSLE patients with extensive
bowel ischemia and/or perforation, reducing the risk of morbidity and mortality.3,4,6 The patient had an additional complication with adhesive small bowel obstruction and intestinal infarction, requiring extensive bowel resections without
any further complications, possible related to low prednisone
dose after the first surgery. Moreover, corticosteroids have already been tested for the prevention of abdominal adhesions
caused by surgical procedures, with limited results.16
In conclusion, LMV should be evaluated in all children and
adolescents with acute abdominal pain and may be an isolated manifestation of lupus activity. This study reinforces the
importance of early diagnosis and prompt treatment for this
severe gastrointestinal vasculitis.
Financial support
FAPESP (grant 08/58238-4 to CAS), CNPQ (300248/2008-3 to
CAS) and Federico Foundation (to CAS).
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES
1. Faco MM, Leone C, Campos LM, Febrônio MV, Marques HH,
Silva CA. Risk factors associated with the death of patients
hospitalized for juvenile systemic lupus erythematosus. Braz
J Med Biol Res. 2007;40(7):993-1002.
2. Campos LM, Omori CH, Lotito AP, Jesus AA, Porta G, Silva CA.
Acute pancreatitis in juvenile systemic lupus erythematosus:
a manifestation of macrophage activation syndrome? Lupus.
2010;19(14):1654-8.
3. Tian XP, Zhang X. Gastrointestinal involvement in systemic
lupus erythematosus: insight into pathogenesis, diagnosis
and treatment. World J Gastroenterol. 2010;16(24):2971-7.
4. Ju JH, Min JK, Jung CK, Oh SN, Kwok SK, Kang KY, et al. Lupus
mesenteric vasculitis can cause acute abdominal pain in
patients with SLE. Nat Rev Rheumatol. 2009;5(5):273-81.
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5. Meyers KE, Pfieffer S, Lu T, Kaplan BS. Genitourinary
complications of systemic lupus erythematosus. Pediatr
Nephrol. 2000;14(5):416-21.
6. Tu YL, Chen LC, Ou LH, Huang JL. Mesenteric vasculitis as
the initial presentation in children with systemic lupus
erythematosus. J Pediatr Gastroenterol Nutr. 2009;49(2):251-3.
7. Chen SY, Xu JH, Shuai ZW, Wang MQ, Wang F, Xu SQ, et al.
A clinical analysis 30 cases of lupus mesenteric vasculitis.
Zhonghua Nei Ke Za Zhi. 2009;48(2):136-9.
8. de Carvalho JF. Mesenteric vasculitis in a systemic lupus
erythematosus patient with a low sledai: an uncommon
presentation. Clinics (São Paulo). 2010;65(3):337-40.
9. Hermann G. Intussusception secondary to mesenteric arteries.
Complication of systemic lupus erythematosus in a 5-year-old
child. JAMA. 1967;200(1):74-5.
10. Tu YL, Yeh KW, Chen LC, Yao TC, Ou LS, Lee WI, et al.
Differences in disease features between childhood-onset and
adult-onset systemic lupus erythematosus patients presenting
with acute abdominal pain. Semin Arthritis Rheum.
2011;40(5):447-54.
11. Hochberg MC. Updating the American College of Rheumatology
revised criteria for the classification of systemic lupus
erythematosus. Arthritis Rheum. 1997;40(9):1725.
12. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus
erythematosus disease activity index 2000. J Rheumatol.
2002;29(2):288-91.
13. Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz
M, et al. The development and initial validation of the
Systemic Lupus International Collaborating Clinics/American
College of Rheumatology damage index for systemic lupus
erythematosus. Arthritis Rheum. 1996;39(3):363-9.
14. Turner HE, Myszor MF, Bradlow A, David J. Lupus or lupoid
hepatitis with mesenteric vasculitis. Br J Rheumatol.
1996;35(12):1309-11.
15. Marinello DK, Rafael D, Paiva Edos S, Dominoni RL. Systemic
lupus erythematosus complicated by intestinal vasculitis and
pneumatosis intestinalis. Rev Bras Reumatol. 2010;50(5):596-602.
16. Attard JA, MacLean AR. Adhesive small bowel obstruction:
epidemiology, biology and prevention. Can J Surg.
2007;50(4):291-300.
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Erratum
The quality of life of patients with lúpus erythematosus
influences cardiovascular capacity in 6-minute walk test
Sandor Balsamoa,b,c,*, Dahan da Cunha Nascimentoc,d, Ramires Alsamir Tibanac,
Frederico Santos de Santanaa,b,c, Licia Maria Henrique da Motaa,
Leopoldo Luiz dos Santos-Netoa
a
Postgraduate Program in Medical Sciences, Medical School, Universidade de Brasília (UnB), Brasília, DF, Brazil
Department of Physical Education, Centro Universitário Euro-Americano (UNIEURO), Brasília, DF, Brazil
c
Research group of strength training and Health (GEPEEFS), Brasília, DF, Brazil
d
Postgraduate Program in Physical Education, School of Physical Education, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil
b
In Table 1, page 84 (Brazilian Portuguese version), where it reads “Esclerose sistêmica (IC 95%)#”, it should read “Diferença entre
médias#”.
Original article: Rev Bras Reumatol. 2013;53(1):75-87.
* Corresponding author.
E-mail: [email protected] (S. Balsamo)
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Editorial
Alexandre e as Diretrizes – a importância da estratégia e as
Diretrizes para diagnóstico e tratamento medicamentoso da
artrite reumatoide
Alexandre, que entraria para a História com o epíteto de “o
Grande”, filho de Felipe e de Olímpia, nasceu na cidade de
Pela, então capital da Macedônia, no ano de 356 a.C. Quando morreu, aos 33 anos, em algum lugar da Babilônia, havia
conquistado todo o mundo até então conhecido – detinha,
entre outros, os títulos de Rei da Macedônia, Rei da Grécia,
Senhor da Ásia, Xá da Pérsia, Faraó do Egito e Hegemônico
da Liga Pan-Helênica. Como seu legado máximo, Alexandre
havia fundido a cultura grega à oriental, formando a base
da posteriormente denominada Civilização Helenística, que
influenciou profundamente diversos aspectos da cultura
ocidental atual.1
E por que falamos de Alexandre, o Grande, em um editorial científico sobre Diretrizes para artrite reumatoide? Porque
Alexandre foi, mais que um grande conquistador, um brilhante estrategista, talvez o maior de toda a História. A palavra
estratégia advém do antigo grego (stratos, “exército”, e ago,
“liderança” ou “comando”), e designava o comandante militar, à época da democracia ateniense. Atualmente, o termo
estratégia pode ser compreendido como uma maneira de planejar o futuro, integrada no processo de tomada de decisão,
considerando-se como base um procedimento formalizado e
articulador de resultados. Usamos assim a figura de um grande estrategista para ilustrar que a elaboração e a publicação
das Diretrizes faz parte da estratégia da Sociedade Brasileira de Reumatologia (SBR) para a disseminação e a implantação de conhecimentos baseados em evidência científica para
diagnóstico e tratamento da artrite reumatoide (AR) no Brasil.
A AR é uma doença sistêmica crônica, geralmente progressiva, que acomete 0,5%–1% da população mundial, e que se
caracteriza pelo comprometimento inflamatório da membrana sinovial, predominantemente das articulações periféricas.
Tratar a dor, impedir ou retardar o dano estrutural articular,
a incapacidade funcional e laboral, além de prevenir a mortalidade precoce dos pacientes acometidos, fazem parte da
luta diária do reumatologista contra essa doença. O sucesso
nessa batalha depende basicamente da adoção de estratégias
adequadas, incluindo o diagnóstico precoce e a instituição de
tratamento adequado o mais cedo possível na história natural
da doença.
A SBR, por meio de sua Comissão de Artrite Reumatoide,
elaborou, ao longo dos últimos dois anos, quatro documentos consensuais que orientam o diagnóstico e o tratamento
da AR no Brasil, incluindo peculiaridades como o manejo das
comorbidades e a vacinação de pacientes imunossuprimidos
pela doença e pelo tratamento.2–5
Os consensos são instrumentos educativos, mais do que
diretrizes normativas, que permitem a seus autores acrescentar dados da experiência e a opinião de especialistas à evidência científica. Se, como publicação, o consenso perde em grau
de recomendação e em força de evidência, ganha como ferramenta educativa ao valorizar a experiência de quem convive
com as dificuldades da prática diária no manejo da doença.6,7
O Projeto Diretrizes, da Associação Médica Brasileira
(AMB) e do Conselho Federal de Medicina, tem por objetivo
produzir orientações diagnósticas, terapêuticas e, quando
aplicável, preventivas, baseadas em evidências científicas,
conciliando informações da área médica a fim de padronizar
condutas que auxiliem o raciocínio e a tomada de decisão do
médico. Os documentos apresentam o grau de recomendação e a força da evidência científica publicada, preservando
em sua elaboração a autonomia dos médicos especialistas
autores dos textos.8
Foi essa então a estratégia da Comissão de Artrite Reumatoide ao elaborar os dois documentos apresentados nessa
edição da Revista Brasileira de Reumatologia – as Diretrizes
para diagnóstico da artrite reumatoide9 e as Diretrizes para
tratamento medicamentoso da artrite reumatoide.10 A elaboração dos textos seguiu de forma criteriosa os preceitos recomendados pela AMB e pelo CFM, e o resultado são respostas
baseadas em evidência para perguntas do tipo: Os novos critérios classificatórios ACR/EULAR 2010 para AR são superiores
aos critérios classificatórios de 1987 na fase inicial da doença?
Os marcadores genéticos (pesquisa dos alelos de HLA-DRB1
– epítopo compartilhado e dos genes PTPN22) são úteis para
a caracterização de pacientes com pior prognóstico da AR?
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138
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 3 7 – 1 3 8
Tratar a doença para atingir a remissão é um alvo factível? O
uso de corticoesteroides na fase inicial da doença melhora o
prognóstico do paciente?
Embora a personalidade e alguns atos de Alexandre
Magno possam ser questionados, estudar o modo como
Alexandre procedia à frente da administração do exército
e as ações levadas a cabo para a conquista da Pérsia e da
Ásia, incluindo as históricas batalhas de Gaugamela, Isso,
Granico e Hidaspes, leva-nos à conclusão do estreito relacionamento entre o sucesso alcançado por Alexandre e
o uso adequado de todo um processo administrativo, formalmente concebido e utilizado para um fim específico, ou
seja, a implementação de estratégias.11 Desejamos que, ao
ler e aplicar as estratégias propostas nas Diretrizes agora
publicadas, nossos colegas reumatologistas, e, em última
análise, seus pacientes, possam ser tão vitoriosos em sua
luta contra a AR como o foi o magnífico estrategista Alexandre em suas muitas batalhas.
“Alexandre, filho de Felipe da Macedônia, oriundo da terra de
Cetim, derrotou também Dario, rei dos persas e dos medos e
reinou em seu lugar. Empreendeu inúmeras guerras, apoderou-se de muitas cidades e matou muitos reis. Avançou até os
confins da terra e apoderou-se das riquezas de vários povos, e
diante dele silenciou a terra.”
Mac 1, 1-3
Licia Maria Henrique da Mota
Faculdade de Medicina, Universidade de Brasília (UnB),
Brasília, DF, Brasil
Comissão de Artrite Reumatoide da Sociedade Brasileira de
Reumatologia
E-mail: [email protected]
Geraldo da Rocha Castelar Pinheiro
Disciplina de Reumatologia, Universidade do Estado do
Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brasil
REFERÊNCIAS
1. Bose P. Alexander the Great’s Art of Strategy. Crows Nest,
N.S.W: Allen & Unwin; 2003.
2. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Fronza LS,
Bertolo MB, et al. 2011 Consensus of the Brazilian Society
of Rheumatology for diagnosis and earlyassessment of
rheumatoid arthritis. Rev Bras Reumatol. 2011;51(3):199-219.
3. da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza
LS, Bertolo MB, et al.; Brazilian Society of Rheumatology.
2012 Brazilian Society of Rheumatology Consensus for
the treatment of rheumatoid arthritis. Rev Bras Reumatol.
2012;52(2):152-74.
4. Pereira IA, Mota LM, Cruz BA, Brenol CV, Fronza LS, Bertolo
MB, et al.; Brazilian Society of Rheumatology. 2012 Brazilian
Society of Rheumatology Consensus on the management
of comorbidities in patients with rheumatoid arthritis. Rev
Bras Reumatol. 2012;52(4):474-95.
5. Brenol CV, Mota LCH, Cruz BA, Pileggi GS, Pereira IA,
Rezende LS, et al. Consenso 2012 da Sociedade Brasileira
de Reumatologia sobre vacinação em pacientes com artrite
reumatoide. Rev Bras Reumatol. 2013;53(1):4-23.
6. da Mota LM. Considerations about the 2011 consensus
of the Brazilian Society of Rheumatology for diagnosis
and early assessment of rheumatoid arthritis. Rev Bras
Reumatol. 2011;51(3):197-8.
7. Mota LM. On mosaics and consensus: Gaudí, Brazil and
rheumatoid arthritis. Ver Bras Reumatol. 2012;52(2):133-4.
8. Projeto Diretrizes. [Accessed on: 22 fevereiro 2013] Available
from: http://www.projetodiretrizes.org.br.
9. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza
LS, Bertolo MB, et al., Sociedade Brasileira de Reumatologia,
Sociedade Brasileira de Pneumologia e Tuberculose, Colégio
Brasileiro de Radiologia. Diretrizes para o diagnóstico da
artrite reumatoide. Rev Bras Reumatol. 2013;53(2):141-57.
10. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza
LS, Bertolo MB, et al., Sociedade Brasileira de Reumatologia.
Diretrizes para o tratamento da artrite reumatoide. Rev
Bras Reumatol. 2013;53(2):158-83.
11. Rodrigues RC. Alexandre, “o Grande”, e a informação para o
planejamento estratégico. Inf Soc. 2007;17(2):74-85.
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Editorial
Síndrome do anticorpo antifosfolipídeo
A síndrome do anticorpo antifosfolipídeo (SAF) é uma doença sistêmica autoimune caracterizada por trombose arterial e
venosa, morbidade gestacional e presença de níveis de anticorpo antifosfolipídeo elevados e persistentemente positivos.1
O tratamento da SAF é cercado de controvérsias, especialmente pela ausência de estudos clínicos de boa qualidade. Na
prevenção primária de trombose, os estudos clínicos apresentam resultados distintos.2,3 O conceito de fatores de risco
associados aos eventos trombóticos e o tipo e o número de
anticorpos antifosfolipídeos positivos são conceitos atuais e
que devem ser levados em conta na decisão terapêutica, seja
medicamentosa ou de mudança de hábitos de vida.
Para prevenção secundária, indica-se a anticoagulação plena por tempo indeterminado, mas o alvo terapêutico ainda é
motivo de discussão. Apesar de estudos retrospectivos sugerirem menor número de recorrências com índice internacional
normalizado (INR) elevado, os estudos prospectivos não corroboram esses achados.4,5 Entretanto, a inclusão de pacientes
com trombose arterial nesses protocolos foi pequena, o que
torna difícil uma conclusão definitiva sobre o INR-alvo nessa
manifestação.
As questões obstétricas também geram discussão: teratogenicidade associada à varfarina6 e esquema posológico da
heparina em pacientes com SAF vascular apresentam poucas
evidências científicas.7
Esforços coletivos internacionais foram criados com o objetivo de desenhar e conduzir estudos prospectivos de boa
qualidade em pacientes portadores de anticorpos antifosfolipídeos, incluindo a criação de um banco de dados multicêntrico.8 Com isso, novas perspectivas se abrem e em um futuro
próximo teremos respostas baseadas em melhores evidências
relativas ao tratamento da SAF, incluindo o uso de hidroxicloroquina para prevenção primária, uso de novos anticoagulantes e terapia biológica.
Diante da necessidade de melhorar o entendimento e o
tratamento, e de estabelecer recomendações para reumatologistas e outros especialistas sobre o manejo da SAF, a comissão da Sociedade Brasileira de Reumatologia (SBR) de SAF
e Vasculopatia, com o apoio da SBR e da Associação Médica
Brasileira (AMB), publica essa diretriz, elaborada a partir da
formulação de nove questões clínicas relevantes e controversas relacionadas ao tratamento da SAF, baseada na melhor
evidência científica disponível.
Finalizada essa primeira publicação, nossa comissão avança para os objetivos traçados para os próximos dois anos:
elaboração e publicação das diretrizes de diagnóstico de SAF
e elaboração e publicação das diretrizes e das cartilhas para
pacientes de Granulomatose com Poliangeite e Arterite de
Takayasu. Além disso, a comissão vem trabalhando junto à
AMB para inclusão na tabela de procedimentos os testes anti-beta2glicoproteína I IgM/IgG, anticardiolipina IgA, antiproteinase 3 e antimieloperoxidase.
Adriana Danowski
Hospital Federal dos Servidores do Estado (HFSE),
Rio de Janeiro, RJ, Brasil
E-mail: [email protected]
Roger A. Levy
Universidade do Estado do Rio de Janeiro (UERJ),
Rio de Janeiro, RJ, Brasil
REFERÊNCIAS
1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL,
Cervera R, et al. International consensus statement on an
update to the classification for definite antiphospholipid
syndrome (APS). J Thromb Haemost. 2006;4:295-306.
2. Tarr T, Lakos G, Bhattoa HP, Shoenfeld Y, Szegedi G, Kiss E.
Analysis of risk factors for the development of thrombotic
complications in antiphospholipid antibody positive lupus
patients. Lupus. 2007;16:39-45.
3. Erkan D, Harrison MJ, Levy RA, Peterson M, Petri M,
Sammaritano L, et al. Aspirin for primary thrombosis
prevention in the antiphospholipid syndrome: a randomized,
double-blind, placebo-controlled trial in asymptomatic
antiphospholipid antibodypositive individuals. Arthritis
Rheum. 2007;56:2382-91.
4. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F,
Musial J, et al. A randomized clinical trial of high-intensity
warfarin vs. conventional antithrombotic therapy for the
prevention of recurrent thrombosis in patients with the
antiphospholipid syndrome (WAPS). J Thromb Haemost.
2005;3:848-53.
5. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J,
Douketis J, et al. A comparison of two intensities of warfarin
for the prevention of recurrent thrombosis in patients with
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the antiphospholipid antibody syndrome. N Engl J Med.
2003;349:1133-8.
6. Levy RA, Jesús GR, Jesús NR. Obstetric antiphospholipid
syndrome: still a challenge. Lupus. 2010;19:457-9.
7. Hunt BJ, Gattens M, Khamashta M, Nelson-Piercy C, Almeida
A. Thromboprophylaxis with unmonitored intermediate-dose
low molecular weight heparin in pregnancies with a previous
arterial or venous thrombotic event. Blood Coagul Fibrinolysis.
2003;14:735-9.
8. APS ACTION – AntiPhospholipid Syndrome Alliance For Clinical
Trials and InternatiOnal Networking. D Erkan, MD Lockshin on
behalf of APS ACTION members. Lupus. 2012;21:695-8.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Documentos de Diretrizes
Diretrizes para o diagnóstico da artrite reumatoide
Guidelines for the diagnosis of rheumatoid arthritis
Sociedade Brasileira de Reumatologia, Sociedade Brasileira de Pneumologia e Tisiologia,
Colégio Brasileiro de Radiologia
Projeto Diretrizes da Associação Médica Brasileira, São Paulo, SP, Brasil
Participantes
Licia Maria Henrique da Mota*, Bóris Afonso Cruz,
Claiton Viegas Brenol, Ivânio Alves Pereira,
Lucila Stange Rezende-Fronza, Manoel Barros Bertolo,
Max Vitor Carioca Freitas, Nilzio Antônio da Silva,
Paulo Louzada-Junior, Rina Dalva Neubarth Giorgio,
Rodrigo Aires Corrêa Lima, Ronaldo Adib Kairalla,
Alexandre de Melo Kawassaki,
Wanderley Marques Bernardo,
Geraldo da Rocha Castelar Pinheiro
C: Relatos de casos (estudos não controlados).
D: Opinião desprovida de avaliação crítica, baseada em
consensos, estudos fisiológicos ou modelos animais.
Objetivo
Estabelecer diretrizes para o manejo da artrite reumatoide no
Brasil, com enfoque no diagnóstico da doença. A finalidade
deste documento é a de sintetizar a posição atual da Sociedade Brasileira de Reumatologia sobre o tema, objetivando
orientar os médicos brasileiros, em especial os reumatologistas, sobre o diagnóstico da artrite reumatoide em nosso país
Elaboração final
12 de abril de 2012
Descrição do método de coleta de evidência
A revisão bibliográfica de artigos científicos dessa diretriz foi
realizada na base de dados MEDLINE. A busca de evidência
partiu de cenários clínicos reais, e utilizou as seguintes palavras-chave (MeSH terms): Arthritis, Rheumatoid, Diagnosis
(Delayed Diagnosis OR Delay OR Early Rheumatoid Arthritis
OR VERA), Prognosis, Criteria (American College of Rheumatology/European League Against Rheumatism OR ACR/EULAR
OR classification), Comparative Study, Smoking (OR tobacco
use disorder), Rheumatoid Factor, Anti-cyclic Citrullinated
Peptide (or anti-CCP), HLA-DRB1 OR PTPN22 OR EPITOPE, extra-articular OR extraarticular OR systemic OR ExRA, Disease Progression, Radiography OR X RAY, ULTRASONOGRAPHY,
MAGNETIC RESONANCE.
Graus de recomendação e força de evidência
A: Estudos experimentais e observacionais de melhor
consistência.
B: Estudos experimentais e observacionais de menor
consistência.
Introdução
A artrite reumatoide (AR) é uma doença inflamatória sistêmica,
crônica e progressiva, que acomete preferencialmente a membrana sinovial das articulações, podendo levar à destruição óssea e cartilaginosa1(D). Registra-se a ocorrência dessa doença
em cerca de 0,5%–1% da população mundial adulta, em todos os
grupos étnicos2(D), predominando no gênero feminino (duas a
três vezes em relação ao gênero masculino). Embora haja registro de AR em todas as faixas etárias, a condição ocorre, sobretudo, em pacientes entre a quarta e sexta décadas de vida3(D).
Estudo multicêntrico brasileiro em amostras populacionais
das macrorregiões do país encontrou prevalência de até 1% da
população adulta4(B), o que corresponderia a uma estimativa
de 1.300.000 pessoas acometidas.
A AR é uma doença crônica, com potencial de dano articular irreversível, acarretando altos custos para o indivíduo acometido
e para a sociedade5(B) 6,7(D).
É inegável que a compreensão da fisiopatogenia da AR, de
seus métodos diagnósticos e do manejo terapêutico sofreram
consideráveis avanços nos últimos anos, destacando-se a importância dada ao período inicial da doença, a chamada AR ini-
* Autor para correspondência.
E-mail: [email protected] (L.M.H. Mota)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
142
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
cial (primeiros 12 meses de sintomas da doença), reconhecidamente uma “janela de oportunidade terapêutica”8(B) 9,10(D).
Apesar desses avanços, os indicadores diagnósticos e prognósticos atuais (clínicos, laboratoriais e radiográficos) têm valor restrito para o diagnóstico precoce e o estabelecimento de
prognóstico individual11(B).
As características demográficas e clínicas da AR são variáveis de acordo com a população acometida12(B). A maior parte das informações disponíveis provém da Europa e Estados
Unidos13,14(D). São poucos os estudos realizados na população
brasileira15,16(B).
A AR acomete pacientes em idade produtiva e pode determinar importantes limitações na capacidade funcional e
perda de capacidade laboral, assim, custos indiretos relacionados a esse contexto devem ser incorporados às análises de
farmacoeconomia17(B).
No Brasil, assim como nos países de primeiro mundo, os
custos relacionados à AR são elevados18(B). Os gastos com os
pacientes com AR assumem maior repercussão nos países
em desenvolvimento, nos quais os recursos financeiros para
a saúde são menos robustos. Isto enfatiza a importância de
estudos que avaliem os custos e a alocação de recursos para
o diagnóstico e o tratamento da doença adaptados à nossa
realidade19(B).
O diagnóstico da AR é estabelecido considerando-se achados clínicos e exames complementares. Nenhum teste isolado, seja laboratorial, de imagem ou histopatológico, confirma
o diagnóstico.
Diversas doenças podem cursar com artrite, fazendo diagnóstico diferencial com a AR20-22(D), conforme mostra a Tabela 1.
Quando a AR se apresenta em sua forma bem-definida, com
todos os achados típicos, o reconhecimento é facilitado. O diagnóstico na fase inicial da doença, contudo, pode ser difícil, já
que alterações sorológicas e radiográficas características muitas vezes estão ausentes23(D).
As manifestações clínicas da AR podem ser divididas em
articulares e extra-articulares. Como é uma doença sistêmica,
sintomas gerais como febre, astenia, fadiga, mialgia e perda
ponderal podem preceder ou acompanhar o início das manifestações articulares24(D).
b)
c)
d)
e)
iniciar e eventualmente persistir como mono ou oligoartrite.
Artrite em mãos e punhos: o acometimento dos punhos,
das metacarpofalangeanas (MCF) e das interfalangeanas
proximais (IFP) é frequente, desde o início do quadro. O acometimento das interfalangeanas distais (IFD) é raro, o que
é útil para diferenciar a AR de outras condições, como a osteoartrite e a artrite psoriásica.
Artrite simétrica: o acometimento simétrico das articulações é comum, embora em se tratando das IFP, das MCF e
das metatarsofalangeanas (MTF), a simetria não necessite
ser completa.
Artrite cumulativa ou aditiva: a artrite costuma ter padrão
cumulativo (acomete progressivamente novas articulações,
sem deixar de inflamar as anteriormente afetadas).
Rigidez matinal: a rigidez matinal prolongada, caracterizada por enrijecimento e sensação de inchaço, percebida
sobretudo pela manhã, é um aspecto quase universal da
inflamação sinovial. Diferente da breve rigidez observada
na osteoartrite (geralmente 5–10 minutos), no caso das doenças inflamatórias a rigidez dura mais de uma hora. Esse
fenômeno está relacionado com a imobilização que ocorre
durante o sono ou o repouso, e não com a hora do dia. A
duração tende a correlacionar-se com o grau da inflamação,
e é um parâmetro que deve ser documentado para acompanhamento da doença25(B) 26(C).
Manifestações extra-articulares
Embora as manifestações articulares sejam as mais características, a AR pode acometer outros órgãos e sistemas. As manifestações extra-articulares mais frequentes incluem quadros
cutâneos, oculares, pleuropulmonares, cardíacos, hematológicos, neurológicos e osteometabólicos. São mais observadas em
pacientes com doença grave e poliarticular, sorologia positiva
Tabela 1 – Diagnóstico diferencial das artrites.
Grupos de doenças
Infecções
Manifestações articulares
As manifestações articulares da AR podem ser reversíveis em
sua fase inicial, porém a sinovite persistente não controlada
determina destruição óssea e cartilaginosa, lesões tendinosas e ligamentares irreversíveis.
A característica básica da manifestação articular da AR é
a inflamação da sinóvia (sinovite), podendo acometer qualquer uma das articulações diartrodiais do corpo.
A queixa clínica é de dor, inchaço e limitação dos movimentos das articulações acometidas. Ao exame físico, observa-se presença de dor, aumento de volume das articulações,
derrame intra-articular, calor e, eventualmente, rubor. Nas
articulações profundas, como os quadris e os ombros, esses
achados podem não ser evidentes24(D).
São características da artrite na AR24(D):
a) Acometimento poliarticular: geralmente mais de quatro
articulações estão envolvidas. No entanto, a doença pode
Espondiloartrites
Doenças reumáticas
sistêmicas
Artrites microcristalinas
Doenças endócrinas
Doenças neoplásicas
Outras
Doenças
Virais (p.ex., dengue, HIV, parvovírus,
citomegalovírus, vírus da hepatite),
bacterianas (p.ex., N. gonorrhoeae,
S. aureus), microbacterianas, fúngicas
e outras
Artrites reativas (C hlamydia,
Salmonella, Shigella, Yersinia),
espondilite anquilosante, artrite
psoriásica, artrites esteropáticas
Lúpus eritematoso sistêmico,
polimiosite/dermatomiosite, esclerose
sistêmica, síndrome de Sjögren,
doença de Behçet, polimialgia
reumática, vasculites sistêmicas e
outras
Gota, doenças por depósito de cristal de
pirofosfato de cálcio ou outros
Hipotireoidismo, hipertireoidismo
Doença neoplásica metastática, linfoma,
síndromes paraneoplásicas e outras
Osteoartrite, hemocromatose,
amiloidose, sarcoidose, doença do soro
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
para fator reumatoide (FR) ou anticorpos antipeptídeos citrulinados cíclicos (anti-CCP) e com nódulos reumatoides 27(B) 28(D).
Estudos brasileiros confirmaram como manifestações iniciais
da doença: acometimento poliarticular, com sinovite persistente em mãos, rigidez matinal prolongada, elevada contagem de
articulações dolorosas e edemaciadas, além de fadiga15,16(B).
1. Diagnosticar a AR nos primeiros 12 meses
de sintomas (AR inicial) Traz benefícios em
relação ao diagnóstico mais tardio com relação a
prognóstico radiográfico e funcional?
A moderna diferenciação entre AR e outras doenças que acometem as articulações data de 1907. Como não há características patognomônicas que distingam as diversas artrites em
sua fase inicial, não se conhece o momento exato em que a
AR se desenvolve como uma entidade própria, distinta de outras doenças articulares12(B).
Definir a AR inicial tem importância tanto teórica quanto
prática, embora cada componente da definição (“AR” e “inicial”) possa ser abordado de forma independente, especialmente considerando-se que os critérios para a classificação
de AR são baseados na doença estabelecida13(D).
Embora a questão seja controversa, a AR inicial poderia
ser definida como a fase inicial da doença, uma “janela de
oportunidade terapêutica”, quando o estabelecimento de terapia adequada poderia modificar a evolução da doença, e
o prognóstico é melhor em relação a fases mais tardias da
evolução14(D).
O tempo de duração dos sintomas para a AR ser definida
como inicial varia amplamente na literatura especializada.
Historicamente, considerava-se “inicial” a AR com duração
inferior a cinco anos15(B). No contexto de “janela de oportunidade”, no entanto, fez-se necessária a redução desse período,
e no princípio da década de 1990 passou-se a considerar AR
inicial aquela com duração de sintomas inferior a 24 meses,
com grande ênfase aos primeiros 12 meses de manifestações
clínicas16(B).
Atualmente, almeja-se avaliar um paciente com sintomas
articulares na primeira oportunidade possível, e a definição
da fase inicial da AR compreende as primeiras semanas ou
meses de sintomas (em geral, menos de 12 meses),
destacando-se como período crítico as primeiras 12 semanas de manifestações como a “AR muito inicial” ou muito precoce (VERA – do inglês, very early rheumatoid arthritis). Aqueles
pacientes com mais de 12 semanas e menos de 12 meses de
sintomas articulares são incluídos na chamada “AR inicial tardia” (LERA – do inglês late early rheumatoid arthritis)17(B).
A proporção de reumatologistas que têm a oportunidade de
avaliar um paciente nas primeiras 6 semanas de sintomas da
doença passou de 9% em 1997 para 17% em 2003, embora nem
todos os casos possam ser avaliados tão rapidamente18(B).
Reconhecendo a imprecisão da definição de AR inicial,
muitos estudos têm sugerido que, entre pacientes com artrite
inflamatória de curta duração (menos de oito semanas), uma
proporção substancial terá resolução espontânea do quadro e
que, entre aqueles com quadro persistente, somente alguns
desenvolverão AR propriamente dita19(B)20-22(D). Dessa forma,
143
é de suma importância determinar marcadores clínicos, sorológicos ou genéticos que permitam a identificação dos pacientes com doença inicial em relação àqueles que evoluirão
com AR e, dessa forma, necessitarão de terapia apropriada
para diminuir a probabilidade de doença persistente e dano
articular.
O tempo médio para que pacientes com AR façam sua primeira visita ao reumatologista pode ser de 17 meses, e para
que utilizem pela primeira vez uma DMCD, de 19 meses. Fatores como educação, número de articulações edemaciadas, idade e ocupação podem ser determinantes dessa demora29(B).
A artrite é caracterizada pela presença de edema articular associado com dor ou rigidez. Os pacientes com artrite de
mais de uma articulação devem ser referidos a um reumatologista, idealmente até seis semanas depois do começo dos
sintomas30(D).
A presença de edema articular somente no primeiro ano
de doença reduz o risco de erosões articulares em cinco anos
(NNT: 4), quando comparado com a presença de edema articular durante todo o período de seguimento31(B).
O diagnóstico de AR antes de três meses do começo de doença VERA é um preditor de remissão clínica (American College of Rheumatology – ACR) e de remissão radiológica (escore
Sharp)32(B).
Alguns fatores quando identificados precocemente permitem projetar se haverá progressão radiológica das lesões da
AR em 12 meses, como o escore Sharp – mTSS, presença de
autoanticorpos como FR e anti-CCP e elevação de provas de
atividade inflamatória – velocidade de hemossedimentação
(VHS) > 28 mm e proteína C-reativa (PCR) com média 10 mg/
L33(B).
Quanto maior o escore de erosão no início do tratamento,
pior o prognóstico radiológico (escore Sharp) em 10 anos de
seguimento34(B).
Os escores Sharp, de erosões e de redução do espaço articular quando mensurados precocemente (primeiro ano) podem predizer o prognóstico segundo a progressão radiológica
em pacientes com AR acompanhados por três anos35(B).
Apesar da instituição precoce (três a seis meses do início
dos sintomas) de tratamento da AR com drogas modificadoras
do curso da doença (DMCD), 63,6% dos casos têm erosão no final de três anos, e isto é devido a características constitutivas
dos pacientes, como presença de autoanticorpos, como o FR,
anti-CCP e tempo de atividade da doença (PCR, edema articular e resposta terapêutica)36(B).
Na AR, o tempo de doença traz impacto prognóstico funcional, medido pelo Health Assessment Questionnaire (HAQ), independente do escore HAQ de base37(B).
A instituição de tratamento com DMCD no primeiro ano
de AR (na média seis meses de sintoma) determina a redução
na progressão radiológica (escore Ratingen) em cinco anos de
seguimento38(B).
Os pacientes que recebem tratamento da AR com menos
de 12 semanas de sintomas apresentam redução na progressão radiológica (escore SHS) em seis anos de seguimento. A
remissão sustentada no tratamento com DMCD é maior em
8% (NNT: 13) nos pacientes com tempo menor que 12 semanas de sintomas39(B).
O tratamento de pacientes com AR com DMCD no primeiro
ano de doença produz melhor evolução funcional (teste KFT)
144
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
e clínica (edema articular), em 10 anos de seguimento, em
comparação com os pacientes tratados entre um e cinco anos
do início da doença40(B).
Recomendação
Diagnosticar a AR nos primeiros 12 meses de sintomas (AR
inicial) é de grande importância, pois o diagnóstico precoce
traz benefícios em relação ao diagnóstico mais tardio com relação a prognóstico radiográfico e funcional.
2. Os novos critérios classificatórios ACR/EULAR
2010 para AR são superiores aos critérios
classificatórios de 1987 na fase inicial da doença?
A classificação da AR era essencialmente baseada nos critérios
introduzidos pelo ACR em 198741(B), apresentados na Tabela 2,
que não apresentavam boa performance na AR inicial42(B). Os
critérios classificatórios para AR do ACR foram desenvolvidos
com base em indivíduos com AR de longa duração, e eram
considerados até então o padrão para a seleção de pacientes
para estudos clínicos. Tais critérios apresentam sensibilidade de 91%–94% e especificidade de 89% para AR estabelecida.
No entanto, eles incluem características menos frequentes na
AR de início recente, como alterações radiográficas (erosões)
e nódulos reumatoides, sendo considerados subótimos para
Tabela 2 – Critérios do American College of
Rheumatology 1987 para classificação da artrite
reumatoide.
Critério
Definição
1.Rigidez matinal
Rigidez matinal com duração de pelo
menos 1 hora até a melhora máxima
2.Artrite de três ou mais Ao menos 3 áreas articulares
áreas articulares
simultaneamente afetadas, observadas
pelo médico (interfalangeanas
proximais, metacarpofalangeanas,
punhos, cotovelos, joelhos, tornozelos
e metatarsofalangeanas)
3.Artrite das articulações Artrite em punhos ou
das mãos
metacarpofalangeanas ou
interfalangeanas proximais
4.Artrite simétrica
Envolvimento simultâneo de áreas de
ambos os lados do corpo
5.Nódulos reumatoides
Nódulos subcutâneos sobre
proeminências ósseas, superfífies
extensoras ou em regiões justaarticulares
6.Fator reumatoide sérico Presença de quantidades anormais de
positivo
fator reumatoide
7.Alterações radiográficas Radiografias posteroanteriores de mãos
e punhos demonstrando rarefação
óssea justa-articular ou erosões
Para a classificação como AR, o paciente deve satisfazer a pelo
menos quatro dos sete critérios. Os critérios 1–4 devem estar
presentes por no mínimo seis semanas.
Modificado a partir de: Arnett FC, Edworthy SM, Bloch DA, McShane
DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum. 1988;31:315–24.
a identificação de indivíduos com AR inicial (sensibilidade de
40%–90% e especificidade de 50%–90%)43(B).
Por isso, tornou-se necessário o estabelecimento de novos
critérios de classificação para a AR, com foco, de maneira especial, na fase precoce da doença14(D).
Os novos critérios classificatórios ACR/EULAR podem ser
aplicados a qualquer paciente, desde que dois requisitos básicos estejam presentes:
1) Deve haver evidência de sinovite clínica ativa no momento
do exame em pelo menos uma articulação.
2) Os critérios só são aplicáveis aos pacientes para os quais
a sinovite não possa ser mais bem explicada por outros
diagnósticos.
Os critérios propostos (Tabela 3) se baseiam em um sistema
de pontuação por meio de um escore de soma direta. As manifestações são divididas em quatro domínios: acometimento
articular, sorologia, duração dos sintomas e provas de atividade inflamatória. A contagem de articulações acometidas pode
utilizar métodos de imagem ultrassonografia (US) e ressonância magnética (RM), em caso de dúvida. Uma pontuação ≥ 6
classifica o paciente como tendo AR44(B). Os critérios podem ser
preenchidos de forma prospectiva ou retrospectiva, se houver
registro adequado.
É importante frisar que, se o paciente apresentar uma história compatível com AR, mesmo que não documentada, e
erosões radiográficas típicas, pode-se proceder diretamente a
classificação como AR, independente do preenchimento dos
critérios14(D).
Os novos critérios 2010 não são diagnósticos, e sim classificatórios. Sua função é basicamente definir populações homogêneas para finalidade de estudo.
O diagnóstico clínico é extremamente complexo, e inclui
diversos aspectos que dificilmente poderiam ser resumidos na
forma de um escore de critérios14(D). Eventualmente, os critérios formais podem servir como um guia para o estabelecimento do diagnóstico clínico.
Vários aspectos referentes aos novos critérios precisam ser
analisados com cuidado antes que eles sejam universalmente
aceitos. Porém, é imprescindível que esses critérios sejam validados em diferentes populações, incluindo coortes brasileiras
de AR inicial.
Em pacientes em uso de metotrexato ou com AR persistente, o critério ACR/EULAR 2010 tem poder discriminatório de
76% e 87%, respectivamente, quando positivo, e de 63% e 46%,
respectivamente, quando negativo45(B).
Utilizando-se como padrão ouro de diagnóstico de AR a necessidade do uso de metotrexato durante o primeiro ano de
acompanhamento, o critério ACR/EULAR 2010 faz diagnóstico
quando positivo em 86% dos casos e 49% quando negativo, em
comparação com 87% e 41%, respectivamente, com o critério
ACR 198746(B).
Comparando-se o critério ACR/EULAR 2010 (escore > 6) e
ACR 1987 (escore > 4) no diagnóstico de pacientes com AR de
menos de 12 meses de doença, obtém-se valor preditivo positivo de 70,7% e 65,3%, respectivamente, e valor preditivo negativo de 76,1% e 79,1%, respectivamente47(B).
Durante o seguimento de pacientes com AR durante 18 meses o poder discriminatório do ACR/EULAR 2010 pode ser comparado com o ACR 1987, conforme a Tabela 4 pode demonstrar.
145
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
Tabela 3 – Critérios classificatórios para a artrite reumatoide 2010 ACR/EULAR.
População-alvo (quem deve ser testado?)
Paciente com pelo menos uma articulação com sinovite clínica definida (edema).*
Sinovite que não seja mais bem-explicada por outra doença.
*Os diagnósticos diferenciais podem incluir condições como lúpus eritematoso sistêmico, artrite psoriásica e gota. Se houver dúvidas quanto
aos diagnósticos diferenciais relevantes, um reumatologista deve ser consultado.
Acometimento articular
(0–5)
Sorologia (0–3)
1 grande articulação
2–10 grandes articulações
0
1
1–3 pequenas
articulações (grandes
não contadas)
4–10 pequenas
articulações (grandes
não contadas)
> 10 articulações (pelo
menos uma pequena)
2
Duração dos sintomas (0–1)
FR negativo E ACPA negativo
FR positivo OU ACPA positivo
em baixos títulos
FR positivo OU ACPA positivo
em altos títulos
0
2
< 6 semanas
≥ 6 semanas
0
1
Provas de atividades
inflamatórias (0–1)
PCR normal E VHS normal
PCR anormal OU VHS
anormal
0
1
3
3
5
Pontuação ≥ 6 é necessária para classificação definitiva de um paciente com AR. O domínio “acometimento articular” refere-se à qualquer
articulação dolorosa ou inchada (excluindo IFD do pé ou mão, primeira MTF e primeira carpometacarpena). Evidência adicional obtida
por exames de imagem pode ser utilizada para confirmação dos achados clínicos. Considera-se, para fins de classificação, como pequenas
articulações as MCF, IFP, MTF (segunda a quinta), primeira interfalangeana e punhos, e como grandes articulações ombros, cotovelos, quadril,
joelhos, tornozelos. Articulações adicionais (temporomandibular, esternoclavicular, acromioclavicular, entre outras) podem ser contadas, na
avaliação de “mais de 10 articulações”, desde que uma pequena articulação (ao menos) esteja acometida.
No domínio “sorologia”, considera-se o resultado de fator reumatoide ou de anticorpos antipeptídos/proteínas citrulinadas negativo se o valor
encontrado for igual ou menor ao limite superior da normalidade para o respectivo laboratório; positivo baixo se o resultado encontrado for
maior que o limite superior da normalidade, mas menor ou igual três vezes o limite superior da normalidade; e positivo alto quando o valor
encontrado for superior a três vezes o limite superior da normalidade.
O domínio “duração dos sintomas” refere-se ao relato do próprio paciente quanto à duração máxima dos sinais e sintomas de qualquer
articulação que esteja clinicamente envolvida no momento da avaliação.
Já as “provas de atividade inflamatória” (velocidade de hemossedimentação e proteína C-reativa) são consideradas normais ou anormais de
acordo com o valor de referência do laboratório utilizado.
Modificado a partir de: Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd. 2010 rheumatoid arthritis classification criteria: an
American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010; 69(9):1580-8.
Tabela 4 – Valores preditivos positivo e negativo dos critérios ACR 1987 e ACR/EULAR 2010 para pacientes com artrite
reumatoide em uso de drogas modificadoras de curso da doença, no início do acompanhamento e após 18 meses.
Início do coorte
ACR/EULAR 2010
Valor preditivo +
Valor preditivo −
75%
66%
Após 18 meses
ACR 1987
85%
59%
O critério 2010, quando aplicado no início do seguimento,
detecta mais pacientes que podem requerer DMCD do que o
ACR 1987, 62% versus 38%, respectivamente, especialmente o
uso de metotrexato em 18 meses de seguimento, 68% versus
42%, respectivamente. Entretanto, mais pacientes falsos positivos são identificados pelo ACR/EULAR 2010: 8% versus 2%48(B).
Utilizando-se o critério ACR 1987 como definição de paciente com AR (sem auxílio radiológico), o critério ACR/EULAR 2010
permite diagnóstico de doença com 59% (valor preditivo positivo) e afasta o diagnóstico em 93% (valor preditivo negativo).
O número de falsos positivos com o ACR/EULAR 2010 está em
17%. Considerando a definição de doença como crônica (cinco anos de seguimento) o valor discriminatório do ACR/EULAR
2010 isolado cai para 68% quando positivo e 61% quando negativo. No entanto, o critério ACR 1987 definiu como AR 11,3% dos
casos a menos do que o ACR/EULAR 201049(B).
ACR/EULAR 2010
73%
69%
ACR 1987
81%
79%
Recomendação
O critério ACR/EULAR 2010 identifica mais pacientes com
AR no início da doença do que o ACR 1987, entretanto o número de falsos positivos também é maior. Utilizando-se critérios de seguimento, como a necessidade do uso de DMCD
ou persistência da doença, os dois critérios têm poder discriminatório semelhante.
3. Tabagismo determina pior prognóstico da
doença articular nos pacientes com AR?
A presença de tabagismo entre pacientes com AR recente
(24 semanas de sintomas) aumenta o risco de não resposta
(ACR50) em 18,3% (NNH: 6)50(B).
146
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Pelo critério EULAR, após três meses de seguimento de pacientes com AR, aqueles tabagistas atuais têm menor índice
de boa resposta em 9% quando comparado com não tabagistas (NNH:11). O aumento do risco de não obter boa resposta é
mantido ao longo de seguimento de cinco anos, para aqueles
pacientes que permanecem fumando. Essa diferença de boa
resposta é um pouco maior quando analisamos o grupo de pacientes em uso de anti-TNF (14%; NNH: 7)51(B).
Os pacientes tabagistas evoluem mais com manifestações
extra-articulares da AR (pleurite, pericardite, doença pulmonar intersticial, neuropatia, glomerulonefrite, vasculites) que
os não tabagistas, com índices maiores (na média) nos escores
DAS-28 e HAQ52(B).
O tabagismo em pacientes com AR aumenta o uso de DMCD
e reduz a resposta clínica (ACR50) em 16% (NNH: 6), sobretudo
em pacientes que fumam mais de 20 maços/ano53(B).
A progressão radiológica em pacientes com AR, em três
anos de seguimento, é semelhante em pacientes tabagistas e
não tabagistas, não correspondendo aos achados clínicos de
menor resposta nos pacientes tabagistas54(B).
Em 24 meses de seguimento, os pacientes tabagistas com AR
apresentam maior atividade da doença (dor e edema articular)
que os pacientes não tabagistas. O escore de dor (Escala Visual
Analógica – EVA) também é superior nos pacientes tabagistas.
Entretanto, não há diferença na progressão radiológica55(B).
Em pacientes com AR com sete meses de sintomas em média, a atividade de doença é maior (medida pelo edema e dor
articular e DAS-28) nos pacientes tabagistas do que naqueles
não tabagistas, em cinco anos de seguimento56(B).
Recomendação
O tabagismo em pacientes com AR aumenta a atividade da doença e reduz a resposta clínica e funcional ao longo do tempo.
Entretanto, não há evidências suficientes de sua influência na
progressão radiológica.
4. O fator reumatoide é um exame adequado para
o diagnóstico e a estratificação de prognóstico da
AR?
O FR é um anticorpo dirigido contra a porção Fc da IgG57(D).
Classicamente associado à AR, é encontrado no soro de cerca
de 70% dos pacientes e correlaciona-se estatisticamente com
pior prognóstico. Níveis mais elevados estão associados com
doença agressiva, presença de nódulos reumatoides e manifestações extra-articulares58(D).
Individualmente, o valor diagnóstico do FR é limitado, já
que 30%–50% dos pacientes, no início do quadro, podem ser
soronegativos para esse autoanticorpo57(D). Além da baixa
sensibilidade, a especificidade do exame também é limitada.
O FR pode ser positivo em pessoas sem artrites; essa prevalência é aumentada com o envelhecimento59(B). O FR pode
ainda estar presente em diversas outras condições, reumatológicas ou não44,60(B). Assim, a negatividade do FR não exclui o
diagnóstico de AR e sua positividade deve ser cuidadosamente interpretada de acordo com os achados clínicos.
Dados brasileiros (coorte incidente de AR inicial) mostram
prevalência de FR em cerca de 50% dos pacientes61(B).
Pacientes com AR e FR positivo, em 20 anos de seguimento,
têm aumento de 17% na mortalidade global (NNH: 6) e de 16%
na mortalidade cardiovascular (NNH: 6)62(A).
A mortalidade de pacientes com AR e FR positivo pode não
ser superior à mortalidade dos pacientes com FR negativo em
14 anos de seguimento. Entretanto, quando analisado frente
ao número de eventos esperados na população, a mortalidade
nos pacientes com FR positivo está aumentada, inclusive a
cardiovascular63(B).
Em pacientes com diagnóstico de AR, onde 24% dos casos
são FR IgM e IgA positivos, a progressão radiológica das lesões
em 10 anos de seguimento está associada e pode ser predita
pelo resultado do FR positivo (IgM ou IgA)64(B).
Em população de AR com FR positivo em 51% dos pacientes, o FR prediz a progressão radiológica quando positivo em
69% dos casos e afasta a progressão quando negativo em 83%.
Em cinco anos de seguimento de pacientes com AR, o FR é
preditor de progressão radiológica (Larsen escore)65(B).
Em três anos de seguimento de pacientes com AR, o
FR é preditor de progressão radiológica (Sharp ou Larsen
escore)35,66(B) e de necessidade de terapia biológica67(B).
Há aumento de 24,3% de risco de progressão radiológica
entre os pacientes com FR (NNH: 4) quando comparado aos
pacientes com FR negativo68(A).
Em probabilidade pré-teste de 35% de diagnóstico de AR,
os resultados de FR (IgM, IgA e IgG), mensurados por ELISA,
quando positivos, elevam a probabilidade diagnóstica para
94% e quando negativos afastam diagnóstico com 85% de
certeza69(B)
Em população de pacientes com 35% de AR, o diagnóstico
utilizando FR (IgM, IgA e IgG) eleva a probabilidade pós-teste
para 96%70(B).
Recomendação
O uso do FR permite estimar o prognóstico dos pacientes com
AR, sobretudo com relação à progressão radiológica e mortalidade. O FR positivo em população com probabilidade pré-teste de 35% eleva a probabilidade diagnóstica para 94%–96%
e afasta diagnóstico quando negativo com probabilidade pós-teste de 85%.
5. A pesquisa de anti-CCP é superior à pesquisa
de fator reumatoide para o diagnóstico de AR?
Recentemente, diversos ACPA emergiram como ferramenta
diagnóstica importante para a AR, com sensibilidade semelhante e especificidade superior a do FR, além de possível participação na fisiopatogenia da doença71(B). Sua função como
possíveis marcadores de atividade da AR é questionável72(B).
Anticorpos anti-peptídeos citrulinados cíclicos
Entre os anticorpos dirigidos contra antígenos do sistema filagrina-citrulina estudados, os anti-CCP demonstraram maior
aplicabilidade clínica. Trata-se de um exame com 70%–75% de
sensibilidade cerca de 95% de especificidade, sendo útil sobretudo no subgrupo de pacientes com artrite na fase inicial
e FR negativo73(B).
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Sua pesquisa é válida na investigação de artrites indiferenciadas. Os anti-CCP são detectados muito precocemente na
evolução da AR e podem ser usados como indicador de progressão e prognóstico da doença41-43,74-78(B)21,79(D).
Outros anticorpos
Outros autoanticorpos vêm sendo utilizados na investigação
da AR. O objetivo é desenvolver métodos com sensibilidade
e especificidade para o diagnóstico mais precoce da doença, marcadores de atividade mais confiáveis e indicadores de
prognóstico. Entre eles, anticorpos contra vimentina citrulinada mutada (anti-MCV)80-82(B), antiqueratina (AKA), fator antiperinuclear (APF)83(B), antifilagrina84(B), ACF85(B) e antiproteína
A2 do complexo de ribonucleoproteína nuclear heterogêneo
(anti-RA33)83(B), anti-interleucina 1 (anti-IL1)86(B), anti-1-αenolase87(B) e antiprodutos finais da glicação avançada88(B).
Esses anticorpos têm, em geral, boa especificidade, mas uma
sensibilidade inferior ao anti-CCP para o diagnóstico da AR.
Os recentes critérios para classificação da AR14(D), estabelecidos em conjunto pelo Comitê do ACR e pela European League
Against Rheumatism (EULAR) 2010, definem no item “autoanticorpos” apenas FR e ACPA. Para efeito desses critérios, os valores de FR ou ACPA são estabelecidos como negativos, títulos
baixos e títulos elevados. Levando-se em consideração que
tanto FR quanto anti-CCP são medidos em UI, considera-se resultado negativo se o valor encontrado for igual ou menor ao
limite superior da normalidade (LSN) para o respectivo laboratório; positivo baixo se o resultado encontrado for maior que o
LSN, mas menor ou igual três vezes o mesmo limite; e positivo
alto quando o valor encontrado for superior a três vezes o LSN.
A presença de pacientes com AR e anti-CCP positivo em
quatro anos de seguimento está associada a padrão de RM com
erosão e edema, enquanto os pacientes anti-CCP negativo se
associam à presença de sinovite89(B).
O anti-CCP é superior ao FR na predição da evolução de artrite indiferenciada para AR (certeza diagnóstica de 93% e 68%,
respectivamente). Permite também estimar melhor a gravidade
da doença no seguimento de sete anos90(B).
Há aumento no risco de 23% da identificação ou presença de
anti-CCP positivo nos pacientes com AR em atividade, quando
comparado com o período antes da doença. E durante seguimento de sete anos as alterações no anti-CCP são mantidas91(B).
Baseado em 15 coortes de AR recente, conclui-se sobre o
uso de anti-CCP (CCP2-segunda geração), que um resultado
positivo permite fazer diagnóstico de AR (RV +12,7), mas um
resultado negativo não afasta essa possibilidade diagnóstica
(RV −0,45). Quando comparamos o FR e o anti-CPP2, verificamos que a sensibilidade de ambos é semelhante (56% e 58%,
respectivamente), entretanto a especificidade do anti-CPP2 é
superior (96% versus 86%, respectivamente). A sensibilidade e
a especificidade do anti-CPP2 são superiores ao anti-CPP1. A
combinação de FR e anti-CPP2, quando positivos, pouco eleva
a certeza diagnóstica em relação ao anti-CPP2 isolado (RV +27
versus 22, respectivamente). A síntese global da evidência nos
permite estimar que a sensibilidade do anti-CPP2 é de 67% e a
especificidade é de 96%. Se considerarmos a prevalência de 42%
para AR conforme os critérios do ACR 1987, o resultado positivo
do anti-CPP2 eleva a probabilidade diagnóstica para 90%, e o
resultado negativo afasta o diagnóstico com certeza de75%92(B).
147
Recomendação
O anti-CCP é um marcador com sensibilidade semelhante a do
FE, mas com especificidade superior, sobretudo na fase inicial
da doença. Recomenda-se a sua pesquisa em pacientes com
suspeita clínica de AR e FR negativo.
6. Os marcadores genéticos (pesquisa dos alelos
de HLA-DRB1 – epítopo compartilhado e dos
genes PTPN22) são úteis para a caracterização de
pacientes com pior prognóstico da AR?
Inúmeros marcadores genéticos foram descritos em associação com a ocorrência da AR. Porém, somente a pesquisa dos
alelos de HLADRB1 (presença do epítopo compartilhado – SE)
e dos genes PTPN22 são as alterações genéticas associadas a
AR bem-estabelecidas, com forte nível de evidência93(D). A interação entre HLA-DRB1, tabagismo e anti-CCP determina um
perfil de doença mais grave e de pior prognóstico. No entanto, apesar de útil para a caracterização de pacientes com pior
prognóstico, os elevados custos da tipificação do HLA-DRB1
ainda limitam sua utilização na prática diária93,94(D).
PTPN22
O polimorfismo do gene PTPN22 está associado à AR em pacientes não europeus, com aumento do risco da doença de 6%
(NNH: 16). Além disso, está associado exclusivamente aos casos de AR com FR positivo12 95(B).
Há uma associação fenotípica genética entre a presença do
alelo PTPN22 e AR ACPA positivo. Entretanto, não há interação
entre o PTPN22 e outros fatores ambientais, como tabagismo
ou modalidade terapêutica96(B).
Nenhuma associação à resposta terapêutica de pacientes
com AR (infliximabe, etanercepte ou adalimumabe) é definida
com a presença de epítopo compartilhado ou polimorfismo no
gene PTPN2297(B).
A presença de polimorfismo no gene PTPN22 (rs2476601)
está correlacionada com redução na remissão sustentada da
AR. Essa correlação (9% de contribuição) é potencializada por
presença e ausência de anticorpos anti-CPP (91% de contribuição), com certeza de 31% e 98%, para predizer ausência e presença de remissão, quando o polimorfismo está presente ou
ausente, respectivamente98(B).
Existe evidência de que a presença da variante PTPN22 está
associada à progressão radiológica da lesão em pacientes com
AR99(B).
PTPN22 E HLA-DRB1 (epítopo compartilhado)
PTPN22 e os alelos HLA-SE não aumentam o valor preditivo do
FR e do anticorpo anti-CPP no diagnóstico de AR100(B). Entretanto, há evidência de que a presença dos alelos HLA-SE e do gene
PTPN22 está associada aos fenótipo CCP e FR positivos em 75% e
69% dos casos, respectivamente101(B).
A presença do alelo HLA-DRB1 (epítopo compartilhado) e de
polimorfismo simples nos gene PTPN22 está associada à atividade de AR. Entretanto, não é possível estabelecer correlação com a
gravidade da doença (progressão radiológica e sintomas)102(B).
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A presença isolada do polimorfismo no gene PTPN22 e do
epítopo compartilhado (HLA-DRB1) não demonstra aumento
de risco para AR. Entretanto, quando associados, aumentam o
risco de AR em 1% (NNH: 100)103(B).
HLA-DRB1 (epítopo compartilhado)
Há relevância prognóstica na presença do alelo HLA-DRB1 nos
pacientes com AR, à medida que o alelo está associado à produção dos anticorpos anti-CPP, antivimentina citrulinada e antifibrinogênio citrulinado104,105(B).
Alelos HLA-DRB1 são significativamente mais expressos nos
pacientes com AR (aumento no risco de 36,0%; NNH: 3), AR ativa
(aumento no risco de 50,0%; NNH: 2), AR e doença erosiva (aumento no risco de 50,0%; NNH: 2), e em pacientes com anticorpo anti-CPP positivo (aumento no risco de 65,6%; NNH: 2)106(B).
A presença do epítopo compartilhado (HLA-DRB1) em pacientes com AR não está correlacionada à progressão radiológica da doença105,107(B). Entretanto, há informação de que os alelos
de epítopos compartilhados, assim como de anticorpos anti-CPP podem estar associados à gravidade do dano articular (escore de erosão e dano radiológico) em pacientes com AR108(B).
Não há valor de predição do HLA epítopo compartilhado na
progressão radiológica de lesão na AR109(B).
A presença dos alelos HLA-DRB1 expressando o epítopo
compartilhado está aumentada em pacientes da América Latina com AR110(B).
A presença de alelos de epítopo compartilhado (DRB1) pode
predizer a mortalidade de pacientes com AR, inclusive a mortalidade cardiovascular111,112(B).
Há associação entre o genótipo DRB1 e os pacientes com AR
FR positivos, com aumento de risco de 3,0%–3,7% (NNH: 30)113(B).
Recomendação
O polimorfismo no gene PTPN22 está associado à AR. Não prediz resposta terapêutica específica a biológicos, mas quando
associado ao anti-CPP, prediz remissão da doença, e pode isoladamente ou combinado ao HLA-DRB1 (epítopo compartilhado) estimar progressão radiológica da lesão ou atividade da
doença. O alelo HLA-DRB1 parece ter uma importância maior
na predição de mau prognóstico da AR, seja de progressão,
atividade ou gravidade, incluindo mortalidade.
7. A ocorrência de manifestações extra-articulares
sinaliza uma doença de evolução mais agressiva?
Embora as manifestações articulares sejam as mais características, a AR pode ocasionar acometimento em outros órgãos
e sistemas. As manifestações extra-articulares mais frequentes incluem quadros cutâneos, oculares, pleuropulmonares,
cardíacos, hematológicos, neurológicos e osteometabólicos.
São mais observadas em pacientes com doença grave e poliarticular, sorologia positiva para FR ou anticorpos anti-CCP e
com nódulos reumatoides27(B)28(D).
A incidência de manifestações extra-articulares na AR é de
47,5%, estando entre elas: cardiovasculares, sanguíneas, oculares e pulmonares. Estão associadas a maior chance de uso
de agentes biológicos114(B).
Doença intersticial pulmonar clinicamente significativa
ocorre em 10% dos pacientes com AR115(B); a mortalidade
desses pacientes depende do tipo de acometimento pulmonar, maior quando o acometimento é difuso116(B). A mortalidade atribuível à doença pulmonar fibrosante é em torno
de 6%115(B); a sobrevida do padrão de pneumonia intersticial
usual é pior, com média de 3,2 anos, enquanto outras formas de doença intersticial apresentam sobrevida maior, de
6,6 anos116(B). Nos pacientes com doença intersticial e AR, o
uso de medicações anti-TNF deve ser judicioso, devido a um
possível aumento de mortalidade nestes pacientes117(B).
A mortalidade de pacientes com AR e doença intersticial
pulmonar é de 7% e o tempo de sobrevida média após o diagnóstico é de três anos. Apesar da associação entre a presença de doença intersticial e atividade da doença, esta última
foi estabelecida apenas por VHS aumentado no estudo em
questão118(B).
A presença de disfunção renal na AR não está associada à atividade, progressão, disfunção ou gravidade da
doença119(B).
Os pacientes com AR e manifestações extra-articulares
têm aumento no risco de eventos cardiovasculares (infarto
agudo do miocárdio, angina, doença coronariana e acidente
vascular cerebral) de 20% (NNH: 5)120(B).
A sobrevida de pacientes de AR com manifestações extra-articulares (18% dos casos) é inferior à esperada para os demais pacientes com manifestações restrita às articulações,
observando-se aumento no risco relativo de morte em sete
anos de seguimento de 27%. Assim como as manifestações
extra-articulares, as comorbidades também contribuem
para maior mortalidade, especialmente as cardiovasculares,
responsáveis por 31% dessas mortes. O aumento na mortalidade está associado a pacientes com maior atividade da doença (FR), pior função (HAQ) e maior progressão radiológica
da lesão121(B).
Em pacientes com AR e manifestações extra-articulares,
os escores de avaliação de atividade da doença como DAS28, o HAQ e o escore radiológico de Larsen tendem a ser
piores, demonstrando maior gravidade da doença. Somente
4,1% dos pacientes apresentam remissão122(B).
No seguimento de 15 anos de pacientes de AR, com e sem
manifestações extra-articulares, a mortalidade está aumentada exclusivamente nos pacientes com manifestações extra-articulares (aumento do risco relativo de 51%), das quais
a pericardite é a mais relevante123(B).
A mortalidade em pacientes com AR e manifestações extra-articulares (prevalência de 7,9%) é de uma morte por 4,3
pacientes/ano, e naqueles sem manifestações articulares, de
uma morte em 11,4 pacientes/ano124(B).
Em pacientes de AR e com manifestações extra-articulares o risco de doenças gastrointestinais graves está aumentado (prevalência de 4,6%). E nesses pacientes, a intensidade
(critério ACR) da doença também é maior, bem como os sinais de progressão radiológica125(B).
Recomendação
Em pacientes com manifestações extra-articulares da AR,
observa-se evolução mais grave da doença, com atividade
mais intensa, redução da capacidade funcional, da resposta
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
terapêutica (menor ocorrência de remissão) e da expectativa
de vida, em relação aos pacientes com manifestações exclusivamente articulares.
8. A radiografia convencional é um exame
adequado para o diagnóstico da AR?
A radiografia convencional é o método de imagem mais utilizado na avaliação de dano estrutural articular na AR. Além
de ser uma ferramenta útil para o diagnóstico, é importante
no monitoramento da progressão da doença, quando repetida em intervalos regulares126(D).
Os achados radiográficos iniciais incluem aumento de
partes moles e osteopenia justarticular. As lesões mais características, como redução do espaço articular e erosões ósseas, aparecem mais tardiamente.
A presença de erosão óssea deve ser considerada como
fator de risco para o desenvolvimento de artrite persistente
quando observada nos estágios iniciais da doença127(B), está
relacionada com limitação funcional e, consequentemente,
com pior prognóstico128(B).
A utilização da radiografia em pacientes com AR para a
identificação de erosões (prevalência de 15%), quando o resultado é positivo, eleva a probabilidade de diagnóstico para
100%, e quando negativo não permite afastar diagnóstico,
pois não reduz a probabilidade (18%)129(B).
Em pacientes com forte suspeita de AR, mas negativos
pelo FR e radiografia, tanto a presença do anti-CCP positivo
como a presença de erosões na RM determinam alta especificidade para o diagnóstico de AR130(B).
Em pacientes com AR, a RM te maior sensibilidade para
detecção de erosões quando comparado com a radiografia
convencional. A presença de erosões na radiografia de articulações MCF é de 89% e nos punhos de 15,8%, o que é inferior ao encontrado na RM: 100% e 69%, respectivamente131(B).
A acurácia diagnóstica da radiografia convencional para a
detecção de erosões ósseas em punho em pacientes com AR
é de 63%, enquanto a da RM é de 77%132(B).
A sensibilidade diagnóstica da radiografia para detecção
de erosões nas articulações MCF de pacientes com AR é de
14%, em comparação com 66% da RM133(B).
Em pacientes com AR seguidos por dois anos, a radiografia pode identificar a progressão das lesões em 40% dos casos
(escore Larsen total), e em 15% pelo escore Larsen nas articulações MCF. A acurácia de identificar progressão é semelhante à da RM134(B).
A detecção das erosões por meio de escore E, em pacientes com AR, é inferior na avaliação radiológica (13,1 ± 8,3)
quando comparado à RM (28,8 ± 10,0)135(B).
Em população de pacientes com AR e erosões articulares
(95% de prevalência), a radiografia é capaz de identificar 59%
dos casos, comparado com 95% na RM136(B).
A radiografia das mãos de pacientes com AR identifica 50%
menos erosões quando comparado à RM, apesar de identificar progressão radiológica em proporção semelhante137(B).
Em pacientes com AR e prevalência de 43% de erosões, a
radiografia, quando o resultado é positivo, aumenta a probabilidade de diagnóstico para 80%, e quando negativo, afasta
o diagnóstico em 85%. Em seguimento de três anos, a iden-
149
tificação das erosões pela radiografia é reduzida para 81% e
60%, respectivamente138(B).
Em população de pacientes com artrite e diagnóstico de
AR em 36% dos casos, o uso da radiografia no diagnóstico aumenta a probabilidade de AR para 50% e quando o resultado
é negativo reduz a probabilidade para 33%139(B).
Avaliando-se pacientes com AR por meio da radiografia,
pouco se aumenta a probabilidade de diferenciação entre os
soropositivos e soronegativos para o anticorpo FR. A partir
de uma população de 59% de prevalência de soropositivos
para FR, a radiografia quando positiva (processo destrutivo)
aumenta essa probabilidade para 66%, e quando negativa,
reduz para 47%140(B).
Recomendação
A radiografia convencional deve ser empregada para avaliação de diagnóstico e prognóstico da doença. Quando necessário e disponível, a US e a RM podem ser utilizadas.
9. A ultrassonografia é superior à radiografia
convencional para o diagnóstico e a determinação
de prognóstico da AR?
A sensibilidade da US musculoesquelética e da RM na detecção de dano estrutural é superior à sensibilidade da radiografia convencional141(D).
A US, quando realizada por operador experiente em doenças musculoesqueléticas, é um método útil na detecção
precoce e no monitoramento de atividade inflamatória e dos
sinais de destruição articular135(B).
Em comparação à RM, é um exame de menor custo,
sem contraindicações para pacientes com implantes metálicos ou com claustrofobia. Além disso, permite exame
dinâmico da articulação, possibilita avaliação comparativa
contralateral, assim como avaliação de outras estruturas
anatômicas134(B)141,143(D).
A utilização do power doppler e do Doppler colorido podem complementar o exame e auxiliar na caracterização da
atividade inflamatória144(D).
O uso da US para identificar inflamação nas articulações
em pacientes com AR permite, quando o resultado é positivo
e negativo, o diagnóstico de certeza em 79% e 55% dos casos,
respectivamente. Esse resultado é semelhante à radiografia
(escore Sharp) quando esta é positiva (74%), e superior quando negativa (38%)145(B).
A detecção de erosões ósseas em pacientes com AR recente, por meio da US, é superior à detecção por meio da
radiografia, tendo a RM como padrão-ouro (neste estudo),
sendo a razão de verossimilhança positiva de 31 e 20, respectivamente. Partindo de prevalência de 50% de lesões,
quando a US é positiva, eleva-se a probabilidade diagnóstica
para 99%, enquanto a radiografia aumenta a probabilidade
para 97%, demonstrando utilidade semelhante para os dois
testes135(B).
A detecção de erosões em pacientes com AR por meio da
US garante, quando positiva, diagnóstico com 82% de certeza
e, quando negativa, 61%, em comparação com a radiografia
(95% e 55%), respectivamente146(B).
150
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A US, na detecção de sinais inflamatórios e de destruição nas articulações interfalangeanas em pacientes com
AR, obtém sensibilidade e especificidade de 59% e 98%, em
comparação com a radiografia, com sensibilidade e especificidade de 42% e 99%, respectivamente. Estes resultados
fornecem certeza diagnóstica quando positivos de 97% e
98%, e quando negativos de 71% e 63%, para a US e radiografia convencional, respectivamente147(B).
A US, na detecção de erosões nas articulações MCF em
pacientes com AR, obtém sensibilidade e especificidade de
79% e 97%, em comparação com a radiografia convencional,
com sensibilidade e especificidade de 32% e 98%, respectivamente. Estes resultados fornecem certeza diagnóstica
quando positivos de 96% e 94%, e quando negativos de 82%
e 46%, para a US e radiografia, respectivamente148(B).
A US detecta erosões nas articulações glenoumerais
em pacientes com AR com sensibilidade e especificidade de 74% e 75%, em comparação com a radiografia, que
demonstra sensibilidade e especificidade de 67% e 100%,
respectivamente. Estes resultados fornecem certeza diagnóstica quando positivos de 75% e 100%, e quando negativos de 74% e 75%, para a US e radiografia convencional,
respectivamente149(B).
A acurácia diagnóstica da US na identificação de erosões
em pacientes com AR é de 84%, superior à da radiografia,
que é de 73%. Entretanto, quando considera-se apenas
quando o resultado é positivo, a US tem razão de verossimilhança inferior (5 versus 13), o que confere menor certeza
diagnóstica150(B).
Em pacientes com AR precoce, a US identifica erosões
em 19,3% dos casos não identificados à radiografia, mas não
faz diagnóstico em 8,8% dos casos identificados à radiografia. A combinação de ambos os métodos permite o diagnóstico de 45,6% de lesões nesses pacientes151(B).
Em pacientes com AR precoce, a US se correlaciona aos
escores de atividade da doença (DAS28) e capacidade funcional (HAQ) ao longo de 12 meses de seguimento152(B).
Em pacientes com AR precoce, a US aumenta a detecção
de erosões em 42,0% dos casos no início do diagnóstico e
no seguimento de nove meses, quando comparado com a
radiografia153(B).
A detecção de lesões articulares em pacientes com AR
é maior pela US do que pela radiografia, sendo 5% maior
no início diagnóstico e 23% maior no seguimento de sete
anos154(B). Em outro estudo, no entanto, a radiografia identifica número maior de erosões em pacientes com AR do
que a US, 37% versus 30%, respectivamente, sendo que em
seis meses o número de progressões identificado é de 48% e
41%, respectivamente155(B).
Considerando o número de erosões umerais (grande tuberosidade, anteromedial e posterolateral) em pacientes
com AR, a US garante certeza diagnóstica quando positiva
em 90% e 40% e quando negativa, em comparação com a
radiografia, em 96% e 39%, respectivamente152(B).
Recomendação
A US pode contribuir com o diagnóstico de erosões articulares
nos pacientes com AR, bem como no seguimento com relação
à progressão da doença.
10. A ressonância magnética é superior à
radiografia convencional e à ultrassonografia para o
diagnóstico e a determinação de prognóstico da AR?
A RM é o método mais sensível para detectar as alterações
da AR em sua fase inicial. Permite avaliar alterações estruturais de partes moles, ossos e cartilagens, além de erosões
antes das radiografias convencionais138(B).
Além dos achados radiográficos convencionais na AR, a
RM é capaz de detectar edema ósseo, que mostrou ser um
preditor de erosão óssea135(B).
No Brasil, fatores como alto custo e falta de padronização
do método limitam a sua utilização na prática clínica.
A utilização da RM no diagnóstico da AR tem elevada
variação nos resultados, na dependência dos critérios utilizados, como também das populações estudadas, com sensibilidade variando de 20%–100%, e especificidade de 0% a
100%136,156-158(B). Quanto ao uso na identificação de progressão
da doença também há importante variação nos resultados,
com sensibilidade de 18% a 100%, e especificidade de 6% a
97%156,159-161(B). Além disso, a sua utilização no manejo de pacientes com AR recente não parece ser custo efetiva, quando
comparada manejo diagnóstico e prognóstico padrão162(B).
Em pacientes com AR, a RM (definição OMERACT) permite
o diagnóstico de erosões (mãos ou punho) com sensibilidade variando de 35% a 90%, e especificidade de 35% a 90%;
de edema ósseo (mãos ou punho ou MCF) com sensibilidade
variando entre 32,5% e 65%, e especificidade entre 82,5% e
100%; e de sinovite (mãos ou punho) com sensibilidade entre
40% e 80%, e especificidade entre 57,5% e 92,5%163(B).
Quando comparado com a RM, na identificação de erosões
MCF e IFP em pacientes com AR, a radiografia convencional
quando positiva faz diagnóstico de certeza em 98%–100%
dos casos, e a US em 86%–97%; e, quando seus resultados
são negativos, em 84% e 93%, respectivamente135,155(B).
A acurácia diagnóstica da US com Doppler comparada
com a RM na identificação de inflamação articular em pacientes com AR é de 75%164(B).
Utilizando a tomografia computadorizada como padrão-ouro no diagnóstico de erosões em punho de pacientes com
AR, a RM faz diagnóstico de certeza quando positiva em 90%
dos casos, comparado à radiografia convencional138,154(B).
Utilizando a RM de alto campo como padrão-ouro no
diagnóstico de erosões em punho e MCF de pacientes com
AR, a RM de extremidades faz diagnóstico de certeza quando positiva em 88%–93% dos casos, comparado à radiografia
convencional em 94%–98% dos casos, e à US em 82%165,166(B).
A combinação dos escores de sinovite, edema e erosões
obtidos pela RM permite identificar a resposta ao tratamento
de pacientes com AR com anti-TNF-α no seguimento de 12
meses167(B).
A RM como método de avaliação funcional no seguimento de pacientes com AR, em comparação com o status funcional (avaliado pelo médico e paciente), permite identificar
melhora apenas em 29% dos casos168(B).
A RM (edema ósseo) e a US (inflamação) permite por semelhante modo identificar a progressão das erosões em pacientes com AR (escore RAMRIS de erosões da RM como padrão ouro) ao longo de 12 meses de seguimento152(B).
151
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A identificação da progressão de erosões em pacientes
com AR durante 5 anos de seguimento é possível pela RM
(OMERACT) em 23% dos casos, comparado com a radiografia
convencional (Larsen escore) em 40% dos casos140(B).
Recomendação
A RM é o método mais sensível para detectar as alterações da
AR em sua fase inicial. Permite avaliar alterações estruturais
de partes moles, ossos e cartilagens, além de erosões antes
das radiografias convencionais. No Brasil, fatores como alto
custo e falta de padronização do método limitam a sua utilização na prática clínica.
A Tabela 5 descreve vantagens e desvantagens dos métodos de imagem utilizados na avaliação de pacientes com AR.
Conclusões
Essa diretriz foi realizada pela Comissão de Artrite Reumatoide da Sociedade Brasileira de Reumatologia com o objetivo de
elaborar recomendações para o diagnóstico e avaliação inicial
da AR no Brasil. Dadas a extensão territorial e a diversidade
entre as macrorregiões brasileiras, é possível que haja características peculiares quanto ao diagnóstico diferencial e ao
acesso a determinadas tecnologias (de laboratório ou de exames de imagem) em diferentes locais.
É importante diagnosticar a AR, sobretudo em sua fase
inicial.
Não diagnosticar, e consequentemente, não tratar de forma adequada um paciente com AR aumenta o risco de evolução com inflamação persistente e dano articular progressivo.
É necessário o pronto envolvimento do reumatologista na
avaliação do paciente com artrite, considerando-se, sobretudo, sua maior experiência e familiaridade com os possíveis
diagnósticos diferenciais e com a abordagem de investigação.
Apesar de haver recentes diretrizes sobre o diagnóstico da
AR, é relevante rever o assunto, considerando aspectos da realidade brasileira.
Desta forma, o propósito final em estabelecer recomendações para AR é definir e embasar os reumatologistas brasileiros, utilizando evidências obtidas em estudos controlados, a
fim de homogeneizar a abordagem diagnóstica da AR dentro
do contexto socioeconômico brasileiro.
Como a evolução de conhecimentos nessa área é bastante
rápida, sugere-se a atualização regular e periódica das recomendações.
Conflitos de interesse
Mota LMH: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Roche e Mantecorp. Recebeu auxílio pessoal ou institucional das empresas Abbott,
AstraZeneca, MSD, Roche e Pfizer. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Abbott, MSD,
Novartis, Roche e Wyeth.
Cruz BA: Participou de estudos clínicos e/ou experimentais patrocinados pela empresa Roche. Recebeu auxílio pessoal ou institucional das empresas Abbott, Bristol-Myers
Squibb, Mantecorp, MSD, Novartis, Roche, Wyeth e Pfizer. Foi
palestrante em eventos ou atividades patrocinadas pelas
empresas Abbott, MSD, Mantecorp, Novartis, Roche e Wyeth.
Brenol CV: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Bristol-Myers Squibb, Pfizer, Roche e Wyeth. Recebeu auxílio
pessoal ou institucional das empresas Abbott, Bristol-Myers Squibb, Mantecorp, MSD, Roche e Wyeth. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Abbott e Roche.
Pereira IA: Participou de estudos clínicos e/ou experimentais patrocinados pela empresa Roche. Recebeu auxílio pessoal ou institucional das empresas Abbott, MSD, Roche, BMS,
Jansen e Pfizer. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Abbott, MSD, BMS, Pfizer, Roche
e Jansen. É membro do conselho consultivo ou diretivo da
indústria farmacêutica ou de comitês normativos de estudos
Tabela 5 – Vantagens e desvantagens dos métodos de imagem utilizados na avaliação de pacientes com artrite
reumatoide.
Métodos
Vantagens
Radiografia convencional
- Baixo custo
- Fácil acesso
Ultrassonografia
- Custo intermediário
- Ausência de radiação ionizante
- Permite exame de várias articulações
- Possibilita guiar intervenções diagnósticas e
terapêuticas
- Detecção de dano estrutural cartilaginoso e ósseo
precocemente
- Detecção de atividade inflamatória com o uso de
power doppler
- Alta sensibilidade
- Ausência de radiação ionizante
- Complementação do exame com contraste
- Detecção de edema ósseo, dano estrutural
cartilaginoso e ósseo preocemente
Ressonância magnética
Desvantagens
- Representação bidimensional de lesão tridimensional
- Exposição à radiação ionizante
- Baixa sensibilidade para dano ósseo precoce
- Exame operador-dependente
- Pouco sensível para detecção de alterações em
articulações profundas (quadril)
- Alto custo
- Disponibilidade limitada do equipamento
- Tempo de exame prolongado
- Limitação a uma articulação por exame (p.ex., joelho,
mão)
152
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 4 1 – 1 5 7
científicos patrocinados pelas empresas Abbott, BMS, Jansen,
Roche, Pfizer e MSD.
Rezende-Fronza LS: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Bristol-Myers Squibb, Pfizer e Roche. Elaborou textos científicos em periódicos
patrocinados pela empresa Pfizer.
Bertolo MB: Foi palestrante em eventos ou atividades patrocinadas pelas empresas Abbott, Pfizer, Sanofi Aventis.
Freitas MVC: Recebeu auxílio pessoal ou institucional das
empresas Abbott, MSD, Pfizer, Roche e Wyeth. Foi palestrante
em eventos ou atividades patrocinadas pelas empresas Abbott, MSD, Pfizer, Roche Wyeth. É membro do conselho consultivo ou diretivo da indústria farmacêutica ou de comitês
normativos de estudos científicos patrocinados pelas empresas AstraZeneca, MSD e Wyeth. Elaborou textos científicos em
periódicos patrocinados pelas empresas Abbott, AstraZeneca,
Bristol-Myers Squibb, Wyeth.
Silva NA: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Bristol-Myers Squibb e Roche. Recebeu auxílio pessoal ou institucional das empresas
Abbott, MSD, Pfizer, Roche e Wyeth. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Janssen, Mantecorp, MSD e Roche.
Louzada-Junior P: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Merck e Roche.
Recebeu auxílio pessoal ou institucional da indústria Abbott.
Foi palestrante em eventos ou atividades patrocinadas pelas
empresas Bristol-Meyers-Squibb, Pfizer e Roche.
Giorgi RD: Recebeu auxílio pessoal ou institucional das
empresas Bristol-Myers Squibb e Roche. Foi palestrante em
eventos ou atividades patrocinadas pelas empresas Bristol-Myers Squibb e Roche. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Bristol-Myers Squibb e
Roche.
Lima RAC: Participou de estudos clínicos e/ou experimentais patrocinados pela empresa Mantecorp e Roche. Recebeu
auxílio pessoal ou institucional das empresas Acteion, Lilly e
Pfizer. Foi palestrante em eventos ou atividades patrocinadas
pelas empresas Acteion, Lilly e Pfizer.
Pinheiro GRC: Recebeu auxílio pessoal ou institucional das
empresas Janssen e Roche.
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Documentos de Diretrizes
Diretrizes para o tratamento da artrite reumatoide
Guidelines for the drug treatment of rheumatoid arthritis
Sociedade Brasileira de Reumatologia
Projeto Diretrizes da Associação Médica Brasileira, São Paulo, SP, Brasil
Participantes
Objetivo
Licia Maria Henrique da Mota*, Bóris Afonso Cruz,
Claiton Viegas Brenol, Ivânio Alves Pereira,
Lucila Stange Rezende-Fronza, Manoel Barros Bertolo,
Max Vitor Carioca Freitas, Nilzio Antônio da Silva,
Paulo Louzada-Junior, Rina Dalva Neubarth Giorgio,
Rodrigo Aires Corrêa Lima, Wanderley Marques Bernardo,
Geraldo da Rocha Castelar Pinheiro
Esta diretriz tem o objetivo de fazer recomendações sobre o
tratamento da artrite reumatoide no Brasil. Embora recentes
diretrizes norte-americanas e europeias para o tratamento da
artrite reumatoide tenham sido publicadas, é importante rever o assunto, considerando aspectos específicos da realidade
brasileira. Desta forma, o propósito final em estabelecer diretrizes consensuais para o tratamento da artrite reumatoide
no Brasil é definir e embasar os reumatologistas brasileiros,
utilizando evidências obtidas em estudos científicos e a experiência de uma comissão de especialistas no assunto, a fim de
homogeneizar a abordagem terapêutica da artrite reumatoide, dentro do contexto socioeconômico brasileiro, mantendo
a autonomia do médico na indicação/escolha das alternativas
terapêuticas disponíveis.
Como há rápida evolução do conhecimento nesse campo
da ciência, sugerimos a atualização dessas diretrizes a cada
dois anos.
Elaboração final
12 de abril de 2012
Descrição do método de coleta de evidência
A revisão bibliográfica de artigos científicos dessa diretriz foi
realizada na base de dados MEDLINE. A busca de evidência
partiu de cenários clínicos reais, e utilizou palavras-chaves
(MeSH terms): Arthritis, Rheumatoid, Therapy (early OR late OR
later OR time factors OR delay), Prognosis, Remission, Steroids, Anti-Inflammatory Agents, Non-Steroidal, NSAIDs, Diclofenac, Ibuprofen, Indomethacin, Piroxicam, COX-2, Celecoxib, Etoricoxib, Disease-modifying antirheumatic drug OR
DMARD, Methotrexate, Gold sodium, Leflunomide, Sulfasalazine, Hydroxychloroquine, Tumor Necrosis Factor-alpha, Adalimumab, Certolizumab, Etanercept, Infliximab, Golimumab,
Rituximab, Tocilizumab, Abatacept.
Graus de recomendação e força de evidência
A: Estudos experimentais e observacionais de melhor
consistência.
B: Estudos experimentais e observacionais de menor
consistência.
C: Relatos de casos (estudos não controlados).
D: Opinião desprovida de avaliação crítica, baseada em
consensos, estudos fisiológicos ou modelos animais
Introdução
A artrite reumatoide (AR) é uma doença sistêmica, inflamatória, autoimune, caracterizada pelo comprometimento da
membrana sinovial preferencialmente das articulações periféricas. Estima-se que a prevalência da AR seja de 0,5%–1%
da população, predominando no gênero feminino e na faixa
etária dos 30 aos 50 anos1,2(B).
O acometimento em geral simétrico das pequenas e grandes articulações é a característica principal da AR; o envolvimento das mãos e pés é comum. O caráter crônico e destrutivo
da doença pode levar à importante limitação funcional, com
perda da capacidade laboral e da qualidade de vida, a menos
que o diagnóstico seja feito em fase inicial da doença e que
o tratamento determine melhora clínica3(B). Além da deformi-
* Autor para correspondência.
E-mail: [email protected] (L.M.H. Mota)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
dade irreversível e da limitação funcional, pacientes com AR e
doença avançada podem apresentar menor sobrevida, o que
confirma a gravidade desta doença4(B)5(D).
Os custos relacionados à AR são elevados, o que decorre
tanto de fatores diretos (gastos com diversos medicamentos,
alguns deles de alto custo, como as drogas biológicas, despesas médicas e hospitalares) quanto indiretos (perda da produtividade pessoal, absenteísmo e pagamento de aposentadorias por invalidez, naqueles com perda total da capacidade
laborativa)6(B).
Nas últimas duas décadas, houve grande avanço no conhecimento dos mecanismos fisiopatológicos da AR, com o
desenvolvimento de novas classes terapêuticas e implementação de diferentes estratégias de tratamento e acompanhamento dos pacientes, como controle intensivo da doença e
intervenção na fase inicial dos sintomas7(D). O período inicial
da doença, em especial seus 12 primeiros meses, a chamada AR inicial5(D), é considerado uma janela de oportunidade
terapêutica, ou seja, um momento em que a intervenção farmacológica rápida e efetiva pode mudar o curso da doença
em longo prazo. Esses fatores resultaram no melhor controle
clínico da doença, com a possibilidade de remissão sustentada da AR7,8(D).
Tratamento da AR
O tratamento da AR inclui educação do paciente e de sua família, terapia medicamentosa, fisioterapia, apoio psicossocial, terapia ocupacional e abordagens cirúrgicas. As terapias medicamentosas, que serão abordadas neste documento, incluem uso
de anti-inflamatórios não hormonais (AINH), corticosteroides,
drogas modificadoras do curso da doença (DMCD) sintéticas e
biológicas e drogas imunossupressoras.
As DMCD devem ser indicadas para todo paciente a partir
da definição do diagnóstico de AR9(B). A utilização de DMCD em
pacientes com artrite indiferenciada e biomarcadores preditores de AR, como a positividade dos anticorpos antipeptídeos citrulinados cícliclos (anti-CCP) e/ou fator reumatoide (FR), pode
ser considerada10(B).
A Tabela 111–44(A)45–64(B)65–80(D) resume as principais DMCD
utilizadas no Brasil, sua apresentação, dose e considerações
sobre monitoração.
1. Tratar a doença com o objetivo de se atingir
remissão é um alvo factível?
Estabelecido o diagnóstico da AR, é importante a avaliação inicial da doença, incluindo aqui a monitoração adequada da atividade da doença, avaliando-se não apenas o acometimento
articular, mas também as manifestações extra-articulares e a
ocorrência de comorbidades.
Alguns dos parâmetros validados que se correlacionam
com a atividade da AR são: escalas visuais da dor pelo paciente, da atividade de doença pelo paciente e pelo médico, número de articulações dolorosas e edemaciadas, instrumentos de
avaliação da capacidade funcional (como o Health Assessment
Questionnaire – HAQ), provas inflamatórias (velocidade de hemossedimentação, VHS, e/ou proteína C-reativa, PCR), fadiga,
159
duração da rigidez matinal, radiografia de mãos, punhos e
pés e índices de qualidade de vida (como o SF-36 – Short form
36)81–83(A)84(B)85,86(C).
Utilizando esses parâmetros, foram criados e validados índices compostos da atividade de doença (ICAD). Os principais
índices são baseado na contagem de 28 articulações (Disease
Activity Score 28), o índice simplificado de atividade de doença
(SDAI –Simplified Disease Activity Index) e o índice clínico de atividade de doença (CDAI – Clinical Disease Activity Index). Esses
índices utilizam uma contagem articular mais simplificada, de
28 articulações (IFP, MCF, punhos, cotovelos, ombros e joelhos
bilateralmente) e determinam um valor numérico para atividade da AR. As Tabelas 2, 3 e 4 detalham melhor como calcular e
utilizar tais índices87–95(A)96(B).
Existe uma boa correlação entre os ICAD (CDAI, SDAI e DAS28), e qualquer um deles pode ser utilizado isoladamente. Pacientes que estão em remissão ou baixa atividade de doença,
por qualquer índice, também apresentam menor progressão
radiográfica e melhor evolução funcional. Portanto, deve-se
sempre objetivar manter o paciente em remissão clínica, ou, se
isso não for possível, ao menos em estado de baixa atividade
de doença87(A).
Em pacientes adultos com AR ativa com tempo de duração
variando entre quatro meses a cinco anos, mas principalmente
entre um a dois anos, o uso de metotrexato (MTX), principalmente em combinação com outras DMCD (ouro, cloroquina
ou sulfassalazina) leva à remissão clínica, medida pelos critérios do American College of Rheumatology (ACR), de 14,0%97(B),
33,3%98(A), 38,0%3(B) e 95%99(A); os melhores resultados são verificados nos primeiros seis meses após o tratamento. Pelo critério DAS-28, o índice de remissão em 24 meses é de 76%100(B).
Em associações de MTX com infliximabe, a remissão em
pacientes com menos de 36 meses de AR medida entre 54 semanas e 24 meses atinge níveis de 70%, pelo critério ACR101(A)
e de 21,3%, pelo critério SDAI102(A). De forma semelhante, associações de MTX com etanercepte alcançam índices
de remissão, em períodos de 12 a 36 meses, de 37% (DAS-44
≤ 1,6)103(A), de 50% (DAS-28 ≤ 2,6)43,45,104(A) e de 50% (DAS-28
≤ 3,2)105(A).
A remissão, medida por meio do parâmetro DAS-28 ≤ 2,6,
em pacientes com AR ativa (12 meses) em uso de adalimumabe e MTX, varia de 43%–45% em 4 a 9 anos28,106(A). A remissão
medida pelo critério SDAI é de 15% em 24 meses107(B). A presença inicial (nos primeiro 12 meses) de remissão nesses pacientes, mensurada por diferentes critérios, é: EULAR (DAS-28) de
47,7%, ACR 70 de 50,8% e DAS-28 de 32,3%108(B).
A resposta ao tratamento da AR recente (menos de 24 meses de doença) com associações de DMCD (MTX, ouro, cloroquina ou sulfassalazina) também tem sido medida por meio da
remissão, em períodos que variam entre 2–11 anos, valendo-se
de vários critérios ou parâmetros, com valores também distintos: ACR (14%–48%)109–113(B), DAS ≤ 2,4 (39%–43%)114,115(B) e DAS28 ≤ 2,6 (23%–51%)116,117(B).
Recomendação
A remissão em pacientes com AR, aferida por qualquer um
dos parâmetros objetivos de atividade da doença (DAS, DAS28, SDAI e CDAI), deve ser considerada como objetivo central
do tratamento desses pacientes.
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Tabela 1 – Drogas modificadoras do curso da doença (DMCD) utilizadas no tratamento da artrite reumatoide no Brasil.
Droga
Apresentação
Dose
Resposta clínica e monitoração
Drogas modificadoras do curso da doença sintéticas
Metotrexato
Comprimidos: 2,5 mg
Solução injetável: 50 mg/2 mL
10–30 mg/semana
(VO, IM ou SC)
Sulfassalazina
Comprimidos: 500 mg
1–3 g/dia (VO)
Leflunomida
Comprimidos: 20 mg
20 mg/dia ou em dias
alternados (VO)
Sulfato de
hidroxicloroquina
Difosfato de
cloroquina
Comprimidos: 400 mg
Até 6 mg/kg/dia (VO)
Comprimidos ou cápsulas:
150 mg ou 250 mg
Até 4 mg/kg/dia (VO)
Sais de ouro
(aurotioglicose ou
aurotiomalato de
sódio)
Solucão injetável:
50 mg/0,5 mL
50 mg/semana (IM profunda),
iniciando-se habitualmente
com 25 mg/semana.
Espaçamento para doses
quinzenais e mensais
após controle do quadro. A
dose cumulativa não deve
ultrapassar 3 g
Considerado atualmente o fármaco padrão no
tratamanto da AR, reduz sinais e sintomas de
atividade da doença, melhora o estado funcional e
reduz a progressão das lesões radiográficas.
Monitoração: hemograma, creatinina e enzimas
hepáticas a cada 4–12 semanas.
Reduz sinais e sintomas de atividade da AR, melhora
o estado funcional e reduz a progressão das lesões
radiográficas. Monitoração: hemograma e enzimas
hepáticas a cada 8–12 semanas. Pode ser usada
associada ao MTX e a outras DMCD.
Reduz sinais e sintomas de atividade da AR, melhora
o estado funcional e reduz a progressão das lesões
radiográficas. Monitoração: hemograma, creatinina
e enzimas hepáticas a cada 4–12 semanas. Pode ser
usada associada ao MTX e a outras DMCD.
Os antimaláricos são atualmente considerados drogas
menos potentes, e devem ser usados em casos
iniciais de AR ou artrite indiferenciada, com baixo
potencial erosivo. Podem ser usados associados
ao MTX ou a outros DMCD. Monitoração: exame
oftalmológico inicial e anual após cinco anos (ou
anualmente desde o princípio, se houver fatores de
risco para maculopatia ou retinopatia).
Eficazes no controle de sintomas e na redução da
progressão radiográfica. São pouco utilizados no
Brasil devido a os efeitos adversos e à dificuldade de
aquisição da droga em nosso meio.
Monitoração: mensal, com hemograma, enzimas
hepáticas e exame sumário de urina.
Drogas modificadoras do curso da doença biológicas
Bloqueadores de
fator de necrose
tumoral
Eficazes no controle de sinais e sintomas da AR e
na redução da progressão radiográfica. Devem ser
preferencialmente prescritos após falha a dois
esquemas com DMCD sintéticas (dos quais um deve
incluir terapia de combinação com DMCD sintéticas,
com MTX preferencialmente como a droga âncora
da combinação), em associação ao MTX ou a outra
DMCD sintética.
Monitoração: avaliação de tuberculose latente antes
do início do tratamento (história clínica, radiografia
de tórax, PPD e/ou IGRA), hemograma e enzimas
hepáticas a cada 4–12 semanas. Monitoração
cuidadosa da ocorrência de infecção, em particular
no primeiro ano de uso.
Adalimumabe
Certolizumabe
Seringas preenchidas: 40 mg
Seringas preenchidas: 200 mg
Etanercepte
Frascos: 25 mg e 50 mg de
solução para reconstituição
Seringas preenchidas: 50 mg
Frascos: 100 mg
Infliximabe
40 mg (SC) a cada 15 dias
400 mg (SC) a cada duas
semanas nas semanas 0, 2 e
4; após, 200 mg a cada duas
semanas ou 400 mg a cada
quatro semanas
50 mg/semana
3–5 mg/kg/dose (IV) nas
semanas 0, 2 e 6, seguida
pela mesma dose a cada 6–8
semanas
(continua)
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Tabela 1 – Drogas modificadoras do curso da doença (DMCD) utilizadas no tratamento da artrite reumatoide no Brasil
(continuação).
Droga
Apresentação
Dose
Resposta clínica e monitoração
Drogas modificadoras do curso da doença biológicas
Golimumabe
Modulador da
coestimulação
Abatacepte
Depletor de
linfócitos B
Rituximabe
Bloqueador do
receptor de IL-6
Tocilizumabe
Caneta aplicadora preenchida: 50 mg (SC) mensalmente
50 mg
Frascos: 250 mg
500 mg (IV) nos pacientes com Eficaz na redução de sinais e sintomas da AR e
menos de 60 kg, 750 mg (IV)
na redução da progressão radiográfica. Pode ser
nos pacientes com 60–100
prescrito após falha de DMCD sintéticas ou após
kg e 1.000 mg (IV) naqueles
falha e/ou intolerância a DMCD biológicas. Uso
com mais de 100 kg, a cada
preferencial associado ao MTX ou a outras DMCD
quatro semanas
sintéticas. Monitoração: hemograma e enzimas
hepáticas a cada 4–8 semanas. Monitorar ocorrência
de infecção.
Frascos: 500 mg
500 mg a 1 g (IV) nos dias 0 e
Eficaz na redução de sinais e sintomas da AR e
14 (1–2 g/ciclo)
na redução da progressão radiográfica. Pode ser
prescrito após falha e/ou intolerância aos anti-TNF
ou a outras DMCD biológicas. Não deve ser prescrito
após falha a DMCD sintéticas, exceto em situações
excepcionais. A presença de FR e/ou anti-CCP prediz
melhor resposta terapêutica ao rituximabe. Deve
ser prescrito preferencialmente associado ao MTX
ou a outra DMCD sintética. Os ciclos podem ser
repetidos em intervalos mínimos de seis meses,
de acordo com a evolução da doença. Monitoração:
hemograma e enzimas hepáticas a cada 4–12
semanas. Avaliar a ocorrência de infecção.
Frascos: 80 mg ou 200 mg
8 mg/kg/dose (IV) a cada
Eficaz na redução de sinais e sintomas da AR e
quatro semanas
na redução da progressão radiográfica. Pode ser
prescrito após falha a DMCD sintéticas ou após
falha e/ou intolerância aos anti-TNF ou a outras
DMCD biológicas. Uso preferencial associado ao
MTX ou a outras DMCD sintéticas, embora possa
ser utilizado em monoterapia. Monitoração:
hemograma, enzimas hepáticas e lipidograma a
cada infusão.
Drogas imunossupressoras
Azatioprina
Comprimidos: 50 mg
Ciclofosfamida
Comprimidos: 50 mg
Frascos: 200 mg ou 1000 mg
Ciclosporina
Consideradas menos eficazes no controle de sinais
e sintomas da AR e na redução da progressão
radiográfica. São opções inferiores às demais
DMCD. Sua principal indicação é para o tratamento
de manifestações extra-articulares e vasculite.
1–3 mg/kg/dia (VO)
2,5 mg/kg/dia (VO) ou
pulsoterapia mensal
com 750 mg a 1 g/m2 de
superfície corporal (IV) a
cada quatro semanas
Comprimidos: 50 mg e 100 mg 3–5,0 mg/kg/dia (VO)
Monitoração: hemograma e enzimas hepáticas a cada
4–8 semanas.
Reservado para pacientes com manifestações extraarticulares graves.
Monitoração: a cada quatro semanas com
hemograma, enzimas hepáticas e exame de urina
(pelo risco de cistite hemorrágica).
Pressão arterial e função renal a cada 2–4 semanas.
AR, artrite reumatoide; DMCD, droga modificadora do curso da doença; IGRA, ensaios de liberação do interferon gama; IM, intramuscular; IV,
intravenoso; MTX, metotrexato; PPD, teste tuberculínico; RTX, rituximabe; SC, subcutânea; VO, via oral.
2. A instituição precoce de tratamento para a AR
traz beneficios em relação ao início de tratamento
mais tardio, com relação a prognóstico clínico e
radiográfico?
Em pacientes que iniciaram o tratamento com DMCD não biológicas, o índice de remissão em 12 meses, definido como escore CDAI < 2,8, foi de 21,3% naqueles com menos de 5 anos
de doença, comparado com 19,6% nos pacientes com duração
de doença entre 6–10 anos, e 13,5% nos com mais de 11 anos
de doença. Há, portanto, maior chance de resposta (remissão),
de 1,7% (NNT = 60) e de 7,8% (NNT = 13) quando o tratamento
com DMCD sintéticas não biológicas é instituído com menos
de 5 anos de doença, quando comparado com pacientes com
diagnóstico entre 6–10 anos, ou mais de 11 anos de doença,
respectivamente51(B).
Já em pacientes que receberam tratamento com DMCD biológica anti-TNF, o benefício do início da terapia antes de 5 anos
de doença é de 4,6% (NNT = 22) e 9,5% (NNT = 10), quando comparado com 6–10 anos ou mais de 11 anos, respectivamente51(B).
A porcentagem de pacientes que obtém remissão sustentada
162
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
Tabela 2 – Cálculo e valor total dos índices compostos da atividade de doença (ICAD).
Elementos
Contagem de articulações
edemaciadas
Contagem de articulações
dolorosas
Reagentes de fase aguda
Avaliação global de saúde
(paciente)
Avaliação global de doença
(paciente)
Avaliação global de doença
(avaliador)
Índice total
(Variação do índice)
SDAI
CDAI
DAS-28 (com 4 variáveis)
(0–28) Soma simples
(0–28) Soma simples
Raiz quadrada da soma simples
(0–28) Soma simples
(0–28) Soma simples
Raiz quadrada da soma simples
PCR (0,1–10 mg/dL)
-
(0–10 cm)
(0–10 cm)
VHS 2–100 mm
ou PCR 0,1–10 mg/dL transformação
logarítmica
0–100 mm
(0–10 cm)
(0–10 cm)
-
Soma simples
(0,1–86)
Soma simples
(0–76)
Requer inserir número na
calculadora (0,49–9,07)
SDAI, índice simplificado de atividade de doença; CDAI, índice clínico de atividade de doença; DAS-28, índice de atividade de doença (28
articulações); PCR, proteína C-reativa; VHS, velocidade de hemossedimentação. Assumindo uma variação entre 2–100 mm/h para a VHS e entre
0,1–10 mg/dL para a PCR.
Tabela 3 – Pontos de corte dos índices compostos de
acordo com a atividade da AR.
Índice
SDAI
CDAI
DAS-28
Estado da atividade
de doença
(Remissão
Baixa
Moderada
Alta
Remissão
Baixa
Moderada
Alta
Remissão
Baixa
Moderada
Alta
Pontos de corte
≤5
> 5 e ≤ 20
> 20 e ≤ 40
> 40
≤ 2,8
≤ 10
> 10 e ≤ 22
> 22
≤ 2,6
> 2,6 e ≤ 3,2
> 3,2 e ≤ 5,1
> 5,1
SDAI, índice simplificado de atividade de doença; CDAI, índice
clínico de atividade de doença; DAS-28, índice de atividade de
doença (28 articulações).
Modificado a partir de Aletaha D, Smolen JS. The Simplified Disease
Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI):
A review of their usefulness and validity in rheumatoid arthritis.
Clin Exp Rheumatol 2005; 23(39):S100–8.
se mantém maior nos pacientes com menos de cinco anos de
doença, ao longo do tratamento.
Em pacientes com diagnóstico de AR e menos de cinco anos
de início dos sintomas, o uso de DMCD sintéticas (MTX, leflunomida, sulfassalazina, cloroquina/idroxicloroquina, sais de
ouro por via parenteral, ciclosporina) antes do primeiro ano
de sintomas produz menor progressão radiográfica da doença (medido pelo dano articular por meio do escore Ratingen),
quando comparado ao início do tratamento em pacientes com
sintomas de duração entre um e cinco anos. Os pacientes com
quatro anos de sintomas têm 0,31% maior chance de progressão das lesões articulares ao ano quando comparado aos pacientes tratados com menos de um ano de sintoma118(B).
O início de tratamento com DMCD precoce (< 9 meses de
início dos sintomas) produz redução relativa de 33% na progressão radiológica da doença no seguimento de três anos119(B).
Tabela 4 – Resposta de acordo com a variação de pontos
dos Índices Compostos de Atividade de Doença.
Índice
Tipo de resposta
Resposta
Boa: queda > 1,2 pontos e o paciente atingindo DASEULAR–DAS28 com baixa atividade (≤ 3,2).
2887,88(A)
Moderada: queda de 1,2 pontos do DAS-28; queda
entre 0,6 e 1,2 pontos com declínio da atividade
da doença de alta para moderada atividade ou de
moderada para baixa atividade.
Boa: queda de 17 pontos.
Resposta
Moderada: queda de 7 pontos.
SDAI90 (A)
Boa: queda de 14 pontos.
Resposta
Moderada: queda de 6 pontos.
CDAI90 (A)
SDAI, índice simplificado de atividade de doença; CDAI, índice
clínico de atividade de doença; DAS-28, índice de atividade de
doença (28 articulações).
Modificado de: Aletaha D, Funovits J, Wards MM, Smolen JS, Kvie TK.
Perception of improvement in patients with rheumatoid arthritis
varies with disease activity levels at baseline. Arthritis Rheum
2009;61:313–20.
Sabe-se também que a instituição de tratamento com 3 g/
dia de sulfassalazina ou > 15 mg/semana de MTX, nos primeiros três meses de início de sintomas, quando comparado com o
início do mesmo tratamento após 12 meses, produz os seguintes resultados: aumento do número de pacientes com resposta
(medido pelo DAS-28 < 3,2) em 32 meses de 40% (NNT=2); redução em quatro vezes na progressão de dano articular (medido
pelo escore radiológico de Larsen); e aumento de 35% (NNT=
3) do número de pacientes que alcançam ACR 50% e 70%120(B).
Entretanto, há evidência de que, em pacientes com início
de sintomas a menos de 24 meses, a instituição de terapia com
DMCD não biológicas com menos de cinco meses de sintomatologia não produziu diferença no índice de resposta medido
pelo ACR (20 ou 50) pelo DAS-44 < 1,6, quando comparado com
os pacientes que iniciaram o tratamento após cinco meses121(B).
Considerando-se quatro meses após o início dos sintomas
como o ponto de corte para demora ou retardo no tratamento
com 1,0 g de sulfassalazina (monoterapia), ou 500 mg de sulfassalazina duas vezes ao dia, 7,5 mg de metotrexato por semana,
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
300 mg de hidroxicloroquina e 5 mg de prednisolona ao dia (terapia combinada), verifica-se que, nos pacientes submetidos à
monoterapia, o índice de remissão da doença é 24% maior (NNT
= 4) quando o tratamento é precoce (< 4 meses), apesar de ser semelhante nos pacientes submetidos à terapia combinada110(B).
Em pacientes com AR em fase inicial tratados por 2 anos
com DMCD (MTX, associado ou não ao adalimumabe), pode-se
demonstrar que o acréscimo de tempo para se obter a remissão (SDAI) no primeiro ano de tratamento está acompanhado
de acréscimo na progressão de dano articular, avaliado por imagem, no segundo ano107(B).
Recomendação
A instituição de tratamento para pacientes com AR deve ser precoce (nos primeiros meses após o início dos sintomas), o que
aumenta o índice de resposta clínica (NNT de 2–4) e reduz a
progressão radiológica de dano articular nos primeiros anos de
tratamento.
3. O uso de corticoesteroides na fase inicial da
doença melhora o prognóstico do paciente?
O efeito mais conhecido e esperado dos corticosteroides na AR é
a melhora do processo inflamatório e da dor. Contudo, atualmente, há evidência para indicá-los como participantes da modificação do curso da doença, em associação com as DMCD14(A)66(D).
A maior parte dos trabalhos sobre o uso de corticosteroide no
tratamento da AR sugere a utilização da prednisona ou prednisolona em doses baixas (≤ 15 mg/dia). Não há estudos comparativos que permitam indicar doses mais altas preferencialmente
no início do tratamento14(A)66(D).
Como os corticosteroides têm vários eventos colaterais, seu
tempo de uso deve ser abreviado ao mínimo possível. Se seu uso
for previsto por três meses ou mais, deve ser feita suplementação de cálcio e vitamina D. A utilização de drogas antirreabsortivas como os bisfosfonatos pode ser considerada em pacientes
com fatores de risco para fraturas ou resultado de densitometria
óssea50(B).
Aconselha-se a utilização de proteção gástrica com inibidor
de bomba de próton em pacientes com uso concomitante de
corticosteroide e anti-inflamatório não esteroidal67(D).
O uso de corticosteroide intra-articular pode ser considerado
a qualquer momento do tratamento, em pacientes que mantenham doença ativa em poucas articulações67(D). Em pacientes
com AR inicial (menos de 12 meses de sintomas) e acometimento de articulações metacarpofalangeanas, a utilização de MTX
associado à infiltração intra-articular de metilprednisolona
pode reduzir a perda óssea nas articulações inflamadas122(B).
A prednisona (dose de 12,5 mg/dia por 2 semanas e 6,25 mg/
dia por 12 meses) associada ao MTX (15 mg/semana), em pacientes com AR inicial (menos de 12 meses de doença), permite
aumento no índice de remissão (segundo o DAS) em 6 meses de
43,4% (NNT: 2)115(B).
Em pacientes com artrite em fases iniciais (menos de 16
semanas de sintomas), o uso de glicocorticoide intramuscular
(uma injeção de 120 mg de metilprednisolona) não traz benefício com relação à remissão dos sintomas ou ao desenvolvimento de AR em 52 semanas123(B).
163
O uso de 1–4 mg de prednisona por dia, durante 24 semanas,
em pacientes com AR, reduz o risco de perda de adesão ao tratamento por falta de eficácia em 31% (NNT: 3)124(A).
Em pacientes com AR, o tratamento associado de MTX (15
mg por semana) e prednisolona (60 mg por dia, com redução
progressiva) durante 24 meses reduz a progressão radiológica,
melhora a resposta funcional (HAQ), mas aumenta o número
de pacientes com perda de adesão ao tratamento em 7% (NNH:
14)125(A).
A combinação de MTX (15 mg/semana) e prednisona (60 mg/
dia) em pacientes com AR leva, em 12 meses, ao aumento no
índice de remissão (DAS ≤ 2,4) em 18% (NNT: 6), aumento na resposta clínica (ACR) e melhora na capacidade funcional (HAQ),
e menor progressão radiológica, em comparação ao tratamento
sem a prednisona56(B)126(A). Entretanto, apesar de não haver aumento nos eventos adversos, os pacientes referem maior intolerância à associação127(B).
O tratamento de pacientes com AR inicial (menos de 12 meses de sintomas) utilizando DMCD associadas com prednisolona (7,5 mg/dia) durante 24 meses reduz a progressão radiológica das lesões articulares (Sharp escore) e aumenta a remissão
da doença (DAS-28) em 22,7% (NNT: 4), com poucos eventos
adversos128(A).
O uso de budesonida (9 mg/dia) ou prednisona (7,5 mg/dia)
em pacientes com AR (menos de 12 meses de doença) por 12 semanas determina melhora na atividade da doença (número de
articulações acometidas) e melhora funcional (HAQ)129(B).
Não há aumento do benefício clínico com o uso de prednisona 10 mg/dia, durante 24 meses, em pacientes com AR em fase
inicial. Entretanto, há evidências da redução de progressão radiológica de lesões articulares, e não há aumento no índice de
fraturas ósseas130,131(A).
A associação de prednisolona (dose inicial de 30 mg/dia e de
manutenção de 4,5 mg/dia) e DMCD em pacientes com AR recente resulta, em 12 meses, apenas redução na progressão radiológica das lesões (Larsen escore)132(B).
Recomendação
O uso de corticosteroide em pacientes com AR em fase inicial,
sobretudo de prednisona diária, associada a drogas modificadoras do curso da doença, principalmente o MTX, por 12 a 24
meses, traz benefício clínico e radiológico. Como os corticosteroides têm vários eventos colaterais, seu tempo de uso deve ser
abreviado ao mínimo possível, bem como sua dose deve ser a
menor possível.
4. A prescrição de anti-inflamatórios altera o
prognóstico da doença, com relação à evolução
clínica e radiográfica?
Os AINH são úteis para diminuir o processo inflamatório e a
dor, principalmente no início da doença, pois as DMCD não
têm ação imediata. Podem ser empregados também quando
não se obtém controle completo da atividade e em reagudizações da doença47(B)65(D).
Pacientes com menos de 12 meses de diagnóstico de AR
submetidos ao tratamento com AINH inicialmente (12 meses) de forma isolada e, se necessário, DMCD, em comparação
164
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
aos que receberam DMCD desde o início do tratamento (sais
de ouro, cloroquina, MTX ou sulfassalazina) têm pior resposta
clínica em cinco anos medida por VHS (em mm/hora), escore
médio de dor (escala visual analógica, VAS-100 mm), escore articular (Índice articular de Thompson – edema e dor articular
– 0 a 534), bem-estar geral (VAS-100 mm), duração da rigidez
matinal (máximo 720 minutos), força de preensão (kPa) aferida por vigorímetro, e incapacidade funcional medida pelo HAQ
(0–3)133(B). Dos pacientes que utilizaram o AINH inicial por 14
meses (na média), 86% desses descontinuam o tratamento por
inefetividade, seguindo com o uso de DMCD por 42 meses (na
média). Em pacientes que permanecem com o uso de AINH até
o final de cinco anos, houve pior evolução clínica e radiológica
em compração aos que descontinuaram o tratamento133(B).
Além disso, pacientes adultos com no mínimo seis meses de doença e antecedente de resposta clínica ao AINH, em
tratamento por 12 semanas com etoricoxibe 90 mg/dia, ou
naproxeno 500 mg duas vezes ao dia, apresentam índices de
descontinuidade por ineficácia variando de 12%–20% e 10%–
50%, respectivamente. No entanto, nos pacientes que permanecem sob tratamento, há sinais de benefício mensurado
pelos escores de avaliação global pelo paciente (PGA, patient
global assessment), Investigator of Global Assessment of Disease
Activity e número de articulações com edema134,135(A).
Pacientes com 12 meses de diagnóstico de AR foram submetidos a tratamento com sulfassalazina 1–2 g/dia comparado a diclofenaco 100 mg/dia. Dos pacientes, 11% e 20% dos
pacientes, respectivamente, não completaram os 12 meses
de tratamento por ineficácia. O número de erosões radiológicas foi significativamente maior nos pacientes tratados com
diclofenaco. Além disso, nos escores de atividade da doença
(VHS e DAS), edema articular, avaliação global pelo paciente e
HAQ, os pacientes tratados com sulfassalazina tiveram resultados 65%–82% superiores ao AINH136(B).
O uso de diclofenaco no tratamento da AR em atividade,
apesar de descontinuidade de 15%, produz resposta significativa em 12 semanas, nos critérios ACR20, avaliação global pelo
paciente, VAS para dor, no escore funcional HAQ e edema articular. Os desfechos medidos pela PCR e VHS não demonstram
benefício significativo137(A).
Paciente com AR há mais de três meses em uso de doses
diferentes de celecoxibe (100 mg ou 200 mg ou 400 mg) ou de
naproxeno (500 mg duas vezes ao dia) apresentam melhora
funcional em 12 semanas (HAQ) e de qualidade de vida (SF36), como também melhora medida pelo ACR20, número de
articulações acometidas, VAS de dor, HAQ e PGA, sem diferenças de resposta entre essas medicações. Entretanto, o naproxeno produz eventos adversos gastrointestinais em maio
número de pacientes138,139(A).
Pacientes com AR de no mínimo seis meses de duração,
em uso de celecoxibe 200 mg ou diclofenaco 75 mg duas vezes
ao dia, por 24 semanas, reduzem, sem diferença entre os tratamentos, o edema e a rigidez articular e os índices do escore
de PGA. Entretanto, os eventos adversos gastrointestinais estão significativamente mais presentes nos pacientes tratados
com diclofenaco140(A).
Há indícios de que o uso de AINH associado a DMCD seja
fator de prognóstico favorável à remissão dos pacientes com
AR141(B). A escolha dos AINH deve ser individualizada, pois
não há superioridade conhecida de qualquer fármaco dessa
classe. Maior controle, substituição, suspensão, menor tempo
de utilização e menores doses devem ser os cuidados, se houver condições clínicas que possam ser agravadas pelos AINH,
como por exemplo, hipersensibilidade prévia a AINH, hipertensão arterial sistêmica, insuficiência cardíaca, insuficiência
renal, doença gastrointestinal, insuficiência arterial, hepatopatia e distúrbios de coagulação48(B).
Para os pacientes com história prévia de doença gastrointestinal, os inibidores seletivos de ciclo-oxigenase 2 (COXIB)
apresentam menor risco em relação aos demais AINH49(B).
Para aqueles com maior risco de doença cardiovascular, o uso
de anti-inflamatórios em geral deve ser cauteloso13(A).
Recomendação
O uso de AINH como início de tratamento isolado nos pacientes com AR em atividade confere resposta clínica inferior nos
primeiros 24 meses quando comparado com o tratamento
associado com DMCD, além de cursar com alto índice de interrupção do tratamento por ineficácia. O índice de eventos
adversos gastrointestinais, associado à descontinuidade do
tratamento, ao curto tempo de avaliação de resposta ao tratamento, bem como ao pior prognóstico clínico radiológico, faz
do tratamento da AR com AINH de forma isolada uma conduta
não recomendada. Aparentemente, há sinais de que o uso de
AINH associado a DMCD na fase inicial seja fator de prognóstico favorável à remissão nos pacientes com AR.
5. O metotrexato deve ser a primeira alternativa de
tratamento?
O MTX é um agente imunomodulador, cuja ação consiste na
inibição da síntese do DNA, RNA, timidinato e proteínas. Os
efeitos anti-inflamatórios do MTX na AR parecem estar relacionados, pelo menos em parte, com a modulação do metabolismo da adenosina e efeitos possíveis nas vias do fator de
necrose tumoral (TNF, tumor necrosis factor). Os efeitos imunossupressores e tóxicos do MTX são devido à inibição da enzima envolvida no metabolismo do ácido fólico, a diidrofolato
redutase, o que evita a redução de diidrofolato a tetraidrofolato ativo. O tempo até a concentração máxima é de 1–5 horas
por via oral (VO) e de 30–60 minutos por via intramuscular (IM)
ou subcutânea (SC). Elimina-sem por via renal entre 40%–90%
de forma inalterada68(D). O MTX é atualmente considerado o
fármaco-padrão no tratamento da AR69(D). Sua capacidade de
reduzir sinais e sintomas de atividade da AR e melhorar o estado funcional do paciente foi demonstrada15(A). Também reduz
a progressão das lesões radiográficas.
Recomenda-se que a dose inicial seja de 10–15 mg/semana, VO ou parenteral (IM ou SC). Caso não se observe melhora
ou controle da doença com a dose inicial, deve-se aumentar
a dose progressivamente a cada 2–4 semanas até alcançar a
dose de 20–30 mg/semana, preferencialmente nas primeiras
12 semanas. A apresentação parenteral pode ser indicada em
pacientes com intolerância gastrointestinal ou resposta inadequada à forma oral70(D).
Os eventos adversos mais frequentemente observados são
anemia, neutropenia, náuseas e vômitos, mucosite e elevação
de enzimas hepáticas. Manifestações menos frequentes in-
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
cluem pneumonia intersticial. Está contraindicado em pacientes que apresentam insuficiência renal, hepatopatias, etilismo,
supressão da medula óssea e em mulheres em idade fértil que
não estejam fazendo anticoncepção. A gestação e a amamentação estão formalmente contraindicadas em pacientes que
fazem uso de MTX. Pode ser usado com cautela em pacientes
com pneumopatias leves e evitado em indivíduos com comprometimento pulmonar moderado ou grave70(D).
Sugere-se que a administração do MTX deva ser associada
ao uso de ácido fólico na dose de 5–10 mg/semana, 24–48 horas
após o MTX, a fim de minimizar eventos adversos70(D).
Recomendação
A eficácia do MTX está bem definida no tratamento da AR ativa
e recente. O MTX é atualmente considerado o fármaco-padrão
no tratamento da AR. Sua capacidade de reduzir sinais e sintomas de atividade da AR e melhorar o estado funcional do paciente foi demonstrada. Também reduz a progressão das lesões
radiográficas.
6. Outras DMCD, como leflunomida, sulfassalazina
e sais de ouro, são quivalentes ao MTX, em termos
de eficácia e segurança, para o tratamento da
doença?
Leflunomida
A leflunomida é um agente imunomodulador que inibe a enzima diidroorotato desidrogenase, envolvida na síntese da pirimidina, apresentando atividade antiproliferativa. A absorção é
pelo trato gastrointestinal e a biotransformação ocorre provavelmente no fígado e parede gastrointestinal, sendo a leflunomida transformada principalmente em M1, o metabólito ativo
responsável por todas as ações da medicação. O tempo para
concentração máxima (pico) da M1 é de 6–12 horas, e a eliminação é renal e intestinal71(D).
A leflunomida melhora a atividade de doença, a qualidade
de vida e reduz a progressão radiográfica18(A)53(B).
É prescrita na dose de 20 mg/dia (VO)18(A)53(B)71(D), mas dose
de 20 mg em dias alternados pode ser utilizada.
Os eventos adversos incluem náuseas, vômitos, dor abdominal e diarreia, alterações das enzimas hepáticas, exantema
cutâneo e hipertensão arterial sistêmica71(D). Está contraindicada em mulheres em idade fértil que não estejam utilizando
métodos anticoncepcionais, como também em pacientes com
insuficiência renal e hepatopatias. A gestação e a amamentação estão formalmente contraindicadas em pacientes que fazem uso de leflunomida, sendo recomendada sua suspensão
até dois anos antes de uma possível gravidez. Em casos de intercorrências, em especial na gravidez, a leflunomida pode ser
eliminada com a utilização de colestiramina na dosagem de 8
g/3 vezes ao dia, por 11 dias71(D).
A comparação entre MTX (25 mg/dia) e leflunomida (20 mg/
dia), associados à prednisona, durante 24 semanas em pacientes com AR há mais de 2,4 anos, não demonstrou diferença na
resposta clínica medida pelo DAS-28142(B).
Em revisão sistemática de Ensaios Clínicos Randomizados
(ECR) que estudaram o uso de leflunomida em pacientes com
165
AR ativa, concluiu-se que não há diferença em relação aos resultados clínicos, quando comparada ao uso de MTX143(A).
Em pacientes com AR em atividade, o uso da leflunomida
(20 mg/dia) em comparação com o MTX (15 mg/semana), por
quatro meses, não demonstrou diferença na resposta clínica
(ACR e VAS) ou funcional (HAQ), mas apresentou melhores resultados segundo os critérios de imagem por RM144(A). Devemos observar, no entanto, que essa comparação foi feita com
doses de MTX submáximas.
Não houve diferença entre leflunomida (20 mg/dia) e MTX
(15 mg/semana) com relação à resposta clínica (ACR) em 24
meses, no tratamento de pacientes com AR, mas a resposta
funcional (HAQ) foi superior com o uso da leflunomida145(A).
Em 24 meses de tratamento da AR com leflunomida (20 mg/
dia) ou MTX (15 mg/semana), os resultados foram semelhantes
comparando-se as duas formas de tratamento quanto ao ACR,
edema articular, avaliações globais e com relação à resposta
radiológica146(A). A resposta funcional (HAQ) também foi semelhante nas duas formas de tratamento146(A).
O uso de leflunomida (20 mg/dia) em pacientes com AR ativa
produziu efeitos semelhantes quanto à progressão radiológica
da doença, quando comparado ao MTX (15 mg/semana)147(B).
A resposta clínica (ACR) e radiológica de pacientes com AR
de duração maior que seis meses foi semelhante quando os
mesmos foram tratados por 52 semanas com leflunomida (20
mg/dia) ou MTX (7,5 mg/semana)148(A). Entretanto, os resultados
funcionais foram melhores em alguns componentes do HAQ e
SF-36 nos pacientes que fizeram uso de leflunomida149(A). Ressaltamos, entretanto, mais uma vez, que a dose de MTX utilizada nesse estudo foi inferior às doses habitualmente utilizadas
no tratamento da AR.
A tolerância ao tratamento de pacientes com AR ativa com
MTX (15 mg/semana) foi superior à terapêutica com leflunomida (20 mg/ dia), mas a eficácia clínica e radiológica em 12 meses
foi semelhante150,151(A)152(B).
Sulfassalazina
A sulfassalazina pertence ao grupo dos salicilatos e sulfamidas.
É desdobrada pelas bactérias intestinais na sulfapiridina e ácido 5-aminosalicílico. A sulfapiridina tem vários efeitos imunomodulatórios, como inibição da produção de prostaglandinas,
de diversas funções neutrofílicas e linfocitárias e da quimiotaxia. É também um inibidor de enzimas dependentes do folato. O
pico de concentração sérica é de aproximadamente 1,5–6 horas,
a meia-vida de eliminação de 5–10 horas, o metabolismo é feito
no trato gastrointestinal (via flora intestinal) e a excreção é renal (75%–91%)16(A).
É considerada mais efetiva que o placebo na redução da
atividade da doença, no controle da dor e na avaliação clínica
global. Confirmou-se sua eficácia clínica e interferência sobre a
progressão radiográfica16(A).
É usualmente prescrita na dose de 1–3g/dia (VO)16,17(A).
Os eventos colaterais incluem intolerância gastrintestinal
(anorexia, náuseas, vômitos), exantema cutâneo, elevação de
enzimas hepáticas, úlceras orais e mielossupressão (leucopenia
com neutropenia). Raramente observam-se pneumonia de hipersensibilidade, manifestações neurológicas ou alterações da
fertilidade masculina. A maioria dos efeitos é de caráter benigno e reversível com a retirada da droga17(A).
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Está contraindicada em pacientes com história de hipersensibilidade a sulfas, salicilatos ou a qualquer componente da fórmula da sulfassalazina e indivíduos com porfiria16,17(A).
Não houve diferença na resposta clínica (DAS ≤ 2,4) de pacientes com AR frente à monoterapia com MTX (15 mg/semana)
ou sulfassalazina (40 mg/kg/dia), apesar de que a combinação
entre as duas formas de tratamento produziu melhores resultados em 18 meses14(A).
Em pacientes com menos de 12 meses de AR, o tratamento
com sulfassalazina (2 g/dia), quando comparado com MTX (15
mg/semana), produziu em 52 semanas resultados semelhantes
(DAS, EULAR e ACR), entretanto sua combinação pareceu aumentar o benefício medido pelo DAS66(D).
Sais de ouro
Os sais de ouro, especificamente sob as formas injetáveis (aurotioglicose e aurotiomalato) são capazes tanto de reduzir os sintomas constitucionais e articulares quanto de retardar a evolução radiográfica da AR22(A). Podem ser usados em monoterapia
ou em combinação com outros agentes23(A).
A dose habitual é de 50 mg/semana, iniciando-se habitualmente com 25 mg/semana, sendo possível o aumento dos intervalos de aplicações para doses quinzenais e mensais após
controle do quadro. A dose cumulativa não deve ultrapassar 3
g22,23(A).
Seu perfil de toxicidade inclui mielotoxicidade (marcadamente trombocitopenia), úlceras orais, reações cutâneas (dermatite esfoliativa), nefropatia (podendo haver proteinúria nefrótica) e doença intersticial pulmonar22,23(A).
Embora tenham sido citados em recentes recomendações
internacionais66(D), atualmente os sais de ouro são muito pouco
utilizados no Brasil, dados os seus eventos adversos e a dificuldade de aquisição da droga em nosso meio.
A comparação entre MTX (15 mg/semana) e sais de ouro (50
mg/semana) no tratamento de pacientes com AR (duração > 4
meses) demonstra melhores resultados clínicos (edema e rigidez articular) no primeiro ano nos pacientes tratados com sais
de ouro, mas semelhança no terceiro ano de seguimento. Há
maior toxicidade no primeiro e no terceiro ano (aumento do risco de 38% – NNH: 3)98,153(A) e semelhança nos resultados quanto
à progressão radiológica em um154(A) e três anos22(A).
O uso de sais de ouro (50 mg/semana) no tratamento de pacientes com AR apresenta eficácia (clínica e funcional) semelhante ao tratamento com MTX (20 mg/semana), mas com aumento de toxicidade de 24% (NNH: 4)154(A).
Recomendação
Leflunomida, sulfassalazina e sais de ouro parecem apresentar
eficácia semelhante à do MTX no tratamento de AR ativa, havendo maior risco de intolerância, toxicidade e descontinuidade com essas drogas, em relação ao MTX.
7. Os antimaláricos são drogas eficazes no
tratamento da AR?
Os antimaláricos vêm sendo usados no tratamento da AR há
mais de 50 anos; eles são seguros e eficazes, sobretudo para
formas iniciais e leves. O mecanismo de ação ainda é pouco
conhecido, mas parece envolver múltiplos fatores: atividade
anti-inflamatória (estabilização das membranas lisossomais,
inibição de enzimas lisossômicas e da quimiotaxia e fagocitose de polimorfonucleares), interferência na produção de prostaglandinas, entre outros19,20(A).
As duas formas disponíveis são o difosfato de cloroquina
e o sulfato de hidroxicloroquina, sendo a última preferível
devido a seu melhor perfil de segurança, sobretudo oftalmológico. A dose máxima diária do difosfato de cloroquina é de
4 mg/kg/dia e do sulfato de hidroxicloroquina de 6 mg/kg/
dia VO, considerando-se o peso ideal do paciente. O início de
ação é lento, levando de 3 a 4 meses para atingir o pico de
eficácia em cerca de 50% dos pacientes.
Os eventos colaterais são diversos e incluem, entre outros, intolerância gastrintestinal (náuseas, vômitos, dor abdominal), hiperpigmentação da pele, cefaleia, tontura, miopatia, e retinopatia. Este último é infrequente, mas indica-se
monitoração oftalmológica regular (avaliação inicial e anual
após cinco anos, ou anual desde o princípio, se houver fatores de risco: pacientes com disfunção renal ou hepática, com
maculopatia, idosos ou dose cumulativa superior a 1.000 g
para o sulfato de hidroxicloroquina ou 460 g para difosfato
de cloroquina)72(D).
Em comparação com placebo, a hidroxicloroquina é eficaz, reduzindo os parâmetros clínicos e laboratoriais (VHS)
analisados, embora isoladamente não tenha alterado a progressão radiográfica19-21(A). Resultados similares foram observados com cloroquina, que apresenta menor custo. São
contraindicadas em pacientes que apresentem alterações
retinianas e de campo visual21(A)72(D).
Embora seu uso seja tradicional no Brasil, muitas vezes
em associação a outras DMCD, atualmente os antimaláricos
são considerados drogas menos potentes, devendo ser usados em casos iniciais de AR ou artrite indiferenciada,
com baixo potencial erosivo.
Existem vários estudos com esquemas terapêuticos dos
quais a hidroxicloroquina participa, entretanto não permitem uma análise específica e individualizada dos efeitos da
hidroxicloroquina no tratamento da AR em fase inicial.
Em pacientes com AR sem resposta ao uso de AINH, o
tratamento com hidroxicloroquina (200–400 mg/dia) por 12
semanas, levou à redução do edema, rigidez e dor articular
(20%, 23% e 26%, respectivamente), e aumentou a resposta
clínica (ACR20) em 20% (NNT: 5). Não houve aumento dos
eventos adversos155(A).
O tratamento com hidroxicloroquina (7 mg/ kg/dia) de pacientes com AR (tempo de doença menor que 24 meses) por
36 semanas reduziu o acometimento articular e a dor, como
também melhorou a resposta funcional20(A). O seguimento
desses pacientes por 36 meses demonstrou melhor evolução
quando comparado a pacientes tratados tardiamente (após
9 meses)156(B).
Não houve diferença na resposta terapêutica e número
de eventos adversos entre três doses diferentes de hidroxicloroquina (400 mg/dia, 800 mg/dia ou 1,2 g/dia) durante 24
semanas no tratamento da AR em fase inicial157(B).
Pacientes (AR com mais de seis meses de doença) tratados previamente com a associação de MTX (15 mg/semana)
e hidroxicloroquina (400 mg/dia) por 24 semanas, se bene-
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ficiaram de esquema de manutenção por mais 12 semanas
contendo hidroxicloroquina158(B).
Em pacientes com AR em fase inicial o tratamento com
hidroxicloroquina (400 mg/dia durante 24 semanas) reduziu
o acometimento articular em 10% (NNT: 10), diminuiu a dor
em 19% (NNT: 5), melhorou a avaliação global do paciente em
16% (NNT: 6) e do médico em 12% (NNT: 8). Houve aumento de
eventos adversos em 13% (NNH: 8)19(A).
A associação entre MTX (15 mg/semana) e hidroxicloroquina (200 mg/dia) no tratamento por seis meses de pacientes
com AR em fase inicial aumentou a resposta clínica e reduziu
a dor e o acometimento articular, em comparação ao tratamento com a monoterapia de hidroxicloroquina159(B).
Associar hidroxicloroquina (400 mg/dia) no tratamento de
pacientes com resposta parcial aos sais de ouro (seis meses)
não trouxe benefício com relação à dor e ao acometimento
articular160(B).
Recomendação
O tratamento da AR em fases iniciais da doença com hidroxicloroquina nas doses de 200–400 mg/dia apresenta benefícios
relacionados a dor, acometimento articular e de resposta clínica, demonstrado por meio de evidências fracas, seja pelas
medidas impróprias utilizadas para demonstrar o benefício,
pelo reduzido tamanho do benefício ou pela fraqueza da evidência de sustentação. Embora seu uso seja tradicional no
Brasil, muitas vezes em associação a outras DMCD, atualmente os antimaláricos são considerados drogas menos potentes,
devendo ser usados em casos iniciais de AR ou artrite indiferenciada, com baixo potencial erosivo.
DMCD biológicas
Um dos mais relevantes avanços em termos de terapia na AR
foi o desenvolvimento das DMCD biológicas. Embora essas
medicações sejam eficazes no controle da AR, ainda são necessários estudos de segurança a longo prazo. Encontram-se
aprovadas pela Agência Nacional de Vigilância Sanitária (ANVISA) para uso no Brasil as seguintes DMCD biológicas:
• Bloqueadores do TNF: adalimumabe, certolizumabe, etanercepte, infliximabe e golimumabe
• Depletor de linfócito B: rituximabe;
• Bloqueador da co-estimulação: abatacepte;
• Bloqueador do receptor de interleucina-6 (IL-6): tocilizumabe
Estão indicadas para os pacientes que persistam com atividade da doença, apesar do tratamento com pelo menos dois
esquemas de DMCD sintéticas (pelo menos um deles sendo
combinação de DMCD). O uso de agentes biológicos deve ser
feito associado a um DMCD, preferencialmente MTX. Excepcionalmente, como discutido abaixo, uma DMCD biológica
pode ser prescrita mais precocemente no curso do tratamento da AR, sobretudo em casos de doença com sinais de pior
prognóstico (elevado número de articulações acometidas,
erosões radiográficas na fase inicial da doença, fator reumatoide e/ou anti-CCP presentes em altos títulos).
Características sociais/educacionais/demográficas das
diferentes macro-regiões brasileiras, como a dificuldade de
167
aplicação de medicação SC por determinados pacientes e
seus familiares, bem como a inexistência de centros de infusão para aplicação de medicação intravenosa em certos
locais, podem determinar a escolha de uma ou outra DMCD
biológica. Os centros de dispensação/infusão públicos ou
privados das drogas devem informar os pacientes e familiares sobre o adequado acondicionamento de cada medicação, ou enviá-las diretamente para o local de infusão, para
evitar perda de eficácia do tratamento. Recomenda-se que
o uso desses fármacos seja indicado e monitorado por um
reumatologista78(D).
A associação de DMCD biológicas não deve ser utilizada
pelo potencial risco de infecções graves
8. A instituição de terapia biológica com drogas
anti-TNF, como o adalimumabe, o certolizumabe,
o etanercepte, o infliximabe e o golimumabe, é
eficaz e segura em pacientes com AR?
Atualmente, as DMCD biológicas mais utilizadas são os bloqueadores do TNF. O TNF é uma potente citocina inflamatória
expressa em grandes quantidades no soro e no líquido sinovial de indivíduos com AR. Ela promove a liberação de outras
citocinas inflamatórias, particularmente as interleucinas IL-1,
IL-6 e IL-8 e estimula a produção de proteases. A inibição do
TNF demonstrou ser uma forma efetiva e rápida de controlar
a atividade da doença79(D).
Em termos de eficácia, não existem dados que permitam
afirmar a superioridade de qualquer um dos cinco agentes
anti-TNF aprovados no Brasil para tratamento da AR55,56(B).
Os anti-TNF devem ser utilizados em associação ao MTX
ou outras DMCD, pois o uso combinado mostrou ser seguro
e propiciou rápido benefício no controle da atividade da doença, comparado ao uso do anti-TNF como monoterapia. Em
pacientes que apresentem contraindicações ao uso de DMCD
sintéticas, os anti-TNF podem eventualmente ser prescritos
em monoterapia77(D)26-31,43,44(A)45,57,58(B).
Adalimumabe
O adalimumabe é um anticorpo monoclonal humano contra o TNF, prescrito para aplicação SC na dose de 40 mg uma
vez a cada 2 semanas28,33-37,45(A).O seguimento de 52 semanas
de pacientes com AR tratados com MTX e adalimumabe (40
mg ou 20 mg em semanas alternadas) demonstrou aumento
na resposta clínica (ACR50) de 32% (NNT: 3) e de 28,2% (NNT:
4), respectivamente, quando comparado com a monoterapia
com MTX. Ocorreu também redução na progressão radiológica e melhora funcional (HAQ), sem aumento nos eventos
adversos161(A)162(B).
O tratamento de pacientes com AR por meio da combinação de adalimumabe 40 mg em semanas alternadas com MTX
(20 mg por semana) aumentou a resposta clínica (ACR50) em
21% (NNT: 5) e 16% (NNT: 6) quando comparado com a monoterapia com adalimumabe e MTX, respectivamente. Houve
também redução na progressão radiológica e aumento na remissão clínica (DAS-28 ≤ 2,6) de 20% (NNT: 5) e de 22% (NNT:
5), quando comparado com a monoterapia com adalimumabe
e MTX, respectivamente57(B).
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A resposta clínica (ACR50) obtida com adalimumabe 40 mg
em semanas alternadas, durante 24 semanas, no tratamento
de pacientes com AR em concomitância com o uso de DMCD
sintéticas, aumentou a resposta clínica (ACR50) em 17,6% (NNT:
6) e não aumentou o risco de eventos adversos e eventos adversos sérios34(A).
A associação de adalimumabe nas doses de 20 mg ou 40 mg
ou 80 mg associado ao MTX (15 mg/semana) durante 24 semanas quando comparado com a monoterapia com MTX, produziu aumento na resposta clínica (ACR50) em 23,8% (NNT: 4),
47,1% (NNT: 2) e 30,4% (NNT: 3), respectivamente, sem diferença
na ocorrência de eventos adversos163(A).
Certolizumabe
O certolizumabe pegol é um fragmento Fab de um anticorpo
anti-TNF humanizado, com alta afinidade ao TNF, conjugado
com duas moléculas de polietilenoglicol. É prescrito para aplicação SC na dose de 400 mg a cada 2 semanas, nas semanas 0,
2 e 4, e, após isso, na dose de 200 mg a cada 2 semanas ou 400
mg a cada 4 semanas30,31,37(A).
O tratamento com certolizumabe 200 mg ou 400 mg a cada
2 semanas, por 52 semanas, associado ao MTX (15 mg/semana), aumentou a resposta clínica (ACR50) em 29,5% (NNT: 3),
reduziu a progressão radiológica das lesões e aumentou a resposta funcional (HAQ), quando comparado com a monoterapia
de MTX. Houve aumento de eventos adversos sérios em 35%
(NNH: 3) com ambos os regimes de certolizumabe. Não houve
diferença de resposta ou eventos adversos entre as doses164(A).
Houve ainda evidências de impacto positivo na qualidade de
vida desses pacientes30(A). Pelo critério RAPID3 houve aumento na remissão de 32% (NNT: 3) nos pacientes tratados com
certolizumabe165(B), e a resposta clínica foi também superior
pelo ACR escore híbrido166(B).
Etanercepte
O etanercepte é uma proteína de fusão composta pelo receptor
solúvel do TNF mais a região Fc da IgG, prescrita na dose de 50
mg em dose única semanal por via SC36(A)43,45,59(B).
Em 52 semanas de seguimento de pacientes com AR pode-se concluir que o tratamento com etanercepte (50 mg/semana)
associado ao MTX (15 mg/semana), quando comparado à monoterapia com MTX, aumentou a remissão da doença em 22,5%
(NNT: 5) e reduziu a progressão radiológica das lesões105(A). Esse
efeito foi mantido após 24 meses de seguimento45(B).
O uso de etanercepte (50 mg/semana) em pacientes com
AR em atividade, durante 24 semanas, associado ou não à sulfassalazina (2–3 g/dia), foi superior quanto à resposta clínica
(ACR50) em 32% a 38% (NNT: 3), entretanto houve aumento no
número de infecções em 19,6% (NNH: 5), bem como de reações
infusionais167(A). Em 24 meses de seguimento, houve menor
descontinuidade no tratamento por ausência de eficácia nos
pacientes submetidos ao tratamento com etanercepte (NNT: 2),
e o benefício permaneceu sustentado. Houve, no entanto, aumento na ocorrência de eventos adversos infecciosos e eventos
adversos da aplicação local168(B).
A análise da resposta clínica de pacientes com AR, pelo ACR-N, em 24 semanas de tratamento com etanercepte (50 mg/semana) associado ao MTX (15 mg/semana) foi maior em 6,1%
(NNT: 17)169(A). Após 52 semanas, a remissão da doença permaneceu evidente nos pacientes que recebem etanercepte, combinado ou não com MTX, sendo de 18,2% (NNT:6) e de 12,4% (NNT:
8), respectivamente170(B). Também em 52 semanas houve redução na progressão radiológica da lesão nesses pacientes171(B).
Pacientes de AR tratados com etanercepte (50 mg/semana)
apresentaram resposta clínica (ACR50) em três anos de 51%,
mantida em cinco anos. Houve redução na atividade da doença
(DAS < 2,4) em 44% dos pacientes. Entretanto, 44% dos pacientes apresentam episódios de infecção, podendo haver a ocorrência de neoplasias e morte relacionada ao tratamento172,173(C).
Em 12 meses de tratamento de pacientes com AR, o uso de
etanercepte 50 mg/semana produziu maior benefício do que a
dose de 20mg/semana. Quando comparado com MTX (15 mg/
semana), a resposta clínica (ACR50) foi semelhante, apesar de
haver maior progressão radiológica das lesões e de eventos adversos nos pacientes tratados com MTX174(A). Esses resultados
foram mantidos em 24 meses de seguimento; a resposta funcional (HAQ) foi melhor em 18% (NNT: 6) nos pacientes que fizeram uso de etanercepte59(B).
Em pacientes com resposta inadequada à associação de
MTX (15 mg/semana) e etanercepte (50 mg/semana), o aumento da dose de etanercepte para 100 mg/semana não melhorou a
resposta clínica desses pacientes175(A).
Infliximabe
O infliximabe é um anticorpo monoclonal anti-TNF quimérico-humano/murino, prescrito na dose inicial de 3 mg/kg administrados via IV, seguida da mesma dose (3 mg/kg) nas segunda e
sexta semanas e, a seguir, a cada oito semanas76(D). Em pacientes com resposta insuficiente, a dose pode ser elevada para 5
mg/kg por infusão, ou o intervalo entre as doses reduzido. Doses maiores trazem pouco benefício terapêutico e maior risco
de complicações infecciosas, pelo que devem ser evitadas no
tratamento da AR27,58(B)36,38,44(A).
Em pacientes com AR não responsivos ao MTX (15 mg/semana), associar infliximabe (3 mg/kg inicialmente nas semanas 0, 2 e 6 e depois a cada 8 semanas), quando comparado à
associação com sulfassalazina e hidroxicloroquina, aumentou
a resposta clínica, pelo critério EULAR, em 14% (NNT: 7), e pelo
critério ACR50 em 10% (NNT: 10)58(B).
O tratamento de pacientes com AR utilizando infliximabe
(3 mg/kg ou 10 mg/kg, nas semanas 0, 2 e 6, e depois a cada 8
semanas) combinado com MTX (15 mg/semana), durante 22 semanas aumentou a resposta clínica em 22,4% (NNT: 5) e 25,7%
(NNT: 4), e a remissão da doença (DAS-28 < 2,6) em 17,0% (NNT:
6) e 18,0% (NNT: 6), respectivamente. Não houve diferenças de
resposta entre os dois regimes de tratamento com infliximabe.
Não houve diferença de eventos adversos com o uso de infliximabe nesses pacientes, independente da dose176(A).
O tratamento de pacientes com AR por meio da associação
entre infliximabe 3 mg/kg ou 6 mg/kg, inicialmente nas semanas 0, 2 e 6, depois a cada 8 semanas e MTX (15 mg/semana),
durante 54 semanas, aumentou a resposta clínica (ACR-N) em
12,5% (NNT: 8) e 20,3% (NNT: 5), respectivamente, a resposta
clínica (ACR50) em 13,5% (NNT: 7) e 18,3% (NNT: 6), reduziu a
progressão radiológica das lesões (escore Sharp) e aumentou a
resposta funcional em 6,2% (NNT: 16) e em 16,0% (NNT: 6), respectivamente. Não houve diferença de eficácia entre os dois re-
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
gimes de tratamento. Com o uso de infliximabe, houve aumento de eventos adversos sérios em 3,5% (NNH: 30), com a dose
de 3 mg/kg e em 2,9% (NNH: 33), com a dose de 6 mg/kg177(A).
Golimumabe
O golimumabe é um anticorpo monoclonal humano anti-TNF
administrado na dose de 50 mg/mês por via SC44,60(B).
O tratamento de pacientes com AR por meio da associação de MTX (15 mg/semana) e golimumabe (50 mg a cada 4
semanas) por 24 semanas demonstra benefício (ACR50) de
10,9% (NNT: 10) e de 13,9% (NNT: 7) no índice de remissão
(DAS-28 ≤ 2,6), quando comparado com à monoterapia com
MTX. Não há aumento de eventos adversos na combinação
em relação à monoterapia44(B). A resposta radiológica (Escore
Sharp) também é superior na combinação de golimumabe 50
mg e MTX178(B).
Em 14 semanas de tratamento de pacientes com AR por
meio da associação de MTX (15 mg/semana) e golimumabe
(50 mg ou 100 mg a cada 4 semanas), houve aumento de resposta clínica em 25,0% (NNT: 4) e 19,4% (NNT:5), respectivamente, e também na remissão (DAS-28), de 14,2% (NNT: 7) e
16,5% (NNT:6), respectivamente. Entretanto, houve aumento
de eventos adversos e eventos adversos sérios, com a dose de
100 mg em comparação à dose de 50 mg179(A). Após o seguimento de 52 semanas, apesar dos índices de resposta clínica
e remissão estarem mantidos, não houve mais diferença com
relação à monoterapia43(B).
Em 24 semanas de tratamento com golimumabe (2 mg/kg
ou 4 mg/kg) associado ao MTX, a percentagem de pacientes
que atinge resposta clínica (ACR50) aumentou em 9,3% (NNT:
10) e 17,7% (NNT: 6), respectivamente, em comparação com a
monoterapia com MTX. A remissão (DAS-29 ≤ 2,6) no mesmo
período foi superior apenas na dose de 4 mg/kg. E não houve
diferença em eventos adversos e adversos sérios entre a combinação de MTX e golimumabe e a monoterapia com MTX180(A).
O tratamento da AR por meio da associação de MTX com
golimumabe nas doses de 50 mg ou 100 mg, a cada 2 ou 4
semanas, por 16 semanas, apresentou aumento na resposta
clínica (ACR50) em todos os regimes, sem diferença entre eles,
e no índice de remissão (DAS-28 ≤ 2,6), sendo que o único regime de tratamento que não demonstrou benefício comparado
com a monoterapia com MTX foi o de 50 mg a cada 4 semanas. Não houve diferença na ocorrência de eventos adversos
entre as diversas formas de tratamento181(A).
Eventos adversos e contraindicações dos bloqueadores de TNF
Os efeitos adversos incluem reações infusionais para as drogas IV (febre, calafrios, dor torácica, oscilação de pressão arterial, dispneia, prurido e/ou urticária) e manifestações nos
locais de injeção para as drogas SC (eritema, prurido, dor local
e/ou urticária). Estas drogas aumentam a chance de infecções,
especialmente no primeiro ano de uso (incluindo infecções
graves e aquelas causadas por patógenos intracelulares como
o bacilo da tuberculose, listeria, histoplasma, micobacterias
atípica, legionella) disfunção cardíaca, doenças desmielinizantes, fenômenos autoimunes (produção de autoanticorpos),
vasculites cutâneas, doença pulmonar intersticial e eventual
aumento do risco de linfoma37,39(A)61,62(B).
169
Anticorpos antiquiméricos humanos (HACA, human anti-chimeric antibody) podem ocorrer com todas as drogas da classe,
mas seu efeito sobre a eficácia da terapia é incerto63,64(B).
As medicações anti-TNF são contraindicadas em mulheres grávidas ou que estejam amamentando, em pacientes
com insuficiência cardíaca congestiva classe III e IV segundo
a classificação da New York Heart Association, em vigência de infecção ativa ou com elevado risco para o desenvolvimento de
infecções (úlcera crônica de membros inferiores, artrite séptica nos últimos 12 meses), infecções pulmonares recorrentes,
esclerose múltipla, e com diagnóstico atual ou pregresso de
neoplasias (menos de cinco anos). Deve-se acompanhar o paciente de maneira cuidadosa, avaliando o possível surgimento
de sinais de infecção, que deve ser tratada de forma pronta e
imediata39(A)61,62(B).
Recomendação
O tratamento de pacientes com AR pode ser realizado com
DMCD biológicas anti-TNF, incluindo adalimumabe (40 mg via
SC a cada 2 semanas), certolizumabe (400 mg via SC a cada 2 semanas, nas semanas 0, 2 e 4, e, após, 200 mg a cada 2 semanas
ou 400 mg a cada 4 semanas ou mensalmente), etanercepte (50
mg via SC a cada 2 semanas ), golimumabe (50 mg via SC a cada
4 semanas ou mensalmente) ou infliximabe (3 mg/kg via IV nas
semanas 0, 2 e 6, e após a cada 8 semanas). Todas as DMCD biológicas anti-TNF devem ser preferencialmente prescritas em
associação a MTX (15 mg por semana) ou a outra DMCD sintética, com benefício clínico, radiológico, de remissão e funcional,
podendo haver aumento do risco de eventos adversos sérios e
de reação local à aplicação.
9. O rituximabe é uma alternativa segura e eficaz
para tratamento de pacientes com AR?
O rituximabe é um anticorpo monoclonal quimérico dirigido
contra o linfócito CD20+, indicado para pacientes com AR em
atividade moderada à grave que tiveram falha terapêutica ao
agente anti-TNF. O rituximabe é administrado na dose de 1.000
mg em duas infusões intravenosas em intervalo de 14 dias.
Cada infusão é precedida da utilização de 100 mg de metilprednisolona IV 60 minutos antes, 1 g de paracetamol e anti-histamínico para diminuir a gravidade e a frequência das reações
infusionais81–83(A)86(C).
Deve-se considerar, dada a gravidade do quadro, que há relatos da ocorrência de leucoencefalopatia multifocal progressiva com o uso de rituximabe182(C).
É utilizado preferencialmente em associação com o MTX,
podendo ser prescrito em associação com outras DMCD. É importante ressaltar que pode haver retardo em 3–4 meses para
que se observe o início da melhora sintomática81–83(A). O rituximabe apresenta melhor resposta terapêutica em indivíduos
com sorologia positiva para FR e/ou anti-CCP84(B).
Os indivíduos com boa resposta ao tratamento podem ser
submetidos a novo curso de rituximabe, caso reativem a doença, em intervalo de tempo não inferior a seis meses81–83(A)86(C).
Os eventos adversos mais frequentes são as reações infusionais que ocorrem em 35% dos pacientes na primeira infusão
e cerca de 10% na segunda infusão. Complicações infecciosas
170
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
podem ocorrer, bem como pneumonia intersticial,neutropenia
e trombocitopenia81–83(A)86(C).
Em pacientes com AR, o uso de rituximabe (duas doses de
500 mg IV com intervalos de 15 dias entre as aplicações) combinado com MTX (10–25 mg/semana), bem como o uso de etanercepte (50 mg/semana) ou adalimumabe (40 mg a cada 15 dias),
não determinou aumento de risco de eventos adversos, inclusive eventos adversos sérios, em relação ao placebo combinado
com metotrexato, durante 24 semanas. Houve aumento no risco
de reações infusionais de 22% (NNH: 5) e de infecções grau 3 de
15% (NNH: 7). Não houve diferença na resposta clínica (ACR50) e
no índice de remissão (DAS-28 < 2,6)183(A).
O tratamento de pacientes com AR (tempo de doença entre
oito semanas a quatro anos) durante 52 semanas com rituximabe de 1 g ou 2 g, associado a MTX, aumentou a resposta clínica
(ACR50) em 17% e 23%, respectivamente, e o índice de remissão
(DAS-28 ≤ 2,6) em 20% e 23%, respectivamente. Houve aumento
também na resposta funcional (HAQ). Não houve aumento na
ocorrência de eventos adversos184(A).
O tratamento de pacientes com AR, cujo quadro não foi responsivo à terapia com MTX, com rituximabe 1 g ou 2 g, após 24
semanas, aumentou a resposta clínica (ACR50) em 17% (NNT: 6).
Não houve aumento nos eventos adversos82(A).
O tratamento de pacientes com AR (resposta inadequada ao
uso de MTX) com rituximabe após 48 semanas, comparando-se
as doses de 1 g, 1 g inicial e depois de 24 semanas, 2 g (escalonado), e 2 g, demonstrou resposta clínica (ACR50) semelhante,
resposta clínica EULAR superior na dose de 2 g em comparação
com 1 g, e remissão (DAS-28 < 2,6) favorável a 1 g em relação à
dose escalonada. Não houve diferença quanto à ocorrência de
eventos adversos185(A).
O tratamento de pacientes com AR não responsiva a drogas
anti-TNF-α e em uso de MTX, com rituximabe 1 g, após 24 semanas, reduziu a progressão radiológica da doença, diminuiu a dor
(FACIT-F), melhorou a resposta funcional (HAQ) e a qualidade de
vida (SF-36)83,186(A). A resposta clínica (ACR50 e EULAR) aumentou em 22% (NNT: 5) e em 43% (NNT: 2), respectivamente81(A).
O tratamento de pacientes com AR e FR positivo, utilizando
a associação de rituximabe e MTX após 24 semanas, comparado com a monoterapia, obteve aumento na resposta clínica
(ACR50) variando de 10%–20%. Um maior número de pacientes
permaneceu sem tratamento adicional por 48 meses, assim
como houve um impacto positivo na capacidade funcional,
(NNT: 4)187(A).
Em pacientes não responsivos ao tratamento com DMCD sintéticas, o uso de rituximabe 1 g ou 2 g, após 24 semanas, aumentou em 20% o número de pacientes com resposta clínica (ACR50
ou EULAR) e reduziu a atividade de doença (DAS-28)188(A).
A combinação de rituximabe (1 g) e MTX (10 mg/semana)
no tratamento de pacientes com AR produziu, em 24 semanas,
melhores resultados quando comparado com a monoterapia
dessas medicações: aumento na resposta clínica (ACR50) de
10%–30%, aumento na resposta clínica (EULAR) e no índice de
remissão da doença (DAS-28). Não houve diferença entre o número de eventos adversos189(A).
Recomendação
Em pacientes com AR com resposta inadequada ao MTX ou outras DMCD sintéticas e a anti-TNF, o uso de rituximabe (doses
de 1 g e 2 g), sobretudo associado ao MTX, melhora a evolução
clínica, radiológica e funcional, podendo haver aumento do risco de eventos adversos.
10. O tocilizumabe é uma droga de comprovada
utilidade para o tratamento de AR?
O tocilizumabe é um anticorpo monoclonal humanizado que
se liga ao receptor de IL-6, inibindo o efeito biológico da IL-6.
Pode ser usado em monoterapia, associado ao MTX ou outras
DMCD. A incidência de infecções e infecções graves é equivalente aos outros agentes biológicos. É prescrito na dose de 8
mg/kg por via IV, a cada 4 semanas87,88(A)96(B).
O uso de tocilizumabe pode ocasionar neutropenia, plaquetopenia e elevação de transaminases como eventos adversos
dose-dependentes. Pode ainda ocorrer elevação de colesterol
total e da lipoproteína de baixa densidade (LDL, low density protein), bem como aumento da ocorrência de infecções87,88(A)96(B).
Deve-se evitar sua utilização em pacientes com maior chance
de perfuração intestinal, como indivíduos que apresentam doença diverticular do cólon89(A).
Pacientes com AR e resposta inadequada ao MTX, quando
recebem tocilizumabe (4 mg/kg ou 8 mg/kg a cada 4 semanas
por 52 semanas) apresentam resultados positivos com relação
à resposta clínica (ACR70), de remissão (DAS < 2,6), funcional
(HAQ) e radiológica (escore Sharp). A progressão radiológica da
doença é reduzida em 74% e 70%, respectivamente, em relação
à monoterapia com o MTX. Há melhora significativa funcional
em ambas as doses, sendo de 15,4% (NNT: 6) e 9,9% (NNT: 10),
respectivamente, a manutenção de resposta funcional > 0,3
unidades. A resposta clínica é de 6,0% (NNT: 16) e 3,5% (NNT:
30), respectivamente. A remissão da doença é de 39,3% (NNT: 2)
e de 22,3% (NNT: 5), respectivamente. Há incidência de 2% de
neoplasiasnos pacientes que recebem tocilizumabe, e 2,5% de
reações anafiláticas severas (4 mg/kg), com aumento no risco
de eventos adversos severos de 5% (NNH: 20)190(A).
Em pacientes com duração de AR entre seis meses e cinco
anos, o uso de 8 mg/kg de tocilizumabe a cada 4 semanas, por 52
semanas, comparado com DMCD sintéticas, levou à redução da
progressão radiológica de doença em 15% (NNT: 7), sendo esse
efeito maior nos pacientes sob alto risco de progressão191(A). A
eficácia clínica (ACR50) foi de 51% (NNT: 2). O índice de remissão 56% maior (NNT: 2) e de resposta funcional de 28% (NNT: 4).
Houve aumento na ocorrência de eventos adversos sérios em
5% com o uso de tocilizumabe (NNH: 20), e incidência de 2% de
neoplasias e 7% de reações infusionais. Não houve diferenças
nos eventos adversos leves e moderados entre as duas formas
de tratamento191(A).
A comparação entre tocilizumabe 8 mg/kg, a cada 4 semanas, com MTX 15 mg/semana durante 24 semanas, no tratamento de pacientes com AR, determina resultado favorável ao
tocilizumabe, com aumento de resposta clínica (ACR50) em
10,6% (NNT: 9) e de remissão da doença (DAS-28 < 2,6) em 21,5%
(NNT: 5). As reações adversas mais frequentes foram infecções,
sem diferença entre as duas formas de tratamento. Houve
aumento de reações infusionais com o tocilizumabe em 3,8%
(NNH: 30)96(A).
Em pacientes com tempo de AR superior a 6 meses, o tratamento com tocilizumabe 8 mg/kg a cada 4 semanas associado
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
a DMCD, quando comparado à monoterapia com essas drogas
(MTX, cloroquina, sais de ouro, sulfassalazina, azatioprina ou
leflunomida), produz, em 24 semanas, aumento na resposta
clínica (ACR50) de 29% (NNT: 3), aumento na remissão (DAS28 < 2,6) e de resposta funcional (HAQ) de 26% (NNT: 4). Há
aumento no risco de ocorrência de eventos adversos de 11,7%
(NNH: 9)192(A).
Pacientes com AR e resposta inadequada ao MTX, quando
recebem tocilizumabe (4 mg/kg ou 8 mg/kg a cada 4 semanas
por 24 semanas), apresentam resultados positivos com relação à resposta clínica (ACR50), de remissão (DAS < 2,6) e funcional (HAQ). Há melhora significativa funcional em ambas
as doses. A resposta clínica é de 20% (NNT: 5) e 33%(NNT: 3),
respectivamente. A remissão da doença é de 12,2% (NNT: 8) e
de 26,2% (NNT:4), respectivamente. Não houve diferença entre
os diversos eventos adversos; a infecção é o mais frequente
deles193(A).
Recomendação
O tratamento de pacientes com AR, sobretudo com resposta inadequada ao MTX, utilizando tocilizumabe associado ao
MTX, ou a DMCD sintéticas, ou como monoterapia, produz
benefício na resposta clínica, funcional, radiológica e de remissão. O tocilizumabe também é eficaz nos pacientes não
responsivos aos anti-TNF. Pode haver aumento do risco de
eventos adversos.
11. O abatacepte é uma opção terapêutica para
pacientes com AR, considerando seu perfil de
segurança e eficácia?
O abatacepte é uma proteína de fusão CTLA-4-IgG, atuando
como inibidor de moléculas de co-estimulação dos linfócitos
T. É indicado para pacientes com AR ativa que tenham apresentado falha terapêutica a DMCD ou aos agentes anti- TNF.
Pode ser utilizado associado aos DMCD ou como monoterapia.
O abatacepte deve ser administrado como infusão IV, durante
30 minutos, na dose de 500 mg nos pacientes com menos de
60 kg, 750 mg nos pacientes entre 60–100 kg e 1.000 mg naqueles com mais de 100 kg de peso corporal. A dose seguinte
deve ser administrada duas e quatro semanas após a dose
inicial,depois a cada quatro semanas40-42 (A). O uso de abatacepte está associado a uma maior ocorrênciade complicações
infecciosas quando comparado ao placebo, assim como observado com outras DMCD biológicas. As reações infusionais
com abatacepte são pouco frequentes e são, principalmente,
reações de hipersensibilidade que se manifestam por exantema ou broncoespasmo. É contraindicado em pacientes com
quadro de doença pulmonar obstrutiva crônica (DPOC), por
exacerbação do quadro de dispneia e maior ocorrência de
infecções40(A)85(C).
O uso de abatacepte (10 mg/kg a cada 4 semanas) em
pacientes com AR de duração média de 8,5 anos produz benefício de 30% (ACR50). A cada três pacientes tratados, há
um paciente em ACR50, não havendo aumento de eventos
adversos194(A).
Pacientes com AR de ao menos 12 meses de duração, não
responsivos ao MTX, submetidos a tratamento com abatacep-
171
te de 500–1000 mg a cada 30 dias, por 12 meses, apresentam
aumento no índice de resposta clínica pelo critério EULAR
de 12,1% (NNT: 9), DAS-28 de 9,9% (NNT: 10) e ACR50 de 9,1%
(NNT: 11). Há melhora funcional (HAQ) de 20,6% (NNT: 5). Não
há aumento de eventos adversos195(A).
Em pacientes com AR não responsivos ao tratamento com
anti-TNF-α, o uso de abatacepte de 500–1.000 mg por seis meses determina resposta clínica pelo critério ACR50 de 16,5%
(NNT: 6), e resposta funcional de 24,0% (NNT: 4). Não há aumento dos eventos adversos196(A). Em 24 meses há resposta
clínica pelo critério ACR50 de 32,3%, e remissão (DAS-28) de
20,3%. A resposta funcional é de 47,9%197(B).
Em um ano de tratamento com abatacepte 500–1.000 mg,
pacientes com AR não respondedores a MTX apresentaram
melhora clínica (ACR50) de 30,1% (NNT: 3). A função física melhorou em 24,7% (NNT: 4), não havendo diferença nos eventos adversos198(A). Em 24 meses de tratamento, os pacientes
apresentaram melhora clínica (ACR50) de 55,6% e remissão
(DAS-28) de 30,9%199(B).
Recomendação
Em pacientes com AR não responsivos ao tratamento com
MTX ou anti-TNF, o uso de abatacepte em doses entre 500–
1.000 mg apresenta aumento na resposta clínica (ACR50), de
remissão (DAS-28) e capacidade funcional (HAQ) em 6–12 meses, com manutenção dos índices em 24 meses, podendo haver aumento do risco de eventos adversos.
12. Há indicação de que algum dos esquemas
de terapia biológica seja superior aos demais no
tratamento de pacientes com AR?
O tratamento de pacientes com AR pela associação de MTX
(15 mg/semana) e golimumabe (50 mg a cada 4 semanas) por
24 semanas demonstra benefício (ACR50) de 10,9% (NNT: 10) e
de 13,9% (NNT: 7) no índice de remissão (DAS-28 < 2,6), quando comparado com à monoterapia com MTX44(A).
O seguimento de 52 semanas de pacientes com AR tratados com MTX e adalimumabe (40 mg em semanas alternadas)
demonstra aumento na resposta clínica (ACR50) de 32% (NNT:
3), quando comparado com a monoterapia de MTX162(A). Há
também redução na progressão radiológica e aumento na remissão clínica (DAS-28 < 2,6) de 23% (NNT: 5) quando comparado com a monoterapia com MTX, respectivamente74(D).
Em 52 semanas de seguimento de pacientes com AR, o
tratamento com etanercepte (50 mg/semana) associado ao
MTX (15 mg/semana), quando comparado à monoterapia com
MTX, aumenta a remissão da doença (DAS-28) em 22,5% (NNT:
5). A resposta clínica (ACR50) é superior em 22% (NNT: 5)105(A).
O tratamento de pacientes com AR com infliximabe 3 mg/
kg, inicialmente nas semanas 0, 2 e 6, e depois a cada oito semanas, combinado com MTX (15 mg/semana) durante 22 semanas, aumenta a resposta clínica (ACR50) em 22,4% (NNT: 5)
e a remissão da doença (DAS-28 < 2,6) em 17,0% (NNT: 6)176(A).
O tratamento com certolizumabe 200 mg a cada 2 semanas, por 52 semanas, associado ao MTX (15mg/semana), aumenta a resposta clínica (ACR50) em 29,5% (NNT: 3), quando
comparado com a monoterapia de MTX. A remissão pelo DAS-
172
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
28 é de 16% (NNT: 6). Há aumento de eventos adversos sérios
em 35% (NNH: 3)164(A)165(B).
O tratamento de pacientes com AR (tempo de doença entre
oito semanas e quatro anos) durante 52 semanas com rituximabe (1,0 g IV com intervalo de infusão de 15 dias), associado
a MTX, aumenta a resposta clínica (ACR50) em 17% (NNT: 6),
e o índice de remissão (DAS-28 ≤ 2,6) em 20% (NNT: 5)184(A).
Pacientes com AR e resposta inadequada ao MTX, quando recebem tocilizumabe (8 mg/kg a cada 4 semanas por 24 semanas) associado ao MTX, apresentam resultados positivos com
relação à resposta clínica (ACR50) e à ocorrência de remissão
(DAS ≤ 2,6). Há melhora significativa funcional com ambas as
doses. A resposta clínica é de 33% (NNT: 3). A remissão da doença é de 26,2% (NNT: 4). Não há diferença entre os diversos
eventos adversos; a infecção é o mais frequente deles193(A).
Pacientes com AR de ao menos 12 meses de duração, não
responsivos ao MTX, submetidos a tratamento com abatacepte de 500–1.000mg a cada 30 dias, por 12 meses, apresentam
aumento no índice de resposta clínica pelo critério DAS-28 de
9,9% (NNT: 10) e ACR50 de 9,1% (NNT: 11)195(A).
A Tabela 5 resume as medidas de ACR50 e DAS-28 expressas pelo benefício estimado por meio do Número Necessário
para Tratar (NNT).
Recomendação
Os diversos esquemas terapêuticos utilizando DMCD biológicas associadas ao uso de MTX nos pacientes com AR, quando
comparados com a monoterapia com MTX, utilizando como
parâmetros ACR50 e DAS-28, apresentam resultados semelhantes, com pequenas variações no NNT (ACR50 de 3–11 e
DAS-28 de 4–10). Não há comparações diretas que permitam
estimar de forma precisa as diferenças de benefício entre os
diversos biológicos.
Estratégias de tratamento da AR no Brasil
As DMCD devem ser iniciadas imediatamente após o diagnóstico. Sempre que necessário, o tratamento deve ser ajustado
em avaliações clínicas frequentes dentro de um período de
30–90 dias.
Estratégias terapêuticas baseadas em metas específicas produzem melhores desfechos clínicos e de capacidade
Tabela 5 – Medidas de ACR50 e DAS-28 espressas pelo
benefício estimado por meio do Número Necessário
para Tratar (NNT).
Índice
Golimumabe
Adalimumabe
Etanercept
Infliximabe
Certolizumabe
Rituximabe
Tocilizumabe
Abatacepte
Estado da
atividade
de doença
50 mg
40 mg
50 mg
3 mg/kg
200 mg
1000 mg
8 mg/kg
500–1000 mg
Pontos de
corte
24 semanas
52 semanas
52 semanas
22 semanas
52 semanas
52 semanas
24 semanas
52 semanas
NNT
ACR50
DAS-28
10
3
5
5
3
6
3
11
7
5
5
6
6
5
4
10
funcional, bem como menor dano estrutural radiológico, em
comparação com tratamentos convencionais94(A). A meta a
ser alcançada é a remissão, ou pelo menos a baixa atividade, avaliada por índices compostos de atividade de doença
(ICAD), considerandose resposta terapêutica a redução do
valor do ICAD, conforme estabelecido no Consenso 2011 da
Sociedade Brasileira de Reumatologia para Diagnóstico e Avaliação Inicial da Artrite Reumatoide5(D).
Primeira linha – drogas modificadoras do curso da doença
sintéticas
O MTX deve ser a DMCD de primeira escolha95(A)66,200(D). Havendo contraindicação, sulfassalazina201(A) ou leflunomida143(A)
podem ser utilizadas como primeira opção202(B). O uso de antimaláricos (difosfato de cloroquina e hidroxicloroquina)203(B)
pode ser indicado apenas para pacientes com doença leve ou
artrite indiferenciada com baixo potencial erosivo. Em casos
excepcionais, como pacientes com hipersensibilidade a outras
DMCD, ou com hepatite viral, sais de ouro podem ser utilizados.
O MTX deve ser prescrito preferencialmente em monoterapia, no início do tratamento128(A).
Não havendo a resposta clínica objetivada (remissão
ou baixa atividade da doença) com dose máxima tolerada
de MTX ou na presença de eventos adversos, recomenda-se a sua troca por outra DMCD em monoterapia ou o uso
de combinações de DMCD. As combinações mais utilizadas
são MTX com cloroquina, com sulfassalazina ou a associação dessas três drogas15(A), bem como MTX associado com
leflunomida204(A). A progressão da terapia deve ser rápida,
com avaliações mensais do paciente nos primeiros seis meses de tratamento, e ajuste de doses e esquemas conforme
necessário. Deve-se aguardar um período máximo de seis
meses para definir ausência de resposta à primeira linha de
tratamento instituída66(D).
Doses baixas de corticosteroides (máximo de 15 mg/dia de
prednisona ou equivalente) podem ser utilizadas no início do
tratamento, bem como anti-inflamatórios, recomendandose,
no entanto, cautela e uso pelo menor tempo possível, para
minorar a ocorrência de efeitos adversos66(D).
Segunda linha – drogas modificadoras da doença biológicas
A terapia imunobiológica na AR está indicada para os pacientes que persistem com atividade moderada à alta de doença
(conforme ICAD), apesar do tratamento com pelo menos dois
dos esquemas propostos na primeira linha de tratamento. As
drogas anti-TNF são a primeira opção no Brasil dentre os biológicos, após a falha aos esquemas com DMCD sintéticas. Isto
é justificável pela mais abrangente experiência pós-comercialização, bem como maior volume de informações de segurança oriundas de estudos clínicos, registros e recomendações
nacionais205(B) e internacionais66(D). Entretanto, outras drogas
como abatacepte e tocilizumabe podem ser prescritas a critério do médico assistente após a falha à DMCD sintética, tendo em vista a publicação de ensaios clínicos randomizados
que embasam essa indicação40,88(A). O emprego de rituximabe
deve ser evitado como biológico de primeira escolha66(D), a
não ser em casos específicos (pacientes com contraindicação
a outros biológicos, preferencialmente que sejam positivos
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
para FR e/ou anti-CCP ou aqueles que apresentam diagnóstico
associado de linfoma, por exemplo).
Em situações excepcionais, a DMCD biológica pode ser indicada após a falha ao primeiro esquema de DMCD sintética
naqueles pacientes com associação/combinação de fatores
de mau prognóstico, incluindo doença com atividade muito
intensa, elevado número de articulações dolorosas/inflamadas, FR e/ou anti-CCP em altos títulos e ocorrência precoce de
erosões radiográficas66(D). Os fatores de pior prognóstico são
mais bem detalhados no Consenso 2011 da Sociedade Brasileira de Reumatologia para Diagnóstico e Avaliação Inicial da
Artrite Reumatoide5(D).
O uso de drogas biológicas como primeira linha para o tratamento da AR não está indicado no Brasil, pois não há evidências da custoefetividade dessa indicação em nosso país.
Terceira linha – falha ou intolerância à droga modificadora
do curso da doença biológica
Em cenários clínicos que cursam com ausência na resposta
ao tratamento biológico inicial, evolução para perda da resposta obtida, ou presença de eventos adversos importantes,
pode ser feita a troca de um agente biológico por outro. Os
biológicos que apresentaram benefícios em ensaios clínicos
randomizados com pacientes que falharam ao anti-TNF são
abatacepte, rituximabe e tocilizumabe206(B). Pacientes que
apresentaram falha ao primeiro agente anti-TNF também
demonstraram benefício com o uso de uma segunda droga
da mesma classe, incluindo adalimumabe, certolizumabe,
etanercepte, infliximabe ou golimumabe em estudos observacionais prospectivos e também randomizado controlado
duplo cego (golimumabe), mas persistem incertezas sobre a
magnitude de seus efeitos terapêuticos e a custo-efetividade
dessa estratégia207(B).
A escolha da sequencia do tratamento a ser empregada
fica a critério médico, a depender de particularidades de
cada caso. Recomendase um período mínimo de três meses
e máximo de seis meses de avaliação clínica para proceder
a troca de esquema terapêutico (mudança entre DMCD biológicas).
Retirada de medicações e eventual suspensão de terapia
Não há dados que permitam definir o tempo de uso de terapia para a AR, e, no momento, a medicação indicada e à qual
o paciente apresente resposta adequada deve ser mantida
por período indefinido, a critério médico. Em caso de resposta completa (remissão) e sustentada (por mais de 6–12
meses), pode-se tentar a retirada gradual e cuidadosa na seguinte sequência: primeiramente AINH, seguidos por corticosteroides e DMCD biológicas, mantendo-se o uso de DMCD
sintéticas208(B). Excepcionalmente, se a remissão se mantiver, pode-se com muita cautela, tentar a retirada da DMCD
sintética66(D). A remissão sustentada livre de drogas é pouco
frequente, especialmente em pacientes com biomarcadores
como anti-CCP e/ou FR.
A figura 1 sintetiza o fluxograma de tratamento medicamentoso para a AR no Brasil, proposto pela Comissão de AR
da SBR.
173
Monitoração do tratamento
Na doença inicial, nos pacientes que tenham doença ativa,
com até 12 meses de sintomas, recomenda-se o acompanhamento intensivo com visitas mensais e progressão medicamentosa rápida quando necessário209(B)210(D). Os esquemas
terapêuticos e os seus possíveis eventos adversos foram abordados nos itens anteriores.
Em cada visita, deve-se avaliar a eficácia e segurança
da inter venção terapêutica, considerando as comorbidades do paciente e visando preferencialmente a remissão
ou menor atividade da doença possível, assim como a melhora funcional e da qualidade de vida. No paciente com a
doença estabelecida, e especialmente naqueles com doença controlada, as visitas podem ser realizadas a cada três
meses108,109,209(B)210(D).
A Tabela 6 resume, de forma esquemática, a frequência de
monitoração dos principais parâmetros considerados para
avaliação adequada de um paciente com AR em tratamento.
Conflitos de interesse
Mota LMH: Participou de estudos clínicos e/ou experimentais
patrocinados pelas empresas Roche e Mantecorp. Recebeu
auxílio pessoal ou institucional das empresas Abbott, AstraZeneca, MSD, Roche e Pfizer. Foi palestrante em eventos ou
atividades patrocinadas pelas empresas Abbott, MSD, Novartis, Roche e Wyeth.
Cruz BA: Participou de estudos clínicos e/ou experimentais
patrocinados pela empresa Roche. Recebeu auxílio pessoal
ou institucional das empresas Abbott, Bristol-Myers Squibb,
Mantecorp, MSD, Novartis, Roche, Wyeth e Pfizer. Foi palestrante em eventos ou atividades patrocinadas pelas empresas
Abbott, MSD, Mantecorp, Novartis, Roche e Wyeth.
Brenol CV: Participou de estudos clínicos e/ ou experimentais patrocinados pelas empresas Bristol-Myers Squibb, Pfizer,
Roche e Wyeth. Recebeu auxílio pessoal ou institucional das
empresas Abbott, Bristol-Myers Squibb, Mantecorp, MSD, Roche e Wyeth. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Abbott e Roche.
Rezende-Fronza LS: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Bristol-Myers Squibb, Pfizer e Roche. Elaborou textos científicos em periódicos
patrocinados pela empresa Pfizer.
Bertolo MB: Foi palestrante em eventos ou atividades patrocinadas pelas empresas Abbott, Pfizer, Sanofi Aventis.
Freitas MVC: Recebeu auxílio pessoal ou institucional das
empresas Abbott, MSD, Pfizer, Roche e Wyeth. Foi palestrante
em eventos ou atividades patrocinadas pelas empresas Abbott, MSD, Pfizer, Roche Wyeth. É membro do conselho consultivo ou diretivo da indústria farmacêutica ou de comitês
normativos de estudos científicos patrocinados pelas empresas AstraZeneca, MSD e Wyeth. Elaborou textos científicos em
periódicos patrocinados pelas empresas Abbott, AstraZeneca,
Bristol-Myers Squibb, Wyeth.
Silva NA: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Bristol-Myers Squibb e Roche. Recebeu auxílio pessoal ou institucional das empresas
Abbott, MSD, Pfizer, Roche e Wyeth. Foi palestrante em even-
174
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
Monoterapia
(preferencialmente MTX)
Em todas as fases:
‡Prednisona até 15 mg/dia
ou equivalente (usar pelo
menor tempo possível)
Primeira
linha
Falha após 3 meses
Resposta parcial ao MTX
Intolerância ao MTX
‡ŽƌƟĐŽŝĚĞ intra-ĂƌƟĐƵlar
e/ou AINH e analgésicos
Falha após 3 meses
Combinação de
DMCD ƐŝŶƚĠƟcas
Troca entre os
DMCD ƐŝŶƚĠƟcas
Falha após 3 meses
Segunda
linha
DMCD ƐŝŶƚĠƟca
(preferencialmente MTX)
+
DMCD biológica
(anƟ-TNF como primeira opção ou ABAT ou TOCI)
Falha após 3–6 meses
Terceira
linha
Falha ou intolerância à DMCD biológica:
Manter DMCD ƐŝŶƚĠƟca (preferencialmente MTX)
e mudar DMCD biológica para outro ĂŶƟ-TNF ou
ABAT ou RTX ou TOCI
Falha após 3–6 meses
Doença ĂƟǀĂ͗
Considerar os ICAD visando remissão,
ou pelo menos baixa ĂƟǀŝĚĂĚĞ de doença
Figura 1 – Fluxograma de tratamento medicamentoso para a AR no Brasil, proposto pela Comissão de AR da SBR.
DMCD, drogas modificadoras do curso da doença; MTX, metotrexato; anti-TNF, medicações antifator de necrose tumoral;
ABAT, abatacepte; RTX, rituximabe; TOCI, tocilizumabe; ICAD, índices compostos de atividade da doença.
Tabela 6 – Monitoração do tratamento da artrite reumatoide.
Parâmetro
Avaliação
inicial
Avaliação
mensal (na AR
inicial)
Consultas
extras
Avaliação a cada
3 meses (na AR
estabelecida)
Avaliação anual
Educação do paciente e
familiares
ICAD +
mHAQ ou HAQ-DI (0–3
pontos)
X
X
X
X
X
X
X
X
X
X
X
FR/anti-CCP
X
Radiografia convencional
(mãos e punhos, pés
e tornozelos, outras
articulações acometidas)
Ressonância ou
ultrassonografia articular
(em caso de dúvida quanto
à sinovite)
Pesquisa de manifestações
extra-articulares*
Avaliação de comorbidades**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(redução mínima desejada de
0,22 pontos)
X
(nos 2 anos iniciais podem
ser repetidos caso sejam
negativos na primeira
avaliação)
X
X
(continua)
175
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3
Tabela 6 – Monitoração do tratamento da artrite reumatoide (continução).
Parâmetro
Avaliação inicial
Provas de atividade
X
inflamatória (VHS e PCR)
Avaliação laboratorial***
X
Avaliação vacinal
X
Tratamento medicamentoso
X
específico para AR****
Tratamento medicamentoso
X
de comorbidades
PPD (ou IGRA) e radiografia do
X
tórax (em caso de prescrição
de DMCD biológica, em
especial anti-TNF)
Terapia ocupacional
X
Reabilitação
X
Avaliação da indicação de
X
órteses
Avaliação de indicação
X
cirúrgica
Coordenação de equipe
X
multidisciplinar
Aconselhamento gestacional
X
Avaliação de infecções
X
(avaliação clínica e
Sorologias (hepatite B
eventualmente exames
e C no início da
complementares)
investigação, HIV
em situações
selecionadas)
Avaliação e orientação
X
quanto a situações de
emergência*****
Avaliação
mensal (na AR
inicial)
Consultas
extras
Avaliação a cada
3 meses (na AR
estabelecida)
Avaliação anual
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ICAD, Índices compostos de atividade de doença (SDAI, índice simplificado de atividade de doença; CDAI, índice clínico de atividade de doença;
DAS-28, índice de atividade de doença – 28 articulações); +, para metas dos ICAD, vide publicação do Consenso 2011 da SBR para Diagnóstico e
Avaliação inicial da AR; mHAQ, Health Assesment Questionnaire modificado; HAQ-DI, Health Assesment Questionnaire – índice de incapacidade;
VHS, velocidade dehemossedimentação; PCR, proteína C-reativa; PPD, teste tuberculínico; IGRA, ensaios de liberação do interferon gama.
*Manifestações extra-articulares: nódulos reumatoides, doença pulmonar intersticial, serosites, inflamação ocular e vasculites.
**Comorbidades: hipertensão arterial, isquemia cardiovascular, diabetes mellitus, aterosclerose, baixa massa óssea, depressão, fibromialgia etc.
***Exames laboratoriais: hemograma, função hepática, lipidograma e função renal; dependendo das comorbidades, considerar exames adicionais.
****Medicação para AR: considerar as questões de eficácia e segurança de cada medicação detalhadas ao longo do texto.
*****Urgências na AR: escleromalácea perfurante, mielopatias, mononeurite múltipla e vasculite, gravidez de pacientes em uso de medicações
teratogênicas.
tos ou atividades patrocinadaspelas empresas Janssen, Mantecorp, MSD e Roche.
Louzada-Junior P: Participou de estudos clínicos e/ou experimentais patrocinados pelas empresas Merck e Roche.
Recebeu auxílio pessoal ou institucional da indústria Abbott.
Foi palestrante em eventos ou atividades patrocinadas pelas
empresas Bristol-Meyers Squibb, Pfizer e Roche.
Giorgi RD: Recebeu auxílio pessoal ou institucional das
empresas Bristol-Myers Squibb e Roche. Foi palestrante em
eventos ou atividades patrocinadas pelas empresas Bristol-Myers Squibb e Roche. Foi palestrante em eventos ou atividades patrocinadas pelas empresas Bristol- Myers Squibb e
Roche.
Lima RAC: Participou de estudos clínicos e/ou experimentais patrocinados pela empresa Mantecorp e Roche. Recebeu
auxílio pessoal ou institucional das empresas Acteion, Lilly e
Pfizer. Foi palestrante em eventos ou atividades patrocinadas
pelas empresas Acteion, Lilly e Pfizer.
Pinheiro GRC: Recebeu auxílio pessoal ou institucional das
empresas Janssen e Roche.
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antirheumatic agents in rheumatoid arthritis in patients with
an inadequate response to conventional disease-modifying
antirheumatic drugs or to an anti-tumournecrosis factor
agent: a meta-analysis. Ann Rheum Dis. 2011;70:266-71.
Malottki K, Barton P, Tsourapas A, Uthman AO, Liu Z, Routh
K, et al. Adalimumab, etanercept, infliximab, rituximab and
abatacept for the treatment of rheumatoid arthritis after the
failure of a tumour necrosis factor inhibitor: a systematic
review and economic evaluation. Health Technol Assess.
2011;15:1-278.
O’Mahony R, Richards A, Deighton C, Scott D. Withdrawal
of disease-modifying antirheumatic drugs in patients with
rheumatoid arthritis: a systematic review and meta-analysis.
Ann Rheum Dis. 2010;69:1823-6.
Grigor C, Capell H, Stirling A, McMahon AD, Lock P,
Vallance R, et al. Effect of a treatment strategy of tight
controlforrheumatoid arthritis (the TICORAstudy): a singleblindrandomised controlledtrial. Lancet. 2004;364:263-69.
Deighton C, O’Mahony R, Tosh J, Turner C, Rudolf M. Guideline
Development Group. Management of rheumatoid arthritis:
summary of NICE guidance. BMJ. 2009;338:b702.
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Documento de diretrizes
Diretrizes para o tratamento da síndrome do anticorpo
antifosfolipídeo
Adriana Danowskia,*, Jozelia Regob, Adriana M. Kakehasic, Andreas Funked,
Jozelio Freire de Carvalhoe, Isabella V. S. Limaf, Alexandre Wagner Silva de Souzag,
Roger A. Levyh
a
Hospital Federal dos Servidores do Estado (HFSE), Rio de Janeiro, RJ, Brasil
Faculdade de Medicina, Universidade Federal de Goiás (UFG), Goiânia, GO, Brasil
c
Departamento Locomotor, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brasil
d
Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brasil
e
Centro Médico Aliança, Salvador, BA, Brasil
f
Universidade Federal da Bahia (UFBA), Salvador, BA, Brasil
g
Disciplina de Reumatologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/Unifesp), São Paulo, SP, Brasil
h
Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brasil
b
informações
resumo
Histórico do artigo:
A síndrome do anticorpo antifosfolipídeo (SAF) é uma doença sistêmica autoimune carac-
Recebido em 11 de dezembro de 2012
terizada por trombose arterial e venosa, morbidade gestacional e presença de níveis séricos
Aceito em 13 de dezembro de 2012
de anticorpos antifosfolipídeos elevados e persistentemente positivos. O tratamento da SAF
ainda é sujeito a controvérsias, já que qualquer decisão terapêutica potencialmente irá con-
Palavras-chave:
frontar-se com o risco de uma cobertura antitrombótica insuficiente ou com o risco excessivo
Síndrome do anticorpo antifosfo-
associado à anticoagulação e seus principais efeitos adversos. Esta diretriz foi elaborada a
lipídeo
partir de nove questões clínicas relevantes e relacionadas ao tratamento da SAF pela Comis-
Tratamento
são de Vasculopatias da Sociedade Brasileira de Reumatologia. O objetivo deste trabalho foi
Gestação
criar uma diretriz que incluísse as questões mais relevantes e controversas no tratamento da
Anticoagulação
SAF, com base na melhor evidência científica disponível. As questões foram estruturadas por
Trombose
meio do P.I.C.O. (paciente, intervenção ou indicador, comparação e outcome/desfecho), o que
possibilitou a geração de estratégias de busca da evidência nas principais bases primárias de
informação científica (MEDLINE/Pubmed, Embase, Lilacs/ Scielo, Cochrane Library, Premedline via OVID). Também realizou-se busca manual da evidência e de teses (BDTD e IBICT). A
evidência recuperada foi selecionada a partir da avaliação crítica, utilizando instrumentos
(escores) discriminatórios de acordo com a categoria da questão terapêutica (JADAD para ensaios clínicos randomizados e New Castle Ottawa Scale para estudos não randomizados). Após
definir os estudos potenciais para sustento das recomendações, eles foram selecionados pela
força da evidência e pelo grau de recomendação, segundo a classificação de Oxford.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
* Autor para correspondência.
E-mail: [email protected] (A. Danowski)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
185
Guidelines for the treatment of antiphospholipid syndrome
abstract
Keywords:
The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by
Antiphospholipid syndrome
arterial and venous thrombosis, gestational morbidity and presence of elevated and per-
Treatment
sistently positive serum titers of antiphospholipid antibodies. The treatment of APS is still
Pregnancy
controversial, because any therapeutic decision potentially faces the risk of an insufficient
Anticoagulation
or excessive antithrombotic coverage associated with anticoagulation and its major adverse
Thrombosis
effects. This guideline was elaborated from nine relevant clinical questions related to the
treatment of APS by the Committee of Vasculopathies of the Brazilian Society of Rheumatology. Thus, this study aimed at establishing a guideline that included the most relevant and
controversial questions in APS treatment, based on the best scientific evidence available. The
questions were structured by use of the PICO (patient, intervention or indicator, comparison
and outcome) process, enabling the generation of search strategies for evidence in the major
primary scientific databases (MEDLINE/PubMed, Embase, Lilacs, Scielo, Cochrane Library, Premedline via OVID). A manual search for evidence and theses was also conducted (BDTD and
IBICT). The evidence retrieved was selected based on critical assessment by using discriminatory instruments (scores) according to the category of the therapeutic question (JADAD scale
for randomized clinical trials and Newcastle-Ottawa scale for non-randomized studies). After
defining the potential studies to support the recommendations, they were selected according
to level of evidence and grade of recommendation, according to the Oxford classification.
© 2013 Elsevier Editora Ltda. All rights reserved.
Introdução
A síndrome do anticorpo antifosfolipídeo (SAF) é uma
doença sistêmica autoimune caracterizada por trombose
arterial e venosa, morbidade gestacional e presença de
níveis séricos de anticorpos antifosfolipídeos elevados e
persistentemente positivos. Hoje é reconhecida como a
causa mais frequente de trombofilia adquirida associada
a tromboses venosas e arteriais.
A classificação atual idealizada para fins de inclusão
em protocolos de pesquisa clínica, mas frequentemente
utilizada no dia a dia para estabelecer o diagnóstico da
SAF1(D) e indicar um tratamento, foi revisada em 2006 e
requer a presença de um critério clínico e um critério laboratorial.
Critérios clínicos
• Trombose vascular: um ou mais episódios de trombose
arterial, venosa ou de pequenos vasos em qualquer órgão ou tecido confirmados por Doppler ou histopatologia, que exclua vasculite;
• Morbidade gestacional:
- Uma ou mais mortes de feto morfologicamente normal com mais de 10 semanas de idade gestacional,
confirmado por ultrassom (US) ou exame do feto;
- Um ou mais nascimentos prematuros de feto morfologicamente normal com 34 semanas ou menos em
virtude de eclâmpsia, pré-eclâmpsia ou causas de insuficiência placentária;
- Três ou mais abortamentos espontâneos antes de 10
semanas de idade gestacional, sem anormalidades
hormonais ou anatômicas maternas, e causas cromossomiais paternas ou maternas excluídas.
Critérios laboratoriais
• Lúpus anticoagulante (LA) presente no plasma em duas ou
mais ocasiões com intervalo mínimo de 12 semanas, detectado de acordo com as recomendações da Sociedade Internacional de Trombose e Hemostasia (ISTH);
• Anticardiolipinas (ACL) IgG ou IgM em títulos moderados
(> 40) a altos (> 80), em duas ou mais ocasiões com intervalo
de, no mínimo, 12 semanas por teste ELISA padronizado;
• Anti-beta2GPI IgG ou IgM presente no plasma em duas ou
mais ocasiões com intervalo mínimo de 12 semanas por teste ELISA padronizado.
A presença de trombose venosa, arterial ou de pequenos vasos é a característica principal dessa doença e a principal causa de morte nesses pacientes, com vasos de qualquer calibre e
qualquer local podendo ser acometidos. Os eventos mais frequentemente relatados são: trombose venosa profunda, embolia
pulmonar e acidente vascular encefálico (AVE). Elevado risco de
recorrência é descrito em pacientes com SAF não tratados (B). 2
O tratamento da SAF ainda é sujeito a controvérsias, já que
qualquer decisão terapêutica potencialmente confronta-se
com risco de uma cobertura antitrombótica insuficiente ou excessiva associada a anticoagulação e a seus principais efeitos
adversos. Atualmente, a indicação de uso perene de anticoagulação oral em casos de trombose arterial, venosa ou microcirculatória é consensual, mas sua intensidade e possibilidade
de interrupção ainda são discutidas. Os novos agentes anticoagulantes (rivaroxabana e dabigatrana), que têm indicação na
prevenção de AVE e embolia sistêmica em pacientes com fibrilação atrial não valvular após artroplastia de quadril ou do joelho, ainda estão sendo estudados em pacientes com SAF, e os
resultados de estudos em curto e médio prazo são esperados
em breve. Certamente, novos agentes anticoagulantes que não
requerem monitoramento e com menor risco de sangramento
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são de grande interesse. Uma vez comprovada sua eficácia e
segurança, consolidarão seu lugar no arsenal do tratamento
da SAF. A despeito disso, o objetivo atual das investigações em
pesquisa é melhorar a abordagem terapêutica da SAF, procurando atuar no processo patogênico desencadeado pelos anticorpos antifosfolipídeo. Entre os candidatos, estão agentes de
uso potencial na profilaxia primária, como hidroxicloroquina
e clopidogrel; aqueles utilizados em situações de maior gravidade, como gamaglobulina endovenosa e rituximabe; e outros
mais recentemente introduzidos que podem reduzir a produção dos anticorpos, como tocilizumabe e belimumabe.
Há ainda a preocupação e o debate sobre a conduta a ser
tomada como tromboprofilaxia primária nos indivíduos com
anticorpos antifosfolipídeos sem eventos trombóticos prévios. Portanto, o objetivo deste trabalho foi estabelecer uma
diretriz que incluísse as questões mais relevantes e controversas no tratamento da SAF, com base na melhor evidência
científica disponível.
Material e métodos
Esta diretriz foi elaborada a partir de nove questões clínicas
relevantes e relacionadas ao tratamento da SAF pela Comissão de Vasculopatias da Sociedade Brasileira de Reumatologia.
As questões foram estruturadas por meio do P.I.C.O. (paciente,
intervenção ou indicador, comparação e outcome/desfecho), o
que possibilitou a geração de estratégias de busca (Anexo 1) da
evidência nas principais bases primárias de informação científica (MEDLINE/Pubmed, Embase, Lilacs, Scielo, Cochrane Library, Premedline via OVID). Também foi realizada busca manual
da evidência e de teses (BDTD e IBICT). A evidência recuperada
foi selecionada a partir da avaliação crítica, utilizando instrumentos (escores) discriminatórios de acordo com a categoria da
questão terapêutica (escala de JADAD para ensaios clínicos randomizados e escala Newcastle-Ottawa para estudos não randomizados). Após definir os estudos potenciais para sustento das
recomendações, eles foram selecionados pela força da evidência
e pelo grau de recomendação, segundo a classificação de Oxford.
Grau de recomendação e força de evidência:
A: estudos experimentais e observacionais de melhor consistência.
B: estudos experimentais e observacionais de menor consistência.
C: relatos de casos (estudos não controlados).
D: opinião desprovida de avaliação crítica, com base em consensos, estudos fisiológicos ou modelos animais.
filaxia contínua (aspirina) não apresentam diferença no risco
de eventos tromboembólicos. Entretanto, pacientes submetidos à tromboprofilaxia em situações de risco (cirurgia/imobilização, gravidez/puerpério) têm redução de risco de 31% para
eventos trombóticos (NNT:3) (B).3
A prevenção primária da trombose em pacientes com anticorpo antifosfolipídeo utilizando dose baixa de aspirina (75
mg/dia) em comparação com aspirina associada à varfarina
demonstra 5% de eventos trombóticos em ambas as formas
de profilaxia e, em 1 a 5 anos, incidência de 4,9 eventos por
100 pacientes⁄ano em ambos os grupos (B).4 Há redução no
risco de eventos trombóticos de 5% (NNT:20) em pacientes
portadores de anticorpo antifosfolipídeo com a prevenção
primária por meio da aspirina e/ou cumarínicos (B).5
A profilaxia (dose baixa de aspirina, varfarina em longo
prazo ou heparina) da trombose em pacientes portadores de
anticorpo antifosfolipídeo (níveis médio/alto de ACL) e hipertensão arterial pode reduzir o risco de eventos em 51,2%
(NNT:2) (B).6 Em populações com anticorpo antifosfolipídeo
positivo, o uso profilático de aspirina pode reduzir o risco de
eventos trombóticos em cerca de 17% dos casos em 120 meses
(NNT:6) (B).7
Entretanto, existem evidências de que não há diferença
entre utilizar ou não a aspirina na profilaxia de eventos trombóticos nesses pacientes, e até de aumento do risco de eventos trombóticos em 6% (NNH:16) nos pacientes que fazem uso
da aspirina (B).8
O benefício do uso de tromboprofilaxia (prevenção primária) é controverso em pacientes sem sintomas clínicos com
presença de anticorpo antifosfolipídeo (B).9
Em gestantes com abortamentos espontâneos consecutivos, sem a presença de anticorpos antifosfolipídeos ou sem a
definição de causa aparente, o uso de aspirina ou enoxaparina
não reduz o risco de novos eventos (A).10
Recomendação
Devido aos controversos resultados do uso da tromboprofilaxia (prevenção primária) de eventos trombóticos nos pacientes com anticorpos antifosfolipídeos, não há como recomendar o uso contínuo da aspirina e/ou cumarínicos nesses
pacientes, reservando seu uso para situações com elevado
risco de trombose.
2. A anticoagulação por tempo indeterminado está
indicada em pacientes com passado de trombose
venosa e presença de anticorpos antifosfolipídeos?
Qual deve ser o INR-alvo?
Resultados
1. Em indivíduos assintomáticos com anticorpos
antifosfolipídeos positivos (LA+ ou ACL ou antibeta2GP IgG ou IgM moderado ou alto) sem
história prévia de trombose, existe benefício na
anticoagulação? E na antiagregação plaquetária?
Pacientes adultos portadores de anticorpo antifosfolipídeo,
em seguimento médio de 36 meses e submetidos à trombopro-
Em pacientes com antecedente de trombose venosa e com
presença de ACL em níveis médios a altos e/ou LA, o uso de
anticoagulação com meta de INR entre 2,0 e 3,0 reduz o risco
de recorrência de maneira semelhante à anticoagulação com
meta de INR entre 3,0 e 4,0, em comparação à ausência de anticoagulação (B).2
Entre pacientes com anticorpos antifosfolipídeos, a comparação entre nenhum tratamento e o uso de anticoagulação
com varfarina em intensidade moderada (alvo de INR entre 2,0
e 3,0) reduz o risco de trombose venosa em 80% a 90% (B).9
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Regimes intensivos de anticoagulação (INR entre 3,5 e 4,5)
em comparação a regimes convencionais (INR entre 2,0 e 3,0)
no tratamento de pacientes com SAF reduzem o risco de recorrência de trombose em índices semelhantes, mas a anticoagulação intensiva aumenta o risco de sangramento leve (B).11,12
O tratamento de pacientes com antecedente de trombose
venosa e SAF com varfarina tendo como meta INR entre 3,0
e 4,0, em comparação com INR entre 2,0 e 3,0, confere índices semelhantes de recorrência: 7,1% e 2,2%, respectivamente
(A).13 O risco de recorrência de trombose em pacientes com SAF
em um ano sem tratamento é de 29%. O uso de anticoagulação com varfarina (INR 2,0–3,0) reduz o risco em 19% (NNT:5),
e quando tem por meta INR > 3,0, associado ou não à aspirina,
reduz o risco em 27,5% (NNT:4). Após seis meses de cessação
do tratamento, o risco aumenta em 100% (NNH:1) (B).14 Em pacientes com passado de trombose (venosa ou arterial) e com
presença de anticorpo antifosfolípide, o tratamento com varfarina (INR entre 2,0 e 2,9) e aspirina (75 mg/dia) leva ao aumento
de 21% no risco de recorrência em 24 meses em comparação à
varfarina (INR > 2,9) e à aspirina (75 mg/dia) (B).15
Pacientes com presença de anticorpos antifosfolipídeos
e antecedente de trombose venosa, quando tratados com
anticoagulação, têm aumento na probabilidade de sobrevida
livre de trombose (recorrência) de 50% e 78% em dois e oito
anos, respectivamente (B).16 Na tromboprofilaxia de pacientes com SAF e antecedente de trombose venosa, recomenda-se a manutenção da anticoagulação em longo prazo por
meio de anticoagulantes orais, tendo como meta INR entre
2,0 e 3,0 (B).17
187
O risco de recorrência de eventos trombóticos em pacientes com anticorpo antifosfolipídeo e antecedente de trombose
arterial em três anos de seguimento em uso de varfarina (INR
alvo de 3,1 a 4,0) ou aspirina (INR alvo de 2,0 a 3,0) é de 21,4%
e de 7,6%, respectivamente (A).12
Há redução de 56% no risco de recorrência de eventos arteriais em pacientes com anticorpo antifosfolipídeo anticoagulados em comparação com nenhum tratamento. Para pacientes que recebem varfarina intensivo (INR > 3,0) com ou
sem aspirina, a probabilidade de que não experimentem novo
evento trombótico em cinco anos é de 90%(B).14
Na tromboprofilaxia de recorrência de eventos arteriais
em pacientes com anticorpos antifosfolipídeos, o tratamento
com varfarina (INR > 2,9) e aspirina (75 mg/dia) reduz o risco
de eventos em 50%, quando comparado apenas com a aspirina na mesma dose. Não há diferença entre a varfarina com
INR maior ou menor que 2,9 no risco de recorrência de eventos trombóticos (B).15
Pacientes com SAF triplo-positivo (com os três testes positivos) têm alta frequência de recorrências, mais frequentemente arterial. Varfarina com meta de INR 2,0–3,0 é mais
efetiva que dose baixa de aspirina ou nenhuma terapia; entretanto, há 30% de recorrência em pacientes em uso de varfarina (meta de INR 2,0–3,0) durante seguimento de seis anos (B).17
Durante cinco anos de tratamento com anticoagulantes
orais, há redução no risco de recorrência de eventos arteriais
em pacientes com SAF de 11%, quando comparado com pacientes sem tratamento (B).19
Recomendação
Recomendação
Pacientes com SAF e antecedente de trombose venosa devem
permanecer anticoagulados por tempo indeterminado, tendo
como meta INR entre 2,0 e 3,0.
3. A anticoagulação por tempo indeterminado
está indicada em pacientes com SAF com passado
de trombose arterial? Qual deve ser o INR alvo?
O índice de recorrência de eventos trombóticos em pacientes com SAF e antecedente de trombose arterial é maior nos
pacientes sem tratamento e menor naqueles recebendo varfarina com INR entre 3,0 e 4,0, quando em comparação com
varfarina em intensidade baixa (INR 2,0–3,0) ou somente com
aspirina. Pacientes com eventos arteriais estão sob maior risco de recorrência do que eventos venosos (B).2
Varfarina e aspirina parecem ser equivalentes para a prevenção de complicações tromboembólicas em pacientes com
um primeiro AVE isquêmico e anticorpos antifosfolipídeos.
Não há diferença no risco de eventos trombóticos arteriais
cerebrais (recorrência) com o uso de varfarina (INR 1,4–2,8) e
aspirina (325 mg/dia) (A).18
O número de eventos arteriais (isquemias cerebrais transitórias, AVEs ou morte por AVE) que ocorrem em pacientes
com antecedente de eventos trombóticos arteriais e anticorpos antifosfolipídeos, em vigência de tromboprofilaxia com
varfarina intensivo (INR 3,5 a 4,5) ou com varfarina padrão
(INR 2,0 a 3,0), é semelhante (B).11
O tratamento de pacientes com antecedente de trombose arterial e anticorpo antifosfolipídeo deve ser realizado em longo
prazo, com varfarina (INR 2,0–3,0 ou INR > 3,0) associado ou não
a antiagregantes. Os estudos prospectivos que não encontraram diferença entre varfarina intensiva e INR padrão incluíram
um grupo pequeno de pacientes com trombose arterial, dificultando, portanto, conclusões definitivas. Os autores sugerem
anticoagulação a longo prazo com varfarina intensiva.
4. A anticoagulação por tempo indeterminado
está indicada em pacientes com SAF que
apresentem somente eventos obstétricos? E a
antiagregação plaquetária?
Em mulheres com SAF obstétrica em uso de aspirina
(75–100 mg/dia) tendo utilizado heparina de baixo peso na
gestação e após seis semanas do parto, o número de eventos trombóticos em 36 meses pode ser de 3,3/100 pacientes/
ano. O fator determinante dos eventos, independente do uso
de anticoagulação ou antiagregante, é a presença de dois ou
mais anticorpos. O índice de eventos nesse último caso é de
4,6/100 pacientes/ano (C).20
A incidência de eventos trombóticos em cinco anos em
gestantes com manifestações obstétricas da SAF pode ser de
2,5%, ocorrendo em uma das pacientes, mesmo na vigência
do uso de aspirina. Cerca de 7,4% dos pacientes utilizando
anticoagulantes podem apresentar fenômenos hemorrágicos (B).21
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O tratamento de mulheres com SAF e manifestações obstétricas com dose baixa de aspirina reduz o risco de eventos
trombóticos em 49% ao longo de oito anos de seguimento (B).22
Em seguimento de nove anos de pacientes com SAF de
diagnóstico obstétrico (eventos obstétricos) e em tratamento
com aspirina em baixas doses (100 mg/dia), em comparação
a pacientes sem anticorpos antifosfolipídeos, há aumento de
risco de embolia pulmonar de 31%, de trombose venosa profunda de 103%, e de AVE de 13% (B).23
Recomendação
Pacientes com diagnóstico de SAF e presença exclusiva de
eventos obstétricos devem ser submetidas à tromboprofilaxia
de longo prazo com aspirina em baixas doses, visando à redução de eventos trombóticos, especialmente arteriais.
5. Gestantes primíparas que apresentem testes
para anticorpos antifosfolipídeos positivos sem
história prévia de trombose devem receber
alguma intervenção?
Em mulheres com testes positivos para anticorpos antifosfolipídeos, consideradas pacientes de baixo risco por não terem
morbidades associadas (nenhum ou um aborto espontâneo
ou nenhuma trombose prévia), o uso de aspirina em baixas
doses não reduz o risco de eventos ou de complicações (B).24
O risco de tromboembolismo venoso em pacientes gestantes sem antecedentes de eventos trombóticos e presença
de anticorpo antifosfolipídeo positivo é semelhante ao risco
de gestante sem anticorpo presente (B).25,26 O risco de eventos trombóticos em pacientes com antecedentes de eventos
obstétricos e anticorpos antifosfolipídeos é de 19% em 12 meses, mas o risco de pacientes com anticorpo antifosfolipídeo
e sem antecedentes é de 0% (zero) (B),27 não havendo justificativa para o tratamento farmacológico (tromboprofilaxia) nessas pacientes (B).28
Recomendação
Pacientes com presença de anticorpos antifosfolipídeos e sem
antecedentes de eventos trombóticos não devem receber tratamento farmacológico durante a gestação.
6. A anticoagulação oral está indicada para as
gestantes (entre 14 e 35 semanas) com SAF e
trombose prévia? Qual deve ser o INR alvo?
Há recomendações para o uso de anticoagulantes orais durante
a gestação (16ª a 36ª semanas), ou até mesmo por seis semanas
após o parto (D),29 em pacientes com anticorpo antifosfolipídeo
e antecedente, sobretudo de trombose arterial, baseando-se na
extrapolação do uso de anticoagulantes orais em pacientes semelhantes, mas sem gravidez, e no fato do menor risco teratogênico dessas medicações nessa fase da gestação (D).30
Em pacientes com SAF, a recorrência de eventos pode ocorrer em 20% dos pacientes mesmo durante a utilização de anticoagulantes orais (80% com INR 2,0–3,0 e 20% com INR > 3,0)
(B).21 O uso de anticoagulante oral (INR 2,0–3,0) em 80% dos pacientes com SAF reduz o risco de recorrência de tromboembolismo em cinco anos em 22% (NNT:5) (B).19 Entretanto, o uso específico em gestantes não foi estudado de maneira apropriada.
Recomendação
Pacientes gestantes com SAF e antecedente de eventos tromboembólicos não devem ser tratadas com anticoagulação
oral, uma vez que seu uso nessa população não foi adequadamente estudado.
7. O uso de heparina está indicado para as
gestantes com SAF com trombose prévia?
Qual esquema posológico deve ser usado
para heparina não fracionada e de baixo peso
molecular?
O tratamento de gestantes com SAF e antecedente de eventos
tromboembólicos (venosos ou arteriais) utilizando dalteparina (5.000 UI/dia subcutânea uma vez ao dia e aumentando
para duas vezes ao dia entre a 16ª e 20ª semana gestacional)
pode determinar redução de 100% nos eventos trombóticos,
em 35 semanas de seguimento (B).31
Em gestantes com história de evento tromboembólico
e SAF, o tratamento com heparina de baixo peso molecular
em dose plena associado à aspirina, durante a gravidez e por
mais seis semanas pós-parto, pode reduzir o risco de recorrência de eventos trombóticos em 100% (NNT:1) (B).32
Já a comparação entre heparina de baixo peso molecular
(enoxaparina 1 mg/kg/dia) associado a 100 mg de aspirina
e varfarina (INR 2–2,5) da 14ª à 34ª semana gestacional em
pacientes com SAF , e com episódio trombótico prévio, demonstra que há aumento de 28,9% no risco de trombose nas
pacientes medicadas com varfarina (NNH: 4) em comparação
com a heparina de baixo peso e a aspirina (B).33
Pacientes gestantes com SAF e episódios prévios de trombose apresentam elevado índice de trombose recorrente, e
devem manter tratamento antitrombótico durante a gestação e no pós-parto. O regime padrão combina o tratamento
com aspirina em baixa dose e heparina (não fracionada ou de
baixo peso molecular). A varfarina, excetuando-se entre a 6ª
e 12ª semanas, pode ser alternativa à heparina, devendo ser
reiniciada após o parto (D).34
Recomendação
O uso de heparina de baixo peso molecular subcutânea (dalteparina 5.000 UI/dia ou enoxaparina 1 mg/kg/dia, duplicando
uma ou outra após a 16ª semana) associado à aspirina (100 mg/
dia) durante a gestação e no pós-parto reduz a ocorrência de
trombose materna e perda fetal. A varfarina é opção após a 13ª
semana gestacional. Apesar da ausência de evidência científica
de boa qualidade, os autores recomendam, com base em séries
e relatos de caso e na experiência pessoal, que as pacientes
gestantes com SAF e trombose prévia mantenham dose plena
e não profilática de heparina de baixo peso molecular associada à aspirina durante a gestação devido ao elevado risco de
novos eventos tromboembólicos nesse período.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
8. Existe diferença no manejo de gestantes com
passado de perdas fetais tardias ou passado
de abortamentos precoces? Há vantagens na
utilização de aspirina?
O tratamento de pacientes com SAF com antecedentes de
abortamentos precoces ou perdas fetais tardias, e em nova
gestação, pode ser realizado com aspirina em baixas doses e
heparina de baixo peso molecular.
Entretanto, sob o mesmo tratamento, os desfechos em
pacientes com antecedentes de abortamentos precoces em
comparação àquelas com perdas fetais tardias são diferentes,
havendo maior número de partos prematuros e neonatos pequenos para a idade gestacional nas pacientes com antecedente de perdas fetais tardias (B).35
A comparação entre heparina de baixo peso e aspirina
isolados no tratamento de gestantes com SAF e antecedente de abortamentos de repetição demonstra aumento de 14%
(NNT:7) na sobrevida fetal e no peso do recém-nascido em pacientes medicadas com heparina (B).36
O uso de aspirina no tratamento de pacientes gestantes
com SAF e abortamentos de repetição não produz benefícios
com relação às complicações pré-natais (por exemplo, parto
prematuro) e com relação aos desfechos neonatais (por exemplo, peso) (B).37
Os desfechos neonatais e obstétricos ocorrem em número
semelhante em pacientes gestantes com presença de anticorpo antifosfolípide e antecedentes de abortamento de repetição tratadas com aspirina e heparina de baixo peso molecular
em comparação com aquelas tratadas apenas com aspirina
(A).38,39 Entretanto, quando a associação da aspirina é realizada com heparina não fracionada, há aumento de 29% (NNT:3)
na sobrevida do recém-nascido (A).40
Recomendação
O tratamento de gestantes com anticorpo antifosfolipídeo e
antecedentes de abortamentos precoces ou tardios deve ser
realizado com heparina (não fracionada ou de baixo peso molecular) e aspirina.
9. Há vantagens na associação de outros
medicamentos (corticoide, imunoglobulina,
rituximabe) ao uso do anticoagulante na
síndrome catastrófica (CAPS)?
Considerando presença ou ausência de um único tratamento, a melhora ocorre em 63,1% dos episódios de CAPS tratados
com anticoagulantes versus 22,2% em episódios não tratados
com anticoagulantes (NNT:2). Além disso, não há diferença de
melhora entre presença ou ausência do tratamento individual
com outros agentes, como corticoides, plasmaférese, imunoglobulina ou antiagregantes. O uso individual de corticoides é o
que produz menor recuperação (B).41,42
Quando há associação de tratamentos, a combinação mais
comum é de anticoagulantes e corticoides, seguida de anticoagulantes, corticoides, plasmaférese e/ou imunoglobulina. Não
há diferença na taxa de recuperação entre as diversas combi-
189
nações, como também entre combinar ou não com anticoagulantes (B).41,42
Recomendação
Não há estudos de boa qualidade comprovando o benefício
da associação de outras medicações ao anticoagulante no tratamento de pacientes com CAPS. Apesar da limitação de evidência científica de boa qualidade, os autores recomendam,
com base em séries e relatos de caso e na experiência pessoal, a associação de corticoide, plasmaférese e/ou rituximabe à terapia anticoagulante, devido à alta mortalidade dessa
condição.
Conflitos de interesse
Os autores declaram a inexistência de conflitos de interesse.
Agradecimentos
Os autores agradecem ao Dr. Wanderley Marques Bernardo,
da Associação Médica Brasileira, pela valiosa colaboração na
realização deste projeto.
Anexo 1: Estratégias de busca e palavras
utilizadas na busca por questão clínica.
PICO 1
Em indivíduos assintomáticos com anticorpos antifosfolipídeo positivos (LA+ ou ACL ou anti- B2GP I IgG ou IgM moderado ou alto) sem história prévia de trombose, existe benefício
na anticoagulação? E na antiagregação plaquetária?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR
Anti-Phospholipid Syndrome OR Antibodies,
Antiphospholipid) AND (Platelet Aggregation Inhibitors OR Anticoagulants OR Coumarins OR Heparin or Aspirin) AND (randomized controlled trial[Publication Type] OR
(randomized[Title/Abstract] AND controlled[Title/Abstract]
AND trial[Title/Abstract]) OR random*[Title/Abstract] OR random allocation[MeSH Terms])
PICO 2
A anticoagulação por tempo indeterminado está indicada em
pacientes com passado de trombose venosa e presença de anticorpos antifosfolipideos? Qual deve ser o INR alvo?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR
Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND (Anticoagulants OR Coumarins OR Heparin) AND
Embolism and Thrombosis AND ((clinical[Title/Abstract] AND
trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical
trial[Publication Type] OR random*[Title/Abstract] OR random
allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)
190
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 8 4 – 1 9 2
PICO 3
A anticoagulação por tempo indeterminado está indicada em
pacientes com SAF com passado de trombose arterial? Qual
deve ser o INR alvo?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR
Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND (Anticoagulants OR Coumarins OR Heparin OR INR)
AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR
clinical trials[MeSH Terms] OR clinical trial[Publication Type]
OR random*[Title/ Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative
study OR Epidemiologic methods)
PICO 4
A anticoagulação por tempo indeterminado está indicada em
pacientes com SAF que apresentem somente eventos obstétricos? E a antiagregação plaquetária?
Pregnancy Complications AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid
Syndrome OR Antibodies, Antiphospholipid ) AND (Platelet
Aggregation Inhibitors OR Anticoagulants OR Coumarins
OR Heparin OR Aspirin) AND ((clinical[Title/Abstract] AND
trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/ Abstract] OR
random allocation[MeSH Terms] OR therapeutic use[MeSH
Subheading] OR Comparative study OR Epidemiologic methods)
OR therapeutic use[MeSH Subheading] OR Comparative
study OR Epidemiologic methods)
PICO 7
O uso de heparina está indicado para as gestantes com SAF
com trombose prévia? Qual esquema posológico deve ser usado para heparina não fracionada e de baixo peso molecular?
Pregnancy AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid
Antibody Syndrome OR Anti-Phospholipid Syndrome OR
Antibodies, Antiphospholipid) AND heparin AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND
((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR
random*[Title/Abstract] OR random allocation[MeSH
Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)
PICO 8
Existe diferença no manejo de gestantes com passado de perdas fetais tardias ou passado de abortamentos precoces? Há
vantagens na utilização de aspirina?
Pregnancy AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND heparin AND ((clinical[Title/
Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH
Terms] OR clinical trial[Publication Type] OR random*[Title/
Abstract] OR random allocation[MeSH Terms] OR therapeutic
use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)
PICO 5
PICO 9
Gestantes primíparas que apresentem testes para anticorpos
antifosfolipídeos positivos sem história prévia de trombose
devem receber alguma intervenção?
Pregnancy AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND ((clinical[Title/Abstract] AND
trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical
trial[Publication Type] OR random*[Title/Abstract] OR random
allocation[MeSH Terms] OR therapeutic use[MeSH Subheading])
PICO 6
A anticoagulação oral está indicada para as gestantes (entre
14 e 35 semanas) com SA F e trombose prévia? Qual deve ser
o INR alvo?
Pregnancy AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND (Embolism and Thrombosis
OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract]
AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR
clinical trial[Publication Type] OR random*[Title/Abstract] OR
random allocation[MeSH Terms]
Há vantagens na associação de outros medicamentos (corticoide, imunoglobulina, rituximabe) ao uso do anticoagulante
na síndrome catastrófica (CA PS)?
(Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome
OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND Catastrophic AND ((clinical[Title/Abstract]
AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR
clinical trial[Publication Type] OR random*[Title/Abstract] OR
random allocation[MeSH Terms] OR therapeutic use[MeSH
Subheading] OR Comparative study OR Epidemiologic methods)
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Artigo original
Treinamento de força versus hidroginástica: uma análise
transversal comparativa da densidade mineral óssea em
mulheres na pós-menopausa
Sandor Balsamoa,b,c,*, Licia Maria Henrique da Motaa, Frederico Santos de Santanaa,b,c,
Dahan da Cunha Nascimentoc,d, Lídia Mara Aguiar Bezerrae, Denise Osti Coscrato Balsamoc,
João Lindolfo Cunha Borgesf, Ana Patrícia de Paulag, Martim Bottaroe
a
Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brasil
Departamento de Educação Física, Centro Universitário Euro-Americano (UNIEURO), Brasília, DF, Brasil
c
Grupo de Estudo e Pesquisa em Exercício de Força e Saúde (GEPEEFS), Brasília, DF, Brasil
d
Programa de Pós-Graduação em Educação Física, Faculdade de Educação Física, Universidade Católica de Brasília (UCB), Brasília, DF, Brasil
e
Faculdade de Educação Física, Universidade de Brasília (UnB), Brasília, DF, Brasil
f
Departamento de Medicina, Universidade Católica de Brasília (UCB), Brasília, DF, Brasil
g
Programa de Pós-Graduação em Ciências para Saúde, Fundação de Ensino e Pesquisa em Ciências da Saúde, Secretaria de Estado de Saúde
do Distrito Federal (FEPECS/SESDF), Ministério da Saúde, Brasília, DF, Brasil
b
informações
resumo
Histórico do artigo:
Introdução: Há um grande número de estudos mostrando que o treinamento de força tem
Recebido em 7 de janeiro de 2012
um efeito positivo sobre a densidade mineral óssea (DMO). Porém, existem poucos estudos
Aceito em 13 de dezembro de 2012
comparando a DMO entre praticantes de hidroginástica e treinamento de força.
Objetivo: Comparar, em uma análise transversal, a DMO de mulheres praticantes de treina-
Palavras-chave:
mento de força com mulheres praticantes de hidroginástica, na pós-menopausa.
Treinamento de força
Métodos: A amostra foi composta de 63 mulheres, divididas em três grupos: treinamento de
Hidroginástica
força (FORÇA: n = 15; 51,4 ± 2,7 anos), hidroginástica (HIDRO: n = 22; 54,5 ± 3,3 anos) e con-
Densidade óssea
troles não treinadas (CONTROLE: n = 26; 52,0 ± 3,3 anos). Todas as voluntárias estavam em
Pós-menopausa
terapia de reposição hormonal há no mínimo um ano. Os grupos FORÇA e HIDRO treinavam
há pelo menos um ano antes do início do estudo (média de anos de treinamento – FORÇA:
4,5 ± 2,0; HIDRO: 4,2 ± 2,2).
Resultados: O grupo FORÇA apresentou maior DMO de corpo total, colo femoral e coluna
lombar L2-L4 quando comparado ao grupo-controle (todos P < 0,05). O grupo HIDRO apresentou maior DMO no corpo total, quadril total e coluna lombar L2-L4 quando comparado
ao grupo-controle (todos P < 0,05). Entretanto, não foram observadas diferenças entre os
grupos FORÇA e HIDRO em nenhum dos sítios avaliados.
Conclusões: Estes achados sugerem que não apenas o treinamento de força, mas também a
hidroginástica podem ser estratégias não farmacológicas para prevenção da perda de DMO
em mulheres na pós-menopausa.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
* Autor para correspondência.
E-mail: [email protected] (S. Balsamo)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
194
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Resistance training versus weight-bearing aquatic exercise: a crosssectional analysis of bone mineral density in postmenopausal women
abstract
Keywords:
Introduction: Many studies have shown that resistance training has a positive effect on bone
Strength training
mineral density (BMD). However, few studies have compared the BMD of individuals under-
Aquatic weight-bearing exercises
going resistance training and those training aquatic weight-bearing exercises.
Bone density
Objective: To compare, in a cross-sectional study, the BMD of postmenopausal women un-
Postmenopause
dergoing resistance training and postmenopausal women training aquatic weight-bearing
exercises.
Methods: The sample comprised 63 women divided into the following three groups: resistance training (STRENGTH: n = 15; 51.4 ± 2.7 years); aquatic weight-bearing exercises (WATER: n = 22; 54.5 ± 3.3 years); and non-trained controls (CONTROL: n = 26; 52.0 ± 3.3 years).
All volunteers were on hormone replacement therapy for at least one year. The STRENGTH
and WATER groups were training for at least one year prior to study beginning (mean years
of training – STRENGTH: 4.5 ± 2.0; WATER: 4.2 ± 2.2).
Results: The STRENGTH group had higher BMD of total body, femoral neck, lumbar spine
L2-L4 as compared with the CONTROL group (all P < 0.05). The WATER group had higher
BMD of total body, total hip, lumbar spine L2-L4 as compared with the CONTROL group (all
P < 0.05). However, no difference was observed between the STRENGTH and WATER groups
regarding the sites assessed.
Conclusions: Those findings suggest that not only the resistance training, but also aquatic
weight-bearing exercises might be a non-pharmacological strategy to prevent BMD loss in
postmenopausal women.
© 2013 Elsevier Editora Ltda. All rights reserved.
Introdução
Há evidência crescente de que a prática de exercício contribua
para a prevenção e tratamento da osteoporose devido ao efeito osteogênico do estímulo mecânico no tecido ósseo.1-3 Foi
sugerido que as atividades que requerem maiores cargas com
menor número de repetições resultem em aumento da densidade mineral óssea (DMO).4 Estudos transversais mostraram
que indivíduos praticantes de treinamento de força apresentaram maior DMO do que inativos.5,6 As recomendações de
especialistas7 e os estudos prospectivos8 ou meta-análises9
mostraram o aumento ou preservação da DMO naqueles indivíduos.
Por outro lado, a prática de hidroginástica foi associada
com uma melhora dos condicionamentos neuromuscular e
funcional10 e da saúde cardiometabólica,11 sendo recomendada para idosos menor capacidade funcional, pois é segura.10,12
Entretanto, nos últimos 20 anos, poucos estudos investigaram
a DMO em praticantes de hidroginástica.13-16 A literatura não
é clara quanto a existência de associação entre hidroginástica
e DMO. A maioria dos estudos obteve resultados conflitantes,
que variaram da piora14 à melhora da saúde óssea.15 Além
disso, até o momento, nenhum estudo analisou comparativamente a DMO de mulheres na pós-menopausa praticantes
de treinamento de força com a DMO de mulheres na pós-menopausa praticantes de hidroginástica, o que constitui a nova
abordagem deste estudo.
Este estudo teve por objetivo verificar, comparativamente, a DMO de mulheres praticantes de treinamento de força,
praticantes de hidroginástica e mulheres não treinadas — todas na pós-menopausa. Foi levantada a hipótese de que as
mulheres na pós-menopausa praticantes de hidroginástica
teriam DMO similar à de mulheres na pós-menopausa praticantes de treinamento de força, e ambos os grupos teriam
maior DMO do que o grupo controle não treinado.
Materiais e métodos
Participantes
Este projeto de pesquisa foi aprovado pelo Comitê de Ética
em Pesquisa Institucional da Universidade Católica de Brasília, segundo as políticas institucionais e a Declaração de Helsinki.17 Todas as participantes eram de Brasília, tendo sido recrutadas por meio de correio eletrônico, panfletos e cartazes
distribuídos na cidade de Brasília. Durante o estudo, um único
reumatologista analisou de maneira ‘cega’ os prontuários médicos e conduziu as entrevistas estruturadas com 95 mulheres. As voluntárias constituíram três grupos: treinamento de
força (FORÇA); hidroginástica (HIDRO); e controle não treinadas (CONTROLE).
Critérios de inclusão
Os critérios de inclusão foram os seguintes: a) todas as participantes deveriam estar na menopausa há pelo menos um ano;
b) todas as participantes deveriam usar terapia de reposição
hormonal (TRH) exclusivamente com estrogênio; c) a inclusão
nos grupos FORÇA e HIDRO exigia o treinamento mínimo por
pelo menos um ano antes do estudo; d) a inclusão no grupo
CONTROLE exigia a não prática de atividades físicas regulares
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 3 – 1 9 8
por pelo menos seis meses antes do estudo. Utilizou-se um
questionário com as três perguntas seguintes para identificar
o tipo de exercício, sua regularidade, frequência, intensidade
e duração: 1) Que tipo de exercício você pratica regularmente
durante uma semana?; 2) Qual a frequência desse exercício
durante uma semana?; e 3) Qual a duração média em minutos
de uma única sessão de exercícios físicos?
Critérios de exclusão
Todas as participantes com as seguintes características foram excluídas: a) uso de medicamento ou tratamento que
afete o metabolismo ósseo, exceto suplementação de cálcio e
TRH; b) tabagismo; c) índice de massa corporal (IMC) < 18 kg/
m2 ou > 30 kg/m2 (obesidade); d) doença que afete o metabolismo ósseo ou a força (hipotireoidismo/fibromialgia/artrite
reumatoide).
Os grupos de treinamento de força e de hidroginástica
O grupo FORÇA realizava treinamento de força tradicional
pelo menos três dias não consecutivos por semana, supervisionado por treinador de educação física, durando cada sessão cerca de 60 minutos. O programa consistiu em uma série
de 10 a 15 repetições de cada exercício (incluindo leg press,
extensão de joelho, flexão de joelho, supino plano sentado, remada sentada/voador dorsal, rosca bíceps e exercício de core).
O grupo HIDRO treinava pelo menos três dias não consecutivos por semana (1 hora cada sessão) com treinador de educação física certificado pela Aquatic Exercise Association (AEA). O
objetivo era atingir uma frequência cardíaca de 60%–80% da
máxima durante a sessão, sendo exercitados os grandes grupos musculares com movimentos de empurrar e puxar, pulos e deslocamentos. Não foi possível controlar exatamente
quantas sessões de t reinamento os grupos FORÇA e HIDRO
realizaram no(s) último(s) ano(s).
Procedimentos
As participantes elegíveis para o estudo compareceram ao laboratório na mesma hora (às 8 e às 12 horas). Tinham que observar as seguintes recomendações antes da visita ao laboratório: evitar a prática de atividades intensas; evitar a ingestão
de cafeína ou derivados do álcool nas 24 horas anteriores ao
teste; e tomar a última refeição (inclusive água) antes do teste
com antecedência de pelo menos duas horas. Todos os testes
foram avaliados pelo mesmo examinador ‘às cegas’.
Medidas antropométricas
Para a avaliação de peso, altura e IMC, pediu-se aos participantes que removessem seus sapatos e qualquer peso que
pudesse interferir nas medidas. Para avaliar a altura, a participante deveria estar descalça, com os calcanhares e tronco
encostados na parede, e cabeça no plano de Frankfurt. O peso
corporal com a participante usando o mínimo de roupas foi
medido com aproximação de 100 g em balança de precisão
(Filizola ID-1500, Brasil), tendo a altura sido medida com aproximação de 5 mm em estadiômetro de parede (Sanny Standard ES 2030, Brasil).
195
Densitometria óssea
As DMOs de corpo inteiro, coluna lombar L2-L4, colo femoral,
quadril total e antebraço – 33% rádio, rádio ultradistal, e rádio
total – foram medidas usando-se absorciometria com raio-X
de dupla energia (DPX-L; Lunar Radiation Corporation, Madison, Wisconsin, EUA), sendo as cintilografias analisadas com
um programa versão 3.6. Antes dos testes, os aparelhos foram
calibrados de acordo com as recomendações do fabricante,
tendo um só examinador realizado todos os exames.
Análise estatística
Os valores são apresentados como média e erro padrão. Utilizou-se um modelo de análise de covariância (ANCOVA) para
um fator, com a medida de DMO como variável dependente,
sendo idade, massa muscular total, massa gordurosa e percentagem de gordura corporal as covariáveis. A correção de
Bonferroni foi usada para ajustar as comparações pré-especificadas, tendo-se adotado na análise o nível de significado
de 5%. O coeficiente de variação (CV) foi usado para calcular
a variação intraparticipante (CV% = [DP/média] x 100). Para
identificar as diferenças percentuais entre os grupos de voluntárias com osteoporose, osteopenia e escores normais, de
acordo com ISCD (2005), o teste de Kruskal-Wallis foi aplicado,
usando-se o teste Mann-Whitney com correção de Bonferroni, considerando-se um nível de significância de P < 0,012. Os
dados foram analisados usando-se SAS para Windows.
Resultados
A amostra deste estudo foi constituída por 63 mulheres menopausadas saudáveis, das quais 32 foram excluídas devido
a: hipotireoidismo (n = 4); fibromialgia (n = 3); IMC < 18 kg/
m2 (n = 3) ou IMC > 30 kg/m2 (n = 14); tabagismo (n = 4); e uso
de medicamento ou tratamento que interfere no metabolismo ósseo (n = 4). Essas 63 mulheres foram assim distribuídas:
grupo FORÇA, 15 mulheres; grupo HIDRO, 22 mulheres; e grupo CONTROLE, 26 mulheres. Tanto no grupo FORÇA quanto no
grupo HIDRO, 90% das participantes treinaram regularmente no ano anterior ao estudo na Associação Cristã de Moços
(ACM).
As principais características dos três grupos (FORÇA, HIDRO e CONTROLE) são mostradas na Tabela 1. Não houve diferenças significativas entre os grupos quanto a IMC, TRH (a
dose de estrogênio variou de 0,3 a 2,5 mg em todos os grupos),
e duração da menopausa em anos. O tempo de treinamento
(anos) nos grupos FORÇA e HIDRO não diferiu (P > 0,05). O
grupo HIDRO teve idade superior em relação aos grupos de
FORÇA e CONTROLE.
O resultado da variável dependente DMO no grupo FORÇA
foi significativamente maior do que no grupo CONTROLE para
corpo total (5,73%), coluna lombar L2-L4 (16,40%) e colo femoral (8,73%) (P < 0,05). Não foi observada diferença significativa
nos demais sítios (quadril total, rádio total, rádio ultradistal e
33% rádio). O grupo HIDRO também mostrou uma DMO significativamente maior do que o grupo CONTROLE para corpo total (6,50%), coluna lombar L2-L4 (17,69%) e quadril total
(9,52%) (P < 0,05). Não foi observada diferença significativa nos
196
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Tabela 1 – Características dos grupos de treinamento de
força (FORÇA), de hidroginástica (HIDRO) e controle não
treinado (CONTROLE) (média ± DP).
Variáveis
FORÇA
(n = 15)
HIDRO
(n = 22)
CONTROLE
(n = 26)
Idade (anos)
IMC (kg/m2)
Tempo de
menopausa (anos)
TRH (anos)
Tempo de
treinamento (anos)
51,4 ± 2,7
24,0 ± 2,7
3,3 ± 2,6
54,5 ± 3,3*
24,7 ± 2,7
5,1 ± 2,5
52,0 ± 3,4
24,0 ± 3,4
3,5 ± 2,8
3,0 ± 1,7
4,5 ± 2,0
3,8 ± 2,5
4,2 ± 2,2
4,0 ± 2,8
—
*P < 0,05 significativamente maior do que os grupos FORÇA e
CONTROLE.
IMC, índice de massa corporal; TRH, terapia de reposição hormonal;
DP, desvio padrão.
demais sítios (colo femoral, rádio total, rádio ultradistal e 33%
rádio) (Tabela 2).
Os grupos FORÇA e HIDRO não diferiram quanto à DMO
de corpo total nem de todos os sítios testados (coluna lombar
L2-L4; colo femoral; quadril total; rádio total; rádio ultradistal;
e 33% rádio) (P > 0,05) (Tabela 2).
O número de participantes com osteopenia na coluna lombar L2-L4 (T-escore de DMO) foi maior no grupo CONTROLE do
que no grupo FORÇA (P < 0,05). Não foi detectada diferença
significativa para outras variáveis (P > 0,05). Outros detalhes
do percentual de voluntárias com osteoporose, osteopenia e
normais são apresentados na Tabela 3.
Discussão
Este estudo teve por objetivo comparar a DMO de mulheres
menopausadas há pelo menos um ano, treinando pelo perío-
do mínimo de um ano, e em uso de TRH. Comparou-se o grupo FORÇA, que realizava treinamento de força, com o grupo
HIDRO, que praticava hidroginástica, e ainda os dois grupos
com controles que não treinavam. Aventou-se a hipótese de
que mulheres menopausadas que praticavam hidroginástica teriam DMO similar àquela de mulheres menopausadas
que realizavam treinamento de força, e as participantes dos
dois grupos teriam DMO maior do que a do grupo CONTROLE. Nossa hipótese foi confirmada, não havendo diferença
significativa entre os grupos HIDRO e FORÇA quanto à DMO
no corpo total e em nenhum dos sítios avaliados. Este estudo
ainda confirma a hipótese inicial de que, comparado ao grupo
CONTROLE, o grupo HIDRO apresentou maior DMO na coluna
lombar L2-L4, quadril total e corpo total. Além disso, o grupo
FORÇA apresentou maior DMO na coluna lombar L2-L4, colo
femoral e corpo total em comparação ao grupo CONTROLE.
Ainda, o grupo CONTROLE apresentou um percentual significativamente maior de participantes com osteopenia na coluna lombar L2-L4 (T-escore) do que o grupo FORÇA.
Os critérios de exclusão do presente estudo determinaram um mínimo de viés e/ou potenciais fatores de confusão que pudessem influenciar os resultados da DMO, tais
como o fato de todas as participantes serem menopausadas
em uso de TRH e terem semelhantes características físicas,
como IMC, composição corporal, peso, altura e condições clínicas. Além disso, nenhuma participante era fumante nem
tinha doença coexistente que afetasse a DMO, e as participantes dos grupos FORÇA e HIDRO estavam em treinamento
por pelo menos um ano antes do estudo. Nossa abordagem
nova revelou que as mulheres menopausadas que praticavam hidroginástica tinham DMO similar à das mulheres
menopausadas que realizavam treinamento de força. Uma
singularidade do nosso estudo é o fato de não ser um estudo de intervenção, sendo essa informação relevante uma
vez que, em um estudo transversal, diferentes esportes e
Tabela 2 – Valores de densidade mineral óssea (DMO) para os grupos de treinamento de força (FORÇA), de hidroginástica
(HIDRO) e controle não treinado (CONTROLE).
Sítio de DMO (g/cm2)
FORÇA (n = 15) HIDRO (n = 22)
Corpo total
CV%
Coluna lombar L2-L4
CV%
Colo femoral
CV%
Quadril total
CV%
Rádio total
CV%
Rádio ultradistal
CV%
33% Rádio
CV%
P+
Grupos*
1,221 ± 0,022
6,2
1,283 ± 0,169
12,6
1,020 ± 0,142
13,2
1,046 ± 0,119
11,1
0,550 ± 0,032
7,7
0,385 ± 0,038
13,9
0,693 ± 0,045
8,0
1,232 ± 0,012
4,0
1,294 ± 0,112
8,6
0,982 ± 0,075
7,6
1,049 ± 0,089
8,5
0,550 ± 0,025
5,5
0,368 ± 0,026
8,3
0,692 ± 0,029
4,9
CONTROLE
(n = 26)
FORÇA vs.
CONTROLE
HIDRO vs.
CONTROLE
FORÇA vs.
HIDRO
1,153 ± 0,014
5,7
1,07 ± 0,03
9,5
0,934 ± 0,023
8,1
0,947 ± 0,085
13,5
0,518 ± 0,038
10,5
0,345 ± 0,034
13,3
0,653 ± 0,049
10,6
0,0163*
0,0019*
1,0000
0,0001*
< 0,0001*
1,0000
0,0374*
0,4725
0,6273
0,1172
0,0276*
1,0000
0,9856
0,2460
1,0000
0,0821
0,1384
1,0000
0,8371
0,2403
1,0000
Valores expressos como média ± erro padrão. + Os valores de P para comparação entre os grupos foram calculados usando ANCOVA (com
idade, massa muscular total, massa gorda e percentagem de gordura corporal como covariáveis). Correção de Bonferroni foi usada para ajustar
comparações pré-especificadas.
* P < 0,05 em relação ao grupo CONTROLE.
CV%, coeficiente de variação percentual (CV% = [DP/média] x 100).
197
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Tabela 3 – Percentual de voluntárias com osteoporose, osteopenia e escores normais de acordo com a ISCD 2005.
(International Society for Clinical Densitometry – The ISCDs official positions – updated 2005 – Washington).
Variável (T-escore)
T-escore: coluna lombar L2-L4
T-escore: colo femoral
T-escore: quadril total
T-escore: rádio ultradistal
T-escore: 33% rádio
T-escore: rádio total
FORÇA, n(%)
HIDRO, n(%)
CONTROLE, n(%)
15 (100)
0 (0)
0 (0)
14 (95)
1 (5)
0 (0)
14 (95)
1 (5)
0 (0)
13 (87)
2 (13)
0 (0)
13 (87)
2 (13)
0 (0)
13 (87)
2(13)
0 (0)
21 (95)
1 (5)
0 (0)
22 (100)
0 (0)
0 (0)
22 (100)
0 (0)
0 (0)
17 (77)
5 (23)
0 (0)
20 (91)
2 (9)
0 (0)
21 (95)
1 (5)
0 (0)
14 (54)
9 (35)*
3 (11)
21 (81)
4 (15)
1 (4)
19 (73)
6 (23)
1 (4)
14 (54)
7 (27)
5 (19)
15 (58)
10 (38)
1 (4)
19 (73)
6 (23)
1 (4)
Normal
Osteopenia
Osteoporose
Normal
Osteopenia
Osteoporose
Normal
Osteopenia
Osteoporose
Normal
Osteopenia
Osteoporose
Normal
Osteopenia
Osteoporose
Normal
Osteopenia
Osteoporose
* O grupo CONTROLE apresentou uma percentagem significativamente maior de participantes com osteopenia em comparação ao grupo FORÇA.
modalidades podem ser comparados. Além disso, respostas
osteogênicas estão associadas com cargas intensas e específicas,4,8 mas não com baixa intensidade e/ou curto período de intervenção.8 Estudos prévios com exercício aquático
haviam investigado um curto período de intervenção para
a modulação óssea15 com baixa intensidade14 em mulheres
osteopênicas.14 No presente estudo, comparou-se a DMO de
corpo total e em sítios diferentes do grupo FORÇA com a
DMO do grupo HIDRO, e a DMO dos dois grupos com a do
grupo CONTROLE.
Alguns estudos prospectivos apresentaram resultados similares ao comparar com o grupo FORÇA e grupo CONTROLE
quanto à DMO de corpo total,18 quadril total7 e colo femoral.8
Kelley et al.9 realizaram meta-análise para avaliar a DMO da
coluna L2-L4. A maioria desses estudos envolveu protocolos
de alta intensidade, explicando a eficiência do estímulo nas
células ósseas progenitoras. É possível que, no presente estudo, não tenha sido identificada significativa diferença entre
os grupos FORÇA e HIDRO porque os dois métodos de treinamento sejam suficientemente positivos para estimular a
DMO. Além disso, nos sítios envolvendo o rádio, nossos resultados diferiram daqueles da meta-análise de Kelley et al.,9
embora tenham disso semelhantes aos de Bassey et al.19 Ao
que parece, é necessário um estímulo mais intenso para melhorar a resposta osteogênica do sítio ‘rádio’.4
Este é o primeiro estudo a relatar que o grupo HIDRO apresentou uma maior DMO de corpo total em comparação ao
grupo CONTROLE. O grupo HIDRO ainda apresentou maior
DMO na coluna e quadril total em comparação ao grupo
CONTROLE. Nossos resultados estão de acordo com os de
Tsukahara et al.16 e Rotstein et al.15 ao demonstrar que o grupo HIDRO também apresentava DMO da coluna e quadril total semelhante à dos controles. Littrell e Snow (em resumo
de comunicação) relataram que, em estudo de curta duração (6 meses), o treinamento aquático preservou a DMO em
mulheres menopausadas em todos os sítios, mostrando que
esse tipo de treinamento é útil para a manutenção da massa
óssea, enquanto que, em grupo controle, a DMO diminuiu.20
Os resultados do presente estudo estão de acordo com os
do estudo experimental de Bravo et al.,14 que não mostrou
diferença significativa na DMO do colo femoral em mulheres osteopênicas após um ano de atividade física aquática
similar à do grupo HIDRO. Rotstein et al.15 não encontraram
diferença significativa na DMO do colo femoral de mulheres
menopausadas saudáveis após apenas sete meses de treinamento. É importante lembrar que a DXA fornece uma medida estática da DMO, não refletindo, consequentemente, a
atividade metabólica. Ay e Yurtkur13,21 estudaram a atividade
hormonal óssea anabólica (IGF-1 e calcitonina) e catabólica
(paratormônio, PTH), e analisaram a DMO usando ultrassom
em mulheres menopausadas após um programa de treinamento aquático. Os resultados mostraram níveis elevados
de calcitonina e IGF-1, melhora dos valores ultrassonográficos e redução do PTH no grupo experimental, enquanto o
oposto ocorreu no grupo controle. Portanto, pode-se afirmar
que o treinamento aquático afeta positivamente o metabolismo ósseo.
Este é o primeiro estudo a comparar a DMO do rádio do
grupo HIDRO ao do grupo CONTROLE. Os resultados sugerem
que essa estratégia de exercício fornece pouco estímulo à
região do antebraço, e talvez os exercícios de flexão e extensão do punho, e preensão palmar não sejam eficientes para
melhorar a DMO nesse sítio.
Quanto à DMO em todos os sítios avaliados, não foram
observadas diferenças significativas entre os grupos FORÇA
e HIDRO. Recentemente, o estudo de Tolomio et al.12 não encontrou diferenças significativas no colo femoral de mulheres
menopausadas com osteoporose. O protocolo experimental
consistiu em um programa de exercícios combinados na água
e no solo. Uma combinação de exercícios de treinamento de
força e aquáticos com carga foi realizada em duas sessões por
semana durante 11 meses.
A maioria dos estudos associa DMO com exercício de força
devido ao seu efeito específico e localizado na massa corporal.4,5 Entretanto, no presente estudo, ainda que significativamente mais idoso que o grupo FORÇA (3 anos), o grupo
198
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HIDRO não apresentou valores mais baixos de DMO nos sítios
avaliados do que o grupo FORÇA.
O presente estudo apresentou limitações. Seu desenho não
foi experimental uma vez que os investigadores não alocaram
as participantes nos grupos. As participantes escolheram fazer exercício (FORÇA/HIDRO) ou não, sendo então observadas
pelos investigadores. A intervenção não foi predefinida pelos
pesquisadores. Deve-se considerar incluir entre as limitações
o efeito de atividades físicas anteriores, especialmente durante o período de aquisição de massa óssea (até atingir a massa
óssea de pico). Concluindo, os achados relatados fornecem
nova evidência de que a realização de hidroginástica produz
um estímulo para o desenvolvimento muscular e fornece movimento contínuo dos membros contra a resistência da água.
Tais resultados têm importantes implicações práticas, sugerindo que não apenas o treinamento de força, mas também a
hidroginástica poderia ser uma estratégia não farmacológica
para a prevenção de perda de DMO em mulheres menopausadas. Essa informação também é importante para profissionais
envolvidos com cuidados de saúde e exercício físico, uma vez
que exercícios aquáticos são muito populares em centros de
saúde e tendem a oferecer pouco risco. No entanto, pesquisa
adicional se faz necessária para embasar essa modalidade de
exercício. Nossos achados sugerem que a hidroginástica possa estimular o desenvolvimento muscular.
Conflitos de interesse
Os autores declaram a inexistência de conflitos de interesse.
REFERÊNCIAS
1. Chodzko-Zajko WJ, Proctor DN,
Fiatarone Singh MA, Minson CT, Nigg CR, Salem GJ, et al.
American College of Sports Medicine position stand. Exercise
and physical activity for older adults. Med Sci Sports Exerc.
2009;41(7):1510-30.
2. Pereira RM, Carvalho JF,
Paula AP, Zerbini C, Domiciano DS, Gonçalves H, et al.
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Roschel H, Sallum AM, Hayashi AP, et al. Therapeutic effects
of exercise training in patients with pediatric rheumatic
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4. Kerr D, Morton A, Dick I, Prince R. Exercise effects on bone
mass in postmenopausal women are site-specific and loaddependent. J Bone Miner Res. 1996;11(2):218-25.
5. Dinc H, Savci G, Demirci A, Sadikoglu MY, Tuncel E,
Yavuz H. Quantitative computed tomography for
measuring bone mineral density in athletes. Calcif Tissue
Int. 1996;58(6):398-401.
6. Karlsson MK, Johnell O, Obrant KJ. Bone mineral density in
weight lifters. Calcif Tissue Int. 1993;52(3):212-15.
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AC, et al. Physical activity and public health in older adults:
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8. Vincent KR, Braith RW. Resistance exercise and bone
turnover in elderly men and women. Med Sci Sports Exerc.
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9. Kelley GA, Kelley KS, Tran ZV. Resistance training and bone
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trials. Am J Phys Med Rehabil. 2001;80(1):65-77.
10. Tsourlou T, Benik A, Dipla K, Zafeiridis A, Kellis S. The
effects of a twenty-four-week aquatic training program on
muscular strength performance in healthy elderly women. J
Strength Cond Res. 2006;20(4):811-18.
11. Meredith-Jones K, Waters D, Legge M, Jones L. Upright waterbased exercise to improve cardiovascular and metabolic
health: a qualitative review. Complement Ther Med.
2011;19(2):93-103.
12. Tolomio S, Lalli A, Travain G, Zaccaria M. Effects of a
combined weight-bearing and non-weight-bearing (warm
water) exercise program on bone mass and quality in
postmenopausal women with low bone-mineral density.
Clin Ter. 2009;160(2):105-9.
13. Ay A, Yurtkuran M. Evaluation of hormonal response and
ultrasonic changes in the heel bone by aquatic exercise in
sedentary postmenopausal women. Am J Phys Med Rehabil.
2003;82(12):942-9.
14. Bravo G, Gauthier P, Roy PM, Payette H, Gaulin P. A weightbearing, water-based exercise program for osteopenic
women: its impact on bone, functional fitness, and wellbeing. Arch Phys Med Rehabil. 1997;78(12):1375-80.
15. Rotstein A, Harush M, Vaisman N. The effect of a water
exercise program on bone density of postmenopausal
women. J Sports Med Phys Fitness. 2008;48(3):352-59.
16. Tsukahara N, Toda A, Goto J, Ezawa I. Cross-sectional and
longitudinal studies on the effect of water exercise in
controlling bone loss in Japanese postmenopausal women. J
Nutr Sci Vitaminol (Tokyo). 1994;40(1):37-47.
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18. Notelovitz M, Martin D, Tesar R, Khan FY, Probart C, Fields C, et al. Estrogen therapy and variable-resistance weight
training increase bone mineral in surgically menopausal
women. J Bone Miner Res. 1991;6(6):583-90.
19. Bassey EJ, Ramsdale SJ. Weight-bearing exercise and ground
reaction forces: a 12-month randomized controlled trial of
effects on bone mineral density in healthy postmenopausal
women. Bone. 1995;16(4):469-76.
20. Littrell TR, Snow CM. Bone Density and Physical Function in
Postmenopausal Women after a 12-month Water Exercise
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21. Ay A, Yurtkuran M. Influence of aquatic and weightbearing exercises on quantitative ultrasound variables
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2005;84(1):52-61.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 9 9 – 2 0 5
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Artigo original
Ausência de associação entre os polimorfismos do gene
interleucina-18 e artrite reumatoide
Ticiana Della Justina Fariasa,&, Luisa Matos do Cantoa,&, Mayara Delagnelo Medeirosa,
Aline Fernanda Rodrigues Sereiaa, Lia Kubelka Fernandes de Carlos Backa,
Filipe Martins de Mellob, Adriana Fontes Zimmermannc, Ivânio Alves Pereirac,
Yara Costa Netto Muniza, Andrea Rita Marreroa, Ilíada Rainha de Souzaa,*
a
Laboratório de Polimorfismos Genéticos, Universidade Federal de Santa Catarina LAPOGE/ (UFSC), Florianópolis, SC, Brasil
Hospital das Clínicas, Faculdade de Medicina, Universidade do Estado de São Paulo (HC-FMUSP), São Paulo, SP, Brasil
c
Serviço de Reumatologia, Hospital Universitário, Universidade Federal de Santa Catarina (HU-UFSC), Florianópolis, SC, Brasil
b
informações
resumo
Histórico do artigo:
Objetivo: Analisar a associação dos polimorfismos do gene interleucina-18 (IL-18) com artri-
Recebido em 2 de fevereiro de 2012
te reumatoide (AR) e com fatores de risco de doenças cardiovasculares (DCV).
Aceito em 13 de dezembro de 2012
Métodos: A amostra foi constituída por 97 pacientes com AR e 151 controles saudáveis. Nos
primeiros, foram analisados fatores de risco de DCV, tais como níveis do colesterol, hi-
Palavras-chave:
pertensão arterial, tabagismo e fator reumatoide, bem como o nível da proteína C-reativa
Interleucina-18
(CRP). O DNA foi extraído e foram analisados os polimorfismos de nucleotídeo único (SNP)
Artrite reumatoide
nas posições -607C/A e -137G/C do gene IL-18 em ambos os grupos. O equilíbrio de Hardy-
Doenças cardiovasculares
-Weinberg (EHW) e o odds ratio (OR) foram realizados, considerando IC 95% e P < 0,05.
Polimorfismo genético
Resultados: As frequências do alelo -607A nos pacientes com AR e nos controles foram de
Brasil
0,443 e 0,424 e do alelo -137C foram de 0,304 e 0,291, respectivamente. As frequências do
genótipo estavam em EHW, exceto em controles no locus -137 (P = 0,006). Não foi encontrada associação dos polimorfismos do gene IL-18 com AR, nem com fatores de risco de
DCV, incluindo o nível do colesterol e de CRP (P > 0,05). Além disso, observaram-se mais
indivíduos fumantes entre pacientes com AR em comparação aos controles (OR = 1,691; P =
0,088), e os níveis de CRP eram ligeiramente mais elevados em pacientes fumantes quando
comparados aos de pacientes não fumantes (OR = 2,673; P = 0,061).
Conclusões: Ao analisar uma amostra de pacientes com AR no sul do Brasil, não foi encontrada
associação dos polimorfismos do gene IL-18 com AR, nem com os fatores de risco de DCV.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
&
Os autores contribuíram igualmente neste manuscrito.
* Autor para correspondência.
E-mail: [email protected] (I.R. de Souza)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
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Lack of association between interleukin-18 polymorphisms and
rheumatoid arthritis
abstract
Keywords:
Objective: To assess the association of the polymorphisms of the interleukin-18 (IL-18) gene
Interleukin-18
with rheumatoid arthritis (RA) and with risk factors for cardiovascular diseases (CVD).
Rheumatoid arthritis
Methods: This sample comprised 97 patients with RA and 151 healthy controls. In the pa-
Cardiovascular diseases
tients, risk factors for CVD were analyzed, such as cholesterol levels, arterial hypertension,
Gene polymorphism
smoking habit, C-reactive protein (CRP) level, and rheumatoid factor. DNA was extracted
Brazil
and the single nucleotide polymorphisms (SNP) at the -607C/A and -137G/C positions of
the IL-18 gene were assessed in both groups. The Hardy-Weinberg equilibrium (HWE) was
calculated and the odds ratio (OR) test performed, considering a 95% CI and P < 0.05.
Results: The frequencies of the -607A allele in patients with RA and in controls were 0,443
and 0.424, respectively, and of the -137C allele, 0.304 and 0.291, respectively. The genotype
frequencies were in HWE, except for controls in the -137 locus (P = 0.006). Association of
the polymorphisms of the IL-18 gene was found with neither RA nor risk factors for CVD,
including cholesterol level and CRP (P > 0.05). In addition, more smokers were found among
patients with RA as compared with controls (OR = 1.691; P = 0.088), and the CRP levels were
slightly higher in patients who smoked than in patients who did not (OR = 2.673; P = 0.061).
Conclusions: In this sample of patients with RA in the South of Brazil, association of the
polymorphisms of the IL-18 gene was observed with neither RA nor risk factors for CVD.
© 2013 Elsevier Editora Ltda. All rights reserved.
Introdução
A artrite reumatoide (AR) é uma doença sistêmica autoimune
caracterizada por inflamação crônica, que leva a destruição
articular e complicações sistêmicas, aumentando a morbimortalidade.1,2 Essa doença afeta 0,5%–1% da população geral
mundial, sendo a incidência maior em mulheres do que em
homens.3 Embora a incidência e as manifestações clínicas da
AR variem em diferentes regiões geográficas, na América Latina, e em especial no Brasil, essas informações são escassas.4,5
Portanto, é importante esclarecer a patogênese da AR em uma
população heterogênea como a do Brasil.
A AR tem etiologia complexa e pouco clara, mas, em indivíduos geneticamente suscetíveis, fatores ambientais específicos podem ativar reações imunes patogênicas, tais como a
formação de autoanticorpo e resposta autorreativa.1-3,6 O início da AR pode ser indicado pelo desenvolvimento de anticorpos antipeptídeo citrulinado cíclico (ACPA) e fator reumatoide
(FR) relacionados à perda de autotolerância.7 Recentemente,
dois subgrupos de AR foram identificados com base na presença ou ausência de ACPA. Pacientes com ACPA apresentam
mais manifestações extra-articulares, tabagismo, e pior prognóstico.2 A principal causa de mortalidade de pacientes com
AR são as doenças cardiovasculares (DCV). Como o risco de
DCV em pacientes com AR é 50% maior do que o da população
geral, acredita-se que outros fatores de risco estejam presentes na AR.8,9 A patogênese de dano cardiovascular acelerado é
causada por fatores de risco cardiovascular tradicionais em
combinação com mecanismos inflamatórios e autoimunes
relacionados à doença.10,11
A inflamação desempenha um papel importante na lesão
aterosclerótica e os pacientes com AR têm maior prevalência
de aterosclerose.12 Nas doenças imunomediadas, tais como a
AR, a lesão vascular aterosclerótica acelerada e precoce pode
ser parcialmente explicada por resposta autoimune humoral
e celular contra antígenos expressos no endotélio.8,13
Citocinas também estão envolvidas em muitos processos
imunes associados à patogênese da AR, especialmente na
manutenção de uma ativa resposta inflamatória. Como as
citocinas estão envolvidas em eventos imunorreguladores e
de destruição tecidual, parece plausível que elas influenciem
na gravidade das manifestações da AR.7 A interleucina-18 (IL18), uma citocina pró-inflamatória produzida na AR por várias
células sinoviais, tais como macrófagos, condrócitos e osteoblastos, induz vias de sinalização comuns a outros membros
da família IL-1, tais como a ativação do fator nuclear-κB (NFκB) e a expressão do interferon-γ.7,14–16
A administração de IL-18 em camundongos leva ao desenvolvimento de artrite inflamatória erosiva, sugerindo sua participação no processo pró-inflamatório in vivo.14 Além disso, a
expressão de mRNA e a concentração da proteína IL-18 detectados em tecidos sinoviais se mostram mais elevados em AR
que em controles osteoartríticos.14 Estrutura, concentração e
regulação de IL-18 podem variar devido a diferenças genéticas
que afetam a expressão do gene da IL-18.16
A condição inflamatória crônica vista na AR eleva os níveis
e a expressão de proteína C-reativa (CRP), fator de necrose tumoral alfa (TNFα), e interleucinas-1, -6, e -1 8, que são importantes fatores de risco para o desenvolvimento de DCV.11,13,19 A
IL-18 é considerada pró-aterogênica, possivelmente atuando
como mediador de inflamação vascular, levando ao aumento
e à vulnerabilidade da placa aterosclerótica e, finalmente, à
sua ruptura.18 Os adipócitos humanos também podem produzir IL-18, contribuindo para as concentrações sistêmicas de
IL-18 e o maior risco de diabetes e DCV, que estão associados
com obesidade e estados de resistência à insulina.19
A concentração plasmática de IL-18 mostrou-se elevada em
pacientes após infarto miocárdico, tendo sido associada com
aterosclerose coronária.20 Variações no gene IL-18 foram asso-
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ciadas com o aumento das concentrações séricas de IL-18 e
maior mortalidade cardiovascular em pacientes com doença
arterial coronária.21 Outros estudos mostraram que polimorfismos do gene IL-18 estão envolvidos no desenvolvimento de
acidente vascular encefálico isquêmico,22 infarto miocárdico
(IM),23 e maior risco de mortalidade cardiovascular.24 Além disso, altos níveis séricos de IL-18 foram associados com fatores de
risco tradicionais, tais como níveis anormais de LDL- e HDL-colesterol, obesidade, resistência à insulina e disfunção celular.20
Embora a produção endógena de IL-18 seja afetada por
múltiplos fatores, diferenças individuais também poderiam
ser determinadas por polimorfismos genéticos, podendo
afetar os níveis de expressão das citocinas envolvidas na
resposta celular do tipo Th1 e Th2. Esse mecanismo poderia
ser responsável por uma elevada resistência a infecções microbianas, mas também por uma maior suscetibilidade a distúrbios autoimunes em indivíduos portadores de alelos IL-18
mais ativos.15
A transcrição do gene IL-18 pode ser afetada pela presença
de polimorfismos em sua região promotora, cujas variantes
poderiam levar a diferenças na ligação ao fator de transcrição. Dois polimorfismos de nucleotídeo único (SNP) na região
promotora nas posições -607C/A e -137G/C foram estudados,
e tais alterações rompem um potencial sítio de ligação da proteína ligadora ao elemento de resposta ao AMPc e do fator
nuclear H4TF-1, respectivamente.15,25
Em pacientes com AR, o aumento das frequências do alelo -607A e/ou do alelo -137C estão relacionadas à deficiência
na transcrição do gene; isso seria benéfico para o indivíduo,
protegendo contra o desenvolvimento de AR. Um estudo demonstrou que o genótipo -607AA está associado com menor
prevalência de AR em uma população chinesa.25
Por outro lado, homozigose para C na posição -607 e para
G na posição -137 promove níveis mais elevados do RNAm de
IL-18 em comparação aos outros genótipos, e tais níveis elevados de IL-18 pró-inflamatória medeiam muitos processos
inflamatórios agudos e crônicos.15,25
Este estudo teve por objetivo analisar a influência dos polimorfismos de IL-18 presentes nos pacientes com AR, assim
como nos fatores de risco para DCV (dislipidemia, pressão arterial e tabagismo).
Métodos
Este estudo avaliou 97 pacientes diagnosticados com AR de
acordo com a classificação do American College of Rheumatology de 1987. Tais pacientes originaram-se do ambulatório
da Divisão de Reumatologia do Hospital Universitário da Universidade Federal de Santa Catarina, Florianópolis, Brasil. Um
grupo controle foi formado com 151 voluntários saudáveis
sem história pessoal ou familiar de doença autoimune. Este
estudo foi aprovado pelo Comitê de Ética local (CEP/UFSC –
172/06). Todos os participantes assinaram o termo de consentimento livre informado. Dados familiares e epidemiológicos
foram coletados através de questionários estruturados. Os dados clínicos foram obtidos dos prontuários médicos.
Os seguintes fatores de risco para DCV tradicionais foram
considerados: elevados níveis de colesterol total (> 200 mg/dL)
e LDL-colesterol (> 100 mg/dL); hipertensão arterial sistêmica
(pressão arterial sistólica ≥ 140 mmHg e/ou pressão arterial
diastólica ≥ 90 mmHg); hábito tabagista; positividade para
FR (> 20 IU/mL); e níveis de CRP acima do valor de referência
(> 5mg/L).
Amostras de sangue periférico foram coletadas para extração de DNA.26 O SNP -607C/A (rs1946518) do gene IL-18 foi
detectado pela reação em cadeia da polimerase (PCR) que detecta o polimorfismo de acordo com o tamanho dos fragmentos gerados pela ação de enzimas de restrição (PCR-RFLP), amplificando um segmento com 301 pares de bases (pb) cobrindo
o sítio polimórfico, usando as sequências de primers da Tabela
1.27 Para detectar o polimorfismo, os produtos da PCR foram
submetidos a digestão pela enzima de restrição MseI (BioLabs
Inc., New England), a 37°C por 12 horas, e então submetidos a
eletroforese em gel de agarose a 3% e corados com brometo de
etídio a 1%. Os produtos da PCR digeridos foram identificados
como indivíduos homozigotos CC quando cortados em fragmentos com 199 e 73 pb, e como indivíduos homozigotos AA
quando cortados em fragmentos com 101, 98 e 73 pb. Os indivíduos heterozigotos CA foram identificados ao apresentar os
fragmentos com 199, 101, 98 e 73 pb (fig. 1a).
O SNP -137G/C (rs187238) do mesmo gene foi detectado
pelo método de reação em cadeia da polimerase com primers
de sequência específica (PCR-SSP), de acordo com Takada et
al. (2002).27 Esse método utiliza um primer reverso comum (R)
e dois primers forward de sequência específica, F1 específico
para o alelo C e F2 específico para o alelo G, amplificando um
produto de 261 pb (Tabela 1). Como controle interno positivo de amplificação, utilizou-se um primer forward controle (F)
para amplificar um fragmento de 446 pb, que cobre o sítio de
polimorfismo (Tabela 1) (fig. 1b). Para confirmação da tipagem,
controles negativos e positivos foram usados para cada genótipo em todos os experimentos nos dois métodos de detecção
de SNP.
A averiguação das frequências dos alelos e genótipos nos
pacientes com AR e controles dos dois SNPs -607 e -137 foi
realizada por contagem direta. Para verificar a distribuição
genotípica, o equilíbrio de Hardy-Weinberg (EHW) foi calculado com o programa GENEPOP.28 Como os dois SNPs estão
localizados no mesmo gene, verificou-se se foram herdados
juntos devido a desequilíbrio de ligação utilizando o programa GENEPOP. Uma vez que os dois SNPs estão ligados, podem
ser considerados um haplótipo, sendo a frequência da combinação haplotípica foi calculada com o programa PHASE.29
Tabela 1 – Sequências de primers usadas para amplificar
os polimorfismos de nucleotídeo único (SNP) -607 e -137
na região promotora do gene da interleucina (IL)-18 pela
reação em cadeia da polimerase (PCR).
Posição
-607
-137
Alelo C
Alelo G
Sequências de primers
F: 5-CTTTGCTATCATTCCAGGAA-3
R: 5-TAACCTCATTCAGGACTTCC-3
controle F: 5-CCAATAGGACTGATTATTCCGCA-3
controle R: 5-AGGAGGGCAAAATGCACTGG-3
F1 específico: 5-CCCCAACTTTTACGGAAGAAAAG-3
F2 específico: 5-CCCCAACTTTTACGGAAGAAAAC-3
F, primer forward; R, primer reverso.
G e C são alelos.
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Figura 1 – Genotipagem para os polimorfismos de IL-18 nas posições -607 (a) e -137 (b). (a) Genotipagem para SNP -607
C/A locus no gene IL-18 pela técnica PCR-RFLP, cujos produtos PCR sofreram digestão MseI (Biolabs, New England) a 37°C
por 12 horas, sendo então submetidos a eletroforese em gel de agarose a 3% e corados com brometo de etídio a 1%.27
(b) Genotipagem para SNP -137 G/C locus no gene IL-18 pela técnica PCR-SSP, cujos produtos PCR são alelo-específicos,
submetidos a eletroforese em gel de agarose a 1,5% e corados com brometo de etídio a 1%.27 Na figura, cada linha
representa um indivíduo. Em (1), os produtos PCR foram amplificados com primer específico para o alelo G (seta). Em (2),
os produtos PCR foram amplificados com primer específico para o alelo C (ponta da seta). O fragmento que foi amplificado
pelos primers específicos tinha 261 pb, enquanto o controle interno estava presente nos dois ensaios e amplificou um
fragmento com 446 pb. Portanto, se as duas bandas estão presentes no gel, o alelo específico está presente (ex. linha 2
representa o genótipo GC).
L, 50bp ladder; 1, produto PCR (301 pb) sem digestão; amostras 2 e 4 foram genotipadas como CA (199, 101, 98 e 73 pb);
amostra 3 foi genotipada como AA (101, 98 e 73 pb) e amostra 5 foi genotipada como CC (199pb e 73pb).
A razão de chance (OR) com intervalo de confiança (IC)
de 95% foi obtida por análise de associação30 dos polimorfismos (alelos, genótipos e haplótipos). A análise foi realizada
separadamente para dados clínicos e epidemiológicos, assim
como para suscetibilidade a AR, sendo posteriormente confirmada utilizando o programa HDS EpiMax Calculator.31 Os
alelos -607A e -137G foram considerados como alelos de risco
para suscetibilidade a AR. Um valor de P < 0,05 foi considerado
significativo.
Resultados
O gênero feminino correspondeu a 88,66% dos pacientes com
AR e a 96,40% dos controles (P > 0,05). A idade média dos pacientes com AR foi de 54,63 ± 12,48 anos e a dos controles,
48,00 ± 15,56 anos (P > 0,05). Embora a etnia euro-brasileira
tenha predominado nos pacientes com AR e nos controles,
a frequência de afro-brasileiros e ameríndio-brasileiros foi
maior entre os pacientes com AR do que entre os controles
(P = 0,027) (Tabela 2).
As frequências alélicas, genotípicas e haplotípicas dos polimorfismos do gene IL-18 foram estimadas nos pacientes e
nos controles. As frequências alélicas são mostradas na Tabela 3. A distribuição das frequências genotípicas dos dois
SNPs estavam de acordo com o EHW nos pacientes com AR e
controles, exceto as frequências genotípicas de -137 SNP nos
controles (P = 0,006) (Tabela 4). Além disso, os polimorfismos
-607 e -137 apresentavam desequilíbrio de ligação nos pacientes com AR e nos controles (P < 0,001), os dois SNPs foram
analisados como haplótipos (Tabela 5). Demonstramos que
as frequências alélicas, genotípicas e haplotípicas do gene IL18 foram semelhantes nos pacientes com AR e nos controles,
e que os polimorfismos do gene IL-18 não foram associados
com o desenvolvimento de AR (P > 0,05).
A prevalência de fatores de risco para DCV nos pacientes com AR foi: hipercolesterolemia, 54,95%; hipertensão
arterial, 56,99%; tabagismo, 41,76%; positividade para FR,
66,27%; e níveis elevados de CRP, 52,38% (Tabela 2). Hipercolesterolemia e hipertensão arterial não foram associados
aos polimorfismos do gene IL-18. Além disso, o tabagismo
nos pacientes com AR apresentou tendência de associação
com positividade para FR (OR = 2,199; IC 95%: 0,739–6,677;
P = 0,182) e níveis elevados de CRP (OR = 2,673; IC 95%: 0,961–
7,546; P = 0,061). A frequência de fumantes foi maior entre
os pacientes com AR do que entre os controles (OR = 1,691;
IC 95%: 0,930–3,079; P = 0,088), mas não foi estatisticamente
significante. Ainda, nem FR nem tabagismo associaram-se
aos polimorfismos -607 e -137. Discussão
Este é um importante estudo, pois analisa pela primeira vez
em uma população brasileira as características genéticas da
citocina pró-inflamatória IL-18 e seu papel na AR. Essa citocina pode estar envolvida na condição inflamatória característica que causa tantos danos aos pacientes com AR.
As frequências genotípicas dos dois SNPs -607 e -137 encontradas no presente estudo assemelham-se às de outros
estudos caso-controle incluindo pacientes caucasianos com
AR, tais como o estudo polonês32 e o espanhol.33 No entanto, diferem das frequências genotípicas relatadas em estudos
asiáticos.25,34 A semelhança com a população europeia quanto
às frequências genotípicas pode ser explicada pela alta prevalência de descendentes europeus em nossa amostra, uma
203
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Tabela 2 – Caracterização clínica e epidemiológica de pacientes com artrite reumatoide e controles do sul do Brasil.
Pacientes, n (%)
Total, n *
Controles, n (%)
Total, n *
86 (88,65)
54,63 (± 12,48)
69 (75,82)
20 (21,98)
2 (2,20)
38 (41,76)
97
97
91
91
91
91
146 (96,40)
48,00 (± 15,56)
121 (88,32)
15 (10,94)
1 (7,29)
39 (29,77)
151
151
137
137
137
131
50 (54,95)
53 (56,99)
55 (66,27)
44 (52,38)
91
93
83
84
DF
DF
DF
DF
Dados epidemiológicos
Gênero feminino
Idade média
Euro-brasileiro
Afro-brasileiro
Ameríndio-brasileiro
Tabagismo
Dados clínicos
Hipercolesterolemia
Hipertensão arterial
Positividade para FR
Altos níveis de CRP
DF, dados faltantes; CRP, proteína C-reativa.
* O valor de n variou devido à disponibilidade de dados.
Tabela 3 – Frequências alélicas dos polimorfismos na região promotora do gene IL-18 (-607C/A e -137G/C) em pacientes
com artrite reumatoide e controles.
SNP-607
Alelo A
SNP-137
Alelo C
Pacientes, n (%)
Total, n *
Controles, n (%)
Total, n *
43 (44,3)
64 (42,4)
1,064 (0,732–1,547)
0,80
30 (30,4)
44 (29,1)
1,063 (0,703–1,606)
0,84
OR, odds ratio (razão de chance); IC, intervalo de confiança 95%.
P < 0,05 foi considerado significativo.
Tabela 4 – Frequências genotípicas dos polimorfismos na região promotora do gene IL-18 (-607C/A e -137G/C) em
pacientes com artrite reumatoide e controles.
-607 Genótipos
CC
CA
AA
(CA+AA) versus CC
EHW
-137 Genótipos
GG
GC
CC
(GC+CC) versus GG
EHW
Pacientes n = 97 (%)
Controles n = 151 (%)
OR (95% IC)
P
31 (32)
46 (47)
20 (21)
—
48 (32)
78 (52)
25 (16)
—
—
χ2 = 0,502
1,0 (Ref.)
0,914 (0,497-1,681)
1,164 (0,522-2,593)
0,947 (0,550-1,729)
—
—
—
0,86
0,83
1,00
0,83
0,33
70 (46)
74 (49)
7 (5)
—
—
χ2 = 5,264
1,0 (Ref.)
0,946 (0,540-1,658)
1,556 (0,452-5,365)
0,999 (0,580-1,720)
—
—
—
0,94
0,62
1,00
0,34
0,006
χ2 = 0,149
—
45 (46)
45 (46)
7 (8)
—
χ2 = 0,599
—
OR, odds ratio (razão de chance); χ2, qui-quadrado; IC, intervalo de confiança 95%; EHW, equilíbrio de Hardy-Weinberg.
P < 0,05 foi considerado significativo.
Os genótipos -607CC e -137GG foram considerados como referência (OR = 1,0).
vez que muitos imigrantes europeus se estabeleceram no sul
do Brasil.35
Um estudo chinês relatou que o genótipo AA do SNP -607
confere proteção contra o desenvolvimento de AR.25 No entanto, aquele estudo não mostrou associação dos dois SNPs
-607 e -137 do gene IL-18 com a suscetibilidade ao desenvolvimento de AR. Da mesma maneira, uma meta-análise recente
sobre doenças autoimunes36 concluiu que tais polimorfismos
não estavam relacionados ao desenvolvimento de AR, como
em outros estudos realizados na Polônia,32 Espanha33 e China.34 O último estudo também mostrou que o SNP -607 não
altera os níveis séricos de IL-18.34
Embora a AR seja doença de etiologia complexa, acredita-se
ser causada pela combinação de suscetibilidade genética e vários fatores ambientais, tais como infeções e características de
estilo de vida; a contribuição exata de cada um desses fatores
para o desenvolvimento de AR em diferentes populações ainda
não está bem entendida e requer mais pesquisas.3,37
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Tabela 5 – Frequências haplotípicas dos polimorfismos na região promotora do gene IL-18 (-607C/A e -137G/C) em
pacientes com artrite reumatoide e controles.
Haplótipo (-607/-137)
C/G
C/C
A/G
A/C
Pacientes 2n = 194(%)
Controles 2n = 302(%)
OR (IC 95%)
P
103 (53)
5 (3)
32 (16)
54 (28)
159 (53)
15 (5)
55 (18)
73 (24)
1,018 (0,698–1,485)
0,512 (0,160–1,534)
0,898 (0,541–1,260)
1,228 (0,798–1,888)
0,99
0,28
0,75
0,38
OR, odds ratio (razão de chance); IC, intervalo de confiança 95%.
P < 0,05 foi considerado significativo.
Demonstramos que os SNPs do gene IL-18 estavam em
desequilíbrio de ligação em pacientes com AR, como já mostrado em estudos anteriores.25,32,33 Não foi encontrada associação dos haplótipos com suscetibilidade à AR, como nos
estudos espanhol34 e chinês.25 No entanto, um estudo da Polônia relatou uma redução significativa no número de indivíduos com diplótipos AC/AC e AG/AG entre pacientes com
AR e controles, sugerindo que esses diplótipos estão relacionados ao desenvolvimento de AR.32 Os polimorfismos na
região promotora do gene IL-18 afetam sua atividade transcricional, mas tal efeito depende de tipos celulares e do ambiente local da citocina. Assim, a interação entre genótipo e
ambiente celular precisa ser avaliada.15
Embora a dislipidemia seja um fator de risco de DCV controverso em AR, estudos mostraram que níveis baixos de colesterol HDL são comuns e podem contribuir para a maior
morbidade cardiovascular nesses pacientes.8,17,38,39 A dislipidemia foi associada com altos níveis de IL-18.20 Entretanto,
nosso estudo mostrou que altos níveis de colesterol total
não se associaram com a presença dos SNPs do gene IL-18
analisados, como relatado em outros estudos.24,40
A hipertensão arterial é comum entre pacientes com AR,
mas a causa desse aumento de prevalência em comparação
à de controles é desconhecida. Vários fatores influenciam a
pressão arterial, tais como obesidade, inatividade física, polimorfismos genéticos específicos, e alguns medicamentos
antirreumáticos.8,37 A hipertensão arterial foi associada com
níveis séricos elevados de IL-18,20 enquanto a expressão do
RNAm dessa citocina em tecidos ateroscleróticos é elevada
na presença do polimorfismo -137GC e da hipertensão arterial
concomitantemente.41 Além disso, um estudo sobre fatores de
risco metabólicos para DCV relatou que o genótipo -137GC aumenta o risco de hipertensão arterial em mulheres africanas
em comparação com indivíduos -137GG.41 No nosso estudo,
entretanto, hipertensão arterial não se associou com polimorfismos do gene IL-18, como demonstrado por Szeto et al.24
O tabagismo é considerado um fator de risco para o desenvolvimento de AR, e fumantes com AR apresentam títulos mais altos de FR e pior prognóstico em termos de incapacidade, dano radiográfico e reposta ao tratamento.38 Não
encontramos associação entre tabagismo e os polimorfismos
do gene IL-18, nem entre tabagismo e FR em pacientes com
AR (OR = 2,2; P > 0,05), o que difere dos dados de uma metanálise realizada recentemente.38 Da mesma forma, a presença de FR não foi associada com polimorfismos do gene
IL-18, como mostrado em outros estudos sobre AR.15,33 Altos
níveis de CRP foram mais frequentes em pacientes com AR
que fumavam, mas tal associação não foi estatisticamente
significante (OR = 2,67; P = 0,061). Os níveis de CRP não se
associaram com polimorfismos do gene IL-18, bem como os
resultados de outros estudos.24
Embora alguns estudos tenham demonstrado que a expressão do gene IL-18 seja maior em pacientes com AR e que
tal citocina deva ser relevante na patogênese da doença, foi
observado que os polimorfismos -607 e -137 do gene IL-18
não desempenham um papel principal na suscetibilidade à
AR na nossa população. Além disso, tais polimorfismos não
foram associados com fatores de risco para DCV nos nossos
pacientes com AR.
A citocina IL-18 apresenta atividades pleiotrópicas na AR,
com uma complexa rede de citocinas do sistema imune. Estudos futuros que considerem novos marcadores que interagem
com IL-18 ou com outros genes que participam da rede de
citocinas deveriam ser realizados para avaliar sua relevância
na patogênese da AR e em e outras doenças inflamatórias.
Suporte financeiro
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento Pessoal de
Ensino Superior (CAPES) e Fundação de Amparo à Pesquisa e
Inovação do Estado de Santa Catarina (FAPESC).
Conflitos de interesse
Os autores declaram inexistência de conflitos de interesse.
Agradecimentos
Este estudo recebeu apoio do Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), da Coordenação
de Aperfeiçoamento Pessoal de Ensino Superior (CAPES) e da
Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC). Os autores agradecem aos pacientes e
voluntários pela cooperação, e aos colegas, pela colaboração.
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R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Artigo de revisão
O que o reumatologista deve saber sobre a vacina contra
febre amarela
Ana Cristina Vanderley Oliveiraa, Licia Maria Henrique da Motaa,b,*,
Leopoldo Luiz dos Santos-Netob, Pedro Luiz Tauilc
a
Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (FMUnB), Brasília, DF, Brasil
Departamento de Clínica Médica, Hospital das Forças Armadas, Brasília, DF, Brasil
c
Programa de Pós-Graduação em Medicina Tropical, Faculdade de Medicina, Universidade de Brasília (FMUnB), Brasília, DF, Brasil
b
informações
resumo
Histórico do artigo:
Os pacientes portadores de doenças reumáticas são mais suscetíveis à infecção, quer seja
Recebido em 2 de dezembro de 2011
pela própria doença de base ou pelo tratamento empregado. É papel do reumatologista pre-
Aceito em 13 de dezembro de 2012
venir as infecções nesse grupo de pacientes e, dentre as estratégias empregadas, encontra-se a vacinação. No grupo das doenças infecciosas que podem ser prevenidas está a febre
Palavras-chave:
amarela. Sua vacina é segura e eficaz na população em geral, mas, assim como as vacinas
Febre amarela
contendo organismos vivos atenuados, deve ser evitada sempre que possível em portado-
Vacina contra febre amarela
res de doenças reumáticas em uso de medicamentos imunossupressores. Sendo a febre
Doenças reumáticas
amarela endêmica em grande parte do Brasil, e estando a vacinação contra essa doença
Agentes imunossupressores
indicada para a população residente em extensa parte do território nacional (além dos viajantes para essas regiões), torna-se essencial que o reumatologista tenha conhecimento da
doença, das indicações e contraindicações da vacina contra a febre amarela. Nosso artigo
tem o objetivo de destacar os principais aspectos que o reumatologista precisa conhecer
sobre a vacina contra a febre amarela, para decidir por sua indicação ou contraindicação
após avaliação do risco-benefício em situações específicas.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
What a rheumatologist needs to know about yellow fever vaccine
abstract
Keywords:
Patients with rheumatic diseases are more susceptible to infection, due to the underlying
Yellow fever
disease itself or to its treatment. The rheumatologist should prevent infections in those
Yellow fever vaccine
patients, vaccination being one preventive measure to be adopted. Yellow fever is one of
Rheumatic diseases
such infectious diseases that can be avoided. The yellow fever vaccine is safe and effective
Immunosuppressive agents
for the general population, but, being an attenuated live virus vaccine, it should be avoided
whenever possible in rheumatic patients on immunosuppressive drugs. Considering that
yellow fever is endemic in a large area of Brazil, and that vaccination against that disease
is indicated for those living in such area or travelling there, rheumatologists need to know
that disease, as well as the indications for the yellow fever vaccine and contraindications
* Autor para correspondência.
E-mail: [email protected] (L.M.H. Mota)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
207
to it. Our paper was aimed at highlighting the major aspects rheumatologists need to
know about the yellow fever vaccine to decide about its indication or contraindication in
specific situations.
© 2013 Elsevier Editora Ltda. All rights reserved.
Introdução
O tratamento das doenças reumáticas tem sido aprimorado
ao longo dos anos.1 A prescrição de drogas imunossupressoras, muitas vezes precoce ou mesmo agressiva, tem o objetivo
de reduzir e eventualmente eliminar a atividade de doença.2
Essa manipulação do sistema imune inerente à terapia associada à disfunção própria da doença autoimune, pode aumentar o risco de infecções nesse grupo de pacientes.2,3 O risco de
infecções graves nessa população é duas vezes maior que na
população em geral.1
A vacinação é um dos métodos mais eficientes na prevenção de doenças infecciosas.2,4 No entanto, em pacientes
reumáticos em uso de imunossupressores, a vacinação merece algumas considerações especiais. Sua eficácia pode estar comprometida em decorrência das alterações do sistema
imune próprias desse grupo.4 Há também o risco de episódios
de reagudização do quadro após a imunização.4,5
As vacinas contendo organismos vivos atenuados devem
ser evitadas sempre que possível em portadores de doenças
reumáticas em uso de imunossupressores.2,4 Tais vacinas representam risco aumentado em pacientes incapazes ou ineficientes em debelar infecções e podem levar a quadros semelhantes à doença primária.2 A vacina contra febre amarela
enquadra-se nessa categoria.2,4
A febre amarela é endêmica em grande parte do Brasil, e
a vacinação contra essa doença é indicada para a população
residente em extensa parte do território nacional (além dos
viajantes para tais regiões). Assim, torna-se essencial que o
reumatologista tenha conhecimento da doença e das indicações e contraindicações da vacina contra a febre amarela,
objetivo de nosso estudo, a fim de que possa decidir por sua
indicação ou contraindicação em situações específicas.
sos urbanos foram identificados em 1942. Desde então, os casos relatados da doença têm sido de transmissão por meio do
ciclo silvestre.6
Sua suscetibilidade é geral, sem etnia ou faixa etária com
maior ou menor suscetibilidade ao vírus.6 Os indivíduos mais
acometidos são homens jovens, pela maior exposição ao
agente transmissor.6 O período médio de incubação é de 3–6
dias.6
O quadro clínico pode variar desde quadros assintomáticos ou febris leves, de curta duração, a uma infecção grave
e fulminante.6, 9 Nas formas moderada e grave, pode haver
falência renal e hepática, dano cardíaco, hemorragia e choque.9 A taxa de letalidade global encontra-se entre 5%–10%.6
Estima-se que apenas 10% dos casos sejam de formas graves,
associadas à elevada taxa de letalidade, variando de 40%–60%
dos casos.6 Segundo dados do Ministério da Saúde, a taxa de
letalidade média é de 52,8%, com variação de 23%–100%.7
A febre amarela não pode ser erradicada, pois trata-se
de uma zoonose.10 Os surtos da doença ocorrem a cada 5–7
anos.7 Não há tratamento específico para a doença.6 Quanto
às medidas gerais a serem tomadas, o combate ao mosquito
Aedes aegypiti é um dos principais aspectos a ser considerado no combate da forma urbana. Além disso, coleta de lixo e
suprimento de água adequados, uso de larvicidas, educação
em saúde por parte das instituições governamentais, aliada
aos cuidados da população, que para diminuir a transmissão
deve evitar situações em que a água fique parada, como em
vasos de plantas, calhas ou piscinas não tratadas. Em relação
à forma urbana, deve-se evitar viagens a áreas silvestres de
regiões com recomendação de vacina em casos em que não
se tenha feito a imunização 10 dias e por 10 anos em relação
à viagem.6–8,10 A vacina antiamarílica é a principal forma de
prevenção da doença.6
Vacina antiamarílica
Febre amarela
A febre amarela é uma doença viral febril hemorrágica, infecciosa, não contagiosa, endêmica em regiões da África e da
América do Sul, causada por vírus de RNA de fita simples.6
No Brasil, desde 2009, o Ministério da Saúde, baseando-se nas
epizootias ocorridas em 2008 e 2009, dividiu as regiões consideradas para a transmissão em áreas com recomendação
de vacina (ACRV), anteriormente chamadas de endêmicas e
de transição, e áreas sem recomendação (ASRV), antes conhecidas como indenes. A ACRV compreende as regiões Norte e
Centro-oeste, os estados do Maranhão e de Minas Gerais e
parte de São Paulo, Piauí, Bahia, Paraná, Rio Grande do Sul e
Santa Catarina.7,8 A doença é transmitida pela picada de insetos hematófagos da família Culicidae, em especial dos gêneros
Aedes e Haemagogus.6 A transmissão é classificada pelo meio
em que ocorre: urbano ou silvestre.6 No Brasil, os últimos ca-
A vacina 17D contra a febre amarela encontra-se disponível
no Brasil desde 1937.10,11 Desde então, mais de 500 milhões de
pessoas foram imunizadas, sendo considerada uma das mais
eficazes e seguras vacinas do mundo.12 Oferece proteção por
pelo menos 10 anos, e até mesmo para a vida toda.6,13 Dentro
de 30 dias, mais de 90% dos vacinados desenvolvem anticorpos contra a febre amarela,9 e cerca de 98%–100% dos indivíduos tornam-se imunizados.13,14 Ainda assim, a Organização
Mundial de Saúde recomenda o reforço a cada 10 anos.13 A
vacinação deve ser realizada a partir dos 9 meses de idade
nas ACRV, segundo o Ministério da Saúde. Em situações de
epidemia ou surto, deve ser feita a partir de 6 meses de idade.7
A cepa 17D original foi desenvolvida a partir de 176 passagens da cepa selvagem Asabi em tecidos de murinos e galináceos.13 As vacinas utilizadas atualmente são derivadas de
duas subcepas – 17DD e 17D204,11,13 obtidas a partir de 287–289
e 235–240 passagens, respectivamente.13 O objetivo das pas-
208
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
sagens é diminuir a virulência.11 No Brasil, a vacina utilizada
é a 17DD, produzida em Biomanguinhos, órgão da Fundação
Oswaldo Cruz.6
Após a imunização, uma baixa viremia é detectada em metade dos vacinados.13 Há rápida indução de resposta humoral,
e a imunoglobulina M (IgM) pode ser detectada em 7–10 dias.13
Títulos de anticorpos neutralizantes tão baixos como 1:10 são
suficientes para conferir proteção.13
A cepa 17D é um potente indutor de resposta T citotóxica
CD4+ e CD8+.13 O sistema imune inato também é envolvido,
pois a cepa 17D replica-se de forma mínima em células dendríticas, podendo levar à apoptose das mesmas.13 Os receptores toll like (TLR) 2, 3, 7, 8 e 9 são estimulados e há aumento de
IFN-α/β/γ, TNF-α e IL-1β.13,15
Efeitos adversos
Embora seja uma vacina segura, a 17DD ainda apresenta efeitos adversos, em geral bem-tolerados. Dor local, inflamação,
cefaleia de fraca intensidade, mialgia, dor lombar e elevação
transitória de transaminases são efeitos considerados leves,
que costumam ocorrer entre 2 e 11 dias da vacinação.13,16
A anafilaxia secundária à vacina contra febre amarela é
outro aspecto relevante, e ocorre na frequência de 0,9–1,8 por
100.000 doses, sendo atribuída à alergia ao ovo ou à gelatina
utilizada em sua produção.12,16,17
Em relação aos efeitos adversos graves (SAEs – serious adverse effects), os mais relevantes são a doença neurotrópica (YEL-AND) e a doença viscerotrópica (YEL-AVD) associadas à vacina
contra febre amarela.6,13,18 De acordo com os dados do Sistema
de Informação do Programa Nacional de Imunizações do Ministério da Saúde, houve 1.994 efeitos adversos reportados no
período de 2000–2008, quando 101.564.083 doses da 17DD foram aplicadas.17 Os SAEs ocorrem mais frequentemente após a
administração da primeira dose. Houve 0,023 casos de choque
anafilático, 9 casos de hipersensibilidade e 0,84 episódios de
YEL-AND a cada 1.000.000 de doses. Foram identificados 26 casos de doença viscerotrópica. Nesse período, foi possível observar aumento das publicações sobre SAEs no país.17
Doença neurotrópica associada à vacina contra febre amarela
(YEL-AND)
A incidência mundial de YEL-AND é estimada entre 0,4 e 9,9 a
cada 100.000 doses.12 É mais frequente em menores de 6 meses de idade, com incidência nessa faixa etária de 0,5–4 casos
a cada 1.000 vacinas.19 Portanto, sua ocorrência diminuiu após
a suspensão da administração nesse grupo etário.20
A doença pode se manifestar como encefalite, meningite,
neuropatia, mielite ou síndrome de Guillain-Barré.12,16,19 Seu
quadro clínico é tipicamente brando, com recuperação completa.19
Doença viscerotrópica associada à vacina contra febre
amarela (YEL-AVD)
Em 2001, foram relatados os primeiros casos de YEL-AVD,18,21,22
embora uma análise retrospectiva indique ocorrência na década de 1970.13 No Brasil, a frequência esperada é de 0,006–
1,32 casos por 100.000 doses.13 O risco de YEL-AVD aumenta
com o passar da idade. O risco para pacientes entre 60 e 69
anos é de 4,2 a cada 100.000 doses, podendo chegar a 12,6 a
cada 100.000 doses nos maiores de 75 anos.16
É um quadro grave, com taxa de letalidade esperada em
torno de 60%.13 Os sintomas iniciam em média quatro dias
após a vacinação, e o quadro é idêntico à infecção pelo vírus
selvagem.6,23
Há poucos estudos sobre a YEL-AVD, devido ao pequeno
número de casos.13 A maioria dos casos relatados, à exceção
do surto em Ica (Peru), estão relacionados a lotes diferentes de
vacinas.13,23 Thomas et al.,24 em uma revisão sistemática, estimaram entre 11,1 e 15,6 SAEs por milhão de doses aplicadas.
O sequenciamento genético de pessoas com YEL-AVD é
idêntico ao das cepas vacinais correspondentes.12, 23 Isso sugere que a YEL-AVD parece estar mais relacionada às condições
do hospedeiro, que não é capaz de controlar a replicação vacinal, do que às mutações do vírus vacinal.12
Considerando esses achados, alguns fatores de risco para
SAEs já foram identificados: idade avançada (maior que 60
anos), gênero masculino, timectomia, uso de imunossupressores.13
Vacina antiamarílica e os pacientes reumáticos
Pacientes reumáticos crônicos em uso de imunossupressores
são mais expostos à infecção e, por isso, a imunização nesse
grupo tem sido cada vez mais estudada e recomendada.1 4
No entanto, segundo as recomendações vigentes, a vacina
antiamarílica deve ser evitada ou até mesmo contraindicada nesse grupo de pacientes, por tratar-se de vacina de vírus vivo atenuado e haver risco de replicação viral vacinal
descontrolada.4,13,25,26 O consenso europeu (European League
Against Rheumatism – EULAR) postula que as vacinas de vírus vivo devem ser evitadas e o risco deve ser balanceado.4
Segundo o Grupo Britânico de Reumatologia Pediátrica, vacinas de vírus vivo são contraindicadas em todos os pacientes
em uso de drogas citotóxicas.27 Já o Consenso de imunização
para crianças e adolescentes com doenças reumatológicas
traz a orientação que “crianças e adolescentes com doenças
reumatológicas que recebem imunossupressores não devem
receber vacinas com vírus vivo” ao tratar especificamente da
febre amarela.26 Da Luz3 afirma que “não se deve administrar
a vacina em pacientes imunocomprometidos, pois apresentam risco elevado de encefalite”. Hayes12 contraindica a vacinação nesse grupo de pacientes e defende a criação de novas vacinas. Todavia, não há recomendações específicas em
relação aos pacientes reumatológicos que se encontram em
áreas de risco, temporariamente ou não, e que são suscetíveis
à doença. Ainda em relação aos pacientes reumáticos, há casos de YEL-AVD relatados em portadores de lúpus eritematoso sistêmico e polimialgia reumática.17,22,23 Portanto, faz-se
necessária uma análise do risco de infecção e dos possíveis
SAEs associados à vacina nessa população.
O grau de imunossupressão deve ser avaliado e varia de
acordo com a doença, as drogas imunossupressoras utilizadas, dose e tempo de medicação.26 A doença influencia na intensidade da imunodeficiência porque também define dose
e duração do tratamento.28 Não há consenso sobre a dose
mínima causadora de imunossupressão clínica, e há poucas
evidências publicadas sobre a imunodeficiência conferida
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 0 6 – 2 1 0
por drogas citotóxicas em doses usadas em doenças reumáticas.27 Em relação aos corticoides, o uso de prednisona
em doses equivalentes a 10 mg/dia não está associado ao
aumento de infecção.28 A prednisona em doses equivalentes
a 2 mg/kg/dia por mais de uma semana ou 1 mg/kg/dia por
mais de um mês contraindicam vacinas de vírus vivo nesses
pacientes.27 O Grupo Britânico de Reumatologia Pediátrica
admite a imunização com vírus vivo em pacientes portadores de artrite idiopática juvenil naqueles que não se encontram em uso de drogas imunodepressoras,27 indicando que a
imunossupressão pode estar mais relacionada à terapêutica
que à doença de base.
Outro fator a ser considerado é a capacidade de soroconversão desses pacientes, que é inversamente proporcional ao
grau de imunossupressão.25 Em relação à resposta imune em
pacientes reumáticos, há um estudo em que foram avaliados
17 pacientes portadores de artrite reumatoide em uso de terapia biológica que foram vacinados contra a febre amarela.
Foram dosadas a IgG e IgM pré- e pós-vacinais, utilizando método com sensibilidade e especificidade semelhantes ao teste de neutralização por redução de placas (padrão ouro para
avaliação da resposta imune protetora). A comparação entre
os títulos de anticorpos de pacientes e controles mostrou uma
tendência de resposta reduzida no grupo do estudo, embora
não tenha sido possível análise estatística devido ao pequeno
número de pacientes.29
Quanto aos efeitos adversos nessa população, o único estudo existente apresenta uma série de casos com 70 pacientes,
com idade média de 46 anos, portadores de diversas doenças
reumáticas que foram inadvertidamente vacinados com a vacina antiamarílica. Daqueles pacientes, 16 (22,5%) relataram
efeitos adversos menores, dado compatível com o esperado
para a população hígida.30
Cabe ainda lembrar que as vacinas em geral podem estar
relacionadas ao desenvolvimento de doenças autoimunes.
Estruturas moleculares virais são capazes de induzir a ativação imune de células do sistema de defesa inato, podendo
levar à inflamação crônica autossustentada.31 O tempo entre
a vacinação e a ocorrência de autoimunidade pode variar
de dias a anos, o que dificulta sua identificação.5 Há relatos
de caso em que a vacina contra a febre amarela desencadeou doenças autoimunes como esclerose múltipla, mielite
transversa e doença de Kawasaki.32–34 Em associação com a
vacina da hepatite A, já foram descritos casos de hepatite
autoimune e a síndrome dos múltiplos pontos brancos evanescentes.35,36 Infecções e imunizações também podem promover a imunomodulação, levando à redução da atividade
inflamatória exarcebada.31 Células T reguladoras ativadas
nesse processo podem ser exploradas no controle da inflamação e autoimunidade.31 A “hipótese higiênica”, semelhante à utilizada na alergologia, sugere que a relativa ausência
de infecções seria responsável pela incidência de doenças
autoimunes.31
Considerações finais
A recomendação atual é que pacientes em uso de imunossupressores não devem ser vacinados contra a doença.2,4 A vacina com o vírus inativado está em desenvolvimento e apresen-
209
ta boa resposta imune protetora em murinos.37 No entanto, a
ocorrência de surtos periódicos traz a possibilidade de novos
casos antes da disponibilização da vacina à população.
O que fazer, então, em casos de pacientes moradores de
áreas endêmicas, próximos a ambientes silvestres ou que
precisem se expor durante o trabalho?
Não há outros estudos que avaliem a resposta ou os efeitos adversos após a vacinação contra a febre amarela em
pacientes reumáticos em uso de imunossupressores. Por
motivos éticos, a vacinação não pode ser aplicada nesses
pacientes com fins de pesquisa científica. Além disso, resultados conclusivos só podem ser fornecidos a partir da avaliação de grande número de pacientes, pois os efeitos adversos parecem ser raros, mesmo nessa população. Para uma
avaliação custo-benefício, é preciso considerar se o risco de
contrair a infecção é maior que o risco de contrair a doença.25
A dose de imunossupressor utilizada é fundamental para
tomada de decisão do médico. Segundo a American Academy of Pediatrics, prednisona em doses equivalentes ou
maiores que 2 mg/kg/dia ou 20 mg por dia contraindicam
a vacinação com vacinas de vírus vivo (Varicella Zoster).38 O
Consenso de imunização para crianças e adolescentes com
doenças reumatológicas, da Sociedade Brasileira de Reumatologia, afirma que a população abordada não deve receber
vacinas com vírus vivo ao tratar sobre vacina antiamarílica,
e que esse tipo de vacina é habitualmente contraindicado
em imunossuprimidos.26
Em casos específicos, pode haver uma janela de oportunidade antes do início do uso de drogas imunossupressoras,
em que as vacinas de vírus vivo podem ser administradas.27
De acordo com a British Society of Rheumatology, a vacinação
deve ocorrer duas semanas antes do início do tratamento.27
Segundo o mesmo grupo, o prazo a ser aguardado para imunização com tais vacinas é de pelo menos três meses.27 Os especialistas argumentam a favor da análise do risco/benefício em
usuários de corticoides e/ou drogas citotóxicas. Os especialistas do EULAR afirmam que tais vacinas devem ser evitadas,
mas que os riscos e benefícios devem ser balanceados.
Cabe ao médico a orientação quanto às ACRV, epidemias e
surtos, bem como a avaliação do risco individualizado de infecção e do grau de imunossupressão de cada paciente para
que se possa indicar ou não a vacina nessa população.
Suporte financeiro
A autora Ana Cristina Vanderley Oliveira recebeu bolsa da
CAPES-CNPq.
Conflitos de interesse
Os autores declaram a inexistência de conflitos de interesse.
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36. Perumalswami P, Peng L, Odin JA. Vaccination as a
triggering event for autoimmune hepatitis. Semin Liver Dis.
2009;29(3):331-4.
37. Monath TP, Lee CK, Julander JG, Brown A, Beasley DW, Watts
DM, et al. Inactivated yellow fever 17D vaccine: development
and nonclinical safety, immunogenicity and protective
activity. Vaccine. 2010;28(22):3827-40.
38. American Academy of Pediatrics. Committee of Infectious
Diseases. Red Book. 28.ed. Elk Groove Village, IL; 2009. p. 72–86.
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 1 – 2 1 4
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Artigo de revisão
Atualização na terapêutica da calcinose em dermatomiosite
Samuel Katsuyuki Shinjo*, Fernando Henrique Carlos de Souza
Serviço de Reumatologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brasil
informações
resumo
Histórico do artigo:
Calcinose é uma afecção do tecido conjuntivo classificada em quatro tipos: metastática,
Recebido em 2 de fevereiro de 2012
idiopática, iatrogênica e distrófica. Esta última é o que acontece, por exemplo, em derma-
Aceito em 13 de dezembro de 2012
tomiosite, principalmente na forma juvenil, e é caracterizada por uma deposição anormal
de sais de cálcio em pele afetada, tecidos subcutâneos, músculos ou tendões, sendo os
Palavras-chave:
níveis séricos de cálcio e fósforo normais. O tratamento da calcinose em dermatomiosite
Revisão
continua sendo um desafio, havendo poucas descrições na literatura, de pouca evidência
Calcinose
científica. Não se apresenta, até o momento, nenhuma terapia altamente eficaz no combate
Dermatomiosite
e resolução dessa comorbidade. No presente trabalho, abordamos o conceito de calcinose,
Terapêutica
particularmente em dermatomiosite, assim como o seu tratamento descrito na literatura.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Update on the treatment of calcinosis in dermatomyositis
abstract
Keywords:
Calcinosis is a connective tissue disorder classified into the following four types: metastat-
Review
ic; idiopathic; iatrogenic and dystrophic. Dystrophic calcinosis can occur, for example, in
Calcinosis
dermatomyositis, mainly in juvenile dermatomyositis, and is characterized by an abnormal
Dermatomyositis
deposition of calcium salts in affected skin, subcutaneous tissues, and muscles or tendons,
Therapy
with normal serum levels of calcium and phosphate. The treatment of calcinosis in dermatomyositis remains a challenge, with few descriptions in the literature of low scientific
evidence. So far, no therapy has proved to be highly effective in the combat and resolution
of that comorbidity. The present study discusses the concept of calcinosis, particularly in
dermatomyositis, as well as its treatment described in the literature.
© 2013 Elsevier Editora Ltda. All rights reserved.
Conceito de calcinose
Calcinose é uma afecção do tecido conjuntivo classificada em
quatro tipos: metastática, idiopática, iatrogênica e distrófica.1,2
A primeira refere-se à deposição de sais de cálcio em tecidos
normais, com aumento sérico de cálcio e/ou fosfato, sendo o
valor do produto destes elementos ≥ 70.1,2 Calcificação idiopática ocorre em tecidos normais, com nível sérico de cálcio
e fosfato normal.1,2 A iatrogênica inclui reação de hipersensibilidade que normalmente começa com livedo reticular progredindo rapidamente para formação de úlceras cutâneas e
* Autor para correspondência.
E-mail: [email protected] (S.K. Shinjo)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
212
R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 2 1 1 – 2 1 4
necrose; é mais relatada em pacientes com insuficiência renal
crônica em hemodiálise.1 A distrófica é a deposição anormal
de sais de cálcio em pele afetada, tecidos subcutâneos, músculos ou tendões, sendo os níveis séricos de cálcio e fósforo
normais.2,3 Esse último tipo é o que acontece, por exemplo, na
dermatomiosite (DM).
Calcinose em dermatomiosite
Em pacientes com DM, a calcinose é muito mais frequente
na faixa pediátrica, na qual está presente em 10%–70% dos
casos.4–9 Nos adultos, a DM é relatada em cerca de 20%,10,11 podendo preceder o diagnóstico da miopatia ou até surgir anos
após. Em geral, o surgimento é mais comum entre o primeiro
e o terceiro ano da doença.6
Na DM, a calcinose pode ser dividida em cinco tipos: (a)
nódulos ou placas endurecidas em regiões subcutâneas ou
periarticulares, (b) tumorações, (c) depósitos na fáscia intermuscular, levando à limitação do movimento dos músculos
acometidos, (d) calcificação distrófica grave na forma similar
a um exoesqueleto e (e) forma mista.4 Sua presença pode levar
a um impacto negativo na qualidade de vida, causando debilidade, incapacidade funcional, contraturas articulares, atrofia
muscular, úlceras cutâneas e, consequentemente, dores locais
e infecções secundárias.
Patogênese e fatores de risco
A etiopatogênese da calcinose em DM é desconhecida. Acredita-se, com base em relatos de caso, que sua presença possa
resultar de acúmulo intracelular de cálcio secundário à alteração da membrana celular. Pode ser desencadeada por traumatismo e/ou inflamação crônica,12,14–31 como, por exemplo,
em casos não respondedores à corticoterapia, na presença de
vasculite cutânea generalizada, fraqueza muscular importante e elevação persistente das enzimas musculares.4–6,13–15
A hipótese de inflamação no local da calcinose é plausível,
uma vez que vários autores têm demonstrado presença de células e citocinas pró-inflamatórias como a IL-116 e TNF-alfa,17
e uma variedade de proteínas relacionadas com a mineralização, como osteopontina, osteonectina, sialoproteína óssea e
hidroxiapatita18 no local da calcinose.17 Esta também tem sido
associada à presença de anticorpos contra proteína 140 kDa19
e de polimorfismo TNF-alfa-308A.16
Fisler et al.20 estudaram 35 casos e encontraram associação
entre calcinose e retardo no diagnóstico e/ou início do tratamento, aumento de enzimas musculares e duração prolongada da doença. Similarmente, Pachman et al.13 observaram
calcinose e retardo no diagnóstico da doença. Já Sallum et al.6
relataram a associação entre desenvolvimento dos nódulos
calcificados, envolvimento sistêmico da miopatia e uso agressivo de medicamentos. Bowyer et al.4 mostraram que terapia
inicial inadequada é importante fator para o desenvolvimento
de calcinose. Além disso, conforme mencionado anteriormente, a calcinose é menos frequente em adultos com DM, o que
levanta a possibilidade de que fatores dependentes da idade
poderiam influenciar no risco do desenvolvimento de calcificações ectópicas.21
Tratamento de calcinose em dermatomiosite
No presente estudo, revisamos de forma sistemática os tratamentos descritos de calcinose em DM. Para tanto, realizamos
pesquisa de literatura nas bases de dados MEDLINE, utilizando
os seguintes termos relacionados: calcinose e dermatomiosite.
Com exceção de 14 casos descritos na literatura nos quais
houve resolução espontânea,1–4,9,22–24 calcinose em DM tende a
evoluir com a progressão da doença. É aventado o conceito de
que uma intervenção terapêutica precoce e agressiva contra a
atividade da DM poderia diminuir as sequelas musculocutâneas da doença, incluindo a própria calcinose.20
Em contrapartida, até o presente momento não há consenso
para o tratamento efetivo da calcinose em DM; os dados disponíveis na literatura baseiam-se apenas em relatos e/ou séries
de casos, particularmente em DM juvenil. Entre as medicações
mencionadas, temos bisfosfonatos, probenecida, varfarina, hidróxido de alumínio, colchicina, diltiazem e infliximabe.
Ambler et al.25 descreveram o caso de uma criança de 8 anos
com DM juvenil crônica com resolução completa da calcinose
após utilizar alendronato 10 mg/dia por 12 meses. O paciente
tinha recebido previamente diltiazem (15 mg, 2x/dia) e probenecida (500 mg, 2x/dia), porém sem resolução da calcinose. De
forma semelhante, Mukamel et al.26 relataram melhora da calcinose em paciente de 6 anos com DM juvenil após introdução
de alendronato (10 mg/dia) por período de 12 meses.
Já Mori et al.27 relataram o uso de etidronato (800 mg/dia)
em uma paciente de 26 anos com DM que, além da calcinose, apresentava osteoporose. Os autores relataram que houve
regressão da calcinose após três meses do início da terapia
medicamentosa. Além disso, houve melhora significativa dos
valores densitométricos após três anos de seguimento. Em
contrapartida, Metzger et al.28 avaliaram o efeito de etidronato
em três pacientes com DM com calcinose durante 12 meses de
seguimento e não observaram efeito satisfatório.
O uso de pamidronato também tem sido descrito.29,30 Três
pacientes com a DM juvenil receberam pamidronato na dose
de 1 mg/kg/dia por três dias consecutivos, repetida mensalmente com resposta satisfatória em todos os casos, havendo
em um desses resolução completa da calcinose.
Com o conceito de que possa diminuir o processo inflamatório local, a probenecida tem sido utilizada, porém com resultados controversos.8,9,31–33
Fuchs et al.34 descreveram um caso de paciente com DM juvenil e com a calcinose localizada na região pré-patelar, a qual
estava acompanhada de inflamação e úlcera cutânea localizada. Houve melhora das lesões cutâneas após dois meses de uso
de colchicina na dose de 1 mg/dia.
Com base na teoria de ter efeito inibitório sobre os canais
de cálcio da membrana celular, o diltiazem tem demonstrado,
principalmente nos casos de DM juvenil, ser uma alternativa
no tratamento.35–39 As doses variaram de 30–180 mg/dia, e foi
introduzido em pacientes com tratamentos mal sucedidos
com bisfosfonato e hidróxido de alumínio. Todos os casos descritos35–39 apresentaram ótima resposta em seguimento destes
por períodos que variaram de 6–12 meses.
Miyamae et al.40 avaliaram o efeito benéfico de talidomida
em uma paciente de 14 anos de idade, com DM juvenil há 10
anos, e que fez uso prévio de pulsoterapia com metilpredni-
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solona, ciclofosfamida, ciclosporina, azatioprina, probenecida,
hidróxido de magnésio, hidróxido de alumínio, além de infliximabe (suspenso por efeitos colaterais) e etanercepte para atividade da doença e progressão da calcinose. Aos 12 anos de idade foi introduzida talidomida (1,3 mg/kg/dia oral no primeiro
mês e, posteriormente, 2 mg/kg/dia) com resposta satisfatória.
Descrições mais antigas evidenciaram bons resultados do
hidróxido de alumínio, todos em casos de DM juvenis, não se
descrevendo efeitos colaterais ao tratamento.41–44 Nakagawa et
al.42 descreveram um caso em que houve resolução quase completa da calcinose após oito meses de tratamento.
A vitamina K apresenta papel importante na ligação do cálcio com os ossos e tecidos.23 Baseando-se nesse conceito, Berger et al.45 e Matsuoka et al.46 utilizaram baixas doses de varfarina em pacientes com DM juvenil com calcinoses nodulares,
e observaram que, após três anos de uso, houve diminuição no
tamanho das lesões.
Regressão de calcinose cutânea seguindo-se a infiltração
intralesional à base de corticosteroide foi descrito por Al-Mayouf et al.47 em paciente de 10 anos e meio com uso prévio
de metotrexato e corticosteroide para a atividade da doença.
Para a calcinose localizada em um dos cotovelos foram utilizados colchicina e infusão trimestral de pamidronato (total de
cinco doses), porém sem êxito. Realizou-se infiltração de corticosteroide utilizando a técnica de Barbotage, com regressão
da calcinose.
Já os procedimentos cirúrgicos têm sido reservados às áreas extensas de calcificação,48,49 com incisão e drenagem local,
mostrando resultados satisfatórios.
Na era da terapia biológica, foi utilizado o infliximabe da
dose de 3 mg/kg, seguindo o mesmo esquema da artrite reumatoide, na terapia de cinco pacientes com DM juvenis refratárias aos tratamentos previamente propostos, apresentando
em todos os casos resposta positiva na regressão da calcinose em períodos que variaram de 8–30 meses após seu início.50
Arabshahi et al.51 relataram o uso de abatacepte (10 mg/kg,
mensal, após aplicação quinzenal no primeiro mês) e de tiossulfato de sódio (tópico, incialmente a 3% e, posteriormente, a
10%, quinzenalmente) em paciente de 14 anos de idade com
DM juvenil há três anos, refratária a corticosteroide, tacrolimo
e imunoglobulina intravenosa humana, e que cursava com a
progressão da calcinose e de lesões cutâneas ulceradas. Com a
terapia instituída, houve redução de inflamação musculocutânea, além de regressão da calcinose.
Em resumo, o tratamento da calcinose tanto na DM adulta
como na juvenil continua a ser um desafio. Há poucas descrições na literatura, de pouca evidência científica, não se apresentando, até o momento, nenhuma terapia altamente eficaz
no combate e na resolução dessa comorbidade.
Conflitos de interesse
Os autores declaram a inexistência de conflitos de interesse.
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REVISTA BRASILEIRA DE
REUMATOLOGIA
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Relato de caso
Condrólise de quadril em uma adolescente: evolução clínica e
radiológica
Ana Paula Sakamotoa, Larissa Lucati Ramosb, Artur da Rocha Corrêa Fernandesc,
Maria Teresa Terreria,*
a
Setor de Reumatologia Pediátrica, Departamento de Pediatria, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
Departamento de Pediatria, Santa Casa de Misericórdia de São Paulo (SCMSP), São Paulo, SP, Brasil
c
Departamento de Diagnóstico por Imagem, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
b
informações
resumo
Histórico do artigo:
A condrólise idiopática de quadril é uma condição rara, caracterizada por destruição pro-
Recebido em 26 de abril de 2011
gressiva da cartilagem articular da cabeça do fêmur e do acetábulo, sem etiologia conheci-
Aceito em 13 de dezembro de 2012
da. A CIQ tem início insidioso e acomete com maior frequência meninas na adolescência.
Os pacientes apresentam dor intensa em quadril, restrição de movimentação e até claudi-
Palavras-chave:
cação. O objetivo do trabalho foi demonstrar um caso dessa doença rara: uma adolescente
Quadril
de 11 anos de idade, com condrólise, em acompanhamento por três anos. As provas de
Adolescente
atividade inflamatória eram normais. Os exames de imagem (radiografia, ultrassonografia
Criança
e ressonância magnética) foram essenciais para o diagnóstico. O tratamento baseou-se no
Condrólise idiopática de quadril
controle da dor e preservação da mobilidade articular, incluindo atividades físicas de baixo
impacto, anti-inflamatórios não hormonais e droga modificadora de doença, com boa resposta após um ano de tratamento. Intervenção cirúrgica não foi necessária.
© 2013 Elsevier Editora Ltda. Todos os direitos reservados.
Chondrolysis of the hip in an adolescent: clinical and radiological outcomes
abstract
Keywords:
Idiopathic chondrolysis of the hip is a rare condition of unknown etiology characterized by
Hip
progressive destruction of the hyaline cartilage that covers the femoral head and acetabu-
Adolescent
lum. Idiopathic chondrolysis of the hip has an insidious beginning and affects more often
Child
female adolescents. Patients report severe hip pain, mobility limitation, and even claudi-
Idiopathic chondrolysis of the hip
cation. This study aimed at reporting one case of that rare disease: an 11-year-old female
adolescent with chondrolysis, followed up for three years. Inflammatory activity tests were
normal. Imaging tests (radiography, ultrasonography and magnetic resonance) were essential for the diagnosis. The treatment was based on pain control and preservation of the
joint mobility, and included low-impact physical activity, non-steroidal anti-inflammatory
drugs, and disease-modifying antirheumatic drugs, with good response after 12 months of
treatment. Surgery was not necessary.
© 2013 Elsevier Editora Ltda. All rights reserved.
* Autor para correspondência.
E-mail: [email protected] (M.T. Terreri)
0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.
216
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Introdução
A condrólise idiopática de quadril (CIQ) é uma condição rara,
caracterizada por diminuição do espaço articular provocada
pelo desaparecimento da cartilagem hialina que recobre a cabeça femoral e o acetábulo, com destruição progressiva da cartilagem, sem etiologia conhecida.1
Em literatura, a descrição de CIQ na faixa etária pediátrica
é rara, sendo restrita, na maioria das vezes, a relatos de caso.2–6
A condrólise pode ocorrer como evento aparentemente idiopático ou pode ser secundária a outras patologias de quadril.7
As causas mais comuns de condrólise secundária são: imobilização prolongada, neoplasias, doença de Legg-Calvé-Perthes
(necrose avascular de cabeça do fêmur), traumatismo, artrite
séptica, artrite idiopática juvenil (AIJ), síndrome de Stickler e
epifisiolistese proximal do fêmur.
A CIQ acomete com mais frequência adolescentes do gênero
feminino (80%) de etnia asiática ou africana. O acometimento
monoarticular é prevalente (60% do lado direito) em relação ao
bilateral (5% dos casos).3,8 Clinicamente, a CIQ caracteriza-se
por dor intensa em quadril, joelho ou em todo o membro inferior, restrição à movimentação, marcha claudicante, podendo
levar ao encurtamento do membro.
O diagnóstico diferencial dessa patologia é difícil, principalmente em relação à AIJ. Entretanto, na CIQ há ausência de sintomas sistêmicos e a investigação laboratorial (hematológica,
microbiológica, imunológica e de reagentes de fase aguda) é
normal.7 Além disso, o acometimento único de quadril é infrequente na AIJ.
Na CIQ juvenil, as imagens radiológicas são úteis na exclusão de causas secundárias.3 A ressonância magnética tem papel
importante no diagnóstico e no acompanhamento da doença.8,9
Alguns autores especulam sobre uma etiologia genética e
hormonal (meninas), porém tais hipóteses ainda não foram
comprovadas.10,11 Morrissy et al.12 sugeriram que esta patologia, assim como a epifisiolistese proximal do fêmur, poderia
representar um tipo soronegativo de resposta imune, uma vez
que a diminuição do espaço articular é semelhante ao da AIJ.12
Outros autores demonstraram que anticorpos e imunocomplexos na sinóvia podem desempenhar um papel importante no
desenvolvimento da condrólise.13–16 Por esse motivo, embora o
tratamento seja discutido e não haja evidências em literatura, anti-inflamatórios não hormonais e drogas antirreumáticas
modificadoras de doença são utilizados. O uso de agentes biológicos, como agentes anti-TNF-alfa, restringe-se a um relato
de caso.10
Em casos graves, quando não há resposta ao tratamento
clínico, pode-se optar por tração cutânea, além de tratamento
cirúrgico. As principais indicações desses procedimentos são:
melhora da dor, correção da deformidade e melhora da amplitude de movimento do quadril.10 O tratamento cirúrgico inclui
capsulectomia com ou sem tenotomia do psoas e/ou adutor,
artrodese do quadril e artroplastia, porém com resultados não
promissores.11,17 A fisioterapia é uma medida importante no
tratamento. A remissão do quadro ocorre em 54% dos casos
conforme a literatura.9
Devido à raridade de relatos de CIQ na faixa etária pediátrica, resolvemos descrever o caso de uma adolescente de 11 anos
de idade.
Relato de caso
Paciente do gênero feminino, branca, 11 anos, com queixa
de dor em quadril esquerdo e claudicação após exercício
físico há um mês e meio. A paciente negou antecedentes
de infecções e/ou trauma. Fez uso de anti-inflamatório não
hormonal por um mês, sem melhora. Também negou acometimento de outras articulações. O exame osteoarticular
revelou dor e limitação à rotação externa e interna do quadril esquerdo e marcha claudicante. Os exames laboratoriais
mostraram hemograma normal velocidade de hemossedimentação de 10 mm na primeira hora, proteína C-reativa
normal e anticorpo antinuclear negativo. Levantou-se a
hipótese diagnóstica de artrite crônica em quadril esquerdo. Introduzido naproxeno 500 mg/dia (12 mg/kg/dia) e solicitada avaliação da oftalmologia para exame de lâmpada
de fenda, que se mostrou normal. O teste tuberculínico foi
negativo.
A radiografia de quadril (posteroanterior e Lauenstein)
mostrou discreta redução de espaço articular e discreta osteopenia à esquerda (fig. 1). A ultrassonografia de quadril mostrou espessamento sinovial e derrame articular à esquerda.
À cintilografia, observou-se aumento de captação no quadril
esquerdo. A ressonância magnética mostrou derrame articular em quadril esquerdo, pequena área de cerca de 8 mm de
hiposinal em T1 e hipersinal em T2 compatível com edema
subcondral relacionado a processo inflamatório, sem lesão de
cartilagem (fig. 2).
Foram feitas as hipóteses diagnósticas de AIJ, necrose
avascular ou condrólise. Pela não resposta ao naproxeno, o
mesmo foi substituído por indometacina 50 mg/dia (1,2 mg/
kg/dia). Após um mês sem melhora, introduziu-se metotrexato 15 mg/semana (0,25 mg/kg/semana) via oral. A indometacina foi mantida, e iniciou-se fisioterapia motora e
natação.
A paciente retornou à consulta cinco meses depois, com
persistência da dor e referindo não fazer uso do metotrexato
há dois meses. As sessões de fisioterapia e a natação foram
mantidas. O exame físico permaneceu inalterado. Três meses
após a reintrodução do metotrexato, a paciente retornou referindo dor aos esforços físicos e claudicação após atividade
física. A dose de metotrexato foi aumentada para 20 mg/1 vez
por semana, subcutâneo (0,4 mg/kg/semana), mantidas a fisioterapia e a natação e solicitados exames. Após seis meses
da reintrodução do metotrexato, a paciente ficou assintomática e sem claudicação. Ao exame físico, apresentou leve limitação dos movimentos do quadril esquerdo.
Após 12 meses, com 24 meses de evolução do quadro e em
uso regular de metotrexato, a paciente permaneceu assintomática e sem limitação de quadril esquerdo. A ultrassonografia de quadril mostrou-se normal, e a ressonância magnética
de quadril esquerdo evidenciou discreto afilamento subcondral lateralmente sem edema e pequeno derrame à esquerda
em T2 com melhora em relação ao exame anterior. Foi iniciada redução lenta e progressiva do metotrexato. Após três
meses, a paciente retornou negando queixas ou claudicação e
sem alterações ao exame físico. Depois de mais quatro meses
sem queixas, o metotrexato foi suspenso. A paciente encontra-se bem. Após período de 12 meses de acompanhamento
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Figura 1 – Radiografia frontal inicial da pelve, na incidência
de Lauenstein (“Rã”). Osteopenia ao nível de quadril
esquerdo e discreta redução do espaço articular.
sem medicação, foi realizada ressonância magnética de quadril esquerdo, que mostrou pequena quantidade de líquido
sinovial e afilamento subcondral e coxofemoral evidente na
porção posterossuperior (área de carga) do quadril, além de
discreto edema subcondral.
Discussão
Apresentamos o caso de uma paciente adolescente com condrólise, relatando queixa inicial de dor crônica em quadril
esquerdo, com claudicação e limitação de movimento do quadril, sem história de trauma, e com exames laboratoriais normais. A paciente evoluiu bem após fisioterapia e a administração de metotrexato e, atualmente está em remissão sem
medicação.
De acordo com a literatura, a CIQ manifesta-se, na maioria
das vezes, por dor em quadril e/ou dor irradiada em joelhos.2
O diagnóstico é clínico e radiográfico.1 Nossa paciente apre-
217
sentou acometimento monoarticular de quadril, como descrito frequentemente em literatura.6 O acometimento descrito
como mais frequente em adolescente do gênero feminino
também coincide com o nosso caso.3 A limitação funcional e
o encurtamento do membro podem levar à claudicação se o
diagnóstico e o tratamento forem feitos tardiamente, ao contrário do ocorrido na paciente em questão.4,12
Os achados radiológicos da paciente mostraram diminuição do espaço articular, além de osteopenia. Dentre as
alterações radiográficas descritas em literatura, incluem-se:
redução do espaço articular, protrusão acetabular, formação
de cistos subcondrais, erosão articular, fechamento prematuro da fise de crescimento e aumento lateral da cabeça do
fêmur.3,6,8,9,12
Na ultrassonografia de nossa paciente, observou-se espessamento sinovial e derrame articular. A ressonância nuclear
magnética mostrou precocemente edema subcondral, derrame articular e edema medular ósseo. De maneira evolutiva,
há perda focal da cartilagem, perda de massa muscular e remodelamento acetabular e femural.7–9
O diagnóstico de CIQ é difícil, e faz-se necessária a exclusão de doenças inflamatórias que cursam com monoartrite.4,8 O diagnóstico diferencial mais importante é em relação à AIJ, a artrite crônica mais frequente na infância. No
entanto, a AIJ dificilmente restringe-se apenas ao quadril,
acometendo geralmente outras articulações.18 Além disso,
a paciente não apresentava alterações laboratoriais (provas
de fase aguda ou presença de autoanticorpos) ou manifestações extra-articulares, como iridociclite. Na ressonância
magnética de pacientes com AIJ observa-se espessamento
sinovial hipervascular (realce sinovial), refletindo intensa
atividade inflamatória.8 Necrose avascular de cabeça do fêmur, epifisiólise e neoplasia foram excluídas pelos exames
de imagem. O trauma como causa de condrólise também foi
afastado pela longa duração dos sintomas e pela evolução do
quadro. Causas infecciosas como tuberculose também foram
afastadas.
Em trabalho conduzido por Van der Hoeven et al.4 foi descrita a presença de anticorpos antinucleares, depósitos de
imunocomplexos e distúrbios imunológicos em alguns pa-
Figura 2 – Ressonância magnética de quadril esquerdo inicial. Plano coronal sequência fast spin-echo ponderada em T1 e T2
evidenciando moderado derrame articular e pequena área com hipossinal em T1 e hipersinal em T2 (seta) compatível com
edema subcondral.
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cientes, fatores da fisiopatologia da CIQ que se assemelham
à AIJ. Tal fato pode justificar o tratamento com medicações
normalmente utilizadas para AIJ, embora não haja evidências
de boa resposta na literatura.
O tratamento tem base no controle da evolução da doença
e dos sintomas, e o uso de anti-inflamatório não hormonal é
preconizado para alívio dos sintomas. Drogas modificadoras
do curso da doença, como o metotrexato, são usadas nos casos não responsivos aos anti-inflamatórios, como o caso de
nossa paciente.10 A fisioterapia e a realização de atividades físicas de baixo impacto são medidas adicionais que devem ser
associadas ao tratamento medicamentoso. Apesar da pouca
adesão ao tratamento no estágio inicial, a paciente evoluiu
com boa resposta nos nove meses após a reintrodução do
metotrexato. O aumento da dose fez-se necessário para alcançar boa resposta. O quadro foi completamente reversível,
assim como descrito em outros trabalhos.2,10 Acreditamos que
o diagnóstico e o tratamento precoces e a instituição rápida
de fisioterapia tenham sido fatores decisivos para a obtenção
de bons resultados.
A boa evolução clínica e radiológica também evitou a necessidade de intervenção cirúrgica. Em uma casuística de 14
pacientes adolescentes com condrólise, cerca de 70% foram
conduzidos à intervenção cirúrgica.19 Dos 14 pacientes avaliados, 4 (28%) apresentaram má evolução.19
A CIQ deve ser considerada no diagnóstico diferencial do
acometimento monoarticular de quadril. Sequ