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ISSN 0482-5004
Impact Factor 2012: 0.864
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Science Edition (2012)
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
MAY/JUNE 2014 • Volume 54 • Number 3
MAIO/JUNHO 2014 • Volume 54 • Número 3
www.reumatologia.com.br
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
Bimonthly Edition (Publicação Bimestral)
Editors (Editores)
Coeditors (Coeditores)
Max Victor Carioca Freitas
Eloísa Silva Dutra de Oliveira Bonfá
Mittermayer Barreto Santiago
Roberto Ezequiel Heymann
Hilton Seda
Paulo Louzada-Junior
Universidade Federal do Ceará, Fotaleza, CE, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
João Carlos Tavares Brenol
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Ricardo Fuller
Universidade de São Paulo, São Paulo, SP, Brazil
Simone Appenzeller
Universidade Estadual de Campinas, Campinas, SP, Brazil
Editorial Board (Conselho Editorial)
Acir Rachid
Universidade Federal do Paraná, Curitiba, PR, Brazil
Adil Muhib Samara
Universidade Estadual de Campinas, Campinas, SP, Brazil
Geraldo da Rocha Castelar Pinheiro
Universidade do Estado do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Gilberto Santos Novaes
Maurício Levy Neto
Universidade de São Paulo, São Paulo, SP, Brazil
Milton Helfenstein Jr.
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Pontifícia Universidade Católica de São Paulo,
São Paulo, SP, Brazil
Natalino H. Yoshinari
Ari Stiel Radu
Isídio Calich
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Nílzio Antônio da Silva
Carlos Alberto von Muhlen
Ivânio Alves Pereira
Percival Degrava Sampaio-Barros
Claudia Goldenstein-Schainberg
Jamil Natour
Cláudio Arnaldo Len
João Francisco Marques Neto
Clóvis Artur Almeida da Silva
José Goldenberg
Alexandre Wagner S Souza
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Faculdade de Medicina da Pontifícia Universidade
Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Cristiano Augusto de Freitas Zerbini
Hospital Heliópolis, São Paulo, SP, Brazil
Daniel Feldman Polak
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Durval Kraychete
Escola Bahiana de Medicina e Universidade
Federal da Bahia, Salvador, BA, Brazil
Universidade Federal de Santa Catarina,
Florianópolis, SC, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
José Roberto Provenza
Universidade Estadual de Campinas, Campinas, SP, Brazil
Jozélio Freire de Carvalho
Centro Médico Aliança, Salvador, BA, Brazil
Lais V. Lage
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de Goiás, Goiânia, GO, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Ricardo M. Xavier
Universidade Federal do Rio Grande do Sul,
Porto Alegre, RS, Brazil
Rina Dalva P. N. Giorgi
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
Roger A. Levy
Universidade Estadual do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Rosa Maria Rodrigues Pereira
Universidade de São Paulo, São Paulo, SP, Brazil
Rozana Mesquita Ciconelli
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Samuel Katsuyuki Shinjo
Universidade de São Paulo, São Paulo, SP, Brazil
Eduardo de Souza Meirelles
Lilian Tereza Lavras Costallat
Eduardo Ferreira Borba Neto
Luís Eduardo Coelho Andrade
Universidade Federal do Paraná, Curitiba, PR, Brazil
Emília Inoue Sato
Luiz Fernando de Souza Passos
Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Fernanda Rodrigues de Lima
Marcelo de Medeiros Pinheiro
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Fernando Queiroz da Cunha
Maria Odete E. Hilário
Francisco Airton Castro Rocha
Marta Maria das Chagas Medeiros
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Amazonas, Manaus, AM, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Sebastião Cézar Radominski
Sheila Knupp de Oliveira
Simone Appenzeller
Universidade de Campinas, Campinas, SP, Brazil
Vera Lúcia Szejnfeld
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Wiliam H. Chahade
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
International Editorial Board (Conselho Editorial Internacional)
Ariel Masetto
Juan Manuel Anaya
Munther Khamashta
Arthur Kavanaugh
Luis Javier Jara
H Ralph Schumacher Jr
Bernardo Pons Estel
Mario Cardiel
Ricardo Cervera Segura
Université de Sherbrooke, Sherbrooke, Canada
University of California, San Diego, USA
Universidad Nacional de Rosario, Rosario, Argentina
Claudio Galarza Maldonado
Hospital Monte Sinai, Cuenca, Equador
Corporación de Investigaciones Biológicas, Medellín, Colômbia
Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
Instituto Nacional de la Nutrición "Salvador Zubiran",
Morrelia, Mexico
Mario Garcia-Carrasco
Ernest Choy
Facultad de Medicina, BUAP, Puebla, Mexico
Jordi Antón López
Universidade Clássica de Lisboa, Lisboa, Portugal
José Antonio Melo Gomes
University of Calgary, Calgary, Canada
King's College, London, UK
Hospital Sant Joan de Déu, Barcelona, Spain
Instituto Português de Reumatologia, Lisboa, Portugal
Mário Viana de Queiroz
Marvin Fritzler
St. Thomas´ Hospital, London, UK
University of Pennsylvania, Philadelphia, USA
Hospital Clinic, Barcelona, Spain
Richard J Wakefield
Chapel Allerton Hospital, Leeds, UK
Thomas Dörner
Charite Hospital, Berlin, Germany
Yehuda Shoenfeld
Chaim Sheba Medical Center, Tel Aviv University,
Tel Hashomer, Israel
BSR Office (Secretaria SBR)
Rogério Quintiliano Amaral
Av. Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94
CEP 01402-000
São Paulo, SP
Fone/fax: 55 (11) 3289-7165
E-mail: [email protected]; [email protected]
website: www.reumatologia.com.br
Brazilian Journal of Rheumatology is listed in Web of Science, MEDLINE, LILACS,
SciELO, Scopus and Index Copernicus databases. BJR is affiliated to the International
Committee of Medical Journal Editors.
A Revista Brasileira de Reumatologia é indexada nas bases de dados Web of Science,
MEDLINE, LILACS, SciELO, Scopus e Index Copernicus. A RBR é filiada ao International
Committee of Medical Journal Editors.
Brazilian Journal of Rheumatology (BJR) is an official publication of the Brazilian Society
of Rheumatology (BSR) in partnership with Elsevier Editora Ltda. and is dedicated to the
medical community in Brazil and Latin America.
Edited by Brazilian Society of Rheumatology.
Published by Elsevier Editora Ltda. © 2014.
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. © 2014.
Todos os direitos reservados e protegidos pela lei 9.610 - 19/02/98. Nenhuma parte desta
publicação poderá ser reproduzida, sem autorização prévia, por escrito, da Elsevier
Editora Ltda. e da SBR, sejam quais forem os meios empregados: eletrônicos, mecânicos,
fotográficos, gravação ou quaisquer outros.
A RBR recebe auxílio financeiro de Fundos Remanescentes da Sociedade Brasileira de
Reumatologia.
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Rheumatology) – ISSN 2255-5021
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INSTRUCTIONS TO AUTHORS
The Brazilian Journal of Rheumatology (BJR), an official organ of Sociedade
Brasileira de Reumatologia (Brazilian Society of Rheumatology), was founded
in 1957 and is published bimonthly. The journal publishes original articles,
review articles, brief communications, case reports and letters to the editors.
To submit a manuscript, please access the site http://ees.elsevier.com/bjr.
Format of the manuscript
The manuscript can be submitted in Portuguese or English, double spaced,
with 2.5 cm margins. Unconventional abbreviations, medical jargon and
telegraphic style should not be used in the text. Citation of drugs and
pharmaceutical products must be done using pharmacological nomenclature,
without any mention to commercial names.
Manuscript structure
Manuscript*, Title Page*, Cover Letter, and Author Agreement* must be
submitted in separate files. Tables and Figures should be numbered as cited
in the text and sent in separate files with corresponding titles and legends.
(*required files)
Title page
The title page should contain: a) the full title; b) the full name of the authors
and institutional affiliation; c) the department and institution where the study
was originated; d) the full e-mail of the corresponding author; e) conflict of
interest and relevant financial agencies; f) a running title with no more than
60 characters.
Author Agreement
It is the document where the authors declare that the manuscript is original, in
addition to approve the manuscript object of the submission, the authorship
and the order of authors listed. It must be signed by all authors. Below is
presented an example.
Dear Editor,
We, the undersigned, declare that this manuscript is original, has not been
published before and is not currently being considered for publication elsewhere.
We would like to draw the attention of the Editor to the following publications
of one or more of us that refer to aspects of the manuscript presently being
submitted.
We confirm that the manuscript has been read and approved by all named
authors and that there are no other persons who satisfied the criteria for
authorship but are not listed. We further confirm that the order of authors
listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the
Editorial process. He/she is responsible for communicating with the other
authors about progress, submissions of revisions and final approval of proofs.
(Signature of all authors)
Original article
The original article should contain: the title page, the abstract page with
keywords, introduction, material and methods or patients and methods, results
and discussion, acknowledgements, references, tables, figures and figure
legends. Original articles should not exceed 5,000 words including references
and excluding the title page, abstract, tables and legends. It is allowed up to
six figures or tables and 50 references.
Abstract page
The abstract page should contain: a) objective, methods, results and
conclusions, with no more than 250 words; b) three to five keywords.
Introduction
As the aim of this section is to define the purpose and the reasons for the
accomplishment of the work, we do not recommend a large literature review.
Patients and methods or Material and methods
This section should include enough information that allows the reproduction of
the work and, when it is relevant, the approval by the institutional Committee
of Ethics. The methods employed in the statistical analysis should always
be quoted.
Results
They should be clear and concise. Tables and graphics should not duplicate
information.
Discussion
It should be concise, interpreting the results in the context of the present literature.
Please do not exceed the limit of half the number of pages of the complete work.
Acknowledgments
Only to people who contributed; i.e., with techniques, discussion and sending
patients. Financial help should be referred in the title page.
References
They should be quoted in the text in Arabic numerals, superscript, with no brackets.
Numbering should be sequencial, according to the quotation order in the text.
Please quote all the authors in works with until six authors; after six authors,
quote the first six followed by the expression et al. Reference Manager or Endnote
programs are strongly recommended for use adopting the Vancouver style.
Examples for reference citation are presented below. Authors should consult
NLM’s Citing Medicine for additional information on the reference formats.
Printed article
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Reference retrieved from electronic address
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink. com.w10069.dotlib.com.
br/content/l05j4j3332041225/fulltext.pdf. [Accessed in February 24, 2008].
Book
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical
microbiology. 4th ed. St. Louis: Mosby; 2002.
Tables and figures
Each Table or Figure should be numbered with Arabic numerals and sent in
an individual file (.jpg, .tif, .png, .xls, .doc) with minimum of 300 dpi. Titles
and legends should be in the same Table/Figure file to wich they refer. Tables
and Figures should include enough information so the reader can understand
them without going to the text.
Photomicrographies should include the appropriated scale.
Review article
Reviews, preferentially systematic, may be submitted to BJR. They should
cover deeply any interesting theme for the rheumatologist. They do not present
a standard structure, neither introduction or conclusion. Please send abstracts
without subdivisions with three to five keywords. Review articles should not
exceed 6,000 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to five figures or tables and 70 references.
Case report
Must have six authors at most. They should include an abstract and keywords,
without subdivisions. The text, however, should present the following sections:
introduction, which should be concise; case report, containing the description and
the evolution of the clinical case, laboratory exams, illustrations and tables (that
substitute the sections material and methods and results); and discussion. It should
not exceed 1,500 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to two figures or tables and 15 references.
Brief communication
It covers a point or a specific detail. It should present an abstract with no
more than 250 words and three to five keywords. The text does not include
subdivisions, and should not exceed 2,500 words including references and
excluding the title page, abstract, tables and legends. It is allowed up to three
figures or tables and 25 references.
Rules for applying the appropriate tense in scientific writing
Context or section
Appropriate verb tense
Abstract
Past tense
Introduction
Most present tense (established facts,
previous published data)
Methods, materials used,
and results
Past tense
Discussion/Conclusion
Mixture of past and present, sometimes
future tense
Attribution
Past tense
Ex.: Andrade et al. reported that...
Description of Tables and
Figures
Present tense
Established knowledge,
previous results etc.
Present tense
General rules to obtain a good scientific writing:
1. Use active voice.
2. Setences must be short, clear and objective.
3. Units of measurement are abbreviated when use with numerical values
(e.g., 1 mg), but are not abbreviated if used without numerical values.
Systeme International d'Únites (SI units) must be used. Remember to
leave a space between the number and unit (e.g., 10 mg/dL), except for
the percentage mark that follows the number without space (e.g., 70%).
The plural form of units of measurement is the same as the singular form
(e.g., 1 mL, 10 mL; 1 h, 10 h). Spell out numbers at the beginning of a
sentence.
4. Define abbreviations the first time they appear. Avoid abbreviations in
tittles and abstracts.
5. Do not use contractions (e.g., doesn't, can't etc.).
Recommended book: Rogers SM. Mastering scientific and medical writing:
a self-help guide. Berlin: Springer; 2007.
Legal and ethical considerations
According to the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals (International Committee of Medical Journal Editors –
February 2006).
Conflict of interest
Public trust in the peer review process and the credibility of published
articles depend in part on how well conflict of interest is handled during
writing, peer review, and editorial decision making. Conflict of interest
exists when an author (or the author’s institution), reviewer, or editor has
financial or personal relationships that inappropriately influence (bias) his
or her actions (such relationships are also known as dual commitments,
competing interests, or competing loyalties). These relationships vary
from those with negligible potential to those with great potential to
influence judgment, and not all relationships represent true conflict of
interest. The potential for conflict of interest can exist whether or not
an individual believes that the relationship affects his or her scientific
judgment. Financial relationships (such as employment, consultancies,
stock ownership, honoraria, paid expert testimony) are the most easily
identifiable conflicts of interest and the most likely to undermine the
credibility of the journal, the authors, and of science itself. However,
conflicts can occur for other reasons, such as personal relationships,
academic competition, and intellectual passion.
Informed consent
Patients have a right to privacy, that should not be infringed without
informed consent. Identifying information, including patients’ names,
initials, or hospital numbers, should not be published in written descriptions,
photographs, and pedigrees unless the information is essential for scientific
purposes and the patient (or parent or guardian) gives written informed
consent for publication. Informed consent for this purpose requires that a
patient who is identifiable be shown the manuscript to be published. Authors
should identify Individuals who provide writing assistance and disclose the
funding source for this assistance. Identifying details should be omitted if
they are not essential.
Complete anonymity is difficult to achieve. However, an informed consent
should be obtained if there is any doubt. For example, masking the eye
region in photographs of patients is inadequate protection of anonymity. If
identifying characteristics are altered to protect anonymity, such as in genetic
pedigrees, authors should provide assurance that alterations do not distort
scientific meaning and editors should so note. When informed consent has
been obtained it should be indicated in the published article.
Ethical treatment
When reporting experiments on human subjects, authors should indicate
whether the procedures followed were in accordance with the ethical
standards of the responsible committee on human experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as
revised in 2000. If doubt exists whether the research was conducted in
accordance with the Helsinki Declaration, the authors must explain the
rationale for their approach, and demonstrate that the institutional review
body explicitly approved the doubtful aspects of the study. When reporting
experiments on animals, authors should be asked to indicate whether the
institutional and national guide for the care and use of laboratory animals
was followed.
Clinical trials registry
Clinical trials must be registered according to WHO recommendation at www.
who.int/ictrp/en/. The definition of clinical trial include preliminary trials
(phase I): any study with prospective recruiting of subjects to undergo any
health-related intervention (drugs, surgical procedures, equipment, behavioral
therapies, food regimen, changes in health care) to evaluate the effects on
clinical outcomes (any biomedical or health-related parameter, including
pharmacokinetics measurements and adverse reactions).
The BJR has the right not to publish trials not complying with these and
other legal and ethical standards determined by international guidelines.
Financing and support
The authors should also inform if they received financing or support
from institutions like CNPq, CAPES, SBR Remaining Funds, Graduated
Institutions, Laboratories etc.
INSTRUÇÕES PARA OS AUTORES
A Revista Brasileira de Reumatologia (RBR), órgão oficial da Sociedade Brasileira de Reumatologia, foi fundada em 1957 e é publicada bimestralmente.
A revista publica artigos originais, artigos de revisão, comunicações breves,
relatos de casos e cartas aos editores.
Resultados
Devem ser claros e concisos. Tabelas e gráficos não devem duplicar informações.
Discussão
O manuscrito deve ser submetido online através do site http://ees.elsevier.com/bjr.
Deve ser concisa, interpretando os resultados no contexto da literatura atual. É
conveniente não ultrapassar a metade do número de páginas do trabalho completo.
Apresentação do manuscrito
Agradecimentos
O manuscrito pode ser submetido em português ou inglês, em espaço
duplo, com margens de 2,5 cm. No texto não devem ser empregadas
abreviaturas não convencionais, gírias (jargões) médicas ou redação tipo
telegráfica. A citação de medicamentos e produtos farmacêuticos deve
ser feita utilizando-se apenas a nomenclatura farmacológica, sem menção
do nome comercial.
Estrutura do manuscrito
Manuscript*, Title Page*, Cover Letter e Author Agreement* devem ser
enviados em arquivos individuais. Tabelas e figuras devem ser numeradas
conforme citadas no texto e enviadas em arquivos separados, com títulos e
legendas correspondentes. (*arquivos obrigatórios)
Página do título
Deve conter: a) título do artigo; b) nome completo dos autores e sua afiliação
institucional; c) departamento(s) e instituição(ões) onde se originou o trabalho; d) nome 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.
Página de resumo
Deve conter: a) objetivo, métodos, resultados e conclusões, não excedendo
250 palavras; b) três a cinco palavras-chave.
Introdução
A finalidade dessa seção é definir o propósito e as razões para a realização
do trabalho. Não se recomenda extensa revisão da literatura.
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.
Apenas às pessoas que contribuíram, por exemplo, com técnicas, discussão e
envio de pacientes. Auxílio financeiro deve ser referido na página do título.
Referências
Devem ser citadas no texto em algarismos arábicos, sobrescritos e depois da
pontuação, sem parênteses ou colchetes. A numeração deve ser sequencial,
de acordo com a ordem de citação no texto. Nas referências com mais de
seis autores, devem ser citados os seis primeiros, seguidos pela expressão
et al. Sugere-se a utilização dos programas Reference Manager ou Endnote,
seguindo-se o estilo Vancouver. Exemplos de referência para diferentes
formatos são apresentados a seguir. Os autores devem consultar o NLM’s
Citing Medicine para mais informações sobre os formatos das referências.
Artigo de revista
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Artigo extraído de endereço eletrônico
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink.com.w10069.dotlib.com.br/
content/l05j4j3332041225/fulltext. pdf. [Accessed in February 24, 2008].
Livro
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.
Tabelas e Figuras
Cada tabela ou figura deverá ser numerada em algarismo arábico e enviada
em arquivo separado (.jpg, .tif, .png, .xls, .doc) com 300 dpi no mínimo.
Título e legenda devem estar no mesmo arquivo da figura ou tabela a que se
referem. Tabelas e ilustrações devem ser autoexplicativas, com informações
suficientes para sua compreensão sem que se tenha de recorrer ao trabalho.
Fotomicrografias devem incluir a escala apropriada.
Artigo de Revisão
Revisões, preferencialmente sistemáticas, podem ser submetidas à RBR,
devendo abordar com profundidade um tema de interesse para o reumatologista. Não apresentam estruturação padronizada, prescindindo de introdução
ou discussão. Devem apresentar resumo sem subdivisões, com três a cinco
palavras-chave, e não devem exceder 6.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Podem
exibir até cinco figuras ou tabelas e até 70 referências.
Relato de Caso
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.
Comunicação breve
Aborda um ponto ou detalhe específico de um tema. Deve incluir resumo
com no máximo 250 palavras, e três a cinco palavras-chave. O texto não
necessita subdivisões, deve ter até 2.500 palavras incluindo-se as referências
e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até
três figuras ou tabelas e até 25 referências.
Regras para aplicar tempos verbais apropriados de acordo com
o contexto ou seção
Contexto ou seção
Resumo
Introdução
Métodos, materiais e
resultados
Discussão/Conclusão
Atribuições
Descrição de Tabelas e Figuras
Conhecimento estabelecido e
resultados prévios
Tempo verbal apropriado
Passado
Presente, quando se referir a fatos estabelecidos e conhecimento prévio
Passado
Combinado de passado (quando se referir a resultados obtidos no trabalho) e
presente (quando se referir a fatos estabelecidos e conhecimento prévio); às
vezes pode ser utilizado o futuro (especialmente quando se referir a perspectivas de trabalhos a serem realizados)
Passado
Ex.: Andrade et al. relataram...
Presente
Presente
Regras gerais para se obter uma boa escrita em um artigo científico:
1. Prefira a voz ativa.
2. As sentenças devem ser curtas, claras e objetivas.
3. A unidade de medida deve ser abreviada quando empregada com
valores numéricos (p. ex., 1 mg), mas escrita por extenso quando
separada de valor numérico. Utilize o Sistema Internacional de
Unidades (SI units) para definir as unidades de medida. Lembre-se
de deixar um espaço entre o número e a unidade (p. ex., 10 mg/dL),
exceto quando for porcentagem, que deve estar junto (p. ex., 70%).
O plural das unidades de medida é a mesma forma do singular (p.
ex., 1 mL, 10 mL; 1 h, 10 h). Quando iniciarem a frase, os números
devem estar por extenso, e não em algarismo arábico.
4. Defina a abreviação na primeira vez que aparecer no texto principal.
Após a definição, use sempre a abreviação em vez da forma por extenso.
Evite o uso de abreviações no título e no resumo.
5. Ao escrever em inglês, não utilize contrações (p. ex., prefira does not em
vez de doesn't).
Livro recomendado: Rogers SM. Mastering scientific and medical writing: a
self-help guide. Berlin: Springer; 2007.
Considerações éticas e legais
A RBR segue as normas do Uniform Requirements for Manuscripts (URM)
Submitted to Biomedical Journals desenvolvidas pelo The International
Committee of Medical Journal Editors (ICMJE) – fevereiro de 2006.
Conflito de interesse
A confiança pública no processo de revisão por pares e a credibilidade
dos artigos publicados dependem, em parte, de como o conflito de
interesse é administrado durante a redação, a revisão por pares e a
decisão editorial. O conflito de interesse existe quando um autor (ou
instituição do autor), revisor ou editor tem relações financeiras ou
pessoais que influenciem de forma inadequada (viés) suas ações (tais
relações são também conhecidas como duplo compromisso, interesses
conflitantes ou fidelidades conflitantes). Essas relações variam entre
aquelas com potencial insignificante até as com grande potencial
para influenciar o julgamento, e nem todas as relações representam
verdadeiro conflito de interesse. O potencial conflito de interesse pode
existir dependendo se o indivíduo acredita ou não que a relação afete
seu julgamento científico. Relações financeiras (tais como emprego, consultorias, posse de ações, testemunho de especialista pago) são os conflitos
de interesse mais facilmente identificáveis e os mais suscetíveis de minar a
credibilidade da revista, dos autores e da própria ciência. No entanto, podem
ocorrer conflitos por outras razões, tais como relações pessoais, competição
acadêmica e paixão intelectual.
Consentimento informado
Os pacientes têm o direito à privacidade, que não deve ser infringida
sem o consentimento informado. A identificação de informações,
incluindo os nomes dos pacientes, iniciais ou números no hospital,
não devem ser publicadas em descrições, fotografias e genealogias, a
menos que a informação seja essencial para os propósitos científicos
e o paciente (ou responsável) dê o consentimento livre e esclarecido
para a publicação.
O consentimento informado para este propósito requer que o manuscrito
a ser publicado seja mostrado ao paciente. Os autores devem identificar
os indivíduos que prestam assistência a escrever e divulgar a fonte de
financiamento para essa assistência. Detalhes identificadores devem ser
omitidos se não são essenciais.
O anonimato completo é difícil de se conseguir; no entanto, no caso
de qualquer dúvida, o consentimento deve ser obtido. Por exemplo,
mascarar a região ocular em fotografias de pacientes é uma proteção
de anonimato inadequada. Se as características de identificação são
alteradas para proteger o anonimato, como na linhagem genética, os
autores devem garantir que as alterações não distorçam o significado
científico. Quando o consentimento informado foi obtido, ele deve ser
indicado no artigo publicado.
Princípios éticos
Ao relatar experimentos em seres humanos, os autores devem indicar
se os procedimentos seguidos estiveram de acordo com os padrões
éticos do comitê responsável por experimentação humana (institucional e nacional) e com a Declaração de Helsinki de 1975, revisado em
2000. Se houver dúvida se a pesquisa foi realizada em conformidade
com a Declaração de Helsinki, os autores devem explicar a razão
para sua abordagem e demonstrar que o corpo de revisão institucional
aprovou explicitamente os aspectos duvidosos do estudo. Ao relatar
experimentos com animais, os autores devem indicar se as orientações
institucionais e nacionais para o cuidado e a utilização de animais de
laboratório foram seguidas.
Registro de ensaios clínicos
Os ensaios clínicos devem ser registrados segundo recomendação da
OMS em www.who.int/ictrp/en/. A definição de ensaios clínicos incluem ensaios preliminares (fase I): um estudo prospectivo com o
recrutamento de indivíduos submetidos a qualquer intervenção relacionada à saúde (medicamentos, procedimentos cirúrgicos, aparelhos,
terapias comportamentais, regime alimentar, mudanças nos cuidados
de saúde) para avaliar os efeitos em desfechos clínicos (qualquer
parâmetro biomédico e de saúde, inclusive medidas farmacocinéticas
e reações adversas).
A RBR tem o direito de não publicar trabalhos que não cumpram estas
e outras normas legais e éticas explicitadas nas diretrizes internacionais.
Financiamento e apoio
Os autores devem, também, informar se receberam financiamento ou apoio
de instituições como CNPq, CAPES, Fundos Remanescentes da SBR,
instituições universitárias, laboratórios etc.
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Founded on July 15, 1948 (Fundada em 15 de julho de 1948)
Executive Board of Directors for the 2012–2014 Biennium
Diretoria Executiva para o Biênio 2012–2014
President (Presidente)
Walber Pinto Vieira, CE
General secretary (Secretário geral)
Francisco José Fernandes Vieira, CE
1st secretary (1º secretário)
Lauredo Ventura Bandeira, SP
2nd secretary (2ª secretária)
Rosa Maria Rodrigues Pereira, SP
Treasurer (Tesoureiro)
José Eyorand Castelo B. Andrade, CE
Vice-treasurer (Vice-tesoureiro)
José Roberto Provenza, SP
Scientific director (Diretor científico)
Mittermayer Barreto Santiago, BA
Elected president (Presidente eleito)
Cesar Emile Baaklini, SP
Rheumatology Aid Fund to
Rheumatology Research and Teaching
Conselho do Fundo de Auxílio a
Pesquisa e Ensino em Reumatologia
Acir Rachid, PR
Adil Muhib Samara, SP
Antônio Carlos Ximenes, GO
Caio Moreira, MG
Cesar Emile Baaklini, SP
Emília Inoue Sato, SP
Fernando de Souza Cavalcanti, PE
Fernando Neubarth, RS
Geraldo da Rocha Castelar Pinheiro, RJ
Geraldo Gomes de Freitas, PE
Hilton Seda, RJ
Iêda Maria Magalhães Laurindo, SP
João Carlos Tavares Brenol, RS
João Francisco Marques Neto, SP
Nílzio Antônio da Silva, GO
Sebastião Cezar Radominski, PR
Walber Pinto Vieira, CE
Wiliam Habib Chahade, SP
Health Economy Commission
Comissão de Economia da Saúde
Coordinator (Coordenadora)
Representatives of PANLAR
Representantes junto à PANLAR
Adil Muhib Samara, SP
Antonio Carlos Ximenes, GO
Fernando Neubarth, RS
Maria Amazile Ferreira Toscano, SC
Mirhelen Mendes de Abreu, 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
Representatives of Ministry of Health
Epidemiology Commission
Representante junto ao Ministério da Saúde
Ana Patrícia de Paula, DF
Mário Soares Ferreira, DF
Comissão de Epidemiologia
Representatives of AMB
Representantes junto à AMB
Eduardo de Souza Meirelles, SP
Gustavo de Paiva Costa, DF
Morton Aaron Scheinberg, SP
Specialist Title Commission
Comissão de Título de Especialista
Coordinator (Coordenadora)
Emília Inoue Sato, SP
Members (Membros)
Fernanda Rodrigues Lima, SP
Gilda Aparecida Ferreira, MG
Ines Guimarães Silveira, RS
José Tupinambá Souza Vasconcelos, PI
Marcelo de Medeiros Pinheiro, SP
Mauro Goldfarb, RJ
Nafice Costa Araujo, SP
Rafael Navarrete, GO
Valeria Valim Cristo, ES
Wilton Silva dos Santos, DF
Coordinator (Coordenadora)
Eutilia Andrade Medeiros Freire, PB
Members (Membros)
Alessandra Souza Braz C. Andrade, PB
Bernardo Matos da Cunha, DF
Camila Cruz Leijoto, RJ
Carlos Augusto F. de Andrade, RJ
Jussara de Almeida L. Kochen, SP
Mirhelen Mendes de Abreu, SP
Pediatric Rheumatology Commission
Comissão de Reumatologia Pediátrica
Coordinator (Coordenador)
Cláudio Arnaldo Len, SP
Members (Membros)
Adriana Maluf Elias Sallum, SP
Ana Paula Vecchi, GO
Andre de Souza Cavalcanti, PE
Blanca Elene Rios Gomes Bica, RJ
Carlos Nobre Rabelo Jr., CE
Claudia Saad Magalhães, SP
Clovis Artur Almeida da Silva, SP
Cynthia Torres Franca da Silva, RJ
Luciana Brandão Paim Marques, CE
Marcia Bandeira, PR
Maria Teresa R. A. Terreri, SP
Tania Caroline Castro, SP
Teresa Cristina Robazzi, BA
Media Commission
Comissão de Comunicação Social
BSR Bulletin (Boletim SBR)
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
Coeditors (Coeditores)
Eloísa Silva Dutra de Oliveira Bonfá, SP
Hilton Seda, RJ
João Carlos Tavares Brenol, RS
Mittermayer Barreto Santiago, BA
Paulo Louzada-Junior, SP
Ricardo Fuller, SP
Simone Appenzeller, SP
BSR Website (Site SBR)
Coordinators (Coordenadores)
Marcelo Cruz Rezende, MS
Maria Roseli Monteiro Callado, CE
Ethics and Discipline Commission
Comissão de Ética e Disciplina
Coordinator (Coordenador)
José Marques Filho, SP
Members (Membros)
Adriana Maria Kakehasi, MG
Antonio Carlos Althoff, SC
Henrique Josef, SP
João Elias Moura Jr., SC
José Geraldo Araújo Paiva, CE
José Roberto Pereira Santos, ES
Teaching and Medical
Education Commission
Comissão de Ensino e Educação Médica
Coordinator (Coordenador)
Francisco Airton Castro da Rocha, CE
Members (Membros)
Cesar Emile Baaklini, SP
Charles Lubianca Kohem, RS
Claudia Diniz Lopes Marques, PE
Elaine Lira Medeiros de Bezerra, RN
Elisa Martins das N. de Albuquerque, RJ
Jozélia Rego, GO
Marcelo Pimenta, GO
Maria José Pereira Vilar, RN
Ricardo Machado Xavier, RS
Congresses, Journeys, and
Events Commission
Comissão de Congressos, Jornadas e Eventos
Coordinators (Coordenadores)
Fernando Neubarth, RS
Georges Basile Christopoulos, AL
José Roberto Provenza, SP
Members (Membros)
Antônio Carlos dos Santos Novaes, SP
Claudia Diniz Lopes Marques, PE
Elda Matilde Hirose Pastor, SP
Francisco Saraiva da Silva Júnior, CE
Hilton Seda, RJ
José Caetano Macieira, SE
Reno Martins Coelho, RJ
Ricardo Fuller, SP
Vasculopathies Commission
Comissão de Vasculopatias Commission of Relations
with Groups of Patients
Coordinator (Coordenador)
Comissão de Relações com
Grupos de Pacientes
Members (Membros)
Coordinators (Coordenadores)
Helenice Alves Teixeira Gonçalves, DF
Members (Membros)
Ana Maria Camargo Gallo, SC
Ana Paula Espinula Gianordoli, ES
Eduardo de Souza Meirelles, SP
Luis Piva Junior, DF
Valderílio Feijó Azevedo, PR
Wanda Heloisa Rodrigues Ferreira, RJ
Occupational Rheumatology Commission
Comissão de Reumatologia Ocupacional
Coordinator (Coordenador)
Milton Helfenstein Junior, SP
Members (Membros)
Anna Beatriz Assad Maia, DF
Antônio Techy, PR
César Augusto Fávaro Siena, SP
Marco Aurélio Goldenfum, RS
BiobadaBrasil Comission
Comissão do BiobadaBrasil
Coordinator (Coordenador)
David Cezar Titton, PR
Members (Membros)
Roger Abramino Levy, RJ Adriana Danowski, RJ
Adriana Maria Kakehasi, MG
Alexandre Wagner S. de Souza, SP
Ana Beatriz S. Bacchiega de Freitas, RJ
Andreas Funke, PR
Carlos Ewerton Maia Rodrigues, CE
Danieli Castro Oliveira de Andrade, SP
Isabella Vargas de Souza Lima, BA
Jozélia Rego, GO
Manuella Lima Gomes Ochtrop, RJ
Image Commission
Comissão de Imagem Coordinator (Ccoordenador)
José Alexandre Mendonça, SP
Members (Membros)
Andrea B. Vannucci Lomonte, SP
Cristiane Kayser Veiga da Silva, SP
Iêda Maria Magalhães Laurindo, SP
Inês Guimarães Silveira, RS
Jamil Natour, SP
Karine Rodrigues da Luz, SP
Laura Maria C. Mendonça, RJ
Simone Appenzeller, SP
Verônica Silva Vilela, RJ
Procedures Commission
Comissão de Procedimentos
Aline Ranzolin, PE
André Luiz Shinji Hayata, SP
Ines Guimarães da Silveira, RS
Mirhelen Mendes de Abreu, SP
Paulo Louzada-Junior, SP
Roberto Ranza, MG
Valéria Cristo Valim, ES
Coordinator (Ccoordenador)
Rheumatoid Arthritis Commission
Lupus Commission
Comissão de Artrite Reumatoide
Coordinator (Coordenadora)
Licia Maria Henrique da Mota , DF Members (Membros)
Bóris Afonso Cruz, MG
Claiton Viegas Brenol, RS
Geraldo da Rocha Castelar Pinheiro, RJ
Ieda Maria Magalhães Laurindo, SP
Jozélio Freire de Carvalho, BA
Manoel Barros Bertolo, SP
Max Victor Carioca Freitas, CE
Nilzio Antônio da Silva, GO
Paulo Louzada-Junior, SP
Rina Dalva Neubarth Giorgi, SP
Rodrigo Aires Corrêa Lima, DF
Jamil Natour, SP
Members (Membros)
Geraldo da Rocha Castelar Pinheiro, RJ
Luiza Helena Coutinho Ribeiro, SP
Monique Sayuri Konai, SP
Rita Nely Vilar Furtado, SP
Comissão de Lúpus
Coordinator (Coordenador)
Evandro Mendes Klumb, RJ
Members (Membros)
Cristina Costa Duarte Lanna, MG
Eduardo Ferreira Borba Neto, SP
Eloisa Silva Dutra de Oliveira Bonfá, SP
Emília Inoue Sato, SP
Francinne Machado Ribeiro, RJ
João Carlos Tavares Brenol, RS
Lilian Tereza Lavras Costallat, SP
Luiz Carlos Latorre, SP
Maria de Fátima Lobato da Cunha, PA
Odirlei Andre Monticielo, RS
Spinal Commission
Ari Stiel Radu Halpern, SP
Carlos Appel da Silva, RS
Jamil Natour, SP
Jose Gerardo de Araújo Paiva, CE
Luíza Helena Coutinho Ribeiro, SP
Maria Amazile Ferreira Toscano, SC
Renê Donizeti Ribeiro de Oliveira, SP
Silvio Figueira Antonio, SP
Osteomethabolic Diseases and
Osteoporisis Commission
Comissão de Doenças
Osteometabólicas e Osteoporose
Coordinator (Coordenador)
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
Spondiloarthropathies Commission
Comissão de Espondiloartropatias
Coordinator (Coordenador)
Célio Roberto Gonçalves, SP
RBE Coordinator (Coordenador RBE)
Percival Degrava Sampaio Barros, SP
Members (Membros)
Antonio Carlos Ximenes, GO
Eduardo de Souza Meirelles, SP
Gustavo Gomes Rezende, MG
Ivânio Alves Pereira, SC
Marcelo Medeiros Pinheiro, SP
Mauro Waldemar Keisermann, RS
Thelma Larocca Skare, PR
Walber Pinto Vieira, CE
Washington Alves Bianchi, RJ
Psoriatic Arthritis Subcommission (Sub-Comissão de Artrite Psoriásica)
Claudia Goldenstein-Schainberg, SP
Roberto Ranza, MG
Rubens Bonfiglioli, SP
Sueli Coelho da Silva Carneiro, RJ
Valderilio Feijó Azevedo, PR
Pain, Fibromyalgia and Other Painful
Syndromes of the Soft Parts Commission
Comissão de Dor, Fibromialgia e Outras
Síndromes Dolorosas de Partes Moles
Coordinator (Coordenador)
Marcelo Cruz Rezende, MS
Members (Membros)
Aline Ranzolin, PE
Daniel Feldman Pollak, SP
Eduardo dos Santos Paiva, PR
José Eduardo Martinez, SP
José Roberto Provenza, SP
Marcos Aurélio Freitas Machado, SP
Nilton Salles Rosa Neto, SP
Rafael Mendonça da Silva Chakr, RS
Roberto Ezequiel Heymann, SP
Documentation and Historical
Registry Commission
Osteoarthrosis Commission
Comissão de Coluna Vertebral
Comissão de Documentação e
Registro Histórico
Comissão de Osteoartrose
Coordinator (Coordenador)
Coordinator (Coordenador)
Coordinator (Coordenador)
Ibsen Bellini Coimbra, SP
Marcos Renato de Assis, SP
Members (Membros)
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
Coordinators (Coordenadores)
Izaias Pereira da Costa, MS
Sandra Lucia Euzébio Ribeiro, AM
Members (Membros)
Ana Carolina de Oliveira S. Montandon, GO
Helena Lucia A. Pereira, AM
Luiz Sergio Guedes Barbosa, MT
Mauro Furtado Cavalcanti, PI
Natalino Hajime Yoshinari, SP
Rejane Maria R. de Abreu, CE
Roberta de Almeida Pernambuco, SP
Coordinator (Coordenador)
Percival Degrava Sampaio-Barros, SP
Members (Membros)
Adriana Fontes Zimmermann, SC
Carolina de Souza Muller, PR
Cláudia Tereza Lobato Borges, MA
Cristiane Kayser Veiga da Silva, SP
Eutília Andrade Medeiros Freire, PB
Giselle Baptista Maretti, RJ
João Francisco Marques Neto, SP
Maria Cecília Fonseca Salgado, RJ
Maria de Fátima Lobato da Cunha Sauma, PA
Mário Newton Leitão de Azevedo, RJ
Sheila Marcia de A. Fontenele, CE
Sjögren Syndrome Commission
(Comissão de Síndrome de Sjögren)
Coordinator (Coordenadora)
Valéria Valim Cristo, ES
Members (Membros)
Érica Vieira Serrano, ES
Leandro Augusto Tanure, MG
Sandra Gofinet Pasoto, SP
Sandra Lucia Euzébio Ribeiro, AM
Virginia Fernandes Moça Trevisani, SP
Rheumatology Society of Mato Grosso do Sul
Sociedade de Reumatologia do Rio de Janeiro
Dr. Evandro Mendes Klumb
Members (Membros)
Rheumatology Society of
Rio Grande do Norte
Reno Martins Coelho, RJ
Adrian Nogueira Bueno, MG
Ana Teresa Amoedo Medrado, BA
Antonio Carlos Scafutto, MG
Claudio Goldenstein Schainberg, SP
Eliezer Rushansky, PE
Evelin D. Goldenberg M. M. da Costa, SP
José Eyorand Castelo B Andrade, CE
José Roberto Silva Miranda, SP
Manoel Barros Bertolo, SP
Rafael de Oliveira Fraga, MG
Ricardo Jorge de Percia Name, RJ
Vander Fernandes, MT
Supervisory Board (Conselho Fiscal)
Fernando Neubarth, RS
Iêda Maria Magalhães Laurindo, SP
Geraldo da Rocha Castelar Pinheiro, RJ
Rheumatology Society Mato Grosso
Associação Mato-Grossense de Reumatologia
Dr. Eduardo Benevides Lindote Filho
Rheumatology Society of Alagoas
Sociedade Alagoana de Reumatologia
Dra. Inês Cristina de Mello
Rheumatology Society of Amapá
Gout Commission
Sociedade Amapaense de Reumatologia
Dr. Alessandro Marcus Pinheiro Melo
(Comissão de Gota)
Rheumatology Society of Amazonas
Coordinator (Coordenador)
Geraldo da Rocha Castelar Pinheiro, RJ
Sociedade Amazonense de Reumatologia
Dra. Maria do Socorro A. de Souza
Members (Membros)
Rheumatology Society of Bahia
(Comissão de Doenças
Endêmicas e Infecciosas)
Sociedade de Reumatologia do Espírito Santo
Dr. José Roberto Pereira Santos
Coordinator (Coordenador)
Coordinators (Coordenadores)
Endemic and Infectious
Diseases Commission
Rheumatology Society of Espírito Santo
Rheumatology Society of Rio de Janeiro
Regionais – SBR
Adil Muhib Samara, SP
Antonio José Lopes Ferrari, SP
Ana Beatriz Vargas dos Santos, RJ
Hellen Mary da Silveira de Carvalho, DF
Sociedade de Reumatologia de Rondônia
Dr. Liszt Jonney Silva dos Santos
(Comissão de Centros de Terapia
Imunobiológica Assistida)
BSR – Regionals
Francisco Alves Bezerra Neto, RN
Matheus Staufackar Carlos, RN
Inês Cristina de Mello Lima, AL
Mauro Furtado Cavalcante, PI
Rheumatology Society of Rondônia
Sociedade de Reumatologia do Mato Grosso
do Sul
Dr. Izaias Pereira da Costa
(Comissão de Defesa Profissional)
Members (Membros)
Sociedade de Reumatologia de Brasília
Dr. Cleandro Pires de Albuquerque
Assisted Therapy Immunobiological
Centers Commission
Professional Defense Commission
Francisco Deoclécio D. Rocha, RN
Vander Fernandes, MT
Rheumatology Society of Brasília
Sociedade Baiana de Reumatologia
Dr. Mittermayer Barreto Santiago
Rheumatology Society of Santa Catarina
Sociedade Catarinense de Reumatologia
Sonia Cristina de Magalhães Souza Fialho
Rheumatology Society of Ceará
Sociedade Cearense de Reumatologia
Dr. José Eyorand Castelo Branco de Andrade
Sociedade de Reumatologia
do Rio Grande do Norte
Dr. Francisco Deoclécio Damasceno Rocha
Rheumatology Society of Rio Grande do Sul
Sociedade de Reumatologia
do Rio Grande do Sul
Dr. Marco Aurélio Goldenfum
Rheumatology Society of Tocantis
Sociedade de Reumatologia do Tocantins
Dra. Daniela Edilma Japiassu Custódio
Rheumatology Society of Goiânia
Sociedade Goiana de Reumatologia
Dra. Rosane Gouveia Vilela Machado
Rheumatology Society of Maranhão
Sociedade Maranhense de Reumatologia
Dra. Raquel Moraes da Rocha Nogueira
Rheumatology Society of Minas Gerais
Sociedade Mineira de Reumatologia
Dr. Boris Afonso Cruz
Rheumatology Society of Pará
Sociedade Paraense de Reumatologia
Dr. Rosana de Britto Pereira Cruz
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 São Paulo
Sociedade Paulista de Reumatologia
Dr. Dawton Torigoe
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 Sergipe
Sociedade Sergipana de Reumatologia
Dra. Regina Adalva de Lucena Couto Ocea
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Avenida Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 – CEP: 01402-000 – São Paulo, SP, Brasil
Phone/Fax:
55 11 3289-7165
E-mail:
[email protected], [email protected]
Website:
www.reumatologia.com.br
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Volume 54. Number 3. May/June 2014
Volume 54. Número 3. Maio/Junho 2014
CONTENTS | SUMÁRIO
Editorial
ScienceDirect: The indexation which RBR lacked
ScienceDirect: a indexação que faltava à RBR
Paulo Louzada-Junior.................................................................................................................................. 165
Original articles | Artigos originais
Inequality in the distribution of rheumatologists in Brazil: correlation with local of medical
residency, Gross Domestic Product and Human Development Index
Inequalidade na distribuição de reumatologistas no Brasil: correlação com local de residência médica,
Produto Interno Bruto e Índice de Desenvolvimento Humano
Cleandro Pires de Albuquerque................................................................................................................... 166
Otorhinolaryngological findings in a group of patients with rheumatic diseases
Achados otorrinolaringológicos em um grupo de pacientes com doenças reumatológicas
Reinaldo Jordão Gusmão, Fernando Laffitte Fernandes, Alexandre Caixeta Guimarães,
Lutiane Scaramussa, Zoraida Sachetto, Henrique Furlan Pauna, Guilherme Machado de Carvalho......... 172
Randomized controlled trial of a therapeutic intervention group in patients with fibromyalgia
syndrome
Estudo randomizado e controlado de uma intervenção terapêutica grupal em pacientes com síndrome
fibromiálgica
Marielza R. Ismael Martins, Cristiane Carnaval Gritti, Randolfo dos Santos Junior,
Maria Carolina Luizetto de Araújo, Lilian Chessa Dias, Marcos Henrique D’all Aglio Foss,
Larissa Batista de Andrade, Carlos Eduardo D’all Aglio Rocha.................................................................. 179
Construction of a manual of work processes and techniques from Centro de Dispensação de
Medicamentos de Alto Custo (CEDMAC), Hospital de Clínicas, Unicamp
Construção do manual de processos de trabalho e técnicas do Centro de Dispensação de Medicamentos de
Alto Custo (CEDMAC) do Hospital de Clínicas da Unicamp
Manoel Barros Bertolo, Bruno Silva de Araújo Ferreira, Adriana G. Mucke Marchiore,
Glaucia Pereira do Amaral Carvalho, Débora Pessoa de Souza, Eliane Molina Psaltikidis......................... 185
Evaluation of respiratory impairment in patients with systemic lupus erythematosus with
the six-minute walk test
Avaliação do comprometimento respiratório em pacientes com lúpus eritematoso sistêmico com o teste de
caminhada de seis minutos
Marivone Arruda Leite, Mônica Corso Pereira, Lílian Tereza Lavras Costallat,
Wander de Oliveira Villalba, Marcos Mello Moreira, Ilma Aparecida Paschoal.......................................... 192
Analysis of the association of fatigue with clinical and psychological variables in a series of
371 Brazilian patients with rheumatoid arthritis
Análise da associação da fadiga com variáveis clínicas e psicológicas em uma série de 371 pacientes brasileiros
com artrite reumatoide
Washington A. Bianchi, Fernanda R. Elias, Geraldo da Rocha Castelar Pinheiro,
Carlos Roberto Machado Gayer, Claudio Carneiro, Rachel Grynzpan, Paulo Hamdan, Sueli Carneiro............ 200
Evaluation of postural control and quality of life in elderly women with knee osteoarthritis
Avaliação do controle postural e da qualidade de vida em idosas com osteoartrite de joelho
Júlia Guimarães Reis, Matheus Machado Gomes, Thamires Máximo Neves, Marina Petrella,
Renê Donizeti Ribeiro de Oliveira, Daniela Cristina Carvalho de Abreu..................................................... 208
Review articles | Artigos de revisão
Pre-operative anesthetic assessment of patients with rheumatoid arthritis
Avaliação anestésica pré-operatória de pacientes com artrite reumatoide
Rodrigo Barbosa Aires, Jozélio Freire de Carvalho, Licia Maria Henrique da Mota.................................... 213
Rituximab for rheumatoid arthritis treatment: a systematic review
Rituximabe para o tratamento da artrite reumatoide: revisão sistemática
Lívia Lovato Pires de Lemos, Juliana de Oliveira Costa, Marina Amaral de Ávila Machado,
Alessandra Maciel Almeida, Mariana Michel Barbosa, Adriana Maria Kakehasi,
Vânia Eloísa de Araújo, Augusto Afonso Guerra Júnior, Francisco de Assis Acurcio.................................. 220
Case report | Relato de caso
IgA nephropathy and polymyositis: a rare association
Nefropatia por IgA e polimiosite: uma rara associação
Thiago Bitar Moraes Barros, Fernando Henrique Carlos de Souza,
Denise Maria Avancini Costa Malheiros, Mauricio Levy-Neto, Samuel Katsuyuki Shinjo......................... 231
Spondyloptosis in athlete
Espondiloptose em atleta
Ana Paula Luppino Assad, Andressa Silva Abreu, Luciana Parente Costa Seguro,
Lissiane Karine Noronha Guedes, Fernanda Rodrigues Lima, Ana Lucia de Sá Pinto................................ 234
First report of mild Brazilian spotted fever associated to arthritis
Primeiro caso de febre maculosa brasileira branda associada à artrite
Virgínia Lucia Nazario Bonoldi, Roberta Gonçalves Marangoni, Giancarla Gauditano, Jonas Moraes-Filho,
Marcelo Bahia Labruna, Natalino Hajime Yoshinari.................................................................................. 237
Brief communication | Comunicação breve
Patients with systemic lupus erythematosus and secondary antiphospholipid syndrome
have decreased numbers of circulating CD4+CD25+Foxp3+ Treg and CD3–CD19+ B cells
Pacientes com lúpus eritematoso sistêmico e síndrome antifosfolípide secundária possuem números reduzidos
de células B CD4+ CD25+ Foxp3+ (células Treg) e células B CD3– CD19+ circulantes
Ester Rosári Raphaelli Dal Ben, Carine Hartmann do Prado, Talita Siara Almeida Baptista,
Moisés Evandro Bauer, Henrique Luiz Staub.............................................................................................. 241
When anti-TNF fails, anti-IL12-23 is an alternate option in psoriasis and psoriatic arthritis
Quando anti-TNF não obtém sucesso, anti-IL-12-23 é opção alternativa na psoríase e na artrite psoriásica
Ricardo Prado Golmia, Ayk Helena Barbosa Martins, Morton Scheinberg.................................................. 247
Articular ultrasonography: interobserver reliability in rheumatoid arthritis
Ultrassonografia articular: confiabilidade interobservadores em artrite reumatoide
Melissa Cláudia Bisi, Aline Defaveri do Prado, Cristina Rabelo, Flávia Brollo,
Inês Guimarães da Silveira, José Alexandre de Mendonça, Henrique Luiz Staub....................................... 250
Retraction | Retratação
Retraction of Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese
patients with Leishmania donovani infection
Retratação de Anticorpos antipeptídeos citrulinados e o fator reumatoide em pacientes sudaneses com
infecção Leishmania donovani
Erik Ahlin, Amir Elshafei, Musa Nur, Sayda Hassan El Safi, Johan Ronnelid, Gehad Elghazali................. 255
Erratum | Errata
Erratum of volume 54, issue 1
Errata do volume 54, número 1............................................................................................................................ 256
2oanos
de experiência1
MAIS LONGO HISTÓRICO DE DADOS DE SEGURANÇA
E EFICÁCIA1-10 NOS TRATAMENTOS DE:
Artrite Reumatoide1, Espondilite
Anquilosante1 e Artrite Idiopática
Juvenil1 – resposta clínica rápida e
sustentada em estudo de até 4 anos.1,11-13
Psoríase1* e Artrite Psoriásica1 –
tratamento eficaz e seguro.14,15
Referências bibliográficas: 1) Bula de Enbrel® PFS. 2) Bula de Remicade®. 3) Bula de Humira®. 4) Bula de Stelara®. 5) Bula de Simponi®. 6) Bula de Cimzia®. 7) Bula de Actemra®. 8) Bula de Mabthera®. 9) Bula de Orencia®. 10) Yamauchi PS, Gindi V, Lowe NJ. The treatment of
psoriasis and psoriatic arthritis with etanercept: practical considerations on monotherapy, combination therapy, and safety. Dermatol Clin. 2004 Oct;22(4):449-59. 11) Davis J C, et al. Efficacy and safety of up to 192 weeks of etanercepte therapy in patients with ankylosing spondylitis.
Ann Rheum Dis, 2008; 67:346–352. 12) Davis J C, et al. Reduction in health related quality of life in patients with ankylosing spondylitis and improvements with etanercept therapy. Arthritis Rheum 2005;53:494–501. 13) Gorman J D, et al. Treatment of ankylosing spondylitis by
inhibition of tumor necrosis factor. N Engl J Med, 2002; 346: 1349-56. 14) Siegfried EC, et al. Intermittent etanercept therapy in pediatric patients with psoriasis. J Am Acad Dermatol. 2010 Nov;63(5):769-74. 15) Sterry W, et al. Comparison of two etanercept regimens for treatment
of psoriasis and psoriatic arthritis: PRESTA randomised double blind multicentre trial. BMJ. 2010 Feb 2;340:c147.
Enbrel®/Enbrel® PFS (etanercepte). Indicações: adulto: artrite reumatoide, espondilite anquilosante, artrite psoriásica e psoríase em placas. Pediátrico: artrite idiopática juvenil (AIJ) poliarticular (4-17 anos) e psoríase em placas (8-17 anos). Contraindicações:
hipersensibilidade ao etanercepte ou a qualquer componente da fórmula do produto. Pacientes com infecção localizada ou generalizada, crônica ou ativa, ou em risco de desenvolvê-la. Advertências e Precauções: foram relatadas reações alérgicas associadas ao Enbrel®/
Enbrel® PFS. Caso ocorra, descontinuar imediatamente a medicação. Imunossupressão: terapia anti-TNF pode comprometer a defesa do hospedeiro contra infecções e doenças malignas. No período pós-comercialização há relatos de doenças malignas em diversos órgãos,
mas ainda não se sabe qual o impacto do tratamento com etanercepte sobre o desenvolvimento e a progressão das malignidades e infecções ativas e/ou crônicas. Há relatos de câncer de pele melanoma e não melanoma com antagonistas de TNF. Exame de pele periódico
recomendado. Reações hematológicas: casos incomuns de trombocitopenia, raros de pancitopenia e muito raros de anemia aplástica, alguns evoluindo para óbito. Cautela em pacientes com história pregressa de discrasia sanguínea. Procurar aconselhamento médico imediato
caso desenvolva sinais e sintomas sugestivos de discrasias sanguíneas ou infecções durante o tratamento. Discrasias confirmadas, etanercepte deve ser descontinuado. Enbrel®/Enbrel® PFS pode estar associado à formação de anticorpos autoimunes. Não administrar
concomitantemente vacinas com microrganismos vivos. Atualizar cartão vacinal de acordo com normas locais antes do início da terapia. Eventos neurológicos: relatos raros de distúrbios desmielinizantes, porém não se sabe qual a relação causal com etanercepte. Recomendase avaliação da relação risco/benefício ao prescrever este medicamento a pacientes com doença desmielinizante ou com risco aumentado de desenvolvê-la. Distúrbios cardíacos: relatos pós-comercialização de piora da insuficiência cardíaca congestiva (ICC), com e sem a
identificação dos fatores precipitantes. Embora não conclusivos, dados de estudo clínico sugerem possível tendência à piora da ICC com etanercepte. Recomenda-se cautela nesses pacientes. Infecções: avaliar pacientes para infecções antes, durante e depois do tratamento
com Enbrel®/Enbrel® PFS. Tuberculose (TB): antes do início da terapia com Enbrel®/Enbrel® PFS, o paciente deve ser avaliado para infecção ativa ou latente. A profilaxia de TB latente deve ser iniciada antes da terapia com Enbrel®/Enbrel® PFS seguindo diretrizes locais.
Havendo TB ativa, o Enbrel®/Enbrel® PFS não deve ser iniciado. Não se sabe se a terapia com Enbrel®/Enbrel® PFS aumenta esse risco. Reativação da Hepatite B: relatada reativação do vírus da hepatite B (HBV) em portadores crônicos usando terapia anti-TNF. Cautela no
uso do etanercepte em portadores do HBV. Monitorar sinais e sintomas de infecção ativa pelo HBV. Hepatite C: relatos de piora embora sem estabelecer relação causal com o etanercepte. Não recomendado em conjunto com tratamento de hepatite alcoólica. Hipoglicemia:
relatada em associação com tratamento para diabetes. Gravidez: ainda não se estabeleceu o uso seguro de Enbrel® durante a gravidez. Lactação: optar entre descontinuar a amamentação ou descontinuar Enbrel® durante lactação. Pediátrico: não usar em menores de 4 anos.
Idosos: não necessita ajuste posológico específico. Dirigir veículos e operar máquinas: não há estudos sobre este tipo de efeito. Gravidez: categoria de Risco B: este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista.
Reações adversas: adulto: reação no local da injeção com eritema, prurido, dor, edema, hemorragia e hematoma. Infecção do trato respiratório superior, infecções por bactérias, microbactérias, vírus, fungos e parasitas (incluindo protozoários). Infecções oportunistas também
foram relatadas (incluindo a listeriose e legionelose). Doenças malignas. Reações muito comuns: infecções (incluindo infecções do trato respiratório superior, bronquite, cistite, infecções da pele). Comuns: reações alérgicas, autoanticorpos, febre, prurido. Incomuns: infecções
sérias (incluindo pneumonia, celulite, artrite séptica, sepse e infecção parasitária), urticária, rash cutâneo, psoríase, vasculite sistêmica (incluindo vasculite ANCA positiva), uveíte, esclerite, trombocitopenia, doença pulmonar intersticial, câncer de pele não melanoma. Raras:
tuberculose, infecções oportunistas (incluindo fúngica invasiva, infecções bacterianas e microbacterianas atípicas e Legionela), reação anafilática, convulsões, evento desmielinizante do SNC, neurite óptica, mielite transversa, vasculite cutânea, síndrome de Stevens-Johnson,
eritema multiforme, lúpus cutâneo, lúpus discoide, síndrome do tipo lúpus, anemia, leucopenia, neutropenia, pancitopenia, elevação de enzimas hepáticas, hepatite autoimune, melanoma, piora da ICC. Muito raras: anemia aplástica, necrólise epidérmica tóxica. Não conhecidas:
listeria, reativação da hepatite B, carcinoma de célula de Merkel, síndrome de ativação de macrófagos. Presença de anticorpo antinuclear, anti-DNA e anticardiolipina. Pediatria: eventos semelhantes aos observados em adultos. Relato de dois casos de varicela e quatro casos
de síndrome de ativação de macrófagos na AIJ. Interações: não recomendado uso de Enbrel®/Enbrel® PFS com anakinra e abatacepte. Uso concomitante de sulfassalazina pode se associar a leucopenia de significância clínica não conhecida. Não há interações de Enbrel®/
Enbrel® PFS com glicocorticoides, salicilatos, anti-inflamatórios não esteroides (AINEs), analgésicos ou metotrexato. Não há interações farmacocinéticas com digoxina e varfarina. Posologia: uso em adultos (≥ 18 anos): artrite reumatoide, espondilite anquilosante e artrite
psoriásica: 50 mg por semana (uma injeção subcutânea utilizando uma seringa de 50 mg, em duas injeções de 25 mg administradas praticamente simultâneas ou 25 mg de Enbrel® duas vezes por semana, com 3 ou 4 dias de intervalo). Psoríase em Placas: 50 mg por semana
(uma injeção subcutânea utilizando uma seringa de 50 mg, em duas injeções de 25 mg administradas praticamente simultâneas ou 25 mg de Enbrel® duas vezes por semana, com 3 ou 4 dias de intervalo). Respostas maiores podem ser obtidas com tratamento inicial por até
12 semanas com 50 mg duas vezes por semana. Pacientes adultos podem ser tratados intermitente ou continuamente, baseados no julgamento do médico e nas necessidades individuais do paciente. Mesma posologia no retratamento. Uso pediátrico: AIJ (≥ 4 e < 18 anos): 0,4
mg/kg (máximo 25 mg por dose) administrada 2 vezes por semana em injeção subcutânea com intervalo de 3-4 dias entre as doses. Pacientes com 31 kg ou menos: a dose deve ser administrada em uma única injeção subcutânea uma vez por semana. Psoríase em placas (≥
8 e < 18 anos): 0,8 mg/kg por semana (máximo 50 mg por dose) administrada 1 vez por semana durante período máximo de 24 semanas. Descontinuar caso paciente não responda após 12 semanas. Mesma dose no retratamento. A cada nova aplicação, usar local diferente
a, pelo menos, 3 cm do local anterior. NÃO aplicar a injeção em áreas com pele sensível, hematoma, avermelhada ou endurecida. VENDA SOB PRESCRIÇÃO MÉDICA. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. MS – 1.2110.0206 (Enbrel®)
e MS – 1.2110.0274 (Enbrel® PFS). Para informações completas, consulte as bulas dos produtos (ENBPOI_14 e ENBPFS_12). Documentação científica e informações adicionais estão à disposição da classe médica mediante solicitação. Wyeth Indústria Farmacêutica Ltda.
Rua Alexandre Dumas, 1.860, São Paulo – SP – CEP 04717-904. Tel.: 08000-160625. www.wyeth.com.br.
INTERAÇÃO MEDICAMENTOSA: NÃO UTILIZAR O PRODUTO EM ASSOCIAÇÃO A ANAKINRA E ABATACEPTE. CONTRAINDICAÇÃO: ENBREL®
PFS (ETANERCEPTE) É CONTRAINDICADO EM PACIENTES COM SEPTICEMIA OU EM RISCO DE DESENVOLVER UMA SEPTICEMIA.
SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.
* Único aprovado para psoríase pediátrica (a partir de 8 anos de idade).1-9
Material para ser entregue exclusivamente a profissionais prescritores ou dispensadores de medicamentos.
Maio/2014.
Wyeth uma empresa do grupo Pfizer.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 5
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Editorial
ScienceDirect: The indexation which RBR lacked
ScienceDirect: a indexação que faltava à RBR
Since 2014, the Brazilian Journal of Rheumatology became indexed to ScienceDirect, which is responsible for nearly a
quarter of the world’s peer-reviewed scientific content. It is
estimated that this indexer receives 15 million views per year.
Its target audience is composed by researchers, health professionals, teachers, and students. At its base, ScienceDirect has
about 12 million scientific articles, 2,200 journals and 26,000
books, and its data are indexed in Scopus. Thus, I believe we
are closing a cycle that began in 2010 with the indexation
in PubMed,1 followed by the inclusion of RBR in the Web of
Science database in 2012,2,3 with its first impact factor at JCR
measured in 2013 (IF=0.864).
RBR is maturing in its scientific content; it represents the
only journal in Latin America in the field of Rheumatology,
and is also the only one included in the three main international scientific publications’ indexers.1-3 RBR is becoming the
main portal of scientific rheumatological divulgation for all
our vast continent. In addition to this, the indexation in ScienceDirect will allow the publication of articles in the online
first system, allowing the already accepted articles to have a
DOI and remain available for consultation in PubMed. I urge
everyone to access the following link for checking out this
new indexation: http://www.journals.elsevier.com/revistabrasileira-de-reumatologia/
In conclusion, the indexation in ScienceDirect is one more
reason for celebration by the Brazilian Society of Rheumatology, which should be congratulated. This achievement is nothing but the result of a hard and persistent work pioneered
decades ago. Now we are seeing the fruits of a small seed
planted so long ago. I have no doubt that this legacy of our
generation will be acknowledged in the future; I also know
that much work lies ahead, always aiming to improve our Brazilian Journal of Rheumatology.
Paulo Louzada-Junior
Faculdade de Medicina de Ribeirão Preto,
Universidade de São Paulo
E-mail: [email protected]
R eferences
1. Santiago MB,FullerR. RBR indexada no MEDLINE. (Editorial).
Rev Bras Reumatol.2010;50:613-15.
2. Louzada-Junior P, Freitas MV. The Brazilian Journal of
Rheumatology over the last ten years: a scientometrics-based
view. Rev Bras Reumatol. 2011;51:1-4.
3. Freitas MV; Heymann RE. O Fator de Impacto. Rev Bras
Reumatol 2013;53:321.
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2014.05.001
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Inequality in the distribution of rheumatologists in Brazil:
correlation with local of medical residency, Gross Domestic
Product and Human Development Index
Cleandro Pires de Albuquerque*
Service of Rheumatology, Medicine Faculty, Universidade de Brasília, Brasília, DF, Brazil
article info
abstract
Article history:
Objective: To assess the distribution of rheumatologists in Brazil and their correlation with
Received on 15 April 2013
Medical Residency specialization offer, Gross Domestic Product (Gdp) And Municipal Hu-
Accepted on 23 August 2013
man Development Index (HDI-M) of units of the federation (UFs).
Methods: Query to various official databases, data summarization by techniques for de-
Keywords:
scriptive statistics and cross-referenced information. For correlation analysis, we used the
Rheumatology
Spearman correlation coefficient (r).
Physician’s distribution
Results: There were 1229 rheumatologists regularly registered in the country. The North-
Health policy
ern region had only 3.6% of the total (n = 44), while the Southeast had 42.2% (n = 519). The
Epidemiology
State capitals, added to the five largest municipalities in each UF, concentrated 75.8% of
these specialists (n = 931). In total, 49.9% of rheumatologists offered treatment at SUS. A
general ratio of 157,809 inhabitants per rheumatologist in Brazil was determined, but with
wide variation among UFs with respect to this ratio. In the years 2000-2012, there were 593
Rheumatology Residency graduated physicians in Brazil. We observed a positive correlation among number of rheumatologists compared with GDP (r = 0.94), HDI-M of the State
capitals (r = 0.77) and number of Rheumatology Residency graduated physicians (r = 0.79)
in UFs.
Conclusions: We noted a strong concentration of rheumatologists in State capitals and
larger municipalities, with noticeable inequalities also between UFs and country regions.
The distribution of these professionals accompanied GDP, HDI-M of the State capital and
number of Rheumatology Residency graduated physicians, suggesting that factors related
to income opportunities and human development and the place of speciality training may
influence the geographical fixation of rheumatologists.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (C.P. Albuquerque).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.08.001
167
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1
Inequalidade na distribuição de reumatologistas no Brasil: correlação
com local de residência médica, Produto Interno Bruto e Índice de
Desenvolvimento Humano
resumo
Palavras-chave:
Objetivo: Avaliar a distribuição dos reumatologistas no Brasil e sua correlação com oferta de
Reumatologia
residência médica (RM) especializada, Produto Interno Bruto (PIB) e Índice de Desenvolvim-
Distribuição de médicos
ento Humano Municipal (IDH-M) das unidades da federação (UFs).
Política de saúde
Métodos: Consulta a várias bases de dados oficiais, sumarização de dados por técnicas es-
Epidemiologia
tatísticas descritivas e cruzamento de informações. Para análise de correlação, utilizou-se
o coeficiente de Spearman (r).
Resultados: Foram encontrados 1.229 reumatologistas registrados regularmente no país. A
região Norte reunia apenas 3,6% desse contingente (n = 44), enquanto o Sudeste, 42,2%
(n = 519). As capitais somadas aos cinco maiores municípios de cada UF concentraram
75,8% desses especialistas (n = 931). No total, 49,9% dos reumatologistas prestavam atendimento pelo Sistema Único de Saúde (SUS). Achou-se razão geral de 157.809 habitantes
para cada reumatologista no Brasil, porém com grande variação entre as UF quanto a essa
proporção. Entre 2000 e 2012, houve 593 concluintes de RM em reumatologia no Brasil.
Achou-se correlação positiva do número de reumatologistas ante o PIB (r = 0,94), o IDH-M
da capital (r = 0,77) e o número de concluintes de RM em reumatologia (r = 0,79) das UF.
Conclusões: Observou-se forte concentração de reumatologistas nas capitais e maiores municípios brasileiros, com inequalidades perceptíveis também entre as UF e as regiões do
país. A distribuição desses profissionais acompanhou o PIB, o IDH-M da capital e o número
de concluintes de RM em reumatologia das UF, sugerindo que fatores relacionados a oportunidades de renda e desenvolvimento humano e ao local de formação especializada podem influir na fixação geográfica dos reumatologistas.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
A recently published study by the Federal Council of Medicine (Conselho Federal de Medicina, CFM) and the Regional
Council of Medicine of São Paulo (Conselho Regional de Medicina do Estado de São Paulo, CREMESP) demonstrates poor
distribution of physicians in the country, not considering any
absolute deficiency in the number of these professionals. This
inequality is observed both in relation to doctors in general as to specialists, who concentrate their activity on State
capitals and larger municipalities, resulting in a shortage of
physicians in the periphery and in the hinterland.1 The Brazilian government has sought strategies to achieve greater
internalization of physicians, some of them questionable, as
the liberal authorization for opening medical schools, which
multiply without strict criteria of geographical necessity, and
the proposal of compulsory civil service, which does not attack the bases of the problem and imposes on this particular
profession a social obligation not uniformly distributed to the
other ones.2
Historically, it has been easier to attract physicians (temporarily) for the poorest and remote areas than to fix the
professionals in these regions, with consequent turnover of
professionals working in the hinterland and in the periphery,
particularly in the case of primary care. The determinants of
the geographical fixation process of the physician are complex and include factors such as the region where the pro-
fessional was born, his/her alma mater, formative content
and experiences during graduation, job/chief satisfaction, adequacy of resources for the professional performance, quality
and safety in the workplace, opportunities for development/
updating of her/his career, personal respect and professional
prestige, opportunities for cultural development, nature of
employment relationship, besides the perception of a remuneration consonant with the investment in training and the
responsibilities of profession, among others.3-5 Studies suggest that the existence of Medical Residency (MR) programs
in a particular locality may have attractive effect, functioning
as a “medical fixator”; furthermore, the regions holding the
higher gross domestic product (GDP) – and therefore with a
greater generation of wealth – also bear the greatest numbers
of these professionals.6-8 Although the priority in the search
for better distribution in the provision of medical services
should be the primary care, we must not lose sight that the
access to specialists continue to be essential in more complex
cases, and this need cannot be fully supplied by telemedicine
capabilities.
In the particular case of rheumatology, there is a current
perception, among physicians and users (patients), of a relative scarcity of these specialists, possibly even in State capitals, resulting in difficulties in accessing their services. In the
UK, the Royal College of Physicians postulated as ideal a ratio
of 1 full-time-available rheumatologist (40 hours per week)
for each 86,000 inhabitants.9 Although an universally recognized methodology to estimate the ideal physician/popula-
168
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1
tion ratio is lacking, and although the needs certainly may
differ between regions and countries, this number gives us a
starting point for comparisons.
This study adopts the premise that the same determinants
of the geographical fixation process of physicians in general
apply to rheumatologists. If this is the case, and if the factors related to the institution where the MR was obtained and
to opportunities for income generation and human development are determinant for the choice of the fixation local by
the physician, then the distribution of rheumatologists in
the country should accompany the levels of indicators that
measure (even partially) such constructs. The objective of this
study is to evaluate the distribution of rheumatologists in
Brazil, as well as its correlation with the number of Rheumatology Residency graduated physicians, GDP and municipal
human development index (HDI-M) from federal units (UFs).
Materials e methods
We conducted a direct research (online) in databases of Conselho Federal de Medicina (CFM), Instituto Brasileiro de Geografia e Estatística (IBGE), Cadastro Nacional de Estabelecimentos de Saúde (CNES) of the Ministry of Health, Comissão
Nacional de Residência Médica (CNRM) of the Ministry of
Education and the United Nations Program for Development
(UNDP).10-15 These databases provide public access via World
Wide Web (Internet). All searches were conducted between
March 1st and March 20th, 2013. The variables analyzed with
their respective original bases were: from CFM, number of
rheumatologists with active registration, by UF and municipalities; IBGE’s residents’ population and GDP by UF and municipalities; from CNES, number of rheumatologists providing
attendance to SUS by UF; from CNRM, number of certificates
of Rheumatology Residency issued by UF; from UNDP, the
HDI-M by UF. The research methodology did not include pediatric rheumatologists, whose CFM registration takes place
nowadays under the designation of area of activity, and not
of specialty.
GDP is defined as the total of goods and services produced,
with the purpose of final consumption, equivalent to the sum
of values added by the various economic activities plus taxes
(free of subsidies) on products.16 GDP represents the sum of
the wealth generated by the different economically active
sectors in a particular region/time period. HDI aims to be a
general, synthetic, measure of human development, calculated from three pillars: (i) health, as measured by life expectancy; (ii) access to knowledge, measured by average years of
adult education and expected years of schooling for children
at early school age; and (iii) income.17
The query to CNES by number of rheumatologists attending at SUS used the option of search by individuals; this technique computes the professional only once, even in the case
of multiple links. We used the number of certificates issued
for Rheumatology Residency as an estimator of the number
of trainees in the specialty, by MR modality, in the UF. All certificates of Rheumatology Residency completion registered
at CNRM from 2000 to 2012 were included. The choice of this
inclusion period was based on two criteria: (a) the registration data of the CNRM prior to 2000 have greater likelihood of
inconsistencies; and (b) the searches aimed to comprise the
latest consolidated information. Information from CFM, CNES
and CNRM was up-to-date with reference to the time of access.10-12 The GDP used refers to the year 2010, and population
data are estimates for the year 2012.13,14 HDI-M was calculated
by UNDP, based on information from the 2000 Brazilian census; the UF’s HDI-M corresponds to the average of its municipalities.15
The Federal District was considered as an equivalent of a
single municipality. Considering the small number of rheumatologists in the country compared to the number of inhabitants, with the aim to avoid notations of the type 1/x or an
excessive number of decimals, in this paper the commonly
reported rates in form of physician/habitants are reported in
its inverse form (inhabitants/physician). UFs are referred to
by their usual abbreviations (ex: DF, GO, PB, RJ, SP, etc.). Data
were summarized by descriptive statistics techniques. In the
correlation analysis, we used the correlation coefficient of
Spearman (r), with a two-tailed significance level of 0.01. The
analyses were performed using SPSS software for Windows.
Results
Table 1 summarizes the results by UF. At the time of the survey, there were 1,229 rheumatologists with active registries
in databases from CFM throughout our country. The Northern region had only 3.6% of the contingent (n = 44); Midwest,
12.1% (n = 149); Northeast, 17.5% (n = 215); South, 24.6% (n =
302); and Southeast, 42.2% (n = 519). The 27 State capitals concentrated 64% of registered rheumatologists (n = 787), 93% of
the rheumatologists in the Northern Region lived in its capitals; in the Midwest, 85%; in the Northeast, 80%; in the South,
52%; and in the Southeast, 56%. Taking the five largest municipalities in each state, a concentration of 75.8% of all registered
rheumatologists (n = 931) was reached. There was only one
rheumatologist with active registry in Acre, while the State of
São Paulo showed 241 active registries.
In our country, 49.9% (n = 614) of the rheumatologists offered their services to SUS, with heterogeneity noted between
the regions: in the Northern Region, this proportion was 70.5%
(n = 31); Midwest, 37.6% (n = 56); Northeast, 58.1% (n = 125);
South, 19.2% (n = 58); and Southeast, 68.2% (n = 354). A general rate of 157,809 inhabitants/rheumatologist was observed.
By region, the rate was 370,867 inhabitants/rheumatologist in
the Northern Region; 250,731 in Northeast; 157,160 in Southeast; 120,819 in Midwest; and 91,827 in South. But UFs differed
considerably in this respect, with a median of 192,624 inhabitants/rheumatologist (interquartile range = 175,981) and extremes of 41,383 in DF and 758,786 in AC. If we consider only
the specialists who offer their services to SUS, the median
was 413,692 inhabitants/rheumatologist (interquartile range
= 338,273), with extremes of 156,071 in RJ and 1,053,583 in PI.
From 2000 to 2012, Brazil has certified 593 Rheumatology
Residency graduated physicians, of whom 66.9% were graduated in the Southeast (n = 397), 12.5% in the Midwest (n = 74),
11.1% in the South (n = 66), 8.4% in the Northeast (n = 50), and
1% in the North (n = 6) region. A strong positive correlation
among number of rheumatologists with respect to GDP (r =
0.94), HDI-M for the capital (r = 0.77) and number of Rheu-
169
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1
Table 1 – Population, number of rheumatologists, GDP, HDI-M, medical resident finishers in rheumatology and habitants/
rheumatologist ratio per state
Region
North
AC
AM
AP
PA
RO
RR
TO
Northeast
AL
BA
CE
MA
PB
PE
PI
RN
SE
Midwest
DF
GO
MS
MT
Southeast
ES
MG
RJ
SP
South
PR
RS
SC
Brazil
Population
Rheumatologist
GDP†
State
Capital
SUS
758.786
3.590.985
698.602
7.792.561
1.590.011
469.524
1.417.694
1
10
4
19
3
1
6
1
10
4
18
2
1
5
0
10
4
12
2
1
2
3.165.472
14.175.341
8.606.005
6.714.314
3.815.171
8.931.028
3.160.748
3.228.198
2.110.867
22
47
38
12
29
30
10
16
11
18
32
33
10
18
26
10
14
11
2.648.532
6.154.996
2.505.088
3.115.336
64
44
26
15
3.578.067
19.855.332
16.231.365
41.901.219
10.577.755
10.770.603
6.383.286
193.946.886
HDI-M††
State
Capital
8.477
59.779
8.266
77.848
23.561
6.341
17.240
0,697
0,753
0,713
0,723
0,735
0,746
0,710
0,754
0,774
0,772
0,806
0,763
0,779
0,800
19
16
17
7
23
24
3
11
5
24.575
154.340
77.865
45.256
31.947
95.187
22.060
32.339
23.932
0,649
0,688
0,700
0,636
0,661
0,705
0,656
0,705
0,682
64
35
19
9
15
20
4
7
149.906
97.576
43.514
59.600
34
148
96
241
17
71
72
130
10
49
104
191
131
114
57
1.229
77
61
19
787
19
29
10
614
RM‡
Hab/Rheum.#
General
SUS
0
6
0
0
0
0
0
758.786
359.099
174.651
410.135
530.004
469.524
236.282
dna
359.099
174.651
649.380
795.006
469.524
708.847
0,739
0,805
0,786
0,778
0,783
0,797
0,766
0,788
0,794
0
11
19
0
0
18
2
0
0
143.885
301.603
226.474
559.526
131.558
297.701
316.075
201.762
191.897
166.604
885.959
506.236
959.188
165.877
372.126
1.053.583
293.473
422.173
0,844
0,776
0,773
0,778
0,844
0,832
0,814
0,821
47
16
11
0
41.383
139.886
96.350
207.689
176.569
307.750
626.272
445.048
82.122
351.381
407.123
1.247.596
0,765
0,773
0,807
0,820
0,856
0,839
0,842
0,841
5
55
63
274
105.237
134.158
169.077
173.864
357.807
405.211
156.071
219.378
217.290
252.483
152.482
3.770.086
0,787
0,814
0,822
dna
0,856
0,865
0,875
dna
37
29
0
593
80.746
94.479
111.987
157.809
556.724
371.400
638.329
315.874
† GDP is the gross domestic product, in millions of reais; †† HDI-M is the human development index per municipality; ‡ RM is the number of
concluders of medical residence in rheumatology between 2000 and 2012; # Hab/Rheum. is the ratio between the number of habitants and the
number of rheumatologists in a given region.; dna = does not apply.
matology Residency graduated physicians in the UF (r = 0.79),
respectively, was found. A moderate correlation between
number of rheumatologists and HDI-M of the UF (r = 0.56) was
observed.
Discussion
We found imbalances in the distribution of rheumatologists
in this country, who were concentrated in State capitals and
larger municipalities, following a similar pattern to that reported by CFM/CREMESP for physicians in general.1 Inequalities were also observed between regions: the seven UFs of
South and Southeast regions gathered about two-thirds of
rheumatologists, with the remainder distributed among the
remaining twenty UFs. North, Northeast and Midwest regions
had the highest concentrations of rheumatologists in the
State capitals, which housed 80% or more of these professionals. In South and Southeast regions, although this phenomenon of concentration also had been observed, it is less intense, with slightly more than half of rheumatologists in the
capitals. The Northern region exhibited the lowest presence
of rheumatologists, both in absolute (number of professionals, n = 44) and relative (370,867 inhabitants/rheumatologist)
terms.
Some UFs reached levels close to or even exceeding the
ideals proposed by the British Royal College of Physicians,9
of about 86,000 inhabitants/rheumatologist (e.g., DF, 41,383;
PR, 80,746; RS, 94,479; MS, 96,350), while still others fell far
short of this level (e.g., AC, 758,786; RO 530,004; MA 559,526;
RR 469,524). Considering only the number of rheumatologists
offering their services to SUS, all UFs were far from optimal
levels of provision, and the best positioned UF was RJ with
156,071 inhabitants/rheumatologist. Data on SUS rheumatologists were generated from CNES, whose records are used
in the calculation of financial transfers for service providers,
with mandatory periodic updating of the system by its administrators.18 In general, CNES is a good indicator of human
resources at SUS, but there is an overestimation bias: the reduction of registered human resources can result in reduced
financial transfer to the management unit. Thus, despite the
requirement for periodic updating, not always a physician
170
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1
who leaves SUS will have his/her registration status at CNES
immediately modified by the administrator. Therefore, the
situation of rheumatologists’ provision to SUS can be even
worse than the picture reported here.
About two-thirds of Rheumatology Residency graduated
physicians attended specialization in the Southeast, and the
state of São Paulo alone accounted for 46.2% (n = 274) of all
graduates. At the other extreme, the entire Northern region accounted for only 1% (n = 6) of these graduates. In 13 UFs, there
was no active program and/or any physician who finished their
Rheumatology Residency in the years 2000-2012. Among these
UFs, four presented general rates larger than 400,000 inhabitants/rheumatologist, namely AC, PA, RO, RR, and MA. Despite
these numbers, the rheumatology specialty is not contemplated as a priority specialty by the national program for supporting the training of medical specialists in strategic areas
(Pró-Residência).19,20 The results presented here argue in favor
of the reconsideration of that position by the officials of Public
Administration. The Brazilian Society of Rheumatology can exercise a preponderant role in this subject.
We observed a strong positive correlation between the
number of rheumatologists and GDP, HDI-M of State capitals and the number of Rheumatology Residency graduated
physicians in each UF, suggesting that some elements related
to income opportunities and human development elements,
besides the place where the specialized training was offered,
may influence the geographical fixation of these specialists.
Póvoa and Andrade observed a greater likelihood of finding
non-native physicians,7 i.e., those coming from other regions,
in UFs with a highest number of MR vacancies, and thus also
in those UFs with the highest GDP per capita, suggesting that
these two factors function as local physician concentrators.
Other studies show that physicians tend to stay in the
place where they did their MR, and that there are more physicians in UFs with greater GDP.6,8 The only moderate correlation with HDI-M of the UF (average of the municipalities) is
not surprising, given the concentration of rheumatologists in
the States’ capitals. Moreover, it seems reasonable to assume
that factors operating at local (municipal) level exert greater
influence on the individual’s choice as to where to fix his/her
living, because the local problems and opportunities will occur mainly at this level.
The study published by CFM/CREMESP, previously cited,
adopted different methodology for its counting of physicians.1 This study used other sources, in addition to the
CFM records, performing data cross-checking with the goal
of identifying specialists. For that research, 1,631 rheumatologists were operating in Brazil in 2012, different from the
1,229 professionals reported here. The system of administrative and notary record of CFM is integrated with those of the
Conselhos Regionais de Medicina (CRMs), so that all specialist
qualification titles registered in CRM are automatically also
included in CFM basis. Thus, a specialists’ underreporting
CRM/CFM system was noted. That is, there were physicians
with a rheumatologist title, obtained either through completion of medical residency or by approval at Brazilian Society of
Rheumatology specific scrutiny; but these entities do not register titles in CRM/CFM system. This underreporting leads to
curious situations, as in Table 1, where it can be seen that the
total rheumatologists registered at CRM/CFM in Rio de Janeiro
was inferior to the number of rheumatologists who worked in
the SUS in that UF.
Therefore, the present work, in considering rheumatologists from CFM records, underestimates by approximately
24.6% the total number of rheumatologists in the country. For
the calculation of inhabitants/rheumatologist rate, the CFM
system search was not restricted to primary enrollments,
considering that a rheumatologist with active registration in
more than one UF will be available to each of them (unevenly,
or not). If only the primary registrations were considered, then
1,187 registered rheumatologists across the country would be
computed, bringing the sub-registry in CFM to 27.2%, compared with the study of CFM/CREMESP. Given this limitation,
we must evaluate to what extent this difference impacts the
results presented here.
First, data on number of rheumatologists in the SUS and
its relationship versus number of inhabitants do not change,
because, at that point, the sources of both studies (CNES and
IBGE) are identical. As for the correlation analysis, we recalculated the tests using the data published by CFM/CREMESP for
number of rheumatologists versus GDP, HDI-M of State capital
and number of MR graduates in rheumatology in each state,
and the coefficients (r) were 0.94, 0.74 and 0.82, respectively
– very similar to our original coefficients. Thus, here the findings also do not change.
However, when relating data from CNES (rheumatologists
in SUS) with those published by CFM/CREMESP (total of rheumatologists), we conclude that only 37.6% of rheumatologists
in the country are available to SUS, compared to those 49.9%
reported here. There are also differences in the inhabitants/
rheumatologist general rates by UF. Fig. 1 associates the results obtained here (from databases of CFM) with those published by CFM/CREMESP. The main differences were seen in SP
and RJ, where – by the methodology of CFM/CREMESP – more
283 and 76 rheumatologists were respectively computed,
compared with our data in this study. As for MG and PE, more
12 and 11 rheumatologists, respectively, were noted. For all remaining states, the differences in absolute numbers between
Fig. 1 – Distribution of rheumatologists by UF by two
counting procedures. Note: In the figure, only the numbers
of CFM/CREMESP study are indicated; the values obtained
from databases of CFM are listed in Table 1.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1
forms of counting ranged from 0 to 5 rheumatologists by UF
(either more or less).
Data of CFM/CREMESP imply that Brazil has an overall
ratio of 118,913 inhabitants/rheumatologist. When analyzed
by UF, the median of this ratio is 174,651 inhabitants/rheumatologist (interquartile range = 144,670), with extremes of
38,385 in DF and 758,786 in AC. These numbers show a better
scenario for the inhabitants/rheumatologist rate, compared
to that obtained from CFM registry data, but do not modify
the pattern of poor distribution of rheumatologists among
UFs, as noted in Fig. 1. Even using CFM/CREMESP data, several
UFs still present inhabitants/rheumatologist general rates
distant from the levels postulated as ideal (e.g., AC, 758,786;
MA, 559,526; RO, 530,004; PA, 432,920; TO, 283,539; BA, 277,948;
AM, 276,230), while others exhibit proper proportions or even
an excess of rheumatologists (e.g., DF, 38,385; SP, 79,964; PR,
81,998; RS, 91,276; MS, 92,781; RJ, 94,368). So, no matter which
data set used, whether CFM’s (methodology adopted for this
study) or CFM/CREMESP’s – the general conclusions of this paper do not change.
In short, we observed imbalance in the distribution of
rheumatologists in our country, with a concentration of these
specialists in Brazilian State capitals and larger municipalities. The South and Southeast gathered about two-thirds of
rheumatologists, the remaining third being distributed by
North, Northeast and Midwest regions. Some units of the
federation reached levels postulated as ideal for the inhabitants/rheumatologist rates (particularly in Southeast, South
and Midwest), while others exhibited severe shortage of these
professionals (especially in North and Northeast). Half or less
of the total number of rheumatologists in Brazil were available to SUS. The distribution of rheumatologists in our country paralleled the GDP, the HDI-M from the state capital and
the number of Rheumatology Residency graduates of UFs,
suggesting that factors related to income opportunities and
human development, besides the site where the specialized
training occurred, may influence the choice of their geographical settlement.
Conflicts of interest
The author declares no conflicts of interest.
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Atlas2003.aspx?indiceAccordion=1&li=li_Atlas2003. Acesso
em: 15 mar. 2013.
16. Brasil, Ministério do Planejamento, Orçamento e Gestão,
Instituto Brasileiro de Geografia e Estatística. Contas
Regionais do Brasil 2010. Rio de Janeiro: IBGE, 2012.
17. Organização das Nações Unidas, Programa das
Nações Unidas para o Desenvolvimento. O que é IDH.
Disponível em: http://www.pnud.org.br/IDH/IDH.
aspx?indiceAccordion=0&li=li_IDH. Acesso em: 20 mar. 2013.
18. Brasil, Ministério da Saúde. Portaria N° 3.462, de 11 de
novembro de 2010. Estabelece critérios para alimentação
dos Bancos de Dados Nacionais dos Sistemas de Informação
da Atenção à Saúde. Diário Oficial da União. 12 nov. 2010;
Seção 1:50.
19. Brasil, Ministério da Educação. Portaria Interministerial N°
1.001, de 22 de outubro de 2009. Institui o Programa Nacional
de Apoio à Formação de Médicos Especialistas em Áreas
Estratégicas — PRÓ-RESIDÊNCIA. Diário Oficial da União. 23
oct 2009; Seção 1:9.
20. Brasil, Ministério da Saúde, Secretaria de Gestão do Trabalho
e da Educação na Saúde. Edital convocatório N° 19, de 21 de
julho de 2010. Diário Oficial da União. 22 jul. 2010; Seção 3:95-8.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Otorhinolaryngological findings in a group of patients with
rheumatic diseases
Reinaldo Jordão Gusmãoa, Fernando Laffitte Fernandesa, Alexandre Caixeta Guimarãesa,
Lutiane Scaramussaa, Zoraida Sachettob, Henrique Furlan Paunaa,*,
Guilherme Machado de Carvalhoa
Otorhinolaryngology, Head and Neck Discipline, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
Rheumatology Discipline, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
a b article info
abstract
Article history:
Introduction: Otorhinolaryngological manifestations of rheumatologic diseases represent a
Received on 26 July 2013
great challenge not only to the generalistphysician but also to the ENT doctor andrheu-
Accepted on 13 October 2013
matologist. They often represent early manifestations of an autoimmune disorder which
requires prompt and aggressive immunosuppressive treatment. Auditory, nasal, laryngeal
Keywords:
and eye symptoms can be the first manifestation of rheumatic diseases and their proper
Autoimmune diseases
assessment helps the doctor to identify signs of disease activity. The objective of this study
Otorhinolaringology
is to identify the ENT manifestations in patients with rheumatic diseases in a high comple-
Rheumatology
xity hospital, regarding facilitating an early diagnosis and treatment.
Methods: We performed clinical and complete otorhinolaryngological evaluations in patients selected from the outpatient rheumatology in a standardized manner by the use of a
standardized form filling during the secondhalf of 2010.
Results: In the study group, systemic lupus erythematosus (SLE) patients had predominantly laryngeal manifestations, while patients with Sjögren’s syndrome showed a higher
prevalence of otologic manifestations. Changes in audiometric tests were found in 53%
of Wegener’s granulomatosis (WG) patients, 80% of relapsing polychondritis (RP), 33% of
systemic lupus erythematosus (SLE) and 50% of Churg-Strauss syndrome (SCS). Regarding
nasal alterations, these were found so prevalent in all conditions, especially Churg-Strauss
syndrome.
Discussion and conclusion: This study demonstrated that most patients treated in our hospital has the ENT signs and symptoms commonly associated in previous studies on rheumatic diseases, but further studies with a larger number of patients must be made to establish
such relations.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (H.F. Pauna).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.10.001
173
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8
Achados otorrinolaringológicos em um grupo de pacientes com doenças
reumatológicas
resumo
Palavras-chave:
Introdução: As manifestações otorrinolaringológicas de doenças reumáticas representam
Reumatologia
um grande desafio não só ao médico generalista, mas também ao otorrinolaringologista
Otorrinolaringologia
e ao reumatologista. Frequentemente representam manifestações iniciais de uma desor-
Doenças autoimunes
dem autoimune que exige um tratamento imunossupressor imediato e agressivo. Sintomas auditivos, nasais, laríngeos e oculares podem ser a primeira manifestação de doenças
reumáticas, e sua correta avaliação auxilia o médico a identificar sinais de atividade da
doença. O objetivo deste trabalho foi identificar as manifestações otorrinolaringológicas
em pacientes com doenças reumáticas em um hospital de alta complexidade, no que se
refere a facilitar diagnóstico e tratamento precoces.
Métodos: Foram realizadas avaliações clínicas e otorrinolaringológicas completas em pacientes selecionados no ambulatório de reumatologia, no segundo semestre do ano de 2010,
de forma padronizada e com utilização de um formulário de preenchimento normatizado.
Resultados: No grupo estudado, pacientes com LES apresentaram predominantemente
manifestações laríngeas, enquanto pacientes com síndrome de Sjögren apresentaram predomínio das manifestações otológicas (100% dos casos). As alterações de exames audiométricos são encontradas em 53% dos casos portadores de GW, 80% de PR, 33% de LES e 50% de
SCS. Quanto às alterações nasais, estas foram encontradas de forma prevalente em todas
as patologias, principalmente a síndrome de Churg-Strauss.
Discussão e conclusão: Este estudo demonstrou que a maioria dos pacientes em seguimento
em nosso serviço apresenta os sinais e sintomas otorrinolaringológicos comumente relacionados em trabalhos prévios sobre doenças reumáticas, porém novos estudos com um
número maior de pacientes devem ser feitos para comprovar tais relações
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Rheumatic diseases have a high prevalence rate worldwide
and a representative functional disability index.1 These conditions comprise a heterogeneous group of entities that
produce systemic changes involving the connective tissue
throughout the body. For this reason they may involve blood
vessels and serous and mucous membranes of all the aerodigestive tract.2 The treatment itself of such diseases with
non-steroidal anti-inflammatory drugs can cause symptoms
in many patients.3 In this sense, much has been discussed
about the current ENT manifestations in patients with rheumatic diseases.4
Ear, nasal, laryngeal and ocular symptoms may be the
first manifestations of various rheumatic diseases, as relapsing polychondritis (RP), systemic lupus erythematosus
(SLE), Wegener’s granulomatosis (WG), Sjögren’s syndrome
(SS) and Churg-Strauss syndrome (CSS),5,6 and this combination is described in several trials. As an example, there
are some case reports of patients with RP in which changes
in pinna, nasal cartilage, nasal septum, larynx and trachea
were found, causing dysphonia, dyspnea and cosmetic deformities.7,8 Allergic rhinitis, chronic sinusitis and serous otitis media are commonly found in patients with CSS,9 while
immunological abnormalities are frequently found in patients with Menière’s disease.10 Sensorineural hearing loss
may be the first manifestation of polyarteritis nodosa,11 as
well as recurrent parotitis for SS12 and chronic otitis media
for ankylosing spondylitis.13
Given the global growth of rheumatic diseases, driven by
population ageing and exposure to a larger number of inducers of autoimmune changes,14 the identification of ENT symptoms in these patients can become an important tool for the
diagnosis and, consequently, for the early treatment of such
diseases. The correct evaluation of rheumatic conditions, particularly in SLE, helps the physician to identify signs of disease activity, which directly affects the patients’ quality of life
and their prognosis.15-17
Thus, the objective of this work is to identify ENT manifestations in patients with rheumatic diseases in a hospital
of high complexity. As this trial was conducted in 2010 and
considering the fact that the old nomenclature for rheumatologic diseases is more widespread in our environment, we
used this nomenclature in the present trial. In the new nomenclature established by the Chapel Hill Consensus in 2012,
Wegener’s granulomatosis became known as granulomatous with polyangiitis, and Churg-Strauss syndrome became
known as eosinophilic granulomatous with polyangiitis.18
Materials e methods
In all patients, complete clinical and ENT evaluations consisting of a detailed history, a thorough ENT physical examination
and audiometry, imitanciometry (acoustic impedance) and
174
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8
nasofiberlaryngoscopy were performed. Sensorineural hearing
loss or sound discrimination impairment with bilateral and
symmetrical occurrence and with subacute evolution were
considered as audiometric alterations.
The assessment was fully standardized, and a normatized
filling form was used during the second half of 2010.
For the selection of patients, we requested from the Department of Rheumatology a random referral of patients for
specialized ENT evaluation, but some specific outpatient services contributed more to the project (such as vasculitis and
Wegener’s granulomatosis outpatient services).
The first five patients in each outpatient rheumatology
should have been referred for a period of 15 days.
Every patient evaluation was performed at the otorhinolaryngology ambulatory of our national reference, tertiary care,
university hospital. The patients were attended and evaluated
by two otolaryngologists randomly selected among the professionals who participated in this trial.
The criteria used were those of the Otorhinolaryngologist
available at the time and who would perform the patient’s assessment.
This trial was evaluated and approved by the Research
Ethics Committee from our institution (Opinion CEP/FCM nº
1187/2011).
Results
Thirty-two selected patients of Rheumatology Discipline Outpatient Clinic (HC/FCM/UNICAMP) were evaluated. In the evaluated sample , the patients were diagnosed as defined by the
criteria of Medical Guidelines of the Brazilian Society of Rheumatology19 for SLE and by the American College of Rheumatology20,21,22,23 for other diseases, with a diagnosis established for
one from five rheumatic diseases: Wegener’s granulomatosis
(WG), Churg-Strauss syndrome (CSS), relapsing polychondritis
(RP), Sjögren’s syndrome (SS) and systemic lupus erythematosus (SLE).
The mean age of the participants was 41.7 years (range 2270 years) and the mean disease duration was 9.12 years (range
1-40 years).
1 – Wegener’s granulomatosis (n = 17)
Among WG patients, nine (53.1%) reported hearing loss and
had low tone threshold results at audiometry. The most fre-
quent type of reduction was that of a bilateral sensorineural pattern, present in five patients (55.6%). In the context
of rhinologic symptoms, nasal obstruction in 11 (64.8%) and
rhinorrhea in ten (58.8%) patients were the most prevalent
symptoms, with compatible changes present in the rhinoscopic exam in 12 (70.2 %) of these patients, and the most
frequent symptoms were coryza, septal perforations, mucosal oedema and turbinate hypertrophy. Complaints related
to the larynx, dyspnea and raucousness were found in six
(35.2%) and seven (41.2%) patients, respectively, being the
most prevalent complaints. Of these, seven (41.2%) patients
had an abnormal physical examination, for instance, hyperaemia of posterior pharynx, inter-arytenoidal oedema and
relative degrees of subglottic stenosis (Table 1).
2 – Recidivant polychondritis (n = 5)
In patients with RP, among the otologic symptoms, the most
frequent complaint was ear itching in three patients (60%),
followed by tinnitus, hearing loss and ear fullness in two
(40%). The changes more often found during the physical
examination were pinna oedema and opacity of the tympanic membrane. The main nasosinusal symptoms were:
presence of nasal obstruction, rhinorrhea and sneezing, reported by two patients (40%), and coryza, mucosal oedema,
pale mucosa, granulation of the turbinates and turbinate
hypertrophy were the primary findings. As to laryngeal
complaints, cough, foreign body sensation, raucousness
and choking were present in two cases (40%). The changes found on physical examination were inter-arytenoidal
oedema, paresis of vocal folds and laryngeal hyperaemia
(Table 2).
3 – Sjögren’s syndrome (n = 5)
For patients with SS, tinnitus and ear fullness were present in
three and four of the five patients, respectively; the most frequent changes were in conductive hearing loss and presence
of a large amount of desquamation in the external auditory canal. Nasal obstruction was present in all patients. In the rhinoscopic examination, hyperaemia and oedema of mucosa were
the observed findings. Dysphonia and raucousness were the
only reported laryngeal symptoms; and the signs found were
salivary gland hypertrophy, dry mouth and inter-arytenoidal
oedema (Table 3).
Table 1 – Presence of otological signs and symptoms
Otalgia
Otorrhea
Tinnitus
Ear fullness
Hearing loss
Hyperacusis
Ear pruritus
Dizziness
Wegener’s
granulomatosis n = 17
Relapsing
Polychondritis n = 5
Syndrome of
Sjögren n = 5
8 (47%)
4 (23%)
7 (41%)
3 (18%)
9 (53%)
0
3 (18%)
1 (6%)
1 (20%)
0
2 (40%)
2 (40%)
2 (40%)
0
3 (60%)
0
0
1 (20%)
3 (60%)
4 (80%)
2 (40%)
0
5 (100%)
1(20%)
Systemic Lupus
Syndrome of
Erythematosus n = 3 Churg-Strauss n = 2
0
0
1 (33%)
0
1 (33%)
0
0
0
0
0
1 (50%)
1 (50%)
1 (50%)
0
0
0
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Table 2 – Presence of nasal signs and symptoms
Relapsing
polychondritis
Nasal
obstruction
Rhinorrhea
Nasal itching
Hyposmia
Anosmia
Cacosmia
Postnasal drip
Wegener’s
granulomatosis n = 17
Relapsing
Polychondritis n = 5
Syndrome of
Sjögren n = 5
Systemic Lupus
Syndrome of
Erythematosus n = 3 Churg-Strauss n = 2
11 (65%)
2 (40%)
5 (100%)
1 (33%)
1 (50%)
10 (59%)
2 (40%)
2 (40%)
1 (33%)
1 (50%)
6 (35%)
6 (35%)
2 (12%)
1 (6%)
5 (29%)
7 (41%)
0
0
0
0
0
2 (40%)
4 (80%)
2 (40%)
0
0
1 (20%)
1 (20%)
0
0
0
0
0
0
1 (50%)
1 (50%)
0
0
1 (50%)
2 (100%)
Table 3 – Aerodigestive pathways/pharyngal symptoms
Dysphonia
Cough
Snoring
Foreign body
sensation
Dysphagia
Odynophagia
Dyspnea
Hemoptysis
Hawk
Heartburn
Gagging
Wegener’s
granulomatosis n = 17
Relapsing
Polychondritis n = 5
Syndrome of
Sjögren n = 5
3 (14%)
4 (23%)
0
1 (6%)
1 (20%)
2 (40%)
0
2 (40%)
2 (40%)
0
0
0
2 (67%)
0
0
0
1 (50%)
1 (50%)
0
0
0
0
6 (35%)
1 (6%)
7 (41%)
1 (6%)
1 (6%)
0
0
1 (20%)
0
2 (40%)
1 (20%)
2 (40%)
0
0
0
0
3 (60%)
2 (40%)
0
0
0
1 (33%)
0
0
0
0
0
0
1 (50%)
1 (50%)
1 (50%)
0
0
4 – Systemic Lupus Erythematosus (n = 3)
Among SLE patients, tinnitus and hearing loss were reported
by one patient (33%), with presence of left ear sensorineural
hearing loss and right ear conducive hearing loss. Among
nasal symptoms, nasal obstruction and rhinorrhea were
also present in one patient, and edema and coryza were the
signs most often found . Dysphonia was present in two cases
(67%), and the presence of glottic cleft during phonation and
inter-arytenoidal oedema were the changes observed.
5 – Churg-Strauss syndrome (n = 2)
One patient (50%) with Churg-Strauss reported tinnitus, ear
fullness and hearing loss, with conductive hearing loss at
audiometry. At rhinoscopy, pale mucosa, turbinate hypertrophy and coryza were observed in patients. The complaints of
dysphonia, cough, dyspnea, haemoptysis, and raucousness
were compatible with the presence of oedema of laryngeal
mucosa, glottic cleft and secretion, observed during the examination of the larynx.
In the evaluation of all the symptoms studied by region,
all SS patients reported the presence of at least one otologic
or nasal symptom, and also had audiometric change. Laryngeal symptoms were more frequent in patients with SLE, being
present in two patients (66%) (Table 4); however, patients with
SLE were those with fewer ear and nasal symptoms, or with
Systemic Lupus
Syndrome of
Erythematosus n = 3 Churg-Strauss n = 2
audiometric changes. These conditions were present in only
one patient (33%) (Tables 5 and 6).
The audiometric changes (indicated in Table 6) found were described as sensorineural hearing loss (SNHL), conductive hearing
loss (CHL) or mixed hearing loss (MHL). In the case of SNHL, the
following distribution was observed: 29% of WG, 60% of PR, 20% of
SJ, 33% of SLE and 0% of CSS. With MHL, no cases were observed.
On the other hand, for CHL another distribution was observed:
23% of WG, 20% of PR, 80% of SJ, 33% of SLE and 50% of CSS.
Discussion
ENT manifestations in autoimmune diseases represent a diagnostic challenge for the rheumatologist, otolaryngologist
and clinician.1,5,15,24,25 Generally, ENT symptoms may represent
an early sign of an undiagnosed autoimmune disorder that
often requires an immediate and aggressive immunosuppressive treatment.25-29 There are diseases of systemic action
that present themselves with localized manifestations, and
the region of the head and neck is an important site of these
manifestations.5
Ear damage have been occasionally reported as a complication in the course of several rheumatic diseases.8,30 It is
common, for example, to find sensorineural hearing loss with
decreased hearing acuity or discrimination of sounds. Uni- or
bilateral sensorineural hearing loss affecting medium and high
frequencies have been reported in patients with SLE, and there
is evidence of a strong association between hearing loss and
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Table 4 – Other head and neck signs and symptoms
Wegener’s
granulomatosis n = 17
Relapsing
Polychondritis n = 5
Syndrome of
Sjögren n = 5
0
3 (18%)
0
1 (20%)
1 (20%)
0
2 (40%)
0
0
Wegener’s
granulomatosis n = 17
Relapsing
Polychondritis n = 5
Syndrome of
Sjögren n = 5
Rhinoscopy,
change in
Otoscopy,
change in
12 (70%)
3 (60%)
5 (100%)
1 (33%)
2 (100%)
7 (41%)
0
0
0
0
Nasofibroscopy,
7 (41%)
3 (60%)
4 (80%)
2 (67%)
2 (100%)
7 (41%)
2 (40%)
5 (100%)
1 (33%)
0
Conjunctivitis
Headache
Facial paralysis
Systemic Lupus
Syndrome of
Erythematosus n = 3 Churg-Strauss n = 2
0
0
0
1 (50%)
1 (50%)
0
Table 5 – Findings of ENT physical examination
Systemic Lupus
Syndrome of
Erythematosus n = 3 Churg-Strauss n = 2
change in
Otoscopy,
change in
Table 6 – Otologic, nasal, and laryngal symptoms and audiometric change in the studied diseases
Wegener’s Granulomatosis
Relapsing Polychondritis
Sjögren’s Syndrome
Systemic Lupus Erythematosus
Churg-Strauss Syndrome
Otologic symptoms
Nasal
symptoms
Laryngeal
symptoms
Audiometric change
9 (53%)
3 (60%)
11 (65%)
2 (40%)
7 (41%)
2 (40%)
9 (53%)
4 (80%)
5 (100%)
1 (33%)
5 (100%)
1 (33%)
3 (60%)
2 (67%)
5 (100%)
1 (33%)
1 (50%)
2 (100%)
1 (50%)
1 (50%)
elevated titres of anticardiolipin antibodies. A sensorineural
hearing loss in the course of Sjögren’s syndrome (SS) is partly
attributed to the presence of high titres of those antibodies.4
A sudden or gradual hearing loss may occur in about 50% of
patients with recidivant polychondritis, and both in these as
in patients with WG, a conductive hearing loss is the main otologic damage. According to literature, audiovestibular deficits
are uncommon in patients with CSS.4 According to the findings
of this trial, ear manifestations in the patients studied confirm
the literature data, maintaining statistical similarity.
In literature we find data on vestibulocochlear system involvement by vascular lesions in the internal auditory artery,
causing sensorineural dysacusis in addition to symptoms
such as dizziness and tinnitus. According to the authors, the
little mention of vestibular symptoms is due to the fact that
the gradual involvement of the vestibular system promotes
labirynthic compensation.31
Laryngeal involvement is extremely rare and the symptoms can range from hoarseness to respiratory distress.32
Smith et al. published two cases with cricoarytenoid ulceration, stenosis and oedema. Kraus and Guerra-Bautista published a case with complete vocal fold paralysis in 1990. Tietel
et al. published, in 1997, a review of cases of laryngeal involvement in SLE, in which laryngeal oedema occurred in 28% of
cases and vocal paralysis in 11%.32
Allergic rhinitis is often present in patients with ChurgStrauss syndrome.4 Symptoms such as nasal itching, airflow
obstruction, coryza and recurrent sinusitis are common manifestations in CSS, GW and PR.9,33 In general, Churg-Strauss
syndrome is characterized by asthma, eosinophilia, and extravascular eosinophilic granulomata. Also, as part of the clinical manifestations of CSS, the first phase of this syndrome is
characterized by asthma possibly associated with allergic rhinitis, and often complicated by nasal polyposis and recurrent
rhinosinusitis.9 The other phases are manifestations of eosinophilia and/or eosinophilic infiltrates in the tissues (lungs,
gastrointestinal tract) or of systemic vasculitis.
In the available literature, three stages of the natural history of CSS are described: (1) prodromal stage, characterized
by asthma and allergy for several years, (2) eosinophilic stage
with peripheral blood eosinophilia and an organic infiltrate
that can decrease or increase over several years, and (3) systemic vasculitis stage, that can be life threatening.30 Still, the
main feature of ENT manifestations in this disease is an allergic rhinitis associated with nasal polyposis.30,33 According
to Bacciu et al., allergic rhinitis is present in 42.8% of CSS patients studied.9
According to literature, in patients with GW, the respiratory tract is involved in 70-100 % of cases, with nasal and paranasal involvement in 80-90 % of cases.4,25,33,34 Chronic nasal
obstruction with a clear rhinorrhea, nasal ulceration and oedema of the mucosa, besides perforation, erosion of the vomer and nasal deformity with “saddle nose” are classic signs
of the disease. We can also observe cases of chronic secretory
otitis media and tympanic membrane perforation, in addition to the cases described of sensorineural dysacusis, vertigo
and tinnitus.4,25,33,34 The prevalence of otologic involvement is
around 35 %, being related to vasculitis and blockage of the
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Eustachian tube due to the involvement of nasopharynx.4,25,33,34
Facial palsy is found in 8-10% of cases and results from vasculitis of facial nerve vasa-vasorum, granulomatous invasion of
middle ear tissue, primary granulomatous lesion of the nerve,
or a combination of these factors.4,25,33,34 Dysphonia, larynx
stridor, wheezing, oral ulceration and oedema and gingivitis
complement the picture of ENT manifestations.4,25,33,34
It is also worth remembering the important complications and cardiovascular events in SLE, with risk of fatal
complications.35 In a transversal trial conducted at Hospital
Universitário Barros Barreto (HUJBB/UFPA) during 1997-2006,
the main complication in SLE patients was the infectious
syndrome (76.4%), followed by renal (33.8%) and thromboembolic (4.2%) events.36 The main sites of infection were pleura
and lungs (45.4%). The middle ear infection represented 1.8%
of the cases.36 On the other hand, as a well-documented complication, we can find nasal septum perforation (which can
manifest with nasal obstruction , epistaxis, posterior nasal
discharge or crust formation into the nasal cavity), being attributed to local inflammation or ischemia.1 Upper airway
obstruction due to laryngeal involvement is a rare, but well
documented, complication of SLE, which usually occurs in
association with other signs and symptoms that indicate active disease.1
Data from the literature show auricular chondritis as the
most frequent and characteristic finding of the disease, present in 85% of cases, and in 40% of them as the initial manifestation.8 This condition may be uni- or bilateral, causing
phlogistic signs, with swelling of the external ear canal, and
that may lead to conductive hearing loss. Vasculitis of the internal auditory artery may cause cochlear and/or vestibular
involvement by cochlear infarct or ischemia, resulting in sensorineural dysacusis.8 Moreover, among the seven diagnostic
criteria established by McAdam et al., four of them involve
the presence of symptoms that affect the upper respiratory
tract or vestibulocochlear system.37
Nasal compromise, arising from nasal chondritis, can result in a “saddle nose” in up to 50% of patients. The diagnosis
of laryngo-tracheo-bronchial chondritis is also crucial due to
its high morbidity and mortality.8
Xerostomia is a common feature of Sjögren’s syndrome,
being usual in patients with primary and secondary syndrome.38 It is the most obvious symptom of this syndrome.36
Patients often exhibit dryness of lips, tongue and pharynx
and consequent painful burning sensation and of mucosa,
accompanied by speech, chewing, swallowing and digesting
food difficulty.32 More than one third of patients present systemic manifestations that can include vasculitis, cryoglobulinemia, autoimmune hepatitis, pulmonary fibrosis, central
nervous system involvement, renal tubular acidosis, B-cell
lymphomas and multiple myeloma.33
Other trials showed oral symptoms of dry mouth in 86%
and eye symptoms in 53% of patients.39 In the same trial,
46% of patients exhibited ocular involvement, demonstrated
by Schirmer test or by Rose Bengal staining; and in 85.7% of
studied cases an involvement of the salivary gland (by scintigraphy, sialography or sialometry) was evidenced.39 The literature review shows that the most obvious oral symptom
is xerostomia, with dryness of lips, tongue and pharynx
and with chewing, swallowing and speech difficulty, as well
177
as increased susceptibility to dental caries and periodontal
disease.36 About a third to half of patients display an usually
symmetrical and recurrent parotid gland hypertrophy.40
Finally, we must consider the large time lag between complaints of rheumatology patients and the correct diagnosis,
already described. The vasculitis involving the airways, for
example, is a common presentation of a vascular disease
involving ANCA (anti-neutrophil cytoplasmic antibody) and
can precede by several years the diagnosis of the disease.33
One should keep in mind that the referral of patients for
this trial occurred unevenly among specific rheumatology
outpatient clinics, according to the aforementioned rheumatologic diseases; then, the patients’ distribution does not
represent the overall distribution of patients with rheumatic
diseases.
Conclusion
This trial demonstrated the various ENT manifestations of a
group of patients with rheumatologic diseases that commonly can be related to rheumatic diseases, according to other
trials. The early identification of these symptoms as a manifestation of such diseases, both by the otolaryngologist as by
the rheumatologist, is critical to the early implementation of
an immunosuppressive treatment, thereby reducing the morbidity and mortality of these conditions.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
We thank all who contributed to the development of our project at the Rheumatology and Otorhinolaryngology, Head and
Neck disciplines at HC/FCM/UNICAMP.
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Randomized controlled trial of a therapeutic intervention
group in patients with fibromyalgia syndrome
Marielza R. Ismael Martinsa,*, Cristiane Carnaval Grittib, Randolfo dos Santos Juniorb,
Maria Carolina Luizetto de Araújob, Lilian Chessa Diasb, Marcos Henrique D’all Aglio Fossa,
Larissa Batista de Andradeb, Carlos Eduardo D’all Aglio Rochaa
Department of Neurological Sciences, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil
Service of Pain Clinics, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil
a b article info
abstract
Article history:
Objective: To evaluate the efficacy of a weekly interdisciplinary program (WIP) consisted
Received on 6 February 2013
of educational activities, physical therapy, stretching, ergonomics, posture guidance com-
Accepted on 15 October 2013
bined with cognitive behavioral strategies and approaches to psychosocial and occupational factors in order to determine whether this intervention would be effective to short
Keywords:
and medium-term improvement of symptoms in these patients.
Fibromyalgia
Methods: This was a single-center study, randomized single blind controlled trial with a
Controlled study
sample test group (T), with a diagnosis of FMS (n = 12), and a control group (C) subjected to
Group intervention
Pain Clinic referral (n = 15). The instruments used at two different times were the Fibromyalgia Impact Questionnaire (FIQ), Visual Analogue Scale (VAS) and Post-Sleep Protocol (PSI).
To assess quality of life, we used the SF-12.
Results: In samples, both groups were predominantly female, mean age of 42.5 ± 9.8 years,
43% married, average schooling of 8.3 ± 4.5 years. It was reported a mean of 4.2 years pain
and an average of two years for the diagnosis of SFM from the group T. There was statistical difference between the groups in terms of efficacy post intervention WIP, in almost all
outcome measures.
Conclusion: It was found that weekly interdisciplinary program (WIP) has contributed to
improving the quality of life of patients with fibromyalgia.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (M.R.I. Martins).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.10.002
180
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4
Estudo randomizado e controlado de uma intervenção terapêutica grupal
em pacientes com síndrome fibromiálgica
resumo
Palavras-chave:
Objetivo: Avaliar a eficácia de um programa interdisciplinar semanal (PIS) composto de ati-
Fibromialgia
vidades educativas, terapias físicas, alongamento, ergonomia, orientações posturais com-
Estudo controlado
binado com estratégias cognitivas e comportamentais e abordagens de aspectos psicosso-
Intervenção grupal
ciais e ocupacionais, a fim de determinar se esta intervenção seria efetiva em curto e médio
prazos para melhora dos sintomas destes pacientes.
Casuística e métodos: Trata-se de um estudo unicêntrico, randomizado, simples cego e controlado com amostra de um grupo-teste (T), com diagnóstico de SFM (n = 12), e de um
grupo-controle (C) submetido a interconsulta na Clínica da Dor (n = 15). Os instrumentos
utilizados em dois momentos distintos foram: Questionário de Impacto de Fibromialgia
(FIQ), Escala Visual Analógica (EVA) e Protocolo Pós-Sono (PSI). Para avaliar a qualidade de
vida, foi utilizado o Questionário SF-12.
Resultados: Na amostra dos dois grupos houve predomínio do gênero feminino, média de
idade de 42,5±9,8 anos, 43% casados e média de escolaridade de 8,3±4,5 anos. Foi relatado
um tempo médio de dor de 4,2 anos e uma média de dois anos para o diagnóstico de SFM
no grupo T. Houve diferença estatística entre os grupos, em relação à eficácia pós-intervenção do PIS, em quase todos os desfechos analisados.
Conclusão: Verificou-se que o programa interdisciplinar semanal (PIS) contribuiu para melhora da qualidade de vida dos pacientes fibromiálgicos.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
The fibromyalgia syndrome (FMS) is a rheumatic syndrome
of unknown etiology that predominantly affects women. It is
characterized by diffuse and chronic musculoskeletal pain, in
addition to specific anatomical sites with pain elicited by palpation, called tender points. Other symptoms such as fatigue,
sleep disturbances, morning stiffness and psychological disorders such as anxiety and depression are often associated.1-3
Statistic data shows that FMS affects 3-5% of general population, occurring in all ages with chronic symptoms that can
fluctuate throughout the day and with inactivity, compromising about a quarter of those affected.3
The clinical picture of FMS is complex, and several works4,5
propose multidisciplinary teams to perform interventions,
highlighting programs with exercise sessions,4 relaxation,5
stress management and compartmental cognitive therapy6
that consist in extending the adherence to treatment and motivating patients to remain active.7
The mean duration of interdisciplinary programs varies
from one to six months, usually performed with groups of 10
and 25 individuals. The justification for choosing this type of
intervention proves itself by improving the quality of life and
health status of patients with FMS.8,9
Regarding the pathogenesis of FMS, it is not well defined
yet, although psychosomatic phenomena occur in most
patients.10 In addition to this possible effect, some areas of
the nervous system functioning may represent a role in the
pathogenesis of FMS, which include: changes in pain sensitivity,11,12 and also on autonomic and neuroendocrine systems.13-15 Bacterial and viral agents may also be related to the
origin of this syndrome,16 and there is some association between the disease and infection by hepatitis virus C.11
Considering that SFM probably has multifactorial etiology
that still remains unclear, recent trials17,18 reported that the
reorientation of attention for the treatment of the patients
to this combination of factors and the education of these patients (so that they can control their symptoms) are measures
that could promote changes in behavior and improve their
functional capacity.
Given this context, the objective of this trial was to evaluate the efficacy of a weekly interdisciplinary program (WIP)
consisting of educational activities, physical therapy, stretching, ergonomics and postural orientations combined with
cognitive-behavioral strategies and approaches to psychosocial and occupational features, in order to determine whether
this intervention would be effective in the short and medium
terms to improve the symptoms of these patients.
Patients and Methods
After approval by the Ethics and Research Committee from
FAMERP (2384/2010) and with the Free and Informed Consent
Form (FICF) already signed, we conducted this single-center,
randomized, single-blind, controlled trial. The trial was conducted in two groups, with a duration of three months, comparing the weekly interdisciplinary program (WIP) to a control intervention consisting of educational guidelines for the
prevention of pain, relaxation techniques, muscle stretching
and body awareness. The sessions lasted 60 minutes each
and happened once a week for 12 weeks for each of the study
groups, being conducted by a physician, occupational thera-
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4
pist, physiotherapist, psychologist and social worker. After
participating in this program, a revaluation was performed
using the same instruments.
To perform WIP, 12 patients diagnosed with FMS (test
group – TG) were recruited according to criteria of the American College of Rheumatology,1 of both genders, with enough
cognitive level to understand the procedures and follow the
directions given. Patients with psychiatric disease and no
clinical follow-up in the Pain Clinic, Hospital de Base, were
excluded. The control group (CG) consisted of patients who
were in interconsultation in the Pain Clinic and without diagnosis of musculoskeletal and neurological disorders, or with
disabling complaints in these systems, with a recommendation for walking (pelvic pain, migraine, inflammatory bowel
pain post-herpetic neuralgia).
CG consisted of subjects matched for age and educational
level in relation to TG (n = 15). The evaluation of the subjects
in both groups was performed using the Fibromyalgia Impact
Questionnaire (FIQ),19 involving 20 questions divided into
10 items (functional capacity, feeling good, work absenteeism, interference of symptoms at work, pain, fatigue, morning stiffness, morning tiredness, anxiety and depression), in
which nine of them have a higher score as the worst condition, with the exception of the item “feeling good”. Seven of
the nine items (4th to 10th) are scored using a visual analogue
scale, i.e., between 0 and 10.
Functional capacity is estimated by answering 10 questions, with answers from 0 to 3, which are added at the end
of the questionnaire, ranging between 0 and 30. The “work absenteeism” and “feeling good” questions are scored on weekdays, originally ranging from 0 to 5; the Visual Analogue Scale
(VAS),20 which consists of measuring the intensity of pain in
the patient and is an important tool to verify more reliably the
evolution of the patient during treatment and even at every
visit, consists of a limited strip of 10 cm in length, representing a continuum of the painful experience; this strip has in
her ends anchor-words: “no pain” and “worst pain possible”.
The participants are instructed to report the intensity of pain
sensation to a point of this line, and the scores can range from
zero to 10 and are obtained by measuring, in millimeters, the
distance between the end anchored by the words “without
pain” and the point marked by the participant; the Post-Sleep
Protocol (PSP),21 which assesses the sleep quality and features
30 items divided into three categories: pre-sleeping (at bedtime), during sleep and post-sleeping (awakening) (30-390;
higher scores are related to better quality of sleep). To assess
the quality of life, the Generic Quality of Life SF-1222 questionnaire was used. It consists of 12 questions that address the
physical component (functional capacity and limitation by
physical aspects) and the mental component (pain, vitality,
social functioning, limitations due to emotional problems and
mental health), and their results are expressed by a score in
a scale of zero to 100 by researched component (worst – best
general health, cutoff score ≤ 50).
To assess depressive and anxiety symptoms, we used the
Hospital Anxiety and Depression (HAD) scale,23 translated and
validated in Brazil, which consists of a self-report instrument
containing 14 multiple choice questions, composed of two interleaved sub-scales: one for anxiety-state (7 questions) and
another for depression-state (7 questions). HAD scores range
181
from 0 to 21 points, and the subjects with scores < 7 are considered without significant clinical symptoms for anxiety
and/or depression; scores ≥ 8 and ≤ 10, with mild symptoms;
scores ≥ 11 and ≤ 14, with moderate symptoms; and scores ≥
15 and ≤ 21, with severe symptoms of anxiety and/or depression.
During the sessions, exercises to strengthen the muscle
and to improve cardiovascular fitness were conducted, consisting of stretching exercises of muscle groups of the shoulder and pelvic girdle, lower limb muscles, gluteus, abdominals
and quadriceps, as well as body correction and awareness,
and ergonomics. The sessions were initiated with relaxation
techniques to combat muscle tension. Educational, psychosocial and occupational programs were also developed to help
understand and manage fibromyalgia, with the monitoring of
vital signs at the beginning and end of each treatment session
and the questioning on the use of drugs by patients. All the
participants were instructed and taught to practice a series of
daily exercises at home. It emphasized the need to maintain
the home exercise program, and guidelines were given on the
correct way to perform ADLs and AVPs.
Analyses were performed using ANOVA. This descriptive
parametric statistical test was selected for inferential analyses, because the dependent variables of this trial were quantitative (interval scale). The significance level used for the tests
was 0.05.
Results
The twenty-seven subjects enrolled in both groups adhered
totally to the program, with no occurrence of sample loss.
The mean age was 42.5 ± 9.8 years, ranging from 28-67
years; most of the participants were female (64%). The mean
duration of pain was 4.2 years, with an average of two years
for the clinical diagnosis of FMS in TG. Table 1 lists the characterization of the sample for the two groups (T and C).
During the experimental phase, all patients in the T group
maintained their pharmacological routine. Significant difference was observed between the groups regarding the functional capacity and work absenteeism, observed in the FIQ
questionnaire. As for the other questionnaires used in this
trial, data of mean and standard deviation (SD) can be obtained from Table 2.
It is important to notice, in Fig. 1, the frequency of depressive and anxiety symptoms. It is noteworthy that 50%
of patients with FMS in T group had depressive symptoms,
and 33% had moderate to severe symptoms. 78% of these individuals had symptoms of anxiety, and in 43% of them the
symptoms were severe.
Discussion
The actions performed in this trial by the weekly interdisciplinary program (WIP) demonstrated that the approach to
individuals with FMS showed statistically significant clinical
effects, as the increase of functional capacity and motivation,
as well as greater control of symptoms such as sleep, anxiety
and depression.
182
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4
With regard to functional capacity, it was found that in
group T the activities in WIP improved the energy that comes
from the symptoms of chronic fatigue and stiffness, corroborating other trials.23,24
Other work on the impairment of muscle contractility in
a group of fibromyalgia patients is associated with a higher
Table 1 – Data on sociodemographic variables for T
(n = 12) and C groups (n = 15)
Variable
Age
Gender
Marital
status
Education
Group
n
Mean ±
SD
Test
Control
Test
Control
Test
12
15
12
15
12
39,5±7,8
45,5±8,3
Control
15
Test
12
%
Female 62
Female 55
Married 52
Single 28
Divorced 20
Married 43
Single 37
Divorced 13
Widowed 7
Fundamental 32
Secondary 48
Superior 20
Fundamental 37
Secondary 45
Superior 18
Formal work 12
Sick-leave aid 58
Retired 4
Informal work 26
Formal work 20
Sick-leave aid 48
Retired 6
Informal work 26
8,3 ± 4,5
years
15
Employment
situation
Test
Control
12
15
perception of effort and reduced maximal exercise capacity. Due to this fact, the inclusion of physical activity in the
treatment of these patients would improve their functional
responses, with decreased fatigue and increased functional
capacity.25
Firestone et al.26 evaluated the impact of a program of group
therapy for patients with fibromyalgia. The sessions consisted of behavioral modifications, stress reduction techniques,
strategies to improve flexibility and physical performance, in
addition to sessions for familial help. The sessions were held
weekly for a period of six months. The authors report promising results obtained in the short and long terms.
There was also a decrease in symptoms of depression and
anxiety in WIP participants.
Among the various factors affecting the QoL of fibromyalgia patients, Aliciati et al.27 suggest that the presence of depression predisposes patients to impaired social functioning,
and Clark et al.23 reported that the inclusion of these patients
in multidisciplinary groups favors the practice of daily living
activities, mobility and quality of body movements and of
physical fitness, thereby improving their quality of life.
Título do Gráfico
80%
70%
60%
50%
DEPRESSION
40%
ANXIETY
30%
20%
10%
0%
GT
GC
Fig. 1 – Distribution of fibromalgics according to the
calculated mean of depression and anxiety symptoms
Table 2 – Change in mean values of FIQ, SF-12 and Post-Sleep Protocol (SIP) questionnaire domains throughout the
follow-up period, expressed as mean ± standard deviation and variation
Instruments applied
FIQ
functional capacity
Feeling good
Work absences
Ability to work
Pain
Fatigue
Sleep
Morning stiffness
Anxiety
Depression
Total FIQ
SF-12
Physical component
Mental component
PSP
At bedtime
Overnight
1st review
Mean and SD
TG GC
2nd review
Mean and SD
TG GC
p value
12.4±7.7 9.3±5.9
2.0±2.6 4.8±2.7
0.0±0.0 0.0±0.1
6.6±2.8 5.1±3.1
7.7±1.8 5.7±3.0
7.5±2.3 5.7±2.0
6.6±3.0 4.1±3.1
7.5±2.5 5.3±7.9
7.6±2.5 4.3±3.3
7.0±2.5 3.4±3.1
64.9±27.7 47.7±37.2
10.8±5.4 8.2±5.8
2.5±2.5 3.7±2.8
0.1±0.6 0.2±0.9
5.7±3.0 2.4±2.8
6.3±2.5 2.2±2.8
6.9±2.5 3.1±3.1
5.8±2.8 2.3±2.3
5.9±3.0 1.8±2.3
6.6±2.3 6.3±2.9
6.2±2.8 5.4±3.2
56.8±27.4 35.6±28.9
0.04*
0.06
0.20
0.03*
0.04*
0.04*
0.06
0.03*
0.03*
0.04*
0.03*
48.5 52.3
38.5 48.5
59.5 62.3
67.5 78.5
0.03*
0.001*
38.6±13.6 51.4±8.6
72.2±8.6 91.2±6.4
53.4±5.6 68.3±7.8
92.3±8.4 98.3±7.4
0.04*
0.03*
* statistically significant difference, p < 0.05.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4
Regarding the prescription of activities and exercises to
patients with FMS, orientations, as well as pharmacological prescriptions with dose, duration and specific intervals,
were performed. The concern in relation to the intensity and
execution of the proposed and previously trained activities
in WIP began gradually, considering the preferences of patients, their comorbidities, medication use, and functional
capacity.
Corroborating this procedure, the trial by Miró et al.28 involved different areas in action groups with expertise on fibromyalgia patients, showing that they are promoters of pain
relief, generating well-being and contributing significantly to
the quality of the patients’ life.
Regarding the sleep, some trials29,30 relate a worst sleeping period to a greater number of tender points in patients
with fibromyalgia. Sleep disturbances were also associated
with chronicity of pain complaints. It is known that individuals with chronic pain, such as those with FMS, have a persistent health condition that changes their life. The goal of their
treatment is to control FMS and not to seek its elimination;
therefore, the sleep pattern assessment becomes a sensitive
indicator that should be considered. In this trial, after the intervention of WIP (with approaches focused on body biomechanics, kinesiology, ergonomics, psychosocial aspects and
improvement of cardiorespiratory capacity), a better sleep
pattern was noted in these individuals.
Follow-up studies with FMS patients are scarce, as well as
those on the health care, that should have an interdisciplinary planning, but they have been performed separately by
each professional.
The actions resultant of WIP revealed that the approach
to patients with FMS should be multifactorial; this strategy
enables the understanding of this syndrome as a summation
of disorders that end up manifesting itself by the association
of a variety of symptoms.
Conclusion
The treatment of fibromyalgia patients should follow multifactorial models; this will allow a systematic development of
the necessary abilities to the transition from rehabilitation in
the maintenance of an active and independent lifestyle.
Conflicts of interest
The authors declare no conflicts of interest.
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33:160-72.
2. Martins MRI, Polvero L, Rocha CE, Foss MH, Santos Junior R.
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inhibition in patients with fibromyalgia but evidence of
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with fibromyalgia: a pilot study. J Back Musculoskelet Rehabil.
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of chronic widespread musculoskeletal pain. Best Pract Res
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and fibromyalgia syndromes. Rheumatol Int. 2003;23:211-5.
12. Buskila D, Atzeni F, Sarzi-Puttini P. Etiology of fibromyalgia: the
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13. Suleı̆manova GP, Grekhov RA, Kharchenko SA, Aleksandrov AV,
Zborovskiı̆ AB. Psychosomatic relationships in patients with
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14. Riberto M, Pato TR. Fisiopatologia da fibromialgia. Acta Fisiatr.
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15. Bellometti S, Galzigna L. Function of the hypothalamic adrenal
axis in patients with fibromyalgia syndrome undergoing mudpack treatment. Int J Clin Pharmacol Res. 1999;19:27-33.
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18. Jahan F, Nanji K, Qidwai W, Qasim R. Fibromyalgia syndrome:
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Oman Med J. 2012;27:192-5.
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LV, Pereira CAB. Validação da versão brasileira do Fibromyalgia
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saúde em pacientes com DPOC: estudo de base populacional
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scale. Acta Psychiatr Scand. 1983;67:361-370.
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Construction of a manual of work processes and techniques
from Centro de Dispensação de Medicamentos de Alto Custo
(CEDMAC), Hospital de Clínicas, Unicamp
Manoel Barros Bertolo a, Bruno Silva de Araújo Ferreirab, Adriana G. Mucke Marchiore b,
Glaucia Pereira do Amaral Carvalho b, Débora Pessoa de Souzab, Eliane Molina Psaltikidis b,*
Discipline of Rheumatology, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil
Clinical Hospital, University of Campinas, Campinas, SP, Brazil
a b article info
abstract
Article history:
The Centers for High Cost Medication (Centros de Medicação de Alto Custo, CEDMAC),
Received on 27 August 2013
Health Department, São Paulo were instituted by project in partnership with the Clini-
Accepted on 28 October 2013
cal Hospital of the Faculty of Medicine, USP, sponsored by the Foundation for Research
Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São
Keywords:
Paulo, FAPESP) aimed at the formation of a statewide network for comprehensive care of
Rheumatology
patients referred for use of immunobiological agents in rheumatological diseases. The
Biological Therapy
CEDMAC of Hospital de Clínicas, Universidade Estadual de Campinas (HC-Unicamp), im-
Hospital Administration
plemented by the Division of Rheumatology, Faculty of Medical Sciences, identified the
Quality Assurance, Health Care
need for standardization of the multidisciplinary team conducts, in face of the specificity
of care conducts, verifying the importance of describing, in manual format, their operational and technical processes. The aim of this study is to present the methodology applied to the elaboration of the CEDMAC/HC-Unicamp Manual as an institutional tool, with
the aim of offering the best assistance and administrative quality. In the methodology
for preparing the manuals at HC-Unicamp since 2008, the premise was to obtain a document that is participatory, multidisciplinary, focused on work processes integrated with
institutional rules, with objective and didactic descriptions, in a standardized format and
with electronic dissemination. The CEDMAC/HC-Unicamp Manual was elaborated in 10
months, with involvement of the entire multidisciplinary team, with 19 chapters on work
processes and techniques, in addition to those concerning the organizational structure and its annexes. Published in the electronic portal of HC Manuals in July 2012 as an
e -Book (ISBN 978-85-63274-17-5), the manual has been a valuable instrument in guiding
professionals in healthcare, teaching and research activities.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (E.M. Psaltikidis).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.10.003
186
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1
Construção do manual de processos de trabalho e técnicas do Centro de
Dispensação de Medicamentos de Alto Custo (CEDMAC) do Hospital de
Clínicas da Unicamp
resumo
Palavras-chave:
Os Centros de Medicação de Alto Custo (CEDMAC) da Secretaria de Saúde do Estado de São
Reumatologia
Paulo foram instituídos por projeto em parceria com Hospital das Clínicas da Faculdade de
Terapia biológica
Medicina da USP, patrocinado pela Fundação de Amparo à Pesquisa do Estado de São Paulo
Administração hospitalar
(FAPESP), visando à formação de rede estadual para atendimento integral dos pacientes
Garantia da qualidade dos cuidados
indicados ao uso de agentes imunobiológicos nas doenças reumatológicas. O CEDMAC do
de Saúde
Hospital de Clínicas da Universidade Estadual de Campinas (HC-Unicamp), implementado
pela Disciplina de Reumatologia da Faculdade de Ciências Médicas, identificou a necessidade de padronização das condutas da equipe multidisciplinar, frente à especificidade
da assistência, verificando a importância da descrição, em formato de manual, dos seus
processos de trabalho e técnicas. O objetivo do estudo foi apresentar a metodologia de
construção do manual do CEDMAC/HC-Unicamp como ferramenta institucional, visando
à qualidade assistencial e administrativa. A metodologia para elaboração dos manuais no
HC-Unicamp, desde 2008, tem como premissas ser participativo, multidisciplinar, focado
em processos de trabalho, integrado às normas institucionais, com descrição objetiva e
didática, formato padronizado e divulgação eletrônica. O Manual do CEDMAC/HC-Unicamp
foi construído em dez meses, com o envolvimento de toda equipe multidisciplinar, tendo
19 capítulos sobre processos de trabalho e técnicas, além dos relativos à estrutura organizacional e anexos. Publicado no portal eletrônico dos Manuais HC, em julho de 2012,
como e-book, com registro ISBN 978-85-63274-17-5. O Manual tem sido valioso instrumento
na orientação dos profissionais da área nas atividades assistenciais, de ensino e pesquisa.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
The treatment of rheumatic diseases has changed markedly
in the last 10 to 15 years, with the emergence of new drugs,
the so-called biological therapies.1
Disease-modifying drugs (DMDs) are conventional therapies that can control about 20% of symptoms in approximately 55%-60% of patients; only 10%-20% attain a response of 70%
of development of arthritis.2-4 However, there is a niche of patients who, even in association with conventional DMARDs,5
do not achieve a good response or are intolerant (e.g., nausea
with methotrexate, diarrhoea with leflunomide, maculopathy
to antimalarials), requiring another pharmacological agent to
improve symptoms and return to their productive lives.
Biologic therapies are so named because they are organic
molecules of high molecular weight and have biological origin, i.e., produced by living beings and containing carbon atoms in their molecular structure. In general, the organic molecules used as substrates are immunoglobulins or antibodies.
However, their greater efficacy with greater specificity justifies the high cost, since the patient will be again a productive member of society. This will be possible after research on
the physiopathogenesis, with biomolecular foundation, and
on the activity in specific and critical points for a particular
disease.6-10
In general, patients are lay people in the medical field, or
even have a low level of education; thus, most of them are not
equipped to handle (storage, application and disposal) self-
administered subcutaneous drugs or would not have a proper
place for infusion of intravenous medications, and also do
not have proper supervision. Being organic molecules, these
drugs are very exquisite, requiring special care in their handling or transport.
This can be observed in medical consultations, considering
that it is the responsibility of the rheumatologist to evaluate
the patient response to the prescribed medication. It is known
that a closer monitoring of patients with rheumatologic disease results in a better response to treatment, compared with
patients in routine visits every 3 to 6 months, as that strategy
enables an earlier intervention.3-5,11
Initially, this conduct of a more rigorous and closer followup may seem more difficult and costly. However, in the study
TICORA, a survey on costs was also done, showing no increase
in financial costs and a better quality of care and improved
response.5
This strategy is practiced at CEDMAC, Health Department,
São Paulo, considering that the visits take place with a shorter
time interval and with the possibility of extra visits to check
for effects and adverse events.
CEDMAC was established from a project developed in partnership between Hospital das Clínicas, Faculty of Medicine,
USP, and Health Department of the State of São Paulo, and
is sponsored by the Foundation for Research Support of the
State of São Paulo (Fundação de Amparo à Pesquisa do Estado
de São Paulo, FAPESP), aimed at the formation of a statewide
network for dispensing costly medication. CEDMAC serves patients with an indication for use of immunobiological agents
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1
in rheumatological diseases, and accompanies the indication,
dispensing and application of these medications. Another
important function of the Centers is the registration of users
for reporting side effects; thus, CEDMAC can feed data into
Brazilian Registry of Biological Rheumatology (BiobadaBrasil).
The role of specialist nurses is also crucial, because in
addition to being familiar with terms and conditions, these
professionals are also aware of the conventional drugs and,
in the case of CEDMAC, of this new class of antirheumatic
drugs. Thus, the specialist nurses interfere in the patients’
education – on what is the disease, treatment options, the
proper use of medication, and improvement in the degree of
fidelity to its use. Thus, these professionals help increase the
response to therapy. In some countries, these professionals
even count joints and advice on contraception.
Another important role of CEDMAC is to establish innovative conduct protocols on biologicals, following the most
current recommendations. By being in the public university
scenario, the scientific knowledge is considered an essential
factor, together with the reduction of costs. One of the main
terms that enter into discussion in the context of biological
drugs, particularly in the use of infusion drugs, is how to reduce the infusion time for each patient, increasing vacancies
and obtaining full efficiency of the service with the highest
quality possible.9,10
Since this is a statewide network of centers for dispensing
and infusion of high-cost drugs (especially biologicals) in the
field of rheumatology, there is the possibility of exchanging
information with other centers, with the aim of standardizing
the care in the State of São Paulo, with sharing of experiences.
The CEDMAC/HC-Unicamp was implemented by the Department of Rheumatology, Faculty of Medical Sciences. Its
main goal is to benefit rheumatological patients with the use
of biological drugs, with respect to guidance on this type of
medication, its proper use and supervision as to their doubts
and responses to therapy. Thereby, the CEDMAC also interferes to avoid the improper use or misuse of medications, as
well as their loss.
Moreover, CEDMAC also must train specialized teams that
will deal with this type of patient and drug, offering appropriate multidisciplinary care and providing more welfare to the
rheumatic patient. In addition, data are generated from standardized consultations, with production of clinical research
and exchange of information and experiences with other
CEDMACs of São Paulo.
Considering the specificity of the assistance offered and
the need for a clear standardization of conducts for the multidisciplinary team, it became important to develop and describe, in manual format, the work processes and techniques
of CEDMAC/HC-Unicamp.
In the literature and in all certification programs adopted
by healthcare institutions, there is consensus on the need of
elaboration of operational manuals, even if the nomenclature
of these documents may vary according to the source consulted: manuals of routines, norms, procedures, techniques,
processes, or of standardized operating procedures.12,13
The manual is an administrative instrument that allow the
organization and standardization of service guidelines in a
health care institution, systematizing activities and their execution by different professionals; moreover, this document
187
establish points of process control and of measurement of
results.14 Manuals give subsidies for training and supervision
of procedures, reducing the risk of adverse events, facilitating
the revision of processes, meeting the requirements of regulatory agencies and offering protection against lawsuits generated by patients or labourers.
It is known that people produce better when following a
standardized routine. This standardization reduces the variability of offered products or services, and this translates
into predictable and reliable processes. The manual should
serve as a reference document, being used for training
teams to operate the work process. Moreover, the manual
can function as a tool which facilitates the dissemination
of institutional knowledge, as a benefit within reach of all
interested.12,15
A discussion that still occurs in the healthcare scenario
relates to the supposed difficulty in developing manuals for
this sector, in which every patient is an unique being, with
an absolutely peculiar clinical picture. In reality, what are intended to standardize are the processes likely to be used, and
not the assistance to be provided.16
A good standardization must demonstrate essential characteristics: it must arise from those professionals who perform the tasks, be the result of consensus, be simple and
based on institutional practice, should address more frequent
and higher risk/complexity situations, be consistent with the
recommendations and literature, follow a standard format
and be accessible to all members of the institution. No single model exists for a manual elaboration. These documents
may vary as to content, level of detail and format, according
to the needs of each institution. Manuals are flexible, never
complete or finished works, and depend on constant review
and updating.17
Objective
To present the methodology of elaboration of the manual of
work processes and techniques for CEDMAC/HC-Unicamp as
an institutional tool, aiming to the best care and administrative quality.
Material and methods
The HC-Unicamp develops, since 2008, a program of institutional elaboration of manuals, entailed to and supported by,
Hospital Superintendence, with clearly defined premises and
logistical support for elaborating and formatting manuals, favoring the adhesion of multidisciplinary teams and the project success.18
The premises of HC-Unicamp Manuals are:
• Participative elaboration – to involve professionals from
different hierarchical levels in the processes’ description
in the area.
• Description by processes, where possible, with multiprofessional, interareas and multidisciplinary approaches – to
involve all professional categories in the preparation of the
manual, and to describe the processes, allowing the dem-
188
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1
onstration of the interrelationship of the multidisciplinary
team and the different areas of the institution.
• Address liability processes of the area – to describe only
proper and specific processes of the area.
• To reflect the reality and current practice – the manual
must not describe idealized processes, but those that, in
fact, are practiced; thus, in practice the motto prevails:
Write what you do and do what is written!.
• Depth and detail are determined by demand and interest
in the area – due to its specificity, each area determines
what are the important processes to be described and
what level of detail is necessary to their reality.
• Objective, didactic and attractive description, with a focus
on target audience – to avoid excessively detailed descriptions that make the reading process a tiresome thing. Use
simple and direct language, favouring clarity.
• A standardized format – operational help for manual formatting and configuration of an institutional document,
in accordance with the recommendations of certification
programs and literature: standardized header and footer
containing institutional logos, authors, implantation date,
revision date, revision number, author and signature of the
professional in charge of the area in question; use of documents and descriptive papers of activities already existing
in the area, with its conversion to standard format.
• Compatibility and integration with manuals from other areas – to avoid repetitions and contradictions among manuals of different areas.
• Priority in dissemination and electronic use – to create,
in the community, the habit of searching for information
in the manuals in electronic format, avoiding the use of
printed copies.18
prepares technical recommendations for occupational safety.
Regarding the use of individual protection, collective protection and protection barriers’ equipment, as prescribed by legislation, in particular the Regulatory Standards of the Ministry
of Labor and Employment and those issued by the National
Health Surveillance Agency (Agência Nacional de Vigilância
Sanitária, ANVISA) and the Brazilian Association of Technical
Standards (Associação Brasileira de Normas Técnicas, ABNT).
After the analyses, utterance of technical recommendations,
and alignment of occupational safety conducts, the manual is
signed by the labor safety technician in charge.18
With the final approval and signature of the professional in
charge of the area in question, the document is converted to
pdf, using a security system that prevents changing contents,
printing and text fragments copying. This measure aims to prevent misuse of the document, especially unnecessary copies
and plagiarism. Moreover, in order to improve the institutional
control of all manuals issued, these are registered in the International Standard Book Number (ISBN) in e-Book format.18
Subsequently, the manual is forwarded to the Division of
Informatics for allocation to a specific directory on the hospital’s central server. In this directory, all books available for
consultation can be found at a portal accessed by care network and intranet (Fig. 1). The access is free throughout HCUNICAMP in more than 1.700 computers. Currently, there are
79 manuals of support, care areas, and management available for consultation.
Although each area has a printed copy of its manual, the
electronic access is highly encouraged because of its advan-
The content of the manual covers:
• Mission and/or objectives of the area;
• Area relationship map – consists in a model that represents
the relationship between supplier, input, process, output and
customers;
• Macroflow of operational process of the area;
• Description of the various processes of the areas, highlighted
in the analytical index;
• Description of the standards of occupational safety in each
specific operational process;
• Annexes relevant to each area, such as: regulatory standards,
bibliographies, used documents and guidance booklets.
After all processes were described in a certain area, the
manual is referred to the Committee on Hospital Infection
Control, that will analyze all procedures and techniques with
which this document interfaces, assessing its compliance to
standards and guidelines established for the infection control
in the institution. If there is any non-compliance, a meeting
is scheduled with the participation of members of the area of
the manual in question and the HC-Manuals project coordinator, besides professionals of CCIH, for the needed conducts’
agreement. After the arrangements, the president of CCIH
signs the processes with which he/she has interface.18
In parallel, the manual is also forwarded to the Labor
Safety Service that performs the analysis of the activities and
Fig. 1 – Images from the manual’s Portal, HC-Unicamp.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1
tages: less paperwork, continuous and simultaneous access to
manuals, frequent updating of content, access to all manuals
and not only to that of a specific area, quick identification of
the desired process and easy consultation.
Results
The manual of work processes for CEDMAC-HC-Unicamp was
elaborated in a period of 10 months, in a participative manner with involvement of the entire multidisciplinary team, and
published in the electronic portal of HC-Manuals in July 2012 in
form of e-Book (ISBN 978-85-63274-17-5).
The organizational structure of CEDMAC was addressed
through:
• Description of the objectives of the area in question, encompassing the intervention in care, teaching and research.
• Map of supplier/process/client relationship that presents
the interrelationships of the area with its key suppliers and
internal and external customers (Fig. 2).
• Macroflow of the operational process that summarizes, in
graphic presentation, the care process (Fig. 2).
In order to provide a basic technical knowledge indispensable to a good care practice by non-specialist professionals
189
of major and secondary levels, a chapter has been prepared
addressing the biological drugs used in CEDMAC (Fig. 3) with
respect to:
• Differences between traditional and biological medicines.
• Classes of biologicals used in rheumatology.
• Major biological drugs used; their characteristics, indications, contraindications and usual dosage.
The structure and operating rules of CEDMAC were described, as well as the duties of the professionals involved,
specifying their accountability for tasks and hierarchical
bonds. The profile of patients and their flow of access to the
service were detailed. The origin of the administered medications, acquisition routine, control and care for their preservation were also described.
Chapters on the technique of preparation and administration for each biological medicine used in CEDMAC were
elaborated: infliximab, adalimumab, etanercept, abatacept,
rituximab, tocilizumab (Fig. 3). Chapters were also prepared
for zoledronic acid and cyclophosphamide that, although not
biologicals, are eventually prescribed and require special care
in their preparation and administration. The most frequent
adverse events in the administration of these drugs and the
recommended actions were also highlighted.
Specific chapters detailed medical procedures and the systematization of nursing care performed in CEDMAC, as well
as for administrative, teaching and research activities.
A total of 19 chapters describing the work process and
techniques were elaborated, besides those relating to the organizational structure and annexes (references, documents
used in the area, a chronological table of educational documents and folders).
Discussion
Fig. 2 – Map of relationship and macro flow of the
operational process of CEDMAC HC-Unicamp.
Despite the hard work represented by the elaboration of the
manual and of the required dedication of the multidisciplinary
team, the results clearly justify it. Throughout the preparation
process, care practices can be revised according to the literature
and manufacturers’ guidelines for their own drugs, in relation
to precautions in storage, preparation, application and user assistance. Small variations in practice between practitioners of
CEDMAC regarding the handling of products were observed;
this way, there is opportunity for adjustments of conduct.
The possession of work processes and of described and accredited techniques facilitates the dissemination of specific
technical knowledge of the area, the integration of new professionals, a continuing education for the multidisciplinary team
and supervision of procedures.
Due to its teaching and research activities (characteristics of
HC-UNICAMP), the manual can also function as a guidance tool
for trainees, including medical residents and graduate students.
In addition to these benefits, with the manual of work processes and techniques from CEDMAC HC-Unicamp, there is
a possibility of exchanging of information and experiences
with other centers of infusion of biologic medicines in the
area of rheumatology.
190
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1
Fig. 3 – Content images of the work manual processes, CEDMAC HC-Unicamp.
Conflicts of interest
The authors declare no conflicts of interest.
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control for rheumatoid arthritis (the TICORA study): a
single-blind randomised controlled trial. Lancet [Internet].
2004;364:263-9. Available at: http://www.ncbi.nlm.nih.gov/
pubmed/15262104.
6. Firth J, Critchley S. Treating to target in rheumatoid
arthritis: biologic therapies. British Journal of Nursing.
2011;20:1284-91.
7. Firth J. Rheumatoid arthritis: treating to target with diseasemodifying drugs. British Journal of Nursing. 2011;20:1240-5.
8. Corominas H, Sánchez-Eslava L, García G, Padró I, Aimarich
C, Gonzàlez J et al. Safety profile of biological intravenous
therapy in a rheumatoid arthritis patients cohort. Clinical
nursing monitoring (Sebiol study). Reumatologia clinica
[Internet]. SEGO; 22 October 2012 [cited 11 February
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pubmed/23099285.
9. EMA – European Medicines Agency. Resumo das
Características do Medicamento – Remicade. 2009. p. 1-56.
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Prescribing Information – Infliximab. 2011. p. 1-47.
11. Verstappen SMM, Jacobs JWG, Van der Veen MJ, Heurkens
HM, Schenk Y, Ter Borg EJ et al. Intensive treatment with
methotrexate in early rheumatoid arthritis: aiming for
remission. Computer Assisted Management in Early
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Rheumatoid Arthritis (CAMERA, an open-label strategy trial).
Annals of the rheumatic diseases [Internet]. November 2007
[cited 11 February 2013];66:1443-9. Available at: http://www.
pubmedcentral.nih.gov/articlerender.fcgi?artid=2111604&tool
=pmcentrez&rendertype=abstract
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sociedade do conhecimento: um roteiro para a ação. Rio de
Janeiro, Campus, 2001.
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Acreditação. Brasília, ONA, 2006. 3ª revisão.
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de Janeiro, Guanabara-Koogan, 2003.
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15. Campos ER, Lima MBBPB, Martinez MHSL, Monticelli NAM.
Metodologia de gestão por processos. Campinas, UNICAMP,
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Belo Horizonte, Desenvolvimento Gerencial, 1999.
17. Porfírio RBM, Munhoz S, Pinter MG. Gerenciamento de
enfermagem em Centro Cirúrgico. In: Enfermagem em
centro cirúrgico e recuperação. São Paulo, Manole, 2007.
18. Psaltikidis EM, Oliveira MA, Kitaka EL, Leichsenring ML,
Fagnani R, Gama J et al. Portal de Manuais do Hospital
de Clínicas da Unicamp: amplo acesso às informações
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Evaluation of respiratory impairment in patients with
systemic lupus erythematosus with the six-minute walk test
Marivone Arruda Leite, Mônica Corso Pereira, Lílian Tereza Lavras Costallat,
Wander de Oliveira Villalba, Marcos Mello Moreira, Ilma Aparecida Paschoal*
Department of Internal Medicine, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
article info
abstract
Article history:
Objective: Evaluate SLE stable patients, without overt respiratory compromise, by means of
Received on 24 April 2013
6MWT.
Accepted on 10 February 2014
Casuistic and methods: Forty-five stable SLE patients were enrolled. The ATS/ERS protocol for
6MWT, was used and two parameters with cut-off points were chosen.
Keywords:
Results: Forty-two patients were women. The mean age was 39 ± 11.4 years; mean duration
Systemic lupus erythematosus
of disease, 121 ± 93.1 months; mean value of MRC, 2 ± 0; mean FVC, 85.9 ± 34.2%; mean
Six-minute walk test
FEV1, 67.5 ± 21.6%; mean MIP, 82 ± 58.4%; mean MEP, 78 ± 37.3%; mean heart rate at rest,
Oxygen saturation
75 ± 12.8 bpm; mean respiratory rate at rest, 19 ± 5.3 bpm; mean 6MWD, 478 ± 82 m; mean
Respiratory function test
SpO2 at rest was 98 ± 0.8%; mean fall in SpO2, 4 ± 6 points. When the study population was
Questionnaires
divided according to the 400-m walk distance cut-off value, the heart rate immediately
before the test was significant lower in those participants who walked less than 400 m (p =
0.0043), just like the value of Borg scale (p = 0.0036); according to the presence of saturation
≥ 4, heart rate at the end of the test was significantly higher in those participants who were
showing desaturation (p = 0.0170); MEP (p = 0.0282) and 6MWD (p = 0.0291) were significantly lower, and MIP showed a tendency towards being smaller (p = 0.0504). FVC < normal
inferior limit was significantly associated with the group with desaturation (p = 0.0274).
Conclusion: Compared to 6MWD, desaturation was better suited to find the patients with the
most compromised indexes in respiratory function tests.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (I.A. Paschoal).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2014.02.017
193
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9
Avaliação do comprometimento respiratório em pacientes com lúpus
eritematoso sistêmico com o teste de caminhada de seis minutos
resumo
Palavras-chave:
Objetivo: Avaliar pacientes com LES estável, sem comprometimento respiratório evidente,
Lúpus eritematoso sistêmico (LES)
por meio do TC6M.
Teste de caminhada de seis
Casuística e métodos: Foram recrutados 45 pacientes com LES estável. Foi utilizado o protoco-
minutos
lo ATS/ERS para TC6M, tendo sido escolhidos dois parâmetros com pontos de corte.
Saturação de oxigênio
Resultados: Quarenta e dois dos pacientes eram mulheres. A média de idade foi 39 ± 11,4 anos;
Teste de função respiratória
a duração média da doença, 121 ± 93,1 meses; valor médio de MRC 2 ± 0; CVF média 85,9 ±
Questionários
34,2%; VEF1 médio 67,5 ± 21,6%; PIM média 82 ± 58,4%; PEM média 78 ± 37,3%; frequência cardíaca média em repouso 75 ± 12,8 bpm; frequência respiratória média em repouso 19 ± 5,3
bpm; Distância média no TC6M 478 ± 82 m; SpO2 média em repouso 98 ± 0,8%; queda média
em SpO2 4 ± 6 pontos. Quando a população em estudo foi dividida de acordo com o valor de
corte de 400 m de distância caminhada, a frequência cardíaca imediatamente antes do teste foi significativamente menor naqueles participantes que caminharam menos de 400 m
(p = 0,0043), da mesma forma que o valor da escala de Borg (p = 0,0036). De acordo com a presença de saturação ≥ 4, a frequência cardíaca ao final do teste estava significativamente mais
elevada naqueles participantes exibindo dessaturação (p = 0,0170); PEM (p = 0,0282) e TC6M
(p = 0,0291) estavam significativamente menores e PIM revelou uma tendência para diminuir (p = 0,0504). CVF < limite inferior do normal foi achado significativamente associado
com o grupo com dessaturação (p = 0,0274).
Conclusão: Comparado com TC6M, a dessaturação foi o indicador mais apropriado para localizar os pacientes com os índices mais comprometidos nos testes de função respiratória.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Systemic lupus erythematosus (SLE) is a progressive autoimmune disease of unknown etiology and a broad spectrum of
clinical manifestations, that has a chronic course with periods of exacerbation and remission. According to American
studies, the disease most frequently affects young women
(9-10:1), with its prevalence ranging from 14 to 50/100.000 inhabitants.1 A study involving Brazilian population observed
a higher incidence in Caucasian patients2 and also in young
women.3 In pulmonary manifestations, we have, by frequency, pleural involvement (pleural effusion, pleuritis). However,
there may be vascular manifestations (pulmonary hypertension, alveolar hemorrhage), interstitial disease (interstitial
pneumonia with possible progression to pulmonary fibrosis),
neurological involvement (phrenic neuropathy and diaphragmatic paralysis), among other problems.4,5
The activation of the endothelial cells and the immunological deregulation, which leads to the production of many
different autoantibodies, are the central pathological disturbances of the disease.5
The endothelial cells produce substances that control vascular tone and activate the immune and coagulation systems
which, in their turn, have the same endothelial cells as targets of the inflammation generated by the immune processes
and the coagulation cascade. Vascular injury is probably the
primary site of lesion in lupus pathogenesis.5 The activation
and damage of the endothelial cells of the immune system
are capable of explaining the involvement of the renal, central
nervous, cardiovascular and respiratory systems in patients
with SLE.6
Apart from serositis, no other pulmonary or respiratory involvement appears in the list of diagnostic criteria proposed
by the American College of Rheumatology (ACR).7 The diagnosis of SLE is not simple and requires the fulfillment of a minimum number of criteria from a set developed by the ACR.8
Various respiratory manifestations of SLE can provoke
acute respiratory symptoms such as pleural thickening, pleural effusion and alveolar hemorrhage; however, some may be
insidious and difficult to diagnose, such as interstitial lung
disease or vascular disease, which are often silent for quite
a long time.
Early diagnosis of respiratory involvement in patients
with lupus is fundamental because it allows the therapeutic
management established in the earliest stages of the disease,
which can prevent the progression to a more dramatic functional impairment. Therefore, it is essential to actively search
for symptoms and to perform tests – preferably little or minimally invasive – which indicate involvement in early disease.
Thus, 6MWT is a submaximal exercise test that has already
been validated in the evaluation of several lung diseases.9-13
This test is easy to be performed, low cost and has a good correlation with other more sophisticated tests such as the diffusion test for carbon monoxide (DLCO) or cardiorespiratory.11,14
This study aimed to evaluate a patient group with stable
SLE, without overt respiratory compromise, by six-minute
walk test (6MWT), a self-paced and submaximal exercise test,
in order to investigate the possibility of an unnoticed respiratory involvement.
194
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9
Methods
This was a cross-sectional study that enrolled stable SLE patients, diagnosed according to the updated and revised American College of Rheumatology (ACR) criteria,7 who attended
the SLE outpatient clinic of the Teaching Hospital of the University of Campinas, between November 2007 and August
2009.
All patients were evaluated in order to check if there was
presence of any respiratory symptom. The patients were clinically stable – during the prior three months – using one or
a combination of the following drugs: hydroxychloroquine,
chloroquine, prednisone, azathioprine, and/or mycophenolate mofetil. None of them had recently changed their therapeuthic regimen. Six months before the study, all patients
were radiographically evaluated by a radiologist and, if it had
been noticed the presence of pleural thickening or pleural
abnormalities suggestive of interstitial involvement or increased cardiac area in some of these patients, they would
not have been included in the study.
Patients would not be considered eligible for the 6MWT
if they had a recent chest X-Ray showing any abnormality,
hemoglobin concentration below normal values, complaints
that could interfere with the walk, if the oxygen saturation
(SpO2) levels in rest were under 90% on ambient air, or the
pulse signal on a pulse oximeter was inadequate due to Raynaud’s phenomenon. Aiming to ensure an accurate assessment of SpO2, the respiratory therapist checked if the pulse
oximeter showed an acceptable pulse signal and if the oximeter light was green and pulsing in synchrony with the heart
rate before beginning all tests.
The study was approved by the Research Ethics Committee
of the Faculty of Medical Sciences of the University of Campinas, and an informed consent was signed by each patient.
The protocol used for the 6MWT was designed to ensure an
accurate assessment of the walking distance and the oxygen
desaturation, as proposed by the American Thoracic Society.8
All patients were tested under standardized conditions by the
same technician (ML). Baseline blood pressure and heart rate
were measured and SpO2 was determined with a Nonin® pulse
oximeter (finger probe) (Nonin Medical, Inc; MN, USA). The
walking course had 30 m of length. The patients walked on
a level surface and were gently encouraged periodically. Assessment of dyspnea by the Borg index was performed at the
beginning and at end of the test. SpO2 was measured at rest
and immediately after the end of the 6-minute period, and
the patients were carefully observed to avoid dangerously exceeding their exercise limits.
For the purpose of data analysis, desaturation was defined
as a decrease in SpO2 of 4 points or more (Δsat = resting saturation – saturation immediately after the 6-minute period),
in comparison with the initial values. Maximal distance was
defined as the maximal achieved walking distance on room
air 6MWT.
Spirometric maneuvers were performed as recommended
by Brazilian guidelines,15 and the curves for forced vital capacity (FVC) and slow vital capacity (VC) were performed using a
flow spirometer (microQuark model; COSMED Srl, Rome, Italy). The measured values were compared with those predicted
for age, sex and height for each patient, and the inferior limit
of the normal value for FVC was used to diagnose the reduction in FVC.16
British MRC (Medical Research Council) questionnaire
modified and translated to Portuguese was used to assess the
degree of shortness of breath (0=o shortness of breath, except
with strenuous exercise; 1=troubled by shortness of breath
when hurrying or walking up a slight hill; 2=walks slower
than people of the same age due to shortness of breath; need
to stop for catch their breath when walking at their own pace;
3=stops to breath after walking for approximately 100 m or
after a few minutes; 4=show themselves with an excessive
shortness of breath; breathless when dressing or undressing).17
The static maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were determined using a
digital manuvacuometer (MVD30-Globalmed). The maneuvers were performed as recommended in ATS/ERS statement
about respiratory muscle testing18, and the normal values
were expressed as percentage of expected values predicted
for Brazilians.19
The quantitative variables measured in these groups were
submitted to the Anderson-Darling test to define their distribution. Variables with normal distribution were analyzed
using the Student t test. Variables identified as not having a
normal distribution were studied with the Wilcoxon test. The
categorical data were compared using chi-square test or Fisher’s exact test when necessary. The statistical software used
was SAS, version 8®. Differences were considered significant
in the face of a p-value < 0.05.
Results
There were forty-five consecutive patients enrolled who
agreed to participate in the study and fulfilled the inclusion
criteria. There were 42 women with 39 ± 11.4 years, in total.
None of the patients were smokers. The duration of the disease was 121 ± 93.1 months in the occasion. The characteristics of the patients and their functional measurements are
detailed in Table 1.
The 6MWD was 478 ± 82 m and the SpO2 at rest was 98 ±
0.8%. The fall in SpO2 at the end of the 6MWT was 4 ± 6 points.
The spirometric evaluation showed FVC of 85.9 ± 34.2 (% of
predicted value) and 21 patients with FVC below the limit of
normality. The MIP was 82 ± 58.4 and MEP was 78 ± 37.3 (% of
predicted value).
For the purpose of data analysis, two main variables were
defined and used to separate the study population in groups:
a fall in saturation (Δsat) ≥ 4% and walking distance < 400 m.
Considering the cut-off value of 400 m of walking distance, no
differences were found between the groups concerning age,
disease duration, height, MIP, MEP, FVC, FEV1, FEV1/FVC, initial
SpO2, Δsat, increase in heart rate, initial respiratory rate, increase in respiratory rate, and increase in the Borg scale value.
In addition, no association was found for the groups regarding
sex, MRC value and the finding of a FVC inferior to the low
limit of predicted value. The heart rate obtained immediately
before the test was significantly smaller in those participants
who walked less than 400 m (p = 0.004) when considering the
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9
Table 1 – Study population characteristics and functional
measurements (n = 45)
Variables
Age (years)
Height (cm)
Duration of disease (months)
MRC questionnaire
FVC (% of predicted value)
FEV1 (% of predicted value)
MIP (% of predicted value)
MEP (% of predicted value)
Heart rate (bpm)
Respiratory rate (cpm)
SpO2 (%)
6MWD (m)
Δ SpO2(%)
Mean±SD
Median
(Min–Max)
39±11.4
161±7.5
121±93.1
2±0.5
85.9±34.2
67.5±21.6
82±58.4
78±37.3
75±12.8
19±5.3
98±0.8
478±82
4±6
39 (17-70)
162 (145-179)
96 (12-373)
2 (0-4)
81(31.6-247.7)
62.3 (30.4-113)
73(13-316)
75 (30-163)
70 (57-99)
18 (12-32)
98 (94-99)
500 (180-600)
1 (0-22)
Mean ± SD, mean ± standard deviation; Median (Min-Max), Median
(minimum and maximum); MRC, Medical Research Council; FVC,
Forced Capacity Value; FEV1, Forced Expired Volume in one second;
MIP, Maximal Inspiratory Pressure; MEP, Maximal Expiratory
Pressure; 6MWD, Six minute walk distance; cpm, cycles per minute;
bpm, beat per minute.
Borg scale value (p = 0.004). The distance walked by the patients in the two groups was also significantly different (p <
0.001): the value in the group ≥ 400 m was 505.3 ± 53.7 m; and
in the group < 400 m was 350.8 ± 70.4 m (Table 2).
When the population studied was divided in two groups,
according to the presence of desaturation ≥ 4 by the end of the
6MWT, no differences were found between the groups concerning age, disease duration, height, FEV1/FVC, initial SpO2,
initial heart rate, initial respiratory rate, increase in respiratory rate, initial value and increase in Borg scale. The heart
rate at the end of the test was significantly higher in those
participants who showed desaturation (p = 0.017). MEP was
significantly lower in the group with desaturation (p = 0.028)
and MIP as well, but it did not reach significance (p = 0.050).
The distance walked by the patients in the two groups was
also significantly different (p = 0.029): the value in the group
with desaturation was 443.1 ± 94.6 m and in the group without desaturation was 497 ± 68.5 m. The ΔSat was also significantly different in the two groups: the value in the group with
desaturation was 11.6 ± 4.6 points; and in the one without
desaturation, the fall was of 0.5 ± 0.9 points. The finding of a
FVC below the limit of the normal expected value was significantly associated with the group with desaturation (p = 0.027)
(Table 2).
Discussion
One finding that seems quite relevant in this study is that,
within a population of SLE patients without relevant respiratory symptoms, the 6MWT can give useful information about
respiratory compromise, especially if there is a reduction in
SpO2 by the end of the test. It was considered a reduction equal
to or greater than 4 points as significant, based on the findings
by Prefaut et al., who validated this cut-off value in a study of
exercise-induced hypoxemia during maximal exercise tests in
195
athletes.20 This 4% fall was defined as accounted for potential
inaccuracy of oximetry plus the effects of metabolic acidosis
on the hemoglobin saturation curve (a right shift).9
Subjects in this study with ΔSat ≥ 4% showed a significant
reduction in walking distance (443 m versus 497 m, p = 0.029),
although both values were way above the accepted inferior
limit for 6MWD. Furthermore, these patients, when compared
to those who did not desaturate had a higher heart rate at the
end of the 6MWT (p = 0.017), lower MEP (p=0.028), lower MIP
(p = 0.050) and a spirometry restrictive defect (FVC below the
lower limit of predicted value, p = 0.027, with a normal FEV1/
FVC ratio).
Conversely, those who walked less than 400 m showed no
significant differences regarding initial saturation or ΔSat ≥
4%. In addition, there were no significant differences between
the groups with 6MWD < 400 m and MWD ≥ 400 m in spirometric values, heart rate, static pressures or severity of dyspnea, either.
These findings suggest the hypothesis that desaturation
during the 6MWT may be a useful tool to evaluate SLE patients without respiratory symptoms – perhaps more sensitive than the 6MWD.
The 6MWT is a standardized submaximal test of exercise
capacity that is self-paced, simple, reproducible and inexpensive. The measured variables are distance walked in 6 minutes (6MWD), symptoms and SpO2 at rest and at the end of
the test.8 Because of its safety profile, physician attendance is
not required, but a health professional, such as physiotherapist or a nurse, with clinical experience should supervise the
patient during the test.
Age, sex, height, weight and ethnicity are important determinants of an individual’s 6MWD. In general, men walk
further than women; and the distance walked declines with
increasing age.21 Equations are available to predict expected
normal values of 6MWD, with some variation in the expected
distances.21,22 A walking distance of less than 350 m has predictive value of increased mortality in a number of cardiopulmonary disorders, such as COPD, interstitial lung disease,
pulmonary arterial hypertension, cystic fibrosis, congestive
heart failure.10,11,14,22-24
Although the 6MWD is a sensitive measurement of walking ability for patients with moderate to severe disease, it is
likely that its sensitivity in patients with better preserved
exercise tolerance may not be so good. A ceiling effect was
reported in patients with pulmonary arterial hypertension
whose 6MWD is greater than 450 m, and this observation may
be true for patients with other conditions.25
From the studies mentioned above, it can be seen that the
cut-off value for the walking distance is not well established;
apparently, it is between 350 m and 450 m.
In this study, only 8 patients walked less than 400 m, with
median value of 367.5 m and mean value of 350.8 ± 70 m.
For the groups separated by the walking distance, the only
statistically significant differences were initial heart rate
(slower for those who walked less) and degree of dyspnea in
Borg scale (smaller for those who walked less). There were no
significant differences for these variables at the end of the
6MWT. It is hard to have an explanation for these findings,
perhaps because of the small number of patients in one of
the groups.
37.7±10.9
118.7±98.5
160.7±8.0
83.5±61.6
78.9±37.1
85.7±35.9
68.5±22.8
0.7±0.2
76.8±12.9
24.3±13.7
19.2±5.2
9±4.8
98.1±0.8
3.7±5.4
8.5±1.7
4.3±2.7
505.3±53.7
39 (17-62)
84 (12-373)
160 (145-179)
73 (29-316)
75 (31-163)
80.4 (31.6-247.7)
67.1 (30.4-113)
0.7 (0.39-0.99)
73 (57-99)
19 (4-60)
18 (12-32)
8 (0-20)
98 (94-99)
1 (0-16)
8 (6-13)
4 (0-10)
510 (401-600)
Median
(Min-Max)
43.1±13.3
129±67.2
163.4±4.1
73.5±42.8
76.3±40.4
87±26.4
62.6±13.9
0.7±0.2
64±4.9
23.9±12.8
19±6.0
8.1±4.2
97.9±0.8
8±7.8
6.8±1.0
5.5±3.2
350.8±70.4
Mean ± SD
40.5(26-70)
126(24-240)
163(157-169)
65(13-137)
71(30-123)
89.7(53-127.3)
58.5(47.5-83.6)
0.6(0.42-0.89)
64(57-70)
18(12-49)
18(12-32)
8(4-16)
98(96-99)
8(0-22)
6.5(6-9)
5.5(1-10)
367.5(180-397)
Median
(Min-Max)
< 400 m (n= 8)
0.307
0.502
0.185
0.835
0.867
0.523
0.352
0.355
0.004
0.917
0.856
0.610
0.369
0.127
0.003
0.330
0.000
p value
38.9±9.2
117±95.8
158.9±5.5
61±33
63.9±35.4
70.1±27.9
57.5±18
0.7±0.1
76±15.8
29.4±12.2
21.4±6.3
10.6±5.1
97.8±1.2
11.6±4.6
7.8±1.4
5.4±3.1
443.1±94.6
Mean ± SD
38.5(17-51)
90(12-312)
160(150-169)
53.5(13-137)
56.5(30-150)
68.2(31.6-127.6)
55.8(30.4-91.3)
0.7(0.49-0.94)
69.5(57-99)
28(15-51)
20(12-32)
10(3-20)
98(94-99)
12(4-22)
8(6-10)
5.5(1-10)
450(180-600)
Median
(Min-Max)
With desaturation (fall in
SpO2 ≥ 4%) (n=16)
38.5±12.6
122.5±93.2
162.4±8.2
93.1±66.3
86.5±36.4
94.7±34.5
73±21.7
0.7±0.2
73.7±11.1
21.3±13.3
17.9±4.2
7.9±4.2
98.2±0.5
0.5±0.9
8.4±1.9
4±2.4
497±68.5
Mean ± SD
39(18-70)
120(12-373)
163(145-179)
84(30-316)
81(32-163)
93(53.4-247.7)
74.7(39.8-113)
0.7(0.39-0.99)
70(57-96)
17(4-60)
18(12-28)
8(0-16)
98(97-99)
0(0-3)
8(6-13)
4(0-9)
512(360-600)
Median
(Min-Max)
Without desaturation
(n=29)
Δ Sat
0.914
0.830
0.091
0.050
0.028
0.015
0.015
0.231
0.952
0.017
0.080
0.080
0.139
0.000
0.396
0.132
0.029
p value
Mean ± SD, mean ± standard deviation; Median (Min-Max), Median (minimum and maximum); 6MWD, 6 minutes walked distance; Δ Sat, Final SpO2 – Initial SpO2; MIP, Maximal inspiratory pressure;
MEP, Maximal expiratory pressure; FVC, Forced Capacity Value; FEV1, Forced Expired Volume in one second; HR, Heart rate; ∆ HR, Final HR – Initial HR; cpm, cycles per minute; ∆ RR, Final RR – Initial
RR; ∆ Borg, Final Borg – Initial Borg.
Differences were considered significant with a p < 0.05.
a
Values expressed as % of predicted value.
Age (years)
Duration of disease (months)
Height (cm)
MIP *
MEP *
FVC *
FEV1*
FEV1/FVC
Heart rate (bpm)
∆ HR (bpm)
Respiratory rate (cpm)
∆ RR (cpm)
Initial SpO2 %
∆ SpO2 (in % points)
Initial Borg
∆ Borg
6MWD (m)
Mean ± SD
≥ 400 m (n=37)
6MWD
Table 2 – Comparison of functional variables and 6MWT parameters between the groups separated by distance and desaturation (n = 45)
196
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9
The relation between walking distance and mortality is
not seen in patients suffering from untreated pulmonary arterial hypertension, in whom desaturation during the 6MWT
was a better predictor of mortality than walking distance: for
every percent decrease in SpO2 there was a 26% increase in
the risk of death.12
The desaturation during 6MWT has demonstrated its value as an index of severity of disease and prognostic factor.
Lama et al. showed that, in patients with interstitial pulmonary fibrosis without resting hypoxemia, desaturation up to
88% at any point during the 6MWT was associated to an increased hazard of death; however, no associations between
6MWD and survival were observed.26
In this study, FVC values below the lower limit of normality, simultaneously reduced FEV1 and normal FEV1/FVC indexes, indicating the presence of a restrictive defect, were
significantly more frequent among patients who showed desaturation. In addition, patients with desaturation had significantly lower MEPs and showed a trend towards significantly
lower MIPs. The 6MWD was not able to detect the patients
who had reductions in FVC, and not even the ones with reduced expiratory pressures. In this study, desaturation was
associated with lower 6MWD, although the mean walking
distance in the group that showed desaturation was much
greater than 350 m.
In our patients, an association between the presence of desaturation (Δsat ≥ 4%) with the values of MIP (p = 0.050) and
MEP (p = 0.028) was observed, suggesting that some impairment of respiratory muscles, not only the diaphragm, was
present.
The presence of unexplained dyspnea, especially in the
supine position, small lung volumes on chest radiographs,
dysfunction and elevation of the diaphragm and pulmonary
function tests displaying patterns of restrictive disease in the
absence of parenchymal involvement prompt the diagnosis of
shrinking lung syndrome.
Some authors found that the ability of the diaphragm to
generate pressure is impaired in patients with the shrinking lung syndrome;27 however, other authors28 were unable
to show a reduced diaphragmatic strength in a cohort of 12
patients.
In a comparison to the 6MWD, desaturation revealed itself as better suited to find patients with the most impaired
indexes in respiratory function tests. A previous published
study, carried out by our group, showed that desaturation
during a 6MWT provides additional information regarding
severity of disease in patients with scleroderma presenting
pulmonary manifestations.13
Inter-test variation is high in cases of oxygen desaturation. This fact implies that therapeutic decisions should not
be based on a single measurement of exertional desaturation
recorded on a 6MWT. This inter-test variation is expressed by
the finding of different values of SpO2 at the end of various
tests performed by the same patient.
In the study by Eaton et al., the value of hemoglobin desaturation upon pulse oximetry was found to be non-reproducible, with unacceptable measurement variation. However,
instead of using the hemoglobin desaturation as a categorical variable, they computed the values of desaturation in two
6MWTs.29 We believe that the important information here is
197
the occurrence of desaturation per se, a fact that is not observed in normal subjects.21 We surely expect the value of desaturation to vary because of different homeostatic situations
at different moments in individuals with pulmonary diseases
and in whom gas exchange abnormalities are probably present.
Except for the involvement of the pleura, the most common pulmonary manifestation of SLE, all other pulmonary
manifestations are infrequent, and many of them may cause
decrease oxygenation during exercise, by different pathogenic mechanisms. Those less common respiratory disorders
in patients with SLE include: interstitial lung disease, acute
lupus pneumonitis, diffuse alveolar hemorrhage, pulmonary
arterial hypertension, thromboembolic disease, acute reversible hypoxemia and shrinking lung syndrome. It is worth reminding that the prevalence of respiratory symptoms and
signs in patients with SLE vary depending on several factors,
most importantly the methods used for diagnosing respiratory tract compromise.
In athletes, the exercise-induced arterial hypoxemia is defined as a reduction in the arterial O2 pressure (PaO2) by more
than 1kPa and/or hemoglobin O2 saturation (SaO2) below 95%,
both determined by blood gas analysis. Desaturation is consistently found during maximal rowing ergometer and is most
pronounced at the end of an exercise bout.30 Exercise-induced
hypoxemia is explained by the interplay of many different factors. Alveolar PO2 must be maintained at a high level, so ventilation becomes a critical issue. A widening of the PAO2-PaO2
difference frequently occurs, indicating that diffusion limitation or a ventilation-perfusion mismatch or shunt may be influencing the transport of oxygen from the alveoli to the pulmonary capillaries. Cardiac output increases greatly, leading to
a fast transit time of red cells in the lungs and further limiting
O2 uptake. It is well known that a post-exercise reduction in
pulmonary diffusion capacity really occurs, and this suggests
damage to the alveolar-capillary membrane.31 All these factors
have been proposed to be involved in exercise- induced hypoxemia, but the six-minute walk test is a submaximal exercise.
Disease states may facilitate the occurrence of desaturation by
all these mechanisms.
Vascular injury with endothelial cell activation and damage
play a central role in the pathogenesis of SLE.5 The vascular endothelial growth factor (VEGF) is the main mediator of angiogenesis, and increased levels of VEGF were found in serum from
patients with rheumatoid arthritis, dermatomyositis/polymyositis, sclerodermapolymyositis, scleroderma complicated by
interstitial lung disease,32 and SLE.33 The mitogen is connected
to vascular hypertrophy, inflammation, tissue remodeling, extracellular matrix synthesis and fibrosis.34 Increased levels of
endothelin-1, a potent vasoconstrictor, were observed in many
collagen-vascular diseases including SLE.
The combination of inflammatory vascular lesion, slightly
elevated arterial pulmonary pressures and initial fibrotic interstitial disease impaired function of diaphragm with exercise
stress, although submaximal, may explain the occurrence of
desaturation during the 6MWT in SLE patients.
Only the follow-up of these patients will be able to clarify the relevance of this desaturation during 6MWT; however,
given the available data from studies that used other diseases,
such as idiopathic pulmonary fibrosis and pulmonary arte-
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rial hypertension, associated with a poor prognosis, a close
monitoring of the patients with SLE who presented desaturation during the 6MWT is advisable. A recently published study
assesses the association between quality of life and distance
walked during the 6MWT in Brazilian premenopausal patients
with SLE and compared with a healthy control group. The authors of this study concluded that patients with SLE walked a
shorter distance during the 6MWT, which was associated with
poorer quality of life.35 In addition to that, the finding of desaturation justifies the indication of a more thorough cardiorespiratory evaluation using echocardiogram, CT scans, measurements of diffusion capacity and total lung capacity.
Conflicts of interest
The authors declare no conflicts of interest.
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Leme CA Jr, Marques-Neto JF et al. Six-minute walk test for
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14. Rostagno C, Olivo G, Comeglio M, Boddi V, Banchelli M,
Galanti G et al. Prognostic value of 6-minute walk corridor
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Q et al. Prognostic value of desaturation during a 6-minute
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M. Vascular endothelial growth factor in systemic lupus
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Analysis of the association of fatigue with clinical and
psychological variables in a series of 371 Brazilian patients
with rheumatoid arthritis
Washington A. Bianchi a,*, Fernanda R. Elias a, Geraldo da Rocha Castelar Pinheiro b,
Carlos Roberto Machado Gayer c, Claudio Carneiro d, Rachel Grynzpan e, Paulo Hamdan f,
Sueli Carneiro f
Department of Rheumatology, Universidade Gama Filho, Rio de Janeiro, RJ, Brazil
Department of Rheumatology, Universidade e Escola de Ciências Médicas, Rio de Janeiro, RJ, Brazil
c Department of Biochemistry, Biologic Institute Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
d School of Medical Sciences and University Hospital, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
e Department of Dermatology, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
f Department of Internal Medicine, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
a b article info
abstract
Article history:
Objectives: Fatigue is a highly subjective and extremely common symptom in patients with
Received on 15 November 2013
rheumatoid arthritis although it is difficult to characterize and define. The aim of this study
Accepted on 29 November 2013
was to assess fatigue in a cohort of Brazilian patients, and to analyze the relationship between fatigue and disease-specific variables.
Keywords:
Methods: 371 Brazilian patients diagnosed with rheumatoid arthritis according to the 1987
Rheumatoid Arthritis
American College of Rheumatology classification criteria were prospectively investigated.
Fatigue
Demographic, clinical and laboratorial data were obtained from hospitals records. The
Disease Activity
number of painful joints, bone mass index, disease duration, quality of life, functional ca-
Quality of Life
pacity, anxiety and depression were recorded. Fatigue was evaluated using the subscale of
Pain
Fatigue Assessment of Chronic Illness Therapy (FACIT-FATIGUE scale).
Results: The median fatigue score was 42.0 (10.0), negatively correlated with functional capacity (-0.507; P < 0.001), anxiety and depression (-0.542 and -0.545; P < 0.001 respectively),
and predominantly with physical domain of Short Form 36-item quality of life questionnaire (SF-36P: 0.584; P < 0.001). The scores were not associated with the erythrocyte sedimentation rate (-0.118; P < 0.05), C-reactive protein (-0.089; P < 0.05), disease activity (-0.250;
P < 0.001) or the number of painful joints (-0.135; P < 0.01). Confidence interval of 95% was
applied for all measures.
Conclusions: In this series of Brazilian patients with rheumatoid arthritis, we suggest a new
significance for fatigue complains as an independent parameter not related with number
of painful joints, disease or inflammatory activity scores. Psychological and functional im-
* Corresponding author.
E-mail: [email protected] (W.A. Bianchi).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.11.002
201
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pairments appear to be more related to fatigue. Additional studies and inclusion of standard measures for monitoring fatigue complains are required.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
Análise da associação da fadiga com variáveis clínicas e psicológicas em
uma série de 371 pacientes brasileiros com artrite reumatoide
resumo
Palavras-chave:
Objetivos: A fadiga é um sintoma altamente subjetivo e extremamente comum em pacien-
Artrite reumatoide
tes com artrite reumatoide, embora seja difícil de caracterizar e definir. O objetivo desse
Fadiga
estudo foi avaliar a fadiga em uma coorte de pacientes brasileiros e analisar a relação entre
Atividade da doença
fadiga e variáveis específicas da doença.
Qualidade de vida
Métodos: Foram prospectivamente investigados 371 pacientes brasileiros diagnosticados
Dor
com artrite reumatoide, de acordo com os critérios de classificação do Colégio Americano
de Reumatologia de 1987. Dados demográficos, clínicos e laboratoriais foram obtidos dos
registros clínicos. Foram registrados o número de articulações dolorosas, índice de massa
corporal, duração da doença, qualidade de vida, capacidade funcional, ansiedade e depressão. A fadiga foi avaliada com o uso da subescala específica da escala Fatigue Assessment of
Chronic Illness Therapy (FACIT-FATIGUE).
Resultados: O escore mediano para fadiga foi 42 (10), negativamente correlacionado com a
capacidade funcional (-0,507; p < 0,001), ansiedade e depressão (-0,542 e -0,545; p < 0,001,
respectivamente) e predominantemente com o domínio físico do questionário Short Form36 para qualidade de vida (SF-36P: 0,584; p < 0,001). Não houve correlação entre os escores
e a velocidade de sedimentação das hemácias (-0,118; p <0,05), proteína C reativa (-0,089;
p < 0,05), atividade da doença (-0,250;p < 0,001) ou número de articulações dolorosas (-0,135;
p < 0,01). Para todas as medidas foi aplicado um intervalo de confiança de 95%.
Conclusões: Nesta série de pacientes brasileiros com artrite reumatoide, sugerimos um novo
significado para as queixas de fadiga como um parâmetro independente não relacionado
com o número de articulações dolorosas ou escores de atividade inflamatória. Parece haver maior relação entre transtornos psicológicos e funcionais com a fadiga. Seriam importantes novos estudos e uso rotineiro de medidas padronizadas para a monitorização das
queixas de fadiga.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to significant morbidity, joint deformity
and an impaired quality of life (QoL). This disease affects
approximately 0.5%-1% of the general population, with considerable variations being observed among different populations.1-3 Although the joints are the major loci of disease activity, fatigue is a notably common and disabling symptom
experienced almost universally by patients with RA (88%98%), who consider the effect and importance of fatigue
similar to pain.4-9
There is no universally accepted definition of fatigue. It
can be either defined as a progressive impairment of capacity to generate muscle or a lessened capacity to work, with
reduced efficiency of accomplishment, that are usually accompanied by feelings of weariness, sleepiness or irritability.10 Belza et al. described fatigue as an “enduring the subjective sensation of generalized tiredness or exhaustion”.11
In the general population, 20% of men and 30% of women
complain about frequent tiredness.12
Fatigue often accompanies various illnesses, and has
been increasingly recognized and studied in a number of
chronic diseases, such as liver disorders, infections and hematological diseases.12
Hewlett et al. observed that RA fatigue is a different phenomenon from normal tiredness because it is extreme, endless and unresolved described as an important and overwhelming complaint.4 Studies examining the predictive
factors of fatigue in RA reported not only physical but also
psychological and social aspects related to fatigue.4,13,14 Pain,
physical disability, inactivity and poorer sleep quality and
psychosocial factors, such as depressive symptoms, anxiety
and social stress (as long-term symptoms or associated conditions) are predictive of fatigue in RA.13,14
During the chronic course of RA, continuing inflammatory activity with periods of prolonged physical inactivity
leads to muscle atrophy and instability of the periarticular
structures with reduced strength and muscular endurance
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that contribute to the onset of fatigue. Ekdahl et al. demonstrated that 80% of patients with RA exhibited changes
in muscle strength and coordination of the lower extremities and decreased aerobic activity. These results were confirmed by Semble et al.15,16 In 1996, Rall et al. evaluated the effect of an exercise program to improve the muscle strength
in patients with RA and observed a significant reduction in
fatigue (38%).17
Due to fatigue’s multifactorial and multidimensional
nature, this condition is difficult to assess. Little is known
concerning the correlations, adequate measurements or the
clinical management and interventions for fatigue.4,18 Persistent fatigue is one of the most significant obstacles to optimizing function in these patients.19
The aim of this study was to analyze aspects of fatigue
in 371 Brazilian RA patients, and the association of fatigue
with disease-specific variables, such as inflammatory activity, pain, QoL, physical function, and psychological complains, such as anxiety and depression.
Methods
A total of 371 patients with RA were recruited at the Department of Rheumatology of Hospital da Santa Casa da
Misericórdia do Rio de Janeiro (HSCMRJ) and Hospital Universitário Pedro Ernesto (HUPE) into this cross-sectional prospective study from 2010-2011. Patients were between the
ages of 18 and 65 years, diagnosed with RA according to the
1987 American College of Rheumatology (ACR) RA classification criteria.20 For all of the patients invited and included
in the study written informed consents were provided. The
research was conducted with approval by and in accordance
with the Ethics Committee of both hospitals.
The patients who were unable to understand and respond the questionnaires or who had any comorbidities
that might interfere with the assessment of fatigue, such as
anemia (hemoglobin > 9.0 mg/dl), endocrine diseases (diabetes type I and II, thyroid diseases), renal failure (creatinine
< 2.0mg/dl), liver diseases including cirrhosis, pulmonary
(Chronic Obstructive Pulmonary Disease) or cardiovascular
disorders, were excluded.
Demographic and clinical data were collected including
duration of disease, number of painful peripheral joints and
body mass index (BMI). Disease activity was clinically measured, using the 28 joint count Disease Activity Score (DAS
28), and biologically, using the erythrocyte sedimentation
rate (ESR) and C-reactive protein (CRP) levels.
Physical function was assessed by the Health Assessment Questionnaire-Disability Index (HAQ DI), where scores
range from 0 to 3, and higher scores indicate lower levels
of physical functioning.21,22 The health-related quality of life
(HRQol) was assessed using physical and mental scores of
the Short-Form 36-Items Health Survey (SF-36P and SF-36M)
generic questionnaire.23
The Hospital Anxiety and Depression Scale (HAD a/d) was
used to evaluate the depression and anxiety symptoms. This
questionnaire has 14 interlaced questions: one-half of the
questions were related to anxiety, and one-half to depression. For each question, a value from 0 to 3 is added to each
domain separately, building the two sub-scales. Patients
with results greater than 8 are considered at risk of anxiety
and/or depression independently.12 All questionnaires used
were validated and culturally adapted to the Portuguese language.12,21–23
Fatigue was evaluated using a subscale of the Functional
Assessment of Chronic Illness Therapy (FACIT), which was
initially validated to assess QoL in patients with cancer or
other chronic illnesses. The scale was used for RA patients,
who only scores the fatigue complains (FACIT-Fatigue). The
total score ranges from 0 to 52, and higher scores represent
less fatigue.24 The FACIT-Fatigue was validated for Portuguese version through an authorization from the site http://
www.facit.org.
Statistical analysis
Calculating the minimum patient number with precision
measurements estimated under parameters of 90% with
confidence interval of 0.20 and α = 0.05, we got a minimum
sample size of 258 patients.
Considering that both departments of Rheumatology
treat approximately 800 patients with RA per year, 30%-40%
of which fulfill the inclusion/exclusion criteria, the sample
size could be about 240 to 320 patients.
Taking into account also that the fatigue complains could
be present in 25% to 60% of RA patients,4,5,10,18,20,25,26,27 we
found a sample size of 200 to 480 of those hospital’s populations.
We decided to establish a final sample size between 320
to 480 patients. After two years of recruitment, 371 patients
with useful data were finely included in this study.
All data were tested for normality by applying the Shapiro-Wilk Test. As all variables showed non-normal distribution, the variables were presented by median (interquartile range). Spearman’s rank correlation coefficient (rs) was
calculated to determine correlations between fatigue and
clinical or psychological measures. All tests were 2-sided,
and P values ≤ 0.05 were considered statistically significant.
Statistical analysis was performed using Statistica software,
version 8.0 (Statsoft. Inc. Tulsa, USA).
Results
A total number of 371 patients were evaluated. The group
studied included 335 women (90.3%) and 36 men (9.7%). The
demographic and clinical data, which are summarized in
Table 1, indicated the majority of our patients were white
(66.8%), followed by mixed-race patients (20.5%), and black
patients (12.7%). The median age was 51 (13) years and the
BMI was 25.0 (3.6). The mean score of fatigue (FACIT–Fatigue)
was 42.0 (10), and the mean number of painful joints was 6
(6). The median disease duration was 6 (6) years.
The median disease activity, as assessed by DAS 28, was
4.7 (2). The median ESR was 33 (27) mm, and the median of
CRP level was 0.8 (1.7).
When the DAS 28 cut-off values for measuring inflammatory disease activity were applied, 7.0% of the patients were
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Table 1 – Baseline characteristics of RA patients (n = 371)
Characteristics
Women
Ethnic group
White
Mixed-race
Black
Age
BMI
Disease duration (year)
Laboratory assessment of disease activity
ESR
CRP
Clinical assessments
DAS 28
HAQ DI
SF-36
Physical domain
Mental domain
HAD a
HAD d
FACIT-Fatigue
Number of Painfull joints
Mean (sd) or n (%)
Median
Min
Max
- CI 95%
+ CI 95%
248 (66.8)
76 (20.5)
47 (1.7)
49.5 (10.2)
25.2 (3,9)
7.8 (5,8)
51.0
25.0
6.0
18.0
16.3
1.0
65.0
43.9
43.0
48.6
24.8
7.2
50.7
25.6
8.4
36.2 (22.7)
1.8 (3.2)
33.0
0.8
2.0
0.1
118.0
33.5
33.9
1.5
38.5
2.2
4.6 (1.4)
1.0 (0.7)
86.9 (8.5)
39.1 (10.5)
47.6 (11.0)
7.0 (3.4)
5.4 (3.6)
39.9 (8.6)
6.83(4.78)
4.7
0.8
87.5
39.5
50.1
7.0
5.0
42.0
6.0
0.0
0.0
51.0
12.1
12.4
0.0
0.0
4.0
0.0
8.1
2.8
99.6
68.3
96.1
20.0
20.0
52.0
28.0
4.4
0.9
86.0
38.1
46.5
6.7
5.0
39.0
6.4
4.7
1.0
87.7
40.2
48.8
7.4
5.7
40.8
7.3
335 (90.3)
in remission (DAS 28 < 2.6), 7.8% had lower disease activity
(DAS 28 ≥ 2.6 ≤ 3.2), 9.7% had moderate disease activity (DAS
28 ≥ 3.2 ≤ 5.1), and 75.5% of the sample had high disease
activity (DAS 28 > 5.1).
The median score of the SF-36 was 87.5 (12.2). The means
of the physical and mental subscales were 39.1 (10.5) and
47.6 (11.0), respectively. The mean of the HAQ DI was 1.0
(0.7). The anxiety and depression questionnaire (HAD a/d)
showed means of 7.0 (3.4) for anxiety, and 5.4 (3.6) for depression, respectively.
The distribution of disease activity (DAS 28) and duration
of illness (years) in this sample of RA patients are shown in
Fig. 1.
The correlations between fatigue (FACIT-Fatigue), quality
of life (SF-36), functional capacity (HAQ DI), painful joints,
anxiety and depression (HAD a/d), DAS 28, ESR and CRP are
shown in Table 2. The correlations of fatigue with QoL, anxiety and depression or functional capacity are shown in the
graphs of Figs. 2 and 3.
Table 3 presents the correlations of fatigue with disease
activity measured by ESR, CRP and DAS 28 and the QoL by
the physical and mental domains of SF-36 (SF-36P and SF36M), functional capacity by HAQ DI, the number of painful
joints, and anxiety or depression as measured by HAD a/d
in patients with moderate and high disease activity (DAS 28
≥ 3.2).
Discussion
This study was the first in our country to analyze a sample of 371 Brazilian patients with RA, assessing fatigue by
FACIT-Fatigue, a 13-items measure of fatigue that previously
showed good internal consistency in patients with RA.
Number of patients
BMI: Bone Mass Index, ESR: Erythrocyte Sedimentation Rate, CRP: C Reactive Protein, DAS 28: 28 Disease Activity Index, HAQ DI: Health
Assessment Questionnaire Disability Index, SF-36: Short-Form 36-item, HAD a/d: Hospital Anxiety and Depression Scale, FACIT-Fatigue: Fatigue
Assessment of Chronic Illness Therapy.
High
Moderate
Low
Remission
Disease duration (years)
Fig. 1 – Distribution of disease duration with disease
activity by DAS28 and number of patients.
In recent years, fatigue has emerged as an important
outcome in RA,4,8,13,14 although the symptoms are largely ignored in terms of clinical care and educational and research
endeavours. The multifactorial and multidimensional characteristics of fatigue demand a broad analysis that takes
into consideration the clinical, cultural and social aspects of
fatigue complaints and includes the patient’s perspective. In
Rio de Janeiro, a cosmopolitan coastal city, the mixed population and the tropical climate with a majority of sunny days
could modify the perception of fatigue and its correlation to
the indices of disease activity, QoL, functional capacity, pain,
anxiety and depression.
Cella D et al. validated the FACIT-Fatigue, comparing it
to other scales such as the Multidimensional Assessment
of Fatigue (MAF) and the SF-36 in 636 patients with RA for
24 weeks in a double blind, randomized trial using anti-TNF
204
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7
alpha monoclonal antibody and placebo, where the psychometric performance of the FACIT-Fatigue scale for assessment of fatigue was comparable to the other scales.24
The demographic findings of gender and ethnicity are
similar to previous reports, which indicate a female and
white predominance, reflecting the typical incidence of RA
Table 2 – Analysis of Spearman’s correlations coefficient of all patients
ESR
ESR
CRP
SF-36P
SF-36M
HAD a
HAD d
DAS 28
HAQ DI
Facit fatigue
Painful joints
0.467*
-0.203*
-0.161*
0.101
0.130*
0.472*
0.190*
-0.118*
0.220*
CRP
SF36-P
SF36-M
HAD-a
HAD-d
DAS28
HAQ-DI
Facit fatigue
Painful joints
0.467*
-0.203*
-0.191*
-0.161*
-0.024
0.121*
0.101
0.072
-0.328*
-0.477*
0.130*
0.103*
-0.406*
-0.437*
0.648*
0.472*
0.356*
-0.439*
-0.131*
0.169*
0.244*
0.190*
0.189*
-0.672*
-0.175*
0.294*
0.347*
0.356*
-0.118*
-0.089
0.584*
0.405*
-0.542*
-0.545*
-0.250*
-0.507*
0.220*
0.203*
-0.293*
-0.019
0.060
0.101*
0.725*
0.219*
-0.135*
-0.191*
-0.024
0.072
0.103*
0.356*
0.189*
-0.089
0.203*
0.121*
-0.328*
-0.406*
-0.439*
-0.672*
0.584*
-0.293*
-0.477*
-0.437*
-0.131*
-0.175*
0.405*
-0.019
0.648*
0.169*
0.294*
-0.542*
0.060
0.244*
0.347*
-0.545*
0.101*
0.356*
-0.250*
0.725*
-0.507*
0.219*
-0.135*
ESR: Erythrocyte Sedimentation Rate, CRP: C-Reactive protein, SF-36: Short-Form 36-item, SF-36P: Short-Form 36-item Physical domain, SF-36M:
Short-Form 36-item Mental domain, HAD a: Hospital Anxiety Scale, HAD d: Hospital Depression Scale, DAS28: Disease Activity Score, HAQ DI:
Health Assessment Questionnaire – Disability Index, and FACIT fatigue: Fatigue Assessment of Chronic Illness Therapy. *Statistically significant
(p < 0.05).
A
A
70
22
20
60
18
16
50
12
40
HAD-a
SF-36F
14
30
10
8
6
20
4
2
10
0
0
95% confidence
0
10
20
30
40
50
-2
60
95% confidence
0
10
20
30
40
50
60
40
50
60
Facit-fatigue
Facit-fatigue
B
B
3,0
22
20
2,5
18
16
2,0
12
1,5
HAD-d
HAQ DI
14
1,0
10
8
6
0,5
4
2
0,0
0
-0,5
95% confidence
0
10
20
30
40
50
Facit-fatigue
Fig. 2 – Spearman’s correlations coefficient between FACIT
fatigue and SF-36 (A) and HAQ DI (B).
60
-2
95% confidence
0
10
20
30
Facit-fatigue
Fig. 3 – Spearman’s correlations coefficient between FACIT
fatigue and HAD a (A) and HAD d (B).
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7
Table 3 – Analysis of Spearman’s correlations coefficient of patients with high and moderate disease activity (n = 316)
n = 316
Facit-fatigue
ESR
CRP
SF-36P
SF36M
HAD a
HAD d
DAS 28
HAQ DI
Painful joints
-0.108
-0.065
0.577*
0.456*
-0.539*
-0.528*
-0.218*
-0.489*
-0.080
ESR: Erythrocyte Sedimentation Rate, CRP: C Reactive Protein, SF36P: Short-Form 36-Item Physical domain, SF-36M: Short-Form 36-Item Mental
domain, HAD a: Hospital Anxiety and Depression Scale-anxiety domain, HAD d: Hospital Anxiety and Depression Scale-depression domain,
DAS 28: Disease Activity Score, HAQ DI: Health Assessment Questionnaire Disability Index, and FACIT fatigue: Fatigue Assessment of Chronic
Illness Therapy. *Statistically significant (p < 0.001).
patients. These results differ in ethnic characteristics of
Brazilian population, in which 47.7% are white according
to data from the Brazilian Institute of Geography and Statistics (IBGE).28
The disease duration was under 10 years, and for the
largest number of patients there had been less than 5 years
since symptoms onset and diagnosis confirmation. The
mean disease activity quantified by DAS 28 score of 4.6,
shown in Table 1, confirms that most of our cohort exhibit
moderate or high disease activity.
Based on our findings, fatigue did not correlate with disease activity. As shown in Table 2, the FACIT-Fatigue has not
demonstrated correlation with CRP, ESR and DAS 28, which
are routinely evaluated as inflammatory disease activity
indexes. The FACIT- Fatigue demonstrated a moderate correlation with functional capacity (HAQ DI), as shown in Fig.
2B, Table 2; anxiety and depression (HAD a/d), shown in Fig.
3, and predominantly with the physical domain of quality
of life (SF-36P), shown in Fig. 2A.
A similar analysis with moderate and high disease activity (DAS 28 > 3.2) subgroups of this sample confirmed the
absence of a correlation between fatigue and disease activity, shown in Table 3. This finding is in accordance with Huyser et al., who suggested that fatigue in RA is not related to
disease activity and showed that many of the variables that
were significantly correlated with fatigue had a psychosocial basis.25 Such factors, as anxiety and higher depressive
symptoms, were significantly associated with increased
fatigue, as was seen in this study (Fig. 3). The best predictors of fatigue were higher levels of pain, more depressive
symptoms and female gender, which were independent
of disease activity.25 Our study showed that the number of
painful joints, measured by the first item of DAS 28, did not
correlate with fatigue independently of the level of pain or
the patient global assessment.
Bergman et al. showed that fatigue is not an inflammatory variable and has virtually no correlation with the number of swollen or tender joints. These researchers showed
a moderate association of fatigue with DAS 28, and 79% of
the complaints could be explained by the patient global assessment.29
Yacoub et al. assessed fatigue in 248 patients with RA,
finding a prevalence of fatigue in approximately 90% and,
in contrast to our results, a significant association with disease activity.30 Thyberg et al. suggested that disease activity
is among the factors closely related to fatigue.31
This study, using the HAD a/d scale, determined a correlation between fatigue and emotional aspects, such as depression and anxiety, shown in Fig. 3 and Table 2, which was
reported by Huyser et al. Depression is a frequent complaint
associated with fatigue in RA patients with a prevalence
of 13%-20%, which is 2 to 3 times higher than observed in
healthy people.25,32,33 The presence of pain, joint swelling
and deformities, as well as functional disabilities and work
or leisure restrictions in RA patients, could explain the
higher number of depression cases. Functional disabilities
result in reduction of self-confidence and QoL, leading to
a depressive mood. Several authors attempted to correlate
depression, anxiety and fatigue.25,34-36 Tack et al. found that
in the RA population, higher fatigue was strongly associated with depressive symptoms, pain, and poorer overall
mood.36 A recent study by Munsterman et al. confirms earlier results that depressive symptoms are associated with
fatigue.27
We observed a moderate correlation of fatigue with QoL
(SF-36) and functional capacity (HAQ DI), as presented in
Fig. 2. Yacoub et al. report that fatigue was significantly associated with functional disability.30 Pollard et al. found similar results with a significant relationship between fatigue
and functional disability, suggesting that severe fatigue had
a negative impact on patients QoL.37 Thyberg et al. suggest
that fatigue is related to physical aspects of disability such
as pain, activity limitation and mental aspects, which may
be a psychological reaction to physical disability.31 Each of
these studies measures fatigue by different questionnaires,
scales and methods, achieving results that are not directly
comparable.
Regarding the application of FACIT–Fatigue as a specific
instrument of fatigue evaluation in RA patients, these data
showed consistency and significant correlation with other
protocols (SF-36, HAD a/d, HAQ DI) demonstrated in Figs.
2 and 3, with significant values being observed in Table 2.
These findings indicate that patient’s complaint of fatigue
is an independent data in the analysis of disease evolution.
We suggest a new significance for fatigue complaints in
RA patients, which is an independent parameter that is not
related to inflammatory activity. Fatigue appears to be related to the physical capacity and emotional symptoms associated with the negative effect of disability on the quality
of life of some patients. Reports in the literature are conflicting, most likely because of the multifactorial etiology of
fatigue and its correlation with physiological, psychological, social, personal and individual disease aspects, as well
as the non-existence of a standardized evaluation method.
These results emphasize the need for a better understanding of fatigue in RA patients with additional studies and an
inclusion of standard measures for monitoring the symptoms and clinical management of fatigue. As recently recommended by OMERACT, psychological and psychosocial
interventions, taking into account considerations that the
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7
patient’s perspective should be considered in studies and
clinical practice to improve the results of treatment of fatigue.38
Conflicts of interest
The authors declare no conflicts of interest.
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Evaluation of postural control and quality of life in elderly
women with knee osteoarthritis
Júlia Guimarães Reisa,*, Matheus Machado Gomesa, Thamires Máximo Nevesa,
Marina Petrellaa, Renê Donizeti Ribeiro de Oliveirab, Daniela Cristina Carvalho de Abreua
Department of Biomechanics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Department of Clinical Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
a b article info
abstract
Article history:
Objective: To assess the balance in dynamic tasks and in the quality of life in elderly women
Received on 8 May 2013
with and without knee osteoarthritis.
Accepted on 12 November 2013
Methods: Elderly women were divided into Group 1 (n = 12), consisting of participants with
bilateral knee osteoarthritis (Kellgreen-Lawrence grade 1 and 2), and Group 2 (n = 12), con-
Keywords:
sisting of controls. A force plate (EMG System do Brazil) was used to assess postural sway in
Osteoarthritis
dynamic tasks, whereas the quality of life was assessed by using the WHOQOL-Bref ques-
Knee
tionnaire.
Elderly
Results: Student’s t-test showed no statistical difference during sitting down and standing
Quality of Life
up from the chair (p > 0.05). However, stair ascent revealed difference in displacement speed (p < 0.05), whereas stair descent showed differences in both displacement speed and
amplitude (p < 0.05). In the questionnaire, Group 1 showed values lower than those in the
control group regarding physical domain (p < 0.05).
Conclusion: Elderly women with knee osteoarthritis seemed to have more difficulty on stair
descent task and had perception of worst physical domain. These findings were observed
in OA group, even in the early stages of the disease, which shows the importance of even
earlier interventions.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (J.G. Reis).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.11.001
209
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2
Avaliação do controle postural e da qualidade de vida em idosas com
osteoartrite de joelho
resumo
Palavras-chave:
Objetivo: Avaliar o equilíbrio em tarefas dinâmicas e a qualidade de vida em idosas com e
Osteoartrite
sem osteoartrite no joelho.
Joelho
Métodos: As idosas foram divididas em: Grupo 1 (n = 12), consistindo de idosas com osteo-
Idosos
artrite bilateral no joelho (Grau Kellgreen-Lawrence 1 e 2); e Grupo 2 (n = 12), consistindo
Qualidade de vida
de controles. Foi empregada uma plataforma de força (EMG System do Brasil) para avaliar
a oscilação postural em tarefas dinâmicas; já a qualidade de vida foi avaliada mediante a
aplicação do questionário WHOQOL-Bref.
Resultados: O teste t de Student não demonstrou diferença estatística durante as ações de
ficar de pé e sentar em uma cadeira (p > 0,05). Contudo, a tarefa de subir escadas revelou
diferença na velocidade de deslocamento (p < 0,05), enquanto a tarefa de descer escadas
demonstrou diferenças tanto na velocidade como na amplitude do deslocamento (p < 0,05).
No questionário, o Grupo 1 demonstrou valores mais baixos do que os obtidos no Grupo de
controle, no que diz respeito ao domínio físico (p < 0,05).
Conclusão: Aparentemente, idosas com osteoartrite no joelho tiveram mais dificuldade na
tarefa de descer escadas e pior percepção de domínio físico. Esses achados foram observados no grupo com OA, mesmo nos estágios iniciais da doença, o que demonstra a importância de intervenções ainda mais precoces.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Methods
The aging process causes changes in several organ systems,
which may result in alterations in people’s lifestyle and in
their quality of life as well. Together with these alterations,
some chronic-degenerative joint diseases like osteoarthritis (OA) can manifest themselves in elderly individuals.1
OA is one of the most common musculoskeletal complaints
worldwide.2 According to the World Health Organisation
(WHO), this is the fourth leading cause of disability among
women.3
Individuals with OA are more likely to have pain, decrease in range of movement (ROM), decline in muscle function4 and balance, thus resulting in functional limitation and
decreased capacity to perform activities of daily living.5-7
About 18% of elderly have difficulty performing one or
more activities of daily living, mainly those requiring muscle
force, mobility and balance such as standing up and sitting
down from a chair, stair ascent and descent.7,8 Limitations in
these tasks can lead to both loss of functional capacity and
reduction in quality of life.4,9
Based on the muscle-joint dysfunctions individuals with
knee OA have, one can question whether the early stages of
this disease interferes with postural control during performance activities of daily living and people’s quality of life,
since there are very few studies on this theme.10-12
Therefore, the objectives of the present study were to
evaluate the balance in dynamic tasks as well as the quality of life regarding physical, social, psychological, environmental and global domains in elderly individuals with and
without knee OA.
The subjects, all female, taking part in the study were divided into two groups: Group 1 (n = 12), consisting of elderly
individuals with bilateral knee OA and mean ± SD age of
67.25 ± 4.65 years, mean weight of 72.09 ± 10.13kg and mean
height of 1.54 ± 0.06m; and Group 2 (n = 12), consisting of
elderly individuals without OA (controls) whose mean age,
mean weight, and mean height were, respectively, 65.58 ±
4.23years, 64.51 ± 8.59kg, and 1.55 ± 0.05m.
Group 1 had knee OA Kellgreen-Lawrence (K/L) grade 1
and 213 diagnosed by a rheumatologist in accordance with
the American College of Rheumatology criteria.14 X-ray radiographs involved antero-posterior and lateral aspects. The
Western Ontario and MacMaster Universities Osteoarthritis
Index (WOMAC) was used to measure pain, with Group 1
having mean score of 0.77 (value ranging from 0 to 1, that is,
no pain to little pain).15
Group 2 was not submitted to X-ray examination for
ethical reasons, with the controls exhibiting no symptom in
lower limbs that could characterize OA. Those individuals, in
both groups, having neurological diseases, vestibulopathies,
neuropathies, history of fracture and lesions in lower limbs
in the last 6 months or other complications that could affect
their balance were excluded from study.
The volunteers were recruited from the Outpatient Rheumatology Center of the Ribeirão Preto School of Medicine
(CSE-FMRP-USP) as well as from the community. The study
was approved by the ethics research committee (protocol
number 291), with all the volunteers signing a free informed
consent before participating in the study.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2
Results
Fig. 1a and 1b show, respectively, amplitude and speed of the
CoP displacement in antero-posterior (AP) direction of subjects from both groups during the tasks of standing up and
sitting down. Student’s t-test showed no difference in the
variables between both groups (p > 0.05). This means that
women with OA exhibited a balance similar to that of controls
performing such activities.
Fig. 2a and 2b show, respectively, amplitude and Fig. 2b of
the CoP displacement in antero-posterior (AP) direction of
subjects during stair ascent and descent task. During stair ascent the Student’s t test revealed difference for displacement
speed (p < 0.05), whereas displacement amplitude was found
to be similar between both groups (p > 0.05). On the other
hand, differences were found in both displacement speed and
b)
a)
14.0
COP Displacement (cm/s)
2.5
OA
Control
COP Speed (cm/s)
12.0
10.0
8.0
6.0
4.0
2.0
0.0
2.0
1.5
1.0
0.5
0.0
Fig. 1 – Values of both amplitude (a) and speed (b) of the
CoP displacement in antero-posterior (AP) direction from
both groups during standing up and sitting down task.
a)
20.0
Ascent
Descent
15.0
10.0
*
5.0
0.0
OA
4.0
COP Speed (cm/s)
To evaluate postural sway in dynamic situations (standing
up and sitting down from a chair, stair ascent and descent), a
force platform (EMG System do Brasil) was used to quantify
both antero-posterior (AP) displacement amplitude and speed
of the center of pressure (CoP). Data were analyzed by using
Matlab software.
During the tasks of standing up and sitting down, elderly
women were asked to stand up from the chair with their arms
crossed over the chest and remain in standing position for
30 seconds, looking at a marker positioned at 1.5 m from the
chair and then sitting down again. The subjects were initially positioned on the chair with knees and hips flexed at 90
degrees.
With regard to task on stairs, the subjects were instructed
to go up and go down 3 steps, each one measuring 17.8 cm
height, 80 cm width, and 30.5 cm depth, using one foot at
once. The platform was placed on the first step of the stairs.
All the tasks were repeated three times.16
The Brazilian version of the validated WHOQOL-Bref
questionnaire, which is the condensed version of the World
Health Organisation Quality of Life Instrument 100 (WHOQOL-100), was used to assess the quality of life. This instrument consists of 26 questions, where 24 encompass four
domains of quality of life (physical capacity, psychological
well-being, social relations, and environmental in which the
subject is inserted), whereas two questions (questions 1 and
2) are on global quality of life.17 Each question has answers
ranging from 1 to 5.
The final scores of each domain are those regarding the
mean scores of each question multiplied by 4, thus resulting
in final scores within a scale ranging from 4 to 20 that is proportional to that from WHOQOL-100 instrument (scale from 0
to 100). Questions 3, 4 and 26 were re-coded as (1 = 5), (2 = 4),
(3 = 3), (4 = 2), (5 = 1), and the higher the score the better the
quality of life.
By using the Shapiro-Wilks normality and the Levene’s variance homogeneity tests, it was observed that the mean values
of the subjects had normality and variance homogeneity. As a
result, the Student’s t test for independent samples was employed for comparison between Groups 1 and 2. Analyses were
performed by using the SPSS software (SPSS for Windows, Version 16.0, SPSS Inc.) The alpha value was set at 0.05.
COP Displacement (cm)
210
b)
3.0
*
1.0
0.0
Control
*
2.0
OA
Control
Fig. 2 – Values of both amplitude (a) and speed (b) of the
CoP displacement in antero-posterior (AP) direction from
both groups during stair ascent and descent task.
amplitude during stair descent task (p < 0.05). Women with
OA showed higher speed and greater amplitude of CoP displacement compared to controls.
Table 1 lists the results for questions 1 and 2 as well as for
the four domains of WHOQOL-Bref instrument regarding both
groups. Women with OA had lower scores for physical domain
compared to controls.
Discussion
During the activities in which there are postural changes (dynamic tasks), it is needed to control the movement of center of pressure in relation to the support base. The balance
control is crucial for performing daily life activities involving
maintenance of static posture as well as complex dynamic
movements.6 Subjects suffering from knee OA have joint and
muscle changes, most frequently associated with local pain
that can, in turn, impair the ability to perform dynamic tasks
and consequently interfere with the quality of life.
Table 1 – Values (mean ± SD) obtained in the
Questionnaire WHOQOL-bref of Osteoarthritis (OA) and
control group
Groups
Question 1
Question 2
Physical Domain
Psychological Domain
Social Domain
Environmental Domain
* Significant T Test
OA
Control
14.5 ± 4.1
13.1 ± 4.0
13.2 ± 2.6
15.0 ± 3.2
16.2 ± 3.0
14.4 ± 1.3
16.0 ± 4.2
16.3 ± 3.6
17.2 ± 1.6
14.4 ± 2.2
17.0 ± 1.4
15.2 ± 2.9
p value
0.41
0.06
0.001*
0.62
0.44
0.44
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2
211
The present study evaluated the balance in elderly individuals with and without knee OA during functional tasks such
as standing up and sitting down from a chair and stair ascent
and descent. Additionally, quality of life was also evaluated in
both groups.
According to Hinman18 (2002), because several daily activities require balance, understanding the impact of knee OA
on the postural sway can help clarify the poor mechanisms
in this population in addition to allowing a more effective
treatment to be established. It is important to use tests that
reflect the dynamism of motion tasks during evaluation of
the balance.19
It was expected that the subjects with knee OA exhibited
changes in their balance while performing the experimental
tasks because of pain, muscular, proprioceptive and ROM alterations, resulting from such a disease. However, the degree
of OA can influence differently in the individuals’ physical
capacity.
The results of this study showed no difference in the
speed, and amplitude of CoP displacement was found between the groups in this study for the tasks of standing up
and sitting down, probably because the subjects with OA were
in the initial stages of the disease. It is also possible that the
task of standing up and sitting down was not difficult enough
to affect the postural control of subjects with OA (K/L grade
1 and 2).
Alencar et al.10 (2007) have evaluated the shift in the center
of gravity in faller and non-faller individuals with knee OA by
using the stand-up test and no difference in the displacement
speed was observed. It is important to keep the control of the
center of gravity while performing a movement in order to
avoid excessive forward or backward displacement.
With regard to stair ascent and descent tasks, it was observed significant differences in AP displacement amplitude
of CoP during stair descent only, and AP displacement speed
of CoP during stair ascent and descent task. The results of the
present study showed that individuals with OA had alterations in postural control during stair ascent and descent, although such changes were greater in the latter task probably.
For some authors, the ability to walk stairs may require
much effort by elderly subjects whose motor function is impaired due to the presence of diseases like osteoarthritis.20,21
In the present study, despite the presence of little or no pain
it was possible to observe changes in postural control at
Group 1.
Other studies have reported that the decrease in muscle
strength over time can impair the capacity to reduce CoP sway
during stair descent, with elderly individuals having more difficulty in keeping their balance while descending stairs rather
than ascending stairs.16,22 In fact, this finding is corroborated
by our results. On the other hand, Mian et al.23 (2007) observed
no difference in the AP displacement between healthy young
and elderly men during the task of stair ascent and descent.
important to evaluate the quality of life of individuals suffering from OA as this information helps determine adequate
interventions as well as their efficacy. An increasingly used
approach is the use of questionnaires containing questions
on the individual’s perception on his or her health.25
The present study has used the WHOQOL-Bref instrument to assess the perception on the global quality of life
of individuals with and without knee OA regarding physical, psychological, social and environmental domains. It was
observed a difference in perception physical domain only,
which involves questions such as: How much does your pain
(physical) prevent you from doing what you need to do? How
much medical treatment do you need to function in your daily life? Do you have enough energy for your daily tasks? How
well do you move? How well do you sleep? How well are you
performing your daily activities? How well are you performing at your job?
Subjects with knee OA had lower scores than that of controls, thus demonstrating that even the early stages of OA
have negatively influenced the perception of them on quality
of life. Alves and Bassitt26 (2013) reported that worse functional capacity was associated with lower quality of life scores after correlation between WOMAC and WHOQOL-OLD in elderly
women with knee OA.
Alexandre et al.27 (2008) observed a negative correlation between functionality domain assessed by questionnaire WOMAC and functional capacity, physical aspect, pain and general
health assessed by SF-36. They suggest that elderly with knee
OA that have more difficulty in performing activities of daily
living (ADL) also have worse perception of important domains
of quality of life. The present study corroborates these findings since subjects with OA had alterations in the postural
control during stair descent and also worse perception of
physical domain in the WHOQOL-OLD.
The decline in physical performance has become an increasing major public health problem because of the higher
number of elderly people.28 Together, pain and functional disability often account for a significant reduction in the quality
of life.27
The present study may have some limitations regarding
small sample size and lack to evaluate variables reflecting the
questions addressed in the WHOQOL-Bref instrument, such
as time spent for performing the tasks and quality of gait.
Although consisting of a small sample size, the present
study evaluated balance and quality of life in women with
initial stages of OA and some significant differences were
observed between groups. Elderly women with knee OA may
have had more difficulty in stair descent task as they exhibited more AP displacement and speed CoP, which is a risky situation for them. Furthermore, subjects with knee OA showed
a lower score in physical domain than that of controls, confirming that the physical changes possibly caused by OA were
perceived by them.
Quality of Life
Conclusion
The evaluation of the functional capacity plays an important
role in understanding the effects of OA on physical deficit and
disability in elderly individuals.24 For Moskowitz12 (2009), it is
Therefore, the worst postural control during stair descent
stairs and lower scores in the physical domain were observed
in OA group, even in the early stages of the disease, which
212
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2
shows the importance of interventions ever earlier to maintain or improve balance in dynamic tasks and physical capacity, since functional deficits due to knee OA could negatively
affect the quality of life. It is expected that the improvement
of physical aspects, provided by physiotherapy treatment, reflects positively on their quality of life. Further studies with a
larger sample should be conducted to confirm these results.
Conflicts of interest
The authors declare no conflicts of interest.
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Wilson PW et al. The effects of specific medical conditions on
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7. Landers KA, Hunter GR, Wetzstein CJ, Bamman MM, Weinsier
RL. The interrelationship among muscle mass, strength,
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8. Gornick ME, Warren JL, Eggers PW, Lubitz JD, De Lew N, Davis
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9. Bennell KL, Hinman RS, Metcalf BR, Crossley KM, Buchbinder
R, Smith M et al. Relationship of knee joint proprioception to
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10. Alencar MA, Arantes PMM, Dias JMD, Kirkwood RN, Pereira
LSM, Dias RC. Muscular function and functional mobility of
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11. Moskowitz RW. The burden of osteoarthritis: clinical and
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12. Salaffi F, Carotti M, Stancati A, Grassi W. Health-related
quality of life in older adults with symptomatic hip and knee
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Aging Clinical and Experimental Research. 2005;17:255-63.
13. Park HJ, Ko S, Hong HM, Ok E, MD, Lee JI. Factors related to
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Rehabil Med. 2013;37:373-8.
14. Altman R, Asch E, Bloch D, Bole D, Borenstein K, Brandt K et
al. Development of criteria for the classification and reporting
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Arthritis Rheum. 1986;29:1039-49.
15. Bellamy N, Watson-Buchanan W, Goldsmith CH, Campbell J.
Validation study of WOMAC: a health status instrument for
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antirheumatic drug therapy in patients with osteoarthritis of
the hip or knee. J Rheumatol. 1988;15:1833-40.
16. Lee HJ, Choub LS. Balance control during stair negotiation in
older adults. J Biomech. 2007;40:2530-6.
17. Fleck MPA, Louzada S, Xavier M, Chachamovich E, Vieira
G, Santos L et al. Aplicação da versão em português do
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“WHOQOL-Bref”. Rev Saúde Pública. 2000;34:178-83.
18. Hinman RS, Bennell KL, Metcalf BR, Crossley KM. Balance
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osteoarthritis: a comparison with matched controls using
clinical tests. Rheumatology. 2002;41:1388-94.
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20. Brechter JH, Powers CM. Patellofemoral joint stress during
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LE. AIMS2: The content and properties of a revised and
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de idosas com osteoartrite de joelho. Einstein. 2013;11:209-15.
27. Alexandre TS, Cordeiro RC, Ramos LR. Fatores associados
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Review article
Pre-operative anesthetic assessment of patients with
rheumatoid arthritis
Rodrigo Barbosa Airesa, Jozélio Freire de Carvalhob, Licia Maria Henrique da Motac,*
Anestesiology Service, Instituto de Cardiologia do Distrito Federal, Brasília, DF, Brazil
Centro Médico do Hospital Aliança, Salvador, BA, Brazil
c Rheumatology Service, Hospital Universitário de Brasília, Universidade de Brasília, Brasília, DF, Brazil
a b article info
abstract
Article history:
The management and surgical interventions of problems directly or indirectly arising from
Received on 25 January 2013
rheumatoid arthritis vary drastically. Anesthesiologists and rheumatologists should be aware
Accepted on 15 August 2013
of the peculiarities of the anesthetic preoperative assessment of these patients, including the
assessment of possible disorders of the airways, in addition to the intra-operative manage-
Keywords:
ment and analysis of relevant pharmacological parameters. It is critical that the anesthetist
Rheumatoid arthritis
is familiar with the peculiarities of the disease and the specific characteristics of drugs used
Anesthesia
in its treatment: thus, he/she will be able to plan the best possible anesthetic technique for
Preoperatory evaluation
the surgery in question, offering safety and comfort to his/her patient. It is up to the rheu-
Surgery
matologist to know the procedure to which the patient will be submitted to and be aware of
the most appropriate anesthetic technique in each case. This will allow a better interaction
between the rheumatologist and the anesthesiologist in the pre-anesthetic evaluation,
through the sharing of relevant information on the articular and systemic involvement by
the disease that might interfere with preoperative and intraoperative management. Furthermore, the information on the pre-anesthetic assessment and the choice of anesthetic technique will enable the rheumatologist to clarify any doubts that his/her patient and family
may have, as well as to guide them as to whether or not the medications in use should be
maintained, and eventually about the need for a supplemental dose of corticosteroid. The
objective of this review is to acquaint the rheumatologist with key concepts related to the
anesthetic preoperative assessment of patients diagnosed with RA, mainly including general
notions that dictate the choice of the anesthetic technique.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (L.M.H. da Mota).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.08.002
214
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9
Avaliação anestésica pré-operatória de pacientes com artrite reumatoide
resumo
Palavras-chave:
O manejo e as intervenções cirúrgicas de problemas decorrentes direta ou indiretamente
Artrite reumatoide
da artrite reumatoide variam drasticamente. O anestesiologista e o reumatologista devem
Anestesia
estar atentos às peculiaridades da avaliação anestésica pré-operatória desses pacientes,
Avaliação pré-operatória
incluindo a avaliação de possíveis distúrbios das vias aéreas, além do manejo intraope-
Cirurgia
ratório e da análise dos parâmetros farmacológicos pertinentes. É essencial que o médico
anestesiologista esteja familiarizado com as peculiaridades da doença e com as características específicas das drogas utilizadas no seu tratamento, pois, assim, ele poderá planejar
da melhor forma possível a técnica anestésica para o ato cirúrgico em questão, oferecendo
segurança e conforto ao paciente. Ao reumatologista, cabe conhecer o procedimento a que
o paciente será submetido e ter noção da técnica anestésica mais indicada em cada caso.
Isso permitirá melhor interação entre o reumatologista e o anestesiologista na avaliação
pré-anestésica, através do compartilhamento de informações relevantes sobre o acometimento articular e sistêmico pela doença que possam interferir com o manejo pré e intraoperatório. Além disso, as informações sobre a avaliação pré-anestésica e a escolha da
técnica de anestesia contribuirão para que o reumatologista possa esclarecer dúvidas que o
paciente e seus familiares porventura apresentem, bem como orientá-los quanto à manutenção ou não das medicações em uso e, eventualmente, da necessidade de suplementação
da dose do corticosteroide. O objetivo desta revisão é familiarizar o reumatolostia com os
principais conceitos relacionados à avaliação anestésica pré-operatória de pacientes com
diagnóstico de AR, incluindo, principalmente, as noções gerais que ditam a escolha da técnica anestésica.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Rheumatoid arthritis (RA) is a systemic, chronic, progressive inflammatory disease, which mainly affects the synovial
membrane, and which can lead to bone and cartilaginous
destruction. The management and surgical interventions of
conditions directly or indirectly arising from RA vary drastically.1,2
Anesthesiologists and rheumatologists should be aware of
the peculiarities of the anesthetic preoperative assessment of
these patients, including the assessment of possible disorders
of the airways, in addition to the intra-operative management
and analysis of relevant pharmacological parameters.3
The objective of this review is to acquaint the rheumatologist with key concepts related to the anesthetic preoperative
assessment of patients diagnosed with RA, mainly including
general notions that dictate the choice of the anesthetic technique.
Methodology
From June to December 2012, a literature review was performed,
including searches using the following databases: Medline
(1990-2012), Cochrane Library, Lilacs, Pubmed (1990-2012) and
Scopus, in English, Portuguese and Spanish languages. The key
words used were “artrite reumatoide” (rheumatoid arthritis),
“avaliação pré-operatória” (preoperative evaluation), “propofol”
(propofol), “etomidato” (etomidate), “anestesia venosa total”
(total intra-venous anesthesia), “anestesia geral” (general anesthesia), “anestesia regional” (regional anesthesia) and “controle
das vias aéreas” (airway control).
Preoperative evaluation
The goals of a preoperative assessment of patients with RA
are assessing the extent of disease involvement, its systemic
consequences and possible adverse effects of therapies in use,
to minimize the risk of anesthetic and surgical procedures.4
In the preoperative evaluation of patients with RA, in addition to a routine history and physical examination applicable
to all patients (a record of the surgical procedure that will be
performed, systemic medical evaluation, a history of drug
use, prior surgeries, allergies, a detailed physical examination
and relevant ancillary tests), an evaluation of the extent of involvement of the disease and its possible implications regarding the anesthetic technique should be performed.
We list the affections (divided by topics) of the sites most
commonly involved by RA which entail special considerations
for the anesthetic procedure.
Cervical spine
Regarding the involvement of peripheral joints, especially the
hands, RA may affect the axial skeleton in the neck.5 This involvement may occur both in an early as in a late stage of
the disease. Most patients are asymptomatic, but about 4085% may have neck pain associated with the radiographic
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9
presence of instabilities (atlanto-axial subluxation and superior migration of the odontoid process).6,7
An interesting prospective observational trial that included 100 patients with early RA (<1 year of symptoms) showed
atlanto-axial subluxation in 12% of the cases within the first
5 years of the disease.8
A radiological evaluation of the cervical region in a neutral
profile, with maximum flexion and extension, prior to elective surgical and endoscopic procedures, can be performed in
patients with RA.6,9 Trials that show the actual cost-effectiveness of this routine assessment in the management of anesthesia and surgery are still lacking.9
Fiber optic laryngoscopes can be employed in the management of patients with RA when general anesthesia with
intubation is considered necessary.10 In this situation, it is important that efforts are employed to prevent hyperextension
of the neck, a common occurrence in airways manoeuvres.
Temporomandibular joint
RA can also affect the temporomandibular joints. For the anesthesia, the implication will be the reduction of mouth opening and a commonly occurring cervical stiffness that make
difficult both the intubation procedures and the positioning
of head and neck in surgeries performed in this region.11
Some authors recommend the use of the Mallampati
score, mouth opening and mandible protrusion as preoperative predictors of temporomandibular dysfunction.12
215
Cardiovascular system
Patients with RA may present early atherosclerosis secondary
to dyslipidemia (particularly a reduction in HDL-cholesterol),
presence of systemic hypertension and smoking.20 The activity of inflammatory disease is also a factor to be considered.21
Heart failure is a major cause of mortality in RA. Thus, a story
addressed to atherosclerotic disease is mandatory in patients
with RA who will be submitted to anesthetic procedures. In
those patients with symptoms or risk factors, an assessment
of cardiovascular situation through non-invasive methods
such as ECG, echocardiography and myocardial scintigraphy
is recommended. If ischemic lesions are detected, catheterization and possible corrections (i.e., angioplasty or CABG) are
mandatory.
Impairment of the conduction system and valvular involvement are also possible.22
The risk for developing cardiovascular disease appears to
be underestimated by the current methods employed; thus,
an even greater attention to this group of patients is necessary.23
Renal system
The use of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclosporine may lead to a risk of
kidney damage in patients with RA.2,24
Gastrointestinal system
Cricoarytenoid dysfunction
The larynx may be affected in approximately 80% of patients with RA.13 Generally, patients are asymptomatic, but in
those cases with symptoms, these can be represented by a
foreign body sensation in the oropharynx, dysphagia, dyspnea,
hoarseness, stridor, and also by an airway obstruction.5,14,15
The direct visualization of the larynx may reveal cricoarytenoid and vocal cords dysfunction during inspiration.16
In patients in whom this disorder is suspected , nasoendoscopy with visualization of the larynx is recommended,
besides the use of the tracheal tube with a smaller diameter,
a quiet intubation without trauma on the laryngeal structures, administration of oxygen by catheter after extubation,
removal of the tracheal tube in an appropriate environment
prepared for emergencies and, in severe cases, the possibility
of a preventive preoperative tracheostomy.15,17
In the postoperative phase of RA patients, after the tracheal extubation the patient should be observed closely for signs
of laryngeal dysfunction and airway obstruction.
Respiratory system
Another important aspect to be considered is the presence
of lung injury. In fact, trials have shown a reduction in vital
capacity and total lung volume in patients with RA, even in
the absence of pulmonary fibrosis.18,19 The presence of rheumatoid nodules is another possible injury that can lead to inflammation with possible dyspnea and accumulation of lung
fluid.18,19 The use of medications such as methotrexate brings
a potential risk of lung disease.19
The almost universal use of NSAIDs in patients with RA carries the risk of gastrointestinal tract injury.24 In fact, trials
show a higher prevalence of gastritis and ulceration with possible risk of bleeding in the digestive tract of these patients.25,26
The prophylaxis of peptic ulcer and gastrointestinal bleeding
should be performed, especially in NSAIDs users. Patients using glucocorticoids and with diverticulitis should be considered at high risk for perforation of the gastrointestinal tract.27
Endocrine system
The Cushing's syndrome characteristic effects of the glucocorticoids are well known. For those patients who are under
prednisone or who used this drug within an year, there is a
need to perform an intravenous injection of hydrocortisone
100 mg at the time of anesthesia induction.28,29
General measures such as prophylaxis of venous thrombosis should also be considered in patients with RA, such as the
use of elastic stockings, adequate hydration and prophylactic
use of heparin. One must bear in mind that these patients
have limited mobility and some of them will have a longer
post-operative recovery than patients not affected by this
condition (50).25
Difficulties may emerge while handling catheters used
for continuous blockages in patients on immunosuppressive therapy, corticosteroids and biologic drugs, due to an
increased risk of infections. Some joint deformities resulting
from RA can impact the conduct of anesthesia and the choice
of the anesthetic technique, because they compromise the
patient positioning during surgery and hinder the access to
216
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9
the techniques of regional blockade, causing difficulties associated with nervous plexus blocks.4
Choice of the anesthetic technique
The choice of anesthetic technique generally depends on the
general condition of the patient and on the type of proposed
surgical procedure; there is not one specific optimal technique for patients with RA.5,30 One should take into account
the risks inherent to each technique, the possible side effects
of the anesthetics used and the experience of the anesthesiologist. Table 1 summarizes the main anesthetic techniques
used, including a brief description of the technique, its indications and absolute and relative contraindications, in addition to considerations on the appropriate choice for patients
diagnosed with RA.
The use of general, inhalatory, total venous or balanced
anesthesia may provide better control of the cardiovascular
and respiratory systems, without imposing a time limit for
the duration of surgery,30 as it occurs with the use of non-continuous techniques of regional anesthesia. The use of general
anesthesia is also useful in situations where there is a need
to keep the patient in unusual or uncomfortable positions, as
it occurs in some orthopedic and neurosurgical procedures.5
Special attention should be paid to a proper protection of the
limbs and neck in order to avoid worsening of pre-existing
injury or the onset of a new lesion.28,31
Another very important aspect in general anesthesia procedures refers to the maintenance of airway patency. In this
situation, the risk is due to pathological changes caused by
RA, which are atlanto-axial subluxation and temporomandibular ankylosis.30 During the manoeuvres of airway instrumentation, one incurs in the risk of worsening the situation and
of possible permanent neurological injury.28,31 Thus, a careful
assessment of the presence and intensity of subluxation is
required in the pre-anesthetic evaluation. In suspected or
proven cases, the tracheal intubation manoeuvres should be
gentle, avoiding sudden or exaggerated manoeuvres. As previously mentioned, the use of fiber optic bronchoscopy is of
great help in such cases, because it allows an adequate access
to the airways with minimal cervical mobilization.30,32 In extreme cases, intubation with the patient awake can be easily
achieved by a suitably trained anesthesiologist, with minimal
sedation.30,32
Also with regard to the airways, the occurrence of ankylosis of the temporomandibular joint can bring additional
risk during anesthesia, since the occurrence of small mouth
openings to less than 2 cm is possible. Such cases will also
benefit from the use of a flexible fiber optic bronchoscope.32,33
An alternative to endotracheal intubation would be the use of
a laryngeal mask, which provides a clear airway with less airway trauma.34 Even so, the anesthesiologist must be careful,
since there are reports that its use can worsen the symptoms
of cricoarytenoid involvement of RA.35
Another aspect to be considered is the effect, on pharmacokinetics, of psychotropic drugs by the organic changes
caused by the disease, or by its treatment. Cardiac changes
could imply in the need of changes in hypnotic inducing
drugs, with an option by less cardiodepressant medications
such as etomidate or midazolam.34,36,37 Hepatic or renal impairment may require drugs with less dependence on its
exception, e.g., cisatracurium, the neuromuscular blocker of
choice in cases of these organ dysfunctions (metabolism by
plasma esterases)38,39 and propofol or etomidate as hypnotic
drugs and remifentanil as an opioid with plasma metabolism.40 All these procedures are important in order to reduce
the risk of drug recirculation, with possible deleterious effects
such as respiratory depression and the eventual risk of an
emergency approach to airways.41,42
An alternative to general anesthesia would be the use of
one of the several techniques of regional anesthesia, in which
sodium channel blocking drugs, the local anesthetics, are applied near peripheral nerves or nerve trunks, with no need
for airway instrumentation.43 The most common contraindications for the use of regional techniques are the use of anticoagulant drugs or of potent antiplatelet agents, patient objections, hemodynamic instability (in neuraxial techniques,
because of the extensive sympathetic blockade) and infection
at the puncture site.
The most common type of anesthesia for procedures on
the lower limbs is the spinal anesthesia with the application
of local anesthetics administered alone or in combination
with opioids for the provision of an effective postoperative
analgesia. The addition of clonidine or soluble opioids (e.g.,
sufentanil) to intratecal bupivacain significantly improves
the duration and quality of spinal anesthesia and provides
an extended perioperative analgesia, without significant side
effects.40,42 There is evidence of increased extent of subarachnoid blockade in patients with rheumatoid arthritis, and
this may justify a reduction of the doses of anesthetics in
these individuals.44 Prolonged postoperative analgesia can be
achieved through a combination of peripheral nerve blocks
(e.g., femoral nerve, lumbosacral plexus, and tibial, saphenous
or fibular nerves); this strategy yields an excellent analgesia
with minimal side effects and less need for systemic opioids.5
Likewise, the anesthesiologist can choose the peridural use
of local anesthetics as the selected technique; in this case he
can recur to continuous techniques with peridural catheters,
which ensures an extension of the anesthetic effect and the
possibility of an efficient post-operative analgesia, contributing to less risk of thromboembolism, facilitating early ambulation and reducing the risk of pulmonary complications such
as atelectasis and pneumonia.45-48
For the upper limbs, the brachial plexus anesthetic blockades fulfil a similar function, providing high quality anesthesia to the surgeon for prolonged periods and also allowing the
option in favour of a continuous technique for the postoperative analgesia.49,50
Also with regard to the choice of drugs, attention should be
paid to the use of drugs to treat the disease or to control the
symptoms. NSAIDs can lead to gastrointestinal haemorrhages, and the steroids may predispose to adrenal insufficiency
in stress situations, such as the surgical procedure, imposing
the need for supplementation in the perioperative period.29
Disease modifying drugs, such as methotrexate and leflunomide, may trigger peripheral neuropathies; their previous
documentation is important in those cases in which the anesthesiologist favoured a regional technique, which use of the
risk of nerve trauma can always be questioned.3
The unconsciousness and analgesia
remain by continuous inhalation of a
halogenated anesthetic. Widely used in
children without orotracheal intubation
or with laryngeal mask.
Description
Surgical procedures with less
painful potential, as very high
inhaled fractions are required
to achieve surgical anesthesia
for major surgery, with the
emergence of side effects such
as myocardial depression and
vasodilatation.
Any surgical procedure.
Indications
The analgesia, loss of consciousness
and muscle relaxation are maintained
through the use of various drugs.
Currently there are infusion pumps
that allow a controlled target infusion
of medication (with the objective of
achieving a certain plasma concentration)
with rapid awakening. Intubation and
controlled ventilation are required.
Balanced general
Association of intravenous drugs and
Any surgical procedure.
anesthesia
inhaled agents, seeking lower doses
of each class, and minimizing the
side effects. Intubation and controlled
ventilation required.
Regional anesthesia Administration of local anesthetics near
Surgical procedure restricted
nerve trunks or plexuses, or at cauda
to the area of coverage of the
equina. Provides analgesia in great
anesthetized nerve trunk or
regions of the body, with consciousness
plexus. The duration of the
and spontaneous ventilation maintained.
surgical act limited to the
duration of the chosen local
anesthetic agent.
General
intravenous
anesthesia
Inhalational
anesthesia
Anesthetic
technique
Hypovolemia,
coagulopathy,
use of potent
antiplatelet agents,
anticoagulants, sepsis,
infection at the
puncture site.
Past or suspected malignant Need for airway manipulation;
hyperthermia, which
allows maintenance of the patient
can be triggered by the
even in awkward positions.
halogenated agent. Allergy
to any of the drugs used.
No agreement by the patient. Provides long-lasting analgesia; can
be difficult to implement due to
improper body positioning; obviate
the manipulation of the airways.
Possible difficulty in
airway control.
Need for airway manipulation;
allows maintenance of the patient
even in awkward positions.
Need for airway manipulation;
allows maintenance of the patient
even in awkward positions.
Considerations for use in
patients with RA
If propofol was the chosen
drug, allergy to any of the
drugs used, mainly to egg
and soy.
Past or suspected malignant
hyperthermia, which
can be triggered by the
halogenated agent.
Absolute
contraindications
Possible difficulty in
airway control.
Possible difficulty in
airway control.
Relative
contraindications
Table 1 – General characteristics of the most commonly used anesthetic techniques and considerations for their indications and contraindications in patients with RA
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9
217
218
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9
Conclusion
With the evolution of RA treatment, the consequent increase
in patients’ life expectancy and reduction of morbidity and
mortality, it will be increasingly common that these people
have a need for any surgical procedure throughout their lives.
It is therefore critical that the anesthetist is familiar with the
peculiarities of the disease and the specific characteristics of
the pharmacological agents used in its treatment. Thus, this
professional can plan in the best possible way the anesthetic
technique for the surgery in question, offering safety and
comfort to his/her patient.
It is up to the rheumatologist to know the procedure that
his/her patient will be submitted to and be aware of the most
appropriate anesthetic technique in each case. This will allow
better interaction between the rheumatologist and the anesthesiologist in the pre-anesthetic assessment, through the
sharing of relevant information on the articular and systemic
involvement by the disease that might interfere with the preoperative and intraoperative management. Furthermore, the
information on the pre-anesthetic assessment and the choice
of anesthetic technique will enable the rheumatologist to
clarify any doubts that his/her patient and family may have,
as well as to guide them as to whether or not the medications
in use should be maintained and eventually about the need
for a supplemental dose of corticosteroid.
Conflicts of interest
The authors declare no conflicts of interest.
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REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Review article
Rituximab for rheumatoid arthrits treatment:
a systematic review
Lívia Lovato Pires de Lemosa,*, Juliana de Oliveira Costab, Marina Amaral de Ávila Machadob,
Alessandra Maciel Almeidab, Mariana Michel Barbosac, Adriana Maria Kakehasid,
Vânia Eloísa de Araújoa, Augusto Afonso Guerra Júniora, Francisco de Assis Acurcioa
Department of Social Pharmaceutics, Pharmacy Faculty, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Department of Preventive and Social Medicine, Medicine Faculty, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
c Center of Research René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil
d Department of Locomotor Apparatus, Medicine Faculty, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
a b article info
abstract
Article history:
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by
Received on 22 March 2013
systemic joint inflammation that often leads to significant disability. Several effective anti-
Accepted on 23 August 2013
TNF agents have been used, but some patients have shown an inadequate response. Rituximab is a therapeutic monoclonal antibody indicated in such cases.
Keywords:
Methods: We conducted a systematic review to access efficacy and safety of rituximab in
Rheumatoid arthritis
patients with active RA which have or have not been treated with anti-TNF agents before,
Rituximab
and to relate outcome with RF and anti-CCP serology. We searched major electronics data-
Systematic review
bases, grey literature and searched for references manually. We used Review Manager®5.1
Safety
for meta-analysis.
Efficacy
Results: We included six RCTs comparing rituximab 1000 mg with placebo. Methotrexate
was used by both groups. Treatment with rituximab was more effective in naïve and in
anti-TNF treatment failure patients - ACR20/50/70 and EULAR response. We observed lower
changes in Total Genant-modified Sharp score, erosion score and joint narrowing scores in
the rituximab group, and SF-36, FACIT-T and HAQ-DI scores were also better in this group.
There were no differences between groups regarding safety outcomes, with exception of
acute injection reactions, which were more common on rituximab group. More RF/anti-CCP
seropositive patients achieved ACR20 than RF/anti-CP negative patients in rituximab group.
Conclusion: Available data support the use of rituximab for the treatment of RA, as it is an
effective and safe option for naïve and anti-TNF treatment failure patients. RF and anti-CCP
seam to influence treatment results, but this inference needs further research.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (L.L.P. Lemos).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.08.003
221
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0
Rituximabe para o tratamento da artrite reumatoide: revisão sistemática
resumo
Palavras-chave:
Introdução: A artrite reumatoide (AR) é uma doença autoimune crônica caracterizada por
Artrite reumatoide
inflamação articular sistêmica que, com frequência, leva a significativa incapacitação. Vá-
Rituximabe
rios agentes anti-TNF têm sido usados efetivamente, mas alguns pacientes demonstraram
Revisão sistemática
resposta inadequada. Rituximabe é um anticorpo monoclonal terapêutico indicado em tais
Segurança
casos.
Eficácia
Métodos: Realizou-se uma revisão sistemática para avaliar a eficácia e a segurança de rituximabe em pacientes com AR ativa previamente tratados ou não com agentes anti-TNF e
para relacionar o desfecho com a sorologia para FR e anti-CCP. Pesquisaram-se importantes
bancos de dados eletrônicos e a literatura não convencional, além de se fazer uma busca
manual de referências. Para a meta-análise, utilizou-se o programa Review Manager® 5.1.
Resultados: Consideramos seis ERCs comparando rituximabe 1000 mg com placebo. Em ambos os grupos usou-se Metotrexato. O tratamento com rituximabe foi mais efetivo em pacientes jamais tratados e nos que não obtiveram sucesso com a terapia anti-TNF – critérios
ACR 20/50/70 e EULAR. No grupo de rituximabe, observaram-se mudanças menos expressivas nos escores de Sharp/Genant, de erosão e de estreitamento do espaço articular; nesse
grupo, os escores SF-36, FACIT-T e HAQ-DI também foram melhores. Não foram notadas
diferenças entre grupos com relação aos desfechos de segurança, com exceção das reações
agudas à infusão, que foram mais comuns no grupo de rituximabe. Ainda no grupo de rituximabe, um número maior de pacientes soropositivos para FR/anti-CCP alcançou ACR20,
em comparação com pacientes negativos para RF/anti-CCP.
Conclusão: Os dados disponíveis falam em favor do uso de rituximabe para o tratamento
da AR, como opção efetiva e segura para pacientes jamais tratados ou que não obtiveram
sucesso com o tratamento anti-TNF. FR e anti-CCP parecem influenciar os resultados do
tratamento, mas essa inferência ainda está à espera de futuras pesquisas.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by symmetrical joint inflammation that
often evolves into erosive joint damage.1-3 Its prevalence
and incidence vary among countries, affecting 2% of Argentina’s population and over 10% of the U.S. population.4 In
addition to the articular manifestations, which can lead to
damage and functional disability, the disease is related to
systemic manifestations and an increase in cardiovascular
mortality.5
The development of anti-TNF monoclonal antibodies shed
light on the treatment of those patients who have failed the
first-line therapy, in which synthetic disease modifying drugs
(DMD) such as methotrexate (MTX), sulfasalazine and leflunomide are used.6-8 However, after one year of treatment, approximately 20% of patients abandoned treatment with antiTNF due to its ineffectiveness.9 To work around this situation,
the use of a different therapeutic target is an interesting alternative.
Rituximab is a monoclonal antibody that selectively depletes peripheral CD20+ B cells. Evidence supports its use in
combination with MTX in patients who have failed anti-TNF
therapy and in those naïve to treatment with these agents.10-13
However, the patients’ response may be incomplete, indicating the necessity to investigate biomarkers that have predic-
tive or prognostic value, to assist in choosing the best treatment strategy. Rheumatoid factor (RF) is an IgM antibody
targeted to the constant region of IgG. The anti-cyclic citrullinated peptide (anti-CCP) antibody has more specificity for
RA, relating to a more aggressive disease. Both markers are
used for the diagnosis of RA and its titration corresponds to
the disease activity.14
The objectives of this review were to evaluate the safety
and efficacy data of rituximab, as well as to illustrate the influence of RF and anti-CCP in the outcome of treatment of
patients with active RA.
Methods
This systematic review (SR) is part of a larger trial that also
includes infliximab, adalimumab and etanercept, designed to
evaluate the efficacy and safety of these agents in the treatment of RA. We conducted this trial according to the Cochrane
handbook15 and prepared the manuscript using PRISMA Statement as reporting guidance.16
Eligibility criteria
Randomized controlled trials (RCTs) comparing a scheme
with rituximab versus without rituximab in the treatment of
RA in patients over 18 years of age were eligible. We excluded
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trials with less than a total of 30 participants, pilot trials and
dosage comparison.
Search for trials
We investigated the databases EMBASE (until April 2012), Cochrane Register of Controlled Trials (CENTRAL; until June 2012),
MEDLINE (via PubMed; until July 2012) and LILACS (until October 2012) in order to to identify potentially eligible articles in
English, Spanish or Portuguese languages. For manual search
we investigated meetings’ annals (American College of Rheumatology, 2010 and 2011; European League Against Rheumatism, 2010, 2011 and 2012) dissertations and theses’ banks
(OpenThesis, National Library of Australia – Trove, Biblioteca
Digital Brasileira de Teses e Dissertações from USP, Theses Database of Capes, Pro Quest Dissertation & Theses Database) and
reference lists of articles included in other SRs. We searched
ongoing trials and unpublished trials in the databases of ClinicalTrials.gov and EUClinical Trials Register records.
deviation as a measure of association. Continuous outcomes
were qualitatively evaluated and presented as mean ± SD.
We planned subgroup analyses considering seropositivity for
RF and anti-CCP and developed a sensitivity analysis using
participant type for primary outcomes. We assessed metaanalyses’ publication bias by funnel chart.
Results
Results of the Search
After review by title and abstract, 249 references for rituximab, infliximab, adalimumab and etanercept were considered eligible. Six RCTs were enrolled on rituximab, comprising
15 published articles (Fig. 1).
Result of Search: 5782
Manual Search: 9
PubMed: 3620
Lilacs: 98
Outcome measurements
Embase: 1577
Central: 487
We considered as primary outcome measures: ACR20, ACR50
and ACR70.17 The secondary outcome measures were EULAR
responses,18 individual components of ACR, disease activity
measured by baseline DAS28-ESR change, SF-36 scores,19,20 fatigue assessed by FACIT-F21 and adverse events (AE) .
Total of included articles in
searchs: 5791
Duplicates: 92
Total of excluded articles by title: 2648
Reason for exclusion:
Study selection and data extraction
Excluded by trial type: 1123
Excluded by participant type: 283
We performed the assessment of the eligibility of the trial and
data collection, in a standard form, in duplicate and, when
necessary, a third reviewer solved disagreements. Authors of
the papers were contacted when there was any difficulty in
extracting data. We organized the trials according to the previous use of DMD.
Total of included articles
after removal of
duplicates: 5699
Statistical analysis
We used the Review Manager® 5.1 software to conduct the
meta-analyses using the random effects model and considered those analyses with I2 > 40% and P value of chi-squared
test < 0.10 with substantial heterogeneity.25 The causes of heterogeneity were investigated by the exclusion of one trial at a
time and subsequent verification of the change in the values
of I2 and P. For dichotomous outcomes, we used the relative
risk (RR) with confidence interval (CI) of 95% and standard
Excluded by outcome type: 1107
Total of articles excluded by abstract:
1912
Reason for exclusion:
Excluded by trial type: 1366
Excluded by participant type: 79
Quality assessment and risk of bias of included trials
We assessed the methodological quality using the modified
Jadad scale22 and the risk of bias by Cochrane Collaboration
tool.23 The trial was considered high risk if presented a possibility of high risk of bias in at least one of the criteria evaluated. We calculated the interobserver agreement using Kappa
statistics24 using SPSS® 17 software, which we considered
excellent for Jadad scale; Kappa = 0.83 ± 0.60 (SD), and substantial for assessing risk bias; Kappa = 0.71 ± 0.69. We also
checked conflicts of interest declared by authors of the included articles.
Excluded by intervention type: 135
Excluded by intervention type: 83
Total of articles included
by title: 3051
Total of articles included
by abstract: 1139
Excluded by outcome type: 384
Articles of observational trials that will be
analysed in a subsequent phase: 890
Total of articles excluded by complete
text: 175
Reason for exclusion:
Excluded by trial type: 96
Excluded by participant type: 02
Excluded by intervention type: 13
Total of RCT articles
included by abstract: 249
Excluded by outcome type: 24
Not found: 40
Total of included articles by complete
text: 74
Adalimumab: 17
Infliximab: 17
Etanercept: 31
Rituximab: 15
Fig. 1 – Flowchart of selection of trials.
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We included 15 trials in progress, and one of them was terminated prematurely in some research centres without stated
justification (2008-002381-55). A trial was completed, but we
could not find the publication of the results (NCT01117129).
We did not include any dissertation or thesis.
an open phase. After 24 weeks of follow-up, those patients
who did not achieve remission were randomized to receive
re-treatment with rituximab or placebo and were followed for
another 24 weeks. We considered the results of this part of the
trial in the meta-analyses.
Trial characteristics
Assessment of methodological quality and risk of bias
The characteristics of RCTs included are shown in Table 1.
We evaluated a total of 2,139 patients with active disease, of
which 1,198 used rituximab 1,000 mg twice with an interval
of 15 days. MTX was used as co-treatment for all patients. The
participants averaged 50 years of age, and 80% were female.
The inclusion criteria of the trials were similar in terms of the
diagnostic criteria – all followed the classification criteria of
the American College of Rheumatology (ACR).26
One trial evaluated outcomes in 52 and 104 weeks of MTX
naïve participants who had, on average, less than one year
of diagnosis.27-29 The baseline data of participants in this trial
were similar to those in the other trials, with the exception of
the radiographic score, much lower in those newly diagnosed
patients. In the other five trials, the participants had active disease despite MTX use and averaged more than seven years of
disease evolution. In two trials, the participants were naïve for
anti-TNF, while the outcomes were presented for 24,30 48 and
104 weeks.31-34 In the other three trials, the participants exhibited treatment failure with anti-TNF agent, while the outcomes
were presented after 24 weeks of follow-up (Table 1).35-41
One trial evaluated the effectiveness of the second administration of rituximab in patients in whom the first application cycle was not sufficient to achieve remission, i.e., DAS28ESR < 2.6.41 In this trial, all participants received rituximab in
All included trials had high methodological quality (Jadad
score, modified = 5). The risk of bias assessment showed that
the methods of generation of allocation sequence and of ensuring allocation confidentiality were considered adequate in
only one RCT.27-29 For the remaining domains, all trials had low
risk of bias (Fig. 2).
Conflicts of interest and publication bias
All included trials were funded by the pharmaceutical industry and only one report36 did not declare a conflict of interests.
The funnel plot suggested publication bias, but this analysis
could not be considered robust, considering that the number
of included trials was small.
Primary outcomes
The meta-analyses that evaluated ACR measures after 24
weeks of treatment included studies whose participants were
naïve or had failed with anti-TNF treatment (n = 1,640). In general, more patients in rituximab group achieved ACR20, ACR50
and ACR70 compared to placebo. However, these analyses
showed substantial heterogeneity, and the subset of patients
naïve to anti-TNF displayed a robust result. But it is notewor-
Table 1 – Summary of characteristics of included trials
Study
N
MTX virgins
IMAGE [29-31]
placebo
249
rituximab
250
Anti-TNF virgins
Edwards [33-36]
placebo
40
rituximab
40
SERENE [32]
placebo
172
rituximab
170
Failure with Anti-TNF
DANCER [37,38]
placebo
122
rituximab
122
REFLEX [39-42]
placebo
201
rituximab
298
SUNRISE [43]
placebo
157
rituximab
318
Women
(%)
Age
(years ± DP)
Disease
duration
(years ± DP)
Previous use of
MMCD (others than
MTX; no. ± DP)
77
85
48,1 (12,7)
47,9 (13,3)
0,91 (1,1)
0,92 (1,3)
30
31
-
80
75
54 (11)
54 (12)
11 (7)
12 (7)
2,6 (1,3)
2,5 (1,4)
-
85,5
81,2
52,16 (12,390)
51,30 (12,644)
7,48 (7,642)
6,61 (7,294)
1,1 (1,10)
1,1 (1,11)
-
79,5
76,2
50,8 (11,7)
52,1 (10,9)
9,6 (7,7)
11,3 (8,5)
2,2
2,5
27
31,1
82
81
52,89 (12,31)
52,24 (12,20)
11,74 (7,68)
12,15 (8,4)
2,4 (1,8)
2,6 (1,8)
IFX: 81; ADA: 18; ETA: 50
IFX: 71; ADA: 23; ETA: 55
79
81
54 (11)
54 (11)
11 (8,5)
12 (9,2)
4,1 (1,9)*
4,1 (2,0)*
ADA adalimumab, ETA etanercepte, IFX infliximab
* Including anti-TNF, † 1, 2, 3 mean one, two and three agents anti-TNF, respectively.
Previous use of anti-TNF
N (%)
1: 53; 2: 35; 3: 12†
1: 57; 2: 32; 3: 11
No. (DP)
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Fig. 2 – Assessment of risk of bias using the Cochrane
Collaboration tool. A. Graph of risk of bias of all trials
included in this review, presented by author names of
each trial and their respective percentages in each item
of the assessment. B. Summary of risk of bias of the trials
(represented by trial names) with their respective result in
each item of assessment.
thy that this subgroup is small, n = 22; then, more studies are
needed to confirm the result (Fig. 3). In the analyses of heterogeneity, it was noted that one trial reported favourable results
with the use of rituximab, a statistically significant result, but
less expressive than the other RCTs.41 After its exclusion of
the meta-analyses, the results favouring the use of rituximab
persisted, and the heterogeneity decreased to ACR20, ACR50
and ACR70, respectively RR (95% IC) = 2.24 (1.86-2.69; I2 = 15 %;
P = 0.32) , RR = 2.86 ( 2.07-3.94; I2 = 0%; P = 0.90) and RR = 3.91
(1.84-8.31; I2 = 50%; P = 0.11).
In the pooled analysis of two trials (n = 579), we did not
perceive any benefits from the use of the biological agent
compared to placebo for ACR20 until 48-52 weeks and 104
weeks of follow-up.27-29,31-34 The ACR50 and ACR70 results did
not favour the use of rituximab until 48-52 weeks, although
they have favoured its use till 104 weeks. This fluctuation of
the presence or absence of benefit may be related to the small
number of participants. Furthermore, the type of patients in
these two trials was different: one trial evaluated MTX-naïve
patients with less than one year of disease evolution,29-31 and
the other evaluated patients naïve to anti-TNF with more
than ten years of diagnosis.31-34
Secondary outcomes
In general, the group of patients who used rituximab achieved
a statistically significant improvement compared to placebo
in all individual components of the ACR, including in relation
to the average change in HAQ-DI score. The meta-analysis of
the number of participants who showed a change in HAQ-DI
score ≥ 0.22 after 24 weeks from baseline (n = 1,161) pointed
to the benefit of rituximab use with substantial heterogeneity, probably due to the SERENE trial.30 The joint analysis of
two trials (n = 562) showed no statistically significant difference between groups after 48-52 weeks. After 72 weeks, there
was no difference between intervention and control groups
of patients with more than ten years of diagnosis.31 But after
104 weeks there was a difference which benefited the use of
rituximab in patients with less than one year of disease progression (Table 2).27-29
After 24 weeks of follow-up, more patients in rituximab
group compared to placebo achieved good (n = 1,637) and moderate (n = 1,393) EULAR responses, but with substantial heterogeneity (data not shown). Regarding good EULAR response, in
the analysis of heterogeneity (and after removal of the SERENE
trial)30 the outcome continued favouring rituximab. The analysis
of the trial that evaluated recently diagnosed patients showed
that the benefit of rituximab remained after 52 and 104 weeks
of follow up.27-29 The heterogeneity of good and moderate EULAR responses diminished with the exclusion of those participants with therapeutic failure with anti-TNF,35,39 and with the
exclusion of participants naïve to anti-TNF, respectively.30-34 The
change of baseline DAS28-ESR was generally higher in rituximab group compared to placebo after 24, 52 and 104 weeks of
follow-up. A pooled analysis of two trials showed no difference
between groups in relation to the outcomes of low activity of
the disease and remission till 24 weeks of follow-up;30,41 however, more patients in rituximab group compared to placebo
achieved these targets after 52 and 104 weeks in the trial that
evaluated patients with less diagnosis time (Table 2).27-29
The summarized physical component (SPC) change of
SF-36 was superior and statistically significant in rituximab
group compared to placebo after 24 and 52 weeks of followup. On the other hand, the results of the summarized mental
component (SMC) change were divergent: two trials showed
no difference between groups and other two showed a statistically significant difference. In joint analyses, the chances
of achieving a mean change of SPC > approx. 5 and SMC >
approx. 5 after 24 weeks of treatment were higher and statistically significant in participants who used rituximab. The
heterogeneity of the first analysis was substantial, but the individual reports favoured rituximab (Table 2).
The group using rituximab had benefits with respect to the
fatigue measured by FACIT-F, as compared to placebo after 24
and 52 weeks of treatment. Likewise, the chance of achieving
a clinically significant lower change after 24 weeks of treatment, i.e., a mean change in FACIT-F score ≥ approx. 3.5, was
higher in participants who used the biological agent (Table 2).
Two trials reported that the participants using rituximab
achieved better results in radiological outcomes than those in
placebo.35-40 A joint analysis (n = 934) showed that the participants treated with the biological agent had lower probability
of progression by the Sharp score (modified) compared to placebo + MTX after 104 weeks of treatment (Table 2).
Regarding safety, there was no difference between intervention and control groups regarding the incidence of severe
AEs, malignancies and death. Infection was the most common
AE in the trials. In any case, the rate of occurrence of serious
infections was low, about 2% after 24 months of treatment
in both groups, increasing to approximately 6% after this pe-
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Subgroup analysis – RF and anti-CCP
riod. Acute reaction to the first infusion was more common in
rituximab group compared to placebo. In the second infusion,
we could observe an opposite association; more patients in
placebo group exhibited a reaction. There were no deaths related to this outcome in the RCTs included (Table 2).
The loss for total follow-up was higher in placebo group
compared to rituximab. Individually, the trials were different as the magnitude of the loss, ranging from 2.5% to 14%
in rituximab group and from 5% to 35% in placebo group. The
losses due to lack of efficacy were more frequent in placebo
group and the rates of loss due to AEs were not different between groups (Table 2).
A.
Rituximabe
Placebo
Events Total Events Total Weight
Study or subgroup
Anti-TNF virgins
With the exception of one trial that included only rheumatoid factor-positive (RF+) participants, the groups of other trials were balanced with regard to the inclusion of positive and
negative participants.31-34 These latter were always minority
and were not included in the overall analysis of a trial.35,36 The
distribution of patients in relation to anti-CCP was reported
by a trial, with homogeneity between groups.41
With respect to ACR20, we could observe a smaller proportion of responders in the FR- group when compared to
FR+. We could also observe that in the group FR+ the number
Risk Ratio
M-H, Random, 95% Cl Year
29
40
15
40 17.4%
Edwards [33]
86
170
40 172 20.3%
SERENE [32]
210
212
37.7%
Subtotal (95% CI)
Total events
115
55
Heterogeneity: Tau2 = 0.00; Chi2 = 0.19, df = 1 (P = 0.67); I2 = 0%
Test for overall effect Z = 5.70 (P < 0.00001)
Risk Ratio
M-H, Random, 95% Cl
1.93 [1.24, 3.01] 2004
2.18 [1.60, 2.96] 2010
2.09 [1.62, 2.70]
Failure with Anti-TNF
DANCER [37]
66
122
1.94 [1.40, 2.70] 2006
34 122 19.9%
REFLEX [39]
152
298
2.85 [2.08, 3.91] 2006
36 201 20.1%
SUNRISE [43]
172
318
1.20 [0.98, 1.46] 2010
71 157 22.3%
Subtotal (95% CI)
738
480 62.3%
1.86 [1.07, 3.22]
Total events
390
141
Heterogeneity: Tau2 = 0.22; Chi2 = 23.54, df = 2 (P = 0.00001); I2 = 92%
Test for overall effect Z = 2.20 (P = 0.03)
Total (95% CI)
948
692 100.0%
1.92 [1.36, 2.73]
Total events
505
196
2
2
2
Heterogeneity: Tau = 0.13; Chi = 26.49, df = 4 (P = 0.00001); I = 85%
Test for overall effect Z = 3.66 (P = 0.0003)
Teste for subgroup differences: Chi2 = 0.15, de = 1 (P = 0.70). I2 = 0%
B.
Rituximabe
Placebo
Study or subgroup
Events Total Events Total Weight
Anti-TNF virgins
Risk Ratio
M-H, Random, 95% Cl Year
Edwards [33]
17
40
5
40 15,8%
SERENE [32]
44
170
16 172 21,8%
Subtotal (95% CI)
210
212 37,6%
Total events
61
21
Heterogeneity: Tau2 = 0.00; Chi2 = 0.14, df = 1 (P = 0.71); I2 = 0%
Test for overall effect Z = 4.61 (P < 0.00001)
0.1 0.2
0.5
Favours placebo
1
2
5
10
Favours Rituximab
Risk Ratio
M-H, Random, 95% Cl
3.40 [1.39, 8.33] 2004
2.78 [1.64, 4.73] 2010
2.93 [1.86, 4.63]
Anti-TNF failure
REFLEX [39]
27
298
3.64 [1.43, 9.30] 2006
5 201 15.1%
DANCER [37]
41
122
2.56 [1.52, 4.31] 2006
16 122 22.0%
SUNRISE [43]
92
318
1.11 [0.81, 1.52] 2010
41 157 25.3%
Subtotal (95% CI)
738
480 62.4%
2.01 [0.95, 4.26]
Total events
160
62
Heterogeneity: Tau2 = 0.34; Chi2 = 11.39, df = 2 (P = 0.003); I2 = 82%
Test for overall effect Z = 1.83 (P = 0.07)
Total (95% CI)
948
692 100.0%
2.33 [1.35, 4.01]
Total events
221
83
2
2
2
Heterogeneity: Tau = 0.28; Chi = 17.97, df = 4 (P = 0.001); I = 78%
Test for overall effect Z = 3.05 (P = 0.002)
Test for subgroup differences: Chi2 = 0.70, de = 1 (P = 0.40). I2 = 0%
C.
Rituximabe
Placebo
Study or subgroup
Events Total Events Total Weight
Anti-TNF virgins
Risk Ratio
M-H, Random, 95% Cl Year
Edwards [33]
9
40
2
40 14.8%
SERENE [32]
17
170
9 172 22.5%
Subtotal (95% CI)
210
212 37.3%
Total events
26
11
Heterogeneitye: Tau2 = 0.01; Chi2 = 1.03, df = 1 (P = 0.31); I2 = 3%
Test for overall effect Z = 2.34 (P = 0.02)
0.1 0.2
0.5
Favours placebo
1
2
5
10
Favours Rituximab
Risk Ratio
M-H, Random, 95% Cl
4.50 [1.04, 19.54] 2004
1.91 [0.88, 4.17] 2010
2.32 [1.15, 4.71]
Anti-TNF failure
DANCER [37]
24
122
4.00 [1.69, 9.44] 2006
6 122 21.6%
REFLEX [39]
36
298
12.14 [2.96, 49.86] 2006
2 201 15.4%
SUNRISE [43]
45
318
1.11 [0.68, 1.81] 2010
20 157 25.7%
Subtotal (95% CI)
738
480 62.7%
3.37 [0.84, 13.52]
Total events
105
28
Heterogeneity: Tau2 = 1.27; Chi2= 15.63, df = 2 (P = 0.003); I2 = 82%
Test for overall effect Z = 1.72 (P = 0.09)
Total (95% CI)
948
692 100.0%
2.94 [1.30, 6.66]
Total events
131
39
2
2
2
Heterogeneity: Tau = 0.61; Chi = 16.70, df = 4 (P = 0.002); I = 76%
Test for overall effect Z = 2.58 (P < 0.010)
Test for subgroup differences: Chi2 = 0.22, de = 1 (P = 0.64). I2 = 0%
0.1 0.2
0.5
Favours placebo
1
2
5
10
Favours Rituximab
Fig. 3 – Forest plot depicting the statistically significant difference between rituximab and placebo in response criteria of the
American College of Rheumatology (ACR) after 24 weeks of treatment. A. ACR20 (20% of improvement). B. ACR50. C. ACR70.
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Table 2 – Joint analysis of the secondary outcomes of efficacy, adverse events e loss of follow-up
Outcome
HAQ-DI < 0,22
24 weeks [32, 36, 37, 40]
48-52 weeks [29, 36]
72 weeks [36]
104 weeks [31]
Good EULAR response
24 weeks [32, 35, 37, 39, 43]
52 weeks [29]
104 weeks [31]
Moderate EULAR response
24 weeks [32, 33, 39, 43]
Low DAS 28 activity
24 weeks [32, 43]
52 weeks [29]
104 weeks [31]
DAS 28 remission
24 weeks [32, 43]
52 weeks [29]
104 weeks [31]
PCS (SF-36) ≥ ~5
24 weeks [32, 40]
52 weeks [29]
MCS (SF-36) ≥ ~5
24 weeks [32, 40]
52 weeks [29]
FACIT-F ≥ ~3.5
24 weeks [37, 40]
52 weeks [29]
No progression at mTSS
24 weeks [29]
52 weeks [29]
96-104 weeks [31,42]
No progression at erosion score
24 weeks [40]
96-104 weeks [31,42]
Serious adverse events
24 weeks [32, 33, 37, 39, 43]
48-52 weeks [29, 33]
104 weeks [31]
Serious infections
24 weeks [32, 33, 37, 43]
48-52 weeks [29, 33]
104 weeks [31]
Reaction at the infusion site
1° infusion [29, 32, 33, 37, 39, 43]
2° infusion [29, 32, 37, 39, 43]
Losses of follow-up
24 weeks [32, 33, 37, 39, 43]
48-52 weeks [29, 33]
72 weeks [36]
104 weeks [31, 36]
Losses by lack of efficacy
24 weeks [33, 37]
48-52 weeks [29, 33]
72 weeks [37]
104 weeks [36]
Losses by AE
24 weeks [32, 33, 37, 39, 43]
48-52 weeks [29, 33]
72 weeks [36]
104 weeks [31, 36]
Rituximab n
Placebo n
RR (95% IC)
P Value
I2 (%)
629
288
40
250
532
274
40
249
1,61 (1,22, 2,12)
1,57 (0,71, 3,44)
4,33 (1,34, 14,05)
1,12 (1,03, 1,21)
0,004
0,02
-
77
82
-
946
250
250
619
249
249
3,37 (1,35, 8,43)
2,32 (1,72, 3,14)
2,10 (1,61, 2,72)
<0,0001
-
84
-
824
569
1,62 (1,10, 2,37)
0,0001
86
488
250
250
329
249
249
1,61 (0,70, 3,72)
2,13 (1,60, 2,84)
1,93 (1,50, 2,48)
0,05
-
73
-
488
250
250
329
249
249
2,05 (0,64, 6,53)
2,40 (1,65, 3,48)
2,49 (1,72, 3,61)
0,06
-
73
-
468
250
373
249
2.48 (1.13, 5.46)
1.21 (1.08, 1.36)
0,0009
-
91
-
468
250
373
249
1,71 (1,36, 2,16)
1,16 (0,98, 1,37)
0,53
-
0
-
420
250
322
249
1,90 (1,60, 2,25)
1,11 (1,00, 1,25)
0,41
-
0
-
244
244
252
232
232
420
1,19 (1,04, 1,36)
1,21 (1,03, 1,41)
1,53 (1,29, 1,81)
0,84
0
268
514
177
420
1,10 (0,95, 1,28)
1,50 (1,26, 1,78)
0,20
39
1028
290
250
727
289
249
0,98 (0,70, 1,38)
0,93 (0,57, 1,52)
0,78 (0,51, 1,19)
0,44
0,91
-
0
0
-
720
290
250
518
289
249
0,86 (0,36, 2,04)
0,68 (0,30, 1,57)
0,63 (0,31, 1,27)
0,74
0,34
-
0
0
-
1280
1238
976
936
1,55 (1,30, 1,86)
0,79 (0,63, 0,99)
0,42
0,83
0
0
1030
290
40
290
727
289
40
289
0,47 (0,29, 0,76)
0,54 (0,04, 7,56)
0,48 (0,28, 0,82)
0,48 (0,28, 0,82)
0,18
0,0004
-
36
92
-
232
290
40
40
189
289
40
40
0,27 (0,16, 0,45)
0,19 (0,08, 0,50)
0,44 (0,15, 1,33)
0,24 (0,09, 0,64)
0,85
0,74
-
0
0
-
1028
290
40
290
727
289
40
289
1,47 (0,53, 4,09)
0,95 (0,17, 5,34)
0,33 (0,04, 3,07)
0,38 (0,17, 0,85)
0,15
0,21
0,67
41
37
0
AE Adverse events, DAS 28 Disease Activity Score 28-joint assessment for swelling and tenderness, EULAR European league Against Rheumatism,
FACIT-F Functional Assessment of Chronic Illness Therapy – Fatigue, HAQ-DI Health Assessment Questionnaire – Disability Index, MCS Mental
Component Summary, mTSS Mean change in Genant-modified Sharp radiographic score, PCS Physical Component Summary, SF-36 Medical
Study Short-Form Health Survey.
227
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0
of participants treated with rituximab achieved ACR20 that
was statistically significant compared to placebo, but with
substantial heterogeneity; RR = 1.71 (1.19-2.48; I2 = 90%; P <
0.00001), and this was explained by the exclusion of any trial.
In FR- group, there was no difference between experimental
and control groups; however, the analysis also showed substantial heterogeneity; RR = 1.16 (0.73-1.85; I2 = 71%; P = 0.02),
with no explanation (Fig. 4).
The IMAGE trial also assessed ACR50, ACR70, good EULAR
response, low activity, and remission of disease according to
DAS28-ESR, percentage of participants without radiological
progression and mean change in modified Sharp score in relation to seropositivity for RF and anti-CCP.27 After 52 weeks
of follow-up, only the mean change in modified Sharp score
was statistically different between rituximab and placebo in
the analysis of participants FR+. In this trial, all participants
FR- were anti-CCP-.
According to Tak et al.,29 after 104 weeks of follow-up the
participants FR+ and/or anti-CCP+ in rituximab group had a
higher probability of not showing radiological progression
compared to placebo; odds ratio (OR, 95% CI) = 2.228 (1.5133.281).29 In the analyses of the participants FR- and anti-CCP-,
rituximab group showed a tendency to higher probability of
non-progression compared to placebo, but without statistical significance; OD = 1.833 (0.558-6.027). Regarding ACR50,
the group differences were statistically significant in the subgroup FR+ and/or anti-CCP+. The participants FR- and antiCCP- that used placebo achieved ACR50 in greater proportion
A.
versus intervention group; however, these analyses were not
statistically significant.
In SERENE trial,30 after 24 weeks of treatment (the controlled trial phase) there was no difference in relation to the
change in DAS28-ESR among patients FR+ and FR- who used
rituximab. In the open phase of the trial (24 to 48 weeks of
treatment), the patients who had not achieved remission
were re-treated with the biological agent; more patients FR+
achieved ACR50 and ACR70, compared to patients FR-.
Discussion
The results of efficacy and safety of this RS point to the benefit of rituximab 1000 mg applied twice at 15-day intervals associated with weekly MTX for the treatment of RA. Regarding
the primary outcomes, greater number of patients achieved
ACR20, ACR50 and ACR70 in rituximab group versus placebo.
This result was obtained for up to 24 weeks of follow-up in patients naïve and in those patients who have failed with antiTNF and with more than seven years of the disease; and for
up to 52 weeks for patients naïve to MTX and anti-TNF and
newly diagnosed. These results can also be applied to good
and moderate EULAR responses.
In comparison to individual components of ACR response
criteria, summarized physical and mental components of SF36, fatigue measured by FACIT-F and in relation to the change
in baseline DAS28-ESR, we noted better results with ritux-
Rituximabe
Placebo
Risk Ratio
Events Total Events Total Weight M-H, Random, 95% Cl Year
Study or subgroup
24 weeks
122 23.8%
134
245
DANCER [37]
34
1.96 [1.44, 2.67]
165 23.0%
131
242
REFLEX [39]
31
2.88 [2.08, 4.04]
118 25.6%
139
244
SUNRISE [43]
51
1.32 [0.98, 1.67]
405 72.3%
731
Subtotal (95% CI)
1.93 [1.07, 3.07]
Total events
404
116
Heterogeneity: Tau2 = 0.14; Chi2 = 15.21, df = 2 (P = 0.0005); I2 = 87%
Test for overall effect Z = 2.78 (P < 0.005)
52 weeks
IMAGE [29]
181
224
145
Subtotal (95% CI)
224
Total events
181
145
Heterogeneity: does not apply
Test for overall effect Z = 3.94 (P < 0.0001)
227
227
27.7%
27.7%
Risk Ratio
M-H, Random, 95% Cl
1.26 [1.13, 1.42]
1.26 [1.13, 1.42]
Total (95% CI)
955
632 100.0%
1.71 (1.19, 2.48]
Total events
585
261
2
2
2
Heterogeneity: Tau = 0.12; Chi = 30.69, df = 3 (P = 0.00001); I = 90%
0.1
0.2
0.5
Test for overall effect Z = 2.86 (P < 0.004)
Favours placebo+MTX
Test for subgroup differences: Ch2 = 3.00, df = 1 (P = 0.08), I2 = 66.7%
Rituximabe
Placebo
Risk Ratio
Events Total Events Total Weight M-H, Random, 95% Cl
24 weeks
21 27.2%
30
63
DANCER [37]
12
0.83 [0.53, 1.31]
44 15.9%
27
66
REFLEX [39]
5
3.60 [1.50, 8.63]
39 28.4%
32
74
SUNRISE [43]
19
0.89 [0.59, 1.34]
104 71.4%
203
Subtotal (95% CI)
1.25 [0.61, 2.57]
Total events
89
36
Heterogeneity: Tau2 = 0.32; Chi2 = 10.61, df = 2 (P = 0.005); I2 = 81%
Test for overall effect Z = 0.61 (P < 0.54)
B. Study or subgroup
52 weeks
IMAGE [29]
17
24
14
Subtotal (95% CI)
24
Total events
17
14
Heterogeneity: does not apply
Test for overall effect Z = 0.52 (P = 0.061)
22
22
28.6%
28.6%
Year
1
2
5
10
Favours rituximab+MTX
Risk Ratio
M-H, Random, 95% Cl
2006
2006
2010
1.11 [0.71, 1.67] 2010
1.11 [0.71, 1.67]
Total (95% CI)
227
126 100.0%
1.16 [0.73, 1.85]
Total events
106
50
2
2
2
Heterogeneity: Tau = 0.15; Chi = 10.42, df = 3 (P = 0.02); I = 71%
Test for overall effect Z = 0.64 (P < 0.52)
Test for subgroup differences: Ch2 = 0.08, df = 1 (P = 0.78), I2 = 0%
0.1 0.2
0.5
Favours placebo+MTX
1
5
10
2
Favours rituximab+MTX
Fig. 4 – Forest-plot depicting the responses of the American College of Rheumatology ACR20 (20% improvement) of
rituximab versus placebo. A. RF-positive patients. B. RF-negative patients.
228
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0
imab. Remission and low disease activity were reported by
three trials, despite all other trials also measured disease activity by DAS28-ESR.27,30,41 These measures were achieved after
52 weeks of treatment for newly diagnosed patients.27
The prevention or minimization of the progression of joint
damage is a mainstay RA treatment; however, only IMAGE27
and REFLEX39 performed an analysis of radiographic progression, and in both trials the participants who used rituximab
achieved better results versus placebo after 104 weeks. We
need more trials to strengthen the results of radiographic
progression.
In this review we observed that the favourable results with
rituximab according to ACR were more expressive in the trial
that studied patients with less than one year of diagnosis,27
which confirms the recommendations of ACR7 and EULAR8
current guidelines, pointing to the fact that the treatment of
RA will be more effective if started early.
SUNRISE41 was responsible for high heterogeneity in various analyses. In this trial, patients who did not achieve remission with an application of rituximab were randomized
to re-treatment from 24th week. This trial showed benefits
of rituximab versus placebo in all parameters measured, but
the results were less significant than those shown by the
other included trials. The authors reported that patients who
achieved ACR20, ACR50 and ACR70 after the first application
of rituximab were more likely to maintain its gains or improve
with re-treatment with rituximab. On the other hand, patients who did not achieve such measures were not benefited
with the second drug application.
Emery et al.42 conducted a joint analysis of three RCTs and
its extensions – SERENE30 and MIRROR,43 with 43 participants
re-treated to achieve clinical remission (Treat to Target – TT)
(n = 236), and DANCER,35 and patients re-treated when necessary (RWN) (n = 257). The groups were homogeneous with
respect to basal data, with the exception of disease duration,
that was 3.6 and 8.5 years, respectively. Both groups have
evolved to improve at every application of rituximab; however, patients in TT group achieved better results than participants RWN, regarding HAQ-DI and DAS-28. In addition, during
the first four applications of rituximab, more patients discontinued the trial in RWN group compared to TT group, mainly
due to an insufficient therapeutic response.
In general, rituximab in association with MTX proved to be
as safe as MTX. Acute infusion reaction was the most common
event and was more frequent in rituximab group compared to
placebo, but only in the first infusion. Van Vollenhoven et al.44
conducted a joint analysis of six RCTs (SERENE,30 DANCER,35
REFLEX,37 SUNRISE,41 MIRROR43 and SIERRA45), including extensions of open phase DANCER and REFLEX trials, and demonstrated that the overall incidence was 359.6 adverse events
per 100 patients-year (95% CI 354.4-364.9). The AE rate was
higher after the first application, falling to 329.44 events per
100 patient-years (320.59-338.53) after the second application,
remaining stable until the subsequent five years of monitoring. The most common event detected was an acute infusion
reaction, occurring in 25% of participants. Other AEs occurring in ≥ 10 % of the assessed population were infections, not
including RA exacerbations. In this review, the mortality rate
was 0.6 per 100 patient-years, and there were no deaths due
to infusion reactions.
Loss of participants is critical in epidemiological trials,
since the analysis, even if done by intention to treat, may be
compromised. In the included RCTs, generally the losses did
not exceed 20% and total loss and loss due to lack of efficacy
were higher in placebo group compared to rituximab. The loss
rates for EA were not different between groups.
Finckh et al.46 conducted a prospective cohort trial to assess which subset of patients with RA and with anti-TNF
failure obtain benefit with the exchange for rituximab versus
exchange for another anti-TNF agent. Blom et al.47 evaluated a
retrospective cohort of patients who had failed with two antiTNF agents and who were treated with a third anti-TNF drug
(n = 64), or with rituximab (n = 90). These authors concluded
that patients using rituximab obtained better results with
respect to disease activity versus patients using anti-TNF
agent.46,47 Both trials concluded that in case of failure with
an anti-TNF treatment, the introduction of a biological agent
with different mechanism of action, such as rituximab, would
be the best conduct, increasing the efficacy of rituximab as
third-line treatment.
Current guidelines from ACR for RA have established, as
an alternative, the use of rituximab if the patient exhibits
low activity associated with a poor prognosis, or moderate/
high activity.7 Current guidelines from EULAR recommend the
use of rituximab only after a failure with anti-TNF, despite
reiterating that the approval of rituximab for use as a second
line option has been discussed in Europe.8 The results of this
trial point to a possible benefit of rituximab for patients naïve to anti-TNF. However, these findings should be evaluated
with caution, since we could not find any RCT to evaluate the
exchange by an anti-TNF, after failure of rituximab. The possibility of use of rituximab as a second line drug and of an
anti-TNF as a third drug needs to be more deeply evaluated.
Data from IMAGE,27 DANCER,35 REFLEX,37 and SUNRISE41
were used in subgroup analysis for seropositivity; we observed
a trend towards greater efficacy of rituximab, compared to
placebo, in the subgroup FR+ and/or anti-CCP+; however, the
observed heterogeneity was high. In any case, we used the
method of random effects, which may have underestimated
differences between groups. The predictive value of assessment of seropositivity needs to be further explored in future
clinical trials, as well as the role of other biomarkers that may
be useful for deciding on the best treatment to be used for
each specific type of patient.
This RS has some limitations. The possibility of selection
bias could not be excluded from most trials. Moreover, all included trials were funded by pharmaceutical industry, which
may have led to an overestimation of the results. Systematic
reviews showed that industry-funded trials tend to show favourable results for its products, compared to not funded trials.48,49
An inherent limitation of clinical trials, which is reflected
in this RS, is the fact that they were conducted in carefully
selected populations. Thus, the profile of patients does not
reflect the reality, especially in relation to treatment adherence (since these patients are followed more strictly) and to
comorbidities, since they exclude patients with multiple comorbidities. Depression, hypertension and diabetes, for example, negatively influence the quality of life, functionality,
results and prognosis of subjects with RA.50
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0
Moreover, the analysis of which type of participant would
be more benefited with the use of rituximab is not conclusive,
since few trials within each group (MTX-naïve and anti-NPTnaïve) were included. In general, the efficacy analyses were
heterogeneous. Nevertheless, it was possible to assess the direction of the effect that showed benefit with the use of rituximab in all outcomes assessed.
Conclusion
The trials included in this RS showed that rituximab is effective and safe compared to placebo for the treatment of RA,
particularly in patients with a recent diagnosis. The effectiveness was also observed both in naïve patients to anti-TNF as
in those whose treatment with these agents had failed. The
use of rituximab was well tolerated by all patient subtypes.
More trials are needed to evaluate the role of RF and anti-CCP
antibody in predicting success in the treatment of RA with
rituximab, but there is indication that RF+ and anti-CCP+ patients exhibit a better response to this biological agent.
Conflicts of Interest
Coauthor Adriana Maria Kakehasi declares conflict of interest, as she received education grant from Abbott.
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47. Blom M, Kievit W, Donders AR, den Broeder AA, Straten VH,
Kuper I et al. Effectiveness of a third tumor necrosis factorα-blocking agent compared with rituximab after failure of 2
TNF-blocking agents in rheumatoid arthritis. J Rheumatol.
2011;38:2355-2361.
48. Bero L, Oostvogel F, Bacchetti P, Lee K (2007) Factors
associated with findings of published trials of drug–drug
comparisons: why some statins appear more efficacious
than others. PLoS Med. 2007; 4:e184. doi:10.1371/journal.
pmed.0040184.
49. Lexchin J, Bero LA, Djulbegovic B, Clark O (2003)
Pharmaceutical industry sponsorship and research
outcome and quality: systematic review. BMJ. 2003;326:1167.
doi:10.1136/bmj.326.7400.1167.
50. Michaud K and Wolfe F. Comorbidities in rheumatoid
arthritis. Best Pract. Res. Clin. Rheumatol. 2007;21:885-906.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 1 – 2 3 3
REVISTA BRASILEIRA DE
REUMATOLOGIA
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Case report
IgA nephropathy and polymyositis: a rare association
Thiago Bitar Moraes Barrosa, Fernando Henrique Carlos de Souzaa,
Denise Maria Avancini Costa Malheirosb, Mauricio Levy-Netoa, Samuel Katsuyuki Shinjoa,*
Service of Rheumatology, Hospital das Clínicas, Medicine Faculty, Universidade de São Paulo, São Paulo, SP, Brazil
Service of Pathology, Hospital das Clínicas, Medicine Faculty, Universidade de São Paulo, São Paulo, SP, Brazil
a b article info
abstract
Article history:
Polymyositis is a systemic and idiopathic inflammatory myopathy that, besides muscle
Received on 30 November 2012
manifestation, may occur with respiratory involvement, gastrointestinal tract and rarely
Accepted on 30 November 2012
renal involvement. In this latter, there are only two cases of IgA nephropathy, but both in
dermatomyositis. On the other hand, we reported, for the first time, a case of IgA nephro-
Keywords:
pathy in polymyositis.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
Inflammatory myopathy
All rights reserved.
IgA nephropathy
Polymyositis
Case report
Nefropatia por IgA e polimiosite: uma rara associação
resumo
Palavras-chave:
A polimiosite é uma miopatia inflamatória idiopática sistêmica que, além da manifestação
Miopatia inflamatória
muscular, pode eventualmente cursar com acometimento respiratório, do trato gastrintes-
Nefropatia por IgA
tinal e, raramente, renal. Neste último caso, há descrição de apenas dois casos de nefro-
Polimiosite
patia por IgA em pacientes com miopatia, ambos em dermatomiosite. Em contrapartida,
Relato de caso
relatamos pela primeira vez esta rara associação em polimiosite.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Polymyositis is classified within the spectrum of idiopathic
inflammatory myopathies, together with dermatomyositis.
It is clinically characterized by progressive proximal muscle
weakness of the limbs, leading to high morbidity and functional disability.
Among the extramuscular manifestations found, the most
common are the respiratory and gastrointestinal involvement
respiratory and of gastrointestinal tract involvement.1,2 Renal involvement in polymyositis is uncommon, with rare descriptions
of nephropathy associated with acute tubular necrosis secondary to rhabdomyolysis and chronic glomerulonephritis.3-9
IgA nephropathy is a primary glomerulonephritis characterized by IgA deposits in the mesangial area of glomeruli.
* Corresponding author.
E-mail: [email protected] (S.K. Shinjo).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2012.11.001
232
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 1 – 2 3 3
Approximately one-third of patients with this type of renal manifestation progresses to chronic renal failure after 20-25 years
of disease.10 Among the systemic diseases, IgA nephropathy is
most commonly associated with Henoch-Schönlein purpura.11
However, its association with idiopathic inflammatory myopathies is extremely rare, with only two cases described, both in
dermatomyositis,12,13 which motivated us to present this case.
Clinical case
Male patient, 35 years-old, white, trader, born in São Paulo.
Previously healthy, presented six months ago with progressive proximal muscle weakness of all four limbs without apparent cause and without constitutional symptoms. When
the patient came to our hospital service, the physical examination showed grade III proximal muscle strength in all four
limbs without skin lesions and/or involvement of other organs, such as lung or kidney. Laboratory tests showed serum
creatine kinase (CK) = 3,545 IU/L (normal range: 24-204 IU/L),
aldolase = 33 IU/L (reference value: 7.5 < IU/L), antinuclear factor and anti-Jo-1 negative, C-reactive protein = 7.8 µg/mL (reference value: < 5 µg/mL), erythrocyte sedimentation rate = 17
mm/1st hour (reference value: < 10 mm/1st hour), electroneuromyography suggestive of proximal inflammatory myopathy
of all limbs without evidence of associated neuropathy. The
muscle biopsy (biceps brachii) revealed the presence of an
endomysial and perimysial inflammatory infiltrate and also
necrosis of the muscle fibers and macrophage invasion, thus
suggesting inflammatory myopathy. During the clinical investigation, neoplastic and metabolic causes were ruled out.
With the presumptive diagnosis of polymyositis, according to the criteria of Bohan and Peter,14 corticosteroids (prednisne 0,5mg/kg/day) and methotrexate (maximum dose
20 mg/week) were initiated. After six months of treatment,
the patient developed acute lung injury secondary to pneumopathy requiring endotracheal intubation and mechanical
ventilation for three weeks. Infection and/or disease activity were discarded. In face of the possibility of lung disease
secondary to methotrexate, this medication was discontinued, and the prednisone dose was optimized. The patient
developed progressive pulmonary improvement without
sequelae. Subsequently, as a steroid sparing drug, azathioprine was introduced (maximum dose of 3 mg/kg/day). Due
to the stability of the disease and to the pulmonary improvement, the dose of prednisone (which at that time was 0.2
mg/kg/day) was gradually reduced. However, with no apparent cause the patient began to show macroscopic hematuria, edema of lower limbs (2+/4+) without hemodynamic and
pressure repercussion. The laboratory examination showed:
urinalysis with pyuria (> 100 leukocytes/field), hematuria
(> 100 erythrocytes/field), moderate erythrocyte dysmorphism
and lipoid casts; 24h-proteinuria = 1.76 g, serum albumin = 3.6
g/dL, serum creatinine = 0.9 mg/dL and negative urine culture. There was no sign of clinical-laboratorial activity of PM
at that time.
We decided then to perform a renal biopsy which showed
14 glomeruli with diffuse segmental endocapillar cell proliferation. One glomerulus showed one cellular crescent and
two fibroblastic crescents. Moreover, the glomerulus exhib-
ited mild tubulointerstitial change, focal tubular atrophy and
interstitial fibrosis. An interlobular artery showed intimal fibrosis. Immunofluorescence showed diffuse deposits of only
IgA in the mesangial region and in the peripheral capillary
wall of the glomerulus (fig. 1), suggestive of IgA nephropathy.
The dose of prednisone (0.2 mg/kg/day) was maintained,
azathioprine was discontinued, and monthly cyclophosphamide (0.75 mg/m2, IV) was initiated for 12 months; with the
patient achieving complete remission of the renal disease.
disease. Subsequently, as a maintenance drug, azathioprine
was reintroduced (maximum dose of 2.5 mg/kg/day). Currently, the patient denotes stability, both from the point of
view of polymyositis as of nephropathy, and without corticosteroid therapy.
Discussion
To our knowledge, this is the first case in the literature that
reports an IgA nephropathy in idiopathic inflammatory myopathy, particularly polymyositis.
A
B
Fig. 1 – Renal biopsy
(A) Optical microscopy. A glomerulus with diffuse
proliferative glomerulonephritis. PAS staining,
(B) Immunofluorescence demonstrating diffuse IgA deposit
in mesangial region and the peripheral capillary wall of the
glomerulus.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 1 – 2 3 3
Renal involvement in idiopathic inflammatory myopathy
is uncommon, including acute tubular necrosis and glomerulonephritis.3-9 In the latter case, Takizawa et al.4 demonstrated
by renal biopsy in a series of 21 cases of dermatomyositis/
polymyositis, that the presence of nephritis was associated
with membranous and proliferative mesangial glomerulonephritis, respectively, in polymyositis and dermatomyositis.
The relationship between IgA nephropathy and idiopathic
inflammatory myopathies is extremely rare. To date, there are
only two case reports, both occuring in dermatomyositis.12,13
Civilibal et al.13 reported a case of newly diagnosed juvenile
dermatomyositis, with hematuria and nephrotic proteinuria
in course, without loss of kidney function. A percutaneous renal biopsy allowed the diagnosis of IgA nephropathy. There
was a favourable response both from the point of view of inflammatory myopathy as of nephropathy, with the maintenance of methotrexate associated with oral corticosteroids.
On the other hand, Yen et al.12 described a young woman who
developed IgA nephropathy after 1.5 years of an established
diagnosis of dermatomyositis while using both azathioprine
and corticosteroids.
Unlike these two cases, in the present trial we present a
male patient with confirmed diagnosis of polymyositis. However, like the case reported by Yen et al.,12 the patient had been
using corticosteroids and immunosuppressive medication,
when evolved with renal dysfunction after 1.5 years, being
subsequently diagnosed with IgA nephropathy.
The association between dermatomyositis and IgA nephropathy is plausible, since both diseases share the involvement of humoral immunity (immunecomplexes).3,15 On the
other hand, the relationship with polymyositis is remote, because in the latter case there is a predominance of cellular
immunity. Thus, in the present clinical case, we strongly suggest the existence of two distinct morbidities.
In short, to our knowledge, we reported for the first time a
case of IgA nephropathy in a patient with polymyositis.
Conflicts of interest
The authors declare no conflicts of interest.
233
REFERENCES
1. Marie I, Hachulla E, Cherin P, Dominique S, Hatron PY,
Devulder B et al. Interstitial lung disease in polymyositis and
dermatomyositis. Arthritis Rheum. 2002;47:614-22.
2. de Merieux P, Verity MA, Clements PJ, Paulus HE. Esophageal
abnormalities and dysphagia in polymyositis and
dermatomyositis. Arthritis Rheum. 1983;26:961-8.
3. Yen TH, Lai PC, Chen CC, Hsueh S, Huang JY. Renal involvement
in patient with polymyositis and dermatomyositis. Int J Clin
Pract. 2005;59:188-93.
4. Takizawa Y, Kanda H, Sato K, Kawahata K, Yamaguchi A,
Uozaki H et al. Polymyositis associated with focal mesangial
proliferative glomerulonephritis with depositions of immune
complexes. Clin Rheumatol. 2007;26:792-6.
5. Dyck RF, Katz A, Gordon DA, Johnson M, Shainhouse Z, Cardella
CJ et al. Glomerulonephritis associated with polymyositis.
J Rheumatol. 1979;6:336-44.
6. Pirovino M, Neff MS, Sharon E. Myoglobulinuria and acute renal
failure with acute polymyositis. NY State J Med. 1979;79:764-7.
7. Tsunemi M, Ishimura E, Tsumura K, Shoji S, Sugimura T,
Nishizawa Y et al. A case of crescentic glomerulonephritis
associated with polymyositis. Nephron. 1993;64:488-9.
8. Valenzuela OF, Reiser IW, Porush JG. Idiopathic polymyositis and
glomerulonephritis. J Nephrol. 2001;14:120-4.
9. Makino H, Hirata K, Matsuda M, Amano T, Ota Z. Membranous
nephropathy developing during the course of dermatomyositis.
J Rheumatol. 1994;21:1377-8.
10. D’Amico G. Natural history of idiopathic IgA nephropathy: role
of clinical and histological prognostic factors. Am J Kidney Dis.
2000;36:227-37.
11. Sanders JT, Wyatt RJ. IgA nephropathy and Henoch-Schönlein
purpura nephritis. Curr Opin Pediatr 2008;20:163-70.
12. Yen TH, Huang JY, Chen CY. Unexpected IgA nephropathy
during the treatment of a young woman with idiopathic
dermatomyositis: case report and review of the literature.
J Nephrol. 2003;16:148-53.
13. Civilibal M, Selcuk Duru N, Ozagari A, Durali K, Elevli M.
Immunoglobulin A nephropathy associated with juvenile
dermatomyositis. Pediatr Nephrol. 2009;24:2073-5.
14. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl
J Med. 1975;292:344-7.
15. Yen TH, Huang JY, Chen CY. Unexpected IgA nephropathy
during the treatment of a young lady with idiopathic
dermatomyositis. Case report and review of the literature.
J Nephrol. 2002;16):148-53.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 4 – 2 3 6
REVISTA BRASILEIRA DE
REUMATOLOGIA
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Case report
Spondyloptosis in athlete
Ana Paula Luppino Assad*, Andressa Silva Abreu, Luciana Parente Costa Seguro,
Lissiane Karine Noronha Guedes, Fernanda Rodrigues Lima, Ana Lucia de Sá Pinto
Rheumatology, Hospital das Clínicas, Medicine School, Universidade de São Paulo, São Paulo, SP, Brazil
article info
abstract
Article history:
The adolescent athletes are at greater risk of low back pain and structural spine injuries.
Received on 20 May 2012
Spondylolysis is responsible for the majority of back pain cases in young athletes, rarely
Accepted on 30 November 2012
occurring in adults. We report a case of a 13-year-old judo female athlete, who came to
our service with 5 months of progressive low back pain during training which was initially
Keywords:
attributed to mechanical causes, without any further investigation by imaging methods.
Spondyloptosis
At admission, the patient had lumbar deformity, antalgic posture and bilaterally positive
Spondylolysis
unipodalic lumbar hyperextension maneuver. After a research which showed spondylopto-
Low back pain
sis, the patient underwent surgery. In this article, we discuss, based on this case report, the
Teenager
diagnostic approach to low back pain in young athletes, since the complaint of chronic back
Ahtlete
pain can be a marker of a structural lesion that may be permanent and bring irreversible
functional loss.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
Espondiloptose em atleta
resumo
Palavras-chave:
Os atletas adolescentes estão sob maior risco de lombalgia e lesões estruturais da coluna.
Espondiloptose
A espondilólise é responsável pela maioria das lombalgias em jovens esportistas e rara-
Espondilólise
mente ocorre em adultos. Relatamos o caso de uma paciente de 13 anos, atleta de judô, que
Lombalgia
chegou a nosso serviço com quadro de cinco meses de lombalgia progressiva durante os
Adolescente
treinos, sendo inicialmente atribuída a causas mecânicas, sem que houvesse uma investi-
Atleta
gação mais detalhada por métodos de imagem. Na admissão já apresentava deformidade
lombar, postura antálgica e manobra de hiperextensão lombar em unipodálico positiva
bilateralmente. Realizou-se investigação, que evidenciou espondiloptose, sendo, então,
submetida a tratamento cirúrgico. Com base neste relato de caso, discutimos a abordagem
diagnóstica de lombalgia em atletas jovens, uma vez que a queixa de lombalgia crônica
pode ser marcador de uma lesão estrutural, a qual pode ser definitiva e trazer perda funcional irreversível.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
* Corresponding author.
E-mail: [email protected] (A.P.L. Assad).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2012.11.002
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 4 – 2 3 6
Introduction
Low back pain is a very common complaint among adolescents. Among the athletes, there is a higher prevalence of
pain and an increased risk of structural damage.1 The sports
gesture is related to the development of joint lesions, for example, repetitive movements of extension and rotation are
associated with lesions of the posterior column, such as
spondylolysis.2
There is a tendency to associate low back pain of the athlete to mechanical factors.3 Among differential diagnoses,
disc disease, muscle contracture, and constitutional deformities like scoliosis and lumbar lordosis should be considered.
Furthermore, it is important to rule out inflammatory diseases that may go unnoticed when there are no other peripheral
symptoms.3,4
In children and teen athletes, the aetiology of low back
pain is different from the causes of adult low back pain.5
Spondylolysis is responsible for the majority of back pain
cases in young athletes, and rarely occurs in the adult ones.6
The patient’s complaint must be taken into consideration.
The history and physical examination are important to establish the underlying cause of low back pain; but imaging
studies may be crucial for an early diagnosis and treatment,
preventing irreversible structural damage and disadvantage
to the daily activities and sports practice.6,7
Case report
JCT, 13, female, born and raised in Mogi das Cruzes city, student and judo athlete for seven years.
The patient came to the Outpatient Sports Medicine Service, Discipline of Rheumatology, HC-FMUSP, complaining of
back pain for five months. She referred back pain associated
with local tumor five months ago. In the beginning of the clinical manifestation, the pain appeared only during her training
activities and had no irradiation, but evolved with pain during resting periods and radiating to the posterior aspect of
the right leg. The patient had no improvement of the picture
with use of nonsteroidal anti-inflammatory agents, as well as
with analgesic measures (thermotherapy and electrotherapy)
performed in the Physical Therapy Department. However, the
girl did not stop her practice, despite the pain.
There was no history of trauma, night pain, fever, asthenia, weight loss, sensory or motor changes in lower limbs or
sphincter alterations, use of supplements or steroids, or any
other morbidity.
She practiced judo competitively for seven years, was an
orange belt, performed physical conditioning with strength
exercises and stretching for an hour, and specific training for
two hours, four times a week.
On physical examination, the patient was in good general
condition, with weight of 45 kg and height of 155 cm, with cardiovascular, pulmonary and abdominal examinations without changes. At musculoskeletal examination, the patient
had an antalgic posture while sitting, wore her arms as support for the weight of the trunk, with postural deviation in antalgic scoliosis, accentuation of physiological lumbar lordosis
235
and with a bone tumour at L5 (Fig. 1). At palpation, we found
painful contracture of the paraspinal musculature. The pain
was triggered by lateralization movement of the trunk, and
lumbar rotation and hyperextension. The unipodalic lumbar
hyperextension maneuver was positive bilaterally.
After a diagnostic hypothesis of spondylolisthesis, we requested imaging studies (Fig. 2) which showed high-grade
spondylolisthesis, or also classified as spondyloptosis.
The patient was symptomatically treated, instructed to
rest and referred to the care of Neurosurgery, which indicated
reduction and fixation of L5-S1.
Discussion
Low back pain is very common in athletes, with an estimated
prevalence of up to 45%, while in non-athletes the prevalence
is 18%.2
Numerous athletes exhibit mechanical low back pain secondary to muscle spasm and ligament injuries. In adults, the
main causes of pain are disc herniation, vertebral body fracture, spinal canal stenosis and degenerative diseases.3
In young patients, although the major cause of low back
pain has muscle origin, some clinical aspects must be considered, as night pain, pain after trauma, hyperextension pain,
presence of a specific painful spot, or any neurologic finding.8
In adolescents, muscle imbalance, incomplete ossification
of the pars articularis, and inadequate training are the risk factors involved in the development of spinal lesions.9 In these
Fig. 1 – Bone tumor topography of L5.
Fig. 2 – Plain radiography with total slippage of L5 on S1, not
reducible with the position (A: neutral, B: in flexion, C: in
extension, D: MRI of vertebral column with spondyloptosis
of L5 on S1, with stenosis of the spinal canal).
236
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 4 – 2 3 6
young athletes, the most common structural change is spondylolysis, i.e., a pars articularis fracture.3,5,8 Spondylolysis is responsible for 47% of all back pain in this population, while in
adults the diagnosis appears in only 5% of cases.10
The athletes with higher risk of developing spondylolysis
and spondylolisthesis are those who practice repetitive spine
extension, flexion and rotation movements, for instance,
practitioners of artistic gymnastics, skating, hockey and soccer players.2 The present case report patient practiced judo,
which involves performing such movements.
The spondylolysis may be asymptomatic, except in the
acute phase of fracture. The patient can present with hyperlordotic posture, and his/her back pain can be reproduced by
hyperextension and rotation of the spine, a maneuver easily
reproducible and that was positive in the present case.6
After spondylolysis, there is an increased risk of an anterior vertebral slip over another – this is called spondylolisthesis. The greatest instability phase occurs during the growth
spurt in adolescence.11
The spondylolisthesis is classified into five grades, with
grade I occurring when there is 25% slippage; grade II, 50 %;
grade III, 75 %; grade IV, 100%; and grade V, also called spondyloptosis, when a total slippage of L5 on S1 occurs.
The symptoms depend on the degree of slip, and can range
from an asymptomatic patient to back pain, with neurological
symptoms associated.
The prevention of injury in young athletes is crucial. This
prevention must be taken with the reversal of risk factors,
such as muscle shortening and imbalance, and the use of incorrect techniques during training. An abrupt change in training volume during the growth spurt should also be considered
as a risk factor.9
In our case, the patient already had pain with five-month
length during workouts, without further investigation by imaging methods that could rule out a possible structural damage or even a recommendation of cessation of training. This
combination of factors certainly contributed to delay in the
diagnosis of spondylolysis, and resulted in the evolution of
the injury to spondyloptosis.
The investigation of spondylolysis by imaging studies
should be done with a request of plain radiography in three
positions, showing the defect in the pars interarticularis (Scotty
dog sign), but with low sensitivity. Computed tomography
(CT) is the gold standard for diagnosis. SPECT can be used to
evaluate the activity of the lesion.6
Bone scintigraphy is recommended for patients with low
back pain, because of its high sensitivity. A CT-scan may be
indicated, when the scintigraphy results positive, to define if
the hypercaptation aetiology represents pars articularis fracture or bone stress reaction, and helps define the degree and
chronicity of the fracture.11,12 MRI is less sensitive than CT for
assessing bone injury, but it can help to assess whether the
injury is acute, when it identifies a local oedema.1,12
When there is suspicion of spondylolisthesis, magnetic
resonance imaging (MRI) or computed tomography (CT) for
evaluating stenosis of the spinal canal and foramina is indicated.6
In our case, we chose to perform MRI due to signs of neurological involvement and the time course of the complaint.
The treatment of spondylolisthesis is controversial. Therapeutic modalities include rest and sometimes orthopaedic
corsets, aiming to avoid hyperextension of the spine. Surgical arthrodesis is indicated for pain refractory to conservative
treatment, or in high-grade spondylolisthesis (slippage greater than 50%), especially in children or adolescents during the
growth spurt, due to the risk of progression and neurological
injury.13
It is expected that young athletes can return to sports activity after successful treatment, even in cases in which surgical treatment was necessary, with the exception of collision
sports,8 as in the case in question.
Therefore, in a teen athlete, it is always important to recognize and investigate the complaint of chronic low back pain
because this symptom may be a marker of a structural lesion
that may be permanent and bring irreversible functional loss.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES
1. Standaert JC. Low back pain in the adolescent athlete. Phys
Med Rehabil Clin N Am. 2008;19:287-304
2. Kujala UM, Taimela S, Erkintalo M, Salminen JJ, Kaprio J.
Low back pain in adolescent athletes. Med Sci Sports Exerc.
1996;28:165-70
3. Jennings F, Lambert E, Fredericson M. Rheumatic diseases
presenting as sports-related injuries. Sports Med.
2008;38:917-30
4. Carlson C. Axial back pain in the athlete: pathophysiology
and approach to rehabilitation. Curr Rev Musculoskelet Med.
2009;2:88-93
5. Baker RJ, Patel D. Lower back pain in the athlete: common
conditions and treatment. Prim Care. 2005;32:201-29
6. Melenger AL, Krivickas LS. Neck and back pain:
Musculoskeletal Disorders. Neurol Clin, 2007;25:419-38
7. Gurd DP. Back pain in the young athlete. Sports Med Arthrosc.
2011;19:7-16
8. Sucato DJ, Micheli LJ, Estes AR, Tolo VT. Spine problems in
young athletes. Instr Course Lect.2012; 61:499-511
9. Purcell L. Causes and prevention of low back pain in young
athletes. Paediatr Child Health. 2009;14:533-8
10. Mohriack R, Silva PDV, Trandafilov MJ, Martins DE,
Wajchenberg M, Cohen M et al. Espondilólise e
espondilolistese em ginastas jovens. Rev Bras Ortop.
2010;45:79-83
11. Zoner CS, Amaral DK, Natour J, Fernandes ARC. Contribuição
dos métodos de diagnóstico por imagem na avaliação da
espondilólise. Rev Bras Reumatol. 2006;46:287-91
12. Masci L, Pike J, Malara F, Phillips B, Bennell K, Brukner P.
Use of the onelegged hyperextension test and magnetic
resonance imaging in the diagnosis of active spondylolysis.
Br J Sports Med. 2006;40:940-6
13. Lonstein JE. Spondylolisthesis in children. Cause, natural
history, and management. Spine. 1999;24:2640
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0
REVISTA BRASILEIRA DE
REUMATOLOGIA
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Case report
First report of mild Brazilian spotted fever associated to
arthritis
Virgínia Lucia Nazario Bonoldia, Roberta Gonçalves Marangonia, Giancarla Gauditanoa,
Jonas Moraes-Filhob, Marcelo Bahia Labrunab, Natalino Hajime Yoshinaria,*
Department of Rheumatology, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
Faculty of Veterinary Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
a b article info
abstract
Article history:
We describe the first Brazilian case of mild Rickettsiosis, complicated by knee monoarthri-
Received on 15 February 2012
tis, in young adult bitten by a tick on his left leg in Camburi zone, located in São Sebastião
Accepted on 18 February 2013
municipality, southern coastal region of the State of São Paulo, in the Atlantic rainforest
region, Brazil. The patient developed inoculation eschar at the tick bite site associated with
Keywords:
enlarged lymph nodes in the left groin, fever, polyarthralgia, headache and macular rash.
Brazilian spotted fever
Twenty days after tick bite episode, he displayed monoarthritis in his right knee. The diag-
Mild rickettsiosis
nosis of mild Rickettsiosis was established by sequential immunological analysis in serum
Arthritis
and synovial fluid, using the indirect immunofluorescence (IF) assay for antibodies reactive
Infectious arthritis
with Rickettsia parkeri and Rickettsia rickettsii. The mild Rickettsiosis is an emerging zoonosis,
that must be investigated by physicians, including rheumatologists, in patients that present macular rash, fever and eventually arthritis, after visiting the southern coastal Atlantic rainforest region in Brazil.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
Primeiro caso de branda maculosa brasileira branda associada à artrite
resumo
Palavras-chave:
Descrevemos o primeiro caso brasileiro de Riquetsiose branda, agravada por monoartrite em
Febre maculosa brasileira
joelho, em adulto jovem picado por carrapato na perna esquerda na região de Camburi, lo-
Riquetsiose branda
calizada no município de São Sebastião, sul da região costeira do estado de São Paulo, Mata
Artrite
Atlântica, Brasil. O paciente apresentou uma escara de inoculação no local da picada do car-
Artrite infecciosa
rapato, associada ao aumento ganglionar em virilha esquerda, febre, poliartralgia, cefaleia
e erupção macular. Vinte dias após o episódio da picada de carrapato, o paciente apresentou monoartrite em joelho direito. O diagnóstico de Riquetsiose branda foi estabelecido pela
análise imunológica sequencial em amostras de soro e líquido sinovial, tendo sido empregada
a técnica de imunofluorescência (IF) indireta para anticorpos reativos contra Rickettsia parkeri
e Rickettsia rickettsii. A Riquetsiose branda é uma zoonose emergente, que deve ser investigada
* Corresponding author.
E-mail: [email protected] (N.H. Yoshinari).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.02.002
238
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0
pelos médicos, incluindo reumatologistas, em pacientes que apresentem erupção macular,
febre e, eventualmente, artrite, após visita ao sul da região costeira da Mata Atlântica no Brasil.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Spotted fever caused by Rickettsia rickettsii is a serious zoonosis transmitted by ticks described in Americas, including in
Brazil.1 The disease can lead to death if not diagnosed and
treated at the onset of clinical symptoms.
Laboratory diagnosis is based on seroconversion of consecutive samples from acute and convalescent phases of the
disease using R rickettsii antigen. The clinical manifestations
of BSF begin about a week after the tick bite with fever, headache, abdominal pain and maculopapular rash. The disease
can progress to respiratory and renal complications, coagulation disorders and encephalitis. Due to the severity of the
illness, antibiotic treatment should be started quickly despite
laboratory analysis.1,2
Paddock et al. identified a new tick-borne Rickettsia of the
spotted fever group that causes disease. Patients exhibited
characteristic skin ulceration at the tick bite site (eschar), followed by maculopapular rash, fever, headache, myalgia and
arthralgia. However, the clinical picture is milder due to the
absence of coagulopathy.3 The etiologic agent was identified
as Rickettsia parkeri, which has a lot of genetic similarity with
R. conorii, R. africae and R. sibirica, species that cause similar
clinical symptoms in the Mediterranean region.4
In Brazil, the etiologic agent of the mild rickettsiosis was
identified in the skin lesion biopsy (eschar) of two patients.
The molecular studies demonstrated that this agent is genetically similar to R. parkeri, R. africae and R. sibirica.5,6 The present
study reports the discovery of the third case of mild rickettsiosis in Brazil, and importantly, for the first time, related to occurrence of monoarthritis following this rickettsial infection.
In Brazil, all three cases were described in the Atlantic Forest,
ecological complex with the occurrence of the Amblyomma
ovale tick infected with the etiologic agent.7
In the fourth week of therapy, prednisone (10 mg/day) was
prescribed associated with doxycycline due to the persistence
of arthritis. After 7 days of therapy, the arthritis worsened
with physical exercise and the prednisone was replaced by
sulfasalazine (1g/ 12/12h). After 3 months of therapy with sulfasalazine, the right knee monoarthritis remitted. Two samples
of blood and synovial fluid were collected (March 1st, 2011, and
March 15th, 2011); the first, after 10 days of antibiotic therapy,
the other, 15 days after this. Additional laboratory tests showed
alanine aminotransferase, alkaline phosphatase, aspartate
aminotransferase, creatinine phosphokinase, gamma glutamyl
transferase, lactic dehydrogenase, glucose, hemogram with
platelets counting, protein electrophoresis, urea, creatinine,
sodium, potassium and anti-streptolisin O levels within reference ranges. Tests for hepatitis B and C, cytomegalovirus, HIV
1 and 2, syphilis, Brazilian borreliosis and bartonellosis were
negative. IgE and C-Reactive Protein were increased, but levels
became normal with treatment. Two serum samples revealed
A
Case report
In February 2011, a 30-year-old man was bitten by a tick on
his left leg while walking on an ecological trail within Atlantic
rainforest area in Camburi, São Sebastião city, southern coastal
region of the State of São Paulo. After 7 days, he presented erythematous skin lesions with central ulceration (eschar) at the
tick bite site (Fig. 1a). After 10 days of the tick bite, he developed fever not measured, polyarthralgia (hands, elbows, wrists,
ankles), myalgia, neck pain, headache, nausea, enlarged lymph
nodes on the left groin and chills, followed by generalized rash
on the trunk and limbs. The patient sought medical care and,
based on suspicion of rickettsial disease, the physician prescribed doxycycline even before the laboratorial tests. After 10
days of treatment, general symptoms had improved, but the
doxycycline was continued due to the emergence of right knee
monoarthritis (Fig. 1b).
B
Fig. 1 – (A) Inoculation eschar on the left leg of a patient
with mild Brazilian spotted fever and acute knee
monoarthritis. (B) Acute monoarthritis in right knee of a
patient with mild Brazilian spotted fever, after a tick bite
episode occurred in the Atlantic rainforest, São Sebastião,
São Paulo State, Brazil.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0
presence of anti-nuclear antibodies (ANA), exhibiting a dense
fine speckled pattern on HEp-2 cells analysis (Table 1).
Paired samples of acute-phase and convalescent-phase of
blood sera and synovial fluids were evaluated under the same
conditions by IF assay for antibodies to R. parkeri and R. rickettsia. The samples were tested with a goat anti-human immunoglobulin (Ig) G for the first and second serum and synovial fluid
samples or a goat anti-human IgM fluorescein isothiocyanate
conjugate (Sigma Diagnostics, St. Louis, MO, USA) for samples
of acute-phase and convalescent-phase of synovial fluids and
a single convalescent-phase sample of serum.
In Table 1, we can see that the titles of the IgM to R. parkeri
and to R. rickettsii in synovial fluid showed increased antibody
reactivity between the first and second samples. Titers of IgG to
R. parkeri and R. rickettsii were always high in synovial fluid. The
IgG titles to rickettsial antigens were high in both sequential
samples of blood serum, but the IgG to R. parkeri showed an
increase in antibody title in blood serum samples.
Discussion and conclusions
We described the third Brazilian case of mild rickettsiosis, at
this time complicated with knee monoarthritis, which appeared
nearly twenty days after tick bite episode. Like the previously described two cases of mild rickettsiosis,5,6 the patient caught the
disease walking on ecological trail, within Atlantic rain Forest.
The specific serologic diagnostic tests for rickettsiosis, performed in serum and synovial fluid samples at acute and convalescent phases of disease confirmed the diagnosis. Moreover,
laboratorial investigations for other infectious diseases were
negative, including the possibility of co-infection with Lyme
like,8 which is transmitted by ticks and causes arthritis. Antinuclear antibodies positivity was not correlated with clinical
findings, and therefore, interpreted as an isolated phenomenon
Table 1 – Sequential Immunofluorescent (IF*) assays
(IgM and IgG) to detect antibodies against R. parkeri
and R. rickettsii in serum and synovial fluid samples.
C-Reactive protein, IgE and antinuclear antibodies
(ANA**) in serum samples of a patient with mild
Brazilian spotted fever and acute knee monoarthritis in
Brazil, 2011.
Serum
IF IgG
R. parkeri
IF IgM
R. parkeri
IF IgG
R. rickettsii
IF IgM
R. rickettsii
IgE (IU/ml)
PCR (mg/L)
ANA
Synovial fluid
March 1
March 15
March 1
March 15
1/1024
1/2048
1/2048
1/2048
-
-
1/256
1/512
1/1024
1/1024
1/2048
1/2048
-
-
1/128
1/256
1240
1,5
783
0,5
-
-
> 1/320
> 1/320
-
-
239
or related to rickettsial infection. The increased level of IgE was
understood as mast cell-dependent allergic response to the tick
bite. This hypothesis is plausible, since the IgE levels decreased
as the disease improved.
In patients with Mediterranean Spotted Fever disease,
caused by R. conorii, arthritis in large joints with joint effusion
in the hips, knees and ankles is described.9 Sundy et al. reported knee acute monoarthritis in patient with RMSF.10 Ding et
al. reported polyarthritis in the wrists, metacarpal phalangeal
and proximal interphalangeal joints in patient who acquired
the illness in travel to Africa, where the disease is caused by R.
parkeri or R. conorii.11
In the present case, the pathogenesis of knee monoarthritis
following mild rickettsiosis infection is uncertain. The joint effusion can result of direct articular infection by rickettsial microorganisms (infectious arthritis) or can reflect synovial inflammation triggered by immune complexes depositions (reactive
arthritis). The identification of rickettsial infection by molecular
procedures in the synovial fluid and eschar biopsy was inconclusive, because PCR was done lately when patient was treated
with doxycycline. We believe that arthritis viewed in this patient
is of reactive origin, since arthritis appeared late, nearly 20 days
from bacteria inoculation. Additionally, this period of time was
enough to produce specific antibodies to rickettsial components.
Outbreak of arthritis in the opposite leg of tick bite and uprising
of antinuclear antibodies are further evidences to suggest occurrence of immunological inflammatory arthritis.
In Rickettsia infection, the IgM and IgG serum levels increase
by the second week of illness, IgM antibodies wane after 3 or
4 months and IgG titers persist for 7 or 8 months.12 We noted
that despite the existence of cross-reactivity between rickettsial species,2 the IgG titer to R. parkeri increased, at least, 1-fold
higher in the serum, although it was a low increase in title,
which did not occur to R. rickettsii. We can see an increase in R.
parkeri IgM titer of paired synovial fluid specimens taken early
and later in the disease course, unlike in R. rickettsii, suggesting more IgM specificity to R. parkeri. In addition, the R. parkeri
rickettsiosis can be associated with the presence of an eschar
at the site of tick bite.3
High titers of IgM antibodies to rickettsial antigens in synovial fluid confirmed the etiology of knee acute arthritis.
We conclude that Brazilian spotted fever is not a single disease, because at least two pathogenic species of Rickettsia are
present in Brazil causing similar symptoms. The mild form of
the disease is reported in the region that attends the Atlantic
Forest and, as described in this current case report, may be associated to arthritis as a complication of systemic disease.
Conflicts of interest
The authors declare no conflicts of interest.
*IF Cut off = 1/64
**Dense fine speckled ANA pattern on HEp-2 cells analysis.
-: not evaluated.
REFERENCES
1. Labruna MB. Ecology of rickettsia in South America. Ann N Y
Acad Sci. 2009 May;1166:156-66.
2. Paddock CD, Finley RW, Wright CS, Robinson HN, Schrodt
BJ, Lane CC et al. Rickettsia parkeri rickettsiosis and its clinical
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7.
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distinction from Rocky Mountain spotted fever. Clin Infect Dis.
2008;47:1188-96.
Paddock CD, Sumner JW, Comer JA, Zaki SR, Goldsmith CS,
Goddard J et al. Rickettsia parkeri: a newly recognized cause of
spotted fever rickettsiosis in the United States. Clin Infect Dis.
2004 Mar 15;38:805-11.
Goddard J. Historical and recent evidence for close
relationships among Rickettsia parkeri, R. conorii, R. africae, and
R. sibirica: implications for rickettsial taxonomy. J Vector Ecol.
2009 Dez;34:238-42.
Spolidorio MG, Labruna MB, Mantovani E, Brandao PE,
Richtzenhain LJ, Yoshinari NH. Novel spotted fever group
rickettsiosis, Brazil. Emerg Infect Dis. 2010 Mar;16:521-3.
Silva N, Eremeeva ME, Rozental T, Ribeiro GS, Paddock CD,
Ramos EA, Favacho AR, Reis MG, Dasch GA, de Lemos ER, Ko
AI. Eschar-associated spotted fever rickettsiosis, Bahia, Brazil.
Emerg Infect Dis. 2011 Fev;17:275-8.
Sabatini GS, Pinter A, Nieri-Bastos FA, Marcili A, Labruna MB.
Survey of ticks (Acari: Ixodidae) and their rickettsia in an
Atlantic rain forest reserve in the State of São Paulo, Brazil. J
Med Entomol. 2010 Set;47:913-6.
8. Yoshinari NH, Mantovani E, Bonoldi VLN, Marangoni RG,
Gauditano G. Doença de Lyme-símile brasileira ou Síndrome
Baggio-Yoshinari: Zoonose exótica e emergente brasileira
transmitida por carrapatos. Rev Assoc Med Bras. 2010;56:3639.
9. Pedro-Botet J, Auguet T, Pallás O, Gimeno JL. Arthritis in
Mediterranean spotted fever. Infection. 1991 Set-Out;19:346-7.
10. Sundy JS, Allen NB, Sexton DJ. Rocky Mountain spotted fever
presenting with acute monoarticular arthritis. Arthritis
Rheum. 1996 Jan;39:175-6.
11. Ding T, Lloyd G, Tolley H, Bradlow A. Tick bite fever and
arthritis associated with travel to Africa. Ann Rheum Dis.
2004 Dez;63:1703-4.
12. Clements ML, Dumler JS, Fiset P, Wisseman CL Jr, Snyder MJ,
Levine MM. Serodiagnosis of Rocky Mountain spotted fever:
comparison of IgM and IgG enzyme-linked immunosorbent
assays and indirect fluorescent antibody test. J Infect Dis.
1983;148:876-80.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Brief communication
Patients with systemic lupus erythematosus and secondary
antiphospholipid syndrome have decreased numbers of
circulating CD4+CD25+Foxp3+ Treg and CD3– CD19+ B cells
Ester Rosári Raphaelli Dal Bena,*, Carine Hartmann do Pradoa,
Talita Siara Almeida Baptistaa, Moisés Evandro Bauer a, Henrique Luiz Staubb
a Laboratory of Immunosenescence, Institute of Biomedical Research, Faculty of Biosciences, Pontifícia Universidade Católica do Rio Grande do
Sul, Porto Alegre, RS, Brazil
b Rheumatology Department, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
article info
abstract
Article history:
Introduction: CD4+CD25+Foxp3+ regulatory T (Treg) cell depletion has been reported in sys-
Received on 20 May 2013
temic lupus erythematosus (SLE) and, recently, in primary antiphospholipid syndrome
Accepted on 16 September 2013
(APS); the issue has not been studied in SLE patients with secondary APS (SLE/APS) so far.
Objective: To quantify total lymphocytes, Treg cells, CD3+CD19– T cells and CD3–CD19+ B cells
Keywords:
in SLE/APS patients and healthy controls.
Systemic lupus erythematosus
Methods: Cell subtypes underwent immunophenotyping using specific monoclonal antibod-
Secondary antiphospholipid
ies (anti-CD3 CY5, anti-CD4 FITC, anti-CD25, anti-Foxp3, anti-CD19 PE) and flow cytometry.
syndrome
Results: Twenty-five patients with SLE/APS (mean age 43.5 years, 96% females, 96% cauca-
Treg cells
sians, mean duration of disease 9.87 years, mean SLEDAI 10 ± 5.77) and 25 age and sex-
CD3–CD19+ B cells
matched controls entered the study. It was realized that the numbers of Treg and CD3–
CD19+ B cells were significantly lower in SLE/APS patients than in controls (all p < 0.05). Treg
and CD3–CD19+ B cells remained numerically low after controlling (ANCOVA) for percentage
of total lymphocytes (p < 0.05). Decreasing levels of circulating Treg and CD3–CD19+ B cells
correlated to higher scores of lupus activity (rs = -0.75, p < 0.0001; rs = -0.46, p = 0.021, respectively). Number of Treg cells and CD3–CD19+ B lymphocytes did not significantly differ
in users or nonusers of chloroquine, azathioprine and corticosteroids (all p > 0.05).
Conclusions: In this preliminary study, patients with SLE and secondary APS showed depletion of Treg and CD3–CD19+ B cells; decreasing numbers of both subtypes correlated to a
higher SLEDAI. Treg cells depletion might contribute to the autoimmune lesion seen in
patients with SLE/APS. The reduced number of CD3–CD19+ B cells seen in these patients
deserves more studies in order to get further elucidation.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
* Corresponding author.
E-mail: [email protected] (E.R.R. Dal Ben).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.09.001
242
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6
Pacientes com lúpus eritematoso sistêmico e síndrome antifosfolípide
secundária possuem números reduzidos de células B CD4+ CD25+
Foxp3+ (células Treg) e células B CD3– CD19+ circulantes
resumo
Palavras-chave:
Introdução: A depleção de células T CD4+ CD25+ Foxp3+ regulatórias (células Treg) foi des­crita
Lúpus eritematoso sistêmico (LES)
em pacientes com lúpus eritematoso sistêmico (LES) e, recentemente, na síndrome antifosfo-
Síndrome antifosfolípide
lípide (SAF) primária; até o momento, o tópico não tinha sido estudado em pacientes com LES
secundária (SAFS)
e com SAF secundária (LES/SAFS).
Células Treg
Objetivo: Quantificar linfócitos totais, células Treg, células T CD3+ CD19– e células B CD3– CD19+
Células B CD3– CD19+
em pacientes com LES/SAF e em controles saudáveis.
Métodos: Subtipos celulares foram imunofenotipados utilizando anticorpos monoclonais específicos (anti-CD3CY5, anti-CD4FITC, anti-CD25, anti-Foxp3, anti-CD19PE) e citometria de fluxo.
Resultados: Participaram do estudo 25 pacientes com LES/SAF (média de idade 43,5 anos, 96%
mulheres, 96% da raça branca, duração média da doença 9,87 anos, SLEDAI médio 10±5,77) e
25 controles compatibilizados para idade e gênero. Foi constatado que os números de células
Treg e de células B CD3– CD19+ estavam significativamente mais baixos em pacientes com LES/
SAF, em comparação com controles (todos p<0,05). As células Treg e as células B CD3- CD19+
permaneceram numericamente baixas em seguida ao controle (ANCOVA) para percentual de
linfócitos totais (p<0,05). Níveis decrescentes de células Treg e células B CD3- CD19+ circulantes
tiveram correlação com escores mais elevados de atividade lúpica (rs=-0,75, p<0,0001; rs=-0,46,
p=0,021, respectivamente). Os números de células Treg e de células B CD3- CD19+ não diferiam
significativamente em usuários ou não usuários de cloroquina, azatioprina e corticosteroides
(todos p>0,05).
Conclusões: Nesse estudo preliminar, pacientes com LES e com SAF secundária demonstraram
depleção de células Treg e de células B CD3- CD19+; a redução numérica dos dois subtipos teve
correlação com aumento de SLEDAI. A depleção de células Treg pode contribuir para a lesão autoimune observada em pacientes com LES/SAFS. O número reduzido de células B CD3- CD19+
observado nesses pacientes está a merecer estudos objetivando um aprofundamento em sua
elucidação.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Systemic lupus erythematosus (SLE) is a multiorganic disease
characterized by immune dysregulation; loss of tolerance to
self-antigens leads to formation of immune complexes.1 Recent data in both human SLE and mouse models have highlighted the role of type I interferon’s (α/β) in the initiation and
perpetuation of the disease.2
Individuals with SLE are more susceptible to thrombosis
than the general population, and the antiphospholipid syndrome (APS) is a well-known risk factor for vascular obstruction in such patients.3 The reason why patients with SLE and
APS produce pathogenic antiphospholipid (aPL) antibodies
has been a matter of intense debate.
CD4+CD25+Foxp3+ regulatory T (Treg) cells are a distinct
thymically derived or inducible subset of T cells with unique
immunosuppressive abilities. Quantitative or functional impairment of Treg lymphocytes seems to direct the immune
system toward autoimmunity.4 It is frequently observed an
imbalance between IL-17 producing T helper (Th17) and Treg
cells during the course of SLE, with marked impairment of the
Treg subset.5 It is noteworthy that the blockage of Treg cells by
interferon-α-producing antigen presenting cells may contribute to loss of peripheral tolerance in SLE.6
A CD4+CD25+Foxp3+ Treg cell dysfunction has been documented in a number of autoimmune disorders.7 In SLE cases,
most studies have shown decreased number of circulating
Tregs in active disease, but data are still conflicting.8
B lymphocytes, in turn, are pivotal cells in SLE; they are
linked to antigen-presentation, autoantibody synthesis and
cytokine production. It is noteworthy that a distinct subset
of B cells shown to exert immunosuppressive effects;9 these
IL-10-producers and regulatory-B cells, knowingly able to suppress T helper cells differentiation, appear to be functionally
impaired in SLE patients.10
Considering the importance of the interplay of T, Treg cells
and B lymphocytes in the immunopathogenesis of SLE (5-7;
9,10) we set up to originally quantify total lymphocytes, Treg
cells, CD3+CD19– T cells and CD3–CD19+ B cells in a Brazilian
survey of patients with SLE/ secondary APS (SLE/APS) and
healthy controls.
Material and methods
This cross-sectional study included patients with SLE and
history of secondary APS from our Outpatient Lupus Clinic.
Clinical and laboratory diagnosis of SLE were based on the
American College of Rheumatology 1997 criteria,11 while the
243
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6
Sidney 2006 criteria was utilized to diagnose APS.12 Lupus activity was assessed by the systemic lupus erythematosus disease activity index, SLEDAI.13
The exclusion criteria were as follows: 1) age below 16
years; 2) infective endocarditis or other current infections; 3)
diabetes mellitus; 4) neoplasms (current or past); and 5) infection by human immunodeficiency virus or Treponema pallidum.
The control group comprised healthy individuals aged more
than 16 years-old, matched by age and sex, and with no APS,
connective tissue disorders, neoplasms or current infections.
Clinical and demographic data were obtained from a chart
review and interview with patients or family after informed
consent. The study was approved by the local ethics committee.
Cell subtypes underwent immunophenotyping using the
specific monoclonal antibodies anti-CD3CY5, anti-CD4 FITC,
anti-CD25, anti-Foxp3 and anti-CD19 PE (Biosciences, San
Jose, CA, USA) and identified by multicolor flow cytometry.14
Quantitative statistical analysis was performed using SPSS
17.0 software (SPSS Inc, Chicago, IL, USA). The significance
level was set at a = 0.05 (two-tailed). The results were shown
as means and standard deviation or by absolute and relative
frequencies. The statistical analysis was performed by Student’s t test and the Mann-Whitney test for the continuous
variables, and chi-square or Fisher’s exact test for categorical
variables. The Pearson test was utilized to correlate circulating cell subtypes with the SLEDAI. An analysis of covariance
(ANCOVA) was performed to evaluate relationships between
variables.
Results
Twenty-five patients with SLE/APS and 25 healthy controls
entered the study. Middle-aged (mean age 43.5 years) females (96%) highly predominated in our SLE/APS survey.
Twenty-four patients (96%) were caucasians. Mean duration
of the disease was 9.87 years, and the average SLEDAI score
was 10 ± 5.77. At the moment of evaluation, arthritis (36%),
oral ulcers (32%), malar rash (24%), seizures (16%), nephritis (12%), and leukopenia (8%) were the most frequent SLE
manifestations. All patients had antinuclear antibodies,
and 40% were positive for anti-dsDNA. Low complement
levels were seen in 8% of patients.
Regarding the APS clinical features, deep vein thrombosis (DVT) was seen in 15 patients (60%), while fetal losses
(so considered after 12 weeks of pregnancy) occurred in
6 patients (24%). Optic neuritis was seen in 4 cases (16%).
Stroke and miscarriages were each diagnosed in 3 cases
(12%). Moderate or high levels of anticardiolipin (aCL) antibodies were detected in 21 patients (84%), whereas lupus
anticoagulant was present in 9 patients (36%). Fourteen patients (56%) were on oral anticoagulation regime with warfarin, and the remaining was being treated with low-dose
aspirin.
Chloroquine, azathioprine and corticosteroids were being utilized by 9 patients (36%), 5 patients (20%) and 16 patients (64%), respectively.
Table 1 compares demographic aspects and lymphocyte
subsets of SLE/APS patients and controls. Both groups were
homogenous regarding age, gender and race. The mean
number of CD4+CD25+Foxp3+ Treg cells and CD3–CD19+ B
cells were significantly lower in patients with SLE/APS
when compared to controls. The mean number of total lymphocytes, CD3+CD19– T cells and CD4+CD25+ lymphocytes
did not significantly differ between groups.
The SLE/APS patients were maintaining a significantly lower number of Treg cells after the control (ANCOVA)
for percentage of total lymphocytes (F = 28.50, p < 0.0001).
The FoxP3 expression in CD4+CD25+ cells, as estimated by
mean fluorescence intensity, did not differ in SLE/APS patients and controls (2660.55 ± 1044.06 vs 2470,65 ± 1732.87;
p = 0.67; respectively). Patients with SLE/APS persisted with
significantly lower percentage of CD3–CD19+ B cells after
controlling for total lymphocytes (F = 13.17; p = 0.002).
Fig. 1 shows the distribution of total lymphocytes,
CD4+CD25+Foxp3+ Treg cells and CD3–CD19+ B lymphocytes
in SLE/APS patients as compared to controls.
The Pearson test for correlation of circulating Treg and
CD3–CD19+ B lymphocytes with the SLEDAI is shown in
Fig. 2. A significant negative correlation of both cell subtypes with the SLEDAI was obtained, indicating that a lower
number of Treg and CD3–CD19+ B cells were linked to increasing scores of lupus activity.
Table 1 – Demographic data and lymphocyte subset in 25 patients with systemic lupus erythematosus/secondary
antiphospholipid syndrome (SLE/APS) and 25 healthy controls
Mean age (years ±SD)
Females
Caucasians
Total lymphocytes
CD3+CD19– T lymphocytes
CD4+CD25+ T lymphocytes
CD4+CD25+Foxp3+ T
lymphocytes
CD3–CD19+ B lymphocytes
SD, standard deviation.
a
Chi-square test.
b
Students t test.
29.42 ± 4.57%
73.72 ± 8.34%
1.28 ± 0.89%
0.74 ± 0.34%
5.71 ± 2.66 %
SLE/APS
Controls
(n = 25)
(n = 25)
43.5 ± 12.84
24 (96%)
24 (96%)
2227.86±528.83 cells/μL
1522.52±527.20 cells/μL
20.50±9.35 cells/μL
21.61±12.70 cells/μL
136.34±92.68 cells/μL
43.80 ± 8,45
24 (96%)
24 (96%)
32.2 ± 2.49%
2523.60±528.83 cells/μL
73.64 ± 7.70%
858.38±194.32 cells/μL
1.81 ± 0.80%
45.68±20.19 cells/μL
1.83 ± 0.77%
46.18±19.43 cells/μL
9.25 ± 3.00%
233.43±75.71 cells/μL
p
0.93a
1.00a
1,00a
0.13b
0,100b
0,81b
<0.0001b
0.006b
244
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6
A)
rs=-0.75, p<0.0001*
%CD4+CD25+FOXP3+
2,00
1,50
1,00
0,50
0,00
0
10
SLEDAI
15
20
25
B)
Fig. 1 – Graphical distribution of total lymphocytes
(A), CD4+CD25+Foxp3+ Treg cells (B) and CD3–CD19+ B
cells (C) in controls and patients with systemic lupus
erythematosus/secondary antiphospholipid syndrome
(SLE/APS).*Students t-test.
rs=-0.46, p=0.021*
20,00
15,00
%CD3-CD19+
Levels of circulating Treg cells did not significantly vary
among users or nonusers of chloroquine, azathioprine and
corticosteroids (p = 0.90; p = 0.76 and p = 0.29 in the chi-square
test, respectively). Similarly, the number of CD3–CD19+ B cells
did not significantly differ in users on nonusers of these medicines (p = 0.462; p = 0.512 and p = 0.341 in the chi-square test,
respectively).
When we compared cell subtypes selectively in 5 patients
with inactive SLE/APS (SLEDAI < 4) and 25 healthy controls,
only the CD3–CD19+ B population remained diminished in the
first group (5.37 ± 1.95% × 9.25 ± 3.00%; p = 0.003; Student’s t
test).
5
10,00
5,00
0,00
0
5
10
15
20
25
SLEDAI
Fig. 2 – Pearson correlation of circulating Treg cells (A)
and CD3–CD19+ B cells (B) with lupus activity assessed by
the systemic lupus erythematosus disease activity index
(SLEDAI). *Student’s t test
Discussion
A number of reports have accounted for a decrease of Treg
cells in patients with SLE.15-17 As far as we are aware, this study
is the first to approach circulating Treg cells and B lymphocytes in Brazilian patients with SLE and secondary APS. Our
survey included predominantly middle-aged white females
with high SLEDAI, and mean disease duration of approximately a decade. Arthritis and oral ulcers were the prominent
SLE findings, while DVT and aCL antibodies were cardinal APS
features.
We have found a decreased number of circulating CD3–
CD19+ B cells in our SLE/APS patients when compared to controls. It is important to say that there was no association of
CD3–CD19+ B cell count with intake of chloroquine, azathioprine and steroids. The reasons for this B cell decrease in SLE/
APS patients are nebulous, but an explanation could be autoantibodies directed to B lymphocytes or intrinsic defects of B
cell subsets. The fact that B cell depletion was confirmed even
in the 5 patients with inactive SLE might support the latter.
We could only suppose the hypothesis that the population
with B cells depletion is the IL-10 producer subset with immunosuppressive properties. It is noteworthy that competent
B cells seem to be important to trigger Treg activity, as shown
in patients with common variable immunodeficiency18.
Reduced numbers of circulating CD4+CD25+Foxp3+ Treg cells
were seen in our SLE/APS patients as compared to controls. As
occurred the with the B cell subtype, Treg cells depletion was
confirmed after controlling (ANCOVA) for total lymphocyte
count. Decreasing levels of circulating Treg cells, just as seen
with the CD3–CD19+ B subset, were correlated with higher
scores of disease activity. Diminished levels of Treg cells have
been associated with active SLE19,20, but other reports21,22 questioned this finding. In our study, Treg cells depletion could be
representative of an intrinsic defect related to previous SLE/
APS, or current SLE activity. Patients with inactive SLE did not
show Treg reduction, which favors the second hypothesis. It
is worthy of note that there was no association between Treg
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6
cells decrease and the intake of chloroquine, azathioprine or
steroids in our patients either.
Our group recently reported low levels of circulating Treg
and also of CD3–CD19+ B cells in patients with primary APS23.
These data, combined with the current study, imply that depletion of both subsets occurs in APS populations as a whole.
If this assumption will be confirmed, the Treg cells decrease
may comprise one of the immune mechanisms leading to
pathogenic aPL responses in primary or secondary APS. Nevertheless, it should be considered that Treg cells decrease in
our SLE/APS patients seemed to relate more to SLE activity
than any other particular factor.
Recent data disclosed that any quantitative analysis of
Tregs in patients with autoimmune disorders have to be seen
with some caution. The reg cells show formidable plasticity and comprise a heterogeneous population of suppressive
cells, non-functional Treg cells and IL-17A-producing Treg
cells acting as effector T lymphocytes. Thus, the simple numeric count of Tregs might not be truly representative of their
functional status.24
Some other limitations of our study must be mentioned.
Even though the majority of our patients showed active SLE,
the APS thrombotic manifestations were not current; newer
studies should investigate the biological function of Treg cells
and B lymphocytes during the thrombotic event and also in a
longitudinal analysis. Given the small sample, we could not
subgroup patients by SLE/APS features or drug dosage. The
small number of patients with inactive SLE restricted the statistical power of the article. The same way, the lack of comparison between patients with SLE and without APS limited
our conclusions.
Up to date, the treatments of SLE and APS have been reasoned in immunosuppression and anticoagulation, respectively. A direct immunomodulatory approach shifting the balance to favor Treg cells is being tried with autologous Treg cell
therapy in type-1 diabetes,25 and such intervention might be
promising for SLE and APS as well. Recently, it was noticed
that Treg cells were able to prolong the interval of remission
induced by conventional cytostatic drugs in (NZB × NZW) F1
lupus mice.26
Although many questions concerning the pathogenesis
of SLE and APS remain undefined, it is possible that the progression of the disease results from a breakdown in Treg-dependent peripheral self-tolerance. In this context, Treg-based
immunotherapy might have a place in the maintenance of
disease remission in this group of patients.
In summary, this preliminary study demonstrated impaired numbers of CD4+CD25+Foxp3+ Treg cells and CD3–CD19+
B lymphocytes in Brazilian patients with SLE and secondary
APS. Lower cell counts were seen in patients with higher SLE
activity. Future studies shall confirm if the decrease of Treg
cell levels is connected to the abnormal immune response
seen in SLE/APS. The decrease of CD3–CD19+ B cells seen in
these patients, and potentially linked to Treg dysfunction, also
justifies new studies in order to search for more clarifications.
Conflicts of interest
The authors declare no conflicts of interest.
245
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a contemporary view of its genetic determination,
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Imunol. 2009;58:3-14.
2. Jorgensen TN, Gubbels MR, Kotzin BL. Links between type I
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3. Burgos PI, Alarcón GS. Thrombosis in systemic lupus
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4. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of
all trades, master of regulation. Nat Immunol. 2008;9:239-44.
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Caterbi S et al. Balance between regulatory T and Th17 cells
in systemic lupus erythematosus: the old and the new. Clin
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6. Yan B, Ye S, Chen G, Kuang M, Shen N, Chen S.
Dysfunctional CD4+,CD25+ regulatory T cells in untreated
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Arthritis Rheum. 2008;58:801-12.
7. Bernard F, Romano A, Granel B. Regulatory T cells
and systemic autoimmune diseases: systemic lupus
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8. Kuhn A, Beissert S, Krammer PH. CD4(+)CD25 (+) regulatory
T cells in human lupus erythematosus. Arch Dermatol Res.
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9. Kitagori K, Kawabata D. B cell abnormality in systemic
lupus erythematosus. Nihon Rinsho Meneki Gakkai Kaishi.
2012;35:495-502.
10. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA,
Ehrenstein MR, Mauri C. CD19(+)CD24(hi)CD38(hi) B cells
exhibit regulatory capacity in healthy individuals but are
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patients. Immunity. 2010;32:129-40.
11. Hochberg MC. Updating the American College of
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12. Miyakis 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
antiphospholipid syndrome (APS). J Thromb Haemost.
2006;4:295-306.
13. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang
CH. Derivation of the SLEDAI. A disease activity index for
lupus patients. The Committee of Prognosis Studies in SLE.
Arthritis Rheum. 1992;35:630-40.
14. Moon HW, Kim BH, Park CM, Hur M, Yun YM, Kim SY, Lee
MH. CD4+CD25highFoxP3+ regulatory T-cells in hematologic
diseases. Korean J Lab Med. 2011;31:231-7.
15. Fathy A, Mohamed RW, Tawfik GA, Omar AS. Diminished
CD4+CD25+ T-lymphocytes in peripheral blood of patients
with systemic lupus erythematosus. Egypt J Immunol.
2005;12:25-31.
16. Mellor-Pita S, Citores MJ, Castejon R, Tutor-Ureta P, YebraBango M, Andreu JL et al. Decrease of regulatory T cells in
patients with systemic lupus erythematosus. Ann Rheum
Dis. 2006;65:553-4.
17. Barreto M, Ferreira RC, Lourenco L, Moraes-Fontes MF,
Santos E, Alves M et al. Low frequency of CD4+CD25+ Treg
in SLE patients: a heritable trait associated with CTLA4 and
TGFbeta gene variants. BMC Immunol. 2009;10:5.
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18. Genre J, Errante PR, Kokron CM, Toledo-Barros M, Câmara
NO, Rizzo LV. Reduced frequency of CD4(+)CD25(HIGH)
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20. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad
S, et al. Global natural regulatory T cell depletion in active
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Decreased levels of circulating CD4+CD25+Foxp3+ regulatory
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H. The plasticity and stability of regulatory T cells. Nat Rev
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25. Thompson JA, Perry D, Brusko TM. Autologous regulatory
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2012;12:623-32.
26. Weigert O, von Spee C, Undeutsch R, Kloke L, Humrich JY,
Riemekasten G. CD4+Foxp3+ regulatory T cells prolong druginduced disease remission in (NZBxNZW) F1 lupus mice.
Arthritis Res Ther. 2013;15:R35.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 7 – 2 4 9
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Brief communication
When anti-TNF fails, anti-IL12-23 is an alternate option in
psoriasis and psoriatic arthritis
Ricardo Prado Golmia, Ayk Helena Barbosa Martins, Morton Scheinberg*
Hospital Israelita Albert Einstein and Clinical Research Center Hospital Abreu Sodré, São Paulo, SP, Brazil
article info
abstract
Article history:
Patients with psoriasis and psoriatic arthritis respond to anti-TNF therapy, but not all pa-
Received on 12 April 2013
tients maintain effective response, and some do not respond. In this article, we demon-
Accepted on 16 October 2013
strate the role of a new pathogenetic pathway to some extent TNF-independent in these
patients. Anti-IL12-23 is a new and alternate mode of therapy for patients with recalcitrant
Keywords:
response to anti-TNF.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
Psoriasis
All rights reserved.
Psoriatic arthrits
Biologic therapy
Quando anti-TNF não obtém sucesso, anti-IL-12-23 é opção alternativa
na psoríase e na artrite psoriásica
resumo
Palavras-chave:
Pacientes com psoríase e artrite psoriásica respondem à terapia anti-TNF, mas nem todos
Psoríase
os pacientes mantêm uma resposta efetiva e alguns não respondem. Nesse artigo, demons-
Artrite psoriásica
tramos o papel de uma nova via patogenética que, até certo ponto, independe de TNF nes-
Terapia biológica
ses pacientes. Anti-IL-12-23 é um modo terapêutico novo e alternativo para pacientes com
resposta recalcitrante à medicação com anti-TNF.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Tumor necrosis factor alpha (TNF-α) is a proinflammatory
cytokine involved in inflammation of the skin and synovium, making it a logical target for the treatment of psoriasis
(Ps) and psoriatic arthritis (Psa). It has been demonstrated
that this cytokine plays a fundamental role in the pathogenesis of both Ps and Psa through several pathogenetic mechanisms, including the expression of adhesion molecules to
the surface of endothelial cells, keratinocytes, and dendritic
cells promoting leukocyte migration.1 In the joints, it triggers the production of a variety of cytokines, which in turn
increase the inflammatory cascade. In the skin, TNF-alpha
* Corresponding author.
E-mail: [email protected] (M. Scheinberg).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.10.004
248
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 7 – 2 4 9
also leads to a decrease in the apoptosis of keratinocytes,
thus contributing to a hyperproliferative epidermis. AntiTNF-alpha has the potential to provide symptomatic relief
and help prevent disease progression in Ps and Psa by decreasing joint and skin inflammation.2
Guidelines derived from evidence based clinical trials and
from clinical practice has established the clinical usefulness
of all the three anti-TNF agents for the treatment of axial
and peripheral P and Psa. These agents selectively block the
role of TNF-alpha and proved to be effective in clinical trials
and also in clinical practice.3 All the three agents – infliximab, etanercept, and adalimumab – have shown marked
improvements in disease activity in the PASI-75 of the skin
and in disease activity indexes ACR20, ACR50, ACR70 when
compared to patients treated with placebo. However, in our
and others’ experience, not all patients respond to these
agents, and in some of them, the initial response is lost
after variable periods of time.4,5 Although switching to another anti-TNF can boost a secondary response, this may
also be variable, and, in some patients, no response at all
can be observed. Currently, two new anti-TNFs are being
evaluated for the treatment of Psa a humanized form of infliximab by subcutaneous route, golimumab and a pegylated
form of anti-TNF, certolizumab pegol. Phase-2 preliminary
studies indicate efficacy similar to the conventional antiTNFs.6,7 Surprise as it may be, a few patients develop Ps after
the treatment with anti-TNFs, and several explanations are
being developed for this enigmatic observation. One of the
most attractive is the switch to another inflammatory pathway after prolonged blockade of TNF.8-10
Ustekinumab is an immunoglobulin, a human monoclonal antibody that binds with great affinity to the shared p40
subunit of human interleukin 12 and 23.11,12 Increased production of IL-23 (but not of IL-12 mRNA) production can be
observed in the skin of Ps patients. IL-23 is essential for the
survival and proliferation of Th17 cells. Previous published
data have shown CD4 and CD8 cells in Ps lesions, and Ps
is considered a Th1 disease. However, it has been demonstrated that the CD4 cells secrete excessive amounts of IL17;
they are Th17 cells, therefore, and one scenario consists in
considering Ps as a Th1/Th17-mixed disease.13
Two clinical studies known as PHOENIX 1 and 2 evaluated
patients with moderate to severe Ps. PHOENIX 1 studied 66
patients randomized to receive 45 mg or 90 mg at the weeks
zero, four, and every 12 weeks. In PHOENIX 2, a similar study
was performed, but in this time with adjustable doses in
case of partial responses, totaling 70% of the patients in
both studies against 3% in the group treated with placebo.
After 52 weeks, besides a good index of response, no serious adverse events happened, except minor symptoms at
upper respiratory tract (apparently common with the use
of any immunobiological agents), neither anaphylaxis nor
presence of tuberculosis, being these symptoms still associated with a very convenient way of administration subcutaneously every two to three months. When compared with
etanercept, it was demonstrated that the response observed
with ustekinumab was superior in efficacy and side effects
(Figs. 1, 2, and 3).14-17 Studies with ustekinumab in Psa are
underway. The superiority of this agent has been demonstrated versus placebo in controlled trials, reducing signs
Fig. 1 – Phoenix 1 & 2: study design.
Fig. 2 – Ustekinumab pasi 75 responses at week 12 (after
doses at weeks 0, 4).
Fig. 3 – Significant efficacy after two injections.
and symptoms in the joints and also in the skin. Phase-3
results are still pending.18,19 Briakinumab (ABT-974) is another fully human monoclonal antibody against the p40
subunit of IL12-23, that is currently under evaluation for
Ps.20 Preliminary results are similar to those observed with
ustekinumab. Finally, as the activation of IL-23 depends on
Th17,future biological agents for Ps and Psa might be directed at Th17 and their secreted product IL-17, a pathway
still not taken in Psoriasis.21 In summary, the current status
on the therapy of Ps and Psa should now include new medications despite the fact that after TNF failure, we still lack
proper guidelines.22,23
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 7 – 2 4 9
Conclusions
It is conceivable that we are not ready to replace anti-TNF as
an alternative for the treatment of Ps, but it is a possibility, in
case of Psa, until the ongoing phase-3 studies are available, it
may also become a possibility in reducing articular signs and
symptoms. So, what is the alternative if anti-TNF fails in patients suffering from Ps and Psa? Our understanding is that until comparative studies be performed, inhibition of new pathogenetic pathways should be considered and evaluated at the
individual level; moreover, blocking IL12-23 is an alternative
pathway initially indicated for the skin, although it also seems
to be helpful in alleviating symptoms of arthritis.24,25
Conflicts of interest
The authors declare no conflicts of interest.
R eferences
1. Bradley JR. TNF-mediated inflammatory disease. J Pathol.
2008;214:149-60.
2. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor
necrosis factor antagonist mechanisms of action: a
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Retrospective study evaluating dose standards for
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6. Voulgari PV. Golimumab: a new anti-TNF-alpha agent for
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7. Patel AM, Moreland LW. Certolizumab pegol: a new biologic
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2010;6:855-66.
8. Grinblat B, Scheinberg M. Unexpected onset of psoriasis
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9. Grinblat B, Scheinberg M. The enigmatic development of
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review. Semin Arthritis Rheum. 2008;37:251-5.
249
10. Laurindo IM, Scheinberg M. Why do some biologic agents
induce psoriasis or psoriasiform lesions? Nat Clin Pract
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11. Gandhi M, Alwawi E, Gordon KB. Anti-p40 antibodies
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12. Elliott M, Benson J, Blank M, Brodmerkel C, Baker D, Sharples
KR, Szapary P.
13. Ann N Y. Ustekinumab: lessons learned from targeting
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Sci. 2009;1182:97-110.
14. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A.
Pathophysiology of psoriasis: recent advances on IL-23 and
Th17 cytokines. Curr Rheumatol Rep. 2007;9:461-7.
15. Leonardi CL, Kimball AB, Papp KA, Yeildin N, Guzzo C,
Wang Y, Li S, Dooley LT, Gordon KB, PHOENIX 1 study
investigators. Efficacy and safety of ustekinumab, a human
interleukin-12/23 monoclonal antibody, in patients with
psoriasis: 76-week results from a randomized, double-blind,
placebo-controlled trial (PHOENIX 1). Lancet. 2008;37:1665-74.
16. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P,
Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich
K; PHOENIX 2 study investigators. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal
antibody, in patients with psoriasis: 52-week results from a
randomised, double-blind, placebo-controlled trial (PHOENIX
2). Lancet. 2008;371:1675-84.
17. Young MS, Horn EJ, Cather JC. The ACCEPT study:
ustekinumab versus etanercept in moderate-to-severe
psoriasis patients. Expert Rev Clin Immunol. 2011;7:9-13.
18. Farhi D. Ustekinumab for the treatment of psoriasis: review
of three multicenter clinical trials. Drugs Today (Barc).
2010;46:259-64.
19. Kavanaugh A, Menter A, Mendelsohn A, Shen YK, Lee S,
Gottlieb AB. Effect of ustekinumab on physical function
and health-related quality of life in patients with psoriatic
arthritis: a randomized, placebo-controlled, phase II trial.
Curr Med Res Opin. 2010;26:2385-92.
20. Cuchacovich R, Espinoza LR.: Ustekinumab for Psa.The
Lancet. 2009;373:605-606.
21. Lima XT, Abuabara K, Limball AB, Lima HC. Briakinumab.
Expert Opin Biol Ther. 2009;9:1107-13.
22. Weinberg JM. The path not taken. Cutis. 2010;86:115-116.
23. Weger W. Current status and new developments in the
treatment of psoriasis and psoriatic arthritis with biological
agents. Br J Pharmacol. 2010;160:810-20.
24. Deighton C. Therapy: what should we do after the failure of a
first anti-TNF? Nat Rev Rheumatol. 2009;5:596-7.
25. Mease P. Update on treatment of psoriatic arthritis. Bull NYU
Hosp Jt Dis. 2012;70:167-71.
26. Wallis DE, Waldron NM, Korendowych E. Ustekinumab for
resistant psoriatic arthritis. J Rheumatol. 2013 Feb;40:207. doi:
10.3899/jrheum.121152.
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Brief communication
Articular ultrasonography: interobserver reliability in
rheumatoid arthritis☆
Melissa Cláudia Bisi a,*, Aline Defaveri do Prado a, Cristina Rabelo b, Flávia Brollo b,
Inês Guimarães da Silveira b, José Alexandre de Mendonça c, Henrique Luiz Staub b
Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
Faculty of Medicine, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
c Pontifícia Universidade Católica de Campinas, Campinas, SP, Brazil
a b article info
abstract
Article history:
Introduction: Ultrasonography (US) has a recent use in Rheumatology, and the reliability of
Received on 17 May 2013
the method in rheumatoid arthritis (RA) patients has yet to be clarified.
Accepted on 27 September 2013
Objective: To test, in a RA survey, the reproducibility of musculoskeletal US performed by
rheumatologists with one-year training through re-analysis by a Rheumatologist experien-
Keywords:
ced in the method.
Rheumatoid arthritis
Patients and methods: This cross-sectional study included consecutive RA patients from our
Ultrasonography
tertiary center. US exam was performed in metacarpophalangeal joints, proximal interpha-
Reproducibility, kappa
langeal joints, and wrists. Presence of synovitis, power Doppler (PD) signal, bone erosions,
and cartilage changes comprised the US parameters evaluated. A kappa value in-between
0.20 and 0.40 was considered fair; in-between 0.41 and 0.60 was moderate; in-between 0.61
and 0.80 was good; and above 0.81 was excellent. Results: We analyzed 1,380 joints of 60
RA patients (78% females, 78% caucasoids). Mean age was 58 ± 11.56 years, mean disease
duration was 9.98 ± 7.79 years, mean DAS28 was 3.82 ± 1.53, and mean HAQ was 0.91 ± 0.67.
Kappa agreement for synovitis ranged from 0.30 to 0.70; for PD signal, from 0.53 to absolute
agreement; for erosions, from 0.70 to 0.97; for cartilage changes, from 0.28 to 0.63.
Conclusion: Although good, moderate and excellent interobserver agreement were obtained
for erosions and PD, concordance for synovitis and cartilage changes were less impressive
in our patients with active RA. Further studies on standardization of scanning technique
are necessary to improve musculoskeletal US reproducibility.
© 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda.
All rights reserved.
☆
Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.
* Corresponding author.
E-mail: [email protected] (M.C. Bisi).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2013.09.002
251
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Ultrassonografia articular: confiabilidade interobservadores em artrite
reumatoide
resumo
Palavras-chave:
Introdução: A ultrassonografia (US) tem uso recente na reumatologia, e a confiabilidade do
Artrite reumatoide (AR)
método em pacientes com artrite reumatoide (AR) ainda está por ser definida.
Ultrassonografia (US)
Objetivo: Testar, em uma pesquisa de AR, a reprodutibilidade da US musculosquelética re-
Reprodutibilidade Kappa
alizada por reumatologistas com treinamento de um ano por meio da reanálise por um
reumatologista com experiência no método.
Pacientes e métodos: Esse estudo transversal incluiu pacientes de AR consecutivos de nosso
centro terciário. O exame US foi realizado nas articulações metacarpofalângicas, articulações interfalângicas proximais e pulsos. Os parâmetros avaliados foram: presença de sinovite, sinal de power Doppler (PD), erosões ósseas e alterações cartilaginosas. Um valor
Kappa entre 0,20 e 0,40 foi considerado razoável; entre 0,41 e 0,60, moderado; entre 0,61 e
0,80, bom; e acima de 0,81, excelente.
Resultados: Analisamos 1380 articulações de pacientes com AR (78% mulheres, 78% caucasoides). Média de idade = 58 ± 11,56 anos, duração média da doença = 9,98 ± 7,79 anos,
DAS28 média = 3,82 ± 1,53 e HAQ média = 0,91 ± 0,67. A concordância de Kappa para sinovite
variou de 0,30-0,70; para sinal PD, de 0,53 até a concordância absoluta; para erosões, de
0,70-0,97; para alterações cartilaginosas, de 0,28-0,63.
Conclusão: Embora tenha sido obtida concordância interobservadores boa, moderada e excelente para erosões e PD, a concordância para sinovite e alterações cartilaginosas foi menos substancial em nossos pacientes com AR ativa. Há necessidade de novos estudos sobre
a padronização da técnica de análise, objetivando a melhora da reprodutibilidade da US
musculosquelética.
© 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda.
Todos os direitos reservados.
Introduction
Materials and methods
Rheumatoid arthritis (RA) is a chronic autoimmune disease
affecting mostly peripheral joints. Radiologically, articular involvement is characterized by cortical bone erosions, culminating with deformities.1
Currently, musculoskeletal ultrasonography (US) has become an important tool in the diagnosis and monitoring of
rheumatic diseases, especially in RA. This method has shown
better sensitivity than clinical evaluation and radiography for
detection of rheumatoid synovitis and joint erosion.2
US have some advantages when compared to other imaging techniques, such as: it is noninvasive, fast, low-cost, and
can display various joints in motion, in addition, can be repeated without major risks, and is well accepted by the patient.3
Despite these significant advantages, sonographic findings
remain highly operator-dependent requiring professional
knowledge in Anatomy, Pathology and techniques allowed
by the US machine.4 This is partly due to the subjective image’s assessment and the low degree of standardization of the
technique, due to the small number of multicenter studies
evaluating the interobserver concordance.5
The current study aims to analyze the interobserver agreement of data obtained by two rheumatologists with one yeartraining in US, in comparison with those ones of an expert on
US. This interobserver concordance among rheumatologists
of different experiences in US has not been detailed in Brazilian RA patients to date.
Patients
Patients with RA according to criteria of the American College of Rheumatology 1987 were recruited at Saint Lucas
Hospital, 6 Pontifical University Catholic of Rio Grande do
Sul (PUC-RS), Porto Alegre, Brazil; for this cross-sectional
study, we excluded patients with a prior history of fracture
or surgery in the dominant hand. The study was approved
by the local ethics committee, and all patients signed a free
consent.
Patients screened were submitted blindly to US examination by a rheumatologist. Another rheumatologist carried out the disease activity score (DAS28) calculation. This
score defines remission when it is below 2.6; low activity
from 2.6 to 3.2; moderate activity from 3.2 to 5.1; and severe
activity > 5.1.7 Patients also responded to the health assessment questionnaire (HAQ); in-between 0 and 1: mild limitation; greater than 1 to 2: moderate limitation; and greater
than 2 to 3: severe limitation.8
Methods
US examination of wrist, second and third proximal interphalangeal and metacarpophalangeal joints were proceeded with high-resolution machine My Lab 60 (ESAOTE,
Genoa, Italy) with high-frequency linear transducer (18
MHz).The PD frequency was from 8.0 to 10.0 MHZ, pulse
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4
repetition frequency (PRF) from 0.5 to 1.0. The examination
was performed on the dominant side dorsal and ventral in
longitudinal and transverse scan, to evaluate the following
parameters: presence of synovitis (qualitative and semiquantitative), signal of power Doppler (PD, qualitative and
semi-quantitative), presence of erosions (qualitative) and
cartilage assessment (qualitative and semi-quantitative
scores).
Images were recorded and archived in Dropbox site, so
that all investigators obtained remote access. The examination was carried out by two rheumatologists with the same
one-year level of US training (EULAR basic and intermediate
courses), one of them the main author of this study. Each
rheumatologist examined independently, at different times,
30 different patients (total database of 60 patients). In addition, each of the two played their own images and recorded
separately assessments to be re-analyzed by a rheumatologist expert on musculoskeletal US. This PhD expert has over
five years of experience in musculoskeletal US and is a national reference in the field. None of the three involved in
the evaluations knew the interpretation of the other. Statistical testing was proceeded using the total data from the two
rheumatologists and re-analysis by the expert.
In the US analysis, synovitis was scored by gray scale
US as: 0 = absence; 1 = mild (discrete hypoechoic image/
anechoic in the joint capsule); 2 = moderate (the joint capsule is elevated parallel to the joint area); and 3 = severe
(important distention of the joint capsule).9
Quantitative evaluation of synovial inflammatory activity through the PD was classified as: 0 = absence (no signal
PD, no intra-articular color signal); 1 = mild (up to 3 color
signals or 2 single and 1 confluent signal in the intra-articular area); 2 = moderate (greater than grade 1 to < 50% of the
intra-articular area filled with color signals); and 3 = severe
(> 50% flow intra-articular area filled with color signals).10
The presence of erosions was evaluated in the transverse and longitudinal plane and rated as follows: 0 = no
erosion; 1 = very small (< 1mm); 2 = small (1-2 mm); 3=moderate (2-4 mm); and 4 = large (> 4 mm). 11
Cartilage assessment was divided in: 0 = normal hyaline
cartilage; 1 = loss of sharpness of the superficial margin of
the hyaline cartilage; 2 = partial thickness defect of cartilage layer; 3 = thickness defect of cartilage with normal
subchondral bone; and 4 = complete loss of cartilage layer
and subchondral bone involvement.12
Statistics
Kappa values were utilized to assess interobserver concordance of variables. The weight kappa was calculated when
the linear correlation was below 50%. The PABAK (prevalenceadjusted bias-adjusted kappa) was utilized for linear correlations above 50%.13 Confidence intervals were obtained using
the standard error (SE) of weight kappa (wk) (nonzero) as follows: [interval lower kappa = -1.96 *SE (wk)] and [high range
kappa = + 1.96 * SE (wk)].13
Kappa values were divided in: < 0.20: poor concordance;
between 0.21 and 0.40: fair; between 0.41 and 0.60: moderate;
between 0.61 and 0.80: good; and between 0.81 and 1: excellent.13 The significance level for statistical tests was 5%. Statistical programs used were SPSS 12.1 and WinPepi for different kappa calculation.
Results
Out of the 60 RA patients, 47 (78%) were females, and also
78% were caucasian. Mean age was 58 ± 11.56 years, while the
mean disease duration was 9.98 ± 7.79 years. Forty-two patients (70%) tested positive for rheumatoid factor. The mean
DAS28 was 3.8, pointing to moderate disease activity, while
the mean HAQ (0.91) indicated mild limitations to our patients.
A total of 1,380 images of the 60 patients were scanned
by the two investigators. Tables 1 and 2 show the agreement
rates of data from the two rheumatologists and the expert.
The kappa values disclosed good to excellent agreement for
erosion (0.70-0.97); moderate to excellent to PD (0.53-1), here
including absolute agreement in the third metacarpophalangeal ventral; and fair to good concordance for synovitis (0.300.70) and cartilage changes (0.28-0.63).
Table 1 – Agreement and kappa values for synovitis and power Doppler
Synovitis
Wrist dorsal
Wrist ventral
2 MCP dorsal
2 MCP ventral
2 MCP radial
3 MCP dorsal
3 MCP ventral
2 PIP dorsal
2 PIP ventral
3 PIP dorsal
3 PIP ventral
Power Doppler
Agreement (%)
Kappa
95% CI
Agreement (%)
Kappa
95% CI
58
64
63
45
66
55
65
81
73
80
0.44
0.47a
0.51a
0.30b
0.56a
0.33a
0.53a
0.63a
0.64a
0.70a
0.27 - 0.61
0.25 - 0.69
0.35 - 0.67
0.13 - 0.47
0.38 - 0.74
0.10 - 0.56
0.31 - 0.75
0.35 - 0.91
0.41 - 0.87
0.38 - 1.02
68
90
91
91
95
100
85
97
84
98
0.53
0.87a
0.89a
0.83a
0.93a
1a
0.77a
0.93a
0.77a
0.97a
0.32 - 0.74
0.84 - 0.90
0.76 - 1.02
0.46 - 1.20
0.75 - 1.11
NC
0.52 - 1.02
0.91 - 0.95
0.55 - 0.99
0.97 - 0.98
a
MCP, metacarpophalangeal joints; PIP, proximal interphalangeal; CI, confidence interval; NC, not calculated.
When agreement > 50%, considered PABAK.
b When agreement < 50%, considered weighted kappa.
a a
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Table 2 – Agreement and kappa values for erosions and cartilage changes
Erosion
2 MCP dorsal
2 MCP ventral
2 MCP radial
3 MCP dorsal
3 MCP ventral
2 PIP dorsal
2 PIP ventral
3 PIP dorsal
3 PIP ventral
Cartilage
Agreement (%)
Kappa
95% CI
Agreement (%)
Kappa
95% CI
93
95
88
85
98
95
93
95
97
0.87
0.90a
0.77a
0.70a
0.97a
0.90a
0.87a
0.90a
0.93a
0.73 - 1.01
0.90 - 0.90
0.60 - 0.94
0.46 - 0.94
0.35 - 1.59
0.36 - 1.44
0.37 - 1.37
0.36 - 1.44
0.32 - 1.54
67
70
-
0.58
0.63a
-
0.37 - 0.79
0.45 - 0.81
-
a
a
MCP, metacarpophalangeal joints; PIP, proximal interphalangeal; CI, confidence interval; NC, not calculated.
When agreement > 50%, considered PABAK.
a
Discussion
The usefulness of US in monitoring structural changes of
rheumatoid joints has been previously reported.14,15 Technological advances have improved the definition of US images,
expanding the spectrum of the method in Rheumatology and
other areas.16,17
The main objective of our study was to evaluate the interobserver concordance of musculoskeletal US in RA patients, an issue yet to be explored. The central idea was to
analyze data from two rheumatologists trained in basic and
intermediate US courses with re-analysis by a rheumatologist
expert in musculoskeletal US.
The great majority (about three quarter) of our survey of
60 RA patients was of caucasian women. The ratio femalemale was similar to that described in Europe and United
States.18 Mean age of our patients was around 60 years, with
mean disease duration of approximately 10 years. Age of disease onset, in our survey by 50 years, was higher than previously reported.18
As a whole, our RA population showed active disease
(mean DAS28 3.8, configuring moderate activity). In fact, only
two patients were in remission (DAS28 ≤ 2.6). As for the HAQ
(mean value 0.91) our survey showed mild functional limitation; only four patients had severe limitations (HAQ > 2.0).
We analyzed a total of 1380 images as to the presence of synovitis, PD signal, bone erosion and cartilage changes. The usual Cohen kappa coefficient was not appropriate for our study,
since we dealt with ordered semiquantitative variables and
great heterogeneity in the prevalence of such variables.19 We
then set up to use the weight kappa when the linear correlation was below 50%, and PABAK for concordances above 50%.20
The highest concordance in our study (good to excellent
kappas; 0.70 to 0.97) concerned the presence of bone erosions.
Kappas for PD were moderate to excellent (0.53 to 1.00), including absolute agreement in the third MCP. By looking at
the pictures, however, we noticed that no patient had positive PD at this location. As to synovitis, data were well less
impressive, with kappas varying from fair to good at the most
(0.30 to 0.70). Worthy of note, synovitis and PD are variables
that must be analyzed dynamically in the US examination; a
subtle change in the transducer angle may spoil the interpretation of these parameters.
The interobserver agreement for musculoskeletal US was
evaluated by Naredo et al. in 2006.21 This project (“Teach the
Teachers”) included 22 rheumatologists and one experienced
radiologist. In hands and wrists, mean kappa value for synovitis was 0.73, just higher than ours; as to erosions, their kappa value (0.64), although conceptually moderate, was lower
than the one we obtained.
Iagnocco et al. reported kappa values for synovitis, tenosynovitis and erosions between 0.73 and 0.89; again, concordance for synovitis, but not for erosions, was higher than
in our study.22 According to Gutierrez et al., 4-week training
for rheumatologists with no experience in US was enough
to achieve moderate to excellent concordance for bone erosions.23
Kappas for cartilage changes can also be interpreted as a
negative surprise in our study (performance fair to good at the
maximum, 0.28 to 0.63). In theory, images of cartilage should
have been more reproducible, since their interpretation is
static. Cartilage evaluation was only recently standardized;24
this implies difficulties in training professionals for this parameter. Knowingly, basic and intermediate US courses tend
to emphasize training for the synovitis and erosion parameters. Slightly differently from our data, Filippucci et al. reported moderate to good interobserver concordance for cartilage
changes (0.56 to 0.76).24
The US has been considered an operator-dependent test.
For this reason, US studies of interobserver reliability are of
great importance. European rheumatologists highly experienced in musculoskeletal US formatted the EULAR Standing Committee for Education and Training in US, in order to
spread US knowledge in Rheumatology to different countries.25 As long as the US standardization takes place, the
amount of evidence-based multicenter studies will naturally
grow.
Despite the overall good concordance obtained for the
majority of variables herein evaluated, we recognize that the
knowledge of musculoskeletal US has a learning curve that is
dependent on the increasing experience of the examiner and
parameters standardization. The US, an emerging extension
of physical exam for the rheumatologist, stands not only as a
diagnostic tool, but also as a parameter of disease monitoring.
Our study presents logistical limitations that should be
mentioned. The RA sample could be larger, for a more reliable
statistics. The US procedures were not carried out simultane-
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4
ously. Lastly, we were not able, for the moment, to compare US
variables with scores of activity and functional impairment.
In summary, in our survey of active RA patients, the majority of the US variables proved reproducible. There was fair
to good interobserver reliability for synovitis and cartilage
changes, moderate to excellent for PD and good to excellent
for bone erosions. Newer studies should better define the usefulness and reproducibility of musculoskeletal US in RA and
other related rheumatic disorders.
Conflicts of interest
The authors declare no conflicts of interest.
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REVISTA BRASILEIRA DE
REUMATOLOGIA
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Retraction
Retraction: “Anti-citrullinated peptide antibodies and
rheumatoid factor in Sudanese patients with Leishmania
donovani infection”
Erik Ahlina, Amir Elshafeib, Musa Nurc, Sayda Hassan El Safid, Johan Ronnelide,
Gehad Elghazalif,*
Msc - Immunobiology, Clinical Immunology Unit, Uppsala University, Uppsala, Sweden
Bachelor of Medicine - Hematology Laboratory of Pathology and Microbiology, Alribat Hospital, Khartoum, Sudan
c
Rheumatologist - Consultant, Unit of Rheumatology, Alribat University Hospital, Khartoum, Sudan
d
Professor of Immunology - Consultant, Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Sudan
e
Associate Professor of Immunology - Consultant, Clinical Immunology Unit, Uppsala University, Uppsala, Sweden.
f Professor of Immunology - Senior Consultant, University of Shendi, Shendi, Sudan; and King Fahad Medical City, Riyadh, Kingdom of
Saudi Arabia
a
b
Retracted article: Ahlin E, Elshafei A, Nur M, El Safi SH, Johan R, Elghazali G. Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection. Rev Bras Reumatol. 2011 Dec;51(6):579-86. DOI: http://dx.doi.
org/10.1590/S0482-50042011000600005
RETRACTION: Ahlin E, Elshafei A, Nur M, El Safi SH, Johan R, Elghazali G. Anti-citrullinated peptide antibodies and rheumatoid
factor in Sudanese patients with Leishmania donovani infection. Rev Bras Reumatol. 2011 Dec;51(6):579-86. English, Portuguese.
PubMed PMID: 22124592 has been retracted.
ABSTRACT: The paper entitled Ahlin E, Elshafei A, Nur M, El Safi SH, Johan R, Elghazali G. Anti-citrullinated peptide antibodies
and rheumatoid factor in Sudanese patients with Leishmania donovani infection. Rev Bras Reumatol. 2011 Dec;51(6):579-86.
English, Portuguese. PubMed PMID: 22124592 has been retracted.
This is due to plagiarism.
The reasons pointed out were:
1) Author Elghazali G did not take part in the production of the data for the paper and has never been a co-author on any version
of the manuscript.
2) A paper with very similar content, which was part of the PhD thesis of author Ahlin E (first author), was accepted for another
journal.
3) The figures in the paper published in this journal were identical to the figures in author Ahlin E’s PhD thesis.
4) The name of author Johan Ronnelid was misspelt in the paper published in our journal (RBR).
* Corresponding author.
E-mail: [email protected] (G. Elghazali).
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2014.05.002
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REVISTA BRASILEIRA DE
REUMATOLOGIA
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Erratum
Erratum of volume 54, issue 1
Errata do volume 54, número 1
On the headings of the pages of the Brazilian Journal of Rheumatology, v. 54, n. 1, where it reads:
REV BRAS REUMATOL 2013;54(1): and the number of the pages comprehending the article,
it should read:
REV BRAS REUMATOL 2014;54(1): and the number of the pages comprehending the article.
0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2014.05.002