BRAZILIAN JOURNAL OF RHEUMATOLOGY
REVISTA BRASILEIRA DE REUMATOLOGIA
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
SEPTEMBER/OCTOBER 2012 • VOLUME 52 • NUMBER 5
SETEMBRO/OUTUBRO 2012 • VOLUME 52 • NÚMERO 5
ISSN: 0482-5004
EDITORIAL | EDITORIAL
661
663
The indexing of the Brazilian Journal of Rheumatology in the Web of Science
A indexação da Revista Brasileira de Reumatologia no Web of Science
Paulo Louzada-Junior, Max Victor Carioca Freitas
665
665
Expression of concern: Ahlin E et al., “Anti-citrullinated peptide antibodies and
rheumatoid factor in Sudanese patients with Leishmania donovani infection”, Rev Bras
Reumatol 2011; 51(6):572–86
Nota de preocupação: Ahlin E et al., “Anticorpos antipeptídeos citrulinados e fator
reumatoide em pacientes sudaneses com infecção por Leishmania donovani”, Rev Bras
Reumatol 2011; 51(6):572–86
Paulo Louzada-Junior, Max Victor Carioca Freitas
ORIGINAL ARTICLE | ARTIGO ORIGINAL
666
672
Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene
tips in patients with fibromyalgia
Melhora da dor, do cansaço e da qualidade subjetiva do sono por meio de orientações
de higiene do sono em pacientes com fibromialgia
Aline Cristina Orlandi, Camila Ventura, Andrea Lopes Gallinaro, Renata Alqualo Costa, Laís Verderame Lage
679
686
Epidemiological profile of patients with extra-articular manifestations of rheumatoid
arthritis from the city of Curitiba, South of Brazil
Perfil dos pacientes com manifestações extra-articulares de artrite reumatoide de um
serviço ambulatorial em Curitiba, Sul do Brasil
Mariana Costa Moura, Paola Tamara Silva Zakszewski, Marília Barreto Gameiro Silva, Thelma Larocca Skare
695
703
Diagnostic performance and clinical associations of antibodies to the chromatin
antigenic system in juvenile systemic lupus erythematosus
Desempenho diagnóstico e associações clínicas dos anticorpos contra componentes da
cromatina no lúpus eritematoso sistêmico juvenil
Silene Peres Keusseyan, Neusa Pereira da Silva, Maria Odete Esteves Hilário, Eunice Mitiko Okuda,
Maria Teresa S. L. R. Ascenção Terreri, Luis Eduardo Coelho Andrade
713
717
Newly diagnosed dermatomyositis in the elderly as predictor of malignancy
Dermatomiosite recém-diagnosticada em idosos como preditiva de malignidade
Fernando Henrique Carlos de Souza, Samuel Katsuyuki Shinjo
722
727
Nailfold capillaroscopy in children and adolescents with rheumatic diseases
Capilaroscopia periungueal em crianças e adolescentes com doenças reumáticas
733
Cross-cultural adaptation and validation of the Brazilian-Portuguese version of the
Bath Ankylosing Spondylitis Functional Index (BASFI)
Adaptação cultural cruzada e validação da versão do Índice Funcional de Espondilite
Anquilosante de Bath (BASFI) para o português do Brasil
737
Daniela Gerent Petry Piotto, Cláudio Arnaldo Len, Maria Odete Esteves Hilário, Maria Teresa Ramos Ascensão Terreri
Karla Garcez Cusmanich, Sérgio Candido Kowalski, Andréa Lopes Gallinaro,Claudia Goldenstein-Schainberg,
Lilian Avila Lima e Souza, Célio Roberto Gonçalves
REVIEW ARTICLE | ARTIGO DE REVISÃO
742
749
Ankylosing spondylitis and uveitis: overview
Espondilite anquilosante e uveíte: revisão
Enéias Bezerra Gouveia, Dório Elmann, Maira Saad de Ávila Morales
757
761
Imaging diagnosis of early rheumatoid arthritis
Diagnóstico por imagem da artrite reumatoide inicial
Licia Maria Henrique da Mota, Ieda Maria Magalhães Laurindo, Leopoldo Luiz dos Santos Neto, Francisco Aires Corrêa Lima,
Sérgio Lopes Viana, Paulo Sérgio Mendlovitz, João Luiz Fernandes
767
774
Selective inhibition of cyclooxygenase-2: risks and benefits
Inibição seletiva da ciclo-oxigenase-2: riscos e benefícios
Reila Tainá Mendes, Cassiano Pereira Stanczyk, Regina Sordi, Michel Fleith Otuki, Fábio André dos Santos, Daniel Fernandes
CASE REPORT | RELATO DE CASO
783
786
Bilateral osteochondrosis of lateral femoral condyles: case report and literature review
Osteocondrose bilateral de côndilos femorais laterais: relato de caso e revisão da literatura
Blanca Elena Rios Gomes Bica, Danilo Garcia Ruiz, Fernanda Frade Paranhos, Antônio Vítor de Abreu,
Mário Newton Leitão de Azevedo
790
793
Reactive haemophagocytic syndrome in a systemic lupus erythematosus patient –
case report
Síndrome de ativação macrofágica em paciente com lúpus eritematoso sistêmico – relato
de caso
Marco Antonio Cuellar Arnez, Mario Newton Leitão de Azevedo, Blanca Elena Rios Gomes Bica
796
798
Spontaneous pneumomediastinum associated with laryngeal lesions and tracheal
ulcer in dermatomyositis
Pneumomediastino espontâneo associado a lesões laríngeas e úlceras traqueais na dermatomiosite
Ascedio Jose Rodrigues, Marcia Jacomelli, Paulo Rogerio Scordamaglio, Viviane Rossi Figueiredo
BRIEF COMMUNICATION | COMUNICAÇÃO BREVE
800
802
Complete heart block in ankylosing spondylitis
Bloqueio cardíaco completo em espondilite anquilosante
Juan Pablo Restrepo,María Del Pilar Molina
804
807
Posterior reversible encephalopathy syndrome (PRES) and systemic lupus
erythematosus: report of two cases
Síndrome da encefalopatia posterior reversível (PRES) e lúpus eritematoso
sistêmico: relato de dois casos
Aline de Souza Streck, Henrique Luiz Staub, Caroline Zechlinski Xavier de Freitas, Luis Marrone, Jaderson Costa, Giovani Gadonski
LETTER TO THE EDITORS | CARTA AOS EDITORES
811
813
APS ACTION in Brazil
APS ACTION no Brasil
Roger Abramino Levy, Guilherme Ribeiro Ramires de Jesús, pelo APS ACTION GROUP
ERRATUM | ERRATA
815
2012 Brazilian Society of Rheumatology Consensus on the management
of comorbidities in patients with rheumatoid arthritis
[Rev Bras Reumatol 2012; 52(4):474-495]
816
Consenso 2012 da Sociedade Brasileira de Reumatologia sobre o
manejo de comorbidades em pacientes com artrite reumatoide
[Rev Bras Reumatol 2012; 52(4):474-495]
Ivânio Alves Pereira, Licia Maria Henrique da Mota, Boris Afonso Cruz, Claiton Viegas Brenol, Lucila Stange Rezende Fronza,
Manoel Barros Bertolo, Max Victor Carioca de Freitas, Nilzio Antônio da Silva, Paulo Louzada-Junior, Rina Dalva Neubarth Giorgi,
Rodrigo Aires Corrêa Lima, Geraldo da Rocha Castelar Pinheiro
EDITORIAL
The indexing of the Brazilian Journal of
Rheumatology in the Web of Science
© 2012 Elsevier Editora Ltda. All rights reserved.
n July 2012 we had excellent news for the Brazilian
Journal of Rheumatology (BJR): it was indexed in
Thomson Reuters’ Web of Science database, considered one of the most prestigious databases in the world of
Scientometrics. This index provides greater visibility to the
journal, which will also have its impact factor measured by
the Journal Citation Reports® (JCR). We are waiting for this
factor in 2013, as BJR was indexed in January 2010.
This is the result of the great effort and dedication of
the Brazilian Society of Rheumatology, both by the editors
who came before us and the Presidents Fernando Neubarth,
Ieda Laurindo, and Geraldo da Rocha Castelar Pinheiro,
who prioritized BJR as our portal to scientific dissemination, allowing investments that made the journal what it is
nowadays.
The inclusion of BJR in the Web of Science was based on
the following justifications offered to Thomson Reuters:
1. BJR is the first rheumatology journal indexed in Medline,
published both in English and Portuguese, directed specifically to South America;
2. The scientific production in South America is growing at
an unprecedented rate, requiring a dedicated portal for the
dissemination of this production;
3. The participation of American, European, and Asian authors
in BJR demonstrates its international character, extending
its reach beyond the borders of South America.
Thus, we have BJR indexed in major databases: SciELO,
Scopus, PubMed (Medline) and the Web of Science, which
increases the journal’s visibility and hence, the number of
citations.
When analyzing RBR according to the databases, some
important information arises, providing an overview of our
journal:
a) BJR still is a journal read in Portuguese
Consulting the SciELO database, we obtained the following
numbers: during the period of January 2010 to August 2012
there were approximately 1.8 million article requests online via SciELO. Of these, 1.6 million (88%) were requests
I
Rev Bras Reumatol 2012;52(5):661-664
from individuals whose native language was Portuguese,
with 170,000 English (10%) and 14,000 Spanish language
requests (2%).
b) BJR is cited basically by Brazilians who publish in
Brazilian journals
During the last 10 years BJR received 1,203 citations, according to SciELO. Of this total, 403 came from BJR itself
(33%). However, the other citations are from Brazilian
journals. The top 10 journals in decreasing order of citations
are: Revista Brasileira de Fisioterapia, Revista da Associação
Médica Brasileira, Fisioterapia e Pesquisa, Arquivos de
Neuro-Psiquiatria, Cadernos de Saúde Pública, Fisioterapia
em Movimento, Anais Brasileiros de Dermatologia, Jornal
Brasileiro de Pneumologia, and Acta Ortopédica Brasileira.
The journals specialized in Physical Therapy are the ones
most often cited BJR in the past two years.
c) The most accessed BJR articles involve fibromyalgia,
soft tissue, and imaging
Among the 10 most accessed articles (2005-2012, SciELO),
three involve fibromyalgia, one painful hip, and one lumbar
pain. Two other address ultrasonography and magnetic resonance imaging in rheumatic diseases. This information seems
to be in accordance with the journals that more often cite BJR,
as they publish many articles about fibromyalgia and soft tissue.
d) The percentage of international collaboration among
BJR authors varies from 10%–15% a year
According to data from SCIMAGO, BBR maintains an
international collaboration that varies from 10% to 15%.
The years 2005 and 2006 were the ones with the most
publications by non-Brazilian authors (approximately 50%
of the authors were not Brazilian).
e) According to Webqualis of 2012 by CAPES, BJR is
classified as B3 in Medicine I area
In March 2012, CAPES established new Webqualis criteria
for the Medicine I area. The impact factor established either by the JCR® or by SCIMAGO (cites per doc/2 years)
between 0.2 and 0.8 classifies the journal as B3. BJR will
possibly have the impact factor by JCR® in 2013 and BjR’s
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EDITORIAL
cites per doc/2 years of 2010 is 0.21. The figures for 2011
are still incomplete, as they were calculated with only half
of the publications of 2011, resulting in cites per doc/2
years of 0.15. We are still waiting for SCIMAGO to finish
this review. Nevertheless, the estimated impact factor for
BJR for 2013 is around 0.2 to 0.3, which would put BJR
in the B3 criterion.
Given this context, we can celebrate BJR’s recent indexing
and the meeting of a goal established shortly after its indexing
in PubMed. However, it is very important that we continue
seeking the improvement of BJR and its greater international
visibility. The editorial policy of BJR should seek to maintain
its stringency in article selection for publication and encourage citation of articles already published, especially in the
last two years.
We consider essential that Brazilian rheumatologists continue sending their original articles for publication at BJR – but
662
also important, considering the need to increase the impact
factor of BJR, that authors seek, whenever appropriate, to
cite the publications of our journal when sending articles to
other journals. This strategy will be essential to increase the
visibility of BJR.
Finally, we would like to give our sincere thanks to our
friend and President of BJR, Geraldo Castelar, for his unconditional support, for his trust regarding the exercise of an
activity so relevant to BJR and for believing in our potential.
It has been a privilege over these two years, to work together
with Geraldo, who has shown to be an excellent manager and
also a great friend.
Paulo Louzada-Junior
Max Victor Carioca Freitas
Editors-in-chief, Brazilian Journal of Rheumatology
Rev Bras Reumatol 2012;52(5):661-664
EDITORIAL
Expression of concern:
Ahlin E et al., “Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese
patients with Leishmania donovani infection”, Rev Bras Reumatol 2011; 51(6):572–86
© 2012 Elsevier Editora Ltda. All rights reserved.
n December 2011, the Brazilian Journal of Rheumatology
(BJR) published the article “Anti-citrullinated peptide
antibodies and rheumatoid factor in Sudanese patients
with Leishmania donovani infection” by Ahlin E, Elshafei A,
Nur M, El Safi SH, Johan R, and Elghazali G. [Rev Bras
Reumatol 2011; 51(6):572–86]. On January 2012, the BJR
received a claim from one of the authors questioning the authorship of the corresponding author and informing that the
article was under submission to another journal, by Ahlin E,
Elshafie AI, Nur MAM, and Rönnelid J. This submission is
on hold, and the authors were all informed of the claim. The
I
case was submitted to the Committee on Publication Ethics
(COPE), which suggested some recommendations. The investigation has not yet reached a conclusion. Pending the results of
the investigations, BJR is publishing this Expression of concern
editorial to alert our readers to the fact that serious questions
have been raised about the authorship in the Ahlin E et al. paper.
Paulo Louzada-Junior
Max Victor Carioca Freitas
Editors-in-chief, Brazilian Journal of Rheumatology
Nota de preocupação:
Ahlin E et al., “Anticorpos antipeptídeos citrulinados e fator reumatoide em pacientes sudaneses
com infecção por Leishmania donovani”, Rev Bras Reumatol 2011; 51(6):572–86
© 2012 Elsevier Editora Ltda. Todos os direitos reservados.
m dezembro de 2011 a Revista Brasileira de Reumatologia
(RBR) publicou o artigo “Anticorpos antipeptídeos citrulinados e fator reumatoide em pacientes sudaneses com
infecção por Leishmania donovani”, por Ahlin E, Elshafei A,
Nur M, El Safi SH, Johan R e Elghazali G [Rev Bras Reumatol
2011; 51(6):572–86]. Em janeiro de 2012 a RBR recebeu uma
reclamação de um dos autores, questionando a autoria do autor
correspondente, e informando que o artigo estava sob submissão em outro periódico, por Ahlin E, Elshafie AI, Nur MAM e
Rönnelid J. Tal submissão está em espera, e todos os autores
foram informados sobre a reclamação. O caso foi submetido
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Rev Bras Reumatol 2012;52(5):665
ao Committee on Publication Ethics (Comitê de Ética de
Publicação – COPE), que sugeriu algumas recomendações. A
investigação ainda não chegou a uma conclusão final. Enquanto
se aguardam os resultados das investigações, a RBR está publicando este editorial de Nota de preocupação com o intuito
de alertar nossos leitores para o fato de que questões sérias
forma levantadas sobre a autoria do artigo de Ahlin E et al.
Paulo Louzada-Junior
Max Victor Carioca Freitas
Editores-chefe, Revista Brasileira de Reumatologia
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ORIGINAL ARTICLE
Improvement in pain, fatigue, and subjective
sleep quality through sleep hygiene
tips in patients with fibromyalgia
Aline Cristina Orlandi1, Camila Ventura2, Andrea Lopes Gallinaro3, Renata Alqualo Costa3, Laís Verderame Lage4
ABSTRACT
Objective: To evaluate the effectiveness of sleep hygiene instructions for women with fibromyalgia. Materials and
methods: Seventy women with fibromyalgia completed the study. The assessment comprised the Fibromyalgia Impact
Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI), and a general questionnaire with personal data and
lifestyle information. All patients received information about the disease and a sleep diary, but only the experimental
group received the sleep hygiene instructions. Patients were asked to practice sleep hygiene, and, after three months,
they were reevaluated by use of the same questionnaires. Results: The mean age in the control group was 55.2 ± 7.12
years, and, in the experimental group, 53.5 ± 8.89 years (P = 0.392). The experimental group showed: a decrease in
the pain Visual Analogue Scale values (P = 0.028), in fatigue (P = 0.021), and in the PSQI component 1 (P = 0.030);
and a significant reduction in the difficulty falling asleep after waking up in the middle of the night (P = 0.031). The
experimental group also showed an increase in the reporting percentage of “silent environment” (ranging from 42.9%
to 68.6%), a decrease in the reporting percentage of “fairly quiet environment” (ranging from 40% to 22.9%), and a
decrease in the reporting percentage of “noisy environment” (ranging from 17.1% to 8.6%). These changes facilitated
falling asleep after waking up in the middle of the night. Conclusion: The sleep hygiene instructions allowed changing
the patients’ behavior, which resulted in pain and fatigue improvement, increased subjective quality of sleep, in addition
to facilitating falling asleep after waking up in the middle of the night.
Keywords: fibromyalgia, sleep disorders, patient education.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Fibromyalgia (FM) is a rheumatic disease characterized by
the presence of musculoskeletal pain and somatic symptoms,
such as fatigue, and mood and sleep disorders, which play an
important role in well-being. Insomnia is reported by 75% of
the patients with FM.1
The literature suggests that, for a significant improvement in sleep quality of individuals with chronic insomnia,
the initial approach should consist of behavioral modification through sleep hygiene.2 Behavioral therapies, such
as sleep hygiene and cognitive therapy, which emphasize
behavioral modification, have been studied and applied
aiming at reducing the dose of medicines used to treat
chronic insomnia, improving the quality of life of those
who depend on hypnotics. Sleep hygiene comprises a set of
instructions aimed at modifying the habits that can affect
sleep health.3 However, there is no proof of the efficacy
of using that technique to improve the sleep quality of
patients with FM. Thus, this study aimed at assessing the
effectiveness of the sleep hygiene instructions provided
to women with FM.
Received on 07/18/2011. Approved on 06/27/2012. The authors declare no conflict of interest. Ethics Committee: 13391640.
Universidade Cidade de São Paulo – Unicid.
1. Physical therapist, Specialist in Rheumatology, Universidade Federal de São Paulo – Unifesp
2. Physical therapist, Master’s degree candidate in Rheumatology, Faculdade de Medicina, Universidade de São Paulo – FMUSP
3. Physical therapist, Master’s degree in Rehabilitation, Unifesp
4. Rheumatologist, Post-PhD, Department of Physiology, Division of Neuroscience, King’s College of London
Correspondence to: Aline Cristina Orlandi. Universidade Cidade de São Paulo. Rua Cesário Galeno, 448/475 – Tatuapé. São Paulo, SP, Brazil. CEP: 03071-000.
E-mail: [email protected]
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Rev Bras Reumatol 2012;52(5):666-678
Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia
MATERIALS AND METHODS
This study included 80 female patients from the Fibromyalgia
Outpatient Clinic of the Discipline of Rheumatology of the
Faculdade de Medicina, Universidade de São Paulo (FMUSP)
and from the Clínica de Fisioterapia, Universidade Cidade de
São Paulo (Unicid). The patients from FMUSP were selected
while waiting for their medical consultation with the rheumatology team. If asked to return to another consultation within
three months, their reassessment would be collected again
while they waited for their medical consultation. If the time
for a new consultation differed from three months, the patients
would be contacted by the authors and another day scheduled
for reassessment. Patients from Unicid were on rehabilitation
treatment at the Clínica Escola de Fisioterapia.
The inclusion criteria were as follows: women aged 18
to 65 years old, diagnosed with FM according to the 1990
American College of Rheumatology criteria.4 Women meeting
those criteria but working at night shifts were excluded from
the study, which was approved by the Committee on Ethics
and Research of the Unicid (protocol # 13391640).
The patients underwent a general assessment comprising personal data, personal habits, and anamnesis. Then, the
following questionnaires were applied: the Pittsburgh Sleep
Quality Index (PSQI),5 specific for assessing quality of sleep
and validated for Brazil,6 that qualifies the patient’s sleep
during the previous month; and the Fibromyalgia Impact
Questionnaire (FIQ),7 specific for assessing the impact of
FM on the patient’s functional capacity and also validated
for Brazil.8 After the assessment, the patients were randomly
divided into two groups (control and experimental groups), by
using envelopes containing the name of one of the two groups.
The control group comprised 41 patients, and the experimental
group, 39 patients. All participants provided written informed
consent before randomization and after being informed about
the inclusion and exclusion criteria.
After the assessment, both groups received a booklet with
basic information about the disease. The experimental group
was also instructed about sleep hygiene (Chart 1). Those instructions provided to the experimental group were obtained
from studies on the treatment of sleep disorders in the elderly9
and non-pharmacological treatment of chronic insomnia.3 Such
instructions have also been used in a study applying sleep
hygiene to patients with FM.10 In addition to providing the
booklets with instructions about sleep hygiene, they were read
and explained to each experimental group patient at a single
meeting. The importance of the daily application of those
instructions for three months was emphasized. In addition,
Rev Bras Reumatol 2012;52(5):666-678
all participants received a “sleep diary” and were instructed
to describe, in the last 15 days of treatment, their nights of
sleep and the hours preceding bedtime. After three months,
the patients returned to the clinic to be reassessed (second
meeting). During those three months, patients and authors
had no contact. Both assessments were performed on medical
consultation days, aiming at minimizing sample loss, which
is common in prospective studies.
In the statistical analysis, the Student t test was used11 to
compare the initial data of participants’ ages. The results from
the PSQI, FIQ, and sleep diary were described according to
the groups and occasions and were compared between the
groups before and after treatment by using the Mann-Whitney
test,11 and in each group before and after treatment by using
the paired Wilcoxon test.11 Habits and characteristics of the
sleep environment were described according to the groups by
using absolute and relative frequencies, and the existence of
an association was assessed with the chi-square test or Fisher
exact test or the likelihood ratio test11 (the last two being used
when the sample was insufficient to perform the chi-square
test). Changes for each habit and characteristic of the sleep
environment were described in each group and compared
before and after the treatment by using the McNemar test.12
Spearman correlation13 between the variation of the FIQ and
the PSQI was calculated to assess the existence of correlation
between them.
All data were analyzed with the SPSS for Windows, version
15.0, adopting 5% as the significance level, and illustrated with
tables and bar graphs.
Chart 1
Sleep hygiene instructions provided to patients of the
experimental group
SLEEP HYGIENE INSTRUCTIONS
Try to go to bed at the same time every day. Your body will be prepared to
sleep always at the same time. You will fall asleep faster in the following
weeks!
Avoid using your bedroom to work, study or eat. It should be only the
place to sleep.
Avoid watching TV before bedtime, because it can make you anxious and
interfere with your sleep!
Relax your mind and body for at least one hour before bedtime. Do not get
involved with great problems at that time of the night.
Avoid coffee, tea and chocolate after 5 p.m.
Avoid alcohol close to bedtime. Although it helps you relax, it can disrupt
sleep later; if possible, take a glass of milk.
If you smoke, refrain from smoking two to three hours before bedtime.
Try to eat light at dinner. Salads and vegetables are a good option. Greasy
food, such as fried food, is heavier and can disrupt sleep!
(Continue...)
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Orlandi et al.
(Continuation of Chart 1)
SLEEP HYGIENE INSTRUCTIONS
Keep your room’s temperature comfortable. A room too hot or cold interferes
with quality of sleep. In addition, dress warmly to avoid possible muscle
“contractures”.
Noise and light can lead to poor sleep. Thus, try to sleep in a silent dark
room.
Regular physical activity can improve the quality of your sleep. But, beware,
try to exercise in the morning or afternoon. If you exercise too close to
bedtime, you might be too energized to fall asleep. The exercise should
be pleasing, leaving you happy and cheered up. In addition to increasing
the quality of your sleep, you will be fit.
Establish a bedtime routine. For example: lock the doors, brush your teeth...
Your body gets used to this routine, and reminds you that bedtime is close,
reducing the time you wait to fall asleep.
Warm bath close to bedtime is recommended to fight insomnia, because
it relaxes your mind and body.
Do not nap more than twice in the same week. This decreases the need
for night sleep.
Table 1
Description of the sleep diary and comparison between the
control and experimental groups
Variable
Group (n = 35)
Mean
SD
P
Sleep 1
Control
Experimental
7.06
7.49
5.95
6.35
0.805
Control
Experimental
5.00
6.60
6.34
6.12
0.132
Control
Experimental
5.71
2.91
6.19
4.35
0.031
Control
Experimental
0.00
0.00
0.00
0.00
1.000
Control
Experimental
0.26
0.60
0.70
1.56
0.630
Control
Experimental
0.51
0.26
1.92
1.12
0.636
Control
Experimental
4.63
6.00
6.70
6.90
0.317
Control
Experimental
7.14
7.51
5.41
5.17
0.763
Control
Experimental
2.14
2.31
0.82
0.92
0.273
Control
Experimental
2.71
2.70
0.78
0.84
0.804
Control
Experimental
23.56
23.51
1.17
1.35
0.760
Control
Experimental
6.90
6.90
1.24
1.51
0.828
(More than 30 minutes to fall asleep)
Sleep 2
(Slept again with difficulty)
Sleep 3
(Slept again easily)
Sleep 4
(Alcohol intake)
Sleep 5
(Inadequate food)
Sleep 6
(Physical activity)
Sleep 7
Make sure you always have a comfortable bed. This is important for you
to fully relax and fall asleep.
(Took medicines)
Avoid “fighting” with the bed. Sleep only the time sufficient for you to feel
good. Do not stay in bed longer than necessary.
(Non-repairing sleep)
When you are sleepless, get up and do something boring or repetitive, such
as to read an uninteresting book.
(Fatigue 0-4)
Say no to medicines! You should take sleeping pills only under medical
supervision!
(Fatigue 0-4)
Sleep 8
Day mean
Night mean
Mean “I went to bed”
(Bed time)
Mean “I got up”
(Getting-up time)
RESULTS
This study assessed 80 female patients, of whom only 70
concluded the study and were included in the analysis. Of the
10 patients not participating in the statistical analysis, six decided not to return to reassessment and four did not complete
correctly the sleep diary. The mean age of the patients in the
control group was 55.2 ± 7.12 years, and in the experimental
group, 53.5 ± 8.89 years (P = 0.392).
Table 1 shows that, regarding the sleep diary, only the
answers to question 3 in the experimental group differed
significantly from those in the control group (P = 0.031). That
question regards the number of days the patient woke up during
the night and had no difficulty to fall asleep again (“Sleep 3”).
The other questions of the sleep diary showed no significant
difference between the groups. In those questions, participants
answered the number of days in which: it took them more than
30 minutes to fall asleep, “Sleep 1”; it took them a long time
to fall asleep again after waking up in the middle of the night,
“Sleep 2”; they drank alcoholic beverages, “Sleep 4”; they ate
inadequately, “Sleep 5”; they exercised at least three hours
from bedtime, “Sleep 6”; they took sleeping pills, “Sleep 7”;
and they had non-repairing sleep, “Sleep 8”. In addition, the
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Results of the Mann-Whitney test. Significance: P < 0.05.
following means were calculated for both groups: mean fatigue
during the day and during the night (“day mean” and “night
mean”); mean bedtime (“bedtime mean”); and mean wake-up
time (“wake-up mean”). None showed statistical differences,
indicating that patients were equally tired, and went to bed and
got up at similar times.
In the experimental group, in which patients received information on both the disease and sleep hygiene, reductions in
the following measures were observed: pain Visual Analogue
Scale (VAS) (P = 0.028); fatigue (P = 0.021); and PSQI component 1 (P = 0.030), which relates to the subjective quality
of sleep. Table 2 shows the variables assessed and the PSQI
and FIQ scores before and after the treatment in both groups.
Figure 1 shows the reduction in the median VAS values
only in the experimental group after treatment. Figure 2 shows
a reduction in the median PSQI component 1 value in the
experimental group after treatment, with an improvement in
the subjective quality of sleep.
The ingestion of coffee, tea, and chocolate (P > 0.999) did
not significantly differ between the groups at both the beginning
Rev Bras Reumatol 2012;52(5):666-678
Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia
Table 2
Description of the sleep quality measures in fibromyalgia and patient’s assessment according to the groups, before and after
treatment, and result of the comparisons
Initial
3 months
Variable
Group
(n = 35)
Mean
SD
Median
Mean
SD
Median
Disease duration (years)
Control
Experimental
5.45
5.80
4.72
4.32
5.0
5.0
5.47
5.75
4.72
4.33
5.0
5.0
0.317
0.317
VAS (pain)
Control
Experimental
7.11
7.66
2.63
1.95
8
8
6.09
6.49
3.53
2.75
8
7
0.131
0.028
Fatigue on the occasion (0:4)
Control
Experimental
2.86
3.11
1.22
0.87
3
3
2.71
2.63
1.23
1.09
3
3
0.369
0.021
Sleep satisfaction (0–5)
Control
Experimental
3.03
3.43
1.82
1.70
4
4
3.23
3.06
1.72
1.43
4
3
0.456
0.162
Control
Experimental
1.54
1.86
0.74
0.81
2
2
1.66
1.51
0.76
0.89
2
1
0.499
0.030
Control
Experimental
1.89
2.06
1.13
1.06
2
2
1.83
1.91
1.36
1.25
3
3
0.908
0.429
Control
Experimental
1.11
1.20
0.90
1.11
1
1
1.03
0.94
1.04
1.19
1
0
0.700
0.271
Control
Experimental
0.17
0.23
0.57
0.55
0
0
0.20
0.20
0.63
0.47
0
0
0.915
0.792
Control
Experimental
2.17
2.20
0.57
0.53
1.94
2.09
0.59
0.51
2
2
0.074
0.285
Control
Experimental
0.94
1.54
1.35
1.48
2
2
0
2
1.23
1.60
1.46
1.46
0
2
0.164
0.928
Control
Experimental
2.14
1.89
1.00
1.02
2
2
1.86
1.74
1.00
0.85
2
2
0.147
0.525
PSQI
Control
Experimental
9.97
9.74
3.04
3.09
10
10
10.97
10.00
3.52
3.96
11
10
0.664
0.065
FIQ (global score)
Control
Experimental
54.59
59.53
16.77
17.98
55.8
63.7
52.75
54.26
18.75
17.86
56.7
56.7
0.768
0.149
Component 1
(Subjective quality of sleep)
Component 2
(Sleep latency)
Component 3
(Sleep duration)
Component 4
(Sleep efficiency)
Component 5
(Sleep disorders)
Component 6
(Use of sleeping pills)
Component 7
(Sleep-related daily dysfunctions)
P
VAS = Visual Analogue Scale; PSQI = Pittsburg Sleep Quality Index; FIQ = Fibromyalgia Impact Questionnaire.
8.2
2.5
8.0
2.0
7.8
Median value
Median value
7.6
7.4
7.2
7.0
6.8
1.5
1.0
0.5
6.6
6.4
0.0
Initial
3 months
Time
Control
Experimental
Figure 1
Median Visual Analogue Scale values according to the groups,
before and after treatment.
Rev Bras Reumatol 2012;52(5):666-678
Initial
3 months
Time
Control
Experimental
Figure 2
Median PSQI component 1 values according to the groups,
before and after treatment.
669
Orlandi et al.
of study and after three months of treatment. Those results were
obtained by use of Fisher exact test.
After receiving treatment for three months, the experimental group showed an increase in the percentage of reports of
“silent environment” (range, 42.9%–68.6%), a reduction in
the percentage of reports of “fairly quiet environment” (range,
40%–22.9%), and a reduction in the percentage of reports of
“noisy environment” (range, 17.1%–8.6%). The control group,
however, showed an increase in the percentage of reports of
“noisy environment” (range, 11.4%–17.1%) after three months
of treatment. Those values, however, showed no statistically
significant differences (P > 0.05), assessed by use of the likelihood ratio test.
After three months of treatment, the experimental group
showed an increase in the percentage of reports of “dark environment” (range, 34.3%–82.9%) and a decrease in the percentage of “poorly lighted environment” (range, 37.1%–5.7%),
and in the percentage of “well lighted environment” (range,
28.6%–11.4%).
Regarding ventilation, after three months of treatment, the
experimental group showed an increase in the percentage of
“non-ventilated environment” (range, 20% - 48.6%), stability
in the percentage of “poorly ventilated environment” (20%),
and a reduction in the percentage of “well ventilated environment” (range, 60% - 31.4%).
Table 3 shows that, when using Spearman correlation for
the changes in the FIQ (final-initial) and the PSQI components
(final-initial), the result observed is a modification in FIQ
Table 3
Spearman correlation between the changes in FIQ (final–initial)
and the changes in the PSQI components (final–initial)
PSQI sleep component (n = 70)
Component 1
(Subjective quality of sleep)
Component 2
(Sleep latency)
Component 3
(Sleep duration)
Component 4
(Sleep efficiency)
Component 5
(Sleep disorders)
Component 6
(Use of sleeping pills)
Component 7
(Sleep-related daily dysfunctions)
Spearman correlation test.
670
Correlation
P
0.116
0.339
0.311
0.009
0.104
0.391
0.188
0.119
0.059
0.629
0.071
0.561
0.159
0.189
directly proportional to that of the PSQI component 2 (r = 0.311
and P = 0.009), corresponding to sleep latency in both groups.
DISCUSSION
The results of this study have shown an improvement in the
subjective sleep quality and in the results of the pain VAS in
patients with FM receiving sleep hygiene instructions.
Question 3 of the sleep diary, regarding the number of
days in which the patient woke up in the middle of the night
and had no difficulty falling asleep again, showed a statistically significant difference, probably due to the instructions
regarding environmental noise and lighting (performed by
most patients).
Thus, sleep hygiene provided benefit in the subjective
quality of sleep, with an improvement in the PSQI component 1 (subjective quality of sleep). When the sleep quality is
benefited, there is also an improvement in pain and fatigue,14
explaining the reduction in the VAS and fatigue in that group.
In another study, patients receiving sleep hygiene instructions
also had favorable results regarding pain and well-being as
compared with a control group.10 Those findings are in accordance with those of a recent study15 suggesting a decrease
in pain in patients with FM obtained through an improvement
in sleep quality, as in the present study.
Other findings in this study correlated PSQI and FIQ: the
greater the change in the PSQI component 2, the greater the change
in FIQ. This means that, when the score of PSQI component 2
(sleep latency) increases, the total FIQ score also increases. This
confirms the importance of assessing sleep quality by use of PSQI,
when the impact of disease on the quality of life of patients with
FM is high. In addition, that finding translates the importance of
global assessment, associated with a treatment involving the different factors affected in the life of those patients.
Studies have applied the cognitive-behavioral therapy
(CBT) to sleep10 and pain16,17 in patients with FM. In their study,
Edinger et al.10 have concluded that CBT applied to sleep is
more effective than sleep hygiene instructions, and those two
interventions are more effective than the medicamentous intervention usually performed in patients with FM. However,
sleep hygiene has provided favorable results regarding pain
and mental well-being, as in our study.
The changes in habits in both groups were not controlled.
Some variables, such as coffee ingestion, type of food, and
characteristics of the sleep environment were assessed before
and after treatment. A statistically significant change was observed only in the sleep environment. Nevertheless, a reduction
in the pain VAS and fatigue values was observed after treatment
Rev Bras Reumatol 2012;52(5):666-678
Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia
in the experimental group. Thus, it is believed that if other sleep
hygiene recommendations are followed, the benefit regarding
sleep will be even greater, thus improving the quality of life
and mental health of patients with FM.
CONCLUSION
A booklet with sleep hygiene instructions allowed changing
the behavior of patients, whose pain and fatigue improved, increasing the subjective quality of sleep, and facilitating falling
asleep after waking up in the middle of the night.
This study shows that sleep hygiene can benefit the quality of sleep of patients with FM. Further studies should be
conducted, more effectively controlling the changes in the life
habits of patients practicing sleep hygiene.
Rev Bras Reumatol 2012;52(5):666-678
The sleep hygiene instructions handed to patients of the
experimental group were obtained from articles about the
non-medicamentous treatment of chronic insomnia and treatment of sleep disorders in the elderly. There are few studies
using those instructions for patients with FM. Thus, there is no
consensus in the literature about evidence-based instructions
and those more indicated for that type of patient, limiting the
results and conclusions.
Neither the medicines used by the patients at the beginning
of the study nor the medicamentous changes asked by the doctors during the three months of study were controlled, limiting
the results and the conclusion. In addition, there was no control
of the baseline characteristics regarding sedentary lifestyle and
body mass index. This study had no blind examiner, which also
limited the results and the conclusion.
671
Melhora da dor, do cansaço e da qualidade subjetiva do sono por meio de orientações de higiene do sono em pacientes com fibromialgia
EVA e do cansaço nesse grupo. Em outro estudo, pacientes
que receberam orientações de higiene do sono apresentaram,
também, resultados favoráveis em relação à dor e ao bem-estar,
quando comparados a um grupo-controle.10 Esses achados vão
ao encontro de um estudo recente15 que sugere a diminuição da
dor de portadores de FM pela melhora da qualidade do sono,
conforme o presente estudo.
Outros achados neste estudo correlacionaram o PSQI e
o FIQ: quanto maior a alteração do componente 2 do PSQI,
maior a alteração do FIQ. Isso significa que quando o escore do componente 2 do PSQI, referente à latência do sono,
aumenta, o escore total do FIQ também sofre aumento. Tal
dado confirma a importância da avaliação da qualidade do
sono, por meio do PSQI, quando o impacto da doença na
qualidade de vida dos portadores é alto. Além disso, esse
achado traduz a importância da avaliação global, associada a
um tratamento envolvendo os mais diversos fatores afetados
na vida desses pacientes.
Estudos aplicam a terapia cognitivo-comportamental
(TCC) em relação ao sono10 e à dor16,17 em portadores de FM.
No estudo de Edinger et al.10 concluiu-se que a aplicação da
TCC, relacionada ao sono, é mais eficaz quando comparada à
aplicação da higiene do sono, sendo essas duas intervenções
mais eficazes que a intervenção medicamentosa usualmente
realizada nos portadores de FM. Porém, a higiene do sono
acarretou resultados favoráveis em relação à dor e ao bem-estar
mental, como em nosso estudo.
As alterações de hábitos de ambos os grupos não foram
controladas. Algumas variáveis, como ingestão de café, tipo
de alimentação e características do ambiente do sono, foram
verificadas antes e após o período de tratamento. Observou-se
alteração estatisticamente significativa apenas no ambiente do
sono. Ainda assim, houve diminuição nos valores da EVA e
do cansaço após o tratamento no grupo-experimental. Dessa
forma, acredita-se que se outros pontos da higiene do sono
forem seguidos haverá ainda maior benefício em relação ao
sono, e, consequentemente, à qualidade de vida e à saúde
mental nas portadoras de FM.
CONCLUSÃO
Uma cartilha com orientações de higiene do sono permitiu
a alteração do comportamento das pacientes, que obtiveram
melhora da dor e do cansaço, aumento da qualidade subjetiva
do sono, além de facilitação do sono após despertar durante
a madrugada.
Este estudo mostra que a higiene do sono pode trazer
benefícios à qualidade do sono da paciente com FM. Novos
Rev Bras Reumatol 2012;52(5):666-678
estudos devem ser realizados, controlando de forma mais eficaz
as alterações nos hábitos de vida das pacientes que realizam
a higiene do sono.
As orientações de higiene do sono entregues às pacientes
do grupo-experimental foram obtidas por meio de artigos para
tratamento não medicamentoso da insônia crônica e tratamento
de distúrbios do sono em pessoas idosas. Há poucos estudos
que utilizaram essas orientações para grupos de FM. Por isso,
não há consenso na literatura sobre as orientações com base em
evidência e mais indicadas para esse tipo de paciente, limitando
os resultados e as conclusões.
Não foram controlados os medicamentos que as pacientes
utilizavam ao início do estudo nem as alterações medicamentosas solicitadas pelos médicos no decorrer dos três meses, o
que limita os resultados e a conclusão. Não houve controle
também das características basais em relação ao sedentarismo
e ao índice de massa corporal. O estudo não apresentou avaliador cego, o que também limita os resultados e a conclusão.
REFERENCES
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Petrie CD, Martin S. Psychometric properties of a single-item scale
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15. Bigatti SM, Hernandez AM, Cronan TA, Rand KL. Sleep
disturbances in fibromyalgia syndrome: relationship to pain and
depression. Arthritis Rheum 2008; 59(7):961–7.
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Cognitive behavioral therapy for the treatment of fibromyalgia
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Rev Bras Reumatol 2012;52(5):666-678
ORIGINAL ARTICLE
Epidemiological profile of patients with extraarticular manifestations of rheumatoid arthritis
from the city of Curitiba, South of Brazil
Mariana Costa Moura1, Paola Tamara Silva Zakszewski1, Marília Barreto Gameiro Silva2, Thelma Larocca Skare3
ABSTRACT
Objectives: To describe the epidemiological profile of patients with extra-articular manifestations of rheumatoid arthritis (ExRA) from an university-affiliated rheumatology center; to report the prevalence of ExRA and to compare it
with available data; and to identify, if possible, ExRA predictors. Methods: This study reviewed 262 medical charts of
patients previously diagnosed with rheumatoid arthritis (RA) according to the 1987 American College of Rheumatology
criteria, and attending that rheumatology center in 2010. The statistical analysis comprised simple mathematical calculations, Student t and chi-square tests, and a significance level of 5% (α = 0.05). Results: During the course of the disease,
120 patients (45.8%) had ExRA. Pulmonary manifestation, rheumatoid nodules and Sjögren’s syndrome were the most
common manifestations found. Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in most
patients tested. Most patients were classified as Steinbrocker functional classes 1 and 2. The mean DAS-28 was 3.629,
and the mean HAQ score, 1.12. Patients with ExRA had longer disease duration (P < 0.05), and current smoking habit
associated with the presence of ExRA (P < 0.05). Conclusions: The prevalence of ExRA during disease course was
45.8%, and current smoking habit correlated with the presence of ExRA.
Keywords: rheumatoid arthritis, health profile, smoking.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Rheumatoid arthritis (RA) is a chronic and multisystemic disease of unknown etiology, characterized by inflammatory synovitis. It is a symmetric and additive polyarthritis with a variable
potential for deformation, usually involving peripheral joints
and the spine. It affects 1% of the general population, being
three times more frequent in women than men. Its prevalence
increases with age, and the difference between the genders
becomes smaller. It usually begins between 35 and 50 years
of age, and its onset relates to genetic predisposition and to the
interaction of environmental agents with that predisposition.1
The inflammatory process can spread to other systems
and organs, causing extra-articular manifestations of RA
(ExRAs), which can affect equally men and women, and
can appear at any age.2 Forty percent of the patients are
estimated to have ExRAs during the course of disease, 15%
being considered severe.3
Some predictors of ExRAs are as follows: male gender;
severe joint disease; low functional capacity; high levels of
inflammatory markers; and high titers of autoantibodies, such
as rheumatoid factor (RF), anti-cyclic citrullinated peptide
antibody (anti-CCP), and antinuclear antibody (ANA). Both
RF and anti-CCP are also related to the severity of ExRA.2,4,5
Smoking, longer duration of disease, and RA associated with
the HLA-DRB1*04 genes are also predictors of ExRAs.
Probably due to interactions between those and other risk factors, more than one ExRA tend to occur in the same patient.
Received on 08/16/2011. Approved on 06/27/2012. The authors declare no conflict of interest. Ethics Committee: 12103/10.
Outpatient Clinic of the Rheumatology Service, Faculdade Evangélica do Paraná, Hospital Universitário Evangélico de Curitiba – HUEC.
1. Undergraduate Student of Medicine
2. Master’s degree in Internal Medicine, Universidade Federal do Paraná – UFPR; Adjunct Professor of Rheumatology, Faculdade Evangélica do Paraná – FEPAR;
President of the Sociedade Paranaense de Reumatologia
3. PhD, Instituto de Pesquisas Médicas, Hospital Universitário Evangélico de Curitiba – HUEC; Chief of the Discipline of Rheumatology, FEPAR; Chief of the
Rheumatology Service, HUEC
Correspondence to: Mariana C. Moura. Rua Professor Duilio A. Calderari, 100. Curitiba, PR, Brazil. CEP: 80040-250. E-mail: [email protected]
Rev Bras Reumatol 2012;52(5):679-694
679
Moura et al.
Rheumatoid nodules are associated with a large spectrum of
severe ExRA.2,6
There are several definitions for ExRAs depending on
the clinical and/or pathological criteria used. The lack of
an international consensus and of a single classification
is partially due to differences observed in rheumatology
texts, case reports, and incidence studies. Other reasons are
discrepancies in the definition of cases and variations in the
inclusion of manifestations other than the classic ExRAs.
Some non-articular findings have been classified as complications of RA rather than ExRAs, while others, which have
been described as neither ExRAs nor complications, have
been included due to their increased risk of RA.7 This limits
comparisons between different studies.
Recent publications have suggested that the use of a similar
criterion would enable a more consistent assessment of the
extension of the extra-articular disease. Turesson et al.8 have
proposed a set of criteria for severe ExRAs, developed to
identify clinically important ExRAs in retrospective structured
studies reviewing medical charts.
Some examples of ExRAs commonly found in the literature
are as follows: rheumatoid nodules; pericarditis; pericardial
effusion; pleuritis; pleural effusion; interstitial pulmonary
disease; pulmonary artery hypertension; Caplan’s syndrome;
Felty’s syndrome; chronic disease anemia; thrombocytosis;
neuropathy; scleritis; episcleritis; sicca syndrome; scleromalacia perforans; glomerulonephritis; cutaneous ulcers;
vasculitides; De Quervain’s tenosynovitis; amyloidosis; and
Sjögren’s syndrome.4–6,8,9
The systemic inflammatory process is the major predictor
of mortality for patients with RA. The presence of ExRAs
determines a five-fold increase in mortality rate as compared
with that of patients without ExRAs, and that increase is
even greater when co-morbidities, such as cardiovascular
and pulmonary diseases, malignancies and dementia, are
considered. Some ExRAs, especially vasculitis, pericarditis,
pleuritis, amyloidosis and Felty’s syndrome, are associated
with a shorter life expectancy as compared with that of patients without ExRAs. There is also a particularly increased
risk of premature death due to cardiovascular disease. The
survival of patients with RA but no ExRA is similar to that
of the general population.2,3,8,10–12
Considering the patients with ExRAs from a referral
service, this study aimed at the following: describing their
epidemiological profile; reporting the prevalence of ExRAs
among them; comparing their ExRAs with data in the literature; and, if possible, identifying predictive factors of those
manifestations.
680
PATIENTS AND METHODS
This is a retrospective study based on data obtained from
the medical charts of patients with RA from the Service of
Rheumatology of the Hospital Universitário Evangélico de
Curitiba (HUEC).
This study included patients diagnosed with RA according to the 1987 American College of Rheumatology (ACR)
classification criteria for RA, and who attended the service of
rheumatology of the HUEC from January to December 2010.
The following patients’ data were collected: gender;
age; city of residence; ethnicity; educational level; current
and previous smoking habit; duration of smoking habit; age
at diagnosis; disease duration; co-morbidities; presence of
ExRA during the course of disease; autoantibodies (RF, ANA,
anti-CCP, anti-Ro and anti-La); global functional class by use
of the Steinbrocker functional classification and the Health
Assessment Questionnaire (HAQ); and parameters of disease
activity by use of the Disease Activity Score 28 (DAS-28).
The latter two corresponded to the last consultation of the year.
Ethnicity was stratified according to the traditional records
of the service as follows: Caucasian; mixed heritage; black;
Asian; and Brazilian native. The educational level was classified according to the records of the service as follows: illiteracy/
incomplete elementary education; complete elementary education; incomplete secondary education; complete secondary
education; incomplete higher education; and complete higher
education. The concomitant conditions not described in the
literature as direct consequences of RA, even though some of
them are more frequently associated with RA, were considered
co-morbidities
The ExRAs were grouped according to affected systems or
organs as follows: rheumatoid nodules; rheumatoid vasculitis;
lymphadenopathy; amyloidosis; Sjögren’s syndrome; and hematological, pulmonary, cardiac, ocular, neurological, renal,
and osteomuscular manifestations. Because of the lack of a
consensus in the current literature regarding the classification
of ExRAs, our findings were described based on an adaptation
of the descriptions found in books and reference articles, such
as the articles by Turesson et al.6,8 and the book Rheumatology.2
Regarding autoantibodies, ANA was assessed by use of
indirect immunofluorescence. The results were standardized
according to the II Brazilian Consensus on ANA Hep-2, and
were positive when titers were > 1:80, according to the laboratory of the HUEC. Rheumatoid factor (IgM) was obtained by
use of the qualitative latex agglutination test, and measurements > 20 UI/mL were considered positive. Anti-CCP (IgG)
was determined by use of the Enzyme-Linked Immunosorbent
Rev Bras Reumatol 2012;52(5):679-694
Epidemiological profile of patients with extra-articular manifestations of rheumatoid arthritis from the city of Curitiba, South of Brazil
Assay (ELISA), with a cutoff point of 20 U/mL. Titers between
20 and 39 U/mL were considered weakly positive; between 40
and 59 U/mL, moderately positive; and over 60 U/mL, strongly
positive. The anti-Ro and anti-La autoantibodies were tested
by use of ELISA.
The Steinbrocker functional classification comprises four
classes, according to the individual’s capacity of performing
daily life tasks. Class 1 corresponds to complete functional
capacity with ability to carry on all usual duties without handicaps; class 2, functional capacity adequate to conduct normal
activities despite handicap of discomfort or limited mobility
in one or more joints; class 3, functional capacity adequate to
perform only few or none of the duties of usual occupation or
of self-care; class 4, largely or wholly incapacitated (patient
bedridden or confined to wheelchair).1
The HAQ involves questions related to daily life, regarding
eight predetermined groups, the result being divided by eight.
The final score represents the individual’s quality of life. The
higher the score, the worse the quality of life.13 The DAS-28
assesses RA activity by use of a mathematical equation that
comprises the following: Visual Analogue Scale for pain score
(ranges from zero to ten, where zero means no pain, and ten
means worst pain imaginable); tender joint count; swollen joint
count; and erythrocyte sedimentation rate (mm/h). Results over
5.1 indicate high disease activity; 3.2–5.1, moderate activity;
2.6–3.2, low activity; and under 2.6, remission.13
This study included 262 medical charts according to
pre-established criteria. Data were inserted into Excel 2007
(Microsoft) sheets and managed to provide the epidemiological
profile through descriptions and simple mathematical calculations, such as percentage and arithmetic mean.
To assess whether disease duration differed between patients with and without ExARs, Student t test was used (ZAR
1999). The chi-square test was used to assess the differences
between the proportions of patients with or without ExARs
regarding several variables, such as ethnicity, current smoking habit, previous smoking habit, RF, anti-CCP, and gender.
There was only one individual of Native Brazilian origin,
a fact that made it impossible to assess him statistically; therefore, he was excluded from the analysis regarding ethnicity. For
all analyses, a significance level of 5% was adopted (α = 0.05).
The statistical analyses were performed using the Statistica
(Statsoft) statistical package and the tables developed with
Excel 2007 (Microsoft).
This study was approved by the Committee on Ethics and
Research of the Sociedade Evangélica Beneficente de Curitiba
(protocol # 12103/10, December 2010) and has no conflict of
interest.
Rev Bras Reumatol 2012;52(5):679-694
RESULTS
During the course of disease, 120 patients had ExRA, corresponding to 45.8% of the patients with RA in the period
studied, and most of them were of the female gender (84.1%).
The mean age was 56 years (range, 29–87 years; mode, 61 years).
The cities of residence were obtained from 101 patients and
were as follow: Curitiba, 64; São José dos Pinhais, 4; Ponta
Grossa, 2; Pinhais, 2; Colombo, 2; Campo Largo, 2; Paranaguá,
2; Araucária, 2; and other cities in the state of Paraná, 21.
Regarding ethnicity, 71 patients (71.7%) were Caucasian, 23
(23.2%) were of mixed heritage, five (5%) were black, and
21 had no ethnic records. Mean age at diagnosis was 44 years
(range, 11–83 years; mode, 50 years). Mean duration of disease
was 12.2 years (range, 0–64 years). Data on education level
were found in 80 medical charts and are shown in Table 1.
Regarding smoking habit, only one medical chart showed
no smoking record. Of the others, 82 patients (69%) were not
current smokers, and 23.5% of the total number of patients were
previous smokers, with a mean duration of tobacco use of 20.2
years – eight patients were excluded from that calculation due
to lack of information. Thirty-seven individuals (31%) were current smokers, with a mean duration of tobacco use of 26 years.
The patients’ major co-morbidities during the study period
are shown in Figure 1. Many of them, such as systemic arterial
hypertension (SAH), dyslipidemia, and hypothyroidism, were
found concomitantly in the same patient. The specifications of
the most common ExRA types, according to affected organs
or systems, are shown in Table 2.
Regarding autoantibodies, RF was positive in 83 patients
(69.2%), and ANA was positive in 32 (27.1%) of the 118
medical charts providing this information, most showing high
titers (> 1:160). Of the 62 patients with data on the anti-CCP
serological test, 48 (77%) were positive. Of the 114 patients
with data on the anti-Ro test, only six (5.3%) were positive.
Of the 115 patients with data on the anti-La test, three (2.6%)
were positive.
Table 1
Educational level, %* (n)
Illiteracy/ incomplete Elementary Education
62.5 (50)
Complete Elementary Education
13.75 (11)
Incomplete Secondary Education
2.5 (2)
Complete Secondary Education
16.25 (13)
Incomplete Higher Education
0
Complete Higher Education
5 (4)
*Total corresponds to 80 individuals whose data were available
681
Moura et al.
Chloroquine –induced maculopathy
7.5
Osteopenia
8.3
Fibromyalgia
13.3
Obstructive ventilatory disorder
12.5
Osteoporosis
13.3
Heart conduction disorders
15
Osteoarthritis
15
Type 2 diabetes mellitus
15.8
Valvular heart disease
15.8
Hypothyroidism
Figure 1
Co-morbidities of patients with
extra-articular manifestations of
rheumatoid arthritis (%).
20.8
Dyslipidemia
23.3
Systemic arterial hypertension
44.1
Table 2
Most common types of extra-articular manifestations of
rheumatoid arthritis, %*(n)
Rheumatoid nodules
21 (25)
—
Hematological
4.2 (5)
Chronic disease anemia
Pulmonary
54.2 (65)
Pulmonary fibrosis
Pulmonary nodules
Pleural effusion
Pulmonary artery hypertension
Cardiac
1.7 (2)
Pericardial effusion
Pericarditis
Ocular
3.4 (4)
Episcleritis
Scleritis
Scleromalacia perforans
Neurological
3.4 (4)
Polyneuropathy
Peripheral mononeuropathy
Renal
0
—
Vasculitides
10 (12)
Raynaud
Ulcer
Others
Osteomuscular
1.7 (2)
De Quervain’s tenosynovitis
Amyloidosis
12.5 (15)
—
Sjögren’s syndrome
18.3 (22)
—
Table 3
Means, standard deviations (SD), sample size (n) and
probability (P) associated with the Student t test
Presence of extraarticular manifestations
n
Mean
SD
P
Yes
120
12.3
9.6
0.002*
No
141
8.9
7.4
0.002*
*P < 0.05.
Table 4
Proportions (data as absolute frequencies) of six distinct
variables associated with the presence or absence of extraarticular manifestations
Yes
No
Female
101
126
Male
19
16
Caucasian
71
89
Mixed heritage
23
18
Black
5
10
Current smoking
(n =260)
No
82
113
Yes
37
28
Previous smoking
(n = 192)
No
53
77
Yes
28
34
RF
(n = 262)
No
36
54
Yes
84
88
Anti-CCP
(n = 111)
No
13
15
Yes
49
34
Gender
(n = 262)
*Regarding the total number of patients. Many of them had more than one ExRA.
Considering functional assessment (Steinbrocker functional
classification), four medical charts showed none. One hundred
patients (86%) provided answers compatible with classes 1 and
2, and 16 (14%) with classes 3 and 4. The mean value of DAS28 for 108 patients who provided that information in 2010 was
3.629 (range, 1.19–7.45). The HAQ score in 2010 was found
in 50 medical charts, its mean value being 1.12 (range, 0–2.8).
The analyses showed that patients with ExRA had longer
disease duration than those with no ExRA (Table 3). The proportions assessed allowed stating that there is difference only
between the proportions of currently smokers with ExRA.
Smoking habit is associated with the presence of ExRA (Table 4).
682
Presence of ExRA
Variable (n)
Ethnicity
(n = 216)
P
0.279
0.244
0.037*
0.564
0.172
0.2453
*P < 0.05. ExRA: extra-articular manifestations of RA; RF: rheumatoid factor.
P values are associated with the chi-square test.
Rev Bras Reumatol 2012;52(5):679-694
Epidemiological profile of patients with extra-articular manifestations of rheumatoid arthritis from the city of Curitiba, South of Brazil
DISCUSSION
The prevalence of ExRA found in this study (45.8%) was similar to that found in a prospective cohort study with a 46-year
follow-up carried out in Minnesota, USA, which reported a
30-year cumulative incidence of 46%,8 and to another found
in a retrospective study carried out in Turkey, which assessed
526 medical charts in 2006 and reported a 38.4% frequency of
ExRA.14 It differs, however, from other publications. A retrospective study carried out in the state of São Paulo has found
a 23.3% prevalence of ExRA in three years,15 and a one-year
follow-up carried out in France in 82 centers has reported an
ExRA prevalence of 8.4%.16 Such differences are due to the
heterogeneity of the classifications used by each author.
The epidemiological profile of the patients with ExRA in
our study differed from that found in the study carried out in
the state of São Paulo, which also comprised patients from
the Brazilian Unified Health Care System.15 The mean disease
duration was an exception, considering that in the study carried
out in the state of São Paulo it was 7.2 years.
Regarding co-morbidities, SAH was found in 44.1% of
the patients with ExRA, which is higher than the 30% of the
general population.17 A Colombian study of 2009 showed
prevalences of 22% and 13% in patients with RA and with
and without ExRA, respectively.10
Type 2 diabetes mellitus was described in 15.8% of the
patients with ExRA, a value similar to that of the general
population (7.6%; range, 5%–10%).18 That co-morbidity has
not been more frequently reported in patients with ExRA or
only RA.
Rheumatoid arthritis per se is known to increase the chance
of cardiovascular diseases and acute ischemic events.10 In addition, severe extra-articular disease predisposes to the occurrence of an earlier first cardiovascular event. The incidence of
acute myocardial infarction can increase up to four times.19,20
Although some patients die due to specific complications of
RA, such as cervical instability or side effects from drugs,
most mortality is due to other associated diseases, particularly
cardiovascular disease.21
Hypothyroidism was identified in 20.8% of the patients, a
prevalence higher than the 1% reported for the general population, and 5% for those over the age of 60 years.22 Dyslipidemia
was found in 23.3% of the patients, below the value expected
for the general population (38% for the male gender, and 40%
for the female gender).23
Approximately 30.8% of the sample studied had valvular
heart disease or heart conduction disorder. Some authors consider those changes part of the ExRAs.9 A methodology that
Rev Bras Reumatol 2012;52(5):679-694
better specifies electrocardiographic findings and considers
the differential diagnosis with the side effects of drugs used
to treat RA, such as antimalarials, would be necessary.1 The
general consensus, however, is not to include that type of heart
involvement in the ExRA group.8
Osteoarthritis (OA) was present in 15% of the patients
studied and was part of the differential diagnosis of RA. The
prevalence of the symptomatic hand OA defined by the ACR
varies from 2% in European population studies to 8% in
North-American studies and 14.9% in studies with an Italian
population.24 A 2010 study showed that the mean age of patients
with OA coincides with the mean age of patients with ExRA.25
Together, osteoporosis and osteopenia were comorbidities
present in 21.8% of the patients. Osteoporosis is a significant
clinical problem in RA. Patients not only have osteopenia and
juxta-articular erosion, but also osteoporosis at sites away
from the inflamed joints. The pathogenesis is multifactorial and disease activity is the major determinant of bone
mass loss, in addition to treatment with glucocorticoids,
reduced mobility, and estrogen and/or androgen deficiency.26
Osteoporosis was diagnosed by use of bone densitometry,
Hologic dual-energy X-ray absorptiometry (DXA), assessing anteroposterior regions of lumbar spine and right femur,
and the results were classified according to the World Health
Organization criteria (osteopenia, T score: −1.0 to −2.4;
osteoporosis, T score ≤ −2.5).
On spirometry, a 12.5% prevalence of obstructive ventilatory disorders was found. That test is routinely performed in all
patients with RA at the Rheumatology Service of the HUEC,
and obstructive ventilatory disorders are frequently found in the
general population. Fibromyalgia was identified in 13.3% of
the patients studied, being considered a differential diagnosis of
RA.27 Its prevalence in the general population is approximately
2%, and it can be found in 25% of the patients with RA. This
has implications for the treatment and impacts the quality of
life assessments and the appearance of psychiatric disorders,
such as depression.28
The prevalence of chloroquine-induced maculopathy was
7.5%. That antimalarial drug is known to cause keratopathy and
retinopathy as side effects, the event being related to the drug
dose and duration of its use. Hydroxychloroquine is known to
have a decreased effect. Careful ophthalmologic follow-up of
patients on that drug should be performed.1,29,30
Pulmonary manifestations were the most frequent ExRAs
found (54.2%), and that frequency was greater than that reported in other studies (10%–20%). A study carried out in São
Paulo has reported a 15% frequency.15 Pulmonary manifestations are believed to appear within the first five years after
683
Moura et al.
the diagnosis of RA. Although pulmonary infections and/or
pulmonary toxicity due to drugs are frequent complications,
pulmonary disease directly associated with RA is more common. Although cardiovascular diseases are responsible for most
deaths related to RA, pulmonary complications are common
and directly responsible for 10%–20% of the deaths directly
attributed to RA.31
Rheumatoid nodules were found in 21% of the patients
studied, as compared with literature reports of 20%–35%.
Those values coincide with that reported in the study carried
out in São Paulo15 (29%) and that by Turesson et al.6 (34%).
Rheumatoid nodules correlate with the appearance of ExRA
and with a poor prognosis of RA in general.1,15,32
Concomitance of secondary Sjögren’s syndrome was found
in 18.3% of the sample studied. A study at the same service
carried out in 2007 reported a 12.1% concomitance of that
syndrome.33 The study carried out in São Paulo has reported
concomitance of that syndrome in 28% of the sample,15 while
Turesson et al.6 have reported it in 11.4% of their sample. It is
the most common ocular manifestation. Secondary Sjögren’s
syndrome is diagnosed at the rheumatology service of the
HUEC according to the European criteria modified by the
American-European Consensus Group for Sjögren’s syndrome
in 2002.34 Other ocular manifestations, such as episcleritis,
scleritis, and scleromalacia perforans, were less frequently
reported (4.2%).
Secondary amyloidosis was found in 12.5% of the patients.
Al-Ghamdi et al.32 and Turesson et al.6 have reported 6% and
0.7%, respectively, in their studies, while Çalgüneri et al.,14
1.1% of the patients. That ExRA is considered rare and usually develops in patients with long-term RA, worsening their
prognosis.29 At the rheumatology service of the HUEC, that
manifestation is screened in patients with disease for more than
five years, by use of abdominal fat biopsy and hematoxylineosin (HE) staining, regardless of the presence of symptoms.
Vasculitides, such as Raynaud’s phenomenon and ulcers,
had been reported by 10% of the patients, a value slightly
over that reported by Turesson et al.35 (3.6%) and Çalgüneri
et al.14 (1.3%). Rheumatoid vasculitis typically affects small
and medium vessels, being associated with high rates of early
mortality, with approximately 40% of the patients dying in
five years. It also has significant morbidity, because of organ
damage caused by vasculitis and consequent to treatment.
Approximately 4% of the sample had hematological
manifestations during the course of disease. Anemia caused
by chronic disease was the most common finding in our group,
in accordance with data in the literature (60% of hematological manifestations).29 Al-Ghamdi et al.32 have reported 8.2%.
684
Neurological ExRAs were found in 3.4% of the patients. In
the literature, that value varies from 0.5% to 80%.36 Clinically
detectable involvement of the peripheral nervous system in
RA is uncommon. It can be asymptomatic at initial stages or
have a large variety of symptoms, such as pain, paresthesia,
and muscle weakness.
Cardiac involvement was identified in 2.5% of the sample.
A French study has reported pericarditis as the major ExRA,
and it correlated with poor prognosis.8,16 Systemic inflammation in RA can lead to cardiac involvement, pericarditis being
the most common, through mechanisms of vasculitis, nodule
formation, amyloidosis, serositis, valvulitis, and fibrosis.29
De Quervain’s tenosynovitis was found in 1.7% of the
patients. One study on hand involvement of patients with RA
has reported a 33% frequency of De Quervain’s tenosynovitis.37
De Quervain’s tenosynovitis is known, similarly to synovitis
(and can have its effects added), to cause joint destruction and
instability and muscle function unbalance. There are not many
studies relating predictors to that type of manifestation. One
study has reported the difficulty in using the hands in the first
two years of disease as a strong predictor, in addition to the
DAS-28 score.37
Regarding renal involvement, glomerulonephrites were not
reported in our sample. Some patients with chronic renal failure
were found; however, due to the existence of co-morbidities,
such as SAH and type 2 DM, and to the lack of biopsy to
confirm the rheumatoid origin of renal failure, they were not
counted as ExRAs.
Positivity for the RF was identified in 69.2% of the patients
with ExRAs, similarly to that reported in a study carried out
in São Paulo and in a Greek retrospective study (68.2% and
69.5%, respectively).15,38 The association of RF and extraarticular disease in RA is well known – the RF is considered
a predictor of ExRA. The influence of each isotype in that
association has been the object of recent studies. One study
published in 1995 compared the incidence of ExRA with the
presence of different RF isotypes (IgA, IgM, and IgG), reporting that 80% of the patients with ExRA were negative for RF
IgA, 70% were positive for IgM, and 64% were positive for
IgG.39 Similarly, a Swiss study of 2007 showed that 90% of
the patients with ExRA were positive for RF IgM, 95% were
positive for IgA, and 86% were positive for IgG.40 Patients
with seronegative RA are believed to have other autoantibody
isotypes, predisposing them to systemic disease.41
Positivity for ANA was identified in 27.1% of the patients
with ExRA tested for ANA, a percentage lower than that reported in other studies. Turesson et al.40 have found positivity
for ANA in 45% of the patients with ExRA, while Al-Ghamdi
Rev Bras Reumatol 2012;52(5):679-694
Epidemiological profile of patients with extra-articular manifestations of rheumatoid arthritis from the city of Curitiba, South of Brazil
et al.42 have reported 38%. Regarding patients undergoing
anti-CCP testing, 77% of them tested positive, in accordance
with data in the literature. In 2007, Turesson et al.5 reported
that anti-CCP was positive in 77% of the patients with ExRAs,
while a Greek study has reported 65.3% of that association.38
The presence of anti-CCP in patients with RA indicates more
severe joint disease. The presence of citrullinated proteins in
inflamed synovia suggests that they play an important role in
the pathogenesis of RA. Regarding extra-articular disease, so
far we do not know whether those proteins are present in extraarticular sites of RA and whether they can contribute to the
local process of disease through an anti-CCP-mediated immune
process.43 The present study found no statistical correlation
between anti-CCP and ExRA, probably due to the scarcity of
results available. Further studies correlating ExRA and antiCCP and including serological testing should be performed.
The anti-Ro antibody is associated with several autoimmune diseases, such as Sjögren’s syndrome, systemic lupus
erythematosus, subacute cutaneous lupus, neonatal lupus, and,
less frequently, systemic sclerosis, and RA. The frequency of
anti-Ro in RA varies in the literature, and this has been attributed to differences in study methodology and populations.
Some studies have reported the association of anti-Ro antibody
with manifestations of severe disease, but that observation has
not been confirmed in other publications.44 Usually, 3%–15%
of the patients with RA have the anti-Ro antibody,45 and there
are no specific data correlating it with ExRAs. In our study,
the association of anti-Ro and ExRAs was observed in 5.3% of
the patients. According to the literature, Sjögren’s syndrome,
peripheral neuropathies, and rheumatoid nodules have been the
ExRAs most frequently found in anti-Ro-positive patients.45
Regarding the anti-La antibody, few publications have
shown its association with RA or ExRAs. It is usually related
to lupus and Sjögren’s syndrome.
The values found for the Steinbrocker functional classification, DAS-28, and HAQ in our study should be considered as
Rev Bras Reumatol 2012;52(5):679-694
providing an idea of functional capacity, disease activity and
quality of life, rather than as reliable data regarding the patients’
real conditions. This is because the values obtained during the
period studied were single and randomly collected. If the objective was to correlate them with ExRAs, values corresponding
to the period the ExRAs appeared should have been obtained.
If the objective was to assess data regarding the year 2010, the
arithmetic mean of the values obtained throughout that year
should have been calculated. Methodological difficulties, in
addition to data unavailability in several cases, led the authors
to exclude them from this study’s analyses.
In this study, the statistical analysis has shown that ExRAs
tend to appear in patients with longer disease duration.
However, that finding has not been confirmed in the literature,
according to which, ExRAs are related to neither disease duration nor its stages.19
Current smoking habit was associated with the presence of
ExRAs in this study. Al-Ghamdi et al.32 have not been able to
find that association due to the insufficient number of smokers
in their sample. Smoking habit, which is a risk factor for RA
in general and has been suggested to predict joint damage, has
also been reported as a predictor of severe ExRAs.8 That association has been reported to be independent of RF, indicating
the direct or indirect involvement of other pathophysiological
mechanisms.6
CONCLUSION
The epidemiological profile of patients with RA and ExRAs
at the service studied was as follows: 56-year-old Caucasian
woman; non-smoker; low educational level; mean age at diagnosis of 44 years; mean disease duration of 12.2 years; and
major diseases associated: SAH, dyslipidemia, and hypothyroidism. The prevalence of ExRAs throughout disease course
was 45.8%, and a correlation between current smoking habit
and appearance of ExRAs was found.
685
Moura et al.
obtiveram 38%. Entre os pacientes com registro de pesquisa
de anti-CCP, 77% tiveram resultado positivo, o que condiz
com os dados encontrados na literatura. No artigo publicado
em 2007 por Turesson et al.,5 o anti-CCP foi positivo em 77%
dos pacientes com MEA, enquanto um estudo grego relatou
65,3% de associação.38 Tem-se observado que a presença
do anticorpo anti-CCP em pacientes com AR indica doença
articular mais grave. A presença das proteínas citrulinadas
em sinóvias inflamadas sugere que desempenhem um papel
importante na patogênese da AR. Em relação à doença extra-articular, ainda não se sabe se essas proteínas estão presentes
em sítios extra- articulares de AR e se elas podem contribuir
para o processo local de doença por um processo imune-mediado por anticorpos anti-CCP.43 No presente estudo não
foi encontrada correlação estatística entre anti-CCP e MEA,
provavelmente devido à pequena quantidade de resultados
disponíveis. Seria interessante a realização de outros estudos
correlacionando MEA e anti-CCP que incluíssem a realização
do teste sorológico nos métodos.
O anticorpo anti-Ro está associado a várias doenças autoimunes, incluindo Síndrome de Sjögren, lúpus eritematoso
sistêmico, lúpus cutâneo subagudo, lúpus neonatal e, menos
frequentemente, esclerose sistêmica e AR. A frequência de antiRo na AR varia muito na literatura, o que tem sido atribuído
a diferenças de métodos e de populações estudadas. Alguns
estudos descrevem a associação do anticorpo anti-Ro com
manifestações de doença grave, observação não confirmada
em outras publicações.44 Em geral, o anticorpo anti-Ro está
associado à AR em 3%–15% dos pacientes,45 e não há dados
específicos correlacionando-o com as MEA. Em nosso estudo
a associação do anti-Ro com as MEA se deu em 5,3%. Na literatura, Síndrome de Sjögren, neuropatias periféricas e nódulos
reumatoides foram as MEA mais frequentes em pacientes com
anti-Ro positivo.45
Em relação ao anti-La, poucas publicações mostram a
associação desse autoanticorpo com a AR ou com as MEA.
Em geral, ele está relacionado ao lúpus e à Síndrome de
Sjögren.
Os valores encontrados para Índice Funcional de
Steinbrocker, DAS-28 e HAQ neste estudo podem ser levados
em consideração mais como uma ideia da capacidade funcional, atividade de doença e qualidade de vida dos pacientes,
e não como um dado fidedigno de suas reais condições. Isso
se dá porque foram colhidos valores únicos e aleatórios do
período estudado. Se o objetivo fosse correlacioná-los com o
aparecimento das MEA, teria que ter sido procurado o valor
correspondente ao período em que apareceram. Se o objetivo
fosse avaliar os dados relativos ao ano de 2010, teria que ter
692
sido calculada a média aritmética dos valores ao longo do ano.
A dificuldade na metodologia, somada à indisponibilidade de
dados em vários casos, levou os autores a optar por excluí-los
das análises da pesquisa.
A análise estatística mostrou que é possível afirmar que as
MEA tendem a aparecer em pacientes com tempo de doença
mais longo. Isso, porém, não é confirmado pela literatura, que
afirma que as MEA não estão relacionadas à duração ou ao
estágio da doença.19
Foi encontrada associação de tabagismo atual com presença
de MEA. O estudo de Al-Ghamdi et al.32 não pôde encontrar
tal associação por insuficiência de amostra de pacientes tabagistas. O tabagismo, que é um fator de risco para AR em geral
e foi sugerido como preditor de dano articular, também tem
sido relatado como preditor de MEA graves.8 Essa associação
tem sido relatada como independente do FR, indicando que
outros mecanismos fisiopatológicos estão envolvidos direta
ou indiretamente.6
CONCLUSÃO
O perfil epidemiológico dos pacientes com MEA da AR no
serviço estudado foi: mulher, 56 anos, caucasiana, idade
média ao diagnóstico de 44 anos, tempo médio de doença
de 12,2 anos, com grau de escolaridade baixo, não tabagista
e com HAS, dislipidemia e hipotireoidismo como principais
doenças associadas. A prevalência de pacientes que tiveram
MEA ao longo do curso da doença foi de 45,8%, e foi possível
encontrar correlação entre tabagismo atual e aparecimento
de MEA.
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Rev Bras Reumatol 2012;52(5):679-694
ORIGINAL ARTICLE
Diagnostic performance and clinical associations
of antibodies to the chromatin antigenic system
in juvenile systemic lupus erythematosus
Silene Peres Keusseyan1, Neusa Pereira da Silva2, Maria Odete Esteves Hilário3,
Eunice Mitiko Okuda4, Maria Teresa S. L. R. Ascenção Terreri5, Luis Eduardo Coelho Andrade6
ABSTRACT
Objectives: To determine the frequency of antibodies to chromatin components in juvenile systemic lupus erythematosus
(JSLE), and to correlate the presence of these autoantibodies with clinical manifestations and disease activity. Methods:
Anti-chromatin (anti-CHR), anti-nucleosome core particle (anti-NCS) and anti-dsDNA antibodies were measured in
175 individuals, including 37 patients with active JSLE and 41 with inactive disease, 47 non-lupus autoimmune disease
patients (non-lupus AD), and 50 healthy children. An in-house ELISA was developed with purified nucleosome core
particles from calf thymus to determine IgG and IgG3 anti-NCS antibodies. Anti-CHR and anti-dsDNA antibodies were
detected by commercial ELISA kits (INOVA). Results: Anti-NCS and anti-CHR antibodies exhibited high specificity
for JSLE and similar frequency in active and inactive JSLE. Anti-CHR and IgG/IgG3 anti-NCS serum levels did not
differ between active and inactive JSLE. SLEDAI correlated with anti-dsDNA antibodies but not with antibodies to
other chromatin components. There was association of anti-dsDNA, anti-CHR and IgG/IgG3 anti-NCS antibodies with
proteinuria and low C4 serum levels. Anti-NCS antibodies in the absence of anti-dsDNA were observed in 14% of the
JSLE patients. Conclusions: Our data indicate that anti-NCS and anti-CHR antibodies are relevant diagnostic markers
for JSLE and appear to be correlated with JSLE lupus nephritis activity. IgG3 isotype anti-NCS antibodies do not seem
to be more relevant than IgG anti-NCS antibodies as markers of disease activity or active nephritis in JSLE.
Keywords: nucleosomes, antinuclear antibodies, systemic lupus erythematosus, nephritis, chromatin.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by a wide range of clinical
manifestations. SLE nephritis bears considerable morbidity
and represents a major threat to long-term quality of life and
survival. Renal involvement has been reported in 40%–80% of
juvenile systemic lupus erythematosus patients (disease onset
before 16 years old) and this high frequency contributes to the
severity of juvenile systemic lupus erythematosus (JSLE).1 SLE
is characterized by the presence of circulating autoantibodies
against nuclear components (ANA).2 More than 100 different
autoantibodies have been identified in the serum of SLE patients3
and some of these are clinically useful as diagnostic markers and
as ancillary parameters for disease activity monitoring.4 Among
the clinically useful SLE autoantibodies, anti-native DNA, antiSm and anti-ribosomal P protein are considered to be specific
diagnostic markers but their modest sensitivity restricts their
diagnostic performance. This scenario has endorsed the search
for novel and more efficient biomarkers for SLE.5
Received on 09/28/2011. Approved on 06/27/2012. The authors declare no conflict of interest. Financial Support: Fundação de Amparo à Pesquisa do Estado de
São Paulo – FAPESP. Ethics Committee: 1149/04.
Universidade Federal de São Paulo – Unifesp.
1. Master in Health Science, Universidade Federal de São Paulo – Unifesp
2. PhD in Pediatrics and Science Applied to Pediatrics, Unifesp; Associate-Professor of Rheumatology, Unifesp
3. Associate-Professor of Pediatric Rheumatology, Discipline of Allergy, Immunology and Rheumatology, Unifesp
4. PhD in Medicine, Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo – SCMSP
5. PhD in Pediatrics and Science Applied to Pediatrics, Unifesp; Adjunct Professor, Discipline of Allergy, Immunology and Rheumatology, Unifesp
6. Adjunct Professor, Rheumatology, Unifesp
Correspondence to: Luis Eduardo Coelho Andrade. Rua Botucatu, 740. CEP: 04023-900. São Paulo, SP, Brazil. E-mail: [email protected]
Rev Bras Reumatol 2012;52(5):695-712
695
Keusseyan et al.
The nucleosome core particle is the fundamental chromatin
unit and is composed of ~146 base pairs of DNA wrapped
around a protein core, an octamer comprising two molecules of
each of the histones H2A, H2B, H3 and H4. The nucleosome
core particles are joined together by a linker DNA, which is
associated with histone H1 located outside the nucleosome core
particles.6 During cell apoptosis, nucleosomes are released in
the intracellular milieu by endonuclease chromatin cleavage.
In physiologic conditions, phagocytes engulf apoptotic cells
and apoptotic bodies to prevent the release of cell constituents
in the extracellular space.7 In the last 15 years, several pieces
of evidence have suggested that the nucleosome is a major
antigenic domain in SLE pathophysiology, and that antibodies
to nucleosome core particles (anti-NCS/CHR) are associated
with organ damage.8–10 Additionally, there is isolated evidence
that IgG3 isotype anti-NCS antibodies might constitute a
selective biologic marker of active SLE, and in particular,
of lupus nephritis.11 Although several studies evaluated the
diagnostic performance of anti-NCS or anti-CHR antibodies
in adult SLE patients, there are only a few studies about these
autoantibodies in JSLE.12–14
The aim of the present study was to investigate the diagnostic performance of antibodies to the chromatin antigenic
system in JSLE as well as their associations with Systemic
Lupus Erythematosus Disease Activity Index (SLEDAI) and
with individual clinical manifestations of the disease, with
emphasis on lupus nephritis.
MATERIALS AND METHODS
Patients and controls
Over a two-year period, 125 patients aged 5–18 years old
were sequentially recruited from the outpatient clinic of the
Department of Pediatrics at Universidade Federal de São Paulo
and Santa Casa de Misericórdia Medical School Hospital, in
São Paulo, Brazil. Disease distribution among patients was:
37 children had active JSLE; 41 had inactive JSLE; 47 had
non-lupus autoimmune diseases (non-lupus AD) comprising
systemic sclerosis (SSc; n = 4), juvenile idiopathic arthritis
(JIA; n = 28), dermatomyositis (DM; n = 7), and chronic
autoimmune hepatitis (n = 8). SLE, JIA, SSc and DM were
diagnosed according to the American College of Rheumatology
criteria and International Autoimmune Hepatitis Group
respectively.15–19 Clinical and laboratory information (renal,
hematological and skin involvement, arthritis, fever, alopecia,
mucous ulcers, chronic headache, neurological manifestations,
vasculitis, and serositis) were obtained for each JSLE patient in
order to determine the disease activity score using SLEDAI.20
696
Inactive JSLE and active JSLE was arbitrarily defined as
SLEDAI ≤ 2 and ≥ 6, respectively.21 Patients with SLEDAI
scores 3, 4, and 5 were excluded from the study. Sera from
50 gender and age-matched healthy children and adolescents
were used as controls. These individuals were relatives from
laboratory staff and otherwise healthy children referred for
small surgical procedures. The study was approved by the
Institutional Ethics Committee (# 1149/04).
Each participant provided 10 mL of blood for laboratory
tests after having the informed consent signed by parents or
legal guardians. The samples were stored at −20ºC until used.
At the time of serum harvest, most JSLE patients were under
treatment with immunosuppressant drugs. Intravenous cyclophosphamide was used in 2.5%, pulse therapy with methylprednisolone in 7.7%, oral prednisone above 0.5 mg/kg/day
in 65.4%, azathioprine in 33.3%, methotrexate in 6.4%, and
hidroxychloroquine in 57.7% of the JSLE patients.
Serologic analysis
Antinuclear antibodies (ANA) were detected by indirect immunofluorescence (IIF) with in-house HEp-2 cells slides according to the standard procedure;22 anti-dsDNA antibodies were
determined by enzyme immunoassay (INOVA Diagnostics,
San Diego, CA), according to the manufacturer’s directions,
and by IIF with in-house C. luciliae slides (CLIF assay) according to standard procedure.23 Antibodies against extractable
nuclear antigens (ENA) were detected by double immunodiffusion against calf spleen extract according to Ouchterlony’s
technique.24 Anticardiolipin antibodies were determined by
in-house enzyme immunoassay as previously described25 and
calibrated with international APL standards (Louisville APL
Diagnostics Inc, Doraville, GA, USA). C3 and C4 serum levels were determined by radial immunodiffusion (The Binding
Site Ltd., Birmingham, UK) according to the manufacturer’s
directions. Two assays were used to measure antibodies
anti-chromatin/nucleosome. Since anti-chromatin and antinucleosome antibodies are normally synonymous we decided
in this study to name the anti-chromatin commercial assay
anti-CHR, and the in-house anti-nucleosome assay, anti-NCS.
Nucleosome core particle preparation and
detection of antibodies to nucleosome core
particles (NCS) and to chromatin (CHR)
The commercial kit QUANTA LiteTM Chromatin using highly
purified calf thymus chromatin without histone H1 and nonhistone proteins (INOVA Diagnostics, San Diego, CA) was
processed according to the manufacturer’s instructions. For
Rev Bras Reumatol 2012;52(5):695-712
Diagnostic performance and clinical associations of antibodies to the chromatin antigenic system in juvenile systemic lupus erythematosus
qualitative assessment, when using the cut-off point of 20 U/mL
suggested by the manufacturer, results were expressed as antiCHR-20. Alternatively, when using the cut-off point of 60 U/mL
(moderate to strong positive sera, according to manufacturer),
results were expressed as anti-CHR-60.
The in-house anti-NCS immunoassay was set up to detect
IgG and IgG3 antibodies against the nucleosome core particles
isolated from calf thymus as previously described,26,27 with
slight modifications. Briefly, 10 g of calf thymus were ground
and homogenized in 140 mL buffer A [0.3 M sucrose, 6 mM
MgCl2, 1.2 mM CaCl2, 10 mM NaHSO3, 10 mM Tris-HCl, and
0.2 mM phenylmethylsulfonyl fluoride (PMSF), pH 7.5] and
passed through cheesecloth and miracloth. Nuclei were isolated
by centrifugation at 3,300 g for 8 minutes at 4ºC, washed twice
in the same buffer, pelleted and resuspended in 8 mL 15 mM
NaCl, 15 mM 2-mercaptoethanol, 60 mM KCl, 0.5 mM spermine, 0.15 mM spermidine, pH 7.4. The volume was adjusted to
yield a final DNA concentration of ~2,500 μg/mL as judged by
optical density at 260 nm. The nuclei suspension was digested
for 2 minutes at 37°C with 40 IU/mg micrococcus nuclease
(Worthington Biochemical Corp., Likewood, NJ) in the presence of 1 mM CaCl2 and the reaction was terminated by the
addition of 2 mM EDTA. The nuclei were pelleted at 8,000 g
for 2 minutes at 4ºC, resuspended in the original volume with
0.2 mM EDTA pH 7.0, and then homogenized in a tight-fitting
Dounce homogenizer. The homogenate was centrifuged again
for 2 minutes at 8,000 g at 4°C and the supernatant containing
the soluble long chromatin was recovered. H1 and non-histone
proteins were stripped by dropwise addition of ice cold 4 M
NaCl to a final concentration 0.5 M NaCl. The non-histone
proteins and H1 were separated from the stripped chromatin
solution by gel filtration in a Sepharose 4B column (Sigma
Chemical, St. Louis, USA) previously equilibrated with 0.45 M
NaCl, 0.2 mM EDTA and 5mM Tris-HCl, pH 7.5. The fractions
containing the nucleosome core particles were selected according to agarose gel electrophoresis pattern and pooled together.
The in-house anti-NCS ELISA was based on the assay
developed by Burlingame and Rubin.27 ELISA plates (NuncMediSorpT Surface, Denmark) were coated with 200 μL/well
purified nucleosome core particles 5 μg DNA/mL in cold
phosphate buffered saline (PBS) for 48 hours at 4°C, and
blocked with 200 μL/well 0.1% gelatin in PBS for 2 hours
at room temperature (RT). Patient samples (200 μL) diluted
1:100 in 0.1% gelatin in PBS were applied to each well and
then allowed to react for 2 hours at RT. Plates were washed
three times with 0.05% Tween 20 in PBS (250 μL/well) and
then incubated for 2 hours at RT with 200 μL/well horseradish peroxidase (HRP) labeled mouse anti-human IgG (Sigma,
Rev Bras Reumatol 2012;52(5):695-712
St. Louis, USA) 1:20,000 in 0.05% Tween 20, 0.1% gelatin,
0.1% BSA, and 0.5% fetal calf serum (FCS) in PBS or HRPlabeled mouse anti-human IgG3 (ZYMED Laboratories, San
Francisco, CA) 1:2,000 in the same buffer. After washing as
before, plates received 200 μL/well peroxidase chromogenic
substrate (10 mg o-phenylenediamine, 10 μL H2O2 in 25 mL
0.1 M citrate buffer, pH 5.0). After incubation under shaking
for 1 hour at RT in a dark chamber the OD was read at 492 nm
after the addition of 50 µL/well of stop solution (1 N H2SO4).
Serum background reactivity was checked in uncoated wells
processed in parallel with the test wells. The cut-off value
was determined as the mean plus three standard deviations of
the OD values obtained with serum samples from 80 healthy
blood donors (0.573 for IgG anti-NCS and 0.400 for IgG3 antiNCS). The cut-off values obtained were compatible with the
cut-off values derived from ROC curve analysis (see results).
Three positive and three negative control samples, obtained
from a private laboratory certified on-site by the US College
of American Pathologists (CAP), were included in each plate.
Statistical analysis
Continuous variables were expressed as mean and standard deviation. Comparison between groups was performed with t-test
(parametric variables) or Mann-Whitney test (non-parametric
variables) for continuous variables and chi-square or Fisher’s
exact test for categorical variables, as needed. Correlations
were determined by Spearman’s correlation for non-parametric
variables. All statistical analyses were performed with SPSS
software (version 15.0 for Windows, Chicago, USA). P < 0.05
was considered significant.
RESULTS
Demographic data
Thirty-seven patients had active JSLE (SLEDAI score ≥ 6)
and 41 had inactive JSLE (SLEDAI score ≤ 2). There was no
significant difference in gender, age, or ethnicity among the
groups of 37 active JSLE (29 girls, 13.2 ± 3.4 years old, 20
Caucasian-descendants), 41 inactive JSLE (35 girls, 12.0 ± 3.0
years old, 23 Caucasian-descendants), 47 non-lupus AD (35
girls, 11.0 ± 3.6 years old, 26 Caucasian-descendants), and 50
healthy controls (35 girls, 14.0 ± 4.3 years old, 22 Caucasiandescendants) (P = 0.153, 0.054, and 0.525, respectively).
Patients with active JSLE had lower disease duration as compared to inactive JSLE (P = 0.013) (Table 1). The clinical and
laboratory features of patients with active and inactive JSLE
are depicted on Table 2. Active nephritis at the moment of
697
Keusseyan et al.
Table 1
Demographic data of patients with active JSLE, inactive JSLE, non-lupus AD, and healthy controls
Active JSLE (n = 37)
Inactive JSLE (n = 41)
Non-lupus AD (n = 47)
Healthy controls (n = 50)
P
Gender (F/M)
31/6
36/5
35/12
35/15
0.153a
Age (years)
13.2 ± 3.4
13.2 ± 3.0
11 ± 3.6
11.5 ± 4.3
0.054a
Disease duration (months)
24 ± 23.4
41.8 ± 30.4
nd
nd
0.013b
Ethnicity (C/NC)
20/17
24/17
26/21
22/28
0.525a
a
b
Mean and standard deviation. Chi-square P value: comparison of all groups; Comparison between active and inactive JSLE patients.
F: female; M: male; C: Caucasian; NC: non Caucasian; JSLE: juvenile systemic lupus erythematosus; AD: autoimmune disease.
Table 2
Clinical and laboratory features of patients with active JSLE, inactive JSLE, non-lupus AD, and healthy controls
Active JSLE % (n = 37)
Inactive JSLE % (n = 41)
Non-lupus AD % (n = 47)
Healthy controls % (n = 50)
Renal involvement
84% (31)
None
nd
nd
Skin involvement
22% (8)
None
nd
nd
Arthritis
19% (7)
None
nd
nd
Hematological involvement
13% (5)
10% (4)
nd
nd
Fever
11% (4)
None
nd
nd
Alopecia
11% (4)
None
nd
nd
Mucous ulcers
8% (3)
None
nd
nd
Chronic headache
8% (3)
None
nd
nd
Neurologic manifestations
5% (2)
None
nd
nd
Vasculitis
5% (2)
None
nd
nd
Serositis
3% (1)
None
nd
nd
nd: not determined; JSLE: juvenile systemic lupus erythematosus; AD: autoimmune disease.
blood withdrawing, defined by proteinuria above 0.5 g/day,
was identified in 15 of the 37 active JSLE patients.
Antibodies to nucleosome core particles (NCS),
chromatin (CHR), and to native DNA (dsDNA)
Among all JSLE patients, anti-dsDNA antibodies were detected
in 29% by ELISA and in 14% by CLIF. IgG anti-CHR-20 and
anti-NCS antibodies were found in 40% and 23% of all JSLE
patients, respectively. IgG3 anti-NCS antibodies were detected
in 18% of all JSLE patients. Table 3 depicts the frequency of
the several autoantibodies in each group as well as data about
sensitivity, specificity, positive predictive value and negative
predictive value for the diagnosis of JSLE calculated against
non-lupus AD patients and healthy children altogether. Among
the analyzed tests, CLIF assay for anti-dsDNA antibodies was
the least sensitive and presented the highest specificity and
positive predictive value. The ELISA assays for anti-dsDNA,
anti-CHR-60, and IgG anti-NCS had equivalent performance
698
in all diagnostic parameters. The anti-CHR-20 assay presented
higher sensitivity but lower specificity and positive predictive
value as compared to the three former ELISA assays. There
was considerable heterogeneity among JSLE sera with respect
to ELISA OD values in the anti-dsDNA, anti-CHR and antiNCS antibody assays (Figure 1). Patients with JSLE presented
significantly higher levels of antibodies to chromatin components than those with non-lupus AD and healthy individuals
(P < 0.01). ANA-HEp-2 and anti-ENA positive tests were
observed, respectively, in 92% and 32% active JSLE, 90% and
27% inactive JSLE, 36% and 0% non-lupus AD patients, and
2% and 0% healthy children. Homogeneous and fine speckled
were the most frequent ANA-HEp-2 patterns found in JSLE
sera positive for any tested chromatin components.
Several parameters of disease activity showed correlation
with antibodies to chromatin components. Anti-dsDNA antibodies (CLIF assay) were more frequent in patients with active
JSLE (SLEDAI ≥ 6) as compared to those with inactive disease
(SLEDAI ≤ 2) (24% vs. 5%, P < 0.001). In addition, SLEDAI
Rev Bras Reumatol 2012;52(5):695-712
Diagnostic performance and clinical associations of antibodies to the chromatin antigenic system in juvenile systemic lupus erythematosus
Table 3
Positivity, sensitivity, specificity, positive predictive value and negative predictive value of different autoantibody assays for the
diagnosis of JSLE in comparison with patients with non-lupus AD and healthy controls altogether
Autoantibody assay positivity (%)
CHR-20
CHR-60
NCS IgG
NCS IgG3
dsDNA
CLIF
dsDNA
ELISA
Active JSLE (n = 37)
43%
27%
27%
22%
24%
38%
Inactive JSLE (n = 41)
36%
22%
19%
15%
5%
22%
Non-lupus AD (n = 47)
11%
4%
2%
4%
0%
6%
Healthy controls (n = 50)
0%
0%
2%
2%
0%
0%
Diagnostic parameters*
Sensitivity
40%
24%
23%
18%
11%
27%
Specificity
96%
98%
98%
95%
100%
97%
PPV
88%
90%
90%
74%
100%
87%
NPV
66%
62%
61%
58%
58%
62%
*Diagnostic parameters were calculated for the diagnosis of JSLE against non-lupus AD patients and healthy children altogether.
PPV: positive predictive value; NPV: negative predictive value; JSLE: juvenile systemic lupus erythematosus; AD: autoimmune disease; CHR-20: commercial anti-chromatin antibody assay with cut-off at 20
U/mL; CHR-60: commercial anti-chromatin antibody assay with cut-off at 60 U/mL; NCS-IgG: in-house anti-nucleosome antibody assay for total IgG antibodies; NCS-IgG3: in-house anti-nucleosome antibody
assay for IgG3 antibodies; CLIF: anti-dsDNA antibody assay based on indirect immunofluorescence on C. luciliae; ELISA: Enzyme-Linked Immunoabsorbent Assay.
Anti-CHR antibodies
IgG anti-NCS antibodies
3.000
450
P < 0.01
300
Units
OD
2.000
1.500
1.000
250
200
150
100
0.500
60
50
20
0
0.000
JSLE
active
JSLE
inactive
non-lupus
AD
healthy
JSLE
active
JSLE
inactive
non-lupus
AD
healthy
Anti-dsDNA antibodies
IgG3 anti-NCS antibodies
4.000
3000
P < 0.01
P < 0.01
2500
P = 0.422
3.000
P = 0.124
2000
U/mL
2.500
OD
P = 0.124
350
P = 0.537
3.500
P < 0.01
400
2.500
2.000
1.500
1500
1000
1.000
500
0.500
0.000
JSLE
active
JSLE
inactive
non-lupus
AD
healthy
0
correlated with ELISA anti-dsDNA antibody levels (r = 0.235;
P = 0.038) but not with antibody levels to anti-CHR and anti-NCS.
Patients with active JSLE did not differ significantly from those
with inactive JSLE with respect to the frequency and O.D. levels of anti-dsDNA (424.8 ± 540.9 UI/mL vs. 208.2 ± 202.9 UI/mL; P = 0.124),
Rev Bras Reumatol 2012;52(5):695-712
JSLE
active
JSLE
inactive
non-lupus
AD
healthy
Figure 1
Distribution of JSLE patients, non-lupus AD patients
and healthy controls according to ELISA serum levels
of antibodies to NCS, CHR
and dsDNA. Dashed lines
correspond to the cut-off
threshold for each assay (for
the anti-CHR assay there
were cut-off levels at 20 U
and 60 U).
Anti-CHR: commercial anti-chromatin antibody assay (with cut-off
at 20 U/mL); IgG anti-NCS: inhouse anti-nucleosome antibody
assay for total IgG antibodies;
IgG3 anti-NCS: in-house antinucleosome antibody assay for IgG3
antibodies; anti-dsDNA: commercial
anti-DNA double helix antibody
assay; ELISA: enzyme-linked immunoabsorbent assay.
anti-CHR-20 (56.3 ± 71.8 U/mL vs. 35.4 ± 43.7 U/mL, P = 0.537),
IgG anti-NCS (0.589 ± 0.528 vs. 0.429 ± 0.336; P = 0.432), and
IgG3 anti-NCS (0.536 ± 0.810 vs. 0.343 ± 0.442; P = 0.422). There
was a significantly higher frequency of proteinuria in patients with
antibodies to any of the tested chromatin components versus those
699
Keusseyan et al.
Table 4
Distribution of 78 JSLE patients according to the presence of autoantibodies to chromatin components and relevant laboratory
parameters
Autoantibodies
Laboratory parameter
dsDNA CLIF
n = 11
dsDNA ELISA
n = 23
CHR-20
n = 33
IgG NCS
n = 18
IgG3 NCS
n = 14
Proteinuria > 0.5 g/24 h
6 (54.5%)*
9 (39.1%)*
11 (33.3%)*
7 (38.9%)*
6 (42.9%)*
Proteinuria < 0.5 g/24 h
5 (45.4%)
14 (60.9%)
22 (66.7%)
11 (61.1%)
8 (57.1%)
Decreased C3
3 (27.3%)
8 (34.8%)
13 (39.4%)*
7 (38.9%)
6 (42.9%)
Normal C3
8 (72.7%)
15 (65.2%)
20 (60.6%)
11 (61.1%)
8 (57.1%)
Decreased C4
4 (36.4%)
10 (43.5%)*
15 (45.5%)*
9 (50%)*
8 (57.1%)*
Normal C4
7 (63.6%)
13 (56.5%)
18 (54.5%)
9 (50%)
6 (42.9%)
* P < 0.05 (P values refer to Chi-square test comparing the presence/absence of each autoantibody with the presence/absence of the analyzed parameter).
CHR-20: commercial anti-chromatin antibody assay with cut-off at 20 U/mL; IgG NCS: in-house anti-nucleosome antibody assay for total IgG antibodies; IgG3 NCS: in-house anti-nucleosome antibody assay
for IgG3 antibodies; CLIF: anti-dsDNA antibody assay based on indirect immunofluorescence on C. luciliae; ELISA: Enzyme-Linked Immunoabsorbent Assay.
without them (Table 4). Correspondingly, the levels of autoantibodies were significantly higher in patients with proteinuria as
compared to those without proteinuria for ELISA anti-dsDNA
(691.1 ± 730.4 vs. 220.4 ± 217.6, P = 0.049) and IgG anti-NCS
antibodies (0.814 ± 0.598 vs. 0.431 ± 0.365, P = 0.019). There
was also a similar trend for anti-CHR antibodies (95.5 ± 93.1
vs. 33.3 ± 40.6, P = 0.093) but not for IgG3 anti-NCS antibodies
(0.811 ± 1.03 vs. 0.340 ± 0.485, P = 0.700). There was association
between decreased C3 levels and the frequency of anti-CHR-20
positive assay. Among JSLE patients with decreased C4 levels
there was higher frequency of positive assays to dsDNA (ELISA),
CHR-20, IgG NCS and IgG3 NCS (Table 4). Antibodies to isolated or combined extractable nuclear antigens were observed in
23 JSLE patients (13 anti-SS-A/Ro, four anti-SS-B/La, six antiSm, and 14 anti-U1-RNP) and there was no association with the
presence of antibodies to chromatin components. Only seven of
the 78 JSLE patients had moderate levels of anti-cardiolipin antibodies [two IgG (2.5%) and five IgM (6.4%)] and no association
was observed between reactivity to cardiolipin and presence of
antibodies to chromatin components. Other clinical manifestations
were equally frequent in JSLE patients with and without any of
the tested antibodies to chromatin components (data not shown).
As depicted on Figure 2 there was good agreement
between the ELISA assays for anti-dsDNA and anti-CHR
antibodies (85% and 87% for CHR-20 and CHR-60, respectively), between anti-dsDNA and IgG anti-NCS antibodies
(86%), and between IgG anti-NCS and anti-CHR antibodies
(78% and 91% for CHR-20 and CHR-60, respectively). In
fact, we found a great similarity between the in-house antiNCS assay and the commercial anti-CHR assay when it was
analyzed using 60 U/mL as cut-off value (anti-CHR-60).
700
Anti-CHR-60 / Anti-dsDNA
Anti-CHR-20 / Anti-dsDNA
20%
4%
28%
57%
9%
67%
IgG Anti-NCS / Anti-dsDNA
14%
1%
IgG Anti-NCS / IgG3 Anti-NCS
15%
19%
8%
3%
4%
10%
67%
Anti-CHR-20 / IgG Anti-NCS
74%
Anti-CHR-60 / IgG Anti-NCS
19%
22%
56%
20%
72%
5%
4%
2%
positive/positive
negative/negative
positive/negative
negative/positive
Figure 2
Concordance between ELISA assays for anti-NCS, anti-CHR-20,
anti-CHR-60, and anti-dsDNA antibodies in JSLE patients.
Anti-CHR-20 and anti-CHR-60 refer to the ELISA anti-CHR
assay with cut-off points at 20 U/mL and 60 U/mL, respectively.
CHR-20: commercial anti-chromatin antibody assay with cut-off at 20 U/mL;
CHR-60: commercial anti-chromatin antibody assay with cut-off at 60 U/mL;
IgG anti-NCS: in-house anti-nucleosome antibody assay for total IgG antibodies; IgG3 anti-NCS: in-house anti-nucleosome antibody assay for IgG3
antibodies; anti-dsDNA: commercial anti-DNA double helix antibody assay;
ELISA: enzyme-linked immunoabsorbent assay.
Rev Bras Reumatol 2012;52(5):695-712
Diagnostic performance and clinical associations of antibodies to the chromatin antigenic system in juvenile systemic lupus erythematosus
Additionally, the agreement rate between IgG anti-NCS
and IgG3 anti-NCS antibodies was 89%. The disagreement
rate between the same pairs of tests ranged from 9%–21%.
In particular, ELISA for anti-dsDNA and ELISAs for antiNCS or anti-CHR showed disagreement rates around 15%.
Regarding the 23 anti-dsDNA ELISA positive patients, 22
were also anti-CHR-20 positive.
DISCUSSION
Previous studies have addressed the analysis of autoantibodies against chromatin components in SLE and related
diseases; however, few surveys have addressed anti-NCS
antibodies in JSLE. In the present study we have observed a
considerable variation in the diagnostic performance of the
tests for diverse antibodies against chromatin components
in JSLE. The traditional CLIF anti-dsDNA was the most
specific and least sensitive test. The ELISA anti-dsDNA
and the anti-CHR-20 were the most sensitive tests, though
slightly less specific. Although SLEDAI correlated only with
anti-dsDNA antibodies, there was association between several
of the tested autoantibodies to chromatin components and
parameters indicative of disease activity, such as proteinuria
and low complement levels.
Nucleosome core particles are the fundamental units of
chromatin and a normal product of cell apoptosis. Apoptosis
defects are well known to be associated with certain animal
models of lupus, and have also been discussed in connection
with human SLE.28–31 Recent evidence obtained in murine models of SLE suggests that nucleosome core particles are a preferential target for lupus autoantibodies and they are accepted
as genuine autoantigens triggering the production of antibodies
against the nucleosome core particles themselves, dsDNA and
histones.32–34 According to recent literature data, the presence
of glomerular extracellular nucleosomes derived, for instance,
from apoptotic cells is a pre-requisite for the binding of antichromatin antibodies to the glomeruli and may be involved in
nephritic processes.33,34 Since humoral autoimmune response
is accepted to be antigen-driven,2 a comprehensive analysis
of autoantibodies against individual components of a supramolecular complex is justified. In addition, technical details in
the preparation of the antigenic substrate may be determinant
in preserving fastidious non-linear epitopes. With respect to
the chromatin system, this is crucial due to the delicate and
complex interaction of native DNA and several histone and
non-histone proteins. Therefore, each methodological platform
favors the exposure of an unique set of epitopes and this may
influence considerably the clinical significance of these tests.35
Rev Bras Reumatol 2012;52(5):695-712
One widely accepted method for nucleosome core particle
purification consists in the solubilization of native chromatin
by microccocal nuclease digestion and removal of H1 histone and other proteins by 0.5 M NaCl extraction at neutral
pH. Most commercial anti-NCS/chromatin kits use poly or
mononucleosomes extracted from calf thymus chromatin as
antigenic substrate. The present study utilized both in-house
and commercial enzyme immunoassays. The anti-chromatin
antibody commercial kit (anti-CHR) (INOVA Diagnostics, San
Diego, CA) and the in-house anti-nucleosome core particle
immunoassay (anti-NCS) used chromatin-derived antigenic
substrates, both isolated and purified from calf thymus and
devoid of H1 histone and non-histone proteins. In addition,
antibodies to dsDNA were determined by an ELISA commercial kit and by indirect immunofluorescence on Crithidia
luciliae (CLIF). The performance variability of the several
assays in the present series of patients is probably due to the
cumulative effect of the differences in the epitope panel offered
by the different antigenic substrates and the heterogeneous
biochemical assay conditions of the different tests. In fact,
the present study did not aim to compare the various tests but
rather to explore the variability in the reactivity of JSLE sera
against different epitope panels in assays targeting apparently
related autoantigens.
The present study confirmed the high specificity of antinucleosome/anti-chromatin antibodies in JSLE (anti-CHR-20,
96% and anti-NCS, 98%) when compared with children with
non-lupus AD and healthy children. This observation is in
agreement with the diagnostic specificity of anti-nucleosome/
anti-chromatin antibodies for adult lupus (mean 95%; range
85%–98.8%). The sensitivity of the various tests for the different autoantibodies against chromatin components was relatively low (11%–40%) when compared to the literature data
on adult SLE.11,36–45 This may be related to specific features of
JSLE and to the ethnic makeup of the studied sample or to the
fact that most JSLE patients were under immunosuppressive
therapy at the moment of serum harvest. In the present study
22 of 23 (96%) anti-dsDNA ELISA positive samples were also
anti-CHR-20 positive. This finding is consistent with the concept that most of the anti-dsDNA antibodies in SLE patients are
a subset of antibodies directed against chromatin.40 However,
14% JSLE patients were reactive in the anti-CHR-20 assay but
not in the dsDNA ELISA assay. Conversely, 1% of the JSLE
samples were anti-dsDNA ELISA positive but anti-CHR-20
negative. On the other hand, 15 of 23 (65%) anti-dsDNA
ELISA positive samples were also positive in the IgG anti-NCS
and anti-CHR-60 assays, and 4% of the JSLE patients were
negative in these assays. Such dissociation has been reported
701
Keusseyan et al.
previously13,38,40,42,43,46–48 and indicates that these autoantibody
systems have complementary roles in the diagnosis of SLE.
This may have an impact in clinical practice inasmuch as the
demonstration of anti-NCS antibodies in the absence of other
autoantibodies may be particularly helpful in patients with few
clinical manifestations (e.g. < 3 classification criteria). In these
cases, early therapy may be helpful.
The present data confirm the importance of defining the
cut-off value according to the studied population in order to
determine the diagnostic accuracy of the various immunoenzyme assays in different ethnic and social frameworks. Using
the cut-off recommended by the manufacturer in our sample,
the commercial anti-chromatin kit (INOVA) display considerably less specificity.
Disease activity, as measured by SLEDAI, was associated
with the presence of anti-dsDNA (CLIF assay) and correlated
with the serum levels of ELISA anti-dsDNA, but was not associated with any of the other tested assays. However, the low
correlation level (r = 0.235) suggests that this parameter should
be used with caution in the clinical practice. Interestingly, however, the presence of antibodies against chromatin components
was largely associated in the literature with markers of active
lupus nephritis. Several studies have previously demonstrated
an association of anti-nucleosome antibodies and disease activity or active nephritis in SLE11,13,14,35,38,40,43,48 It has been also
pointed that anti-nucleosome antibodies are highly correlated
with renal failure and progression to kidney transplantation
in SLE.49 The present study confirmed such association also
for JSLE and further extended the observation to several autoantibody specificities within the supra-molecular chromatin
system. Despite the wide dispersion of the serum levels of these
autoantibodies in patients with active and inactive disease, they
were associated with markers of active nephritis. This suggests
that there may be an intra-individual association of disease
activity with anti-nucleosome and anti-dsDNA antibody serum
levels. Therefore, prospective longitudinal studies are warranted in order to further explore this possibility.
702
The behavior of anti-nucleosome antibodies in adult
lupus has been analyzed according to the antibody isotype
(IgG and IgM classes and IgG subclasses) by Amoura et al.11
Interestingly, IgG3 anti-NCS antibodies were present in high
levels only in active SLE patients, predominantly in active
lupus nephritis. When testing for IgG3 anti-NCS antibodies
in JSLE we did confirm that IgG3 anti-NCS antibodies were
associated with markers of active lupus nephritis such as
proteinuria and low C4 serum level. There was a diagnostic
sensitivity of 18% and specificity of 95% for JSLE diagnosis.
However, the frequency of IgG3 anti-NCS was similar in
children with active and inactive JSLE and IgG3 anti-NCS
serum levels did not correlate with SLEDAI. In summary,
this is the first report on JSLE regarding a comprehensive
survey of autoantibodies against several autoantigens of the
chromatin complex, including IgG3 anti-NCS antibodies. We
have found high specificity and moderate sensitivity of these
antibodies for the diagnosis of JSLE, signaling them as helpful tools in the differential diagnosis of JSLE among systemic
autoimmune diseases. There was a moderate disagreement
rate between anti-NCS/chromatin and anti-dsDNA antibodies, indicating that these are complementary autoantibodies
for lupus diagnosis. The association of anti-NCS/chromatin
antibodies with proteinuria and low C4 levels suggests a possible role for these antibodies as markers of lupus nephritis
activity. Further longitudinal studies are warranted to define
the clinical utility of anti-NCS/chromatin antibodies in the
monitoring of JSLE activity.
ACKNOWLEDGMENTS
The authors acknowledge Rufus Burlingame, Ph.D., for
technical supervision on nucleosome purification and
anti-nucleosome ELISA set up as well as for general
advising on the project. This study was supported by São
Paulo State Research Foundation (FAPESP) through grant
#05/00658-0.
Rev Bras Reumatol 2012;52(5):695-712
Desempenho diagnóstico e associações clínicas dos anticorpos contra componentes da cromatina no lúpus eritematoso sistêmico juvenil
de anticorpos IgG3 anti-NCS em casos de LESJ, confirmamos
que esses anticorpos estavam associados com marcadores de
nefrite lúpica ativa, como proteinúria e baixo nível sérico de
C4. Havia sensibilidade de 18% e especificidade de 95% para o
diagnóstico de LESJ. Contudo, a frequência de IgG3 anti-NCS
foi semelhante em crianças com LESJ ativo e inativo, mas os
níveis séricos de IgG3 anti-NCS não se correlacionaram com
o SLEDAI. Em suma, este é o primeiro relato de LESJ sobre
uma pesquisa abrangente de autoanticorpos contra vários autoantígenos do complexo da cromatina, incluindo anticorpos
IgG3 anti-NCS. Constatamos especificidade elevada e sensibilidade moderada desses anticorpos para o diagnóstico de LESJ,
sinalizando-os como ferramentas úteis no diagnóstico diferencial de LESJ entre doenças autoimunes sistêmicas. Houve
uma taxa de discordância moderada entre anticorpos anti-NCS/
cromatina e anti-dsDNA, indicando que tais marcadores são
autoanticorpos complementares para o diagnóstico de lúpus. A
associação de anticorpos anti-NCS/cromatina com proteinúria
e baixos níveis de C4 sugere um possível papel desempenhado
por esses anticorpos como marcadores de atividade da nefrite
lúpica. Portanto, é justificável a realização de outros estudos
longitudinais para definir a utilidade clínica de anticorpos
anti-NCS/cromatina na monitorização da atividade de LESJ.
6.
7.
8.
9.
10.
11.
12.
13.
14.
AGRADECIMENTOS
Os autores agradecem ao Dr. Rufus Burlingame pela supervisão
técnica na purificação do nucleossomo e na montagem do teste
ELISA para detecção dos anticorpos antinucleossomo, bem
como pela orientação geral do projeto. Esse estudo foi apoiado
pela FAPESP (Fundação de Amparo à Pesquisa do Estado de
São Paulo) por meio do subsídio nº 05/00658-0.
15.
16.
17.
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Piette JC et al. Testing for anti-nucleosome antibodies in daily
practice: a monocentric evaluation in 1696 patients. Lupus 2003;
12(11):833–7.
42. Cairns AP, McMillan SA, Crockard AD, Meenagh GK, Duffy EM,
Armstrong DJ et al. Antinucleosome antibodies in the diagnosis of
systemic lupus erythematosus. Ann Rheum Dis 2003; 62(3):272–3.
43. Cervera R, Viñas O, Ramos-Casals M, Font J, García-Carrasco M,
Sisó A et al. Anti-chromatin antibodies in systemic lupus
erythematosus: a useful marker for lupus nephropathy. Ann Rheum
Dis 2003; 62(5):431–4.
44. González C, Garcia-Berrocal B, Herráez O, Navajo JA, GonzálezBuitrago JM. Anti-nucleosome, anti-chromatin, anti-dsDNA and
anti-histone antibody reactivity in systemic lupus erythematosus.
Clin Chem Lab Med 2004; 42(3):266–72.
45. Ghirardello A, Doria A, Zampieri S, Tarricone E, Tozzoli R,
Villalta D et al. Antinucleosome antibodies in SLE: a two-year
follow-up of 101 patients. J Autoimmun 2004; 22(3):235–40.
46. Gómez-Puerta JA, Molina JF, Anaya JM, Molina J. Clinical
significance of anti-chromatin antibodies in systemic lupus
erythematosus. Lupus 2001; 10(supp 1):S73.
47. Braun A, Sis J, Max R, Mueller K, Fiehn C, Zeier M et al. Antichromatin and anti-C1q antibodies in systemic lupus erythematosus
compared to other systemic autoimmune diseases. Scand J
Rheumatol 2007; 36(4):291–8.
48. Sardeto GA, Simas LM, Skare TS, Nisihara RN, Utiyama SR.
Antinucleosome in systemic lupus erythematosus. A study in a
Brazilian population. Clin Rheumatol 2011; 31(3):553–6.
49. Stinton LM, Barr SG, Tibbles LA, Yilmaz S, Sar A, Benedikttson H
et al. Autoantibodies in lupus nephritis patients requiring renal
transplantation. Lupus 2007; 16(6):394–400.
Rev Bras Reumatol 2012;52(5):695-712
ORIGINAL ARTICLE
Newly diagnosed dermatomyositis in the
elderly as predictor of malignancy
Fernando Henrique Carlos de Souza1, Samuel Katsuyuki Shinjo2
ABSTRACT
Objective: Dermatomyositis (DM) symptoms may be a clue to the existence of a hidden cancer. Enhancing early detection
is essential, but there are no studies evaluating short-term predictive factors in this disease. Methods: This is a singlecenter retrospective study, including patients diagnosed with DM meeting at least four of the five Bohan and Peter’s
criteria (1975), from 1991 to 2011. This study assessed malignancies occurring in up to 12 months after the diagnosis of
DM. Results: Neoplasm was found in 12 out of 139 patients (skin, gastrointestinal tract, prostate, thyroid, breast, lungs,
and genitourinary tract). Patients with neoplasm had a higher mean age than controls (56.8 ± 15.7 vs. 40.3 ± 13.1 years,
respectively, P = 0.004, odds ratio 1.09; 95% confidence interval: 1.04–1.14). No statistical differences were observed
regarding gender, ethnicity, frequency of constitutional symptoms, organ and systemic involvements, and/or laboratory alterations. Conclusion: In newly diagnosed DM, age at disease diagnosis was a predictive factor of malignancy.
Keywords: dermatomyositis, myositis, risk factors, neoplasms, aging.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by clinical findings such as progressive,
symmetric proximal muscle weakness in the four limbs, in
addition to the presence of typical cutaneous changes, such
as heliotrope rash and Gottron’s papules.
The risk of developing neoplasias in idiopathic inflammatory myopathies is greater than that in the general population,1–23
mainly in DM1,4–7,12,15–17 and in the first years following the disease diagnosis.1–6,8,10,13,21 The risk factors described in the literature are as follows: atypical cutaneous manifestations;12,16–18,21
persistently high erythrocyte sedimentation rate (ESR);12,17
refractoriness to treatment in the elderly;20,21 rapid progression to muscle weakness;12,16–22 presence of myositis-specific
autoantibodies (anti-p155 or anti-p155/p140 antibodies);23
cutaneous necrosis or periungual erythema;12,16,17,21 dysphagia;24
no lung impairment;24 gender;4,5,10,19,21 and advanced age on the
occasion of disease diagnosis.5,7,19,21,24
However, those studies have analyzed predictive factors of
malignancy in a general population of inflammatory myopathies1–8,10,14–16,19,21 and/or independently of disease duration at
the time of cancer diagnosis.1–3,5,7,10,12–19,21,23
This study assesses the prevalence and possible factors associated with neoplasias in a population constituted only by patients
with DM diagnosed in the preceding year (newly diagnosed).
PATIENTS AND METHODS
This retrospective study assessed 139 patients diagnosed with
DM, meeting at least four of the five criteria proposed by
Bohan and Peter.25,26 Those patients were on an outpatient clinic
follow-up at our tertiary service from 1991 to 2011. Patients
with amyopathic DM or diagnosed with possible or probable
DM were not included. This study was approved by the local
Ethics Committee [HC 0039/10].
Demographic, clinical, and laboratory data were obtained
from a systematic review of the patients’ medical records. The
Received on 10/28/2011. Approved on 06/27/2012. The authors declare no conflict of interest. Ethics Committee: HC 0039/10.
Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – HC-FMUSP.
1. Assistant Physician of the Rheumatology Service, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – HC-FMUSP
2. PhD in Sciences; Assistant Physician of the Rheumatology Service, HC-FMUSP; Collaborating Professor of the Discipline of Rheumatology, FMUSP
Correspondence to: Samuel Katsuyuki Shinjo. Disciplina de Reumatologia, Faculdade de Medicina, Universidade de São Paulo. Av. Dr. Arnaldo, 455, 3º andar,
sala 3150 – Cerqueira César. São Paulo, SP, Brazil. CEP: 01246-903. E-mail: [email protected]
Rev Bras Reumatol 2012;52(5):713-721
713
Souza et al.
manifestations assessed were limited to up to one year after
the diagnosis of DM. The following parameters were assessed:
constitutional symptoms; cutaneous changes (heliotrope rash,
Gottron’s papules, ulcers, rash, calcinosis); joint involvement
(arthralgia and/or arthritis); dysphagia; dysphonia; dyspnea;
and muscle strength of the limbs (grade 0: no muscle contractility; grade I: signs of discrete contractility; grade II: range
of motion that does not overcome gravity; grade III: normal
range of motion that overcomes gravity; grade IV: full motion
against gravity and certain degree of resistance; grade V: full
motion against marked resistance and gravity).27 The serum
level of creatine kinase measured at the time of the initial
diagnosis of DM by use of the automated kinetic method was
also assessed. Complementary tests (electroneuromyography,
muscle biopsy – brachial biceps or vastus lateralis muscles),
when performed, were requested as routine in the first medical
consultations. Electroneuromyography was considered positive in the presence of inflammatory proximal myopathy of
the limbs with no neuropathy associated. The muscle biopsy
was considered diagnostic when perifascicular atrophy with
or without inflammatory infiltrate was evidenced.
This study assessed neoplasias occurring in up to one
year after the diagnosis of DM and confirmed by anatomopathological analysis. In our service, screening for neoplasia
in all patients suspected of having initial DM is routine, with
assessment of breasts, genitourinary and gastrointestinal
tracts, lungs, hematologic system (particularly lymphoma),
and skin.
The results were expressed as mean ± standard deviation (SD) or percentage. The Student t test was used for
the statistical analysis of parametric data, and the Fisher
exact test for categorical data. The 95% confidence interval
(95% CI) was calculated by use of binomial distribution.
The disease duration and adjusted age, odds ratio (OR),
and 95% CI were calculated by using a non-conditional
logistic model. Those calculations were performed by using the version 7.0 of the STATA software (STATA, College
Station, TX, USA). Values of P < 0.050 were considered
statistically significant.
and gastrointestinal tracts, lungs, prostate, thyroid, and skin.
Metastasis was identified in four (33.3%) patients at the time neoplasia was diagnosed. Of the 12 patients affected, 11 (91.7%)
were females and 10 (83.3%) were white (Table 1).
Patients who had neoplasia (group A) were compared with
those who did not (group B) (Table 1). The mean age at the
time DM was diagnosed in group A was 56.8 ± 15.7 years
(35–84 years), and, in group B, 40.3 ± 13.1 years (20–78 years)
(P = 0.004). Even after analyzing age quartiles, statistical
difference was observed between the groups (OR, 1.09; 95%
CI: 1.04–1.14).
However, no differences were found in the groups regarding clinical laboratory manifestations and complementary
tests (electroneuromyography and muscle biopsy) (Table 1).
Chart 1
Types of neoplasia seen in patients with newly
diagnosed dermatomyositis
Spinocellular carcinoma in the lower limbs
Ulcerated well-differentiated keratinizing squamous cell carcinoma
Pulmonary spinocellular carcinoma, metastasis
Pulmonary epidermoid carcinoma, metastasis
Ovarian adenocarcinoma
Basal cell carcinoma of the face
Thyroid carcinoma
Colon adenocarcinoma, metastasis
Invasive epidermoid carcinoma of the uterus
Ductal carcinoma of the breast
Ovarian undifferentiated adenocarcinoma
Prostate adenocarcinoma, metastasis
Table 1
Demographic, clinical and laboratory data of patients with
dermatomyositis with and without neoplasia
Neoplasia (+)
(n = 12)
Neoplasia (−)
(n = 127)
P
Female gender (%)
11 (91.7)
100 (78.7)
0.459
White color (%)
10 (83.3)
123 (89.0)
1.000
Mean ± SD (years)
56.8 ± 15.7
40.3 ± 13.1
0.004
Variation (years)
35–84
20–78
0.022
Age at DM diagnosis
RESULTS
In the period studied, 139 patients diagnosed with DM, meeting at least four of the five Bohan and Peter’s criteria, were
assessed, 12 of whom (8.6%) had a history of neoplasia in the
first 12 months of disease.
Chart 1 lists the types of cancer found in the patients,
which were in the following sites: breasts, genitourinary
714
Percentile (%)
20–31 years
0
38 (29.9)
32– 41 years
2 (16.7)
33 (26.0)
42–51 years
4 (33.3)
29 (22.8)
52–88 years
6 (50.0)
27 (21.3)
(Continue...)
Rev Bras Reumatol 2012;52(5):713-721
Newly diagnosed dermatomyositis in the elderly as predictor of malignancy
(Continuation of Table 1)
Neoplasia (+)
(n = 12)
Neoplasia (−)
(n = 127)
P
Constitutional symptoms (%) 5 (41.7)
60 (47.2)
0.770
Bedridden (%)
24 (18.9)
0.128
Clinical manifestations
5 (41.7)
Cutaneous (%)
Heliotrope rash
9 (75.0)
108 (85.0)
0.404
Gottron’s papules
10 (83.3)
123 (96.9)
0.085
Ulcers
2 (16.7)
18 (14.2)
0.684
Rash
6 (50.0)
63 (49.6)
1.000
Calcinosis
0
9 (7.1)
1.000
Muscle (muscle strength)
Upper limbs (%)
Grade V
1 (8.3)
7 (5.5)
0.524
Grade IV
9 (75.0)
97 (76.4)
1.000
Grade III
2 (16.7)
21 (16.5)
1.000
Grade II
0
2 (1.6)
1.000
Grade V
2 (16.7)
4 (3.1)
0.085
Grade IV
8 (66.7)
96 (75.6)
1.000
Grade III
2 (16.7)
24 (18.9)
1.000
Grade II
0
3 (2.4)
1.000
Articular (%)
8 (66.7)
50 (39.4)
0.123
Dysphagia (%)
8 (66.7)
49 (38.6)
0.071
Dysphonia (%)
4 (33.3)
20 (15.7)
0.221
Dyspnea (%)
4 (33.3)
39 (30.7)
1.000
2758.7 ± 3945.4
3783.3 ± 5617.1 0.450
6–210 U/L
2 (18.2)
25 (26.0)
211–823 U/L
5 (45.5)
22 (22.9)
824–4880 U/L
2 (18.2)
25 (26.0)
4881–22000 U/L
2 (18.2)
24 (25.0)
Lower limbs (%)
Laboratory changes
Creatine kinase
Mean ± SD (U/L)
Percentile (%)
0.537
Complementary tests
Electroneuromyography* (n) 10/11
80/120
0.171
Muscle biopsy** (n)
80/83
1.000
9/9
DM: dermatomyositis; SD: standard deviation. *Presence of proximal inflammatory myopathy of the
limbs; **Compatible with inflammatory myopathy.
DISCUSSION
This study found an 8.6% prevalence of neoplasia in individuals with newly-diagnosed DM, age being a risk factor associated with malignancy in that population.
Differently from the studies available in the literature,1–8,10,14–16,20 we assessed the prevalence and possible predictive factors of cancer in a population comprising only DM. In
Rev Bras Reumatol 2012;52(5):713-721
addition, we restricted our sample to patients diagnosed with
DM, whose disease duration did not exceed one year, unlike
other studies.1–3,5,7,10,12–19,21,23 That restriction is important because patients with a longer disease duration can have other
parameters related to cancer development, such as the chronic
use of immunosuppressive drugs.
András et al.8 have reported that malignancy may precede
myopathy by two years, while Maoz et al.16 have described
neoplasias in DM even after five years of disease. In general,
the prevalence and incidence of neoplasias in the general
population of DM ranges from 9.4%–28%.3,4,13,15 Considering
that cancer is more frequent in the first year of disease,1–3,5,6,10
in this study, it was found in 8.6% of the patients, representing,
thus, a prevalence within the expected range.
The sites of neoplasia usually found in DM are as follows: pulmonary,2,3,5,16 ovarian,2,3,5,16,28 nasopharyngeal,16,29
pancreatic,3 gastric,3,16 colorectal,3,16 uterine,3,5 breast,8,16
thyroidal,16 and hematological, including lymphomas.2,3,16 In
this study they were in accordance with those reported in the
literature and were as follows: pulmonary, ovarian, uterine,
thyroidal, hematological, colorectal, cutaneous, and prostatic.
In addition, one third of the patients already had metastasis at
the time cancer was diagnosed.
In our study we observed that age at the time of disease
diagnosis was a predictive factor of the development of
malignancy in DM, in accordance with other studies in the
literature.5,7,10,20–22,24 In addition, similarly to Sigurgeirsson et
al.4 and Stockton et al.,5 we showed that the neoplasias affected
predominantly women, although other studies have reported a
higher incidence among men.10,19,21
Other risk factors reported in the literature are as follows:
cutaneous necrosis or periungual erythema,12,16,17,21 persistently
high ESR values,12,17 refractoriness to treatment in elderly patients,20,21 presence of myositis-specific autoantibodies, such
as anti-p155 and anti-p155/140 antibodies,23 no pulmonary
involvement,24 dysphagia,24 and amyopathic DM.30
In this study neither cutaneous necrosis nor refractoriness to
treatment was observed. Regarding pulmonary involvement and
presence of dysphagia, the same distribution was found in patients
with and without neoplasias. In amyopathic DM, the incidence
of neoplasias is higher than in classic DM.30 In the presence of
neoplasia, it is difficult to differentiate whether the patients
really have amyopathic DM or whether the manifestations
are paraneoplastic; thus, we limited our analysis only to DM
meeting at least four of the five Bohan and Peter’s criteria.
Because this was a retrospective study, we had some limitations such as unavailability to some laboratory tests (ESR,
C-reactive protein, aldolase) of some patients. In addition,
715
Souza et al.
the possible autoantibodies related to the neoplasias were not
assessed in this study.
Our study emphasizes the concept that patients with
DM should be routinely screened for neoplasias, mainly
those with newly diagnosed DM. Among other predictive
716
factors of cancer, DM initiating at advanced age should be
considered, when a more extensive assessment for cancer is
recommended.
In conclusion, we showed that age was a factor associated
with malignancy in newly-diagnosed DM.
Rev Bras Reumatol 2012;52(5):713-721
Souza et al.
de neoplasia, torna-se difícil discernir se os pacientes de
fato apresentam DM amiopática ou se seriam manifestações
paraneoplásicas; portanto, restringimos a análise apenas às
DM definidas.
Por ser um estudo retrospectivo, tivemos algumas limitações,
como a disponibilidade completa de alguns exames laboratoriais (VHS, proteína C-reativa, aldolase) de todos os pacientes.
Além disso, quanto aos possíveis autoanticorpos relacionados
às neoplasias, estes não foram analisados no presente trabalho.
Nosso estudo reforça o conceito de que o rastreamento
de neoplasias deve ser realizado rotineiramente em pacientes
portadores de DM, principalmente nos casos recém-diagnosticados. Entre outros fatores preditivos de câncer, devemos
levar em consideração as DM que se iniciam em pacientes de
idade tardia, podendo-se apoiar a recomendação de uma avaliação mais extensa para o câncer nesse subgrupo de pacientes.
Em conclusão, mostramos que a idade foi um fator associado à malignidade em DM recém-diagnosticada.
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721
ORIGINAL ARTICLE
Nailfold capillaroscopy in children and
adolescents with rheumatic diseases
Daniela Gerent Petry Piotto1, Cláudio Arnaldo Len2, Maria Odete Esteves Hilário3, Maria Teresa Ramos Ascensão Terreri4
ABSTRACT
Objective: To assess nailfold capillaroscopy in children and adolescents with autoimmune rheumatic diseases (juvenile
idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, scleroderma and mixed connective tissue
disease) and relate it to clinical and laboratory findings and disease activity. Methods: Cross-sectional study assessing
147 patients by use of nailfold capillaroscopy as follows: 60 with juvenile idiopathic arthritis; 30 with systemic lupus
erythematosus; 30 with juvenile dermatomyositis; 20 with localized scleroderma; four with systemic sclerosis; and three
with mixed connective tissue disease. Clinical and laboratory tests and nailfold capillaroscopy were performed in all
patients. The nailfold capillaroscopy was performed with an optical microscope (at 10- and 16-time magnifications) by
the same observer. Results: Most patients (76.2%) had normal nailfold capillaroscopy. The major changes in nailfold
capillaroscopy, characterizing the scleroderma pattern, were observed in patients with juvenile dermatomyositis, systemic scleroderma and mixed connective tissue disease. There was no association between nailfold capillaroscopy and
disease activity in patients with juvenile idiopathic arthritis, systemic lupus erythematosus and localized scleroderma.
Disease activity and capillaroscopy were associated in patients with juvenile dermatomyositis. Conclusion: Nailfold
capillaroscopy is a useful method to diagnose autoimmune rheumatic diseases and monitor disease activity.
Keywords: diagnostic equipment, juvenile rheumatoid arthritis, dermatomyositis, child, systemic scleroderma.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Nailfold capillaroscopy (NFC) plays an important role in the
assessment of autoimmune rheumatic diseases (AIRD) with
vascular structural changes. It is easily performed, applicable,
non-traumatic, and of low cost, being thus useful for the
diagnosis and follow-up of those diseases. It is also used to
distinguish primary from secondary Raynaud’s phenomenon
(RP), to predict the prognosis of AIRD (such as in systemic
scleroderma – SSc), and to assess disease activity (such as in
dermatomyositis).1–3
NFC has proved to be very useful in the diagnosis of the
scleroderma spectrum disorders in adults and children. The
scleroderma pattern (SD-pattern), characterized by capillary
dilation and avascular areas (vascular deletion), resulting in
a reduction in the number of capillaries, is found in approximately 80% of the patients with SSc, but can also be seen in
patients with dermatomyositis and mixed connective tissue
disease (MCTD).4–6
This study aimed at characterizing NFC in children and
adolescents with AIRD [juvenile idiopathic arthritis (JIA),
systemic lupus erythematosus (SLE), juvenile dermatomyositis
(JDM), SSc, and MCTD] and at assessing its relationship to
clinical and laboratory changes and disease activity.
METHODS
This study assessed 147 children and adolescents cared for at
the pediatric rheumatology outpatient clinic from March 2008
to November 2009. It was a convenience sample composed
Received on 11/08/2011. Approved on 06/27/2012. The authors declare no conflict of interest. Financial Support: FAPESP, nº 07/55617-1. Ethics Committee: 1082/07.
Pediatric Rheumatology Sector, Department of Pediatrics, Universidade Federal de São Paulo – Unifesp.
1. Master’s degree in Sciences, Universidade Federal de São Paulo – Unifesp
2. PhD in Pediatrics and Sciences Applied to Pediatrics, Unifesp; Adjunct Professor of the Discipline of Allergy, Clinical Immunology and Rheumatology,
Rheumatology Sector, Department of Pediatrics, Unifesp
3. PhD in Pediatrics and Sciences Applied to Pediatrics, Unifesp; Associate Professor of the Discipline of Allergy, Clinical Immunology and Rheumatology,
Pediatric Rheumatology Sector, Unifesp
4. PhD in Pediatrics and Sciences Applied to Pediatrics, Unifesp; PhD in Pediatrics, Albert-Ludwigs Universität Freiburg; Adjunct Professor of the Discipline of
Allergy, Clinical Immunology and Rheumatology, and Chief of the Pediatric Rheumatology Sector, Unifesp
Correspondence to: Maria Teresa R. A. Terreri. Rua Ipê, 112/111 – Vila Clementino. CEP: 04022-005. São Paulo, SP, Brazil. E-mail: [email protected]
722
Rev Bras Reumatol 2012;52(5):722-732
Nailfold capillaroscopy in children and adolescents with rheumatic diseases
as follows, according to the respective diagnostic or classification criteria:7–12 60 patients with JIA (oligoarticular, 20;
polyarticular, 20; and systemic, 20); 30 patients with SLE; 30
patients with JDM; 20 patients with localized scleroderma;
four patients with SSc; and three patients with DMTC.
Patients up to the age of 21 years accepting to participate in
the study and with satisfactory nailfold conditions to undergo
NFC were included.
Anamnesis and physical examination were performed on
the day of NFC, focusing on the following: cutaneous changes
(skin thickening, Gottron’s sign, heliotrope rash, photosensitivity and periungual hyperemia); calcinosis; digital
ulcers; RP; arthritis/arthralgia; esophageal and pulmonary
changes (dysphagia and dyspnea, respectively); assessment of muscle strength in JDM, by use of the Childhood
Myositis Assessment Scale (CMAS);13 assessment of disease
activity in JIA,14 in localized scleroderma,15 and in SLE (by
use of the Systemic Lupus Erythematosus Disease Activity
Index – SLEDAI).16
Laboratory assessment comprised complete blood count,
acute-phase tests [erythrocyte sedimentation rate (ESR) and
C-reactive protein (CRP)], serum levels of muscle enzymes
[glutamic-oxaloacetic transaminase (GOT), glutamic-piruvic
transaminase (GPT), creatine kinase (CK), and lactic dehydrogenase (LDH)], autoantibodies [antinuclear antibody
(ANA), anti-double stranded DNA antibody (anti-ds-DNA),
extractable nuclear antigen antibody (ENA), rheumatoid factor (RF), anti-DNA topoisomerase-1 antibody (anti-Scl 70),
anti-polymyositis-scleroderma antibody (anti-PM-Scl), anticardiolipin immunoglobulin G and immunoglobulin M (ACL
IgG and ACL IgM, respectively)], and hemolytic complement
(CH100 and C2). Pulmonary function test (PFT), echocardiography and esophagogastroduodenography (EGD) were
performed in patients with SSc and MCTD.
NFC was performed by the same examiner (MTRAT)
using an optical microscope (at 10- and 16-time magnifications), equipped with a graded ruler coupled with the right
objective, allowing counting the number of capillaries per
millimeter. The patients were instructed not to remove their
fingernail cuticles for one month to avoid microtraumas that
could jeopardize the exam. The fingers were examined (except for the thumbs). On semiquantitative analysis, according
to the method proposed by Andrade et al.,17 the following
parameters were assessed: integrity of the nailfold; number
of micro-hemorrhages and their distribution pattern (focal or diffuse); number of capillaries per millimeter; vascular deletion
score (avascular areas); atypical capillaries, such as dilated,
‘giant’, crossed, bushy and bizarre capillaries; subpapillary
Rev Bras Reumatol 2012;52(5):722-732
venous plexus visualization score; and predominant capillary pattern.17
Capillaries were considered dilated when the loops were
widened in all three branches (afferent, transition and efferent), with calibers ranging from four to nine times the
normal dimension. ‘Giant’ capillary loops were defined as
extremely widened loops, with calibers 10 or more times
greater than those of the normal adjacent loops. For recording dilated and ‘giant’ capillaries, the mean number of
capillaries in each finger with those changes was calculated.
Deletion was defined as the absence of two or more successive capillaries. To quantify the degree of focal deletion
or avascular area, a 0–3 scale was used according to the
extension of the lesions:18 0: no deletion area; 1: one or two
discontinuous deletion areas; 2: more than two discontinuous deletion areas; 3: extensive and confluent avascular
areas. The vascular deletion score was calculated by adding
the scores of each finger and then dividing by the number
of fingers with deletion.
NFC was considered normal in the presence of parallel nondysmorphic capillaries and lack of deletion areas. Unspecific
microangiopathy was defined as dilated capillaries and other
morphological changes in the absence of deletion areas. The
SD-pattern was characterized by dilated or ‘giant’ capillary
loops and vascular deletion areas.
All participants provided written informed consent to participate in the study, which had been previously approved by
the Ethics Committee of the Hospital São Paulo.
RESULTS
This study assessed 147 patients by use of NFC. Table 1 shows
demographic data and the presence of RP. Table 2 shows the
NFC findings and disease activity of the patients with AIRD.
Most patients (76.2%) assessed had normal NFC.
Of the 20 patients with oligoarticular JIA, seven (35%)
showed clinical activity, two (10%) had chronic anterior uveitis, and 12 (60%) were positive for ANA. Regarding NFC, all
patients had normal results. Of the patients with polyarticular
JIA, five (25%) had RP, seven (35%) were positive for ANA,
11 (55%) had clinical activity, most patients had normal NFC
results, and only one patient had unspecific microangiopathy.
Of the patients with systemic JIA, 12 (60%) showed clinical
activity, 17 (85%) had normal NFC results, one (5%) had unspecific microangiopathy, one (5%) had the SD-pattern, and
one (5%) was inconclusive due to poor visualization of the
capillaries. Only two (10%) patients showed capillary tortuosity. No changes on NFC, such as tortuosity, were observed in
723
Piotto et al.
Table 1
Demographic data and presence of Raynaud’s phenomenon in patients with autoimmune rheumatic diseases (n = 147)
Variables
JIA
n = 60
SLE
n = 30
JDM
n = 30
LSc
n = 20
SSc
n=4
MCTD
n=3
Female gender, n (%)
32 (53.3)
25 (83.3)
20 (66.6)
12 (60)
4 (100)
0
Caucasian race, n (%)
42 (70)
23 (76.7)
23 (76.7)
19 (95.0)
4 (100)
3 (100)
Current age (years), mean ± SD
11.5 ± 4.7
14.4 ± 3.3
10.7 ± 3.6
12.1± 3.3
11.2 ± 5.5
13.7 ± 1.5
Disease duration (years), mean ± SD
6.2 ± 4.3
4.4 ± 2.7
4.0 ± 3.3
5.5 ± 3.3
5.3 ± 3.6
8.7 ± 4.0
Raynaud’s phenomenon, n (%)
12 (20)
11 (36.6)
6 (20)
8 (40)
4 (100)
3 (100)
JIA: juvenile idiopathic arthritis; SLE: systemic lupus erythematosus; JDM: juvenile dermatomyositis; LSc: localized scleroderma; SSc: systemic scleroderma; MCTD: mixed connective tissue disease.
Table 2
Nailfold capillaroscopy and disease activity in patients with autoimmune rheumatic diseases (n = 147)
JIA
n = 60
SLE
n = 30
JDM
n = 30
LSc
n = 20
SSc
n=4
MCTD
n=3
56 (93.3)
28 (93.4)
8 (26.7)
20 (100)
0
0
Unspecific microangiopathy, n(%)
2 (3.3)
1 (3.3)
0
0
0
0
SD-pattern, n (%)
1 (1.7)
1 (3.3)
22 (73.3)
0
3 (75)
3(100)
Inconclusive, n (%)
1 (1.7)
0
0
0
1 (25)
0
Disease activity, n (%)
30 (50)
6 (20)
26 (86.6)
7 (35)
4(100)
3 (100)
P
0.249
0.730
0.002
—
—
—
Normal, n (%)
JIA: juvenile idiopathic arthritis; SLE: systemic lupus erythematosus; JDM: juvenile dermatomyositis; LSc: localized scleroderma; SSc: systemic scleroderma; MCTD: mixed connective tissue disease.
the oligoarticular and polyarticular subtypes. Twelve (20%)
patients showed RP, which was associated with NFC changes
(P = 0.013). In addition, no association of NFC with disease
activity, presence of RF and ANA was observed in the three
JIA subtypes (Table 2).
Of the 30 patients with SLE, six (20%) showed clinical and laboratory activity on the examination. Regarding
NFC, only two (6.6%) patients showed changes (incipient
SD-pattern and unspecific microangiopathy). Four patients
positive for anti-RNP showed no changes on NFC. No
elongated, tortuous, and crossed capillaries were observed.
Nailfold capillaroscopy associated with neither SLEDAI nor
RP presence (Table 2).
Of the 30 patients with JDM assessed, 26 (86.6%) were on
the active phase of the disease. Regarding NFC, 22 of the 26
exams (84.6%) performed during the active phase of the disease showed the SD-pattern, while the four exams performed
during disease remission were normal (P = 0.002) (Table 2).
Thus, in 26 of the 30 patients (86.6%) assessed, the clinical
and laboratory data were associated with the NFC findings. No
association was observed between the NFC results and cutaneous changes, muscle weakness, increased levels of muscle
enzymes, or acute phase tests.
724
Regarding NFC findings, the deletion score and number of
dilated and bushy capillaries were statistically greater in the
group with active disease (P = 0.004, P = 0.001, P = 0.009,
respectively). No association was observed between the
deletion score, number of dilated bushy capillaries and
megacapillaries, and cutaneous and muscular changes, when
the variables were assessed separately. The capillaroscopic
changes and their association with disease activity are shown
in Table 3.
Table 3
Distribution of the patients with juvenile dermatomyositis
according to capillaroscopic changes and disease activity
Capillaroscopic changes
(mean)
Active disease
(n = 26)
Inactive disease
(n = 4)
P
N. micro-hemorrhages+
2.15
2.5
0.677
N. capillary dilation
1.77
0.12
0.001*
++
N. megacapillaries
0.18
0
0
N. bushy capillaries++
0.45
0.03
0.009*
2.06
0.5
0.004*
++
Deletion score
+++
*Student t test. +Sum of the number of hemorrhages/number of fingers with hemorrhage; ++Sum
of the number of changes/total number of fingers assessed; +++Sum of the deletion score/number of
fingers with deletion.
Rev Bras Reumatol 2012;52(5):722-732
Nailfold capillaroscopy in children and adolescents with rheumatic diseases
All 20 patients with localized scleroderma had normal
NFC. No association with disease activity was observed.
Four patients with SSc were assessed. On clinical exam,
all had RP, cutaneous thickening and sclerodactyly. Three
(75%) had healed digital ulcers. No patient had fever, dyspnea, arthritis, or arthralgia. Two female patients reported
dysphagia and had changes on EGD, and, on lung computed
tomography, pulmonary fibrosis. All echocardiographies
performed were normal. Three of four (75%) children
showed the SD-pattern with reduced capillary density, severe capillary deletion, and ‘giant’ and dilated capillaries.
In one female patient, NFC could not be performed because
of poor visualization of the capillaries due to important
skin thickening.
Three patients diagnosed with MCTD were assessed. All
underwent echocardiography, PFT and EGD, which resulted
normal. On NFC, the SD-pattern was observed with reduced
capillary density, severe deletion and few dilated capillaries.
All patients had active disease.
DISCUSSION
NFC has proved to be very useful for the diagnosis of the AIRD
of the scleroderma spectrum. The SD-pattern is considered
highly specific and sensitive to the diagnosis of SSc, being
found in up to 80% of the patients, but can also be seen in
patients with dermatomyositis and MCTD.4–6
The SD-pattern has not been described in JIA.19 Only
non-specific changes, such as capillary tortuosity and elongation, increased subpapillary venous plexus visualization,
and micro-petechiae, can be found. Those changes are more
often found in patients with polyarticular JIA and positive
for RF and ANA.19,20 In our study, those changes were not
found, maybe because of the small amount of patients
with those antibodies. However, patients with RP show
more changes on NFC, indicating that they probably have
vasculopathy.
SLE is a multisystemic disease that can affect all organs
in the body. Vascular lesions are the pathological markers
of that condition and comprise hemorrhages, digital infarctions, and cutaneous lesions. Several authors have described
unspecific changes on NFC, such as elongated, tortuous, and
crossed capillaries in approximately 30% of those patients.
Such findings do not depend on the presence of the RP.21–23
Reduced capillary density and increased capillary diameters
occur more frequently in individuals with the RP.24 The
SD-pattern is rare and described in 5%–10% of the patients
Rev Bras Reumatol 2012;52(5):722-732
with SLE. In our study no elongated, tortuous, and crossed
capillaries were found; however, the NFC changes (SDpattern and unspecific microangiopathy) were associated
with the RP, as reported in the literature. In a study with
children and adults, the SLEDAI and presence of anti-RNP
antibodies were associated with changes on NFC.25 In our
study the four patients positive for anti-RNP showed no
changes on NFC.
In JDM the SD-pattern is present in approximately 60%
of the pateints.6 Although usually undistinguishable from the
changes found in scleroderma, the microangiopathy of dermatomyositis shows more bushy capillaries, with exuberant
branching.26 In addition, the changes seen in dermatomyositis usually have a more dynamic character than those from
scleroderma, and can rapidly subside with disease control,
as seen in our study. Several studies have reported that the
intensity of the morphological changes on NFC correlate with
the clinical course and the more severe forms of disease, such
as ulcerative complications and calcinosis.27–30 In our study,
disease activity was associated with capillaroscopic changes,
indicating that NFC is an adequate method to monitor the
course of JDM.
SSc is characterized by autoimmune changes, microvascular abnormalities and fibrosis of the skin and
internal organs. The early diagnosis and assessment of the
manifestations that indicate disease activity are not always
easy to obtain; thus, NFC is a method that allows the early
detection of microvascular changes, characterized in 90%
of the patients as the SD-pattern.5,31 All our patients with
SSc had the SD-pattern on NFC. An association with more
severe deletion on NFC, pulmonary fibrosis, and digital
ulcers in adults has been reported.32–34 However, because
of the small number of patients, we could not assess that
association in children.
Localized (cutaneous) scleroderma usually shows no
changes on NFC, as reported in our study.35 A study with 27
adults with localized scleroderma has reported that the only
two patients with SD-pattern changes on NFC progressed to
SSc.36 In our study no patient progressed to the systemic form
of the disease.
On NFC, MCTD shows the SD-pattern in approximately
60% of the adults.31 Most of those patients develop sclerodermic manifestations.35 So far, studies have not been conducted
with children. In our cohort all patients had the SD-pattern
on NFC.
NFC proved to be an important method to aid the diagnosis
of AIRD with vascular structural changes. It was also useful to
725
Piotto et al.
assess disease activity in JDM. Because it is relatively simple,
easily performed and provides valuable information, the benefits easily overcome the costs. However, full training with
an expert is required. Although the diagnostic criteria do not
726
include NFC, it is a complementary and useful test to assess the
microcirculation of patients, being, thus, one more tool, along
with clinical and laboratory findings, to aid rheumatologists
in diagnosing AIRD.
Rev Bras Reumatol 2012;52(5):722-732
Capilaroscopia periungueal em crianças e adolescentes com doenças reumáticas
A CPU foi importante como método auxiliar no diagnóstico das DRAI que apresentam alterações estruturais
vasculares. Também foi útil para avaliar a atividade na DMJ.
Por se tratar de um método relativamente simples, facilmente
executável, que traz informações valiosas, os benefícios facilmente ultrapassam os custos. Entretanto, um treinamento
completo com o especialista se faz necessário. Embora os
critérios diagnósticos não incluam a CPU, ela se mostra um
teste complementar e útil na avaliação da microcirculação
dos pacientes e que, em alguns casos, pode ser útil no diagnóstico, o que a torna uma ferramenta a mais na consulta dos
reumatologistas, adicionalmente a outros achados clínicos e
laboratoriais.
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Rev Bras Reumatol 2012;52(5):722-732
ORIGINAL ARTICLE
Cross-cultural adaptation and validation of
the Brazilian-Portuguese version of the Bath
Ankylosing Spondylitis Functional Index (BASFI)
Karla Garcez Cusmanich1, Sérgio Candido Kowalski2, Andréa Lopes Gallinaro3,
Claudia Goldenstein-Schainberg4, Lilian Avila Lima e Souza1, Célio Roberto Gonçalves4
ABSTRACT
Objective: To conduct a cross-cultural adaptation of the Bath Ankylosing Spondylitis Functional Index (BASFI) into
Brazilian-Portuguese language and to assess its measurement properties. Methods: The BASFI was translated by four
rheumatologists and three English teachers. The translated questionnaire was applied to ankylosing spondylitis patients
by trained observers, and self-administered in three moments: days 1, 2, and 14. The validity was assessed analyzing
the association of BASFI and functional capacity measures (cervical rotation, intermalleolar distance, Schober’s test
and occiput-to-wall distance). The internal consistence was tested by Cronbach’s α coefficient and the reliability by testretest (intraclass correlation coefficient – ICC). Results: A total of 60 patients with ankylosing spondylitis was included:
85% male, mean age 47 ± 12 years, and mean disease duration 20 ± 11 years. The intra-observer test-retest (two-week
interval) reliability showed a high ICC (0.999, 95% CI: 0.997–0.999) and a high internal consistency (Cronbach’s α
coefficient: 0.86, CI 95%: 0.80–0.90). Considering the validity, the BASFI indices were correlated with cervical rotation (0.53, P < 0.001) and with intermalleolar distance (0.50, P < 0.001). Conclusion: The BASFI Brazilian-Portuguese
version is reliable and valid for assessment of patients with ankylosing spondylitis.
Keywords: ankylosing spondylitis, translation, questionnaires, BASFI, health status.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Ankylosing spondylitis (AS) is a chronic rheumatic disease
with a worldwide prevalence of up to 0.9%.1 Men are more
commonly affected than women, similar to other spondyloarthritis HLA-B27-positive related diseases.2 The sacroiliac
joints are affected and, to a varying degree, the spinal column,
while peripheral joints may be involved, specially in the lower
limbs. Patients commonly experience pain, morning stiffness
and disability, generally increasing with long standing disease.3
There is no single “gold standard” management and prognostic factors for AS because of its heterogeneous nature,
long standing characteristic and, until recently, lack of appropriate, validated outcome measures.4 As consequence, the
optimal quantitative measures to monitor status and to assess
long-term prognosis are often derived from patient self-report
questionnaires. This has resulted in significant increase in the
availability of patient-assessed health instruments which aim to
measure aspects of health from the perspective of the patient.
These instruments usually contain multiple items or questions
to reflect the broad nature of health status, disease, or injury.5,6
In fact, an interesting systematic literature review
(1988–2004) have been done to retrieve references related to the development and evaluation of multi-item
Received on 04/03/2012. Approved on 06/26/2012. The authors declare no conflict of interest.
Departament of Rheumatology, Faculdade de Medicina, Universidade de São Paulo – FMUSP.
1. Master in Science, Faculdade de Medicina, Universidade de São Paulo – FMUSP
2. PhD in Rheumatology, Universidade Federal de São Paulo – Unifesp
3. Master in Rehabilitation, Unifesp
4. PhD in Rheumatology, FMUSP
Correspondence to: Célio Roberto Gonçalves. Disciplina de Reumatologia, Faculdade de Medicina da Universidade de São Paulo. Av. Dr. Arnaldo, 455/3190 –
Cerqueira César. São Paulo, SP, Brazil. CEP: 01246-903. E-mail: gonç[email protected]
Rev Bras Reumatol 2012;52(5):733-741
733
Cusmanich et al.
patient-assessed health instruments (12 AS-specific and
three arthritis-specific). Among the instruments evaluated,
both The Bath Ankylosing Spondylitis Functional Index
(BASFI) and Dougados Functional Index (DFI) demonstrated acceptable levels of reliability with good evidence
for construct validity and similar levels of responsiveness
following drug therapy evaluation. The BASFI is an AS
specific functional index, worldwide accepted, has shown
better content validity, and it is more responsive following
physical therapy.7
Recently, the Assessment in Ankylosing Spondylitis Group
(ASAS) have recommended several domains for the evaluation
of patients with AS in both clinical research and routine practice, which include the analysis of functional disability, spinal
stiffness, and pain.8 In this regard, patient-assessed instruments
with measurement properties to support their role in evaluation
should be identified to fulfill these domains.9
Therefore, with increasing numbers of multinational
and multicultural research projects, the need to adapt
health status measures for use in other than the source
language has also grown rapidly. Because there was no
Brazilian-Portuguese version of this instrument to assess
AS functional ability, we decided to translate and culturally adapt the BASFI, based on its strong measurement
properties, described in the literature. Thus, in order to
develop a Brazilian-Portuguese version of the BASFI, the
aim of the present study was to do a cross-cultural adaptation
of the BASFI into Brazilian-Portuguese and to validate it
in AS patients, following the international guidelines.10
The BASFI satisfies the criteria required for a functional
index because it is quick and easy to complete, reliable, and
sensitive to change across the whole spectrum of disease.
The validity and reliability of the original BASFI English
version, as well as other language’s versions, has been
demonstrated.11–15 In addition, the BASFI questionnaire has
been approved by OMERACT IV filter for use as functional
index in spondyloarthritis.16
PATIENTS AND METHODS
Sixty patients were consecutively selected from the
Rheumatology Division of the Universidade de São Paulo
during a period of six months. The inclusions are based on
the diagnosis of AS accordingly to the New York criteria.17
All patients had to be able to answer the questionnaires and an
informed consent was obtained from all participants. Patients
who were attending any rehabilitation intervention/program
were excluded.
734
BASFI
This self-assessment instrument was designed by a team of
medical professionals and patients and consists of eight specific
questions regarding physical function in AS and two questions
reflecting the patient’s ability to cope with everyday life.18 Each
question is answered on a 10 cm horizontal Visual Analogue
Scale, scoring from 0–10. The questionnaire is easily understood and can be self-administered or applied by an interviewer.
All results are the arithmetic sum of the answers, considering
that 0 is no disability and 10 is the maximum disability. The
BASFI satisfies the criteria required for a functional index and
it is brief and easy to be completed, reliable, and sensitive to
change across the whole spectrum of disease.18
Translation process
The translation of the BASFI was done into three steps. First,
four rheumatologists fluent in English and one English teacher
translated the original BASFI (English version) into BrazilianPortuguese (T1). Secondly, this version (T1) was back-translated
into English by a second English teacher (blinded about the
disease and from the objectives of the study) (BT1). Afterwards,
a third English teacher translated the BT1 into BrazilianPortuguese (T2). Finally, the committee, composed by the
rheumatologists and English teachers involved in the translation
process, consensually defined the final version (T12).
This study was approved by the Ethics Committee of the
Hospital de Clínicas, Medical School, Universidade de São
Paulo and the author of BASFI have formally allowed and
authorized its translation into Brazilian-Portuguese language
and to culturally adapt it.
BASFI application
On day 1 (D1) all patients who fulfilled the inclusion criteria
had their physical parameters taken by a trained physical
therapist (PT). The measures evaluated were: cervical rotation (CR) (goniometer), intermalleolar distance (IMD) (cm),
Schober test (ST) and occiput-to-wall distance (OWD) (cm).
Afterwards, all patients were interviewed by the first observer
(O1) to fill out the questionnaire (BASFI). All patients were
interviewed by a second observer (O2) in the same day (D1),
to assess the inter-observer test-retest reliability. On day 2
(D2) all patients filled the BASFI at home (self-administered)
and were instructed not to change their daily activities and
to answer the questionnaires in the morning period. On the
fourteenth day (D14) all patients were interviewed again by
the same first observer (O1) to fill the BASFI questionnaire
and were blinded from their previous answers (D1).
Rev Bras Reumatol 2012;52(5):733-741
Cross-cultural adaptation and validation of the Brazilian-Portuguese version of the Bath Ankylosing Spondylitis Functional Index (BASFI)
Statistical analysis
All data was given as measures of central tendency and
dispersion. Reliability (intra-, inter-observer and observer X
self-administered) were analyzed by the intraclass correlation coefficient (ICC) and the internal consistency was tested
by the Cronbach’s α coefficient. Multiple linear regressions
were applied for evaluation of the construct validity between
BASFI indices and physical measures (CR, IMD, ST, OWD).
A P < 0.05 was considered statistically significant.
RESULTS
A total of 60 AS patients participated in the study. Eighty
five percent were men, mean age of 47 ± 12 years and mean
disease duration of 20 ± 11 years. Educational level was
divided according to years at school and more than a half
of the patients studied less than five years (56.7% < 5 years,
21.7% from 5–9 years, 13.3% from 9–12 years and only
8.3% > 12 years).
Mean total score of BASFI obtained in this group was
4.45 ± 2.43. For validity, the BASFI indices were correlated
to CR (mean 29.3 ± 20.6 grade, 0.53, P < 0.001/exponential),
IMD (mean 61.9 ± 25.3 cm, 0.50, P < 0.001/cubic). The BASFI
indices were not significantly correlated to the ST (mean
2.9 ± 2.97 cm, 0.85, P = 0.51) and OWD (mean 8.2 ± 6.93 cm,
0.22, P = 0.09).
Multiple regression was applied to assess the influence of
the variables age, disease duration and education level in the
BASFI indices. There was no statistical significant influence
of those variables in the BASFI indices (data not shown).
The inter-observer reliability (ICC) was 0.95, 95% CI:
0.91–0.97. In the observer X self-administered reliability
(ICC) the result was 0.96, 95% CI: 0.93–0.96 while in the
intra-observer reliability (ICC) the figure was 0.999, 95% CI:
0.997–0.999. The internal consistency (Cronbach’s α) was
0.86, 95% CI: 0.80–0.90.
DISCUSSION
At literature we have found some physical and cultural characteristics in AS patients around the world. Much of results
differ between countries. Our results suggest that the selfadministered Brazilian BASFI can be a useful alternative either
in further studies or in clinical practice.
In our study, mean BASFI results were similar to a Spanish
study (4.3 ± 2.4) and one from United Kingdom (5 ± 2.6).11,19
The clinical characteristics of our patients and disease
Rev Bras Reumatol 2012;52(5):733-741
severity were similar. Our patients have longer disease than
Spanish group (11 ± 7.8) and also the United Kingdom group
(9.9 ± 9.8).
In contrast of two recent Turkish studies, our patients
were older with more disease duration and worse BASFI
results compared to their data.20,21 Furthermore, in our study
the BASFI results had no correlation with age. This is in line
with Turkish and Finnish studies. In the Finnish study only DFI
showed correlation with age.13,15 However, the BASFI Chinese
version showed weak correlations both with age and disease
duration.22 In fact, it is possible that not only age but other
variables combined result in disease severity and functional
disability so that, as a consequence, a patient could be older
but with less severe disease, while a younger patient could
have more severe disease.
The reliability (ICC) of the present study was very good
considering both the intra-observer (D1 X D14) and observer
vs. self-administered approach (D1 X D2) (0.99 and 0.96,
respectively). The inter-observer reliability (at the same day)
also showed good results (0.95, 95% CI: 0.91–0.97). The
same trend was found in one study whose BASFI test-retest
Spearman’s rank correlation coefficient was 0.91 (P < 0.0001)
for the global BASFI score.11 These results are also in line
with another study that applied the BASFI (self-administered
approach in D1 and D2) and their results showed also an
excellent reliability (ICC = 0.99).15 In addition, the test-retest
reliability of BASFI was good, with a high intraclass correlation coefficient between the two time points (24 hours interval,
ICC = 0.93).13 In opposite direction, a Mexican-Spanish version
found worse results than the studies described above. There was
an acceptable 24-hour test-retest (ICC = 0.68).14 The internal
consistency (Cronbach’s α = 0.86) in the present study was
similar to other international studies.7,11,22,23
Most cross-cultural studies showed good BASFI validity,
comparing its indices with clinical measurements but with
differences in correlation. In the literature two studies found
that the BASFI showed a negative correlation with Schober’s
test of −0.444,21,24 one of them with significant correlation
of −0.31.22 In the present study we found no statistically significant correlation between the BASFI and the Schober’s test
(0.85, P = 0.518).
BASFI showed a positive correlation with OWD22,24 and no
correlation in another21 (0.33, 0.535 respectively). We found
no statistically significant correlation between the BASFI with
the OWD (0.22, P = 0.095). The selection bias could explain the
lack of correlation between BASFI scores, the Schober’s test
and OWD in our study. The majority of patients had long term
disease duration and had no significant physical limitation.
735
Cusmanich et al.
One study showed negative but weak correlation between
the BASFI with the measurements of lumbar flexion (r = −0.38,
P = 0.001) and cervical rotation (r = 0.28, P = 0.013).13 We have
found significant correlations between BASFI with intermalleolar and cervical rotation.
Some studies describe patients’ difficulty in fulfilling the
BASFI in a self-administered approach.25 That could be related
to low socioeconomic level, because it was not observed in the
developed countries.11,15 In Yanik’s study (Turkish patients),
36% of the patients’ educational level was primary school and
the questionnaire was well performed by the patients.13 In addition, Spanish patients also had no problems in understanding the
questionnaire and spent a short time completing it.11 Although the
BASFI is a self-administered questionnaire, we also applied it by
face-to-face interviews, considering the low educational level of
736
our sample (57% < 5 years of schooling) and our patients had no
difficulties in answer our Brazilian BASFI version in both formats.
Our study had some weaknesses, including selection bias,
because only patients attending our University tertiary facility
were enrolled. The small sample size probably precluded the
validity, considering the narrow physical functional disability
of the patients. Therefore, further studies should also enroll
patients from the community, considering different disease
durations and disability levels.
In conclusion, the Brazilian-Portuguese version of BASFI
contributes to underscore the international findings, such as
feasibility, good reliability, and internal consistency.11,13,15
Therefore, the Brazilian-Portuguese version of BASFI can be
applied in AS patients. Further studies are necessary to corroborate its measurement properties.
Rev Bras Reumatol 2012;52(5):733-741
Cusmanich et al.
com outro estudo que aplicou o BASFI (abordagem autoaplicável em D1 e D2), e seus resultados também demonstraram
uma excelente CIO (0,99).15 Além disso, a confiabilidade do
teste-reteste de BASFI era boa, com alto CCI entre os dois
pontos de tempo (intervalo de 24 horas, CIO = 0,93).13 Na
direção oposta, uma versão castelhana do México constatou
resultados piores que os estudos descritos anteriormente.
Havia uma CIO aceitável de 0,68 no teste-reteste de 24 horas.14 A consistência interna (coeficiente α de Cronbach de
0,86) no presente estudo era semelhante à de outros estudos
internacionais.7,11,22,23
A maioria dos estudos culturais cruzados demonstrou
boa validade do BASFI, comparando-se seus índices com
medições clínicas, mas com diferenças na correlação. Na literatura especializada, dois estudos verificaram que o BASFI
mostrou uma correlação negativa com o teste de Schober de
−0,444,21,24 um deles com correlação significativa de −0,31.22
No presente estudo não descobrimos qualquer correlação estatisticamente significativa entre o BASFI e o teste de Schober
(0,85; P = 0,518).
O BASFI demonstrou correlação positiva com a DOP22,24 e
nenhuma correlação com outro índice21 (0,33, 0,535 respectivamente). Não constatamos qualquer correlação estatisticamente
significativa entre o BASFI e a DOP (0,22; P = 0,095). O viés
de seleção pode explicar a falta de correlação entre os escores
do BASFI, o teste de Schober e a DOP em nosso estudo. A
maioria dos pacientes tinha a doença há muito tempo e não
apresentava qualquer limitação física significativa.
Um único estudo revelou correlação negativa, mas fraca,
entre o BASFI e as medidas de flexão lombar (r = −0,38,
P = 0,001) e rotação cervical (r = 0,28, P = 0,013).13 Verificamos
correlações significativas entre o BASFI e a distância intermaleolar e rotação cervical.
Alguns estudos descrevem a dificuldade dos pacientes em
preencher o BASFI em uma abordagem autoaplicável.25 Isso
pode estar relacionado com o baixo nível socioeconômico, pois
não foi observado nos países desenvolvidos.11,15 No estudo de
Yanik (pacientes da Turquia), o nível educacional de 36% dos
pacientes era primário e o questionário foi bem respondido
pelos pacientes.13 Além disso, os pacientes espanhóis também
não tiveram problemas na compreensão do questionário, e
gastaram pouco tempo para concluí-lo.11 Embora o BASFI seja
um questionário autoaplicável, também o aplicamos por meio
de entrevistas diretas (presencial), considerando-se o baixo
nível educacional de nossa amostra (57% tinham menos de
cinco anos de escolaridade), e nossos pacientes não tiveram
dificuldades em responder à nossa versão brasileira do BASFI
em ambos os formatos.
740
Nosso estudo tinha alguns pontos fracos, incluindo o viés
de seleção, pois foram inscritos somente pacientes atendidos
em nossa instituição de educação terciária da Universidade.
O pequeno tamanho da amostra provavelmente excluiu a
validade, considerando-se a estreita incapacidade funcional física dos pacientes. Portanto, outros estudos também
deverão inscrever os pacientes da comunidade, levando-se
em conta as diferentes durações da doença e os níveis de
incapacidade.
Em suma, nosso estudo contribuiu para reforçar as descobertas internacionais, como viabilidade, boa confiabilidade
e consistência interna do BASFI. 11,13,15 Portanto, a versão do
BASFI para o português do Brasil é viável para ser aplicado em
pacientes com EA. No entanto, outros estudos são necessários
para comprovar suas propriedades métricas.
REFERENCES
REFERÊNCIAS
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Sieper J, Braun J, Rudwaleit M, Boonen A, Zinc A. Ankylosing
spondylitis: an overview. Ann Rheum Dis 2002; 61(Suppl 3): iii8–18.
2. Zink A, Braun J, Listing J, Wollenhaupt J. Disability and handicap
in rheumatoid arthritis and ankylosing spondylitis – results from the
German rheumatological database. German Collaborative Arthritis
Centers. J Rheumatol 2000; 27(3):613–22.
3. Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, Distler A
et al. Prevalence of spondylarthropathies in HLA-B27 positive and
negative blood donors. Arthritis Rheum 1998; 41(1):58–67.
4. Robertson LP, Davis MJ. A longitudinal study of disease activity
and functional status in a hospital cohort of patients with ankylosing
spondylitis. Rheumatology (Oxford) 2004; 43(12):1565–8.
5. Pincus T, Sokka T. Complexities in the quantitative assessment of
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Clin Exp Rheumatol 2005; 23(5 Suppl 39):S1–9.
6. Van Der Heijde D. Assessment of SpondyloArthritis International
Society (ASAS). Assessment of Ankylosing Spondylitis. Patientreported instruments (BASFI). Available from: http:⁄ ⁄www.asasgroup.org. [Acessed on February 2nd, 2011]
7. Haywood KL, Garratt AM, Dawes PT. Patient-assessed health in
ankylosing spondylitis: a structured review. Rheumatology (Oxford)
2005; 44(5):577–86.
8. Braun J, Van der Berg R, Baraliakos X, Boehm H, BurgosVargas R, Collantes-Estevez E et al. Update of the ASAS/EULAR
recommendations for the management of ankylosing spondylitis.
Ann Rheum Dis 2011; 70(6):896–904.
9. van der Heijde D, Bellamy N, Calin A, Dougados M, Khan MA,
van der Lindsen S. Preliminary core sets for endpoints in ankylosing
spondylitis. Assessments in Ankylosing Spondylitis Working Group.
J Rheumatol 1997; 24(11):2225–9.
10. Beaton DE, Bombardier C, Guillemin F, Ferraz MB. Guidelines
for the process of cross-cultural adaptation of self-report measures.
Spine (Phila Pa 1976) 2000; 25(24):3186–91.
11. Ariza-Ariza R, Hernández-Cruz B, Navarro-Sarabia F. Physical
function and health-related quality of life of Spanish patients with
ankylosing spondylitis. Arthritis Rheum 2003; 49(4):483–7.
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Adaptação cultural cruzada e validação da versão do Índice Funcional de Espondilite Anquilosante de Bath (BASFI) para o português do Brasil
12. Akkoc Y, Karatepe AG, Akar S, Kirazli Y, Akkoc N. A Turkish
version of the Bath Ankylosing Spondylitis Disease Activity Index:
reliability and validity. Rheumatol Int 2005; 25(4):280–4.
13. Yanik B, Gursel YK, Kutlay S, Ay S, Elhan AH. Adaptation of
the Bath Ankylosing Spondylitis Functional Index to the Turkish
population, its reliability and validity: functional assessment in AS.
Clin Rheumatol 2005; 24(1):41–7.
14. Cardiel MH, Londoño JD, Gutiérrez E, Pacheco-Tena C, VázquezMellado J, Burgos-Vargas R. Translation, cross-cultural adaptation, and
validation of the Bath Ankylosing Spondylitis Functional Index (BASFI),
the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and
the Dougados Functional Index (DFI) in a Spanish speaking population
with spondyloarthropathies. Clin Exp Rheumatol 2003; 21(4):451–8.
15. Heikkila S, Viitanen JV, Kautianen H, Kauppi M. Evaluation of
the Finnish versions of the functional indices BASFI and DFI in
spondylarthropathy. Clin Rheumatol 2000; 19(6):464–9.
16. van der Heijde D, van der Linden A, Dougados M, Bellamy N,
Russell AS, Edmonds J. Ankylosing spondylitis: plenary discussion
and results of voting on selection of domains and some specific
instruments. J Rheumatol 1999; 26(4):1003–5.
17. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic
criteria for ankylosing spondylitis. A proposal for modification of the
New York criteria. Arthritis Rheum 1984; 27(4):361–8.
18. Calin A, Garrett S, Whitelock H, Kennedy LG, Mallorie P, O’Hea J
et al. A new approach to defining functional ability in ankylosing
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Functional Index. J Rheumatol 1994; 21(12):2281–5.
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19. Roussou E, Sultana S. Spondyloarthritis in women: differences in
disease onset, clinical presentation, and bath Ankylosing Spondylitis
Disease activity and functional indices (BASDAI and BASFI)
between men and women with spondyloarhritides. Clin Rheumatol
2011; 30(1):121–7.
20. Bodur H, Ataman S, Rezvani A, Buğdaycı DS, Cevik R, Birtane M
et al. Quality of life and related variables in patients with ankylosing
spondylitis. Qual Life Res 2010; 20(4):543–9.
21. Ozdemir O. Quality of life in patients with ankylosing spondylitis:
relationships with spinal mobility, disease activity and functional
status. Rheumatol Int 2011; 31(5):605–10.
22. Wei JC, Wong RH, Huang JH, Yu CT, Chou CT, Jan MS et al.
Evaluation of internal consistency and re-test reliability of Bath
ankylosing spondylitis indices in a large cohort of adult and
juvenile spondylitis patients in Taiwan. Clin Rheumatol 2007;
26(10):1685–91.
23. Ruof J, Sangha O, Stucki G. Evaluation of a German version
of the Bath Ankylosing Spondylitis Functional Index (BASFI)
and Dougados Functional Index (DFI). Z Rheumatol 1999;
58(4):218–25.
24. Ozer HT, Sarpel T, Gulek B, Alparslan ZN, Erken E. Turkish version
of the Bath Ankylosing Spondylitis Functional Index: reliability and
validity. Clin Rheumatol 2005; 24(2):123–8.
25. Van Tubergen A, Debats I, Ryser L, Londoño J, Burgos-Vargas R,
Cardiel MH et al. Use of a numerical rating scale as an answer
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741
REVIEW ARTICLE
Ankylosing spondylitis and uveitis: overview
Enéias Bezerra Gouveia1, Dório Elmann2, Maira Saad de Ávila Morales3
ABSTRACT
The present article reviews the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of ankylosing spondylitis and its association with ocular changes. The authors used the PubMed (MEDLINE), LILACS, and Ophthalmology
Library databases. Ankylosing spondylitis is a chronic inflammatory disease that usually affects the axial skeleton and
can progress to stiffness and progressive functional limitation. Ankylosing spondylitis usually begins around the second
to third decade of life, preferentially in HLA-B27-positive white males. Its etiology and pathogenesis are not completely
understood, and its diagnosis is difficult. Clinical control and treatment are frequently satisfactory. Acute anterior uveíte
is the most common extra-articular manifestation, occurring in 20%–30% of the patients with ankylosing spondylitis.
Approximately half of the acute anterior uveíte cases are associated with the presence of the HLA-B27 antigen. It can be
the first manifestation of an undiagnosed rheumatic disease, usually having a good prognosis and appropriate response to
treatment. In conclusion, for better assessment and treatment of patients with uveitis, ophthalmologists and rheumatologists should work together.
Keywords: ankylosing spondylitis; anterior uveitis; HLA-B27; tumor necrosis factor alpha.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Ankylosing spondylitis (AS) is the prototype of a group of
inflammatory diseases formerly known as spondyloarthropathies, and currently called spondyloarthritides, which share
epidemiological, clinical, anatomopathological, radiological,
and immunogenetic features. Spondyloarthritides comprise
AS, reactive arthritis (formerly known as Reiter’s syndrome),
psoriatic arthritis, inflammatory bowel disease-related spondyloarthritis, and undifferentiated spondyloarthritis.1
AS is a chronic, progressive inflammatory disease that
affects primarily the sacroiliac joints and the axial skeleton
(spine) and, less frequently, peripheral joints and other extraarticular organs such as the eyes, skin, and cardiovascular
system. The major functional losses occur during the first 10
years of disease. It usually begins in the second or third decade
of life, preferentially in HLA-B27-positive Caucasian males.1
Its etiology and pathogenesis are not completely understood, but the most prevalent hypothesis involves immune
mediation as its major mechanism, including several cytokines,
such as tumor necrosis factor (TNF), interaction between T cell
response, genetic factors, environmental factors, and bacterial antigens. There is a strong association between AS and
HLA-B27, with approximately 92% of the Caucasian patients
with AS being HLA-B27-positive. That prevalence is lower in
other ethnical groups.2,3
The use of non-steroidal anti-inflammatory drugs (NSAIDs)
and practice of physical exercise constitute the treatment of
choice, although they are considered palliative measures that
neither change the course of disease nor prevent structural damage. When symptoms are refractory to NSAIDs, corticosteroids
can be used in specific cases, as well as several antirheumatic
drugs such as sulfasalazine, methotrexate, and, more recently,
anti-TNF, which seem to change the course of disease.
Regarding extra-articular manifestations, the most frequent
is anterior uveitis, observed in up to 40% of the patients on
long-term follow-up, usually associated with HLA-B27
positivity and rarely resulting in sequelae.2–5 Anterior uveitis
Received on 08/29/2011. Approved on 06/27/2012. The authors declare no conflict of interest.
Sociedade Médica de Mossoró – SOMMOS.
1. Ophthalmologist, Specialist in Uveitis, Faculdade de Medicina, Universidade de São Paulo – FMUSP
2. Rheumatologist, Hospital do Servidor Público Estadual de São Paulo; Specialist in General Rheumatology, Medical School of Paris – Lariboisiere – Saint
Louis Université Paris VII
3. Master’s degree in Ophthalmology, Universidade de São Paulo – USP; Collaborating Physician, Escola Paulista de Medicina, Universidade Federal de São
Paulo – EPM/Unifesp
Correspondence to: Enéias Bezerra Gouveia. Av. Rio Branco, 1456 – Centro. Mossoró, RN, Brazil. CEP: 59621-400. Email: [email protected]
742
Rev Bras Reumatol 2012;52(5):742-756
Ankylosing spondylitis and uveitis: overview
includes terms such as iritis (inflammation of the eye’s iris,
with inflammatory cells in the anterior chamber and no involvement of the anterior vitreous), iridocyclitis (primary inflammation
of the iris and secondary inflammation of the ciliary body;
inflammatory cells present in both the anterior chamber and
anterior vitreous), and cyclitis (inflammation of mainly the
ciliary body).
Uveitis related to HLA-B27 are characterized by acute,
unilateral recurring (affects each eye at a time) iridocyclitis
of sudden onset, with a moderate to severe amount of fibrin
and cells in the anterior chamber. It usually responds to topical corticosteroid treatment and mydriatic drugs prescribed to
prevent posterior synechia.
This study reviews the epidemiology, pathogenesis,
clinical findings, diagnosis, and treatment of the important
association between AS and ocular involvement, showing
the need for close collaboration of rheumatologists and
ophthalmologists in managing the disease. The authors used
the PubMed (MEDLINE), LILACS, and Ophthalmology
Library databases.
EPIDEMIOLOGY
AS usually begins in the second or third decade of life, affecting mainly men, at the 3:1 ratio.5,6 The disease pattern varies
according to gender, being more severe in men7 and having a
late onset in women,7 who have a more significant extraspinal
involvement.8,9
The prevalence of AS is 0.1%–1.4%, varying according
to both geography and ethnical groups; however, there is a
strong correlation between the prevalence of HLA-B27 and
that of spondyloarthritides in a certain population.10 Positivity
for HLA-B27 in patients with AS can vary from 80% to 98%,
being greater in non-mixed Caucasian populations of North
Europe.11 Because HLA-B27 is extremely rare in African
black populations, AS is rare in those populations; in Brazil,
a country with intense ethnical miscegenation, AS and other
spondyloarthritides are usually found in mulattos (due to the
influence of the Caucasian genetic ancestry), being extremely
rare in non-mixed blacks.12
Patients with severe and prolonged AS develop extraarticular manifestations, such as defects in cardiac conduction, aortic regurgitation, pulmonary fibrosis, neurological
sequelae, and amyloidosis.1,3 Acute anterior uveitis (AAU)
occurs in approximately 20%–30% of the patients with AS,
being considered the most common extra-articular manifestation.2,5 It relates to neither joint disease exacerbation nor
severity.13
Rev Bras Reumatol 2012;52(5):742-756
PATHOGENESIS
The exact cause of AS remains unknown, but the combination
of genetic and environmental factors seems to be important
in its pathogenesis.
Genetic predisposition and immune mechanism
Studies have shown the involvement of immunity in the inflammatory process of AS, with increased serum levels of IgA and
relationship with HLA-B27. There is a strong association of
AS with the major histocompatibility complex (MHC) class I
HLA-B27 molecule and the response of T cells as the key to
pathogenesis. Although no specific and single agent has been
identified as the cause of the disease, the interrelation between
AS and inflammatory bowel disease suggests that bacterial
enteritis (Klebsiella, Chlamydia, Campylobacter, Shigella, and
K. pneumoniae) might trigger an immune response to the prolonged exposure to intestinal bacteria. That cytolytic response
would lead to tissue damage and inflammation spreading.14–16
Based on histopathological data, there is evidence that
entheseal fibrocartilage (attachment of a tendon to bone) is
the first and major target in immune response. Theoretically,
immunocompetent cells could have access to fibrocartilaginous
antigens derived from bone marrow blood vessels.17 Genes
other than HLA are believed to be involved, such as HLA-B60,
HLA-B61, HLA-DR8, HLA-DRB1, and MICA.11 In addition
to the presence of HLA-B27 in the short arm of chromosome
6, susceptible regions were identified in chromosomes 1p, 2q,
6p, 9q, 10q, 16q, and 19q.16,18–20
Positivity to the HLA-B27 antigen also seems to imply
higher levels of TNF in the aqueous humor of patients with
active uveitis.19 A recent study has shown a female protective
factor attributed to estrogens, which induces the constitutive
synthesis of nitric oxide, the reduction in the expression of
adhesion molecules (E-selectin) and the modulation of genes
that promote the appearance of pro-inflammatory cytokines,
such as interleukins IL-1, IL-6 and TNF-α.21
Environmental factors
The fact that only a small proportion of HLA-B27-positive
patients develop the disease can be explained by the existence
of different types of alleles, showing the importance of environmental factors.19
Studies have reported that HLA-B27-positive transgenic
rats develop a disease similar to spondyloarthritis, with manifestations such as sacroiliitis, enthesitis, arthritis, ocular inflammation, and bowel inflammation. The rats non-exposed
743
Gouveia et al.
to environmental germs do not develop the disease. Once
introduced into regular environments and exposed to bacteria,
they develop spondyloarthritis findings.
HLA-B27 AND AAU ASSOCIATION
The MHC is responsible for encoding molecules that present
antigens to the immune system. In human beings, the major
histocompatibility complex is called human leukocyte antigen
system (HLA). Because of easy access, leukocytes are the cells
most often used to study the HLA, being present in the surface
of most nucleated cells. It has been determined that some human diseases are associated with the presence or absence of
certain HLA antigens. Five series of HLA have been identified.
The following loci have been identified in chromosome 6: A,
B, C, D, or DR (D-related).18
Although the mechanism by which HLA-B27 predisposes
to the appearance of diseases has not been completely elucidated, infections are believed to be among the triggering factors
of uveitis in HLA-B27-positive patients.13
The HLA-B27 antigen is considered a genetic marker associated with spondyloarthritis. Its incidence varies according
to the methodology used (microcytotoxicity, flow cytometry,
and C-reactive protein), the population studied,11,22 the type
of disease (95% in Caucasians with AS)23, and, occasionally,
microbial agents.23
The association between HLA-B27 and AAU was first reported by Brewerton et al. em 1973,24 being currently well established
as a distinct nosological entity, with peculiar characteristics, such
as earlier onset, unilateral involvement, and greater frequency of
relapse, diversity, severity, complications, and possibility of low
visual acuity19 as compared with those of HLA-B27-negative
patients. Approximately 30%–50% of the cases of AAU are associated with the presence of the HLA-B27antigen,25,26 and, in
approximately 90% of those cases, AS can be diagnosed.
Carvalho et al.,27 studying 100 patients with non-granulomatous uveitis, have reported that 38 patients had a disease of
the spondyloarthritis group as the underlying disease, and that
HLA-B27-positive individuals had a 3.8-fold greater chance of
developing uveitis than the HLA-B27-negative ones. In Brazil,
Moraes, in 1996, found a 66.6% correlation between anterior
uveitis and HLA-B27 as compared to 3.5% in the control group.28
DIAGNOSIS AND CLINICAL FINDINGS
The diagnosis is established by the combination of clinical
findings and the radiological evidence of sacroiliitis defined
by the modified 1984 New York criteria.29
744
Making an early diagnosis of AS was difficult, because
disease onset is insidious and sacroiliitis is not evident on plain
X-ray until the disease is at an advanced stage. Thus, the time
interval between symptom onset and AS diagnosis could be
as long as 5–10 years. Currently, the diagnosis is established
earlier because some risk factors, such as absence of rheumatoid factor, HLA-B27 seropositivity, family history, male
gender, disease onset prior to the age of 40 years, and frequent
gastroenteritis30 are considered. In addition to those probable
factors, magnetic resonance (MR) is used to ensure the axial
and peripheral nature of the disease; however, because of its
cost, MR has not become routine.
The modified 1984 New York criteria are as follows: 1)
clinical criteria: pain, of insidious onset, in lumbar spine and
morning stiffness for more than three months, improved by
exercise but not relieved by rest; limitation of lumbar spine
motion in both the sagittal and frontal planes; limitation of
chest expansion relative to normal values for age and gender;
and 2) radiological criterion: bilateral grade 2–4 or unilateral
grade 3–4 sacroiliitis on X-ray.29
Definite AS is diagnosed if the radiological criterion is
present plus at least one clinical criterion. In the absence of
radiological findings, individual probability can be calculated
depending on typical AS manifestations. Thus, probable AS
is considered if three clinical criteria are present alone, or if
the radiological criterion is present with no clinical signs or
symptoms.29
According to the Brazilian Consensus of Spondyloarthropathies,30 the modified New York criteria and the European
Spondyloarthropathy Study Group (ESSG) criteria (Table 1)
Table 1
Criteria
New York criteria (1984)
ESSG criteria (1991)
- Low back pain
- Limitation of lumbar spine motion
in both the sagittal and frontal
planes
- Limitation of chest expansion
- Bilateral grade 2–4 sacroiliitis
- Unilateral grade 3–4 sacroiliitis
- Inflammatory spinal pain OR synovitis
(asymmetric, lower extremities) AND at
least one of the criteria below:
- Positive family history (AS, psoriasis,
anterior uveitis, inflammatory bowel
disease)
- Cutaneous psoriasis
- Urethritis or acute diarrhea within
four weeks before onset of arthritis
- Pain alternating between the two
buttocks
- Enthesopathy (insertion of the
Achilles tendon or plantar fascia)
- Sacroiliitis (bilateral grade 2–4 or
unilateral grade 3–4)
ESSG: European Spondyloarthropathy Study Group; AS: ankylosing spondylitis.
New York criteria: AS is defined when the fourth or fifth criterion is present plus some clinical criteria.30
ESSG criteria: AS is diagnosed in the presence of at least one major and one minor criterion.31
Rev Bras Reumatol 2012;52(5):742-756
Ankylosing spondylitis and uveitis: overview
continue to be widely used. It is worth noting that, similarly to
most classifications, such criteria are useful for population studies and to assess individual patients, but the diagnosis of spondyloarthritis should not be ruled out if the criteria are not met.31
New criteria were discussed on the 73rd Annual Scientific
Meeting of the American College of Rheumatology in 2009
and are the first to include MR to aid with the diagnosis of
axial spondyloarthritides – providing a better analysis of the
inflammatory process before it becomes a lesion anatomically
visualized on conventional X-ray – and also with the patients’
follow-up. However, rheumatologists should improve their
knowledge about the different lesions observed on MR of the
axial skeleton and sacroiliac joint and should know how to
differentiate them from non-inflammatory causes.31
The laboratory findings are unspecific, consisting in
changes common to chronic diseases, being as follows: normochromic and normocytic anemia; mild leukocytosis; increased
erythrocyte sedimentation rate (ESR); increased C-reactive
protein; and elevations in alkaline phosphatase and IgA.30
The HLA-B27 test is useful only as an adjuvant to diagnosis.
Its presence is neither necessary nor sufficient to establish the diagnosis, but it is useful to support the calculation of the probability
of developing AS. Thus, the HLA-B27 test should be considered,
especially in patients with inflammatory spinal pain, because such
patients have greater probability of a definite diagnosis of AS.32
The AS manifestations are as follows:
1) Systemic
The classic presentation begins with insidious inflammatory spinal pain and morning stiffness, relieved by exercise,
and worsened with rest or inactivity. Other manifestations of
seronegative spondyloarthritides include asthenia, fatigue, mild
weight loss, and elevated body temperature.1–3,30
The spinal disease begins at the sacroiliac joint (bilateral
lumbosacral region), and most patients have mild or intermediate
chronic disease with remission periods. The spinal pain rarely
persists active, and the disease progresses upwards along the
spine. Patients with AS can have peripheral arthritis and peripheral
enthesitis (inflammation of the attachment of a tendon to bone),
which occur in 33% of the patients, are painful, commonly involving the insertion of the calcanean tendon and the plantar fascia
in the calcaneus. All those symptoms can occur alone. Later, the
following can be found: a reduction and even straightening of
lumbar lordosis; atrophy of the buttocks; accentuation of thoracic
kyphosis; destructive arthropathy of the hip or shoulders, resulting
in flexion limitations and deformities; and straightening of the
cervical spine, projecting the head forwards.1–3,30
Extra-articular involvements usually occur in subsequent
progressive stages, and joint disease control has no relation to
Rev Bras Reumatol 2012;52(5):742-756
the appearance or severity of visceral changes. The longer the
disease course, the greater the chances of visceral involvement.13
The major cardiorespiratory manifestations are cardiac
conduction disorders, aortic regurgitation, pericarditis, and
apical pulmonary fibrosis. Renal involvement, represented
by IgA nephropathy and amyloidosis, can occur. Regarding
gastrointestinal involvement, asymptomatic inflammation of
the proximal colon and terminal ileum can be seen. Regarding
neurological involvement, the following can occur: peripheral
neuropathy; cauda equina syndrome in patients with long-term
severe disease; cervical myelopathy due to atlantoaxial joint
subluxation; and mucocutaneous lesions.1–3,30
Radiology is important to establish the diagnosis, and the
radiological changes reflect disease progression. The most frequent radiological changes occur in the axial skeleton; however,
those occurring in the sacroiliac joints are characteristic of the
diagnosis. In the progressive form, we can find blurring of the
joint edges, joint pseudoenlargement, subchondral bone sclerosis,
erosions of the joint edges, formation of bone bars, narrowing of
joint spaces, and joint fusion. In the spine, especially in lumbar
spine, the following can be found: erosions of the vertebral bodies’ angles; osteitis; square appearance of the vertebral bodies;
syndesmophyte formation; calcifications of the intervertebral
discs; and narrowing of joint spaces, culminating in fusion of the
interapophyseal joints, producing the “bamboo spine” (Figure 1).
Figure 1
Final stage of a patient with AS showing syndesmophytes in
lumbar spine, resulting in bamboo spine.
Source: http://quemdividemultiplica.blogspot.com/2010/02/espondiliteanquilosante.html.
745
Gouveia et al.
On X-ray, the Ferguson view and oblique view provide
better visualization of the sacroiliac joints. Computed tomography and MR can detect lesions of early AS with greater
consistency than radiography, because they detect early sacroiliitis, erosions and enthesitis, and are useful to monitor the
progression of the sclerosis of the sacroiliac joint.1–3,31 Thus,
MR has been introduced as a tool for the early detection of
osteoarticular inflammation (“pre-radiographic” phase) and
for patients’ follow-up, as a way to prevent the radiological
progression of the disease, especially of bone neoformation,
thus determining the best treatment for suppressing inflammation at an early phase, before cartilage damage and bone
erosions occur.31
2) Ocular
Most patients with acute uveitis seek emergency services,
where uveitis is classified according to the International Uveitis
Study Group classification (location, clinical course, laterality), and the possibility of primary ophthalmologic disease is
ruled out. Then, the standard protocol for the first episode of
uveitis is applied, consisting of blood count, biochemistry,
ESR, urinalysis, serology for syphilis, and chest X-rays (the
last two are performed because of the lack of a characteristic
pattern of syphilis and sarcoidosis).33
In the presence of recurring non-granulomatous uveitis,
which is the most frequent type in patients with AS, MR of
the sacroiliac region should be requested, and, if possible,
HLA-B27. All patients with recurring AAU of non-ophthalmologic etiology should be referred to the rheumatologist for
complementary investigation with diagnostic purpose.
AUU is both the most common extra-articular manifestation and the most frequent ocular involvement. Its accumulated
prevalence in the population is approximately 0.1%, representing 30%–70% of all types of uveitis.19,23,24 In approximately
25% of the anterior uveitis cases, no associated systemic disease can be evidenced, and 50% of them have the HLA-B27
histocompatibility allele.34
AUU is an acute inflammation of the anterior segment of the
eye, defined as recurring non-granulomatous iritis or iridocyclitis of sudden onset, with duration shorter than three months,
which can become chronic with innumerous sequelae.35 The
patient complains of ocular hyperemia, pain, photophobia,
lacrimation and visual blurring. Keratic precipitates on the
cornea, never of the mutton-fat type, flare, and a large amount
of cells in the anterior chamber can be seen. If treatment is not
initiated, the iris can develop edema with posterior synechiae
(Figure 2). Another characteristic of the AAU associated with
AS is the lack of the simultaneous involvement of both eyes,
which can be alternate.34
746
Figure 2
Anterior uveitis.
In cases of severe anterior uveitis, even when inflammation
has already been treated, an irreversible and chronic break
in the blood aqueous barrier can occur, with an elevation in
protein levels;36 it should not be considered a parameter of
relapse or therapeutic failure.
When the uveitis has a chronic course, the following complications can occur, mainly in HLA-B27-positive patients:
seclusion and pupillary occlusion; low visual acuity; cataract;
secondary glaucoma; cystoid macular edema (CME); macular
hole; and folds of the internal limiting membrane of the retina in
the macular area.37 Anterior uveitis of prolonged and uncontrollable course is a risk factor for the extension of inflammation to
the posterior segment of the eye, and the following have been
reported: vitreitis; papillitis; retinal vasculitis; CME; epiretinal
membrane; and pars plana exudate.38
Mechanical ptosis, superficial keratitis, episcleritis, scleritis,
and corneal ulcer are other possible ocular manifestations.37,38
TREATMENT AND PROGNOSIS
The treatment of AS is aimed at relieving pain and inflammation and at maintaining the best possible posture and joint
function, to prevent or minimize sequelae, with consequent
improvement in the patients’ quality of life. It involves
educational, pharmacological, physical or rehabilitation,
radiotherapy and surgical measures, and, thus, should be
multidisciplinary and multiprofessional.
The treatment of choice currently used for symptomatic
patients consists in using NSAIDs along with physical therapy,
although those are palliative measures and do not change disease course. Most patients use NSAIDs most of their treatment
time, and more than one third requires another generation of
Rev Bras Reumatol 2012;52(5):742-756
Ankylosing spondylitis and uveitis: overview
NSAIDs.1–3 In case of refractoriness or intolerance to NSAID
treatment, oral corticosteroid, sulfasalazine, methotrexate or
biologics should be instituted.
Corticosteroids are occasionally useful to control symptoms
for a short period, since they do not change the disease course
and increase the tendency towards osteoporosis.
The use of slow-acting drugs, inducers of remission, for
treating axial disease in AS has been discouraging, although
some results have been obtained with the peripheral disease.
Sulfasalazine is often used to treat AS, especially in the presence of peripheral joint involvement, and to prevent recurrent
episodes of uveitis.39 Methotrexate has been used in severe
cases of active AS non-responsive to NSAIDs and sulfasalazine, and has shown better results in patients with peripheral
involvement.40
The disease-modifying antirheumatic drugs that block
TNF-alpha, when coupling to TNF, prevent it from binding
to lymphocyte Fc receptors and their consequent changes in
cellular immunity. They are infliximab, etanercept and adalimumab. Studies have shown that those agents have short-,
mid- and long-term sustained efficacy and should be used as
monotherapy. They start acting rapidly and have proved to
reduce spinal inflammatory activity.41–43
The choice of treatment depends on the severity of inflammatory findings and the response to medications. Uveitis
usually responds well to topical corticosteroids, which control
inflammation – and should be associated with a mydriatic drug
to prevent posterior synechiae − and decrease ciliary muscle
spasm, thus reducing pain. Lack of response to topical corticosteroids and progression to chronic inflammation have been
reported in only 13%–19% of the HLA-B27-positive uveitis
cases, when periocular corticosteroid injection is preferred to
systemic corticosteroids.44
Sulfasalazine, a conjugate of sulfapyridine and 5-aminosalicylate, has a local anti-inflammatory action, inhibiting the
synthesis of prostaglandins. It is a good indication in cases of
recurring AAU in AS, because most crises occur during the
period of disease activity, and sulfasalazine is a good drug to
treat AS, mainly in patients with the peripheral component.39
Methotrexate is an antimetabolic agent, whose major mechanism of action is the competitive inhibition of the enzyme
dihydrofolate reductase, which plays a central role in folic acid
reduction, thus interfering in cell reproduction. Methotrexate
is a base drug commonly used in AS, but it neither associates
with a reduction in the number of uveitis crises nor modifies
disease course.40
Although HLA-B27-positive anterior uveitis is the most
common form of intraocular inflammation, satisfactory
Rev Bras Reumatol 2012;52(5):742-756
therapeutic strategies to prevent its recurrence could not be
established.
The great perspectives on the treatment of AS are biologic
drugs, which are claimed to provide for the first time more than
only pain relief. The TNF inhibitors, such as infliximab, etanercept and adalimumab, act specifically in the disease inflammatory process, and should influence its progression. There
are promising results in cases of refractory uveitis, mainly in
cases of inflammation in the posterior segment, contributing
to visual recovery.41,43
A recent study has shown an incidence of anterior uveitis
in AS of 6.8 per 100 patient-years in the group treated with
TNF inhibitors as compared with 15.6 per 100 patient-years in
the control group treated with placebo. Thus patients with AS
treated with anti-TNF agents show a significant decrease in the
number of anterior uveitis flares;42 however, their indication
should be limited due to the reports of severe side effects, such
as exacerbation of demyelinating diseases, bilateral anterior
neuropathy, tuberculosis, histoplasmosis and sudden death in
patients with congestive heart failure.
Complications of AS are consequent to joint and spine
disease or extra-articular manifestations. A minority of
patients develop vertebral fusion, which results in severe
kyphosis and limited spine mobility, including the cervical
region. Fusion increases susceptibility to fracture, even
resulting from small traumas. Occasionally, the hip and
shoulder joints develop arthropathy, requiring total joint
replacement.1–3,30
According to most studies, the prognosis of AAU in patients
with AS is usually excellent with only topical treatment, and
only patients with involvement of the posterior pole or high
tendency towards recurrence or chronicity would benefit from
immunosuppressive drugs.30,31 It is worth noting that CME is
not a signal of involvement of the posterior pole, and, thus,
does not imply the necessary use of immunosuppressive drugs.
Systemic AS also has a good prognosis, as long as the
disease management comprises a global approach. A long
treatment with anti-inflammatory drugs is usually required.
Some indicators of poor prognosis of the disease are as follows:
involvement of peripheral joints; disease onset during youth;
and poor response to NSAIDs.1–3,30
CONCLUSION
Because uveitis can be the initial manifestation of spondyloarthritides, and especially a key symptom for the diagnosis of
AS, the joint work of ophthalmologists and rheumatologists
is fundamental to the earlier diagnosis and effective treatment
747
Gouveia et al.
of those patients, and to the management of cases requiring
immunosuppressive drugs.
It is worth emphasizing the need for the accurate rheumatological investigation of HLA-B27-soropositive young
748
males with idiopathic and recurring AAU, and it should be
periodically repeated, because the installation of systemic clinical findings of AS is frequent on a second occasion, sometimes
even a few years after.44
Rev Bras Reumatol 2012;52(5):742-756
Espondilite anquilosante e uveíte: revisão
principalmente nos casos de inflamação no segmento posterior,
contribuindo para recuperação visual.41,43
Em um estudo recente foi demonstrada incidência de uveíte
anterior em pacientes com EA de 6,8 por 100 pacientes ao ano
no grupo tratado com inibidores da TNF, comparado com 15,6
por 100 pacientes ao ano em um grupo-controle tratado com
placebo. Conclui-se que os pacientes portadores de EA tratados
com anti-TNF apresentaram redução significativa no número
de uveítes anteriores com flare;42 no entanto, os registros de
efeitos colaterais sérios podem limitar sua indicação, já que
incluem exacerbação de doenças desmielinizantes, neuropatia
anterior bilateral, tuberculose, histoplasmose e morte súbita em
pacientes com insuficiência cardíaca congestiva.
As complicações da EA ocorrem como consequência de doença articular e da coluna vertebral ou manifestações extra-articulares. Uma minoria dos pacientes desenvolve fusão vertebral,
que resulta em grave cifose e limitação da mobilidade espinal,
incluindo a região cervical. A fusão aumenta a suscetibilidade
à fratura, mesmo aos pequenos traumas. Ocasionalmente, as
articulações dos quadris e dos ombros desenvolvem artropatia,
necessitando de total substituição articular.1–3,30
De acordo com a maioria dos estudos, o prognóstico da
UAA em paciente com EA é geralmente excelente apenas com
o tratamento tópico, e somente os pacientes com acometimento
do polo posterior ou com alta tendência de recorrência ou
cronicidade seriam beneficiados com imunossupressor.30,31
Devemos frisar que o EMC não é um sinal de envolvimento
do polo posterior e, portanto, não necessariamente implica na
necessidade de uso de imunossupressor.
A EA sistêmica também apresenta bom prognóstico, desde
que haja uma abordagem global de atendimento. Frequentemente
é necessário um longo período de tratamento com anti-inflamatórios. Temos alguns indicadores de prognóstico pobre da doença,
que consistem em envolvimento das articulações periféricas,
início na juventude e resposta pobre aos AINH.1–3,30
CONCLUSÃO
Como a uveíte pode ser a manifestação inicial de uma espondiloartrite e, em particular, um sintoma-chave no diagnóstico
da EA, é fundamental a contribuição mútua entre os oftalmologistas e reumatologistas para diagnóstico e tratamento mais
precoces e efetivos desses pacientes, bem como para o manejo
dos casos de prescrição dos imunossupressores.
Reforçamos a necessidade de uma investigação reumatológica apurada em pacientes do gênero masculino, jovens, com
UAA idiopática e recorrente e HLA-B27-soropositivos, que
deve ser periodicamente repetida, uma vez que é frequente a
Rev Bras Reumatol 2012;52(5):742-756
instalação do quadro clínico sistêmico de EA em um segundo
momento – às vezes até mesmo após alguns anos.44
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diagnóstico e prognóstico. Rev Bras Oftalmol 1996; 55(5):53–62.
29. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic
criteria for ankylosing spondylitis. A proposal for modification of the
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30. Barros PD, Azevedo VF, Bonfiglioli R, Campos WR, Carneiro SC,
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www.congessesupdate.com.br/acr2009/artigo05.htm. [Accessed in
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32. Khan MA, Khan MK. Diagnostic value of HLA-B27 testing
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36. Ladas JG. Laser flare-cell photometry: methodology and clinical
applications. Surv Ophthalmo 2005; 50(1):27–47.
37. Chang JH. Acute anterior uveitis and HLA-B27. Surv Ophthalmol
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38. Rodriguez A, Akova YA, Pedroza-Seres M, Foster CS. Posterior
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Rev Bras Reumatol 2012;52(5):742-756
REVIEW ARTICLE
Imaging diagnosis of early rheumatoid arthritis
Licia Maria Henrique da Mota1, Ieda Maria Magalhães Laurindo2, Leopoldo Luiz dos Santos Neto3,
Francisco Aires Corrêa Lima4, Sérgio Lopes Viana5, Paulo Sérgio Mendlovitz6, João Luiz Fernandes7
ABSTRACT
Early diagnosis of rheumatoid arthritis is essential for its proper management. Currently, the initial phase of rheumatoid
arthritis is known to provide a window of therapeutic opportunity. Although the diagnosis is primarily clinical, the development and improvement of laboratory and imaging methods have contributed to earlier diagnosis and determination of
procedures in early rheumatoid arthritis. In this article, the authors review the role of the major imaging methods used for
assessing early rheumatoid arthritis, especially conventional radiography, ultrasonography, and magnetic resonance imaging.
Keywords: early rheumatoid arthritis, conventional radiography, ultrasonography, magnetic resonance imaging.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Rheumatoid arthritis (RA) is a progressive systemic chronic
inflammatory disease that affects primarily the synovial membrane and can lead to bone and cartilaginous destruction.1 It
is a frequent condition (1%–2% of the world population) that
affects all ethnical groups.2
In the past years, the generalization of the concept of “initial” or “early” RA and the existence of a window of therapeutic
opportunity – time during which the institution of adequate
therapy for the disease would result in marked clinical improvement – have strengthened the notion that early diagnosis and
treatment can modify the course of disease.3
Concomitantly, laboratory and imaging tests have been
developed or refined, contributing to the earlier diagnosis
and prognostication of initial RA; in addition, changes in the
therapeutic approach of RA have been instituted, with the use
of new classes of drugs.4
The diagnosis of RA is established considering the association
of clinical findings, and neither a laboratory test, nor a histological
finding, nor an imaging test alone can confirm it. When RA is fully
expressed with all its classic features, its recognition is simple.
Its diagnosis in its early stage, however, is particularly difficult,
because serological and radiological characteristics often lack.5
Although the identification of initial RA is primarily clinical, several complementary tests can be used to establish the
diagnosis, make the differential diagnosis, determine prognosis, and follow disease up. This study is a brief review about the
major imaging tests used for diagnosing and managing initial
RA, especially conventional radiography, ultrasonography
(US), and magnetic resonance imaging (MRI).
IMAGING TESTS
Several imaging tests are used to assess RA, such as conventional radiology, US, bone scan, computed tomography (CT),
MRI, and bone densitometry.6
Bone scan, despite having high sensitivity to detect conditions leading to increased metabolic activity, such as joint
inflammation, has low specificity and spatial resolution.
Although CT has high spatial resolution, its limited contrast
resolution restricts its use for soft tissue assessment and does
Received on 09/06/2011. Approved on 06/27/2012. The authors declare no conflict of interest.
Service of Rheumatology, Hospital Universitário de Brasília, Universidade de Brasília – HUB-UnB; Service of Rheumatology, Hospital das Clínicas, Faculdade
de Medicina, Universidade de São Paulo – HC-FMUSP.
1. PhD in Medical Sciences, Faculdade de Medicina, Universidade de Brasília – FM-UnB; Rheumatologist, Service of Rheumatology, Hospital Universitário
de Brasília – HUB-UnB
2. Collaborating Professor, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – HC-FMUSP
3. Associate Professor of Internal Medicine and of the Service of Rheumatology, HUB-UnB
4. Rheumatologist of the Service of Rheumatology, HUB-UnB
5. Radiologist, Hospital da Criança de Brasília José Alencar e Clínica Vila Rica, Brasília/DF
6. Radiologist, HUB-UnB
7. Radiologist, Image Memorial, Salvador/BA
Correspondence to: Licia Maria Henrique da Mota. Centro Médico de Brasília. SHLS 716/916, bloco E, salas 501/502 – Asa Sul. Brasília, DF, Brazil.
CEP: 70390-904. Email: [email protected]
Rev Bras Reumatol 2012;52(5):757-766
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Mota et al.
not allow the detection of medullary bone edema, reducing
its use in early RA. Bone densitometry is the best method to
detect bone mass loss, which is unspecific, but provides little
additional information other than that; in addition, bone densitometry still lacks standardization for the specific finality of
assessing disease activity.7
More recently, molecular imaging methods, such as
positron emission tomography (PET/CT) and single photon emission computed tomography (SPECT), have been
used to diagnose, characterize, and monitor the activity
of inflammatory diseases, such as RA. 7–9 For example,
(19)F-fluorodeoxyglucose PET/CT accurately detects inflammatory activity in large joints of patients with RA, and may
be helpful for the early assessment of RA extent.7 Although
the real role of those new techniques in the investigation of
RA has not been established, they hold great promise, and,
in the future, may play a more critical role in the diagnosis
and assessment of disease activity.8
Currently, the three imaging methods most used to assess RA,
because of the longer time of use and the experience accumulated,
are as follows: conventional radiography; US; and MRI.
Radiography
Figure 1
Early rheumatoid arthritis (disease duration shorter than six
months): radiograph, anteroposterior view, of the proximal
portion of the right hand and wrist, revealing periarticular.
Thickening of the soft tissues of the wrist is evident. Erosive
joint disease still not identified.
Conventional radiography (both in its analogical and digital forms)
is still the imaging modality of choice in assessing RA, being
indispensable for all patients already at their first medical consultation, because radiographic changes are part of the diagnostic
criteria for RA.10 In addition, the test is relatively inexpensive and
almost universally available. However, the method is not sensitive
to demonstrate the earliest changes of disease, mainly bone erosions; edema of the soft tissues and juxta-articular osteoporosis
are some of the first radiographic findings (Figure 1). On radiography, the first sites affected are usually metacarpophalangeal
joints (especially the second and third ones), metatarsophalangeal joints (especially the fifth), proximal interphalangeal joints,
and ulnar and radial styloid processes.11
The most characteristic lesions appear later on radiography, and include narrowing of the joint space (due to cartilage
destruction) and bone erosions (Figure 2). Patients with RA
assessed with conventional radiography at an early stage of
disease showed erosions as follows: on the first assessment,
only 13%; after 12 months, 28%; after 24 months, 75%; and
after 60 months of follow-up, 90%.12,13
In late stages, sequelae such as deformities, subluxations,
and ankylosis can be observed. None of those changes is
pathognomonic, but their presence, especially if symmetrical,
in association with clinical findings strongly suggests disease.
All patients should undergo a baseline initial radiography that
Figure 2
The patient is a 28-year-old female with symptoms compatible
with rheumatoid arthritis for eight months. Plain radiograph,
anteroposterior view, of the left hand and wrist showing characteristics of erosive rheumatoid arthritis in its early stage:
small erosions in the carpometacarpal joints; minute erosions
in the joint between the scaphoid and trapezium (left image);
small erosion in the distal pole of the scaphoid (right image).
The joint spaces are preserved, and neither deformities nor
changes in bone alignment are observed.
758
Rev Bras Reumatol 2012;52(5):757-766
Imaging diagnosis of early rheumatoid arthritis
allows radiographic follow-up, aiming at assessing disease
progression and response to treatment.11
Ultrasonography
US is an inexpensive exam that allows good assessment of
soft tissues. The technique detects synovial thickening; presence of fluid in joints, bursae, and tendon sheaths; structural
abnormalities of tendons, ligaments, and entheses; and superficial erosions.14,15 However, it is examiner dependent, has low
reproducibility, and has not been completely standardized to
assess initial RA.16 It does not allow assessing changes deeply
located in the joints. In addition, the ultrasound beam does not
penetrate bone, and, thus, bone assessment is restricted to the
cortical surface and available acoustic windows. Techniques
such Doppler can be useful in assessing disease activity, differentiating between active (pannus) and inactive inflammatory
tissue. US may be useful to quantify disease progression and may
monitor response to treatment in RA.17 However, the quantification of inflammatory activity on US is yet to be standardized.15
patients; the position and the time required for the test might
not be tolerated by elderly and/or debilitated patients, and some
contraindications such as cardiac pacemaker holders or patients
with ferromagnetic aneurysm clips still persist.21
Attempts to reduce the costs of MR include the use of new
techniques. The isolated assessment of the fist of the dominant
hand seems adequate to evaluate patients with initial RA,
showing good sensitivity and specificity for the early detection of the typical changes of the disease.22 A new technique
proposed (modified “praying hands”) has proved to be, as
compared with the traditional technique, equally sensitive
to detect changes compatible with the early stage of disease,
with a great advantage regarding the duration of the test. This
would allow cost reduction and an increase in the number of
exams performed in a certain time period.23
Figures 3 and 4 exemplify different imaging exams and
their findings in patients with symptoms compatible with RA
Magnetic resonance
Of the imaging techniques currently available, MRI is undoubtedly the most sensitive for detecting the changes of RA. It allows
assessing all structures affected, such as soft tissues, bones and
cartilages, and detecting early erosions (up to three years before
conventional radiography). The pattern and site of the changes
might have a prognostic implication.16 The use of paramagnetic
contrast agents (gadolinium compounds) is formally indicated in
patients with RA, potentiating the detection of synovial thickening and anomalously enhanced areas, indicative of inflammatory
activity in both soft tissues and bone; enhanced areas in medullary bone are seen even prior to the appearance of erosions and
indicate increased risk for their development.16
Erosions and the tenosynovial component of RA are also
properly demonstrated on MRI, even with virtually normal
radiographies. The CIMESTRA study has shown that the detection of bone edema on MRI in initial RA is the best predictor
of radiographic progression of bone erosion after a two-year
follow-up.18 That result has been confirmed by a recent systematic review, which has suggested that performing MRI at an early
stage of disease can be useful to increase its predictive value.19
In addition to its high cost and limited availability,20 the
disadvantages of MRI comprise the lack of method standardization and of a cutoff point for lesion definition (changes
similar to erosions and synovitis have already been described
in healthy individuals with no clinical evidence of RA).
Moreover, sedation might be required for claustrophobic
Rev Bras Reumatol 2012;52(5):757-766
Figure 3
(A) Radiograph of the right wrist showing gross erosions in
the tip of the ulnar styloid process, marked osteoporosis in the
neighboring medullary bone, and thickening of adjacent soft
tissues. (B) Ultrasonography of the same wrist showing cortical
irregularity of the tip of the ulnar styloid process, corresponding
to the erosions seen on plain radiographs, and hypoechogenicity
(H) around the 5th and 6th extensor tendon compartments, due to
rheumatoid tenosynovitis, which cannot be directly demonstrated
on radiography. (C) Fat suppression T2-weighted axial view of
the same patient. The erosions of the ulnar styloid process are due
to severe extensor carpi ulnaris tenosynovitis, and synovial fluid
and thickening are identified (darker linear structures amidst the
fluid) distending its sheath; those findings, at a milder intensity,
are also seen in other extensor compartments and alongside the
flexor tendons. Fluid in the distal radioulnar joint and medullary
bone edema of the ulnar epiphysis are also seen.
759
Mota et al.
for up to 12 months. Table 1 compares advantages and disadvantages of the major imaging tests used to assess initial RA.24
CONCLUSIONS
Figure 4
Plain radiograph (A) and fat suppression T2-weighted magnetic
resonance imaging (B), coronal view, of the right wrist of a
patient with a 10-month disease. The radiographic findings are
still very subtle, consisting in regional soft tissue thickening,
mild osteoporosis, and poorly defined radiolucency in carpal
bones. The magnetic resonance imaging, however, is clearly
abnormal, with significant joint effusion, extensive medullary bone edema (both showing as clearer areas on the dark
background) and cortical bone erosions in the proximal and
distal carpal rows (solutions of continuity filled with fluid and
surrounded by bone edema).
The diagnosis of initial RA is primarily clinical, but several
complementary tests can be used, such as imaging exams. Of the
recent advances, MRI has gained increasing importance, showing
high sensitivity at very early stages. In addition, methods, such as
PET/CT and SPECT, have been used to diagnose, characterize
and monitor the activity of inflammatory diseases such as RA.
On conventional radiography, erosions remain as the key
measure for the structural outcome in initial RA, and their use
has been recommended by a European committee of rheumatologists after a detailed review of all evidence available.25
Although plain radiographs remain essential for the initial assessment of patients with RA, several studies have suggested the
use of ultrasonography and MRI as the imaging exams of choice
for assessing early RA.26 Enhanced MRI, in particular, is extremely
sensitive, allowing the detection of areas de intraosseous inflammation before overt erosions develop. Technical refining of those
methods is being studied and shows promising results. However,
standardizing those methods in the context of rheumatoid disease,
in addition to defining their real role in prognostication and assessment of response to treatment, are still required.
Table 1
Radiographic methods most frequently used for assessing early rheumatoid arthritis
Radiographic methods Advantages
Disadvantages
Conventional
radiography
- Low cost
- Wide availability and easy access
- Standardization available
- Easy reproducibility
- Valid assessment methods
- ACR criteria
- Allows some differential diagnoses
Ultrasonography
- Non-invasive method
- Relatively low cost
- No ionizing radiation
- Detection of inflammatory and destructive changes
- Allows assessing several joints
- Can guide diagnostic interventions, such as biopsies
- Allows therapeutic procedures, such as infiltrations
- In association with Doppler allows detecting synovitis
- Depends on the examiner
- Difficult objective documentation
- Low reproducibility
- No standardization
- Difficult visualization of some joints (wrists)
- Questionable prognostic value
Magnetic resonance
imaging
- Safe method
- No ionizing radiation
- High sensitivity
- Assessment of all structures affected
- Differential diagnosis of undifferentiated polyarthritis
- Monitoring of therapeutic response
- Complementation with contrast media
and use of dynamic techniques
- Detection of bone edema is an independent
predictor of bone erosion
- High costs
- Limited availability of the equipment
- MRI exams require extended periods of time
- Limited to one joint per exam
- Correlation with clinical prognosis is still questionable
- Two-dimensional representation of a three-dimensional lesion
- Ionizing radiation
- Relative insensitivity to early bone damage
- Insufficient to assess soft tissues
ACR: American College of Rheumatology.
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Rev Bras Reumatol 2012;52(5):757-766
Diagnóstico por imagem da artrite reumatoide inicial
8.
CONCLUSÕES
O diagnóstico da AR inicial é eminentemente clínico, mas
diversos exames complementares podem ser utilizados,
incluindo exames de imagem. Entre os recentes avanços,
a RM vem ganhando destaque com elevada sensibilidade
em fases bastante precoces. Além disso, métodos como
PET/TC e SPECT têm sido utilizados para diagnosticar,
caracterizar e monitorar a atividade de doenças inflamatórias, incluindo a AR.
As erosões radiográficas à radiografia convencional permanecem como medida-chave do desfecho estrutural na AR
inicial, e seu uso foi recomendado por um comitê europeu de
reumatologistas, após detalhada revisão de toda a evidência
disponível.25
Embora as radiografias simples permaneçam indispensáveis na avaliação inicial de todo paciente com AR, há muitos
estudos sugerindo o uso da US e da RM como métodos de
imagem de eleição, no estado atual da ciência, para a avaliação de pacientes reumatoides na fase precoce da doença.26
A RM contrastada, em particular, é extremamente sensível,
permitindo detectar áreas de inflamação intraóssea antes
mesmo do desenvolvimento de erosões francas. Refinamentos
técnicos desses métodos estão em estudo e mostram resultados promissores. Ainda é necessário, entretanto, padronizar
tais métodos no contexto da doença reumatoide e definir seu
real papel na determinação do prognóstico e na avaliação da
resposta ao tratamento.
9.
10.
11.
12.
13.
14.
15.
16.
17.
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REVIEW ARTICLE
Selective inhibition of cyclooxygenase-2:
risks and benefits
Reila Tainá Mendes1, Cassiano Pereira Stanczyk2, Regina Sordi3,
Michel Fleith Otuki4, Fábio André dos Santos5, Daniel Fernandes4
ABSTRACT
The cyclooxygenase (COX) inhibitors are the most common drugs used worldwide. COX corresponds to an evolutionarily
conserved class of enzymes and has two main isoforms: COX-1, which is largely associated with physiological functions,
and COX-2, which is largely associated with pathological functions. Their subproducts have an important role in inflammation and pain perception. The COX-2 selective inhibition was designed to minimize gastrointestinal complications of
non-selective inhibition. However, this exclusive COX-2 inhibition was associated with serious cardiovascular events,
for causing an imbalance between prostacyclin and thromboxane production. The objective of this study is to discuss the
mechanisms underlying the cardiovascular effects, pointing out the advantages and disadvantages of the selective or nonselective COX inhibitors.
Keywords: cyclooxygenase 2 inhibitors, cardiovascular diseases, pharmacology.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Nonsteroidal anti-inflammatory drugs (NSAIDs) represent
one of the most diverse classes of drugs clinically available
in Brazil. This reflects the continuing need for analgesia in a
world population with a high prevalence of chronic pain.1 In
recent data, the anti-inflammatory drugs available in Brazil
totaled 66 different compounds: 21 steroidal anti-inflammatory
drugs (corticosteroids) and 45 NSAIDs. Of the NSAIDs, 42
correspond to non-selective inhibitors and three to selective
inhibitors of cyclooxygenase-2 (COX-2). In addition to these
45, there are also four different associations of compounds.2,3
Although these drugs have diverse chemical structures,
they exert their therapeutic effect by their common COX
inhibition property. Despite the therapeutic effectiveness, the
use of NSAIDs is limited due to their common side effects,
mainly due to gastroduodenal ulcers.4,5 In the early 90’s, two
COX isoforms were clearly identified: COX-1, which appeared
to be a constitutive isoform, and COX-2, an inducible form
associated with inflammation.
This finding led to the theory that COX-1 inhibition causes
unwanted gastrointestinal effects, whereas COX-2 inhibition
is responsible for the therapeutic effects.6 Considering this
new paradigm, there was a great effort from both the pharmaceutical industry and the academic environment to search for
selective COX-2 inhibitors. The effort was initially rewarded
in 1999 with the launching of the first selective COX-2 inhibitors in the market, celecoxib and rofecoxib. Despite the initial
enthusiasm generated by these drugs, the course of history did
not show the expected outcome and some of these drugs have
been withdrawn from the market, as they cause cardiovascular
complications.
Received on 10/03/2011. Approved on 06/27/2012. The authors declare no conflict of interest. Financial Support: Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico – CNPq; Fundação Araucária.
Universidade Estadual de Ponta Grossa – UEPG.
1. Master’s Degree Student in Dentistry of Universidade Estadual de Ponta Grossa – UEPG
2. Undergraduate Student in Dentistry, UEPG
3. PhD Student in Pharmacology, Universidade Federal de Santa Catarina – UFSC
4. PhD in Pharmacology; Adjunct Professor of the Department of Pharmaceutical Sciences, UEPG
5. PhD in Periodontics; Associate Professor of the Department of Dentistry, UEPG
Correspondence to: Daniel Fernandes. Av. General Carlos Cavalcanti, 4.748 – bloco M – Sala 94 – Uvaranas. Ponta Grossa, PR, Brazil. CEP: 84030-900.
E-mail: [email protected]
Rev Bras Reumatol 2012;52(5):767-782
767
Mendes et al.
This review aimed to retell this story, in an attempt to
reconcile the pharmacology of COX inhibition with different
cardiovascular phenotypes observed in human clinical trials.
for the two first steps in the synthesis of prostanoids and the
subsequent steps are dependent on tissue-specific enzymes.
Prostanoids are important inflammatory mediators. We
emphasize the importance of prostaglandins PGE2 and PGI2,
as they are potent vasodilator agents in addition to potentiating the increase in permeability induced by mediators such as
histamine and bradykinin.10 Moreover, due to bradykinin and
histamine potentiation, these PGs are also involved in hyperalgesia.11 Prostanoids exert their effects through G-protein
coupled receptors,12 activating different intracellular signaling
pathways.
In the early 70’s, Flower and Vane 13 demonstrated that
acetaminophen was capable of inhibiting COX activity in the
brain much more efficiently than in other tissues. This study
supported the theory that there is a variant of the COX enzyme
in the brain, and that acetaminophen is a selective inhibitor
of this enzyme, identified in the cerebral cortex of dogs and
called COX-3; it is, however, an alternative splice of COX-1.14
NSAIDs relieve pain, fever, and inflammation by inhibiting
COX enzyme.15 In turn, NSAIDs are divided into traditional and
selective inhibitors. The latter selectively inhibit COX-2 and
appeared in order to reduce gastrointestinal effects of traditional
inhibitors. However, this selectivity results in an imbalance
between anti- and pro-thrombotic factors, with a predominance
of thromboxane (TXA2) at the expense of prostacyclin (PGI2),
which triggers a series of cardiovascular complications.
PROSTANOID SYNTHESIS
Arachidonic acid is an essential fatty acid obtained from the
diet, or indirectly, through the conversion of linoleic acid.7
This fatty acid is the precursor of a large family of bioactive compounds known as eicosanoids. Due to the biological
potency of these compounds, arachidonic acid is maintained
at very low levels in the cell through its esterification with
membrane phospholipids. Thus, free arachidonic acid availability is described as the limiting step in the production of
eicosanoids.8 Arachidonic acid is released from the plasma
membrane through the action of the phospholipase A2 enzyme,
activating a metabolic cascade that initiates through the action
of prostaglandin G/H synthase, commonly called COX.
COX enzymes are highly conserved evolutionarily and
there are two forms, COX-1 and COX-2, which are encoded
by two different genes.9 Both COX-1 and COX-2 form an
unstable prostaglandin endoperoxide, PGH2, from arachidonic
acid. PGH2 is converted by the several enzymes and also by
non-enzymatic mechanisms into thromboxane and prostaglandin series D, E, F, ad I (Figure 1), which are compounds collectively known as prostanoids. COX is therefore responsible
Phospholipase A2
CH3
Arachidonic acid
COX-2
COX-1
PGH2
PGI
synthase
PGD
isomerase
TxA
synthase
PGF
isomerase
PGE
isomerase
Non-enzymatic formation
PGI2
PGD2
TxA2
PGE2
PGF2α
IP
IP
Endothelium,
Vascular smooth
muscle cell,
Kidneys, Platelets,
Brain
TPα
TPβ
Platelets,
Vascular smooth
muscle cell,
Macrophages,
Kidneys
DP1
DP2
Mastocyte, Brain,
Airways
EP1
EP2
EP3
EP4
Brain, Kidneys,
Vascular smooth muscle cell,
Platelets
FPα
FPβ
Uterus,
Vascular smooth
muscle cell,
Eyes
Figure 1
Mediators derived from cyclooxygenase (COX) and
site of action. Arachidonic
acid, which is normally esterified to membrane phospholipids, is released by
the action of phospholipase
A2 enzyme. Once released,
arachidonic acid can be converted to several biologically active compounds by
the initial action of COX-1
or COX-2 enzyme and sequentially, by other tissuespecific enzymes and also by
non-enzymatic mechanisms.
The produced prostanoids
(PGE 2, PGF 2, PGD 2, PGI 2
and TXA2) exert their main
effects by the activation of
7-transmembrane receptors.
Adapted from Grosser et al.21
768
Rev Bras Reumatol 2012;52(5):767-782
Selective inhibition of cyclooxygenase-2: risks and benefits
SELECTIVE COX-2 INHIBITORS: RISE AND FALL
Gastrointestinal complications are recognized as the main
limitation for the chronic use of NSAIDs. These complications are mainly due to the inhibition of prostanoids produced
by COX-1, which are responsible for gastric epithelial cytoprotection.16,17 Thus, the demonstration of the existence of a
second enzyme, which differently from COX-1 did not seem
to be constitutively expressed in tissues and of which expression was induced by inflammatory mediators, generated great
enthusiasm.18
Considering the new facts, it was suggested that the COX-2
was the main, if not the only, source of prostaglandin production during the inflammatory process.18 Meanwhile, COX-1,
which is constitutively expressed in many tissues, was considered primarily responsible for homeostatic functions and the
only isoform involved in gastroduodenal mucosal protection.16
This fact led to the hypothesis that COX-2 selective inhibition
had anti-inflammatory, analgesic and antipyretic effects, without the gastrointestinal toxicity of traditional anti-inflammatory
drugs. This hypothesis directed the search for and the development of selective drugs for COX-2.19
In 1999, less than a decade after the discovery of COX-2,20
the first selective COX-2 inhibitors (Coxibs), celecoxib and
rofecoxib, entered the market. In 2001, the sales volume of
rofecoxib reached US$ 2.5 billion in the market in 80 countries,
thanks to its dynamic marketing campaign.4,21,22 Lumiracoxib
and etoricoxib emerged as the second generation of Coxibs23
(Table 1).24,25
Despite of the great and fast success of Coxibs, it soon
became apparent that selective COX-2 inhibition was much
more complex than what was suggested by the simplistic initial
hypothesis. Controlled clinical trials showed that Coxibs increase the risk of cardiovascular complications,15,26–28 affecting
approximately 1%–2% patients a year included in randomized
controlled trials. These data led to the withdrawal of rofecoxib
in 2004, followed by valdecoxib in 2005.29 It is estimated that
rofecoxib caused nearly 28,000 heart attacks and sudden deaths
in the United States between 1999 and 2003.30 Some studies
also indicate that, together, rofecoxib and celecoxib have
caused more than 26,000 deaths during the first five years of
their release in the U.S. market.31
The withdrawal of rofecoxib from the market by Merck
in 2004 was followed by a heated debate in the scientific and
popular press about the use and safety of Coxibs.29,30,32 This
case disclosed the deficiency that can precede the approval
of a drug. The approval of the first three Coxibs (celecoxib,
valdecoxib and rofecoxib) was based on clinical studies of
short duration and with only a few hundred volunteers.33–36
Interestingly, the possibility of cardiovascular risks caused
by these drugs had already been anticipated, even before
the approval of the first class representatives.37,38 Moreover,
increased cardiovascular risk with rofecoxib was already
visible in the initial clinical trial,39 and yet further studies
were carried out, which exposed patients to this risk for a
prolonged period of time.
It is noteworthy, however, that although the Coxibs are
associated to a lesser extent to adverse effects on the digestive
system, data from the literature suggest that selective COX-2
inhibitors are not devoid of such effects. These drugs are
associated with the loss of healing activity in patients who
already have ulcers, as well as decrease in protective activity
against invading microorganisms into the bloodstream, such
as Helicobacter pylori.40 In an observational study, it was
Table 1
Selective COX-2 Inhibitors
Compound
(commercial name )
Year of
appearance
Situation
Oral
bioavailability
Half-life (h)
T max (h)
IC50 Ratio3
Rofecoxib1 (Vioxx)
1999
Removed in 2004
92%–93%
17
2–3
272
Celecoxib1 (Celebra)
1999
Available in market
22%–40%
12
2–4
30
Valdecoxib1 (Bextra)
2001
Removed in 2005
83%
8
2–3
51
Parecoxib1 (Bextra IM/IVpro-drug of valdecoxib)
2001
Hospital use only
—
0.3
IV: 0.04
IM: 0.2
51
Etoricoxib2 (Arcoxia)
2002
Dose of 120 mg
removed in 2008
100%
22
1
344
Lumiracoxib2 (Prexige)
2005
Removed in 2008
74%
4
2–3
700
1 st
1 generation of Coxibs; 22nd generation of Coxibs; 3Ratio of values of CI50 (CI50 COX-1/CI50 COX-2; the higher the value, the higher the COX-2 selectivity).
CI50: necessary concentration of the drug to inhibit 50% of COX-1 or 50% of COX-2.
Adapted from Hinz et al.,24 and Patrignani et al.25
Rev Bras Reumatol 2012;52(5):767-782
769
Mendes et al.
demonstrated that patients with a previous history of ulcers
and gastrointestinal complications associated with the use of
traditional anti-inflammatory drugs may have the same adverse
effects when using selective COX-2 inhibitors.41 The risk of
gastric ulcers was reduced, but not eliminated.42
Currently, in Brazil, only celecoxib and etoricoxib are
commercialized, both with prescription retention and clear
indication of cardiovascular complication risks.43
BIOLOGICAL BASIS FOR CARDIOVASCULAR
COMPLICATIONS
As described initially, the prostanoids are a family of bioactive
lipid mediators produced by COX from arachidonic acid. PGI2,
one of the most important prostanoids in the control of homeostasis of cardiovascular system, is a potent vasodilator and
additionally, inhibits platelet aggregation, leukocyte adhesion
and proliferation of vascular smooth muscle cells. Therefore,
PGI2 has a protective effect in the atherogenic process. The
effects of PGI2 contrast with those of TXA2, which cause
platelet aggregation, vasoconstriction and vascular proliferation (Figure 2).27 Thus, the balance between TXA2 produced
by platelets and PGI2 produced by endothelial cells is crucial
for cardiovascular health.44,45
The first evidence of the importance of the balance between
TXA2 and PGI2 came from studies with aspirin. Aspirin irreversibly inhibits COX-1 through the acetylation of the active
site of the enzyme. Unlike endothelial cells that can synthesize
a new COX-1 enzyme in a few hours, the platelet is devoid
Increased cardiovascular risk
Prostacyclin - PGI2
Receptors IP
Platelet antiaggregant
Vasodilator
Inhibits leukocyte adhesion
Reduces vascular remodeling
Thromboxane A2 - TXA2
Receptors TP
Platelet aggregant
Vasoconstrictor
Promotes leukocyte adhesion
Increases vascular remodeling
Figure 2
Vascular effects of prostacyclin (PGI2) and thromboxane A2
(TXA2). Prostacyclin and thromboxane have opposite effects
on the cardiovascular system.
Adapted from Mitchell; Warner.4
770
of nucleus, making it unable to restore the inhibited enzymes.
Thus, aspirin permanently inhibits the metabolization of arachidonic acid by platelet COX-1. It is also important to remember
that the platelet does not have COX-2. Thus, regular doses of
aspirin cause a cumulative and almost complete inhibition of
platelet COX-1, barely affecting endothelial COX. Stated in
another way, aspirin reduces TXA2 formation by the platelet
with minimal effect on PGI2 production by endothelial cells.
This production shift in favor of PGI2 generates an antithrombotic environment, which has already been well-documented.
The daily use of low-dose aspirin in patients at risk reduces
the occurrence of thrombotic events.46
According to the initial hypothesis that COX-2 is not
constitutively present in tissues, being expressed only during
the development of an inflammatory response, it is logical to
assume that, in individuals presenting no vascular inflammation, the selective inhibitors of this enzyme would not affect
the balance between PGI2 and TXA2.
However, it soon became evident that COX-2 was expressed not only during inflammation, but could be present
in several tissues during physiological conditions,47 including
vascular cells.48 Studies in healthy volunteers have shown
that selective COX-2 inhibitors reduce prostacyclin (PGI2)
formation.37,38 Taken into account with other studies,49,50 these
data indicate that 60%–70% of PGI2 production in healthy
humans is derived from COX-2. Thus, COX-2 would be the
predominant COX isoform in the vascular endothelium, and
would be directly associated with prostacyclin production in
normal circulation. This view differs from the initial hypothesis that COX-2 was expressed only during inflammation.
Corroborating this idea, some studies have shown that shear
stress, which is constantly created by the pressure and movement of blood within the vascular lumen, may cause COX-2
expression (Figure 3).51,52 This would explain the absence of
COX-2 in cultured endothelial cells, 6 as they are not exposed
to mechanical stress.
However, despite the evidence indicating that COX-2 can
be an enzyme constitutively expressed on endothelial cells,
these findings are not uniform. Several studies using immunohistochemistry analysis have shown that blood vessels of
healthy individuals express COX-1, with minimal evidence of
constitutively expressed COX-2.53–55
Nonetheless, if on the one hand there is no consistent
evidence of constitutive expression of COX-2 in healthy
vessels, on the other hand there seems to be no doubt of an
induction in COX-2 expression in atherosclerotic lesions.
Interestingly, the urinary excretion of PGI2 metabolites increases in patients with acute coronary syndrome 56 or soon
Rev Bras Reumatol 2012;52(5):767-782
Selective inhibition of cyclooxygenase-2: risks and benefits
Flow signal
Mechanotransmission
COX-1
?
Gene expression
COX-2
Blood flow
Figure 3
Shear stress effect (parallel to the
surface of endothelial cells) generated by blood flow. The mechanical
stimulus generated by blood flow in
the endothelial cell can activate signal
transduction factors, which in turn can
lead to increased COX expression.
Shear
stress
Endothelial cell
Smooth muscle cell
after a vascular intervention,57 which can be interpreted as a
vascular defense mechanism to prevent thrombotic events.
Corroborating this idea, several studies showed COX-2
expression in atherosclerotic lesions.54,55,58 Platelets do not
express COX-2 – then, as expected, COX-2 inhibitors do
not inhibit TXA2 production by platelets. The conclusion
from these observations is that inhibition of PGI2 production
from COX-2 may generate an imbalance in the relationship
between TXA2 and PGI2, thus increasing the probability of
a thrombotic event (Figure 4).
CARDIOVASCULAR RISKS WITH TRADITIONAL
NSAIDS
The selectivity for COX isoforms can be seen as a continuous
variable among the drugs that inhibit these enzymes;15 there
is no absolute selectivity for either isoform. Even a selective
inhibitor for COX-2 will also inhibit COX-1 at sufficiently
high concentrations.21 Moreover, some drugs said to be nonselective at low concentrations, such as diclofenac, selectively
inhibit COX-2.21 Yet, in spite of being classified as a traditional
NSAID, this drug has COX-2 selectivity that is similar to
that of celecoxib.59 Therefore, all anti-inflammatory drugs,
selective COX-2 inhibitors or not, can be associated, albeit
at different degrees, with an increased risk of cardiovascular
adverse events.60
The Food and Drug Administration draws attention to the
fact that both selective and nonselective inhibitors can increase
Rev Bras Reumatol 2012;52(5):767-782
Protective effect
Prostacyclin
Prostacyclin
Coxibs
Coxibs
Stimulus
?
COX-1
COX-1
COX-2
COX-2
Healthy endothelial cell
Inflamed endothelial cell
Figure 4
Balance between pro-atherogenic and anti-atherogenic mediators. In a normal state (healthy endothelial cell), PGI2
production is largely dependent on COX-1. However, in a
vascular injury situation (inflamed endothelial cell), COX-2
expression is induced in endothelial cells, contributing to PGI2
production, in opposition to the atherogenic effects of TXA2
produced by COX-1 from the platelets. The use of selective
anti-inflammatories for COX-2 (Coxibs) may reduce PGI2
production, generating an imbalance between TXA2 and PGI2.
the risk of cardiovascular disorders.61 Epidemiological data
suggest that both Coxibs and traditional NSAIDs have the
potential to trigger heart problems, especially when used at
high doses and for long periods of time. Thus, the risks (cardiovascular) and benefits (GI) of Coxibs should be taken into
consideration, and their indication should be individualized
to each patient.28
771
Mendes et al.
In a meta-analysis that assessed the risk of cardiovascular
events with the chronic use of anti-inflammatory drugs, diclofenac and ibuprofen (traditional non-selective drugs), as
well as etoricoxib and lumiracoxib (COX-2 selective drugs)
increased the odds of cardiovascular events by more than 30%.
This study evaluated 31 randomized clinical trials, in which
they evaluated the cardiovascular risk of seven NSAIDs: ibuprofen, diclofenac, etoricoxib, rofecoxib, naproxen, celecoxib
and lumiracoxib.60
Regarding the risk of cerebrovascular disorders, nonselective inhibitors showed to be more deleterious than the selective ones. Ibuprofen (which belongs to the class of traditional
anti-inflammatory drugs) showed a 3.36-fold higher chance
for the occurrence of the event, vs. 2.86 for diclofenac, 2.67
for etoricoxib and 1.76 for naproxen.
As for the risk of cardiovascular death, etoricoxib showed
a higher chance for the occurrence of the event (4.07 times),
followed by diclofenac (3.98), ibuprofen (2.39), celecoxib
(2.07), lumiracoxib (1.89) and rofecoxib (1.58). These data
show that the cardiovascular risk is not restricted to selective
COX-2 anti-inflammatory drugs.60
McGettigan and Henry,62 in their meta-analysis, agree
with the fact that there is cardiovascular risk with traditional inhibitors. The authors even showed that some traditional
NSAIDs can be more deleterious than Coxibs. In this study,
diclofenac showed relative risk for cardiovascular events of
1.40 (considering the observational studies), a higher risk
than that demonstrated for celecoxib, of which risk was
1.01.62 Together with this deleterious cardiovascular effect
also associated with traditional inhibitors, patients with
arthritis treated with diclofenac showed identical rates of
thrombotic cardiovascular events when compared to patients
who received etoricoxib.63
It is also important to remember that both traditional
NSAIDS and Coxibs, albeit in different proportions, increase
blood pressure in a dose-dependent manner.26,64 This effect is
a consequence of hydroelectrolytic balance alterations and
vascular reactivity.65 Nevertheless, the increase in blood pressure, regardless of the risk of thrombosis, may contribute to
an increased risk in cardiovascular complications due to the
use of these drugs.
However, there is still a lack of controlled randomized,
large-scale clinical trials, for several of the traditional NSAIDs,
making it difficult to obtain conclusive findings about the risk
of cardiovascular complications that occur with the use of
these drugs.
We must also remember that NSAIDs are a group of rather
heterogeneous chemical compounds, so it is not surprising that
772
each individual compound has different characteristics with
the potential to affect their risk-benefit ratio, such as half-life,
potency and COX-2 selectivity. All these drug-inherent factors integrate with basal cardiovascular risk to determine the
likelihood of cardiovascular complications in patients.21 Thus,
results obtained with a particular drug cannot be readily shared
with all class of NSAIDs.
This dynamic association between the pharmacological properties of a drug with cardiovascular risk is well
illustrated by diclofenac. Diclofenac has a short half-life
(1–2 hours) and therefore it is prescribed in large doses to
produce the drug concentration deemed necessary for an
effective anti-inflammatory and analgesic effect between
dose intervals. As diclofenac is one of the most potent
COX inhibitors and has reasonable COX-2 selectivity,
even similar to that of celecoxib, its plasma concentration exceeds by several times the concentration required
to inhibit only COX-2, also inhibiting COX-1.19 With the
elimination of the drug and consequent decrease in plasma
concentration, COX-2 inhibition remains, whereas COX-1 inhibition disappears.66 The discordant rates of COX isoform
inhibition in vivo results in a small selectivity window for
COX-2, called the risk window.15 Drugs such as ibuprofen
and naproxen do not have this window, as their COX-1
inhibition exceeds that of COX-2 during the entire time
interval between doses.21
The cardiovascular risks of selective COX-2 inhibitors
are yet to be elucidated; thus, no cardiovascular risk prediction may be based on this selectivity60 and it is not possible to
affirm that the use of a traditional inhibitor is safe regarding
this adverse effect.
Sheinberg 67 criticizes the fact that there is greater
control only for selective inhibitors. It is worth remembering that the gastrointestinal risks of non-selective
anti-inflammatory drugs are as severe as cardiovascular
risks of selective inhibitors; both can be potentially fatal.
Actions such as retaining the Coxibs prescription and the
less restrictive sales of non-selective inhibitors erroneously
suggest that the latter do not have risks, and also make
their use indiscriminate.67
PERSPECTIVES FOR THE USE OF SELECTIVE
COX-2 INHIBITORS
COX is the most common target of anti-inflammatory
drugs.68 In clinical practice, choosing a traditional NSAID or
Coxib has always been a challenge.42 For cases of acute pain
in patients with a history of gastrointestinal complications,
Rev Bras Reumatol 2012;52(5):767-782
Selective inhibition of cyclooxygenase-2: risks and benefits
Coxibs are an excellent choice, as their use for a short period
of time brings no risk of gastrointestinal or cardiovascular
complications.15 For instance, in cases of primary dysmenorrhea, orthopedic surgeries and dental procedures, where
the use of anti-inflammatory drugs usually do not exceed
one week, Coxibs can be a safe and effective option for
many patients.
It is noteworthy the fact that the cardiovascular risks associated with Coxibs (present when there is chronic use) does
not make them less indicated than nonselective inhibitors, as
the latter are also associated with cardiovascular events60 and
their gastrointestinal risks are as severe as the possible cardiac
risks with Coxibs.67
Rev Bras Reumatol 2012;52(5):767-782
CONCLUSION
Considering the increasing use of anti-inflammatories, it is
worth noting that selective inhibition of COX-2 arose in order
to eliminate the undesirable effects of non-selective inhibition
of COX, such as gastrointestinal adverse events. In contrast,
the decrease (not elimination) of gastrointestinal side effects resulted in the appearance of cardiovascular events. Considering
the pros and cons of both classes of COX inhibitors, both are
valid options as anti-inflammatory drugs. However, each case
must de analyzed, as well as the particularities and needs of
each patient, aiming to attain the correct indication of each
class of COX inhibitors.
773
Mendes et al.
PERSPECTIVAS PARA USO DE INIBIDORES
SELETIVOS DE COX-2
A COX é o alvo mais comum de fármacos e analgésicos
anti-inflamatórios.68 Na prática clínica, optar por um AINE
tradicional ou por um Coxib sempre foi um desafio.42 Para casos
de dor aguda em pacientes com histórico de complicações gastrintestinais, os Coxibs tornam-se uma excelente opção, uma
vez que a utilização desses fármacos por um curto período de
tempo não representa risco de complicações cardiovasculares
nem gastrintestinais.15 Como exemplo, nos casos de dismenorreia primária, cirurgias ortopédicas e procedimentos odontológicos, em que a utilização de anti-inflamatórios geralmente
não ultrapassa uma semana, os Coxibs podem ser uma opção
segura e eficaz para muitos pacientes.
Vale salientar que o risco cardiovascular dos Coxibs (presente quando do uso crônico dos mesmos) não os torna menos
indicados que os inibidores não seletivos, uma vez que esses
últimos também se associam a eventos cardiovasculares60 e que
seus riscos gastrintestinais são tão graves quanto os possíveis
riscos cardíacos dos Coxibs.67
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
CONCLUSÃO
Tendo em vista o crescente consumo de anti-inflamatórios,
é válido salientar que a inibição seletiva da COX-2 surgiu a
fim de se eliminarem os efeitos indesejáveis da inibição não
seletiva da COX, como os eventos adversos gastrintestinais.
Em contrapartida, a redução (e não a eliminação) dos efeitos
colaterais gastrintestinais culminou com o aparecimento de
eventos cardiovasculares. Considerando-se os prós e os contras
de ambas as classes de inibidores da COX, as duas são opções
válidas como fármacos anti-inflamatórios. No entanto, deve-se
analisar cada caso, bem como a particularidade e a necessidade
de cada paciente, almejando a correta indicação de cada classe
dos inibidores da COX.
15.
16.
17.
18.
19.
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Rev Bras Reumatol 2012;52(5):767-782
CASE REPORT
Bilateral osteochondrosis of lateral femoral
condyles: case report and literature review
Blanca Elena Rios Gomes Bica1, Danilo Garcia Ruiz2, Fernanda Frade Paranhos3,
Antônio Vítor de Abreu4, Mário Newton Leitão de Azevedo5
ABSTRACT
Osteochondrosis is an injury on subchondral ossification with predominance of immature skeleton and whose etiology
remains unknown. It may affect the femoral condyles (usually the medial condyle) and the involvement is mostly unilateral. The authors draw the attention to this usually late diagnosis due to its infrequent occurrence and report a child’s
rare case of bilateral osteochondrosis on lateral femoral condyles, stressing that just one similar case has been described
in the orthopaedic literature up to the present time.
Keywords: osteochondrosis, pediatrics, rheumatology, orthopedics, osteochondritis.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
CASE REPORT
Osteochondrosis is a disease characterized by detaching a cartilaginous segment along with the adjacent subchondral bone in
a given joint. It can be defined as a breakdown on subchondral
ossification.1 Traumatic,2 ischemic,3 hereditarian,1 metabolic,
and nutritional4 mechanisms have been studied and proposed
as causal factors, but its etiology remains unknown.
All joints can be affected. In respect of femurs, the most
common osteochondrosis affects proximal femoral epiphysis
(Legg-Calvé-Perthes’ disease), but it can affect femoral condyles, specially the medial ones. It is mostly unilateral, but
could be multifocal in some cases.5 Bilateral osteochondrosis
on lateral femoral condyles is an uncommon finding and for
this reason the authors draw the attention to this usually late
diagnosis.
We report a child’s case having bilateral osteochondrosis
on lateral femoral condyles, stressing that just one similar
case has been described in the orthopaedic literature up to the
present time.6
An eutrophic and previously healthy, male, 10-year-old patient
who presented a blunt trauma on the right knee evolving with
a gradual and slow increase of volume in both knees during
a year as well as it was associated with local heat and with
functional limitation with no response to rest and non-hormonal
anti-inflammatory drugs.
After six months of inconclusive diagnostic medical research in another hospital, he was referred to the Rheumatology
Service of the Hospital Universitário Clementino Fraga Filho
at the Universidade Federal do Rio de Janeiro presenting a
peculiar bulky edema in both knees associated with pain and bilateral hallux valgus deformity (Figure 1). He reported neither
complaints relating to other joints nor constitutional symptoms
such as fever and weight loss. The biopsy of proximal third of
the tibia showed no significant bone changes.
The laboratorial medical research revealed an increase
in inflammatory markers (erythrocyte sedimentation rate in
74 mm/h and C-reactive protein in 12,71 mg/L). The complete
Received on 03/15/2011. Approved on 06/27/2012. The authors declare no conflict of interest.
Rheumatology Service, Universidade Federal do Rio de Janeiro – UFRJ.
1. Adjunct Professor, Faculdade de Medicina, Universidade Federal do Rio de Janeiro – UFRJ
2. Rheumatologist; Master in Internal Medicine, UFRJ; Professor of Medicine, Faculdade ITPAC Porto Nacional
3. Postgraduated degree in Rheumatology, UFRJ
4. Associate Professor, Orthopedics and Traumatology Service, Faculdade de Medicina, UFRJ
5. Associate Professor, Faculdade de Medicina, UFRJ
Correspondence to: Danilo Garcia Ruiz. Rua 02, quadra 07 S/N, Jardim dos Ipês. Porto Nacional, TO, Brazil. CEP: 77500-000. E-mail: [email protected]
Rev Bras Reumatol 2012;52(5):783-789
783
Bica et al.
A
B
Figure 2
(A) Computed tomography on knees showing sclerosis on femoral lateral condyles, irregularity of joint surface, joint effusion
and synovial thickening with linear calcifications. (B) Bilateral
epiphysiodesis on knees performed with cannulated screws as
a first surgical attempt for correcting valgus knee.
Figure 1
A peculiar bulky edema on knees and bilateral valgus in a
child affected by osteochondrosis on femoral lateral condyles.
blood count, renal and hepatic functions, protein and hemoglobin
electrophoresis, and ferritin results were normal. The search
for mycobacterium, fungi, and bacteria in the synovial fluid was
negative. Hormonal disorders and osteometabolic diseases have
been excluded by the endocrinology unit, as the serum levels for
calcium, phosphorus, albumin, alkaline phosphatase, parathormone, TSH, 25(OH)vitamin D, besides 24-hour phosphaturia, and
calciuria levels were normal. Syringomyelia and osteochondrodysplasia have been excluded by resonance magnetic imaging of
lumbosacral spine, knee x-rays and computed tomography (CT),
as well as the hypothesis for juvenile idiopathic arthritis disease.
The CT scan of the knees showed differences in height
and sclerosis on lateral femoral condyles, an irregularity on
joint surface, joint effusion and suprapatellar bursa bilateral
distension, besides synovial thickening with linear calcifications (Figure 2a). The magnetic resonance imaging of the knees
showed synovitis, joint effusion and bone erosion specially in
femoral lateral compartment.
Due to the fast disalignment progression together with
high gait disturbance, the patient was submitted to surgery
for correcting bilateral valgus knee (epiphysiodesis performed
with cannulated screws, Figure 2b) and a new biopsy has been
performed this time from femoral distal epiphyses in which it
showed femoral condylar osteochondrosis.
784
Four months after the epiphysiodesis procedure it was still
possible to be observed the progression of limb axis deviation,
when a new procedure was performed for reducing valgus
knee by placing a bilateral external fixation. After 11 months
two other orthopedic surgical procedures were needed for
releasing the left knee adherences along with the right femur
ostetomy following Ilizarov’s device femorotibial transarticular mounting as well as the common fibular nerve neurolysis.
Four months later the osteosynthesis was performed by using
external fixation on left tibia.
Currently, 36 months after the beginning of clinical picture,
the patient is asymptomatic, using bilateral external fixation on
lower limbs and walking with the aid of crutches.
DISCUSSION
The diagnosis of osteochondrosis is extremely important for
the physician and particularly for the pediatrician. It is well
known that osteochondrosis is a heterogeneous clinical condition regarding its clinical presentation and severity. However,
osteochondrosis have been described in medical literature for
a long time.
The first reports on Osteochondritis deformans juvenalis
date from the early decades of 20th century and they are posterior to descriptions by Legg, Perthes and Calvé as to defining
a defect on epiphyseal closing line at proximal femurs.7 Later
on, other anatomical sites which shared similar clinical features
have been identified and named according to the writers who
studied and reported them as follows: the involvement of the
second metatarsal head was the so-called Freiberg’s Disease;
the involvement of calcaneum was the so-called Sever’s
Disease, among others.1
Rev Bras Reumatol 2012;52(5):783-789
Bilateral osteochondrosis of lateral femoral condyles: case report and literature review
The term osteochondrosis then arises for the purpose of
unifying and describing a group of disorders including the
predominance of immature skeleton as well as the preferential
involvement of epiphyseal bone, besides fragmentation, bone
collapse, and reossification along with the reconstitution of the
bone contour.8 Most recent scientific publications choose to
classify osteochondrosis based on the involvement anatomical
sites which lead to the traditional divisions in axial skeleton osteochondrosis and apendicular skeleton upper and lower ends.9
Its etiology was a reason for several studies, but it still
remains unknown. In 1915, Allison believed that a circulatory
disorder would explain the defect on the epiphyseal closing
line at proximal femurs7 and the poor blood perfusion was
demonstrated by several studies using animal models.3 In the
30’s it was described a possible association to hypothyroidism with delay in the epiphyseal closing and osteochondritis
in boys10 and nowadays it is well known the importance of
endocrine, metabolic, and nutritional factors both in physiology and pathology of cartilage.4
In the 60’s it was raised some reports on osteochondritis
of humeral head similar to Perthes Disease on hips with no
etiological association to traumas,11 but the history has showed
that the repetitive efforts and traumas play a definite role on
the pathogenesis of osteochondrosis.2
Regarding the involvement sites, the osteochondrosis of
distal femur affects more frequently the femoral medial condyles unilaterally (85% of cases),1 but it can evolve in varied
sites – the reports are from bilateral patella osteochondrosis12
to multiple osteochondrosis.5
The deforming and progressive, chronical clinical presentation towards the reported case has been showed to be a
challenge. It was needed to be considered diverse differential
diagnoses such as: juvenile idiopathic arthritis, chronical infectious diseases, falciform anaemia, osteometabolic diseases,
and syringomyelia.
Rev Bras Reumatol 2012;52(5):783-789
Although comprising hundreds of clinical entities, osteochondral lesions and bone dysplasias present specific features
which have not been observed in our patient. The spondyloepiphyseal dysplasia, for example, affect multiple bones; the
achondroplasia courses with short limbs and the increased
lumbar lordosis; the enchondromatosis is a disorder usually
unilateral in growth plate and affects the development of long
bones.13
Other important differential diagnosis which also affects the
femoral condyles is the osteochondritis dissecans.14 However, it
preferentially reaches the medial condyles, it is usually limited
to the femoral epiphysis,15 it is also associated to repetitive
trauma (as it happens in jogging), and both the bone necrosis
and the clinical aggression are not frequent, such as in the
presented report. It may still have association with meniscus
and/or ligamentous abnormalities like looseness.15 The magnetic resonance imaging is the selection diagnostic method for
demonstrating earlier bone and cartilaginous changes when
compared to the conventional radiography.16
The treatment for osteochondritis dissecans and for femoral
condyles osteochondrosis is similar. There is a good response
when it is proposed a conservative maneuver (maintenance
of daily activities and strengthening of quadriceps) for those
lesions which have been identified before surgical and epiphyseal closing related to the cases presenting evidences of free
intra-articular fragments and functional impairment.14
The present study reports a child’s clinical case with histopathological, radiological and clinical findings compatible to
the diagnosis of bilateral osteochondrosis on femoral condyles,
which has been diagnosed after 12 months of evolution, evolving with a presence of severe deformities and it is in need of
multiple surgeries due to a long diagnostic delay. Up to the present time, just another case of bilateral and deforming femoral
osteochondrosis has been described in medical literature, but
affecting predominantly the hips.6
785
Bica et al.
O termo osteocondrose surge, então, para unificar e descrever um grupo de desordens que inclui a predileção pelo
esqueleto imaturo e o envolvimento preferencial de osso
epifisário, além de fragmentação, colapso ósseo e reossificação com reconstituição do contorno ósseo.8 Publicações mais
recentes optam por classificar as osteocondroses baseadas no
local anatômico de acometimento, gerando as divisões em
osteocondrose do esqueleto axial, das extremidades superior
e inferior do esqueleto apendicular.9
Sua etiologia foi motivo de diversos estudos, mas permanece desconhecida. Em 1915, Allison acreditava que um distúrbio circulatório explicaria o defeito na linha de fechamento
epifisário na região proximal dos fêmures7 e a má perfusão
sanguínea foi demonstrada por diversos estudos em modelos
animais.3 Na década de 1930 descreveu-se uma possível associação de hipotireoidismo com retardo no fechamento epifisário
e osteocondrite em meninos,10 e hoje sabe-se da importância
de fatores endócrinos, metabólicos e nutricionais tanto na
fisiologia quanto na patologia da cartilagem.4
Na década de 1960 surgiram relatos de osteocondrite da
cabeça umeral similar à Doença de Perthes dos quadris sem
associação etiológica com traumas,11 mas o transcorrer da
história mostrou que esforço repetitivo e traumas têm papel
definitivo na patogênese da osteocondrose.2
Quanto aos locais de acometimento, a osteocondrose da
porção distal do fêmur afeta mais frequentemente os côndilos femorais mediais unilateralmente (85% dos casos),1
mas pode desenvolver-se em locais variados – os relatos vão
desde osteocondrose bilateral de patela12 à osteocondrose
múltipla.5
A apresentação clínica crônica, progressiva e deformante
do caso relatado mostrou-se um desafio. Houve necessidade
de se considerar diversos diagnósticos diferenciais, como artrite idiopática juvenil, doenças infecciosas crônicas, anemia
falciforme, doenças osteometabólicas e siringomielia.
As osteocondrodisplasias, apesar de compreenderem
centenas de entidades clínicas, apresentam características
próprias não observadas em nosso paciente. As displasias
espondiloepifisárias, por exemplo, afetam múltiplos ossos;
a acondroplasia cursa com membros curtos e lordose lombar
aumentada; a encondromatose é um distúrbio da placa de crescimento geralmente unilateral e que afeta o desenvolvimento
de ossos longos.13
Outro importante diagnóstico diferencial por também afetar
os côndilos femorais é a osteocondrite dissecante.14 Contudo,
ela atinge preferencialmente os côndilos mediais, geralmente é
limitada à epífise femoral,15 está associada a trauma repetitivo
788
(como em decorrência de corridas), e não são frequentes a
necrose óssea nem a agressividade clínica, como no relato
apresentado. Pode haver ainda associação com meniscos e/ou
anormalidades ligamentares como frouxidão.15 A ressonância
magnética é o método diagnóstico de escolha por demonstrar
as alterações ósseas e cartilagíneas mais precocemente que a
radiografia convencional.16
O tratamento da osteocondrite dissecante e da osteocondrose de côndilos femorais é semelhante. Há boa resposta quando
se propõe manejo conservador (manutenção das atividades
cotidianas e fortalecimento dos quadríceps) para lesões identificadas antes do fechamento epifisário e cirúrgico para os
casos com evidências de fragmentos livres intra-articulares e
prejuízo funcional.14
O presente estudo relata o caso clínico de uma criança com
achados clínicos, radiológicos e histopatológicos compatíveis
com o diagnóstico de osteocondrose bilateral de côndilos femorais, diagnosticado após 12 meses de evolução, que evoluiu
com graves deformidades e necessidade de múltiplas cirurgias
pelo longo retardo diagnóstico. Até o momento, apenas outro
caso de osteocondrose femoral deformante e bilateral foi
descrito na literatura médica, com a diferença de afetar predominantemente os quadris.6
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the medial femoral condyle associated with malformation of the
menisci. Orthopedics 2008; 31(5):504.
16. Sakamato FA, Aihara AY, Fernandes ARC, Natour J. Osteocondrite
(osteocondrose) dissecante (OCD). Rev Bras Reumatol 2004;
44(2):155–9.
789
CASE REPORT
Reactive haemophagocytic syndrome in a systemic
lupus erythematosus patient – case report
Marco Antonio Cuellar Arnez1, Mario Newton Leitão de Azevedo2, Blanca Elena Rios Gomes Bica3
ABSTRACT
The macrophagic syndrome or reactive haemophagocytic syndrome (RHS) is a complication resulting from systemic
inflammatory diseases and may also be related to malign neoplasias, immunodeficiencies and to a variety of infections
caused by virus, bacteria, and fungus. It is characterized by an excessive activation of macrophages and histiocytes
along with intense hemophagocytosis in bone marrow and reticulum-endothelial system, causing the phagocytosis of
erythrocytes, leukocytes, platelets, and their precursors. The clinical manifestations are fever, hepatosplenomegaly,
lymphadenomegalies, neurological involvement, variable degrees of cytopenias, hyperferritinemia, liver disorders, intravascular coagulation, and multiple organs failure. We report a rare case of recurrent RHS complication in a systemic
lupus erythematosus male patient after two years. Although extremely rare it has evolved with an improvement after a
pulse methilprednisolone and cyclophosphamide therapy.
Keywords: reactive macrophage syndrome, hemophagocytic lymphohistiocytosis, systemic lupus erythematosus.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
The reactive haemophagocytic syndrome (RHS), well-known
as hemophagocytic lymphohistiocytosis, is a potentially
lethal, rare, clinical, and pathological condition characterized by a massive production of proinflammatory cytokines,
which causes clinical manifestations and frequently results
in multiple organs failure. The clinical picture presents fever,
hepatosplenomegaly, pancytopenia, limphadenopathy, neurological involvement, and comsumption coagulopathy.1,2 It can
be associated with systemic infections, immunodeficiencies,
lymphoproliferative, and autoimmune diseases. Among the
inflammatory diseases the juvenile idiopathic arthritis with
systemic onset is the most frequently described disorder.3–5 Its
clinical presentation in juvenile systemic lupus erythematosus
(SLE)6 and in juvenile dermatomyositis7 is sporadic.
We report a case involving a patient diagnosed with SLE
who presented with two RHS episodes. The clinical picture was
controlled with the recognition of complication and appropriate
treatment based on corticotherapy, pulses of cyclophosphamide
(CPM) and cyclosporine.
CASE REPORT
A 49-year-old male patient presented with polyarthralgia,
weight loss of 15 kg in a year, evening fever, night sudoresis,
positive antinuclear factor, pointed pattern (1:200), anti-RNP
antibodies (1:500), positive anti-Ro and anti-Sm antibodies,
polyclonal hypergammaglobulinemia, hemolytic anemia, and
1 g/24 hours proteinuria. He was diagnosed with SLE and
treated using pulse therapy associated with methylprednisolone (three pulses) and CPM (12 monthly pulses), followed by
prednisone and azathioprine, obtaining a controlled disease.
Four years later the patient returned reporting daily fever
(39°C–40°C) for a month, generalized weakness, dorsalgia,
sudoresis, and discrete weight loss, when he was readmitted to
hospital for better investigation. The routine laboratory examinations showed increased levels of transaminases, leukopenia,
Received on 04/14/2011. Approved on 06/27/2012. The authors declare no conflicts of interest.
Rheumatology Service, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro – HUCFF-UFRJ.
1. Postgraduate in Rheumatology, Universidade Federal do Rio de Janeiro – UFRJ; Master’s degree candidate in Internal Medicine, Rheumatology Service, UFRJ
2. PhD in Internal Medicine, UFRJ; Associate Professor in Rheumatology, Faculdade de Medicina, UFRJ
3. Adjunct Professor in Rheumatology, Faculdade de Medicina, UFRJ; Head of the Rheumatology Service, Hospital Universitário Clementino Fraga Filho – HUCFF-UFRJ
Correspondence to: Marco Antonio Cuellar Arnez. Hospital Universitário Clementino Fraga Filho. Universidade Federal do Rio de Janeiro. Av. Prof. Rodolpho Paulo
Rocco, 255 – Cidade Universitária – Ilha do Fundão. Rio de Janeiro, RJ, Brazil. CEP: 21941-913. E-mail: [email protected]
790
Rev Bras Reumatol 2012;52(5):790-795
Reactive haemophagocytic syndrome in a systemic lupus erythematosus patient – case report
Table 1
Laboratory findings at admission during hospital stay
Date
HCTO
HB
PTL
LC
ESR
GOT/GPT
10/20/2005
39.1
12.1
120,000
3,990
74
104/60
10/26/2005
32.4
102,000
3,650
10/31/2005
287/156
85
96/93
11/01/2005
LDH
Hyperferritinemia
808
15,900
9,314
11/03/2005
26.8
91,000
3,480
65
118/82
11/08/2005
22.8
8,58
116,000
3,700
104
100/77
11/10/2005
26.7
171,000
5,510
100
63/77
12/16/2005
39.2
207,000
6,700
37
12.1
7,590
422
HCTO: hematocrit; HB: hemoglobin; PTL: platelets; LC: leucocytes; ESH: erythrocyte sedimentation rate; GOT: glutamic-oxaloacetic transaminase; GPT: glutamic-pyruvic transaminase; LDH: lactate dehydrogenase.
thrombocytopenia, positive direct Coombs, elevated erythrocyte sedimentation rate, hyperferritinemia, in addition to a
1240-mg proteinuria level in 24-hour specimen of urine along
with negative blood culture and urine culture (Table 1).
The echocardiogram revealed grade I diastolic dysfunction
with a mild increase in the volume of right heart cavities associated with a slight tricuspid incompetence and 37-mmHg
pulmonary arterial pressure. It was detected hepatomegaly. The
peripheral blood exam showed anisopoikilocytosis, tear shaped
erythrocytes, acanthocytes, neutrophils presenting the PelgerHuet anomaly, and a mild thrombocytopenia. The bone marrow
aspiration procedure revealed erythroid hypoplasia, interrupted
maturation with a discrete dyserythropoietic anemia, presence
of histiocytes which have phagocytes absorbing erythroid and
myeloid line cells, normal hypogranular myeloid cells, and
megakaryocytes. The patient improved his clinical picture
after being treated with methylprednisolone pulse therapy.
Two years later the patient returned with worsening of
overall health status, presenting fever up to 40°C and dyspnea to minimal efforts which started 18 days before his
return. He was admitted to the hospital and the antibiotic
therapy was introduced evolving with disorientation. The
patient underwent cranial computed tomography which
presented no changes. The cerebrospinal fluid (CSF)
analysis showed 101 cell/m 3, with 94% mononucleated
cells, 100 mg/dL protein and 22 mg/dL glucose. The patient
underwent therapy with acyclovir.
The patient presented an increase in hepatic enzymes,
pancytopenia, moderate anemia and hyperferritinemia. CSF
cultures were negative for fungi, acid-fast bacilli, bacteria,
mycobacteria, and cytomegalovirus. The patient evolved to
acute lung edema and to acute respiratory distress, being performed orotracheal intubation and mechanical ventilation. It
Rev Bras Reumatol 2012;52(5):790-795
was introduced the pulse of methylprednisolone therapy for
three days with no significant improvement. Cyclosporine has
been gradually introduced for controlling the clinical picture.
The patient was discharged from hospital and treated with low
doses of corticoids and cyclosporine.
DISCUSSION
We describe a rare case involving a patient with SLE who
developed an episode of RHS with recurrence of this complication after two years. There are several triggering factors but
the infectious processes are important starting elements for
this complication.8,9
The clinical manifestations can be explained by overproduction of pro-inflammatory cytokines (interleukin 1, tumoral
necrosis factor, gamma-interferon, among others), which are
responsible for this severe complication.10–12
The diagnostic difficulty is due to the fact that disease activity shares common signs and symptoms, in addition to clinical
pictures associated with infectious agents.13,14 According to
many authors the presence hiperferritinemia is a highly suggestive sign of reactive macrophage disease and this factor
associated with the bone marrow aspirate has defined RHS
clinical features.15 The patient presented the diagnostic criteria
for hemophagocytic syndrome proposed by the Histiocyte
Society16 and by Imashuku,17 Tsuda,18 and Ishikura,8 characterized by the presence of fever, cytopenia, hyperferritinemia, an
increase in lactate dehydrogenase, and prominent hemophagocytosis in bone marrow aspirate. Although the SLE in itself
may trigger this severe complication,19 we can not exclude the
possibility that an infectious clinical picture may have been
the starting point in our patient’s second episode, considering that the CSF clinical features were compatible with viral
791
Arnez et al.
infection. The clinical features such as fever, pancitopenia,
and hiperferritinemia have also suggested the possibility of
recurrent RHS which improved after immunosupression, but
with no confirmation due to lack of exams showing the clinical
picture as peripheral blood studies and myelogram. In many
cases is not possible to determine the triggering etiological
factor of hemophagocytosis.
Good responses to the pulse methylprednisolone and
cyclophosphamide therapies following the cyclosporine
792
treatment have already been described in medical literature
presenting satisfactory results in many case reports.8
The difficulty for excluding an associated infection delays
the beginning of immunosuppressive therapy, which is critical for treatment and for this incident evolutionary process.
Hemophagocytosis must be suspected in patients with systemic inflammatory diseases such as SLE and those patients
who present with clinical and/or laboratorial manifestations
suggestive of RHS.
Rev Bras Reumatol 2012;52(5):790-795
Síndrome de ativação macrofágica em paciente com lúpus eritematoso sistêmico – relato de caso
melhorou com imunossupressão, porém sem confirmação por
falta de exames que caracterizam o quadro como estudo de
sangue periférico e mielograma. Em muitos casos não se consegue determinar a causa desencadeante da hemofagocitose.
A boa resposta ao tratamento com pulsoterapia de metilprednisolona e ciclofosfamida seguida do tratamento com
ciclosporina já está descrita na literatura, com resultados
satisfatórios em diversos relatos de casos.8
A dificuldade de descartar infecção associada retarda o
início da terapia imunossupressora, crucial para o tratamento
e a boa evolução dessa intercorrência. Deve-se suspeitar de
hemofagocitose em pacientes com doenças inflamatórias sistêmicas como o LES e que apresentem manifestações clínicas
e/ou laboratoriais sugestivas da SAM.
8.
9.
10.
11.
12.
13.
REFERENCES
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol
2002; 14(5):548–52.
Romanou V, Hatzinikolaou P, Mavragani KI, Meletis J, Vaiopoulos G.
Lupus erythematosus complicated by hemophagocytic syndrome. J
Clin Rheumatol 2006; 12(6):301–3.
Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome:
a potentially fatal complication of rheumatic disorders. Arch Dis
Child 2001; 85(5):421–6.
Grom AA. Natural killer cell dysfunction: a common pathway in
systemic-onset juvenile rheumatoid arthritis, macrophage activation
syndrome, and hemophagocytic lymphohistiocytosis? Arthritis
Rheum 2004; 50(3):689–98.
Avcin T, Tse SM, Schneider R, Ngan B, Silverman ED. Macrophage
activation syndrome as the presenting manifestation of rheumatic
diseases in childhood. J Pediatr 2006; 148(5):683–6.
Javier RM, Sibilia J, Offner C, Albert A, Kuntz JL. Macrophage
activation in lupus. Rev Rheum Ed Fr 1993; 60(11):831–5.
Kobayashi I, Yamada M, Kawamura N, Kobayashi R, Okano M,
Kobayashi K. Platelet-specific hemophagocytosis in a patient with
juvenile dermatomyositis. Acta Paediatr 2000; 89(5):617–9.
Rev Bras Reumatol 2012;52(5):789-794
14.
15.
16.
17.
18.
19.
Kumakura S, Ishikura H, Kondo M, Murakawa Y, Masuda J,
Kobayashi S. Autoimmune-associated hemophagocytic syndrome.
Mod Rheumatol 2004; 14(3):205–15.
Janka GE. Hemophagocytic syndromes. Blood Rev 2007;
21(5):245–53.
Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A,
Jacob CM et al. Síndrome de ativação macrofágica associada
com artrite idiopática juvenil sistêmica. J Pediatr (Rio J) 2004;
80(6):517–22.
Rosa DJ, Nogueira CM, Bonfante HL, Machado LG, Rodrigues DO,
Fernandes GC et al. Síndrome de ativação macrofágica após o uso
de Leflunomida em paciente com doença de Still do adulto. Relato
de caso. Rev Bras Reumatol 2007; 47(3):219–22.
Behrens EM. Macrophage activation syndrome in rheumatic disease:
what is the role of the antigen presenting cell? Autoimmun Rev
2008; 7(4):305–8.
Tanaka Y, Seo R, Nagai Y, Mori M, Togami K, Fujita H et al.
Systemic lupus erythematosus complicated by cytomegalovirusinduced hemophagocytic syndrome and pneumonia. Nihon Rinsho
Meneki Gakkai Kaishi 2008; 31(1):71–5.
Arceci RJ. When T cells and macrophages do not talk: the
hemophagocytic syndromes. Curr Opin Hematol 2008; 15(4):359–67.
Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M
et al. Contemporary classification of histiocytic disorders. The
WHO Committee On Histiocytic/Reticulum Cell Proliferations.
Reclassification Working Group of the Histiocyte Society. Med
Pediatric Oncol 1997; 29(3):157–66.
Henter JI, Elinder G, Ost A. Diagnostic guidelines for
hemofaphagocytic lymphohistiocytosis. The FHL Study Group of
the Histiocyte Society. Semin Oncol 1991; 18(1):29–33.
Imashuku S. Differential diagnosis of hemophagocytic syndrome:
underlying disorders and selection of de most effective treatment.
Int J Hematol 1997; 66(2):135–51.
Tsuda H. Hemophagocytic syndrome (HPS) in children and adults.
Int J Hematol 1997; 65(3):215–26.
Papo T, André MH, Amoura Z, Lortholary O, Tribout B, Guillevin L
et al. The spectrum of reactive hemophagocytic syndrome in systemic
lupus erythematosus. J Rheumatol 1999; 26(4): 927–30.
795
CASE REPORT
Spontaneous pneumomediastinum associated with
laryngeal lesions and tracheal ulcer in dermatomyositis
Ascedio Jose Rodrigues1, Marcia Jacomelli2, Paulo Rogerio Scordamaglio1, Viviane Rossi Figueiredo3
ABSTRACT
We described a 41-year-old woman with dermatomyositis, interstitial lung disease, and cutaneous vasculopathy who
developed a pneumomediastinum. The routine bronchoscopy investigation found pale lesions in the larynx, that extended
to the tracheobronchial tree, and deep ulcers in the membranous wall of the trachea. The histopathology examination
revealed an inflammatory process that was diagnosed secondary to the vasculitis, but no infections. Superior and inferior
airway lesions in the same patient with dermatomyositis is a very rare condition. The association of dermatomyositis
with deep mucosal ulcers and pneumomediastinum is not clear, but a bronchoscopic examination should be used to
improve evaluation.
Keywords: dermatomyositis, bronchoscopy, pneumomediastinum diagnosis.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Dermatomyositis (DM) is a general inflammatory connective
tissue disease of unknown cause involving mainly the muscles
and the skin. Pulmonary complications are frequent and may
lead to death.1 The usual respiratory manifestations are interstitial pneumonitis, infection, dysfunction of the respiratory
muscle, drug-induced disease, and pneumomediastinum (PM).
Spontaneous pneumomediastinum (SPM) has been described in DM as a rare complication, which carries a poor
prognosis.2 Several reports have described mortality rates
ranging from 37.5%–52.5%, following the onset of PM. The
precise mechanism has not been clarified, and it is believed
that PM could be related to interstitial pneumonitis.3,4 The
rupture of the alveoli adjacent to vessels due to vasculitis may
be a cause.1,3,5 Kono et al.6 first described bronchial necrosis
as an airway manifestation in DM. They hypothesized that
vasculopathy was a possible cause of necrosis and may occur
after PM.
We report in this study an association between laryngeal
lesions, tracheal and bronchial ulcers, and PM in a woman
with DM.
CASE REPORT
A 41-year-old woman with DM and progressive interstitial
lung disease with severe cutaneous activity, despite the use
of corticosteroids and immunosuppressive agents, evolved
with subcutaneous emphysema. The clinical examinations
and laboratory evaluations showed the following: serum
creatine kinase (CK) and aldolase at normal levels. The
chest x-ray and computerized tomography revealed PM.
Fiberoptic bronchoscopy was performed to evaluate the
airways, and during the inspection was revealed: pale symmetrical lesions in the mucosa of the false vocal cords in
the larynx, deep mucosal ulcerations in the posterior wall
of the trachea ranging in size from 0.5–1.0 cm, and two flat,
pale mucosal lesions surrounded by a hyperemic halo (may
Received on 04/25/2011. Approved on 06/27/2012. The authors declare no conflict of interest.
Respiratory Endoscopy Service of the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – HC-FMUSP.
1. Assistant Physician of the Respiratory Endoscopy Service, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – HC-FMUSP
2. PhD in Pulmonology, FMUSP; Assistant Physician of the Respiratory Endoscopy Service, HC-FMUSP
3. PhD in Pulmonology, FMUSP; Director of the Respiratory Endoscopy Service, HC-FMUSP
Correspondence to: Ascedio Jose Rodrigues. Serviço de Endoscopia Respiratória, HC-FMUSP – Prédio dos Ambulatórios, 6º andar – bloco 3. Av. Dr. Enéas de
Carvalho Aguiar, 255 – Cerqueira César. São Paulo, SP, Brazil. CEP: 05017-000. E-mail: [email protected]
796
Rev Bras Reumatol 2012;52(5):796-799
Spontaneous pneumomediastinum associated with laryngeal lesions and tracheal ulcer in dermatomyositis
correspond to points of possible initial ulcer) situated in the
membranous wall of the trachea and posterior wall of the
main right bronchus with diffuse mucosal hyperemia of the
tracheobronchial tree as well.
Biopsy of all visible lesions (more than one procedure)
was performed with flexible biopsy forceps. The culture of
the fragments was negative for fungus, mycobacterium, virus, and unspecified infection. The histological examination
showed an unspecified inflammatory disease with predominant
polymorphonuclear infiltrate.
The patient died due to sepsis that did not respond to antibiotic treatment.
DISCUSSION
Bradley3 described the first case of PM associated with DM
in 1986. In the English and French literature4,7 25 cases have
been reported. Most of the patients had interstitial lung disease and cutaneous vasculitis (periungual infarct or ulcerous
lesions). PM occurred during treatment with corticoids, and
the patients had normal CK levels, like our patient. Kono
et al.6 reported on a patient with DM who had ulcerative
skin lesions, white plaques on the bronchial mucosa at the
carina and the main, lobar, and segmental bronchi in the
lungs, immature lung disease, and PM. A biopsy showed
subepithelial necrosis of the bronchial wall with epithelial
squamatization, which are reminiscent of the macroscopic
signals in our case.
Rev Bras Reumatol 2012;52(5):796-799
The mechanism of SPM in DM has not yet been explained.
It is known that the majority of patients reported on in the
literature had interstitial lung disease and just a few patients
had cutaneous vasculopathy solely. In almost half of the cases,
CK levels were normal and most patients were treated with
systemic corticotherapy. Kono et al.6 assumed that necrosis of
the bronchial wall attributable to vasculopathy could be the
plausible mechanism.
This report provides a description of laryngeal lesions associated with tracheobronchial ulcers in DM, suggesting that
manifestation of disease in the superior airway is possible. A
differential diagnosis of infectious diseases is essential for
establishing the appropriate treatment for immunocompromised patients, because diseases may differ even with similar
clinical picture. In our case, the bronchoscopic analysis associated with the absence of specific signals in the histological
examination suggested the hypothesis of vasculitis of the
tracheobronchial mucosa as the cause of the ulcers, which
could be a possible origin of the PM corresponding to the
activity of interstitial disease.
CONCLUSION
The possibility of diffuse compromise of the airways caused
by the pathological activity of DM must be considered. The
relation between the airway lesion and PM in DM needs to be
evaluated in further studies. A careful bronchoscopic examination is a powerful tool for the investigation of these patterns.
797
Pneumomediastino espontâneo associado a lesões laríngeas e úlceras traqueais na dermatomiosite
profundas de mucosa na parede posterior da traqueia (os tamanhos das úlceras variavam de 0,5−1,0 cm), bem como duas
lesões planas pálidas na mucosa, circundadas por um halo
hiperêmico (pode corresponder a pontos da possível úlcera
inicial) e localizadas na parede membranácea da traqueia e na
parede posterior do brônquio principal direito com hiperemia
difusa da mucosa da árvore traqueobrônquica.
Realizou-se a biopsia de todas as lesões visíveis (mais
de um procedimento) com pinças flexíveis de biopsia. Os
fragmentos foram submetidos à cultura e exibiram resultados
negativos quanto à presença de fungo, micobactéria, vírus e
infecção inespecífica. O exame histológico revelou doença
inflamatória inespecífica com infiltrado polimorfonuclear
predominante.
A paciente veio a óbito por sepse irresponsiva à
antibioticoterapia.
DISCUSSÃO
Bradley3 descreveu o primeiro caso de PM associado à DM
em 1986. Nas literaturas inglesa e francesa4,7 foram relatados
25 casos. A maioria dos pacientes tinha doença pulmonar
intersticial e vasculite cutânea (infarto periungueal ou lesões
ulcerosas). O PM ocorreu durante o tratamento com corticoides, mas os pacientes apresentavam níveis normais de CK, de
maneira semelhante à nossa paciente. Kono et al.6 relataram
placas brancas na mucosa brônquica ao nível da carina traqueal e nos brônquios principais, lobares e segmentares nos
pulmões, além de doença pulmonar imatura e PM, em um
paciente com DM que exibia lesões cutâneas ulcerativas. O
exame de biopsia demonstrou necrose subepitelial da parede
brônquica com descamação epitelial, o que lembra os sinais
macroscópicos de nosso caso.
O mecanismo de PME em DM ainda não foi esclarecido.
Sabe-se que a maioria dos pacientes relatados na literatura
tinha doença pulmonar intersticial e apenas alguns pacientes
exibiam somente a vasculopatia cutânea. Em quase metade dos
casos os níveis de CK permaneceram normais, e a maioria
dos pacientes foi tratada com corticoterapia sistêmica. Kono
et al.6 admitiram que a necrose da parede brônquica atribuível
à vasculopatia pudesse ser um mecanismo plausível.
Rev Bras Reumatol 2012;52(5):796-799
Este relato de caso fornece uma descrição de lesões laríngeas
associadas a úlceras traqueobrônquicas em DM, sugerindo
que a manifestação da doença nas vias aéreas superiores seja
possível. É essencial a determinação do diagnóstico diferencial
para doenças infecciosas a fim de estabelecer o tratamento adequado em pacientes imunocomprometidos, já que as doenças
podem diferir até mesmo com quadro clínico semelhante. Em
nosso caso, a análise broncoscópica associada à ausência de
sinais específicos no exame histológico sugeriu a hipótese
de vasculite da mucosa traqueobrônquica como causa das úlceras,
o que pode ser uma possível origem do PM correspondente à
atividade de doença intersticial.
CONCLUSÃO
É imprescindível considerar a possibilidade de comprometimento difuso das vias aéreas causado pela atividade
patológica da DM. A relação entre a lesão das vias aéreas e a
ocorrência de PM em casos de DM ainda precisa ser avaliada
em estudos futuros. O exame broncoscópico cuidadoso e
rigoroso é uma ferramenta poderosa para a investigação
desses padrões.
REFERENCES
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
Barvaux VA, Van Mullem X, Pieters TH, Houssiau FA. Persistent
pneumomediastinum and dermatomyositis: a case report and review
of the literature. Clin Rheumatol 2001; 20(5):359–61.
Masrouha KZ, Kanj N, Uthman I. Late-onset pneumomediastinum
in dermatomyositis. Rheumatol Int 2009; 30(2):291–2.
Bradley JD. Spontaneous pneumomediastinum in adult
dermatomyositis. Ann Rheum Dis 1986; 45(9):780–2.
Cicuttini FM, Fraser KJ. Recurrent pneumomediastinum in adult
dermatomyositis. J Rheumatol 1989; 16(3):384–6.
Korkmaz C, Ozkan R, Akay M, Hakan T. Pneumomediastinum
and subcutaneous emphysema associated with dermatomyositis.
Rheumatology (Oxford) 2001; 40(4):476–8.
Kono H, Inokuma S, Nakayama H, Suzuki M. Pneumomediastinum
in dermatomyositis: association with cutaneous vasculopathy. Ann
Rheum Dis 2000; 59(5):372–6.
Jansen TL, Barrera P, van Engelen BG, Cox N, Laan RF,
van de Putte LB. Dermatomyositis with subclinical myositis and
spontaneous pneumomediastinum with pneumothorax: case report
and review of the literature. Clin Exp Rheumatol 1998; 16(6):733–5.
799
BRIEF COMMUNICATION
Complete heart block in ankylosing spondylitis
Juan Pablo Restrepo1, María Del Pilar Molina2
ABSTRACT
Ankylosing spondylitis (AS) is a chronic rheumatic disease of young men that affects mainly the axial skeleton and is
associated with HLA-B27 in 90% of the cases. Incidence of cardiovascular involvement in AS ranges between 10%–30%;
conduction disturbances have been described in 1%–9% of the patients with AS. The majority of the series show a
relationship with longstanding disease. To our knowledge, this is the first report of complete heart block in early AS.
Keywords: ankylosing spondylitis, HLA-B27 antigen, heart block.
© 2012 Elsevier Editora Ltda. All rights reserved.
INTRODUCTION
Ankylosing spondylitis (AS) is a chronic rheumatic disease
of young men that affects mainly axial skeleton and is associated with HLA-B27 in 90% of the cases. Cardiovascular
manifestations can occur in patients with chronic disease. We
describe a 22-year-old man who presented complete heart
block associated to AS.
tests were normal, with implantation of a DDD-R pacemaker.
The patient now has a BASDAI of 0.4, BASMI of 2 and is
completely asymptomatic.
CASE REPORT
A 22-year-old Colombian male otherwise healthy presented
with insidious onset of low back pain improved by exercise
and not relieved by rest over 1.5 years. He had been treated
with nonsteroidal anti-inflammatory drugs (NSAIDs) for
several months with no response. His initial Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) and Bath
Ankylosing Spondylitis Metrology Index (BASMI) were 4.8
and 2, respectively. The sacroiliac X-rays showed a bilateral
sacroiliitis grade 3 (Figure 1) and HLA-B27 was positive. The
patient denied skin, ocular, bowel, and genitourinary associated
disease. A diagnosis of AS was done based on modified New
York classification criteria for AS.1 Adalimumab was initiated
at the conventional dose and six months later the patient had
total resolution of his main complaint. Two months ago he
had a syncopal episode; during his hospitalization a resting
electrocardiography was performed detecting a complete atrioventricular block (Figure 2); echocardiogram and laboratory
Figure 1
Bilateral sacroiliitis grade 3.
Figure 2
Surface electrocardiogram showing complete atrioventricular
block with ventricular ectopic beats.
Received on 10/03/2011. Approved on 06/27/2012. The authors declare no conflict of interest.
Universidad del Quindío, Colombia.
1. Rheumatologist; Professor, Universidad del Quindío
2. General Practitioner
Correspondence to: Juan Pablo Restrepo. Cra 13 No 1-35, consultorio 412, Armenia. Quindío, Colombia. E-mail: [email protected]
800
Rev Bras Reumatol 2012;52(5):800-803
Complete heart block in ankylosing spondylitis
DISCUSSION
AS is a chronic rheumatic disease of young men that affects
mainly the axial skeleton and is associated with HLA-B27 in
90% of the cases.2 Incidence of cardiovascular involvement
in AS ranges between 10%–30%.3 The most common lesions
include aortitis, aortic valvular incompetence, and conduction
disturbances. In the latter group can be observed atrioventricular blocks, bundle branch blocks, and intraventricular blocks.
Atrioventricular conduction blocks have been found in 1%–9%
of patients with AS.4 Initially they appear in an intermittent
manner and could progress to complete and definitive atrioventricular block. Ninety-nine percent of patients with cardiac
complications are male.5
There seems to be a relationship between a definitive pacemaker implantation and positive results for HLA-B27. It was
Rev Bras Reumatol 2012;52(5):800-803
found that 15%–20% of patients with definitive pacemaker
implantation were HLA-B27-positive.6 Two complementary
theories may explain the conduction disturbances: anomalies in
the atrioventricular nodal artery and inflammation in the intraventricular septum.7 The risk of cardiac complications increases
with age of patient, duration of AS, presence of HLA-B27,
and peripheral joint involvement.8 Cardiovascular features
typically occur in longstading AS. Kinsella et al.9 reported a
mean duration of AS of 21 years; the Brunner group reported
a mean duration of 33 years.10 Confirming previous findings,
Dik et al. found no second/third degree atrioventricular block
after up to 11 years of follow-up.11 This group defined as
“early” an AS with diagnosis duration of less than two years.
Our case report suggests cardiac monitoring in early stages of
AS subgroup HLA-B27-positive in order to possibly diagnose
conduction disturbances.
801
Bloqueio cardíaco completo em espondilite anquilosante
Figura 2
Eletrocardiograma de superfície, exibindo bloqueio atrioventricular completo com batimentos ectópicos ventriculares.
testes laboratoriais encontravam-se normais com o implante
de marca-passo do tipo DDD-R. Atualmente, o paciente apresenta um BASDAI de 0,4 e um BASMI de 2, além de estar
completamente assintomático.
DISCUSSÃO
A EA é uma doença reumática crônica de homens jovens que
afeta principalmente o esqueleto axial e está associada ao
HLA-B27 em 90% dos casos.2 A incidência de envolvimento
cardiovascular em casos de EA varia entre 10%−30%.3 As
lesões mais comuns incluem aortite, incompetência valvular
aórtica e distúrbios de condução. No último grupo podem ser
observados bloqueios atrioventriculares, bloqueios de ramo
do feixe de His e bloqueios intraventriculares. Foram encontrados bloqueios de condução atrioventricular em 1%−9% dos
pacientes com EA.4 Em princípio, esses bloqueios aparecem de
forma intermitente, mas podem evoluir para bloqueio atrioventricular completo e definitivo. Dos pacientes com complicações
cardíacas, 99% são do gênero masculino.5
Parece haver uma relação entre o implante de marcapasso definitivo e os resultados positivos para HLA-B27.
Foi constatado que 15%−20% dos pacientes com implante
de marca-passo definitivo eram positivos para o HLA-B27.6
Duas teorias complementares podem explicar os distúrbios
de condução: anomalias na artéria do nó atrioventricular e
inflamação no septo intraventricular.7 O risco de complicações
cardíacas aumenta com a idade do paciente, a duração da EA,
a presença de HLA-B27 e o envolvimento de articulações periféricas.8 As alterações cardiovasculares tipicamente ocorrem
na EA de longa data. Kinsella et al.9 relataram uma duração
média de EA de 21 anos; já o grupo do pesquisador Brunner
Rev Bras Reumatol 2012;52(5):800-803
relatou uma duração média de 33 anos.10 Confirmando os
achados prévios, Dik et al. não constataram nenhum bloqueio
atrioventricular de segundo/terceiro grau até depois de 11
anos de acompanhamento.11 Esse grupo de pesquisadores
definiu como “precoce” uma EA com diagnóstico de menos
de dois anos. Nosso relato de caso sugere a monitoração cardíaca nos estágios iniciais do subgrupo acometido por EA e
HLA-B27 positivo para diagnosticar os possíveis distúrbios
de condução.
REFERENCES
REFERÊNCIAS
1.
van der Linden S, Valkenburg H, Cats A. Evaluation of the diagnostic
criteria for ankylosing spondylitis: a proposal for modification of the
New York criteria. Arthritis Rheum 1984; 27(4):361–8.
2. Peeters A, ten Wolde S, Sedney M, de Vries RR, Dijkmans BA.
Heart conduction disturbance: an HLA-B27 associated disease. Ann
Rheum Dis 1991; 50(6):348–50.
3. Kazmierczak J, Peregud-Pogorzelska M, Biernawska J, PrzepieraBedzak H, Goracy J, Brzosko I et al. Cardiac arrhythmias and
conduction disturbances in patients with ankylosing spondylitis.
Angiology 2008; 58(6):751–6.
4. Bergfeldt L. HLA B27-associated cardiac disease. Ann Intern Med
1997; 127(8 Pt 1):621–9.
5. Sukenik S, Pras A, Buskila D, Katz A, Snir Y, Horowitz J.
Cardiovascular manifestations of ankylosing spondylitis. Clin
Rheumatol 1987; 6(4):588–92.
6. Bergfeldt L, Vallin H, Edhag O. Complete heart block in HLA B27
associated disease. Electrophysiological and clinical characteristics.
Br Heart J 1984; 51(2):184–8.
7. Momeni N, Taylor N, Tehrani M. Cardiopulmonary manifestations
of ankylosing spondylitis. Int J Rheumatol 2011; 2011:728471.
8. Ulusoy V, Ateş A, Çiçekcioğlu H, Acvioğlu Y, Karaaslan Y. Thirddegree heart block developing in a female patient with HLA-B27
positive ankylosing spondylitis. Rheumatol Int 2006; 26(8):779–80.
9. Kinsella D, Johnson L, Ian R. Cardiovascular manifestations of
ankylosing spondylitis. Can Med Assoc J 1974; 111(12):1309–11.
10. Brunner F, Kunz A, Weber U, Kissling R. Ankylosing spondylitis
and heart abnormalities: do cardiac conduction disorders, valve
regurgitation and diastolic dysfunction occur more often in male
patients with diagnosed ankylosing spondylitis for over 15 years
than in the normal population? Clin Rheumatol 2006; 25(1):24–9.
11. Dik V, Peters M, Dijkmans P, Van der Weijden M, De Vries MK,
Dijkmans BA et al. The relationship between disease-related
characteristics and conduction disturbances in ankylosing
spondylitis. Scand J Rheumatol 2010; 39(1):38–41.
803
BRIEF COMMUNICATION
Posterior reversible encephalopathy
syndrome (PRES) and systemic lupus
erythematosus: report of two cases
Aline de Souza Streck1, Henrique Luiz Staub2, Caroline Zechlinski Xavier de Freitas1,
Luis Marrone3, Jaderson Costa4, Giovani Gadonski5
ABSTRACT
The posterior reversible encephalopathy syndrome (PRES) is a novel entity clinically manifested by headache, changes
of sensorium, seizures, and visual loss. PRES pathogenesis has not been fully clarified. The entity can be associated to a
variety of clinical conditions, mainly hypertension, renal insufficiency and immunosuppressive therapy. A possible link
of autoimmune disorders with PRES has been recently hypothesized. We herein describe two cases of systemic lupus
erythematosus whereby PRES was triggered by different factors.
Keywords: systemic lupus erythematosus, neuropsychiatric manifestations, posterior encephalopathy syndrome.
© 2012 Elsevier Editora Ltda. All rights reserved.
A posterior leukoencephalopathy characterized by transient
headache, changes of mental status, seizures, and visual loss
was originally described in 1996; white-matter vasogenic
edema of occipital, and parietal lobes was a remarkable feature
of those 15 patients then reported.1 In 2000, Casey et al.2 proposed the term posterior reversible encephalopathy syndrome
(PRES) for this entity.
The pathogenesis of PRES is not yet fully understood.
Auto-regulatory failure with resultant vasodilatation, as seen
in hypertensive encephalopathy, is often cited as the underlying
mechanism. Vasospasm with ischemic abnormalities are also
postulated.3 On magnetic resonance imaging (MRI), parietooccipital subcortical T2 hyperintensity without enhancement is
typical. Other structures such as the brain stem, cerebellum, and
frontal and temporal lobes may also be involved. Abnormalities
of the subcortical white-matter are the rule, but the cortex and
the basal ganglia are eventually affected.4
PRES could result from a number of associated morbidities, including autoimmune disorders. To date, the issue has
been rarely addressed in the Rheumatology scenario. We herein
describe two cases of PRES in patients with systemic lupus
erythematosus (SLE).
Case 1: A 30-year-old Caucasian woman diagnosed with
SLE at the age 19 was on methylprednisolone (MP) pulse
therapy 1 g/daily due to an anti-DNA positive nephritis. On
day four of the treatment the patient suddenly presented
severe headache and right hemianopsia. Mental status was
normal. At that time, her blood pressure was 160/80 mmHg
and her creatinine was 1.31 mg/dL (six months before the
creatinine was 0.72 mg/dL). Sodium and potassium levels
were normal. A cranial computed tomography (CT) was
unremarkable. A brain MRI with T2 and fluid-attenuated
inversion recovery sequences (MRI-T2/FLAIR) showed a
subcortical T2 hyperintensity without enhancement on both
Received on 11/01/2011. Approved on 06/27/2012. The authors declare no conflict of interest.
Department of Rheumatology, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS.
1. Rheumatologist, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS
2. Rheumatologist; Professor of the Department of Rheumatology, Hospital São Lucas, PUCRS
3. Neurologist, Member of the Neurology Service of the Hospital São Lucas, PUCRS
4. Neurologist; Professor of the Department of Neurology of the Hospital São Lucas, PUCRS
5. Nephrologist, Member of the Nephrology Service of the Hospital São Lucas, PUCRS
Correspondence to: Henrique Luiz Staub. Av. Ipiranga, 6690/220 – Jardim Botânico. Porto Alegre, RS, Brazil. CEP: 90610-000. E-mail: [email protected]
804
Rev Bras Reumatol 2012;52(5):804-810
Posterior reversible encephalopathy syndrome (PRES) and systemic lupus erythematosus: report of two cases
occipital lobes (Figure 1). MP pulse therapy was interrupted,
and analgesics were prescribed. The vision abnormalities
improved after 72 hours and resolved within five days. After
ten days, the patient was asymptomatic. Three weeks later a
new brain MRI-T2/FLAIR showed no subcortical or cortical
T2 hyperintensity in the occipital region.
Case 2: A 39-year old Caucasian woman with SLE diagnosed two years before was on low-dose prednisone and
therapy with azathioprine due to thrombocytopenia. Owing
to a recent episode of severe hemolytic anemia (hemoglobin
1.7 g/L), the patient was submitted to MP pulse therapy and
intravenous immunoglobulin infusion. Subsequently, a bacterial pneumonitis and a catheter infection required intensive
care and a long in-patient stay. After recovery, the patient
was discharged from Hospital in a good general state. A
week later, the patient returned to Hospital due to an acute
cholangitis, which demanded endoscopic treatment followed
by cholecystectomy. Subsequently, the patient evolved with
multiple intra-hepatic abscesses. After two weeks in the infirmary receiving antibiotics, the patient, who had concomitant
autoimmune hemolysis, showed elevation of blood pressure,
headache, seizure, and mental confusion. A cranial CT was
normal, as well as the cerebrospinal fluid exam. The cerebral
MRI-T2/FLAIR revealed typical features of PRES in the subcortex of occipital and parietal lobes (Figure 2). Neurological
improvement was obtained by adjusting blood pressure levels.
A brain MRI carried out two weeks later showed impressive
regression of findings attributable to PRES (Figure 3). After
one month, the patient died due to a refractory sepsis.
PRES is an enigmatic disorder potentially triggered by a
variety of conditions, most commonly hypertensive crisis, renal
insufficiency, and immunosuppressive therapy.5 Other possible
etiologies include eclampsia,6 transplantation,7 and systemic
infections.8 A 58-year-old woman receiving gemcitabine and
cisplatin chemotherapy for a gallbladder tumor developed
PRES, according to a 2009 report.9 Our group recently described a case of a 74-year-old woman with pancreatic tumor
who also developed PRES after gemcitabine therapy.10 Of
Figure 1
Brain MRI-T2/FLAIR showing subcortical T2 hyperintensity
without enhancement in occipital lobes.
Figure 2
Brain MRI-T2/FLAIR showing T2 subcortical hyperintensity
without enhancement in parieto-occipital lobes before treatment.
Rev Bras Reumatol 2012;52(5):804-810
805
Streck et al.
Figure 3
Brain MRI-T2/FLAIR after two weeks of treatment.
interest, in a series of 120 cases of PRES, autoimmune disorders were identified in 45% of the patients.11
The first description of PRES in SLE patients is as recent
as 2006. The pathogenesis of PRES in patients with SLE is
probably multifactorial: hypertension, nephritis, disease activity and immunosuppressive drugs have all been implicated. The
distinctive role of immune mechanisms in the physiopathology
of PRES can be clouded by these concurrent conditions.12
In the first case herein reported, PRES was diagnosed in
a patient with active lupus nephritis undergoing MP pulse
therapy. Both renal disease and MP infusion could be triggered
PRES in this case, but the rapid neurological improvement after
withdrawal of MP favored the last hypothesis. In the second
806
patient, PRES appeared to be associated to active disease
(hemolysis), infection (hepatic abscesses), and a hypertensive
crisis, probably the latter being more relevant given the clinical
response to anti-hypertensive drugs. Of interest, visual changes
were present only in the first case. In the second case, differently from the first, parietal lesions were seen in addition to
occipital changes.
Looking at the recent literature, PRES manifested by
seizures and loss of vision was reported in a case of SLE
in 2007.13 In 2008, four new cases of PRES were described
in adults with SLE.14 A woman with lupus nephritis and
PRES developed intraparenchymal and subarachnoid
hemorrhage, according to a 2010 report.15 Recently, Balint
syndrome (a disorder of inaccurate visually guided saccades,
optic ataxia, and simultanagnosia) presented as PRES in a SLE
patient.16 Of note, two reports accounted for the occurrence of
PRES in juvenile SLE.17,18
Varaprasad et al.19 reviewed the features of 13 patients
with SLE and PRES from 2006–2010: all had active disease
and hypertension. Six patients had PRES as part of their initial
presentation of SLE, and nine had nephritis. Four patients were
on cyclophosphamide therapy when they developed PRES.19
Of interest, an association of PRES with lupus activity had
already been postulated.11,20
Even though the classical neurolupus includes seizures
and psychosis, a number of other features such as myelopathy, optic neuropathy, meningitis, cognitive dysfunction, and
antiphospholipid-related cerebral infarction could been seen in
SLE.21 PRES has been claimed as a particular form of neurological manifestation of SLE with characteristic MRI findings
and a usual good outcome. Antihypertensive, antiepileptic, and
supportive care are the mainstay of treatment.12,22
In summary, we herein report the first two cases of PRES
in Brazilian patients with SLE. MP pulse therapy, disease
activity, hypertension, and infection were possible triggers. In
practical terms, patients with SLE presenting headache, altered
sensorium, seizures and visual loss should be suspected of
PRES. Whether the intrinsic mechanisms leading to PRES in
SLE patients are associated to comorbidities or to the disease
itself, it should be solved in the future.
Rev Bras Reumatol 2012;52(5):804-810
Síndrome da encefalopatia posterior reversível (PRES) e lúpus eritematoso sistêmico: relato de dois casos
Figura 3
RM-T2/FLAIR de crânio após duas semanas de tratamento.
hipertensiva, insuficiência renal e terapia imunossupressora.5
Outras possíveis etiologias incluem eclampsia,6 transplantes7
e infecções sistêmicas.8 Uma paciente de 58 anos em quimioterapia com gemcitabina e cisplatina para tumor de vesícula
desenvolveu PRES, de acordo com descrição de Kwon et al.9
Nosso grupo recentemente descreveu o caso de uma paciente
de 74 anos com tumor pancreático que também evoluiu com
PRES após terapia com gemcitabina.10 De interesse, em uma
série de 120 casos de PRES, foram identificadas desordens
autoimunes em 45% dos pacientes.11
A primeira descrição de PRES em lúpicos foi muito recente (2006). A patogênese da PRES em pacientes com LES
é provavelmente multifatorial: hipertensão arterial, nefrite,
atividade da doença e drogas imunossupressoras têm sido
implicadas. Um papel para mecanismos imunes na fisiopatologia da PRES pode estar obscurecido por essas condições
concorrentes.12
No primeiro caso aqui reportado, a PRES foi diagnosticada
em uma paciente com nefrite lúpica ativa sob pulsoterapia de
MP. Tanto a doença renal quanto a infusão de MP podem ter deflagrado a PRES nesse caso, mas a rápida melhora neurológica
Rev Bras Reumatol 2012;52(5):804-810
após a suspensão da MP favorece a última hipótese. No segundo paciente, a PRES pareceu estar associada à doença ativa
(hemólise), infecção (abscessos hepáticos) e crise hipertensiva,
provavelmente a última sendo mais relevante, devido à resposta
clínica a drogas anti-hipertensivas. Destaca-se que alterações
visuais estiveram presentes somente no primeiro caso. No
segundo caso, diferente do primeiro, lesões parietais foram
observadas em adição às alterações occipitais.
Revisando a literatura recente, a PRES manifestada por
convulsões e perda visual foi reportada em um caso de LES
em 2007.13 Em 2008, quatro novos casos de PRES foram
descritos em adultos com LES.14 Uma paciente com nefrite
lúpica e PRES evoluiu com hemorragia intraparenquimatosa e subaracnoide, de acordo com descrição de 2010.15
Recentemente, a síndrome de Balint (entidade caracterizada
por sacadas visuais imprecisas, ataxia óptica e simultagnosia)
se apresentou como PRES em paciente com LES.16 Digno de
nota, duas descrições apontaram para a ocorrência de PRES
no LES juvenil.17,18
Varaprasad et al.19 revisaram os dados de 13 pacientes com
LES e PRES entre 2006–2010: todos tinham doença ativa e
hipertensão arterial. Seis pacientes tiveram PRES como parte de
sua apresentação inicial do LES, e nove apresentavam nefrite.
Quatro pacientes estavam sob terapia com ciclofosfamida quando desenvolveram PRES.19 Interessante notar que a associação
de PRES com atividade lúpica já havia sido postulada.11,20
Embora o neurolúpus clássico inclua convulsões e psicose,
uma variedade de outros achados como mielopatia, neuropatia
óptica, meningite, disfunção cognitiva e infartos cerebrais
associados a anticorpos antifosfolípides podem ser vistos na
doença.21 A PRES poderia representar uma forma particular de
manifestação neurológica do LES, com achados característicos
na RM e prognóstico geralmente favorável. Anti-hipertensivos,
anticonvulsivantes e cuidados de suporte compreendem o pilar
do tratamento.12,22
Em suma, reportamos aqui os primeiros dois casos de PRES
em pacientes brasileiros com LES. Pulsoterapia de MP, doença
ativa, hipertensão e infecção foram possíveis “gatilhos”. Em
termos práticos, pacientes com LES que apresentem cefaleia,
sensório alterado, convulsões e perda visual são suspeitos de
apresentarem PRES. Se os mecanismos intrínsecos que geram
PRES em pacientes com LES são associados a comorbidades
ou à doença em si, são questões a serem resolvidas no futuro.
REFERENCES
REFERÊNCIAS
1.
Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A et al.
A reversible posterior leukoencephalopathy syndrome. N Engl J
Med 1996; 334(8):494–500.
809
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2.
Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior reversible
encephalopathy syndrome: utility of fluid-attenuated inversion
recovery MR imaging in the detection of cortical and subcortical
lesions. AJNR Am J Neuroradiol 2000; 21(7):1199–206.
3. Schwartz RB. Hyperperfusion encephalopathies: hypertensive
encephalopathy and related conditions. Neurologist 2002; 8(1):22–34.
4. Lamy C, Oppenheim C, Méder JF, Mas JL. Neuroimaging in
posterior reversible encephalopathy syndrome. J Neuroimaging
2004; 14(2):89–96.
5. Petrović B, Kostić V, Sternić N, Kolar J, Tasić N. Posterior
reversible encephalopathy syndrome. Srp Arh Celok Lek 2003;
131(11–12):461–6.
6. Schwartz RB, Feske SK, Polak JF, DeGirolami U, Iaia A, Beckner KM
et al. Preeclampsia-eclampsia: clinical and neuroradiographic
correlates and insights into the pathogenesis of hypertensive
encephalopathy. Radiology 2000; 217(2):371–6.
7. Bartynski WS, Tan HP, Boardman JF, Shapiro R, Marsh JW.
Posterior reversible encephalopathy syndrome after solid organ
transplantation. AJNR Am J Neuroradiol 2008; 29(5):924–30.
8. Bartynski WS, Boardman JF, Zeigler ZR, Shadduck RK, Lister J.
Posterior reversible encephalopathy syndrome in infection, sepsis,
and shock. AJNR Am J Neuroradiol 2006; 27(10):2179–90.
9. Kwon EJ, Kim SW, Kim KK, Seo HS, Kim do Y. A case
of gemcitabine and cisplatin associated posterior reversible
encephalopathy syndrome. Cancer Res Treat 2009; 41(1):53–5.
10. Marrone LC, Marrone BF, de la Puerta Raya J, Gadonski G,
da Costa JC. Gemcitabine monotherapy associated with posterior
reversible encephalopathy syndrome. Case Rep Oncol 2011; 4(1):82–7.
11. Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA.
Posterior reversible encephalopathy syndrome: associated clinical and
radiologic findings. Mayo Clin Proc 2010; 85(5):427–32.
12. Kur JK, Esdaile JM. Posterior reversible encephalopathy syndrome –
an underrecognized manifestation of systemic lupus erythematosus.
J Rheumatol 2006; 33(11):2178–83.
810
13. Ozgencil E, Gülücü C, Yalçýn S, Alanoğlu Z, Unal N, Oral M
et al. Seizures and loss of vision in a patient with systemic lupus
erythematosus. Neth J Med 2007; 65(7):274.
14. Leroux G, Sellam J, Costedoat-Chalumeau N, Le Thi Huong D,
Combes A, Tieulié N et al. Posterior reversible encephalopathy
syndrome during systemic lupus erythematosus: four new cases and
review of the literature. Lupus 2008; 17(2):139–47.
15. Chen HA, Lin YJ, Chen PC, Chen TY, Lin KC, Cheng HH.
Systemic lupus erythematosus complicated with posterior reversible
encephalopathy syndrome and intracranial vasculopathy. Int J Rheum
Dis 2010; 13(4):e79–82.
16. Kumar S, Abhayambika A, Sundaram AN, Sharpe JA. Posterior
reversible encephalopathy syndrome presenting as Balint syndrome.
J Neuroophthalmol 2011; 31(3):224–7.
17. Punaro M, Abou-Jaoude P, Cimaz R, Ranchin B. Unusual neurologic
manifestations (II): posterior reversible encephalopathy syndrome
(PRES) in the context of juvenile systemic lupus erythematosus.
Lupus 2007; 16(8):576–9.
18. Muscal E, Traipe E, de Guzman MM, Myones BL, Brey RL,
Hunter JV. MR imaging findings suggestive of posterior reversible
encephalopathy syndrome in adolescents with systemic lupus
erythematosus. Pediatr Radiol 2010; 40(7):1241–5.
19. Varaprasad IR, Agrawal S, Prabu VN, Rajasekhar L, Kanikannan MA,
Narsimulu G. Posterior reversible encephalopathy syndrome in
systemic lupus erythematosus. J Rheumatol 2011; 38(8):1607–11.
20. Baizabal-Carvallo JF, Barragán-Campos HM, Padilla-Aranda HJ,
Alonso-Juarez M, Estañol B, Cantú-Brito C et al. Posterior reversible
encephalopathy syndrome as a complication of acute lupus activity.
Clin Neurol Neurosurg 2009; 111(4):359–63.
21. Hanly JG. Neuropsychiatric lupus. Rheum Dis Clin North Am 2005;
31(2):273–98.
22. Ishimori ML, Pressman BD, Wallace DJ, Weisman MH. Posterior
reversible encephalopathy syndrome: another manifestation of CNS
SLE? Lupus 2007; 16(6):436–43.
Rev Bras Reumatol 2012;52(5):804-810
LETTER TO THE EDITORS
APS ACTION in Brazil
© 2012 Elsevier Editora Ltda. All rights reserved.
T
he 13th International Congress on antiphospholipid
antibodies (aPL) occurred in Galveston, Texas, in April
2010. The topics discussed were diverse – among them,
new pathophysiological mechanisms, 1 other aPL associated with
antiphospholipid syndrome (APS),2 and controversies regarding
both clinical and obstetric manifestations.3 Another important
part of the Congress was the creation of six “task forces” to
evaluate the quality of information we have on APS, review
controversies, and decide what direction research must go.
The “task forces” had the following topics: laboratory
criteria; obstetric APS; catastrophic APS; neurological manifestations; management of thrombosis in patients with APS;
and clinical research. The latter group was chaired by Doruk
Erkan and Michael D. Lockshin, from Hospital for Special
Surgery, Cornell University Medical Center, New York, and
focused on evaluating the limitations of clinical research on
the theme, creating guidelines so that researchers can improve the
quality of studies, and formulating ideas to develop a multicenter well-designed clinical trial.
This task force reported that five elements hindered APS
clinical trials and the development of evidence-based treatment: 1) the detection of aPL is based on partially standardized
or non-standardized tests; clinical and basic studies included
patients with heterogeneous aPL profiles and different risks of
clinical events; 2) clinical and basic studies on APS included
patients from a heterogeneous group with different aPL-related
manifestations, of which some were controversial; 3) the
quantification and stratification of the risk of thrombosis and/
or adverse obstetric events are rarely incorporated into APS
clinical research; 4) most APS clinical studies included patients
with tests that were positive only on one occasion and/or with
low aPL titers measured by ELISA, as well as the fact that most
studies were retrospective and not population-based, with few
prospective and/or controlled studies; 5) the lack of understanding of particular mechanisms of clinical events mediated by
aPL limits the optimal clinical trial design. The conclusion was
that there was urgent need for an international collaborative
approach to design and conduct prospective, large-scale, and
Rev Bras Reumatol 2012;52(5):811-814
well-designed clinical trials in clinically significant patients
with persistent aPL.4
The same group met again in November 2010 in Miami, when
the APS ACTION – the Antiphospholipid Syndrome Alliance for
Clinical Trials and International Networking – was created with
the primary objective of facilitating the design of multicenter,
prospective multidisciplinary, and high-quality studies on the
disease, in addition to the formation of an international database.
The APS ACTION will provide guidelines for the creation of
studies and will mainly standardize the patients included based on
the clinical and laboratory criteria for APS described in 2006.5 The
group has currently 32 members from 19 centers in 10 countries.
The first step, perhaps the most ambitious one, is the database
creation. Considering that the clinical manifestation of the disease (thrombosis and/or obstetric complications) is a rare event,
the initial proposal is to follow 2,000 patients with persistently
positive aPL for 10 years, with regular assessments, as well as
data collection in the event of thrombosis. This database will
allow us to estimate the risk of recurrence and factors that influence the onset of the thrombotic event, in addition to better study
the association with manifestations that were not included in the
international criterion of 2006, such as thrombocytopenia and
migraine. Another important part is the monitoring of patients
with APS who had only obstetric complications (APS-OB),
assessing whether the risk of venous or arterial thrombosis is
higher than that for the general population.
This question is the justification for the second study proposed by APS ACTION: the use of hydroxychloroquine as the
primary prophylaxis for thrombosis in patients with persistently
positive aPL. The rationale for use hydroxychloroquine is the
decrease in thrombotic events in patients with systemic lupus
erythematosus and positive aPL. The patients will be randomized to receive hydroxychloroquine or just for routine followup and thrombotic events will be reported should they occur.
In August 2012 the inclusion of participating centers from
different parts of the world was concluded, as can be checked
on the website apsaction.org. The database has already been approved by the regulatory agencies in New York and Galveston,
811
LETTER TO THE EDITORS
in the USA; in Brescia, Italy; in Athens, Greece; and in Rio de
Janeiro, Brazil. Approval is awaited in other centers in China,
Japan, Israel, Colombia, Jamaica, Canada, England, Holand,
Italy, and Brazil. Two papers submitted as ACR abstracts, by
the APS ACTION Young Scholars were accepted for presentation: Andreoli L, Banzato A, Chighizola CB, Pons-Estel GJ,
Ramires de Jesus G, Lockshin MD, and Erkan D on Behalf of
APS ACTION. The Estimated Prevalence of Antiphospholipid
Antibodies in General Population Patients with Pregnancy Loss,
Stroke, Myocardial Infarction, and Deep Vein Thrombosis. November 13, 2012, Presentation Time: 3:15 PM - 3:30 (oral);
and Chighizola CB, Ramires de Jesus G, Andreoli L, Banzato A,
Pons-Estel GJ, Lockshin MD, and Erkan D on Behalf of APS
ACTION. The Estimated Prevalence of Antiphospholipid
Antibodies in the General Population with Pregnancy Morbidity.
- November 13, 2012, 9:00 AM - 6:00 PM (poster).
812
The possibility of being able to treat patients with APS
based on well-designed, multicenter studies with a significant
number of patients appears to be very close. We also expect
that initial data from APS ACTION and further studies on
this disease, a relatively recent one, can be shown at the 14th
International Congress on Antiphospholipid Antibodies, which
will be held in Rio de Janeiro from 18th–21st of September,
2013 (www.kenes.com/ APLA-LACA).
Roger Abramino Levy, for APS ACTION GROUP
PhD in Biological Sciences, Universidade Federal do Rio de Janeiro – UFRJ;
Adjunct Professor of the Discipline of Rheumatology,
Universidade do Estado do Rio de Janeiro – UERJ.
Guilherme Ribeiro Ramires de Jesús, for APS ACTION GROUP
Gynecologist and Obstetrician, UERJ;
Post-Graduated in Fetal Medicine, Instituto Fernandes Figueira – IFF/Fiocruz
Rev Bras Reumatol 2012;52(5):811-814
CARTA AOS EDITORES
apenas acompanhamento rotineiro, e os eventos trombóticos
serão relatados, caso ocorram.
No mês de agosto foi concluída a inclusão dos centros colaboradores ao redor do mundo, como pode ser consultado no
website apsaction.org. O banco de dados já foi aprovado pelas
agências regulatórias em Nova Iorque e Galveston, nos EUA;
em Brescia, Itália; em Atenas, na Grécia; e no Rio de Janeiro.
Aguarda aprovação em outros centros na China, no Japão, em
Israel, Colombia, Jamaica, Canadá, Inglaterra, Holanda, Itália e
Brasil. Dois estudos submetidos como abstracts ao ACR, pelos
jovens colaboradores do APS ACTION, foram aceitos para apresentação: Andreoli L, Banzato A, Chighizola CB, Pons-Estel GJ,
Ramires de Jesus G, Lockshin MD, and Erkan D on Behalf of
APS ACTION. The Estimated Prevalence of Antiphospholipid
Antibodies in General Population Patients with Pregnancy Loss,
Stroke, Myocardial Infarction, and Deep Vein Thrombosis. November 13, 2012, Presentation Time: 3:15 PM - 3:30 (oral); e
Chighizola CB, Ramires de Jesus G, Andreoli L, Banzato A, PonsEstel GJ, Lockshin MD, and Erkan D on Behalf of APS ACTION.
The Estimated Prevalence of Antiphospholipid Antibodies in the
General Population with Pregnancy Morbidity. - November 13,
2012, 9:00 AM - 6:00 PM (poster).
A possibilidade de podermos tratar pacientes com SAF
a partir de estudos bem-desenhados, multicêntricos e com
um número significativo de pacientes parece estar próxima.
Esperamos também que dados iniciais do APS ACTION e novos
estudos sobre essa doença, relativamente recente, possam ser
814
apresentados no 14º Congresso Internacional sobre Anticorpos
Antifosfolípide, que ocorrerá, em conjunto com o IV Congresso
Latino-Americano de Autoimunidade, no Rio de Janeiro, de 18
a 21 de setembro de 2013 (www.kenes.com/APLA-LACA).
Roger Abramino Levy, pelo APS ACTION GROUP
Doutor em Ciências Biológicas, Universidade Federal do Rio de Janeiro – UFRJ;
Professor-Adjunto da Disciplina de Reumatologia,
Universidade do Estado do Rio de Janeiro – UERJ.
Guilherme Ribeiro Ramires de Jesús, pelo APS ACTION GROUP
Ginecologista e Obstetra, UERJ;
Pós-Graduação em Medicina Fetal, Instituto Fernandes Figueira – IFF/Fiocruz
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ERRATUM
2012 Brazilian Society of Rheumatology
Consensus on the management of comorbidities
in patients with rheumatoid arthritis
[Rev Bras Reumatol 2012; 52(4):474-495]
Ivânio Alves Pereira, Licia Maria Henrique da Mota, Boris Afonso Cruz, Claiton Viegas Brenol,
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It should read:
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In Page 476, where it reads:
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It should read:
Treatment with other DMARDs and biologics, such as the drugs of the anti-TNF class, and mainly with the
IL-6 receptor inhibitor (tocilizumab) have controlled inflammation and increased the previously reduced
HDL and TC associated with inflammation, without interfering with the atherosclerotic index (TC/HDL),
and without increasing clinical cardiovascular events so far.42–45
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© 2012 Elsevier Editora Ltda. All rights reserved.
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