RBR 54(2) - Sociedade Brasileira de Reumatologia

Transcription

ISSN 0482-5004
Impact Factor 2012: 0.864
© Thomson Reuters Journal Citation Reports,
Science Edition (2012)
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
MARCH/APRILt7PMVNFt/VNCFS
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www.reumatologia.com.br
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
Bimonthly Edition (Publicação Bimestral)
Editors (Editores)
Coeditors (Coeditores)
Max Victor Carioca Freitas
Eloísa Silva Dutra de Oliveira Bonfá
Mittermayer Barreto Santiago
Roberto Ezequiel Heymann
Hilton Seda
Paulo Louzada-Junior
Universidade Federal do Ceará, Fotaleza, CE, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil
Pontifícia Universidade Católica do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
João Carlos Tavares Brenol
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Ricardo Fuller
Simone Appenzeller
Universidade Estadual de Campinas, Campinas, SP, Brazil
Editorial Board (Conselho Editorial)
Acir Rachid
Geraldo da Rocha Castelar Pinheiro
Maurício Levy Neto
Universidade Federal do Paraná, Curitiba, PR, Brazil
Universidade do Estado do Rio de Janeiro,
Gilberto Santos Novaes
Alexandre Wagner S Souza
Natalino H. Yoshinari
Pontifícia Universidade Católica de São Paulo,
São Paulo, SP, Brazil
Ari Stiel Radu
Isídio Calich
Nílzio Antônio da Silva
Adil Muhib Samara
Milton Helfenstein Jr.
Carlos Alberto von Muhlen
Ivânio Alves Pereira
Percival Degrava Sampaio-Barros
Faculdade de Medicina da Pontifícia Universidade
Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
Universidade Federal de Santa Catarina,
Florianópolis, SC, Brazil
Claudia Goldenstein-Schainberg
Jamil Natour
Universidade Federal do Rio Grande do Sul,
Porto Alegre, RS, Brazil
Cláudio Arnaldo Len
João Francisco Marques Neto
Rina Dalva P. N. Giorgi
Clóvis Artur Almeida da Silva
Cristiano Augusto de Freitas Zerbini
Hospital Heliópolis, São Paulo, SP, Brazil
Daniel Feldman Polak
Durval Kraychete
Escola Bahiana de Medicina e Universidade
Federal da Bahia, Salvador, BA, Brazil
Eduardo de Souza Meirelles
Eduardo Ferreira Borba Neto
José Goldenberg
José Roberto Provenza
Jozélio Freire de Carvalho
Universidade Federal de Goiás, Goiânia, GO, Brazil
Ricardo M. Xavier
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
Roger A. Levy
Universidade Estadual do Rio de Janeiro,
Rosa Maria Rodrigues Pereira
Centro Médico Aliança, Salvador, BA, Brazil
Rozana Mesquita Ciconelli
Lais V. Lage
Samuel Katsuyuki Shinjo
Lilian Tereza Lavras Costallat
Sebastião Cézar Radominski
Luís Eduardo Coelho Andrade
Sheila Knupp de Oliveira
Emília Inoue Sato
Luiz Fernando de Souza Passos
Universidade Federal do Rio de Janeiro,
Universidade Federal do Amazonas, Manaus, AM, Brazil
Fernanda Rodrigues de Lima
Marcelo de Medeiros Pinheiro
Fernando Queiroz da Cunha
Maria Odete E. Hilário
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Francisco Airton Castro Rocha
Marta Maria das Chagas Medeiros
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Simone Appenzeller
Universidade de Campinas, Campinas, SP, Brazil
Vera Lúcia Szejnfeld
Wiliam H. Chahade
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
International Editorial Board (Conselho Editorial Internacional)
Ariel Masetto
Juan Manuel Anaya
Munther Khamashta
Université de Sherbrooke, Sherbrooke, Canada
Corporación de Investigaciones Biológicas, Medellín, Colômbia
St. Thomas´ Hospital, London, UK
Arthur Kavanaugh
Luis Javier Jara
H Ralph Schumacher Jr
University of California, San Diego, USA
Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
University of Pennsylvania, Philadelphia, USA
Bernardo Pons Estel
Mario Cardiel
Ricardo Cervera Segura
Universidad Nacional de Rosario, Rosario, Argentina
Instituto Nacional de la Nutrición "Salvador Zubiran",
Morrelia, Mexico
Hospital Clinic, Barcelona, Spain
Hospital Monte Sinai, Cuenca, Equador
Mario Garcia-Carrasco
Chapel Allerton Hospital, Leeds, UK
Ernest Choy
Facultad de Medicina, BUAP, Puebla, Mexico
Claudio Galarza Maldonado
King's College, London, UK
Mário Viana de Queiroz
Jordi Antón López
Universidade Clássica de Lisboa, Lisboa, Portugal
Hospital Sant Joan de Déu, Barcelona, Spain
Marvin Fritzler
José Antonio Melo Gomes
University of Calgary, Calgary, Canada
Instituto Português de Reumatologia, Lisboa, Portugal
Richard J Wakefield
Thomas Dörner
Charite Hospital, Berlin, Germany
Yehuda Shoenfeld
Chaim Sheba Medical Center, Tel Aviv University,
Tel Hashomer, Israel
BSR Office (Secretaria SBR)
Rogério Quintiliano Amaral
Av. Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94
CEP 01402-000
São Paulo, SP
Fone/fax: 55 (11) 3289-7165
E-mail: [email protected]; [email protected]
website: www.reumatologia.com.br
Brazilian Journal of Rheumatology is listed in Web of Science, MEDLINE,
LILACS, SciELO, Scopus and Index Copernicus databases. BJR is affiliated to the
International Committee of Medical Journal Editors.
A Revista Brasileira de Reumatologia é indexada nas bases de dados Web of
Science, MEDLINE, LILACS, SciELO, Scopus e Index Copernicus. A RBR é filiada
ao International Committee of Medical Journal Editors.
Brazilian Journal of Rheumatology (BJR) is an official publication of the Brazilian
Society of Rheumatology (BSR) in partnership with Elsevier Editora Ltda. and is
dedicated to the medical community in Brazil and Latin America.
Edited by Brazilian Society of Rheumatology.
Published by Elsevier Editora Ltda. © 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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Content dedicated to the medical community. Material de distribuição exclusiva à classe médica.
INSTRUCTIONS TO AUTHORS
The Brazilian Journal of Rheumatology (BJR), an official organ of Sociedade
Brasileira de Reumatologia (Brazilian Society of Rheumatology), was founded
in 1957 and is published bimonthly. The journal publishes original articles,
review articles, brief communications, case reports and letters to the editors.
To submit a manuscript, please access the site http://ees.elsevier.com/bjr.
Format of the manuscript
The manuscript can be submitted in Portuguese or English, double spaced,
with 2.5 cm margins. Unconventional abbreviations, medical jargon and
telegraphic style should not be used in the text. Citation of drugs and
pharmaceutical products must be done using pharmacological nomenclature,
without any mention to commercial names.
Manuscript structure
Manuscript*, Title Page*, Cover Letter, and Author Agreement* must be
submitted in separate files. Tables and Figures should be numbered as cited
in the text and sent in separate files with corresponding titles and legends.
(*required files)
Title page
The title page should contain: a) the full title; b) the full name of the authors
and 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.
Apenas às pessoas que contribuíram, por exemplo, com técnicas, discussão e
envio de pacientes. Auxílio financeiro deve ser referido na página do título.
Referências
Devem ser citadas no texto em algarismos arábicos, sobrescritos e depois da
pontuação, sem parênteses ou colchetes. A numeração deve ser sequencial,
de acordo com a ordem de citação no texto. Nas referências com mais de
seis autores, devem ser citados os seis primeiros, seguidos pela expressão
et al. Sugere-se a utilização dos programas Reference Manager ou Endnote,
seguindo-se o estilo Vancouver. Exemplos de referência para diferentes
formatos são apresentados a seguir. Os autores devem consultar o NLM’s
Citing Medicine para mais informações sobre os formatos das referências.
Artigo de revista
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Artigo extraído de endereço eletrônico
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink.com.w10069.dotlib.com.br/
content/l05j4j3332041225/fulltext. pdf. [Accessed in February 24, 2008].
Livro
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.
Tabelas e Figuras
Cada tabela ou figura deverá ser numerada em algarismo arábico e enviada
em arquivo separado (.jpg, .tif, .png, .xls, .doc) com 300 dpi no mínimo.
Título e legenda devem estar no mesmo arquivo da figura ou tabela a que se
referem. Tabelas e ilustrações devem ser autoexplicativas, com informações
suficientes para sua compreensão sem que se tenha de recorrer ao trabalho.
Fotomicrografias devem incluir a escala apropriada.
Artigo de Revisão
Revisões, preferencialmente sistemáticas, podem ser submetidas à RBR,
devendo abordar com profundidade um tema de interesse para o reumatologista. Não apresentam estruturação padronizada, prescindindo de introdução
ou discussão. Devem apresentar resumo sem subdivisões, com três a cinco
palavras-chave, e não devem exceder 6.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Podem
exibir até cinco figuras ou tabelas e até 70 referências.
Relato de Caso
Introdução
Deve incluir resumo e palavras-chave, sem necessidade de subdivisões. O texto,
porém, apresenta as seguintes seções: introdução, que deve ser concisa; relato de
caso, contendo a descrição e a evolução do quadro clínico, exames laboratoriais,
ilustrações e tabelas (que substituem as seções material e métodos e resultados);
e discussão. Deve conter no máximo seis autores, e não deve exceder 1.500
palavras, incluindo-se as referências e excluindo-se a página do título, resumo,
tabelas e legendas. Pode exibir até duas figuras ou tabelas e até 15 referências.
A finalidade dessa seção é definir o propósito e as razões para a realização
do trabalho. Não se recomenda extensa revisão da literatura.
Comunicação breve
Página de resumo
Deve conter: a) objetivo, métodos, resultados e conclusões, não excedendo
250 palavras; b) três a cinco palavras-chave.
Pacientes e métodos ou Material e métodos
Deve incluir informações suficientes que permitam a reprodução do trabalho e,
quando pertinente, a aprovação pelo Comitê de Ética institucional. Os métodos
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Discussão/Conclusão
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Conhecimento estabelecido e
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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:
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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.
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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
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General secretary (Secretário geral)
Francisco José Fernandes Vieira, CE
1st secretary (1º secretário)
Lauredo Ventura Bandeira, SP
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Rosa Maria Rodrigues Pereira, SP
Treasurer (Tesoureiro)
José Eyorand Castelo B. Andrade, CE
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Scientific director (Diretor científico)
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Elected president (Presidente eleito)
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Adil Muhib Samara, SP
Antônio Carlos Ximenes, GO
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Fernando Neubarth, RS
Geraldo da Rocha Castelar Pinheiro, RJ
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Hilton Seda, RJ
Iêda Maria Magalhães Laurindo, SP
João Carlos Tavares Brenol, RS
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Tânia Carolina Monteiro de Castro, SP
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Collaborator (Colaborador)
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Brazilian Journal of Rheumatology
Revista Brasileira de Reumatologia
Editors (Editores)
Max Victor Carioca Freitas, CE
Roberto Ezequiel Heymann, SP
Eloísa Silva Dutra de Oliveira Bonfá, SP
Hilton Seda, RJ
Mittermayer Barreto Santiago, BA
Paulo Louzada-Junior, SP
Ricardo Fuller, SP
Simone Appenzeller, SP
Representante junto ao Ministério da Saúde
Ana Patrícia de Paula, DF
Mário Soares Ferreira, DF
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João Elias Moura Jr., SC
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Ana Paula Vecchi, GO
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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
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José Caetano Macieira, SE
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Alexandre Wagner S. de Souza, SP
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Andreas Funke, PR
Carlos Ewerton Maia Rodrigues, CE
Danieli Castro Oliveira de Andrade, SP
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Cristiane Kayser Veiga da Silva, SP
Inês Guimarães Silveira, RS
Jamil Natour, SP
Karine Rodrigues da Luz, SP
Laura Maria C. Mendonça, RJ
Simone Appenzeller, SP
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André Luiz Shinji Hayata, SP
Ines Guimarães da Silveira, RS
Roberto Ranza, MG
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Ieda Maria Magalhães Laurindo, SP
Jozélio Freire de Carvalho, BA
Manoel Barros Bertolo, SP
Max Victor Carioca Freitas, CE
Nilzio Antônio da Silva, GO
Rina Dalva Neubarth Giorgi, SP
Rodrigo Aires Corrêa Lima, DF
Jamil Natour, SP
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Monique Sayuri Konai, SP
Rita Nely Vilar Furtado, SP
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Evandro Mendes Klumb, RJ
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Cristina Costa Duarte Lanna, MG
Eduardo Ferreira Borba Neto, SP
Eloisa Silva Dutra de Oliveira Bonfá, SP
Francinne Machado Ribeiro, RJ
Lilian Tereza Lavras Costallat, SP
Luiz Carlos Latorre, SP
Maria de Fátima Lobato da Cunha, PA
Odirlei Andre Monticielo, RS
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
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Charlles Heldan de Moura Castro, SP
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Laura Maria C. de Mendonça, RJ
Mailze Campos Bezerra, CE
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Vera Lúcia Szejnfeld, SP
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Célio Roberto Gonçalves, SP
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Washington Alves Bianchi, RJ
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Roberto Ranza, MG
Rubens Bonfiglioli, SP
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Rafael Mendonça da Silva Chakr, RS
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Lipe Goldenstein, BA
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Izaias Pereira da Costa, MS
Sandra Lucia Euzébio Ribeiro, AM
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Natalino Hajime Yoshinari, SP
Rejane Maria R. de Abreu, CE
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Percival Degrava Sampaio-Barros, SP
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Giselle Baptista Maretti, RJ
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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)
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Leandro Augusto Tanure, MG
Sandra Gofinet Pasoto, SP
Sandra Lucia Euzébio Ribeiro, AM
Virginia Fernandes Moça Trevisani, SP
Assisted Therapy Immunobiological
Centers Commission
(Comissão de Centros de Terapia
Imunobiológica Assistida)
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Members (Membros)
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Ana Teresa Amoedo Medrado, BA
Antonio Carlos Scafutto, MG
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Eliezer Rushansky, PE
Evelin D. Goldenberg M. M. da Costa, SP
José Eyorand Castelo B Andrade, CE
José Roberto Silva Miranda, SP
Manoel Barros Bertolo, SP
Rafael de Oliveira Fraga, MG
Ricardo Jorge de Percia Name, RJ
Vander Fernandes, MT
Supervisory Board (Conselho Fiscal)
Sociedade de Reumatologia de Rondônia
Dr. Liszt Jonney Silva dos Santos
Rheumatology Society of Espírito Santo
Sociedade de Reumatologia do Espírito Santo
Dr. José Roberto Pereira Santos
Rheumatology Society of Mato Grosso do Sul
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do Sul
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Rheumatology Society of Rio de Janeiro
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Rio Grande do Norte
Sociedade de Reumatologia
do Rio Grande do Norte
Dr. Francisco Deoclécio Damasceno Rocha
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Sociedade de Reumatologia
do Rio Grande do Sul
Dr. Marco Aurélio Goldenfum
Rheumatology Society of Tocantis
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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
Professional Defense Commission
BSR – Regionals
Rheumatology Society of Minas Gerais
(Comissão de Defesa Proﬁssional)
Regionais – SBR
Rheumatology Society Mato Grosso
Sociedade Mineira de Reumatologia
Dr. Boris Afonso Cruz
Francisco Deoclécio D. Rocha, RN
Vander Fernandes, MT
Associação Mato-Grossense de Reumatologia
Dr. Eduardo Benevides Lindote Filho
Members (Membros)
Rheumatology Society of Alagoas
Francisco Alves Bezerra Neto, RN
Matheus Staufackar Carlos, RN
Inês Cristina de Mello Lima, AL
Mauro Furtado Cavalcante, PI
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
Sociedade Amazonense de Reumatologia
Dra. Maria do Socorro A. de Souza
Members (Membros)
Rheumatology Society of Bahia
Antonio José Lopes Ferrari, SP
Ana Beatriz Vargas dos Santos, RJ
Hellen Mary da Silveira de Carvalho, DF
Sociedade Baiana de Reumatologia
Dr. Mittermayer Barreto Santiago
Endemic and Infectious
Diseases Commission
(Comissão de Doenças
Endêmicas e Infecciosas)
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 Santa Catarina
Rheumatology Society of Piauí
Sociedade Catarinense de Reumatologia
Sonia Cristina de Magalhães Souza Fialho
Sociedade Piauiense de Reumatologia
Dra. Aline do Socorro Miranda Ribeiro
Rheumatology Society of Ceará
Rheumatology Society of Sergipe
Sociedade Cearense de Reumatologia
Dr. José Eyorand Castelo Branco de Andrade
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:
REVISTA BRASILEIRA DE
REUMATOLOGIA
Volume 54. Number 2. March/April 2014
Volume 54. Número 2. Março/Abril 2014
CONTENTS | SUMÁRIO
Original articles | Artigos originais
Effects of one minute and ten minutes of walking activity in rats with arthritis induced by
complete Freund’s adjuvant on pain and edema symptoms
Efeitos de um minuto e dez minutos de deambulação em ratos com artrite induzida por adjuvante completo de
Freund sobre os sintomas de dor e edema
Raquel Pinheiro Gomes, Elisângela Bressan, Tatiane Morgana da Silva, Monique da Silva Gevaerd,
Carlos Rogério Tonussi, Susana Cristina Domenech ...................................................................................
83
Study of self-medication for musculoskeletal pain among nursing and medicine students at
Pontifícia Universidade Católica - São Paulo
Estudo da automedicação para dor musculoesquelética entre estudantes dos cursos de enfermagem e medicina da
Pontifícia Universidade Católica - São Paulo
José Eduardo Martinez, Giovanni Augusto Farina Pereira, Luiz Gustavo Martinelli Ribeiro,
Ricardo Nunes, Daniel Ilias, Luiz Gustavo Moretti Navarro ......................................................................
90
Translation, cultural adaptation and validation into Portuguese (Brazil) in Systemic Sclerosis
Questionnaire (SySQ)
Tradução, adaptação cultural e validação para a língua portuguesa (Brasil) do Systemic Sclerosis
Questionnaire (SySQ)
Roberta Ismael Lacerda Machado, Lais Medeiros Souto, Eutilia Andrade Medeiros Freire ........................
95
Immediate infusional reactions to intravenous immunobiological agents for the treatment of
autoimmune diseases: experience of 2126 procedures in a non-oncologic infusion centre
Reações infusionais imediatas a agentes imunobiológicos endovenosos no tratamento de doenças autoimunes:
experiência de 2.126 procedimentos em um centro de infusão não oncológico
Ingrid Bandeira Moss, Monique Bandeira Moss, Debora Silva dos Reis, Reno Martins Coelho .................
102
Is swimming able to maintain bone health and to minimize postmenopausal bone resorption?
A natação é capaz de manter a saúde do tecido ósseo e minimizar a reabsorção óssea pós menopausa?
Tâmara Kelly Delgado Paes Barreto, Fabiana Soares Bizarria, Marcos Paulo Galdino Coutinho,
Patrícia Verçoza de Castro Silveira, Karina de Carvalho da Silva, Ana Cristina Falcão Esteves,
Sílvia Regina Arruda de Moraes ................................................................................................................
110
Protocol for physical assessment in patients with fibromyalgia syndrome
Protocolo para avaliação física em portadores de síndrome de fibromialgia
Michele R. dos Santos, Claudia M.C. Moro, Dilmeire S.R. Vosgerau ..........................................................
117
Periodontitis exposure within one year before anti-diabetic treatment and the risk of
rheumatoid arthritis in diabetes mellitus patients: a population-based cohort study
Exposição à periodontite no intervalo de um ano antes do tratamento antidiabético e risco de artrite reumatoide
em pacientes com diabete mellitus: estudo de coorte populacional
Hsin-Hua Chen, Der-Yuan Chen, Shih-Yi Lin, Kuo-Lung Lai, Yi-Ming Chen, Yiing-Jenq Chou,
Pesus Chou, Ching-Heng Lin, Nicole Huang .............................................................................................
124
Review articles | Artigos de revisão
Incidence of neoplasms in the most prevalent autoimmune rheumatic diseases:
a systematic review
Incidência de neoplasias nas doenças reumatológicas autoimunes mais prevalentes: uma revisão sistemática
Roberta Ismael Lacerda Machado, Alessandra de Sousa Braz, Eutilia Andrade Medeiros Freire ..............
131
Evaluation protocols of hand grip strength in individuals with rheumatoid arthritis:
a systematic review
Protocolos de avaliação da força de preensão manual em indivíduos com artrite reumatoide:
uma revisão sistemática
Ana Paula Shiratori, Rodrigo da Rosa Iop, Noé Gomes Borges Júnior, Susana Cristina Domenech,
Monique da Silva Gevaerd .........................................................................................................................
140
Case reports | Relatos de caso
Chronic lymphomonocytic meningoencephalitis, oligoarthritis and erythema nodosum:
report of Baggio-Yoshinari syndrome of long and relapsing evolution
Meningoencefalite linfomonocitária crônica, oligoartrite e eritema nodoso: relato de síndrome de Baggio-Yoshinari
de longa e recorrente evolução
Nilton Salles Rosa Neto, Giancarla Gauditano, Natalino Hajime Yoshinari ...................................................
148
Severe leukopenia in a rheumatoid arthritis patient treated with a methotrexate/leflunomide
combination
Leucopenia grave em paciente com artrite reumatoide tratada com combinação de metotrexato e leflunomida
Paola Toth, Roberto Bernd ...............................................................................................................................
152
Fatal cryptococcal meningitis in a juvenile lupus erythematosus patient
Meningite criptocócica fatal em paciente com lúpus eritematoso sistêmico juvenil
Erica G. Cavalcante, João D. Montoni, Guilherme T. Oliveira, Lucia M.A. Campos, Jose A. Paz,
Clovis A. Silva ..................................................................................................................................................
155
Erratum | Errata
Erratum of the erratum of “Guidelines for the diagnosis of rheumatoid arthritis”
Errata da errata de “Diretrizes para o diagnóstico da artrite reumatoide”
Licia Maria Henrique da Mota, Bóris Afonso Cruz, Claiton Viegas Brenol, Ivânio Alves Pereira,
Lucila Stange Rezende-Fronza, Manoel Barros Bertolo, Max Vitor Carioca Freitas, Nilzio Antônio da Silva,
Paulo Louzada-Junior, Rina Dalva Neubarth Giorgi, Rodrigo Aires Corrêa Lima, Ronaldo Adib Kairalla,
Alexandre de Melo Kawassaki, Wanderley Marques Bernardo, Geraldo da Rocha Castelar Pinheiro ...........
159
Erratum of “Adalimumab in rheumatoid arthritis treatments: a systematic review and
meta-analysis of randomized clinical trials”
Errata de “Adalimumabe no tratamento da artrite reumatoide: uma revisão sistemática e metanálise de ensaios
clínicos randomizados”
Marina Amaral de Ávila Machado, Alessandra Almeida Maciel, Lívia Lovato Pires de Lemos,
Juliana Oliveira Costa, Adriana Maria Kakehasi, Eli Iola Gurgel Andrade, Mariangela Leal Cherchiglia,
Francisco de Assis Acurcio ..............................................................................................................................
160
Erratum of “Psychiatric comorbidities in patients with systemic lupus erythematosus:
a systematic review of the last 10 years”
Errata de “Comorbidades psiquiátricas em pacientes com lúpus eritematoso sistêmico: uma revisão sistemática
dos últimos 10 anos”
Nadja Maria Jorge Asano, Maria das Graças Wanderley de Sales Coriolano, Breno Jorge Asano,
Otávio Gomes Lins ..........................................................................................................................................
161
Erratum of “Enteropathic arthritis in Brazil: data from the Brazilian Registry of
Spondyloarthritis”
Errata de “Artrite enteropática no Brasil: dados do Registro Brasileiro de Espondiloartrites”
Gustavo G. Resende, Cristina C. D. Lanna, Adriana B. Bortoluzzo, Célio R. Gonçalves,
Percival D. Sampaio-Barros, José Antonio Braga da Silva, Antonio Carlos Ximenes, Manoel B. Bértolo,
Sandra L. E. Ribeiro, Mauro Keiserman, Rita Menin, Thelma L. Skare, Sueli Carneiro,
Valderílio F. Azevedo, Walber P. Vieira, Elisa N. Albuquerque, Washington A. Bianchi,
Rubens Bonfiglioli, Cristiano Campanholo, Hellen M. S. Carvalho, Izaias P. Costa, Angela P. Duarte,
Charles L. Kohem, Nocy Leite, Sonia A. L. Lima, Eduardo S. Meirelles, Ivânio A. Pereira,
Marcelo M. Pinheiro, Elizandra Polito, Francisco Airton C. Rocha, Mittermayer B. Santiago,
Maria de Fátima L. C. Sauma, Valeria Valim .................................................................................................
162
R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 2 ) : 8 3 – 8 9
REUMATOLOGIA
Original article
Effects of one minute and ten minutes of walking activity in
rats with arthritis induced by complete Freund’s adjuvant on
pain and edema symptoms
Raquel Pinheiro Gomesa, Elisângela Bressanb, Tatiane Morgana da Silvaa,
Monique da Silva Gevaerda, Carlos Rogério Tonussib, Susana Cristina Domenecha,*
a
Multisetorial Analyses Laboratory, Department of Health Sciences, Center of Health & Sports Sciences, Universidade do Estado de Santa
Catarina (UDESC), Florianópolis, SC, Brazil
b
Laboratory of Neurobiology of Nociception, Department of Pharmacology, Universidade Federal de Santa Catarina (UFSC), Florianópolis,
SC, Brazil
article info
abstract
Article history:
This study evaluated the effects of two protocols of exercise on nociception, edema and
Received 9 February 2013
cell migration in rats with CFA-induced arthritis. Female Wistar rats (200 – 250 g, n = 50)
Accepted 14 July 2013
was monoarthritis-induced by complete Freund’s adjuvant (CFA; Mycobacterium butyricum,
0.5 mg/mL; 50 μL) into the right knee joint (TF; n = 24) or right ankle joint (TT; n = 26). Inca-
Keywords:
pacitation was measured by the paw elevation time (TEP; s) in 1-min periods of observation.
Physical activity
The edema of the knee or ankle joints was evaluated by the variation of the articular diam-
Arthritis
eter (DA, cm) and by the paw volume variation (EP, mL), respectively. Both were measured
Articular incapacitation
during 10 consecutive days. Two protocols of exercise were performed: (a) in the constant
CFA
exercise group (TF, n = 6; TT, n = 6) performing 1 minute of daily exercise on the cylinder; (b)
variable exercise group (TF, n = 6; TT, n = 7), the exercise increased by 1 minute per day. The
control groups (TF, n = 12; TT, n = 13) didn´t perform the exercise. After 10 days, the animals
were euthanized for total (CT; cells/mm3) and differential leukocyte counts (mononuclear
— MON, and polymorphonuclear — PMN, cells/mm3) of the articular inflammatory exudate.
The variable exercise protocol inhibited incapacitation and edema for both joints. However,
cell migration decreased only in the TF. The constant exercise reduced edema in both joints,
and cell migration was decreased in the TT. However, the incapacitation was not reduced.
Variable exercise seemed to be more effective in reducing the inflammatory parameters
than constant exercise.
© 2014 Elsevier Editora Ltda. All rights reserved.
* Corresponding author.
E-mail: [email protected] (S.C. Domenech).
0482-5004/$ - see front matter. © 2014 Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2014.03.001
84
Efeitos de um minuto e dez minutos de deambulação em ratos com
artrite induzida por adjuvante completo de Freund sobre os sintomas de
dor e edema
resumo
Palavras-chave:
Este estudo avaliou o efeito de dois protocolos de exercício na nocicepção, edema e migração
Atividade física
celular em ratos com artrite induzida por CFA. Ratos Wistar fêmeas (200 – 250 g, n = 50) foram
Artrite
induzidos à monoartrite por adjuvante completo de Freund (CFA, Mycobacterium butyricum;
Incapacitação articular
0,5 mg/mL; 50 μL) na articulação do joelho direito (TF; n = 24) ou tornozelo direito (TT; n = 26).
CFA
A incapacitação articular foi mensurada pelo tempo de elevação da pata (TEP; s) em 1 minuto
de avaliação. O edema do joelho ou tornozelo foi avaliado pela medida do diâmetro articular
(AD, cm) e pelo edema de pata (EP, mL), respectivamente. Ambos foram avaliados durante
10 dias consecutivos. Dois protocolos de exercício foram realizados: (a) exercício constante
(TF, n = 6; TT, n = 6), realizando 1 minuto diário de exercício no cilindro (3 r.p.m.); (b) exercício variável (TF, n = 6; TT, n = 7), exercício com aumento de 1 minuto por dia, totalizando 10
minutos no último dia. Os grupos-controle (TF, n = 12; TT, n = 13) não realizaram exercício.
Após 10 dias, os animais foram eutanasiados para contagem total (células/mm3) e diferencial
(mononucleares e polimorfos nucleares; células/mm3) de leucócitos do tecido inflamado. O
exercício variável inibiu a incapacitação e o edema em ambas as articulações. Entretanto,
reduziu a migração total de leucócitos apenas na articulação TF. O exercício constante inibiu
o edema nas duas articulações e reduziu a migração total de leucócitos da articulação TT.
Porém, não reduziu a incapacitação. O exercício variável pareceu ser mais efetivo em reduzir
os parâmetros inflamatórios em comparação com o exercício constante.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Considering the functional limitations resulting from rheumatoid arthritis (RA), early diagnosis and prompt treatment
are essential for the control of disease activity and for the
disability and irreversible joint damage prevention.1 In clinical practice, usually the patient starts treatment in the acute
phase only with analgesic action and after the reduction of
pain and swelling, starts the process of carefully strengthening joint protection. Only at a late stage the patients begin
physical reconditioning.1 Until recently, health professionals (physicians, physiotherapists and others) suggested that
their RA patients avoid exercise and keep resting.2 Meanwhile, it is still advisable not to perform exercises during
crises.3 However, the chronic nature of RA leads to inactivity
that can cause muscle weakness, joint stiffness and limitation of joint movement.4
Studies published by Vlieland suggest that patients with
rheumatoid arthritis can benefit from physical activity safely.5
Shih and colleagues also argue that the practice of physical
activity has shown benefits for individuals with RA, by significantly decreasing pain and improving gait and overall
function.6 Thus, physical activity seems to be associated with
better quality of life among individuals with arthritis.7 Considering the degree of physical and mental impairment, the
disabling potential of RA and the improve of quality of life
generated by physical activity, research has become necessary to verify the influence of exercise on the functional clinical status of patients with this disease, even in small daily
doses of movement.
Studies performed in humans are difficult to control, because repeated tests become strenuous and drug intake or
daily habits can interfere with the inflammatory process and
the response to exercise. In vivo studies in animals, using experimental models of arthritis induction, may produce more
information on this issue. The induced arthritis by Complete
Freund's Adjuvant (CFA) is a suitable model, because it mimics the signs and symptoms of human RA, including histopathological changes, cellular infiltration, hypersensitivity
and edema in the affected joint.8 Thus, this study aims to
evaluate the effect of daily walking activity, lasting 1 minute
and 10 minutes, on the parameters of disability, joint swelling
and leukocyte migration into the knee joint or ankle of rats
with CFA induced arthritis.
Materials e methods
Animals
The experiments were performed using female Wistar (250300 g) rats, aged approximately two months, allocated in standardized boxes, containing six animals per box, animals were
kept at controlled temperature (20 ± 1°C) and with a dark/light
cycle of 12 h using artificial lighting. The animals were fed
with standard laboratory food and water was available ad libitum. All experiments were conducted according to the ethical
guidelines of the International Association for Study of Pain
(IASP) and approved by the local Ethics Committee for Animal
(se (CEUA - UFSC, protocol number 1160066, and CETEA/CAV UDESC protocol number 01/26/06).9
Drugs and reagents
The following substances were used: Complete Freund's Adjuvant - CFA Mycobacterium tuberculosis (1 mg/mL, Sigma®),
Freund's Complete Adjuvant - CFA Mycobabterium butyricum
(0.5 mg/mL, Difco®); sodium chloride isotonic solution (0.9%,
Aster®), halothane gas (250 mL, 1:1 v/v, 2- 4%, diluted in hospital O2, Cristalia®), iodinated alcohol (1%, Rialcool®), aqueous
solution of lauryl sulphate (2.5%, Vetec®).
85
nuclear cells, PMN, polymorphonuclear) using an optical microscope (100 × magnification). Data was expressed as MON/
mm3 and PMN/mm3. Immediately after collection of pure synovial fluid, the joint cavity was washed with 100 mL of 0.9%
saline containing EDTA (5%) and then it was diluted in Turk
solution (1:20) for 5 minutes. This fluid was used for total
leukocyte count (TC; cells/mm3), with the aid of a Neubauer
chamber and an optical microscope (40× magnification).11 The
synovial fluid collection for leukocyte count was performed
only on the 10th day of the experiment.
Joint incapacitation test
Experimental procedures
Joint disability was measured using the right paw elevation
time (PET), in seconds, with the help of the registry system
proposed by Ferreira and Tonussi, which allows the evaluation of nociception declared by animals.10 In this log system,
the animals are forced to walk on a stainless steel cylinder (30
cm in width and 30 cm in diameter) rotating continuously at
a constant speed of 3 rpm for 60 seconds. Metallic shoes were
adjusted on the hind legs; only the right paw shoe was connected to a computer to record the total time of non-contact
of the paw with the surface of the cylinder during a period of
60 seconds. The animals were accustomed to the shoes, by
placing them on the animals for at least one hour before testing. The PET of naïve animals, that is, without any intra-articular treatment, is approximately 10 seconds. The increase
in PET after intra-articular injection of phlogistic agents indicates development of joint disability.10 PET was registered
immediately before stimulation with CFA (baseline value) and
after 24 h, during all days of the experiment.
Assessment of joint swelling
After CFA induction of arthritis, the rats were monitored daily
for joint swelling. For the evaluation of tibiofemoral joint swelling (TF), the change in joint diameter (JD cm) was registered
with the help of a non digital caliper (accuracy, 0.05 mm).11 The
evaluation of the tibiotarsal joint (TT) or paw edema (EP mL)
was carried out with the aid of a plastic bucket filled with lauryl sulphate in water (2.5%) coupled to a precision electronic
balance (Acculab, V-121). For this procedure, the animal was restrained with the help of a polyethylene cone and its paw was
inserted to immediately above the tibiotarsal joint.
The displacement of the liquid column inside the bucket
was registered in milliliters. Each gram of paw weight corresponds to 1 mL of liquid displaced from the bucket.12 To ensure that the measurements were made at exactly the same
articulation, daily markings were done using a waterproof
pen. The edema was measured immediately before stimulation with CFA (baseline measurement) and after 24h, before
the evaluation of joint incapacitation at each day of the experiment.
Synovial fluid leukocyte count
After euthanasia, the joint capsule was exposed to collect 5
mL of synovial fluid to prepare synovial fluid smears on glass
slides. The smear of synovial fluid from each animal was
stained with May-Grünwald stain and Giemsa, which was
used to obtain the differential leukocyte count (MON, mono-
Arthritis induction was performed by two injections of CFA
(Mycobacterium butyricum, 0.5 mg/mL, 50 μL). The first injection, administered intradermally (id), was given at the base
of the tail. The second injection, administered intra-articularly (i.art), was given at the femorotibial (TF, n = 24) or tibiotarsal (TT, n = 26) joint of the animals, 21 days after the
first injection of CFA. For both injections, the animals were
anesthetized with halothane gas (3%).
The animals were subdivided into the following groups:
experimental (E1 or E10), groups of constant and variable exercise respectively, and controls (C1 and C10) of constant and
variable groups, respectively.
The animals in the experimental group underwent two
exercise protocols: A) constant exercise, in which the animals performed 1 minute of daily walking activity for 10 consecutive days, and B) variable exercise in which the animals
performed the ambulation exercise with gradual increase of
1 minute per day, to the amount of ten minutes in the 10th
(consecutive) day. Both protocols were performed in a stainless steel cylinder at 3 rpm of continuous speed.
The animals in the control groups (C1 and C10) did not
excercise. With the exception of the 1st, 5th and 10th days,
when they were evaluated for joint incapacitation. However,
these animals were handled daily only for edema assessment . Also, they were placed daily in the cylinder (without
movement), with the objective of exposing them to the apparatus, which can be a source of stress for these animals.
The data for edema (JD or EP) was expressed as the difference between the baseline measurement and the measures
taken each day during the 10 days of evaluation. The data for
disabling joint (PET) were expressed as they were measured;
this way, the "day zero" corresponds to the baseline measurement and the subsequent days correspond to the ten
days of exercise treatment. At the end of the experiments,
on the 10th day, the analysis of synovial fluid leukocyte
count (MON, PMN and TC) was performed.
Statistical analysis
The results obtained were analysed with the Shapiro-Wilk
test to verify the normality of the data. Later the Student t
test was applied to detect differences between experimental groups (E1 and E10) and their respective controls (C1 and
C10) at a significance level of 5%. Statistical analysis was performed using SPSS for Windows® v.20.0.
86
Constant exercise
According to the results, constant exercise caused a decrease
in PET during the experiment for TF joint, but no significant
differences were observed compared to the control group. For
TT joint, there was only a trend towards the reduction of PET
on the 10th day compared to the control group (Fig. 1A and A’).
For the joint swelling assessment, it was found that walking for 1 minute produced a significant reduction of JD in TF
joint (p <0.001) and of EP in TT joint (p < 0.001) against controls
during all the experimental time (Fig. 1B and B’).
In leukocyte migration, constant exercise produced no
significant change in the TF joint compared to control group.
However, in TT joint a significant reduction in leukocyte migration was noted, both for TC, as for PMN and MON, in the E1
group compared to the C1 group (Fig. 1C and C’).
Variable exercise
PET(s)
50
40
30
20
10
0
0
1
2
A'
60
3 4 5 6 7 8
Time after CFA (days)
CFA TT E1
PET(s)
50
40
30
20
10
0
0.8
B
In the present study we observed that exercise, especially
the variable modality, had an effect in nociception reduction at the two joints evaluated. Additionally, both exercise
protocols, constant and variable, demonstrated an effect on
edema reduction at these two joints. The constant exercise
decreased the amount of leukocytes only in TT joint. The
variable exercise reduced the number of leukocytes in TF
joint, showing only a statistical trend for TT joint, regardian
a decrease of mononuclear cells. This shows that exercise
has some effect in reducing the inflammatory exudate.
Several studies in the literature6,7,13-18,22 show that exercise in patients with arthritis decreases their pain, regulates blood pressure, increases muscle and bone strength,
increases lean mass and decreases fat mass, improving
psychological well-being, reducing the risk of depression
and improving moods.13 According to the U.S. Department
of Health and Human Services, these benefits occur with-
CFA TF C1
CFA TF E1
0.6
0.4
***
0.2
0.0
0
9 10
CFA TT C1
1.0
Discussion
1.6
1.4
1.2
1
2
B'
***
0.6
0.4
0.2
0
1
2
3 4 5 6 7 8 9 10
0 1
2
3 4 5 6 7 8 9 10
C
CFA TF C1
CFA TF E1
20
15
10
0
30
CFA TT C1
CFA TT E1
0.8
25
5
3 4 5 6 7 8 9 10
1.0
0.0
30
cells x 103/mm3
CFA TF C1
CFA TF E1
Joint swelling (mL)
A
60
Articular diameter (cm)
The results revealed that variable exercise caused a reduction
in PET during the experiment for TF joint, but with a significant difference compared to the control group in the 10th day
of evaluation (p < 0.01). But in TT joint we observed a significant decrease in PET control group (p < 0.01) from the fifth day
of evaluation on (Fig. 2A and A’).
The variable exercise protocol also promoted a significant
reduction of JD in TF joint (p < 0.001) and of EP in TT joint
(p < 0.001), when compared to the control group during the
whole time of the experiment (Fig. 2B and B’).
As for the leukocyte migration, the variable exercise protocol significantly reduced the concentration of TC (p ≤ 0.01),
PMN (p ≤ 0.01) and MON (p ≤ 0.05) in TF joint compared to
the control group. On the other hand, in TT joint a significant change in the leukocyte migration due to the variable
exercise was not observed. There could only be seen a trend
toward reduction of mononuclear cells (Fig. 2 C and C’).
cells x 103/mm3
Results
25
MON
C'
PMN
TC
CFA TT C1
CFA TT E1
20
15
**
10
5
0
*
MON
**
PMN
TC
Fig. 1 – Effect of constant exercise on joint disability (A and A’), on swelling (B, B’) and on leukocyte migration of (MON,
mononuclear cells, PMN, polymorphonuclear, and TC, total cells) (C and C’) of tibiofemoral (above, CFA TF E1) and tibiotarsal
(below, CFA TT E1) joints of female rats with CFA-induced (0.5 mg/mL, Mycobabterium butyricum, 50 μL) arthritis. The control
groups (CFA TF C1 and CFA TT C1) did not carry out the exercise. Both groups received intra-articular CFA (n = 25). * p ≤ 0.05,
Student’s t test for independent samples.
87
PET(s)
50
40
30
20
**
10
0
0
1
2
3 4 5 6 7 8
0.8
CFA TF C10
CFA TF E10
0.6
0.4
***
0.2
0.0
9 10
30
B
cells x 103/mm3
CFA TF C10
CFA TF E10
Articular diameter (cm)
1.0
A
60
25
15
10
1
2
3 4 5 6 7 8 9 10
0
40
30
**
20
**
10
0
B'
1.4
CFA TT C10
CFA TT E10
1.2
1.0
0.8
0.6
0.4
***
0.2
0
1
2
3
4
5
6
7
8
9 10
0.0
0
1
2
3
4
5
6
7
8
9
10
cells x 103/mm3
PET(s)
50
1.6
Joint swelling (mL)
A'
60
**
5
0
CFA TF C10
CFA TF E10
20
30
CFA TT C10
CFA TT E10
C
25
**
*
MON
C'
PMN
TC
CFA TT C10
CFA TT E10
20
15
10
5
0
MON
PMN
TC
Fig. 2 – Effect of constant exercise on joint disability (A and A’), on swelling (B, B’) and on leukocyte migration (MON,
mononuclear cells, PMN, polymorphonuclear, and TC, total cells) (C and C’) of tibiofemoral (above, CFA TF E10) and
tibiotarsal (below, CFA TT E10) joints of female rats with CFA-induced (0.5 mg/mL, Mycobabterium butyricum, 50 μL) arthritis.
The control groups (CFA TF C10 and CFA TT C10) did not carry out the exercise. Both groups received intra-articular CFA
(n = 26). * p ≤ 0.05, Student’s t test for independent samples.
out adverse effects on immune function or in the disease
state.13
More specifically in relation to the analgesic effects of
exercise, other studies have shown that physical activity decreases pain in patients with RA.2,6,7,14-18 Astrand, in his studies,
suggested that physical activity is a therapeutic modality for
pain relief in patients with RA, bringing benefits in mobility
of periarticular structures, including joint capsules, tendons
and muscles.18 Ekdhal et al. suggest that this hypoalgesic effect is due to the release of β-endorphins caused by exercise.19
However, in our experiment we did not verify the possibility
of endorphins release.
On the other hand, studies of Raja et al. argue that mobilization within the limits of range of motion in an inflamed
joint can lead to sensitization of primary afferent nociceptors, and even a slight movement of the joint can cause pain.20
Schaible and Grubb agree with this theory, assuming that in
the disease associated with joint pain, this feeling is induced
or aggravated during movement.21 Taking into account that
the joint incapacitation test evaluates spontaneous pain during mobilization, the results obtained in this study regarding
variable exercise effects contradict these theories, showing
that nociception was reduced in the animals that took part in
the exercise. Even in relation to the constant exercise, where
no statistical significance was perceived, the curve showed a
tendency to decrease nociception.
It is noteworthy that in this study a monoarthritis was
created, i.e., the induction of arthritis in only one paw; during the walking activity in the joint incapacitation test, the
animals remained with three "pain-free" paws for support.
In this case, it is not possible to say that these animals did
not feel pain in the other paws. In humans, this would not be
possible, because of the bipedal support and the symmetrical characteristic of RA. These considerations complicate the
linking of these findings to humans; however, it is believed
that, even with these differences, the performance of physical activity contributes effectively to a clinical improvement
in RA, in view of the large number of publications, including
papers in humans, advocating this practice.6,7,13-18,22
Although rehabilitation programs consider therapeutic exercises for the treatment of RA symptoms, as far as we know
there is no research carried on the reduction of edema and
leukocyte migration promoted by exercise.22 On the contrary,
some authors, like Marques and Kondor, claim that the increase in edema in patients with osteoarthritis is indicative
of excessive exercise.23 According to Kavuncu and Evcik, walking can increase the intra-articular pressure in patients with
knee inflammation and swelling, and that this activity should
be performed only at remission of the disease.22
Animal studies developed by Butler et al. showed that after
six injections of 0.05 mL of CFA containing 300 mg of Mycobacterium butyricum in a TT joint of rats submitted to a protocol
of progressive swimming (increasing from 5 to 15 minutes)
with frequency of three times a week for 4 weeks, no change
was perceived with respect to joint swelling and mobility.
However, regarding the pain threshold in response to the paw
pressure test, a decrease was observed in the experimental
versus control group.24
These studies contradict the results presented in this paper. However, the type of physical activity, the intensity of exercise performed or even the form of assessment chosen may
have contributed to these differences. The evaluation of pain
88
threshold used by Butler et al. is not a model that evaluates
the spontaneous pain caused by movement.24
Lana et al. studied the effects of high and low intensity
exercise on the acute inflammatory response to induced arthritis in Wistar rats.25 The exercises consisted of walking on
a treadmill; the low-intensity activity consisted of 60 minutes
of treadmill/day at a speed of 5 m/min for 12 weeks, and the
high-intensity activity consisted of a progressive training
that, at the end of the experiment, reached a cumulative time
of 75 min and a speed of 25 m/ min.
The inflammatory response was induced by carrageenan
(0.5%, 0.1 mL, TT) and the inflammatory edema volume was
measured by plethysmography 24 hours after induction.
Compared to untrained animals, an increase in the volume
of acute inflammatory edema in animals that underwent
low intensity activity was observed; however, the response
was more evident in animals that underwent high-intensity
exercise.
The authors admit that exercise is a form of stressful
stimulus that could promote changes in homeostasis, with
the reorganization of responses mainly in the neuroendocrine system, probably generating an increase of endogenous
glucocorticoids concentration in serum. However, this was
not observed with high-intensity exercise, which, according
to the authors, gives evidence of the influence of intensity,
frequency and duration of exercise on edema.25 It is noteworthy that this study evaluated a lasting activity in an acute inflammatory response, which makes difficult the comparison
against the findings obtained in the present study.
Indeed, the type of physical activity and the exercise intensity can interfere with the results obtained in RA patients.
Rall and Roubenoff suggest that during the active phase of
the disease, exercises with no weight-lifting are suitable and
that in those patients with controlled disease, activities with
load may be prescribed.26 In fact, very vigorous exercise is not
recommended for patients with active disease.15 The Expert
Arthritis and Physical Activity Panel at a meeting held in 2003
by specialists recommend that people with arthritis should
safely perform 30 minutes of physical activity of moderate intensity at least three times a week.27
Finally, the proposal of this experiment was to demonstrate that a small amount of exercise performed from the
beginning of the disease does not affect the joint and also can
benefit in nociception and in the parameters of joint inflammation, such as edema and leukocyte migration. However,
this study was performed in animals, which makes it difficult
to relate to humans. A continuation of the study is suggested
in humans, to evaluate different types of physical activity,
or even different walking times, with frequent evaluation of
pain and edema in patients with rheumatoid arthritis.
Conclusion
In conclusion, the walking activity, especially the variable modality, decreased nociception, edema and leukocyte migration
in animals with CFA-induced arthritis. These data show that
exercises can be performed shortly after the establishment
of the diagnosis of RA, without risk of joint injury; the exercise is useful as adjunctive treatment of the disease and has
great importance for the prognosis, as well as for improving
the quality of life of patients.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES
1. Laurindo IMM, Pinheiro GRC, Ximenes AC, Bertolo MB,
Xavier RM, Giorgi RDN et. al. Consenso Brasileiro para o
Diagnóstico e Tratamento da Artrite Reumatoide. Rev Bras
de Reumatol. 2002;42:355-361.
2. Benhamou M-AM. Reconditioning in patients with
rheumatoid arthritis. Ann Readapt Med Phys. 2007;50:382385.
3. Cailliet R. Dor no joelho. 3th ed. Porto Alegre: Artmed
editora; 2001.
4. Carvalho MRP, Salles CAF, Tebexreni AS, Barros Neto TL,
Confessor YQ, Natour J. Artrite reumatoide: treinamento
cardiovascular. Rev Bras de Reumatol. 2000;40:77-80.
5. Vlieland TPM. Rehabilitation of people with rheumatoid
arthritis. Best Pract Res Clin Rheumatol. 2003;17:847-861.
6. Shih M, Hootman JM, Kruger J, Helmick CG. Physical activity
in men and woman with arthritis. National Health Interview
Survey, 2002. Am J Prev Med. 2006;30:385-393.
7. Abell JI, Hootmann JM, Zack MM, Moriarty D, Helmick CG.
Physical activity and health related quality of life among
people with arthritis. J Epidemiol Community Health.
2005;59:380-385.
8. Barton NJ, Stevens DA, Hughes JP, Rossi AG, Chessell IP,
Reeve AJ et al. Demonstration of a novel technique to
quantitatively assess inflammatory mediators and cells in
rat knee joints. J Inflamm 2007. 4(13). Available from http://
www.journal-inflammation.com/content/4/1/13/ [Accessed
in February 8, 2013].
9. IASP (International Association for Study of Pain). Ethical
guidelines for investigation of experimental pain in
conscious animals. Pain. 1983;16:109-10.
10. Tonussi CR, Ferreira SH. Rat knee-joint carrageenin
incapacitation test: an objective screen for central and
peripheral analgesics. Pain. 1992;48:421-7.
11. Bressan E, Cunha FQ, Tonussi CR. Contribution of TNFa,
IL-1b and CINC-1 for articular incapacitation, edema and
cell migration in a model of LPS-induced reactive arthritis.
Cytokine. 2006;36:83-89.
12. Daher JB, Melo MD, Tonussi CR. Evidence for a spinal
serotonergic control of the peripheral inflammation in the
rat. Life Sci. 2005;76:2349-2359.
13. U.S. Department Of Health And Human Services. Healthy
People 2010: Understanding and Improving Health. 2nd
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2000. Available from http://www.healthypeople.gov/2010/
document/pdf/uih/2010uih.pdf?visit=1 [Accessed in
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14. Rall LC, Roubenoff R. Benefits of exercise for patients with
rheumatoid arthritis. Nutr Clin Care. 2000;3:209-15.
15. Van Den Ende CHM, Vliet Vlieland TPM, Muneke MW, Hazes
MW. Dynamic exercise therapy in rheumatoid arthritis: A
systematic rewiew. Br J Rheumatol. 1998;37:677-687.
16. Ottawa Panel Evidence-Based Clinical Practice Guidelines
for Therapeutic Exercises in the Management of
Rheumatoid Arthritis in Adults. Phys Ther. 2004;84: 934-972.
17. Callahan LF, Mielenz T, Freburger J, Shreffler J, Hootman J,
Rady T, et al. A randomized controlled trial of the People
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With Arthritis Can Exercise program: Symptoms, function,
physical activity and psychosocial outcomes. Arthrit Care
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Astrand P. Exercise physiology and its role in disease
prevention and rehabilitation. Arch Phys Med Rehab.
1987;68:305-309.
Ekdhall C, Elkmann R, Anderson SL, Melander A, Svensson
B. Dynamic training and circulating levels of corticotropinreleasing factor, beta-lipotropin and betaendorphin in
rheumatoid arthritis. Pain. 1990;40:35-42.
Raja SN, Meyer RA, Ringkamp M, Campbell JN. Peripheral
neural mechanisms of nociception. In: Textbook of pain. P.D.
Wall & R. Mellzzack. 4th ed. Churchill Livingston: London;
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Schaible HG, Grubb BD. Afferent and spinal mechanisms of
joint pain. Pain. 1993;55:5-54.
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Marques AP, Kondo A. A fisioterapia na osteoartrose: uma
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Butler SH, Godefroy F, Besson JM, Weil-Fugazza J. Increase
in “pain sensitivity” induced by exercise applied during the
onset of arthritis in a model of monoarthritis in the rat. Int J
Tissue React. 1991;13:299-303.
Lana AC, Paulino CA, Gonçalves ID. Efeitos dos exercícios
físicos sobre o edema inflamatório agudo em ratos Wistar.
Rev Bras Med Esporte; 2008;14:33-37.
Rall LC, Rosen CJ, Dolnikowski G, Hartman WJ, Lundgren N,
Abad LW, et al. Protein metabolism in rheumatoid arthritis
and aging. Effects of muscle strength training and tumor
necrosis factor-α. Arthritis Rheum. 1996;39:1115-24.
Work Group Recommendations. Exercise and Phisical
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2003;49:453-454.
REUMATOLOGIA
Original article
Study of self-medication for musculoskeletal pain among
nursing and medicine students at Pontifícia Universidade
Católica - São Paulo
José Eduardo Martineza,*, Giovanni Augusto Farina Pereirab, Luiz Gustavo Martinelli Ribeirob,
Ricardo Nunesb, Daniel Iliasb, Luiz Gustavo Moretti Navarrob
a
b
Department of Medicine and Medical and Health Sciences, Pontifícia Universidade Católica de São Paulo (PUC-SP), Sorocaba, SP, Brazil
Pontifícia Universidade Católica de São Paulo (PUC-SP), Sorocaba, SP, Brazil
article info
abstract
Article history:
Objective: To study the self-medication for pain among students of medicine and nursing of
Received 26 July 2012
the PUCSP compared with students from other knowledge areas.
Accepted 26 August 2013
Material and methods: Data were obtained in two groups: A - students from the health knowledge area, and B - students of law and engineering. It was used a questionnaire developed
Keywords:
by the authors. Statistical analysis used the Chi-square test and the Fischer.
Pain
Results: In relation to gender, there is a predominance of women in the health group and
Analgesics
a male majority in other one. In the health group there was a greater number of medi-
Self-medication
cal students, and in the control group of engineering. It is observed a high degree of selftreatment in both groups. It appears that participants in the health group have used more
anti-inflammatory drugs and opioid than the others subjects studied.
Conclusion: The frequency of medication for pain is higher in the group of health students,
and self-medication is equally practiced among students of health and other areas.
Estudo da automedicação para dor musculoesquelética entre estudantes
dos cursos de enfermagem e medicina da Pontifícia Universidade
Católica - São Paulo
resumo
Palavras-chave:
Objetivo: Estudar a automedicação para dor entre estudantes de cursos de medicina e enfer-
Dor
magem da PUCSP em comparação com estudantes das outras áreas de conhecimento.
Analgésicos
Material e métodos: Esses dados foram obtidos em dois grupos: A – estudantes da área da
Automedicação
saúde e B – estudantes da área de ciências humanas e exatas. Utilizou-se um questionário
elaborado pelos autores. A análise estatística usou o teste do qui-quadrado e de Fischer.
Resultados: Na área de saúde há um predomínio do gênero feminino, e nas outras áreas um
predomínio masculino. Na área de saúde a maior parte dos estudantes cursa medicina, e
E-mail: [email protected] (J.E. Martinez).
91
nas outras áreas engenharia. Observa-se um alto índice de automedicação em ambos os
grupos, constatando-se que os participantes do grupo da área de saúde usam significativamente mais opioides e anti-inflamatórios que os demais estudados.
Conclusão: A frequência do uso de medicamentos para dor é maior no grupo de estudantes
da área de saúde, e a automedicação é praticada igualmente entre estudantes da área de
saúde e das demais áreas.
Introduction
Material and methods
Pain is defined as “a sensory and emotional experience associated with existing or potential tissue damage, reported
as if the injury already existed.” Pain is classified as acute or
chronic. The occurrence of acute pain indicates injury and
exhibits a physiological factor of defense. On the other hand,
chronic pain in general has no physiological value and corresponds to an adaptation mechanism.1-4 Moreover, Woolf5
divides pain in adaptive pain, associated with the protection of the body and with promotion of wound healing (nociceptive and/or inflammatory origin), and maladaptive pain,
which is related to pathological CNS activity (neuropathic
and/or functional origin).
Pain should be treated with analgesics and non-pharmacological measures. Among these, we emphasize healthcare
education, exercise, and physical medicine. According to
Teixeira,4 physical medicine provides comfort, cures physical dysfunctions, normalizes physiological dysfunctions and
reduces the fear associated with the mobilization or immobilization of body parts. The modalities used in physical
medicine are acupuncture, thermotherapy, massotherapy,
mobilization, electroanalgesia and psicoprophylaxis (meditation, hypnosis, relaxation, etc.).3,4,6
Pharmacological therapy is aimed at treating short-term
pain, enabling the individual to achieve mobility.3,4 Analgesia obtained through drugs does not eliminate the cause of
pain, but its proper use may lead to an improved quality of
life since it facilitates the treatment of the causal factor, and
possibly prevents the acute to chronic pain progression.4 The
drugs used include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and possibly antidepressants
and anticonvulsants as adjuvants.3-5,7-10 The indiscriminate
use of these drugs should be avoided, because of its adverse
effects. One of the central aspects regarding the appropriate use of drugs involves self-medication. Arrais et al.11 refer to self-medication as a procedure characterized by the
initiative of a patient, or of his (hers) parents, to obtain or
produc,e and use a product which, he (she) believes, will
benefit the treatment of diseases or for relieving the symptoms.12 Another term used, according to Bestane et al.,13 is
“oriented self-medication”, which refers to the reuse of old
prescriptions not intended for continuous use.
Theoretically, healthcare professionals and students
know the medications and their risks, so they should avoid
self-medication. The aim of this study was to evaluate the
proper use of pain medication for pain management by
healthcare students, compared to students from other
knowledge areas.
1) Patients: 247 medicine and nursing students at the Pontifícia Universidade Católica de São Paulo (PUC-SP) were
studied.
2) A control group of 252 law and engineering students was
also studied.
3) Study Design: A cross-sectional descriptive cohort study.
4) Elaboration and application of a questionnaire containing
the following variables: demographic data, student data,
number of analgesics used in the last year, presence or
absence of medical indication, incidence in both groups
of drugs’, with and without prescription, adverse effects.
5) Statistical analysis: chi-square or Fisher’s exact test were
applied (Siegel, 2006), aiming to compare groups A and B
in relation to percentage of use, prescriptions obtained,
appearance of adverse effects and type of drug used. The
level of significance was p < 0.05%, or 5%.18
6) Ethical aspects: This project and the obtained informed
consent were approved by the Ethics in Research Committee of Faculdade de Ciências Médicas e da Saúde, PUC-SP.
Results
Table 1 shows the distribution of subjects according to gender, age and area of knowledge. Regarding gender, in group
A (healthcare subjects) there is a predominance of females;
in group B there is a male predominance. In group A, most
students pertained to medicine area; in group B, there was a
predominance of subjects in the engineering field.
Table 2 shows the frequency and percentage of analgesics
used in the last year. More individuals in group A used analgesics, compared to group B.
Table 3 shows the origin of the pharmacological indication,
with or without prescription. A high rate of self-medication
in both groups was observed, without statistically significant
difference.
Table 4 shows the frequency of reported adverse effects after
the use of analgesics in both groups. There is a low incidence of
adverse effects in both groups, without a statistically significant
difference.
Table 5 shows the distribution of analgesics use in relation
to pharmaceutical specialties. In group A, analgesics (45.5%)
and anti-inflammatory drugs (55.3%) intake was significantly
higher than opioids (4.4%), and antidepressants (4.0%) consumption. In group B (control), the chi-square test showed
that analgesic consumption (43.2%) was significantly higher
than all other drugs. This test also revealed that anti-inflam-
92
matory drugs (23.0%) were more used than opioids (1.6%) and
antidepressants (2.8%). Comparing the two groups, the statistical analysis showed that the use of anti-inflammatory drugs
in group A (55.3%) was significantly higher than the control
group (23%). As well as with opioids, the results were not significant, but suggest greater use in group A (4.4%). In relation
to analgesics and antidepressant drugs, no significant difference between the two groups was observed.
Discussion
Self-medication can induce harmful consequences, regardless of disease, symptom or medication used. In the case of
pain, this is even truer. The need for quick relief and the negative impact that pain causes in quality of life imply that the
rate of self-medication in this area is quite notorious.
Analgesics and NSAIDs have a similar mechanism of action; both are cyclooxygenase (COX) inhibitors. These en-
Table 1 – Demographics and area of activity data.
Variable
Age m (SD)
Gender n (%)
Male
Female
Student area
n (%)
Medicine
Nursing
course
Law
Engineering
Total
Healthcare
area
Other areas
Total
22.35 (5.56)
22.08 (9.94)
22.09 (9.94)
110 (42.6)
137 (56.8)
148 (57.4)
104 (43.2)
258 (100)
241 (100)
185 (74.9)
62 (25.1)
247 (100)
185 (37.1)
62 (12.4)
121 (48.1)
131 (51.9)
252 (100)
121 (24.2)
131 (26.3)
499 (100)
zymes are classified into: (1) COX-1, a constitutional enzyme
expressed in most tissues including circulating platelets and
is involved in tissue homeostasis; and (2) COX-2, induced by
activated inflammatory cells (IL-1 and TNF-α-mediators), is
responsible for the production of prostanoid mediators of
inflammation, and it is also a CNS constitutive enzyme.7,9,10
Recently the existence of COX-3 was described, but its actions
are not yet fully understood.7,9 Analgesics exert their function mainly by inhibiting COX-2 by reducing the production
of prostaglandins, bradykinins and serotonin, which are the
main nociceptor stimulants, thus leading to analgesia.7,9
NSAIDs, however, have analgesic, antipyretic and anti-inflammatory effects.7,9 The analgesic effect is similar
to that quoted as the mechanism of action of analgesic
drugs.7,9 The antipyretic effect is result of COX-2 inhibition
in the central nervous system, which prevents the set point
rise of the hypothalamic thermostat.7,9 Finally, the antiinflammatory effect occurs by COX inhibition which interrupts the production and activation process of inflammatory mediators.5,7,9,10
Both analgesics and NSAIDs have similar adverse effects,
due to their mechanisms of action. For NSAIDs, these effects
involve gastrointestinal disorders (dyspepsia, diarrhea, nausea, vomiting, gastric ulceration and bleeding),7,9,10 allergic
skin reactions7,9 and renal effects,7,9 (chronic nephritis, papillary necrosis, and acute reversible renal insufficiency).
Table 3 – Indication obtained by medical appointment,
or not.
Prescription
Yes n (%)
No n (%)
Total n (%)
63 (40.1)
46 (38.6)
109
94 (59.9)
73 (61.4)
155
157 (100)
119 (100)
264
Healthcare
Other areas
Total
p < 0.05 or no significant.
Table 2 – Frequency of use of pain medication in the last
year.
Table 4 – Frequency of adverse effects.
Groups
Prescription
Health
Other areas
Total
Used n (%)
Not used n (%)
Total n (%)
157 (63.8)
119 (47.2)
276
90 (36.2)
133 (52.8)
223
247 (100)
252 (100)
498
p < 0.0001.
Yes n (%)
No n (%)
Total n (%)
25 (17.2)
15 (12.6)
40
120 (82.8)
104 (87.4)
224
145 (100)
119 (100)
264
Healthcare
Other areas
Total
p < 0.05 or no significant.
Table 5 – Distribution of drugs used according to pharmaceutical class.
Groups
Simple analgesics
Anti-inflammatory agents
Opioids
Antidepressives
Total
Healthcare
Other
p
Yes
No
% Yes
Yes
No
% Yes
113
145
11
10
279
135
117
237
238
727
45.56
55.34
4.4
4.0
38.37
109
58
4
7
178
143
194
248
245
830
43.2
23.0
1.6
2.8
17.7
Observations:
Group A (healthcare) has 157 participants who used drugs.
Group B (other areas) has 119 participants who used drugs.
A participant may have used more than one drug.
> 0.05
< 0.01
> 0.05
> 0.05
Drugs characterized as opioids are used as analgesic, antitussive and antidiarrheal agents.7,9 The opioid receptors are:
μ (mu), κ (kappa) and δ (delta).7,9 Each of these receptors is
involved with specific effects of opioids, and the μ and δ receptors have similar actions in the same regions.7,9 The analgesia is produced at central level through interaction with
opioid receptors present in the CNS, because these have the
ability to directly inhibit the ascending transmission of nociceptive information coming from the dorsal horn of the
spinal cord, and also have the ability to activate pain inhibitory descending pathways.5,7,9 The interaction of receptors
with their agonists leads to a reduction of cyclic-AMP (cAMP)
within neurons, inhibiting the opening of calcium channels
in the presynaptic neuron, thereby inhibiting the release of
neurotransmitters.5,7,9 Moreover, the decrease of intracellular
cAMP stimulates the opening of potassium channels in the
postsynaptic neuron, causing a hyperpolarization that prevents the passage of nerve impulses by the ascending nociceptive pathway; thus, analgesia is produced.5,7,9 Furthermore,
the μ/δ receptors produce analgesia within the descending
circuits of pain control partly by removing the inhibition mediated by gamma-aminobutyric acid (GABA) neurons that
project to the rostral ventromedial (RVM) part of medulla in
the gray periaqueductal (PA) substance, as well as of neurons
projecting from the RVM to the spinal cord.7 The modulatory effects of pain by κ agonists in the brain stem seem to
antagonize the effects of μ receptor agonists.7,9 Opioid drugs
can produce many adverse effects such as sedation, euphoria,
dysphoria, constipation, nausea, vomiting, pruritus, dizziness
and respiratory depression, along with causing tolerance and
dependence.7,9
Antidepressant agents can be used as adjuvant medication in the treatment of pain.3,4,7-9 The classes of antidepressant agents used are: monoamine oxidase inhibitors
(MAOIs), tricyclic antidepressants (TCAs) and selective serotonin re-uptake inhibitors (SSRIs).7,9 MAOIs inhibit the action
of the enzyme monoamine oxidase (MAO), which is responsible for the degradation of monoamines (dopamine, norepinephrine and serotonin, for instance), thereby maintaining a high concentration of monoamines of inhibitory pain
pathways in the synaptic cleft.7,9 TCAs and SSRIs decrease
the neurotransmitter re-uptake in inhibitory pain pathways
at the synaptic clefts, thus increasing the concentration of
these peptides in the synapses and thereby increasing the
stimulus in the postsynaptic neuron.7,9 Antidepressants increase the efferent pathway of pain inhibition, producing
analgesia.7,9 Furthermore, TCAs are weak agonists of μ opioid
receptors, helping to obtain an analgesic effect.9 Antidepressants can cause several adverse effects such as sedation, anticholinergic effects (dry mouth, constipation, blurred vision,
urinary retention, etc.), postural hypotension, convulsions,
impotence, weight gain, liver damage (rare), nausea and agitation.7-9 The analgesic effect of TCAs is well documented;
however, the analgesia produced by the use of MAOIs and
SSRIs needs further studies.8
The degree of knowledge on this topic can generate an
awareness of the risk of self-medication but, on the other
hand, can cause a false sense of security in the use of these
drugs, since access to such information is more expressive.
Although healthcare students have greater knowledge, it is
93
known that even experienced professionals are cautious
about the use and prescription of these medications.
Among lay population, Pereira et al.14 reported that 51% of
drugs were indicated by mothers and 7.8% by fathers; 20.1%
by pharmacy employees, 15.3% resulted from the use of old
prescriptions for the child or other family member, and 1.8%
by media influence. According to the article "Prevalence and
factors associated with self-medication: results from the
Bamburgh project",15 the 16 non-prescription drugs more
commonly consumed by self-medication were analgesics/
antipyretics (47.6%), followed by drugs acting on the digestive tract, that is, antispasmodics, antidiarrheals, and antacids (8.5%); antibiotics or chemotherapeutic agents (6.2%) and
vitamins, tonics or anti-anemic drugs (4.7%).
On the other hand, among healthcare professionals, Hem
et al.,16 in a cohort composed by young Norwegian doctors,
found a prevalence of 54% between the fourth and fifth year
after graduation; and among those who used drugs in the
year prior to the interview, 90% were self-prescriptions.
Now Tomasi et al.17 in their cross-sectional study found that
47% of healthcare workers reported drug using in the last
15 days, especially analgesics (27%), regardless of having,
or not, a health problem. Moreover, these authors observed
that self-medication was common practice since one fourth
of the respondents stated that most drugs used had no prescription. Also in this work, 43% of physicians reported selfmedication.
In our study the frequency of analgesic use was also significant, and it occurred most often through self-medication.
This is true for both groups. The group A used significantly
more pain medication than the other students. One aspect
that may have reinforced this habit was the low frequency of
adverse effects experienced by the subjects.
The group A used proportionately more anti-inflammatory and opioid drugs. We attribute this difference to the
greater knowledge and access to these drugs, although they
increase the risk of complications.
We can conclude that the frequency of drug use for pain
is higher in the group of healthcare students (group A), and
self-medication is practiced equally among healthcare students and group 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 ( 2 ) : 9 5 – 1 0 1
REUMATOLOGIA
Original article
Translation, cultural adaptation and validation into portuguese
(Brazil) in Systemic Sclerosis Questionnaire (SySQ)
Roberta Ismael Lacerda Machadoa, Lais Medeiros Soutoa,
Eutilia Andrade Medeiros Freireb,c,*
a
Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil
Rheumatology Service, Hospital Universitário Lauro Wanderley, João Pessoa, PB, Brazil
c
Department of Internal Medicine, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil
b
article info
abstract
Article history:
Introduction: Systemic sclerosis (SSc) is a multisystem disease, autoimmune disorder char-
acterized by a fibroblastic disfunction, with significant impact on quality of life (QoL), mea-
Accepted 2 September 2013
sured by instruments or questionnaires that usually were formulated in other languages
and in different cultural contexts.
Keywords:
Objective: Translate into Brazilian Portuguese, cross cultural adaptation and assess the reli-
Systemic sclerosis
ability and validity of the Systemic Sclerosis Questionnaire (SySQ).
Quality of life
Methodology: Translation and adaptation: into Portuguese and cross-cultural adaptation
Validation of questionnaire
was performed in accordance with studies on questionnaire translation methodology into
other languages. Reliability: it was analyzed using three interviews with different interviewers, two on the same day (interobserver) and the third within 14 days of the first assessment (intraobserver).Validity was assessed by correlating clinical and quality of life
parameters with the domain scores of Sysc. Statistical analysis: a descriptive analysis of
the study sample. Reproducibility was assessed using an intraclass correlation coefficient
(ICC). Internal consistency was assessed using Cronbach’s alpha coefficient. To assess validity we used Spearman correlation coefficient. Five percent was the level of significance
adopted for all statistical tests.
Results: In the evaluation of the questionnaires, the results were similar to the original
questionnaire, the internal consistency ranging between 0.73 and 0.93 for each item. The
interobserver reproducibility was very good for all domains (α = 0.786 to 0.983) and intraobserver agreement was considered very good for general symptoms domain (ICC = 0.916),
good for musculoskeletal symptoms domain (ICC = 0.897) and cardiopulmonary domain
(ICC = 0.842) and reasonable for gastrointestinal symptoms domain (ICC = 0.686).
Conclusion: The Brazilian Portuguese version of SySQ proved to be reproducible and valid for
our population, using a recognized methodology for translation and cultural adaptation of
questionnaires, as well as to assess the reproducibility and validity.
E-mail: [email protected] (E.A.M. Freire).
96
Tradução, adaptação cultural e validação para a língua portuguesa
(Brasil) do Systemic Sclerosis Questionnaire (SySQ)
resumo
Palavras-chave:
Introdução: A esclerose sistêmica (ES) é uma doença multissistêmica, autoimune, caracte-
Esclerose sistêmica
rizada por disfunção fibroblástica e vasculopatia, causando grande impacto na qualidade
Qualidade de vida
de vida (QV). Esta é mensurada por instrumentos ou questionários, geralmente formulados
Validação de questionário
em outros idiomas e inseridos em contextos culturais distintos.
Objetivo: Traduzir, adaptar culturalmente e validar para a língua portuguesa (Brasil) o questionário do Systemic Sclerosis Questionnaire (SySQ) de QV em ES.
Metodologia: Tradução e adaptação: etapa realizada de acordo com metodologia específica de tradução de questionários. Confiabilidade: foi analisada através de três entrevistas,
realizadas por diferentes entrevistadores, sendo duas no mesmo dia (interobservação) e
uma terceira após 14 dias (intraobservação). Validade: avaliada pela correlação clínica e
parâmetros de QV com os domínios do Sysc. Análise estatística: realizada análise descritiva da amostra. A reprodutibilidade foi avaliada através de um coeficiente de correlação
intraclasse (ICC) e a consistência interna pelo coeficiente alfa de Cronbach, já para analisar
a validade utilizou o coeficiente de correlação de Spearman.
Resultados: Foram observados 16 pacientes portadores de ES. Os nossos resultados foram
semelhantes aos do questionário original, com a consistência interna variando entre 0,73
e 0,93 para cada item. A reprodutibilidade interobservador foi muito boa para todos os domínios (α = 0,786 a 0,983), e a intraobservador foi muito boa para o domínio de sintomas
gerais (CCI = 0,916), boa para os domínios de sintomas musculoesqueléticos (CCI = 0,897) e
cardiopulmonares (CCI = 0,842) e razoáveis para o de sintomas gastrintestinais (CCI = 0,686).
Conclusão: A versão na língua portuguesa do SySQ mostrou-se reprodutível e válida para
nossa população através de metodologia reconhecida para tradução e adaptação cultural
de questionários.
Introduction
Systemic sclerosis (SSc) is a multisystemic autoimmune disease characterized by fibroblast dysfunction, along with microvascular involvement, culminating in skin and internal organs fibrosis.1 Clinically, the extent of cutaneous and internal
organ involvement by this disease and its severity vary a great
deal.2 The disease usually follows a chronic, monophasic and
indolent course, and only in rare cases relapses occur.
The course of the disease is slow and indolent without
major complications that interfere significantly with the
quality of life of the affected individual. Nevertheless SSc can
exhibit progressive cutaneous and vascular involvement, resulting in considerable morbidity with impaired physical
and functional appearance, which can lead to a decreased
social adequacy. Severe gastrointestinal, renal, and cardiac
affections, hypertension and/or interstitial lung disease contribute to the mortality rate of the disease, as well as to individual and social performance. Compared with systemic
sclerosis, few clinical conditions cause such functional and
organic limitations; these issues should be addressed specifically during the evaluation of these patients.
In the last two decades, the results of the assessment
focused on the patient's opinion demonstrate a significant
role in the study of chronic diseases, in addition to the morbidity and mortality traditionally measured. In the American College of Rheumatology (ACR), the outcome measures
in clinical trials committee, OMERACT (Outcome Measures
in Rheumatology Clinical Trials)3 has recognized the importance of the measurement of function and welfare from the
perspective of the patient,as a criteria to determine clinical
improvement.
Physiological measures provide essential information to
clinicians, but often correlate less with functional capacity
and welfare; aspects which patients are familiar and most
interested in.
These assessment measures, increasingly used in clinical
trials, are instruments or questionnaires that, for the most
part, were formulated in English, targeted for it’s use in the
English-speaking population and can be generic or specific
for certain conditions. In order for them to be used in other
populations, measures should follow pre-established norms
published in the literature for its translation in a specific cultural context.4 And for the clinical use in a specific population, their psychometric properties also must to be validated
locally, in order to make sure that they are reliable for the assessment of what they propose. The properties of a measure
are its reliability, validity and responsiveness.5
Ruof et al.6 developed a questionnaire often reported by
patients with this disease covering the functional impact
of systemic sclerosis as well as general and visceral symptoms: the Systemic Sclerosis Questionnaire (SySQ) (Fig. 1).
The questionnaire was developed in German, containing 32
questions divided into 4 categories (general, gastrointestinal, musculoskeletal and cardiopulmonary symptoms).
97
QUESTIONNAIRE OF QUALITY OF LIFE IN SYSTEMIC
SCLEROSIS
Thank you for completing this questionnaire. It will let
us know more about day-to-day problems that affect
patients with systemic sclerosis. It will also help us to
better understand and maybe permit us to improve the
treatment of this disease. For each item, mark only one
number that best demonstrates the effect/importance
in your life. Please do not ask for help to answer these
questions, because you are the best person to know about
your illness and how it affects you. There are no right or
wrong answers.
Please use this scale to answer the following questions:
1 without difficulty;
2 with little difficulty;
3 with great difficulty;
4 impossible.
Can you ...
01. Cutting meat with a knife? 1 2 3 4
02. Bathing and drying yourself alone? 1 2 3 4
03. Putting on socks? 1 2 3 4
04. Rubbing cream on your body? 1 2 3 4
05. Opening and closing a tap? 1 2 3 4
06. Getting up from a chair that does not have armrests? 1 2
34
07. Lie down and get up from bed? 1 2 3 4
08. Walking on a flat street? 1 2 3 4
09. Climbing stairs? 1 2 3 4
10. Eating large pieces of food without cutting them? 1 2 3
4
11. Eating an apple? 1 2 3 4
1 no;
2 light;
3 moderate;
4 strong.
Do you feel...
01. Pain in fingers when touching or holding objects? 1 2 3
4
02. Stiffness in your hands? 1 2 3 4
03. Stiffness in the arms? 1 2 3 4
04. Stiffness in the legs? 1 2 3 4
05. Pain in your hands when it's cold? 1 2 3 4
06. Pain in your feet when it gets cold? 1 2 3 4
07. Shortness of breath when walking on a flat street? 1 2 3 4
08. Shortness of breath when climbing a ladder (2 stairs with about
10 steps) 1 2 3 4
09. Shortness of breath when changing clothes? 1 2 3 4
Do you have ...
10. Cough? 1 2 3 4
11. Chest catarrh? 1 2 3 4
12. Difficulty with deep breathing? 1 2 3 4
1 No;
2 Occasionally;
3 Several times;
4 Always.
1 No;
2 Occasionally;
3 Several times;
4 Always.
Do you...
01. Feel weak hands when holding objects? 1 2 3 4
02. Drop objects you are holding from your hand? 1 2 3 4
03. Feel pain in your hands? 1 2 3 4
04. Have cold hands? 1 2 3 4
05. Have difficulty to swallowing? 1 2 3 4
06. Feel pain when swallowing food? 1 2 3 4
07. Choke during meals? 1 2 3 4
08. Have heartburn? 1 2 3 4
09. Feel that the food is returning after swallowing it? 1 2 3 4
PUNCTUATION
General symptoms (G1 a G8)
Gastrointestinal symptoms
(GI 1 A G17)
Musculoskeletal symptoms
(ME1 a ME11)
Cardiopulmonary symptoms
(CP1 a CP6)
Score
Min – Max
0 - 24
0-21
0-33
0-18
Fig. 1 – Questionnaire of quality of life in systemic sclerosis
translated and adapted into brazilian portuguese.
The Likert scale (graded 1-4) was used to score the items
due to its ease of understanding, referring to the ability
to perform an activity (1 means “without difficulty” and 4
means “unable”), intensity of symptoms (0 corresponds to
“absent” and 4 to “very intense”) and frequency of symptoms (1 equals to “never” and 4 to “always”). Without a doubt,
the Likert scale is a valid and reproducible measure in this
population.
In Brazil, we have no specific questionnaires to assess
SSc patients validated for use in our population. The aim of
this study was to translate into Brazilian Portuguese, adapt
cultural differences and validate the SySQ questionnaire, so
that it can be used in clinical practice and in clinical trials
involving SSc patients in Brazil.
Methodology
For our sample composition, 16 SSc patients seen at the Rheumatology Service of the Federal University of Paraíba, from
various locations in the State of Paraíba, were randomly selected, fulfilling the inclusion criteria of the study: age between 18 and 65 years, diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology
(ACR), and absence of dementia or cognitive impairment.
Participants were characterized based on a protocol containing sociodemographic and clinical data. They were assessed by
the Health Assessment Questionnaire with the visual analogue
scale (VAS) for functional status, for systemic sclerosis (sHAQ)
and for quality of life by the Medical Outcomes Study 36-Item
Short Form Health Survey (SF-36). The questionnaires were applied to patients by interviewers, given the socio-cultural level
98
of the population studied. Data were cataloged in an Excel 2010
worksheet and analyzed using SPSS version 20.
Translation and cultural adaptation
The translation and cultural adaptation followed the methodology used by other studies, according to Falcão et al.7 The
instrument was first translated into Portuguese by a translator fluent in German (creating the first version in Portuguese).
The initial translation was reverted to the original language
(back translation), and was then compared to the original instrument. The discrepancies found were reviewed by a rheumatologist and a general practitioner, together with translators who participated in the previous steps, adapting them to
generate a second version in Portuguese.
At this step, the semantic equivalence was analyzed based
on vocabulary and grammar correspondence, idiomatic
equivalence, translation of idiomatic expressions and also
conceptual equivalence, since the terms could have semantic
equivalence without conceptual equivalence.
Then, this version was applied to a group of five patients,
being added to each of the questions the "not applicable" option, in order to identify questions that were not understood
or that are not regularly used by our population, and thus
considered culturally inappropriate.
The questions with more than 25% of responses "not applicable" were analyzed by the committee, and then replaced
by others with the same concept. These changes led to new
versions of the questionnaire, which were reapplied to these
patients until no item was considered "not applicable" by
more than 15% of patients, generating the final Brazilian Portuguese version of the questionnaire.
Assessment of psychometric measures of the questionnaire
The reliability of the final version of the translated questionnaire was evaluated through three interviews with each patient, two held on the same day by two different interviewers
(interviewer 1 and 2) to evaluate the interobserver reproducibility, and the third interview was done 14 days after the first
assessment by the interviewer 1, to address intraobserver reproducibility. In the first case, we used the intraclass correlation coefficient (ICC); for internal analysis of the questions
consistency, Cronbach's alpha was calculated.
Validation
The validity of the questionnaire was assessed by checking the
ratio of its scores by domain area with preexisting questionnaires of functional assessment (HAQ and sHAQ) and of quality
of life (SF-36). The Spearman correlation coefficient was used.
Results
Sixteen SSc patients, 13 females (13/16) and 3 males (3/16),
were analyzed. The mean age was 45.5 years, and the sociodemographic and clinical characterization is described in Table 1.
The questionnaire was translated according to the above
methodology. In the pre-test, two questions were consid-
ered as “not applicable” by patients. The question “Você
consegue levantar-se de uma cadeira sem a ajuda dos braços?”
(“Can you get up from a chair without help of your arms?”)
was not understood by four of the five patients who reported not understand the meaning of “arm”, if it was their own
arm or the arm of the chair. After consideration of the committee, the question was changed to “Você consegue levantarse de uma cadeira que não tenha apoio para os braços?” (“Can
you get up from a chair that does not have armrests?”).
Another question not understood was “Você tem regurgitação?” (“Do you have regurgitations?”). Again, when four
out of five patients did not understand it, an additional explanation was needed: “O alimento volta após as refeições?”
(“Does the food pours back after meals?”). This question
was modified by the committee to “Sente que o alimento volta
após engolir?” (“Do you feel that the food returns after swallowing it?”). These changes have generated a new version
of the questionnaire, which was reapplied to the group of
five patients until no item was considered “not applicable”
by more than 15% of patients after the questions were reformulated.
The scores obtained by patients in each SySQ domain
are presented in Table 2.
Table 1 – Socioeconomic and clinical characteristics of 16
patients with systemic sclerosis.
Gender
Male
Female
Age (years)
Mean
Ethnicity
White
Black
Brown
Education
Illiterate
Incomplete Elementary School
Full Elementary School
Incomplete High School
Full High School
Incomplete Higher Education
Full Higher Education
Form of clinical involvement
General symptoms
Gastrointestinal
Musculoskeletal
Cardiopulmonary
Renal
Subtype of systemic sclerosis
Diffuse
Limited
Sine scleroderma
Overlapping
Systemic lupus erythematosus
Rheumatoid arthritis
Patients with Raynaud phenomenon
Mean time (years)
Severity (0 - 10)
Mean of attacks per week
Disease duration (years)
Mean
Gender
3
13
44.96
5
3
8
0
9
1
2
3
0
1
16
6
10
10
0
12
2
0
2
1
1
15
5
4.81
4.93
9.33
99
The internal consistency among domains and for each domain is shown in Table 3, using Cronbach's alpha, as well as
the interobserver reproducibility, through the intraclass correlation coefficient.
We compared the translated questionnaire with other instruments already validated in the literature: the generic quality of life questionnaire SF-36, the questionnaire of functional
assessment HAQ plus visual analog scale for symptoms of SSc,
composing the Scleroderma HAQ (sHAQ).
The SySQ domains were compared to SF-36 domains, as
shown in Table 4. The general symptoms domain of SySQ
revealed a strong correlation with the social aspects domain of SF-36, and a moderate correlation with the pain,
general condition and vitality domains of the latter questionnaire.
A strong correlation between the musculoskeletal symptoms domain and the emotional domain of SF-36 was also
found, besides a moderate correlation with functional capacity, pain, and physical and social aspects domains of SF36. The cardiopulmonary symptoms domain of SySQ had
strong correlation with the functional capacity domain of
SF-36 and moderate correlation with the domains physical
aspects, pain, and general condition. The gastrointestinal
symptoms domain of SySQ had no correlation with SF-36.
Table 5 shows the level of correlation between domains
of SySQ and HAQ, but there was no relevant statistical sig-
Table 2 – Scores obtained by domain of SySQ questionnaire of 16 patients with systemic sclerosis.
Domains
Minimum
Maximum
Mean
Standard Deviation
0
0
1
0
21
21
24
16
9.8
7.4
12.2
5
6.9
4.9
7.2
4.8
General symptoms (0-24)
Gastrointestinal symptoms (0-21)
Musculoskeletal symptoms (0-33)
Cardiopulmonary symptoms (0-18)
Table 3 – Internal consistency and reproducibility of the SySQ questionnaire in 16 patients with systemic sclerosis, using
Cronbach’s alpha and intraclass correlation coefficient, respectively.
Domains
Interobserver
Intraobserver
0.983
0.786
0.959
0.924
0.916
0.647
0.897
0.842
0.765
General symptoms
Gastrointestinal symptoms
Musculoskeletal symptoms
Cardiopulmonary symptoms
Internal consistence among domains
Table 4 – Correlation among SySQ and SF-36 domains.
SySQ SF-36
Functional capacity
Physical aspects
Pain
General state
Vitality
Social aspects
Emotional aspects
Mental health
a
b
General symptoms
Gastrointestinal
symptoms
Musculoskeletal
symptoms
Cardiopulmonary
symptoms
-0.459
-0.473
-0.559b
-0.600b
-0.619b
-0.707b
-0.390
-0.246
-0.190
-0.344
0.255
0.164
0.025
0.203
0.258
-0.19
-0.656b
-0.633b
-0.662b
-0.672b
-0.352
-0.541a
-0.782b
-0.457
-0.725a
-0.545b
-0.502a
-0.511a
-0.094
-0.288
-0.160
-0.090
p < 0.05.
p < 0.01.
Table 5 – Correlation among SySQ domains and of HAQ and sHAQ domains.
SySQ HAQ e sHAQ
Dressing up
Stand up
Eating
Walk
Personal hygiene
Reaching objects
Grasping objects
Other activities
General symptoms
Gastrointestinal
symptoms
Musculoskeletal
symptoms
Cardiopulmonary
symptoms
0.150
-0.083
0.253
-0.011
-0.84
0.152
0.272
0.019
0.184
0.118
0.199
0.091
0.172
0.079
0.222
0.156
0.061
0.188
0.158
0.207
0.134
0.134
0.238
0.179
0.162
0.199
0.929
0.104
0.002
0.203
0.230
0.231
100
Table 6 – Correlation among SySQ domains and the Visual Analogue Scale for SS (sHAQ) domains.
SySQ EVA
Raynaud’s phenomenon
Gastrointestinal
Lung involvement
Pain
Disease severity
a
General symptoms
Gastrointestinal
symptoms
Musculoskeletal
symptoms
Cardiopulmonary
symptoms
0,133
0,108
-0,215
0,189
0,407
0,351
0,203
0,724a
0,07
0,024
0,058
0,340
-0,003
-0,003
0,281
0,400
0,389
0,344
0,099
0,380
p < 0,01
nificance. In the other hand, Table 6 shows the correlation
between the SySQ domains with the domains of visual analogue scale (VAS) for SSc of sHAQ. Strong correlation was
found between the gastrointestinal symptoms domain of
SySQ and pulmonary involvement of sHAQ.
Discussion
Assessment measures focused on the patient’s perception
have been increasingly used as tools to determine clinical improvement in clinical trials and in the clinical practice. For
clinical use in a given population, these measures need to
have the psychometric properties assessment validated locally in order to make sure they actually measure what they
purport to measure.
In Brazil, we lack specific instruments in Portuguese to
evaluate SSc patients; unlike other rheumatic diseases, specific questionnaires to evaluate patients with this condition
are scarce in the literature. The Health Assessment Questionnaire (HAQ) Disability Index (a questionnaire that assesses
functional capacity, developed with the cooperation of rheumatoid arthritis patients) is commonly used in clinical trials
involving these patients.
Ruof et al.6 developed a self-administered questionnaire in
German covering specific (general, gastrointestinal and cardiopulmonary) symptoms and functional limitations caused
by SSc. The general symptomatology described was pain,
stiffness and skin coolness. The musculoskeletal symptoms
analyzed were changes in performance of complex motor
functions, hand strength, elevation of extremities and gait.
The cardiopulmonary symptoms evaluated were dyspnea and
upper airway symptoms (cough, expectoration and limitation
of inspiration); the gastrointestinal symptoms were heartburn, regurgitation and difficulty swallowing and feeding.
A limitation of this questionnaire is that it does not evaluate important items such as Raynaud's phenomenon and renal involvement which are not covered by SySQ. Nevertheless,
this questionnaire captures more appropriately the visceral
symptoms of the disease, when compared to other published
instruments.
In our study, the translated questionnaire proved to be reproducible, which attests to its reliability, suggesting that it
can be used to evaluate SSc patients. In Brazil, this measure
is important, because some questions had to be modified in
the process of cultural adaptation. Our results resemble those
obtained from the original questionnaire, which showed internal consistency ranging from 0.73 to 0.93 for each item. Despite the small sample size, justified by the rarity of the dis-
ease, no major damage was caused to the statistical analysis
used, due to the rigor of the methodology adopted.
The interobserver reproducibility was good for all domains
(α ranging from 0.786-0.983). The intraobserver reproducibility
was considered very good for the general symptoms domain
(ICC = 0.916), good for the musculoskeletal symptoms (ICC =
0.897) and cardiopulmonary (ICC = 0.842) domains, and reasonably good for the gastrointestinal symptoms (ICC = 0.686)
domain. Therefore, the questionnaire is considered to be reproducible. Similarly, the original instrument obtained α ≥
0.65 for all domains.
To test the validity of the questionnaire, we compared its
scores with those obtained by previously validated questionnaires in the literature, bearing in mind that they would not
be the best tools to compare, since, unlike SySQ, they are not
specific to the disease.
Among all SySQ domains, “musculoskeletal symptoms”
was the one that showed the highest number of clinically
satisfactory correlations with the SF-36 domains, followed by
general and cardiopulmonary symptoms domains, since this
is a more comprehensive questionnaire. The gastrointestinal
symptoms domain showed correlation only with pulmonary
involvement domain of sHAQ.
Cruz-Dominguez et al.8 translated the questionnaire into
Spanish with the collaboration of Mexican patients, with similar results but with a weak correlation with disease severity
index (p = 0.526, p <0.0001). Our service does not have the required exams for the classification of disease severity; therefore, this topic was excluded from the assessment of patients.
There was no statistically significant correlation with the
HAQ domains, a functional assessment questionnaire, which
can be explained by the fact that SySQ may be a more comprehensive questionnaire regarding symptoms caused by SSc.
Khanna and Merkel9 claim that there was great progress
in the development and validation of assessment measures
in SSc, with these measures moving increasingly toward the
realm of systems specifically involved with SSc.
One shortcoming of this questionnaire is that it does not
assess Raynaud's phenomenon or renal involvement, important manifestations of the disease, but the author suggests
the use of a visual analogue scale for Raynaud's phenomenon
and physical (blood pressure determination) and laboratory
(serum urea and creatinine) exams for renal involvement.6
The version of SySQ into Brazilian Portuguese proved to be
reproducible and valid for use in our population, using recognized methodology for translation and doing the needed cultural adaptation of the questionnaires, as well as to assess its
reproducibility and validity. Studies that assess its response
sensitivity to clinical changes over time are needed.
Funding
3.
Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq. Programa de Bolsas de Iniciação Científica
da Universidade Federal da Paraíba (PIBIC/UFPB).
4.
5.
6.
7.
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2. Della Rossa A, Valentini G, Bombardieri S, Bencivelli W,
Silman AJ, D’Angelo S, et al. European multicentre study
to define disease activity criteria for systemic sclerosis. I.
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Furst DE. Outcome measures in rheumatologic clinical
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Ciconelli RM. Medidas de avaliação de qualidade de vida.
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 2 ) : 1 0 2 – 1 0 9
REUMATOLOGIA
Original article
Immediate infusional reactions to intravenous
immunobiological agents for the treatment of autoimmune
diseases: experience of 2126 procedures in a non-oncologic
infusion centre
Ingrid Bandeira Mossa, Monique Bandeira Mossa,b, Debora Silva dos Reisa,
Reno Martins Coelhoa,*
a
b
Center of Diagnostic Investigation – Infusion Centre, Rio de Janeiro, RJ, Brazil
Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
article info
abstract
Article history:
Introduction: With the increasing use of immunobiological drugs (IBD), the knowledge about
Received 18 June 2013
their effectiveness and safety has increased.
Accepted 28 October 2013
Objective: To analyze the immediate infusional reactions (IIR) to intravenous IBD: infliximab
(IFX), rituximab (RTX), abatacept (ABT) and tocilizumab (TCZ) on the treatment of autoim-
Keywords:
mune diseases.
Immediate infusional reactions
Method: 2126 infusions performed in the Infusion Centre - CID in 268 patients were ana-
Immunobiological
lyzed. The used drug, its clinical indication, infusion time, and use of premedication were
Autoimmune diseases
determined by the prescribing physician. All intercurrences presented during infusion and/
or during a thirty minutes observation period were considered as IIR. The approach adopted in IIR followed the protocols of the Infusion Centre - CID.
Results: Regarding the type of IBD, the infused drugs given were: IFX (1584, 74.5%), TCZ (226,
10.63%), RTX (185, 8.7%) and ABT (131, 6,16%). IIR were described in 87 procedures (9.4%):
77 - IFX group and 10 - RTX group. IIR were not described in ABT and TCZ groups. Most were
considered as mild (n = 5; 41.17%) or moderate (n = 50, 58.81%) reactions; there were no serious reactions. Regarding to discontinue infusions, 79 (92.9%) were resumed and completed
successfully. Only six (0.28% of infusions) were not completed because of IIR.
Conclusion: Despite the differences between the number of procedures per drug, ours is a
“real life” analysis, where the incidence of IIR was similar to that described in the literature.
The low incidence of IIR corroborates the safety data, both quantitatively and qualitatively,
and underscores the importance of specialized medical support during infusion.
E-mail: [email protected] (R.M. Coelho).
103
Reações infusionais imediatas a agentes imunobiológicos endovenosos
no tratamento de doenças autoimunes: experiência de 2.126
procedimentos em um centro de infusão não oncológico
resumo
Palavras-chave:
Introdução: Com o crescimento do uso de drogas imunobiológicas (IBD) ampliamos o conhe-
Reações infusionais imediatas
cimento sobre sua eficácia e segurança.
Imunobiológicos
Objetivo: Analisar as reações infusionais imediatas (RII) às IBD endovenosas – infliximabe
Doenças autoimunes
(IFX), rituximabe (RTX), abatacepte (ABT) e tocilizumabe (TCZ) – no tratamento de doenças
autoimunes.
Método: Avaliamos 2.126 infusões feitas no CID (Centro de Infusão) em 268 pacientes. A
droga usada, a indicação clínica, o tempo de infusão e o uso de pré-medicação foram determinados pelo médico prescritor. Foram consideradas RII todas as intercorrências apresentadas durante a infusão e/ou período observacional de 30 minutos. A conduta adotada nas
RII seguiu os protocolos do CID.
Resultados: Em relação ao tipo de IBD, as infusões foram distribuídas em: IFX (1.584; 74,5%),
TCZ (226; 10,63%), RTX (185; 8,7%) e ABT (131; 6,16%). As RII foram descritas em 87 procedimentos (4,09%): 77 no grupo IFX e 10 no grupo RTX. Não foram descritas RII nos grupos de
ABT e TCZ. A maioria foi considerada leve (n = 5; 41,17%) ou moderada (n = 50; 58,81%) e não
houve reações graves. Das infusões interrompidas, 79 (92,9%) foram reiniciadas e concluídas com êxito. Apenas seis (0,28%) não foram concluídas por causa das RII.
Conclusão: Apesar da diferença entre o número de procedimentos por droga, trata-se de
uma análise de “vida real”, na qual a incidência de RII foi semelhante à descrita na literatura. A baixa incidência de RII corrobora os dados de segurança tanto de forma quantitativa
como qualitativa e ressalta a importância do acompanhamento médico especializado durante a infusão.
Introduction and objectives
With the growing use of immunobiological drugs (IBD) in
the treatment of various autoimmune diseases, it has been
possible to increase our knowledge about their effectiveness
and safety.
Currently several substances with different mechanisms
of action and routes of administration are available, and their
use is becoming increasingly common in specialties such as
Rheumatology, Dermatology and Gastroenterology.1
Much of the knowledge about immediate infusional reactions (IIR) of intravenous (IV) IBD is based on results of phase
II and III clinical studies, or on experiences during oncology
treatment protocols.2,3 It is therefore necessary to deepen
these studies in patients with autoimmune diseases, as well
as to apply them in groups of patients in everyday clinical
practice;. the “real life”. This study aimed to describe the prevalence, severity and outcomes of IIR from the use of IV IBD in
a Non-Oncology Infusion Centre (CID) – a “real life” scenario
of the application of these drugs in the treatment of different
autoimmune diseases.
Materials e methods
Sample
A total of 2126 infusions of IBD IV: infliximab (IFX), tocilizumab (TCZ), rituximab (RTX) and abatacept (ABT), were
performed in a total of 268 patients undergoing treatment
for autoimmune diseases (rheumatoid arthritis, ankylosing
spondylitis, psoriatic arthritis, inflammatory bowel disease,
psoriasis, systemic lupus erythematosus, Sjogren's syndrome,
systemic vasculitis, uveitis, dermatomyositis, pemphigus and
antiphospholipid antibody syndrome), were evaluated. These
infusions were held on the premises of the Infusion Centre CID, from October 2006 to November 2011.
The administered drug and its dose, clinical indication,
infusion time (provided the adherence to the minimum
infusional time of each drug given in the package insert:
IFX,4 2 hours; TCZ,5 1 hour; RTX,6 4 hours; ABT,7 30 m) and
with or without premedication were determined by the attending physician, according to prescriptions and medical
reports, except for the RTX group, in which pre-infusional
medication was used in all procedures, which necessarily
included corticosteroids and anti-histamines PO or IV. The
premedication used during IFX, TCZ and ABT infusions varied according to the prescription of the attending physician,
but in all cases consisted of corticosteroids IV and/or antihistamines PO or IV.
Regarding the dose of IV IBD, only in RTX group a standard
dose of 1 g/infusion was used. For the other drugs, the dosage
established by the prescribing physician was kept. The different doses used in groups IFX, TCZ and ABT, as well as the drip
type used for drug infusion are detailed in Table 1. An infusion
pump was only used in RTX infusions.
All infusions were performed intravenously and preceded
by medical evaluation. Vital signs measurements were performed during and at the end of infusional period.
104
No data on the use of concomitant drugs, disease activity
indexes or treatment failure were collected.
Immediate reactions
For the present study, IIR were considered as the intercurrences, symptomatic or not, present during the infusion and/or
subsequent observational period of 30 minutes. These IIR were
classified according to the type of event, severity and time of
event after the start of infusion (Table 2). To facilitate the reaction classification, these were grouped according to systems,
adopting the following division: angioedematous, cutaneous,
gastrointestinal, hemodynamic, musculoskeletal, neurological, respiratory or mixed (when there was multisystemic involvement). To assess the severity of IIR, the National Cancer
Institute event severity scale8 was used (Table 2). The approach
adopted in IIR followed the protocols for intercurrences of the
Infusion Centre - CID, dividing cases regarding the use or lack
of rescue medication, with or without temporary interruption
of the infusion and/or cessation of infusion (Table 2).
in absolute percentage (%), considering the total number of
infusions; and relative percentage (%), considering the subgroups analyzed (type of drug and IIR). Due to the retrospective nature of the analysis, informed consents were not obtained, but patients' data were protected by numeric codes.
Results
IBD infusions
During the period between October 2006 and November
2011, a total number of 268 patients with autoimmune diseases were treated with IV IBD at the Infusion Centre, totalling 2126 infusions performed. Regarding the type of drug
used, the infusions were distributed as follows, in order of
prevalence: IFX, n = 1584 (74.50%); TCZ, n = 226 (10.63%); RTX,
Table 2 – Classification of the severity of IIR according to
NCI and Infusion Centre - CID protocol of intercurrences.
Adapted from Common Adverse Events Terminology
Criteria v4.02 (CTCAE).8
Severity of IIR
Data was stored using a Microsoft Access 2007 database and
analyzed with Prism 4.0 software. The results were presented
Grade
Table 1 – Distribution of IIR by drug × number of drug
infusions and elapsed infusion time.
Infliximab
1584
Reactions = 77
n (%)
Rituximab
185
Reactions = 10
n (%)
Total
2126
87
n (%)
13 (16.88)
23 (29.87)
18 (23.37)
16 (20.77)
7 (9.09)
6 (60)
4 (40)
-
19 (21.83)
27 (31.03)
18 (9.19)
16 (18.39)
7 (8.04)
21 (27.27)
26 (33.76)
16 (20.77)
5 (6.49)
9 (11.68)
2 (20)
3 (30
1 (10)
4 (40)
21 (26.25)
28 (35)
19 (22.5)
6 (6.25)
13 (17.56)
69 (89.61)
10
79 (90.8)
4 (5.19)
0
4 (4.59)
2 (2.59)
0
2 (2.29)
2 (2.59)
0
2 (2.29)
Number of infusions
1st
2nd to 4th
5th to 8th
9th to 16th
After 16th
1 - mild
2 – mild/
moderate
Infusion Time
< 30 min.
30-60 min.
60-120 min.
> 120 min.
NI
3 – moderate
Outcome
Resumed after
initial measures,
and finalized
Suspension of
procedure after
initial measures
New IIR after
initial steps successful
completion
New IIR after
initial steps suspension of
procedure
4 – severe
5 – severe
Description
Mild and transient
response, no indication
of interruption of the
infusion; no indication
of intervention
Indication for therapy or
discontinuation of the
infusion, but with no
immediate response to
symptomatic treatment
(e.g., antihistamines,
NSAIDs, narcotics, IV
fluids), Prophylactic
medications indicated
for ≤ 24 hours
Brief or prolonged
interruption of
the infusion (e.g.,
no rapid response
to symptomatic
medications);
recurrence of
symptoms after
initial improvement:
hospitalization
indicated for other
clinical sequelae
Life-threatening
consequences; urgent
intervention indicated
Death
Infusion Centre CID - Intercurrence
Protocol
Procedure adopted
at the Infusion
Centre - CID
No need for
intervention.
Temporary
interruption of the
infusion, use of
rescue medication, if
necessary; infusion
resumed after
complete resolution
of symptoms.
Temporary
interruption of the
infusion and use of
rescue medication;
infusion resumed
after complete
resolution of
symptoms. Consider
discontinuation of
the procedure.
Interruption of the
infusion and use of
rescue medication
and hemodynamic
support.
Discontinuation of
the procedure.
Death
105
n = 185 (8.7%); and ABT, n = 131 (6.16%) (Fig. 1). The distribution
of patients by drug and means of infusions performed in each
group are presented as follows: IFX = 168 (62.68%) patients
with a mean of 9.42 infusions/patient (1-32); RTX = 59 (22.01%)
patients with a mean of 3.13 infusions/patient (1-12); TCZ = 26
(9.70%) patients with a mean of 8.60 infusions/patient (1-23);
and ABT = 15 (5.59%) patients with a mean of 8.70 infusions/
patient (1-39).
It is important to note that, considering the characteristics of the study, a single patient may have been subjected to
more than one type of treatment. Regarding the distribution
of the registered diagnosis, the most frequent diagnosis was
rheumatoid arthritis, n = 805 (37.86%), followed by inflammatory bowel disease, n = 416 (19.56%), ankylosing spondylitis,
n = 376 (17.68%), psoriasis, n = 237 (11,14%), psoriatic arthritis, n = 185 (8.7%), and others (systemic lupus erythematosus,
Sjogren's syndrome, systemic vasculitis, uveitis, dermatomyositis, pemphigus and antiphospholipid antibody syndrome),
n = 107 (5.03%). All RTX infusions were preceded by pre-medication, also used in 530 IFX infusions (33.45%), 1 TCZ infusion
(0.44%) and 1 ABT infusion (0.76%). As to the dose used, 925
IFX infusions (58.39%) doses applied were between 3 and 5
mg/kg, 582 infusions (36.74%) with doses > 5 mg/kg and 77
infusions (4.86%) with doses < 3 mg/kg. In TCZ group, doses ≤
8 mg/kg were used in 143 procedures (63.27%); in 83 infusions
(36.72%) doses > 8 mg/kg were used. For the ABT group, the
most widely used dose was 750 mg/infusion, totalling 99 infusions (75.57%), followed by 500 mg, with 22 infusions (16.79%)
and 250 mg, with 10 infusions (7.63%).
cardia, changes in blood pressure) (19.54%), 9 angioedematous (10.34%), 7 gastrointestinal (nausea, vomiting, abdominal
pain) (8.04%), 5 respiratory (bronchospasm, dyspnea, coughing)
(5.74%), 5 musculoskeletal (low back pain, arthralgia, myalgia)
(5.74%), and 3 neurological (headache, drowsiness, confusion)
(3.44%) reactions (Table 3). In the present study, the relation between IIR and underlying disease was not addressed.
Regarding post-IIR outcomes in 60 cases of IIR (68.96% of
total IIR), the drip was discontinued as an initial measure, and
in 72 cases (82.75%) the use of rescue medication (antihistamines, corticosteroids, analgesics, adrenaline) was required
(Table 3). Of the IFX related IIR, 36 (46.75%) occurred until the
fourth infusion, and 54 (70.12%) until the eighth; in the majority of the cases, 47 (61.03%), IIR occurred within the first hour
of the procedure (Table 1). Regarding infusions of RTX, the 10
IIR cases reported occurred until the fourth infusion of the
drug, and eight (80%) were reported at the first infusion of the
application cycle (D0) and 2 (20%) during the second infusion
(D15). Importantly, the two cases of IIR in D15 occurred in patients who had already suffered IIR in D0.
Regarding the dose used, most of the IFX related IIR occurred at doses of 3 mg/kg and 5 mg/kg (50 - 64.93%), followed
by doses > 5 mg/kg (26 - 33.76%) and < 3 mg/kg (1 - 1.29%).
In the present study, the use of premedication was determined by the prescribing physician. The preparation was
Table 3 – Classification of IIR by drug, severity, clinical
presentation and behaviour.
Infliximab
1584
n (%)
Immediate infusion reactions (IIR)
Of 2126 infusions, IIR were documented in 87 procedures
(4.09% of total infusions), with 77 events in the IFX group
(88.50% of total reactions and 4.86% of IFX infusions) and 10
in the RTX group (11.49% of total reactions and 5.40% of RTX
infusions). In groups ABT and TCZ, IIR were not described (Fig.
1, Table 3).
Regarding severity, IIR classified as moderate were the
most frequent, reported in 50 (57.47%) infusions; followed by
mild IIR, occurring in 37 procedures (42.52%) (Table 3). No serious reaction was reported.
In terms of clinical presentation, the most common reactions were purely cutaneous (rash, itching, redness, urticariform lesions), described in 21 IIR (24.13%) cases, followed by
19 mixed (multisystemic) (21.83%), 17 hemodynamic (tachy2126
(100)
N total (%)
IIR (%)
1584
(74.5)
Rituximab
185
n (%)
Total
2126
n (%)
77 (4.86)
1507 (95.14)
10 (5.40)
175 (95.60)
87 (4.09)
2039 (95.91)
33 (42.87)
44 (57.13)
-
4 (40)
6 (60)
-
37 (42.52)
50 (57.47)
-
6 (7.79)
19 (24.67)
5 (6.49)
3 (30)
2 (20)
2 (20)
9 (10.34)
21 (24.13)
7 (8.04)
1 (1.29)
4 (5.19)
2 (20)
1 (10)
3 (3.44)
5 (5.74)
5 (6.4)
17 (22.07)
-
5 (5.74)
17 (19.54)
19 (24.67)
1 (1.29)
-
19 (21.83)
1 (1.14)
56 (72.72)
21 (27.27)
4 (40)
6 (60)
60 (68.96)
27 (31.03)
65 (84.41)
12 (15.58)
7 (70)
3 (30)
72 (82.75)
15 (17.24)
Immediate infusional reaction (IIR)
Yes
No
Severity
Mild
Moderate
Severe
Reaction type
Angioedema
Purely cutaneous
Purely
gastrointestinal
Purely neurological
Purely
musculoskeletal
Purely respiratory
Purely
hemodynamic
Multisystemic
Other
Infusion interruption
87
(4.09)
total
77
(4.86)
IFX
185
(8.7)
RTX
10
(5.4)
226
(10.63)
TCZ
0
131
(6.16)
Yes
No
0
ABT
Rescue medicationa
Yes
No
a
Fig. 1 – Total and percentage of infusions and IIR by drug.
Antihistamines, corticosteroids, analgesics, adrenaline.
106
prescribed in 33.72% of infusions, and in 52.87% of IIR cases,
patients were pre-medicated. Of the six procedures in which
the infusion could not be completed due to IIR, 3 (50%) were
preceded by premedication.
Of all IIR observed, 79 (90.8%) cases were solved using initial manoeuvres (interruption of the infusion and/or use of
rescue medication) and the procedure was successfully concluded, with no further intercurrences. In two IFX infusions,
there was no recurrence of reactive symptoms after initial
measures, even after required further intervention, which resulted in a successful procedure. In 6 infusions, all from the
IFX group (7.79% of IIR cases with IFX use and 0.37% of total
IFX infusion), it was not possible to complete the procedure
due to the severity or non-resolution of the reactive picture,
and the infusion was discontinued. All IIR related to RTX were
reversed and the procedure was completed successfully. As
an overall result, of the 2126 procedures, only 6 (0.28%) were
not completed due to IIR.
Discussion
General reactions
Essentially, the infusional reactions are classified in allergic
(IgE-mediated or of hypersensitivity type I) and non-allergic
(non-IgE, generally attributed to cytokine release) reactions.9,10
The majority of infusional reactions related to the infusion
of monoclonal antibodies pertain to the non-allergic type,11
but in practice, as the symptoms are very similar, it is difficult to classify clearly the nature of the reaction, especially
for autoimmune diseases, which exhibit differentiated pathophysiological patterns in relation to neoplastic diseases.3 In
practice, we found that the reactions mediated by the release
of cytokines, in contrast to those that are mediated by IgE,
usually resolved with temporary drip suspension and by administration of antihistamines; these procedures allowed to
return to infusion.
Acute reactions to the infusions of monoclonal antibodies are described mostly as mild to moderate [levels 1 and 2,
according to the classification published by the National Cancer Institute (Table 2)], and the incidence of severe reactions
is small.11-14 In studies using monoclonal antibodies to treat
cancer, the reactions are described as more frequent during
the first infusions, and generally managed successfully after
a temporary reduction or cessation of infusion and the use of
an appropriate rescue medication. Most patients tolerate well
the subsequent infusions with the use of premedication.6,15,16
The results of this study are in line with literature data, since
most of the observed reactions allowed resuming the infusion
after initial measures and occurred more often in the initial
procedures.
One added obstacle in the analysis of comparative studies is the lack of standardization of nomenclature and of the
reaction classification of the series, since the designation “infusional reaction” can be found as “allergic reaction”, “acute
infusional reaction”, “immediate infusional reaction” and
other terms, generating a possible bias in the interpretation
of results. In our analysis, considering that all intercurrences
were classified as IIR, without distinction as to whether or not
allergic in nature, the results should be interpreted considering this broader and less specific concept. It is also necessary
to emphasize that the overall percentages of IIR observed in
our study may also have been influenced by the pre-medical
consultation conducted by medical staff of the Infusion Centre - CID before every infusion, with the main goal of an early
detection of absolute contraindications prior to the infusion.
Infliximab
IFX is a chimeric (murine-human) monoclonal antibody that
binds to TNF (tumour necrosis factor), used successfully for
the control of several autoimmune diseases.1 Among the IV
IBD evaluated in this study, IFX is the one that has most indications in the package insert (i.e., rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel
disease and psoriasis). Since the recommended dosages are
different for each disease indicated (from 3 to 10 mg/kg/infusion),4 it was necessary to divide the analyzed procedures by
dose/kg body weight (Table 1).
In a study that compared percentage of discontinuation
of IFX, etanercept and adalimumab (two other IBD acting on
TNF, but whose route of administration is subcutaneous), the
proportion of discontinuations caused by IIR in IFX users was
23.9%, above the average of the other anti-TNF (16%) and of
each drug considered individually.17 Possibly because IFX is
the only anti-TNF agent for IV use available in Brazil, it is the
drug most related to IIR occurrence in its group. In the literature, the risk of IIR in IFX users ranges from 0.8% to 8.8%
by infusion.18-24 In most cases, the IIR are considered mild or
moderate. Reports describe a frequency of severe reactions
around 0.5%, and only 2% of patients discontinued the treatment due to infusional reaction.
In patients with Crohn's disease, the reported frequency of
IIR is 4%-5%, half of which occur until the third infusion (25%
until the second infusion).25 These values are closer to those
observed in our study (4.86%), which included patients with
different pathologies.
We emphasize that from the procedures analyzed at the
Infusion Centre - CID, in 21 cases of IIR (27.27%) there was no
need to interrupt the drip, and in two cases even after a recurrent reactive manifestation, it was possible to complete the
procedure. Only in 6 procedures (7.79% of IIR and 0.37% of all
infusions of IFX performed) the infusion was not completed
when it became imperative to discontinue the medication.
The symptoms most frequently described in IIR are headache, dizziness, nausea, rash and pruritus.21,23,24,26 In our study
a greater relative proportion of hemodynamic changes (hypoor hypertension, tachycardia) was noted, being second in frequency only for cutaneous reactions.
Despite the high frequency of reactions described in the
literature, and despite some studies that encourage the use
of premedication in IFX infusions, most of the studies with
an adequate design do not recommend the use of antihistamines or steroids in preparation for infusion in patients naïve
to transfusional reactions.21,27,28 Regarding the use of premedication, in 52.87% of cases of IIR premedication was used suggesting that the use of this strategy did not help avoid the
occurrence of IIR. We emphasize that in some premedication
cases its use occurred in patients who had previously suffered
of IIR, which determines a bias in data analysis. However, we
emphasize the low frequency of IIR among patients not premedicated (5%), which agrees with the literature and suggests
that the routine use of premedication is not justified in patients naïve to previous reactions. Likewise, and even in face
of the small number of events, the use of the drug preparation
apparently did not change the IIR outcome, since there was
no difference for this criterion among the suspended procedures due to IIR.
Tocilizumab
TCZ is a recombinant humanized monoclonal antibody that
blocks interleukin-6 receptor that plays a fundamental role
in the pathophysiology of rheumatoid arthritis. The reported
frequency of infusional reactions in the literature is around
7%. The most common symptoms are transient elevation of
blood pressure, redness at the site of venipuncture, headache, nausea and rashes.29,30 Usually, IIR are mild and transient, allowing the treatment maintenance. The absence of
IIR related to TCZ in this study should be interpreted with
caution, due to the small number of procedures performed,
226, which accounted for only 10.63% of all procedures. We
believe that the results obtained in our study favour the infusional safety of TCZ.
Rituximab
RTX is a chimeric (murine-human) anti-CD20 monoclonal
antibody originally used for the treatment of non-Hodgkin
lymphoma protocols, and is also approved for the treatment
of rheumatoid arthritis.6 In other autoimmune diseases such
as systemic lupus erythematosus, dermatomyositis and some
systemic vasculitides. RTX has shown efficacy and presents
itself as a good off-label therapeutic option. Compared to
studies of non-Hodgkin lymphoma and leukemias, diseaser
where RTX is commonly used for extended amounts of time,
the knowledge about the use of this drug for autoimmune diseases is still limited.18 Perhaps this is one reason to explain the
large discrepancy between data about RTX infusional safety.
As determined in previous studies and recommendations
of the manufacturer,6 infusions of RTX must be preceded by
some drug preparation (antihistamines, corticosteroids and
acetaminophen). This protocol, developed for the treatment
of lymphoma, is also adopted in the care of patients with
autoimmune diseases, and has been used in infusions performed at the Infusion Centre - CID.31,32
Studies show that the incidence of IIR related to RTX use
can be greater than 70%, but there is evidence that this number may vary according to the indicated disease, and the reactions are more frequent in the treatment of neoplasms (12%
in systemic vasculitis, 27% in rheumatoid arthritis and 77%
in non-Hodgkin lymphoma), for unknown reasons.33 A study
that analyzed the safety of RTX only for autoimmune diseases
in 370 patients showed a much lower incidence of IIR (around
18%), and only 2.4% of treatment discontinuations for severe
reaction were required. When a secondary analysis was taken, it was found that the risk of reaction per patient did not
exceed 2%, and there was no statistically significant difference between the conditions.35
107
Similar to anti-TNF reactions, the RTX reactions are more
common during the initial infusions, and occur most frequently within the first two hours of infusion. The proportion
of IIR dropped by half from the first to the fourth infusion.12,34
The most common symptoms reported are urticaria, hypotension, angioedema, hypoxia and bronchospasm, but there
are also reports of respiratory failure, myocardial infarction,
cardiogenic shock and severe anaphylaxis.28
As severity, most IIR are of mild to moderate intensity. The
literature describes around 10% of severe reactions, in rare
cases leading to death. Certain information of particular interest is that 80% of cases of death related to the infusion of
RTX occurred at the first round of infusion of the drug.34 In
our series, the incidence of IIR related to RTX (in 69.72% of
cases with indication of rheumatoid arthritis treatment) was
much lower (5.40%), however with a similar pattern to that
described in the literature. All IIR were considered of mild or
moderate intensity (no severe reactions in this series), and occurred until the second infusion, 60% of them during the first
procedure. Despite the reactions presented, all 185 infusions
of RTX held at the Infusion Centre - CID in the study period
were completed successfully. During no procedure the discontinuation of the infusion due to IIR was needed.
Abatacept
ABT is a fusion protein that blocks and modulates a key costimulatory signal, promoting downregulation of T cells.7 The
condition most commonly used for are rheumatoid arthritis36,37 and juvenile idiopathic arthritis.38
The frequency of IIR assigned to ABT use in the literature
is about 9%.39 Specific studies in juvenile idiopathic arthritis
show percentages around 4%.38 A systematic review describes
that the rate of discontinuation of ABT because of serious
adverse events (including severe anaphylaxis) is significantly lower than that of IFX.39 A subgroup analysis, however,
pointed out that the frequency of adverse events is higher
in patients with chronic obstructive pulmonary disease and
diabetes mellitus. Considering that it was not the aim of our
study to evaluate the relationship of IIR with comorbidities,
it was not possible to attribute the absence of IIR to the use
of ABT due to patient characteristics; however, it should be
emphasized that the existence of obstructive lung disease is
a contraindication related to the use of ABT.
Regarding the absence of IIR in the 131 infusions (6.16% of
infusions) of ABT in this study, the same comments for the
TCZ group and the expectation of equally promising results
in relation to the infusional safety profile of this drug are pertinent.
We recognize that the main limitation of the combined
data analysis in our study was the discrepancy among the
number of IFX infusions, when compared to the other three
drugs. Some conditions justify this finding:
1) The time span of these drugs in the Brazilian market for
non-oncological use: Infusions performed from October
2006 on were evaluated, when IFX was the only available
drug in Brazil. The first infusion of the other drugs at the
Infusion Centre - CID occurred in September 2007 (ABT),
October 2007 (RTX) and September 2009 (TCZ).
108
2) Number of indications in the package insert: IFX has five
indications: rheumatoid arthritis, ankylosing spondylitis,
psoriatic arthritis, Crohn's disease, ulcerative colitis and
psoriasis, while other drugs have only one indication:
rheumatoid arthritis.
3) Posologic schedule (frequency of infusion): IFX: infusions
every 6-8 weeks, with plus 3 infusions/year in the case of
induction therapy; RTX: maximum of 4 infusions/year (2
infusions, twice a year); TCZ: infusions every 4 weeks; and
ABT: infusions every 4 weeks, plus one infusion/year in
case of induction therapy.
Thus, the presented results cannot be interpreted in a
comparative manner between different drugs, but are significantly useful to reflect the practical treatment routine of autoimmune diseases with IV IBD.
9.
10.
11.
12.
13.
14.
15.
Conclusions
Despite a heterogeneous distribution of the number of procedures for these drugs, we believe that the results reflect the
analysis of a “real life” sample, where the frequency of IIR was
not higher than that described in the literature. The form of
presentation, behaviour, severity and outcomes were similar
to those described in different series.
We emphasize that the low prevalence of IIR corroborates
security data, both quantitatively and qualitatively, of the
various IV IBD. However, we must emphasize that, despite
the expansion of the experience with the use of these drugs,
a specialized medical monitoring is still considered essential during infusion, either in the immediate handling of the
event, as for the decision of infusion resuming.
IBM received payments for lectures from laboratories Abbvie
and Pfizer. RMC participated on boards of Janssen laboratory,
and also received payments for lectures from AstraZeneca,
Bristol, Roche and Janssen laboratories. The other authors declare no conflicts of interest.
16.
17.
18.
19.
20.
21.
22.
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REUMATOLOGIA
Original article
Is swimming able to maintain bone health and to minimize
postmenopausal bone resorption?
Tâmara Kelly Delgado Paes Barretoa, Fabiana Soares Bizarriab,
Marcos Paulo Galdino Coutinhoa, Patrícia Verçoza de Castro Silveiraa,
Karina de Carvalho da Silvac,*, Ana Cristina Falcão Estevesd,
Sílvia Regina Arruda de Moraesd
a
Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil
Hospital Agamenon Magalhães, Recife, PE, Brazil
c
Faculdade Boa Viagem, Recife, PE, Brazil
d
Department of Anatomy, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil
b
article info
abstract
Article history:
Objective: We studied the effect of swimming on the somatic and bone growth of female rats.
Methods: 40 neonate Wistar female rats were separated into: monosodium glutamate group
(GluM, n = 20) and received MSG solution (4.0 mg/g) on alternate days during the first 14 days
after birth, and Saline group (SAL, n = 20) which received saline solution for the same period
Keywords:
of time and at the same dose. At 60 days of age, GluM group was ovariectomized (GluMO) and
Bone tissue
SAL group just suffered surgical stress. Subsequently, half the animals in each group started
Monosodium glutamate
swimming, resulting in groups: sedentary saline (SALsed, n = 10), swimming saline (SALswi,
Ovariectomy
n = 10), sedentary ovariectomized Glutamate (GluMOsed, n = 10) and swimming ovariecto-
Swimming
mized Glutamate (GluMOswi, n = 10). At the end of the experiment, we measured the animals’ longitudinal length and weight; their radius was weighed and its length measured.
Results: The animals of the GluMOsed group had lower body weight and longitudinal length
compared to SALsed. Swimming decreased body weight, but had no influence on the
longitudinal length of the GluMOswi group compared to GluMOsed group. Longitudinal
length and body weight were lower in SALswi animals compared to SALsed animals. Radius
weight and length of GluMOsed animals were lower than in SALsed animals. There was no
difference in these parameters between GluMOsed and GluMOswi groups; however, these
parameters were lower in SALswi animals compared to SALsed animals.
Conclusion: Swimming does not influence previously affected bone tissue during the neonatal period, however it may cause damage to healthy bone tissue.
E-mail: [email protected] (K.C. Silva).
111
A natação é capaz de manter a saúde do tecido ósseo e minimizar a
reabsorção óssea pós-menopausa?
resumo
Palavras-chave:
Objetivo: Estudou-se o efeito da natação sobre o crescimento somático e ósseo de ratas.
Tecido ósseo
Métodos: usaram-se 40 ratas Wistar neonatas separadas em grupo glutamato monossódico
Glutamato monossódico
(GluM, n = 20), que recebeu solução de MSG (4 mg/g), em dias alternados, nos primeiros 14
Ovariectomia
dias de vida; e Grupo Salina (SAL, n = 20), que recebeu solução salina na mesma dose e no
Natação
mesmo período. Aos 60 dias de vida, o grupo GluM foi ovariectomizado (GluMO) e o SAL
passou apenas pelo estresse cirúrgico. Posteriormente, metade dos animais de cada grupo
iniciou o treinamento de natação, o que resultou nos grupos Salina sedentário (SALsed,
n = 10), Salina natação (SALnat, n = 10), Glutamato ovariectomia sedentário (GluMOsed,
n = 10) e Glutamato ovariectomia natação (GluMOnat, n = 10). Ao término do experimento,
os animais tiveram o comprimento longitudinal mensurado e foram pesados; o rádio foi
pesado e o comprimento, avaliado.
Resultados: Os animais do grupo GluMOsed apresentaram peso corpóreo e comprimento
longitudinal menores em relação ao SALsed. A natação diminuiu o peso corpóreo, porém
não exerceu influência no comprimento longitudinal dos animais do grupo GluMOnat em
relação ao GluMOsed. Peso corpóreo e comprimento longitudinal foram menores nos animais do grupo SALnat quando comparados aos do SALsed. Peso e comprimento do rádio
dos animais do grupo GluMOsed foram menores do que os do SALsed. Não houve diferença
desses parâmetros entre os grupos GluMOsed e GluMOnat. Contudo, foram menores nos
animais do grupo SALnat em relação ao SALsed.
Conclusão: O treino de natação não exerce influência no tecido ósseo previamente afetado
durante o período neonatal e ainda pode causar prejuízo ao tecido ósseo sadio
Introduction
The longitudinal bone growth is driven by genetic factors1
and by a complex network of endocrine signals, including
growth hormone, glucocorticoids, estrogens, vitamin D and
leptin,2 among others.
Studies have shown that the administration of monosodic glutamate (MSG) in neonatal period3,4 affects the
growth and development of rodents, especially during the
period of sexual maturation.4 This is possible because MSG
causes permanent damage to the brain,3 more specifically
in the nucleus arcuate (ARC) and ventromedial (VMH) hypothalamic nuclei,5 which leads to an anatomical and functional reorganization of the hypothalamus and adenohypophysis.4 As a result, the damage in ARC is associated with
a deficiency in the secretion of growth hormone-releasing
hormone (GHRH) and gonadotropin-releasing hormone
(GnRH), causing changes in hormone secretion from adenohypophysis’ growth hormone (GH) and also in the secretion of gonadotropins.5 In other words, a reprogramming
of the development of the neonatal animal occurs,4 which
explains the linear body growth delay and hypogonadism.5
Therefore, the bone metabolism in women, as well as in
rats of both sexes suffering hormonal injury, is increased,6
leading to a prevalence of resorption over bone formation,
which is a condition found in osteoporosis.7
The ovariectomy in rats is a widely used model,8,9 which
lead to estrogen deficiency and therefore bone loss.9,10 This
model may provide information related to human bone loss
in postmenopausal women.11-13
Among the preventive resources against osteoporosis,
physical activity is one of the best non-pharmacological
methods,14 considering that bone tissue responds positively
to mechanical stimulation such as exercise,15 which stimulates osteogenesis,10 increases and maintain bone mineral
density,14 reduces the fall of BMD,16 in addition to providing greater resistance to the bone;17 therefore, the physical
activity is essential to decrease skeletal fragility.14 On the
other hand, some studies have shown that vigorous exercise can cause premature damage to bone tissue.18
Thus, we are not sure exactly the intensity, type and duration of exercise that can promote skeletal health. Studies on the influence of swimming on bone are still controversial and inconclusive;15,19 the available literature shows
that swimming is effective in preventing bone loss in the
femur and vertebrae20 but few studies investigate the effect of swimming in other bones, such as the radius, were
published.21
Therefore, this study aimed to evaluate whether swimming could affect bone tissues previously exposed to conditions that would lead to a loss of bone mass.
Materials e methods
Animals
A total of 40 newborn Wistar female rats from the breeding colony of the Department of Nutrition, UFPE, were used.
The animals were kept in a vivarium at the Department of
Anatomy at room temperature of 22°±1°C and at a 12/12 h
112
light/dark cycle in collective cages (maximum of four animals/cage) with free access to food and filtered water. This
study was approved by the Ethics Committee on Animal Experimentation of the Universidade Federal de Pernambuco
(office No. 018024/2007-11), consistent with the guidelines
suggested by Comitê Brasileiro de Experimentação Animal
(COBEA).
Experimental model
After birth, the animals were randomly divided into two
groups: Monosodic Glutamate (GluM, n = 20) and Saline
(SAL, n = 20). The GluM animals received a solution of
monosodiuc glutamate subcutaneously at a dose of 4.0
mg/g body weight on alternate days during the first 14 days
of their lives22 and the SAL group received saline at the
same dose and period of time.
Surgical procedure
At the age of 60 days, all animals of GluM group were ovariectomized (GluMO) with bilateral removal of the ovaries.
Initially, the animals were anesthetized with ketamine
and xylazine chlorhydrate and then placed on a surface
in ventral decubitus to perform a trichotomy. Then, in the
middle region of the animal dorsum was incised and, with
the aid of surgical scissors, the subcutaneous tissue was divulsioned from the lateral abdominal muscle wall. Shortly
afterwards, an incision 1 cm below the costal cage was performed. With the help of tweezers, the ovary was located;
it was ligated at the end of the fallopian tube with suture,
and the ovary was removed. Then, the muscles and skin
of the animal were sutured. The animals of the SAL group
were only subjected to surgical stress, without removal of
the ovaries.
After surgery, the rats were treated with Pentabiotic, a
topical veterinary antibiotic.
Training of animals
One week before surgery, half the animals in each group
started the adaptation phase of the freestyle swimming
exercising (Table 1) program,10 resulting in GluMOswi (n =
10) and SALswi (n = 10) groups, which were submitted to a
swimming training held from Monday to Friday in a plastic
tank with a capacity of 500 L, with a swimming surface area
of 0.90 m2 and with a resistance coupled to a thermostat,
allowing the maintenance of the water temperature around
32°-34°C. The water was changed daily.
The female rats were monitored throughout the exercise,
so that the animals did not touch the sides of the container.
After surgery, the animals were left to rest for a week,
and after the third week, they resumed the swimming
training with a progressive duration, starting with 15 minutes/day until reaching 60 minutes/day between the 5th
and 12th weeks.10
The animals that were not submitted to the swimming
protocol were kept into separate cages containing approximately 2 cm of water for the same period in which the other groups were submitted in the swimming training. Thus
Table 1 – Training protocol.
Weeks
Duration
1ª
1st day: 5 minutes
2nd day: 10 minutes
3rd day: 10 minutes
4th day: 15 minutes
5th day: 15 minutes
Surgery
Surgical recovery
1st day: 15 minutes
2nd day: 20 minutes
3rd day: 25 minutes
4th day: 30 minutes
5th day: 40 minutes
1st day: 45 minutes
2nd day: 50 minutes
3rd day: 55 minutes
4º day: 60 minutes
5º day: 60 minutes
60 minutes
Week-end
2ª
3ª
4ª
5ª – 12ª
they were subjected to a similar water stress, without performing the physical effort.
After swimming, the animals were dried with a towel
and then encased in a timber heating lined chamber (surface area, 0.25 m2) with an average heating temperature of
32°-36°C for a period of 10 minutes.
Material collection
After completing the swimming period, the animals were
weighed using an electronic scale (Marte, model S-4000,
with 0.1 g sensitivity). Then, the animals were anesthetized via intramuscular injection, using xylazine chlorhydrate (0.0 g 3 mL/100 g weight) and ketamine (0.25 mL/100
g weight). After that, the animals were placed on a flat surface in a prone position and had the longitudinal length
measured from snout to the anus23 using a calliper (Western, 0.02 mm). Then, an incision in the forepaw root region
was performed. The muscles and tendons were removed
and the radius was proximally and distally disjointed with
the aid of surgical scissors and, then, thoroughly dissected
to remove soft tissues.
After a proper dissection of the bone, we measured its
length with a calliper (Western, 0.02 mm). The radius was
positioned with the anterior surface facing up and the measurement of the bone was done from the radial head to the
styloid process. Soon after, the radius was weighed and its
density was measured using a hydrostatic weighing digital
balance (AND model HR-200, 0.1 mg sensitivity). After this
procedure, the bone was fixed in buffered formalin (10 mL
of 37% formalin and 27 mL of 0.1 M phosphate buffer pH
7.0) at 50 times the volume of the sample and then the bone
was stored in glass containers.
Data analysis
For data analysis, SigmaStat 32 program was used; Student
t test was applied for parametric values, and Mann-Whitney test was used for non-parametric values. The significance level was set at 95%.
113
Results
GluMOsed animals had lower body weight compared to SALsed
group (p < 0.001). The swimming exercise decreased the body
weight of GluMOswi animals compared to GluMOsed group (p
= 0.026), and also caused a reduction in body weight of SALswi
animals compared to SALsed (p < 0.001) group (Table 2).
The longitudinal length of GluMOsed animals was lower
compared to SALsed (p < 0.001) group. There was no change
in this parameter between GluMOsed and GluMOswi groups
(p = 0.224), nevertheless the exercise caused a reduction in
longitudinal length of SALswi animals compared to SALsed
group (p = 0.028) (Table 2).
The weight of the radius in GluMOsed animals was lower
compared to SALsed group (p < 0.001). There was no difference in this parameter between GluMOsed and GluMOswi
groups (p = 0.054); however, the weight of the radius was
lower in the SALswi animals versus SALsed group (p < 0.001)
(Table 3).
Likewise, the length of the radius of GluMOsed animals
was lower when compared to SALsed (p < 0.001) animals.
There was no change in this parameter between GluMOsed
and GluMOswi groups (p = 0.232), but the length of the radius
of SALswi animals was lower compared to SALsed group (p
= 0.001) (Table 3).
Discussion
The pre and postnatal life, including weaning stage, is crucial
for brain development.24 Some studies have shown that animals subjected to the application of monosodic glutamate
(MSG) in the postnatal period showed longitudinal growth
delay, as this substance is able to destroy specific cells in
hypothalamus arcuate nucleus (ARC), which is the site of
production of growth hormone-releasing hormone (GHRH);
that in consequence leads to a decreased secretion of growth
hormone (GH).3,5,24 The injury occurred in the hypothalamus,
generated by the application of high doses of MSG administered immediately after birth, is attributed to animals’ brain
immaturity.25
In the present study, the rats treated with MSG showed
lower longitudinal length and body weight versus those in
the control group. Maiteret al.,3 Rol de Lama et al.26 and Ćirić
et al.4 exposed animals to the same damage, using MSG in
the same dose for the first ten days of life. These authors
also observed a reduction in the linear growth of the animals. Furthermore, Schoelch et al.5 found a reduction in
body weight even in animals subjected to the application of
MSG in lower dose, compared to that used in our experiment
(3 mg/g body weight), and with a shorter duration (during
the first nine days of life), indicating that MSG can play a
negative role in the body size of the animal, even when applied in smaller quantities and for less time.
In addition to these effects, MSG also promotes impaired
secretion of gonadotropin-releasing hormone (GnRH), interfering negatively in the secretion of sex hormones.5 Because
of that, the animals develop hypogonadism, which may lead
to an increase of bone resorption and, therefore, to osteopenia.27,28 In the present study, to further accentuate the
hormonal loss, pubescent female rats underwent a surgical
procedure to remove their ovaries. This experimental model
has been applied in recent years,9,13,29 to demonstrate the effect of postmenopausal estrogen deficiency in bone structure quality.11-13,30
As a result, the skeleton becomes unable to adapt to applied loads,31 making it liable to fractures.32 This study aimed
Table 2 – Values of body weight and longitudinal length of the experimental groups.
Groups
SALsed
SALswi
GluMOsed
GluMOswi
Body weight (g)
Longitudinal length (mm)
257.6 ± 17.14
225.2 ± 16.71a
220.2 ± 24.30b
194.4 ± 23.30c
214.94 ± 4.50
209.53 ± 5.56a
192.89 ± 4.87b
189.81 ± 6.02
a
Corresponds to the analysis between SALsed and SALswi groups.
Corresponds to the analysis between SALsed and GluMOsed groups.
c
Corresponds to the analysis between GluMOsed and GluMOswi groups.
Values expressed as mean ± standard deviation, using Student’s t-test (p <0.05).
b
Table – 3 Values of radius weight and length of the experimental groups.
Groups
SALsed
SALswi
GluMOsed
GluMOswi
a
Radius weight (g)
Radius length (mm)
0.098 ± 0.005
0.090 ± 0.002a
0.060 ± 0.003b
0.057 ± 0.001
24.20 ± 0.31
23.61 ± 0.36a
21.54 ± 0.50b
21.26 ± 0.50
Corresponds to the analysis between SALsed and SALswi groups.
Corresponds to the analysis between SALsed and GluMOsed groups
Values expressed as mean ± standard deviation, using Student’s t-test for parametric data and Mann-Whitney test for non-parametric data (p
<0.05).
b
114
to evaluate the radius, because fractures in the distal region
of this bone are among the most common in humans affected by osteoporosis, showing increasing incidence,33 and
with a higher prevalence in women.34
It was also noted that MSG associated with ovariectomy
caused damage to the bone structure of the radius. The
length and weight of this bone were lower in MSG-treated
rats, these parameters were compared to the control animals. This result can be explained by the imbalance caused
by MSG in the ovarian hormonal metabolism in female rats,
considering that this substance alters the gonadal development, thus decreasing the secretion of estrogen.5,27,28
In mammals, longitudinal bone growth occurs rapidly in
prenatal life and early postnatal period. However, after this
phase, the growth rate declines and then ceases.35 In rats,
animals often used as experimental models, the critical period of growth occurs between 21-35 days after birth, and
a decrease of growth occurs between 35-80 days.36 In this
study, it is assumed that early administration of MSG negatively affected the bone development process, considering
that this substance was applied at a time when the bone had
not yet undergone the more critical period of development;
so,it is expected that the damaged bone tissue would behave
in a negative way to the main period of bone development.
According to Ćirić et al.,4 the neonatal exposure to glutamate
affects the growth and development of rats, especially during the period of sexual maturation. This means that the
pubertal period is characterized by a greater vulnerability
as well as more sensitivity to the manifestation of external
influences, particularly in females.4
Both MSG-treated female rats that underwent surgery to
remove their ovaries as well as those in the control group
who underwent the same surgical stress, but had their ovaries preserved, were submitted to a swimming practice.
There is evidence that high impact exercises are beneficial
for providing an increase in bone mass,31 and that aquatic
exercises without impact, such as swimming, are considered
to have relatively little effect in the prevention of osteopenia.37
The female rats that received MSG as well as those in
the control group who practiced swimming, exhibited lower
body weight at the end of the experiment. This may have
occurred because of increased energy expenditure with the
exercise. The increase in energy expenditure by moderateintensity exercise can be effective in preventing or reducing
weight gain.38
It was noted in this study that the swimming practice had
no influence on the animal's longitudinal length, its weight
and in the length of the radius of MSG-treated animals, as
compared to animals that also received the substance, but
did not swim. According to Frost,39 Crossley et al.,40 and Magkos et al.,15 the bone tissue responds to mechanical loading:
part of this force is absorbed by the body during the load exercise, being attenuated in the joint structures, whereas another part of the force is transmitted to the skeleton, causing deformation and possible increase in bone mass. Bone
that undergoes little stress does not promote osteogenesis,
and lacking bone cell response. Therefore, it is assumed that
the bone tissue could be most benefited with high-impact
exercises.41
Much research on the relationship between swimming
and bone mass have been conducted in young people and in
athletes, and few benefits were cited.10 In this study, it was
found that swimming training was capable of causing damage to healthy bone tissue of animals, by reducing the weight
and length of the radius. These same animals also showed
decreased longitudinal length at the end of the experiment,
when compared to sedentary animals. Thus, although physical activity is a variable positively related to high values of
bone mineral density,10 strenuous exercise can have negative
consequences on the skeleton, particularly in an immature
skeleton, which can delay the maturation of collagen and
decrease the bone development, as noted in the tibia of animals subjected to exhaustive treadmill exercise.18
In this study it is assumed that the frequency and duration of swimming had been gruelling for the animals, thus
causing damage to the bony structure of the radius. These
findings corroborate Bourring et al.42 conclusions; these authors showed that physical activity can also cause deleterious effects on bone, such as lowering of its longitudinal
length and reducing the height and number of bone trabeculae, with a consequent increase in the intertrabecular
space and significant decrease of the average thickness of
osteoid, suggesting a decreased osteoblastic activity at the
cellular level.42
This result can also be explained by the study by Simkin
et al.43 These authors submitted 40 rats to swimming training, and observed that the movements made by the animals
during the swimming practice differ from the usual movements made on land. During swimming, the mice not only
flex and extend the upper limbs; swimming promotes their
rotation and abduction as well. Whereas, in terrestrial locomotion there are only two phases (flexion and extension)
and the animals are subject to the action of gravity only in
flexion; on the other hand, during the swimming exercise a
continued resistance of the water in all phases of the movement occurs, generating higher amount of weariness. Therefore, strenuous exercises can lead to muscle fatigue which,
in turn, increases the risk of bone stress and of stress fractures. Thus, they should be avoided.44
Conclusion
In the conditions under which this experiment was conducted, the results suggest that swimming does not influence
bone tissue previously challenged and may cause damage to
the structure of healthy bone tissue.
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REUMATOLOGIA
Original article
Protocol for physical assessment in patients with
fibromyalgia syndrome
Michele R. dos Santos, Claudia M.C. Moro*, Dilmeire S.R. Vosgerau
Postgraduate Program in Health Technology, Pontifícia Universidade Católica do Paraná (PPGTS/PUC-PR), Curitiba, PR, Brazil
article info
abstract
Article history:
Introduction: Fibromyalgia syndrome (FMS) is a chronic disease that causes pain and fatigue,
Received 15 April 2013
presenting a negative impact on quality of life. Exercise helps maintaining physical fitness
and influences directly on the improvement of quality of life.
Objective: Develop a protocol for health-related physical fitness assessment of patients with
Keywords:
FMS with tests that are feasible and appropriate for this population.
Fibromyalgia
Method: An exploratory and analytical literature review was performed, seeking to deter-
Protocol
mine the tests used by the scientific community. With this in mind, we performed a litera-
Physical assessment
ture revision through the use of virtual libraries databases: PubMed, Bireme, Banco de Teses
e Dissertações da Capes and Biblioteca Digital Brasileira de Teses e Dissertações, published
in between 1992-2012.
Results: A variety of tests was found; the following, by number of citations, stood out: Body
Mass Index (BMI) and bioimpedance; 6-minute walk; handgrip strength (dynamometer,
1RM [Repetition Maximum]); Sit and reach and Shoulder flexibility; Foot Up and Go, and
Flamingo balance.
Conclusion: These are the tests that should make up the protocol for the physical evaluation
of FMS patients, emphasizing their ease of use.
Protocolo para avaliação física em portadores de síndrome de fibromialgia
resumo
Palavras-chave:
Introdução: A síndrome da fibromialgia (SFM) é uma doença crônica que provoca dor e fadiga
Fibromialgia
e apresenta impacto negativo na qualidade de vida. O exercício auxilia na manutenção da
Protocolo
aptidão física e influencia diretamente na melhoria da qualidade de vida.
Avaliação física
Objetivo: Elaborar um protocolo para avaliação física relacionada à saúde de portadores da
SFM com testes que sejam viáveis e apropriados para esse público.
Método: Foi feita uma revisão da literatura de forma exploratória e analítica, para determinar os testes usados pela comunidade científica. Com isso, fez-se um levantamento bibliográfico por meio do banco de dados das bibliotecas virtuais PubMed, Bireme, Banco de Teses
e Dissertações da Capes e Biblioteca Digital Brasileira de Teses e Dissertações publicados
entre 1992 e 2012.
E-mail: [email protected] (C.M.C. Moro).
118
Resultados: Demonstraram uma variedade de testes, em que se destacaram, em número
de citações, os seguintes: Índice de Massa Corporal (IMC) e Bioimpedância; Caminhada de
6 minutos; Força de preensão manual (dinamômetro), 1 RM [Repetição Máxima]); Sentar e
alcançar e Flexibilidade de ombro; Levantar e ir – Foot Up and Go e Equilíbrio do flamingo.
Conclusão: Estes são os testes que devem compor o protocolo para avaliação física de portadores de SFM. Ressalte-se que esse protocolo é de fácil utilização.
Introduction
Fibromyalgia syndrome (FMS) is a chronic disease of unknown origin characterized by diffuse muscle pain, sleep
disturbances, fatigue and presence of multiple painful
points, the so-called tender points.1,2 Many patients with
FMS express anxiety and depression, that affect their quality of life.3
Exercise is an important factor for improving the quality of life of the patient, but it should be designed not to
be strenuous.2 The exercise is responsible for acquiring and
maintaining physical fitness, which is defined as the set of
attributes that people have or develop related to the ability
to perform physical activities.4 Because of the pain, many
patients with FMS have great difficulty in starting an exercise program.5 Thus, it is imperative that we specify exercises that influence the improvement of physical conditioning,
but without causing pain.5
This facilitates the adhesion of FMS patients to an exercise program and minimizes the negative impact of lack of
conditioning. It is important to note that untrained muscles
are more prone to injury during activities,6 and this can result in more pain, making these patients more sedentary individuals (i.e. who do not engage in exercise regularly) and
deconditioned.6
To maintain a good health/quality of life, it is necessary
for the individual to keep on good levels the four physical
capacities related to health: cardiovascular fitness, muscular strength and endurance, flexibility and appropriate body
composition.4 This strategy should be considered for all individuals, including those with FMS. Sedentary people tend
to have progressively lower levels of physical fitness, health
and quality of life.7
One of the critical objectives of exercise intervention programs is the promotion of health, and they should focus on
the improvement of physical fitness-related components.
For that to happen, it is necessary to measure and monitor
the fitness levels.8
Thus, the physical educator who works with patients with
FMS needs to know about the fitness level of those patients
needing help, performing a physical assessment. The measurement of fitness levels is done through tests and physical evaluations specific to each tested component that vary
according to the approach, purpose and target population.8
Thus, the purpose of this narrative review is to identify
the most commonly applied tests in the literature for the
physical evaluation of patients with FMS, with the objective
of developing a protocol for specific physical assessment for
this population. Considering that, although there are evalu-
ating methods for FMS,9 until now no protocol or guideline
for the evaluation of physical capacity of this target population has been developed.
Materials and methods
This research is characterized as a narrative review, because
it describes and discusses the development of the topic from
a theoretical and contextual points of view.10 Ours is not a
systematic review because, although we clearly present the
stages of the research, the data is not interpreted in order
to assess the applicability of the results, as dictated by the
systematic review.10
A literature search, using the databases PubMed (http://
www.pubmed.com.br), Bireme (http://brasil.bvs.br/), as
well as the Banco de Teses e Dissertações da Capes (http://
capesdw.capes.gov.br/capesdw/) and the Biblioteca Digital
Brasileira de Teses e Dissertações (http://bdtd.ibict.br/), was
conducted.
During the article selection, the terms “flexibilidade”,
“composição corporal”, “capacidade cardiorrespiratória”,
“capacidade aeróbica” and “força muscular” (Brazilian Portuguese) and its English versions, i.e. “flexibility”, “body
composition”, “cardiorespiratory fitness”, “aerobic fitness”
and “muscle strength”, were used. To these terms the words
“fibromialgia” and “fibromyalgia” (for the English versions)
were added to the data entry field. In the research of dissertations, only the term fibromyalgia was used.
After the research material collection (articles, dissertations and theses), an exploratory analysis of the collected
documents was conducted, by reading the abstracts in order
to identify those who have had some kind of test for fitness
assessment in patients with FMS.
Regarding dissertations and theses, at first the selection was made by title and then, if in doubt, by summary
analysis. When, even after reading the summaries, the relevance of the document was unclear, our procedure was: for
articles the full text was read, and for the theses its study
methodology was read. Usually this strategy brought us
more detailed information regarding the use, or lack, of the
standardized tests.
Our inclusion criteria were: the articles should contain,
in their methodology, a clear description of the tests applied, and should have been published from 1992-2012 (corresponding to the last 20 years). The articles reporting that
a physical assessment had been carried out without mentioning the test used were discarded, as well as those that
did not provide any information on physical assessment by
using tests, rather by questionnaires instead.
119
As exclusion criteria for theses and dissertations, we
chose to exclude those texts which, in their title, did not indicate the presence of an exercise, as well as when, in the
methodology, did not describe clearly the tests used for the
evaluation.
In addition to the common health-related variables of
physical assessment, such as cardiorespiratory fitness, body
composition, muscular strength and endurance, and flexibility, the variables “agility” and “balance” were also analyzed,
as some articles have described the latter as important
physical skills to be considered in FMS patients, since, due to
pain and difficulty to perform exercise, this population also
has a tendency to show a decline in these abilities.
For better understanding, the information contained in
the articles were listed in tables and charts, and a list of tests
suggested or mentioned in each article for each of the four
main physical factors evaluated, but also for agility and balance, was elaborated.
The tables were arranged to display the number of times
each test was mentioned. In some articles more than one
test to evaluate a given physical skill was used, but as the
purpose of this study is to identify the most commonly applied tests for physical evaluation, all tests were listed separately.
A clustering of articles of the same research group was
also conducted, with the aim to emphasize whenever a given
test was used by different studies and groups; yet these articles are presented in the same table indicating the amount
of tests per research. For example, the Body Mass Index (BMI)
test was quoted 19 times by 11 different groups.
To present the possibility of combining and using more of
a test to assess physical skills, shown in the studies, charts
with the percentage reported in the literature were created.
Table 2 lists the tests applied to assess cardiorespiratory
capacity, and 41 studies conducted by 28 different research
groups were identified. The total number of tests (44) is higher
than the number of studies, because some of them used more
than one test. Individually, the 6-minute walk test (6MWT),
with 54.55%, was the most quoted test, and by different research groups (42.86%).
Regarding the use of combined tests to assess cardiorespiratory fitness, it was observed that the 6-minute walk is the
most frequent test in the combination of tests (59%). Tests for
thoracic expansion, submaximal cycle ergometer and anaerobic threshold and VO2max, with a 7% incidence, belong to the
second group of most common applied tests.
There were found 58 studies that quoted tests for evaluation of muscular strength and endurance, conducted by 34
different groups. Table 3 lists these tests, noting that the total amount of 82 quoted in the studies is due to the fact that
several studies applied more than one test. It is observed that
the use of “handgrip” (dynamometer) (24.39%) and “isometric
Table 1 – List of tests used for body composition
assessment.
Tests
BMI (Body Mass
Index)
Bioimpedance
Waist
circumference
Skin folds
WHR (Waist-Hip
Ratio)
Total
Quantity
%
By research
group
%
19
61.29
11
57.89
7
3
22.58
9.68
3
3
15.79
15.79
1
1
3.23
3.23
1
1
5.26
5.26
31
100.00
19
100.00
Results
We identified a total of 84 articles and four theses that contained tests for physical evaluation of FMS patients, totalling
88 documents.
In the first survey, 223 articles and 235 theses and dissertations with the words/terms used searched in the article title
were found, but after reading the abstracts, 138 were excluded; and after reading the titles and summaries of dissertations and theses, 231 more were excluded, because they did
not meet the inclusion criteria.
Of the 88 documents analyzed, 23 contained information
on tests for body composition assessment by 13 different research groups. Table 1 lists these tests, and also shows the
number of times each one was named by each research group.
We must emphasize that some studies quote more than one
test. Thus, the amount of 31 refers to the number of tests indicated in the 23 studies collected. It was observed that the
most commonly used test for body assessment is BMI; also,
this test is also the most quoted by different research groups.
In the selected studies it was observed that BMI, in addition to being the most individually quoted test, better combines the evaluation of body composition (52%), and also appears more often in combination with other tests, especially
with bioimpedance (17%).
Table 2 – List of tests for cardiorespiratory fitness
assessment.
Tests
6-minute walk
Anaerobic
threshold
and VO2max
(maximal
oxygen
consumption)
by gas
analysis
Submaximal
cycle
ergometer
10-meter walk
Chest
expansion
Treadmill test
(20' with
deliberate
speed)
Bench test
Maximum load
Total
Quantity
%
By research
group
%
24
4
54.55
9.09
15
4
42.86
11.43
4
9.09
4
11.43
4
3
9.09
6.82
4
3
11.43
8.57
2
4.55
2
5.71
2
1
44
4.55
2.27
100.00
2
1
35
5.71
2.86
100.00
120
Table 3 – List of tests for muscle strength and endurance
assessment.
Tests
Quantity
%
By research
group
%
Handgrip
strength
(dynamometer)
Isometric force
apparatus
30-second sit to
stand from a
chair test
Isokinetic
strength
apparatus
1RM (Repetition
Maximum)
Leg
Biceps curl test
Pelvic elevation
Standing flexion
Phantom chair
(wall squat)
Abdominal and
lumbar
Total
20
24.39
13
22.41
18
21.95
12
20.69
15
18.29
9
15.52
10
12.20
8
13.79
For the combination of balance and agility tests, the flamingo balance stood out with 31%, followed by Foot Up and
Go and Flamingo balance with Foot Up and Go (25%).
Given these results, the protocol for physical assessment
of FMS patients should be made up of the four main physical
skills (body composition, cardiorespiratory fitness, muscular
strength and endurance, and flexibility) with agility and balance being added; we suggest, for that protocol, the tests presented in Table 6.
Discussion
8
9.76
6
10.34
4
2
2
1
1
4.88
2.44
2.44
1.22
1.22
3
2
2
1
1
5.17
3.45
3.45
1.72
1.72
1
1.22
1
1.72
82
100.00
58
100.00
This study aimed to identify the most commonly used tests
for the physical assessment of FMS patients presented in the
literature, in order to generate a testing protocol that is viable
and more suitable for the physical assessment of this population, facilitating the choice of the tests.
Firstly, it was found that, unlike what happens to the general public, for which body composition, cardiorespiratory fit-
Table 4 – List of tests for flexibility assessment.
Tests
strength apparatus” (21.95%) tests is very similar. The least
applied tests were: Leg (4.88%), biceps curl test (2.44%), pelvic
lift (2.44%), standing flexion (1.22%), phantom chair (1.22%),
and abdominal and lumbar tests (1.22%).
About 24 possible combinations of tests to assess muscle
strength and endurance were identified. It was found that the
isometric force apparatus is still the most quoted in the studies (21%), followed by handgrip strength (14%) and isokinetic
strength apparatus and 1 RM (11%).
It was observed that with the combination of more than
one test, the 30-second sit to stand from a chair test is the
most used along with others, in combination with grip
strength (dynamometer) and isokinetic strength apparatus
(2%), isometric and isokinetic strength apparatuses (2%),
biceps curls and handgrip strength (2%), leg test (2%), also
combined with isometric force apparatus (2%), isokinetic
strength apparatus (2%), handgrip strength (9%), and biceps
curl (2%).
Table 4 shows the tests used to assess flexibility. In the
evaluation of physical fitness, 25 studies, written by 17 research groups, were found; stressing that more than one
test was quoted by some studies. Thus, the total number is
35. The three most commonly used tests are sit and reach
(42.86%), shoulder flexibility (28.57%) and 3rd finger to the
ground (17.14%).
For the combined tests for flexibility assessment, we found
equilibrium in the use of tests: sit and reach (31%), sit and
reach and shoulder flexibility together (27%), followed by 3rd
finger to ground (19%).
For assessment of balance and agility, 16 studies were
found; the number of 22 appears because some studies have
quoted more than one test, and were conducted by 8 different
groups that quoted assessment tests for this physical skill.
Table 5 lists these tests for evaluation. Foot Up and Go (45.45%)
and flamingo balance (40.91%) stood out.
Sit and Reach
Shoulder
flexibility
3rd finger to
the ground
Joint range of
motion
Passive
flexibility
Total
Quantity
%
By research
group
%
15
10
42.86
28.57
9
4
40.91
18.18
6
17.14
5
22.73
3
8.57
3
13.64
1
2.86
1
4.55
35
100.00
22
100.00
Table 5 – List of tests for balance and agility assessment.
Tests
Quantity
%
By research
group
%
Foot Up and
Go (dynamic
balance and
motor agility)
Flamingo
balance
(static
equilibrium)
FAB (Fullerton
Advanced
Balance rotating 360
degrees;
retrieve
object with
closed eyes
on a surface)
Vibratory
platform
Berg Balance
Scale
Total
10
45.45
5
41.67
9
40.91
4
33.33
1
4.55
1
8.33
1
4.55
1
8.33
1
4.55
1
8.33
22
100.0
12
100.0
Table 6 – Protocol for Physical Assessment in FMS
patients.
Physical fitness
Body composition
Cardiorespiratory fitness
Muscular strength and
endurance
Flexibility
Agility and Balance
Test
Bioelectrical impedance and
BMI.
Note: Possibility of a choice
between one test, or both
combined.
6-Minute walk.
Isometric strength apparatus
(ideal); 30-second sit to stand
from a chair test, combined
with handgrip strength
(dynamometer), or 1-RM test.
Sit and reach or 3rd finger to the
ground test, combined with
shoulder flexibility test.
Flamingo Balance with Foot Up
and Go
ness, muscular strength and endurance and flexibility were
defined as physical skills related to health components,4 in
the case of the physical evaluation in FMS patients is important to pay attention to the balance and agility as physical
skills related to health. Because of the pain, these individuals
have difficulty in performing daily activities and beginning a
physical exercise program, 5 affecting significantly their agility and balance.
Thus, there is a need to specify exercises that influence
the improvement in physical condition without causing pain,5
considering the physical skills related to health, with the addition of agility and balance.
It was observed that in the past 20 years, very few studies
have specifically addressed physical assessment as a major
component of the study, being considered as a means to an
end, i.e., the physical assessment only as a means to evaluate
the effectiveness of a particular type of treatment of patients
with SFM. In addition, there is no protocol or guideline for the
evaluation of the physical skills in this target population.
The physical assessment is required to lend a parameter
to the organization of an exercise intervention program, in
order to promote health and improve health-related physical
fitness components.8 Thus, it is important to establish a protocol that suits the profile of individuals with FMS, defining
the tests that will promote a better measurement of physical
fitness levels without causing pain or discomfort and allowing the test performance by the patient assessed.
Examining Table 1 it was observed that, in the case of a
body composition assessment, the tests most frequently used
were BMI with 61.29% (being quoted 19 times in the literature and 11 times by different research groups) and bioimpedance with 22.58% (being quoted 7 times in the literature and
3 times by different research groups). Therefore, these tests
may be considered the most commonly used and possibly the
most suitable protocols for the physical evaluation of patients
with FMS, and could even be combined for a more accurate
measurement of body composition.
The bioimpedance test is a test in which an electric current
passes through the body via two pairs of adhesive electrodes
placed on the right hand and foot, with the aim to evaluate
the percentage of fat, lean body mass and hydration, allow-
121
ing one to calculate the ideal range of weight for the subject
tested, according to age and sex.11
BMI is equal to body mass divided by height squared.12
This is an inexpensive and easily applicable test; on the other
hand, bioimpedance requires a specific device to obtain body
measurements. In a study comparing bioimpedance and anthropometry, it was demonstrated that the body composition
may equivalent tests of simple measure, such as BMI and
bioimpedance, showing that both tests are reliable.13 Thus,
the choice of the best test will depend on to the possibilities
of the evaluator, i.e., whether he has, or not, the equipment
available and if has been trained to use it.
Regarding the assessment of cardiorespiratory fitness, the
most prominent test was 6MWT with 54.55% of our search
(quoted 24 times in the literature and 15 times by different research groups). The other tests mentioned did not reach 10% of
publications, suggesting that 6MWT is the most suitable test for
the target population, without need of a supplementary test.
The 6MWT evaluates the individual's aerobic endurance;
the subject must try to cover the longest distance in 6 minutes.12 This is a practical, simple and inexpensive test that
requires a short corridor of 30 meters (ranging from 20 to 50
meters) and a timer, without need of any other equipment or
of advanced training for technicians.14 The 6MWT has good
applicability, since walking is a daily activity that almost all
patients are able to perform.
To evaluate the muscular strength and endurance, the
tests most appropriate, according to the publications, are:
grip strength (dynamometer) with 24.39%, isometric force apparatus, 21.95%, and 30-second sit to stand from a chair test,
18.29%. It was found that most of the selected articles advise
the combination of more than one test for muscle strength
and endurance assessment; so, one should consider the combination of the most prominent tests. Thus, we included the
1RM test.
The handgrip test measures the maximal voluntary handgrip strength using a dynamometer.15 The isometric force device (most often a dynamometer) is a test that evaluates most
muscle groups, with reference to any type of process directed
towards force measurement and pressure distribution.16
The 30-second sit to stand from a chair test intends to assess the strength and endurance of the lower extremities by
the number of executions in 30” (get up and sit down) without
the use of the upper limbs.12 The 1RM test aims to find the
maximum load that an individual can perform in only one
repetition of a certain exercise with the use of weight machines, free weights, washers; devices that allow the execution of resistance exercises and progressive loading.8
Importantly, the device of isometric strength and 1RM can
evaluate upper and lower limbs; the difference is that to perform the isometric strength test, it is indispensable to use a
specific device that must be well calibrated and available for
the assessment. The sit and stand in the chair test evaluates
only lower limbs; then, it must be combined with another
test. The same applies to handgrip strength (dynamometer)
that only assesses the strength of upper limbs. We suggest
the combination of 30-second sit to stand from a chair and
handgrip tests.
In the analysis of Table 4, it was found that for the evaluation of the flexibility, the most frequently used tests were: to
122
sit and reach 42.86%; shoulder flexibility test 28.57%; and 3rd
finger on the ground 17.14% of studies. The combination of sit
and reach test and shoulder flexibility stand out in 27% of the
publications.
The sit and reach test measures with efficacy the lower
body flexibility (flexion of hips and spine),17 conducted with
the patient seated with one leg bent and the preference leg
extended; the participant must bring his hands up to the toes
of the extended leg without flexing it.12
The 3rd finger to the ground test means to assess the mobility of the entire spine and pelvis,18 thus being equivalent to
the sit and reach test. To carry out this test, the operator asks
the patient to make an anterior trunk flexion, aiming to reach
the ground; knee flexion is not allowed. The distance from
the tip of 3rd finger (always of the right hand) to the ground
should be measured with a measuring tape or ruler.19
On the other hand, the shoulder flexibility test assesses
the general movement of the shoulder: adduction, abduction,
and internal and external rotation.20 This test is performed
with the patient in a standing position, who lifts his dominant hand and tries to reach a point as low as possible toward
the middle of the back, with palm down and fingers extended
(elbow pointed upward).12 The patient moves the hand of his
other arm in a inferior-posterior direction, with his palm facing upward, and reaching as far as possible in an attempt to
touch (or overlap) the middle fingers of both hands.12
We suggest a combination of the shoulder flexibility test
with one of the other two tests (sit and reach and 3rd finger
to ground tests).
For the assessment of balance and agility, the Foot Up and
Go test (dynamic balance and motor agility) was the most
mentioned, with 45.45%; followed by the flamingo balance
test (static balance) with 40.91%. We noted a frequent combination of these two tests (31%), suggesting that they may be
appropriate for patients with FMS.
The Foot Up and Go test begins with the patient participating fully seated on a chair (upright posture), hands on thighs
and feet flat on the ground. At the signal "start" the participant rises from the chair, walks as fast as possible around the
cone (by either of its sides) and returns to the chair in order
to walk as quickly as possible (without running) around the
cone and back. The cone must be at a distance of 2.44 m from
the chair.12
The flamingo balance test is performed with the subject
with one foot on the longitudinal axis of the beam (steel or
wood beam, 50 cm long, 3 cm wide and 4 cm in height) and,
bending the free leg, grabs his dorsal forefoot with the hand
on the same side, mimicking the position of flamingo.21 Then,
the participant attempts to maintain his balance in this position for 1 minute.21
Both tests are easy to apply and have a good applicability
in the evaluation of physical mobility and balance.12
Through this literature review, it was found that the most
commonly used tests to assess the health-related physical
skills are components of Rikli and Jones’12 battery to assess
elderly people. This is because even with SFM affecting patients of any age, due to their pain the patients have low engagement in physical exercise programs, meaning a negative
impact on quality of life and difficulty in performing daily
activities.
Nevertheless, it is important to note that the selected studies were conducted on subjects with a mean age ≥ 30 years,
who tend to have a history of this syndrome. Few studies were
based on younger subjects with a more active lifestyle, which
would allow the use of more intensive testing for the person
assessed. However, the proposed protocol also applies to this
population.
The proposed protocol should be used for physical evaluation of FMS patients, which is consistent with what has been
alredy used by the medical and academic community for the
assessment of this group of individuals.
The tests defined in this study are easily performed and
can be used both in the gym as well as in physiotherapy clinics. Despite the physical assessment being carried out by
physical educators, physical therapists also work with human
movement, conducting examinations and guiding physical
activity for their patients. Some tests require specific equipment, but other viable options that use simple materials, allowing its easy application, stand out.
There is no standardization of tests for physical assessment of patients with FMS and just a 6-minute walk test has
been validated for this population.22 Thus, we intend, in future
studies, to validate the proposed protocol.
Conclusion
Through this research it was concluded that few studies have
addressed the physical evaluation as a focus of study. Thus,
there is no explicit indication of an accepted standardization
for the set of tests for health-related physical assessment
of patients with FMS. Therefore, the evaluator must decide
which tests are more suitable, according to the experience
and life story of his patients.
Therefore, this study aimed to create a protocol based on
the literature, which can serve as a parameter for decision
making in choosing the most appropriate tests.
Thus, according to publications of the past 20 years, the
tests that should make up the physical assessment protocol
for patients with FMS are:
• Body composition: BMI and bioimpedance (combined or
not).
• Cardiorespiratory capacity: 6-minute walk.
• Muscular strength and endurance: Grip strength (dynamometer), isometric force apparatus, 30-second sit to
stand from a chair test, and 1 RM test. The isometric force
apparatus test and 1 RM test can be used alone. Lift from
the chair and dynamometer can be combined.
• Flexibility: Combination of sit and reach test and shoulder
flexibility.
• Balance and agility: Combination of Foot Up and Go test
(dynamic balance and motor agility) and flamingo balance
(static balance).
It follows that the standardization of tests for physical
evaluation of FMS patients is important to assist in a proper
physical assessment. The above tests are consistent with the
ability of achievement of this target population; therefore,
they are suitable for assessing health-related physical com-
ponents thereof. The protocol created is easy to use and it can
be applied in the gym as well as in physiotherapy clinics.
We recommend the use of this protocol, and intend to perform a validation of the tests contained therein through future prospective studies.
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bioquímicos sanguíneos em mulheres da normalidade à
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with fibromyalgia. J Rheumatol. 2000,27:2666-70.
REUMATOLOGIA
Original article
Periodontitis exposure within one year before anti-diabetic
treatment and the risk of rheumatoid arthritis in
diabetes mellitus patients: a population-based cohort study
Hsin-Hua Chena,b,c,d,e, Der-Yuan Chena,b,c,e,f, Shih-Yi Linb,g, Kuo-Lung Laia,b, Yi-Ming Chena,b,
Yiing-Jenq Choub,d, Pesus Choub,d, Ching-Heng Linf, Nicole Huangb,d,h,i,*
a
Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
c
School of Medicine, Chung-Shan Medical University, Taichung, Taiwan
d
Institute of Public Health and Community Medicine Research Center, National Yang-Ming University, Taiwan
e
Institute of Biomedical Science, Chung-Hsing University, Taichung, Taiwan
f
Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan
g
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
h
Institute of Hospital and Health Care Administration, National Yang Ming University, Taipei, Taiwan
i
Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
b
article info
abstract
Article history:
Objective: To examine whether a history of periodontitis (PD) before anti-diabetic treatment
Received 15 August 2013
is associated with risk of rheumatoid arthritis (RA) development in newly-treated diabetes
Accepted 7 October 2013
mellitus (DM) patients.
Methods: We conducted a population-based retrospective cohort study using the 1997-2009
Keywords:
National Health Insurance (NHI) claims data of one million representative individuals from
Diabetes mellitus
all NHI enrollees. Adults with DM (aged ≥20 years) starting anti-diabetic treatment during
Periodontitis
2001–2009 were classified as newly-treated DM patients. We identified 7097 DM subjects
with PD history within one year before initiating anti-diabetes treatment (index date). By
Risk
matching these 7097 subjects for age on the index date, sex, and year of the index date, we
Administrative database
randomly extracted 14,194 DM subjects without PD history within one year before antidiabetic treatment. Adjusted hazard ratios (aHRs) with a 95% confidence interval (CI) were
calculated by applying Cox proportional hazards models to quantify the association between PD history and RA risk.
Results: Compared with DM patients without PD exposure within one year before anti-diabetic
treatment, crude HR and adjusted HR of RA among DM patients with PD exposure within one
year before anti-diabetic treatment were 4.51 (95% CI, 1.39–14.64) and 3.77 (95% CI, 1.48–9.60).
Conclusion: PD exposure within one year before anti-diabetic treatment was associated with
increased RA risk in newly treated DM patients. The lack of knowledge about individual
smoking status is a major limitation of this study.
E-mail: [email protected] (N. Huang).
125
Exposição à periodontite no intervalo de um ano antes do tratamento
antidiabético e risco de artrite reumatoide em pacientes com diabete
mellitus: estudo de coorte populacional
resumo
Palavras-chave:
Objetivo: Examinar se uma história de periodontite (PD) antes do tratamento antidiabético
Diabetes melittus
está associada a risco de ocorrência de artrite reumatoide (AR) em pacientes com diabetes
Periodontite
melittus (DM) tratados de novo.
Artrite reumatoide
Métodos: Fizemos um estudo retrospectivo populacional com os dados de reivindicações do
Risco
National Health Insurance (NHI) de 1997-2009 referentes a um milhão de indivíduos represen-
Banco de dados administrativos
tativos da totalidade de matriculados. Adultos com DM (≥ 20 anos) que iniciaram o tratamento antidiabético durante 2001-2009 foram classificados como pacientes DM tratados de
novo. Identificamos 7.097 indivíduos DM com história de PD em um intervalo de um ano antes do tratamento antidiabético (data-índice). Na equiparação desses 7.097 indivíduos para
idade por ocasião da data-índice, gênero e ano da data-índice, extraímos aleatoriamente
14.194 pacientes DM sem história de PD em um intervalo de um ano antes do tratamento
antidiabético. As razões de risco ajustadas (aRR) com um intervalo de confiança (IC) de 95%
foram calculadas mediante a aplicação do modelo de riscos proporcionais de Cox com o
objetivo de quantificar a associação entre história de PD e risco de AR.
Resultados: Em comparação com pacientes DM sem exposição à PD no intervalo de um ano
antes do tratamento antidiabético, RR bruta e RR ajustada para AR entre pacientes DM e
com exposição à PD no intervalo de um ano antes do tratamento antidiabético foram, respectivamente, 4,51 (IC 95%, 1,39-14,64) e 3,77 (IC 95%, 1,48-9,60).
Conclusão: A exposição à PD no intervalo de um ano antes do tratamento antidiabético foi
associada a maior risco de AR em pacientes DM tratados de novo. A ausência do status de
tabagismo em nível individual é importante limitação desse estudo.
Introduction
Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by chronic synovial inflammation with
periarticular osteoporosis and bone erosion, associated with
an increased risk of cardiovascular disease comparable to
that of diabetes mellitus (DM).1 Although the exact etiology
is still unknown, the interaction between environmental factors and genetic factors has been found to play a role in RA
pathogenesis.2 Smoking is a well-known risk factor,3-10 and
recently periodontitis (PD) has emerged as another environmental risk factor for RA.11,12 PD is a common chronic, microbially triggered an inflammatory disorder that causes an
irreversible loss of the supporting tooth structures, and may
ultimately lead to tooth loss.13 It affects approximately half of
the population aged ≥ 30 years in the United States.14,15 One
of the major PD-related pathogens, Porphyromonas gingivalis (P.
gingivalis), is the only microorganism that produces peptidylarginine deiminase, which may cause citrullination.16 In genetically susceptible individuals, the breakdown of immune
tolerance to citrullinated peptides may lead to the production
of anti-cyclic citrullinated peptide (anti-CCP) antibodies, associated with RA development.17 The presence of P. gingivalis
DNA in the serum and synovial fluid and a strong correlation
between the presence of anti-CCP antibodies and the presence of PD in RA patients support this hypothesis.18-20
In recent years, increasing evidence has indicated a bidirectional association between DM and PD.21,22 PD is associated
with increased incident DM risk, poor glycemic control, and
DM complications,23-26 probably due to the higher levels of
systemic proinflammatory mediators that exacerbate insulin resistance.22 A number of observational studies also show
a greater prevalence, severity, extent, or progression of one
or more PD indicators in DM patients, with type 1, type 2, or
gestational diabetes, as compared to those in non-DM subjects.27-35
Hyperglycemia has been found to modify PD expression,36
by interfering with the host response and causing an excessive inflammatory response to infection,37,38 as well as by the
interaction of the receptor for advanced glycation end products (RAGE) with its ligands in gingiva.22,36,39 Several previous
studies have shown that DM patients have defective neutrophil function,40-42 which may lead to impaired clearance of
P. gingivalis, the major periodontal bacterium related to RA
pathogenesis.17 In diabetic mice, inoculation with P. gingivalis leads to prolonged and exaggerated systemic cytokine expression and inflammatory infiltrates in a model of calvarial
infection.37,38 Hence, we hypothesize that the prolonged challenge presented by the oral bacteria as a result of the defective
host response, together with the exaggerated and sustained
inflammatory response to the bacteria, may cause more severe PD in DM subjects than in non-DM subjects with PD. Recent studies show a dose-dependent association between PD
exposure and RA risk.11,12 Because hyperglycemia is present
for some time before commencing anti-diabetic treatment in
DM patients,43 we hypothesize that among newly-treated DM
patients, those who had PD exposure within one year before
126
anti-diabetic treatment may have a higher risk of RA development than those without PD exposure within one year before
anti-diabetic treatment.
To the best of our knowledge, no population-based cohort study has examined whether RA risk differs between
newly-treated adults with and without a history of PD
before anti-diabetic treatment. Recently, the Taiwanese
National Health Insurance Research Database (NHIRD)
had facilitated population-based longitudinal studies. We
therefore took advantage of this resource to conduct this
cohort study to estimate the hazard ratios (HRs) for the association between PD history and RA development in newly-treated DM patients.
Methods
Data source
The source of data was the NHIRD, which covered claims of
ambulatory care, inpatient services and dental services, and
prescriptions during 1997-2009. In March 1995, the National
Health Insurance (NHI) program was implemented, and it has
since covered more than 98% of the population. The National
Health Research Institute, which manages the NHIRD, has
released comprehensive NHI-related administrative claims
data for research. In 2000, the NHIRD randomly selected one
million participants to form a representative database for
study purposes. Here we used one million representative
subjects from the multiple datasets of the NHIRD: ambulatory and inpatient claims files, enrollment files, and the NHI
catastrophic illness files, all from 1997-2009. The NHI catastrophic illness files were established to track patients with
major or catastrophic illnesses, including cancer, end-stage
renal disease, mental illness, congenital illness, and several
autoimmune diseases, including RA. The Bureau of National
Health Insurance (BNHI) routinely reviews the original medical charts of all patients who applied for catastrophic illness
registration to validate the diagnoses. The American College
of Rheumatology classification criteria for RA (1987) was
used to validate RA diagnosis for the period 1997–2009.44 The
ambulatory and inpatient files include information on date
of visit/admission, diagnoses, examinations, procedures,
and medical expenses. The enrollment files provide enrollment and demographic information. Although the dataset
lacked laboratory and radiographic data, the BNHI periodically audited the accuracy of diagnoses by randomly sampling patient charts to check claims.45 The Ethics Committee
of Clinical Research at Taichung Veterans General Hospital
approved this study.
Study samples
DM subjects
In this retrospective cohort study, we identified patients who
had at least one diagnosis of DM [International Classification
of Diseases, 9th Revision, Clinical Modification (ICD9-CM) code
250×] with concurrent prescription of any anti-diabetes medication for more than 28 days after January 1, 2001 and classified these as DM subjects.
Subjects with and without PD history
In Taiwan, BNHI covers the cost of dental scaling a maximum
of twice per year for each individual, with the aim of improving dental health. For these patients, dentists may perform
scaling for these people with a concurrent PD coding (ICD9CM codes 523.3–5). Therefore, we defined PD exposure as having a diagnosis of PD (ICD9-CM codes 523.3–5) together with
concurrent antibiotic therapy, or with periodontal treatment
other than dental scaling by certified dentists. PD history was
defined as having PD during the one year before the index
date. Patients who had not been diagnosed with periodontal
disease (ICD9-CM Codes 523×) within one year before the index date were classified as patients with no PD history.
Exclusion criteria
All individuals diagnosed with RA (ICD9-CM code 714.0) before the index date or aged younger than 20 years on the index date were excluded.
Matched study subjects
The first date of anti-diabetic treatment was defined as the
index date. First, we identified a total of 7097 DM subjects
with PD history. To match these DM subjects with PD history
in terms of age on the index date (i.e., 20–34, 35–49, 50–64,
≥ 65 years), sex, and the year of the index date, we randomly
selected 14,194 DM subjects with no PD history.
Outcome variable
Patients who had ambulatory visits coded for RA (ICD9-CM
Code 714.0) and certificates of the catastrophic illness for RA
were classified as RA cases. The outcome variable was the
time (in years) from the index date to the date of their first
ambulatory care visit with a concurrent RA diagnosis. If the
study subjects withdrew from the Taiwanese NHI system for
any reason, such as death or moving away, the date of withdrawal was selected as the censored date, otherwise the last
date of the dataset (December 31, 2009) was used.
Potential confounders
The study included the insurable wage and urbanization level
of the study subjects as potential confounders. In Taiwan, the
insurable wage was calculated from the average monthly income of the participants, which served as an economic index.
If the insurable earnings of the subject was zero, the insurable wage was treated as dependence. The insurable wage
was converted from new Taiwan dollars (TWD) to USD using a
conversion rate of 30 TWD to 1 USD. The insurable wage was
transferred to ordinal variables (i.e., dependence, 1–700 USD
and > 700 USD). We selected 700 USD as the cut-off value for
insurable wage because it was the median of the insurable
wages among subjects whose insurable earnings were not
zero. Based on the previously stratified seven clusters [from
level 1 (most urbanized) to level 7 (least urbanized), in Taiwan,46 the urbanization level was converted into 3 levels: urban (levels 1–2), suburban (levels 3–4), and rural (levels 5–7).
We compared baseline characteristics based on PD history
using a t-test for continuous variables, and Pearson’s χ2 or
127
Fisher’s exact test for categorical variables. Adjusting for age,
sex, insurable wage and urbanization level of subjects, Cox
proportional regression analysis was used to estimate incident RA risk associated with PD history, as shown by adjusted
hazard ratios (HRs) with 95% confidence intervals (CIs). A twotailed P-value of < 0.05 was considered statistically significant.
All statistical calculations were performed using SPSS version
18.0 for Windows (SPSS, Inc., Chicago, IL).
Sensitivity analysis
We conducted lag analyses by advancing the RA diagnosis
date by 3 months, 6 months, and 1 year and examined the
potential impact of insidious RA onset. We then repeated
the Cox proportional regression analyses after excluding those whose follow-up time was less than 3 months,
6 months, or 1 year, and subtracting the follow-up time by
3 months, 6 months and 1 year respectively, as the revised
follow-up time.
Results
A total of 21,291 DM subjects were followed for a median
(interquartile range) of 3.4 (1.5, 5.9) years; of these, 19 subjects developed incident RA. The demographic and clinical
data according to PD history are shown in Table 1. The mean
patient age ± SD was 57.5 ± 12.8 years and women comprised
43.3% of all study subjects.
Among the 7,097 DM subjects with a history of PD exposure within one year before the index date, 12 subjects
developed RA after 26,910 person/years of follow-up and
the incidence was 44.6 cases per 105 person/years. Among
the 14,194 DM subjects without PD history, 7 subjects developed RA after. From 54,002 person/years of follow-up,
the incidence was 13 cases per 100,000 person/years. Compared with subjects without PD history, the crude HR of incident RA among those with PD history was 4.51 (95% CI
1.39–14.64). As shown in Table 2, after adjusting for age, sex,
insurable wage, and urbanization level of the subjects, the
adjusted HR (aHR) of RA associated PD history remained
statistically significant (aHR, 3.77; 95% CI 1.48–9.60). The
survival curve for incident RA among DM individuals is
shown in Figure 1.
Table 3 shows the results of sensitivity analyses conducted by varying the lag time of RA diagnosis considering the
insidious RA onset. The association between PD history and
RA risk remained statistically significant after varying the
lag time.
Discussion
This study is the first population-based cohort study to use
administrative data to examine the strength of the association between PD history within one year before anti-diabetic
treatment and RA risk in newly-treated DM patients. This
study focuses on PD exposure history within one year before
anti-diabetic treatment because we hypothesize that hyperglycemia may exist during this period, and thus interact
with PD to drive an increased RA risk. The main finding of
our study is that the association between PD history and RA
development is statistically significant among newly treated
DM individuals. In addition, if the lag time of RA diagnosis is
considered, this association became stronger.
The results of this cohort study further supports the theory that PD history is associated to RA development, which
was also suggested by the results of two recent case–control studies.11,12 However, the results of another large cohort
study on American women indicated that PD was not associated with RA risk.47 Of note, DM status was not taken into
account in this previous cohort study, and no male subjects
were included.47
The main strength of this study is that the use of population-based samples of Taiwanese women and men could
avoid selection bias and the results should be applicable to
the general population of Taiwan. Furthermore, to increase
Table 1 – Comparison of demographic data for patients
based on periodontitis (PD) history within one year
before the index date in newly-treated diabetic patients.
Variable
Female
Age (years)
20–34
35–49
50–64
≥ 65
Urbanization level
Urban
Suburban
Rural
Insurance amount
(USD)
Dependence
1–700
>700
PD history
(n = 7097)
No PD
history
(n = 14194)
p
3074 (43.3)
6148 (43.3)
1.000
1.000
238 (3.4)
1660 (23.4)
3121 (44.0)
2078 (29.3)
476 (3.4)
3320 (23.4)
6242 (44.0)
4155 (29.3)
2748 (38.7)
2854 (40.2)
1495 (21.1)
4873 (34.3)
5990 (42.2)
3331 (23.5)
< 0.001
< 0.001
440 (6.2)
3069 (43.2)
3588 (50.6)
894 (6.3)
6919 (48.7)
6381 (45.0)
RA, rheumatoid arthritis; DM, diabetes mellitus; PD history, a history
of periodontitis within one year before anti-diabetic treatment.
Table 2 – Adjusted hazard ratios (HRs) with 95%
confidence intervals (CIs) of RA risk associated with
variables in newly-treated DM patients.
Variável
A history of PD
Female
Age, incremental year
Urbanization level
Urban
Suburban
Rural
Insurable wage (USD)
Dependence
1–700
> 700
HR (95% CI)
p value
3.77 (1.48–9.60)
6.04 (1.73–21.05)
1.04 (1.00–1.08)
0.006
0.005
0.085
Reference
1.34 (0.44–4.14)
1.67 (0.50–5.54)
0.608
0.405
Reference
3.35 (0.43–26.00)
1.43 (0.13–15.33)
0.248
0.767
RA, rheumatoid arthritis; DM, dabetes mellitus; PD, periodontitis;
USD, United States dollar.
128
the accuracy of diagnoses. Moreover, the non-differential
misclassification of RA and PD diagnoses would have biased the results towards the null. Second, use of the NHIRD
precluded further adjustment of unmeasured potential confounders, such as serum glucose level, glycated hemoglobin,
anti-CCP antibodies, HLA-DRB1, and smoking status of subjects. Third, the small number of incident RA cases limits
the number of covariates for adjustment. Finally, the results
of this population-based study in Taiwan might not be used
to generalize other ethnic populations.
Free of rheumatoid arthritis rate
1.0000
0.9995
0.9990
History of periodontitis
Conclusion
No
Yes
0.9985
0.9980
0
2
4
6
8
This nonselective, population-based cohort study indicates
that PD history within one year before anti-diabetic treatment is associated with increased RA risk in newly treated
DM patients. Further clinical and basic studies need to be
performed to elucidate whether the degree of hyperglycemia
interacts with RA risk associated with PD exposure.
Time (year)
Fig. 1 – Free of incident rheumatoid arthritis rates among
subjects with diabetes mellitus stratified by periodontitis
history.
Table 3 – Sensitivity analyses for RA risk associated
with PD history by varying the lag time of RA diagnosis,
as shown by adjusted hazard ratios (HRs) with 95% (CIs).
Lag time
No lag time
3 months
6 months
1 year
PD history
No PD
history
n, RA/total
(%)
n, RA/total
(%)
12/7097 (0.17)
12/6801 (0.18)
11/6529 (0.17)
9/5918 (0.15)
7/14194 (0.05)
5/13654 (0.04)
5/13034 (0.04)
4/11835 (0.03)
HR (95% CI)
3.77 (1.48–9.60)
5.31 (1.86–15.14)
4.86 (1.68–14.08)
5.12 (1.57–16.74)
RA, rheumatoid arthritis; DM, diabetes mellitus; PD, periodontitis;
PD history, a history of periodontitis within one year before antidiabetic treatment.
Cox regression analyses were conducted after adjusting for age,
sex, urbanization level, and insurable wage of subjects.
internal validity, this study matched study subjects with regarding age, sex, and the year of the index date, and further adjusted potential confounders including the insurable
wage and urbanization level of subjects. However, a number of limitations must be considered. First, the accuracy
of diagnoses in administrative data is an area of concern.
Bias due to misclassification or miscoding of PD and RA can
still occur despite regular audit of the quality of claims carried out by periodically sampling patient charts, which is
randomly performed by the BNHI. However, the accuracy of
RA diagnosis is of less concern, because the issue of a catastrophic illness certificate for RA diagnosis requires validation by at least two qualified rheumatologists and involves
checking the medical charts, radiographic findings, and laboratory data. In addition, the inclusion of periodontal treatment in the diagnostic criteria of PD also helps increase
Authors' contributions
Dr Hsin-Hua Chen had full access to all data in the study and
takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Hsin-Hua Chen, Der-Yuan Chen,
Nicole Huang, Pesus Chou.
Data acquisition: Hsin-Hua Chen, Ching-Heng Lin.
Data analysis and interpretation: Hsin-Hua Chen, Der-Yuan Chen, Shih-Yi Lin, Nicole Huang, Pesus Chou.
Drafting of the manuscript: Hsin-Hua Chen, Yi-Ming Chen,
Kuo-Lung Lai.
Critical revision of the manuscript for important intellectual content: Der-Yuan Chen, Nicole Huang, Shih-Yi Lin.
Statistical analysis: Hsin-Hua Chen, Ching-Heng Lin.
Funding
This study was supported by grant TCVGH-1023805C from Taichung Veterans General Hospital, Taiwan.
Conflicts of interests
The authors declare no conflict of interest.
Acknowledgements
We would like to thank the Biostatistics Task Force of Taichung
Veterans General Hospital, Taichung, Taiwan, ROC, for assistance with statistical analysis. We thank the members of the
Bureau of National Health Insurance, Department of Health,
and the National Health Research Institutes for providing and
managing the National Health Insurance Research Database.
This study was supported by grant TCVGH-1023805C from Taichung Veterans General Hospital, Taiwan.
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REUMATOLOGIA
Review article
Incidence of neoplasms in the most prevalent autoimmune
rheumatic diseases: a systematic review☆
Roberta Ismael Lacerda Machadoa, Alessandra de Sousa Brazb,c,*,
Eutilia Andrade Medeiros Freireb,c
a
Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil
Department of Internal Medicine, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil
c
Rheumatology Service, Hospital Universitário Lauro Wanderley, João Pessoa, PB, Brazil
b
article info
abstract
Article history:
This article is a systematic review of the literature about the coexistence of cancer and
autoimmune rheumatic diseases, their main associations, cancers and possible risk factors
associated, with emphasis on existing population-based studies,
besides checking the
relation of this occur with the use of the drugs used in the treatment of autoimmune disKeywords:
eases. A search was conducted of scientific articles indexed in the Cochrane / BVS, Pubmed
Neoplasm
/ Medline and Scielo / Lilacs in the period from 2002 to 2012. Also consulted was the IB-
ICT (Brazilian digital library of theses and Masters), with descriptors in Portuguese and
Sjögren’s syndrome
English for “Systemic sclerosis”, “Rheumatoid Arthritis”, “ Systemic Lupus Erythematosus”
and “Sjögren’s syndrome”, correlating each one with the descriptor AND “neoplasms”. The
Systemic sclerosis
results showed that in the database IBICT a thesis and a dissertation for the descriptor
SLE met the inclusion criteria, none met RA one thesis to SS. Lilacs in the database/Scielo
found two articles on “Rheumatoid Arthritis” AND “neoplasms”. In Pubmed/Medline the
inicial search resulted in 118 articles, and 41 were selected. The review noted the relationship between cancer and autoimmune rheumatic diseases, as well as a risk factor for protection, although the pathophysiological mechanisms are not known.
☆
Study conducted at Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil.
E-mail: [email protected] (A.S. Braz).
132
Incidência de neoplasias nas doenças reumatológicas autoimunes mais
prevalentes: uma revisão sistemática
resumo
Palavras-chave:
O presente artigo é uma revisão sistemática da literatura que aborda a coexistência de
Neoplasias
neoplasias e doenças reumatológicas autoimunes, suas principais associações, tipos de
Lúpus eritematoso sistêmico
cânceres e os possíveis fatores de riscos associados, com ênfase nos estudos de base po-
Artrite reumatoide
pulacional existentes, além de verificar a relação dessa ocorrência com o uso dos fármacos
Síndrome de Sjögren
utilizados no tratamento de doenças autoimunes. Foi realizada uma busca de artigos cien-
Esclerose sistêmica
tíficos indexados na Cochrane/BVS, Pubmed/Medline e Scielo/Lilacs no período de 2002 a 2012.
Também foi consultada a IBICT (biblioteca digital brasileira de teses e mestrados), com os
descritores em português e inglês para as palavras: “Esclerose sistêmica”, “Artrite reumatoide”, “Lúpus Eritematoso Sistêmico” e “Síndrome de Sjögren”, correlacionando cada um
com o descritor AND “neoplasias”. Os resultados mostraram que, na base de dados IBICT,
preencheram os critérios de inclusão uma tese e uma dissertação para o descritor LES, nenhuma para AR e uma tese para SS. Na base de dados Lilacs/Scielo foram encontrados dois
artigos sobre “Artrite Reumatoide” AND “neoplasias”. No Pubmed/Medline, a busca inicial
resultou em 118 artigos; destes, preencheram os critérios e foram secionados 41 artigos.
Esta revisão observou relação entre neoplasias e as doenças reumatológicas autoimunes,
tanto como fator de risco quanto de proteção, embora os mecanismos fisiopatológicos não
estejam totalmente elucidados.
Introduction
The coexistence of rheumatic diseases with malignancies of
various origins has been reported in the literature. Neoplastic changes can induce rheumatic paraneoplastic syndromes,
which also may be late complications of a rheumatic disease.1
Rheumatologic paraneoplastic syndromes may occur during the course of neoplastic disease, manifesting simultaneously with the development of a neoplasia, may precede
the diagnosis by several years or develop some time after a
neoplasia diagnosis. It is often difficult to differentiate them
from the idiopathic form and it is believed that the presence
of such changes can be considered as predictor of malignancy
and of adverse outcomes.2-5
According to Szekanecz,6 neoplasms differ from paraneoplastic syndromes due to the fact that the latter are not related to direct invasion of the tumor or metastasis, but to a
variety of biological mediators derived from it, such as hormones, peptides, antibodies, cytotoxic lymphocytes and autocrine and paracrine mediators.
Autoimmune rheumatic diseases are chronic diseases,
more common in females. Among these, the most prevalent
include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS) and systemic sclerosis
(SSc).7,8 Such autoimmune disorders are associated with the
activation of autoreactive T and B lymphocytes and with the
release of proinflammatory cytokines that can possibly increase the risk of cancer.9 Taking into account that autoimmune diseases are chronic disorders and prevalent in the
population, one can expect that patients with such diseases
are most likely to develop neoplasias.10
The participation of immunosuppressive drugs in the
treatment of autoimmune rheumatic diseases has also
been described in the pathogenesis of malignancy. The
potential mechanisms described include interruption of
immunological surveillance and destruction of malignant
cells, increased susceptibility to contamination with oncogenic infectious agents, for instance, viral agents, pharmacological effects of the alkylating agents or antimetabolites
on deoxyribonucleic acid (DNA), and the specific effects on
the immune system, which can increase or decrease the
chances of a transformed cell to survive and proliferate.11
In the literature, data related to this topic is scarce, especially in Brazil. This paper aims to conduct a systematic
review of literature on the subject, because of its importance in clinical practice, and verify the main associations
between the most prevalent autoimmune rheumatic diseases and the types of cancer present, in addition to addressing the possible implications of using drugs in these
circumstances.
Methodology
Search criteria
For this study, a systematic review technique was chosen.
The search for scientific articles indexed in Cochrane/VHL,
Pubmed/Medline and SciELO/Lilacs databases from 2002 to
2012. The IBICT (Brazilian digital library of theses and Masters
programs) was also consulted, using the descriptors in portuguese and their corresponding in english: “Rheumatoid arthritis”, “SLE”, “Systemic sclerosis” and “Sjögren's syndrome”,
correlating each with the descriptor AND “neoplasms”.
Inclusion and exclusion criteria
Full articles published in english and portuguese from 2002
to 2012,which addressed the neoplasia occurrence in the
133
above autoimmune rheumatic diseases were included in
the study. Articles describing the association of cancer and
the main drugs used in the treatment of these autoimmune rheumatic diseases (methotrexate, azathioprine, cyclophosphamide, and immunobiological agents) were also
selected.
In the present review, case reports or articles that related neoplasms and dermatomyositis and/or polymyositis were not included to avoid confusion, since there is a
strong association of these conditions with paraneoplastic
syndromes. We also excluded studies associating the occurrence of neoplasms with vasculitis, due to important
differences in the pathogenesis of these diseases with the
autoimmune diseases selected, and also to the fact that
these are uncommon syndromes, not meeting the purposes
of this study.
Selection of studies
The analysis of titles and abstracts, according to the eligibility criteria, was performed by two independent reviewers. In
cases of disagreement, they were analyzed by a third reviewer.
Discussion
Systemic lupus erythematosus and neoplasia
SLE is a heterogeneous systemic disease manifesting in mild,
moderate or severe clinical form that can escalate with multiple organs and/or systems involvement. Due to the modernization of its therapy and to the improvements in the prognosis of the disease in general, the survival rates of patients
increased and in consequence chronic organ damage and late
complications (such as malignancy) became decisive for the
morbidity and mortality of these patients.12
The common pathogenic pathways for LES and neoplasms
have been described, and reinforced by the following concepts: a high frequency of malignancies in patients with autoimmune diseases; neoplastic disorders in autoimmune diseases may occur as paraneoplastic syndromes; and the fact
that immunosuppressive therapy may increase the risk of
118 articles related to the descriptors in the English language: neoplasia
AND systemic lupus erythematosus; neoplasia AND systemic sclerosis;
neoplasia AND rheumatoid arthritis; neoplasia AND Sjögren's syndrome.
Presentation of results
After the election of articles, a reading and analysis of the association among cancer and selected rheumatic diseases was
made. Population studies were described according to the author, year, studied population, observation on the occurrence
of neoplasia in patients with autoimmune diseases, main
malignancies observed in each disease and standardized incidence ratio in the 95% confidence interval (CI). of Studies
relating the main drugs used in the therapy of these diseases
and their possible associations with oncogenesis were also
analyzed.
77 articles did not meet the criteria for
inclusion/exclusion: case reports, articles
about PNS and specific treatment of
cancer.
41 articles related to established
criteria.
Fig. 1 – Algorithm of the methodology of selection of papers
found in Pubmed/Medline. PNS, paraneoplastic syndromes.
Table 1 – Main cancers in each autoimmune disease and
their standardized incidence ratio (SIR) in a confidence
interval (CI) of 95%.
Results
Autoimmune disease
In the IBICT database, the following results concerning the
initial search were obtained: no thesis for “Systemic sclerosis"
AND “neoplasms”, one thesis/dissertation on “Systemic sclerosis” AND “neoplasms”, one thesis on “rheumatoid arthritis”
AND “neoplasms”, four theses/dissertations on “Systemic Lupus Erythematosus” AND “neoplasms”, and also four theses
for “Sjögren's syndrome” AND “neoplasms”. One thesis and
one dissertation for the descriptor SLE, one dissertation for
the descriptor LES, none for AR and one thesis for SS met the
inclusion criteria. In the Lilacs/Scielo database, two articles
were found for “Rheumatoid Arthritis” AND “neoplasms”, but
only one of them approached the studied matter .
In Pubmed/Medline database, the initial search yielded
118 articles. Reports of paraneoplastic syndromes and articles
about cancer treatments in patients with the assessed rheumatic diseases were excluded from the study. Thus, we selected 41 articles that met the inclusion criteria described above
(Fig. 1). The articles obtained, organized by author and year,
neoplasia and standardized incidence ratio (SIR) in the 95%
confidence interval (CI) are shown in Table 1, and the main
population studies by author and year are shown in Table 2.
General risk
Blood cancer
Non-Hodkgin’s lymphoma
Lung cancer
Hepatobiliary cancer
Vulvovaginal cancer
Prostate cancer
Sjogren's syndrome
Overall risk
Non lymphoid overall risk
Lymphoma
Systemic sclerosis
Overall risk
Lung cancer
Blood cancer
Overall risk
Blood cancer
Non-Hodgkin’s lymphoma
Lung cancer
Colorectal cancer
Breast cancer
Standardized incidence ratio
(SIR)/Confidence interval (CI)
of 95%/References
1.2519 / 1.1523/1.1421
2.7523
2.8619/ 3.6423
1.7319 /1.3723
2.623/ 2.721
3.2721
0.7222
3.2527
1.526
37.526 / 48.127
1.533
1.633
2.533
1.0541
2.7427
3.5427
1.6341
0.7741
0.8441
134
Table 2 – Population studies according to author/
year/country and observations about emergence of
malignancies in patients with autoimmune diseases.
Authors/year
Bjornadal et al.,
200220
Bernatsky et al.,
200623
Parikh-Patel
et al., 200821
Bernatsky et al.,
201122
Lazarus et al.,
200626
Zhang et al.,
201027
Olesen et al.,
201033
Chen et al.,
201137
Population basis/year of
research
Observation
5.715 LES patients; Sweden
(1964-1995)
9.547 LES patients;
international multicentric
(1970-2001)
443 cases of
neoplasia
431 cases of
neoplasia
observed; 114
deaths
30.478 LES patients; USA
1.273 cases of
(1991-2002)
neoplasia
6.068 men with LES; followProstate cancer
up for 6.3 years; Canada
considered as
a protective
factor
112 patients with SS; London 25 cases of
(1979-2006)
neoplasia
1.320 patients with SS;
Follow-up for
Peking (1990-2005)
4.4 years:
29 cases of
neoplasia
2.040 patients with SSc;
Follow-up for
Denmark (1977-2006)
6.4 years:
222 cases of
neoplasia.
23.644 patients with RA;
935 cases of
Taiwan (1996-2007)
cancer
SLE, systemic erithematous lupus; SS, Sjögren syndrome; SSc,
systemic sclerosis; RA, rheumatoid arthritis.
malignancies occurrence.13 Added to this, in a recent publication the presence of antiphospholipid antibodies was considered a risk factor for the occurrence of thrombotic events and
for the development of cancer.14
Regarding etiopathogeny, LES as well as various other malignancies have in common a genetic predisposition to environmental factors (such as ultraviolet radiation, infection by
viruses such as Epstein-Barr virus [EBV], smoking and obesity), and hormonal changes related to these two conditions
(prolactin, estrogen and growth hormones, among others).15
Disproportionate humoral responses are considered fundamental in the pathogenesis of systemic autoimmune diseases such as SLE and SS. Among these, an abnormal regulation of the cell cycle is observed, which interferes with cell
proliferation, differentiation and apoptosis, causing B cell
longevity. In these processes, cytokines such as interleukin-6
(IL-6), 10 (IL-10) and B-cell activating factor (BAFF) have played
an important role.16,17
It is believed that because of chronic antigenic stimulation,
B cells contribute to the increased circulating levels of BAFF,
and the impaired autoregulation of these cytokines may trigger a vicious cycle in which high levels of proliferation and
induction of BAFF or its ligand enhance the activation of the
humoral immune system. A similar pathogenic mechanism
has been described in B-cells related malignancies.12,18
For several authors, there has been an increased incidence
of malignancies in patients with SLE.13,19-22
A population-based cohort evaluated 5,715 patients hospitalized for SLE between 1964 and 1995, according to the
National Swedish Cancer Registry. Altogether, 443 cases of
malignancies were assessed. The overall risk was increased
by 25% (Standardized incidence rate [SIR] = 1.25, CI 95% = 1.141.37). Non-Hodgkin lymphoma risk increased almost three
times (SIR = 2.86, CI 95% = 1.96-4.04), thus providing a greater
incidence for neoplasia in patients with SLE. There was also
an increased risk of lung (SIR = 1.73, CI 95% = 1.25-2.32) and
squamous cell skin (SIR = 1.53, CI 95% = 0.98 -2.28) cancer,
which was more pronounced in cases with more than 15
years of follow-up.19
In 2006, Bernatsky et al. conducted an international multicenter study that included patients with SLE from 23 registered centers, to analyze the causes of mortality of this
disease; a major cause analyzed was the presence of cancer.
Patients at each center were linked to regional cancer registries that provided epidemiological data and 9,547 patients
were observed for an average period of eight years.
Within the observation time, 431 cases of cancer were
registered. The data confirmed an increased risk of cancer
among patients with SLE. For all cancers combined, the estimated SIR was 1.15 (CI 95% = 1.05-1.27); for all hematological
malignancies, 2.75 (95 % CI = 2.13-3,49), and for non-Hodgkin
lymphoma, 3.64 (CI 95% CI = 2.63-4.93). The findings also suggested an increased risk of lung (SIR = 1.37, CI 95% = 1.05-1.76)
and hepatobiliary (SIR = 2.60, CI 95 % = 1.25-4,78) cancer.23
In another cohort including individuals with SLE from the
state of California (USA) from 1991 to 2002, the risk of occurrence of malignancies was studied. From the 30,478 patients
diagnosed with SLE, 1,273 had a form of cancer. The overall
cancer risk was significantly elevated (SIR = 1.14, CI 95% =
1.07-1.20). This study demonstrated an increased risk of malignancies of the genital tract, including vaginal and vulvar
(SIR = 3.27, CI 95% = 2.41-4.31), as well as liver (SIR = 2.70, CI
95% = 1.54-4.24) cancer.21
In 2011, Bernatsky et al. analyzed 6,068 men suffering from
SLE. The development of prostate cancer in this sample was
lower than expected for the general population, with an estimated incidence rate for risk of prostate cancer development
in this population of 0.72 (CI 95% = 0.57-89). Thus, according to
the findings of this study, LES was a protective factor against
this type of cancer. One of the hypotheses proposed to explain
these results is the occurrence of low levels of adrenal hormones in these patients.22
Sjögren's syndrome and neoplasia
Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands and persistent dysregulation of the immune system. SS is associated with
a 44-fold risk increase for non-Hodgkin development, and Masaki and Sugai24 in 2004 estimated in their review that about 5%
of cases of primary SS could develop this complication.
Similarly to what occurs in SLE, in SS the participation of
environmental factors (EBV, cytomegalovirus, retroviruses,
hepatitis C virus or ultraviolet radiation) and the genetic predisposition (histocompatibility antigen [HLA] of B8, DR2, DR3
and DQ types) change of the immune system are described;
particularly at populations of CD4+ T cells or humoral production of antibodies production (anti-SSA/Ro, anti-SSB/
La and anti-muscarinic receptor type 3 antibody), as well as
cytokines present such as interferon-gamma. In some cases,
monoclonal B-cell proliferation occurs and this may lead to
lymphomas.18,25
In 2006, Lazarus et al.26 performed a retrospective analysis
of 112 patients from the outpatient services at the University
College London Hospital during 1979. The patients were followed for a mean period of 10.8 years since the diagnosis of
primary SS (pSS). The appearance of neoplasia was reported
in 25 patients, with 11 cases of lymphoma (eight of mucosa-associated lymphoid tissue/MALT type, one well-differentiatied high-grade non-Hodgkin lymphoma, and two with
unknown subtypes). Therefore, a significantly increased incidence of lymphoma in patients with pSS compared with the
general population (SIR = 37.5, CI 95% = 20.7-67.6) was demonstrated. For cancers not originated in the lymphoid tissue, the
observed increase in incidence was small and not statistically
significant (SIR = 1.5, CI 95% = 0.9-2.6).26
A retrospective analysis at Peking Union Medical College
Hospital from 1990 to 2005 recruited 1,320 SS patients that
were followed for a mean of 4.4 years. Among them, 29 patients (2.2%) developed neoplasms during follow-up. The total
SIR and SIR value for lymphomas were 3.25 and 48.1, respectively. In this study, different types of malignancies were observed: eight lymphomas, two myelomas and 19 solid tumors
(invasive thymoma, breast cancer, lung cancer, gastrointestinal adenocarcinoma, hepatoma, squamous cell carcinoma
of the tongue, cervical cancer, renal cell carcinoma, thyroid
carcinoma and mucoepidermoid carcinoma of the parotid
gland). At the risk factor analysis, it was observed that hyperplasia of the parotid glands, monoclonal immunoglobulins
and the presence of hypergammaglobulinemia were identified as the main mechanisms involved in the pathogenesis of
SS, compared with neoplasias.27
Systemic sclerosis and neoplasia
Systemic sclerosis (SSc) is a complex immune connective
tissue disorder that leads to vascular damage and overproduction of extracellular matrix via activated fibroblasts. Its
pathogenesis involves the interaction between endothelial
cells, lymphocytes, macrophages, fibroblasts and the activation of several cytokines and growth factors important in the
development of fibrosis. Immunological reactions involved in
SSc have been associated with the development of malignancies, and high concentrations of pro-fibrotic cytokines such as
transforming growth factor beta (TGF-β) were found in some
types of cancer (breast, ovary and kidney).28,29
Another possible hypothesis for such association is the
presence of SSc antigens expressed in tumoral cells. Most of
SSc autoantigens are nucleolar and play a key role in ribosome synthesis and in mitogenesis. Probably these proteins
are related to the rapid proliferation of malignant cells. Genetic mutations or post-translational modifications can produce protein products with conformational changes that accumulate in malignant tissue and create new epitopes.30
The association between cancer and SSc with fibrotic lung
involvement was first described in 1953.31 During 2005, Daniels and Jett found an increased risk of lung cancer in patients
with disorders associated with pulmonary fibrosis, including
systemic scleroderma. In this scenario, the suggested pathogenesis is that recurring injury and chronic inflammation re-
135
sult in genetic mutations and possible malignancy; however,
this hypothesis needs further studying.32
Olesen et al.33 assessed patients with an initial diagnosis of
SSc selected from the Danish National Registry that included
inpatients and outpatients during the period from 1977 to
2006. About 2,040 patients were evaluated and followed for
a mean period of 6.4 years. Among these patients, 222 cancer
cases were identified. The general SIR for cancer was 1.5 (CI
95% = 1.3-1.7); for men, SIR = 2.2 (CI 95% = 1.7-2.8) and for
women, SIR = 1.3 (CI 95% = 1.1-1.6). The most common cancers
were lung (SIR = 1.6, CI 95% = 1.2-2.0) and hematologic (SIR =
2.5, CI 95% = 1.5-4.0) cancer.33
Rheumatoid arthritis and neoplasia
Rheumatoid arthritis (RA) is a disease that affects primarily joints and cartilage through the development of pannus,
a product of inflammatory cells and cytokins that transform
synoviocytes into locally invasive and destructive cells. Although predominantly joint affecting, RA can evolve with extra-articular manifestations affecting the skin, vessels, heart,
lungs and peripheral nerves, as well as a significant association with focal and systemic malignancy.34
The possible mechanisms for the increased risk of hematological cancers in this pathology include: persistent immune stimulation (which can lead to clonal selection and
predispose CD5+ B cells to malignant transformation), decreased number and function of suppressor T cells (including
those directed against prooncogenic Epstein-Barr virus) and
decreased activity of natural killer cells in the synovial fluid,
tissue, blood and lymph.35
According to Askling et al.,36 who examined the risk of cancer in a cohort study comparing RA patients versus the general population, there was little evidence of an increased cancer
risk for most types of non-hematological cancers, but there
was a moderate increase in the risk of developing lung cancer. In contrast, this study showed an approximate two-fold
higher risk of lymphoma in patients with RA compared to the
general population. However, these authors stated that the
determinants of this association between RA and lymphoma
remain unknown.
A cohort evaluated the association between RA and malignancy in Asian populations. The study included 23,644 patients with RA who had no previous history of malignancies,
obtained through National Health Insurance Administration
of Taiwan database between 1996 and 2007. Among patients
with RA, 935 cancer cases were observed. This group showed
an increased risk, especially for hematological cancers (SIR =
2.74, 95 % CI = 2.68-2.81). The relative risk of cancer was higher
among young people.
Most cases of cancer were detected at the first year after
RA diagnosis. The relative risk for cancer decreased with an
increasing duration of the study and between hematological cancers, non-Hodgkin's lymphoma had the highest risk
of development (SIR = 3.54, CI 95% = 3.45-3.63). Among solid
tumors, the risk of kidney, vaginal and vulvar cancer were the
greatest. A decreased risk of cervix and nonmelanoma skin
cancer in patients with RA was also observed.37
Thompson, Rider and Poper (2011) conducted a meta-analysis on the risk of infection and malignancies in patients with
136
RA treated with anti-TNFα. Regarding the analysis for association of malignancy, the survey of literature data from six randomized clinical trials showed that malignancies occurred in
19 of 2,183 patients (0.87%) who received at least one dose of a
TNFα inhibitor, and in 10 of 1,236 patients (0.81%) in the control group. The risk of malignancy did not increase in patients
treated with a TNFα inhibitor, compared to control patients
treated with methotrexate (SIR = 1.08, CI 95% = 0.50-2.32).
The results of this meta-analysis provide continuous support to the existing data showing that the overall increased
risk for malignancies was not observed with anti-TNFα.38
The study by Dixon et al.39 corroborated the hypothesis of
a null association of cancer with the use of anti-TNFα, even
in patients with a history of neoplasia. An analysis was conducted on patients enrolled by the British Society of Rheumatology Biologics Registers (RSRBR) diagnosed with RA and
who were starting an anti-TNFα drug as their first biological
agent. Patients enrolled within six months after the start of
biologic therapy were excluded. Rates of malignancy for 177
patients treated with anti-TNFα and for 117 patients with active RA treated with disease-modifying antirheumatic drugs
(DMARDs) were compared, all of them with a history of prior
malignancy.
The rates of malignancy incidence were of 25.3 events/1000
person per year in anti-TNFα group and 38.3/1,000 person per
year in the DMARD cohort, generating a relationship of age
and standardized incidence ratio of 0.58 (95 % CI = 0.23-1.43)
for the cohort using anti-TNFα versus DMARD’s. Of the patients previously afflicted with melanoma, 3 (18%) out of 17
in the cohort of anti-TNFα developed a malignant event, compared with 0 out of 10 in the DMARD cohort.39
According to the British Society for Rheumatology guidelines for the use of anti-TNFα, instruct that “caution should
be exercised with the use of anti-TNFα therapies in patients
with previous malignancy; however, the potential benefits of
this treatment should be considered against the potential
risk of recurrence of a particular malignancy. If the patient
was recurrence free of any malignant tumor for the last 10
years, there is no evidence of a contraindication to antiTNFα therapy.”40
Smitten et al. (2008)41 conducted a meta-analysis that evaluated 21 publications found on Medline from 1990 to 2007,
from which 13 articles reported an increased SIR for general
malignancies; 14 for lymphoma, 12 for lung cancer, 10 for
colorectal cancer, and nine for breast cancer. Compared to the
general population, global estimates suggest that RA patients
have an increase of approximately twice the risk of lymphoma (SIR = 2.08, CI 95% = 1.80-2.39) and a higher risk of Hodgkin’s lymphoma as well as non-Hodgkin’s lymphoma. The
risk of lung cancer also increased (SIR = 1.63, CI 95% = 1.431.87). In contrast, a decreased risk was observed for colorectal
(SIR = 0.77, CI 95% = 0.65-0.90) and breast (SIR = 0.84, CI 95%
= 0.79 -0.90) cancer. For general malignancy, SIR rate was 1.05
(CI 95% = 1.01-1.09).41
Therapy and the risk of malignancies
Besides pathogenic mechanisms that suggest an increased
susceptibility of patients for cancer occurrence (impaired immune surveillance and destruction of cancerous cells, pos-
sible association of infection and uncontrolled lymphocyte
proliferation by oncogenes), the therapy used in autoimmune
rheumatic diseases has been described as a potentially carcinogenic factor (Table 3).11
The principal DMARDs classes used in rheumatology and
for the therapy of the above-mentioned diseases include immunosuppressive and/or alkylating agents. Among the immunosuppressive agents commonly used as DMARDs in autoimmune diseases, methotrexate (MTX) and azathioprine
are the most commonly prescribed, and the development of
malignancies associated with their long-term use has been
previously studied.
MTX is a dihydrofolate reductase antagonist, when present it inhibits DNA synthesis and inhibits the proliferation
of B and T lymphocytes. In 1997, Bologna et al.42 analyzed the
possible relationship of an increased incidence of tumors
and treatment with MTX in patients with rheumatoid arthritis. The study included 426 patients treated with MTX,
from which eight cases of neoplasia were detected. In the
other hand, in the control group with 420 patients who had
never been treated with MTX, it was observed a development of six cases of neoplasia. The authors concluded that
there was no statistically significant difference between
groups and that further studies were required, since the
drug could be a precipitating factor for tumorigenesis in
predisposed patients.
According to Sobral (2006),43 neoplasias that requirse
treatment with MTX are rare. However, Wolfe and Michaud
(2004)44 and Franklin et al.45 have found a higher incidence of
malignancies, particularly lymphomas, in RA patients treated with immunosuppressants. Although it is not possible to
differentiate the cause, it is usually associated with intense
lymphocytic inflammatory activity or the use of immunosuppressive drugs to control severe active disease.44,45
Azathioprine is an immunosuppressive antimetabolite
that acts by inhibiting the biosynthesis of adenine and gua-
Table 3 – Medication and its possible oncogenic
mechanism.
Drug
Methotrexate42
Azathioprine43.46
Cyclophosphamide43.46-48
Biological agents50-54
Pathogenic paths
Antagonizes dihydrofolate reductase,
inhibits DNA synthesis and
proliferation of B and T cells
Exhibits no increased risk42
Inhibits the biosynthesis of adenine
and guanine, interfering with cell
multiplication
Inactivate body immunosurveillance.
Possible increased risk of
lymphoproliferative disorders43,46
Crosslinkage with DNA strands prevent
replication
Increased risk of cervical intraepithelial
neoplasm48
Immunomodulation
Infliximab and adalimumab with an
increased risk of cancer, especially
lymphoma and rectal, breast and
lung cancer51
Abatacept: no increased risk of
malignancies was found53,54
nine, interfering with cell multiplication. The risk for oncogenesis is described as a limiting factor for its use on a large
scale. The oncogenic risk is related to the inactivation of body
immunosurveillance, combined with immunological changes
in patients with autoimmune diseases. The main risk is associated with lymphoproliferative diseases and premalignant
cervical atypia.43,46
Alkylating agents have as primary target the cell cycle;
these pharmaceuticals interrupt or disturb key steps in
cell proliferation and consequently lead to replicating cells
death.43 According to Almeida et al.,46 alkylating agents crosslink with DNA strands preventing its replication and thereby
destroying the cells at rest or in active cell division. Consequently, cytotoxicity occurs by cross-reactivity with the other
DNA strand.
In autoimmune rheumatic diseases, the most widely used
alkylating agent is cyclophosphamide. Silva et al.47 reported
that the treatment with alkylating agents may induce secondary hematologic malignancies, including acute leukemias. In
patients with SLE, Ognenovski et al.48 reported a higher incidence of cervical intraepithelial neoplasias in patients taking
cyclophosphamide.
In this context, biological agents are mainly used in RA
therapy. These include antagonists of tumor necrosis factor α (anti-TNF-α), interleukin-1 receptor, IL-6 receptor and
B cell surface markers (anti-CD20) as well as lymphocyte
costimulation modulators.49 In Brazil there are five types of
anti-TNF-α agents: Etanercept, Infliximab, Adalimumab, Certolizumab pegol and Golimumab. The latter two were recently
released for use in this country.
In a meta-analysis published in 2012, Solomon, Mercer and
Kavanaugh50 analyzed publications related to the use of biological agents and on the development of malignancies.
The drugs studied were abatacept, atanercept, adalimumab, infliximab, anakinra and rituximab in the treatment of RA.
In most studies analyzed, an increased incidence of cancer in
patients treated with anti-TNF agents was not demonstrated.
However, in a meta-analysis of clinical trials Bongartz et al.51
have demonstrated an association between infliximab and
adalimumab with increased risk of cancer, especially lymphoma, colorectal, breast and lung types.
It has been shown that IL-6 is involved in the pathophysiology and prognosis of prostate cancer, hence anti-IL-6, a biological agent, appears to be involved in its prevention. However, there are no studies on the use of this drug as a protective
factor for this neoplasia yet.52
Simon et al.53 catalogued a total of 4,134 RA patients treated with abatacept evaluated in seven trials, and 41,529 RA
patients treated with non-biologic DMARDs in five observational cohorts. From the patients treated with abatacept, 51
malignancies were detected, however these findings were not
higher than the expected from the five cohorts of RA control
cases. The values of SIR comparing RA patients against the
general population were consistent with those reported in
the literature. The overall incidence of malignancies (excluding nonmelanoma skin cancer), and of breast cancer, colorectal cancer, lung cancer and lymphoma in the abatacept group
was the expected in a comparable population with RA. These
data suggest that there are no new safety signs regarding malignancies; therefore, this issue should be monitored.
137
Corroborating the above hypothesis, Genovesel et al.54
studied 1,167 RA patients treated with abatacept for a period
of five years, without identifying an increased SIR among users of this agent.
Final considerations
The development of this review revealed a shortage of articles addressing the subject, in particular Brazilian studies,
as well as epidemiological studies about the topic. Despite
this limitation, this study found a relationship between neoplasias and the autoimmune rheumatic diseases analyzed,
both as risk factors and as protective factors, although the
pathophysiological mechanisms involved are not well understood. Hematologic cancers were observed in all conditions studied, especially lymphoma. In the particularities of
each disease, lung cancer was strongly associated with SLE,
SSc and RA, followed by colorectal and liver cancers. SLE represented a possible protective factor against prostate cancer,
which was explained due to hormonal aspects of the disease
in SLE patients.
The principal neoplasias were analyzed according to
their incidence in each group of rheumatic diseases, and
the carcinogenic potential of drugs used in the therapy of
rheumatic diseases cannot be ignored, especially azathioprine and cyclophosphamide in RA and/or SLE patients. The
authors also highlight the lack of Brazilian epidemiological
studies addressing this association.
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REUMATOLOGIA
Review article
Evaluation protocols of hand grip strength in individuals with
rheumatoid arthritis: a systematic review
Ana Paula Shiratori, Rodrigo da Rosa Iop, Noé Gomes Borges Júnior,
Susana Cristina Domenech, Monique da Silva Gevaerd*
Postgraduate Program in Human Movement Sciences, Centro de Ciências da Saúde e do Esporte (CEFID), Universidade do Estado de Santa
Catarina (UDESC), Florianópolis, SC, Brazil
article info
abstract
Article history:
Hand grip strength is a useful measurement for individuals with rheumatoid arthri-
Received 20 November 2012
tis, since this disease is often associated with functional anomalies of the hands and
Accepted 14 May 2013
a consequent reduction in muscular strength. Thus, the standardization of the test
protocol is important in relation to make reproducible and reliable studies. The aim
Keywords:
of this systematic review was to verify the parameters associated with the measure-
ment of the hand grip strength in individuals with rheumatoid arthritis. The review
Handgrip strength
was carried out according to the recommendations of PRISMA, based on the data-
Measurement parameters
bases of the Web of Science and the Journals Website of the Brazilian governmen-
Dynamometry
tal agency CAPES. The following inclusion criteria were established: articles whose
themes involved dynamometry to measure the hand grip in adult patients with
rheumatoid arthritis, published in English between 1990 and 2012. The articles were
selected by two independent reviewers. Initially, 628 articles were identified, and
in the final review only 40 were included in the qualitative synthesis, that is, those
in which the main tool used to evaluate the hand grip strength was the Jamar®.
In relation to the hand grip strength parameters feedback type, hand dominance, repetitions, contraction intensity, acquisition time and rest period many data are imprecise and were not detailed in the method description. It is clear that there is a need for
the standardization of a protocol which establishes the type of dynamometer and the
parameters to be evaluated and also takes into consideration the clinical conditions of
patients with rheumatoid arthritis.
E-mail: [email protected] (M.S. Gevaerd).
141
Protocolos de avaliação da força de preensão manual em indivíduos com
artrite reumatoide: uma revisão sistemática
resumo
Palavras-chave:
A força de preensão manual é uma medida útil nos indivíduos com artrite reumatoide, pois
Artrite reumatoide
a doença está muitas vezes associada a anormalidades funcionais das mãos e consequente
Preensão manual
redução da força muscular. Dessa forma, a padronização do protocolo do teste é importante
Parâmetros de medida
por tornar os estudos reprodutíveis e confiáveis. Essa revisão sistemática teve como finali-
Dinamometria
dade verificar os parâmetros de medida da força de preensão manual em indivíduos com
artrite reumatoide. A revisão foi realizada de acordo com as recomendações PRISMA, nas
bases de dados web of science e no Portal de Periódicos da CAPES. Foram estabelecidos os
seguintes critérios de inclusão: artigos cujos temas envolvessem a dinamometria de preensão manual em pacientes adultos com artrite reumatoide, no idioma inglês, publicados
entre 1990 e 2012. Os artigos foram selecionados por dois revisores independentes. Inicialmente foram identificados 628 artigos, sendo que na revisão final apenas 40 artigos foram
incluídos na síntese qualitativa; destes, verificou-se que o principal instrumento utilizado
para avaliação da força de preensão manual foi o Jamar®. Em relação aos parâmetros da
força de preensão manual: tipo de feedback, dominância, repetições, intensidade da contração, tempo de aquisição e tempo de descanso, muitos dados são imprecisos e não foram
criteriosos na descrição do método. Evidencia-se a necessidade de padronização de um
protocolo que estabeleça o tipo de dinamômetro, os parâmetros a serem avaliados e ainda
leve em consideração as condições clínicas dos pacientes com artrite reumatoide.
Introduction
Rheumatoid arthritis (RA) is a major challenge to clinicians,
rheumatologists, physiotherapists and researchers, not only
because of its increasing long-term mortality, but also by work
incapacitation, and the evidence of producing joint damage,
weakness, fatigue, and general functional decline.1,2
In these individuals, handgrip is a useful parameter of evaluation,3 since muscle weakness is a common symptom, of disuse atrophy, which results in systemic inflammation as well as
of pain and joint stiffness.4
In the clinical context, handgrip strength serves several
purposes, it is recommended for clinical diagnosis, for the
evaluation and comparison of surgical techniques, for the documentation of the progress during rehabilitation, the response
to treatment and the level of disability after injury.5,6
Handgrip strength can also be used as an indicator of overall strength and general health,7 commonly used in professional environments to evaluate the performance of athletes
who depend on an adequate level of grip strength to maximize
control and performance and to reduce possible injuries.8
Despite the handgrip being a routine measure in the evaluation of patients with RA, little attention has been paid to the
importance of standardization of the test protocol for patients
with this disease. The use of a standard protocol is important
to improve the accuracy and consistency of the test, since differences in the protocols used can affect the reproducibility
of measurements and the comparison of the absolute values
to other studies.9
Given the importance of a standard protocol for the handgrip test in patients with RA, our study aims to conduct a sys-
tematic review to investigate the disease’s treatment stateof-the-art, verifying which are the most used protocols for
handgrip strength evaluation in RA patients .
Method
This systematic review was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)10 which consists of
a checklist of 27 items and a flow diagram and includes items
deemed essential for a clear reporting of systematic reviews.
Eligibility criteria
The review included only observational and uncontrolled
studies in English, encompassing adults with RA and handgrip strength dynamometry, published between 1990 and
2012, available in complete form. Randomized clinical trials
(RCTs) were not included, because in an initial search the
terms associated with a sensible search list for RCTs developed by Robinson and Dickersin (2002)11 did not yield any result.
The outcomes included were: type of dynamometer handgrip strength test (feedback, dominance, repetition, intensity
of contraction, acquisition time, and rest time) and strength
analysis. Feedback is understood as the stimulus needed
to maximize the individual's performance in the handgrip
strength test, which may be visual or verbal. The following
exclusion criteria were adopted: juvenile arthritis and/or other rheumatic diseases, review articles, meetings’ proceedings,
conference summaries and duplicate records.
142
Search strategy
The following electronic databases were searched: Web of Science and the online periodicals portal CAPES (Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior), using as
search strategy the following combination of terms in English: “(Grip strength maximal isometric* OR handgrip muscle
strength* OR hand-grip dynamometry* OR handgrip strength*
OR handgrip strength test contraction speed*)” AND “rheumatoid arthritis”.
In sequence, with the aid of database tools, a search refinement was performed using the following keywords: “rheumatoid arthritis”, “arthritis rheumatoid”, “muscle strength”,
“hand”, “hand strength”, “grip strength”, “isometric contraction”, “mortality” and “grip”.
Study selection and data extraction
The first selection of articles was carried out from title reading, and the second selection was conducted from the analysis of abstracts and keywords. To manage duplicate files, we
used EndNote Web (version 3.3), a management system of
references. The titles and abstracts of all articles identified by
the search strategy were independently assessed by two of
the authors of this paper (APS and RRI).
In this second phase the reviewers independently evaluated the full papers and made their selections, according
to the eligibility criteria previously specified. The outcomes
were: pneumatic dynamometer, Jamar and digital dynamometer, measured in N (Newton) or kgf; in relation to the
handgrip parameters; the outcomes were: type of feedback
(visual or verbal), dominance (right or left), number of repetitions, intensity contraction (maximum strength), acquisition
time and rest (in seconds or minutes, and the kind of strength
analysis (best result or average).
Assessment of risk of bias
No method to assess the risk of bias in included studies was
used for studies of different design.
Results
A total of 628 articles were identified by the reviewers, and
420 were obtained from the CAPES website (SciVerse, ScienceDirect, MEDLINE, Science Citation Index Expanded, OneFile,
SpringerLink, Oxford Journals, Social Sciences Citation Index,
Future Science Medicine, PloS, American Psychological Association, Karger Journals, Wiley, Bentham Science) and 208
from Web of Science. After refinement, the search was restricted to 301 articles, 93 of which were obtained from the
Newsletters’ Website of CAPES and 208 from Web of Science.
Initially, 75 articles were selected based on a title analysis; of
these, only 22 articles were chosen because abstract and keyword analysis excluded several articles not meeting the inclusion criteria. Finally, 13 articles that were not available in its
totality were excluded. Thus, 40 articles total were included in
our qualitative synthesis, according to the flow diagram presented in Fig. 1.
Registers identified by searching
the database
(n = 628)
Registers identified by refining
the database
(n = 301)
Registration excluded based on title
(n = 226)
Selected registers
(n = 75)
Register deleted based on abstract,
keywords and inclusion and exclusion
criteria (n = 22)
Selected registers
(n = 53)
Register deleted for not being
fully available (n = 13)
Studies included in qualitative
synthesis
(n = 40)
Fig. 1 – Flow diagram of the steps for article selection.
Discussion
Equipment and techniques for measuring handgrip
For grip strength evaluation there are several devices available, used both in clinical practice and in research. Main
dynamometers are hydraulic, pneumatic, or digital.9 Table 1
shows the main dynamometers and their characteristics.
Among them, Jamar® hydraulic dynamometer (Fig. 2)12 is
the most mentioned in the literature, considered as the gold
standard for the handgrip strength test.9 In this review, 19
(47.5%) studies were found to include this device as an instrument for measuring handgrip strength. On the other hand,
the use of a pneumatic dynamometer was reported in 10 (25%)
studies, and the use of a digital dynamometer was reported in
8 (20%) studies. In only 3 (7.5%) articles the type of equipment
used was not cited, as can be seen in Tables 2 and 3.
The Jamar® device enables a discrete handle adjustment13,14 with 5 positions: I - 3.5 cm; II - 4.8 cm; III - 6.0 cm; IV
- 7.3 cm; and V - 8 6 cm.15 From the papers documenting the
use of Jamar® device, only three studies16-18 described the position adopted during the test application. Silva, Jones et al.16
standardized the position II for both genders; Escott, Ronald
et al.17 and Bogoch, Escort et al.18 used positions II, III and IV
for testing. However, none of these studies justified the criteria adopted for determining a position.
Studies were published19-21 that report the influence of the
hand and handle sizes in the performance of grip strength.
143
Table 1 – Types of dynamometers and their characteristics.
Type of dynamometer
Hydraulic
Pneumatic
Digital
Measurement parameter
Handhold grip
Maximum strength
With slight handle adjustment (5 different
positions)
Pressure
Without handle adjustment
Maximum strength, time to peak strength, fatigue
With or without continuous handle
rate, area under the curve, rate of strength
adjustment
development
Unit
Newton
mmHg
Newton
N/C, Not cited; RH, Right hand; DomH, Dominant hand; Smax, Maximum strength.
Some digital dynamometers feature continuous adjustment of the handle, allowing adaptation to the size of the
hand and possible deformities present. This adjustment26 is
an important factor in strength performance, since the size
of the hand influences the performance of the test.15
Protocols for handgrip measurement
Fig. 2 – Jamar dynamometer.
Source: Pamela D’Scalona, et al. (2009).12
The American Society of Hand Therapy establishes the position II as the standard handle size.22
Pneumatic dynamometers are instruments that measure
pressure, not manual strength. This pressure depends on the
compression of air through a rubber bulb.22 This type of dynamometer lacks the feature of adjusting the grip, for compression. In this case, the pressure is dependent on the area
where the strength is applied; thus, the size of the hand can
influence the measurement.9 In the papers examined, three
studies regulated the initial cuff pressure at 20 mmHg,3,23,24
other two studies regulated the initial pressure at 30 mmHg25
or 40 mmHg2. The other five studies did not show this information on the methodology session.
Digital dynamometers allow the evaluation of strength ×
time curve, providing other parameters for strength analysis, such as time to reach maximum strength, fatigue rate,
and area under the curve, among others.26,27 This way of
analyzing the strength is advantageous in the evaluation of
hand disorders,28 since one of the parameters considered as
an indicator of manual dysfunction is the rate of strength
development.26
Regarding digital dynamometers, none of the studies (8
articles) presented the description of handle adjustment.
Several aspects can affect the outcome of the handgrip test,
and many of these are involved in defining the test application protocol, such as number of repetitions performed, type of
feedback,29 hand dominance, and fatigue.30
By setting the protocol to be applied to the handgrip strength
test, the contraction intensity shall be established: maximum
or submaximal. In special populations, such as arthritic people,
there are factors that can influence the intensity of the contraction election. The presence of pain, synovitis, erosion and
joint deformity are direct factors; on the other hand, motivation, pain tolerance and use of analgesics are indirect factors.31
The test of maximum strength in arthritic people is considered a test of physical function based on individual performance, providing quantitative and reproducible information
about the current state of patient and disease prognosis.32 This
test is also used as a predictive measure of nutritional status,33 morbidity and mortality.34 The evaluation of maximum
strength is well established in the literature, so that there is
normative data for the healthy population.33,35 These data
may serve as a comparison parameter to arthritic individuals;
thereby the use of the maximum contraction intensity parameter has this advantage. Of the studies analyzed, 15 (37.5%)
evaluated maximum strength only; the other studies did not
present this information.
Regarding the number of test repetitions, 14 (35%) articles
documented three attempts, 4 (10%) had only two repeats, and
22 (55%) did not report the number of repetitions performed.
The recommendations of the American Society of Hand Therapistis36 and of the American Society for Surgery of the Hand37
are that three steps are performed. However, there is disagreement in the form of analysis of such measures, which can be
made from a single trial,28 from the best obtained value,38 or
from values’ average.2 The average of three attempts has the
highest test-retest reliability. Therapists and physicians suggest this form of analysis, rather than just an attempt, or the
analysis of the best value among three attempts, both for clinical assessment of the patient and for research purposes.22 In
the study from Haidar, Kumar et al.,39 it was found that both
the average of three attempts as the value of a single measurement showed high consistency, with no significant difference between methods.
Pneumatic
Jamar®
Pneumatic
Digital
Pneumatic
Jamar®
Pneumatic
Digital
Digital
Jamar®
Pneumatic
Jamar®
Jamar®
Jamar®
Digital
Jamar®
Digital
Jamar®
Jamar®
Digital
Dynamometer
type
N/C, not cited; RH, right hand; Smax, maximun strenght.
Ferraz et al. (1992)
Hakkinen, Malkia et al. (1997)
Sugimoto, Takeda et al. (1998)
Fraser, Vallow et al. (1999)
Torrens, Hann et al. (2000)
Buljina, Taljanovic et al. (2001)
Gordon, West et al. (2001)
Häkkinen, Sokka et al. (2003)
Lefevre-Colau, Poiraudeau et al. (2003)
Poulis, Kretsi et al. (2003)
Zijlstra, Heijnsdijk-Rouwenhorst et al. (2004)
Bodur, Yilmaz et al. (2006)
Hakkinen, Kautiainen et al. (2006)
Odegard, Landewe et al. (2006)
Bearne, Coomer et al. (2007)
Durez, Fraselle et al. (2007)
Goodson, Mcgregor et al. (2007)
Slatkowsky-Christensen, Mowinckel et al. (2007)
Van Der Giesen, Nelissen et al. (2007)
Adams, Burridge et al. (2008)
Reference (year)
N/C
N/C
N/C
Visual and verbal
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
Verbal
N/C
Feedback
type
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
Only RH
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
Dominance
Table 2 – Parameters of protocols for measuring handgrip in rheumatoid arthritis.
3
N/C
N/C
3
N/C
3
N/C
N/C
3
N/C
3
3
N/C
2
3
N/C
3
2
2
N/C
Smax
Smax
N/C
Smax
N/C
N/C
N/C
Smax
N/C
N/C
Smax
Smax
Smax
Smax
Smax
Smax
N/C
N/C
Smax
N/C
Contraction
intensity
Handgrip parameters
Repetitions
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
3 seg.
N/C
N/C
N/C
N/C
N/C
Acquisition
time
15 s
N/C
N/C
1 min
N/C
N/C
N/C
N/C
1 min
N/C
N/C
N/C
N/C
N/C
30 s
N/C
N/C
N/C
N/C
N/C
Rest time
Average
Average
Average
Average
N/C
Average
N/C
Summation
Average
N/C
Average
Average
Average
Average
Average
N/C
Average
Average
Average
N/C
Strength
analysis
144
Jamar®
Jamar®
Digital
Jamar®
Jamar®
Jamar®
Pneumatic
N/C
N/C
Digital
Jamar®
Pneumatic
Jamar®
Jamar®
N/C
Jamar®
Digital
Jamar®
Pneumatic
Pneumatic
Dynamometer
type
N/C
N/C
N/C
Verbal
N/C
Verbal
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
Feedback
type
N/C, not cited; RH, right hand; DomH, dominant hand; Smax, maximum strength.
Formsma, Van Der Sluis et al. (2008)
Oken, Batur et al. (2008)
Ronningen e Kjeyen (2008)
Silva, Jones et al. (2008)
Silva, Lombardi et al. (2008)
Van Der Giesen, Nelissen et al. (2008)
Veehof, Taal et al. (2008)
Chung, Burns et al. (2009)
Chung, Burke et al. (2009)
Flint-Wagner, Lisse et al. (2009)
Flipon, Brazier et al. (2009)
Mathieux, Marotte et al. (2009)
Poole (2009)
Escott, Ronald et al. (2010)
Hayashibara, Hagino et al. (2010)
Jain, Ball et al. (2010)
Meireles, Jones et al. (2010)
Bogoch, Escort et al. (2011)
Nolte, Van Rensburg et al. (2011)
Speed e Campbell (2012)
Reference (year)
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
Start DomH
N/C
N/C
N/C
N/C
N/C
N/C
N/C
Only RH
Dominance
Table 3 – Parameters of protocols for measuring handgrip in rheumatoid arthritis.
N/C
N/C
N/C
3
N/C
2
3
N/C
N/C
3
N/C
N/C
3
3
N/C
N/C
N/C
N/C
N/C
3
Repetitions
N/C
N/C
N/C
N/C
N/C
Smax
Smax
N/C
N/C
N/C
N/C
N/C
Smax
N/C
N/C
N/C
N/C
N/C
N/C
Smax
Contraction
intensity
Handgrip parameters manual
N/C
N/C
10 s
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
3s
Acquisition
time
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
N/C
2 min
Rest time
N/C
N/C
Average
Average
N/C
Average
Average
N/C
N/C
Average
N/C
N/C
Average
Average
N/C
N/C
N/C
N/C
N/C
Average
Strength
analysis
145
146
The resting time interval between trials influences the
performance of the strength, because this variable is directly
related to muscle fatigue. Of the articles analyzed, 35 (87.5%)
studies did not show the break time allowed in their methodology. Other authors have used intervals of 15s;40 30s;24 1
minute;41,42 and 2 minutes.2 When comparing the resting time
at 15 s, 30 s and 60 s, it was found that there was no significant
difference between the three breaks in strength application ,
however, the decline in strength was lower at 60 s.43 It is considered cautious a rest period of at least 1 minute, to counteract the effects of fatigue.28,31,39,43,44
By analyzing the acquisition time of the handgrip strength
test, it was found in 37 (92.5%) articles there was no description of this variable; in the remaining articles, three seconds,3,24 and ten seconds were used.45 According to Kamimura
and Ikuta,28 there are few studies that focus on the influence
of sustained strength time in the results. In a study comparing the contraction time of six vs. ten seconds, it was found
that both showed a significant interclass correlation coefficient using a confidence interval of 95%.28
It is known that there are differences in grip strength between the dominant and non-dominant hand. Studies reveal
that the dominant hand has higher strength compared with
the non-dominant hand;30 there is also a relationship with
gender, so that men have higher strength compared to women.46 This difference between hands is about 10%.44 In some
handgrip protocols, hand dominance is considered and usually the test begins with the dominant hand.39 Of the studies
surveyed, 37 (92.5%) articles did not consider the hand dominance at the beginning of the test. Only Mathieux, Marotte et.
al.47 specify that the participants must start the test with the
dominant hand. Two studies evaluated the test on only one
side – determining the protocol with only the right hand.2,14
The last parameter analyzed refers to the feedback at the
moment of the strength accomplishment, and that can contribute to achieve the best performance from the individual
under consideration. Some authors adopted into their protocol the use of verbal feedback16,38,48 and others have adopted
both verbal and visual feedback.42 Other studies (36 articles
– 90%) reported no information about feedback. The use of
feedback is a variable not well established in the literature
involving individuals with arthritis, and also in other types
of populations. There is a gap regarding the use of any type
of feedback during handgrip strength tests; in this sense, Mathiowetz, Weber et al.22 raise the question of the influence of
feedback on the outcome of grip strength.
Conclusion
Jamar dynamometer stands out as the most widely used
type of dynamometer. As for the protocol, three repetitions
at maximum intensity of contraction were reported. As for
strength analysis, both average and best result were observed.
From this review, a great variability of handgrip protocols
between studies was perceived, and in many of these studies
the protocol used was not fully disclosed.
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REUMATOLOGIA
Case report
Chronic lymphomonocytic meningoencephalitis,
oligoarthritis and erythema nodosum: report of BaggioYoshinari syndrome of long and relapsing evolution☆
Nilton Salles Rosa Netoa,*, Giancarla Gauditanob, Natalino Hajime Yoshinaria
a
b
Faculdade de Medicina , Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
Service of Rheumatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil
article info
abstract
Article history:
The Brazilian human borreliosis, also known as Baggio-Yoshinari Syndrome (BYS), is a tick-
Received 30 October 2011
borne disease but whose ticks do not pertain to the Ixodes ricinus complex. It is caused
by Borrelia burgdorferi sensu lato microorganisms and resembles clinical and laboratory
features of Lyme disease (LD). BYS is also distinguished from LD by its prolonged clinical
Keywords:
evolution, with relapsing episodes and autoimmune dysfunction. We describe the case of
Borrelia burgdorferi
a young female who, over one year, progressively presented with oligoarthritis, cognitive
Borrelia infections
impairment, menigoencephalitis and erythema nodosum. Diagnosis was established by
Brazil
means of the clinical history and a positive serology to Borrelia burgdorferi sensu strictu. The
Spirochaetales
patient received Ceftriaxone 2 g IV/day during 30 days, followed by 2 months of doxicy-
Tick-borne diseases
cline 100 mg bid. Symptoms remitted and the Borrelia serology tests returned to normality.
BYS is a new disease described only in Brazil, which has a raising frequency and deserves
the attention from the country´s medical board because of clinical, epidemiological and
laboratory differences from LD. Despite the fact that it is a hard-to-diagnose zoonosis, it is
important to pursuit an early diagnosis because the symptoms respond well to antibiotics
or it might be resistant to treatment and may evolve to a chronic phase with both articular
and neurological sequelae.
☆
Study conducted at Service of Rheumatology, Hospital das Clínicas, Medicine School, Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil.
E-mail: [email protected] (N.S. Rosa-Neto).
149
Meningoencefalite linfomonocitária crônica, oligoartrite e eritema
nodoso: relato de síndrome de Baggio-Yoshinari de longa e recorrente
evolução
resumo
Palavras-chave:
A borreliose humana brasileira, também conhecida como Síndrome de Baggio-Yoshinari
Borrelia burgdorferi
(SBY), é uma enfermidade infecciosa própria do território brasileiro, transmitida por car-
Infecções por Borrelia
rapatos não pertencentes ao complexo Ixodes ricinus, causada por espiroqueta do gênero
Brasil
Borrelia e que apresenta semelhanças clínicas e laboratoriais com a Doença de Lyme (DL).
Spirochaetales
A SBY distingue-se da DL por apresentar evolução clínica prolongada, com episódios de
Doenças transmitidas por
recorrência e importante disfunção autoimune. Descreveremos o caso de uma paciente
carrapatos
jovem, que desenvolveu progressivamente durante cerca de um ano oligoartrite de grandes articulações, seguida de distúrbio do cognitivo, meningoencefalite e eritema nodoso. O
diagnóstico foi firmado devido à concomitância de queixas articulares e neurológicas com
sorologia positiva para Borrelia burgdorferi sensu stricto. A paciente foi medicada com ceftriaxone 2 g/EV/dia por 30 dias, seguido de dois meses de doxiciclina 100 mg duas vezes ao dia.
Houve remissão dos sintomas e normalização dos exames sorológicos para a borreliose. A
SBY é uma zoonose emergente descrita apenas no Brasil, cuja frequência tem crescido bastante, e que, em razão das importantes diferenças nos aspectos epidemiológicos, clínicos e
laboratoriais em relação à DL, merece especial atenção da classe médica do país. Trata-se
de zoonose camuflada e de difícil diagnóstico, mas este deve ser perseguido com tenacidade, pois a enfermidade responde aos antibióticos no estágio inicial, podendo evoluir com
sequelas neurológicas e articulares nos casos reconhecidos tardiamente ou recorrentes.
Introduction
Brazilian human borreliosis or Baggio-Yoshinari Syndrome
(BYS) is an endemic anthropozoonosis proper to Brazil, caused
by spirochetes of the genus Borrelia, transmitted by ticks of the
genus Amblyomma and Rhipicephalus, which have clinical similarities with Lyme disease (LD).1-8 BYS can be distinguished
from LD, since the transmission vectors for this latter disease
belong to the Ixodes ricinus species. Furthermore, from a clinical standpoint, this Brazilian disease evolves with symptomatic and immunological disorder recurrence.1,5-7
Researchers at the Medical Research Laboratory, Medicine
School, Universidade de São Paulo (LIM -17) suggest that the
biodiversity conditions particular to the Brazilian territory,
such as the presence of exotic vectors and favorable ecological conditions, have allowed for bacteria of the Borrelia burgdorferi complex sensu lato, to adapt to the country1,6,7,9 and develop a zoonosis with typical clinical and laboratory aspects.
The dissemination of clinical and laboratory knowledge
about BYS has been a great challenge, because even with a
different clinical and laboratory picture of LD, there is huge
resistance from national and international scholars to admit
the existence of this Brazilian zoonosis. Concepts such as prolonged latent infection caused by spirochetes in the form of
cysts, clinical recurrence, different serologic diagnosis from
standards adopted by the Centers for Disease Control and Prevention (CDC), and the therapeutic strategies for use of antibiotics during extended periods of time are not acceptable for
certain countries of the northern hemisphere.
However, to deny its existence as an emerging clinical entity would be gross negligence, especially when there is evi-
dence that the disease may progress to develop severe joint
and neurological sequelae, if not treated properly.6,10 In this
paper, we describe an illness of prolonged evolution and recurrent symptoms, in that the diagnosis of BYS was established after the onset of meningoencephalitis with positive
serology for B. burgdorferi, according to LIM-17 adopted standards.
Case report
Female, 35 years old, white, coming from the city of Cotia,
São Paulo, where she lives since childhood. At 23, the patient showed additive polyarthritis, affecting hands, elbows,
shoulders, knees and ankles. She recounts being treated with
benzathine penicillin after hypothesis of rheumatic fever;
however, due to the persistence of symptoms, she sought a
rheumatologist who diagnosed rheumatoid arthritis, being
treated with sulfasalazine, with improvement. She ceased
medication after five years of clinical remission. She denied
having erythema migrans (EM) and an infectious or surgical history. In June 2006 the patient displayed arthritis in her
knees and left ankle, with erythematous spots on her legs.
The case evolved to slow logical reasoning, amnesia for recent
events, nervousness, depression and difficulty planning activities, dysgraphia, loss of balance and appearance of intermittent diplopia episodes with an increasing visual impairment.
She reported febrile episodes (unmeasured). The patient lives
in an urban area with dogs at home, but always goes to a farm
in Ibiuna, Sao Paulo, where horses and cows are raised. The
patient did not recall tick bites in the past 12 months, but relates that it had occurred several times before.
150
In December 2006 the patient was admitted for evaluation
of cerebellar ataxia and neuritis of the 2nd cranial nerve. On
admission, she was in good general condition, pale, normotensive and afebrile, without lymphadenomegaly. Upon inspection, the patient had hyperchromic macules, with palpable nodules in the anterior region of both legs, with no other
mucocutaneous lesions. Cardiopulmonary and abdominal
workup revealed no changes.
Arthritis showed up on her knees and left ankle, with preservation of small joints, without joint limitation or deformities.
The patient was lucid and oriented in time and space, alert
and cooperative, amnesic to recent events, but with remote
memory preserved. A nontoxic march with grade V driving
force in all members was observed, with a mild dysmetria
of the left arm. Sensitivity and reflexes were preserved and
there was no sign of meningeal irritation.
Laboratory tests revealed normocytic and normochromic
anemia, erythrocyte sedimentation rate = 85 mm/1st hour
and C-reactive protein = 99 mg/L. The tuberculin test was
negative, as well as antinuclear and rheumatoid factors. A
CSF analysis revealed pleocytosis at the expense of lymphomonocytic cells. Search for infectious and parasitic agents
(toxoplasmosis, tuberculosis, hepatitis B and C, herpes simplex, cytomegalovirus, cysticercosis, HIV, HTLV, mumps, cryptococcosis, trypanosomiasis, malaria) were negative in serum
and CSF. The magnetic resonance imaging revealed enlargement of the basal cisterns, with a hyperintense signal on T2
and FLAIR at cerebral white matter, in the precentral gyrus at
the left and in orbital gyrus at the right, without anomalous
impregnation after the contrast.
Spontaneous neurological improvement was noted; afterwards, the patient was referred for outpatient follow-up. The
CSF samples confirmed the diagnosis as chronic lymphocytic
meningoencephalitis (Table 1).
In April 2007 the patient had intermittent episodes of diplopia and skin lesions, whose biopsy showed chronic septal
panniculitis consistent with erythema nodosum. Serology for
B. burgdorferi was requested, including ELISA IgM/IgG 1/800 reagent negative and a Western blot that revealed presence of
one IgM band and 3 IgG bands.
Given the clinical laboratory and epidemiological characteristics, the diagnosis of BYS was established. Ceftriaxone 2
g/day for 30 days was introduced, followed by doxycycline 200
mg/day for two months. There was improvement in the cog-
nitive dysfunction at the end of the first cycle of antibiotics,
with disappearance of erythema nodosum and arthritis resolution. Due to the persistence of cerebellar dysfunction, the
patient was readmitted for investigation in July 2007.
The neurological examination revealed decreased speed
of movement to the left, dysdiadocokinesia, intention tremor
and nystagmus evoked to the left. The neuropsychological assessment showed impairment in information processing as
well as nominative and visual-spatial difficulties. Then, we
decided to prescribe five days of pulse therapy with methylprednisolone 1 g, followed by five days of prednisone 60 mg/
day. Doxycycline was maintained for 60 days, in association
with 250 mg of chloroquine diphosphate. The serology for B.
burgdorferi became negative during the evolution, according to
data from Table 2.
Currently, the patient is asymptomatic, without changes
in the brain resonance, but with some memory impairment.
Discussion
In this paper, the case of a patient with late diagnosed BYS
and with severe neurological injury associated with joint and
cutaneous manifestations is presented. A positive serology for
B. burgdorferi (sensu stricto) helped confirm the diagnosis. Positive epidemiological history, presence of cognitive impairment
and neuropsychiatric symptoms, along with a good response to
treatment with disappearance of antibodies anti-spirochetes,
were equally relevant to the diagnosis.
In Brazil, this zoonosis may have a long latency period between initial infection and the onset of symptoms, as well as
with relapsing episodes during its evolution. Generally, the joint
condition of BYS emerges in large joints, especially the knees,
and can evolve to simulate rheumatoid arthritis, as it was in
this case.5,6,8 In this country, whenever there is presence of oligoarthritis of large joints, an investigation of BYS is mandatory,
and one should search both the epidemiological and clinical
histories.
LIM-17 adopts as diagnostic criteria for BYS the presence of
major (positive epidemiology, MS or systemic symptoms, and
positive serology) and minor (a history of systemic episodes
compatible with BYS, symptoms of chronic fatigue or cognitive
dysfunction, autoimmune disorders and visualization of spirochetes in peripheral blood) parameters.11 The patient visited risk
Table 1 – Evolutionary analysis of the cerebrospinal fluid (CSF).
CSF
Date
Leukocytes (/mm3)
Neutrophils
Lymphocytes
Monocytes
Glucose (mg/dL)
Proteins (mg/dL)
B. burgdorferi
ELISA IgM
ELISA IgG
Ref, reference value.
Ref
0-5
50 - 90
< 40
Internal
medicine ward
Internal
medicine ward
Outpatient´s
unit
Outpatient´s
unit
Outpatient´s
unit
Neurology
ward
Dec 13, 06
960
1
94
3
41
62
Dec 15, 06
160
3
90
6
44
49
Mar 19, 07
65
7
76
17
55
38
Apr 04, 07
81
42
41
15
48
43
July 13, 07
190
6
73
19
63
32
July 30, 07
18
0
67
21
80
30
-
-
-
Negative
Negative
Negative
Negative
-
151
Table 2 – Evolutive analysis of serology for Borrelia burgdorferi.
B. burgdorferi Serology
Data
ELISA IgM
ELISA IgG
WB IgM
WB IgG
Ref
1/100
1/400
a
a
Outpatient´s unit
Outpatient´s unit
Neurology ward
Outpatient´s unit
Outpatient´s unit
Apr 11, 07
Neg
1/800
1b
3b
Aug 11, 07
1/100
Neg
2b
3b
Aug 23, 07
Neg
Neg
2b
Neg
Sept 26, 07
Neg
Neg
Neg
Neg
Nov 14, 07
Neg
Neg
Neg
Neg
Neg, negative; Ref, reference value.
a
WB is considered positive with presence of at least 4 IgG bands, or at least 2 IgM bands; or at least 2 IgG bands and 1 IgM band simultaneously.
Ceftriaxone was initiated on June 29, 2007.
areas, socialized with domestic animals and had episodes of tick
bites. The BYS vectors often infest animals living close to man.1,6
The fact that the patient denied recent tick bites is not surprising, as the contagion may have occurred months or years before
the current symptoms.
The concomitant occurrence of meningoencephalitis and
the involvement of the second cranial nerve, associated with the
joint manifestation, is a relevant aspect. Shinjo et al.,10 studied
30 patients with BYS neuroborreliosis, and found that 73.6% had
recurrence episodes, 56.7% had concomitant neurologic complaints with arthritis, and meningoencephalitis was identified
in 33.3% of cases.
The encephalomyelitis of human borreliosis may be confused with multiple sclerosis (EM).12,13 In this report, the exuberance of the inflammatory symptoms, the multiplicity of systemic complaints, a positive serology for B. burgdorferi and the good
response to antibiotics excluded this diagnostic option. Other
causes of infectious and autoimmune encephalomyelitis were
also excluded.
There is no mention about MS in our patient's history, but it
should be noted that this initial injury, which arises at the point
of inoculation of spirochetes, occurs in less than 50% of cases
in Brazil.6,8 Interestingly, other atypical cutaneous presentations
have been reported, such as panniculitis, lymphocytoma and
scleroderma-like plate.6,8,11,14 There is no record of erythema nodosum associated with BYS, but there are reports of erythema
nodosum in patients with LD.15
This paper confirms the existence of recurring outbreaks in
BYS patients. This finding is highly relevant, since the current
symptoms are not always associated with epidemiological and
clinical data of the past. However, due to the severity of illness, a
good response of the condition to the treatment with antibiotics
in its early stages, and the possibility of preventing progression
to chronicity, physicians of different specialties should be vigilant for suspected cases of Brazilian human borreliosis.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
REFERENCES
15.
1. Mantovani E. Identificação do agente etiológico da Doença
de Lyme-símile brasileira (Síndrome de Baggio-Yoshinari):
Tese de Doutorado apresentada à Faculdade de Medicina
da Universidade de São Paulo; 2010: 117 pp. Disponível
em http://www.teses.usp.br/teses/disponiveis/5/5164/tde04112010-145154/pt-br.php
Azulay RD, Azulay-Abulafia L, Sodré CT, Azulay DR, Azulay
MM. Lyme disease in Rio de Janeiro, Brazil. Int J Dermatol.
1991;30:569-71.
Yoshinari NH, Barros PJ, Cruz FCM, Oyafuso LK, Mendonça
M, Baggio D. Clínica e sorologia da doença de Lyme no
Brasil. Rev Bras Reumatol. 1992;32.
Melo IS, Gadelha AR, Ferreira LC. Estudo histopatológico
de casos de eritema crônico migratório diagnosticados em
Manaus. An Bras Dermatol. 2003;78:9.
Yoshinari NH, de Barros PJ, Bonoldi VL, Ishikawa M, Battesti
DM, Pirana S et al. [Outline of Lyme borreliosis in Brazil].
Rev Hosp Clin Fac Med Sao Paulo. 1997;52:111-7.
Yoshinari NH, Mantovani E, Bonoldi VL, Marangoni RG,
Gauditano G. [Brazilian lyme-like disease or BaggioYoshinari syndrome: exotic and emerging Brazilian tickborne zoonosis]. Rev Assoc Med Bras. 2010;56:363-9.
Gouveia EA, Alves MF, Mantovani E, Oyafuso LK, Bonoldi
VL, Yoshinari NH. Profile of patients with Baggio-Yoshinari
Syndrome admitted at “Instituto de Infectologia Emilio
Ribas”. Rev Inst Med Trop Sao Paulo. 2010;52:297-303.
Costa IP, Bonoldi VLN, Yoshinari NH. Perfil clínico e
laboratorial da Doença de Lyme símile no Estado de Mato
Grosso do Sul: análise de 16 pacientes. Rev Bras Reumatol.
2001;41:8.
Derdáková M, Lencáková D. Association of genetic
variability within the Borrelia burgdorferi sensu lato with
the ecology, epidemiology of Lyme borreliosis in Europe.
Ann Agric Environ Med. 2005;12:165-72.
Shinjo SK, Gauditano G, Marchiori PE, Bonoldi VLN, Costa IP,
Mantovani E et al. Manifestação neurológica na síndrome
de Baggio-Yoshinari (síndrome brasileira semelhante à
doença de Lyme). Rev Bras Reumatol. 2009;49:13.
Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML,
Yoshinari NH. Description of Lyme disease-like syndrome
in Brazil. Is it a new tick borne disease or Lyme disease
variation? Braz J Med Biol Res. 2007;40:443-56.
Kristoferitsch W. Neurological manifestations of Lyme
borreliosis: clinical definition and differential diagnosis.
Scand J Infect Dis Suppl. 1991;77:64-73.
Schumutzhardt E. Multiple Sclerosis and Lyme borreliosis.
Wien Klin Wochenschr. 2002;114:5.
Yoshinari N, Spolidorio M, Bonoldi VL, Sotto M. Lyme
disease like syndrome associated lymphocytoma: first case
report in Brazil. Clinics (Sao Paulo). 2007;62:525-6.
Simakova AL, Popov AF, Dadalova OB. Ixodes tick-borne
borreliosis with erythema nodosum. Med Parazitol (Mosk).
2005;4:2.
REUMATOLOGIA
Case report
Severe leukopenia in a rheumatoid arthritis patient treated
with a methotrexate/leflunomide combination☆
Paola Toth, Roberto Bernd*
Service of Internal Medicine, Hospital do Servidor Público Estadual (HSPE), São Paulo, SP, Brazil
article info
abstract
Article history:
A rheumatoid arthritis patient was treated for two years with methotrexate and lefluno-
Received 24 August 2011
mide combination therapy. The evolution was uneventful until she had clopidogrel, simv-
astatin, isosorbide, aspirin and omeprazole added to medication due to acute myocardial
infarction. Four weeks after this, she was hospitalized with severe leukopenia.
Keywords:
Arthritis, rheumatoid
Methotrexate
Leukopenia
Polypharmacy
Leucopenia grave em paciente com artrite reumatoide tratada com
combinação de metotrexato e leflunomida
resumo
Palavras-chave:
Apresentamos o caso de uma paciente com artrite reumatoide tratada por dois anos com
Artrite reumatoide
associação de metotrexato e leflunomida. A paciente foi internada com leucopenia grave
Metotrexato
quatro semanas após acrescentar ao esquema medicamentoso as drogas clopidogrel, iso-
Leucopenia
sorbida, sinvastatina, AAS e omeprazol.
Polimedicação
Introduction
Methotrexate (MTX) is considered as a basic drug for most therapeutic regimes for rheumatoid arthritis worldwide.1 However,
its use as monotherapy, or associated only with low dose corticosteroids, is often insufficient for remission induction or to
☆
achieve acceptable levels of disease activity. Therefore, various
combination therapies have been tested in order to increase
the efficiency of MTX. Among these, the association with leflunomide (LEF) proved the most effective, with synergistic effects
demonstrated in several studies.2 Nevertheless, the possibility
of cumulative toxicity of the two drugs is always a concern,
whenever this drug combination is prescribed.
Study conducted at Service of Internal Medicine, Hospital do Servidor Publico Estadual de São Paulo, São Paulo, SP, Brazil.
E-mail: [email protected] (R. Bernd).
Case report
In January 2011, a 68-year-old woman was hospitalized in
the Department of Internal Clinic of HSPE with dyspnea on
exertion, fatigue, lack of appetite, diarrhea, cough, fever and
chills. The patient showed a regular general state and her
admission was justified by the results of a CBC in the emergency department: Hemoglobin (HB): 10 mg/dL (HTC: 31.2,
MCV: 92.3, MCHC: 32.0, RDW: 16.5); leukocytes: 980/mm3
(neutrophils, 500; lymphocytes, 300; eosinophils, 80; and
monocytes, 100); platelets: 182.000/mm3.
Her pathological history revealed rheumatoid arthritis
for six years, mainly with proximal interphalangeal joints,
metacarpophalangeal joints and wrists involved. In January
2008 she started treatment with methotrexate 15 mg weekly
with folic acid supplementation at a dose of 5 mg two days
after taking MTX. In January 2010 the patient had persistent
synovitis in the mentioned joints, requiring 10 mg/day of
prednisone to control the painful symptoms. On this occasion, the addition of leflunomide 20 mg/day started, with reduction of methotrexate to 10 mg weekly and maintenance
of the replacement schedule of folic acid.
With this therapeutic regime, the patient obtained good
clinical response, remission of synovitis and progressive improvement of joint pain. She did not relate significant side
effects during the year of 2010.
In October 2010, her medical record indicated outpatient
care; the patient was virtually symptom free and without synovitis. In this occasion, a CBC yielded the following results:
HB 10.8 mg/dL; leukocytes: 4850/mm3 (neutrophils, 3500;
eosinophils, 200; lymphocytes, 700; and monocytes, 450);
platelets: 290.000/mm3. Liver enzymes values were within
the normal range.
In December 2010, the patient was admitted to the Coronary Care Unit of HSPE with typical precordial pain, and
a diagnosis of acute myocardial infarction (AMI) was confirmed. Due to this event, she began clopidogrel, aspirin, isosorbide, simvastatin and omeprazole continuously, in addition to medication for rheumatoid arthritis, and maintained
this therapeutic regime until new hospitalization, reported
above, four weeks after AMI.
153
In the last follow-up (May, 2011), the patient was asymptomatic, with the following laboratory data: ALT: 12 U/L, AST
13 U/L; hemoglobin: 12.6 mg/dL; MCV 88.3 fL; WBC: 8700/
mm3 (neutrophils, 6700; eosinophils, 300; lymphocytes, 1200;
monocytes, 500); platelets: 398,000.
Discussion
Although not all mechanisms by which MTX exerts its antiinflammatory activity in rheumatoid arthritis are known,
its primary pharmacological action is to block the enzyme
folate reductase by interfering with the synthesis of nucleotides in the purine pathway.
Leflunomide (LEF) inhibits the synthesis of nucleotides
in the pirimidine pathway, with a possible synergistic action
with MTX in reducing the activity of immunocompetent cells.
The concomitant use of MTX and LEF provides additional
benefits, compared to each of these agents as monotherapy.2
However, the combination of MTX with LEF is considered
risky, for there is the possibility of an additive toxicity of
both drugs on liver, lung and bone marrow. For that reason,
their association is formally contraindicated in USA. In Brazil, Australia and New Zealand, many rheumatologic centers
accept this association, which is considered safe in relation
to the possibility of liver toxicity.3 Thus, this combination
was seen as another step in RA therapeutic pyramid.4
In the present case, a LEF-MTX combination showed a
good result in the control of rheumatoid disease, providing
a smooth evolution until a new clinical event (AMI) required
the addition of drugs of common usage for the clinical situation related, but this new circumstance probably interacted in the genesis of myelotoxicity, resulting in leukopenia.
Among the drugs with positive interaction with MTX, we
found ASA5 and omeprazole in the patient’s prescription.
These drugs can increase the persistence and availability of
MTX in plasma.6,7
Progression
REFERENCES
In the ward, the patient received antibiotic coverage according to the protocol for patients with febrile leukopenia. Considering the possibility of myelotoxicity, MTX and LEF were
suspended, the dose of prednisone was increased to 20 mg/
day, and folinic acid was initiated at a dose of 15 mg/day.
On this therapeutic scheme the patient showed rapid improvement. A CBC obtained three days after the beginning
of the replacement with folinic acid showed the following
results: HB: 8.7 mg/dL (HTC 28, MCV 81); leukocytes: 3.130
(neutrophils, 220; eosinophils, 200; lymphocytes, 430; monocytes, 300); platelets: 202,000; VHS: 80.
Given a favorable and constant evolution, the patient was
discharged after 10 days without antibiotics and only with
her heart medication plus folinic acid 15 mg/d and prednisone 5 mg/d.
1. Cronstein B. Methotrexate - the anchor drug - an
introduction. Clin Exp Rheumatol. 2010; (Suppl. 61):S1-S2.
2. Singer O, Gibofsky A. Methotrexate versus leflunomide
in rheumatoid arthritis: what is new in 2011? Curr Opin
Rheumatol 2011;23:288-292.
3. Alves JANR, Fialho SCMS, Morato EF, Castro GRW,
Zimmermann AF, Ribeiro GG, et al. Toxicidade hepática é
rara em pacientes com artrite reumatoide usando terapia
combinada de leflunomida e metotrexato. Rev Bras Reumatol.
2011;51:138-144.
4. Savage RL. Leflunomide in combination therapy for
rheumatoid arthritis. Drug Saf. 2010;33: 523-526.
5. Jacomini LCL, Silva NA. Risks of drug nutrient interaction for
the elderly in long-term care institutions. Rev Bras Reumatol.
2011;51: 161-174.
154
6. Santucci R, Leveque D, Kemmel V, Lutz P, Gérout AC, NGuyen
A, et al. Severe intoxication with methotrexate possibly
associated with concomitant use of proton pump inhibitors.
Anticancer Res. 2010;30:963-966.
7. Bagatini F, Blatt CR, Maliska G, Trepash GV, Pereira
IA, Zimmermann AF, et al. Potenciais interações
medicamentosas em pacientes com artrite reumatoide. Rev
Bras Reumatol. 2011;51:20-39.
REUMATOLOGIA
Case report
Fatal cryptococcal meningitis in a juvenile lupus
erythematosus patient
Erica G. Cavalcantea, João D. Montonib, Guilherme T. Oliveiraa, Lucia M.A. Camposb,
Jose A. Paza, Clovis A. Silvaa,*
a
Unit of Pediatric Rheumatology, Instituto da Criança do Hospital de Clínicas da Faculdade de Medicina da Universidade de São Paulo
(ICr-HC-FMUSP), São Paulo, SP, Brazil
b
Unit of Pediatric Nephrology, Instituto da Criança do Hospital de Clínicas da Faculdade de Medicina da Universidade de São Paulo
(ICr-HC-FMUSP), São Paulo, SP, Brazil
article info
abstract
Article history:
Cryptococcosis is a fungal infection caused by Cryptococcus neoformans, generally associated
Received 3 November 2011
with immunodeficiency and immunosuppressive agents, and it is rarely reported in system-
ic lupus erythematosus (SLE), particularly in juvenile SLE (JSLE). From January 1983 to June
2011, 5,604 patients were followed at our University Hospital and 283 (5%) of them met the
Keywords:
American College of Rheumatology (ACR) classification criteria for SLE. Only one (0.35%) of
Meningitis, cryptococcal
our JSLE patients had cryptococcal meningitis and is described in this report. A 10-year old
Infection
girl was diagnosed with JSLE. By the age of 15 years, she presented persistent headaches,
Lupus erythematosus, systemic
nausea and vomiting for a 5 day period without fever, after a cave-exploring trip. At that
moment, she was under 10 mg/day of prednisone, azathioprine and hydroxychloroquine. A
lumbar puncture was performed and India ink preparation was positive for cryptococcosis,
cerebrospinal fluid culture yielded Cryptococcus neoformans and serum cryptococcal antigen
titer was 1:128. Azathioprine was suspended, and liposomal amphotericin B was introduced.
Despite of treatment, after four days she developed amaurosis and fell into a coma. A computer tomography of the brain showed diffuse ischemic areas and nodules suggesting fungal
infection. Four days later, she developed severe sepsis and vancomycin and meropenem were
prescribed, nevertheless she died due to septic shock. In conclusion, cryptococcal meningitis
is a rare and severe opportunistic infection in juvenile lupus population. This study reinforces the importance of an early diagnosis and prompt introduction of antifungal agents,
especially in patients with history of contact with bird droppings.
E-mail: [email protected] (C.A. Silva).
156
Meningite criptocócica fatal em paciente com lúpus eritematoso
sistêmico juvenil
resumo
Palavras-chave:
Cryptococose é uma infecção fúngica causada pelo Cryptococcus neoformans, geralmente as-
Meningite criptocócica
sociada com imunodeficiências e drogas imunossupressoras, e foi raramente descrita em
Infecção
pacientes com lúpus eritematoso sistêmico (LES), particularmente em LES juvenil (LESJ).
Lúpus eritematoso cutâneo
De janeiro de 1983 a junho de 2011, 5.604 pacientes foram seguidos em nosso Hospital
Universitário e 283 (5%) casos preencheram critérios de classificação diagnóstica do Colégio
Americano de Reumatologia para LESJ. Apenas um (0.35%) destes apresentou meningite
cryptocócica. Esta paciente teve diagnostico de lúpus aos 10 anos de idade. Aos 15 anos, ela
apresentou cefaleia, náuseas e vômitos durante 5 dias, sem febre, após viagem a região de
cavernas. Neste momento, ela estava em uso de prednisona 10 mg/dia, azatioprina e hidroxicloroquina. Foi realizada punção lombar e a tintura da Índia foi positiva para cryptococo,
a cultura do liquido cerebroespinhal também foi positiva para Cryptococcus neoformans e a
pesquisa de antígeno cryptocócico sérico foi positiva em título de 1:280. Azatioprina foi suspensa e anfotericina B liposomal (3 mg/Kg/dia) foi iniciada. No entanto, quatro dias após ela
desenvolveu amaurose e coma. A tomografia computadorizada de crânio demonstrou áreas
isquêmicas e nódulos sugestivos de infecção fúngica. Após quatro dias, ela desenvolveu
sepse grave e vancomicina e meropenem foram iniciados, entretanto foi a óbito devido choque séptico. Portanto, meningite cryptocócica foi uma rara e grave infecção oportunista em
uma população de lúpus juvenil. Este estudo reforça a importância do diagnóstico precoce
e da pronta introdução de agentes antifúngicos, principalmente em pacientes com história
de contato com excrementos de pássaros.
Introduction
Infections are frequently observed in systemic lupus erythematosus (SLE) patients with high morbidity and mortality
rates, and bacteria, virus, protozoa and fungi are considered
the main cause.1,2
Cryptococcosis is a fungal infection caused by Cryptococcus neoformans, associated generally with primary or secondary immunodeficiency and with immunosuppressive agents.3
The central nervous system (CNS) is the most common site of
infection,3 with insidious and non-specific signs and symptoms of meningitis.4 Worthy of note, cryptococcocal infection
is rarely reported in adults with SLE,5-10 especially in juvenile
SLE (JSLE) patients.4,8
From January 1983 to June 2011, from 5,604 patients in
follow-up at the Pediatric Rheumatology Unit of the Instituto
da Criança da Faculdade de Medicina da Universidade de São
Paulo, 283 (5%) of them met the American College of Rheumatology (ACR)11 classification criteria for SLE. Only one (0.35%)
of our JSLE patients had cryptococcal meningitis and is described herein. This study was approved by the Local Ethics
Committee of our University Hospital.
Case report
A 10-year old girl was diagnosed with JSLE based on malar
rash, photosensitivity, oral ulcers, antinuclear antibodies
(ANA) (1/200, dense fine speckled pattern), and the presence of anti-double-stranded DNA (anti-dsDNA) and anti-
Sm antibodies, fulfilling the ACR classification criteria for
SLE.11 At that moment, her SLE Disease Activity Index 2000
(SLEDAI-2K)12 was 6 and she was treated with prednisone
(2.0 mg/kg/day), progressively diminished to 10 mg/day, and
hydroxychloroquine. At the age of 14, she was hospitalized
due to arthritis in the knees, malar rash, cutaneous vasculitis
(tender finger nodules in hands and lower limbs) and arterial hypertension. Her laboratory exams revealed hemoglobin 11.5 mg/L, hematocrit 34%, white blood cell count 7,200/
mm3 (84% neutrophils, 8% lymphocytes, 1% eosinophils and
7% monocytes), platelets 180,000/mm3, proteinuria (0.5 g/24h),
abnormal urinalysis (81,000 leukocytes/mL, 21,000 erythrocytes/mL and granular casts), urea 52 mg/dL (normal 10-42),
creatinine 0.8 mg/dL (normal 0.6-0.9), C3 0.15mg/dL (normal
0.5-1.8) and C4 0.01 mg/dL (normal 0.1-0.4). The erythrocyte
sedimentation rate was 33mm/1st hour and C-reactive protein
7.9 mg/dL (normal < 5). Immunological tests showed positive
anti-dsDNA and negative lupus anticoagulant, IgG and IgM
anticardiolipin antibodies, and her SLEDAI-2K12 was 32. Renal
biopsy showed diffuse proliferative lupus nephritis (class IV
of the World Health Organization - WHO classification). She
was treated with three pulses of intravenous methylprednisolone associated with seven monthly sessions of intravenous
cyclophosphamide (IVCYC (0.5-1.0 g/m2/month)) following
this treatment every 3 months for six months. At the age of
15 years, she was treated with azathioprine (3.0 mg/kg/day).
After 3 months, she displayed persistent headaches, nausea
and vomiting for 5 days, that started twenty days after a trip
to a cave region in the rural zone of São Paulo state, Brazil.
She was promptly hospitalized due to severe headache, vomiting, lethargy, arterial hypertension and nuchal rigidity. She
did not have fever. At that moment, she was under 10 mg/
day of prednisone, azathioprine and hydroxychloroquine.
Laboratory tests revealed hemoglobin 13.3 mg/L, hematocrit
40%, white blood cell count 10,300/mm3 (94% neutrophils, 2%
lymphocytes and 4% monocyte), platelets 127,000/mm3, proteinuria (1.25 g/24h), urea 48 mg/dL, creatinine 0.6 mg/dL, C3
0.6 mg/dL and C4 0.09 mg/dL. Immunological tests were negative for anti-dsDNA, lupus anticoagulant, and IgG and IgM anticardiolipin antibodies. The SLEDAI-2K was 6. A lumbar puncture was performed with opening pressure of 48 cm H2O and
cerebrospinal fluid (CSF) analysis showed a white blood cell
count of 500/mm3 (mononuclear cells 26% and neutrophils
74%), hyperproteinorrhachia (66 mg/dL) and hypoglycorrhachia (16 mg/dL in CSF to 94 mg/dL in serum). A CSF India ink
preparation was positive for Cryptococcus, CSF culture yielded
Cryptococcus neoformans and serum cryptococcal antigen titer
by latex agglutination method was 1:128 (normal < 1:10). The
computed tomography (CT) scan of the brain was normal.
Azathioprine was suspended, and liposomal amphotericin
B (3 mg/Kg/day) was promptly introduced. However, despite
this treatment, four days later she developed amaurosis with
optical nerve atrophy followed by a coma. At that moment,
the brain CT scanning showed diffuse ischemic areas and
nodules suggesting fungal infection. After four days, she presented fever, bacterial pneumonia and severe sepsis. Vancomycin and meropenem treatment started and she required
invasive mechanical ventilation. She died due to septic shock
three days later.
Discussion
We reported a single case of fatal cryptococcal meningitis in
a large population of JSLE, showing the rare frequency of this
fungal infection. Importantly, in all of our lupus patients with
clinical signs and symptoms of meningitis, we promptly have
been indicated brain CT scanning and CSF analysis. In our
Pediatric University Hospital, routine evaluation of CSF in all
JSLE patients with the above clinical findings include an India
ink preparation.
Cryptococcosis is a life-threatening fungal infection
caused by Cryptococcus neoformans, acquired mainly by inhalation of aerosolized particles,4,8 associated with birds droppings, particularly pigeon, and bats droppings.13 This infection
is habitually insidious4 and its symptoms range from asymptomatic disease, limited to the lung, to severe infection,3,4 as
observed in our case.
Almost all symptoms of cryptococcal meningitis such as
headaches, vomiting and nausea, are nonspecific and so it
could be confused with active CNS manifestation of lupus.4,5,8,9
Our patient presented persistent and severe headaches, associated to vomiting and meningeal sign, which led to the
suspicion of CNS infection even when clinically afebrile, with
prompt diagnose and treatment. However, the five days prior
to the onset of symptoms certainly were decisive to the unfavorable outcome.
Worthy of note, is that high mortality by this fungal infection has been described in immunosuppressed patients, such
as adult and pediatric lupus erythematosus patients.5-9 The
main predisposing factors for symptomatic and severe infec-
157
tion were the use of steroids and immunosuppressive agents
(especially cyclophosphamide and azathioprine)3,4,5,6,7,8 and a
high SLEDAI score,4,6,7 as observed herein. Likewise, intrinsic
immunological abnormalities in humoral and cellular function seen in lupus patients may contribute to this opportunistic infection.14
The elevated opening pressure upon lumbar puncture5,8,11
and CSF analysis found in this infection is rather similar to
tuberculosis and viral meningitis.4,8 Remarkably, the diagnosis
of Cryptococcus neoformans meningitis should be confirmed by
the identification of this fungi in Indian ink preparation and/
or by a positive culture in CSF analysis. Additionally, cryptococcal antigen in the blood or and CSF may help the diagnosis.4,5,8,9 Intracranial massive lesions may also be evidenced in
CNS of these patients,13 as observed in the brain CT scan of
the present case.
The treatment of CNS cryptococcosis includes amphotericin B alone or associated with flucytosine. The mechanisms
of these drugs are disruption of fungal cell membrane and
inhibition of fungal DNA and protein synthesis, respectively.13
Death due to this cryptococcal meningoencephalitis in SLE is
rare in the literature.6,7 The main causes of mortality in SLE
with this infection are meningitis and septic shock,6 as evidenced in our case. Unfortunately, the family did not give permission to perform necropsy.
In conclusion, cryptococcal meningitis is a rare and severe
opportunistic infection in pediatric lupus population. This
study reinforces the importance of an early diagnosis and
prompt introduction of antifungal agents, especially in patients with ahistory of contact with bird droppings.
Acknowledgements
This study was supported by Fundação de Amparo à Pesquisa
do Estado de São Paulo - FAPESP (grant #08/58238-4 to CAS)
and by CNPQ (302724/2011-7 to CAS to CAS), Federico Foundation to CAS and by Núcleo de Apoio à Pesquisa “Saúde da
Criança e do Adolescente” da USP (NAP-CriAd).
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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 2 ) : 1 5 9
REUMATOLOGIA
Erratum
Erratum of the erratum of “Guidelines for the diagnosis of
rheumatoid arthritis”
Errata da errata de “Diretrizes para o diagnóstico da artrite reumatoide”
Licia Maria Henrique da Motaa,*, Bóris Afonso Cruza, Claiton Viegas Brenola,
Ivânio Alves Pereiraa, Lucila Stange Rezende-Fronzaa, Manoel Barros Bertoloa,
Max Vitor Carioca Freitasa, Nilzio Antônio da Silvaa, Paulo Louzada-Juniora,
Rina Dalva Neubarth Giorgia, Rodrigo Aires Corrêa Limaa, Ronaldo Adib Kairallab,
Alexandre de Melo Kawassakib, Wanderley Marques Bernardoc,
Geraldo da Rocha Castelar Pinheiroa
a
Sociedade Brasileira de Reumatologia, São Paulo, SP, Brazil
Sociedade Brasileira de Pneumologia e Tisiologia, Brasília, DF, Brazil
c
Associação Médica Brasileira, São Paulo, SP, Brazil
b
In the erratum of the original article “Guidelines for the diagnosis of rheumatoid arthritis” (Rev Bras Reumatol 2013;53(2):141157) published in Rev Bras Reumatol 2013;53(3):318, where it reads:
Licia Maria Henrique da Motaa,*, Bóris Afonso Cruza, Claiton Viegas Brenola, Ivânio Alves Pereiraa, Lucila Stange Rezende-Fronzaa, Manoel
Barros Bertoloa, Max Vitor Carioca Freitasa, Nilzio Antônio da Silvaa, Paulo Louzada-Juniora, Rina Dalva Neubarth Giorgia, Rodrigo Aires Corrêa Limaa, Ronaldo Adib Kairallab, Alexandre de Melo Kawassakib, Wanderley Marques Bernardoc, Geraldo da Rocha Castelar Pinheiroa
a
c
b
It should read:
Licia Maria Henrique da Motaa,*, Bóris Afonso Cruza, Claiton Viegas Brenola, Ivânio Alves Pereiraa, Lucila Stange Rezende-Fronzaa, Manoel
Barros Bertoloa, Max Vitor Carioca Freitasa, Nilzio Antônio da Silvaa, Paulo Louzada-Juniora, Rina Dalva Neubarth Giorgia, Rodrigo Aires Corrêa Limaa, Ronaldo Adib Kairallab, Alexandre de Melo Kawassakib, Wanderley Marques Bernardoc, Geraldo da Rocha Castelar Pinheiroa
a
c
b
E-mail: [email protected] (L.M.H. Mota).
REUMATOLOGIA
Erratum
Erratum of “Adalimumab in rheumatoid arthritis treatments:
a systematic review and meta-analysis of randomized clinical
trials”
Errata de “Adalimumabe no tratamento da artrite reumatoide: uma revisão
sistemática e metanálise de ensaios clínicos randomizados”
Marina Amaral de Ávila Machadoa,*, Alessandra Almeida Maciela,
Lívia Lovato Pires de Lemosb, Juliana Oliveira Costaa, Adriana Maria Kakehasic,
Eli Iola Gurgel Andraded, Mariangela Leal Cherchigliae, Francisco de Assis Acurciof
a
Post-Graduation Program in Public Health, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Post-Graduation Program in Medications and Pharmaceutical Care, School of Pharmaceutical Sciences, Universidade Federal de Minas
Gerais, Belo Horizonte, MG, Brazil
c
Department of Musculoskeletal System, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
d
Post-Graduation Program in Demographics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
e
Post-Graduation Program in Public Health, Universidade de São Paulo, São Paulo, SP, Brazil
f
Post-Graduation Program in Animal Sciences, School of Veterinary Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
b
The article “Adalimumab in rheumatoid arthritis treatments: a systematic review and meta-analysis of randomized clinical
trials” (Rev Bras Reumatol 2013;53(5):419-430) was wrongly classified as an original article, but should be considered a review
article instead.
E-mail: [email protected] (M.A.A. Machado).
REUMATOLOGIA
Erratum
Erratum of “Psychiatric comorbidities in patients with systemic
lupus erythematosus: a systematic review of the last 10 years”
Errata de “Comorbidades psiquiátricas em pacientes com lúpus eritematoso: uma
revisão sistemática dos últimos 10 anos”
Nadja Maria Jorge Asanoa,*, Maria das Graças Wanderley de Sales Coriolanob, Breno Jorge
Asanoc, Otávio Gomes Linsd
a
Department of Internal Medicine, Universidade Federal de Pernambuco, Recife, PE, Brazil
Department of Anatomy, Universidade Federal de Pernambuco, Recife, PE, Brazil
c
School of Medicine, Universidade Federal de Pernambuco, Recife, PE, Brazil
d
Department of Neuropsychiatry, Universidade Federal de Pernambuco, Recife, PE, Brazil
b
The article “Psychiatric comorbidities in patients with systemic lupus erythematosus: a systematic review of the last 10 years”
(Rev Bras Reumatol 2013;53(5):431-437) was wrongly classified as an original article, but should be considered a review article
instead.
E-mail: [email protected]; [email protected] (N.M.J. Asano).
REUMATOLOGIA
Erratum
Erratum of “Enteropathic arthritis in Brazil: data from the
Brazilian registry of spondyloarthritis”
Errata de “Artrite enteropática no Brasil: dados do Registro Brasileiro de
Espondiloartrites”
Gustavo G. Resende a,*, Cristina C. D. Lannaa, Adriana B. Bortoluzzob, Célio R. Gonçalvesc,
Percival D. Sampaio -Barrosc, José Antonio Braga da Silvad, Antonio Carlos Ximenese,
Manoel B. Bértolo f, Sandra L.E. Ribeiro g, Mauro Keisermanh, Rita Menini,
Thelma L. Skare j, Sueli Carneirok, Valderílio F. Azevedol, Walber P. Vieiram,
Elisa N. Albuquerquen, Washington A. Bianchio, Rubens Bonfiglioli p,
Cristiano Campanholoq, Hellen M. S. Carvalhor, Izaias P. Costas, Angela P. Duartet,
Charles L. Kohemu, Nocy Leitev, Sonia A. L. Limaw, Eduardo S. Meirelles x,
Ivânio A. Pereiray, Marcelo M. Pinheiro z, Elizandra Polito A, Francisco Airton C. RochaB,
Mittermayer B. SantiagoC, Maria de Fátima L. C. SaumaD, Valeria ValimE
a
Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
Instituto Insper de Educação e Pesquisa, São Paulo, SP, Brasil
c
Disciplina de Reumatologia, Universidade de São Paulo, São Paulo, SP, Brasil
d
Universidade de Brasília, Brasília, DF, Brasil
e
Hospital Geral de Goiânia, Goiânia, GO, Brasil
f
Universidade de Campinas, Campinas, SP, Brasil
g
Universidade Federal do Amazonas, Manaus, AM, Brasil
h
Pontifícia Universidade Católica, Porto Alegre, RS, Brasil
i
Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brasil
j
Hospital Evangélico de Curitiba, Curitiba, PR, Brasil
k
Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
l
Universidade Federal do Paraná, Curitiba, PR, Brasil
m
Hospital Geral de Fortaleza, Fortaleza, CE, Brasil
n
Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
o
Santa Casa do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
p
Pontifícia Universidade Católica, Campinas, SP, Brasil
q
Santa Casa de São Paulo, São Paulo, SP, Brasil
r
Hospital de Base, Brasília, DF, Brasil
s
Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brasil
t
Universidade Federal de Pernambuco, Recife, PE, Brasil
u
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
v
Faculdade de Medicina Souza Marques, Rio de Janeiro, RJ, Brasil
w
Hospital do Servidor Público Estadual, São Paulo, SP, Brasil
b
E-mail: [email protected] (G.G. Rezende).
163
x
Instituto de Ortopedia e Traumatologia, Universidade de São Paulo, São Paulo, SP, Brasil
Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil
z
Universidade Federal de São Paulo, São Paulo, SP, Brasil
A
Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil
B
Universidade Federal do Ceará, Fortaleza, CE, Brasil
C
Escola de Medicina e Saúde Pública, Salvador, BA, Brasil
D
Universidade Federal do Pará, Belém, PA, Brasil
E
Universidade Federal do Espírito Santo, Vitória, ES, Brasil
y
In the original article “Enteropathic arthritis in Brazil: data from the Brazilian registry of spondyloarthritis” (Rev Bras Reumatol
2013;53(6):452-459), where it reads:
Gustavo G. Resendea,*, Cristina C. D. Lannaa, Adriana B. Bortoluzzob, Célio R. Gonçalvesc, Percival D. Sampaio-Barrosc, José Antonio Braga da
Silvad, Antonio Carlos Ximenese, Manoel B. Bértolof, Sandra L.E. Ribeirog, Mauro Keisermanh, Rita Menini, Thelma L. Skarej, Sueli Carneirok,
Valderílio F. Azevedol, Walber P. Vieiram, Elisa N. Albuquerquen, Washington A. Bianchio, Rubens Bonfigliolip, Cristiano Campanholoq, Hellen
M. S. Carvalhor, Izaias P. Costas, Angela P. Duartet, Charles L. Kohemu, Nocy Leitev, Sonia A. L. Limaw, Eduardo S. Meirellesx, Ivânio A. Pereiray,
Marcelo M. Pinheiroz, Elizandra PolitoA, Francisco Airton C. RochaB, Mittermayer B. SantiagoC, Maria de Fátima L. C. SaumaD, Valeria ValimE
a
Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Instituto Insper de Educação e Pesquisa, São Paulo, SP, Brazil
c
Disciplina de Reumatologia, Universidade de São Paulo, São Paulo, SP, Brazil
d
Universidade de Brasília, Brasília, DF, Brazil
e
Hospital Geral de Goiânia, Goiânia, GO, Brazil
f
Universidade de Campinas, Campinas, SP, Brazil
g
Universidade Federal do Amazonas, Manaus, AM, Brazil
h
Pontifícia Universidade Católica, Porto Alegre, RS, Brazil
i
Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil
j
Hospital Evangélico de Curitiba, Curitiba, PR, Brazil
k
Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
l
m
Hospital Geral de Fortaleza, Fortaleza, CE, Brazil
n
Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
o
Santa Casa do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
p
Pontifícia Universidade Católica, Campinas, SP, Brazil
q
Santa Casa de São Paulo, São Paulo, SP, Brazil
r
Hospital de Base, Brasília, DF, Brazil
s
Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brazil
t
Universidade Federal de Pernambuco, Recife, PE, Brazil
u
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
v
Faculdade de Medicina Souza Marques, Rio de Janeiro, RJ, Brazil
w
Hospital do Servidor Público Estadual, São Paulo, SP, Brazil
x
Instituto de Ortopedia e Traumatologia, Universidade de São Paulo, São Paulo, SP, Brazil
y
Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
z
A
Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
B
C
Escola de Medicina e Saúde Pública, Salvador, BA, Brazil
D
Universidade Federal do Pará, Belém, PA, Brazil
E
Universidade Federal do Espírito Santo, Vitória, ES, Brazil
b
It should read:
Gustavo G. Resendea,*, Cristina C. D. Lannaa, Adriana B. Bortoluzzob, Célio R. Gonçalvesc, José Antonio Braga da Silvad, Antonio Carlos Ximenese, Manoel B. Bértolof, Sandra L.E. Ribeirog, Mauro Keisermanh, Rita Menini, Thelma L. Skarej, Sueli Carneirok, Valderílio F. Azevedol, Walber
P. Vieiram, Elisa N. Albuquerquen, Washington A. Bianchio, Rubens Bonfigliolip, Cristiano Campanholoq, Hellen M. S. Carvalhor, Izaias P. Costas,
Angela P. Duartet, Charles L. Kohemu, Nocy Leitev, Sonia A. L. Limaw, Eduardo S. Meirellesx, Ivânio A. Pereiray, Marcelo M. Pinheiroz, Elizandra
PolitoA, Francisco Airton C. RochaB, Mittermayer B. SantiagoC, Maria de Fátima L. C. SaumaD, Valeria ValimE, Percival D. Sampaio-Barrosc
164
a
Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
Instituto Insper de Educação e Pesquisa, São Paulo, SP, Brasil
c
Disciplina de Reumatologia, Universidade de São Paulo, São Paulo, SP, Brasil
d
Universidade de Brasília, Brasília, DF, Brasil
e
Hospital Geral de Goiânia, Goiânia, GO, Brasil
f
Universidade de Campinas, Campinas, SP, Brasil
g
Universidade Federal do Amazonas, Manaus, AM, Brasil
h
Pontifícia Universidade Católica, Porto Alegre, RS, Brasil
i
Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brasil
j
Hospital Evangélico de Curitiba, Curitiba, PR, Brasil
k
Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
l
Universidade Federal do Paraná, Curitiba, PR, Brasil
m
Hospital Geral de Fortaleza, Fortaleza, CE, Brasil
n
Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
o
Santa Casa do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
p
Pontifícia Universidade Católica, Campinas, SP, Brasil
q
Santa Casa de São Paulo, São Paulo, SP, Brasil
r
Hospital de Base, Brasília, DF, Brasil
s
Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brasil
t
Universidade Federal de Pernambuco, Recife, PE, Brasil
u
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
v
Faculdade de Medicina Souza Marques, Rio de Janeiro, RJ, Brasil
w
Hospital do Servidor Público Estadual, São Paulo, SP, Brasil
x
Instituto de Ortopedia e Traumatologia, Universidade de São Paulo, São Paulo, SP, Brasil
y
Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil
z
Universidade Federal de São Paulo, São Paulo, SP, Brasil
A
Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil
B
Universidade Federal do Ceará, Fortaleza, CE, Brasil
C
Escola de Medicina e Saúde Pública, Salvador, BA, Brasil
D
Universidade Federal do Pará, Belém, PA, Brasil
E
Universidade Federal do Espírito Santo, Vitória, ES, Brasil
b

RBR 54(2) - Sociedade Brasileira de Reumatologia

Transcription

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