Jan/Feb - Sociedade Brasileira de Reumatologia

Transcrição

#3";*-*"/+063/"-0'3)&6."50-0(:t+"/'&#]3&7*45"#3"4*-&*3"%&3&6."50-0(*"+"/'&7]70-t/]
Moderna caneta
aplicadora com
formato anatômico
1
O primeiro anti-TNF subcutâneo
com uma única aplicação mensal.1
Desde o lançamento, o primeiro anti-TNF
com indicação para Artrite Reumatoide, Artrite
Psoriásica e Espondilite Anquilosante.1
Moderna caneta aplicadora.
Basta um único movimento.
Apenas uma única administração
no mesmo dia em cada mês.1
Anticorpo monoclonal humano.1
ISSN 0482-5004
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
JANUARY/FEBRUARYt7PMVNFt/VNCFS
+"/&*30'&7&3&*30t7PMVNFt/ÞNFSP
Baixa incidência de reações no local da aplicação.1
REFERÊNCIA BIBLIOGRÁFICA: 1. Bula de Simponi. BULA RESUMIDA. SIMPONI® (GOLIMUMABE). Forma farmacêutica e apresentações: Embalagem com 1 caneta aplicadora SmartJect com solução injetável de SIMPONI® 50 mg/0,5 mL. As embalagens de
SIMPONI® devem ser mantidas sob refrigeração (2ºC a 8ºC), protegidas da luz e não devem ser congeladas. Não agitar. A caneta aplicadora SmartJect deve ser mantida na embalagem original para proteger da luz. Uso adulto e pediátrico. Uso subcutâneo.
Indicações: tratamento da artrite reumatóide (AR) ativa em pacientes adultos, quando a resposta à terapia com medicamento antirreumático modificador da doença (DMARD), incluindo metotrexato (MTX), foi inadequada ou em pacientes adultos não tratados
previamente com MTX. SIMPONI® pode ser usado em pacientes previamente tratados com um ou mais inibidor(es) de TNF; tratamento de artrite psoriásica ativa em pacientes adultos, quando a resposta à terapia prévia com DMARD foi inadequada; tratamento
da espondilite anquilosante (EA) ativa em pacientes adultos quando a resposta à terapia convencional foi inadequada. SIMPONI® também demonstrou melhorar a função física e a qualidade de vida relacionada à saúde. Posologia: para todas as indicações,
SIMPONI® 50 mg é administrado na forma de uma injeção subcutânea uma vez ao mês, no mesmo dia do mês. Contraindicações: hipersensibilidade à golimumabe ou a qualquer um dos excipientes. Precauções e advertências: Houve relatos de infecções
bacterianas (incluindo septicemia e pneumonia), micobacteriana (tuberculose), fúngica invasiva e oportunistas, até mesmo fatalidades, em pacientes recebendo agentes bloqueadores de TNF, incluindo SIMPONI®. SIMPONI® não deve ser administrado em
pacientes com infecção ativa e clinicamente importante. Deve-se ter precaução quando considerar o uso de SIMPONI® em pacientes com infecção crônica ou histórico de infecção recorrente. Os pacientes devem ser aconselhados a evitar a exposição
a fatores de risco em potencial para infecção quando apropriado. Os pacientes devem ser avaliados quanto a fatores de risco para tuberculose e testados quanto à tuberculose latente antes do tratamento com SIMPONI®. O tratamento da tuberculose
latente deve ser iniciado antes da terapia com SIMPONI®. O uso de agentes bloqueadores de TNF foi associado com a reativação do vírus da hepatite B em pacientes portadores crônicos. Os portadores crônicos de hepatite B devem ser adequadamente
avaliados e monitorados antes e durante o tratamento com SIMPONI®, assim como por vários meses após a sua descontinuação. Desconhece-se o papel potencial da terapia bloqueadora de TNF no desenvolvimento de malignidades. Deve se tomar
cuidado ao considerar a terapia bloqueadora de TNF para pacientes com histórico de malignidade, ou quando se considera a continuação do tratamento em pacientes que desenvolvem malignidade; insuficiência cardíaca congestiva; eventos neurológicos;
reações hematológicas; vacinas; reações alérgicas. Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica. Interações medicamentosas: não foi realizado nenhum estudo de interação. A combinação de SIMPONI® e
anacinra e abatacepte não é recomendada. Vacinas de vírus vivos não devem ser administradas concomitantemente com SIMPONI®. Embora o uso concomitante de MTX resulte em maiores concentrações mínimas no estado de equilíbrio de SIMPONI®
em pacientes com AR, AP e EA, os dados não sugerem necessidade de ajuste de dose de SIMPONI® ou MTX. Reações adversas mais freqüentes: Infecção do trato respiratório superior (nasofaringite, faringite, laringite e rinite), infecções bacterianas
(como celulite), infecções virais (como gripe e herpes), bronquite, sinusite e infecções fúngicas superficiais, aumento na alanina aminotransferase, aumento no aspartato aminotransferase, anemia, tontura, parestesia, hipertensão, constipação, alopecia,
pirexia, reação no local da aplicação (eritema no local da aplicação, urticária, induração, dor, hematoma, prurido, irritação, parestesia). Superdose: recomenda-se que o paciente seja monitorado quanto a quaisquer sinais ou sintomas de efeitos adversos
e o tratamento sintomático apropriado seja instituído imediatamente. Venda sob prescrição médica. Ao persistirem os sintomas o médico deverá ser consultado. Schering-Plough Indústria Farmacêutica Ltda. MS- 1.0171.0184. Distribuído por Janssen-Cilag
Farmacêutica. Informações adicionais para prescrição: vide bula completa. INFOC 0800.7013017 – www.janssen.com.br - Cód.Set2011_B-simponi31-pro(caneta).doc. CONTRAINDICAÇÕES: ESTE MEDICAMENTO É CONTRAINDICADO PARA USO POR
PACIENTES COM HIPERSENSIBILIDADE À SUBSTÂNCIA ATIVA OU A QUALQUER UM DOS EXCIPIENTES. INTERAÇÕES MEDICAMENTOSAS: A COMBINAÇÃO DE SIMPONI® E ANACINRA OU ABATACEPTE NÃO É RECOMENDADA.
www.reumatologia.com.br
JULHO DE 2012 | MATERIAL DESTINADO À CLASSE MÉDICA
An_Simponi Simples.indd 1
RBR - Capas montadas.indd 1
7/13/12 10:29 AM
20/03/2013 17:27:35
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
Bimonthly Edition (Publicação Bimestral)
Editors (Editores)
Coeditors (Coeditores)
Max Victor Carioca Freitas
Eloísa Silva Dutra de Oliveira Bonfá
Mittermayer Barreto Santiago
Universidade Federal do Ceará, Fotaleza, CE, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil
Roberto Ezequiel Heymann
Hilton Seda
Paulo Louzada-Junior
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Pontifícia Universidade Católica do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
João Carlos Tavares Brenol
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Ricardo Fuller
Simone Appenzeller
Universidade Estadual de Campinas, Campinas, SP, Brazil
Editorial Board (Conselho Editorial)
Acir Rachid
Geraldo da Rocha Castelar Pinheiro
Maurício Levy Neto
Universidade Federal do Paraná, Curitiba, PR, Brazil
Universidade do Estado do Rio de Janeiro,
Gilberto Santos Novaes
Alexandre Wagner S Souza
Natalino H. Yoshinari
Pontifícia Universidade Católica de São Paulo,
São Paulo, SP, Brazil
Ari Stiel Radu
Isídio Calich
Nílzio Antônio da Silva
Universidade Federal de Goiás, Goiânia, GO, Brazil
Carlos Alberto von Muhlen
Ivânio Alves Pereira
Percival Degrava Sampaio-Barros
Faculdade de Medicina da Pontifícia Universidade
Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
Universidade Federal de Santa Catarina,
Florianópolis, SC, Brazil
Claudia Goldenstein-Schainberg
Jamil Natour
Universidade Federal do Rio Grande do Sul,
Porto Alegre, RS, Brazil
Cláudio Arnaldo Len
João Francisco Marques Neto
Rina Dalva P. N. Giorgi
Clóvis Artur Almeida da Silva
José Goldenberg
Cristiano Augusto de Freitas Zerbini
José Roberto Provenza
Adil Muhib Samara
Hospital Heliópolis, São Paulo, SP, Brazil
Milton Helfestein Jr.
Ricardo M. Xavier
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
Roger A. Levy
Universidade Estadual do Rio de Janeiro,
Rosa Maria Rodrigues Pereira
Jozélio Freire de Carvalho
Centro Médico Aliança, Salvador, BA, Brazil
Rozana Mesquita Ciconelli
Lais V. Lage
Samuel Katsuyki Shinjo
Lilian Tereza Lavras Costallat
Sebastião Cézar Radominski
Luís Eduardo Coelho Andrade
Universidade Federal do Paraná, Curitiba, PR, Brazil
Sheila Knupp de Oliveira
Emília Inoue Sato
Luiz Fernando de Souza Passos
Universidade Federal do Rio de Janeiro,
Daniel Feldman Polak
Durval Kraychete
Escola Bahiana de Medicina e Universidade
Federal da Bahia, Salvador, BA, Brazil
Eduardo de Souza Meireles
Eduardo Ferreira Borba Neto
Universidade Federal do Amazonas, Manaus, AM, Brazil
Fernanda Rodrigues de Lima
Marcelo de Medeiros Pinheiro
Fernando Queiroz da Cunha
Maria Odete E. Hilário
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Francisco Airton Castro Rocha
Marta Maria das Chagas Medeiros
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Simone Appenzeller
Universidade de Campinas, Campinas, SP, Brazil
Vera Lúcia Szejnfeld
Wiliam H. Chahade
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
International Editorial Board (Conselho Editorial Internacional)
Ariel Masetto
Juan Manuel Anaya
Munther Khamashta
Université de Sherbrooke, Sherbrooke, Canada
Corporación de Investigaciones Biológicas, Medellín, Colômbia
St. Thomas´ Hospital, London, UK
Arthur Kavanaugh
Luis Javier Jara
H Ralph Schumacher Jr
University of California, San Diego, USA
Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
University of Pennsylvania, Philadelphia, USA
Bernardo Pons Estel
Mario Cardiel
Ricardo Cervera Segura
Universidad Nacional de Rosario, Rosario, Argentina
Instituto Nacional de la Nutrición "Salvador Zubiran",
Morrelia, Mexico
Hospital Clinic, Barcelona, Spain
Hospital Monte Sinai, Cuenca, Equador
Mario Garcia-Carrasco
Chapel Allerton Hospital, Leeds, UK
Ernest Choy
Facultad de Medicina, BUAP, Puebla, Mexico
Thomas Dörner
King's College, London, UK
Mário Viana de Queiroz
Charite Hospital, Berlin, Germany
Jordi Antón López
Universidade Clássica de Lisboa, Lisboa, Portugal
Yehuda Shoenfeld
Hospital Sant Joan de Déu, Barcelona, Spain
Marvin Fritzler
José Antonio Melo Gomes
University of Calgary, Calgary, Canada
Chaim Sheba Medical Center, Tel Aviv University,
Tel Hashomer, Israel
Claudio Galarza Maldonado
Richard J Wakefield
Instituto Português de Reumatologia, Lisboa, Portugal
RBR 53(1).indb 1
20/03/2013 16:25:44
BSR Office (Secretaria SBR)
Rogério Quintiliano Amaral
Av. Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94
CEP 01402-000
São Paulo, SP
Fone/fax: 55 (11) 3289-7165
E-mail: [email protected]; [email protected]
website: www.reumatologia.com.br
Brazilian Journal of Rheumatology is listed in Web of Science, MEDLINE,
LILACS, SciELO, Scopus and Index Copernicus databases. BJR is affiliated to the
International Committee of Medical Journal Editors.
A Revista Brasileira de Reumatologia é indexada nas bases de dados Web of
Science, MEDLINE, LILACS, SciELO, Scopus e Index Copernicus. A RBR é filiada
ao International Committee of Medical Journal Editors.
Brazilian Journal of Rheumatology (BJR) is an official publication of the Brazilian
Society of Rheumatology (BSR) in partnership with Elsevier Editora Ltda. and is
dedicated to the medical community in Brazil and Latin America.
Edited by Brazilian Society of Rheumatology.
Published by Elsevier Editora Ltda. © 2013.
Tradução | Translation: Stela Maris Costalonga
All rights reserved and protected by law 9.610 - 19/02/98. No part of this publication
may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording or any information storage and
retrieval system, without permission in writing from BSR and the Publisher.
BJR receives finnancial support from Fundos Remanescentes da Sociedade
Brasileira de Reumatologia.
A Revista Brasileira de Reumatologia (RBR) é uma publicação oficial da Sociedade
Brasileira de Reumatologia (SBR) em conjunto com Elsevier Editora Ltda., distribuída
exclusivamente à classe médica do Brasil e da América Latina.
Editada por Sociedade Brasileira de Reumatologia.
Publicada por Elsevier Editora Ltda. © 2013.
Todos os direitos reservados e protegidos pela lei 9.610 - 19/02/98. Nenhuma parte desta
publicação poderá ser reproduzida, sem autorização prévia, por escrito, da Elsevier
Editora Ltda. e da SBR, sejam quais forem os meios empregados: eletrônicos, mecânicos,
fotográficos, gravação ou quaisquer outros.
A RBR recebe auxílio financeiro de Fundos Remanescentes da Sociedade Brasileira de
Reumatologia.
RJ:
SP:
Website:
E-mail:
Tel.: 21 3970-9300 Fax: 21 2507-1991
Tel.: 11 5105-8555 Fax: 11 5505-8908
www.elsevier.com
[email protected]
No responsibility is assumed by Elsevier or BSI for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained
in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Although all advertising material is expected to conform to ethical (medical)
standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such
product or of the claims made of it by its manufacturer.
A Elsevier não assume nenhuma responsabilidade por qualquer injúria e/ou danos a pessoas ou bens como questões de
responsabilidade civil do fabricante do produto, de negligência ou de outros motivos, ou por qualquer uso ou exploração
de métodos, produtos, instruções ou ideias contidas no material incluso. Devido ao rápido avanço no campo das ciências
médicas, em especial, uma verificação independente dos diagnósticos e dosagens de drogas deve ser realizada. Embora
todo o material de publicidade deva estar em conformidade com os padrões éticos (médicos), a inclusão nesta publicação
não constitui uma garantia ou endosso da qualidade ou valor de tal produto ou das alegações feitas pelo seu fabricante.
EM 6813
Content dedicated to the medical community. Material de distribuição exclusiva à classe médica.
RBR 53(1).indb 2
20/03/2013 16:25:44
INSTRUC TIONS TO AUTHORS
The Brazilian Journal of Rheumatology (BJR), an official organ of Sociedade
Brasileira de Reumatologia (Brazilian Society of Rheumatology), was founded
in 1957 and is published bimonthly. The journal publishes original articles,
review articles, brief communications, case reports and letters to the editors.
To submit a manuscript, please access the site http://ees.elsevier.com/bjr.
Format of the manuscript
The manuscript can be submitted in Portuguese or English, double spaced,
with 2.5 cm margins. Unconventional abbreviations, medical jargon and
telegraphic style should not be used in the text. Citation of drugs and
pharmaceutical products must be done using pharmacological nomenclature,
without any mention to commercial names.
Manuscript structure
Manuscript*, Title Page*, Cover Letter, and Author Agreement* must be
submitted in separate files. Tables and Figures should be numbered as cited
in the text and sent in separate files with corresponding titles and legends.
(*required files)
Title page
The title page should contain: a) the full title; b) the full name of the authors
and their most important academic degree; c) the department and institution
where the study was originated; d) the full address and e-mail of the
corresponding author; e) conflict of interest and relevant financial agencies;
f) a running title with no more than 60 characters.
Author Agreement
It is the document where the authors declare that the manuscript is original, in
addition to approve the manuscript object of the submission, the authorship
and the order of authors listed. It must be signed by all authors. Below is
presented an example.
Dear Editor,
We, the undersigned, declare that this manuscript is original, has not been
published before and is not currently being considered for publication elsewhere.
We would like to draw the attention of the Editor to the following publications
of one or more of us that refer to aspects of the manuscript presently being
submitted.
We confirm that the manuscript has been read and approved by all named
authors and that there are no other persons who satisfied the criteria for
authorship but are not listed. We further confirm that the order of authors
listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the
Editorial process. He/she is responsible for communicating with the other
authors about progress, submissions of revisions and final approval of proofs.
(Signature of all authors)
Original article
The original article should contain: the title page, the abstract page with
keywords, introduction, material and methods or patients and methods, results
and discussion, acknowledgements, references, tables, figures and figure
legends. Original articles should not exceed 5,000 words including references
and excluding the title page, abstract, tables and legends. It is allowed up to
six figures or tables and 50 references.
Abstract page
The abstract page should contain: a) objective, methods, results and
conclusions, with no more than 250 words; b) three to five keywords.
Introduction
As the aim of this section is to define the purpose and the reasons for the
accomplishment of the work, we do not recommend a large literature review.
Patients and methods or Material and methods
This section should include enough information that allows the reproduction of
the work and, when it is relevant, the approval by the institutional Committee
of Ethics. The methods employed in the statistical analysis should always
be quoted.
RBR 53(1).indb 3
Results
They should be clear and concise. Tables and graphics should not duplicate
information.
Discussion
It should be concise, interpreting the results in the context of the present literature.
Please do not exceed the limit of half the number of pages of the complete work.
Acknowledgments
Only to people who contributed; i.e., with techniques, discussion and sending
patients. Financial help should be referred in the title page.
References
They should be quoted in the text in Arabic numerals, superscript, with no brackets.
Numbering should be sequencial, according to the quotation order in the text.
Please quote all the authors in works with until six authors; after six authors,
quote the first six followed by the expression et al. Reference Manager or Endnote
programs are strongly recommended for use adopting the Vancouver style.
Examples for reference citation are presented below. Authors should consult
NLM’s Citing Medicine for additional information on the reference formats.
Printed article
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Reference retrieved from electronic address
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink. com.w10069.dotlib.com.
br/content/l05j4j3332041225/fulltext.pdf. [Accessed in February 24, 2008].
Book
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical
microbiology. 4th ed. St. Louis: Mosby; 2002.
Tables and figures
Each Table or Figure should be numbered with Arabic numerals and sent in
an individual file (.jpg, .tif, .png, .xls, .doc) with minimum of 300 dpi. Titles
and legends should be in the same Table/Figure file to wich they refer. Tables
and Figures should include enough information so the reader can understand
them without going to the text.
Photomicrographies should include the appropriated scale.
Review article
Reviews, preferentially systematic, may be submitted to BJR. They should
cover deeply any interesting theme for the rheumatologist. They do not present
a standard structure, neither introduction or conclusion. Please send abstracts
without subdivisions with three to five keywords. Review articles should not
exceed 6,000 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to five figures or tables and 70 references.
Case report
Must have six authors at most. They should include an abstract and keywords,
without subdivisions. The text, however, should present the following sections:
introduction, which should be concise; case report, containing the description and
the evolution of the clinical case, laboratory exams, illustrations and tables (that
substitute the sections material and methods and results); and discussion. It should
not exceed 1,500 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to two figures or tables and 15 references.
Brief communication
It covers a point or a specific detail. It should present an abstract with no
more than 250 words and three to five keywords. The text does not include
subdivisions, and should not exceed 2,500 words including references and
excluding the title page, abstract, tables and legends. It is allowed up to three
figures or tables and 25 references.
20/03/2013 16:25:44
Rules for applying the appropriate tense in scientific writing
Context or section
Appropriate verb tense
Abstract
Past tense
Introduction
Most present tense (established facts,
previous published data)
Methods, materials used,
and results
Past tense
Discussion/Conclusion
Mixture of past and present, sometimes
future tense
Attribution
Past tense
Ex.: Andrade et al. reported that...
Description of Tables and
Figures
Present tense
Established knowledge,
previous results etc.
Present tense
General rules to obtain a good scientific writing:
1. Use active voice.
2. Setences must be short, clear and objective.
3. Units of measurement are abbreviated when use with numerical values
(e.g., 1 mg), but are not abbreviated if used without numerical values.
Systeme International d'Únites (SI units) must be used. Remember to
leave a space between the number and unit (e.g., 10 mg/dL), except for
the percentage mark that follows the number without space (e.g., 70%).
The plural form of units of measurement is the same as the singular form
(e.g., 1 mL, 10 mL; 1 h, 10 h). Spell out numbers at the beginning of a
sentence.
4. Define abbreviations the first time they appear. Avoid abbreviations in
tittles and abstracts.
5. Do not use contractions (e.g., doesn't, can't etc.).
Recommended book: Rogers SM. Mastering scientific and medical writing:
a self-help guide. Berlin: Springer; 2007.
Legal and ethical considerations
According to the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals (International Committee of Medical Journal Editors –
February 2006).
Conflict of interest
Public trust in the peer review process and the credibility of published
articles depend in part on how well conflict of interest is handled during
writing, peer review, and editorial decision making. Conflict of interest
exists when an author (or the author’s institution), reviewer, or editor has
financial or personal relationships that inappropriately influence (bias) his
or her actions (such relationships are also known as dual commitments,
competing interests, or competing loyalties). These relationships vary
from those with negligible potential to those with great potential to
influence judgment, and not all relationships represent true conflict of
interest. The potential for conflict of interest can exist whether or not
an individual believes that the relationship affects his or her scientific
RBR 53(1).indb 4
judgment. Financial relationships (such as employment, consultancies,
stock ownership, honoraria, paid expert testimony) are the most easily
identifiable conflicts of interest and the most likely to undermine the
credibility of the journal, the authors, and of science itself. However,
conflicts can occur for other reasons, such as personal relationships,
academic competition, and intellectual passion.
Informed consent
Patients have a right to privacy, that should not be infringed without
informed consent. Identifying information, including patients’ names,
initials, or hospital numbers, should not be published in written descriptions,
photographs, and pedigrees unless the information is essential for scientific
purposes and the patient (or parent or guardian) gives written informed
consent for publication. Informed consent for this purpose requires that a
patient who is identifiable be shown the manuscript to be published. Authors
should identify Individuals who provide writing assistance and disclose the
funding source for this assistance. Identifying details should be omitted if
they are not essential.
Complete anonymity is difficult to achieve. However, an informed consent
should be obtained if there is any doubt. For example, masking the eye
region in photographs of patients is inadequate protection of anonymity. If
identifying characteristics are altered to protect anonymity, such as in genetic
pedigrees, authors should provide assurance that alterations do not distort
scientific meaning and editors should so note. When informed consent has
been obtained it should be indicated in the published article.
Ethical treatment
When reporting experiments on human subjects, authors should indicate
whether the procedures followed were in accordance with the ethical
standards of the responsible committee on human experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as
revised in 2000. If doubt exists whether the research was conducted in
accordance with the Helsinki Declaration, the authors must explain the
rationale for their approach, and demonstrate that the institutional review
body explicitly approved the doubtful aspects of the study. When reporting
experiments on animals, authors should be asked to indicate whether the
institutional and national guide for the care and use of laboratory animals
was followed.
Clinical trials registry
Clinical trials must be registered according to WHO recommendation at www.
who.int/ictrp/en/. The definition of clinical trial include preliminary trials
(phase I): any study with prospective recruiting of subjects to undergo any
health-related intervention (drugs, surgical procedures, equipment, behavioral
therapies, food regimen, changes in health care) to evaluate the effects on
clinical outcomes (any biomedical or health-related parameter, including
pharmacokinetics measurements and adverse reactions).
The BJR has the right not to publish trials not complying with these and
other legal and ethical standards determined by international guidelines.
Financing and support
The authors should also inform if they received financing or support
from institutions like CNPq, CAPES, SBR Remaining Funds, Graduated
Institutions, Laboratories etc.
20/03/2013 16:25:44
INSTRU˙
ES PARA OS AUTORES
A Revista Brasileira de Reumatologia (RBR), órgão oficial da Sociedade Brasileira de Reumatologia, foi fundada em 1957 e é publicada bimestralmente.
A revista publica artigos originais, artigos de revisão, comunicações breves,
relatos de casos e cartas aos editores.
Resultados
Devem ser claros e concisos. Tabelas e gráficos não devem duplicar informações.
Discussão
O manuscrito deve ser submetido online através do site http://ees.elsevier.com/bjr.
Deve ser concisa, interpretando os resultados no contexto da literatura atual. É
conveniente não ultrapassar a metade do número de páginas do trabalho completo.
Apresentação do manuscrito
Agradecimentos
O manuscrito pode ser submetido em português ou inglês, em espaço
duplo, com margens de 2,5 cm. No texto não devem ser empregadas
abreviaturas não convencionais, gírias (jargões) médicas ou redação tipo
telegráfica. A citação de medicamentos e produtos farmacêuticos deve
ser feita utilizando-se apenas a nomenclatura farmacológica, sem menção
do nome comercial.
Apenas às pessoas que contribuíram, por exemplo, com técnicas, discussão e
envio de pacientes. Auxílio financeiro deve ser referido na página do título.
Estrutura do manuscrito
Manuscript*, Title Page*, Cover Letter e Author Agreement* devem ser
enviados em arquivos individuais. Tabelas e figuras devem ser numeradas
conforme citadas no texto e enviadas em arquivos separados, com títulos e
legendas correspondentes. (*arquivos obrigatórios)
Página do título
Deve conter: a) título do artigo; b) nome completo dos autores e sua titulação
mais importante; c) departamento(s) e instituição(ões) onde se originou o trabalho; d) nome, endereço completo e e-mail válido do autor responsável para
correspondência; e) conflito de interesse e agências financiadoras relevantes;
f) título resumido com no máximo 60 caracteres.
Author Agreement
É o documento no qual os autores declaram a originalidade do manuscrito,
além de aprovarem o artigo objeto da submissão, a autoria e a ordem da lista
de autores. Deve ser assinado por todos os autores. A seguir é apresentado
um modelo.
Caro Editor,
Os autores, abaixo assinados, declaram que este manuscrito é original,
não foi publicado antes e não se encontra submetido para qualquer outra
publicação.
Gostaríamos de pedir a atenção do Editor para a presente publicação de nós
autores, referente a aspectos do presente manuscrito submetido.
Confirmamos que o manuscrito foi lido e aprovado por todos os autores
signatários e que não há nenhum outro autor a fazer parte senão os listados.
Confirmamos também que a ordem dos autores listada no manuscrito foi
aprovada por todos.
Entendemos que o Autor para Correspondência será o único contato para o
processo editorial. Ele será o único responsável pela comunicação com os
demais autores acerca do progresso da submissão, da revisão do manuscrito
e de sua aprovação final.
(Assinatura de todos os autores)
Artigo Original
Deve conter: página do título, página de resumo com palavras-chave, introdução, material e métodos ou pacientes e métodos, resultados e discussão,
agradecimentos, referências, tabelas, figuras e legendas das figuras. Não
deve exceder 5.000 palavras, incluindo-se as referências e excluindo-se a
página do título, resumo, tabelas e legendas. Pode exibir até seis figuras ou
tabelas e até 50 referências.
Referências
Devem ser citadas no texto em algarismos arábicos, sobrescritos e depois da
pontuação, sem parênteses ou colchetes. A numeração deve ser sequencial,
de acordo com a ordem de citação no texto. Nas referências com mais de
seis autores, devem ser citados os seis primeiros, seguidos pela expressão
et al. Sugere-se a utilização dos programas Reference Manager ou Endnote,
seguindo-se o estilo Vancouver. Exemplos de referência para diferentes
formatos são apresentados a seguir. Os autores devem consultar o NLM’s
Citing Medicine para mais informações sobre os formatos das referências.
Artigo de revista
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Artigo extraído de endereço eletrônico
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink.com.w10069.dotlib.com.br/
content/l05j4j3332041225/fulltext. pdf. [Accessed in February 24, 2008].
Livro
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.
Tabelas e Figuras
Cada tabela ou figura deverá ser numerada em algarismo arábico e enviada
em arquivo separado (.jpg, .tif, .png, .xls, .doc) com 300 dpi no mínimo.
Título e legenda devem estar no mesmo arquivo da figura ou tabela a que se
referem. Tabelas e ilustrações devem ser autoexplicativas, com informações
suficientes para sua compreensão sem que se tenha de recorrer ao trabalho.
Fotomicrografias devem incluir a escala apropriada.
Artigo de Revisão
Revisões, preferencialmente sistemáticas, podem ser submetidas à RBR,
devendo abordar com profundidade um tema de interesse para o reumatologista. Não apresentam estruturação padronizada, prescindindo de introdução
ou discussão. Devem apresentar resumo sem subdivisões, com três a cinco
palavras-chave, e não devem exceder 6.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Podem
exibir até cinco figuras ou tabelas e até 70 referências.
Relato de Caso
Introdução
Deve incluir resumo e palavras-chave, sem necessidade de subdivisões. O texto,
porém, apresenta as seguintes seções: introdução, que deve ser concisa; relato de
caso, contendo a descrição e a evolução do quadro clínico, exames laboratoriais,
ilustrações e tabelas (que substituem as seções material e métodos e resultados);
e discussão. Deve conter no máximo seis autores, e não deve exceder 1.500
palavras, incluindo-se as referências e excluindo-se a página do título, resumo,
tabelas e legendas. Pode exibir até duas figuras ou tabelas e até 15 referências.
A finalidade dessa seção é definir o propósito e as razões para a realização
do trabalho. Não se recomenda extensa revisão da literatura.
Comunicação breve
Página de resumo
Deve conter: a) objetivo, métodos, resultados e conclusões, não excedendo
250 palavras; b) três a cinco palavras-chave.
Pacientes e métodos ou Material e métodos
Deve incluir informações suficientes que permitam a reprodução do trabalho e,
quando pertinente, a aprovação pelo Comitê de Ética institucional. Os métodos
empregados na análise estatística devem sempre ser citados.
RBR 53(1).indb 5
Aborda um ponto ou detalhe específico de um tema. Deve incluir resumo
com no máximo 250 palavras, e três a cinco palavras-chave. O texto não
necessita subdivisões, deve ter até 2.500 palavras incluindo-se as referências
e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até
três figuras ou tabelas e até 25 referências.
20/03/2013 16:25:44
Regras para aplicar tempos verbais apropriados de acordo com
o contexto ou seção
Contexto ou seção
Resumo
Introdução
Métodos, materiais e
resultados
Discussão/Conclusão
Atribuições
Descrição de Tabelas e Figuras
Conhecimento estabelecido e
resultados prévios
Tempo verbal apropriado
Passado
Presente, quando se referir a fatos estabelecidos e conhecimento prévio
Passado
Combinado de passado (quando se referir a resultados obtidos no trabalho) e
presente (quando se referir a fatos estabelecidos e conhecimento prévio); às
vezes pode ser utilizado o futuro (especialmente quando se referir a perspectivas de trabalhos a serem realizados)
Passado
Ex.: Andrade et al. relataram...
Presente
Presente
Regras gerais para se obter uma boa escrita em um artigo científico:
1. Prefira a voz ativa.
2. As sentenças devem ser curtas, claras e objetivas.
3. A unidade de medida deve ser abreviada quando empregada com
valores numéricos (p. ex., 1 mg), mas escrita por extenso quando
separada de valor numérico. Utilize o Sistema Internacional de
Unidades (SI units) para definir as unidades de medida. Lembre-se
de deixar um espaço entre o número e a unidade (p. ex., 10 mg/dL),
exceto quando for porcentagem, que deve estar junto (p. ex., 70%).
O plural das unidades de medida é a mesma forma do singular (p.
ex., 1 mL, 10 mL; 1 h, 10 h). Quando iniciarem a frase, os números
devem estar por extenso, e não em algarismo arábico.
4. Defina a abreviação na primeira vez que aparecer no texto principal.
Após a definição, use sempre a abreviação em vez da forma por extenso.
Evite o uso de abreviações no título e no resumo.
5. Ao escrever em inglês, não utilize contrações (p. ex., prefira does not em
vez de doesn't).
Livro recomendado: Rogers SM. Mastering scientific and medical writing: a
self-help guide. Berlin: Springer; 2007.
Considerações éticas e legais
A RBR segue as normas do Uniform Requirements for Manuscripts (URM)
Submitted to Biomedical Journals desenvolvidas pelo The International
Committee of Medical Journal Editors (ICMJE) – fevereiro de 2006.
Conflito de interesse
A confiança pública no processo de revisão por pares e a credibilidade
dos artigos publicados dependem, em parte, de como o conflito de
interesse é administrado durante a redação, a revisão por pares e a
decisão editorial. O conflito de interesse existe quando um autor (ou
instituição do autor), revisor ou editor tem relações financeiras ou
pessoais que influenciem de forma inadequada (viés) suas ações (tais
relações são também conhecidas como duplo compromisso, interesses
conflitantes ou fidelidades conflitantes). Essas relações variam entre
aquelas com potencial insignificante até as com grande potencial
para influenciar o julgamento, e nem todas as relações representam
verdadeiro conflito de interesse. O potencial conflito de interesse pode
RBR 53(1).indb 6
existir dependendo se o indivíduo acredita ou não que a relação afete
seu julgamento científico. Relações financeiras (tais como emprego, consultorias, posse de ações, testemunho de especialista pago) são os conflitos
de interesse mais facilmente identificáveis e os mais suscetíveis de minar a
credibilidade da revista, dos autores e da própria ciência. No entanto, podem
ocorrer conflitos por outras razões, tais como relações pessoais, competição
acadêmica e paixão intelectual.
Consentimento informado
Os pacientes têm o direito à privacidade, que não deve ser infringida
sem o consentimento informado. A identificação de informações,
incluindo os nomes dos pacientes, iniciais ou números no hospital,
não devem ser publicadas em descrições, fotografias e genealogias, a
menos que a informação seja essencial para os propósitos científicos
e o paciente (ou responsável) dê o consentimento livre e esclarecido
para a publicação.
O consentimento informado para este propósito requer que o manuscrito
a ser publicado seja mostrado ao paciente. Os autores devem identificar
os indivíduos que prestam assistência a escrever e divulgar a fonte de
financiamento para essa assistência. Detalhes identificadores devem ser
omitidos se não são essenciais.
O anonimato completo é difícil de se conseguir; no entanto, no caso
de qualquer dúvida, o consentimento deve ser obtido. Por exemplo,
mascarar a região ocular em fotografias de pacientes é uma proteção
de anonimato inadequada. Se as características de identificação são
alteradas para proteger o anonimato, como na linhagem genética, os
autores devem garantir que as alterações não distorçam o significado
científico. Quando o consentimento informado foi obtido, ele deve ser
indicado no artigo publicado.
Princípios éticos
Ao relatar experimentos em seres humanos, os autores devem indicar
se os procedimentos seguidos estiveram de acordo com os padrões
éticos do comitê responsável por experimentação humana (institucional e nacional) e com a Declaração de Helsinki de 1975, revisado em
2000. Se houver dúvida se a pesquisa foi realizada em conformidade
com a Declaração de Helsinki, os autores devem explicar a razão
para sua abordagem e demonstrar que o corpo de revisão institucional
aprovou explicitamente os aspectos duvidosos do estudo. Ao relatar
experimentos com animais, os autores devem indicar se as orientações
institucionais e nacionais para o cuidado e a utilização de animais de
laboratório foram seguidas.
Registro de ensaios clínicos
Os ensaios clínicos devem ser registrados segundo recomendação da
OMS em www.who.int/ictrp/en/. A definição de ensaios clínicos incluem ensaios preliminares (fase I): um estudo prospectivo com o
recrutamento de indivíduos submetidos a qualquer intervenção relacionada à saúde (medicamentos, procedimentos cirúrgicos, aparelhos,
terapias comportamentais, regime alimentar, mudanças nos cuidados
de saúde) para avaliar os efeitos em desfechos clínicos (qualquer
parâmetro biomédico e de saúde, inclusive medidas farmacocinéticas
e reações adversas).
A RBR tem o direito de não publicar trabalhos que não cumpram estas
e outras normas legais e éticas explicitadas nas diretrizes internacionais.
Financiamento e apoio
Os autores devem, também, informar se receberam financiamento ou apoio
de instituições como CNPq, CAPES, Fundos Remanescentes da SBR,
instituições universitárias, laboratórios etc.
20/03/2013 16:25:45
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Founded on July 15, 1948 (Fundada em 15 de julho de 1948)
Executive Board of Directors for the 2012–2014 Biennium
Diretoria Executiva para o Biênio 2012–2014
President (Presidente)
Walber Pinto Vieira, CE
General secretary (Secretário geral)
Francisco José Fernandes Vieira, CE
1st secretary (1º secretário)
Lauredo Ventura Bandeira, SP
2nd secretary (2ª secretária)
Rosa Maria Rodrigues Pereira, SP
Treasurer (Tesoureiro)
José Eyorand Castelo B. Andrade, CE
Vice-treasurer (Vice-tesoureiro)
José Roberto Provenza, SP
Scientific director (Diretor científico)
Mittermayer Barreto Santiago, BA
Elected president (Presidente eleito)
Cesar Emile Baaklini, SP
Rheumatology Aid Fund to
Rheumatology Research and Teaching
Conselho do Fundo de Auxílio a
Pesquisa e Ensino em Reumatologia
Acir Rachid, PR
Adil Muhib Samara, SP
Antônio Carlos Ximenes, GO
Caio Moreira, MG
Emília Inoue Sato, SP
Fernando de Souza Cavalcanti, PE
Fernando Neubarth, RS
Geraldo da Rocha Castelar Pinheiro, RJ
Geraldo Gomes de Freitas, PE
Hilton Seda, RJ
Iêda Maria Magalhães Laurindo, SP
João Carlos Tavares Brenol, RS
João Francisco Marques Neto, SP
Nílzio Antônio da Silva, GO
Sebastião Cezar Radominski, PR
Wiliam Habib Chahade, SP
Members (Membros)
Ana Cristina de Medeiros Ribeiro, SP
Claiton Viegas Brenol, RS
Eduardo de Souza Meirelles, SP
Jussara de Almeida L. Kochen, SP
Rafael Mendonça da Silva Chakr, RS
Representante junto ao Ministério da Saúde
Ana Patrícia de Paula, DF
Mário Soares Ferreira, DF
Comissão de Epidemiologia
Specialist Title Commission
Comissão de Título de Especialista
Coordinator (Coordenadora)
Members (Membros)
Fernanda Rodrigues Lima, SP
Gilda Aparecida Ferreira, MG
Ines Guimarães Silveira, RS
José Tupinambá Souza Vasconcelos, PI
Marcelo de Medeiros Pinheiro, SP
Mauro Goldfarb, RJ
Nafice Costa Araujo, SP
Rafael Navarrete, GO
Valeria Valim Cristo, ES
Wilton Silva dos Santos, DF
RBR 53(1).indb 7
Editorial Council (Conselho Editorial)
Kaline Medeiros Costa Pereira, SP
Edgard Torres dos Reis Neto, SP
Editors (Editores)
Tânia Carolina Monteiro de Castro, SP
Frederico Augusto Gurgel Pinheiro, SP
Collaborator (Colaborador)
Plínio José do Amaral, SP
Brazilian Journal of Rheumatology
Revista Brasileira de Reumatologia
Editors (Editores)
Max Victor Carioca Freitas, CE
Roberto Ezequiel Heymann, SP
Eloísa Silva Dutra de Oliveira Bonfá, SP
Hilton Seda, RJ
Mittermayer Barreto Santiago, BA
Paulo Louzada-Junior, SP
Ricardo Fuller, SP
Simone Appenzeller, SP
Epidemiology Commission
Representantes junto à AMB
Gustavo de Paiva Costa, DF
Morton Aaron Scheinberg, SP
BSR Bulletin (Boletim SBR)
Coeditors (Coeditores)
Representatives of Ministry of Health
Representatives of AMB
Comissão de Comunicação Social
Comissão de Economia da Saúde
Mirhelen Mendes de Abreu, SP
Representantes junto à PANLAR
Antonio Carlos Ximenes, GO
Maria Amazile Ferreira Toscano, SC
Media Commission
Health Economy Commission
Representatives of PANLAR
Maria Teresa R. A. Terreri, SP
Tania Caroline Castro, SP
Teresa Cristina Robazzi, BA
BSR Website (Site SBR)
Coordinators (Coordenadores)
Marcelo Cruz Rezende, MS
Maria Roseli Monteiro Callado, CE
Ethics and Discipline Commission
Eutilia Andrade Medeiros Freire, PB
Comissão de Ética e Disciplina
Members (Membros)
Coordinator (Coordenador)
Alessandra Souza Braz C. Andrade, PB
Bernardo Matos da Cunha, DF
Camila Cruz Leijoto, RJ
Carlos Augusto F. de Andrade, RJ
Jussara de Almeida L. Kochen, SP
Pediatric Rheumatology Commission
Comissão de Reumatologia Pediátrica
José Marques Filho, SP
Members (Membros)
Adriana Maria Kakehasi, MG
Antonio Carlos Althoff, SC
Henrique Josef, SP
João Elias Moura Jr., SC
José Geraldo Araújo Paiva, CE
José Roberto Pereira Santos, ES
Cláudio Arnaldo Len, SP
Members (Membros)
Adriana Maluf Elias Sallum, SP
Ana Paula Vecchi, GO
Andre de Souza Cavalcanti, PE
Blanca Elene Rios Gomes Bica, RJ
Carlos Nobre Rabelo Jr., CE
Claudia Saad Magalhães, SP
Clovis Artur Almeida da Silva, SP
Cynthia Torres Franca da Silva, RJ
Luciana Brandão Paim Marques, CE
Marcia Bandeira, PR
Teaching and Medical
Education Commission
Comissão de Ensino e Educação Médica
Francisco Airton Castro da Rocha, CE
Members (Membros)
Charles Lubianca Kohem, RS
Claudia Diniz Lopes Marques, PE
Cristina Costa Duarte Lanna, MG
Elaine Lira Medeiros de Bezerra, RN
20/03/2013 16:25:45
Elisa Martins das N. de Albuquerque, RJ
Jozélia Rego, GO
Marcelo Pimenta, GO
Maria José Pereira Vilar, RN
Ricardo Machado Xavier, RS
Samuel Katsuyuki Shinjo, SP
Congresses, Journeys, and
Events Commission
Comissão de Congressos, Jornadas e Eventos
Georges Basile Christopoulos, AL
Commission of Relations
with Groups of Patients
Osteoarthrosis Commission
Spinal Commission
Comissão de Osteoartrose
Comissão de Coluna Vertebral
Ibsen Bellini Coimbra, SP
Marcos Renato de Assis, SP
Members (Membros)
Members (Membros)
Antônio Carlos dos Santos Novaes, SP
Claudia Diniz Lopes Marques, PE
Elda Matilde Hirose Pastor, SP
Francisco Airton Castro da Rocha, CE
Francisco Saraiva da Silva Júnior, CE
Hilton Seda, RJ
José Caetano Macieira, SE
Reno Martins Coelho, RJ
Ricardo Fuller, SP
Ari Stiel Radu Halpern, SP
Carlos Appel da Silva, RS
Jamil Natour, SP
Jose Gerardo de Araújo Paiva, CE
Luíza Helena Coutinho Ribeiro, SP
Renê Donizeti Ribeiro de Oliveira, SP
Silvio Figueira Antonio, SP
Vasculopathies Commission
Comissão de Doenças
Osteometabólicas e Osteoporose
Comissão de Relações com
Grupos de Pacientes
Comissão de Vasculopatias Coordinators (Coordenadores)
Roger Abramino Levy, RJ
Helenice Alves Teixeira Gonçalves, DF
Members (Membros)
Members (Membros)
Ana Maria Camargo Gallo, SC
Ana Paula Espinula Gianordoli, ES
Luis Piva Junior, DF
Valderílio Feijó Azevedo, PR
Wanda Heloisa Rodrigues Ferreira, RJ
Adriana Danowski, RJ
Adriana Maria Kakehasi, MG
Alexandre Wagner S. de Souza, SP
Andreas Funke, PR
Carlos Ewerton Maia Rodrigues, CE
Isabella Vargas de Souza Lima, BA
Jozélia Rego, GO
Occupational Rheumatology Commission
Image Commission
Comissão de Reumatologia Ocupacional
Milton Helfenstein Junior, SP
Members (Membros)
Anna Beatriz Assad Maia, DF
Antônio Techy, PR
César Augusto Fávaro Siena, SP
Marco Aurélio Goldenfum, RS
BiobadaBrasil Comission
Comissão do BiobadaBrasil
David Cezar Titton, PR
Members (Membros)
Aline Ranzolin, PE
André Luiz Shinji Hayata, SP
Ines Guimarães da Silveira, RS
Roberto Ranza, MG
Valéria Cristo Valim, ES
Rheumatoid Arthritis Commission
Comissão de Artrite Reumatoide
Licia Maria Henrique da Mota , DF
Members (Membros)
Bóris Afonso Cruz, MG
Claiton Viegas Brenol, RS
Ieda Maria Magalhães Laurindo, SP
Jozélio Freire de Carvalho, BA
Lucila Stange Rezende Fronza, PR
Manoel Barros Bertolo, SP
Max Victor Carioca Freitas, CE
Nilzio Antônio da Silva, GO
Rina Dalva Neubarth Giorgi, SP
Rodrigo Aires Corrêa Lima, DF
RBR 53(1).indb 8
Osteomethabolic Diseases and
Osteoporisis Commission
Sebastião Cezar Radominski, PR
Members (Membros)
Ana Patricia de Paula, DF
Caio Moreira, MG
Charlles Heldan de Moura Castro, SP
Cristiano Augusto de F. Zerbini, SP
Elaine de Azevedo, SP
Laura Maria C. de Mendonça, RJ
Mailze Campos Bezerra, CE
Marco Antonio Rocha Loures, PR
Vera Lúcia Szejnfeld, SP
Comissão de Imagem Spondiloarthropathies Commission
Coordinator (Ccoordenador)
Comissão de Espondiloartropatias
José Alexandre Mendonça, SP
Members (Membros)
Andrea B. Vannucci Lomonte, SP
Cristiane Kayser Veiga da Silva, SP
Inês Guimarães Silveira, RS
Jamil Natour, SP
José Carlos Amaral Filho, MS
Karine Rodrigues da Luz, SP
Simone Appenzeller, SP
Verônica Silva Vilela, RJ
Procedures Commission
Comissão de Procedimentos
Coordinator (Ccoordenador)
Jamil Natour, SP
Members (Membros)
Luiza Helena Coutinho Ribeiro, SP
Monique Sayuri Konai, SP
Rita Nely Vilar Furtado, SP
Lupus Commission
Comissão de Lúpus
Evandro Mendes Klumb, RJ
Members (Membros)
Cristina Costa Duarte Lanna, MG
Eduardo Ferreira Borba Neto, SP
Eloisa Silva Dutra de Oliveira Bonfá, SP
Francinne Machado Ribeiro, RJ
Lilian Tereza Lavras Costallat, SP
Luiz Carlos Latorre, SP
Maria de Fátima Lobato da Cunha, PA
Odirlei Andre Monticielo, RS
Célio Roberto Gonçalves, SP
RBE Coordinator (Coordenador RBE)
Percival Degrava Sampaio Barros, SP
Members (Membros)
Antonio Carlos Ximenes, GO
Gustavo Gomes Rezende, MG
Ivânio Alves Pereira, SC
Marcelo Medeiros Pinheiro, SP
Mauro Waldemar Keisermann, RS
Thelma Larocca Skare, PR
Washington Alves Bianchi, RJ
Psoriatic Arthritis Subcommission
(Sub-Comissão de Artrite Psoriásica)
Claudia Goldenstein-Schainberg, SP
Roberto Ranza, MG
Rubens Bonfiglioli, SP
Sueli Coelho da Silva Carneiro, RJ
Valderilio Feijó Azevedo, PR
Pain, Fibromyalgia and Other Painful
Syndromes of the Soft Parts Commission
Comissão de Dor, Fibromialgia e Outras
Síndromes Dolorosas de Partes Moles
Marcelo Cruz Rezende, MS
Members (Membros)
Aline Ranzolin, PE
Daniel Feldman Pollak, SP
Eduardo dos Santos Paiva, PR
José Eduardo Martinez, SP
Marcos Aurélio Freitas Machado, SP
Nilton Salles Rosa Neto, SP
Rafael Mendonça da Silva Chakr, RS
Roberto Ezequiel Heymann, SP
20/03/2013 16:25:45
Documentation and Historical
Registry Commission
Comissão de Documentação e
Registro Histórico
Joaquim Jaguaribe Nava Ribeiro, RJ
Members (Membros)
Célio Roberto Gonçalves, SP
Henrique Josef, SP
José Eduardo Gonçalves, CE
José Knoplich, SP
José Marques Filho, SP
Lauredo Ventura Bandeira, SP
Lipe Goldenstein, BA
Plínio José Amaral, SP
Systemic Sclerosis Commission
Comissão de Esclerose Sistêmica
Percival Degrava Sampaio-Barros, SP
Members (Membros)
Adriana Fontes Zimmermann, SC
Carolina de Souza Muller, PR
Cláudia Tereza Lobato Borges, MA
Cristiane Kayser Veiga da Silva, SP
Eutília Andrade Medeiros Freire, PB
Giselle Baptista Maretti, RJ
João Francisco Marques Neto, SP
Maria Cecília Fonseca Salgado, RJ
Maria de Fátima Lobato da Cunha Sauma, PA
Mário Newton Leitão de Azevedo, RJ
Sheila Marcia de A. Fontenele, CE
Sjögren Syndrome Commission
(Comissão de Síndrome de Sjögren)
Valéria Valim Cristo, ES
Members (Membros)
Érica Vieira Serrano, ES
Leandro Augusto Tanure, MG
Sandra Gofinet Pasoto, SP
Sandra Lucia Euzébio Ribeiro, AM
Virginia Fernandes Moça Trevisani, SP
Ana Beatriz Vargas dos Santos, RJ
Eduardo dos Santos Paiva, PR
Hellen Mary da Silveira de Carvalho, DF
Rheumatology Society of Ceará
Endemic and Infectious
Diseases Commission
Rheumatology Society of Goiânia
(Comissão de Doenças
Endêmicas e Infecciosas)
Izaias Pereira da Costa, MS
Sandra Lucia Euzébio Ribeiro, AM
Members (Membros)
Ana Carolina de Oliveira S. Montandon, GO
Helena Lucia A. Pereira, AM
Luiz Sergio Guedes Barbosa, MT
Mauro Furtado Cavalcanti, PI
Natalino Hajime Yoshinari, SP
Rejane Maria R. de Abreu, CE
Roberta de Almeida Pernambuco, SP
Assisted Therapy Immunobiological
Centers Commission
(Comissão de Centros de Terapia
Imunobiológica Assistida)
Reno Martins Coelho, RJ
Members (Membros)
Adrian Nogueira Bueno, MG
Ana Teresa Amoedo Medrado, BA
Antonio Carlos Scafutto, MG
Claudio Goldenstein Schainberg, SP
Eliezer Rushansky, PE
Evelin D. Goldenberg M. M. da Costa, SP
José Eyorand Castelo B Andrade, CE
José Roberto Silva Miranda, SP
Manoel Barros Bertolo, SP
Rafael de Oliveira Fraga, MG
Ricardo Jorge de Percia Name, RJ
Vander Fernandes, MT
Supervisory Board (Conselho Fiscal)
Sociedade Cearense de Reumatologia
Dr. José Eyorand Castelo Branco de Andrade
Sociedade Goiana de Reumatologia
Dra. Ana Carolina Oliveira e Silva Montandon
Rheumatology Society of Maranhão
Sociedade Maranhense de Reumatologia
Dra. Raquel Moraes da Rocha Nogueira
Rheumatology Society Mato Grosso
Associação Mato-Grossense de Reumatologia
Dr. Vander Fernandes
Rheumatology Society of Minas Gerais
Sociedade Mineira de Reumatologia
Dr. Rafael de Oliveira Fraga
Rheumatology Society of São Paulo
Sociedade Paulista de Reumatologia
Dr. Paulo Louzada-Junior
Rheumatology Society of Pará
Sociedade Paraense de Reumatologia
Dr. Otávio Augusto Gomes da Paz
Rheumatology Society of Paraíba
Sociedade Paraibana de Reumatologia
Dra. Danielle Christinne Soares Egypto de Brito
Rheumatology Society of Paraná
Sociedade Paranaense de Reumatologia
Dr. Eduardo Santos Paiva
Rheumatology Society of Pernambuco
Sociedade Pernambucana de Reumatologia
Dra. Lílian David de Azevedo Valadares
Rheumatology Society of Piauí
Sociedade Piauiense de Reumatologia
Dra. Aline do Socorro Miranda Ribeiro
Rheumatology Society of Espírito Santo
Sociedade de Reumatologia do Espírito Santo
Dr. José Roberto Pereira Santos
Rheumatology Society of Mato Grosso do Sul
Professional Defense Commission
BSR – Regionals
(Comissão de Defesa Profissional)
Regionais – SBR
Sociedade de Reumatologia
do Mato Grosso do Sul
Dr. Marcelo Cruz Rezende
Rheumatology Society of Alagoas
Rheumatology Society of Rio de Janeiro
Francisco Deoclécio D. Rocha, RN
Vander Fernandes, MT
Sociedade Alagoana de Reumatologia
Dra. Inês Cristina de Mello
Sociedade de Reumatologia do Rio de Janeiro
Dr. Evandro Mendes Klumb
Members (Membros)
Rheumatology Society of Amazonas
Francisco Alves Bezerra Neto, RN
Matheus Staufackar Carlos, RN
Inês Cristina de Mello Lima, AL
Mauro Furtado Cavalcante, PI
Sociedade Amazonense de Reumatologia
Dra. Maria do Socorro A. de Souza
Rheumatology Society of
Rio Grande do Norte
Rheumatology Society of Bahia
do Rio Grande do Norte
Dr. Francisco Deoclécio Damasceno Rocha
Gout Commission
Sociedade Baiana de Reumatologia
Dra. Liliana D’Almeida Galrão
(Comissão de Gota)
Rheumatology Society of Brasília
Sociedade de Reumatologia de Brasília
Dr. Cleandro Pires de Albuquerque
do Rio Grande do Sul
Dr. Marco Aurélio Goldenfum
Members (Membros)
Rheumatology Society of Santa Catarina
Rheumatology Society of Sergipe
Antonio José Lopes Ferrari, SP
Sociedade Catarinense de Reumatologia
Dr. Gláucio Ricardo Werner de Castro
Sociedade Sergipana de Reumatologia
Dra. Regina Adalva de Lucena Couto Ocea
Rheumatology Society of Rio Grande do Sul
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Avenida Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 – CEP: 01402-000 – São Paulo, SP, Brasil
Phone/Fax:
55 11 3289-7165
E-mail:
[email protected], [email protected]
Website:
www.reumatologia.com.br
RBR 53(1).indb 9
20/03/2013 16:25:45
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
JANUARY/FEBRUARY 2013 • VOLUME 53 • NUMBER 1
JANEIRO/FEVEREIRO 2013 • VOLUME 53 • NÚMERO 1
ISSN: 0482-5004
EDITORIAL | EDITORIAL
1
2
Vaccination for patients with rheumatoid arthritis: a pressing need
Vacinação para pacientes com artrite reumatoide: uma necessidade premente
Claiton Viegas Brenol, Gecilmara Salviato Pileggi
ORIGINAL ARTICL ES | ARTIGOS ORIGINAIS
4
13
2012 Brazilian Society of Rheumatology Consensus on vaccination of patients with
rheumatoid arthritis
Consenso 2012 da Sociedade Brasileira de Reumatologia sobre vacinação em
pacientes com artrite reumatoide
Claiton Viegas Brenol, Licia Maria Henrique da Mota, Bóris Afonso Cruz, Gecilmara Salviato Pileggi, Ivânio Alves Pereira,
Lucila Stange Rezende, Manoel Barros Bertolo, Max Victor Carioca Freitas, Nilzio Antônio da Silva, Paulo Louzada-Junior,
Rina Dalva Neubarth Giorgi1, Rodrigo Aires Corrêa Lima, Geraldo da Rocha Castelar Pinheiro
24
29
Primary Sjögren’s syndrome prevalence in a major metropolitan area in Brazil
Prevalência da síndrome de Sjögren primária em importante área metropolitana no
Brasil
Valéria Valim, Eliana Zandonade, Ana Maria Pereira, Odvaldo Honor de Brito Filho, Erica Vieira Serrano, Carlos Musso,
Raquel Altoé Giovelli, Rozana Mesquita Ciconelli
35
41
Frequency of sexual dysfunction in women with rheumatic diseases
Frequência de disfunção sexual em mulheres com doenças reumáticas
Clarissa de Castro Ferreira, Licia Maria Henrique da Mota, Ana Cristina Vanderley Oliveira, Jozélio Freire de Carvalho,
Rodrigo Aires Corrêa Lima, Cezar Kozak Simaan, Francieli de Sousa Rabelo, José Abrantes Sarmento, Rafaela Braga de
Oliveira, Leopoldo Luiz dos Santos Neto
47
51
HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity
in Syria
Associação do alelo HLA-DRB1 com suscetibilidade a artrite reumatoide e gravidade
da doença na Síria
Jamil Mourad, Fawza Monem
57
61
Clinical and laboratory features of patients with rheumatoid arthritis diagnosed at
rheumatology services in the Brazilian municipality of Cascavel, PR, Brazil
Estudo clínico e laboratorial de pacientes com artrite reumatoide diagnosticados em
serviços de reumatologia em Cascavel, PR, Brasil
Juliano Maximiano David, Rodrigo Antonio Mattei, Juliana Lustoza Mauad, Lauren Gabrielle de Almeida,
Márcio Augusto Nogueira, Poliana Vieira da Silva Menolli, Rafael Andrade Menolli
RBR 53(1).indb Miolo11
20/03/2013 16:25:46
66
70
Characteristics of NK cell activity in patients with systemic sclerosis
Características de atividade das células natural killer em pacientes com esclerose
sistêmica
Patricia Hartstein Salim, Mariana Jobim, Markus Bredemeier, José Artur Bogo Chies, João Carlos Tavares Brenol,
Luiz Fernando Jobim, Ricardo Machado Xavier
75
81
The quality of life of patients with lupus erythematosus influences cardiovascular
capacity in 6-minute walk test
Qualidade de vida de pacientes com lúpus eritematoso influencia a capacidade
cardiovascular em teste de caminhada de 6 minutos
Sandor Balsamo, Dahan da Cunha Nascimento, Ramires Alsamir Tibana, Frederico Santos de Santana,
Licia Maria Henrique da Mota, Leopoldo Luiz dos Santos-Neto
REVIEW ARTIC LES | ARTIGOS DE REVISˆ O
88
94
Ultrasonography in rheumatoid arthritis: what rheumatologists should know
Ultrassonografia em portadores de artrite reumatoide: o que o reumatologista clínico
deve saber
Carlos Frederico Arend
101
105
Dermatomyositis and polymyositis: from immunopathology to immunotherapy
(immunobiologics)
Dermatomiosite e polimiosite: da imunopatologia à imunoterapia (imunobiológicos)
Samuel Katsuyuki Shinjo, Fernando Henrique Carlos de Souza, Julio Cesar Bertacini de Moraes
CA SE REPO RTS | RELATOS DE CA SO
111
115
Concurrent rheumatoid arthritis and ankylosing spondylitis in one patient: the
importance of new classification criteria
Concomitância de artrite reumatoide e espondilite anquilosante em um único paciente:
importância dos novos critérios de classificação
Valderilio Feijó Azevedo, Pedro Grachinski Buiar
120
123
Thrombotic thrombocytopenic purpura at presentation of juvenile systemic lupus
erythematosus patients
Púrpura trombocitopênica trombótica na apresentação de pacientes com lúpus
eritematoso sistêmico juvenil
Lucia M. A. Campos, Maria Silvia Spadoni, Cintia M. Michelin, Adriana A. Jesus, Jorge D. A. Carneiro,
Clovis Artur Almeida da Silva
LETTER TO THE EDITORS | CA RTA AO EDITORES
127
129
Biosimilars require scientifically reliable comparative clinical data
Biossimilares necessitam de dados clínicos comparativos cientificamente confiáveis
Valderílio Feijó Azevedo
C ORRIGENDUM | C ORRIGENDUM
132
133
Posterior reversible encephalopathy syndrome (PRES) and systemic lupus
erythematosus: report of two cases
[Rev Bras Reumatol 2012; 52(5):804–10]
Síndrome da encefalopatia posterior reversível (PRES) e lúpus eritematoso sistêmico:
relato de dois casos
Streck A de S, Staub HL, de Freitas CZ, Marrone L, Costa J, Gadonski G
20/03/2013 16:25:46
134
135
Anti-C1q, anti-chromatin/nucleosome, and anti-dsDNA antibodies in juvenile
systemic lupus erythematosus patients
Anticorpos anti-C1q, anticromatina/nucleossomo e anti-dsDNA em pacientes com lúpus
eritematoso sistêmico juvenil
Jesus AA, Campos LM, Liphaus BL, Carneiro-Sampaio M, Mangueira CL, Rosseto EA, Silva CA, Scheinberg M
AC K NOW LEDGEMENTS | AGRADEC IMENTOS
136
136
Acknowledgements to the referees
Agradecimento aos pareceristas
20/03/2013 16:25:46
EDITORIAL
Vaccination for patients with
rheumatoid arthritis: a pressing need
© 2013 Elsevier Editora Ltda. All rights reserved.
I
n the city of Rio de Janeiro, at the beginning of the 20th
century, the physician Oswaldo Cruz, a Brazilian science
pioneer, conducted the first vaccination campaign in Brazil.1
In his fight to promote mass vaccination against smallpox, the
sanitarian faced innumerous obstacles, such as the population’s
ignorance about the vaccine and a fierce political opposition
originated from several sectors of the society, including his
medical colleagues. The dissemination of rumors against the
vaccine collaborated with the almost total lack of adhesion of the
population of the city of Rio de Janeiro to the vaccination campaign. That, along with several protests against the government,
generated a social convulsion that culminated with the Vaccine
Revolt, a true urban battle with dozens of deaths and hundreds
of wounded people. Thousands of other victims of the Vaccine
Revolt would appear in the following years, with the suspension
of obligatory vaccination and advance of the epidemic.
More than 100 years after the Oswaldo Cruz’s initiative, the
lessons learned over the decades led to the development of a successful and internationally recognized immunization program
in Brazil. However, a significant part of the population with
chronic inflammatory diseases, despite being more susceptible
to infections, still remains unprotected.2,3 That is the case of
patients with rheumatoid arthritis (RA).
Based on the current scientific knowledge, one can state that
patients with RA, in addition to being at higher risk for infections,4 have an increased infection-related mortality, up to ten
times that of the general population.5 Of the factors implicated in
the susceptibility to infections, the earlier and more intense exposure to immunosuppressive drugs and biologics stands out.6,7
Considering that vaccination is the preventive measure
with the greatest impact on reducing the occurrence of infection at any age group, it is mandatory to review and update the
Rev Bras Reumatol 2013;53(1):1–3
vaccine chart of patients with rheumatic disorders. In addition,
knowing that the specific prescription of vaccines during the
clinical follow-up of those patients has a positive impact on the
increase of vaccine coverage, work groups of specialists have
been formed to establish vaccine guidelines in rheumatology,
reflecting an increasing concern worldwide in recent years.8,9
The Rheumatoid Arthritis Committee of the Brazilian
Society of Rheumatology has developed the consensus
published in this journal10 aimed at summarizing the recommendations for vaccinating patients with RA, considering the
epidemiological scenario of endemic diseases in Brazil, such as
yellow fever. Thus, the 2012 Brazilian Society of Rheumatology
Consensus on vaccination of patients with rheumatoid arthritis
was aimed at standardizing and encouraging the indication of
immunization by rheumatologists and other professionals who
manage those patients.
Finally, we believe that the implementation of those recommendations is perfectly feasible in Brazil. Therefore, it is
fundamental to promote continuous medical education and
patients’ instruction, and to review the subject periodically, so
that an updated approach based on scientific evidence can be
incorporated into clinical practice.
Claiton Viegas Brenol
Adjunct professor, Department of Internal Medicine, Medical School,
Universidade Federal do Rio Grande do Sul – UFRGS; Coordinator of the
Rheumatoid Arthritis Outpatient Clinic, Rheumatology Service, Hospital de
Clínicas de Porto Alegre – HCPA
Gecilmara Salviato Pileggi
Physician, Pediatric Rheumatology Sector, Pediatric Department, Hospital
das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de
São Paulo - HC-FMRP-USP
1
20/03/2013 16:25:48
EDITORIAL
Vacinação para pacientes com artrite
reumatoide: uma necessidade premente
N
o Rio de Janeiro do início do século XX, o médico
Oswaldo Cruz, um dos pioneiros da ciência brasileira, conduziu a primeira campanha de vacinação
no país.1 Em sua luta para promover a vacinação em massa
contra a varíola, o sanitarista enfrentou incontáveis obstáculos, como a falta de informação da população sobre a vacina e
uma ferrenha oposição política originada em diversos setores
da sociedade, incluindo colegas médicos. A disseminação de
boatos contra a vacina colaborou para a falta de apoio quase
total dos cidadãos cariocas à campanha. Tudo isso, e uma
série de conflitos com o governo vigente, acabou por gerar
uma convulsão social que culminou na Revolta da Vacina,
verdadeira batalha urbana com dezenas de mortos e centenas
de feridos. Milhares de outras vítimas da Revolta surgiriam
nos anos seguintes, com a revogação da obrigatoriedade da
vacinação e o avanço da epidemia.
Mais de 100 anos após a iniciativa de Oswaldo Cruz, as
lições aprendidas ao longo das décadas levaram ao desenvolvimento de um exitoso e internacionalmente reconhecido
programa de imunização no Brasil. No entanto, ainda hoje
uma parcela significativa da população portadora de doenças
inflamatórias crônicas, apesar de mais suscetíveis a infecções,
permanece desprotegida.2,3 É o caso dos pacientes portadores
de artrite reumatoide (AR).
Com base no conhecimento científico atual, podemos
afirmar que os pacientes com AR, além de apresentarem risco
aumentado para infecções,4 têm a mortalidade relacionada a
esses eventos até 10 vezes maior em relação à população geral.5
Entre os fatores implicados na suscetibilidade para infecções,
a exposição de maneira cada vez mais precoce e intensa ao
tratamento com imunossupressores e agentes biológicos ocupa
lugar de destaque.6,7
Tendo em vista que a vacinação é a medida preventiva de
maior impacto na diminuição da ocorrência de infecção em
qualquer faixa etária, torna-se mandatório revisar e atualizar o
cartão vacinal dos pacientes com doenças reumáticas. Sabendo
também que a prescrição específica de vacinas durante o
2
seguimento clínico desses pacientes tem impacto positivo no
aumento da cobertura vacinal, têm sido formados grupos de
trabalho por especialistas para estabelecer diretrizes vacinais
na área da reumatologia, refletindo uma preocupação mundial
crescente nos últimos anos.8,9
Nesse contexto, a Comissão de Artrite Reumatoide da
Sociedade Brasileira de Reumatologia desenvolveu o consenso publicado neste periódico10 com o objetivo de sintetizar
recomendações para a indicação de vacinas nos pacientes
portadores de AR, contemplando o cenário epidemiológico de
doenças endêmicas no Brasil, como a febre amarela. Assim,
o Consenso 2012 da Sociedade Brasileira de Reumatologia
sobre vacinação em pacientes com artrite reumatoide tem
como propósito final uniformizar e incentivar a indicação de
imunizações pelos reumatologistas e demais profissionais que
lidam com esses pacientes.
Finalmente, acreditamos que a implementação dessas
recomendações é perfeitamente viável no Brasil. Para isso, é
fundamental promover a educação médica continuada e a orientação dos pacientes, bem como revisar o tema periodicamente,
para incorporar condutas baseadas em evidências científicas
atualizadas na prática clínica.
Claiton Viegas Brenol
Professor Adjunto, Departamento de Medicina Interna, Faculdade
de Medicina, Universidade Federal do Rio Grande do Sul – UFRGS;
Coordenador do Ambulatório de Artrite Reumatoide, Serviço de
Reumatologia, Hospital de Clínicas de Porto Alegre – HCPA
Gecilmara Salviato Pileggi
Médica, Setor de Reumatologia Pediátrica, Departamento de Pediatria,
Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto,
Universidade de São Paulo - HC-FMRP-USP
REFERENCES
REFERÊNCIAS
1.
Scliar M. Oswaldo Cruz: entre micróbios e barricadas. Rio de Janeiro:
RelumeDumará; 1996.
20/03/2013 16:25:48
EDITORIAL
2.
3.
4.
5.
6.
Desai SP, Turchin A, Szent-Gyorgyi LE, Weinblatt M,
Coblyn J, Solomon DH, et al. Routinely measuring and reporting
pneumococcal vaccination among immunosuppressed rheumatology
outpatients: the first step in improving quality. Rheumatology
(Oxford)2011;50(2):366–72.
Marchand-Janssen C, Loulergue P, Mouthon L, Mahr A,
Blanche P, Deforges L, et al. Patients with systemic inflammatory
and autoimmune diseases are at risk of vaccine-preventable illnesses.
Rheumatology (Oxford) 2011;50(6):1099–105.
Falagas ME, Manta KG, Betsi GI, Pappas G. Infection-related
morbidity and mortality in patients with connective tissue diseases:
a systematic review. ClinRheumatol2007;26(5):663–70.
Naz SM, Symmons DP. Mortality in established rheumatoid arthritis.
Best Pract Res ClinRheumatol2007;21(5):871–83.
Tak PP, Kalden JR. Advances in rheumatology: new targeted
therapeutics. Arthritis Res Ther 2011;13(Suppl 1):S5.
7.
da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS,
Bertolo MB, et al. 2012 Brazilian Society of Rheumatology
Consensus for the treatment of rheumatoid arthritis. Rev Bras
Reumatol2012;52(2):152–74.
8. Silva CAA, Terreri MT, Barbosa CM, Hilário MO, PIllegi GS, et al.
Consenso de imunização para crianças e adolescentes com doenças
reumatológicas. Rev Bras Reumatol 2009; 49(5):562–89.
9. van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF,
et al. EULAR recommendations for vaccination in adult patients
with autoimmune inflammatory rheumatic diseases.Ann
RheumDis2011;70(3):414–22.
10. Brenol CV, da Mota LMH, Cruz BA, Pileggi GS, Pereira IA,
Rezende LS, et al. Consenso 2012 da Sociedade Brasileira de
Reumatologia sobre vacinação em pacientes com artrite reumatoide.
Rev Bras Reumatol 2013; 53(1):XX-XX
3
20/03/2013 16:25:48
ORIGINAL ARTICLE
2012 Brazilian Society of Rheumatology
Consensus on vaccination of patients with
Claiton Viegas Brenol1, Licia Maria Henrique da Mota2, Bóris Afonso Cruz3, Gecilmara Salviato Pileggi4,
Ivânio Alves Pereira5, Lucila Stange Rezende6, Manoel Barros Bertolo7, Max Victor Carioca Freitas8,
Nilzio Antônio da Silva9, Paulo Louzada-Junior10, Rina Dalva Neubarth Giorgi11,
Rodrigo Aires Corrêa Lima12, Geraldo da Rocha Castelar Pinheiro13
ABSTRACT
Objective: To elaborate recommendations to the vaccination of patients with rheumatoid arthritis (RA) in Brazil.
Method: Literature review and opinion of expert members of the Brazilian Society of Rheumatology Committee of
Rheumatoid Arthritis and of an invited pediatric rheumatologist. Results and conclusions: The following 12 recommendations were established: 1) Before starting disease-modifying anti-rheumatic drugs, the vaccine card should be
reviewed and updated; 2) Vaccines against seasonal influenza and against H1N1 are indicated annually for patients
with RA; 3) The pneumococcal vaccine should be indicated for all patients with RA; 4) The vaccine against varicella
should be indicated for patients with RA and a negative or dubious history for that disease; 5) The HPV vaccine should
be considered for adolescent and young females with RA; 6) The meningococcal vaccine is indicated for patients
with RA only in the presence of asplenia or complement deficiency; 7) Asplenic adults with RA should be immunized against Haemophilus influenzae type B; 8) An additional BCG vaccine is not indicated for patients diagnosed
with RA; 9) Hepatitis B vaccine is indicated for patients with RA who are negative for antibodies against HBsAg;
the combined hepatitis A and B vaccine should be considered; 10) Patients with RA and at high risk for tetanus, who
received rituximab in the preceding 24 weeks, should undergo passive immunization with tetanus immunoglobulin in case of exposure; 11) The YF vaccine is contraindicated to patients with RA on immunosuppressive drugs;
12) The above described recommendations should be reviewed over the course of RA.
Keywords: rheumatoid arthritis, vaccination, immunization, adult.
Received on 07/03/2012. Approved on 08/14/2012. The authors declare no conflict of interest.
Sociedade Brasileira de Reumatologia – SBR.
1. Adjunct Professor, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul – UFRGS; Coordinator, Rheumatoid Arthritis Outpatient
Clinic, Hospital de Clínicas de Porto Alegre – HCPA
2. Collaborating Professor of Internal Medicine and of the Service of Rheumatology, Medical School, Universidade de Brasília – FM-UnB; PhD in Medical
Sciences, FM-UnB
3. Master’s degree in Epidemiology; Chief, Service of Rheumatology, BIOCOR Institute, Belo Horizonte, MG
4. Attending Physician, Sector of Pediatric Rheumatology, Hospital de Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo –
HC-FMRP-USP
5. Professor, Discipline of Rheumatology, Universidade do Sul de Santa Catarina – UNISUL; Chief, Service of Rheumatology, Hospital of the Universidade
Federal de Santa Catarina – HU-UFSC
6. Rheumatologist, Hospital das Clínicas, Universidade Federal do Paraná – HC-UFPR; Ex-fellow, Service of Rheumatology, Vienna General Hospital (AKH), Austria
7. Assistant Professor, PhD and Coordinator of the Discipline of Rheumatology, Medical Sciences School, Universidade Estadual de Campinas – Unicamp
8. Adjunct Professor, Immunology, Medical School, Universidade Federal do Ceará – FM-UFC
9. Full Professor of Rheumatology, Medical School, Universidade Federal de Goiás – UFG
10. Professor with habilitation thesis, FMRP-USP
11. Chief Physician, Sector of Diagnosis and Therapy, Service of Rheumatology, Hospital do Servidor Público Estadual de São Paulo – HSPE-FMO
12. Rheumatologist; Chief, Service of Rheumatology, Hospital Universitário de Brasília, UnB
13. Associated Professor, Discipline of Rheumatology, Medical Sciences School, Universidade do Estado do Rio de Janeiro – FCM-UERJ
Correspondence to: Claiton Viegas Brenol, M.D., PhD. Serviço de Reumatologia do Hospital de Clínicas de Porto Alegre. Rua Ramiro Barcelos, 2350, sala
645. CEP: 90035-003. Porto Alegre, RS, Brazil. E-mail: [email protected]
4
20/03/2013 16:25:48
2012 Brazilian Society of Rheumatology Consensus on vaccination of patients with rheumatoid arthritis
INTRODUCTION
Patients with rheumatoid arthritis (RA) are at increased risk
for infections.1,2 Infectious outcomes in RA are among the
major causes of death in those patients, and the mortality related to those events can be up to ten times that of the general
population.3 Patients with severe disease and/or comorbidities
are most often affected.1,4
Several factors have been associated with that increased
susceptibility to infections. One of those major factors is the
use of immunomodulators for the treatment of the disease
itself, in particular biologics, whose indication has been
increasingly frequent and early in the course of disease.
The introduction of new agents in the therapeutic arsenal of
rheumatology interferes with several points of the immune
system.5
Knowing that vaccination is the most effective preventive
measure for reducing the occurrence of infection at any age
group, the vaccine chart should be reviewed and updated before starting either synthetic or biological disease-modifying
anti-rheumatic drugs (DMARDs) (Table 1). However, that is
often neglected in routine rheumatological practice, leaving
a large number of patients unprotected against infectious
diseases that could be prevented. Several studies have shown
that the vaccine coverage of patients with rheumatic diseases
worldwide is suboptimal.6–8
Some of the vaccines available can have their immunogenicity reduced depending on the patient’s immunosuppression
status; however, international experience has shown that the
administration of most vaccines comprised in the vaccine
calendar is safe, considering that they neither worsen the
activity nor reactivate manifestations of rheumatic diseases.9
The present consensus aimed at reviewing the literature
and elaborating recommendations for the indication of vaccines in patients with RA, considering the epidemiological
scenario and the resources of medical care in Brazil. The purpose of this document is to summarize the current position of
the Brazilian Society of Rheumatology (SBR) on the subject,
to guide Brazilian physicians, especially rheumatologists.
METHOD OF CONSENSUS ELABORATION
The method for elaborating the recommendations included
a literature review and the opinion of expert members
of the SBR Committee of Rheumatoid Arthritis and of
an invited pediatric rheumatologist. The bibliographic
survey included publications in the MEDLINE, SciELO,
PubMed and EMBASE databases up to February 2012.
The recommendations were written and reassessed by all
participants during multiple rounds of questioning and corrections performed via internet. Based on the considerations,
the experts provided recommendations on the vaccination of
patients diagnosed with RA (Table 2).
Inactivated or Recombinant Vaccines
The great advantage of inactivated vaccines is the total lack
of infectious potential of the pathogenic agent: such vaccines
do not trigger the disease, but maintain the immunologic characteristics of the agent. Inactivated or recombinant vaccines,
however, have the disadvantage of inducing a suboptimal
immune response, requiring sometimes the association of
adjuvants or transporting proteins and the administration of
booster shots.
Adhesion to the Brazilian guidelines is recommended for
the following vaccines that do not contain live organisms: influenza vaccine (intramuscular – IM); pneumococcal vaccine
(13V-conjugated and 23-polysaccharide); tetanus vaccine;
diphtheria vaccine; pertussis vaccine; Haemophilus influenzae
type B (Hib) vaccine; hepatitis A and B vaccine; poliomyelitis
vaccine (inactivated – VIP); meningococcal vaccine; human
papillomavirus (HPV) vaccine; typhoid fever vaccine (IM);
and rabies vaccine.10 Such vaccines can be safely administered,
preferentially 14 days before starting DMARDs, in an attempt
to reach the expected immunogenicity. When the vaccine chart
cannot be updated prior to the beginning of treatment, all those
vaccines can be administered to patients with RA, even those on
corticosteroids (CS) and/or synthetic or biological DMARDs,
based on their safety demonstrated in several studies;9,11 the
response, however, might be impaired.
Influenza virus vaccine
Respiratory infections are common among patients with RA
and have high mortality rate.12 Vaccination against influenza
has proved to reduce the number of hospital admissions and
mortality due to respiratory infections in elderly patients,
being effective even in patients on DMARDs.13
Response to the influenza vaccine seems not to be impaired in patients on anti-TNF agents, even when associated
with methotrexate (MTX). 14–16 However, one author has
reported a reduced response to that vaccine in patients on
infliximab or etanercept associated with MTX.17 Likewise,
one study conducted in Brazil assessing the vaccine against
H1N1 influenza has found, in addition to a good safety profile,
a reduction in the seroprotection of patients with RA, regardless of disease activity. Methotrexate was the only DMARD
associated with a reduced response to that vaccine.11
5
20/03/2013 16:25:48
Brenol et al.
There is also evidence of an impaired response to pneumococcal and influenza vaccines when administered to patients
on rituximab.13,18,19 The response to the influenza vaccine
(including vaccine against influenza A and H1N1) is particularly impaired when administered early, 4–8 weeks after the
administration of rituximab. Thus, influenza vaccines should
be administered before starting rituximab or 6 months after
its first infusion and 4 weeks before its next dose.20
The influenza vaccine is considered safe, and has been used
in Brazil in annual campaigns for the population aged 60 years
and over and for adults and children over the age of 6 months
in special clinical situations, such as patients with RA.10 It is
contraindicated only to patients with history of allergy to egg
or to the vaccine itself, as well as to those who had GuillainBarré syndrome up to 6 weeks after receiving that vaccine.
Seasonal and H1N1 influenza vaccines are indicated annually to patients with RA.
Pneumococcal vaccine
Bacterial infections of the respiratory tract are more common
in patients diagnosed with RA as compared with the general
population and contribute to increase morbidity and mortality.21,22 Thus, vaccination against Streptococcus pneumoniae
(pneumococcus) is highly relevant for patients with RA.
Table 1
Immunization schedule according to vaccine and age group for adults in Brazil
Age group (years)
Vaccine
18–26
Influenza¥
27–49
50–59
60–64
≥ 65
1 annual dose
Vaccine availability
Public health units/ CRIE
Booster shot of
dT every 10
years
Public health units
Acellular vaccine at
private clinics
Tdap: tetanus, diphtheria,
pertussis¥
Complete basic vaccination schedule: booster shot with Tdap and, then,
one dose of dT every 10 years#
IPV (Salk)¥
Complete basic vaccination schedule: booster shot with 1 dose##
CRIE/private clinics
Tdap + IPVϴ
Complete basic vaccination schedule: booster shot with Tdap from the age of 7 years onwards
and, then, 1 dose of dT every 10 years#
Private clinics
HPV¥
3 doses (women)
(0, 2 and 6
months)
Private clinics
Pneumococcal 23
(polysaccharide)*,¥
1 or 2 doses
Conjugated pneumococcal
13**
1 dose or more**
Conjugated meningococcal¥
1 dose, even for individuals vaccinated during childhood or more than 5 years before
Public health units
Hepatitis A
¥
Hepatitis B¥
Combined hepatitis A and Bϴ
Varicella***
,¥
Yellow fever***
Herpes-zoster***
2 doses, minimum interval of 6 months
3 doses (0, 1 and 6 months)
Public health units
3 doses (0, 1 and 6 months)
Private clinics
2 doses, 8-week interval (negative history for varicella-zoster virus infection or vaccination)
1 dose every 10 years for those living in endemic areas or traveling to such areas
Public health units
,¥
Measles, mumps,
rubella***,¥
1 dose
Single dose if the vaccination schedule
is complete. Two doses (minimum
interval of 30 days) for those who had
received one previous dose
1 dose
Private clinics
1 dose
Public health units
CRI E: reference center for special immunobiological drugs; dt: adult combined vaccine against diphtheria and tetanus; Tdap: combination vaccine with acellular pertussis of the adult type; IP V : inactivated
polio vaccine; HPV : human papilloma virus.
¥For all individuals of that category who meet the age criteria and need immuniz ation (with neither vaccination card nor evidence of previous infections).
ϴCom bined vaccines, option: to reduce the number of injections.
*For patients with functional or anatomical asplenia or complement deficiency.
* For patients without a good response to the pneumococcal 23 vaccine.
* Li ve, attenuated vaccines. Con traindicated to immunosuppressed individuals and pregnant women, except when the risk s for acquiring the disease surpass the potential risk s of vaccination. G reater care
should be taken on the first vaccination.
#
W ith incomplete or unkn own basic vaccination schedule (fewer than 3 previous doses of dT, D TP or D TaP vaccines): complete the 3-dose schedule, administering 1 dose of Tdap and 1 or 2 doses of dT
(schedule: 0–2–6
months) to provide 3 doses of the tetanus component. In both cases, if the Tdap vaccine cannot be used, replace it with the dT vaccine.
# #
Un vaccinated adults should receive primary vaccination with IPV . Adults without vaccination documentation should be considered unvaccinated. Two doses of IP V at 4 –8 -week interval are recommended; a
3rd dose should be administered 6 –1 2 months after the 2nd dose. H ousehold contacts of immunosuppressed patients should be vaccinated.
6
20/03/2013 16:25:48
Table 2
Recommendations of the Brazilian Society of Rheumatology on vaccination of patients diagnosed with rheumatoid arthritis
Recommendation 1
Before starting synthetic or biological DMARDs, the vaccine card should be reviewed and updated.
Recommendation 2: influenza vaccine
Vaccines against seasonal influenza and against H1N1 are indicated annually for patients with RA.
Recommendation 3: pneumococcal vaccine
The pneumococcal vaccine should be indicated for all patients with RA and can be more effective when administered before starting synthetic or
biological DMARDs. When patients are on immunosuppressive agents, the response to vaccine should be assessed.
Recommendation 4: HPV vaccine
The HPV vaccine should be considered for adolescent and young females with RA, preferably before starting sexual life.
Recommendation 5: meningococcal vaccine
The meningococcal vaccine is indicated for patients with RA only in the presence of asplenia or complement deficiency. It should also be considered in
the presence of outbreaks and severe immunosuppression.
Recommendation 6: Haemophilus influenzae type B vaccine
Asplenic adults with RA should be immunized against Haemophilus influenzae type B.
Recommendation 7: hepatitis A and B vaccine
Hepatitis B vaccine is indicated for patients with RA who are negative for antibodies against HbsAg, preferably before starting treatment with biological
DMARDs. The combined hepatitis A and B vaccine should be considered.
Recommendation 8: Combined vaccine against diphtheria, tetanus and acellular pertussis (DTaP/Tdap) and combined vaccine against diphtheria and
tetanus (dT)
Patients on immunosuppressive drugs should undergo the same vaccine schedule recommended for healthy individuals. Patients with RA and at high risk
for tetanus, who received rituximab in the preceding 24 weeks, should undergo passive immunization with tetanus immunoglobulin in case of exposure.
Recommendation 9: BCG vaccine
An additional BCG vaccine is not indicated for patients diagnosed with RA, because all the Brazilian population is already vaccinated right after birth.
Recommendation 10: vaccines comprising live attenuated viruses
These vaccines should be administered 2−4 weeks before beginning immunosuppressive therapy, 2 weeks after discontinuation of synthetic DMARDs,
4 weeks after discontinuation of CS, 12 weeks after discontinuation of immunoglobulins, cytotoxic drugs or alkylating agents. For biological DMARDs,
a period corresponding to 4 half-lives should be observed after drug suspension.
Recommendation 11: vaccine against varicella
The vaccine against varicella should be indicated for patients with RA and a negative or dubious history for that disease and/or previous vaccination,
preferably before starting immunosuppression, or when patients are on low CS doses and usual MTX doses.
Recommendation 12: vaccine against YF
The YF vaccine is contraindicated for patients with RA on immunosuppressive drugs, such as synthetic and biological DMARDs. Physicians should
provide their patients with information on endemic areas, individualized risk of infection, and each patient’s immunosuppression status, so that the
indication of vaccine to that population in specific and very particular situations can be assessed.
Recommendation 13
The above described recommendations should be reviewed over the course of RA. Whenever possible, the vaccine status should be updated, even when
synthetic DMARDs are used and preferably before starting biological therapy.
D M ARD
: disease-modifying anti-rheumatic drug; RA : rheumatoid arthritis; H P V : human papilloma virus; C S: corticosteroid; Y F: yellow fever; BC G : Bacillus C almette-G ué rin.
In Brazil, the pneumococcal vaccine available for adults
is the 23-valent polysaccharide vaccine (Pn23), a polyvalent vaccine prepared from purified polysaccharides of the
bacterial capsule, containing 23 serotypes of Streptococcus
pneumoniae.10 However, it is associated with low immune
response when compared with conjugated formulations
(pneumo 7, 10 and 13).
The isolated use of MTX or its combination with some
anti-TNF agents (adalimumab, etanercept and infliximab) can
reduce the efficacy of the vaccine, while the isolated use of
those biologics does not influence the response to vaccine.15,17
In 2011, that finding was confirmed by a study performed with
conjugated vaccine against 7 pneumococcal serotypes (Pn7) in
patients with RA and spondyloarthritides.23 A single administration of the Pn23 vaccine offers up to 10-year protection against
the development of pneumococcal pneumonia in patients with
RA on MTX.24 The safety profile seems appropriate, which was
a conclusion common to all those studies.
The additional benefit of the association of the Pn23
vaccine with conjugated vaccines has not yet been shown
in patients with RA, but the response to the Pn23 vaccine
should be monitored, mainly when administered to patients
on synthetic or biological DMARDs. When inappropriate, the
administration of a conjugated vaccine should be indicated,
knowing that it is much more immunogenic than the Pn23
vaccine.
7
20/03/2013 16:25:48
Brenol et al.
Usually, the Pn23 vaccine is well tolerated. The adverse
events are mild, of short duration and limited to the vaccine
application site. More intense local reactions are most often
observed after early revaccination, especially in individuals
with high titers of antibodies against the pneumococcus.10
In Brazil, the Pn23 vaccine is used to immunize institutionalized individuals aged 60 years and over. In that population, a single dose of the vaccine is administered with only
one booster shot 5 years after the initial dose. It can also
be indicated to individuals with chronic diseases, such as
heart diseases, lung diseases, diabetes, and other conditions
considered to increase the risk for pneumococcal disease,
such as functional or anatomical asplenia and complement
deficiency.10,25
The pneumococcal vaccine should be indicated for all patients with RA, and can be more effective when administered
before beginning synthetic or biological DMARDs.
HPV vaccine
The HPV is a sexually transmitted virus, highly prevalent in
Brazil.26 There are more than 100 types of HPV, of which approximately 30 types affect men and women. HPV infection
is the major risk factor for uterine cervix cancer, being also
associated with tumors of the penis, anus, mouth and throat.
HPV also causes genital warts or condyloma acuminatum.27
The quadrivalent vaccine is highly effective to prevent
infections by the subtypes 16 and 18 (the most oncogenic
subtypes) and 6 and 11 (responsible for genital warts). Several
countries recommend vaccination against HPV in young
women, ideally before initiating sexual activity. The Brazilian
Ministry of Health does not recommend that as a public health
guideline,28 but the Brazilian Agency of Sanitary Surveillance
(ANVISA) indicates that vaccination in women aged 11 to
26 years. That vaccine is administered via IM, in 3 doses on
the months 0, 1–2 and 6.27 Few adverse events of that vaccine
have been described, and some patients can have mild local
reactions.
Unlike systemic lupus erythematosus, a condition in which
the incidence of HPV infection is known to be increased,26
in RA, data are less well-known. In 2008, a Mexican study
showed that 1 in every 3 women with RA can have HPV infection, and more than 90% of the patients have the high-risk
viral subtype.29
Studies on the efficacy and safety of the HPV vaccine in patients with RA or other rheumatic diseases still lack. However,
because the vaccine contains no viral genetic material and its
basis is L1 capsid proteins, it is considered safe for patients
with autoimmune diseases, even when immunosuppressed.
8
Other international societies of specialists have suggested
that patients with autoimmune diseases might benefit from
that vaccine.9
The HPV vaccine should be considered for adolescents
and young women with RA, preferably before initiating their
sexual life.
Meningococcal vaccine
Meningococcal vaccine is indicated to prevent invasive disease
caused by Neisseria meningitidis, especially in conditions of
particular susceptibility to meningococcus, such as patients
with asplenia and complement deficiency. The meningococcal serogroup C conjugate vaccine is currently available at the
Brazilian public health system. It can be administered via IM
from the age of 2 months onward, with no upper age limit.10
Although the incidence of meningococcal disease in adults is
low, vaccination is recommended when possible or in case of
outbreaks, or travels that entail risk. The quadrivalent meningococcal conjugate vaccine (types A.C, W135 and Y) should
be considered an option to immunize adolescents and adults.
Studies on the efficacy and safety of the meningococcal
vaccine in patients with RA still lack. The experience is higher
with pediatric patients. It has been proven safe and effective
in children and adolescents with juvenile idiopathic arthritis
(JIA), even when on immunosuppressive drugs.30,31 The adverse
events that might occur in the general population are local
reactions, low fever and irritability.
The meningococcal vaccine is indicated for patients with
RA, mainly those with asplenia and complement deficiency.
Haemophilus influenzae type B vaccine
The Hib is a capsulate bacterium that causes invasive diseases,
such as meningitis, epiglottitis, septicemia, osteomyelitis and
arthritis. Patients with RA and other rheumatic diseases are at
greater risk of developing infections related to that bacterium,
having, thus, indication for immunization.32
Similarly to the meningococcal vaccine, the Hib vaccine is
conjugated, comprises polysaccharides of the bacterial capsule,
and is administered via IM. That vaccine is part of the Brazilian
vaccination calendar, and should be administered to children
and adolescents up to the age of 19 years.33
Patients with rheumatic disease and indication for vaccination against Hib should be immunized as soon as their
diagnosis is made, preferentially before beginning the immunosuppressive therapy, because of the possible interference
with vaccine response.34
In addition to the indication of Hib vaccination for children and adolescents with rheumatic disease, asplenic adults
20/03/2013 16:25:49
with RA should also be immunized. Studies on safety and
efficacy in patients with RA still lack.13
Hepatitis A and B vaccine
There is no evidence that infections by hepatitis A (HVA)
or B (HVB) viruses are more prevalent in patients with RA.
However, screening of liver diseases and preventive measures
against liver diseases are highly recommended in that group
of patients due to their frequent use of hepatotoxic drugs,
and the fact that Brazil has changed its endemic situation
of hepatitis A, being currently considered of intermediate
risk, meaning an increase in the number of susceptible adult
individuals.35
In Brazil, vaccines available against HVA and HVB are
produced by using recombinant DNA technology, and the
combined formulation of both exist. The hepatitis A and B
vaccines are considered safe.10 They might cause local reactions, fever in the first 24 hours, fatigue, headache, irritability
and gastrointestinal discomfort.
In RA, the safety and efficacy of the hepatitis B vaccine
have been assessed in a prospective study. 36 Vaccination
against hepatitis B has been associated with neither a significant deterioration of any clinical or laboratory measure of
the disease, nor other important adverse events. Regarding
efficacy, 15 of 22 (68.2%) patients responded to vaccination,
with titers of antibodies against HBsAg of 10 IU/L after 7
months. The response rate was lower than that of the general
population (85%–95%). In addition, the use of anti-TNF
agents might significantly reduce the vaccine response. 37
Studies of HVA in patients with RA still lack.
The hepatitis B vaccine should be indicated for patients
with RA when their serology against HBsAg is negative, preferably before beginning treatment with biological DMARDs.
The hepatitis A vaccine should be indicated for patients
with RA because of their increased susceptibility to infection
by that virus in our population, and because of the additional
risk of hepatitis A-associated macrophage activation syndrome (MAS) and fulminant hepatitis in patients on chronic
non-steroidal anti-inflammatory drugs (NSAIDs).38,39
Combined vaccine against diphtheria,
tetanus and acellular pertussis (DTaP/Tdap)
and combined vaccine against diphtheria
and tetanus (dT)
The DTaP is a combined vaccine against diphtheria, tetanus
and pertussis, in which the pertussis component is acellular.34
Adult and elderly individuals with a complete basic vaccination schedule should receive a booster shot with Tdap
(combination vaccine with acellular pertussis of the adult
type) every 10 years. The combined vaccine against diphtheria and tetanus (dT) is indicated for adolescents and adults.
Individuals with an incomplete basic vaccination schedule
(who have received fewer than 3 doses of the tetanus component during their lives) should complete their 3-dose schedule,
receiving 1 dose of Tdap and 1 or 2 doses of dT according
to the 0–2–6-month schedule. The Tdap vaccine is strongly
indicated for the elderly. Individuals who have received the
dT vaccine at least 2 years before should receive 1 dose of
the Tdap vaccine.34
The Brazilian Ministry of Health recommends the vaccine with whole cell pertussis (DTP for children or dT for
adolescents and adults). The World Health Organization
(WHO) and the Pan-American Health Organization continue
to recommend the DTP vaccine for most countries, assuring
its efficacy and safety. The DTaP vaccine is not part of the
routine calendar. Several developed countries indicate the
acellular forms as follows: DTaP for individuals < 7 years
and Tdpa for adolescents and adults.
After completing the vaccination schedule, the vaccine
should be administered every 10 years, and, in case of pregnancy or wounds suspected of causing tetanus, every 5 years.
The vaccines against tetanus, diphtheria and pertussis are
safe for adults and children with rheumatic diseases. The same
vaccination schedule of healthy individuals is recommended
for patients on immunosuppressive drugs.
Patients with RA and at high risk for tetanus, who received
rituximab in the preceding 24 weeks, should undergo passive immunization with tetanus immunoglobulin in case of
exposure.18,19
LIVE ATTENUATED VACCINES
This group includes the following vaccines: MMR (measles,
mumps and rubella) triple vaccine; Bacillus Calmette-Guérin
(BCG) vaccine; vaccine against influenza (nasal); vaccine
against varicella; vaccine against herpes zoster; typhoid fever
vaccine; vaccine against poliomyelitis (oral polio vaccine –
OPV); vaccine against smallpox; and vaccine against yellow
fever (YF).
The Brazilian guidelines for vaccination with live attenuated vaccines against MMR, varicella and booster shot of YF
should be applied to patients with RA, except when they are
known to be immunosuppressed, on high doses of CS, alkylating agents and/or biologics, until further data are available.
Those vaccines can be used for rheumatologic patients on usual
doses of synthetic DMARDs.
9
20/03/2013 16:25:49
Brenol et al.
Vaccines in this group should be preferably indicated 2–4
weeks before beginning the immunosuppressive therapy, to
assure that viral replication is over before the change in the
patient’s immune competence due to the use of the medication.
Otherwise, when the immunosuppressive treatment has already
started, vaccination should be postponed for at least 1 month
after CS therapy discontinuation, 3 months after cytotoxic
and human immunoglobulin treatment discontinuation, and 6
months after rituximab discontinuation. For the other biological DMARDs, a period corresponding to 4 half-lives should be
observed after drug suspension.
However, some specific situations, such as the occasional
use of the YF vaccine in the population of endemic areas, should
be considered.40
BCG vaccine
Mycobacterium tuberculosis infection remains the most lethal
infectious disease in the world, accounting for approximately
1.7 million deaths per year. Brazil ranks the 17th position out of
the 22 countries responsible for 80% of all cases of tuberculosis
(TB) in the world.10,41 Patients with RA are at increased risk
for TB, especially with the advent of anti-TNF-alpha therapy.
Patients with RA on synthetic DMARDs have an incidence
of TB 2- to 10-times greater than that of the general population.
When patients are on TNF-alpha inhibitors, their incidence of
TB is 6 to 10 times greater than that of patients who are not
on biologics; in addition, their rate of TB is 30 times higher
than that of the general population, reaching 144 per 100,000
person-years.41 If preventive measures against TB are not
adopted before the use of anti-TNF-alpha therapy, the risk is
even higher.43
The BIOBADA Brasil, the Brazilian registry of patients
with rheumatic diseases on biologics, shows 3 cases of TB out
of 466 patients with RA on anti-TNF-alpha therapy.22
The BCG vaccine, the only licensed vaccine against
TB, is elaborated from attenuated bacteria of bovine origin
(Mycobacterium bovis), which is similar to the microorganism
causing TB (Mycobacterium tuberculosis).10
In Brazil, the BCG vaccine is primarily indicated for children aged 0 to 4 years, being mandatory for those under the age
of 1 year. According to most studies, its efficacy is 50% (range,
10%–66%) for all forms of the disease, but it is insufficient to
protect against the pulmonary forms (efficacy lower than 50%
in the majority of the most consistent studies). It protects against
tuberculous meningitis, disseminated forms of the disease
(range of efficacy, 68%–100%), and leprosy. The immunity is
maintained for 10–15 years. The BCG vaccine does not protect
individuals already infected with Mycobacterium tuberculosis.
10
An additional BCG vaccine for patients with RA is not indicated, because, in most of those patients, TB is due to disease
reactivation or new infection, forms that the vaccine does not
prevent. In addition, the efficacy of the BCG vaccine has not
been proven in adults. The fact that it has an attenuated mycobacterium is another relevant factor supporting its contraindication
in patients with RA.10,41
Vaccine against varicella and herpes zoster
Patients with RA are at higher risk of developing herpes zoster
infection versus general population.44 That risk is even greater
in patients on CS therapy and biologics.44,45
The vaccine against varicella contains live attenuated viruses
derived from the Oka strain, and is administered subcutaneously.10 It has been proven to reduce the number of infections
and complications, such as postherpetic neuralgia in immunosuppressed patients (on chemotherapy and post-transplantation),
as compared to those reporting infection with the wild virus in
childhood.10,46
The vaccine against herpes zoster, still not available in
Brazil, also had its efficacy confirmed in adults over the age of
60 years47 and in patients with chronic inflammatory diseases
over the age of 50 years.48 According to those studies, that vaccine is indicated for patients over the age of 50 years and diagnosed with rheumatic diseases based on the American College
of Rheumatology criteria, even when they are on DMARDs
at usually recommended doses.49 The use of low doses of immunosuppressive drugs, such as MTX (< 0.4 mg/kg/week) and
azathioprine (< 3.0 mg/kg/day), is not considered sufficiently
immunosuppressive to jeopardize that vaccine’s safety, not
constituting a contraindication to its administration.49
The vaccine against varicella should be indicated for patients with RA and with a negative or dubious history for that
disease and/or previous vaccination, preferably before starting
immunosuppression. It is contraindicated when patients are
immunosuppressed, receiving the following: high doses of
systemic CS (> 20 mg of prednisone per day or equivalent) for
2 weeks or longer; pulse therapy; cytotoxic or alkylating agents;
synthetic DMARDs at doses above those recommended; or immunobiological therapy.50
The vaccine against varicella might be indicated for patients
with stable disease on low CS doses and usual MTX doses. If
either the virus or infectious symptoms persist after vaccination,
treatment with acyclovir is a possibility.49,50
Vaccine against yellow fever
Yellow fever is a noncontagious viral hemorrhagic febrile
disease, transmitted by the bite of insects, especially those
20/03/2013 16:25:49
of the Aedes and Haemagogus genera.51 In Brazil, the endemic
area comprises mainly the Northern and West-Central regions,
corresponding to approximately 68% of the territory.52 The
overall lethality ranges from 5%–10%. It is estimated that
only 10% of the cases are severe forms, associated with high
lethality (range, 40%–60% of the cases). There is no specific
treatment for the disease, the YF vaccine being the major
preventive measure.51
The 17D vaccine against YF provides protection for at
least 10 years, and even for the entire life.52,53 Within 30 days,
more than 90% of vaccinated individuals develop antibodies
against the disease.54 Of those individuals, 98%–100% become
immunized.55,56
The YF vaccine is contraindicated to patients with RA
on immunosuppressive drugs, because it is a live, attenuated
vaccine, and there is risk of an uncontrolled vaccine viral
replication.9,54,57 Cases of YF vaccine-associated viscerotropic
disease have been reported in patients with systemic lupus
erythematosus and rheumatic polymyalgia.58−60
Another factor to be considered is the seroconversion
ability of those patients, which is inversely proportional to the
immunosuppression degree.57
Anaphylaxis secondary to the YF vaccine is another
relevant aspect, occurring at the frequency of 0.8 to 1.8 per
100,000 doses, being attributed to allergy to egg or to the
gelatin used in the vaccine’s production.61,62 The most relevant
severe adverse events are YF vaccine-associated neurotropic
and viscerotropic diseases,52,54,63 having the latter an expected
lethality of around 60%.54
Only 2 studies have assessed the response to YF vaccination in rheumatic patients on immunosuppressive agents and
their adverse events.40,64
Regarding adverse events in rheumatic patients, the only
existing study has reported a case series of 70 patients with
several rheumatic diseases, who had been inadvertently immunized with the YF vaccine. All of them had already been
previously vaccinated against YF. Of the 70 patients, 16
(22.5%) reported minor adverse events, a figure compatible
with that expected for the healthy population.40
Regarding the immune response in rheumatic patients, a
study has assessed 17 patients with RA on biological therapy,
who received the YF vaccine. Comparing the antibody titers
between patients and controls, a trend of reduced response in
the group of patients with RA was observed, although a statistical analysis could not be performed because of the small
number of patients.64
The WHO recommends vaccination of the population
residing in endemic areas and of travelers to those regions,
with a boost every 10 years.53 The current recommendation
is that immunosuppressed patients should not be vaccinated
against the disease.9,65 Thus, the YF vaccine is contraindicated
to patients with RA on immunosuppressive drugs, including
synthetic and biological DMARDs.
Vaccination against YF in patients with RA living in endemic areas, close to the wild or who will be exposed during work
is controversial, and, so far, no consensus has been achieved.
A risk-benefit analysis requires considering whether the risk of
contracting the natural infection é higher than that of experiencing a severe adverse event.57 Physicians should provide their
patients with information on endemic areas, individualized
risk of infection, and each patient’s immunosuppression status,
so that the indication of vaccine to that population in specific
and very particular situations can be assessed; the decision to
vaccinate, however, is up to each patient.65
Vaccine against measles, mumps and rubella
(MMR or triple viral vaccine)
The triple viral vaccine is a combined vaccine containing
live, attenuated viruses, and which protects against measles,
mumps and rubella (MMR). It is administered subcutaneously.
Usually, the MMR vaccine causes few adverse events, being
well tolerated. All individuals should receive or have received
2 doses of the MMR vaccine, with a minimum interval of 1
month. More than 2 doses are not necessary.
It is worth noting that, as the MMR vaccine became part
of the official Brazilian vaccination calendar only in 2003,
most patients with RA might not have received that vaccine.
The MMR vaccine is indicated to childbearing age women,
because of the risk of congenital rubella, and to all patients with
a negative serology or who travel to endemic areas, except for
the restrictions applied to vaccines of live, attenuated viruses.
Only 2 studies have assessed the safety of the MMR vaccine
(booster shot) to patients with JIA. Both studies evidenced appropriate safety and immunogenicity.66,67 Studies on the safety
of the MMR vaccine to adults with RA still lack.
CONCLUSIONS
Safe and effective vaccination is crucial for patients with RA,
because of their increased risk of infection. Vaccination is
no longer exclusive to children, and currently adolescents,
adults, pregnant women and the elderly have specific and
individualized immunization programs.
The vaccine chart should be updated as soon as the diagnosis of RA is established, preferably before starting DMARDs.
The recommendations of the SBR Committee for RA followed
11
20/03/2013 16:25:49
Brenol et al.
the Brazilian guidelines for vaccination, because those guidelines consider local epidemiology, resources and health policies. Vaccines against Hib, pneumococcus, meningococcus,
HPV, hepatitis A, and varicella-zoster virus (VZV) are not
universally recommended in the Brazilian guidelines, but are
considered important in the management of those patients.
There are specific recommendations for those vaccines.
Several recommendations proposed have not been based
on the best degree of scientific evidence, and some limitations
should be highlighted in the present study. To properly assess
the efficacy of a certain vaccine, studies aimed at assessing
the number of infections prevented with the intervention
should have been conducted. That type of study cannot be
performed because of the number of patients required, the
follow-up time necessary, and ethical issues; thus, the results
analyzed in this study were based on intermediate outcomes
(immunogenicity).
Usually, vaccines have good immunogenicity in patients
with RA, except for some conditions depending on the type
and dose of the immunosuppressive treatment and the type of
vaccine. Patients on MTX showed a reduced response to the
Pn23, while the T-dependent response to conjugated or live,
attenuated vaccines was considered adequate. Responses to
several vaccines (influenza, VZV) were reduced in patients on
high doses of either CS or azathioprine. The use of rituximab
12
is related to a reduction in the T-dependent and T-independent
responses to vaccines. To yield an adequate and safe immune
response, vaccination should be ideally performed before the
introduction of immunosuppressive drugs.
Regarding safety, both disease activity and adverse events
were studied. It is worth emphasizing that there is no study
with satisfactory statistical power to assess adverse events
in patients with RA for most vaccines. However, the administration of inactivated vaccines during the use of CS, usual
doses of DMARDs, and anti-TNF seems to be safe. Because
data on vaccines with live components are still scarce, their
indication is limited to booster doses of the varicella, YF and
MMR vaccines, apparently safe in patients on regular doses
of MTX and low doses of CS. The first dose of those vaccines should be administered before starting the treatment of
patients with RA, observing the already described intervals.
This study aimed at establishing consensual guidelines for
the vaccination of patients diagnosed with RA, by using evidence obtained from the best studies available, to standardize
the indication of immunization by rheumatologists and other
professionals managing those patients, considering specific
aspects of the Brazilian reality. We believe that implementing
those guidelines is perfectly feasible in Brazil, considering
that the Brazilian Immunization Program (PNI) is one of the
most successful public health initiatives in Brazil.
20/03/2013 16:25:49
Consenso 2012 da Sociedade Brasileira de Reumatologia sobre vacinação em pacientes com artrite reumatoide
pelo risco da rubéola congênita, ou para todos os pacientes
que apresentem sorologia negativa ou viajarem para áreas
endêmicas, salvo as restrições já colocadas para as vacinas
de vírus vivos atenuadas.
Há apenas dois estudos que avaliaram a segurança da SCR
(dose de reforço) em pacientes com AIJ. Ambos evidenciaram
segurança e imunogenicidade adequadas.66,67 Não há estudos
em adultos com AR.
CONCLUSÕES
Vacinação segura e eficaz é crucial para pacientes com AR,
dado o risco aumentado de infecção. Vacinação deixou de
ser exclusividade da criança, e hoje adolescentes, adultos,
gestantes e idosos têm programas de imunização específicos
e individualizados.
A atualização do cartão vacinal deve ser indicada tão logo
se realize o diagnóstico de AR e, preferencialmente, antes da
introdução de DMCD. As recomendações da Comissão de
AR da SBR seguiram as diretrizes nacionais de vacinação,
uma vez que esses documentos levam em consideração a
epidemiologia local, recursos e políticas de saúde. Vacinas
contra Hib, pneumococo e meningococo, HPV, hepatite A e
vírus varicela-zóster (VZV) não são universalmente incluídas
nas diretrizes nacionais, mas são considerados importantes no
manejo desses pacientes. Para essas vacinas, há recomendações específicas.
Muitas dessas recomendações desenvolvidas não têm
como base o melhor grau de evidência científica, e algumas
limitações devem ser ressaltadas no presente trabalho. Para
avaliar adequadamente a eficácia de determinada vacina, seria
necessária a condução de estudos com o objetivo de avaliar
número de infecções evitadas com a intervenção. Como esse
tipo de estudo é inviável pelo número de pacientes necessários,
pelo tempo de acompanhamento e pelos condicionamentos
éticos, os resultados analisados baseiam-se em desfechos
intermediários (imunogenicidade).
Em geral, a imunogenicidade das vacinas é boa em pacientes AR, salvo algumas exceções, a depender do tipo e da dose
de tratamento imunossupressor, bem como do tipo de vacina.
Pacientes utilizando MTX apresentaram redução na resposta
da Pn23, enquanto a resposta T dependente para vacinas
conjugadas ou vivas atenuadas foi considerada adequada. As
respostas a várias vacinas (gripe, VZV) foram reduzidas em
pacientes em uso de altas doses de CE ou azatioprina. O uso de
rituximabe está relacionado à redução da resposta às vacinas
tanto de células T independentes quanto T dependentes. Para
viabilizar uma resposta adequada com segurança, o ideal é
que a vacinação ocorra antes de drogas imunossupressoras
serem introduzidas.
Do ponto de vista de segurança, tanto a atividade da doença
quanto os eventos adversos foram estudados. Não existem estudos com poder estatístico satisfatório para observar eventos
adversos em população de pacientes de AR para a maioria das
vacinas. No entanto, a administração das vacinas inativadas
parece ser segura durante a utilização de CE, DMCD em
doses usuais e anti-TNF. Quanto às vacinas de componentes
vivos, como os dados ainda são escassos, sua indicação fica
limitada às doses de reforço das vacinas contra varicela, FA
e SCR, aparentemente seguras em pacientes utilizando doses
regulares de MTX e baixas doses de CE. A primeira dose dessas
vacinas deve geralmente ser administrada antes do início do
tratamento dos pacientes com AR, respeitando os intervalos
já descritos anteriormente.
O propósito final deste trabalho foi estabelecer diretrizes
consensuais para vacinação nos pacientes com diagnóstico
de AR, utilizando evidências obtidas nos melhores estudos
disponíveis, a fim de homogeneizar a indicação de imunizações pelos reumatologistas e demais profissionais que lidam
com esses pacientes, considerando aspectos específicos da
realidade brasileira. Acreditamos que a implementação dessas
orientações é perfeitamente viável no Brasil, tendo em vista
que o Programa Nacional de Imunizações (PNI) é uma das
iniciativas de saúde pública mais bem-sucedidas em nosso país.
REFERENCES
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
Falagas ME, Manta KG, Betsi GI, Pappas G. Infection-related
morbidity and mortality in patients with connective tissue diseases:
a systematic review. Clin Rheumatol 2007; 26(5):663–70.
Michaud K, Wolfe F. Comorbidities in rheumatoid arthritis. Best
Pract Res Clin Rheumatol 2007; 21(5):885–906.
Naz SM, Symmons DP. Mortality in established rheumatoid arthritis.
Best Pract Res Clin Rheumatol 2007; 21(5):871–83.
Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE.
Predictors of infection in rheumatoid arthritis. Arthritis Rheum
2002; 46(9):2294–300.
Tak PP, Kalden JR. Advances in rheumatology: new targeted
therapeutics. Arthritis Res Ther; 13 Suppl 1:S5.
Desai SP, Turchin A, Szent-Gyorgyi LE, Weinblatt M, Coblyn J,
Solomon DH, et al. Routinely measuring and reporting pneumococcal
vaccination among immunosuppressed rheumatology outpatients:
the first step in improving quality. Rheumatology (Oxford) 2011;
50(2):366–72.
Lanternier F, Henegar C, Mouthon L, Blanche P, Guillevin L,
Launay O. Low influenza-vaccination rate among adults receiving
immunosuppressive therapy for systemic inflammatory disease. Ann
Rheum Dis 2008; 67(7):1047.
21
20/03/2013 16:25:50
Brenol et al.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Marchand-Janssen C, Loulergue P, Mouthon L, Mahr A, Blanche P,
Deforges L, et al. Patients with systemic inflammatory and autoimmune
diseases are at risk of vaccine-preventable illnesses. Rheumatology
(Oxford); 50(6):1099–105.
van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF,
Dougados M, et al. EULAR recommendations for vaccination in
adult patients with autoimmune inflammatory rheumatic diseases.
Ann Rheum Dis 2011; 70(3):414–22.
Brasil. Ministério da Saúde. Manual de vigilância epidemiológica de
eventos adversos pós-vacinação. 2.ed. Brasília, 2008; p.184.
Ribeiro AC, Guedes LK, Moraes JC, Saad CG, Aikawa NE, Calich AL,
et al. Reduced seroprotection after pandemic H1N1 influenza adjuvantfree vaccination in patients with rheumatoid arthritis: implications for
clinical practice. Ann Rheum Dis 2011; 70(12):2144–7.
Coyne P, Hamilton J, Heycock C, Saravanan V, Coulson E, Kelly CA.
Acute lower respiratory tract infections in patients with rheumatoid
arthritis. J Rheumatol 2007; 34(9):1832–6.
van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF,
Dougados M, et al. EULAR recommendations for vaccination in
adult patients with autoimmune inflammatory rheumatic diseases.
Ann Rheum Dis 2011; 70(3):414–22.
Kubota T, Nii T, Nanki T, Kohsaka H, Harigai M, Komano Y, et al.
Anti-tumor necrosis factor therapy does not diminish the immune
response to influenza vaccine in Japanese patients with rheumatoid
arthritis. Mod Rheumatol 2007; 17(6):531–3.
Kaine JL, Kivitz AJ, Birbara C, Luo AY. Immune responses following
administration of influenza and pneumococcal vaccines to patients
with rheumatoid arthritis receiving adalimumab. J Rheumatol 2007;
34(2):272–9.
Fomin I, Caspi D, Levy V, Varsano N, Shalev Y, Paran D, et al.
Vaccination against influenza in rheumatoid arthritis: the effect of
disease modifying drugs, including TNF alpha blockers. Ann Rheum
Dis 2006; 65(2):191–4.
Kapetanovic MC, Saxne T, Nilsson JA, Geborek P. Influenza
vaccination as model for testing immune modulation induced by
anti-TNF and methotrexate therapy in rheumatoid arthritis patients.
Rheumatology (Oxford) 2007; 46(4):608–11.
Bingham CO, 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M,
Codding C, et al. Immunization responses in rheumatoid arthritis
patients treated with rituximab: results from a controlled clinical trial.
Arthritis Rheum 2010; 62(1):64–74.
Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G,
Dorner T, et al. Updated consensus statement on the use of rituximab
in patients with rheumatoid arthritis. Ann Rheum Dis 2011;
70(6):909–20.
Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G,
Dorner T, et al. Updated consensus statement on the use of rituximab
in patients with rheumatoid arthritis. Ann Rheum Dis 2011;
70(6):909–20.
Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE.
Frequency of infection in patients with rheumatoid arthritis compared
with controls: a population-based study. Arthritis Rheum 2002 Sep;
46(9):2287–93.
Titton DC, Silveira IG, Louzada-Junior P, Hayata AL, Carvalho HM,
Ranza R, et al. Brazilian biologic registry: BiobadaBrasil
implementation process and preliminary results. Rev Bras Reumatol
2011; 51(2):152–60.
22
23. Kapetanovic MC, Lindqvist E, Geborek P, Saxne T, Eberhard K.
Long-term mortality rate in rheumatoid arthritis patients with
disease onset in the 1980s. Scand J Rheumatol 2011; 40(6):433–8.
24. Coulson E, Saravanan V, Hamilton J, So KL, Morgan L, Heycock C,
et al. Pneumococcal antibody levels after pneumovax in patients
with rheumatoid arthritis on methotrexate. Ann Rheum Dis 2011;
70(7):1289–91.
25. Imunizações ABd. Calendário de Vacinação do adulto e do idoso
2011. Available from: http://www.sbim.org.br/calendario-devacinacao/adultos-e-idosos/. [Accessed on Feb/2012].
26. Klumb EM, Pinto AC, Jesus GR, Araujo M, Jr., Jascone L,
Gayer CR, et al. Are women with lupus at higher risk of HPV
infection? Lupus; 19(13):1485–91.
27. WHO position on HPV vaccines. Vaccine 2009; 27(52):7236–7.
28. Brasil. Ministério da Saúde. Relatório final do grupo de trabalho
instituído pela portaria MS 310, de 10 de fevereiro de 2010. In:
Ministério da Saúde INdC, editor. 2010.
29. Nath R, Mant C, Luxton J, Hughes G, Raju KS, Shepherd P, et
al. High risk of human papillomavirus type 16 infections and
of development of cervical squamous intraepithelial lesions in
systemic lupus erythematosus patients. Arthritis Rheum 2007;
57(4):619–25.
30. Zonneveld-Huijssoon E, Ronaghy A, Van Rossum MA, Rijkers GT,
van der Klis FR, Sanders EA, et al. Safety and efficacy of
meningococcal c vaccination in juvenile idiopathic arthritis.
31. Silva CAA, Terreri MTRA, Barbosa CMPL, Hilário MOE,
Pillegi GCS, Ferriani VPL, et al. Immunization consensus for
children and adolescents with rheumatic diseases. Rev Bras
Reumatol 2009; 49(5):562–89.
32. Davies K, Woo P. Immunization in rheumatic diseases of childhood:
an audit of the clinical practice of British Paediatric Rheumatology
Group members and a review of the evidence. Rheumatology
(Oxford) 2002; 41(8):937–41.
33. Silva CA, Terreri MT, Aikawa NE, Carvalho JF, Pileggi GC,
Ferriani VP, et al. Vaccination practice in children with rheumatic
disease. Rev Bras Reumatol 2010; 50(4):351–61.
34. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde.
Departamento de Vigilância Epidemiológica. Manual dos Centros
de Referência para Imunobiológicos Especiais (CRIES). Brasília:
Ministério da Saúde; 2006.
35. Migowski E. Hepatite A, uma doença benigna? Available from:
www.apamt.org.br/anais_2008/jornada2008-anais/conferencias/
hepatiteA-uma_doenca_benigna.pdf. [Accessed on 11, Feb 2012].
36. Elkayam O, Yaron M, Caspi D. Safety and efficacy of vaccination
against hepatitis B in patients with rheumatoid arthritis. Ann Rheum
Dis 2002 Jul; 61(7):623–5.
37. Garrido Lopez BC, Navarro Compain MV, Navarro Sarabia F.
Vaccines and chemo-prophylaxis in rhemautoid arthritis: is a
vaccine calendar necessary? Reumatol Clin 2011; 7(6):412–6.
38. Russo RA, Rosenzweig SD, Katsicas MM. Hepatitis A-associated
macrophage activation syndrome in children with systemic
juvenile idiopathic arthritis: report of 2 cases. J Rheumatol 2008;
35(1):166–8.
39. Pham H, Geraci SA, Burton MJ. Adult immunizations: update on
recommendations. Am J Med 2011; 124(8):698–701.
20/03/2013 16:25:50
Consenso 2012 da Sociedade Brasileira de Reumatologia sobre vacinação em pacientes com artrite reumatoide
40. Mota LM, Oliveira AC, Lima RA, Santos-Neto LL, Tauil PL.
Vacci n ation against yellow fever am ong patients on
immunosuppressors with diagnoses of rheumatic diseases. Rev
Soc Bras Med Trop 2009; 42(1):23–7.
41. Manual de Recomendações para o Controle da Tuberculose no
Brasil In: Saúde Md, editor. Brasília 2010.
42. Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J,
Ustianowski A, et al. Drug-specific risk of tuberculosis in patients
with rheumatoid arthritis treated with anti-TNF therapy: results
from the British Society for Rheumatology Biologics Register
(BSRBR). Ann Rheum Dis 2010; 69(3):522–8.
43. Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD.
Treatment of rheumatoid arthritis with tumor necrosis factor
inhibitors may predispose to significant increase in tuberculosis
risk: a multicenter active-surveillance report. Arthritis Rheum
2003; 48(8):2122–7.
44. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA,
Testa MA, et al. The risk of herpes zoster in patients with
rheumatoid arthritis in the United States and the United Kingdom.
45. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K,
Richter C, et al. Risk of herpes zoster in patients with rheumatoid
arthritis treated with anti-TNF-alpha agents. JAMA 2009;
301(7):737–44.
46. Brisson MEW, Gay NJ, Law B, De Serres G. Modelling the impact
of immunization on the epidemiology of varicella zoster virus.
Epidemiol Infect 2000; 125(3):651–69.
47. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE,
Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic
neuralgia in older adults. N Engl J Med 2005; 352(22):2271–84.
48. Zhang J, Delzell E, Xie F, Baddley JW, Spettell C, McMahan RM,
et al. The use, safety, and effectiveness of herpes zoster vaccination
in individuals with inflammatory and autoimmune diseases:
a longitudinal observational study. Arthritis Res Ther 2011;
13(5):R174.
49. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of
herpes zoster: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep 2008;
57(RR-5):1-30; quiz CE2-4.
50. Pileggi GS, de Souza CB, Ferriani VP. Safety and immunogenicity
of varicella vaccine in patients with juvenile rheumatic diseases
receiving methotrexate and corticosteroids. Arthritis Care Res
(Hoboken) 2010; 62(7):1034–9.
51. Vasconcelos PF. Yellow Fever. Rev Soc Bras Med Trop 2003;
36(2):275–93.
52. Camara FP, Gomes AL, Carvalho LM, Castello LG. Dynamic
behavior of sylvatic yellow fever in Brazil (1954–2008). Rev Soc
Bras Med Trop 2011;44(3):297–9.
53. Barrett AD, Teuwen DE. Yellow fever vaccine – how does it work
and why do rare cases of serious adverse events take place? Curr
Opin Immunol 2009; 21(3):308–13.
54. Vellozzi C, Mitchell T, Miller E, Casey CG, Eidex RB, Hayes EB.
Yellow fever vaccine-associated viscerotropic disease (YEL–AVD)
and corticosteroid therapy: eleven United States cases, 1996–2004.
Am J Trop Med Hyg 2006; 75(2):333–6.
55. Monath TP, Cetron MS, McCarthy K, Nichols R, Archambault WT,
Weld L, et al. Yellow fever 17D vaccine safety and immunogenicity
in the elderly. Hum Vaccin 2005; 1(5):207–14.
56. Bruyand M, Receveur MC, Pistone T, Verdiere CH, Thiebaut R,
Malvy D. Yellow fever vaccination in non-immunocompetent
patients. Med Mal Infect 2008; 38(10):524–32.
57. Whittembury A, Ramirez G, Hernandez H, Ropero AM,
Waterman S, Ticona M, et al. Viscerotropic disease following
yellow fever vaccination in Peru. Vaccine 2009; 27(43):5974–81.
58. Martin M, Tsai TF, Cropp B, Chang GJ, Holmes DA, Tseng J, et
al. Fever and multisystem organ failure associated with 17D-204
yellow fever vaccination: a report of four cases. Lancet 2001;
358(9276):98–104.
59. Martins RM, Maia MLS, Santos EM, Cruz RLS, Santos PG,
Carvalho SMD, et al. Yellow Fever Vaccine Post-marketing
Surveillance in Brazil. Procedia in Vaccinology 2010; 2:178–83.
60. Hayes EB. Is it time for a new yellow fever vaccine? Vaccine
2010; 28(51):8073–6.
61. Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF,
Marano N, et al. Adverse event reports following yellow fever
vaccination. Vaccine 2008; 26(48):6077–82.
62. Vasconcelos PF, Luna EJ, Galler R, Silva LJ, Coimbra TL,
Barros VL, et al. Serious adverse events associated with yellow
fever 17DD vaccine in Brazil: a report of two cases. Lancet 2001;
358(9276):91–7.
63. Scheinberg M, Guedes-Barbosa LS, Mangueira C, Rosseto EA,
Mota L, Oliveira AC, et al. Yellow fever revaccination during
infliximab therapy. Arthritis Care Res (Hoboken) 2010; 62(6):
896–8.
64. Kavanaugh A. Infection prophylaxis in antirheumatic therapy:
emphasis on vaccination. Curr Opin Rheumatol 2009; 21(4):
419–24.
65. Oliveira ACV ML, Santos-Neto LL, Tauil PL. What a
Rheumatologist needs to know about yellow fever vaccine. Rev
Bras Reumatol [In Press]. 2012
66. Heijstek MW, Pileggi GC, Zonneveld-Huijssoon E, Armbrust W,
Hoppenreijs EP, Uiterwaal CS, et al. Safety of measles, mumps
and rubella vaccination in juvenile idiopathic arthritis. Ann Rheum
Dis 2007; 66(10):1384–7.
67. Borte S, Liebert UG, Borte M, Sack U. Efficacy of measles, mumps
and rubella revaccination in children with juvenile idiopathic
arthritis treated with methotrexate and etanercept. Rheumatology
(Oxford) 2009; 48(2):144–8.
23
20/03/2013 16:25:50
ORIGINAL ARTICLE
Primary Sjögren’s syndrome prevalence in
a major metropolitan area in Brazil
Valéria Valim1, Eliana Zandonade2, Ana Maria Pereira3, Odvaldo Honor de Brito Filho4,
Erica Vieira Serrano3, Carlos Musso5, Raquel Altoé Giovelli6, Rozana Mesquita Ciconelli7
ABSTRACT
There has been no previous prevalence study about of Sjögren’s syndrome (SS) in Brazil. The aim was to evaluate the SS
prevalence in a general population in Vitória, ES, Brazil. This was an epidemiological, observational, and cross-sectional
study conducted on 1,205 randomized people, aged 18–65 years, who lived in Vitória. The subjects were screened for
xerostomia and xerofphthalmia through home interviews. Those with sicca symptoms were asked to report to a hospital
for further medical evaluation, unstimulated salivary flow, Schirmer I test, blood analysis and minor labial salivary biopsy.
Sicca symptoms were found in 18% (217 subjects) of the sample. Of the 217 subjects with sicca symptoms, 127 (58%)
were available for examination. In this sample, 61.7% were female and 46.8% were under medication. Sicca syndrome
was confirmed in 12% by at least one examination (salivary flow or Schirmer I). Two patients (0.17%) matched four
criteria according to American-European Criteria (95% CI = 0.020–0.5983).
Keywords: primary Sjögren syndrome, prevalence, minor salivary biopsy, epidemiology.
INTRODUCTION
Primary Sjögren’s syndrome (pSS) is an autoimmune systemic disease characterized not only by lymphocytic infiltration of exocrine glands, but also by its effect on some
organs like lungs, nerves, blood, and kidneys.1 Its symptom
is usually presented by dryness of the mouth and eyes.2
The pSS is one of the most common autoimmune diseases.
But it has a low rate of diagnosis because dry complaints are
not systematically investigated by physicians.3
Published studies of pSS prevalence have shown different
results, ranging from 0.04% to 4.8%.4–14These differences
can be explained because of the use of different diagnostic
criteria, tests, and reference values to assess the dysfunction
of lachrymal and salivary glands. Another reason could be that
many studies were performed in different countries including
those on specific populations.
Over the years, many different criteria have been proposed: Boston (1965), Japanese (1971), San Francisco (1975),
Copenhagen (1976), San Diego (1986), Greek (1986), and
European (1993). The currently accepted criteria are those of
the American-European Consensus Group (2002).15 The main
contributions and differences of those criteria include: the
San Francisco Criteria, which proposed histological criteria
for salivary biopsy; the San Diego Criteria, which included
SS-A and/or SS-B autoantibodies as required criteria, the
European Criteria, which considered antinuclear antibodies, rheumatoid factor, and lachrymal biopsy as criteria. In
general, the criteria developed by the American scientific
committee took into account specific and objective tests like
biopsy and autoantibodies. On the other hand, the European
PRONUCLEAR Project – Brazilian Society of Rheumatology.
Rheumatology Service, Department of Internal Medicine, Hospital Universitário, Universidade Federal do Espírito Santo.
1. PhD in Rheumatology, Universidade Federal de São Paulo – Unifesp; Adjunct Professor, Department of Internal Medicine, Universidade Federal do Espírito
Santo – UFES; Head of the Rheumatology Service, Hospital Universitário, UFES
2. PhD in Statistics, Universidade de São Paulo – USP; Associate Professor, Statistics Department, UFES
3. Master Degree in Public Health, UFES
4. Dentistry, UFES
5. PhD in Pathology, USP; Pathologist, Hospital Universitário Cassiano Antonio Moraes; Adjunct Professor, UFES; Professor, Universidade Vila Velha
6. Master Degree Student, UFES
7. PhD in Rheumatology, Unifesp; Tenured Professor of Rheumatology, Unifesp
Correspondence to: Valéria Valim. Rua Almirante Soido, 271, Torre 1/501, Praia de Santa Helena. CEP: 29055-020. Vitória, ES, Brazil. E-mail: [email protected]
24
20/03/2013 16:25:50
criteria emphasized on clinical dryness symptoms. Based
on the European criteria, it was possible to classify people
with only sicca symptoms and dysfunctional lachrymal and
salivary tests as SS. The American-European classification
criteria maintained the same clinical questions and tests
for glandular dysfunction for screening of dryness. Also, it
included requirement of positive biopsy or anti-SS-A/SS-B
to fulfill diagnosis.15
Using the preliminary European criteria,16 the estimated
prevalence in women living in a rural community in Greece
was 0.6%.4 Similar results were found for those in Slovenia
(0.6%) and Denmark (0.6%–2.1%).10,11 Using the Copenhagen
criteria, the prevalence was 2.7% in Sweden and 0.7% in
China.6,12 In a study conducted in the USA by Hochberg
(1996), the prevalence was 0.04% for those aged between 65
and 84 years. This low rate is because autoantibodies were
used to classify the patients.13 In others studies the prevalence of SS was between 2% and 4.8%.5,12,15 In the United
Kingdom, the prevalence was estimated to be 3%–4%, using
the preliminary European criteria.8 Using the AmericanEuropean consensus, the prevalence rates are ranging from
0.1% to 0.4%.9
There has been no previous study about SS prevalence in
Brazil. Hence, the objective of this study was to determine the
pSS prevalence in a Brazilian city, using a randomized sample.
MATERIAL AND METHODS
This study was an epidemiological, observational, and crosssectional one on 1,205 randomized subjects, aged 18–65
years, who lived in Vitória, the capital of Espírito Santo
State, located in the southeast region of Brazil. Vitória is an
island, with an area of 93,381 km2 surrounded by mangroves;
40% is mountainous with tropical climate, and has an annual
average temperature of around 23 °C. In 2010, the population was around 320,156 inhabitants and 95% of adults were
literate. There is a mix of different ethnic groups in Brazil,
including indigenous, blacks, and Caucasians (Portuguese,
French, German, and Italian people).
The sample was proportional to the 2000 demographic
census data of the Brazilian Institute of Geography and
Statistics (IBGE, in Portuguese). It was probabilistic, by
conglomerates, multiple stages within homogeneous strata
with the sampling unit being the domicile. In the socioeconomic class definition, the monthly revenue of the head of
the household is expressed in ranges based on minimum
wage (MW). These ranges are the following: up to 2 MW
(US$ 318.00), from 2 to 5 MW (US$ 318.00 to 795.00),
from 5 to 10 MW (US$ 795.00 to 1,590.00), and more than
10 MW (US$ 1,590.00). The average obtained was 7.5 MW
(US$ 1,193.18) with a standard deviation of 4.55 MW
(US$ 723.86). Adopting a procedure where the size of the
sample is proportional to the population, and considering
the population size as infinite (large), the desired precision
of 0.7%, and a significance level of 5%, the sample size was
calculated to be 1,158 individuals. At the end of the study,
the confidence interval was calculated on the basis of the
derived result.
During the first part of the study, randomized home visits
were performed. About six standard questions (sicca symptoms) from the American-European criteria15 were asked.
The interviewers were undergraduate health-care students
who were trained to conduct these interviews.
The choice of households was randomized according to
the following criteria: domiciled unit located on the farthest
right side of the map, on the right side of the street. The way
to be followed was always by the right, clockwise, and then
skipping three houses between each visited one. The choice
of the person in the house to be included in the interview was
also randomized according to gender, age, and date of birth.
In the second phase, all patients were evaluated by a
rheumatologist medical doctor. Complementary exams
were performed to investigate rheumatic disease, including
Schirmer test, unstimulated salivary flow, rheumatoid factor,
antinuclear antibodies (ANA), anti-SS-A/Ro, anti-SS-B/La,
and salivary lip biopsy. Patients with positive HIV/HTLV
tests and lymphoma were excluded.
Unstimulated whole salivary flow in 15 min was collected
in the morning (8–10 h) and stored in clean plastic containers. The sample was weighed in a precision balance. It was
considered that saliva has 1 mg to each 1 mL. Patients were
instructed not to eat food or drink beverages with caffeine, or
smoke, or chew bubble gum on the day of the examination.
Room temperature was maintained between 20 °C and 30 ºC,
and air conditioning was turned off.
Blood samples were collected and stored at −20 ºC for
autoantibody identification, virus C, and HIV analysis. All
individuals were asked to undergo salivary lip biopsy.17 The
salivary glands were formalin-fixed until histopathological
analysis was performed by an expert pathologist. In minor
salivary glands (obtained through normal-appearing mucosa)
focal lymphocytic sialoadenitis, with a focus score ≥1, defined
as a number of lymphocytic foci (which contain more than 50
lymphocytes) per 4 mm2 of glandular tissue was considered
as SS. Patients who had dry eyes or dry mouth symptoms
plus positive autoantibody (SS-A or SS-B) or ≥1 focus score
25
20/03/2013 16:25:50
Valim et al.
were considered positive for SS. Also, patients who fulfilled
four-criteria (out of the six) were classified as SS according
to the American-European criteria.15
Characteristics of the population were described. The chisquare test was used to compare patients with and without
dryness symptoms. For the quantitative variables, Student
t-test was used. For the ones with non-normal distributions,
Mann-Whitney test was used. For all tests, the significance level was 5%. To evaluate data normal distribution,
Kolmogorov-Smirnoff test was performed.
The study had approval from the Research Ethics
Committee of the Universidade Federal do Espírito Santo,
and all participants were informed about the research and
had given their written informed consent.
RESULTS
A total of 1,205 participants were interviewed and were
representative of the general population of Vitória city. All
individuals accepted to answer questionnaires and to complete the first stage (Figure 1). In this sample, 50.8% were
women, 45.3% were married, 47.5% were Caucasian, aged
36.2 (13.6) years (Table 1). After home screening for sicca
syndrome, 18% (217) of the participants showed oral or visual
dryness. The most common complaint was the sensation or
feeling of having sand or gravel in the eyes followed by dry
mouth. Out of the 217 individuals, 58% (127) were evaluated
for Schirmer test, unstimulated whole salivary flow, blood
analysis, and minor labial salivary biopsy. Several reasons for
nonperformance of the examinations were observed: forgot
to follow up, change of address, lack of time, or had given up
on examinations. Only one patient disagreed to undergo all.
Trying to understand any bias that could have happened,
the 90 individuals with sicca symptoms who were not available for examinations (second phase) were compared with
those 127 who had undergone tests, including salivary lip
biopsy. Participants who came to examination were older
(44.77 ± 13.1 vs. 36.1 ± 13.5; P = 0.001; t test). No other
statistical difference was found (Table 2).
At least one positive test for dryness was observed in
12% of the participants. Visual dryness without oral manifestation was observed in 41.1% and isolated oral dryness
in only 24.4%.
In the final analysis, two individuals have achieved at
least four criteria and could be classified as SS according
American-European criteria. Thus, the prevalence observed
was 0.17% (CI = 0.0201–0.05983) (Figure 1). Both Sjögren
patients were female, non-white, and married; one was 41
26
1,205 individuals were
interviewed (home visits)
217 with sicca
symptoms (18%)
988 without any sicca
symptoms (82%)
127 were included in 2nd Phase and
underwent complementary exams
including lip biopsy (58%)
90 did not undergo the lip
biopsy and other exams
0.17% was classified as Sjögren’s
Syndrome according AmericanEuropean Criteria
2 patients fulfilled
at least 4 criteria
Figure 1
Flowchart of the sample.
Table 1
Demographic characteristics of the sample
Variable
Category
Count
%
Gender
Female
Male
614
591
51.0
49.0%
Ethnicity*
Caucasian
Black
Indigenous
Mixed origin
554
207
2
403
47.5
17.8
0.2
34.6
Marital status*
Single
Married
Widow
Divorced
513
534
42
90
43.5
45.3
3.6
7.6
Social class*
A
B
C
D
359
322
445
60
30.3
27.2
37.5
5.0
Variable
Mean
SD
Min–max
Age
36.2
13.6
18–65
n = 1,205. The differences correspond to information loss. SD = standard deviation.
years old and the other, 46 years old. One was using medication and both did not have comorbidities (Table 3).
DISCUSSION
This study provided the first Brazilian data about pSS prevalence. Brazil has a continental extension and it would be very
hard to perform this methodology and design for all states.
The mixed-race ethnic groups of Vitória city represent the
most important ethnicities of Brazilian population.
20/03/2013 16:25:50
Table 2
Demographic and sicca symptoms comparisons between individuals that have performed exams in second phase compared to
others who did not perform tests (non-participants second phase)
Variable
Category
Gender
Non-participants 2nd phase
Performed tests
P*
n
Col %
n
Col %
Female
Male
57
35
62
38
79
45
63.7
36.3
0.903
Ethnicity
Caucasian
Black
Mixed origin
34
24
33
37.4
26.4
36.3
51
21
47
42.9
17.6
39.5
0.307
Marital status
Single
Married
Widow
Divorced
24
52
7
8
26.4
57.1
7.7
8.8
49
61
6
5
40.5
50.4
5
4.1
0.115
- Have you had daily, persistent, troublesome
dry eyes for more than 3 months?
- Do you have a recurrent sensation of sand
or gravel in the eyes?
- Do you use tear substitutes more than
3 times a day?
- Have you had a daily feeling of dry mouth
for more than 3 months?
- Have you had recurrently or persistently
swollen salivary glands as a3?
- Do you frequently drink liquids to aid in
swallowing dry food?
35
37.6
38
30.6
0.281
29
31.2
48
38.7
0.251
13
14
16
12.9
0.818
48
51.6
55
48.4
0.289
5
5.4
7
5.7
0.920
19
20.4
30
24.4
0.512
Sicca symptom
(answer yes)
*Ch i-square test.
Table 3
Classification criteria for primary Sjögren’s syndrome in patients
Ro/La
≥ 1 focus score/4 mm2
Criteria number
Ocular dryness
Mouth dryness
Schirmer test
Salivary flow
Medicine
4
Yes
Yes
Pos
4,269
Yes
Neg
Yes
4
Yes
Yes
Pos
2,868
No
Neg
Yes
M edicine = antihypertensives, antidepressants, diuretics. Schirmer (mm/5 min); Salivary fl ow (mL/ 15 min).
Many studies were performed in different countries,
including specific populations, like old people and patients
of outpatient rheumatology clinic. 4−9,13,14 However, there
has been no previous study in the Brazilian population.
Prevalence studies have shown different results. The large
variability could be explained by differences in genetic and
environmental factors, but primarily it may also reflect on
differences in the methodology. The prevalence found, of
0.17%, agrees with that observed in other studies that have
used American-European criteria.9
Many classification criteria for SS had been proposed,
modified, and revised before and during the International
Symposia in Copenhagen in 1986.13 Nowadays, in spite of
some limitations, the American-European Consensus is used
widely to classify SS.15 These criteria have included oral
and visual dryness associated with sialoadenitis or positive
autoantibodies (SS-A/Ro and SS-B/La).
In the sample, only two individuals fulfilled at least four
criteria classified as SS. It is possible that patients with three
or two criteria including positive lip biopsy can be classified
as SS in the future. Being strict in requiring four positive findings to diagnose pSS, according to the American-European
consensus, those mild, atypical, and initial diseases might
have been excluded. The rigor of the current criteria, insidious disease onset, and wide spectrum of systemic clinical
manifestation could underestimate the prevalence.
It was a limitation of the study not performing all
complementary exams included in the American-European
consensus. Perhaps, individuals with negative Schirmer test
or normal salivary flow could present other positive dry tests
like Bengal Rose, scintigraphy, and sialography. Unstimulated
salivary flow and Schirmer test were chosen because they
are easy and cheap to perform. In addition, these tests have
shown good correlation and sensitivity for SS diagnosis.18
27
20/03/2013 16:25:50
Valim et al.
Among the interviewed patients without dryness symptoms (988 from 1,205), it could be possible to find SS
because the sicca syndrome cannot be present in early SS
and in patients with a predominance of systemic symptoms.
However, this difficulty is related to aspects of SS disease
and limitation of classification criteria, which explains how
hard it is to carry out randomized clinical trials.
Another limitation of the study was that only 58% of the
invited individuals came to the second phase, i.e., for salivary biopsy and autoantibody evaluation. A prevalence of
SS considering only participants of second phase that came
to complementary exams could result in an under-estimate
of SS in the population as a whole. This limitation is also
present in other studies.5–9 People who performed exams
were older than nonparticipants of the second phase of the
study. Perhaps, older people are more responsible or have a
28
better understanding of the importance of the study. Also, it
is possible and expected that the nonparticipants have had
milder dryness. That’s why we believe that the prevalence
would not be so higher if all individuals with dryness were
included in the second phase of the study.
Previous studies failed to determine histological abnormalities because many patients disagreed to submit for
biopsy.4–14 However, disagree to invasive exams is common
in large population studies. A positive point of this study
was that biopsy was done for all participants with dryness
symptoms, who came back for tests, and not just for those
with positive tests for glandular dysfunction or positive
autoantibodies.
In conclusion, the prevalence of pSS in Vitória, ES, Brazil,
was 0.17% according to American-European criteria. It is
possible that it could be underestimated.
20/03/2013 16:25:50
Prevalência da síndrome de Sjögren primária em importante área metropolitana no Brasil
excluído casos mais leves, atípicos e iniciais da doença. Esse
rigor, um início insidioso da doença e o amplo espectro de
manifestações clínicas sistêmicas podem ter subestimado a
prevalência da síndrome.
A não realização de todos os exames complementares
incluídos no Consenso Americano-Europeu foi uma limitação
deste estudo. É possível que indivíduos com teste de Schirmer
negativo ou fluxo salivar normal apresentem outros testes para
secura positivos, como Rose Bengal, cintilografia e sialografia. Fluxo salivar não estimulado e teste de Schirmer foram
escolhidos por serem de fácil execução e baixo custo. Além
disso, esses testes mostraram boa correlação e sensitividade
para o diagnóstico de SS.18
Entre os entrevistados sem sintomas de secura (988 de
1205), poderia ser possível encontrar SS, uma vez que a
síndrome “sicca” pode não estar presente na SS precoce e
em pacientes com predominância de sintomas sistêmicos.
Entretanto, tal dificuldade relaciona-se a aspectos da SS e
limitação dos critérios classificatórios, explicando como é
difícil conduzir ensaios clínicos randomizados.
Outra limitação deste estudo foi que apenas 58% dos indivíduos entrevistados participaram da segunda fase do estudo,
isto é, submeteram-se à biopsia de glândula salivar e pesquisa
de autoanticorpos. A prevalência de SS, considerando-se
apenas os participantes da segunda fase que se apresentaram
para os exames complementares, pode ter resultado em uma
subavaliação da SS na população como um todo. Essa limitação também está presente em outros estudos.5–9 Os indivíduos
que se submeteram aos exames eram mais velhos que aqueles
que não participaram da segunda fase deste estudo. Talvez os
indivíduos mais idosos sejam mais responsáveis ou entendam
melhor a importância deste estudo. Além disso, é possível
e esperado que aqueles que não participaram apresentassem
grau de secura menor. Por isso acreditamos que a prevalência
não seria tão maior se todos os indivíduos com secura fossem
incluídos na segunda fase deste estudo.
Estudos anteriores falharam em determinar as alterações
histológicas, pois muitos pacientes recusaram se submeter
à biopsia.4–14 No entanto, a não concordância com exames
invasivos é comum em grandes estudos populacionais. Um
aspecto positivo deste estudo foi que a biopsia foi realizada
em todos os participantes com secura, que retornaram para
os exames, e não apenas naqueles com testes positivos para
disfunção glandular ou positivos para os autoanticorpos.
Concluindo, a prevalência de SSp, de acordo com os
critérios americano-europeus, em Vitória, Espírito Santo,
Brasil, foi de 0.17%. É possível que tal prevalência tenha
sido subestimada.
REFERENCES
REFERÊNCIAS
1.
Kassan SS, Moutsopoulos HM. Clinical manifestations and
early diagnosis of Sjögren’s syndrome. Arch Intern Med 2004;
164(12):1275–84.
2.
Daniels TE, Whitcher JP. Association of patterns of labial salivary
gland inflammation with keratoconjunctivitis sicca: analysis of 618
patients with suspected Sjögren’s syndrome. Arthritis Rheum 1994;
37(6):869–77.
3.
Valim V. Avaliação da Prevalência de Síndrome Seca em pacientes
procedentes do Serviço de Reumatologia do Hospital Universitário
Cassiano Antônio De Moraes [abstract]. Rev Bras Reumatol 2003;
43:s39 (abstract PO 143).
4.
Dafni UG, Tzioufas AG, Staikos P, Skopouli FN, Moutsopoulos HM.
Prevalence of Sjögren’s syndrome in a closed rural community. Ann
Rheum Dis 1997; 56(9):521–5.
5.
Sánchez-Guerrero J, Pérez-Dosal MR, Cárdenas-Velázques F,
Pérez-Reguera A, Celis-Aguilar E, Soto-Rojas AE, et al. Prevalence
of Sjögren’s syndrome in ambulatory patients according to the
American-European Consensus Group criteria. Rheumatology
2005; 44(2):235–40.
6.
Zhang NZ, Shi CS, Yao QP, Pan GX, Wang LL, Wenet ZX, et al.
Prevalence of primary Sjögren’s syndrome in China. J Rheumatol
1995; 22(4):659–61.
7.
Drosos AA, Andonopoulos AP, Costopoulos JS, Papadimitriou CS,
Moutsopoulos HM. Prevalence of primary Sjögren’s syndrome in an
elderly population. Br J Rheumatol 1988; 27(2):123–7.
8.
Thomas E, Hay EM, Hajeer A, Silman AJ. Sjögren’s syndrome: a
community-based study of prevalence and impact. Br J Rheumatol
1998; 37(10):1069–76.
9.
Bowman SJ, Ibrahim GH, Holmes G, Hamburger J, Ainsworth JR.
Estimating the prevalence among Caucasian women of primary
Sjögren’s syndrome in two general practices in Birmingham, UK.
Scand J Rheumatol 2004; 33(1):39–43.
10. Tomsic M, Logar D, Grmek M, Perkovic T, Kveder T. Prevalence of
Sjögren’s syndrome in Slovenia. Rheumatology 1999; 38(2):164–70.
11. Bjerrum KB. Keratoconjunctivitis sicca and primary Sjögren’s
syndrome in a Danish population aged 30–60 years. Acta Opthalmol
Scand 1997; 75(3):281–6.
12. Jacobsson LT, Axell TE, Hansen BU, Henricsson VJ, Larsson A,
Lieberkind K, et al. Dry eyes or mouth. An epidemiological study
in Swedish adults, with special reference to primary Sjögren’s
syndrome. J Autoimmun 1989; 2(4):521–7.
13. Hochberg MC. The prevalence of dry eye, dry mouth, autoimmunity
and primary Sjögren’s syndrome in the general population [Abstract].
Arthritis Rheum 1996; 39:S66.
14. Whaley K, Williamson J, Wilson T, McGavin DD, Hughes GR,
Hughes H. Sjögren’s syndrome and autoimmunity in a geriatric
population. Age Ageing 1972; 1(4):197–206.
15. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander
EL, Carsons SE, et al. Classification criteria for Sjögren’s syndrome:
a revised version of the European criteria proposed by the AmericanEuropean Consensus Group. Ann Rheum Dis 2002; 61(6):554–8.
33
20/03/2013 16:25:51
Valim et al.
16. Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli
W, Bernstein RM, et al. Preliminary criteria for the classification
of Sjögren’s syndrome. Results of a prospective concerted action
supported by the European Community. Arthritis Rheum 1993;
36(3):340–7.
34
17. Langerman AJ, Blair EA, Sweiss NJ, Taxy JB. Utility of lip biopsy
in the diagnosis and treatment of Sjögren’s syndrome. Laryngoscope
2007; 117(6):1004–8.
18. Strickland RW, Tesar JT, Berne BH, Hobbs BR, Lewis DM,
Welton RC. The frequency of sicca syndrome in an elderly female
population. J Rheumatol 1987; 14(4):766–71.
20/03/2013 16:25:51
ORIGINAL ARTICLE
Frequency of sexual dysfunction in
women with rheumatic diseases
Clarissa de Castro Ferreira1, Licia Maria Henrique da Mota2, Ana Cristina Vanderley Oliveira1,
Jozélio Freire de Carvalho3, Rodrigo Aires Corrêa Lima4, Cezar Kozak Simaan5, Francieli de Sousa Rabelo6,
José Abrantes Sarmento7, Rafaela Braga de Oliveira7, Leopoldo Luiz dos Santos Neto8
ABSTRACT
Objective: To assess the prevalence of sexual dysfunction in women followed up at the Rheumatology Outpatient
Clinic of the Hospital Universitário de Brasília and of the Hospital das Clínicas da Universidade de São Paulo with the
following rheumatic diseases: systemic lupus erythematosus; rheumatoid arthritis; systemic sclerosis; antiphospholipid
antibody syndrome; and fibromyalgia. Methods: The Female Sexual Function Index (FSFI), obtained by applying a
19-item questionnaire that assesses six domains (sexual desire, arousal, vaginal lubrication, orgasm, sexual satisfaction and pain), was used. Results: This study assessed 163 patients. The mean age was 40.4 years. The prevalence of
sexual dysfunction was 18.4%, but 24.2% of the patients reported no sexual activity over the past 4 weeks. Patients
with fibromyalgia and systemic sclerosis had the highest sexual dysfunction index (33%). Excluding patients with no
sexual activity, the sexual dysfunction rate reaches 24.2%. Conclusion: The prevalence of sexual dysfunction found in
this study was lower than that reported in the literature. However, 24.2% of the patients interviewed reported no sexual
activity over the past 4 weeks, which might have contributed to the low sexual dysfunction index found.
Keywords: sexuality, sexual dysfunction, rheumatic diseases, quality of life, sexual behavior.
INTRODUCTION
Sexuality is part of human life and of quality of life, accounting for individual well-being. It relates not only to sexual
intercourse itself, but also to a whole spectrum that ranges
from self-image and self-valuing to relationship with the
‘Other’. Appropriate sexual activity comprises phases from
sexual arousal to relaxation, with pleasure and satisfaction.1
Sexual dysfunction is a change in a phase of the sexual
activity that can culminate in frustration, pain, and a reduction
in the number of sexual intercourses.2 Some studies have shown a prevalence of sexual dysfunction in the general female
population of as much as 40%.3 Chronic diseases are known
to influence the quality of sexual life, but their effect is little
studied, and sexual dysfunction, little diagnosed.2 This is due
to two reasons: patients do not report their sexual dysfunctions
because of shame or frustration, and physicians rarely ask their
patients about those dysfunctions.3,4
When asked, health professionals allege to have little time
for consultation, lack of privacy in their medical offices, and
lack of ability to discuss the issue. In addition, patients tend
Received on 12/06/2011. Approved on 12/13/2012. The authors declare no conflict of interest. Ethics Committee: FM 030/2010.
Hospital Universitário de Brasília, Universidade de Brasília – HU-UnB.
1. Rheumatologist, Service of Internal Medicine, Hospital das Forças Armadas
2. PhD in Medical Sciences, Medical School, Universidade de Brasília – FMUnB; Collaborating Professor of Internal Medicine and of the Service of Rheumatology, FMUnB
3. PhD in Rheumatology; Visiting Professor, Medical School, Universidade Federal da Bahia – UFBA
4. Rheumatologist, Hospital Universitário de Brasília – HUB-UnB, Hospital de Base do Distrito Federal
5. Master’s degree in Pathology, UnB; Rheumatologist; Professor of Internal Medicine, FMUnB
6. Rheumatologist, Health Secretariat of the Distrito Federal
7. Resident physician in Rheumatology, HUB-UnB
8. PhD in Pathology, UnB; Professor of Internal Medicine, FMUnB
Correspondence to: Licia Maria Henrique da Mota. Campus Universitário Darcy Ribeiro. Universidade de Brasília. Asa Norte. CEP: 70910-900. Brasília, DF,
Brazil. E-mail: [email protected]
35
20/03/2013 16:25:51
Ferreira et al.
to avoid speaking about that subject. Recently, the Association
Nationale de Défense Contre l’Arthrite Rhumatoïde (French
Association for Rheumatoid Arthritis) has sent, via e-mail, a
questionnaire about sexuality to their members. Only 38%
responded, and 70% reported a negative impact of the disease
on their sexual life. Seventy-two per cent reported never having
spoken with their physicians about sexuality.4
Studies on the Brazilian population that could help to
delineate the real impact of rheumatic diseases on sexual
functioning still lack. Knowing the extension of the problem
is necessary, so that therapeutic possibilities can be provided,
because sexual dysfunction is one of the major determinants
of reduced quality of life.
This study aimed at assessing the prevalence of sexual
dysfunction in women followed up in the Rheumatology
Outpatient Clinic of the Hospital Universitário de Brasília
(HUB) and the Hospital das Clínicas of the Universidade de
São Paulo (HC-FMUSP), who have the following rheumatic
diseases: systemic lupus erythematosus (SLE); rheumatoid
arthritis (RA); systemic sclerosis (SSc); antiphospholipid
antibody syndrome (APLS); and fibromyalgia (FM).
PATIENTS AND METHODS
This study assessed 163 women followed up at the
Rheumatology Outpatient Clinic of the HUB and HC-FMUSP
(patients with APLS). Those women had been diagnosed with
RA, SLE, SSc, FM, and APLS.
The presence of sexual dysfunction was identified by use of
the Female Sexual Function Index (FSFI), obtained by applying
the questionnaire proposed by Rosen et al.,5,6 which is widely
used in several countries and whose Portuguese version has been
validated7 (Table 1). That questionnaire contains 19 items that
assess the following six domains: sexual desire; arousal; vaginal
Table 1
Female sexual function index (FSFI)
Instructions
This questionnaire asks about your sexual life over the past 4 weeks. Please answer the questions as honestly and clearly as possible.
Your answers will be kept secret. To answer the questions, use the following definitions:
Sexual activity: comprises caressing, foreplay, masturbation (“jerking off”/female masturbation) and sexual act.
Sexual act: penetration (insertion) of the penis into the vagina.
Sexual stimulus: includes situations such as fondling the partner, sexual auto-stimulation (masturbation) or sexual fantasy (thoughts).
Sexual desire or drive: includes the disposition to engage in sexual activity, to feel receptive to
the sexual initiative of a partner, and to think about or fantasize with sex.
Sexual excitement or arousal: sensation that includes physical and mental aspects. It might include sensations
such as genital heat or swelling, lubrication (feeling wet/“wet vagina”) or muscle contractions.
PLEASE, JUST SELECT ONE ANSWER PER QUESTION.
Name:
Registry number:
QUESTIONS
1) Over the past 4 weeks, how often did you feel sexually aroused
(“turned on”) during sexual activity or intercourse?
1. No sexual activity.
2. Almost always or always.
3. Most times (more than half the time).
4. Sometimes (about half the time).
5. A few times (less than half the time).
6. Almost never or never.
2) Over the past 4 weeks, how would you rate your level of sexual
arousal (“turn on”) during sexual activity or intercourse?
2. Very high.
3. High.
4. Moderate.
5. Low.
6. Very low or none at all.
3) Over the past 4 weeks, how often did you feel sexual desire or interest?
36
4) Over the past 4 weeks, how would you rate your level (degree) of
sexual desire or interest?
1. Very high.
2. High.
3. Moderate.
4. Low.
5) Over the past 4 weeks, how confident were you about becoming
sexually aroused during sexual activity or intercourse?
2. Very high confidence.
3. High confidence.
4. Moderate confidence.
5. Low confidence.
6. Very low or no confidence.
6) Over the past 4 weeks, how often have you been satisfied with your
arousal (excitement) during sexual activity or intercourse?
20/03/2013 16:25:51
Table 1 (continued)
Female sexual function index (FSFI)
7) Over the past 4 weeks, how often did you become lubricated
(“wet”) during sexual activity or intercourse?
8) Over the past 4 weeks, how difficult was it to become lubricated
(“wet”) during sexual activity or intercourse?
2. Extremely difficult or impossible.
3. Very difficult.
4. Difficult.
5. Slightly difficult.
6. Not difficult.
9) Over the past 4 weeks, how often did you maintain your lubrication
(“wetness”) until completion of sexual activity or intercourse?
10) Over the past 4 weeks, how difficult was it to maintain your
lubrication (“wetness”) until completion of sexual activity or
intercourse?
3. Very difficult.
4. Difficult.
6. Not difficult.
11) Over the past 4 weeks, when you had sexual stimulation or
intercourse, how often did you reach orgasm (climax)?
12) Over the past 4 weeks, when you had sexual stimulation or
intercourse, how difficult was it for you to reach orgasm (climax)?
3. Very difficult.
4. Difficult.
6. Not difficult.
13) Over the past 4 weeks, how satisfied were you with your ability to
reach orgasm (climax) during sexual activity or intercourse?
2. Very satisfied.
3. Moderately satisfied.
4. About equally satisfied and dissatisfied.
5. Moderately dissatisfied.
6. Very dissatisfied.
14) Over the past 4 weeks, how satisfied have you been with the
amount of emotional closeness during sexual activity between you and
your partner?
2. Very satisfied.
15) Over the past 4 weeks, how satisfied have you been with your
sexual relationship with your partner?
2. Very satisfied.
16) Over the past 4 weeks, how satisfied have you been with your
overall sexual life?
2. Very satisfied.
17) Over the past 4 weeks, how often did you experience discomfort
or pain during vaginal penetration?
18) Over the past 4 weeks, how often did you experience discomfort
or pain following vaginal penetration?
19) Over the past 4 weeks, how would you rate your level (degree) of
discomfort or pain during or following vaginal penetration?
2. Very high.
3. High.
4. Moderate.
5. Low.
SCORING SYSTEM
Domain
Questions
Score
range
Multiplication Minimum Maximum
factor
score
score
Desire
1, 2
1–5
0.6
1.2
6.0
Arousal
3, 4, 5, 6
0–5
0.3
0.0
6.0
Lubrication 7, 8, 9, 10
0–5
0.3
0.0
6.0
Orgasm
0–5
0.4
0.0
6.0
Satisfaction 14, 15, 16
0 (ou 1) –5 0.4
0.8
6.0
Pain
0–5
0.0
6.0
11, 12, 13
17, 18, 19
0.4
37
20/03/2013 16:25:51
Ferreira et al.
lubrication; orgasm; sexual satisfaction; and pain. Individual
domain scores are obtained by adding the scores of the individual items that comprise the domain and multiplying the sum
by the domain factor. The full scale score is obtained by adding
the six domain scores. Values ≤ 26 indicate sexual dysfunction.
The study’s inclusion criteria were as follows: 18–69-year-old women diagnosed with specific diseases (RA, SLE, SSc,
FM, APLS) by a rheumatologist according to the American
College of Rheumatology criteria and Sidney criteria for
APLS,8–13 and who had had at least one sexual intercourse in
life. Those who refused to participate in the study and those
whose questionnaires were not fully completed were excluded.
The following demographic and clinical data of the participants were collected: diagnosis; disease duration; age; religion;
educational level; marital status; medications used; date of
the last period; and use of hormone replacement therapy. This
study was approved by the Committee on Ethics and Research
of the Universidade de Brasília.
Statistical analysis
Categorical variables were described as absolute frequency
and percent relative frequency. Quantitative variables were
described as mean ± standard deviation, when their distribution was symmetrical, or as median and interquartile interval,
when asymmetrical.
RESULTS
This study selected 181 patients, 18 of whom were excluded due to the following reasons: misunderstanding in
questionnaire completion (5); virginity (1); and incomplete
questionnaire (items left unanswered) (12). The disease distribution of the 163 patients remaining in the study was as
follows: SLE, 82 patients; RA, 24; FM, 15; SSc, 3; and APLS,
39 (all patients with primary APLS) (Table 2).
The mean age of the patients was 40.4 years. The characteristics of the participants according to their diseases are
shown in Table 3. Regarding menstruation, 46% had regular
cycles and 28.7% were in menopause. Only one patient was
on hormone replacement therapy. Most patients (76%) had
more than 7 years of schooling and only 1.2% were illiterate.
Table 2
Demographic data and menstrual cycle of all patients studied
and drugs used
Total number of patients
Sample
163 (100%)
Religion
Catholic
Evangelical
Baptist
Others or no religion
51.5%
23.75%
1.25%
32.7%
Marital status
Long-term companionship
Single
Separated
Widow
65.1%
21.73%
7.45%
5.6%
HRT
0.6%
Menstrual cycles
46.25%
Menopause
28.7%
Drugs
3.47
H R T = H ormone replacement therapy.
Table 3
Demographic data, disease duration, educational level (years of schooling) and frequency of sexual dysfunction in several
rheumatic diseases studied
General
SLE
RA
FM
SSc
APLS
Number of patients
163 (100%)
82 (50%)
24 (14.7%)
15 (9.2%)
3 (1.8%)
39 (24%)
Mean
40.4
36.1
41.2
50.4
45
40.1
Age (SD)
10.9
10.1
8.5
7.5
—
11.4
Median
40
34
40
51
45
40
Disease duration (years)
—
7.6
8.3
6.2
2.5
9.4
Schooling
Illiterate
1 to 7 years
> 7 years
1.2%
22.6%
76%
1.2%
15.8%
83%
4.2%
25%
71%
0
60%
40%
0
100%
0
0
15%
85%
Sexual dysfunction
18.4%
22%
8.3%
33.3%
33.3%
10.2%
No sexual activity
24.2%
17%
17%
47%
0
36%
SD : standard deviation; SLE : systemic lupus erythematosus; RA: rheumatoid arthritis; FM : fibromyalgia; SSc: systemic sclerosis; AP LS : antiphospholipid syndrome.
38
20/03/2013 16:25:51
The patients reported the following marital status:
married, 51.5%; single, 21.7%; living with partner, 13.6%;
separated, 7.4%; and widow, 5.6%. For the purpose of this
study, those married and those living with their partners were
gathered in one group, called the long-time companionship
group, corresponding to 65.1% of the interviewees. Most
participants reported being Catholic (41.2%).
The prevalence of sexual dysfunction was 18.4%, but
24.2% of the patients reported no sexual activity over the
previous 4 weeks. The prevalence of sexual dysfunction
according to the subgroups of disease was as follows: FM
and SSc, 33.3% of the patients (the highest rate); SLE, 22%
of the patients; RA, 8.3% of the patients; and APLS, 10.2%
of the patients. Excluding the patients with no recent sexual
activity, the prevalence of sexual dysfunction reaches 24.2%.
The mean number of medications per patient was 3.4. The
most used drugs were fluoxetine and tricyclic antidepressants
(18.7%). Both drugs were more often used by patients with
FM (12 patients), followed by those with SLE (7), RA (3)
and SSc (2). The mean FSFI score of patients on fluoxetine
or tricyclic antidepressants was 30.4. Patients not on those
drugs had a mean score of 19.51.
DISCUSSION
Rheumatic diseases can interfere with sexual function due to
factors related to both the disease itself and its treatment.1,14
Pain, morning stiffness, joint edema and fatigue might both
lead to a decrease in sexual drive and impair sexual intercourse. In addition, low self-esteem and negative body image,
which usually affect individuals with rheumatic diseases, are
relevant psychological factors. The drugs used to treat those
diseases can also reduce libido.2,15,16
A few studies have assessed the impact of rheumatic diseases on sexual function. A study conducted in Cleveland, USA,
has shown a lower frequency of sexual activity and reduced
vaginal lubrication in patients with SLE as compared with
controls.14 Patients with SLE have also reported an increase
in vaginal discomfort or pain during intercourse; however,
sexual drive, motivation, arousal and climaxing were similar
to those in controls.14,17
The prevalence of sexual dysfunction found in this study
was lower than that reported in the literature. Research with
individuals with RA has shown a 50%–60% impact on their
quality of sexual life.1 Abdel-Nasser et al.18 have studied 52
women with RA, 60% of whom had reported a decrease in their
sexual drive and satisfaction, as well as in sexual performance.
Ayden et al.1, using the FSFI questionnaire in patients with
FM, have reported 54.2% of sexual dysfunction versus 15.8%
in controls. However, Impens et al.19 have applied that same
questionnaire to patients with SSc and have found a mean score
of 24, but with a high sexual abstinence rate (40%).
An Egyptian study14 on RA has reported sexual dysfunction in 60% of the patients studied, with libido loss or decrease
in 46% of them, and that correlated with disease activity
parameters. Joint pain can restrict certain sexual positions,
mainly in the presence of knee or hip joint impairment.18
Other studies have also shown a trend towards more sexual
dysfunction in patients with RA.1,4,14 In this study, sexual
dysfunction was found in 8.3% of the patients with RA, which is lower than that reported in other studies on the theme.
The few studies on SSc have shown a reduction in sexual
activity due to psychological and physical factors, such as
vaginal dryness and ulcerations.19,20 In addition, skin thickness might lead to joint contractures, resulting in difficulties
to sexual relationship.20 Our study assessed only 3 patients
with SSc, which hinders other conclusions about the theme.
Regarding FM, depression seems to be the determinant
factor for sexual dysfunction,21 which, in those patients, manifests mainly as a reduction in sexual drive21,1 and in orgasm
rate, in addition to pain during sexual intercourse.22 In our
study, the patients with FM had the highest sexual dysfunction
rate (33%) and the highest percentage of sexual abstinence
(47%), in accordance with reports in the literature. Depression
is extremely common in FM, being associated with reduced
libido and self-esteem, being, thus, an important factor in
sexual dysfunction.1
In addition, the use of antidepressants worsens or contributes to worsen the quality of sexual life. As much as 60% of
patients on serotonin uptake inhibitors have sexual dysfunction.16 Tricyclic antidepressants, serotonin uptake inhibitors
and monoamine oxidase inhibitors are the antidepressants that
most reduce libido.15 In this study, a considerable increase
in the FSFI score of the patients on fluoxetine and tricyclic
antidepressants was observed, as compared to those not using
those drugs (30.4 versus 19.51).
Of the patients interviewed, 24.2% reported no sexual
activity over the previous 4 weeks, which might have contributed to the low sexual dysfunction rate found in our study.
Some of those patients might have some degree of sexual
dissatisfaction or difficulty, which might lead to abstinence
or a reduction in the frequency of sexual intercourses.
The educational level was high, with 76% of the participants having more than 7 years of schooling. Nevertheless,
difficulty in understanding the questions might have occurred.
39
20/03/2013 16:25:52
Ferreira et al.
The questionnaire is a self-report tool (except in cases of
illiteracy, when the doctor met the answers), but many patients asked about the meaning of certain items. In addition,
17 patients were excluded because of a misunderstanding
in questionnaire completion or lack of answer to any item.
40
The quality of sexual life is still rarely assessed during medical consultations. Further studies are required to delineate
the impact of disease on sexuality and to make rheumatologists aware of the importance of discussing those questions
with their patients.
20/03/2013 16:25:52
Ferreira et al.
REFERENCES
REFERÊNCIAS
1.
Tristano AG. The impact of rheumatic diseases on sexual function.
Rheumatol Int 2009; 29:853–60.
2. Clayton A, Ramamurthy S. The impact of physical illnesses on sexual
dysfunction. Adv Psychosom Med 2008; 29:70–88.
3. Lara LAS, Silva ACJRS, Romão APMS, Junqueira FRR. Abordagem
das disfunções sexuais femininas. Rev Bras Ginecol Obstet 2008;
30:312–21.
4. Perdriger A, Solano C, Gossec L. Why should rheumatologists evaluate
the impact of rheumatoid arthritis on sexuality? J Bone Spine 2010;
77:493–5.
5. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R,
et al. The female sexual function index (FSFI): a multidimensional
self-report instrument for the assessment of female sexual function. J
Sex Marital Ther 2000; 26:191–208.
6. Wiegel M, Meston C, Rosen R. The female sexual function index
(FSFI):cross-validation and development of clinical cutoff scores. J
Sex Marital Ther 2005; 31:1–20
7. Pacagnella RC, Martinez EZ, Vieira EM. Validade de construto de uma
versão em português do Female Sexual Function Index. Cad Saúde
Pública 2009; 25(11):2333–44.
8. Hochberg MC. Updating the American College of Rheumatology
revised criteria for the classification of systemic lupus erythematosus.
Arthritis Rheum 1997; 40:1725.
9. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C,
Goldenberg DL, et al. The American College of Rheumatology 1990
criteria for the classification of fibromyalgia: report of the multicenter
criteria commitee. Arthritis Rheum 1990; 33:160–72.
10. Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association 1987
revised criteria for classification of rheumatoid arthritis. Arthritis
Rheum 1998; 31:315–24.
46
11. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd,
et al. 2010 Rheumatoid Arthritis Classification Criteria. Arthritis Rheum
2010; 62:2569–81.
12. Subcommittee for scleroderma criteria of the American Rheumatism
Association Diagnostic and Therapeutic Criteria Committee.
Preliminary criteria for the classification of systemic sclerosis
(scleroderma). Arthritis Rheum 1980; 23:581–90.
13. Myakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R,
et al. International consensus statement on an update of the classification
criteria for definite antiphospholid syndrome (APS). J Thromb
Haemostat 2006; 4:295-306.
14. Ǿstensen M. New insights into sexual function and fertility in rheumatic
diseases. Best Pract Res Clin Rheumatol 2004; 18:219–232.
15. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry
2000; 61(Suppl 11):28–36.
16. Lee KU, Lee YM, Nam JM, Lee HK, Kweon YS, Lee CT,
et al. Antidepressant-induced sexual dysfunction among newer
antidepressants in a naturalistic setting. Psychiatry Investig 2010;
7:55–9.
17. Araújo DB, Borba EF, Abdo CHN, Souza LA, Goldstein-Schainberg C,
Chahade WH, et al. Função sexual em doenças reumáticas. Acta
Reumatol Port 2010; 35:16–23.
18. Abdel-Nasser AM, Ali EI. Determinants of sexual disability and
dissatisfaction in female patients with rheumatoid arthritis. Clin
Rheumatol 2006, 25:822–30.
19. Impens AJ, Rothman J, Schiopu E, Cole JC, Dang J, Gendrano N, et
al. Sexual activity and functioning in female scleroderma patients. Clin
Exp Rheumatol 2009; 27:S38–S43.
20. Schouffoer AA, van der Marel J, Ter Kuile MM, Weijenborg PT,
Voskuyl A, Vliet Vlieland CW, et al. Impaired sexual function in
women with systemic sclerosis: a cross-sectional study. Arthritis
Rheum 2009; 15:1601–8.
21. Orellana C, Gratacós J, Galisteo C, Larrosa M. Sexual dysfunction
in patients with fibromyalgia. Curr Rheumatol Rep 2009; 11:437–42.
22. Kalichman L. Association between fibromyalgia and sexual dysfunction
in women. Clin Rheumatol 2009; 28:365–9.
20/03/2013 16:25:52
ORIGINAL ARTICLE
HLA-DRB1 allele association with rheumatoid
arthritis susceptibility and severity in Syria
Jamil Mourad1, Fawza Monem2
ABSTRACT
Introduction: Rheumatoid arthritis (RA) is a complex multifactorial chronic disease. The importance of human leukocyte
antigen as a major genetic risk factor for RA was studied worldwide. Although it is widely distributed in different Syrian
areas, studies of human leukocyte antigen (HLA) alleles’ role are absent. Objective: The aim of our study was to determine
the association of HLA-DRB1 alleles with the susceptibility and severity of RA in Syria. Patients and methods: Eightysix RA patients and 200 healthy controls from Syria were genotyped using polymerase chain reaction with sequencespecific primer (PCR-SSP). Anti-CCP antibodies were measured by ELISA. Rheumatoid factor (RF), C-reactive protein
(CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS-28) values were obtained from patients’
medical records. DAS-28 was used to assess the clinical severity of the patients. Results: The HLA-DRB1*01, *04, and
*10 frequencies showed a strong association with the disease susceptibility (OR = 2.29, 95% CI = 1.11–4.75, P = 0.022;
OR = 3.16, 95% CI = 2.08–4.8, P < 0.0001; OR = 2.43, 95% CI = 1.07–5.51, P = 0.029 respectively), while the frequencies of HLA-DRB1*11, and *13 were significantly lower in RA patients than in controls (OR = 0.49, 95% CI = 0.3–0.8,
P = 0.004; OR = 0.32, 95% CI = 0.15–0.69, P = 0.002, respectively). The other HLA-DRB1 alleles showed no significant
difference. The frequency of anti-CCP antibodies was higher in shared epitope (SE) positive patients compared with
SE-negative patients (OR = 5.5, 95% CI = 2–15.1, P = 0.00054). DAS-28 of RA patients didn't show significant difference
between the SE negative and the SE positive groups. Conclusion: Our results indicate that HLA-DRB1*01, *04, and *10
alleles are related with RA, while HLA-DRB1*11 and *13 protect against RA in the Syrian population.
Keywords: HLA-DR4 antigen, rheumatoid arthritis, disease susceptibility, Syria.
INTRODUCTION
Rheumatoid arthritis (RA) is one of the complex immunemediated diseases with unknown etiology and an estimated
population prevalence of 1%.1 It is characterized by chronic
inflammation, synovitis, pain, and progressive destruction
of both the articular cartilage and bone leading to functional
disability.2 The chance of developing the disease is 2–3 times
more frequent in women than men. The peak age on onset of the
disease is in the 40s, although it can occur at any age.3 Genetic
and environmental risk factors play key roles in the disease
pathogenesis.1,4 The inheritance probability of RA is estimated
to be around 60%.4,5
The human leukocyte antigen (HLA) is found to be the
most important genetic risk factor for RA, which accounts
for 30%1,5 to 50% of overall genetic susceptibility to RA.6
The shared epitope (SE) hypothesis described the relationship
between HLA-DRB1 and RA.7,8 HLA-DRB1 alleles encoding
the SE (DRB1*01, *04, *10, and *14) are associated with
structural severity of RA and have been more recently related
with production of anti-citrullinated peptide autoantibodies (anti-CCP).5,6 On the other hand, SE negative genotypes
(mainly DRB1*11 and *13) provide protection against RA
susceptibility.6,9
The major relationship of particular HLA alleles with RA
is not constant in all human populations, different geographical areas, or among different ethnic groups.1 Despite of the
Department of Biochemistry and Microbiology, School of Pharmacy, Damascus University.
1. Pharmacist Biologist, Maters Degree in Clinical Laboratory Diagnosis, University of Damascus
2. Professor, School of Pharmacy, University of Damascus
Correspondence to: Jamil Mourad. School of Pharmacy of Damascus University. Mazze Street. Damascus, Syria. E-mail: [email protected]
47
20/03/2013 16:25:52
Mourad et al.
wide distribution of RA in Syria, the HLA-DRB1 studies are
still absent. Hence, the aim of our study is to determine the
association of HLA-DRB1 alleles in the disease susceptibility
and severity in Syria.
The study was designed as a case-control study. Blood samples
were obtained from 86 patients (mean age 41.41 ± 10.57
years; 69 women, 17 men) admitted to the Department of
Rheumatology, Ibn Nafis Hospital, Almowasat and Al-Assad
Hospitals, Damascus University, between January 2010 and
September 2011. All patients fulfilled the American College
of Rheumatology (ACR) criteria.10 Two hundred healthy unrelated volunteers (mean age 40.21 ± 10.11 years; 160 women
and 40 men) matched by age, gender, and ethnic origin were
allocated as controls. An informed consent was obtained from
all patients and healthy individuals. The project was approved
by the Ethical Committee of Damascus University.
The detection of anti-CCP IgG antibodies was performed
using second-generation ELISA kit (Euroimmun, Lübeck,
Germany). Serum samples presenting results > 5 RU/mL were
considered to be positive for anti-CCP antibodies. Rheumatoid
factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS-28) values
were adopted from patients’ medical records. DAS-28 was used
to assess the clinical severity of the patients.11 Genomic DNA
of patients with RA (n = 86) and healthy controls (n = 200)
were isolated from 300 μL aliquots of peripheral anticoagulated
venous blood samples by using the High Pure PCR Template
Preparation Kit (Roche, Mannheim, Germany). Genotyping
of HLA-DRB1 was performed by polymerase chain reaction
with sequence-specific primers (PCR-SSP) using Micro SSPT
Generic HLA Class II (DRB) (One Lambda Inc., CA, USA).
Odds ratio (OR) and 95% confidence interval (95% CI)
were calculated to estimate the strengths of the associations.
Chi-squared and Student’s t-test were used in the statistical
analysis. Differences were considered to be significant at
P < 0.05.
RESULTS
Demographic data and clinical findings of 86 RA patients
diagnosed according to modified ACR criteria are given in
Table 1. Frequencies of HLA-DRB1 alleles of RA patients
and normal individuals are summarized in Table 2. In RA
patients, HLA-DRB1 *01, *04, and *10 allele frequencies
were higher than controls (OR = 2.29, 95% CI = 1.11–4.75,
48
P = 0.022; OR = 3.16, 95% CI = 2.08–4.8, P < 0.0001; and
OR = 2.43, 95% CI = 1.07–5.51, P = 0.029, respectively). In
contrast, DRB1 *11 and *13 alleles were more frequent in
controls (OR = 0.49, 95% CI = 0.3–0.8, P = 0.004; OR = 0.32,
95% CI = 0.15–0.69, P = 0.002, respectively). The allele
frequency differences of DRB1*03, *07, *08, *09, *12, *14,
*15, and *16 were not statistically significant (95% CI of *16
overlapped 1). Compared with controls, frequencies of SE positive alleles (the sum of DRB1*01, *04, *10, *14) were higher
in RA patients (OR = 3.41, 95% CI = 2.35–4.95, P < 0.0001).
Anti-CCP antibody was present in 60.46% and RF in
63.95% of the RA patients. Frequencies of anti-CCP antibodies and RF were higher in SE-positive patients compared to
SE-negative patients (OR = 5.5, 95% CI = 2–15.1, P < 0.001;
OR = 5.45, 95% CI = 2–14.87, P < 0.001, respectively)
(Table 3).
Disease severity presented by DAS-28 values showed no
significance between SE negative and SE positive RA patients
(Figure 1).
DISCUSSION
Different literatures investigated the biogeographic distribution
of RA-DRB1 alleles in various ethnicities and races around
the world.1,5,12 HLA-DRB1*04 allele has been reported to be
linked to RA in many populations.13–25 DRB1*04 was frequent
in RA patients in Morocco26 and Zahedan southeast Iran,27 but
Table 1
Demographic and clinical characteristics of patients with
Characteristics
RA (n = 86)
Age, mean (± SD) years
41.41 (10.57)
Disease duration, mean (± SD) years
11.26 (6.25)
Women
69 (80.23%)
Men
17 (19.77%)
Women:Men ratio
4:1
RF positive patients
55 (63.95%)
Anti-CCP positive patients
52 (60.46%)
Anti-CCP (RU/mL)
110.82 (105.12)
CRP (mg/L)
31.14 (38.4)
ESR (mm/hr)
56.71 (29.67)
DAS-28, mean (SD)
6.12 (1.4)
V alues are mean (SD ) or number (% ) unless otherwise indicated.
n: number of RA patients; SD : standard deviation; RF: rheumatoid factor; Anti-C C P : anti-citrullinated
peptide antibodies; R U: relative units; C RP : C -reactive protein; ESR: erythrocyte sedimentation rate;
D AS-28: disease activity score 28.
20/03/2013 16:25:53
HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria
Table 2
The distribution of HLA-DRB1 allele frequencies in RA patients and controls
RA (2n = 172)
Controls (2n = 400)
Genotype
HLA-DRB 1
n
AF (%)
n
AF (%)
OR (95% CI)
P
DRB1*01
15
9.0
16
4
2.29 (1.11–4.75)
0.022
DRB1*03
13
7.8
38
10
0.78 (0.40–1.50)
0.455
DRB1*04
60
36.1
58
15
3.16 (2.08–4.80)
< 0.0001
DRB1*07
12
7.2
44
10
0.61 (0.31–1.18)
0.137
DRB1*08
2
1.2
7
1.5
0.66 (0.14–3.21)
0.605
DRB1*09
1
0.6
2
0.5
1.16 (0.10–12.92)
0.901
DRB1*10
12
7.2
12
3
2.43 (1.07–5.51)
0.029
DRB1*11
24
14.5
99
25
0.49 (0.30–0.80)
0.004
DRB1*12
0
0.0
6
1.5
0.00
0.106
DRB1*13
8
4.8
53
13.5
0.32 (0.15–0.69)
0.002
DRB1*14
10
6.0
23
6
1.01 (0.47–2.17)
0.976
DRB1*15
10
6.0
37
9.5
0.61 (0.29–1.25)
0.170
DRB1*16+
5
3.0
3
0.5
3.96 (0.94–16.77)
0.044
SE positive
97
56.4
110
30.5
3.41 (2.35–4.95)
<0.0001
V alues are number (% ) unless otherwise indicated.
AF: allele frequency; SE positive: the sum of D RB1*01 , * 04 , * 10, and * 14 alleles; OR:
the chi-square test. D ifferences were considered significant at P < 0.05.
+ Not significant because 95% CI of *16 overlapped 1.
odds ratio; 95% C I: confidence interval at 95% . H LA frequencies observed in patients and controls were compared using
SE negative
SE positive
Table 3
Association of HLA-DRB1 shared epitopes alleles with antiCCP and rheumatoid factor antibodies in rheumatoid arthritis
patients (n = 86)
SE negative
(n = 25)
OR
(95% CI)
P
Anti-CCP
positive
44 (72.13%)
8 (32%)
5.5
(2–15.1)
0.00054
Anti-CCP
negative
17 (27.87%)
17 (68%)
RF positive
46 (73.77%)
9 (32%)
5.45
(2–14.87)
0.00055
RF negative
15 (26.23%)
16 (68%)
V alues are number (% ) unless otherwise indicated. P resence of anti-C C P antibodies and R F in
SE-positive or SE-negative RA patients was compared using the chi-square test. D ifferences were
considered to be significant at P < 0.05.
SE: shared epitopes; OR: odds ratio; 95% CI : confidence interval at 95% .
surprisingly with no significance. On the other hand, Peruvian28
and Mexican American29 populations showed no significant
correlation between HLA-DRB1*04 and RA susceptibility.
Other alleles were associated with RA proneness as DRB*01
in Brazilians,30 Mexicans,31 Spanish,14 Italians,20 French,24
Turkish,25,32 Finnish,17 and Japanese;33 DRB1*09 in Turkish,25
Malaysians, 34 and Koreans; 35 DRB1*10 in Brazilians, 30
Iranians,27 Saudi Arabians,16 Taiwanese,36 Asians,37 and African
6.00
Means DAS 28 Value
SE positive
(n = 61)
8.00
P = 0.56
SE status
Error bars: + /- SD
4.00
n = 61
n = 25
2.00
.00
RA Patiens
Figure 1
Relation between shared epitopes and DAS-28 in 86 rheumatoid arthritis patients.
The DAS-28 values were compared between SE negative and
SE positive RA patients using Student’s t-test. Differences were
considered to be significant at P < 0.05.
n: number of RA patients carrying the alternative genotype.
49
20/03/2013 16:25:53
Mourad et al.
Americans,22 and DRB1*14 in Peruvians,28 Ecuadorians,38 and
Mexican Americans.29 Uncommonly, HLA-DRB1*08 was reported for its association with RA in Saudi Arabians16 and HLADRB1*15 in Japanese.33 In accordance to the nearby populations
(Middle Eastern and Mediterranean), our results showed that RA
susceptibility is predominantly associated with DRB1*01, *04,
and *10 alleles. Albeit not significant, DRB1*09, *14, and *16
were more frequent in RA patients than controls.
The protective effect of certain HLA-DRB1 alleles against
RA has been reported in several reviews5,12,39,40 and revealed
in different populations. HLA-DRB1*03 was informed to be
protective against RA in Iranians27 and Asians;19 DRB1*06 in
Saudis;16 DRB1*07 in Slovakians,23 Finnish,17 and Tunisians;13
DRB1*08 in Mexican Americans;29 DRB1*11 in Peruvian28
and African Americans;22 whereas DRB1*13 in Turkish,25,32
Finnish,17 Asians,19 and Slovakians.23 In this study HLADRB1*11 and *13 were negatively associated with RA reflecting a probable protective effect in our population.
The relation between the SEs and the severity of RA has not
been clearly verified.41 The DRB1*0401 allele is indicated to
50
increase the severity of RA in northern Europe,42 Netherlands,43
northern Italy,44 and Caucasians;45,46 whereas DRB1*0405 allele is specified in Korea.47 In contrary, our study showed no
significant correlation of disease severity, assessed by mean
DAS-28 values, between the SE positive and SE negative patients. These results comply with studies carried out in Turkey32
and Greece.48 Our study supported previously reported relationship of SE positive alleles in the productions of anti-CCP and
RF sero-positivity.5,6,30,43 Even the less, results in this study may
not reflect the relationship between HLA-DRB1 and disease
severity because of limited number of patients.
Our study was limited by the inability to perform fourdigit subtyping of all DRB1 alleles. However, a significant
relation between SE-containing main alleles (the sum of
DRB1*01, *04, *10, and *14) in patients with RA was resolute
(OR = 3.41, 95% CI = 2.35–4.95, P < 0.0001).
In conclusion, HLA-DRB1*01, *04, and *10 alleles were
identified as related with RA and HLA-DRB1*11 and *13 were
detected as protective in our population. No significance was
observed between SEs alleles and RA severity.
20/03/2013 16:25:53
Mourad et al.
seguem: DRB*01 em brasileiros,30 mexicanos,31 espanhóis,14
italianos,20 franceses,24 turcos,25,32 finlandeses17 e japoneses;33
DRB1*09 em turcos,25 malaios34 e coreanos; 35 DRB1*10 em
brasileiros,30 iranianos,27 sauditas,16 taiwaneses,36 asiáticos37 e
afro-americanos;22 e DRB1*14 em peruanos,28 equatorianos38
e méxico-americanos.29 Houve raros relatos da associação de
AR com HLA-DRB1*08 em sauditas16 e com HLA-DRB1*15
em japoneses. 33 À semelhança das populações vizinhas
(Oriente Médio e Mediterrâneo), nossos resultados mostraram
que a suscetibilidade à AR está predominantemente associada aos alelos DRB1*01, *04 e *10. Embora de maneira
não significativa, os alelos DRB1*09, *14 e *16 foram mais
frequentes em pacientes com AR do que em controles.
O efeito protetor de certos alelos HLA-DRB1 contra AR
foi relatado em várias revisões5,12,39,40 e mostrado em diferentes
populações. As seguintes relações de proteção contra AR foram
relatadas: alelo HLA-DRB1*03 em iranianos27 e asiáticos;19
DRB1*06 em sauditas;16 DRB1*07 em eslovacos,23 finlandeses17 e tunisianos;13 DRB1*08 em méxico-americanos;29
DRB1*11 em peruanos28 e afro-americanos;22 e DRB1*13 em
turcos,25,32 finlandeses,17 asiáticos19 e eslovacos.23 Neste estudo,
os alelos HLA-DRB1*11 e *13 associaram-se negativamente
com AR, refletindo provável efeito protetor na população síria
estudada.
A relação entre os ECs e a gravidade da AR ainda não foi
esclarecida.41 Há relatos de que o alelo DRB1*0401 aumente a
gravidade da AR no norte da Europa,42 na Holanda,43 no norte
da Itália44 e em caucasianos,45,46 enquanto o alelo DRB1*0405
é específico da Coreia do Sul.47 Por outro lado, nosso estudo
mostrou não haver correlação significativa da gravidade da
doença, avaliada pelo DAS-28, com pacientes EC-positivos
e EC-negativos. Tais resultados concordam com estudos conduzidos na Turquia32 e na Grécia.48 Nosso estudo confirmou o
relato anterior de relação entre alelos EC-positivos e a produção
de anti-CCP e soropositividade para FR.5,6,30,43 No entanto, os
resultados deste estudo podem não refletir a relação entre os
alelos HLA-DRB1 e a gravidade da doença devido ao número
limitado de pacientes.
Nosso estudo foi limitado pela impossibilidade de realizar
subtipagem de 4 dígitos de todos os alelos DRB1. Entretanto,
encontrou-se relação significativa entre os principais alelos
contendo EC (a soma de DRB1*01, *04, *10 e *14) em pacientes com AR (OR = 3,41, IC 95% = 2,35–4,95, P < 0,0001).
Concluindo, identificou-se uma relação dos alelos HLADRB1*01, *04 e *10 com AR, tendo os alelos HLA-DRB1*11
e *13 sido identificados como protetores na população síria
estudada. Não se observou significância entre os alelos com
ECs e gravidade da AR.
54
REFERENCES
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Kochi Y, Suzuki A, Yamada R, Yamamoto K. Genetics of rheumatoid
arthritis: underlying evidence of ethnic differences. J Autoimmun
2009; 32(3-4):158–62.
Neumann E, Lefèvre S, Zimmermann B, Gay S, Müller-Ladner U.
Rheumatoid arthritis progression mediated by activated synovial
fibroblasts. Trends Mol Med 2010; 16(10):458–68.
Suchomel P, Buchvald P, Choutka O. Rheumatoid Arthritis. In:
Suchomel P, Choutka O (eds.). Reconstruction of Upper Cervical
Spine and Craniovertebral Junction. Berlin Heidelberg: Springer;
2011, p. 235–46.
Hoovestol RA, Mikuls TR. Environmental Exposures and
Rheumatoid Arthritis Risk. Curr Rheumatol Rep 2011;1–9.
de Vries R. Genetics of rheumatoid arthritis: time for a change! Curr
Opin Rheumatol 2011; 23(3):227–32.
Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of
rheumatoid arthritis: what have we learned? Immunogenetics 2011;
63(8):459–66.
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis.
An approach to understanding the molecular genetics of susceptibility
to rheumatoid arthritis. Arthritis Rheum 1987; 30(11):1205–13.
Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope.
Curr Opin Rheumatol 2010; 22(3):293–8.
Gibert M, Balandraud N, Touinssi M, Mercier P, Roudier J,
Reviron D. Functional categorization of HLA-DRB1 alleles in
rheumatoid arthritis: the protective effect. Hum Immunol 2003;
64(10):930–5.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
revised criteria for the classification of rheumatoid arthritis. Arthritis
Rheum 1988; 31(3):315–24.
Prevoo MLL, Van’t Hof MA, Kuper HH, van Leeuwen MA,
van De Putte LBA, van Riel PL. Modified disease activity scores that
include twenty-eight-joint counts development and validation in a
prospective longitudinal study of patients with rheumatoid arthritis.
Newton JL, Harney SM, Wordsworth BP, Brown MA. A review
of the MHC genetics of rheumatoid arthritis. Genes Immun 2004;
5(3):151–7.
Dhaouadi T, Sfar I, Abdelmoula L, Bardi R, Jendoubi-Ayed S,
Makhlouf M, et al. Association of specific amino acid sequence
(QRRAA) of HLA-DRB1*0405 with rheumatoid arthritis in a
Tunisian population. Arch Inst Pasteur Tunis 2010; 87(1-2):53–9.
Balsa A, Minaur NJ, Pascual-Salcedo D, McCabe C, Balas A,
Fiddament B, et al. Class II MHC antigens in early rheumatoid
arthritis in Bath (UK) and Madrid (Spain). Rheumatology 2000;
39(8):844–9.
Hajeer AH, Dababneh A, Makki RF, Thomson W, Poulton K,
González-Gay MA, et al. Different gene loci within the HLA-DR
and TNF regions are independently associated with susceptibility
and severity in Spanish rheumatoid arthritis patients. Tissue Antigens
2000; 55(4):319–25.
Al-Swailem R, Al-Rayes H, Sobki S, Arfin M, Tariq M. HLA-DRB1
association in Saudi rheumatoid arthritis patients. Rheumatol Int
2006; 26(11):1019–24.
20/03/2013 16:25:54
Associação do alelo HLA-DRB1 com suscetibilidade a artrite reumatoide e gravidade da doença na Síria
17. Laivoranta-Nyman S, Möttönen T, Hermann R, Tuokko J,
Luukkainen R, Hakala M, et al. HLA-DR-DQ haplotypes and
genotypes in Finnish patients with rheumatoid arthritis. Ann Rheum
Dis 2004; 63:1406–12.
18. Delgado-veja AM, Anaya JM. Meta-analysis of HLA-DRB1
polymorphism in Latin American patients with rheumatoid arthritis.
Autoimmun Rev 2007; 6(6):402–8.
19. Jun KR, Choi SE, Cha CH, Oh HB, Heo YS, Ahn HY, et al.
Meta-analysis of the Association between HLA-DRB1 Allele and
Rheumatoid Arthritis Susceptibility in Asian Populations J Korean
Med Sci 2007; 22(6):973.
20. Bongi SM, Porfirio B, Rombola G, Palasciano A, Beneforti E,
Bianucci G. Shared-epitope HLA-DRB1 alleles and sex ratio in Italian
patients with rheumatoid arthritis. Joint Bone Spine 2004; 71(1):24–8.
21. Xue Y, Zhang J, Chen YM, Guan M, Zheng SG, Zou HJ. The HLADRB1 shared epitope is not associated with antibodies against cyclic
citrullinated peptide in Chinese patients with rheumatoid arthritis.
22. Hughes LB, Morrison D, Kelley JM, Padilla MA, Vaughan LK,
Westfall AO, et al. The HLA-DRB1 shared epitope is associated with
susceptibility to rheumatoid arthritis in African Americans through
European genetic admixture. Arthritis Rheum 2008; 58(2):349–58.
23. Stark K, Rovensky J, Blazickova S, Grosse-Wilde H, Ferencik S,
Hengstenberg C, et al. Association of common polymorphisms in
known susceptibility genes with rheumatoid arthritis in a Slovak
population using osteoarthritis patients as controls. Arthritis Res Ther
2009; 11(3):R70.
24. Reviron D, Foutrier C, Guis S, Mercier P, Roudier J. DRB1 alleles in
polymyalgia rheumatica and rheumatoid arthritis in southern France.
Eur J Immunogenet 2001; 28(1):83–7.
25. Uçar F, Karkucak M, Alemdaroglu E, Capkin E, Yücel B, Sönmez M,
et al. HLA-DRB1 allele distribution and its relation to rheumatoid
arthritis in eastern Black Sea Turkish population. Rheumatol Int 2012;
32:1003-7..
26. Atouf O, Benbouazza K, Brick C, Bzami F, Bennani N, Amine B, et
al. HLA polymorphism and early rheumatoid arthritis in the Moroccan
population. Joint Bone Spine 2008; 75(5):554–8.
27. Sandoughi M, Fazaeli A, Bardestani G, Hashemi M. Frequency
of HLA-DRB1 alleles in rheumatoid arthritis patients in Zahedan,
southeast Iran. Ann Saudi Med 2011; 31(2):171–3.
28. Castro F, Acevedo E, Ciusani E, Angulo JA, Wollheim FA, SandbergWollheim M. Tumour necrosis factor microsatellites and HLADRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients
with rheumatoid arthritis. Ann Rheum Dis 2001; 60(8):791–5.
29. del Rincon I, Escalante A. HLA-DRB1 alleles associated with
susceptibility or resistance to rheumatoid arthritis, articular
deformities, and disability in Mexican Americans. Arthritis Rheum
1999; 42(7):1329–38.
30. Louzada-Junior P, Freitas MVC, Oliveira RDR, Deghaide NHS,
Conde RA, Bertolo MB, et al. A majority of Brazilian patients with
rheumatoid arthritis HLA-DRB1 alleles carry both the HLA-DRB1
shared epitope and anti-citrunillated peptide antibodies. Braz J Med
Biol Res 2008; 41:493–9.
31. Ruiz-Morales JA, Vargas-Alarcón G, Flores-Villanueva PO, VillarrealGarza C, Hernández-Pacheco G, Yamamoto-Furusho JK, et al.
HLA-DRB1 alleles encoding the “shared epitope” are associated with
susceptibility to developing rheumatoid arthritis whereas HLA-DRB1
alleles encoding an aspartic acid at position 70 of the beta-chain are
protective in Mexican Mestizos. Hum Immunol 2004; 65(3):262–9.
32. Kinikli G, Ates A, Turgay M, Akay G, Kinikli S, Tokgoz G. HLADRB1 genes and disease severity in rheumatoid arthritis in Turkey.
33. Yukioka M, Wakitani S, Murata N, Toda Y, Ogawa R, Kaneshige T,
et al. Elderly-onset rheumatoid arthritis and its association with
HLA-DRB1 alleles in Japanese. Rheumatology 1998; 37(1):98–101.
34. Kong KF, Yeap SS, Chow SK, Phipps ME. HLA-DRB1 genes and
susceptibility to rheumatoid arthritis in three ethnic groups from
Malaysia. Autoimmunity 2002; 35(4):235–9.
35. Lee HS, Lee KW, Song GG, Kim HA, Kim SY, Bae SC. Increased
susceptibility to rheumatoid arthritis in Koreans heterozygous
for HLA-DRB1*0405 and *0901. Arthritis Rheum 2004;
50(11):3468–75.
36. Liu SC, Chang TY, Lee YJ, Chu CC, Lin M, Chen ZX, et al.
Influence of HLA-DRB1 genes and the shared epitope on genetic
susceptibility to rheumatoid arthritis in Taiwanese. J Rheumatol
2007; 34(4):674–80.
37. Griffiths B, Situnayake RD, Clark B, Tennant A, Salmon M,
Emery P. Racial origin and its effect on disease expression and
HLA-DRB1 types in patients with rheumatoid arthritis: a matched
cross-sectional study. Rheumatology (Oxford) 2000; 39(8):857–64.
38. Arias MVA, Domingues EV, Lozano RB, Flores CV, Peralta MM,
Salinas CZ. Study of Class I and II HLA alleles in 30 Ecuadorian
patients with rheumatoid arthritis compared with alleles from
healthy and affected subjects with other rheumatic diseases. Rev
Bras Reumatol 2010; 50(4):423–33.
39. Perricone C, Ceccarelli F, Valesini G. An overview on the genetic
of rheumatoid arthritis: A never-ending story. Autoimmun Rev
2011; 10(10):599–608.
40. Feitsma AL, van der Helm-van Mil AHM, Huizinga TWJ,
de Vries RRP, Toes REM. Protection against rheumatoid arthritis
by HLA: nature and nurture. Ann Rheum Dis 2008; 67(Suppl
3):iii61–3.
41. Gorman JD, Criswell LA. The shared epitope and severity of
rheumatoid arthritis. Rheum Dis Clin North Am 2002; 28(1):59–78.
42. Gorman JD, Lum RF, Chen JJ, Suarez-Almazor ME, Thomson G,
Criswell LA. Impact of shared epitope genotype and ethnicity
on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis
patients. Arthritis Rheum 2004; 50(2):400–12.
43. van Gaalen FA, van Aken J, Huizinga TW, Schreuder GM,
Breedveld FC, Zanelli E, et al. Association between HLA class II
genes and autoantibodies to cyclic citrullinated peptides (CCPs)
influences the severity of rheumatoid arthritis. Arthritis Rheum
2004; 50(7):2113–21.
44. Salvarani C, Macchioni PL, Mantovani W, Bragliani M, Collina E,
Cremonesi T, et al. HLA-DRB1 alleles associated with rheumatoid
arthritis in Northern Italy: correlation with disease severity. Br J
Rheumatol 1998; 37(2):165–9.
45. Mewar D, Marinou I, Coote AL, Moore DJ, Akil M, Smillie D, et al.
Association between radiographic severity of rheumatoid arthritis
and shared epitope alleles: differing mechanisms of susceptibility
and protection. Ann Rheum Dis 2008; 67(7):980–3.
46. Fries JF, Wolfe F, Apple R, Erlich H, Bugawan T, Holmes T, et
al. HLA-DRB1 genotype associations in 793 white patients from
a rheumatoid arthritis inception cohort: frequency, severity, and
treatment bias. Arthritis Rheum 2002; 46(9):2320–9.
55
20/03/2013 16:25:54
Mourad et al.
47. Kim HY, Min JK, Yang HI, Park SH, Hong YS, Jee WH, et al.
The impact of HLA-DRB1*0405 on disease severity in Korean
patients with seropositive rheumatoid arthritis. Br J Rheumatol
1997; 36(4):440–3.
56
48. Boki KA, Drosos AA, Tzioufas AG, Lanchbury JS, Panayi GS,
Moutsopoulos HM. Examination of HLA-DR4 as a severity marker
for rheumatoid arthritis in Greek patients. Ann Rheum Dis 1993;
52(7):517–9.
20/03/2013 16:25:54
ORIGINAL ARTICLE
Clinical and laboratory features of patients
with rheumatoid arthritis diagnosed at
rheumatology services in the Brazilian
municipality of Cascavel, PR, Brazil
Juliano Maximiano David1, Rodrigo Antonio Mattei2, Juliana Lustoza Mauad1, Lauren Gabrielle de Almeida1,
Márcio Augusto Nogueira3, Poliana Vieira da Silva Menolli4, Rafael Andrade Menolli5
ABSTRACT
Introduction: Brazilian epidemiological studies on rheumatoid arthritis are scarce, thus all data currently available originate
from the international literature. Objectives: To determine the incidence and some clinical and laboratory characteristics of
patients with rheumatoid arthritis in the municipality of Cascavel, state of Paraná, Brazil. Patients and methods: Data were
collected between August 2010 and July 2011 in all health services of the municipality of Cascavel that provided health care
in Rheumatology: a university-affiliated hospital, a public outpatient clinic and four private clinics. Results: We identified
38 patients diagnosed with rheumatoid arthritis, resulting in an estimated incidence of 13.4 cases per 100,000 inhabitants/
year. Thirty two patients were females, whose mean age was 47.6 years. The age group with the highest incidence was
over 40 years. The mean time between first symptoms and diagnosis was 12.4 months. Rheumatoid factor was positive in
68.4% of the patients, and 18.4% already had radiological abnormalities at diagnosis. The pharmacological treatment of
patients was also assessed and proved to be in accordance with those found in the literature. Conclusion: The incidence
of rheumatoid arthritis obtained in the municipality of Cascavel was lower than those reported in international studies.
Keywords: rheumatoid arthritis, epidemiology, Brazil.
INTRODUCTION
Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease of autoimmune character and unknown etiology,
which affects large and small joints symmetrically. It is more
prevalent in women (female/male ratio of 2:1), and its incidence increases with age.1
Rheumatoid arthritis affects approximately 0.5%–1% of
the population, and, although not directly life-threatening, it
causes a reduction in the patient’s quality of life and severe
economic damages to society.2
The incidence of RA varies according to the population and geographic area studied. Most epidemiological
studies have been conducted in developed countries, while
reports on the incidence of RA in developing countries
have been rare. Studies have shown a lower prevalence of
RA in developing countries as compared with developed
countries.3
Received on 12/14/2011. Approved on 12/13/2012. The authors declare no conflict of interest. Ethics Committee: 239/2010.
Universidade Estadual do Oeste do Paraná – UNIOESTE.
1. Medical student, Universidade Estadual do Oeste do Paraná – UNIOESTE
2. Pharmacist; Resident in Pharmaceutical Sciences; Clinical Analyses
3. Rheumatologist; Assistant Professor, UNIOESTE
4. Master’s degree in Collective Health; Assistant Professor, UNIOESTE
5. Master’s degree; Assistant Professor, UNIOESTE
Correspondence to: Rafael Andrade Menolli. Centro de Ciências Médicas e Farmacêuticas. Rua Universitária, 2069 – Bairro Universitário. CEP: 85819-110.
Cascavel, PR, Brazil. E-mail: [email protected]
57
20/03/2013 16:25:54
David et al.
This study aimed at assessing the incidence of RA in a
Brazilian municipality and describing the clinical and laboratory
characteristics of patients with RA.
This study was approved by the Committee of Ethics and
Research (nº 239-2010) of the Western Paraná State University
(UNIOESTE), and its authors declare no conflict of interest.
RESULTS
This study comprised the review of the medical records of
patients diagnosed with RA in the municipality of Cascavel,
state of Paraná (PR), Brazil, from August 2010 to July 2011.
All rheumatology services of that municipality took part in
this study as follows: a university-affiliated hospital of Western
Paraná (Hospital Universitário do Oeste do Paraná – HUOP); the
regional center of specialties of the intermunicipal health consortium of Western Paraná (Centro Regional de Especialidades
do Consórcio Intermunicipal de Saúde do Oeste do Paraná –
CRE-CISOP); and four private rheumatology clinics.
Data were collected through active search in the medical
records of patients whose diagnosis of RA had been confirmed
by a rheumatologist. Data were recorded in a specific spreadsheet, constructed and validated to minimize differences in
data recording across different services. The following data
were assessed: gender; age range; time from the first complaint
until RA diagnosis; clinical and laboratory manifestations;
and drug therapy. Clinical and laboratory data were assessed
regarding their compliance with the 1987 American College of
Rheumatology (ACR) criteria.4 The new 2010 ACR-EULAR
criteria were not used, because they had not been published by
the beginning of this study.
This study’s exclusion criteria were as follows: 1) patients
diagnosed with RA not living in the municipality of Cascavel; 2)
residents of the municipality of Cascavel diagnosed with RA by a
rheumatologist, but who did not meet the minimum ACR criteria.
The municipality of Cascavel is located in the Western region
of the state of Paraná, in the Southern region of Brazil. In 2010,
its population was 283,193 inhabitants (146,434 women and
139,771 men), according to data from the Brazilian Institute of
Geography and Statistics (IBGE).5 Those figures were used to
calculate the incidence of RA. The municipality of Cascavel is
a regional pole of health care in the state of Paraná, providing
health services in different medical specialties to the so-called
Western macro-region, which comprises 25 municipalities
and has approximately 470,000 inhabitants. It is not a specific
pole for the treatment of RA, but offers specialized health care
in private clinics and at the Brazilian Public Unified Health
Care System (SUS), through the CRE-CISOP and the HUOP
outpatient clinic.
Data were presented as frequencies, medians, and means ±
standard deviations, with 95% confidence interval (CI).
This study identified 38 patients diagnosed with RA and living in
the municipality of Cascavel. The incidence of cases of RA at the
services assessed was 13.42 cases per 100,000 inhabitants/year.
Of the 38 patients, 32 were females and 6, males. The incidence
for the female gender was 21.9/100,000 inhabitants/year, and
for the male gender, 4.3/100,000 inhabitants/year, resulting in
female/male ratio of 5.3:1.
The mean age at the time of diagnosis was 47.6 ± 16.7 years
(95% CI: 42.2–53.0), ranging from 17 to 76 years (median of
38 years). The mean time between the appearance of the first
symptoms and disease diagnosis was 12.4 ± 12.6 months (95%
CI: 7.8–17.0), ranging from 1 month to 60 months (median of
9 months). Table 1 shows the incidence and frequency of RA
per age group.
In this study, the compliance with the 1987 ACR criteria
for the diagnosis of RA was as follows: 22 patients met 4 of the
7 criteria; 12 patients met 5 criteria; 2 patients met 6 criteria;
and 1 patient met 7 criteria. The most frequently met criterion
was that of radiographic changes, observed in 7 patients, 6 of
whom were of the female gender. Table 2 shows the clinical
and laboratory manifestations comprising the ACR diagnostic
criteria detected in the patients.
When diagnosed with RA, the patients also underwent the
following laboratory tests: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Those measurements were
elevated in 31 (81.6%) and 26 (68.4%) patients, respectively.
58
Table 1
Frequency of cases and incidence of rheumatoid arthritis
according to the age group of patients diagnosed at
rheumatology services in the municipality of Cascavel, PR,
Brazil, in 2010–2011
n
Frequency of
Population
cases (%)
Incidence/
100,000
inhabitants
< 20
1
2.7
91,964
1.09
20–29
7
18.9
53,969
12.97
Age group
(years)
30–39
3
8.1
46,545
6.45
40–49
9
24.3
40,217
22.38
50–59
8
21.6
27,795
28.78
60–69
5
13.5
15,294
32.69
20/03/2013 16:25:54
Clinical and laboratory features of patients with rheumatoid arthritis diagnosed at rheumatology services in the Brazilian municipality of Cascavel, PR, Brazil
Table 2
Clinical and laboratory manifestations comprised in the ACR
diagnostic criteria detected in the patients studied
ACR
ACR criteria
n (%)
Edema in at least 3 joints
38 (100%)
Edema in hand joints
38 (100%)
Symmetrical edema
35 (92.1%)
Rheumatoid factor
26 (68.4%)
Morning stiffness
15 (39.5%)
Radiological changes
7 (18.4%)
Subcutaneous nodules
5 (13.2%)
= American C ollege of Rh eumatology.
Table 3
Drug treatment prescribed for patients diagnosed with
rheumatoid arthritis in the municipality of Cascavel, PR, Brazil
Drug
n (%)
Methotrexate
31 (81.6%)
Prednisone
27 (71.1%)
Non-steroidal anti-inflammatory drugs
17 (44.7%)
Hydroxychloroquine
6 (15.8%)
Sulfasalazine
1 (2.6%)
Table 4
Drug associations prescribed for patients diagnosed with
rheumatoid arthritis in the municipality of Cascavel, PR, Brazil
Drug
n (%)
MTX + hydroxychloroquine
4 (10.5%)
MTX + leflunomide
1 (2.6%)
MTX + sulfasalazine
1 (2.6%)
MTX + cyclophosphamide
1 (2.6%)
Prednisone + NSAIDs
15 (39.5%)
M TX = methotrexate; NSAID s = non-steroidal anti-infl ammatory drugs.
Table 3 shows the specific drugs for RA used to treat the
patients. Disease-modifying anti-rheumatic drugs (DMARDs)
and non-steroidal anti-inflammatory drugs (NSAIDs) listed in
Table 3 were used in combination for some patients. Table 4
shows such combinations.
Compared with international indices, the incidence of
RA found in the municipality of Cascavel (13.4/100,000
inhabitants/year) is lower than those of Northern Europe and
the USA,8 which ranged from 20 and 50 cases per 100,000
inhabitants/year. The incidence of RA found in the municipality of Cascavel is closer to those found in Southern Europe (9
to 24 cases per 100,000 inhabitants/year).7,3 One reason for
that might be the climate similarity between those countries
and Southern Brazil (temperate climate).7,9 Table 5 lists the
incidence data.
Studies on the incidence of RA in Brazil lack, hindering
comparisons with other Brazilian places; however, data on
the prevalence of RA in Brazil show lower indices than those
reported in other places worldwide.6,10,11
In addition to the variations in methodology and criteria
between studies, another explanation for the lower prevalence
and incidence of RA found in developing countries might be
the lower degree of urbanization of those countries and the
greater difficulty patients face in reaching health care centers
in developing countries.12
Data from the Norfolk Arthritis Register have shown incidences of RA for the female and male genders of 54/100,000
inhabitants/year and 24.5/100,000 inhabitants/year, respectively, evidencing an approximately twice greater incidence
of RA in the female gender.13 Those data are similar to those
reported by Symmons et al.14 in another European study.
The female/male ratio in the municipality of Cascavel was
higher than that found in developed countries, although the
incidences for both men and women were smaller. That difference in the incidences in our study might be related to the
Table 5
Comparison of the incidence of rheumatoid arthritis in the
municipality of Cascavel, PR, Brazil, with international data
(cases/100,000 inhabitants)
Author, study site
Time period
Total of RA
cases (n)
Incidence
(per 100,000
inhabitants)
Present study,
municipality of
Cascavel (Brazil)
2010–2011
38
13.4
Doran et al.,17
Rochester (USA)
1985–1994
147
32.7
Carbonell et al.,18
Spain
2004–2005
362
8.3
DISCUSSION
Kaipiainen1985
Seppanen et al.,24 Finland
413
39
Epidemiological studies on RA are mostly limited to developed countries,3,6 the incidence of RA in developing countries
being unknown.3,6–8
Pedersen et al.,25
Southern Denmark
1995–2001
505
35
Drosos et al.,26 Greece
1987–1995
428
20
59
20/03/2013 16:25:54
David et al.
cultural attitude of the Brazilian male to search medical care
only in the presence of symptoms, in addition to the difficulty
in accessing health care services.15 Another Brazilian study
has also reported a markedly high female/male ratio.10
The mean age found in this study coincides with that
reported in the literature for the peak incidence of RA, that
is, after the fourth decade of life.1 Brazilian and international
studies have reported similar age groups.16,17
Considering the RA classification criteria, our study’s
data suggest lower positivity for the criterion ‘presence or
absence of subcutaneous nodules’ as compared with the study
carried out in the state of São Paulo in 200716 (18% and 29%,
respectively). This might be explained by the fact that the
study from the state of São Paulo assesses prevalence, considering both new and old cases, while ours considered only
the new cases, in which the characteristics of RA have not
developed in its full severity. A French study,17 involving 14
rheumatology centers in the period from 2002 to 2005, has
assessed 579 patients meeting the 1987 ACR criteria for the
diagnosis of RA and reported the following results: arthritis
in at least 3 joints, 95.7%; symmetrical arthritis, 92.9%; and
morning stiffness, 95%. Comparing with our study, except
for morning stiffness, those values do not differ much (100%,
92.1% and 39.5%, respectively), which might be explained
by the fact of it being a study on prevalence.
Regarding positivity for the rheumatoid factor, our data
are very similar to those of two other Brazilian studies (68.4%
in the municipality of Cascavel, 71% in the municipality of
São Paulo,15 and 63% in the municipality of Montes Claros10),
although the other Brazilian studies were on prevalence.
However, comparing with studies on incidence, the presence of the rheumatoid factor is greater than that reported in
international studies.18,19
The immediate beginning of treatment is important to
reduce disease activity and prevent lesions that can generate functional disabilities. That treatment can be as follows:
non-medicamentous; symptomatic; and with DMARDs. The
symptomatic treatment should be performed with NSAIDs,
and, when necessary, prednisone can be associated. If prednisone is used for a long time, calcium and vitamin D should
be associated to prevent bone damage.20 Only 17 patients
(44.7%) were on NSAIDs during the period studied. That is
in accordance with the literature, which recommends the use
of NSAIDs at lower doses and for the shortest time possible
to avoid complications. If the treatment with NSAIDs is
60
not effective to control pain, therapy with DMARDs should
be considered.20 Of the 17 patients on NSAIDs, 2 were on
monotherapy, because they had mild symptoms of the disease.
The most common adverse effects in patients on NSAIDs
are gastrointestinal symptoms,20 explaining the large number
of patients on a proton-pump inhibitor for gastric protection.
In our study, omeprazole was used by 10 patients (26.3%).
In our study, 27 patients (71.1%) were on glucocorticoids,
which are mainly used to control the exacerbations of the
disease for both new and old cases.
Regarding DMARDs, 25 of 38 patients (65.8%) diagnosed
with RA in the period studied and undergoing treatment, used
methotrexate (MTX) in monotherapy. MTX is recommended
for all patients diagnosed with RA, regardless of disease
duration. It is considered the standard drug for the treatment
of RA, because it is the best tolerated.20–22 In addition, 2
patients (5.3%) used hydroxychloroquine in monotherapy.
That drug is recommended for those who do not have a poor
prognosis and whose disease activity is low. Drug treatment
can also involve associations of 2 or more DMARDs. The
best association is MTX and hydroxychloroquine, indicated
for patients with moderate disease activity,21 and used for
4 patients (10.5%) in our study. Other associations recommended are MTX with leflunomide, for patients with long
disease duration and low disease activity, and MTX with
sulfasalazine, for patients with high disease activity and
worse prognosis.22 In our study, each of those associations
was used by 1 patient (2.6%).
The importance of studying the epidemiology of RA is
based on the need of assessing the impact of that disease on
the population health and also intended to help with the calculation and priorities of organizing health care.23 Nevertheless,
studies on the incidence of RA face some difficulties, such
as establishing the point at which the disease actually starts,
defining which criterion should be used for diagnosis, and the
delay between symptom onset and medical care, which can
falsely reduce the estimates on the incidence of that disease.8,23
New criteria have been defined by the 2010 ACR-EULAR
to help with the early diagnosis of RA.8 That might improve
studies on incidence, because many rheumatologists identify
and treat patients with RA based on their professional experience, even if the patient does not meet the 1987 ACR criteria.23
Further studies involving other Brazilian regions should
be carried out to establish whether that is a characteristic
finding of the Brazilian population or only an isolated finding.
20/03/2013 16:25:54
Estudo clínico e laboratorial de pacientes com artrite reumatoide diagnosticados em serviços de reumatologia em Cascavel, PR, Brasil
Faz-se necessário desenvolver mais estudos envolvendo
outras regiões para estabelecer se este resultado é um achado
característico da população do país ou somente um achado
isolado.
REFERENCES
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Da Mota LM, Cruz BA, Brenol CV, Pereira IA, Fronza LS,
Bertolo MB, et al. 2011 Consensus of the Brazilian Society of
Rheumatology for diagnosis and early assessment of rheumatoid
arthritis. Rev Bras Reumatol 2011; 51(3):199–219.
Avouac J, Gossec L, Dougados M. Diagnostic and predictive value
of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis:
a systematic literature review. Ann Rheum Dis 2006; 65:845–51.
Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence
of rheumatoid arthritis, based on the 1987 American College of
Rheumatology criteria: a systematic review. Semin Arthritis Rheum
2006; 36:182–8.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
revised criteria for the classification of rheumatoid arthritis. Arthritis
Rheum 1988; 31:315–24.
Instituto Brasileiro de Geografia e Estatística (IBGE). Censo 2010.
Available from: www.ibge.gov.br [Acessed on 10, Dec 2011].
Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis.
Autoimmun Rev 2005; 4(3):130–6.
Tobon GJ, Youinou P, Saraux A. The environment, geo-epidemiology,
and autoimmune disease: Rheumatoid arthritis. Autoimmun Rev
2010; 9:A288–92.
Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid
arthritis. Best Pract Res Clin Rheumatol 2010; 24:733–45.
Chopra A, Abdel-Nasser A. Epidemiology of rheumatic
musculoskeletal disorders in the developing world. Best Pract Res
Clin Rheumatol 2008; 22:583–604.
Senna ER, De Barros AL, Silva EO, Costa IF, Pereira LV,
Ciconelli RM, et al. Prevalence of rheumatic diseases in Brazil: a
study using the COPCORD approach. J Rheumatol 2004; 31:594–7.
Aho K, Kaipiainen-Seppanen O, Heliovaara M, Klaukka T.
Epidemiology of rheumatoid arthritis in Finland. Semin Arthritis
Rheum 1998; 27:325–34.
Kalla AA, Tikly M. Rheumatoid arthritis in the developing world.
Best Pract Res Clin Rheumatol 2003; 17(5):863–75.
Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis
Clin North Am 2001; 27:269–81.
14. Brasil. Ministério da Saúde. Política Nacional de Atenção Integral
à Saúde do Homem 2009. Available from: http//:dtr2001.saude.gov.
br [Acessed on 28, Feb 2012].
15. Louzada-Junior P, Souza BDB, Toledo RA, Ciconelli RM. Análise
descritiva das características demográficas e clínicas de pacientes
com artrite reumatoide no estado de São Paulo, Brasil. Rev Bras
Reumatol 2007; 47:84–90.
16. Fautrel B, Combe B, Rincheval N, Dougados M. Level of
agreement of the 1987 ACR and 2010 ACR/EULAR rheumatoid
arthritis classification criteria: an analysis based on ESPOIR cohort
data. Ann Rheum Dis 2012; 71(3):386–9.
17. Doran MF, Pond GR, Crowson CS, O’Fallon WM, Gabriel SE.
Trends in incidence and mortality in rheumatoid arthritis in
Rochester, Minnesota, over a forty-year period. Arthritis Rheum
2002; 46:625–31.
18. Carbonell J, Cobo T, Balsa T, Descalzo MA, Carmona L; SERAP
Study Group. The incidence of rheumatoid arthritis in Spain:
results from a nationwide primary care registry. Rheumatol 2008;
47:1088–92.
19. Bértolo MB, Brenol CV, Schainberg CG, Neubarth F, Lima FAC,
Laurindo IM, et al. Atualização do consenso brasileiro no
diagnóstico e tratamento da artrite reumatoide. Rev Bras Reumatol
2007; 47:151–9.
20. Rudolf M, Deighton C, Bosworth A, Hall J, Hammond A,
Hennel S, et al. Rheumatoid Arthritis. National clinical guideline
for management and treatment in adults. NICE Clinical Guidelines.
London: Royal College of Physicians; 2009, n. 79.
21. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR,
et al. American College of Rheumatology 2008 recommendations
for the use of nonbiologic and biologic disease-modifying
antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008
15; 59:762–84.
22. Boonen A, Severens JL. The burden of illness of rheumatoid
arthritis. Clin Rheumatol 2011; 30(Suppl 1):S3–8.
23. Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M, et
al. The prevalence of rheumatoid arthritis in the United Kingdom:
new estimates for a new century. Rheumatology (Oxford) 2002;
41:793–800.
24. Kaipiainen-Seppanen O, Aho K, Isomaki H, Laakso M. Incidence
of rheumatoid arthritis in Finland during 1980-1990. Ann Rheum
Dis 1996; 55:608–11.
25. Pedersen JK, Kjær NK, Svendsen AJ, Hørslev-Petersen K.
Incidence of rheumatoid arthritis from 1995 to 2001: impact
of ascertainment from multiple sources. Rheumatol Int 2009;
29:411–15.
26. Drosos AA, Alamanos I, Voulgari PV, Psychos DN, Katsaraki A,
Papadopoulos I, et al. Epidemiology of adult rheumatoid arthritis
in northwest Greece 1987–1995. J Rheumatol 1997; 24:2129–33.
65
20/03/2013 16:25:55
ORIGINAL ARTICLE
Characteristics of NK cell activity in
patients with systemic sclerosis
Patricia Hartstein Salim1, Mariana Jobim2, Markus Bredemeier3, José Artur Bogo Chies4,
João Carlos Tavares Brenol5, Luiz Fernando Jobim6, Ricardo Machado Xavier7
ABSTRACT
Introduction: Previous studies have shown an increased expression of natural killer (NK) cells in the peripheral blood
of patients with systemic sclerosis (SSc). NK cells are part of innate immunity, recognizing infected cells through killer
immunoglobulin-like receptors (KIR), which show marked polymorphism. A novel model has been proposed predicting the activity of NK cells, evaluating whether there is excessive activation (EA), excessive inhibition (EI) or balance
(B) (neutral). Objective: To evaluate the activity of NK cells in patients with SSc and compare it with that of a control
group. Method: This study comprised 110 patients with SSc and 115 healthy controls. A novel model that predicts the
activity of NK cells was used. For that, cells with their respective KIR/HLA-C and Bw4 ligands were considered. The
activity of NK cells was defined as EA, EI, or B. Results: Our results showed that 63.5% of healthy controls had the
KIR phenotype characterized by EI, as compared with 39.1% of the patients with SSc (P = 0.001). Considering only
KIR2DL2-positive individuals, 34.7% of EI was found in healthy controls and 10.9% in patients with SSc (P < 0.001).
Conclusion: In our study, the model that predicts the action of NK cells showed that healthy controls have higher frequency of EI as compared with SSc patients, suggesting a protective effect of the EI profile against the development
of SSc. These results suggest a potential role of NK cells in the pathogenesis of SSc, but further studies should be
conducted to confirm our data.
Keywords: killer immunoglobulin-like receptor, natural killer cell, systemic scleroderma, autoimmunity.
INTRODUCTION
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by endothelial dysfunction and tissue fibrosis. It
is a diffuse connective tissue disease that can affect several
organic systems, especially the digestive and respiratory systems. Systemic sclerosis has two presentation forms, limited
and diffuse, which are differentiated based on the extension
of skin involvement.1 Its major characteristics are excessive
collagen deposition, vascular lesions, and changes in cellular
and humoral immunity.2
There is evidence that certain genetic characteristics
favor the progression of chronic inflammation to fibrosis.
Participation of the immune system has been suggested due
to the presence of mononuclear cellular infiltrates in lesions,
abnormalities in T helper cells and in monocyte function,3
release of several cytokines, and reduced activity of natural
killer (NK) cells.4
Received on 12/20/2011. Approved on 12/13/2012. The authors declare no conflict of interest. Ethics Committee: 05-549. Financial Support: Coordenação de
Aperfeiçoamento de Pessoal de Ensino Superior (Capes), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundo de Incentivo à
Pesquisa e Eventos do HCPA (Fipe-HCPA).
Serviço de Reumatologia and Serviço de Imunologia, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul –
HCPA-UFRGS.
1. PhD candidate in Medical Sciences, Universidade Federal do Rio Grande do Sul – UFGRS
2. PhD in Medicine, UFGRS; Immunologist Physician, Hospital de Clínicas de Porto Alegre – HCPA, UFGRS
3. PhD in Medicine, UFGRS; Physician, Rheumatology Service, Hospital Nossa Senhora da Conceição, Grupo Hospitalar Conceição – HNSC-GHC
4. PhD in Life Sciences, Specialist in Immunology, Université de Paris V; Associate Professor, Department of Genetics, UFGRS
5. PhD in Medicine, UFGRS; Associate Professor, Department of Internal Medicine, UFGRS
6. PhD in Medicine, Immunologist Physician, Chief, Service of Immunology, HCPA-UFRGS; Associate Professor, Department of Internal Medicine, UFGRS
7. PhD in Immunology, Shimane Medical University; Associate Professor, UFGRS; Chief, Service of Rheumatology, HCPA-UFRGS
Correspondence to: Ricardo Machado Xavier. Serviço de Reumatologia do Hospital de Clínicas de Porto Alegre. Rua Ramiro Barcelos, 2350, sala 645.
CEP: 90035-003. Porto Alegre, RS, Brazil. E-mail: [email protected]
66
20/03/2013 16:25:55
The NK cells have receptors, denominated ‘killer immunoglobulin-like receptors’ (KIR), which belong to the family of
the immunoglobulins present on cell surface. According to their
functional groups, those receptors are classified as inhibitory
(prevent target cell lysis) or activatory (cause target cell lysis).5
The inhibitory receptor recognizes the specific HLA class I
antigen, preventing the attack of NK cells against normal cells;
conversely, the activatory receptor is triggered when inhibitory KIR receptors do not recognize the target cell, activating
NK cells for destruction.6 The ability to attack ‘self’ cells that
do not express HLA-I is known as ‘missing self-recognition’.
That hypothesis has been supported by several independent
observations, demonstrating that HLA antigens really protect
cells against lysis by NK cells, providing negative signs that
inhibit the activity of NK cells.7
Theoretically, any inhibitory ligand combination KIR-HLA
should be able to neutralize activation. The function of NK cells
is regulated by positive and negative signals transmitted by
pairs of activatory and inhibitory receptors. In vivo, NK cells
are controlled by inhibitory receptors for self HLA-I ligands.8
Thus, effector functions occur only when activation signals can
surpass inhibitory signaling. That is obtained through either the
predominance of the activation of receptor-ligand interactions
or lack of the inhibitory ligand of the receptor.9
A novel model has been recently proposed by Nelson et
al.,10 predicting that, depending on the genotype, individuals
could be classified into one of three groups, according to the
activity characteristics of their NK cells: 1) mainly controlled
by inhibitory receptors (major inhibition); 2) controlled equally
by inhibitory and activating receptors (relatively neutral); or 3)
mainly controlled by activating receptors (major activation).
Similarly, individuals lacking ligands for inhibitory receptors
(such as homozygous for HLA-Cw group 1 or 2 ligands) will
have fewer NK cells under inhibitory control than individuals
with all ligands present.
So far, only two studies have assessed the activity of NK
cells according to that novel model – one in diabetes11 and the
other in psoriasis.12 Because of the scarcity of studies on the
subject, this study aimed at assessing the activity of NK cells
in a group of patients with SSc as compared to a control group.
All participants were instructed about this research. They
provided written informed consent, and their decision did
not affect the physician-patient relationship. This study was
approved by the Ethics Committee of the Hospital de Clínicas
de Porto Alegre (HCPA).
Patients
This study included 110 patients with SSc originating from
the Rheumatology Outpatient Clinic of the HCPA. All
patients had been diagnosed according to either the 1987
American College of Rheumatology criteria13 or the LeRoy
and Medsger’s criteria for the classification of early SSc.14
Patients with overlap syndromes with other diffuse connective tissue diseases (except for Sjögren’s syndrome) were
excluded from the study.
Controls
The control group comprised 115 unrelated individuals,
originating from the Immunology Service of the HCPA, who
voluntarily registered to donate bone marrow (REDOME).
Individuals with chronic and acute diseases were excluded
from the sample, as were those with a family history of genetic disorders (X chromosome-linked diseases, autosomal
diseases or chromosomal abnormalities).
Immunogenetic study
The DNA samples were extracted according to the salting
out15 method and amplified according to the polymerase chain
reaction (PCR) technique. The sequence of primers for PCR
has been described by Gómez-Lozano et al.16
The following mixture was used for DNA amplification:
1 μL of 10x buffer; 50 nM of MgCl2; 25 mM of dNTPs; 0.5 U
taq polymerase; 10 ηg of DNA; 100 nm of internal control;
and 500 mM of specific primer. The initial temperature for
amplification was 94ºC for 3 minutes. Then, there were 4 cycles
of 15 seconds at 94ºC, 15 seconds at 65ºC, and 30 seconds
at 72ºC. Then, there were 21 cycles of 15 seconds at 94ºC,
15 seconds at 60ºC, and 30 seconds at 72ºC. To finish, 5 cycles
of 15 seconds at 94ºC, 60 seconds at 55ºC, and 120 seconds at
72ºC. The product was maintained for 420 seconds at 72ºC.
The PCR product was analyzed by use of 1% agarose
gel electrophoresis (p/v) and tris-acetate-EDTA (TAE) buffer. Electrophoresis ran for 20 minutes at 200 V and room
temperature. After electrophoresis was complete, the gel was
stained with ethidium bromide, and the bands visualized and
photographed under ultraviolet light.
The model that predicts the activity of NK cells was applied as
follows: a) KIR2DS1 and/or KIR2DS2 with homozygous HLACw for group 1 or 2 (combination of susceptibility – excessive
activation); b) KIR2DS1 and/or KIR2DS2 with heterozygous
HLA-Cw group; c) lack of KIR2DS1 or KIR2DS2 with homozygous HLA-Cw group (relatively neutral combination – balance);
67
20/03/2013 16:25:55
Salim et al.
patients according to the presence or absence of that gene (Table
3). Considering only 2DL2-positive patients, we observed that the
control group had excessive inhibition (34.7%) as compared to
patients with the disease (10.9%), with a statistically significant
difference (< 0.001). Analyzing balanced or over-active NK cells
in the presence of the 2DL2 gene, no statistically significant difference was observed. Patients with SSc had 10.2% of excessive
activation and 10% of balance, similarly to controls, who had
16.5% and 11.3%, respectively. Assessing patients who lack the
KIR2DL2 gene, different results were found. The frequency of
excessive inhibition in patients (29.1%) is similar to that of the
control group (26.1%). Thus, the balanced or excessively activated
state of NK cells is less frequent in healthy individuals (2.6% and
6.1%, respectively) as compared to patients with SSc (20.9% and
20.9%, respectively).
and d) lack of KIR2DS1 or KIR2DS2 with heterozygous HLACw group (combination of protection – excessive inhibition). The
results were assessed by use of Pearson’s chi-square test and the
SPSS 16.0 software. Statistical significance was adopted as a P
value ≤ 0.05.
RESULTS
Table 1 shows the patients’ genetic profile. Presence of all KIR
genes tends to provide protection against the development of SSc.
That genetic profile was evidenced in 1.77% of the patients with
SSc as compared to 13.9% of the controls (P < 0.001). The other
genetic profiles showed no significant difference.
Activation of NK cells can be predicted by the possible
combination of receptor activation or inhibition with the HLA-C
molecule. That indicates that, depending on the genotype, an individual can have more over-active or balanced or over-inhibited
NK cells. In this study, patients with SSc had excessive activation
as compared with controls (Table 2). Of the 110 patients with SSc,
34 (29.6%) had over-active NK cells as compared with 22 of 115
(19.1%) controls. Analyzing excessive inhibition in each group,
the control group had that profile more often.
Previous studies have evidenced that the presence of the
inhibitory KIR2DL2 gene might be related to protection against
the development of SSc. To test that hypothesis, we stratified the
DISCUSSION
Systemic sclerosis is a complex multifactorial disease. The most
accepted hypothesis for its pathogenesis is that immune system
activation is triggered by the interaction between environmental
factors and genetic predisposition.17 Some genetic factors can
influence the susceptibility to the development of SSc. Family
history is the major risk factor identified; however, the absolute
risk for each family member is low (< 1%). The relative risk for
Table 1
Frequency of the genetic profile of the KIR system in patients with systemic sclerosis (n = 110) and controls (n = 115)¥
KIR profile
2DL1
2DL2
2DL3
2DS1
2DS2
2DS3
2DS4
3DS1
3DL1
SSc (%)
Control group (%)
#1
+
−
+
−
−
−
+
−
+
23.4
24.3
#2
+
−
+
+
−
−
+
+
+
4.34
7.0
#3
+
−
+
-
+
−
+
−
+
6.08
0.0
#4
+
−
+
+
+
−
+
+
+
1.77
0.0
#5
+
+
+
+
+
+
+
+
+
1.77a
13.9a
#6
+
+
+
−
+
−
+
−
+
9.73
13.9
#7
+
−
+
−
−
−
+
+
+
9.73
0.0
#8
+
+
−
−
−
−
+
−
+
0.0
6.1
#9
+
+
+
+
+
−
+
+
+
0.0
4.3
#10
+
+
+
−
+
+
+
−
+
2.6
4.3
#11
+
+
−
−
+
+
+
−
+
4.34
3.5
#12
+
−
+
+
+
+
+
+
+
5.21
0.0
#13
+
−
−
−
−
−
+
−
+
3.5
0.0
22.6
21.7
Others*
SSc: systemic sclerosis.
¥
Statistical analysis performed with Fisher exact and Pears on’ s chi-square tests.
*G enetic profile observed in only one person was combined (others).
a
P = 0.00085; odds ratio = 0.11; 95% confidence interval (0.012–0 .4 97). The other genetic profiles showed no statistical significance.
68
20/03/2013 16:25:55
Table 2
Analysis of the activity of natural killer cells in patients with
systemic sclerosis (n = 110) and control group (n = 115)
Controls
SSc
n
%
n
%
Excessive activation
22
19.1
34
29.6
Balance
20
17.4
36
31.3
Excessive inhibition
73
63.5
40
39.1
P*
0.001
SSc: systemic sclerosis.
*Pears on’ s chi-square test.
Table 3
Prediction of the activity of natural killer cells in patients
and controls stratified according to the presence or absence
of KIR2DL2
KIR2DL2 positive
KIR2DL2 negative
EA
B
EI
EA
B
EI
Controls
16.5%
11.3%
34.7%
2.6%
6.1%
26.1%
Patients
10.2%
10.0%
10.9%
20.9%
20.9%
29.1%
P*
NS
NS
< 0.001
< 0.001
0.001
NS
EA: excessive activation; B: balance; EI: excessive inhibition; NS: non-significant.
*Pears on’ s chi-square test.
first-degree relatives ranges from 10 to 16, and, for monozygous
twins, from 10 to 27.18 Several studies have suggested that genetic
susceptibility alone is not enough to induce disease.
In our study, 9.73% of the patients with SSc had activating
2DS2 and inhibitory 2DL2, and lack of activating 2DS1, 2DS3
and 3DS1, as compared to 13.9% of the control group, and, thus,
protection might also be provided by that profile. The profile
‘absence of inhibitory 2DL2 and of activating 2DS1, 2DS2 and
2DS3’ was found only in patients with SSc (9.73%). Conversely,
the profile ‘presence of inhibitory 2DL2 and absence of the
activating genes’ was only found in the control group (6.1%),
and the presence of all genes (including the activating 2DS2 and
inhibitory 2DL2) was more often found in the control group than
in patients with SSc. Such data show the importance of inhibitory 2DL2 for the development of SSc, and are in accordance
with a previous study that showed an increase in the frequency
of activating KIR2DS2 in the absence of inhibitory KIR2DL2
in patients with SSc.19 Recently, using data of the same patients
involved in the present study, we have reported a protective
effect of the inhibitory 2DL2 gene against the development of
SSc.20 That combination of KIR genes has also been observed
in the pathogenesis of other rheumatic diseases. In rheumatoid
arthritis, the presence of KIR2DS2 has been related to vasculitis;21 in psoriatic arthritis, KIR2DS2 in the absence of KIR2DL2
ligands has been associated with a higher risk of developing
that disease.11 In addition, the involvement of the KIR2DS2+/
KIR2DL2− combination in the pathogenesis of Sjögren’s syndrome has been suggested.22
Recent studies have suggested that HLA-I genes might play a
role in susceptibility to autoimmune diseases and their expression,
such as rheumatoid arthritis, ankylosing spondylitis and systemic
lupus erythematosus, through the interaction with KIR receptors.
Based on the idea that an activating KIR, such as KIR2DS2, can
favor the development of SSc in the absence of the ligand for any
KIR2DL1 or KIR2DL2/3 (that is, homozygous for a group of
HLA-Cw ligands), the novel model proposed by Nelson et al.10
was used. That is in accordance with our understanding of KIR
expression and function, and has a more robust statistical support
for the role played by KIR in susceptibility to SSc than that of
the previous model.
Previous studies associating the KIR genes in SSc have
evidenced important results regarding susceptibility to that
disease. However, no previous study has assessed the activity
profile of NK cells in patients and controls – genes were assessed
in isolation only. Our study showed that healthy individuals
have excessive inhibition as compared to patients with SSc
(P < 0.001). That is in accordance with a study performed with
patients with diabetes,23 in which excessive inhibition was found
in controls (25.71%) as compared to patients (1.02%). However,
another study assessing that model in patients with psoriasis has
reported no statistical difference between patients and controls
(P = 0.822).12
Stratifying patients according to the gene associated with
SSc (KIR2DL2), we found excessive inhibition in KIR2DL2positive controls (P < 0.001). When that gene was absent, there
was prevalence of excessive activation (P < 0.001) and balance
(P = 0.001) in patients with SSc, suggesting an important role of
that gene in the development of SSc. Such observations further
corroborate the hypothesis of a dominant protection provided by
some inhibitory KIR genes.
CONCLUSION
Imbalance between the number of activating/inhibitory KIR genes
seems to play an important role in susceptibility to and protection
against SSc. When certain models are used in data analysis, the
interaction between KIR/HLA-C genes might indicate the role of
NK cells in the pathology of SSc. Additional levels of variations,
such as allelic polymorphisms, require further investigation, and
new studies on the association of KIR genes with other autoimmune disorders are necessary. The results suggest that experiences
with the function of NK cells can provide more information.
69
20/03/2013 16:25:55
Salim et al.
Quando estratificamos os pacientes pelo gene que estava
associado à ES (KIR2DL2), encontramos excesso de inibição
nos controles com presença do KIR2DL2 (P < 0,001). Quando
esse gene estava ausente, houve prevalência de excesso de
ativação (P < 0,001) e de equilíbrio (P = 0,001) nos pacientes
com ES, sugerindo papel importante desse gene no desenvolvimento da doença. Essas observações corroboram ainda
mais a hipótese de uma proteção dominante conferida por
alguns genes KIR inibitórios.
8.
9.
10.
11.
CONCLUSÃO
O desequilíbrio entre o número de KIR ativador/inibidor parece ser importante para a suscetibilidade e a proteção contra
a doença. Se modelos perspicazes são utilizados na análise de
dados, a interação entre os genes KIR/HLA-C pode indicar o
papel das células NK na patologia da doença. Níveis adicionais de variações, como polimorfismos alélicos, precisam ser
investigados, assim como são necessários novos estudos de
associação de genes KIR com outras desordens autoimunes.
Os resultados sugerem que as experiências com a função das
células NK podem ser mais informativas.
REFERENCES
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T,
Medsger TA Jr., et al. Scleroderma (systemic sclerosis):
classification, subsets and pathogenesis. J Rheumatol 1988;
15:202–6.
Sato S, Fujimoto M, Hasegawa M, Takehara K, Tedder TF. Altered
B lymphocyte function induces systemic autoimmunity in systemic
sclerosis. Mol Immunol 2004; 41:1123–8.
Krieg T, Abraham D, Lafyatis R. Fibrosis in connective tissue
disease: the role of the myofibroblast and fibroblast-epithelial cell
interactions. Arthritis Res Ther 2007; 9(Suppl 2):S4.
Kraling BM, Maul GG, Jimenez SA. Mononuclear cellular
infiltrates in clinically involved skin from patients with systemic
sclerosis of recent onset predominantly consist of monocytes/
macrophages. Pathobiology 1995; 63:48–52.
Moretta A, Sivori S, Vitale M, Pende D, Morelli L, Augugliaro R,
et al. Existence of both inhibitory (p58) and activatory (p50)
receptors for HLA-C molecules in human natural killer cells. J
Exp Med 1995; 182:875–9.
Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A.
Different checkpoints in human NK-cell activation. Trends
Immunol 2004; 25:670–8.
Yu J, Venstrom JM, Liu XR, Hasan RS, O’Reilly R, Pring J, et al.
Breaking tolerance to self, circulating natural killer cells expressing
inhibitory KIR for non-self HLA exhibit effector function following
T-cell depleted allogeneic hematopoietic cell transplantation. Blood
2009; 113:3875.
74
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Boyton RJ, Altmann DM. Natural killer cells, killer immunoglobulinlike receptors and human leucocyte antigen class I in disease. Clin
Exp Immunol 2007; 149:1–6.
Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural
killer cells. Nature 2009: 457 (7229), 557.
Nelson GW, Martin MP, Gladman D, Wade J, Trowsdale J,
Carrington M. Cutting edge: heterozygote advantage in autoimmune
disease: hierarchy of protection/susceptibility conferred by HLA
and killer Ig-like receptor combinations in psoriatic arthritis. J
Immunol 2004; 173:4273–6.
Martin MP, Nelson G, Lee JH, Pellett F, Gao X, Wade J, et al.
Cutting edge: susceptibility to psoriatic arthritis: influence of
activating killer Ig-like receptor genes in the absence of specific
HLA-C alleles. J Immunol 2002; 169:2818–22.
Jobim M, Jobim LF, Salim PH, Cestari TF, Toresan R, Gil BC, et
al. A study of the killer cell immunoglobulin-like receptor gene
KIR2DS1 in a Caucasoid Brazilian population with psoriasis
vulgaris. Tissue Antigens 2008; 72:392–6.
Subcommittee for scleroderma criteria of the American
Rheumatism Association Diagnostic and Therapeutic Criteria.
Preliminary criteria for the classification of systemic sclerosis
(scleroderma). Committee. Arthritis Rheum 1980; 23:581–90.
LeRoy EC, Medsger TA Jr. Criteria for the classification of early
systemic sclerosis. J Rheumatol 2001; 28:1573–6.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure
for extracting DNA from human nucleated cells. Nucleic Acids
Res 1988; 16:1215.
Gómez-Lozano N, Vilches C. Genotyping of human killer-cell
immunoglobulin-like receptor genes by polymerase chain reaction
with sequence-specific primers: an update. Tissue Antigens 2002;
59:184–93.
Tan FK. Systemic sclerosis: the susceptible host (genetics and
environment). Rheum Dis Clin North Am 2003; 29:211.
Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD,
Mayes MD. Familial occurrence frequencies and relative risks for
systemic sclerosis (scleroderma) in three United States cohorts.
Momot T, Koch S, Hunzelmann N, Krieg T, Ulbricht K,
Schmidt RE, et al. Association of killer cell immunoglobulin-like
receptors with scleroderma. Arthritis Rheum. 2004; 50:1561–5.
Salim PH, Jobim M, Bredemeier M, Chies JA, Schlottfeldt J,
Brenol JC, et al. Killer cell immunoglobulin-like receptor (KIR)
genes in systemic sclerosis. Clin Exp Immunol 2010; 160:325–30.
Majorczyk E, Pawlik A, Łuszczek W, Nowak I, Wiśniewski A,
Jasek M, et al. Associations of killer cell immunoglobulin-like
receptor genes with complications of rheumatoid arthritis. Genes
Immun 2007; 8:678–83.
Lowe DP, Cook MA, Bowman SJ, Briggs DC; UK Sjögrens Interest
Group. Association of killer cell immunoglobulin-like receptors
with primary Sjögren’s syndrome. Rheumatology (Oxford) 2009;
48:359–62.
Shastry A, Sedimb SK, Rajalingam R, Nikitina-Zake L, Rumba I,
Wigzell H, et al. Combination of KIR 2DL2 and HLA-C1 (Asn
80) confers susceptibility to type 1 diabetes in Latvians. Int J
Immunogenet 2008; 35:439–46.
20/03/2013 16:25:56
ORIGINAL ARTICLE
The quality of life of patients with
lupus erythematosus influences cardiovascular
capacity in 6-minute walk test
Sandor Balsamo1, Dahan da Cunha Nascimento2, Ramires Alsamir Tibana3, Frederico Santos de Santana4,
Licia Maria Henrique da Mota5, Leopoldo Luiz dos Santos-Neto6
ABSTRACT
Objective: To assess the association between quality of life and distance walked in the 6-minute walk test (6MWT)
in Brazilian premenopausal patients with systemic lupus erythematosus (SLE) and compare their results with those
of healthy controls. Methods: Twenty-five premenopausal (18–45 years) patients diagnosed with low-activity SLE
(mean SLEDAI: 1.52 ± 1.61) and 25 controls were matched for age, physical characteristics, and physical activity
level (International Physical Activity Questionnaire/s-IPAQ). Both groups should not be involved in regular physical
activity for at least six months before the study. The 6MWT distance (American Thoracic Society protocol), posttest
heart rate (HRpost), posttest oxygen saturation (SpO2post) and the Borg scale of subjective perception of effort (SPE/
CR10) were evaluated. The quality of life was assessed by use of the Short Form Health Survey 36 (SF-36). Results:
Patients with SLE had a significantly poorer quality of life, a shorter 6MWT distance (598 ± 45 m versus 642 ± 14 m, P
< 0.001), and greater values of SPE/CR10 (6.28 ± 2.0 versus 5.12 ± 1.60, P ≤ 0.05) and HRpost (134 ± 15 bpm versus
123 ± 23 bpm, P ≤ 0.05) when compared with controls. The linear regression model suggested that quality of life was
a significant predictor of 70% of the 6MWT distance. Conclusion: When compared with controls, patients with SLE
walked a shorter distance in the 6MWT, which was associated with poorer quality of life.
Keywords: systemic lupus erythematosus, physical fitness, quality of life, 6-minute walk test.
INTRODUCTION
Patients with systemic lupus erythematosus (SLE) are at increased risk for acute myocardial infarction, up to seven times
that of the healthy population.1,2 In addition to a greater cardiovascular risk, women with SLE have lower cardiorespiratory
capacity as compared with that of healthy women.3
Another aspect that might aggravate their cardiovascular risk
is the high percentage of physically inactive patients,4 directly
affecting their quality of life.5 Previous studies have reported an
association between lower oxygen consumption (direct measure
of peak oxygen) and worse quality of life in patients with SLE.5
However, the conventional test is time-consuming, requires
specialized equipment, which has a high cost and is not practical
for hospitals, clinics and physical activity centers.
A practical strategy to aid in the assessment of the clinical
status for the patient’s cardiovascular prognosis is the 6-minute
walk test (6MWT). The 6MWT requires a walkway with at
Received on 01/07/2012. Approved on 12/13/2012. The authors declare no conflict of interest. Ethics Committee: 074//2005.
Post-Graduation Program in Medical Sciences, Medical School, Universidade de Brasília – FM-UnB; Service of Rheumatology, Hospital Universitário de Brasília
– HUB-UnB; Laboratory of Physical Fitness and Rheumatology - LAR/HUB; Department of Physical Education, Centro Universitário UNIEURO, Strength Exercise
and Health Study and Research Group – GEPEEFS; Programa de Pós-Graduação em Educação Física da Universidade Católica de Brasília - UCB-DF.
1. PhD in Medical Sciences, Faculdade de Medicina, Universidade de Brasília – FM-UnB; Laboratory of Physical Fitness and Rheumatology – LAR/HUB; Physical
Education Professor, Department of Physical Education, UNIEURO/GEPEEFS
2. Master degree student of Physical Education, UCB-DF; Researcher, GEPEEFS/UNIEURO
3. Master in Physical Education, UCB-DF; Researcher, GEPEEFS/UNIEURO
4. Master in Physical Education, UnB; LAR/HUB; Physical Education Professor, Department of Physical Education, UNIEURO/GEPEEFS;
5. PhD in Medical Sciences, FM-UnB; Collaborating Professor, Internal Medicine and Service of Rheumatology, FM-UnB
6. Associated Professor, Internal Medicine and Service of Rheumatology, FM-UnB
Correspondence to: Sandor Balsamo. Programa de Pós Graduação em Ciências Médicas, Faculdade de Medicina. Universidade de Brasília – UnB. Campus Universitário Darcy Ribeiro. CEP: 70910-900. Brasília, DF, Brasil. E-mail: [email protected]
75
20/03/2013 16:25:56
Balsamo et al.
least 30 meters and an oximeter.6 However, so far, no study
has assessed the 6MWT in patients with SLE and compared
its results with those of healthy women. In addition, it is not
clear whether there is an association between the distance
walked in the 6MWT and the quality of life of patients with
SLE. The results of that investigation might aid health professionals to control the quality of life and to assess clinical
aspects and the cardiovascular capacity of patients with SLE,
in addition to providing comparative parameters with the
healthy population.
The present study aimed at: 1) assessing the association
between the distance walked in the 6MWT and the quality of life of premenopausal patients with low activity SLE;
2) comparing the results with those of healthy women matched
for gender, age, physical activity level and physical characteristics. The hypothesis of the present study was that patients with
SLE would walk a shorter distance in the 6MWT, which would
be associated with an impaired quality of life.
MATERIAL AND METHODS
Study participants and design
This study was conducted from January, 20th 2009 to January,
31st 2011, and was approved by the Committee of Ethics
and Research of the Medical School of the Universidade
de Brasília (FM-UnB) (protocol CEP-FM 074//2005), in
accordance with the Helsinki declaration.7 It is part of the
LUPUSFIT study, a research project aimed at assessing
the various aspects related to physical fitness and health of
Brazilian females with SLE – linked to the laboratory of physical fitness and rheumatology (LAR) of Hospital Universitário
de Brasília (HUB). All participants provided written informed
consent to undergo all tests. Twenty-five premenopausal patients with SLE met the American College of Rheumatology
(ACR) criteria8,9 and were on regular follow-up at the service
of rheumatology of the HUB. Twenty-five healthy women
(controls) were matched for gender, age, physical activity
level and physical characteristics.
This study included female patients with SLE according
to the ACR criteria,8,9 who were on regular follow-up at the
service of rheumatology of the HUB and had low disease activity (SLEDAI ≤ 5). All study participants should be between 18
and 45 years of age, and not exercising for at least 6 months
before the beginning of this study (on average, less than once
a week). To identify the type of exercises, their regularity,
frequency, intensity and duration, a questionnaire10 with the
following three questions was used: 1) What type of physical
exercise do you practice regularly during the week?; 2) What is
76
the week frequency of that exercise?; and 3) What is the mean
duration, in minutes, of a single session of physical exercise?
Patients with SLE and the following characteristics were
excluded from the study: SLEDAI > 5; serum creatinine
≥ 4,770 mg/dL or 265 mmol/L, hematocrit ≤ 30%, nephritis and/
or leukopenia; beta-blocker use, previous history of myocardial
infarction, cardiomyopathy and/or systemic arterial hypertension; diabetes mellitus; neurological disorders; hypothyroidism;
fibromyalgia; locomotor disorders (fractures and prostheses)
and/or osteoporosis; rheumatoid arthritis (RA); Sjögren’s syndrome; cancer; age < 18 years; age > 45 years; geographical
difficulties (living far from the city of Brasília); body mass index
(BMI) < 18 kg/m2; body surface > 30 kg/m2 (obesity); tobacco
use; pregnancy; and regular exercise practice (on average, at
least twice a week).
METHODS
The study participants visited the laboratory of human performance of the Centro Universitário Euroamericano (UNIEURO)
twice, at a minimum interval of 48 hours and maximum interval
of 72 hours, always at the same time (between 2PM and 4PM).
In the 24 hours preceding their visits to that laboratory, the
participants had to avoid any intense activity and the consumption of caffeine and alcoholic beverages. Their last meal should
precede the test by at least 2 hours and the participants should
not be menstruating on the day of the test. On their first visit,
the quality of life questionnaire was applied, anthropometric
measures were taken, and the 6MWT performed. On their second
visit, the 6MWT was repeated.
Physical activity level
Aiming at assessing the patient’s daily physical activity level,
the Physical Activity Questionnaire-Short Form (IPAQ-S),11,12
validated to the Brazilian population,12 was used. That questionnaire was applied individually by the major investigator and
comprised questions about the frequency (days per week) and
duration (minutes per day) of activities involving moderate and
vigorous physical exertion in four domains: work commuting;
household chores; leisure; and the number of hours that patients
with SLE and controls remained seated during the week and
during the weekend. According to their physical activity levels,
patients were classified as follows: active; irregularly active;
and sedentary.
Quality of life
Quality of life was assessed by use of the Short Form Health
Survey 36 (SF-36),13 containing 36 items grouped into eight
20/03/2013 16:25:56
The quality of life of patients with lupus erythematosus influences cardiovascular capacity in 6-minute walk test
domains: physical functioning; role limitation due to physical
health; bodily pain; general health perception; vitality; social
functioning; role limitation due to emotional problems; and
mental health. Each domain’s score ranges from 0 to 100,
the highest score indicating better health conditions related
to quality of life.
Anthropometric measures
One single observer assessed the following measures:
height; body mass, BMI (kg/m2); and body composition [fat
percentage; three skinfold measurements: triceps, suprailiac
and thigh; Lange Skinfold Calipers (Cambridge Scientific
Industries, Cambridge, MD)].14
The 6-minute walk test
The 6MWT was performed according to the American Thoracic
Society protocol.6 Functional capacity was determined by the
distance walked in a covered 30-meter walkway. After the
6MWT, the following were used: an oximeter (NONIN, model
9500, USA), to assess posttest heart rate (HRpost) and posttest
oxygen saturation (SpO2post); and the Borg scale of subjective
perception of effort (SPE), ranging from 0 to 10 (SPE/CR-10;
0 = rest, 10 = maximum effort possible).15
A minimum sample of 25 volunteers for each group, with test
power of 90%, was estimated to indicate a difference between
the groups, the size of the effect being 0.97. The sample size
was calculated based on a pilot study.3,16 Normality of the data
was assessed by using the Kolmogorov-Smirnov test. The
variables with a normal distribution were shown as mean ±
standard deviation; those without a normal distribution were
shown as median with an interquartile interval.
To compare the means of the measures of the distance
walked during the 6MWT, HRpost, SpO2post and SPE/
CR10 between both groups, the Student t test was used for
independent samples in the variables with a Gaussian distribution, in which the difference between the means with a
95% confidence interval (95% CI) was obtained. When no
normality was observed in the groups, the nonparametric
Mann-Whitney test was used.
The Pearson’s chi-square test was used to assess the association between the group and the physical activity level.
In accordance with Tench et al.,5 the forward linear regression model was used to assess the relationship between the
dependent variable ‘distance walked’ in the 6MWT and the
independent variable ‘quality of life’ (SF-36), and between the
independent variable 6MWT in patients with SLE. The SAS
for Windows 9.2 (SAS Institute Inc., Cary, NC, USA) was
used in the analyses. A 5% significance level was adopted.
RESULTS
Study participants
From January 20th 2009 to January 31st 2011, 25 patients with low activity SLE [mean SLEDAI: 1.52 ± 1.61;
variation: 0–5; 9 patients (36%) had a score of 0] were
assessed. Mean disease duration was 5.3 ± 4.6 years
(range: 1–20 years). The patients were on regular treatment as follows: prednisone = 21/25 (84%), mean dose
= 6.07 ± 2.18 mg/day, range = 5–20 mg/day; azathioprine = 8/25 (32%), mean dose = 87.50 ± 46.88 mg/day,
range = 50–200 mg/day; chloroquine diphosphate = 17/25
(68%), mean dose = 205.88 ± 66.44 mg/day; and hydroxychloroquine = 2/25 (8%), mean dose = 400 ± 0.0 mg/day.
Twenty-five healthy women matched for age and physical
characteristics were selected (Table 1).
International Physical Activity Questionnaire
Compared with controls, the patients with SLE did not statistically differ regarding their physical activity level (P = 0.127),
which was as follows: 17/25 (68%) were considered active;
3/25 (12%) were considered irregularly active; and 5/25
(20%) were considered sedentary. The physical activity level
of the control group was as follows: 23/25 (92%) patients
were considered active; 1/25 (4%) were considered irregularly
active; and 1/25 (4%) were considered sedentary. The patients
with SLE did not statistically differ regarding the time they
remained seated during the week (SLE = 251.00 ± 148.16
hours versus controls = 287.00 ± 215.76 hours; P = 0.80), and
during the weekend (SLE = 266.00 ± 146.46 hours versus
controls: 253.80 ± 200.08 hours; P = 0.40).
Quality of life
Table 2 shows data regarding the patients’ quality of life.
The SF-36 showed that patients with SLE had a worse quality of life in the following domains: general health perception; physical functioning; role limitation due to emotional
problems; social functioning; role limitation due to physical
health; and mental health (all, P < 0.05). Neither vitality nor
bodily pain differed (both, P > 0.05).
The 6-minute walk test
Table 3 shows data regarding the 6MWT. Compared with
controls, the patients with SLE walked a shorter distance
(P < 0.001) and had higher SPE/CR10 (P < 0.05) and HRpost
77
20/03/2013 16:25:56
Balsamo et al.
Table 1
Physical characteristics of patients with systemic lupus erythematosus and healthy women (control group)*
Variable
SLE (n = 25)
Control (n = 25)
Difference between means (95% CI)#
P
Age, years, median (IQR)+
29.9 (6.8)
29.2 (8.0)
—
0.7671
Body mass, kg
57.7 ± 6.7
58.3 ± 8.2
0.69 (−3.5; 4.9)
0.7462
Height, cm
158.0 ± 0.1
158.0 ± 0.1
−0.01 (−0.5; 0.0)
0.6573
Lean body mass, kg
38.0 ± 4.8
38.5 ± 3.8
0.49 (−2.0; 2.9)
0.6966
BMI, kg/height2
23.0 ± 2.9
23.5 ± 3.3
0.47 (−1.3; 2.2)
0.5998
SLE : systemic lupus erythematosus; 95% C I: 95% confidence interval; IQR: interquartile range; BM I: body mass index.
*V alues expressed as mean ± standard deviation, unless otherwise specified.
#
Cal culated only when the Student t test was used.
+
These variables do not have normal distribution, being, thus, expressed as median.
Table 2
Results regarding quality of life (SF-36) of patients with systemic lupus erythematosus and in healthy women (control group)*
Variable
SLE (n = 25)
Control (n = 25)
Difference between means (95%CI)#
P
Physical functioning, median (IQR)+
61.6 (24.4)
81.2 (14.5)
—
0.0029
Role limitations due to physical health, median (IQR)+
53.0 (41.0)
78.0 (25.3)
—
0.0375
+
Bodily pain, median (IQR)
64.4 (25.7)
72.9 (22.0)
—
0.2752
General health perceptions
51.1 ± 17.8
67.5 ±16.3
16.3 (6.6; 26.1)
0.0014
Quality of life, SF-36
+
Vitality, median (IQR)
54.8 (11.5)
55.2 (10.3)
—
0.9686
Social functioning, median (IQR)+
68.4 (24.0)
83.8 (18.3)
—
0.0266
Role limitations due to emotional problems
41.2 (39.9)
73.1 (36.0)
—
0.0073
50.0 ± 13.2
58.5 ± 10.5
8.5 (1.74; 15.4)
0.0150
+
Mental health, median (IQR)
SLE : systemic lupus erythematosus; 95% C I: 95% confidence interval; IQR: interquartile range; SF-36 : Short Form H ealth Survey 36 .
* V alues expressed as mean ± standard deviation, unless otherwise specified.
#
+
Table 3
Results of the 6-minute walk test of patients with systemic lupus erythematosus and healthy women (control group)*
Variable
SLE (n = 25)
Control (n = 25)
Difference between means (95% CI)#
P
6MWT
598.1 ± 45.5
642.4 ± 39.1
44.3 (20.2; 68.5)
0.0006
SPE/CR10, median (IQR)
6.2 ± 2.0
5.1 ± 1.6
0.0358
SpO2PRE, (%), median (IQR)+
98.1 (0.6)
97.6 (1.3)
0.3588
SPO2POST, (%), median (IQR)
98.1 ± 1.3
98.0 ± 1.0
HRPRE, BPM
80.5 ± 10.3
81.7 ± 14.9
1.2 (−6.1; 8.5)
0.7432
HRPOST, BPM
134.3 ± 15.5
123.0 ± 23.6
−11.2 (−22.6; 0.0)
0.0544
+
+
0.5864
SLE : systemic lupus erythematosus; 95% CI : 95% confidence interval; IQR : interquartile range; 6 M W T: 6 -minute walk test; SP E/C R1 0: subjective perception of effort in each series, scale from 0 to 10; SpO 2P R E:
peripheral oxygen saturation at rest prior to the 6M W T; SpO 2P O ST: peripheral oxygen saturation after the 6 M W T; H RP R E: heart rate at rest prior to the 6 M W T; FC P O ST: heart rate after the 6 M W T; BP M : beats
per minute.
* V alues expressed as mean ± standard deviation, unless otherwise specified.
#
+
78
20/03/2013 16:25:56
The quality of life of patients with lupus erythematosus influences cardiovascular capacity in 6-minute walk test
(P = 0.05) than controls. Patients with SLE did not differ regarding SpO2post (P = 0.35).
Linear regression model
The final linear regression model for 6MWT, which included
the SF-36 variables (mental health, physical functioning, social
functioning and role limitation due to emotional problems),
accounted for 70% of the distance walked in the 6MWT
(P ≤ 0.01) (Table 4).
DISCUSSION
The present study aimed at: 1) assessing the association between distances walked in the 6MWT and the quality of life of
premenopausal patients with low activity SLE; 2) comparing
those results with those of healthy women matched for gender,
age, physical activity level and physical characteristics. In addition, HRpost, SpO2post, and SPE/CR10 were assessed. The
results of the tests confirm our hypothesis that the patients with
SLE walked a shorter distance in the 6MWT as compared with
controls. The linear regression model showed that the quality of life was a significant predictor of 70% of the distance
walked in the 6MWT.
We know no previous evidence of the association between
the distance walked in the 6MWT and the quality of life of
patients with SLE. This study provides evidence that the
quality of life of patients with SLE, per se, is associated with
a reduction in the cardiovascular capacity assessed by use of
the 6MWT. In addition, in a practical and simple way, the
6MWT confirmed the results of the study by Tench et al.,5 in
which high-cost equipment has been used to assess cardiovascular capacity, and which has shown an association of the
cardiovascular capacity, assessed by use of the treadmill test
and bicycle ergometer, with quality of life.5
Table 4
Linear regression model of the 6-minute walk test
Standard
R2
error
P
Functional
2.26
capacity (SF-36)
0.33
0.20
< 0.0001
Social aspects
(SF-36)
−1.14
0.31
0.44
0.0014
Emotional
−0.68
aspects (SF-36)
0.18
0.60
0.0010
Mental health
(SF-36)
0.44
0.70
0.0155
Dependent
variable
Independent
variable
6MWT
PE
−1.16
R 2: coefficient of determination; P E = parameter estimate; 6 M W T: 6 -minute walk test; SF-36 : Short
Form Health Survey 36.
However, Bostrom et al.17 have reported that 26% of
the patients undergoing treadmill tests do not achieve the
minimum velocity of 5 km/h,5 possibly due to biomechanical
issues.17 Similarly, when the tests are performed on a bicycle
ergometer, the major limitation is that 50% of the patients
have peripheral fatigue prior to central fatigue.18 In addition,
the conventional test is time-consuming, requires specialized
equipment, which has a high cost and is not practical for hospitals, clinics and physical activity centers. Thus, the 6MWT
might be a more practical tool to aid with the cardiovascular
clinical prognosis of patients with SLE.
The only study performed so far with the 6MWT was that
by Hougthon et al.,18 showing that young patients with SLE
walked a shorter distance than that predicted for the same
age group. However, this is the first study using the 6MWT
to compare the cardiovascular capacity of adult patients with
SLE and controls. The results of the present study confirm the
findings of several studies in which patients with SLE have
lower cardiovascular capacity and higher values of SPE and
HR than those of controls.3 However, the previous studies
have been performed with treadmills or bicycle ergometers.3
The shorter distance walked and the worse quality of life
of patients with SLE might relate to the time for disease diagnosis,19 depression, and cognitive dysfunction.20 Tench et al.5
have reported that the lower cardiovascular capacity might be
associated with the fatigue of patients with SLE. That symptom is also associated with a reduced functional performance21
and might relate to the cycle that reduces physical fitness
(muscle strength/cardiovascular capacity), thus reducing the
ability to perform daily activities3 and impairing the quality
of life of those patients. Another explanation might be the
type I and II muscle fiber atrophy,22,23 and the mitochondrial
damage due to long-term corticosteroid therapy.24
Some limitations of this study should be considered.
1) The generalization of our results should be limited due to
the homogeneity of the sample studied. The patients studied
originated from one single hospital, and their physical characteristics, age, and physical activity level were similar to
those of the control group. In addition, the sample size was
relatively small. However, the homogeneity of both groups
strengthens the internal validity of this study, minimizing
potential confounding factors attributed to that aspect, such
as perimenopause, fibromyalgia, tobacco use, obesity, and
beta-blocker and statin use. In the present study, those factors
were similar in patients with SLE and controls. In addition,
only patients with low activity SLE participated in this
study. All those aspects were methodologically controlled to
minimize interference in the distance walked in the 6MWT.
79
20/03/2013 16:25:57
Balsamo et al.
2) The cross-sectional nature of this study establishes no
cause-effect relationship. However, the objective of this
study was to raise hypotheses for future studies aimed at
assessing the clinical effects of exercise on the health and
quality of life of patients with SLE. In addition, the 6MWT
was used, a test that, considering the reality of the Brazilian
Unified Health System (SUS), might have greater practical
applicability for cardiovascular prognosis, differently from
conventional tests.
Concluding, the present study evidenced that factors related
to quality of life are predictors of cardiovascular capacity. We
80
investigated that association by using the 6MWT in patients
with SLE. In addition, reduced cardiovascular capacity and
SLE are associated with increased morbidity and mortality.
Thus, assessing cardiovascular capacity by use of the 6MWT
and encouraging the practice of exercises might improve the
quality of life of patients with SLE. Those possible benefits,
however, should be assessed in further studies.
This article is part of the PhD thesis of Sandor Balsamo held at
the Post-Graduate Medical Sciences, Faculdade de Medicina,
Universidade de Brasília.
20/03/2013 16:25:57
Balsamo et al.
à homogeneidade da amostra estudada. As pacientes do estudo
eram de um mesmo centro hospitalar, e eram similares ao
grupo-controle quanto a características físicas, idade e nível
de atividade física. Além disso, contamos com uma amostra
relativamente pequena. Por outro lado, a homogeneidade
entre os dois grupos reforça a validade interna do estudo,
minimizando os potenciais fatores de confusão atribuídos
a esses aspectos, como a perimenopausa, a fibromialgia, o
tabagismo, a obesidade, o uso de betabloqueador e a estatina.
No presente estudo, esses fatores foram semelhantes entre
pacientes com LES e grupo-controle. Além disso, apenas as
pacientes com LES em baixa atividade da doença participaram
do estudo. Todos esses aspectos foram metodologicamente
controlados para que fossem mínimas as interferências sobre
a distância percorrida no 6TC; 2) a natureza da seção transversal do estudo não estabelece relação de causa e efeito. No
entanto, o objetivo foi levantar hipóteses para futuros estudos
que visem analisar os efeitos clínicos do exercício na saúde
e na qualidade de vida de pacientes com LES. Ao mesmo
tempo, foi utilizado o 6TC, que para a realidade do Sistema
Único de Saúde (SUS) pode ter maior aplicabilidade prática
para prognóstico cardiovascular – diferentemente dos testes
convencionais.
Em conclusão, o presente estudo forneceu evidências de
que fatores relacionados à qualidade de vida são preditores
para capacidade cardiovascular. De forma inédita, investigamos esta associação por meio do 6TC em pacientes com
LES. Além disso, a diminuição da capacidade cardiovascular
e o LES estão associados ao aumento da morbimortalidade.
Portanto, avaliar a capacidade cardiovascular pelo 6TC e
incentivar a prática de exercícios poderá implicar melhora da
qualidade de vida de pacientes com LES. Contudo, esses possíveis benefícios devem ser examinados em estudos futuros.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Este artigo é parte da tese de Doutorado de Sandor Balsamo
realizado no programa de Pós-graduação em Ciências Médicas
da Faculdade de Medicina da Universidade de Brasília.
REFERENCES
17.
REFERÊNCIAS
1.
2.
Westerweel PE, Luyten RK, Koomans HA, Derksen RH,
Verhaar MC. Premature atherosclerotic cardiovascular disease in
systemic lupus erythematosus. Arthritis Rheum 2007; 56:1384–96.
Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr., JansenMcWilliams L, et al. Age-specific incidence rates of myocardial
infarction and angina in women with systemic lupus erythematosus:
comparison with the Framingham Study. Am J Epidemiol 1997;
145:408–15.
86
18.
19.
Balsamo S, Santos-Neto LD. Fatigue in systemic lupus erythematosus:
An association with reduced physical fitness. Autoimmun Rev 2011;
10:514–8.
dos Santos FM, Borges MC, Correia MI, Telles RW, Lanna CC.
Assessment of nutritional status and physical activity in systemic
lupus erythematosus patients. Rev Bras Reumatol 2010; 50:631–8.
Tench C, Bentley D, Vleck V, McCurdie I, White P, D'Cruz D.
Aerobic fitness, fatigue, and physical disability in systemic lupus
erythematosus. J Rheumatol 2002; 29:474–81.
Brooks D, Solway S, Gibbons WJ. ATS statement on six-minute walk
test. Am J Respir Crit Care Med 2003; 167:1287.
Gandevia B, Tovell A. Declaration of Helsinki. Med J Aust 1964;
2:320–1.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF,
et al. The 1982 revised criteria for the classification of systemic lupus
erythematosus. Arthritis Rheum 1982; 25:1271–7.
Hochberg MC. Updating the American College of Rheumatology
Valkeinen H, Hakkinen A, Alen M, Hannonen P, Kukkonen-Harjula K,
Hakkinen K. Physical fitness in postmenopausal women with
fibromyalgia. Int J Sports Med 2008; 29:408–13.
Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML,
Ainsworth BE, et al. International physical activity questionnaire:
12-country reliability and validity. Med Sci Sports Exerc 2003;
35:1381–95.
Matsudo SM, Araújo T, Matsudo VR, Andrade D, Andrade E,
Oliveira LC, et al. Questionário internacional de atividade física
(IPAQ): estudo de validade e reprodutibilidade no Brasil. Rev Bras
Ativ Física & Saúde 2001; 6:5–18.
Stoll T, Gordon C, Seifert B, Richardson K, Malik J, Bacon PA, et al.
Consistency and validity of patient administered assessment of quality
of life by the MOS SF-36; its association with disease activity and
damage in patients with systemic lupus erythematosus. J Rheumatol
1997; 24:1608–14.
Jackson AS, Pollock ML, Ward A. Generalized equations for predicting
body density of women. Med Sci Sports Exerc 1980; 12:175–81.
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports
Exerc 1982; 14:377–81.
Balsamo S, Nascimento DC, Tibana RA, Santana FS, Mota LMH,
Kircheheim RAFV, et al. Functional capacity, physical fitness
fatigue in women with systemic lupus erythematosus. In: Brazilian
Rheumatology Congress in 27th Annual Scientific Meeting 18-22
September 2010; Brazil, Rio Grande do Sul. Bras J Rheumatol 2010;
50:182. [Abstract].
Bostrom C, Dupre B, Tengvar P, Jansson E, Opava CH, Lundberg IE.
Aerobic capacity correlates to self-assessed physical function but not
to overall disease activity or organ damage in women with systemic
lupus erythematosus with low-to-moderate disease activity and organ
damage. Lupus 2008; 17:100–4.
Houghton KM, Tucker LB, Potts JE, McKenzie DC. Fitness, fatigue,
disease activity, and quality of life in pediatric lupus. Arthritis Rheum
2008; 59:537–45.
Freire EA, Maia IO, Nepomuceno JC, Ciconelli RM. Damage index
assessment and quality of life in systemic lupus erythematosus
patients (with long-term disease) in Northeastern Brazil. Clin
Rheumatol 2007; 26:423–8.
20/03/2013 16:25:57
Qualidade de vida de pacientes com lúpus eritematoso influencia a capacidade cardiovascular em teste de caminhada de 6 minutos
20. Kiani AN, Petri M. Quality-of-life measurements versus disease activity
in systemic lupus erythematosus. Curr Rheumatol Rep 2010; 12:250–8.
21. Stockton KA, Kandiah DA, Paratz JD, Bennell KL. Fatigue,
muscle strength and vitamin D status in women with systemic lupus
erythematosus compared to healthy controls. Lupus 2012; 21(3):271– 8.
22. Lim KL, Abdul-Wahab R, Lowe J, Powell RJ. Muscle biopsy
abnormalities in systemic lupus erythematosus: correlation with clinical
and laboratory parameters. Ann Rheum Dis 1994; 53:178–82.
23. Oxenhandler R, Hart MN, Bickel J, Scearce D, Durham J, Irvin W.
Pathologic features of muscle in systemic lupus erythematosus:
a biopsy series with comparative clinical and immunopathologic
observations. Hum Pathol 1982; 13:745–57.
24. Mitsui T, Umaki Y, Nagasawa M, Akaike M, Aki K, Azuma H, et
al. Mitochondrial damage in patients with long-term corticosteroid
therapy: development of oculoskeletal symptoms similar to
mitochondrial disease. Acta Neuropathol 2002; 104:260–6.
87
20/03/2013 16:25:57
REVIEW ARTICLE
Ultrasonography in rheumatoid arthritis:
what rheumatologists should know
Carlos Frederico Arend1
ABSTRACT
Ultrasonography has recently gained prestige as an adjuvant method for the diagnosis and therapeutic follow-up of
rheumatoid arthritis, although radiography remains the imaging modality traditionally and widely used for those purposes. The great advantage of the ultrasonographic study, which has motivated enthusiastic research in the area, resides
in its capacity to detect synovitis and bone erosion at a pre-radiographic phase, which has been increasingly valued
in preventing late and definitive structural damage. Because that is a relatively new subject, several scientific articles
have been published in recent years about the potential applications of ultrasonography in individuals with rheumatoid
arthritis, some of which directed to researchers and others to clinical rheumatologists. This study aimed at assessing the
currently available bibliography on the subject and at describing only the concepts that are of practical applicability in
the daily routine of clinical rheumatologists.
Keywords: ultrasonography, rheumatoid arthritis, review, color Doppler ultrasonography.
INTRODUCTION
Rheumatoid arthritis (RA) is a multifactorial, symmetric,
peripheral, chronic polyarthritis, whose prevalence is estimated as 1% of the population. The synovial membrane is
the target structure of the autoimmune attack. Most patients
have a cyclic course of clinical remissions and relapses, which
tends to result in progressive joint destruction and deformity.
Radiography has been traditionally used in the search for imaging diagnostic criteria and in patients’ follow-up. However,
radiographically demonstrable findings, such as joint space
reduction, subluxation, or bone erosion, represent irreparable
anatomic changes. However, specialized literature has recently recommended an emphasis on RA screening and early
treatment, aimed at preventing the progression to irremediable
late deformity.1 The theoretical motivation for searching for
an early diagnosis lies in the greater metabolic activity of the
disease’s early stages.2 That phase represents an important
window of opportunity to prevent definitive structural damage. Ultrasonography enables the specific follow-up of that
group of patients, by demonstrating pre-radiographic changes
still at a reversible phase or even already irreversible small
changes. As an alternative, magnetic resonance imaging can
also detect initial RA changes, but with its inherent limitations
of cost and availability (Table 1).
Because that is a relatively new subject, several scientific
articles have been published in recent years about the potential applications of ultrasonography in individuals with RA,
some of which directed to researchers and others to clinical
rheumatologists. This study aimed at assessing the currently
available bibliography on the subject and at describing only
Table 1
Comparison between different imaging diagnostic methods
regarding their capacity to detect some of the most common
abnormalities in individuals with initial rheumatoid arthritis
Radiography
Ultrasonography
Magnetic
resonance
imaging
—
—
+++
Synovitis
+
++
+++
Bone erosion39
+
++
—
++
Bone edema
absent / + low / + + intermediate / + + + high
Received on 11/08/2011. Approved on 11/26/2012. The author declares no conflict of interest.
Radimagem Diagnóstico por Imagem, Porto Alegre, RS, Brazil.
1. Radiologist, Radimagem Diagnóstico por Imagem, Porto Alegre, RS, Brazil
Correspondence to: Carlos Frederico Arend. Cristóvão Colombo, 1691. CEP: 90560-001. Porto Alegre, RS, Brazil. E-mail:[email protected]
88
20/03/2013 16:25:57
the concepts that are of practical applicability in the daily
routine of clinical rheumatologists.
ULTRASONOGRAPHY FOR ASSESSING SYNOVITIS
Synovitis, either proliferative or exudative, is the earliest
change that can be ultrasonographically graded. Its quantification via grayscale ultrasound usually uses a semiquantitative
scale with three levels of intensity, indicating mild, moderate
or marked synovial changes3,4 (Figure 1).
On imaging, proliferative synovitis manifests as distension of the articular capsule by a poorly compressed,
hypoechoic tissue, which initially tends to establish in the
following joints: metacarpophalangeal, metatarsophalangeal
or proximal interphalangeal (Figure 2 A and B). The search
for occasional synovial vascularization on color or power
Doppler imaging is very useful complementary information
for therapeutic monitoring, because increased blood flow is
Grade 1
Grade 2
Grade 3
Figure 1
Synovitis grading in metacarpophalangeal, metatarsophalangeal and interphalangeal joints on ultrasonography. Note that
normal synovium is imperceptible. Initially, the articular capsule distension is proximal, only progressing distally in more
severe cases. Modified from Fernandes et al.40
present during the active phase of disease. In addition, spectral analysis of the pathologic flow reveals a pattern of low
resistance in the acute active phase and elevated resistance in
the chronic active phase5–8 (Figure 2 E, F and G). The cutoff
point of the several quantitative indices to characterize high
or low resistance is currently controversial and object of much
study in the literature, although an absent or reverse diastolic
flow surely indicates high resistance.
Although proliferative synovitis and exudative synovitis
(joint effusion) can only be differentiated via gray scales in
last-generation equipment (Figure 3 A, B and C), in most
cases the major diagnostic clue is synovial fluid compressibility (Figure 3, D, E and F). An insignificant amount of
fluid in the plantar or dorsal recess of metatarsophalangeal
joints is a normal finding, which should not be considered
pathological.
Synovitis of the distal radioulnar joint, usually extending
to the ulnar styloid process and contiguous structures, is such
a characteristic finding that it is even considered pathognomonic of RA (Figure 4 A and B). Usually, but not always,
the change is bilateral. On the dorsal face of the intercarpal
joints, that finding is equally considered typical (Figure 4 C
and D). Synovitis can also affect synovial sheaths. In fact, the
histopathological analysis of the synovial tendon sheath reveals an incredible similarity with that of the joint synovium
in individuals with RA, including hyperplasia of the lining
cells and leukocyte infiltration, mainly CD4+ T cells and
CD68+ macrophages.9 Thus, the differential diagnosis with
systemic inflammatory arthropathy should be considered in
the presence of synovitis in unusual sheaths, rarely associated
with trauma or overuse, such as that of the long flexor of the
thumb (Figure 4 E and F), extensor carpi ulnaris, and flexor
carpi radialis (Figure 4 G and H). Distally, the most affected
sheaths are those of the extensor tendons of the second and
third fingers.10–12 Synovitis in the tendon sheaths of the toes
is rare, being usually associated with systemic inflammatory
arthropathy, either in the flexor (Figure 4 I and J) or extensor
(Figure 4 K and L) region.
Ultrasonography can be used to monitor the response to
treatment by assessing the reduction in synovitis intensity
on the grayscale test and/or in synovial vascularization by
use of color or power Doppler imaging.13 Several ultrasonographic scores of synovial impairment have been proposed
in the literature and all have been mainly aimed at detecting changes in the inflammatory activity by assessing the
smallest possible number of joints to reduce the time of
exam.14–18 In our opinion, such protocols are still primarily
aimed at the communication between researchers, their use
89
20/03/2013 16:25:58
Arend
F
A
B
E
G
C
D
Figure 2
Ultrasonographic manifestations of rheumatoid arthritis. (A) Positioning of the transducer. (B) Corresponding image demonstrating the head of the metatarsal bone (met), the base of the proximal phalanx (fp) and typical proliferative synovitis (*),
grade 2/3, affecting the metatarsophalangeal joint of the fifth toe. Synovitis is the earliest ultrasonographic change that can be
demonstrated in individuals with rheumatoid arthritis, being a strong predictor of erosion. (C) Positioning of the transducer.
(D) Corresponding image of the proximal interphalangeal joint, demonstrating the head of the proximal phalanx (fp), the
base of the middle phalanx (fm) and typical proliferative synovitis (*), grade 2/3, and a small bone erosion (arrow head).
(E) Positioning of the transducer. (F) Corresponding image of the proximal interphalangeal joint, showing flow inside the
synovium, indicating disease activity. (G) Corresponding spectral analysis demonstrating anterograde diastolic synovial flow.
The spectral analysis of synovial flow helps to differentiate the active acute phase, which has low resistance index, from the
active chronic phase, which has high resistance index.5–8 The appropriate adjustment of the equipment should prioritize the
search for low velocity flow, with reduced wall filter, reduced frequency of pulse repetition (around 800 Hz) and color gain
at high levels. Care should be taken not to excessively compress the transducer against the epidermal surface, whose small
vessels can collapse, temporarily interrupting flow.41
B
A
C
D
E
F
Figure 3
Differentiation between joint effusion and synovitis. (A) Positioning of the transducer. (B) Corresponding image demonstrating
the head of the metacarpal bone (met), base of the proximal phalanx (fp) and distension of the articular capsule by anechoic
fluid (*). (C) Magnetic resonance imaging, sagittal plane, STIR-weighted image, confirming joint effusion (arrow head). (D)
Positioning of the transducer. (E) Corresponding image at the level of the metatarsophalangeal joint, demonstrating the head
of the metatarsal bone (met), base of the proximal phalanx (fp) and distension of the articular capsule by hypoechoic material
(*), compatible with grade 2 synovitis or effusion. (F) Compressive study, showing the wide compressibility of the finding
(arrow head), because of its fluid content, indicating effusion rather than synovial proliferation.
90
20/03/2013 16:25:58
G
A
B
H
I
C
D
J
K
E
F
L
Figure 4
Ultrasonographic manifestations of rheumatoid arthritis. (A) Positioning of the transducer. (B) Corresponding image revealing
extensive proliferative synovitis (*) contiguous with the ulnar styloid process (peu). The deep face of the ligaments that unite
the carpal bones is lined by synovial cells, and, in non-sealed sites, the inflammatory process extends to adjacent soft tissues.
(C) Positioning of the transducer. (D) Corresponding image demonstrating the exuberant intercarpal proliferative synovitis
(*), which dorsally displaces the tendons (t) of the forth extensor compartment (arrow head). An important differential diagnosis of that image pattern is the short extensor of the fingers muscle, a variant of the normality that can be present in the
region and whose echogenicity is similar to that of synovitis. In the differentiating process, the examiner should note that the
muscle, unlike synovitis, tends to affect the areas between the tendons of the fourth compartment and not only the tendons’
deeper areas. In addition, the dynamic examination during extension of the fingers contracts the muscle mass and tends to
increase its cross-sectional area, which does not occur with synovitis. (E) Positioning of the transducer. (F) Corresponding
image demonstrating fluid distension of the radial sheath (*) due to exudative synovitis of the long flexor of the thumb (flp).
Note the swollen median nerve (arrow head), due to secondary carpal tunnel syndrome. (G) Positioning of the transducer.
(H) Corresponding image showing excessive fluid (*) surrounding the carpal radial flexor tendon (frc), due to synovitis. Note
the median nerve (nm) on the same imaging plane. (I) Positioning of the transducer. (J) Corresponding image demonstrating
fluid distension of the sheath (*) of the flexors (t) of the third finger (3). (K) Positioning of the transducer. (L) Corresponding
image demonstrating fluid distension of the sheath (*) of the extensors (t) of the fourth finger (4).
91
20/03/2013 16:25:58
Arend
on routine clinical practice being based on fragile scientific
evidence. Ultrasonographic contrast media have also been
tested in the search for a better differentiation between active
and inactive synovitis, but their use is equally experimental
and should not be incorporated to routine clinical practice,
at least for now.19
B
A
ULTRASONOGRAPHY FOR
ASSESSING BONE EROSION
Bone erosion results from the colagenase produced on the
interface between synovium, bone and joint cartilage, typically observed in the periphery of the joint space, where bone
is not covered by cartilage.20 Erosions develop predominantly
during the first two years of disease (in aggressive disease, in
the first 6 months)21 and have a marked predilection for the
ulnar styloid process, capitate bone, pyramidal bones, semilunar bones, and radial face of the second and third metacarpophalangeal joints, most notably in the head of metacarpal
bones22 (Figure 2 C and D). Because of the ease of access, the
search for erosions in the margins of the metacarpophalangeal
and metatarsophalangeal joints of the first and fifth fingers is
probably more accurate than the study of the other toes and
fingers, which do not allow satisfactory medial and lateral
access. It is worth noting that, when assessing the dorsal
face of the head of metacarpal and metatarsal bones, a small
anatomic bone indentation usually present in those regions
should not be considered an erosion23 (Figure 5).
Semiquantitative scores for different degrees of erosion
have already been published aiming at treatment monitoring,24–27 but they still require more comprehensive studies,
confirming their accuracy and reproducibility. In accordance
with the literature, we observed that the clinical remission of
RA under treatment is usually accompanied by an improvement in synovitis, but not in the erosions already formed.
ULTRASONOGRAPHY FOR THE DIFFERENTIAL
DIAGNOSIS OF RHEUMATOID ARTHRITIS
The ultrasonographic documentation of synovitis or bone
erosion does not exclusively indicate the diagnosis of RA in
its early phase. In fact, spontaneous resolution is observed
in half of the cases of synovitis with less than 6 months of
evolution.28,29 In the other half, the course tends to be of a
chronic and persistent disease. Some patients with chronic
and persistent disease develop full criteria for RA, while
others remain with the diagnosis of undifferentiated arthritis.
In screening incipient RA, it is worth noting that it should
92
D
C
Figure 5
Anatomical trap. (A) Positioning of the transducer. (B)
Corresponding image showing the head of the metacarpal
bone (met), the base of the proximal phalanx (fp), joint cartilage (*), the extensor tendon (te) and the dorsal triangular
structure (t), and a small anatomical indentation in the head
of the metacarpal bone (arrow head), which should not be
mistaken for erosion. (C) Positioning of the transducer. (D)
Corresponding image showing the head of the metacarpal
bone (met), the base of the proximal phalanx (fp) and bone
erosion (arrow head), the latter on a typical location. Note
the position of the transducer and the magnitude of the bone
anatomical indentation, shallower and more centrally located
than erosion.
be differentiated from undifferentiated arthritis and other
inflammatory polyarthralgias in their initial phase, mainly
psoriatic arthritis and systemic lupus erythematosus, whose
findings might be similar with identical distribution.23,30–32
When present, both subcutaneous edema33–35 and bone erosion
in the margins of the distal interphalangeal joint 36,37 suggest
psoriatic arthritis as the initial hypothesis. The lack of such
findings, however, does not contribute to the differential
diagnosis. Based on clinical and serological characteristics,
it is currently possible to predict with good accuracy which
patients with undifferentiated arthritis will progress to RA, a
20/03/2013 16:25:59
task much better performed by the attending physician than
by the ultrasonographist.38
CONCLUSION
Ultrasonography has recently gained prestige as an adjuvant
method for the diagnosis and therapeutic follow-up of RA,
although radiography remains the imaging modality traditionally and widely used for those purposes. The great advantage
of the ultrasonographic study, which has motivated enthusiastic
research in the area, resides in its capacity to detect synovitis
and bone erosion at a pre-radiographic phase. That generates
information that can be used for diagnostic or therapeutic purposes, with a potential impact on the patients’ quality of life.
93
20/03/2013 16:26:00
Ultrassonografia em portadores de artrite reumatoide: o que o reumatologista clínico deve saber
sugerem artrite psoriásica como hipótese inicial. A ausência
desses achados, no entanto, não contribui para o diagnóstico
diferencial. Com base em características clínicas e sorológicas,
é atualmente possível prognosticar com boa acurácia quais
pacientes com artrite indiferenciada progredirão para AR, em
uma tarefa mais bem executada pelo médico assistente do que
pelo ultrassonografista.38
9.
10.
11.
CONCLUSÃO
12.
A ultrassonografia ultimamente vem ganhando prestígio como
método adjuvante no diagnóstico e acompanhamento terapêutico da AR, embora a radiografia ainda seja a modalidade
de imagem tradicionalmente utilizada em larga escala com
esses propósitos. O grande trunfo do estudo ultrassonográfico,
que vem motivando pesquisas entusiastas na área, reside em
sua capacidade de detectar sinovite e erosão óssea em fase
pré-radiográfica, gerando informação que pode ser utilizada
com intuito diagnóstico ou terapêutico, de potencial impacto
na melhora da qualidade de vida dos pacientes.
REFERENCES
13.
14.
15.
REFERÊNCIAS
1.
2.
3.
4.
5.
6.
7.
8.
Egsmose C, Lund B, Borg G, Pettersson H, Berg E, Brodin U, et
al. Patients with rheumatoid arthritis benefit from early 2nd line
therapy: 5 year follow-up of a prospective double blind placebo
controlled study. J Rheumatol 1995; 22(12):2208–13.
Lindqvist E, Jonsson K, Saxne T, Eberhardt K. Course of
radiographic damage over 10 years in a cohort with early rheumatoid
arthritis. Ann Rheum Dis 2003; 62(7):611–6.
Szudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS,
Ostergaard M. Interobserver agreement in ultrasonography of the
finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003;
48(4):955–62.
Weidekamm C, Koller M, Weber M, Keinberger F. Diagnostic value
of high resolution B mode and Doppler sonography for imaging
of hand and finger joints in rheumatoid arthritis. Arthritis Rheum
2003; 48(2):325–33.
Kane D, Balint PV, Sturrock R, Grassi W. Musculoskeletal
ultrasound – a state of the art review in rheumatology. Part 1: Current
controversies and issues in the development of musculoskeletal
ultrasound in rheumatology. Rheumatology 2004; 43(7):823–8.
Kane D, Grassi W, Sturrock R, Balint PV. Musculoskeletal
ultrasound – a state of the art review in rheumatology. Part 2:
Clinical indications for musculoskeletal ultrasound in rheumatology.
Rheumatology 2004; 43(7):829–38.
Wakefield RJ, Brown AK, O’Connor PJ, Emery P. Power Doppler
sonography: improving disease activity assessment in inflammatory
joint disease. Arthritis Rheum 2003; 48(2):285–8.
Newman JS, Adler RS, Bude RO, Rubin JM. Detection of softtissue hyperemia: value of power Doppler sonography. AJR Am J
Roentgenol 1994; 163(2):385–9.
16.
17.
18.
19.
20.
21.
22.
23.
Kaibara N, Yamada H, Shuto T, Nakashima Y, Okazaki K,
Miyahara H, et al. Comparative histopathological analysis
between tenosynovitis and joint synovitis in rheumatoid arthritis.
Histopathology 2008; 52(7):856–64.
Boutry N, Lardé A, Lapègue F, Solau-Gervais E, Flipo RM,
cotton A. Magnetic resonance imaging appearance of the hands
and feet in patients with early rheumatoid arthritis. J Rheumatol
2003; 30(4):671–9.
Tehranzadeh J, Ashikyan O, Anavim A, Tramma S. Enhanced
MR imaging of tenosynovitis of hand and wrist in inflammatory
arthritis. Skeletal Radiol 2006; 35(11):814–22.
Wakefield RJ, O’Connor PJ, Conaghan PG, McGonagle D,
Hensor EM, Gibbon WW, et al. Finger tendon disease in
untreated early rheumatoid arthritis: a comparison of ultrasound
and magnetic resonance imaging. Arthritis Rheum 2007;
57(7):1158–64.
Ribbens C, André B, Marcelis S, Kaye O, Mathy L, Bonnet V, et
al. Rheumatoid hand joint synovitis: gray-scale and power Doppler
US quantifications following anti-tumor necrosis factor-alpha
treatment: pilot study. Radiology 2003; 229(2):562–9.
Ellegaard K, Torp-Pedersen S, Terslev L, DanneskioldSamsøe B, Henriksen M, Bliddal H. Ultrasound Colour Doppler
measurements in a single joint as measure of disease activity in
patients with rheumatoid arthritis assessment of current validity.
Rheumatology 2009; 48(3):254–7.
Scheel AK, Hermann KG, Kahler E, Pasewaldt D, Fritz J,
Hamm B, et al. A novel ultrasonographic synovitis scoring system
suitable for annalysing finger joint inflammation in rheumatoid
arthritis. Arthritis Rheum 2005; 52(3):733–43.
Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM,
Hartung W, et al. Evaluation of a novel 7 joint ultrasound score
in daily rheumatologic practice; a pilot project. Arthritis Rheum
2009; 61(9):1194–201.
Naredo E, Gamero F, Bonilla G, Uson J, Carmona L, Laffon A.
Ultrasonographic assessment of inflammatory activity In
rheumatoid arthritis: comparison of extended versus reduced joint
evaluation. Clin Exp Rheumatol 2005; 23(6):881–4.
Loeuille D, Sommier JP. ScUSI, an ultrasound inflammatory score,
predicts Sharp’s progression at 7 months in RA patients. Arthritis
Rheum 2006; 54(Suppl):S139.
Klauser A, Frauscher F, Schirmer M, Halpern E, Pallwein L,
Herold M, et al. The value of contrast-enhanced color Doppler
ultrasound in the detection of vascularization of finger joints
in patients with rheumatoid arthritis. Arthritis Rheum 2002;
46(3):647–53.
Farrant JM, Grainger AJ, O’Connor PJ. Advanced imaging in
rheumatoid arthritis. Part 2. Erosions. Skeletal Radiol 2007;
36(5):381–9.
Combe B. Should patients with recent-onset polyarthritis receive
aggressive treatment? Joint Bone Spine 2004; 71(6):475–80.
Tan AL, Tanner SF, Conaghan PG, Radjenovic A, O’Connor P,
Brown AK, et al. Role of metacarpophalangeal joint anatomic
factors in the distribution of synovitis and bone erosion in early
rheumatoid arthritis. Arthritis Rheum 2003; 48(5):1214–22.
Boutry N, Lardé A, Demondion X, Cortet B, Cotten H, Cotten A.
Metacarpophalangeal Joints at US in Asymptomatic Volunteers
and Cadaveric Specimens. Radiology 2004; 232(3):716–24.
99
20/03/2013 16:26:02
Arend
24. Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS,
Østergaard M. Interobserver agreement in ultrasonography of the
finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003;
48(4):955–62.
25. Rosenberg C, Etchepare F, Fautrel B, Bourgeois P. Diagnosis of
synovitis by ultrasonography in RA: a one-year experience is enough
for reliability on static images. Joint Bone Spine 2009; 76(1):35–8.
26. Bajaj S, Lopez-bem R, Oster R, Alarcón GS. Ultrasound detects
rapid progression of erosive disease in early rheumatoid arthritis:
a prospective longitudinal study. Skeletal Radiol 2007; 36(2):
123–8.
27. El Mediany Y, Youssef S, Mehanna AN, El Gaafary M. Development
of a scoring system for assessment of outcome of early undifferentiated
inflammatory synovitis. Joint Bone Spine 2008; 75(2):155–62.
28. Tunn EJ, Bacon PA. Differentiating persistent from self-limiting
symmetrical synovitis in an early arthritis clinic. Br J Rheumatol
1993; 32(2):97–103.
29. Harrison BJ, Symmons DP, Brennan P, Barrett EM, Silman AJ.
Natural remission in inflammatory polyarthritis: issues of definition
and prediction. Br J Rheumatol 1996; 35(11):1096–100.
30. Rauch J, Massicotte H, Tannenbaum H. Hybridoma anti-DNA
autoantibodies from patients with rheumatoid arthritis and systemic
lupus erythematosus demonstrate similar nucleic acid binding
characteristics. J Immunol 1985; 134(1):180–6.
31. Ghanem N, Uhl M, Pache G, Bley T, Walker UA, Langer M. MRI
in psoriatic arthritis with hand and foot involvement. Rheumatol Int
2007; 27(4):387–93.
32. Wright S, Filippucci E, Grassi W, Grey A, Bell A. Hand arthritis in
systemic lupus erythematosus: an ultrasound pictorial essay. Lupus
2006; 15(8):501–6.
33. Milosavljevic J, Lindqvist U, Elvin A. Ultrasound and power Doppler
evaluation of the hand and wrist in patients with psoriatic arthritis.
Acta Radiol 2005; 46(4):374–85.
100
34. McGonagle D. Imaging the joint and enthesis: insights into
pathogenesis of psoriatic arthritis. Ann Rheum Dis 2005; 64(Suppl
2):ii58–60.
35. Healy PJ, Groves C, Chandramohan M, Helliwell PS. MRI
changes in psoriatic dactylitis-extent of pathology, relationship
to tenderness and correlation with clinical indices, Rheumatology
2008; 47(1):92–5.
36. Wiell C, Szkudlarek M, Hasselquist M, Møller JM, Vestergaard A,
Nørregaard J, et al. Ultrasonography, magnetic resonance imaging,
radiography, and clinical assessment of inflammatory and
destructive changes in fingers and toes of patients with psoriatic
arthritis, Arthritis Res Ther 2007; 9(6):R119.
37. Tan AL, Benjamin M, Toumi H, Grainger AJ, Tanner SF, Emery P,
et al. The relationship between the extensor tendon enthesis and
the nail in distal interphalangeal joint disease in psoriatic arthritis-a
high-resolution MRI and histological study. Rheumatology 2007;
46(2):253–6.
38. Raza K, Filer A. Predicting the development of RA in patients with
early undifferentiated arthritis. Best Pract Res Clin Rheumatol
2009; 23(1):25–36.
39. Baillet A, Gaujoux-Viala C, Mouterde G, Pham T, Tebib J,
Saraux A, et al. Comparison of the efficacy of sonography,
magnetic resonance imaging and conventional radiography for
the detection of bone erosions in rheumatoid arthritis patients:
a systematic review and meta-analysis. Rheumatology (Oxford)
2011; 50(6):1137–47.
40. Fernandes EA, Junior MRC, Mitraud ASAV, Kubota ES,
Fernandes ARC. Ultra-sonografia na artrite reumatoide: aplicabilidade
e perspectivas. Rev Bras Reumatol 2008; 48(1):25–30.
41. Arend CF. Top ten pitfalls to avoid when performing musculoskeletal
sonography: What you should know before entering the examination
room. Eur J Radiol 2013 [In press]. http://dx.doi.org/10.1016/j.
ejrad.2013.01.022
20/03/2013 16:26:02
REVIEW ARTICLE
Dermatomyositis and polymyositis: from
immunopathology to immunotherapy
(immunobiologics)
Samuel Katsuyuki Shinjo1, Fernando Henrique Carlos de Souza2, Julio Cesar Bertacini de Moraes2
ABSTRACT
Idiopathic inflammatory myopathies (IIM), which include dermatomyositis (DM) and polymyositis (PM), are chronic
systemic diseases associated with high morbidity and functional disability. Current treatment is based on the use of
glucocorticoids and immunosuppressive drugs, but a considerable number of patients is refractory to traditional therapy.
That has led to the attempted use of biologics based on the physiopathogenesis of IIM. From the immunopathological
viewpoint, PM and DM differ: the former is more related to cellular immunity, while the latter, to humoral immunity. In
both, however, elevated concentrations of proinflammatory interleukins (TNF, IL-1, IL-6) and increased expression of
molecules related to costimulation of T lymphocytes have been described; thus, the use of biologics in those conditions
seems reasonable. Considering the biologics available, open-label studies are scarce, comprising mainly case reports
and series. TNF blockers have yielded conflicting results, with no evidence of good response to treatment. The antiCD20 therapy has the most promising results. Data on T lymphocyte costimulation blockade and anti-IL-6 therapy are
extremely scarce, preventing any consideration. Thus, the use of biologics in IIM still remains an unconquered frontier.
Biologics may have an important role in the management of IIM refractory to conventional therapy, but further prospective studies based on objective parameters of response to treatment are needed. So far, anti-CD20 therapy seems to be
the most promising treatment for refractory IIM.
Keywords: dermatomyositis, polymyositis, biological therapy, immunotherapy.
INTRODUCTION
Dermatomyositis (DM) and polymyositis (PM) are part of the
idiopathic inflammatory myopathies (IIM), a heterogeneous
group of chronic systemic autoimmune myopathies, associated with high morbidity and functional disability. Each has
different epidemiological, histological, immunohistochemical,
pathological, and clinical characteristics, as well as different
disease courses.
Being uncommon diseases, drug therapy for DM and
PM is mainly based on case reports or series. In general,
corticosteroids have been recommended as first-line drugs, and,
as corticosteroid-sparing agents, several immunosuppressive
drugs. However, a significant number of patients do not respond
satisfactorily to those traditional treatments. In such cases, biologics are used based on the physiopathology of DM and PM.
MATERIALS AND METHODS
A systematic review of the articles available in the literature
was performed, including articles published up to January
2012. The review was based on a bibliographic search in
the Medical Literature Analysis and Retrieval System online
Service of Rheumatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – FMUSP.
1. PhD in Sciences; Attending Physician, Service of Rheumatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo – HC-FMUSP;
Collaborating Professor, Discipline of Rheumatology, FMUSP
2. Attending Physician, Service of Rheumatology, HC-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. CEP: 01246-903. São Paulo, Brazil. E-mail: [email protected]
101
20/03/2013 16:26:02
Shinjo et al.
(MEDLINE) database. The following terms were assessed: dermatomyositis, biologics, immunobiologicals, immunopathology,
polymyositis, drug therapy, and treatment.
Immunopathology
Polymyositis is characterized by an infiltrate of CD8+ T lymphocytes and macrophages in muscle fibers, which express
increased MHC class I antigen levels1 and release perforin
granules, resulting in lysis of the muscle fibers.2 In DM, B
lymphocytes play a relevant role in the disease pathogenesis
due to the presence of autoantibodies, the deposition of immune complexes in the dermal-epidermal junction of skin
lesions, and the presence of B lymphocytes around inflamed
muscle fibers3,4 and perivascular areas.5,6
Cytokines and chemokines
Cytokines and chemokines produced by muscle fibers, and
inflammatory and endothelial cells can contribute to the
pathogenesis of myopathies. Proinflammatory cytokines,
such as interleukins 1α (IL-1 α) and IL-1 β, tumor necrosis
factor α (TNF-α), interferons α and β (IFN-α and INF-β),
and high-mobility group protein B1 (HMGB1), in addition to
chemokines [such as α-chemokines (CXCL9 CXCL10) and
β chemokines (CCL2, CCL3, CCl4, CCL19, CCL21)], are
present in the muscle tissue of patients with DM and PM.3−6
Other cytokines, such as IL-15 and IL-18, have been
recently described, suggesting they might play a role in
the pathogenesis and activity of myositis, requiring further
studies.7−12
The treatment of the myopathies refractory to conventional treatment might, at least theoretically, be targeted at
blocking those cytokines and chemokines.
Tumor necrosis factor
The TNF has been correlated with the pathogenesis of IIM.8−12
Using immunohistochemistry and in situ hybridization, Kuru
et al.8 have shown that muscle fibers of patients with DM
and PM express and synthesize TNF, while Lundberg et al.9
have shown increased levels of messenger RNA (mRNA) of
TNF in muscle biopsies. Shimizu et al.12 have found increased
serum levels of soluble TNF receptors in DM and PM. The
levels of other cytokines, such as TNF β, IL-1α, IL-1β, IL-2
and IFN-γ, are also increased in muscle biopsies of patients
with DM and PM, contributing to the local inflammation
cascade.8−15
It is worth noting that TNF, IL-1 and IFN induce the expression of MHC class I antigen by muscle fibers,1 and both
regulate muscle metabolism and regeneration.15
102
Interleukin 1
Muscle weakness has been suggested not to correlate with
the presence of inflammatory cell infiltrates; however, the
presence of IL-1 detected in endothelial cells of patients with
muscle weakness and no inflammatory cell infiltrate suggests
the participation of proinflammatory interleukins.16,17 TNF
has catabolic effects and works together with IL-1, leading
to skeletal muscle mass loss.18 The increased expression of
IL-1 (IL-1 α, IL-1 β, IL-1 Ra), on its turn, correlates with the
increase in IL-1 receptor in muscle fibers,19 intensifying the
immune mechanism of myositis.
IL-1α, which is markedly expressed in the muscle tissue
of patients with myositis, can stimulate the production of
prostaglandin E2 (PGE2) in skeletal muscle.19
Interleukin 6
The serum levels of IL-6 are also elevated and correlate with
the activity of DM.20 An increase was observed in the expression of mRNA of IL-6 in muscle tissues of patients with PM
and DM, but not in normal muscles.20 Okiyama et al.21 have
shown that IL-6 is expressed in macrophages infiltrating
muscle tissues, and that the administration of monoclonal
anti-IL-6 receptor antibodies prevented the appearance and
progression of the inflammatory myopathy.
Interferon
In the muscle tissue and peripheral blood of patients with DM
and PM, IFN gene expression has been observed and can be
associated with disease activity.22,23
Interferon activates natural killer cell cytotoxicity, promotes T lymphocyte activation and survival, and dendritic
cell maturation,22,23 in addition to enhancing MHC class I expression by muscle fibers.1 On the other hand, IFN-regulated
proteins (IP-10, I-TAC, MCP-1 and MCP-2) are elevated and
play a role in recruiting lymphocytes for muscle inflammation sites.24
The fact that the muscle fibers of patients with IIM express MHC class I antigens implicates that such fibers might
behave as antigen-presenting cells for CD8+ T lymphocytes.
Based on that hypothesis, Murata et al.25 have shown that
muscle fibers of patients with PM also express the costimulatory molecule BB-1. On the other hand, CD8+ T lymphocytes around those fibers expressed CD28 and CTLA-4
(CD152). Behrens et al.26 have reported that muscle fibers
expressed BB-1 after stimulation with either IFN-γ or TNF-α.
The use of biologics is supported by those immunopathological findings, particularly in cases of IIM refractory to
corticosteroids and several immunosuppressive drugs.
20/03/2013 16:26:02
Dermatomyositis and polymyositis: from immunopathology to immunotherapy (immunobiologics)
Immunotherapy/Immunobiologics
Anti-TNF therapy
Infliximab
Infliximab is a chimeric monoclonal antibody against TNF-α,
composed by a sequence of peptides, 75% human and 25%
murine.27
Some reports have shown an improvement in the muscle
strength of patients with IIM, and a reduction in the serum
levels of muscle enzymes after the treatment with biologics
of the anti-TNF-α type.27−38 However, results are not homogeneous. Efthimiou et al.39 have published a retrospective
study with 2 patients with DM refractory to conventional
treatment (methotrexate and azathioprine). One of the
patients had previously used etanercept and intravenous
human immunoglobulin, with no change in the myopathic
findings. Both patients were treated with infliximab at the
dose of 3 mg/kg at intervals similar to those recommended
for rheumatoid arthritis. After a mean follow-up of 15.2
months, the patients showed no significant reduction in the
serum levels of creatine kinase, and only one of them showed
a mild improvement in muscle strength within the first three
months of treatment. However, the results of an open-label
study with infliximab as the first treatment option, published
by Hengstamn et al.34 and using a dose of 10 mg/kg of
weight associated with methotrexate, at intervals of 0, 2, 6,
22, 38 and 46 weeks, have not been conclusive due to the
high relapse rate and difficulty to include cases, leading to
an early end of the study. Another open-label pilot study
of infliximab in 13 patients with refractory inflammatory
myopathies (5 with PM; 4 with DM; and 4 with inclusion
body myositis) used methotrexate as the immunosuppressive
agent. The infliximab dose used was 5 mg/kg of body weight
at weeks 0, 2, 6 and 14. Four patients discontinued the study
(3 due to adverse events and 1 due to the presence of ovarian
malignancy). Of the 9 patients completing the study, only 3
had at least a 20% improvement in 3 or more International
Myositis Assessment and Clinical Studies Group (IMACS)
variables (disease activity score).35
Adalimumab
Adalimumab is a fully human monoclonal antibody that
blocks the TNF-α molecule directly.40
The use of adalimumab for systemic autoimmune diseases, mainly rheumatoid arthritis, can induce the development
of inflammatory myopathies (all descriptions were DM).40−46
That is probably the reason why, due to fear of exacerbating
the inflammatory myopathy, there is no description of the
use of adalimumab as drug therapy for patients with either
PM or DM.
Etanercept
Etanercept is a soluble recombinant TNFα receptor, composed
of a dimeric fusion protein with a constant region of human
IgG1 and variable regions of murine antibody.47
Iannone et al.38 have reported 5 patients with DM refractory to corticotherapy and to immunosuppressive agents
(combination of methotrexate and azathioprine), who received etanercept subcutaneously (25 mg, 2x/week) for a
minimum of 3 months. The patients showed no improvement
in the cutaneous findings, worsened their muscle weakness,
and increased their serum levels of muscle enzymes.
Sprott et al.37 have reported the case of a patient with
PM refractory to conventional drug treatment (methotrexate,
azathioprine and/or intravenous human immunoglobulin in
association with corticosteroids). Because of disease refractoriness, etanercept (25 mg, 2 x/week, subcutaneously)
was initiated, and corticotherapy was later suspended due to
stability of the clinical and laboratory findings.
Efthimiou et al.39 have reported the cases of 8 patients
(3 with DM) refractory to methotrexate, azathioprine and
intravenous human immunoglobulin, who underwent adjunct therapy with etanercept and/or infliximab; 6 patients
responded. Of those 8 patients, 6 received etanercept (25 mg,
2 x/week), 1 receives infliximab and 1 received sequential
therapy with 2 agents. The problem with that report is the
concomitance of therapies, which can be a confounding factor
in the improvement reported. Six of the 8 patients studied
underwent monthly pulse therapy with methylprednisolone,
and all of them received intravenous human immunoglobulin
(2 g/kg of body weight) associated with etanercept.
Rituximab
Rituximab is a chimeric monoclonal antibody directed against
CD20 antigen present on the surface of B cells. Its administration leads to the selective depletion of CD20+ B lymphocytes.
Recently rituximab has been used for refractory DM and
PM,7,48−56 considering the important role of B and T lymphocytes in mediating IIM activity.57−60 However, the efficacy of
rituximab in the treatment of PM7,55,56 contradicts the models
proposed for the disease pathogenesis, because the depletion
of B lymphocytes in PM leads to a satisfactory clinical and
laboratory response. In the case of PM, the predominance of
the cytotoxic CD8+ T lymphocytic infiltrate in muscles6,57,60
suggests a more important role of B lymphocytes in the
103
20/03/2013 16:26:02
Shinjo et al.
pathogenesis of PM than previously recognized, acting as
costimulatory or antigen presenting cells.
In 2005, a small open-label study with rituximab
(100 mg/m2 for 4 weeks) was performed with 6 patients
with DM refractory to conventional drug treatment (1 had
no previous drug treatment and 1 was refractory to previous use of etanercept).48 Improvement was observed in
muscle strength, muscle enzymes and skin lesions, with a
peak improvement in muscle strength after 12 to 36 weeks
of treatment. All patients had depletion of B lymphocytes.
Four patients experienced a return of symptoms that coincided with the return of B lymphocytes. Other parameters,
including rash, alopecia and reduced forced vital capacity,
improved. Chung et al.50 treated 8 patients with DM refractory to multiple immunosuppressive drugs, one of whom
after etanercept failure, with 2 infusions of rituximab (1 g
each, 2 weeks apart). Three patients had improvement of
their muscle strength, but significant change was observed
in neither the levels of muscle enzymes nor the severity of
skin lesions after 24 weeks of drug infusion.
In 2005, Lambotte et al.55 reported the case of a patient
with PM, whose clinical and laboratory findings improved
after receiving rituximab (375 mg/m2/week for 4 weeks).
Another study has reported the treatment with rituximab
(375 mg/m2/week for 4 weeks) of 4 other patients with PM
refractory to corticosteroids and methotrexate⁄azathioprine.
In analysis of 28 weeks of medication, all patients improved
their muscle strength, and 2 achieved normal strength. The
creatine kinase level normalized and the corticosteroid dose
was reduced in all cases.56
Tocilizumab
Tocilizumab is a humanized monoclonal anti-IL-6 antibody.
The only study in the literature61 describes 2 male patients
diagnosed with PM, both positive for anti-Jo-1 antibody.
One patient, refractory to corticosteroid (1 mg/kg/day),
azathioprine (100 mg/day) and cyclosporine (100−150 mg/
day), received tocilizumab (8 mg/kg, monthly, intravenous).
After 1 year using the drug, corticosteroid was suspended,
and cyclosporine (100 mg/day) maintained. There was
evidence of progressive improvement in the muscle strength
104
and laboratory findings. The other patient was refractory to
corticosteroid (1 mg/kg/day), azathioprine, cyclosporine and/
or methotrexate. Initially he received tocilizumab monthly
(8 mg/kg, intravenous), and after the forth dose, the interval
was reduced to 3 weeks. After 12 cycles of tocilizumab, associated with methotrexate, the patient showed stability of
the clinical and laboratory findings.
Abatacept
Abatacept is a human recombinant fusion protein, containing the extracellular domain of CTLA-4, which binds to the
CD 80/86 receptor of an antigen-presenting cell. That interaction blocks the activation of the CD 28 receptor in T cells.62
Literature review shows only one case report 63 of a
51-year-old female patient with PM refractory to corticosteroid and methotrexate/azathioprine, who received abatacept
(750 mg intravenously, monthly). Her clinical and laboratory
findings improved at the beginning of treatment, with normalization of the creatine kinase, aldolase and lactic dehydrogenase levels 3 months after beginning the applications.
The response persists after 3 years of follow-up.
FINAL CONSIDERATIONS
The use of biologics for patients with DM and PM remains
an unconquered frontier. The literature review yielded a few
articles, comprising small non-controlled studies, mainly case
reports and series. The TNF blocking agents have conflicting results. In addition, development of IIM during their use
have been reported. So far, the most encouraging evidence
originates from the anti-CD20 therapy with satisfactory results reported, but still requiring further investigation. The
IL-6 inhibition and costimulation blockade in IIM have been
only anecdotally reported, and, so far, no conclusion has been
extracted from them.
Thus, biologics might play a relevant role in the management of IIM refractory to conventional therapy. However,
evidence justifying that approach might only be produced by
use of new prospective studies based on objective parameters
of response to treatment. So far, anti-CD20 therapy seems to
be the most promising treatment for refractory IIM.
20/03/2013 16:26:02
Shinjo et al.
infiltrado de linfócitos T CD8+ citotóxicos nos músculos6,57,60
sugere papel mais importante para os linfócitos B na patogênese da PM anteriormente reconhecida, atuando talvez como
coestimulador ou apresentador de antígenos.
Em 2005, foi realizado pequeno estudo aberto com rituximabe (100 mg/m2 por 4 semanas) em 6 pacientes com
DM refratários ao tratamento medicamentoso convencional,
sendo 1 desses sem tratamento medicamentoso prévio e 1
refratário ao uso preliminar de etanercepte.48 Houve melhora
de força muscular, enzimas musculares, lesões cutâneas,
com pico de melhora da força muscular após 12 a 36 semanas de tratamento. Os linfócitos B foram depletados em
todos os pacientes. Em 4 casos, a recidiva dos sintomas
correlacionou-se ao retorno de linfócitos B. Houve melhora
de outros parâmetros, incluindo rash, alopecia e capacidade
vital forçada. Chung et al.50 trataram 8 pacientes com DM
refratários a múltiplos imunossupressores, 1 deles após
falha com etanercepte, com 2 infusões de rituximabe (1 g
com intervalo de 2 semanas). Três apresentaram melhora da
força muscular, mas não houve mudança significativa das
enzimas musculares e da graduação de lesões cutâneas após
24 semanas de infusão da droga.
Em 2005, Lambotte et al.55 relataram caso de PM que teve
melhora clinicolaboratorial com a aplicação de rituximabe
(375 mg/m2/semana por 4 semanas).
O tratamento (375 mg/m2/semana por 4 semanas) de outros 4 casos de pacientes com PM, que falharam ao tratamento
com corticosteroide e metotrexato⁄azatioprina, foi relatado.
Em análise de 28 semanas após uso da medicação, todos os
pacientes apresentaram melhora da força muscular, com 2
casos atingindo força normal. O nível de creatinoquinase
normalizou e a dose de corticosteroide foi reduzida em todos
os os casos.56
Tocilizumabe
É um anticorpo monoclonal humanizado anti-IL-6. O único
relato de caso na literatura61 descreve 2 pacientes do gênero
masculino com diagnóstico de PM, ambos com anticorpo
anti-Jo-1 positivo. O primeiro, refratário a corticosteroide
(1 mg/kg/dia), azatioprina (100 mg/dia) e ciclosporina
(100−150 mg/dia), recebeu tocilizumabe (8 mg/kg, mensal,
intravenosa). Após cerca de 1 ano de uso da medicação, o
corticosteroide foi suspenso e mantido ciclosporina (100 mg/
dia), com evidência de melhora progressiva da força muscular
e do perfil laboratorial. O segundo paciente foi refratário a
corticoterapia (1 mg/kg/dia), azatioprina, ciclosporina e/ou
metotrexato. Recebeu inicialmente tocilizumabe (8 mg/kg,
mensal, intravenoso), com redução do intervalo para 3 em
108
3 semanas após a 4ª dose. Após 12 ciclos de tocilizumabe, associado ao uso de metotrexato, houve estabilidade
clinicolaboratorial.
Abatacepte
O abatacepte é uma proteína de fusão humana recombinante
que contém o domínio extracelular do CTLA-4, que se liga
ao receptor CD 80/86 de uma célula apresentadora de antígeno. Essa interação bloqueia a ativação do receptor CD 28
na célula T.62
A revisão da literatura revela apenas 1 relato de caso63 de
paciente do gênero feminino, de 51 anos, com PM refratária
à corticosteroide e a metotrexato/azatioprina, que recebeu
abatacepte (750 mg mensal intravenosa). Houve melhora clinicolaboratorial logo ao início do tratamento, com normalização
da creatinoquinase, aldolase e desidrogenase láctica passados
3 meses do início das aplicações, com manutenção de resposta
em 3 anos de seguimento.
CONSIDERAÇÕES FINAIS
Dessa maneira, o uso de imunobiológicos em casos de DM e
PM ainda permanece como fronteira a ser explorada. A revisão da literatura se mostra escassa, com trabalhos pequenos e
não controlados, formados principalmente por relatos e séries
de casos. Os agentes bloqueadores de TNF têm resultados
conflitantes, e há relatos de desenvolvimento de MII durante
o uso desses fármacos. As evidências mais animadoras, até o
momento, vêm da terapia anti-CD-20, com resultados satisfatórios nos trabalhos existentes, mas ainda necessitando de
investigação mais criteriosa. A inibição da IL-6 e o bloqueio
da coestimulação nas MII apresentam apenas raros relatos
anedóticos, dos quais, por enquanto, não é possível tirar
qualquer conclusão.
Assim, a terapia biológica pode ter papel relevante no
tratamento das MII refratárias à terapia convencional; no
entanto, somente com novos estudos prospectivos com base
em parâmetros objetivos de resposta ao tratamento poder -se-á
produzir evidências que justifiquem essa conduta. Até o presente momento, a terapia anti-CD20 parece ser a mais promissora
no tratamento das MII refratárias.
REFERENCES
REFERÊNCIAS
1.
Nyberg P, Wikman AL, Nennesmo I, Lundberg I. Increased
expression of interleukin 1alpha and MHC Class I in muscle tissue
of patients with chronic, inactive polymyositis and dermatomyositis.
J Rheumatol 2000; 27(4):940–8.
20/03/2013 16:26:03
Dermatomiosite e polimiosite: da imunopatologia à imunoterapia (imunobiológicos)
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A,
Pongratz D, et al. Differential expression of perforin in muscleinfiltrating T cells in polymyositis and dermatomyositis. J Clin Invest
1996; 97(12):2905–10.
Emslie-Smith AM, Engel AG. Microvascular changes in early and
advanced dermatomyositis: a quantitative study. Ann Neurol 1990;
27(4):343–56.
Engel AG, Arahata K. Mononuclear cells in myopathies: quantitation
of functionally distinct subsets, recognition of antigen-specific
cell-mediated cytotoxicity in some diseases, and implications for
the pathogenesis of the different inflammatory myopathies. Hum
Pathol 1986; 17(7):704–21.
Botet JC, Grau JM, Casademont J, Urbano-Márquez A, Rozman C.
Characterization of mononuclear exudates in idiopathic inflammatory
myopathies. Virchows Arch A Pathol Anat Histopathol 1988;
412(4):371–4.
Dalakas MC. The future prospects in the classification, diagnosis and
therapies of inflammatory myopathies: a view to the future from the
‘bench-to-bedside’. J Neurol 2004; 251(6):651–7.
Noss EH, Hausner-Sypek DL, Weinblatt M. Rituximab as therapy
for refractory polymyositis and dermatomyositis. J Rheumatol 2006;
33(5):1021–6.
Kuru S, Inukai A, Kato T, Liang Y, Kimura S, Sobue G. Expression
of tumor necrosis factor-alpha in regenerating muscle fibers in
inflammatory and non-inflammatory myopathies. Acta Neuropathol
2003; 105(3):217–24.
Lundberg IE, Nyberg P. New developments in the role of cytokines in
inflammatory myopathies. Curr Opin Rheumatol 1998; 10(6):521–9.
Prieur AM, Dayer A, Roux-Lombard P, Dayer JM. Levels of
cytokine inhibitors: a possible marker of disease activity in childhood
dermatomyositis and polymyositis. Clin Exp Rheumatol 1997;
15(2):211–4.
Werth VP, Callen JP, Ang G, Sullivan KE. Associations of
tumor necrosis factor alpha and HLA polymorphisms with adult
dermatomyositis: implications for a unique pathogenesis. J Invest
Dermatol 2002; 119(3):617–20.
Shimizu T, Tomita Y, Son K, Nishinarita S, Sawada S, Horie T.
Elevation of serum soluble tumour necrosis factor receptors in
patients with polymyositis and dermatomyositis. Clin Rheumatol
2000; 19(5):352–9.
Tateyama M, Nagano I, Yoshioka M, Chida K, Nakamura S,
Itoyama Y. Expression of tumor necrosis factor-alpha in muscles of
polymyositis. J Neurol Sci 1997; 146(1):45–1.
Lundberg I, Brengman JM, Engel AG. Analysis of cytokine
expression in muscle in inflammatory myopathies, Duchenne
dystrophy, and non-weak controls. J Neuroimmunol 1995;
63(1):6–16.
Lundberg IE, Barbasso S, Ulfgren AK, Gracie JA, McInnes IB.
Expression of IL-18 in muscle tissue of patients with treatment
resistant idiopathic inflammatory myopathies. Arthritis Res Ther
2005; 7(Suppl 1):P57.
Lundberg I, Ulfgren AK, Nyberg P, Andersson U, Klareskog L.
Cytokine production in muscle tissue of patients with idiopathic
inflammatory myopathies. Arthritis Rheum 1997; 40(5):865–74.
Lepidi H, Frances V, Figarellla-Branger D, Bartoli C, MachadoBaeta A, Pellissier JF. Local expression of cytokines in idiopathic
inflammatory myopathies. Neuropathol Appl Neurobiol 1998;
24(1):73–9.
18. Garcia-Martínez C, Agell N, Llovera M, López-Soriano FJ,
Argilés JM. Tumor necrosis factor-alpha increases the ubiquitinization
of rat skeletal muscle proteins. FEBS Lett 1993; 323(3):211–4.
19. Grundtman C, Salomonsson S, Dorph C, Bruton J, Andersson U,
Lundberg IE. Immunolocalization of interleukin-1 receptors in the
sarcolemma and nuclei of skeletal muscle in patients with idiopathic
inflammatory myopathies. Arthritis Rheum 2007; 56(2):674–87.
20. Fall N, Bove KE, Stringer K, Lovell DJ, Brunner HI, Weiss J, et al.
Association between lack of angiogenic response in muscle tissue
and high expression of angiostatic ELR-negative CXC chemokines in
patients with juvenile dermatomyositis: possible link to vasculopathy.
Arthritis Rheum 2005; 52(10):3175–80.
21. Okiyama N, Sugihara T, Iwakura Y, Yokozeki H, Miyasaka N,
Kohsaka H. Therapeutic effects of interleukin-6 blockade in a murine
model of polymyositis that does not require interleukin-17A. Arthritis
Rheum 2009; 60(8):2505–12.
22. Bilgic H, Ytterberg SR, Amin S, McNallan KT, Wilson JC,
Koeuth T, et al. Interleukin-6 and type I interferon-regulated genes
and chemokines mark disease activity in dermatomyositis. Arthritis
Rheum 2009; 60(11):3436–46.
23. De Paepe B, De Keyzer K, Martin JJ, De Bleecker JL. Alphachemokine receptors CXCR1-3 and their ligands in idiopathic
inflammatory myopathies. Acta Neuropathol 2005; 109(6):576–82.
24. Caproni M, Torchia D, Cardinali C, Volpi W, Del Bianco E,
D’Agata A, et al. Infiltrating cells, related cytokines and chemokine
receptors in lesional skin of subjects with dermatomyositis. Br J
Dermatol 2004; 151(4):784–91.
25. Murata K, Dalakas MC. Expression of the costimulatory molecule
BB-1, the ligands CTLA-4 and CD28, and their mRNA in
inflammatory myopathies. Am J Pathol 1999; 155(2):453–60.
26. Behrens L, Kerschensteiner M, Misgeld T, Goebels N, Wekerle H,
Hohlfeld R. Human muscle cells express a functional costimulatory
molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in
inflammatory lesions. J Immunol 1998; 161(11):5943–51.
27. Lipsky PE, van der Heijde DM, St. Clair EW, Furst DE,
Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the
treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial
in Rheumatoid Arthritis with Concomitant Therapy Study Group. N
Engl J Med 2000; 343(22):1594–602.
28. Hengstman G, Van Den Hooven F, Barrera P, Netea MG, Pieterse A,
van de Putte LB, et al. Successful treatment of dermatomyositis and
polymyositis with anti-tumor-necrosis-factor-alpha preliminary
observations. Eur Neurol 2003: 50(1):10–5.
29. Labioche I, Liozon E, Weschler B, Loustaud-Ratti V, Soria P, Vidal E.
Refractory polymyositis responding to infliximab: extended followup. Rheumatology (Oxford) 2004; 43(4):531–2.
30. Uthman I, El-Sayad J. Refractory polymyositis responding to
infliximab. Rheumatology (Oxford) 2004; 43(9):1198–9.
31. Anandacoomarasamy A, Howe G, Manolios N. Advanced refractory
polymyositis responding to infliximab. Rheumatology (Oxford)
2005; 44(4):562–3.
32. Dold S, Justiniano ME, Marquez J, Espinoza LR. Treatment of early
and refractory dermatomyositis with infliximab: a report of two cases.
Clin Rheumatol 2007; 26(7):1186–8.
33. Musial J, Undas A, Celinska-Lowenhoff M. Polymositis associated
with infliximab treatment for rheumatoid arthritis. Rheumatology
(Oxford) 2003; 42(12):1566–8.
109
20/03/2013 16:26:03
Shinjo et al.
34. Hengstamn GJ, De Bleeker JL, Feist E, Vissing J, Denton CP,
Manoussakis MN, et al. Open-label trial of anti-TNF-alpha in
dermato and polymositis treated concomitantly with methotrexate.
Eur Neurol 2008; 59(3−4):159–63.
35. Dastmalchi M, Grundtman C, Alexanderson H, Mavragani CP,
Einarsdottir H, Helmers SB, et al. A high incidence of disease
flares in an open pilot study of infliximab in patients with
refractory infl ammatory myopathies. Ann Rheum Dis 2008;
67(12):1670–7.
36. Miller FW, Leitman SF, Cronin ME, Hicks JE, Leff RL, Wesley R,
et al. Controlled trial of plasma exchange and leukapheresis
in polymyositis and dermatomyositis. N Engl J Med 1992;
326(21):1380–4.
37. Sprott H, Glatzel M, Michel BA. Treatment of myositis with
etanercept (Enbrel), a recombinant human soluble fusion protein
of TNFα type II receptor and IgG1. Rheumatology (Oxford) 2004;
43(4):524–6.
38. Iannone F, Scioscia C, Falappone PCF, Covelli M, Lapadula G. Use
of Etanercept in the Treatment of Dermatomyositis: A Case Series.
J Rheumatol 2006; 33(9):1802–4.
39. Efthimiou P, Schwartzman S, Kagen LJ. Possible role for tumour
necrosis factor inhibitors in the treatment of resistant dermatomyositis
and polymyositis: a retrospective study of eight patients. Ann Rheum
Dis 2006; 65(9):1233–6.
40. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH,
Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis
factor alpha monoclonal antibody, for the treatment of rheumatoid
arthritis in patients taking concomitant methotrexate: the ARMADA
trial. Arthritis Rheum 2003; 48(1):35–45.
41. Nagashima T, Minota S. Dermatomyositis in patients with rheumatoid
arthritis during adalimumab therapy. J Rheumatol 2011; 38(3):574.
42. Klein R, Rosenbach M, Kim EJ, Kim B, Werth VP, Dunham J. Tumor
necrosis factor inhibitor-associated dermatomyositis. Arch Dermatol
2010; 146(7):780–4.
43. Brunasso AM, Scocco GL, Massone C. Dermatomyositis during
adalimumab therapy for rheumatoid arthritis. J Rheumatol 2010;
37(7):1549–50.
44. Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana D,
Bertolaccini L, et al. Autoimmune diseases induced by TNFtargeted therapies: analysis of 233 cases. Medicine (Baltimore)
2007; 86(4):242–51.
45. Souza FH, Levy-Neto M, Shinjo SK. Adalimumab inducedinflammatory myopathy in rheumatoid arthritis. Acta Reumatol
Port 2011 (in press).
46. Liozon E, Ouattara B, Loustaud-Ratti V, Vidal E. Severe polymyositis
and flare in autoimmunity following treatment with adalimumab in
a patient with overlapping features of polyarthritis and scleroderma.
110
47. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH,
Keystone EC, et al. A comparison of etanercept and methotrexate
in patients with early rheumatoid arthritis. N Engl J Med 2000;
343(22):1586–93.
48. Levine TD. Rituximab in the treatment of dermatomyositis: an openlabel pilot study. Arthritis Rheum 2005; 52(2):601–7.
49. Chiappetta N, Steier J, Gruber B. Rituximab in the treatment of
refractory dermatomyositis. J Clin Rheumatol 2005; 11(5):264–6.
50. Chung L, Genovese MC, Fiorentino DF. A pilot trial of rituximab
in the treatment of patients with dermatomyositis. Arch Dermatol
2007; 143(6):763–7.
51. Feist E, Dörner T, Sörensen H, Burmester GR. Longlasting
remissions after treatment with rituximab for autoimmune myositis.
J Rheumatol 2008; 35(6):1230–1.
52. Yañez VJ, Cisternas MM, Saldías VH, Saldías PF. Dermatomiositis
refractaria asociada a neumonía en organización tratada con
rituximab. Reporte de um caso. Rev Med Chile 2009; 137(1):88–93.
53. Ramón SS, Ravell JC, la Torre I. Long-term remission of severe
refractory dermatopolymyositis with a weekly-scheme of
immunoglobulin followed by rituximab therapy. Rheumatol Int
2010; 30(6):817–9.
54. Lee MA, Hutchinson DG. Spontaneous pneumomediastinum
secondary to refractory dermatomyositis successfully treated with
rituximab. Clin Rheumatol 2010; 29(8):945–6.
55. Lambotte O, Kotb R, Maigne G, Blanc FX, Goujard C, Delfraissy JF.
Efficacy of rituximab in refractory polymyositis. J Rheumatol 2005;
32(7):1369–70.
56. Mok CC, Ho LY, To CH. Rituximab for refractory polymyositis:
an open-label prospective study. J Rheumatol 2007; 34(9):1864–8.
57. Christopher-Stine L, Plotz PH. Adult inflammatory myopathies. Best
Pract Res Clin Rheumatol 2004; 18(3):331–44.
58. Rider LG, Miller FW. Laboratory evaluation of the inflammatory
myopathies. Clin Diagn Lab Immunol 1995; 2(1):1–9.
59. Eisenstein DM, O’Gorman MR, Pachman LM. Correlations
between change in disease activity and changes in peripheral blood
lymphocyte subsets in patients with juvenile dermatomyositis. J
Rheumatol 1997; 24(9):1830–2.
60. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body
myositis. N Engl J Med 1991; 325(21):1487–98.
61. Narazaki M, Hagihara K, Shima Y, Ogata A, Kishimoto T, Tanaka T.
Therapeutic effect of tocilizumab on two patients with polymyositis.
Rheumatology (Oxford) 2011; 50(7):1344–6.
62. Mease PJ. In: Klippel JH, Stone JH, Crofford LJ, White PH
(eds.). Primer on the Rheumatic Diseases. 3.ed. Springer/Arthritis
Foundation; 2008.
63. Musuruana JL, Cavallasca JA. Abatacept for treatment of refractory
polymyositis. Joint Bone Spine 2011; 78(4):431–2.
20/03/2013 16:26:03
CA SE REPO RT
Concurrent rheumatoid arthritis and ankylosing
spondylitis in one patient: the importance of
new classification criteria
Valderilio Feijó Azevedo1, Pedro Grachinski Buiar2
ABSTRACT
We report the case of concomitant ankylosing spondylitis and rheumatoid arthritis in a 65-year-old Caucasian male,
who had symmetric polyarthritis with erosion of the metacarpophalangeal joint on conventional X-ray, inflammatory
low back pain with HLA-B27 positivity, and sacroiliitis. Laboratory analysis showed high levels of rheumatoid factor
and anti-cyclic citrullinated peptide antibody (anti-CCP). Clinical features of previously reported cases were compared
with those of our case. This is the first case report on the coexistence of both diseases in the same patient, for whom antiCCP testing and the latest versions of axial ASAS criteria and ACR/EULAR criteria for the classification of ankylosing
spondylitis and rheumatoid arthritis, respectively, were used.
Keywords: rheumatoid arthritis, spondylitis ankylosing, disease classification, rheumatoid factor, HLA antigens.
INTRODUCTION
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS)
are chronic and progressive inflammatory joint diseases that
lead to joint damage and functional disability. In the past,
AS was included in the RA spectrum and considered an
axial variant of that. Since the 1950s, when the rheumatoid
factor (RF) ‘appeared’, several different characteristics have
been established to differentiate those two rheumatologic
disorders.1 Currently, each disease has its own well-defined
diagnostic criteria. To such criteria, laboratory tests that
identify antibodies and genes related to each disease, such as
HLA-DR4 and HLA-B27, have been added. The anti-cyclic
citrullinated peptide antibody (anti-CCP), currently used
in the diagnosis of RA, has been the main focus of studies.
Coexistence of RA and AS in the same patient is rare. Of the
almost 50 cases described in the literature, a large number
was reported more than 30 years ago, when specific laboratory tests were not available and the classification criteria of
both diseases were still largely debated.
Many of those cases have been published as an extremely
rare occurrence.2–4 In 1979, Major et al.2 reported 2 cases and
commented on 21 others that had already been described in
the English literature. In 1995, Toussirot et al.3 reported 3
more cases and, reviewing the literature, found 44 previous
cases. Since then, some more cases have been added, but the
frequency of their report has decreased. In this article, we report
the diagnosis of RA and AS in the same patient by using the
ASsessment in Ankylosing Spondylitis (ASAS) group criteria
for axial AS and the 2010 American College of Rheumatology/
European League Against Rheumatism (ACR/EULAR) criteria along with anti-CCP testing for RA, which had not been
performed in previous reports. Among the updated 2010 ACR/
EULAR criteria for RA, anti-CCP testing is worthy of note.5
CASE REPORT
The patient is a 65-year-old retired Caucasian male, long-time
smoker and alcohol drinker, who was admitted due to polyarthralgia and weight loss (5 kg in approximately 1.5 month).
Universidade Federal do Paraná – UFPR.
1. Assistant Professor of Rheumatology, Universidade Federal do Paraná – UFPR
2. Medical school student, UFPR; Academic Coordinator, Scientific Initiation in Spondyloarthritis
Correspondence to: Valderilio Feijó Azevedo. Rua Lamenha Lins, 1110, ap. 11 – Rebouças. CEP: 80220-080. Curitiba, PR, Brazil. E-mail: [email protected]
111
20/03/2013 16:26:03
Azevedo et al.
The patient reported low back and chest pain initiated approximately 1 year and 4 months before, which worsened at night
and improved with physical activities, in addition to morning
stiffness for approximately 40 minutes. He also complained
of mild pain in his right tarsal joints and right knee, with no
edema associated, and that, two months before admission,
moderate pain initiated on mobilization of both elbows and
metacarpophalangeal joints. He denied cough, night sweating
and fever in the period. He also denied any similar previous
history, urethritis, intestinal symptoms or even a previous
diagnosis of rheumatic disorder.
On physical examination, the patient was lucid and oriented, with a facial expression of pain. His general state of
health was good. His cervical spine was stiff and had bilateral
limited mobility (< 45o). On palpation, his lumbar spine was
painful at the L3-L5 level. Schöber’s tests, 10.0–11.6 cm; chest
expandability, 2.1 cm; occipital-wall distance, 0 cm. His shoulders and elbows evidenced, bilaterally, an increase in volume
and temperature, and limited mobility (extension). Both hands
showed Bouchard and Herberden nodules, and atrophy of the
interosseous muscles. His knees were tender on palpation and
clicked with motion. A small erythematous cutaneous lesion
was identified on the right knee, and was biopsied. No nodules
were identified. His blood pressure was 145x95 mm Hg, heart
rate, 125 bpm, and respiratory rate, 20 rpm. His laboratory
exams were as follows: erythrocyte sedimentation rate (ESR),
111 mm/1h (up to 32.5 mm/1h); C-reactive protein (CRP),
9 mg/dL (normal: 0.5 mg/dL); hematocrit, 36.2%; hemoglobin,
11 g/dL; platelets, 429,000/mm3; leukocytes, 8120/mm3; RF,
633 IU/mL. Radiographies of the sacroiliac and lumbar spinal
joints evidenced sclerosis of the sacroiliac joints bilaterally
without erosions (grade 2), more evident on the right side, and
syndesmophytes on L4 and L5 (Figure 1a). The biopsy of the
skin lesion of the right knee revealed superficial perivascular
chronic dermatitis, whose cause was not established, and not
compatible with a psoriatic lesion. The exam was positive for
HLA-B27. The patient was discharged following improvement
after treatment with non-steroidal anti-inflammatory drugs
and sulfasalazine. His scores were as follows: BASFI = 6.5;
BASDAI = 5.8; DAS-28 = 5.5.
The patient returned only after one year, reporting general
improvement of the pain in his knees, shoulders and hands. He
also reported mild pain on the left second and third fingers two
months before. The physical examination then showed the following: edema of the right second metacarpophalangeal joint,
left second and third metacarpophalangeal joints and left elbow; pain on bone palpation of all metacarpophalangeal joints;
edema and pain on palpation of the left acromioclavicular
112
joint; increased volume and pain of the left second, third and
fourth metacarpophalangeal joints; and increased volume of
the right second metatarsophalangeal joint. His laboratory
findings were as follows: RF, 526 IU/mL; CRP, 4.64 mg/
dL; and ESR, 42 mm/1h. Radiography of his hands showed
mild erosion of the right first metacarpophalangeal joint,
reduced joint space, and reduced juxta-articular bone density
(Figure 1b). The anti-CCP antibody titer was 525 (strong
positivity > 60 Au).
His 2010 ACR/EULAR score for RA was 8 (positive
diagnosis). At the time, the patient was diagnosed with RA
and AS, and the following drugs were prescribed: diclofenac
(150 mg/day), prednisone (7.5 mg/day) and methotrexate
(15 mg/week). Currently, the patient is being followed up
on the outpatient clinic, with indication for treatment with a
biologic agent (tumor necrosis factor inhibitor – anti-TNF).
Figure 1
(A) Discrete erosion of the right first metacarpophalangeal
joint, reduced joint space, and decreased juxta-articular
bone density. (B) Sclerosis of the sacroiliac joints bilaterally
without erosions, more evident at the right side (grade 2), and
syndesmophytes on L4 and L5.
20/03/2013 16:26:03
Concurrent rheumatoid arthritis and ankylosing spondylitis in one patient: the importance of new classification criteria
DISCUSSION
Physiopathological, clinical and diagnostic differences between RA and AS have been well established. Rheumatoid arthritis has prevalence of 1%–2% in the Caucasian population
and is associated with the HLA-DR4 or DR1 genes (present
in 60% of the patients).6 Its incidence peaks between the ages
of 40 and 70 years, and RA is more prevalent in the female
sex. Ankylosing spondylitis has prevalence of 0.2%–0.9% in
the Caucasian population and is associated with the HLA-B27
gene (present in approximately 95% of individuals with
AS).7–9 Although our patient can be considered elderly, AS
has an incidence peak between the ages of 20 and 45 years,
showing male predominance.7 Rarely it occurs at more advanced ages. Although HLA-B27 has gained importance, in
the genetic group with that histocompatibility antigen, the
risk of developing AS is lower than 50%.9
Rheumatoid arthritis usually manifests as symmetric
polyarthritis that affects the small joints of the hands and feet,
metacarpophalangeal, metatarsophalangeal, and proximal
interphalangeal joints, rarely affecting entheses. It can affect the cervical spine. However, AS occurs most often as an
inflammatory low back pain, which can be accompanied by
enthesitis and asymmetrical oligoarthritis, preferably of axial
and large joints, such as shoulders, hips and knees, its major
characteristic being the involvement of the sacroiliac joints,
and, at advanced stages, vertebral ankylosis at all levels.10
The most common extra-articular manifestations of RA
are subcutaneous nodules, keratoconjunctivitis sicca, pleural and pericardial involvement, and vasculitis. Ankylosing
spondylitis, however, can manifest as psoriasis, acute anterior
uveitis, fibrosis of the pulmonary apex, inflammatory bowel
disease, heart valve problems, and heart electrical conduction
disorders.11 Aggravation of gastrointestinal lesions and peptic
ulcers with the use of non-steroidal anti-inflammatory drugs
and disease-modifying antirheumatic drugs (DMARDs) is
common in both diseases.12
In RA, there is evidence of bone resorption in the form of
erosions. In AS, there is bone erosion associated with bone
neoformation in the form of syndesmophytes. It is worth noting that finding bilateral sacroiliitis is highly suggestive of AS.
In our patient’s case, the radiologic findings of juxta-articular
osteopenia, erosion of the right first metacarpophalangeal joint,
and bilateral sacroiliitis with syndesmophytes on L4 and L5
supported both diagnoses.
The CRP and ESR levels are parameters frequently used
to show inflammatory activity, being also criteria for the
clinical activity monitoring of both diseases, being elevated
in most patients with active RA, but also in 50%–60% of the
patients with active AS.13 The RF is almost always present in
patients with RA (around 70%–90%), and their levels can be
directly correlated with disease severity. Nevertheless, the RF
is not specific, being also present in a series of other clinical
conditions. Although 10%–15% of the patients with spondyloarthritis might have RF, their titers are usually lower,6 unlike
this case, whose titers were elevated. A extremely specific test
developed at the end of the 1970s is anti-CCP antibody testing. Although present in only 67% of the patients with RA,
according to the meta-analysis carried out in 2005 by Visser,14
a positive result is highly specific (> 96%) for the diagnosis
of RA. It is currently considered the most specific marker for
the diagnosis of RA, as recently reported by Zhao et al.15 AntiCCP antibodies and RF are not usually found in patients with
AS.6 Our patient had high titers of RF and anti-CCP antibodies associated with the arthritis of the hands, feet and elbows,
indicating RA concomitant with AS, HLA-B27 positive, with
inflammatory low back pain and sacroiliitis.
The classification criteria for RA have been recently reviewed by the ACR and the EULAR.5 According to the new
ACR/EULAR classification (2010) for RA, patients have to
add 6 points of some characteristics, considering that they
have at least one synovitis not explained by another disease.
According to such classification criteria for RA, our patient
had the involvement of 2 large and 3 small joints, high titers of
RF and anti-CCP antibodies, abnormal CRP and ESR levels,
and symptoms for over 6 weeks. Considering all that, his total
score was 8, and he could be classified as having RA.
According to the modified New York criteria for AS, our patient had bilateral sacroiliitis (grade 2, right side), characteristic
inflammatory low back pain, and reduced low back mobility
and chest expandability. Furthermore, according to the ASAS
classification criteria for axial spondyloarthritis, our patient
had his diagnosis confirmed by being HLA-B27 positive and
having sacroiliitis, in addition to inflammatory low back pain
and high CRP levels.
Based on the criteria cited, our patient can be classified as
having both diseases: RA and AS. According to the literature,
45 cases of the concomitance of both diseases have been
reported.3
Most of the previous reports have used clinical data and
not all have assessed the presence of either HLA-B27 to support the hypothesis of AS or RF to support the hypothesis of
RA (Table 1). Toussirot et al.3 have reported a prevalence of
6.6% of HLA B27-positive patients with RA and of 8.3% of
RF-positive patients with AS versus a prevalence of 9.8% of
controls, although the results had no statistical significance.
113
20/03/2013 16:26:04
Azevedo et al.
Table 1
Review of the reports about patients with concomitant rheumatoid arthritis and ankylosing spondylitis
Reference
First symptom
(n of cases)
Nodules
PEA
RF
HLA-DR4
Anti-CCP
Low back
pain
Sacroiliitis
Syndesmophytes
HLA-B27
Rosenthal et al.
Low back pain (1)
+
ND
+
ND
ND
+
+
+
ND
Rotés Querol
et al.
Low back pain (7)
2+
3+
7+
ND
ND
7+
7+
2+
7+
Luthra et al.
Low back pain (2)
2+
2+
2+
ND
ND
2+
2+
2+
2+
Good et al.
Low back pain (3)
0+
3+
3+
ND
ND
3+
3+
3+
3+
Fallet et al.
Low back pain (5)
Polyarthritis (7)
Oligoarthritis (1)
Cervical pain (1)
Iritis (1)
6+
14+
15+
7+
ND
11+
15+
11+
15+
Clayman et al.
Low back pain (1)
+
+
+
ND
ND
+
+
+
+
Espinoza et al.
Low back pain (1)
+
+
+
ND
ND
+
+
+
+
Major et al.
Low back pain (2)
Low back pain (1)
Polyarthritis (1)
ND (3)
1+; 5 ND 7+
7+
3+; 2 ND
ND
2+; 5 ND
7+
2+; 3 ND
5+
Lavery et al.
Low back
trauma (1)
+
+
+
ND
ND
+
+
+
+
AlarcónSegovia et al.
Low back pain (1)
+
+
+
+
ND
+
+
+
+
Sattar et al.
Polyarthritis (1)
−
+
+
+
ND
+
+
+
+
Helfgott et al.
Low back pain (1)
+
+
+
+
ND
+
+
+
+
Martinez et al.
Oligoarthritis (1)
−
+
+
+
ND
+
+
+
+
Toussirot et al.
Polyarthritis (2)
Cervical pain (1)
1+
2+;
1 ND
2+
0+
ND
3+
+
1+
1+; 2 ND
Genc et al.
Polyarthritis (1)
−
+
−
−
ND
+
+
+
+
Our report
Low back pain (1)
−
+
+
ND
+
+
+
+
+
Total: 47 cases
Low back pain (18)
Low back pain (8)
Polyarthritis (12)
Oligoarthritis (2)
Cervical pain (2)
Low back trauma (1)
Iritis (1)
ND (3)
21+
40+
45+
10+
1+
38+
45+
31+
42+
(+ ): presence of the item/symptom; (–) : absence of the item/symptom; (ND ): presence/absence of the item not specified by the author; P EA: peripheral erosive arthritis; RF: rheumatoid factor.
F* or this review table, only articles published in English were considered.
This is the first case report using the last updates of the AC R/ EULAR
and the ASAS classification criteria for RA and AS, respectively, and anti-C C P antibody testing. W e consider appropriate
that future reports about the concomitance of RA and AS use anti-C C P testing in addition to the latest criteria for the diagnosis and classification of that rare association.
114
20/03/2013 16:26:04
Azevedo et al.
Tabela 1
Revisão dos relatos publicados de pacientes com artrite reumatoide e espondilite anquilosante de ocorrência simultânea
Referência
Primeiro sintoma
(nº de casos)
Nódulos
AEP
FR
HLA-DR4
Anti-CCP
Dor lombar Sacroiliíte
Sindesmófitos
HLA-B27
Rosenthal et al.
Dor lombar baixa (1)
+
ND
+
ND
ND
+
+
+
ND
Rotés Querol
et al.
Dor lombar (7)
2+
3+
7+
ND
ND
7+
7+
2+
7+
Luthra et al.
Dor lombar (2)
2+
2+
2+
ND
ND
2+
2+
2+
2+
Good et al.
0+
3+
3+
ND
ND
3+
3+
3+
3+
Fallet et al.
Dor lombar (5)
Poliartrite (7)
Oligoartrite (1)
Dor cervical (1)
Irite (1)
6+
14+
15+
7+
ND
11+
15+
11+
15+
Clayman et al.
+
+
+
ND
ND
+
+
+
+
Espinoza et al.
+
+
+
ND
ND
+
+
+
+
Major et al.
Dor lombar (2)
Poliartrite (1)
ND (3)
1+;
5 ND
7+
7+
3+; 2 ND
ND
2+; 5 ND
7+
2+; 3 ND
5+
Lavery et al.
Trauma lombar (1)
+
+
+
ND
ND
+
+
+
+
AlarcónSegovia et al.
+
+
+
+
ND
+
+
+
+
Sattar et al.
Poliartrite (1)
−
+
+
+
ND
+
+
+
+
Helfgott et al.
Dor lombar (1)
+
+
+
+
ND
+
+
+
+
Martinez et al.
Oligoartrite (1)
−
+
+
+
ND
+
+
+
+
Toussirot et al.
Poliartrite (2)
Dor cervical (1)
1+
2+;
1 ND
2+
0+
ND
3+
+
1+
1+;
2 ND
Genc et al.
Poliartrite (1)
−
+
−
−
ND
+
+
+
+
Nosso relato
Dor lombar (1)
−
+
+
ND
+
+
+
+
+
Total: 47 casos
Dor lombar (18)
Poliartrite (12)
Oligoartrite (2)
Dor cervical (2)
Trauma lombar (1)
Irite (1)
ND (3)
21+
40+
45+
10+
1+
38+
45+
31+
42+
(+ ): presença do item/sintoma; (–) : ausên cia do item/sintoma ; (ND ): presenç a/ausê ncia do item não especificado pelo autor; AEP : artrite erosiva perifér ica; FR: fator reumatoide.
a*P ra esta tabela de revisão, desconsideramos os artigos não publicados em lí ngua inglesa.
Este é o primeiro relato de caso em que foram usadas as ú ltimas atualiz aç ões dos critér ios de classificaç ã o do AC R/ EULAR
e grupo ASAS para AR e EA, e teste laboratorial para dosagem do anti-C C P .
Con sideramos adequado que futuros relatos de concomitân cia de AR e EA possam utiliz ar a dosagem do anti-C C P , alé m de crité rios mais atualiz ados para o diagnó stico e classificaç ã o desta rara ocorrê ncia.
REFERENCES
4.
REFERÊNCIAS
1.
2.
3.
Benedek TG. How did ankylosing spondylitis become a separate
disease? Clin Exp Rheumatol 2009; 27(4 Suppl 55):S3–9.
Major P, Resnick D, Dalinka M, Kline P. Coexisting rheumatoid
arthritis and ankylosing spondylitis. AJR Am J Roentgenol 1980;
134(5):1076–9.
Toussirot E, Acquaviva PC. Coexisting rheumatoid arthritis and
ankylosing spondylitis discussion of 3 cases with review of the
literature. Clin Rheumatol 1995; 14(5):554–60.
118
5.
6.
Fallet GH, Mason M, Berry H, Mowat A, Boussina I, Gerster JC.
Coexistence of rheumatoid arthritis and ankylosing spondylitisreport of 10 cases. J Rheumatol Suppl 1977; 3:70–3.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham
CO, et al. 2010 Rheumatoid arthritis classification criteria: an
American College of Rheumatology/European League Against
Rheumatism collaborative initiative. Arthritis Rheum 2010;
62(9):2569–81
van der Horst-Bruinsma IE, Lems WF, Dijkmans BA. A systematic
comparison of rheumatoid arthritis and ankylosing spondylitis.
Clin Exp Rheumatol 2009; 27(4 Suppl 55):S43–9.
20/03/2013 16:26:06
Concomitância de artrite reumatoide e espondilite anquilosante em um único paciente: importância dos novos critérios de classificação
7.
van der Linden SM, Valkenburg HA, de Jongh BM, Cats A. The
risk of developing ankylosing spondylitis in HLA-B27 positive
individuals. A comparison of relatives of spondylitis patients with
the general population. Arthritis Rheum 1984; 27:241–9.
8. Will R, Edmunds L, Elswood J, Calin A. Is there a sexual inequality
in ankylosing spondylitis? A study of 498 women and 1202 men.
J Rheumatol 1990; 17:1649–52.
9. Maksymowych WP, Brown MA. Genetics of ankylosing
spondylitis and rheumatoid arthritis: where are we at currently,
and how do they compare? Clin Exp Rheumatol 2009; 27(4 Suppl
55):S20–5.
10. Khan MA. Ankylosing spondylitis: clinical aspects. The
spondylarthritis. A. Calin, Taurog J (eds.). Oxford University
Press, 1998.
11. H e e n e m a n S , D a e m e n M J . C a r d i o v a s c u l a r r i s k s i n
spondyloarthritides. Curr Opin Rheumatol 2007; 19(4):358–62.
12. de Leest H, van Dieten H, van Tulder M, Lems WF, Dijkmans BA,
Boers M. Costs of treating bleeding and perforated peptic ulcers
in The Netherlands. J Rheumatol 2004; 31:788–91.
13. Spoorenberg A, van der Heijde D, de Klerk E, Dougados M,
de Vlam K, Mielants H, et al. Relative value of erythrocyte
sedimentation rate and C-reactive protein in assessment of disease
activity in ankylosing spondylitis. J Rheumatol 1999; 26(4):980–4.
14. Visser H. Early diagnosis of rheumatoid arthritis. Best Pract Res
Clin Rheumatol 2005; 19(1):55–72.
15. Zhao J, Liu X, Wang Z, Liu R, Li Z. Is it necessary to combine
detection of anticitrullinated protein antibodies in the diagnosis of
rheumatoid arthritis? J Rheumatol 2010; 37(12):2462−5.
119
20/03/2013 16:26:06
CA SE REPO RT
Thrombotic thrombocytopenic purpura at
presentation of juvenile systemic lupus
erythematosus patients
Lucia M. A. Campos1, Maria Silvia Spadoni2, Cintia M. Michelin3,
Adriana A. Jesus1, Jorge D. A. Carneiro1, Clovis Artur Almeida da Silva4
ABSTRACT
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening hematological abnormality characterized by
thrombocytopenia and microangiopathic hemolytic anemia, with neurological abnormalities and/or renal disease. TTP
has been rarely reported in juvenile systemic lupus erythematosus (JSLE) patients and, to our knowledge, its prevalence
in a paediatric lupus population has not been studied. Therefore, from January 1983 to December 2010, we reviewed
the charts of 5,508 patients followed-up at the Paediatric Rheumatology Unit of our university hospital. We identified
279 (5.1%) JSLE cases that met the American College of Rheumatology classification criteria. Two (0.7%) of them had
TTP, both at JSLE onset, and were described herein. Both patients had fever, microangiopathic hemolytic anemia (with
schistocytes in blood smears), and thrombocytopenia. The male patient had hemiparesis and proteinuria and the female
patient had persistent headache and hematuria. Both were treated with intravenous methylprednisolone and courses of
plasma exchange therapy at TTP diagnosis. After treatment, TTP did not recur and their hematocrit, platelet count, and
lactic dehydrogenase remained normal. In conclusion, TTP is a rare and severe manifestation at JSLE onset. The case
reports reinforce the importance of early diagnosis and early aggressive treatment for patients with TTP, due to its high
morbidity.
Keywords: thrombotic thrombocytopenic purpura, systemic lupus erythematosus, child, plasmapheresis.
INTRODUCTION
Juvenile systemic lupus erythematosus (JSLE) is the prototype
of autoimmune disease and may affect multiple organs and
systems. Hematologic abnormalities, such as anemia, leukopenia, thrombocytopenia, and clotting defects, are well-known
characteristics of this disease.1
Thrombotic thrombocytopenic purpura (TTP) is a rare
and life-threatening disease. This hematological disorder is
characterized by thrombocytopenia, microangiopathic hemolytic anemia, and neurological and/or renal abnormalities.2–5
Remarkably, it is a microvascular occlusive disorder, with fragmented blood cells and schistocytes in the peripheral blood.3
TTP has been rarely reported in JSLE patients.2–9 This
manifestation may occur before lupus diagnosis2, at presentation,3,4,6–8 or during the course of the disease.5,9 However, to
our knowledge, the prevalence of this severe manifestation in
paediatric lupus population has not been studied.
Therefore, we reviewed our data from January 1983 to
December 2010 and included the 5,508 patients of Paediatric
Rheumatology Unit, Instituto da Criança, Faculdade de
Medicina, Universidade de São Paulo. We identified 279
Received on 05/15/2011. Accepted on 11/26/2012. The authors declare no conflict of interest. Financial Support: Fundação de Amparo à Pesquisa do Estado de
São Paulo (FAPESP – grant 08/58238 to Clovis Artur Almeida da Silva), Conselho Nacional de Desenvolvimento Científico – CNPQ (300248/2008-3 to Clovis
Artur Almeida da Silva), and Federico Foundation to Clovis Artur Almeida da Silva.
Paediatric Rheumatology and Haematology Units, Instituto da Criança; Division of Rheumatology, Fundação Pró-Sangue/Hemocentro de São Paulo, Hospital
das Clínicas, Faculdade de Medicina da Universidade São Paulo, and Centro de Hematologia de São Paulo, São Paulo, Brazil.
1. PhD in Sciences, Faculdade de Medicina, Universidade de São Paulo – FMUSP
2. Medical Student, Pontifícia Universidade Católica de São Paulo/Sorocaba – PUC-Sorocaba
3. Post-graduation Student of Medicine, FMUSP
4. Head of the Paediatric Rheumatology Unit with Habilitation Thesis, Instituto da Criança, Hospital das Clínicas – ICr-HC-FMUSP
Correspondence to: Prof. Clovis Artur Silva. Rua Araioses, 152/81 – Vila Madalena. CEP: 05442-010. São Paulo, SP, Brazil. E-mail: [email protected]
120
20/03/2013 16:26:06
Thrombotic thrombocytopenic purpura at presentation of juvenile systemic lupus erythematosus patients
(5.1%) cases that met the American College of Rheumatology
(ACR)10 classification criteria for JSLE. Two (0.7%) of
them had TTP at presentation of JSLE and were described
herein. These case reports were approved by the Local Ethics
Committee of our University Hospital.
CASE REPORTS
Case 1
A 10.5 year-old boy had a diffuse petechial rash, oral and
nasal spontaneous bleeding, macroscopic hematuria, and
hematemesis, in conjunction with high fever for 15 days.
Then, the patient had seizures and was hospitalized in our
service due to right proportional hemiparesis and dysarthria
secondary to stroke on left frontal area. He also had anorexia,
photosensitivity, malar and palmar erythema, arthralgia, and
hepatomegaly. At that moment, laboratory exams revealed
hemoglobin 5.7 g/L, hematocrit 17%, reticulocytes 13%, white
blood cell (WBC) count 4,800/mm³ (64% neutrophils, 31%
lymphocytes, 2% eosinophils, and 3% monocytes), platelets
8,000/mm³, lactic dehydrogenase (LDH) 4,069 U/L (normal
141–231), negative direct Coombs test, D-dimer 4,632 ng/mL
(normal < 500), C-reactive protein (CRP) 13.5 mg/dL (normal
< 5), urinalysis with 102,000 erythrocytes and granular casts,
urea 40 mg/dL, creatinine 0.45 mg/dL, proteinuria 1.35 g/day,
aspartate aminotransferase (AST) 191 IU/L (normal 10–36),
alanine aminotransferase (ALT) 50 IU/L (normal 24–49),
gamma-glutamyl transpeptidase (GGT) 49 g/dL (normal
14–26), total bilirubin 1.94 mg/dL (normal 0–1), indirect
bilirubin 1.37 mg/dL (normal 0.1–1), fibrinogen 241 mg/dL
(normal 220–496), normal clotting test, albumin 3.7 g/dL
(normal 3.8–5.6), haptoglobin 75 mg/dL (normal 30–200), C3
140 mg/dL (normal 67–149), C4 28 mg/dL (normal 10–38),
and ferritin 3,807 mg/mL (normal 36–311). The blood smears
showed microangiopathic anemia, with presence of several
schistocytes. The von Willebrand factor was 316% (normal
60%–150%). An auto-antibodies analysis revealed positive
antinuclear antibodies (ANA) 1/160 (speckled pattern), IgG
anticardiolipin 25 GPL, IgM anticardiolipin 7 MPL, and negative anti-double stranded DNA (anti-dsDNA), lupus anticoagulant and anti-Sm antibodies. The carotid ultrasonography
was normal and the brain computer tomography evidenced
an ischemic brain vascular accident on the left frontal area.
Therefore, TTP and JSLE were diagnosed. At that moment,
the Systemic Lupus Erythematosus Disease Activity Index
2000 (SLEDAI-2K) score was 32.11 The patient was treated
with three intravenous methylprednisolone pulses followed
by prednisone (60 mg/day), nine sequential courses of plasma
exchange therapy and chloroquine. After that his hematocrit, platelet count and LDH remained normal, and without
evidence of antiphospholipid antibodies. However, he had
persistent neurological sequelae with hemiparesis and TTP
remission for a period of 13 months.
Case 2
A 10.4 year-old girl had pale skin, petechial rash, haematomas, epistaxis, fever, alopecia, vomiting, severe and persistent
headache, and arthritis in knees for 10 days. She was hospitalized, and her laboratory exams revealed hemoglobin 6.4 g/L,
hematocrit 19%, reticulocytes 18%, WBC count 6,300/mm³
(79% neutrophils, 17% lymphocytes, 0% eosinophils, and 4%
monocytes), platelets 10,000/mm³, LDH 2,700 U/L, negative
direct Coombs test, D-dimer 1,611 ng/mL, CRP 1.2 mg/dL,
urinalysis with 42,000 erythrocytes, urea 53 mg/dL, creatinine
0.48 mg/dL, proteinuria 0.24 g/day, haptoglobin 8 mg/dL, AST
171 IU/L, ALT 212 IU/L, total bilirubin 2.08 mg/dL, indirect
bilirubin 1.79 mg/dL, fibrinogen 53 mg/dL, normal clotting test,
albumin 3.2 g/dL, ferritin 500 mg/mL, lipase 290 mg/dL (normal 145–226), C3 138 mg/dL, and C4 12 mg/dL. Blood smears
showed microangiopathic anemia with several schistocytes.
The von Willebrand factor-cleaving protease (ADAMTS-13)
activity was < 1% (normal > 5%). Brain computer tomography and echocardiogram were normal. Immunological tests
revealed positive ANA 1:1280 (speckled pattern), anti-Sm,
anti-RNP and IgM anticardiolipin (17 MPL), being negative
for other serum antibodies: anti-dsDNA, anti-Ro, anti-La,
IgG anticardiolipin, lupus anticoagulant, anti-nucleosome,
and anti-ribosomal P antibodies. Therefore, TTP and JSLE
were diagnosed. At that moment, the SLEDAI-2K score was
17.11 The patient was treated with three intravenous methylprednisolone pulses followed by prednisone (60 mg/day) and
18 sequential courses of plasma exchange therapy. After that,
she was treated with azathioprine and chloroquine. Prednisone
dose was progressively tapered to 15 mg/day. After six months,
her hematocrit, platelet count and LDH remained normal with
TTP remission, and without evidence of antiphospholipid
antibodies.
DISCUSSION
To our knowledge, this is the first study that evaluated the
prevalence of TTP in a large population of JSLE in a tertiary
Paediatric University Hospital and evidenced a rare prevalence
of this hematological abnormality at lupus onset.
TTP is a severe hematological disorder which is characterized by the involvement of the central nervous system
121
20/03/2013 16:26:06
Campos et al.
microangiopathic hemolytic anemia, and thrombocytopenia.4,5,9
Hemolysis with detection of elevated reticulocyte count and/or
decrease of haptoglobin, and elevated LDH levels have also be
observed in patients with TTP,7,8,9 as detected in our cases. The
Coombs test is generally negative, as also evidenced herein.2
Of note, the TTP involvements are similar to lupus manifestations, especially neuropsychiatric and renal involvements.2
Recently the two hematological abnormalities (platelets counts
lower than 100,000/mm3 concomitantly with microangiopathic
hemolytic anemia with presence of schistocytes in peripheral
blood smears) were considered essential to TTP diagnosis, with
exclusion of other diseases, such as autoimmune hemolytic
anemia, disseminated intravascular coagulation, cancer, drug
toxicity, and malignant hypertension.12
In addition, TTP is a microvascular occlusive disorder,
that may lead to microthrombi and ischemia, particularly in
brain and renal glomeruli.2,9 In fact, neurological features (such
as headache,2,6 seizures, hemiparesis,2 and transitory mental
confusion4) and renal abnormalities2,9 are common clinical
manifestations of TTP. Importantly, to our information, the
occurrence of ischemic brain vascular accident with neurological sequelae, as evidenced in one of our cases, has not been
previously described in paediatric lupus population.
The pathogenesis of TTP is unknown. This abnormality
may occur due to some genetic deficiency13 or due to the acquired form, which is a result of the presence of autoantibody
against the protease that cleaves the von Willebrand factor,
named ADAMTS-13 (a disintegrin and metalloprotease with
a thrombospondin type 1 motifs 13).9 In fact, the reduction of
this protease releases the von Willebrand factor multimers and
determines thrombi formation in this disease.13
This hematological abnormality can be associated with autoimmune disease, in both adult6 and paediatric lupus.2,3 Indeed,
TTP associated with JSLE and lupus nephritis9 has been rarely
described, affecting mainly females2–4,6,9 at disease onset.3,4,6–8
The most important differential diagnosis of TTP in lupus
patients are: macrophage activation syndrome,14 disseminated
122
intravascular coagulation, Evans syndrome (autoimmune
hemolytic anemia and idiopathic thrombocytopenic purpura),9 antiphospholipid antibody syndrome, eclampsia, and
hemolytic uremic syndrome.12 In the latter, fever is rarely
observed and renal abnormalities are more severe when
compared to TTP.9
The treatment of TTP in JSLE patients consists of concomitant plasmapheresis and glucocorticoids therapy2,9 until
clinical and laboratory improvement, mainly the normalization
of hematocrit, platelets’ count and LDH9, as evidenced in our
two cases. The mean number of therapeutic plasma exchange
sessions reported in the literature varied from 5–14.4,6,7,9 Other
treatments to refractory or severe TTP associated with lupus
included immunosuppressive drugs, such as cyclophosphamide
and mycophenolate mofetil,5 intravenous immunoglobulin8
and rituximab.9
Regarding the outcome, death due to multiple organ failure8
and reminiscent occasional headache2 have also been previously described. Our case 1 had a relevant ischemic brain
vascular accident with persistent neurological sequelae.
The possible limitation for this study could be the retrospective medical records analysis, and this haematological
manifestation could be underestimated. A future prospective
and multicentre study is necessary.
In conclusion, TTP is a rare and severe manifestation at
lupus onset. The case reports reinforce the importance of early
diagnosis and early aggressive treatment for patients with TTP
due to high morbidity.
ACKNOWLEDGMENTS
This study was sponsored by Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP – grant 08/58238
to Clovis Artur Almeida da Silva), Conselho Nacional de
Desenvolvimento Científico – CNPQ (300248/2008-3 to
Clovis Artur Almeida da Silva), and Federico Foundation
to Clovis Artur Almeida da Silva.
20/03/2013 16:26:06
Púrpura trombocitopênica trombótica na apresentação de pacientes com lúpus eritematoso sistêmico juvenil
DISCUSSÃO
Até onde sabemos, este é o primeiro estudo a avaliar a prevalência de PTT em uma grande população de LESJ de um hospital
universitário pediátrico terciário, tendo evidenciado uma rara
prevalência dessa alteração hematológica quando da instalação
de lúpus.
A PTT é um distúrbio hematológico grave que se caracteriza
por envolvimento do sistema nervoso central, anemia hemolítica
microangiopática e trombocitopenia.4,5,9 Hemólise com contagem
elevada de reticulócitos e/ou diminuição da haptoglobina e níveis
altos de LDH também foram relatados em pacientes com PTT,7,8,9
como visto nos nossos casos. O teste de Coombs é geralmente
negativo, como foi nos nossos casos.2
É importante ressaltar que as manifestações da PTT são
semelhantes às do lúpus, em especial as neuropsiquiátricas e
renais.2 Recentemente, as duas alterações hematológicas (contagem de plaquetas inferior a 100.000/mm3 concomitante com
anemia hemolítica microangiopática e esquizócitos em esfregaços de sangue periférico) foram consideradas essenciais para o
diagnóstico de PTT, excluindo-se outras doenças, como anemia
hemolítica autoimune, coagulação intravascular disseminada,
câncer, toxicidade a drogas e hipertensão maligna.12
Além disso, a PTT é um distúrbio microvascular oclusivo,
que pode levar a microtrombos e isquemia, particularmente no
cérebro, e glomérulos renais.2,9 Na verdade, as alterações neurológicas (cefaleia,2,6 convulsões, hemiparesia2 e confusão mental
transitória4) e renais2,9 são manifestações clínicas comuns da PTT.
É importante notar que a ocorrência de acidente vascular cerebral
isquêmico com sequelas neurológicas, como evidenciado em
um de nossos casos, não foi previamente descrita na população
pediátrica com lúpus.
A patogênese da PTT é desconhecida. Essa anormalidade
pode decorrer de alguma deficiência genética13 ou ser adquirida,
resultando da presença de autoanticorpos contra a protease que
cliva o fator de von Willebrand, a ADAMTS-13 (uma desintegrina e metaloproteinase com domínio trombospondina tipo 1).9
A redução dessa protease libera multímeros do fator de von
Willebrand e determina a formação de trombos nessa doença.13
Essa anormalidade hematológica pode se associar a doença
autoimune, tanto no lúpus adulto6 quanto pediátrico.2,3 A descrição de PTT associada à LESJ e à nefrite lúpica9 é rara, afetando
principalmente o sexo feminino2–4,6,9 no início da doença.3,4,6–8
Os diagnósticos diferenciais mais importantes da PTT em
pacientes com lúpus são: síndrome de ativação macrofágica;14 coagulação intravascular disseminada; síndrome de Evans (anemia
hemolítica autoimune e púrpura trombocitopênica idiopática);9
síndrome do anticorpo antifosfolípide; eclampsia; e síndrome
hemolítico-urêmica.12 Na última, a febre é rara e as alterações
renais são mais graves que na PTT.9
O tratamento da PTT em pacientes com LESJ consiste em
plasmaferese concomitante com terapia com glicocorticoides,2,9
até melhora clínica e laboratorial, em especial normalização de
hematócrito, contagem de plaquetas e LDH,9 como visto nos
nossos dois casos. O número médio de sessões de plasmaferese
relatado na literatura variou de 5 a 14.4,6,7,9 Outros tratamentos
para PTT refratária ou grave associada com lúpus incluíram imunossupressores, como ciclofosfamida e micofenolato mofetil,5
imunoglobulina endovenosa8 e rituximabe.9
Com relação ao desfecho, morte por falência de múltiplos
órgãos8 e cefaleia reminiscente ocasional2 também já foram descritas. No nosso primeiro caso, houve um importante acidente
vascular cerebral isquêmico com persistente sequela neurológica.
Uma limitação deste estudo pode ter sido a análise retrospectiva de dados médicos, com subestimação da manifestação
hematológica. Um estudo prospectivo e multicêntrico se faz
necessário.
Concluindo, a PTT é uma manifestação rara e grave no
início do lúpus. Os casos relatados reforçam a importância do
diagnóstico precoce e tratamento agressivo de pacientes com
PTT devido à sua alta morbidade.
AGRADECIMENTOS
Este estudo foi patrocinado pela Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP – bolsa 08/58238
para Clovis Artur Almeida da Silva), pelo Conselho Nacional de
Desenvolvimento Científico e Tecnológico – CNPq (300248/20083 para Clovis Artur Almeida da Silva), e pela Federico Foundation ,
para Clovis Artur Almeida da Silva.
REFERENCES
REFERÊNCIAS
1.
Faco MM, Leone C, Campos LM, Febrônio MV, Marques HH,
Silva CA. Risk factors associated with the death of patients
hospitalized for juvenile systemic lupus erythematosus. Braz J Med
Biol Res 2007; 40(7):993–1002.
2.
Brunner HI, Freedman M, Silverman ED. Close relationship between
systemic lupus erythematosus and thrombotic thrombocytopenic
purpura in childhood. Arthritis Rheum 1999; 42(11):2346–55.
3.
Sakarcan A, Stallworth J. Systemic lupus erythematosus and
thrombotic thrombocytopenic purpura: a case and review. Pediatr
Nephrol 2001; 16(8):672–4.
Chak WK, Lam DS, Lo WH, Hui CM, Wong SN. Thrombotic
thrombocytopenic purpura as a rare complication in childhood
systemic lupus erythematosus: case report and literature review.
Hong Kong Med J 2003; 9(5):363–8.
4.
125
20/03/2013 16:26:06
Campos et al.
5.
6.
7.
8.
9.
Yuen LK, Lai WM, Tong PC, Poon WT, Tse KC, Chiu MC.
Recurrent thrombotic thrombocytopenic purpura in a young boy
with systemic lupus erythematosus. J Clin Rheumatol 2007;
13(4):224–8.
Aleem A, Al-Sugair S. Thrombotic thrombocytopenic purpura
associated with systemic lupus erythematosus. Acta Haematol
2006; 115(1-2):68–73.
Guvenc B, Unsal C, Gurkan E, Canataroğlu A, Saritas B, Evran M.
Systemic lupus erythematosus and thrombotic thrombocytopenic
purpura: a case report. Transfus Apher Sci 2004; 31(1):17–20.
Zhang W, You X, Dong Y. Systemic lupus erythematosus and
thrombotic thrombocytopenic purpura: report of three cases. Chin
Med J (Engl) 2004; 117(4):637–40.
Binder WD, Traum AZ, Makar RS, Colvin RB. Case records of the
Massachusetts General Hospital. Case 37-2010. A 16-year-old girl
with confusion, anemia, and thrombocytopenia. N Engl J Med 2010;
363(24):2352–61.
126
10. Hochberg MC. Updating the American College of Rheumatology
Arthritis Rheum 1997; 40(9):1725.
11. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus
disease activity index 2000. J Rheumatol 2002; 29(2):288–91.
12. Lansigan F, Isufi I, Tagoe CE. Microangiopathic haemolytic anaemia
resembling thrombotic thrombocytopenic purpura in systemic lupus
erythematosus: the role of ADAMTS13. Rheumatology (Oxford)
2011; 50(5):824–9.
13. Zipfel PF, Heinen S, Skerka C. Thrombotic microangiopathies: new
insights and new challenges. Curr Opin Nephrol Hypertens 2010;
19(4):372–8.
14. Campos LM, Omori CH, Lotito AP, Jesus AA, Porta G, Silva CA.
Acute pancreatitis in juvenile systemic lupus erythematosus:
a manifestation of macrophage activation syndrome? Lupus 2010;
19(14):1654–8.
20/03/2013 16:26:06
LETTER TO THE EDITORS
Biosimilars require scientifically reliable
comparative clinical data
I
n Brazil, the Law 9787 of February 10, 1999, authorized
the commercialization by any pharmaceutical company of
drugs, whose patent protection expired, in a standardized
packaging with a yellow band and a ‘G’ of ‘generic’. Generic
drugs are usually cheaper, because, after the expiration of the
patent protection of their brand-name pharmaceutical products,
manufacturers need neither to invest in clinical research, nor to
redo the trials that confirm the efficacy and safety of a certain
drug. Such costs are inherent to certain phases of the process
of research and discovery of new pharmaceutical drugs, and
have already been conducted by the innovator company that
had first obtained patent on a certain drug. Thus, manufacturers of generic drugs can sell their copies with the same quality
of the brand-name pharmaceutical product at a lower price.
However, biological drugs differ between themselves regarding complexity and cannot be approved in the same way of
synthetic generic drugs or with the same criterion used for
synthetic generics.1
There is worldwide consensus that a similar biotherapeutic product is a biopharmaceutical product approved via a
regulatory pathway, which comprises biological and clinical
comparison with the brand-name product counterpart, in addition to a strict assessment of its immunogenic potential.2
These requirements for a biological molecule to be named
‘similar biotherapeutic product’ is included in the World Health
Organization (WHO) guidelines on evaluation of similar biotherapeutic products, and are considered the minimum conditions required for approval for market and selling.2,3
Similarly to other emerging countries, from the economic
viewpoint, Brazil has a promising market of similar biotherapeutic products to manufacturers and/or traders of copies, patients and payers, including the Federal Government. However,
the approval for marketing and selling similar biotherapeutic
products, unlike generic drugs, without the conduction of
quality clinical trials, represents a real threat to patients. The
Brazilian Sanitary Surveillance Agency (ANVISA) has established a review of its previous normalization to approve similar
biotherapeutic products by use of the RDC 55, published at the
end of 2010.4 However, that normalization diverges in certain
aspects from the WHO guidelines, particularly in establishing
two regulatory pathways for approval, individual and comparative, in the extrapolation of therapeutic indications and in
differences in the emphasis given to the design and statistical
considerations of the trials; nevertheless, the practical application of the latter has not yet been completely clarified by that
agency to the scientific community.5
An interesting exercise recently published in the medical
literature, and conducted in a meeting sponsored by the WHO
in Seoul, South Korea, illustrates the relevance of the need
for a case-to-case approach when comparing clinical data
between similar biotherapeutic products and their brand-name
pharmaceutical counterparts.6 That is the only way to ensure the
adequate efficacy and safety of similar biotherapeutic products
to any studied indication.
The fact that small biochemical and biological differences might cause significant clinical differences makes us
believe that one biosimilar product must at least be as effective and safe as its brand-name pharmaceutical counterpart.
Comparative randomized clinical trials are currently considered the best experimental design to assess treatment-related
questions.
In a phase 3 study, a similar biotherapeutic product can be
assessed by use of statistical designs, such as the equivalence
and non-inferiority approaches comparing them with controls.
The former has the greatest affinity with the nature of the
biosimilarity process (to ensure that a similar biotherapeutic
product is neither more nor less effective than a brand-name
pharmaceutical product counterpart at the same dose and for
the same route of administration).7 Non-inferiority studies
are justified and accepted mainly when the innovative product already has a large safety margin, and they are aimed at
determining whether the similar biotherapeutic product is at
least as effective as its brand-name pharmaceutical product
counterpart, or even a little less effective, but within a certain
127
20/03/2013 16:26:06
LETTER TO THE EDITORS
pre-established limit, that is, within an acceptable range.8 In
addition, one copy might have a better efficacy profile, above
that range, but the non-inferiority result will be equally valid.
Theoretically, a similar biotherapeutic product could be better
assessed by use of equivalence studies, which are more restrict,
implying that neither better nor worse results should exist
within the pre-established range. The non-inferiority margin
is based on previous studies performed with the brand-name
pharmaceutical product counterpart, preferably in comparison
with a placebo.
It is worth noting that in the non-inferiority study, the populations studied and the outcomes should be equal to those of
the study providing the characteristics of the brand-name pharmaceutical product counterpart. Superiority studies, as shown
in Figure 1, are not meant to comparison between biological
innovations and copies, but might be used to demonstrate
the better efficacy profile of molecules known as biobetters.
Another important aspect relates to the size of the sample
that should be included in the comparative study between an
innovation and its copy. That sample size will depend mainly
on the value stipulated for the non-inferiority margin and data
variability.9 Very wide non-inferiority or equivalence margins
usually require small sample sizes, while narrower margins
require a larger number of patients. Unfortunately, so far the
sample sizes of non-inferiority or equivalence studies involving similar biotherapeutic products have been very small. In
addition, it is worth noting that occasional losses of patients
per group in a study, mainly due to flaws in the interpretation of tests and patient’s withdrawal, should be replaced to
maintain the statistical power of the project. In Brazil, copies
of recombinant erythropoietin have been approved after an
open study with 25 patients in phase 1–2a studies.10 Studies
like those would not be adequate for the current approval of
copies of fusion proteins or monoclonal antibodies, whose
patents expire.
The choice of a clinical trial design depends on several
factors, and the specific design selected for a particular trial
should be explicitly justified in the protocol of that trial. The
selection of the endpoints of primary efficacy and of the
statistical design of the main study, as well as the calculation
of the appropriate sample size to ensure statistical power, is
a multi-step process. To be properly assessed, that process
128
requires clear understanding of the comparability margins
(sometimes called comparability limits or, simply, margins)
for a certain endpoint, which ultimately translates better efficacy. According to the WHO, the selected margin should
represent the largest difference in efficacy/safety that matters
in clinical practice.
Similarly, regarding the treatment of individuals with
rheumatoid arthritis, only margins properly defined to detect
significant differences between a certain anti-TNF biosimilar
and its brand-name pharmaceutical product counterpart, based
on the efficacy measured by the impact of both treatments on
the ACR20 index, could be accepted. By definition, any difference in result contained within that variation would have
no clinical relevance. By nature, the comparability margins
for a certain endpoint result from clinical reasoning, being
frequently neither well established nor universally accepted.
Thus, the choice of the sample size should be well justified by
the sponsors of the study, being usually a combination of the
opinion of experts and previously published analyses.
In addition, ANVISA representatives should also agree
with those margins before the study is initiated. Thus, it
is understandable that experts of the Brazilian Society of
Rheumatology, with a large experience in managing patients
with rheumatoid arthritis and spondyloarthritides, be previously consulted by the sponsors of the study to provide an
opinion about and agree on the size of those margins, in cases
in which the endpoints are related to rheumatic disorders. The
combination should not be based on ‘guesses’, requiring a deep
search in the literature about the most impacting clinical outcomes related to the current treatment of rheumatic disorders.
The scientific community of Brazilian rheumatology waits
for the results of high-quality clinical trials developed by
manufacturers responsible for new biosimilars of biological
molecules used in their clinical practice.
The author declares receiving no incentive for this article’s
publication; he reports being part of the advisory boards of the
Janssen, Abbott and Pfizer pharmaceutical companies.
PhD in Health Sciences, Pontifícia Universidade Católica do Paraná - PUC-PR;
Professor of Rheumatology, Universidade Federal do Paraná - UFPR;
Coordinator of the Spondyloarthritis Ambulatory, Hospital de Clínicas, UFPR
20/03/2013 16:26:07
CAR TA AOS EDITORES
aceitável.8 É possível, inclusive, que uma cópia tenha melhor
perfil de eficácia, acima dessa variação, havendo um bônus,
mas o resultado de não inferioridade será igualmente válido.
Por conceito, um biossimilar poderia ser mais bem avaliado
por estudos de equivalência, pois são mais restritos e implicam
que não deveria haver resultado nem melhor nem pior, dentro
da variação preestabelecida. A margem de não inferioridade tem
base em estudos prévios feitos com o medicamento original, de
preferência em comparação a placebo.
No desenho do estudo de não inferioridade, devemos
lembrar que as populações estudadas e os desfechos devem
igualmente ao estudo que forneceu as características do comparador original. Estudos de superioridade, como demonstrado
na Figura 1 não se prestam à comparação entre inovadores e
cópias biológicas, mas podem ser empregados para a demonstração de melhor perfil de eficácia de moléculas conhecidas
como biobetters. Outro aspecto importante diz respeito ao
tamanho da amostra de pacientes que devem ser incluídos no
estudo comparativo entre um inovador e sua pretensa cópia.
Esse tamanho amostral dependerá, sobretudo, do valor estipulado para a margem de não inferioridade e da variabilidade dos
dados.9 Margens de não inferioridade ou de equivalência muito
amplas requerem, muitas vezes, pequenos tamanhos amostrais,
enquanto margens mais estreitas requerem maior número de
pacientes. Infelizmente, os tamanhos amostrais de estudos
de equivalência ou não inferioridade entre biossimilares, até
aqui, têm sido frequentemente muito pequenos. Além disso, é
preciso salientar que eventuais perdas de pacientes por grupo,
principalmente por conta de falhas na interpretação de exames,
desligamentos da pesquisa etc., devem ser repostas, de modo
a manter o poder estatístico do projeto. No Brasil, cópias de
eritropoetinas recombinantes foram aprovadas após estudo
aberto com tamanho amostral de 25 pacientes em estudos de
fase 1–2a.10 Certamente, estudos nesse molde seriam inviáveis
para a atual aprovação de cópias de proteínas de fusão ou
anticorpos monoclonais que perdem suas patentes.
A escolha do desenho de um ensaio clínico é dependente
de muitos fatores, e o desenho específico selecionado para
um estudo particular deve ser explicitamente justificado no
protocolo do ensaio proposto. A seleção dos endpoints de
eficácia primária e o desenho estatístico do estudo principal,
bem como o cálculo do tamanho amostral apropriado para
assegurar seu poder estatístico, são um processo de muitas
etapas. Esse processo requer claro entendimento sobre o que
são as margens de comparabilidade (algumas vezes chamadas
limites de comparabilidade ou somente margens), para que
determinado endpoint particular, que traduza melhor eficácia
em última análise, seja adequadamente avaliado. A OMS muito
130
bem explicitou em seus guias que “a margem selecionada deve
representar a mais larga diferença em eficácia/segurança que
importa na prática clínica”.
De forma analógica, somente margens adequadamente
definidas para detectar diferenças significantes no tratamento
de portadores de artrite reumatoide entre um determinado biossimilar de um agente anti-TNF e seu comparador, tomando por
base a eficácia medida por impacto de ambos os tratamentos no
índice ACR20, poderiam ser aceitas, porque, por definição, não
haveria relevância clínica de qualquer diferença de resultado
que estivesse contido dentro dessa variação. Por natureza, as
margens de comparabilidade para um dado endpoint são em
última análise um juízo clínico e frequentemente não estão
bem-estabelecidas ou universalmente aceitas. Portanto, a
escolha do tamanho dessa margem deve ser bem-justificada
pelos patrocinadores do estudo, usualmente uma combinação
da opinião de experts e de análises prévias publicadas.
Além disso, representantes da ANVISA também devem
concordar com elas antes que se inicie o estudo. Dessa forma, faz sentido que especialistas da Sociedade Brasileira de
Reumatologia, com grande experiência no tratamento de
portadores de artrite reumatoide e espondiloartrites, sejam
previamente consultados pelos patrocinadores para opinar
e concordar com o tamanho dessas margens, nos casos em
que os endpoints estejam relacionados a tais enfermidades. A
combinação não deveria ser pautada somente por “achismos”,
sem um estudo aprofundado da literatura sobre os desfechos
clínicos mais impactantes relacionados ao tratamento atual de
enfermidades reumatológicas.
A comunidade científica da reumatologia brasileira aguarda
os resultados de ensaios clínicos de alta qualidade desenvolvidos por fabricantes responsáveis pela entrada de novos biossimilares de moléculas biológicas usadas em nossa prática clínica.
O autor declara não ter recebido qualquer incentivo para a
publicação deste artigo; declara fazer parte de advisory boards
dos laboratórios Janssen, Abbott e Pfizer.
Doutor em Ciências da Saúde, Pontifícia Universidade Católica do Paraná PUC-PR; Professor de Reumatologia, Universidade Federal do Paraná;
Coordenador do Ambulatório de Espondiloartrites, Hospital de Clínicas, UFPR
REFERENCES
REFERÊNCIAS
1.
Azevedo VF, Felippe LR, Machado DM. Opinião de uma amostra
de reumatologistas brasileiros sobre biossimilares. Rev Bras
Reumatol 2011; 51(6):.662–71.
20/03/2013 16:26:07
CAR TA AOS EDITORES
2.
World Health Organization. Guidelines on Evaluation of
Similar Biotherapeutic Products (SBPs), 2010. Available from:
http://www.who.int/biologicals/areas/biological_therapeutics/
BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf
3.
Expert committee on biological standardization Geneva, 19 to 23
October 2009. Guidelines on evaluation of Similar Biotherapeutic
Products (SBPs).Adopted by the 60th meeting of the WHO Expert
Committee on Biological Standardization.
4.
ANVISA. Registro de Produtos Biológicos. Baes Legais e Guias
– Coletânea. Resolução – RDC n 55, de 16 de dezembro de 2010.
Available from: http://portal.anvisa.gov.br/wps/wcm/connect/935
aed0048bd2755a7cdaf9a6e94f0d0/Registro_Produtos_Biologicos_
Hemoterapicos_10102011_WEB.pdf?MOD=AJPERES.
5.
Castanheira LG, Barbano DB, Rech N. Current development in
regulation of similar biotherapeutic products in Brazil. Biologicals;
2011; 39(5):308–11.
6.
Fletcher MP. Biosimilars clinical development program:
confirmatory clinical trials: a virtual/simulated case study
comparing equivalence and non-inferiority approaches.
Biologicals 2011; 39(5):270–7.
7. Njue C. Statistical considerations for confirmatory clinical trials
for similar biotherapeutic products. Biologicals 2011; 39(5):266–9.
8. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ,
CONSORT Group. Reporting of non inferiority and equivalence
randomized trials: an extension of the CONSORT statement.
JAMA 2006; 295:1152–60.
9. Chow SC, Shao J, Wang H. Sample size calculations in clinical
research. 2. ed. Boca Raton: Chapman & Hall/CRC Biostatistical
series; 2008.
10. Bio-Manguinhos, Fundação Oswaldo Cruz. Eritropoietina
Humana Recombinante – Monografia do produto. Available
from: http://www.fiocruz.br/bio_eng/media/monografia_epo.pdf.
Accessed on Feb 28, 2012.
131
20/03/2013 16:26:07
C ORRIGENDUM
Posterior reversible encephalopathy syndrome
(PRES) and systemic lupus erythematosus:
report of two cases
Streck A de S, Staub HL, de Freitas CZ, Marrone L, Costa J, Gadonski G
In page 804, where it reads:
Aline de Souza Streck1, Henrique Luiz Staub2, Caroline Zechlinski Xavier de Freitas1, Luis Marrone3,
Jaderson Costa4, Giovani Gadonski5
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
It should read:
Luis Marrone 1, Aline de Souza Streck 2, Caroline Zechlinski Xavier de Freitas 2, Jaderson Costa 3,
Giovani Gadonski4, Henrique Luiz Staub5
1. Neurologist, Member of the Neurology Service of the Hospital São Lucas, Pontifícia Universidade Católica
do Rio Grande do Sul – PUCRS
2. Rheumatologist, Hospital São Lucas, PUCRS
3. Neurologist; Professor of the Department of Neurology of the Hospital São Lucas, PUCRS
4. Nephrologist, Member of the Nephrology Service of the Hospital São Lucas, PUCRS
5. Rheumatologist; Professor of the Department of Rheumatology, Hospital São Lucas, PUCRS
132
RBR 53(1).indb 132
20/03/2013 16:26:07
C ORRIGENDUM
Anti-C1q, anti-chromatin/nucleosome, and
anti-dsDNA antibodies in juvenile systemic
lupus erythematosus patients
Jesus AA, Campos LM, Liphaus BL, Carneiro-Sampaio M, Mangueira CL, Rosseto EA, Silva CA, Scheinberg M
In page 971, where it reads:
Clovis Artur Almeida da Silva6, Morton Scheinberg7
6. Associate Professor, Pediatric Department, HC-FMUSP; Chief of the Pediatric Rheumatology Unit,
HC-FMUSP
7. Associate Professor of Immunology, HCFMUSP; Scientific Director, Hospital Abreu Sodré - AACD;
Physician, Hospital Israelita Albert Einstein
It should read:
Morton Scheinberg6, Clovis Artur Almeida da Silva7
6. Associate Professor of Immunology, HCFMUSP; Scientific Director, Hospital Abreu Sodré - AACD;
Physician, Hospital Israelita Albert Einstein
7. Associate Professor, Pediatric Department, HC-FMUSP; Chief of the Pediatric Rheumatology Unit,
HC-FMUSP
134
RBR 53(1).indb 134
20/03/2013 16:26:07
ACKN OW LEDGEMENTS | AGR ADECI MENTOS
The Editors-in-Chief of the Brazilian Journal of Rheumatology,
Dr. Paulo Louzada-Junior and Dr. Max Vitor Carioca Freitas, wish to express their
appreciation to all the following who have acted as referees in preparing Volume 52:
Os editors-chefe da Revista Brasileira de Reumatologia, Dr. Paulo LouzadaJunior and Dr. Max Vitor Carioca Freitas, gostariam de expressar sua apreciação
a todos os que atuaram como pareceristas na preparação do Volume 52:
Adriana Fontes Zimmermann, Adriana Maluf Elias Sallum, Ajax Mercês Atta, Alessandra Dellavance,
Alexandre Wagner Silva de Souza, Aline Ranzolin, Ana Maria Ferreira Roselino, Ana Patricia de Paula,
Andreas Funke, Antonio Pazin Filho, Ari Stiel Radu Halpern, Boris Afonso Cruz, Carlos Alberto von Mühlen,
Célio Roberto Gonçalves, Charlles Heldan de Moura Castro, Claiton Viegas Brenol, Claudia Diniz Lopes
Marques, Claudia Saad Magalhães, Claudio Arnaldo Len, Clovis Artur Almeida Da Silva, Cristane Kayser
Veiga da Silva, Cristiano Augusto de Freitas Zerbini, Cristina Costa Duarte Lanna, Daniel Feldman Pollak,
David Cezar Titton, Dawton Torigoe, Durval Campos Kraychete, Eduardo de Souza Meirelles, Eduardo dos
Santos Paiva, Eduardo Ferreira Borba Neto, Elcio dos Santos Oliveira Vianna, Emilia Inoue Sato, Eutilia
Andrade Medeiros Freire, Fabiola Reis de Oliveira, Fernando Antonio Glasner da Rocha Araujo, Fernando
Bellissimo Rodrigues, Flavio Calil Petean, Flavio Roberto Sztajnbok, Francisco Airton Castro Da Rocha,
Francisco de Assis Pereira, Francisco Jose Albuquerque Paula, Francisco Saraiva Da Silva Jr., Gecilmara
Cristina Salnato Pileggi, Gilberto Santos Novaes, Gilda Aparecida Ferreira, Henrique Josef, Ines Guimarães
da Silveira, Isabella Vargas de Souza Lima, Isidio Calich, Ivanio Alves Pereira, Ivone Minhoto Meinão, Izaias
Pereira da Costa, Jamil Natour, Jeova Keny Baima Colares, João Carlos Tavares Brenol, José Ajax Nogueira
Queiroz, Jose Alexandre Mendonça, Jose Antonio Baddini Martinez, José Carlos Mansur Szajubok, José
Eduardo Martinez, José Eleuterio Junior, José Goldenberg, Jose Roberto Provenza, José Tupinambá Souza
Vasconcelos, Jozélio Freire de Carvalho, Julio Cesar Moriguti, Lais Verderame Lage, Leonardo Domingues
Romeiro, Licia Maria Henrique da Mota, Lilian Tereza Lavras Costallat, Lucia Maria M de Arruda Campos,
Luciana Martins de Carvalho, Lucienir Maria da Silva, Luis Eduardo Coelho Andrade, Luiz Carlos Latorre,
Luiz Fernando de Souza Passos, Manoel Ricardo Alves Martins, Marcello Henrique Nogueira-Barbosa,
Marcelo de Medeiros Pinheiro, Marco Andrey Cipriani Frade, Marcos de Carvalho Borges, Marcos Renato
de Assis, Maria José Pereira Vilar, Maria Odete Odete Esteves Hilário, Maria Roseli Monteiro Callado,
Maria Teresa Terreri, Mario Newton Leitão de Azevedo, Marta Maria Das Chagas Medeiros, Mauricio Levy
Neto, Mauro Goldfarb, Milton Helfenstein Júnior, Mittermayer Barreto Santiago, Morton Aaron Scheinberg,
Natalino Hajime Yoshinari, Nereida Kilza Da Costa Lima, Neusa Pereira da Silva, Nilzio Antonio da Silva,
Odirlei Andre Monticielo, Percival Degrava Sampaio-Barros, Rene Donizeti Ribeiro de Oliveira, Ricardo
Fuller, Ricardo Machado Xavier, Rina Dalva Neubarth Giorgi, Roberto Ezequiel Heymann, Roberto Ranza,
Roger Abramino Levy, Rosa Maria Rodrigues Pereira, Rozana Mesquita Ciconelli, Samuel Katsuyuki Shinjo,
Sandra Gofinet Pasoto, Sandra Lúcia Euzébio Ribeiro, Sergio Couto Luna Almeida, Simone Appenzeller,
Teresa Cristina Martins Vicente Robazzi, Valderilio Feijó Azevedo, Valeria Valim, Vander Fernandes, Vera
Lucia Szejnfeld, Vilma dos Santos Trindade Viana, Virginia Fernades Moça Trevisan, Virginia Paes Leme
Ferriani e Wilson de Melo Cruvinel.
136
Rev Bras Reumatol 2013;53(1):136
20/03/2013 16:26:07

Jan/Feb - Sociedade Brasileira de Reumatologia

Transcrição

Documentos relacionados

PDF - Respiratory Research

Crystal structure of transthyretin in complex with

management system certificate

color and genomic ancestry of brazilians studied with

lessons from the Sustainable Urban Social Housing Initiative

university of porto, portugal 13 14 june 2011 jocelyn benoist

Tuesday 25th August 2015 Dear parents, As you

[+] here

A PUTATIVE GAIN-OF-FUNCTION MUTATION IN CRHR1 GENE

the rheumatic diseases portuguese register

Scholarship Fund - Instituto Embraer

Maintenance of remission following 2 years of standard treatment

Vasculitis