BRAZILIAN JOURNAL OF RHEUMATOLOGY • JAN/FEB | REVISTA BRASILEIRA DE REUMATOLOGIA JAN/FEV | VOL. 55 • N. 1 | 2015
ISSN 0482-5004
Impact Factor 2013: 0.993
© Thomson Reuters Journal Citation Reports,
Science Edition (2013)
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
JANUARY/FEBRUARY 2015 • Volume 55 • Number 1
JANEIRO/FEVEREIRO 2015 • Volume 55 • Número 1
ELSEVIER
www.reumatologia.com.br
REVISTA BRASILEIRA DE REUMATOLOGIA
BRAZILIAN JOURNAL OF RHEUMATOLOGY
Official Organ of Brazilian Society of Rheumatology
Órgão Oficial da Sociedade Brasileira de Reumatologia
Bimonthly Edition (Publicação Bimestral)
Editors (Editores)
Coeditors (Coeditores)
Max Victor Carioca Freitas
Eloísa Silva Dutra de Oliveira Bonfá
Mittermayer Barreto Santiago
Roberto Ezequiel Heymann
Hilton Seda
Paulo Louzada-Junior
Universidade Federal do Ceará, Fotaleza, CE, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil
Pontifícia Universidade Católica do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
João Carlos Tavares Brenol
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Ricardo Fuller
Simone Appenzeller
Universidade Estadual de Campinas, Campinas, SP, Brazil
Editorial Board (Conselho Editorial)
Acir Rachid
Geraldo da Rocha Castelar Pinheiro
Universidade Federal do Paraná, Curitiba, PR, Brazil
Universidade do Estado do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Adil Muhib Samara
Universidade Estadual de Campinas, Campinas, SP, Brazil
Gilberto Santos Novaes
Alexandre Wagner S Souza
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Pontifícia Universidade Católica de São Paulo,
São Paulo, SP, Brazil
Ari Stiel Radu
Isídio Calich
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade de São Paulo, São Paulo, SP, Brazil
Carlos Alberto von Muhlen
Ivânio Alves Pereira
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 de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Cláudio Arnaldo Len
João Francisco Marques Neto
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Clóvis Artur Almeida da Silva
Universidade de São Paulo, São Paulo, SP, Brazil
Cristiano Augusto de Freitas Zerbini
Hospital Heliópolis, São Paulo, SP, Brazil
Daniel Feldman Polak
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Durval Kraychete
Escola Bahiana de Medicina e Universidade
Federal da Bahia, Salvador, BA, Brazil
Eduardo de Souza Meireles
Universidade de São Paulo, São Paulo, SP, Brazil
Eduardo Ferreira Borba Neto
Universidade Estadual de Campinas, Campinas, SP, Brazil
Maurício Levy Neto
Universidade de São Paulo, São Paulo, SP, Brazil
Milton Helfenstein Jr.
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Natalino H. Yoshinari
Universidade de São Paulo, São Paulo, SP, Brazil
Nílzio Antônio da Silva
Universidade Federal de Goiás, Goiânia, GO, Brazil
Percival Degrava Sampaio-Barros
Universidade de São Paulo, São Paulo, SP, Brazil
Ricardo M. Xavier
Universidade Federal do Rio Grande do Sul,
Porto Alegre, RS, Brazil
Rina Dalva P. N. Giorgi
José Goldenberg
Hospital do Servidor Público Estadual de São Paulo
"Francisco Morato de Oliveira", São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Roger A. Levy
José Roberto Provenza
Universidade Estadual do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
Jozélio Freire de Carvalho
Centro Médico Aliança, Salvador, BA, Brazil
Lais V. Lage
Universidade de São Paulo, São Paulo, SP, Brazil
Lilian Tereza Lavras Costallat
Universidade Estadual de Campinas, Campinas, SP, Brazil
Luís Eduardo Coelho Andrade
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Emília Inoue Sato
Luiz Fernando de Souza Passos
Rosa Maria Rodrigues Pereira
Universidade de São Paulo, São Paulo, SP, Brazil
Rozana Mesquita Ciconelli
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Samuel Katsuyki Shinjo
Universidade de São Paulo, São Paulo, SP, Brazil
Sebastião Cézar Radominski
Universidade Federal do Paraná, Curitiba, PR, Brazil
Sheila Knupp de Oliveira
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Federal do Amazonas, Manaus, AM, Brazil
Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ, Brazil
Fernanda Rodrigues de Lima
Marcelo de Medeiros Pinheiro
Simone Appenzeller
Universidade de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade de Campinas, Campinas, SP, Brazil
Fernando Queiroz da Cunha
Maria Odete E. Hilário
Vera Lúcia Szejnfeld
Universidade de São Paulo, Ribeirão Preto, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Universidade Federal de São Paulo, São Paulo, SP, Brazil
Francisco Airton Castro Rocha
Marta Maria das Chagas Medeiros
Wiliam H. Chahade
Universidade Federal do Ceará, Fortaleza, CE, Brazil
Universidade Federal do Ceará, Fortaleza, CE, Brazil
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. © 2015.
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. © 2015.
Todos os direitos reservados e protegidos pela lei 9.610 - 19/02/98. Nenhuma parte desta
publicação poderá ser reproduzida, sem autorização prévia, por escrito, da Elsevier
Editora Ltda. e da SBR, sejam quais forem os meios empregados: eletrônicos, mecânicos,
fotográficos, gravação ou quaisquer outros.
A RBR recebe auxílio financeiro de Fundos Remanescentes da Sociedade Brasileira de
Reumatologia.
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Content dedicated to the medical community. Material de distribuição exclusiva à classe médica.
INSTRUCTIONS TO AUTHORS
The Brazilian Journal of Rheumatology (BJR), an official organ of Sociedade
Brasileira de Reumatologia (Brazilian Society of Rheumatology), was founded
in 1957 and is published bimonthly. The journal publishes original articles,
review articles, brief communications, case reports and letters to the editors.
To submit a manuscript, please access the site http://ees.elsevier.com/bjr.
Format of the manuscript
The manuscript can be submitted in Portuguese or English, double spaced,
with 2.5 cm margins. Unconventional abbreviations, medical jargon and
telegraphic style should not be used in the text. Citation of drugs and
pharmaceutical products must be done using pharmacological nomenclature,
without any mention to commercial names.
Manuscript structure
Manuscript*, Title Page*, Cover Letter, and Author Agreement* must be
submitted in separate files. Tables and Figures should be numbered as cited
in the text and sent in separate files with corresponding titles and legends.
(*required files)
Title page
The title page should contain: a) the full title; b) the full name of the authors
and their most important academic degree; c) the department and institution
where the study was originated; d) the full address and e-mail of the
corresponding author; e) conflict of interest and relevant financial agencies;
f) a running title with no more than 60 characters.
Author Agreement
It is the document where the authors declare that the manuscript is original, in
addition to approve the manuscript object of the submission, the authorship
and the order of authors listed. It must be signed by all authors. Below is
presented an example.
Dear Editor,
We, the undersigned, declare that this manuscript is original, has not been
published before and is not currently being considered for publication elsewhere.
We would like to draw the attention of the Editor to the following publications
of one or more of us that refer to aspects of the manuscript presently being
submitted.
We confirm that the manuscript has been read and approved by all named
authors and that there are no other persons who satisfied the criteria for
authorship but are not listed. We further confirm that the order of authors
listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the
Editorial process. He/she is responsible for communicating with the other
authors about progress, submissions of revisions and final approval of proofs.
(Signature of all authors)
Original article
The original article should contain: the title page, the abstract page with
keywords, introduction, material and methods or patients and methods, results
and discussion, acknowledgements, references, tables, figures and figure
legends. Original articles should not exceed 5,000 words including references
and excluding the title page, abstract, tables and legends. It is allowed up to
six figures or tables and 50 references.
Abstract page
The abstract page should contain: a) objective, methods, results and
conclusions, with no more than 250 words; b) three to five keywords.
Introduction
As the aim of this section is to define the purpose and the reasons for the
accomplishment of the work, we do not recommend a large literature review.
Patients and methods or Material and methods
This section should include enough information that allows the reproduction of
the work and, when it is relevant, the approval by the institutional Committee
of Ethics. The methods employed in the statistical analysis should always
be quoted.
Results
They should be clear and concise. Tables and graphics should not duplicate
information.
Discussion
It should be concise, interpreting the results in the context of the present literature.
Please do not exceed the limit of half the number of pages of the complete work.
Acknowledgments
Only to people who contributed; i.e., with techniques, discussion and sending
patients. Financial help should be referred in the title page.
References
They should be quoted in the text in Arabic numerals, superscript, with no brackets.
Numbering should be sequencial, according to the quotation order in the text.
Please quote all the authors in works with until six authors; after six authors,
quote the first six followed by the expression et al. Reference Manager or Endnote
programs are strongly recommended for use adopting the Vancouver style.
Examples for reference citation are presented below. Authors should consult
NLM’s Citing Medicine for additional information on the reference formats.
Printed article
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Reference retrieved from electronic address
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink. com.w10069.dotlib.com.
br/content/l05j4j3332041225/fulltext.pdf. [Accessed in February 24, 2008].
Book
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical
microbiology. 4th ed. St. Louis: Mosby; 2002.
Tables and figures
Each Table or Figure should be numbered with Arabic numerals and sent in
an individual file (.jpg, .tif, .png, .xls, .doc) with minimum of 300 dpi. Titles
and legends should be in the same Table/Figure file to wich they refer. Tables
and Figures should include enough information so the reader can understand
them without going to the text.
Photomicrographies should include the appropriated scale.
Review article
Reviews, preferentially systematic, may be submitted to BJR. They should
cover deeply any interesting theme for the rheumatologist. They do not present
a standard structure, neither introduction or conclusion. Please send abstracts
without subdivisions with three to five keywords. Review articles should not
exceed 6,000 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to five figures or tables and 70 references.
Case report
Must have six authors at most. They should include an abstract and keywords,
without subdivisions. The text, however, should present the following sections:
introduction, which should be concise; case report, containing the description and
the evolution of the clinical case, laboratory exams, illustrations and tables (that
substitute the sections material and methods and results); and discussion. It should
not exceed 1,500 words including references and excluding the title page, abstract,
tables and legends. It is allowed up to two figures or tables and 15 references.
Brief communication
It covers a point or a specific detail. It should present an abstract with no
more than 250 words and three to five keywords. The text does not include
subdivisions, and should not exceed 2,500 words including references and
excluding the title page, abstract, tables and legends. It is allowed up to three
figures or tables and 25 references.
Rules for applying the appropriate tense in scientific writing
Context or section
Appropriate verb tense
Abstract
Past tense
Introduction
Most present tense (established facts,
previous published data)
Methods, materials used,
and results
Past tense
Discussion/Conclusion
Mixture of past and present, sometimes
future tense
Attribution
Past tense
Ex.: Andrade et al. reported that...
Description of Tables and
Figures
Present tense
Established knowledge,
previous results etc.
Present tense
General rules to obtain a good scientific writing:
1. Use active voice.
2. Setences must be short, clear and objective.
3. Units of measurement are abbreviated when use with numerical values
(e.g., 1 mg), but are not abbreviated if used without numerical values.
Systeme International d'Únites (SI units) must be used. Remember to
leave a space between the number and unit (e.g., 10 mg/dL), except for
the percentage mark that follows the number without space (e.g., 70%).
The plural form of units of measurement is the same as the singular form
(e.g., 1 mL, 10 mL; 1 h, 10 h). Spell out numbers at the beginning of a
sentence.
4. Define abbreviations the first time they appear. Avoid abbreviations in
tittles and abstracts.
5. Do not use contractions (e.g., doesn't, can't etc.).
Recommended book: Rogers SM. Mastering scientific and medical writing:
a self-help guide. Berlin: Springer; 2007.
Legal and ethical considerations
According to the Uniform Requirements for Manuscripts Submitted to
Biomedical Journals (International Committee of Medical Journal Editors –
February 2006).
Conflict of interest
Public trust in the peer review process and the credibility of published
articles depend in part on how well conflict of interest is handled during
writing, peer review, and editorial decision making. Conflict of interest
exists when an author (or the author’s institution), reviewer, or editor has
financial or personal relationships that inappropriately influence (bias) his
or her actions (such relationships are also known as dual commitments,
competing interests, or competing loyalties). These relationships vary
from those with negligible potential to those with great potential to
influence judgment, and not all relationships represent true conflict of
interest. The potential for conflict of interest can exist whether or not
an individual believes that the relationship affects his or her scientific
judgment. Financial relationships (such as employment, consultancies,
stock ownership, honoraria, paid expert testimony) are the most easily
identifiable conflicts of interest and the most likely to undermine the
credibility of the journal, the authors, and of science itself. However,
conflicts can occur for other reasons, such as personal relationships,
academic competition, and intellectual passion.
Informed consent
Patients have a right to privacy, that should not be infringed without
informed consent. Identifying information, including patients’ names,
initials, or hospital numbers, should not be published in written descriptions,
photographs, and pedigrees unless the information is essential for scientific
purposes and the patient (or parent or guardian) gives written informed
consent for publication. Informed consent for this purpose requires that a
patient who is identifiable be shown the manuscript to be published. Authors
should identify Individuals who provide writing assistance and disclose the
funding source for this assistance. Identifying details should be omitted if
they are not essential.
Complete anonymity is difficult to achieve. However, an informed consent
should be obtained if there is any doubt. For example, masking the eye
region in photographs of patients is inadequate protection of anonymity. If
identifying characteristics are altered to protect anonymity, such as in genetic
pedigrees, authors should provide assurance that alterations do not distort
scientific meaning and editors should so note. When informed consent has
been obtained it should be indicated in the published article.
Ethical treatment
When reporting experiments on human subjects, authors should indicate
whether the procedures followed were in accordance with the ethical
standards of the responsible committee on human experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as
revised in 2000. If doubt exists whether the research was conducted in
accordance with the Helsinki Declaration, the authors must explain the
rationale for their approach, and demonstrate that the institutional review
body explicitly approved the doubtful aspects of the study. When reporting
experiments on animals, authors should be asked to indicate whether the
institutional and national guide for the care and use of laboratory animals
was followed.
Clinical trials registry
Clinical trials must be registered according to WHO recommendation at www.
who.int/ictrp/en/. The definition of clinical trial include preliminary trials
(phase I): any study with prospective recruiting of subjects to undergo any
health-related intervention (drugs, surgical procedures, equipment, behavioral
therapies, food regimen, changes in health care) to evaluate the effects on
clinical outcomes (any biomedical or health-related parameter, including
pharmacokinetics measurements and adverse reactions).
The BJR has the right not to publish trials not complying with these and
other legal and ethical standards determined by international guidelines.
Financing and support
The authors should also inform if they received financing or support
from institutions like CNPq, CAPES, SBR Remaining Funds, Graduated
Institutions, Laboratories etc.
INSTRUÇÕES PARA OS AUTORES
A Revista Brasileira de Reumatologia (RBR), órgão oficial da Sociedade Brasileira de Reumatologia, foi fundada em 1957 e é publicada bimestralmente.
A revista publica artigos originais, artigos de revisão, comunicações breves,
relatos de casos e cartas aos editores.
Resultados
Devem ser claros e concisos. Tabelas e gráficos não devem duplicar informações.
Discussão
O manuscrito deve ser submetido online através do site http://ees.elsevier.com/bjr.
Deve ser concisa, interpretando os resultados no contexto da literatura atual. É
conveniente não ultrapassar a metade do número de páginas do trabalho completo.
Apresentação do manuscrito
Agradecimentos
O manuscrito pode ser submetido em português ou inglês, em espaço
duplo, com margens de 2,5 cm. No texto não devem ser empregadas
abreviaturas não convencionais, gírias (jargões) médicas ou redação tipo
telegráfica. A citação de medicamentos e produtos farmacêuticos deve
ser feita utilizando-se apenas a nomenclatura farmacológica, sem menção
do nome comercial.
Estrutura do manuscrito
Manuscript*, Title Page*, Cover Letter e Author Agreement* devem ser
enviados em arquivos individuais. Tabelas e figuras devem ser numeradas
conforme citadas no texto e enviadas em arquivos separados, com títulos e
legendas correspondentes. (*arquivos obrigatórios)
Página do título
Deve conter: a) título do artigo; b) nome completo dos autores e sua titulação
mais importante; c) departamento(s) e instituição(ões) onde se originou o trabalho; d) nome, endereço completo e e-mail válido do autor responsável para
correspondência; e) conflito de interesse e agências financiadoras relevantes;
f) título resumido com no máximo 60 caracteres.
Author Agreement
É o documento no qual os autores declaram a originalidade do manuscrito,
além de aprovarem o artigo objeto da submissão, a autoria e a ordem da lista
de autores. Deve ser assinado por todos os autores. A seguir é apresentado
um modelo.
Caro Editor,
Os autores, abaixo assinados, declaram que este manuscrito é original,
não foi publicado antes e não se encontra submetido para qualquer outra
publicação.
Gostaríamos de pedir a atenção do Editor para a presente publicação de nós
autores, referente a aspectos do presente manuscrito submetido.
Confirmamos que o manuscrito foi lido e aprovado por todos os autores
signatários e que não há nenhum outro autor a fazer parte senão os listados.
Confirmamos também que a ordem dos autores listada no manuscrito foi
aprovada por todos.
Entendemos que o Autor para Correspondência será o único contato para o
processo editorial. Ele será o único responsável pela comunicação com os
demais autores acerca do progresso da submissão, da revisão do manuscrito
e de sua aprovação final.
(Assinatura de todos os autores)
Artigo Original
Deve conter: página do título, página de resumo com palavras-chave, introdução, material e métodos ou pacientes e métodos, resultados e discussão,
agradecimentos, referências, tabelas, figuras e legendas das figuras. Não
deve exceder 5.000 palavras, incluindo-se as referências e excluindo-se a
página do título, resumo, tabelas e legendas. Pode exibir até seis figuras ou
tabelas e até 50 referências.
Apenas às pessoas que contribuíram, por exemplo, com técnicas, discussão e
envio de pacientes. Auxílio financeiro deve ser referido na página do título.
Referências
Devem ser citadas no texto em algarismos arábicos, sobrescritos e depois da
pontuação, sem parênteses ou colchetes. A numeração deve ser sequencial,
de acordo com a ordem de citação no texto. Nas referências com mais de
seis autores, devem ser citados os seis primeiros, seguidos pela expressão
et al. Sugere-se a utilização dos programas Reference Manager ou Endnote,
seguindo-se o estilo Vancouver. Exemplos de referência para diferentes
formatos são apresentados a seguir. Os autores devem consultar o NLM’s
Citing Medicine para mais informações sobre os formatos das referências.
Artigo de revista
1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD,
Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy
in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy.
Rheumatology (Oxford) 2004; 43(12):1587-8.
Artigo extraído de endereço eletrônico
2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in
the treatment of avascular necrosis: a systematic review. Clin Rheumatol
2008. Available from: http://www.springerlink.com.w10069.dotlib.com.br/
content/l05j4j3332041225/fulltext. pdf. [Accessed in February 24, 2008].
Livro
3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.
Tabelas e Figuras
Cada tabela ou figura deverá ser numerada em algarismo arábico e enviada
em arquivo separado (.jpg, .tif, .png, .xls, .doc) com 300 dpi no mínimo.
Título e legenda devem estar no mesmo arquivo da figura ou tabela a que se
referem. Tabelas e ilustrações devem ser autoexplicativas, com informações
suficientes para sua compreensão sem que se tenha de recorrer ao trabalho.
Fotomicrografias devem incluir a escala apropriada.
Artigo de Revisão
Revisões, preferencialmente sistemáticas, podem ser submetidas à RBR,
devendo abordar com profundidade um tema de interesse para o reumatologista. Não apresentam estruturação padronizada, prescindindo de introdução
ou discussão. Devem apresentar resumo sem subdivisões, com três a cinco
palavras-chave, e não devem exceder 6.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Podem
exibir até cinco figuras ou tabelas e até 70 referências.
Relato de Caso
Introdução
Deve incluir resumo e palavras-chave, sem necessidade de subdivisões. O texto,
porém, apresenta as seguintes seções: introdução, que deve ser concisa; relato de
caso, contendo a descrição e a evolução do quadro clínico, exames laboratoriais,
ilustrações e tabelas (que substituem as seções material e métodos e resultados);
e discussão. Deve conter no máximo seis autores, e não deve exceder 1.500
palavras, incluindo-se as referências e excluindo-se a página do título, resumo,
tabelas e legendas. Pode exibir até duas figuras ou tabelas e até 15 referências.
A finalidade dessa seção é definir o propósito e as razões para a realização
do trabalho. Não se recomenda extensa revisão da literatura.
Comunicação breve
Página de resumo
Deve conter: a) objetivo, métodos, resultados e conclusões, não excedendo
250 palavras; b) três a cinco palavras-chave.
Pacientes e métodos ou Material e métodos
Deve incluir informações suficientes que permitam a reprodução do trabalho e,
quando pertinente, a aprovação pelo Comitê de Ética institucional. Os métodos
empregados na análise estatística devem sempre ser citados.
Aborda um ponto ou detalhe específico de um tema. Deve incluir resumo
com no máximo 250 palavras, e três a cinco palavras-chave. O texto não
necessita subdivisões, deve ter até 2.500 palavras incluindo-se as referências
e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até
três figuras ou tabelas e até 25 referências.
Regras para aplicar tempos verbais apropriados de acordo com
o contexto ou seção
Contexto ou seção
Resumo
Introdução
Métodos, materiais e
resultados
Discussão/Conclusão
Atribuições
Descrição de Tabelas e Figuras
Conhecimento estabelecido e
resultados prévios
Tempo verbal apropriado
Passado
Presente, quando se referir a fatos estabelecidos e conhecimento prévio
Passado
Combinado de passado (quando se referir a resultados obtidos no trabalho) e
presente (quando se referir a fatos estabelecidos e conhecimento prévio); às
vezes pode ser utilizado o futuro (especialmente quando se referir a perspectivas de trabalhos a serem realizados)
Passado
Ex.: Andrade et al. relataram...
Presente
Presente
Regras gerais para se obter uma boa escrita em um artigo científico:
1. Prefira a voz ativa.
2. As sentenças devem ser curtas, claras e objetivas.
3. A unidade de medida deve ser abreviada quando empregada com
valores numéricos (p. ex., 1 mg), mas escrita por extenso quando
separada de valor numérico. Utilize o Sistema Internacional de
Unidades (SI units) para definir as unidades de medida. Lembre-se
de deixar um espaço entre o número e a unidade (p. ex., 10 mg/dL),
exceto quando for porcentagem, que deve estar junto (p. ex., 70%).
O plural das unidades de medida é a mesma forma do singular (p.
ex., 1 mL, 10 mL; 1 h, 10 h). Quando iniciarem a frase, os números
devem estar por extenso, e não em algarismo arábico.
4. Defina a abreviação na primeira vez que aparecer no texto principal.
Após a definição, use sempre a abreviação em vez da forma por extenso.
Evite o uso de abreviações no título e no resumo.
5. Ao escrever em inglês, não utilize contrações (p. ex., prefira does not em
vez de doesn't).
Livro recomendado: Rogers SM. Mastering scientific and medical writing: a
self-help guide. Berlin: Springer; 2007.
Considerações éticas e legais
A RBR segue as normas do Uniform Requirements for Manuscripts (URM)
Submitted to Biomedical Journals desenvolvidas pelo The International
Committee of Medical Journal Editors (ICMJE) – fevereiro de 2006.
Conflito de interesse
A confiança pública no processo de revisão por pares e a credibilidade
dos artigos publicados dependem, em parte, de como o conflito de
interesse é administrado durante a redação, a revisão por pares e a
decisão editorial. O conflito de interesse existe quando um autor (ou
instituição do autor), revisor ou editor tem relações financeiras ou
pessoais que influenciem de forma inadequada (viés) suas ações (tais
relações são também conhecidas como duplo compromisso, interesses
conflitantes ou fidelidades conflitantes). Essas relações variam entre
aquelas com potencial insignificante até as com grande potencial
para influenciar o julgamento, e nem todas as relações representam
verdadeiro conflito de interesse. O potencial conflito de interesse pode
existir dependendo se o indivíduo acredita ou não que a relação afete
seu julgamento científico. Relações financeiras (tais como emprego, consultorias, posse de ações, testemunho de especialista pago) são os conflitos
de interesse mais facilmente identificáveis e os mais suscetíveis de minar a
credibilidade da revista, dos autores e da própria ciência. No entanto, podem
ocorrer conflitos por outras razões, tais como relações pessoais, competição
acadêmica e paixão intelectual.
Consentimento informado
Os pacientes têm o direito à privacidade, que não deve ser infringida
sem o consentimento informado. A identificação de informações,
incluindo os nomes dos pacientes, iniciais ou números no hospital,
não devem ser publicadas em descrições, fotografias e genealogias, a
menos que a informação seja essencial para os propósitos científicos
e o paciente (ou responsável) dê o consentimento livre e esclarecido
para a publicação.
O consentimento informado para este propósito requer que o manuscrito
a ser publicado seja mostrado ao paciente. Os autores devem identificar
os indivíduos que prestam assistência a escrever e divulgar a fonte de
financiamento para essa assistência. Detalhes identificadores devem ser
omitidos se não são essenciais.
O anonimato completo é difícil de se conseguir; no entanto, no caso
de qualquer dúvida, o consentimento deve ser obtido. Por exemplo,
mascarar a região ocular em fotografias de pacientes é uma proteção
de anonimato inadequada. Se as características de identificação são
alteradas para proteger o anonimato, como na linhagem genética, os
autores devem garantir que as alterações não distorçam o significado
científico. Quando o consentimento informado foi obtido, ele deve ser
indicado no artigo publicado.
Princípios éticos
Ao relatar experimentos em seres humanos, os autores devem indicar
se os procedimentos seguidos estiveram de acordo com os padrões
éticos do comitê responsável por experimentação humana (institucional e nacional) e com a Declaração de Helsinki de 1975, revisado em
2000. Se houver dúvida se a pesquisa foi realizada em conformidade
com a Declaração de Helsinki, os autores devem explicar a razão
para sua abordagem e demonstrar que o corpo de revisão institucional
aprovou explicitamente os aspectos duvidosos do estudo. Ao relatar
experimentos com animais, os autores devem indicar se as orientações
institucionais e nacionais para o cuidado e a utilização de animais de
laboratório foram seguidas.
Registro de ensaios clínicos
Os ensaios clínicos devem ser registrados segundo recomendação da
OMS em www.who.int/ictrp/en/. A definição de ensaios clínicos incluem ensaios preliminares (fase I): um estudo prospectivo com o
recrutamento de indivíduos submetidos a qualquer intervenção relacionada à saúde (medicamentos, procedimentos cirúrgicos, aparelhos,
terapias comportamentais, regime alimentar, mudanças nos cuidados
de saúde) para avaliar os efeitos em desfechos clínicos (qualquer
parâmetro biomédico e de saúde, inclusive medidas farmacocinéticas
e reações adversas).
A RBR tem o direito de não publicar trabalhos que não cumpram estas
e outras normas legais e éticas explicitadas nas diretrizes internacionais.
Financiamento e apoio
Os autores devem, também, informar se receberam financiamento ou apoio
de instituições como CNPq, CAPES, Fundos Remanescentes da SBR,
instituições universitárias, laboratórios etc.
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Founded on July 15, 1948 (Fundada em 15 de julho de 1948)
Executive Board of Directors for the 2014–2016 Biennium
Diretoria Executiva para o Biênio 2014–2016
President (Presidente)
Cesar Emile Baaklini
General secretary (Secretário geral)
Jose Eduardo Martinez
Roberto Acayaba de Toledo
Roberto Bernd – SP
Roberto Cordeiro de A Teixeira
Rubens Bonfiglioli
Sandra Lúcia Euzébio Ribeiro
Vitalina Souza Barbosa
Wilton Silva dos Santos
1st secretary (1º secretário)
Silvio Figueira Antonio
2nd secretary (2ª secretário)
Washington Alves Bianchi
Treasurer (Tesoureiro)
Jose Roberto Provenza
Vice-treasurer (Vice-tesoureiro)
Luiz Carlos Latorre
Scientific director (Diretor científico)
Paulo Louzada Jr.
Elected president (Presidente eleito)
Georges Basile Christopoulos
Representatives of PANLAR
Representantes junto à PANLAR
Adil Muhib Samara
Antonio Carlos Ximenes
Fernando Neubarth
Maria Amazile Ferreira Toscano
Representatives of Ministry of Health
Representantes junto ao Ministério da Saúde
Ana Patrícia de Paula
Mário Soares Ferreira
Representatives of AMB
Representantes junto à AMB
Eduardo de Souza Meirelles
Gustavo de Paiva Costa
Ivone Minhoto Meinão
Specialist Title Commission
Comissão de Título de Especialista
President (Presidente)
Emília Inoue Sato
Members (Membros)
Geraldo Castelar Pinheiro
Gilda Aparecida Ferreira
Inês Guimarães Silveira
João Elias Moura Junior
José Gerardo Araujo Paiva
Lissiane Karine Noronha
Marcelo de Medeiros Pinheiro
Marília Barreto Gameiro Silva
Mauro Goldfarb
Michel Alexandre Yazbek
Nafice Costa Araujo
René Donizette Ribeiro de Oliveira
Ricardo Xavier
Rheumatology Aid Fund to
Rheumatology Research and Teaching
Conselho do Fundo de Auxílio a
Pesquisa e Ensino em Reumatologia
Acir Rachid
Adil Muhib Samara
Antônio Carlos Ximenes
Caio Moreira
Cesar Emile Baaklini
Emília Inoue Sato
Fernando de Souza Cavalcanti
Fernando Neubarth
Georges Basile Christopoulos
Geraldo da Rocha Castelar Pinheiro
Hilton Seda
Iêda Maria Magalhães Laurindo
João Carlos Tavares Brenol
João Francisco Marques Neto
Nílzio Antônio da Silva
Sebastião Cezar Radominski
Wiliam Habib Chahade
Health Technology Evaluation Comission
Comissão de Avaliação de Tecnologia em Saúde
President (Presidente)
Mirhelen Mendes de Abreu
Members (Membros)
Adriana Maria Kakehasi
Ana Cristina de Medeiros Ribeiro
Clayton Viegas Brenol
Eduardo de Souza Meirelles
Jussara de Almeida L. Kochen
Rafael Mendonça da Silva Chakr
Epidemiology Commission
Comissão de Epidemiologia
Coordinator (Coordenadora)
Rozana Mesquita Ciconelli
Members (Membros)
Alessandra Souza Braz C. Andrade
Bernardo Matos da Cunha
Camila Cruz Leijoto
Carlos Augusto F. de Andrade
Eutilia Andrade Medeiros Freire
Jussara de Almeida Kochen
Pediatric Rheumatology Commission
Comissão de Reumatologia Pediátrica
Claudio Arnaldo Len
Clovis Artur Almeida Junior
Cristina Medeiros de Magalhães
Daniela Gerent Petry Piotto
Flavia Patrícia Teixeira Santos
Flavio Roberto Sztajnbok
Lucia Maria Arruda Campos
Marcia Bandeira
Sheila Knupp Feitosa de Oliveira
Silvana Brasilia Sacchetti
Virginia Paes Leme Ferriani
Media Commission
Comissão de Comunicação Social
BSR Bulletin (Boletim SBR)
Editorial Council (Conselho Editorial)
Edgard Torres dos Reis Neto
Sandra Hiroko Watanabe
Editors (Editores)
Renê Donizeti Ribeiro de Oliveira
Tania Carolina Monteiro de Castro
Collaborator (Colaborador)
Plínio José do Amaral
Brazilian Journal of Rheumatology
Revista Brasileira de Reumatologia
Editors (Editores)
Marcos Renato de Assis
Roberto Ezequiel Heymann
Editores Adjuntos
Clayton Viegas Brenol
Marcelo de Medeiros Pinheiro
Simone Appenzeller
Coeditors (Coeditores)
Francisco Airton Castro da Rocha
Max Victor Carioca Freitas
Mittermayer Barreto Santiago
Paulo Louzada Junior
Ricardo Fuller
Ricardo Machado Xavier
BSR Website (Site SBR)
Coordinators (Coordenadores)
Antonio Carlos Monteiro Ribas
Marcelo Cruz Rezende
Maria Roseli Monteiro Callado
Ethics and Discipline Commission
Comissão de Ética e Disciplina
President (Presidente)
José Marques Filho
Members (Membros)
Antonio Carlos Althoff
Camila Souto Oliveira
Henrique Josef
José Roberto Pereira Santos
Lilian Schade
Rita de Cassia Correa Miguel
President (Presidente)
Maria Teresa S L R A Terreri
Members (Membros)
Ana Julia Pantoja Moraes
André de Souza Cavalcanti
Claudia Saad Magalhães
Teaching and Medical
Education Commission
Comissão de Ensino e Educação Médica
President (Presidente)
Jozelia Rêgo
Members (Membros)
Cassia Bossi Semmelmann
Charles Lubianca Kohem
Claudia Diniz Lopes Marques
Edgar Baldi Junior
Elaine Lira Medeiros de Bezerra
Elisa Martins das N. de Albuquerque
Izaías Pereira da Costa
Marcelo Pimenta
Maria Jose Pereira Vilar
Congresses, Journeys, and
Events Commission
Comissão de Congressos, Jornadas e Eventos
Coordinators (Coordenadores)
Fernando Neubarth
Georges Basile Christopoulos
José Roberto Provenza
Osteoarthrosis Commission
Comissão de Osteoartrose
President (President)
Ibsen Bellini Coimbra
Members (Membros)
Claudia Diniz Lopes Marques
Elda Matilde Hirose Pastor
Fernando Neubarth
Francisco Airton Castro da Rocha
Glaucio Ricardo Werner de Castro
Hilton Seda
Jose Caetano Macieira
Maria Luiza R Andrade Machado
Ricardo Fuller
Vasculopathies Commission
Presidente (President)
Comissão de Relações com
Grupos de Pacientes
Members (Membros)
Helenice Alves Teixeira Gonçalves
Members (Membros)
Ana Paula Espinula Gianordoli
Carlos Eugenio Ribeiro Parolini
Luis Piva Junior
Valderílio Feijó Azevedo
Wanda Heloisa Rodrigues Ferreira
Roger Abramino Levy
Adriana Danowski
Alexandre Wagner S. de Souza
Ana Beatriz S. Bacchiega de Freitas
Ana Luisa Garcia Calich
Andreas Funke
Danieli Castro Oliveira de Andrade
Gilda Aparecida Ferreira
Henrique de Ataide Mariz
Jozélia Rego
Manuella Lima Gomes Ochtrop
Mauricio Levy Neto
Occupational Rheumatology Commission
Comissão de Reumatologia Ocupacional
Image Commission
President (Presidente)
Comissão de Imagem Milton Helfenstein Junior
President (Presidente)
Members (Membros)
Anna Beatriz Assad Maia
Antônio Techy
Marco Aurélio Goldenfum
BiobadaBrasil Comission
Comissão do BiobadaBrasil
President (Presidente)
Ieda Maria Magalhães Laurindo
Members (Membros)
Aline Ranzolin
André Luiz Shinji Hayata
David Cezar Titton
Ines Guimarães da Silveira
Julio Cesar Bertacini de Moraes
Mirhelen Mendes de Abreu
Paulo Louzada-Junior
Roberto Ranza
Valéria Cristo Valim
Rheumatoid Arthritis Commission
Comissão de Artrite Reumatoide
Spinal Commission
Comissão de Coluna Vertebral
Coordinator (Coordenador)
Silvio Figueira Antonio
Members (Membros)
Ari Stiel Radu Halpern
Carlos Appel da Silva
Jamil Natour
Jose Gerardo de Araújo Paiva
Luíza Helena Coutinho Ribeiro
Marcos Renato de Assis
Maria Amazile Ferreira Toscano
Renê Donizeti Ribeiro de Oliveira
Comissão de Vasculopatias Commission of Relations
with Groups of Patients
President (Presidente)
Odirlei André Monticielo
Simone Appenzeller
José Alexandre Mendonça
Members (Membros)
Andrea Barranjard Vanucci Lomonte
Cristiane Kayser Veiga da Silva
Ieda Maria Magalhāes Laurindo
Inês Guimarães Silveira
Jamil Natour
Karina Rossi Bonfiglioli
Karine Rodrigues da Luz
Laura Maria C de Mendonça
Simone Appenzeller
Veronica Silva Vilela
Procedures Commission
Comissão de Procedimentos
President (Presidente)
Jamil Natour
Members (Membros)
Daniele Freitas Pereira
Geraldo da Rocha Castelar Pinheiro
Luiza Helena Coutinho Ribeiro
Monique Sayuri Konai
Rita Nely Vilar Furtado
Presidente (President)
Osteomethabolic Diseases and
Osteoporisis Commission
Comissão de Doenças
Osteometabólicas e Osteoporose
Marco Antonio A da Rocha Loures
Members (Membros)
Ana Patricia de Paula
Caio Moreira
Charlles Heldan de Moura Castro
Cristiano Augusto F. Zerbini
Elaine de Azevedo
Jaime Sanson Danowiski
Laura Maria C. de Mendonça
Mailze Campos Bezerra
Rosa Maria Rodrigues Pereira
Sebastião Cezar Radominski
Vera Lucia Szejnfeld
Spondiloarthropathies Commission
Comissão de Espondiloartropatias
Coordinator (Coordenador)
Célio Roberto Gonçalves
RBE Coordinator (Coordenador RBE)
Percival Degrava Sampaio Barros
Members (Membros)
Antonio Carlos Ximenes
Bruno Schau de Araujo Lima
Eduardo de Souza Meirelles
Ivanio Alves Pereira
Marcelo de Medeiros Pinheiro
Mauro Waldemar Keiserman
Ricardo da Cruz Lage
Thelma Larocca Skare
Walber Pinto Vieira
Washington Alves Bianchi
Psoriatic Arthritis Subcommission
(Sub-Comissão de Artrite Psoriásica)
Claudia Goldenstein-Schainberg
Roberto Ranza
Roberto Ranza
Sueli Coelho da Silva Carneiro
Valderilio Feijó Azevedo
Licia Maria Henrique da Mota
Lupus Commission
Members (Membros)
Comissão de Lúpus
RBE
Boris Afonso Cruz
Cleandro Pires de Albuquerque
Deborah Pereira Goncalves
Geraldo da Rocha Castelar Pinheiro
Ieda Maria Magalhães Laurindo
Ivanio Alves Pereira
Jozelio Freire de Carvalho
Manoel Barros Bertolo
Maria Raquel da Costa Pinto
Paulo Louzada Jr.
Ricardo Machado Xavier
Rina Dalva Neubarth Giorgi
Rodrigo Aires Corrêa Lima
President (Presidente)
General Coordinator (Coordenador Geral)
Eduardo Ferreira Borba Neto
Percival Degrava Sampaio-Barros
Members (Membros)
Area Coordinator (Coordenadores de Área)
Cristina Costa Duarte Lanna
Elisa Martins das N. de Albuquerque
Eloisa Silva Dutra de Oliveira Bonfá
Emilia Inoue Sato
Evandro Mendes Klumb
Francinne Machado Ribeiro
João Carlos Tavares Brenol
Lilian Tereza Lavras Costallat
Luis Carlos Latorre
Maria de Fátima Lobato da Cunha Sauma
Carla Gonçalves Schahin Saad
Julio Cesar Bertacinni
Pain, Fibromyalgia and Other Painful
Syndromes of the Soft Parts Commission
Comissão de Dor, Fibromialgia e Outras
Síndromes Dolorosas de Partes Moles
President (Presidente)
Eduardo dos Santos Paiva
Members (Membros)
Aline Ranzolin
Daniel Feldman Pollak
Fernando Augusto Chiuchetta
José Eduardo Martinez
José Roberto Provenza
Marcelo Cruz Rezende
Marcos Aurélio Freitas Machado
Marcos Renato de Assis
Milton Helfenstein Junior
Nilton Salles Rosa Neto
Rafael Mendonça da Silva Chakr
Rafael Navarrete Fernandez
Roberto Ezequiel Heymann
Documentation and Historical
Registry Commission
Comissão de Documentação e
Registro Histórico
President (Presidente)
Tania Sales de Alencar Fidelix
Virginia Fernandes Moça Trevisani
Professional Defense Commission
Supervisory Board (Conselho Fiscal)
Walber Pinto Vieira
Geraldo da Rocha Castelar Pinheiro
Ieda Maria Magalhães Laurindo
(Comissão de Defesa Profissional)
Presidents (Presidente)
BSR – Regionals
Jaime Baião
Abel Pereira de Souza Junior
Regionais – SBR
Members (Membros)
Angelita Carlotto de Abreu
Cassia Bossi Semmelmann
Francisco Alves Bezerra Neto
Francisco Deoclécio D. Rocha
Ines Cristina de Mello Lima
Matheus Staufackar Carlos
Mauro Furtado Cavalcanti
Vander Fernandes
Vidal de Souza
Rheumatology Society of Mato Grosso
Rheumatology Society of Alagoas
Ana Rosa Araujo Gonçalves
Rheumatology Society of Amapá
Alessandro Marcus Pinheiro Melo
Rheumatology Society of Amazonas
Maria do Socorro A de Souza
Rheumatology Society of Bahia
Mittermayer Barreto Santiago
Henrique Josef
Gout Commission
Members (Membros)
(Comissão de Gota)
Célio Roberto Gonçalves
Hilton Seda
Joaquim Jaguaribe Nava Ribeiro
José Eduardo de C Gonçalves
José Knoplich
José Marques Filho
Lauredo Ventura Bandeira
Lipe Goldenstein
Plinio José Amaral
President (Presidente)
Systemic Sclerosis Commission
Endemic and Infectious
Diseases Commission
Rheumatology Society of Espírito Santo
(Comissão de Doenças
Endêmicas e Infecciosas)
Rheumatology Society of Mato Grosso do Sul
Presidents (Presidentes)
Rheumatology Society of Rio de Janeiro
Izaias Pereira da Costa
Sandra Lucia Euzébio Ribeiro
Rheumatology Society of Rio Grande do Norte
Comissão de Esclerose Sistêmica
President (Presidente)
Mauro Waldemar Keiserman
Members (Membros)
Adriana Fontes Zimmermann
Alex Magno Coelho Horimoto
Alexandre Wagner S de Souza
Andrea Tavares Dantas
Carolina de Souza Muller
Claudia Tereza Lobato Borges
Cristiane Kayser Veiga da Silva
Eutilia Andrade Medeiros Freire
Gisele Baptista Maretti
João Francisco Marques Neto
Lilian Scussel Lonzetti
Maria Cecilia Fonseca Salgado
Maria de Fátima Lobato da Cunha Sauma
Mario Newton Leitão de Azevedo
Markus Bredemeier
Percival Degrava Sampaio-Barros
Sheila Marcia de A Fontenele
Virginia Fernandes Moça Trevisani
Sjögren Syndrome Commission
(Comissão de Síndrome de Sjögren)
President (Presidente)
Valéria Valim Cristo
Members (Membros)
Leandro Augusto Tanure
Leandro Lara Prado
Marilena Leal M S Fernandes
Samia Araujo de Sousa Studart
Sandra Gofinet Pasoto
Sandra Lúcia Euzébio Ribeiro
Geraldo da Rocha Castelar Pinheiro
Members (Membros)
Adil Muhib Samara
Antonio José Lopes Ferrari
Ana Beatriz Vargas dos Santos
Eduardo dos Santos Paiva
Hellen Mary da Silveira de Carvalho
Members (Membros)
Rheumatology Society of Santa Catarina
Sonia Cristina de Magalhaes Souza Fialho
Rheumatology Society of Ceará
Jose Eyorand Castelo Branco de Andrade
Rheumatology Society of Brasília
Ana Patricia de Paula
Rheumatology Society of Rondônia
Liszt Jonney Silva Dos Santos
Rheumatology Society of Acre
Maria Luiza Abrahão Barbosa
Jose Roberto Pereira Santos
Izaias Pereira Da Costa
Evandro Mendes Klumb
Francisco Alves Bezerra Neto
Ana Carolina de Oliveira S.Montandon
Gecilmara Cristina Salnato Pileggi
Helena Lúcia Alves Pereira
Natalino Hajime Yoshinari
Rejane Maria R de Abreu Vieira
Roberta de Almeida Pernambuco
Rheumatology Society of Rio Grande do Sul
Assisted Therapy Immunobiological
Centers Commission
Rheumatology Society of Maranhão
(Comissão de Centros de Terapia
Imunobiológica Assistida)
Rheumatology Society of Minas Gerais
President (Presidente)
Rheumatology Society of Pará
Antonio Scafuto Scotton
Members (Membros)
Adrian Nogueira Bueno
Ana Tereza Amoedo Medrado
Claudia Goldenstein Schainberg
Eliezer Rushansky
Evelin D. Goldenberg M. M.da Costa
José Eyorand Castelo B. de Andrade
José Roberto Silva Miranda
Manoel Barros Bertolo
Rafael de Oliveira Fraga
Reno Martins Coelho
Ricardo Jorge de Percia Name
Vander Fernandes
Marco Aurelio Goldenfum
Rheumatology Society of Tocantins
Daniela Edilma Japiassu Custódio
Rheumatology Society of Goiás
Gustavo Pavlik Haddad
Raquel Moraes Da Rocha Nogueira
Gustavo Lamego de Barros Costa
Rosana de Britto Pereira Cruz
Rheumatology Society of Paraíba
Danielle Christ Soares Egypto de Brito
Rheumatology Society of Paraná
Marco Antônio Araujo da Rocha Loures
Rheumatology Society of São Paulo
Dawton Torigoe
Rheumatology Society of Pernambuco
Lilian David de Azevedo Valadares
Rheumatology Society of Piauí
Aline do Socorro Miranda Ribeiro
Rheumatology Society of Sergipe
Regina Adalva de Lucena Couto Ocea
Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia)
Avenida Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 – CEP: 01402-000 – São Paulo, SP, Brasil
Phone/Fax:
55 11 3289-7165
E-mail:
[email protected], [email protected]
Website:
www.reumatologia.com.br
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Volume 55. Número 1. Janeiro/Fevereiro 2015
Volume 55. Number 1. January/February 2015
CONTENTS | SUMÁRIO
Original articles | Artigos originais
Consensus of the Brazilian Society of Rheumatology for the diagnosis, management and
treatment of lupus nephritis
Consenso da Sociedade Brasileira de Reumatologia para o diagnóstico, manejo e tratamento da nefrite lúpica
Evandro Mendes Klumb, Clovis Artur Almeida Silva, Cristina Costa Duarte Lanna, Emilia Inoue Sato,
Eduardo Ferreira Borba, João Carlos Tavares Brenol, Elisa Martins das Neves de Albuquerque,
Odirlei Andre Monticielo, Lilian Tereza Lavras Costallat, Luiz Carlos Latorre,
Maria de Fátima Lobato da Cunha Sauma, Eloisa Silva Dutra de Oliveira Bonfá,
Francinne Machado Ribeiro .......................................................................................................................
1
Assessing the magnitude of osteoarthritis disadvantage on people’s lives: the MOVES study
Avaliação da magnitude da desvantagem da osteoartrite na vida das pessoas: estudo MOVES
Luís Cunha-Miranda, Augusto Faustino, Catarina Alves, Vera Vicente, Sandra Barbosa ........................
22
Comparison of the Disease Activity Score-28 and Juvenile Arthritis Disease Activity Score in
the juvenile idiopathic arthritis
Comparação entre o Disease Activity Score-28 e o Juvenile Arthritis Disease Activity Score na artrite idiopática juvenil
Renata Campos Capela, José Eduardo Corrente, Claudia Saad Magalhães ..............................................
31
The association of fibromyalgia and systemic lupus erythematosus change the presentation
and severity of both diseases?
A associação fibromialgia e lúpus eritematoso sistêmico altera a apresentação e a gravidade de ambas as doenças?
Ana Luiza P. Kasemodel de Araújo, Isabella Cristina Paliares, Maria Izabel P. Kasemodel de Araújo,
Neil Ferreira Novo, Ricardo Augusto M. Cadaval, José Eduardo Martinez ................................................
37
Evaluation of grip strength in normal and obese Wistar rats submitted to swimming with
overload after median nerve compression
Avaliação da força de preensão em ratos Wistar, normais e obesos, submetidos à natação com sobrecarga após
compressão do nervo mediano
Josinéia Gresele Coradinia, Camila Mayumi Martin Kakihata, Regina Inês Kunz,
Tatiane Kamada Errero, Maria Lúcia Bonfleur, Gladson Ricardo Flor Bertolini ........................................
43
Evaluation of performance of BASDAI (Bath Ankylosing Spondylitis Disease Activity Index)
in a Brazilian cohort of 1,492 patients with spondyloarthritis: data from the Brazilian
Registry of Spondyloarthritides (RBE)
Avaliação do desempenho do BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) numa coorte brasileira
de 1.492 pacientes com espondiloartrites: dados do Registro Brasileiro de Espondiloartrites (RBE)
Izaias Pereira da Costa, Adriana B. Bortoluzzo, Célio R. Gonçalves, 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,
Angela L.B. Pinto Duarte, Charles L. Kohem, Nocy H. Leite, Sonia A.L. Lima, Eduardo S. Meirelles,
Ivânio A. Pereira, Marcelo M. Pinheiro, Elizandra Polito, Gustavo G. Resende, Francisco Airton C. Rocha,
Mittermayer B. Santiago, Maria de Fátima L.C. Sauma, Valéria Valim, Percival D. Sampaio-Barros .......
48
Review articles | Artigos de revisão
Possible changes in energy-minimizer mechanisms of locomotion due to chronic low back
pain - a literature review
Possíveis alterações no mecanismo minimizador de energia da caminhada em decorrência da dor lombar
crônica - revisão de literatura
Alberito Rodrigo de Carvalho, Alexandro Andrade, Leonardo Alexandre Peyré-Tartaruga ......................
55
Monitoring the functional capacity of patients with rheumatoid arthritis for three years
Acompanhamento da capacidade funcional de pacientes com artrite reumatoide por três anos
Leda M. de Oliveira, Jamil Natour, Suely Roizenblatt, Pola M. Poli de Araujo, Marcos B. Ferraz ..............
62
Case reports | Relatos de caso
Coexisting systemic lupus erythematosus and sickle cell disease: case report and literature review
Coexistência de lúpus eritematoso sistêmico e doença falciforme: relato de caso e revisão da literatura
Teresa Cristina Martins Vicente Robazzi, Crésio Alves, Laís Abreu, Gabriela Lemos ...............................
68
Two pairs of brothers with juvenile idiopathic arthritis (JIA): case reports
Dois pares de irmãos com artrite idiopática juvenil (AIJ): relato de casos
Teresa Cristina M.V. Robazzi, Gabriela Rios, Catarina Castro .................................................................
75
Macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis
Síndrome de ativação macrofágica em paciente com artrite idiopática juvenil sistêmica
Anna Carolina Faria Moreira Gomes Tavares, Gilda Aparecida Ferreira, Luciano Junqueira Guimarães,
Raquel Rosa Guimarães, Flávia Patrícia Sena Teixeira Santos .................................................................
79
Brief Communications | Comunicação Breve
Analysis of the influence of pharmacotherapy on the quality of life of seniors with
osteoarthritis
Análise da influência da farmacoterapia sobre a qualidade de vida em idosos com osteoartrite
Katia F. Salvato, João Paulo M. Santos, Deise A.A. Pires-Oliveira, Viviane S.P. Costa, Mario Molari,
Marcos T.P. Fernandes, Regina C. Poli-Frederico, Karen B.P. Fernandes ....................................................
83
Letter to the editor | Carta ao editor
Efficacy and safety of intra and periarticular corticosteroids injections in treatment of lupus
arthritis
Eficácia e segurança das injeções intra-articulares e periarticulares de corticosteroides no tratamento da artrite lúpica
Filipa Teixeira, Daniela Peixoto, Carmo Afonso, Domingos Araújo ...........................................................
89
Erratum | Errata
Erratum on “Epidemiologic profile of juvenile-onset compared to adult-onset
spondyloarthritis in a large Brazilian cohort”
Errata de “Perfil epidemiológico da espondiloartrite de início juvenil comparada com a espondiloartrite de início
na vida adulta em uma grande coorte brasileira”
Angela P. Duarte, Cláudia D.L. Marques, Adriana B. Bortoluzzo, Célio R. Gonçalves,
José Antonio Braga da Silva, Antonio Carlos Ximenes, Manoel B. Bértolo, Sandra Lúcia E. Ribeiro,
Mauro Keiserman, Thelma L. Skare, Sueli Carneiro, Rita Menin, Valderilio F. Azevedo, Walber P. Vieira,
Elisa N. Albuquerque, Washington A. Bianchi, Rubens Bonfiglioli, Cristiano Campanholo,
Hellen M.S. Carvalho, Izaias P. Costa, Charles L. Kohem, Nocy Leite, Sonia A.L. Lima,
Eduardo S. Meirelles, Ivânio A. Pereira, Marcelo M. Pinheiro, Elizandra Polito, Gustavo G. Resende,
Francisco Airton C. Rocha, Mittermayer B. Santiago, Maria de Fátima L.C. Sauma, Valéria Valim,
Percival D. Sampaio-Barros ......................................................................................................................
91
Erratum of supplement 54, number 1, of Revista Brasileira de Reumatologia
Errata do suplemento 54, número 1, da Revista Brasileira de Reumatologia
Diego da Silva Lima, Kamila Abtibol Alves, Renan Danilo Lima da Rocha, Fernanda de Sá Barreto Lócio,
Caroline Pamponet da Fonseca Oliveira, Domingos Sávio Nunes de Lima, Luiz Fernando de Souza Passos .....
93
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Consensus of the Brazilian Society of
Rheumatology for the diagnosis, management and
treatment of lupus nephritis
Evandro Mendes Klumb a,∗ , Clovis Artur Almeida Silva b , Cristina Costa Duarte Lanna c ,
Emilia Inoue Sato d , Eduardo Ferreira Borba e , João Carlos Tavares Brenol f ,
Elisa Martins das Neves de Albuquerque a , Odirlei Andre Monticielo g ,
Lilian Tereza Lavras Costallat h , Luiz Carlos Latorre i ,
Maria de Fátima Lobato da Cunha Sauma j , Eloisa Silva Dutra de Oliveira Bonfá e ,
Francinne Machado Ribeiro a
a
Discipline of Rheumatology, Faculdade de Ciência Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Department of Pediatrics, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
c Department of the Locomotor System, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
d Discipline of Rheumatology, Faculdade de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
e Discipline of Rheumatology, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
f Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
g Discipline of Rheumatology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
h Discipline of Rheumatology, Faculdade de Medicina, Universidade Estadual de Campinas, Campinas, SP, Brazil
i Service of Rheumatology, Hospital de Heliópolis, São Paulo, SP, Brazil
j Discipline of Rheumatology, Faculdade de Medicina, Universidade Federal do Pará, Belém, PA, Brazil
b
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To develop recommendations for the diagnosis, management and treatment of
Received 26 August 2014
lupus nephritis in Brazil.
Accepted 14 September 2014
Method: Extensive literature review with a selection of papers based on the strength of scien-
Available online 16 January 2015
tific evidence and opinion of the Commission on Systemic Lupus Erythematosus members,
Brazilian Society of Rheumatology.
Keywords:
Results and conclusions: (1) Renal biopsy should be performed whenever possible and if this
Systemic lupus erythematous
procedure is indicated; and, when the procedure is not possible, the treatment should be
Lupus nephritis
guided with the inference of histologic class. (2) Ideally, measures and precautions should be
Therapeutics
implemented before starting treatment, with emphasis on attention to the risk of infection.
Brazil
(3) Risks and benefits of treatment should be shared with the patient and his/her family. (4)
Consensus
The use of hydroxychloroquine (preferably) or chloroquine diphosphate is recommended for
all patients (unless contraindicated) during induction and maintenance phases. (5) The evaluation of the effectiveness of treatment should be made with objective criteria of response
(complete remission/partial remission/refractoriness). (6) Angiotensin-converting enzyme
inhibitors and/or angiotensin receptor blockers are recommended as antiproteinuric agents
∗
Corresponding author.
E-mail: [email protected] (E.M. Klumb).
http://dx.doi.org/10.1016/j.rbre.2014.09.010
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
2
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
for all patients (unless contraindicated). (7) The identification of clinical and/or laboratory signs suggestive of proliferative or membranous glomerulonephritis should indicate
an immediate implementation of specific therapy, including corticosteroids and an
immunosuppressive agent, even though histological confirmation is not possible. (8)
Immunosuppressives must be used during at least 36 months, but these medications can
be kept for longer periods. Its discontinuation should only be done when the patient could
achieve and maintain a sustained and complete remission. (9) Lupus nephritis should be
considered as refractory when a full or partial remission is not achieved after 12 months
of an appropriate treatment, when a new renal biopsy should be considered to assist in
identifying the cause of refractoriness and in the therapeutic decision.
© 2014 Elsevier Editora Ltda. All rights reserved.
Consenso da Sociedade Brasileira de Reumatologia para o diagnóstico,
manejo e tratamento da nefrite lúpica
r e s u m o
Palavras-chave:
Objetivo: Elaborar recomendações para o diagnóstico, manejo e tratamento da nefrite lúpica
Lúpus eritematoso sistêmico
no Brasil.
Nefrite lúpica
Método: Revisão extensa da literatura com seleção dos artigos com base na força de evidência
Terapêutica
científica e opinião dos membros da Comissão de Lúpus Eritematoso Sistêmico da Sociedade
Brasil
Brasileira de Reumatologia.
Consenso
Resultados e conclusões: 1) A biópsia renal deve ser feita sempre que possível e houver
indicação e quando não for possível, o tratamento deve ser orientado com base na inferência da classe histológica. 2) Devem ser implementados medidas e cuidados idealmente
antes do início do tratamento, com ênfase na atenção ao risco de infecção. 3) Devem-se
compartilhar riscos e benefícios do tratamento com os pacientes e familiares. 4) O uso
da hidroxicloroquina (preferencialmente) ou difosfato de cloroquina é recomendado para
todos os pacientes (exceto contraindicação) durante as fases de indução e manutenção.
5) A avaliação da eficácia do tratamento deve ser feita com critérios objetivos de resposta
(remissão completa/remissão parcial/refratariedade). 6) Os inibidores da enzima conversora
da angiotensina ou bloqueadores dos receptores da angiotensina são recomendados como
antiproteinúricos para todos os pacientes (exceto contraindicação). 7) A identificação de
sinais clínicos e/ou laboratoriais sugestivos de GN proliferativa ou membranosa deve indicar
início imediato de terapia específica incluindo corticosteroides e agente imunossupressor,
mesmo que não seja possível comprovação histológica. 8) O tempo de uso dos imunossupressores deve ser no mínimo de 36 meses, mas eles podem ser mantidos por períodos mais
longos. A sua suspensão só deve ser feita quando o paciente atingir e mantiver remissão
completa sustentada. 9) Deve-se considerar NL refratária quando a remissão completa ou
parcial não for alcançada após 12 meses de tratamento adequado, quando uma nova biópsia renal deve ser considerada para auxiliar na identificação da causa da refratariedade e
decisão terapêutica.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune
inflammatory disease which ethiopathogenesis involves multiple genes and hormonal and environmental factors. SLE is
a pleomorphic disease with wide phenotypic variability of
presentation, severity and clinical course, usually progressing with periods of activity and remission. Most patients
exhibit a relatively benign course, but overall survival is lower,
when compared to the general population, with a standardized mortality ratio from 2.4 to 6.4.1 The main causes of
death are infection, disease activity, cardiovascular disease,
kidney damage and cancer (A).1–3 The morbidity and mortality are particularly high in patients with renal impairment
(C).2–9 Glomerulonephritis (GN) is the most frequent cause for
the use of high doses of corticosteroids (CS) and immunosuppressants, being also the condition that requires more
hospitalizations and the main factor related to increased mortality. Progression to end stage renal disease, or more recently,
established renal failure (ERF), defined by a glomerular filtration rate (GFR) ≤15 mL/min, requiring renal replacement
therapy, occurs in 10–30% of patients, especially those with
proliferative glomerulonephritis (PGN).10,11 At the same time,
in SLE patients on dialysis, the 5-year survival is lower than
that of individuals on dialysis without SLE.9
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
The renal involvement in SLE occurs clinically in about
60% of patients and can determine tubular, interstitial, vascular and glomerular changes; but is the involvement of
the latter compartment that determines most of the signs
and symptoms of lupus nephritis (LN) (B).12 Similarly to the
demonstrations in other systems, LN also shows different
degrees of severity, with periods of activity and remission,
which determine the choice of therapeutic agents to be used
(B).13 In clinical practice, it is not always possible to perform
a kidney biopsy, although this is a relatively simple procedure
when performed by experienced professionals.14 The biopsy
allows the recognition of diagnostic and prognostic markers
that may influence the therapeutic choice. For patients not
undergoing a kidney biopsy and for all patients in the course
of evolution, clinical and laboratory markers that help characterize the severity and activity of GN are used (B),15 guiding
the use of immunomodulatory and/or immunosuppressant
agents.
The main goal of the treatment is to achieve a complete
remission (CR), which is associated with a good long-term
prognosis.11,16 However, despite current therapeutic regimens,
less than 50% of patients with LN achieve CR after the first 6
months of treatment (B).17–19
This consensus aims to present the main recommendations for the clinical management of LN, involving diagnosis,
prognosis, treatment (induction and maintenance), care during the use of pharmacological agents, immunosuppressionadjuvant therapy, refractory case approaches and identification of associated comorbidities, all contextualized to the
reality of our country.
Materials and methods
This consensus was developed after a systematic review of
the literature, in association with the opinion of 13 rheumatologists with clinical experience in LN, 11 of them being
members of the SLE Commission of SBR, besides two guests
(CAAS and EMNA). The systematic review of the literature,
including the prior selection of a number of issues previously
identified by the working group and the voting of recommendations, was performed according to a modified Delphi
method. The databases included MEDLINE, SciELO, PubMed
and EMBASE until November 2013. After consideration of the
data obtained in the literature, the participants expressed
their opinion on each topic in discussions via Internet, and
voted on recommendations confidentially. Voting occurred in
face-to-face meetings held in May and July 2014 in a hierarchical manner, according to the following alternatives: (a) I
completely agree; (b) I agree with some reservation; (c) I agree
with many reservations; (d) I reject with reservations; (e) I completely reject. In cases of non-agreement of at least 70% of
the participants (for options a, b or c), new discussions were
held, followed by adjustments for the recommendation and
a new round of voting, until this minimum percentage was
reached. For each recommendation, the percentages of agreement among the participants were informed. When possible,
the levels of evidence were expressed according to the Oxford
classification:
3
A –Experimental or observational studies of greater consistency.
B – Experimental or observational studies of lower consistency.
C – Case reports (non-controlled studies).
D – Opinion without critical evaluation, based on consensuses, physiological studies or animal models.
Renal biopsy
Recently, the ACR (American College of Rheumatology)20
and the EULAR (European League Against Rheumatism), in
combination with two European groups of Nephrology (European Renal Association – European Dialysis and Transplant
Association)21 published recommendations for the management of SLE patients with renal involvement, based on
histological findings.
A renal biopsy should be performed whenever possible,20,21
considering that clinical, immunological and laboratory
parameters are not predictors of the histological findings.20–22
This procedure may better guide the treatment and prognosis,
and should always be performed by experienced and qualified
professionals.23
EULAR recommends obtaining a renal biopsy whenever
there is any sign of renal involvement, especially proteinuria
≥0.5 g/24 h accompanied by glomerular dysmorphic hematuria and/or cellular casts (C).21 ACR recommends a biopsy
(unless strongly contraindicated) whenever there are signs of
renal involvement with an elevated serum creatinine with no
apparent cause (not related to SLE), proteinuria ≥1.0 g/24 h or
an isolated proteinuria ≥0.5 g/24 h associated with hematuria
and/or cellular casts (C).20 When GFR <30 mL/min, the decision
to obtain a biopsy should take into consideration the normal
kidney size (>9 cm) and/or evidence of active renal disease.21
The histological pattern of LN should follow the new definitions, revised by international societies of nephrology and
pathology,24,25 known as the classification of lupus nephritis of the International Society of Nephrology/Renal Pathology
Society 2003 (ISN/RPS 2003) (C) (Table 1). According to these
guidelines, glomeruli and the tubulointerstitial region should
be evaluated, with descriptions of activity and chronicity,
besides the vascular component that is usually associated
with antiphospholipid antibody syndrome (APS) (C).20,21,24,25 A
sample is considered adequate if it has more than 8 glomeruli,
and immunofluorescence or immunohistochemistry is recommended to identify complement and immunoglobulin
deposits. If possible, electron microscopy should also be performed, because this examination facilitates the evaluation of
proliferative and membranous lesions (C).21,24,25
Usually there is no need for a repeat biopsy in the case
of new outbreaks of renal activity26,27 because this procedure
does not provide additional information about renal outcomes
in the long term.28 However, in patients without adequate
response to treatment, repeat biopsy may help in the identification of the cause of refractoriness20,21,29 and assist in
therapeutic decision.21,29
In this consensus, we recommend obtaining a renal biopsy
whenever the patient exhibits an elevated serum creatinine
with no apparent cause, and when this finding is potentially
associated with SLE, with isolated proteinuria ≥1.0 g/24 h or
4
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
Table 1 – Classification of the International Society of Nephrology/Renal Pathology Society 2003 for lupus nephritis.
Class I – minimal mesangial LN
Normal glomeruli under light microscopy (LM), but with immune deposits under immunofluorescence (IF).
Class II – proliferative mesangial LN
Pure mesangial hypercellularity of any degree or mesangial matrix expansion under MO with immune deposits in the mesangium. There may
be few and isolated subepithelial or subendothelial deposits visible under IF or electron microscopy (EM), but not under MO.
Class III – focal LN
Active or inactive, focal, segmental or global, endo- and extracapillary glomerulonephritis (GN) involving <50% of all glomeruli, typically with
subendothelial immune deposits, with or without mesangial alterations. It is further classified into: A, active; A/C, active/chronic; C, inactive
chronic.
Class IV – diffuse LN
Active or inactive, segmental or global, endo and extracapillary glomerulonephritis (GN) involving ≥50% of all glomeruli, typically with
subendothelial immune deposits, with or without mesangial alterations. It is divided into segmental diffuse (IV-S), in which ≥50% of
glomeruli involved present segmental lesions (involving less than half of the tuft) and into global diffuse (IV-G), in which ≥50% of glomeruli
involved have global lesions (involving more than half of the tuft). This class includes cases with diffuse wire-loop deposits with little or no
glomerular proliferation. It is further classified into: A, active; A/C, active/chronic; C, inactive chronic.
Class V – membranous LN
Global and segmental subepithelial immune deposits or its morphological sequelae under MO and IF or EM, with or without mesangial changes.
May occur in combination with class III or IV.
Class VI – advanced sclerosis
Global glomerular sclerosis in ≥90%, with no residual activity.
Adapted from Weening et al., 2004.24,25
AB, antibody; GN, glomerulonephritis; IF, immunofluorescence; EM, electron microscopy; OM, optical microscopy; LN, lupus nephritis.
proteinuria ≥0.5 g/24 h associated with glomerular dysmorphic hematuria and/or the presence of cellular casts. These
changes must be confirmed in a second biopsy (Table 2).
Evaluation of LN without renal biopsy: inference of
histological class for a therapeutic decision and
progression assessment
In most cases of NL, clinical, serologic and laboratory tests
cannot accurately predict the histological findings, nor could
they differentiate other possible causes of renal disease.20–22
However, this dataset can be very useful in the clinical monitoring of nephritis and, in particular, assisting in the diagnosis
of renal disease activity.30
The active urinary sediment, defined by the presence of
hematuria (with a dysmorphic glomerular pattern), leukocyturia and presence of cellular casts, is admittedly one of
the most important parameters for characterization of an
active glomerulonephritis. Proteinuria, measured in 24 h or
inferred by the relationship proteinuria/creatininuria (R P/C)
in a random spot urine sample, may also indicate inflammatory activity.30,31 The positivity or increase in titers of
anti-dsDNA antibodies and low blood levels of complement,
especially with low levels of C3, are also considered as an evidence of renal involvement, but these indicators should not be
used in isolation to define this condition.30 The reduction in
glomerular filtration, nephrotic proteinuria and the presence
of hypertension (HBP) suggest greater severity and a worse
prognosis.32,33
In patients with APS associated with SLE, the presence of
HBP and renal dysfunction should be considered as an alert
to the possibility of a vasculopathy associated with antiphospholipid antibodies (aPl), especially when there are no signs
of GN detected in urinary sediment.34
In recent years, several new noninvasive urinary biomarkers were described, including lidocalin-type prostaglandin
D synthase (l-PGDS), ␣(1)-acid glycoprotein (AAG), transferrin (TF), ceruloplasmin (CP), neutrophil gelatinase-associated
lipocalin (NGAL) and monocyte chemotactic protein 1 (MCP1).35 The combination of these biomarkers with laboratory
parameters of renal function is promising to histologic class
inference and to quantify activity and chronicity (B).35 The
anti-ribosomal P antibody, in the absence of anti-dsDNA, has
also been described as possibly associated with membranous
nephritis in SLE patients, and with a predictive value of better
renal prognosis (B).36,37
The determination of histological class based only on clinical and laboratory parameters is limited. However, the sum of
some elements may suggest one or another particular class – a
necessary inference in daily clinical practice. Patients exhibiting an elevated creatinine (with no other apparent cause),
associated with proteinuria >0.5 g/24 h or R P/C >0.5 and recent
HBP and/or an active urinary sediment (dysmorphic hematuria and/or cellular casts), and hypertension, particularly if
accompanied by low blood levels of complement and antidsDNA, probably present PGN (class III or IV). On the other
hand, it is more likely that patients with proteinuria >2 g/24 h
or R P/C >2, with no urinary sediment activity or hypertension,
especially without anti-dsDNA and with normal complement
levels, are suffering from membranous GN (class V). However,
we cannot exclude an early-stage proliferative lesion, or even
its association, in these patients. In exclusively mesangial
lesions (Class I or II), proteinuria is generally <1 g/24 h or R P/C
<1, serum creatinine levels are normal and patients usually are
not hypertensive. However, in patients with these changes, we
cannot exclude the possibility of early-phase proliferative or
membranous GN. Except in these typical forms, class inferences have very little accuracy, and this is also valid for the
possibility of class overlapping (Table 2).
5
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
Table 2 – SBR recommendations for lupus nephritis management.
Recommendations
Agreement
Indications for renal biopsy
Perform a renal biopsy whenever possible and when indicated.
Elevation of serum creatinine with no apparent cause and potentially associated with SLE.
Isolated proteinuria >1.0 g/24 h (or R P/C >1.0).
Proteinuria ≥ 0.5 g/24 h associated with glomerular dysmorphic hematuria and/or cellular casts.
Note: changes must be confirmed with a second test.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
Inference of histological class
Possibility to make some inference based on clinical and laboratory criteria.
a) 0.54; b) 0.46
Creatinine elevation (with no other cause) associated with proteinuria >0.5 g/24 h or R P/C >0.5 and recent HBP
and/or active urinary sediment: consider as proliferative GN (class III or IV), especially if accompanied by low
blood levels of complement and anti-ds-DNA AB.
a) 0.9; b) 0.1
Proteinuria >2 g/h or R P/C >2, with no activity in urinary sediment or hypertension, and mostly without
anti-ds-DNA AB and normal complement levels, suggestive of membranous GN (class V). However, we cannot
exclude proliferative lesion.
a) 0.9; b) 0.1
Proteinuria <1 g/24 h or R P/C <1 with normal creatinine and without HBP suggests mesangial GN (class II).
However, we cannot exclude initial-stage proliferative or membranous GN.
a) 1.0
Also consider the possibility of other causes of renal injury at all stages of evolution of LN (APSN, renal vein
thrombosis, TIN, ATN, diabetic nephropathy, hypertensive nephropathy and/or nephropathy secondary to
infection).
Care for immunosuppressed patients
Vaccine update.
Avoid live virus vaccines.
Tuberculosis (latent or disease) screening.
Continuous evaluation for infections throughout the period of immunosuppression.
Share risks and benefits of treatment with patient and his/her family.
Guidance on contraception (avoiding estrogens), and risks of pregnancy during treatment.
Empirical antiparasitic treatment.
Consider prophylaxis for Pneumocystis jirovecii in cases of previous infection or in patients with lymphopenia
<500 mm3 .
Prescribe hydroxychloroquine for patients, unless contraindicated.
Obtain an informed and free consent form (IFCF).
Response criteria
The treatment efficacy evaluation should be made with objective criteria of response.
Complete remission: proteinuria <0.5 g/24 h or R P/C <0.5 and normal GFR; or reduction ≤10% of previous value
for the patient or ULN of method (if the first is not available) and a normal urinalysis.
Partial remission: reduction >50% of initial proteinuria with a value <3.0 g/24 h or R P/C <3.0, normal GFR or
reduction ≤10% of the previous value of the patient, or ULN of method (if the first is not available) and a
normal urinalysis.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 0.9; b) 0.1
Agreement: the numbers in each recommendation express the percentages of agreement among the members, according to the classification
used.
AB, antibody; GN, glomerulonephritis; HBP, systemic arterial hypertension; ULN, upper limit of normal; APSN, nephropathy of antiphospholipid
syndrome; ATN, acute tubular necrosis; TIN, tubulointerstitial nephritis; R P/C, ratio proteinuria/creatininuria in a random urine sample; GFR,
glomerular filtration rate.
For the purpose of analyzing the response to treatment,
we established criteria that are similar to those adopted by
EULAR21 and ACR.38 Complete remission (CR) was defined as
a proteinuria <0.5 g/24 h or R P/C <0.5, and normal or reduced
GFR <10% of the previous value of the patient or of the upper
limit of normal (ULN) for the method (if the first option is not
available) and a normal urinalysis. Partial remission (PR) was
defined as a reduction of >50% of the initial proteinuria, with
a value <3.0 g/24 h or R P/C <3.0, and a normal GFR or a reduction of <10% of the previous value or of ULN for the method
(if the first option is not available) and a normal urinalysis
(Table 2).
Care for immunosuppressed patients
The immunosuppression caused by disease and/or its
treatment increases the risk of infection, including the
opportunistics,39 and often the differential diagnosis with
disease activity is a challenging task in clinical practice.40
Infections are associated with increased morbidity and mortality in SLE2,3 and, therefore, prevention strategies, such as
vaccination, use of antimicrobials and antiparasitic drugs,
preferably before the start of immunosuppressive therapy,
should be implemented. Moreover, tuberculosis can also be a
factor of disease activation.41 Risk factors for major infections
6
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
are: leukopenia/lymphopenia, low blood levels of complement, hypogammaglobulinemia, splenectomy, and the use of
CS and immunosuppressants,42 usual conditions during the
whole treatment of LN, so that a continuous assessment must
be made for the presence of infection throughout the period
of immunosuppression.
On the other hand, it was demonstrated that the use
of hydroxychloroquine (HCLQ) is associated with a lower
frequency of infections in patients with SLE.43 Due to the morbidity and mortality related to infections, the sharing of risks
and benefits of treatment with the patient and his/her family
is strongly sugested, as well as providing specific clarification
on the medications used, including signing of an Informed
Consent Form.
All patients should also be counseled about contraception
and pregnancy risks during treatment (Table 2).
Vaccination
An update of the vaccination card should always be performed, preferably with the disease in an inactive period
and before the implementation of any synthetic or biological immunosuppressive therapy.44,45 Vaccines without living
organism – (influenza IM); pneumococcal; tetanus; diphtheria; pertussis; Haemophilus type B; viral hepatitis A and B,
poliomyelitis (inactivated – IPV); meningococcal; HPV; typhoid
fever (IM); and rabies – are safe at any stage of treatment and
often determine an adequate immunogenicity.46,47 In this context, the most important vaccines are:
(a) Pneumococcal (23-valent polysaccharide): must be administered every five years48 as recommended by the Programa
Nacional de Imunizações (PNI) (National Immunization
Program) of Brazil. However, the Sociedade Brasileira de
Imunização (SBIM) (Brazilian Society of Immunization) in
agreement with the Centers for Disease Control of the
United States, has recommended that the vaccine used in
immunosuppressed individuals must be the pneumococcal conjugate vaccine, followed by polysaccharide vaccine
after 8 weeks (CDC, 2011);
(b) Influenza: the vaccine must be administered annually49 ;
(c) Diphtheria and tetanus (dT): follow PNI guidelines.
The live virus vaccines (MMR, herpes zoster and yellow
fever) should be avoided and used only in special cases, after
a joint evaluation with an infectologist (Table 2).42
Antimicrobial prophylaxis
(a) Tuberculosis: the treatment of latent tuberculosis, especially in the case of positive epidemiological data, should
be considered in cases with tuberculin test – PPD ≥5 mm
(if the patient is using CS) or with a chest radiograph suggestive of prior untreated tuberculosis.50
(b) Pneumocystis jirovecii: indication of prophylaxis before the
onset of immunosuppression in cases of previous infection by this organism and in patients with lymphopenia
<500 mm3 , especially if associated with a genetic or
acquired hypocomplementemia.51
(c) Antiparasitic agents: before immunosuppression, an
empiric treatment with broad spectrum anthelmintics
(e.g., albendazole or ivermectin) is recommended, especially in patients with positive epidemiological data – an
almost universal condition in our country (Table 2).
Mesangial glomerulonephritis (classes I and II)
– induction and maintenance therapy
For most patients with mesangial GN, the treatment is offered
only with CS and HCLQ. However, for those patients who
experience persistent proteinuria >1.0 g/24 h (or R P/C >1.0),
one must consider the combination of azathioprine (AZA) or
mycophenolate mofetil (MMF) (Table 3).
Proliferative glomerulonephritis – remission
induction therapy
Better-quality randomized controlled studies evaluating different treatment regimens in LN had as inclusion criteria the
confirmation and classification of nephritis according to renal
biopsy. This approach has the advantage of avoiding an aggressive treatment for mild cases, with no indicative factors of
severity, as well as the implementation of ineffective treatments in patients with chronic and irreversible changes. It is
recognized that the treatment is urgent and it must be intensive in proliferative forms of LN (classes III and IV, with or
without association with class V), in which the risk of progression to renal failure is high.21 The target to be achieved in
six months (induction period) is CR.
Since studies published in the 80s, the superiority of
cyclophosphamide (CY) has been acknowledged, as compared
to the isolated use of CS in the treatment of PGN.52 The use of
CY for prolonged periods was more effective for the prevention of relapse and for maintaining renal function53 ; however,
this drug is associated with multiple side effects, particularly
gonadal insufficiency.54
In a controlled, randomized, multicentre study on LN (class
III/IV and V[16%]), the effectiveness of MMF was not inferior
to intravenous (IV) CY in a conventional scheme,55 confirming
earlier studies.56,57 Meta-analyses also showed that CY and
MMF have comparable efficacy (A).58–60
Cyclophosphamide may be used in low doses (Scheme Euro
Lupus Trial – ET), consisting of the administration of 500 mg
IV every 2 weeks for 3 months (total dose of 3 g), followed by
maintenance with AZA61 ; or at high doses (classical scheme –
“NIH”) of 0.5–1.0 g/m2 of body surface area (BSA) IV at monthly
intervals for 6 months, followed by applications at quarterly
intervals for another 18 months.52 In a study comparing highdose (for 12 months) versus low dose (for three months) of CY,
both followed by AZA, the authors observed after 10 years
no difference in the doubling of creatinine value, evolution
to ERF and mortality.7 It should be emphasized that these
results were obtained in studies with European patients,
whose severity of nephritis tends to be lower than that
observed in African descendants.10,61 A systematic review
7
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
Table 3 – SBR recommendations for the treatment of lupus nephritis including proliferative and mesangial types.
Recommendations
Agreement
Adjuvant measures for all histologic classes
The use of hydroxychloroquine (preferably) or chloroquine is recommended for all patients (unless
contraindicated) during induction and maintenance phases.
ACE inhibitors and/or ARBs are recommended as antiproteinuric agents for all patients (unless
contraindicated).
Prevent and treat risk factors for cardiovascular disease: physical inactivity, dyslipidemia (LDL <100 mg/dL),
diabetes, obesity, HBP (BP <130 × 80 mmHg) and smoking.
Encourage a diet rich in calcium and consider supplementation, when necessary.
Consider supplementation of vitamin D (25 (OH) (if vitamin D serum levels >30 ng/mL).
Avoid nephrotoxic drugs, especially non-steroidal anti-inflammatory agents.
Protocol for induction and maintenance in mesangial GN (classes I and II)
For patients with persistent proteinuria ≥1.0 g/24 h or R P/C ≥1.0: induction and maintenance of remission,
consider AZA or MMF.
Protocol for induction in proliferative GN (classes III and IV)
Target to be achieved in six months is RC.
The identification of clinical and/or laboratory signs suggestive of proliferative GN should indicate an
immediate specific therapy, including CS and an immunosuppressant agent, even in cases when histological
confirmation is not possible.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
The treatment should begin with MP pulse therapy [0.5–1.0 g IV (or 10–30 mg/kg/day in PSLE patients) for 3
days]. Doses of prednisone between 0.5 and 1.0 mg/kg/day for 3–4 weeks, with subsequent reduction and with
the goal of achieving a dose of 5–10 mg/day for 6 months.
a) 0.9; b) 0.1
In conjunction with CS, include CY IV 0.5–1.0 g/m2 BSA monthly for 6 months, or CY IV 0.5 g every 15 days for 3
months, or MMF (2–3 g/day).
a) 0.9; b) 0.1
In patients with severity criteria, consider CY as a first option, taking into account its availability, absorption
and tolerance to medication and treatment adherence.
Lack of response or worsening of renal disease after 3 months of an appropriate therapy suggests the need to
consider an early change of the induction protocol.
After 6 months of treatment at this stage, if CR or PR were not achieved, the patient should be considered as
refractory to induction; in this case, a new therapy with MP and replacement of CY by MMF, or of MMF by CY,
are recommended.
a) 0.9; b) 0.1
Protocol for maintaining proliferative GN (classes III and IV)
AZA or MMF are indicated for patients who have achieved CR or PR in the induction phase.
These medications must be used for at least 36 months, but they can be kept for longer periods. Their
suspension should only be performed after achieving and maintaining a complete and continuous remission.
The doses of corticosteroids should be reduced progressively and, if possible, discontinued, ideally after
achieving and maintaining a complete and sustained remission.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 0.9; b) 0.1
Agreement: the numbers in each recommendation express the percentages of agreement among the members, according to the classification
used.
AZA, azathioprine; ARB, angiotensin receptor blockers; ACEI, angiotensin-converting enzyme inhibitors; CY, cyclophosphamide; CS, corticosteroids; GN, glomerulonephritis; HBP, systemic arterial hypertension; MMF, mycophenolate mofetil; MP, methylprednisolone; CR, complete
remission; PR, partial remission; R P/C, proteinuria/creatininuria ratio in a random urine sample; BSA, body surface area; GFR, glomerular
filtration rate.
of ten randomized controlled trials found that low doses of
CY, when compared to higher doses, had similar efficacy in
reducing relapses, but with lower infection rates (A).62
The use of CY PO was evaluated retrospectively in a
series of patients with LN (class III, IV and V). The dose of
1.0–1.5 mg/kg/day for an average use of 4 months was effective
in controlling LN, with frequency of side effects and the need
for discontinuation of the medicament occurring in less than
10% of the patients, without difference in response between
Euro- and African descendants.63 Previous studies have shown
efficacy of CY PO in Chinese patients, comparable to CY IV
(C).64.65
In a subgroup exploratory analysis of ALMS study, it was
observed that although CY and MMF IV have presented similar
efficacy, race, ethnicity, and geographic region factors seem to
have influenced the response to treatment of LN. Groups of
African American and Hispanic patients appear to have had
a better response to MMF versus CY, and Asian patients had
more side effects to MMF. But, as this was a subgroup analysis,
these results cannot be considered conclusive (C).66
In another post hoc analysis evaluating only 32 patients with
severe renal impairment (creatinine clearance <30 mL/min) it
was observed that the reduction of proteinuria and serum creatinine was comparable in patients using MMF and CY, with
no significant difference in the frequency of side effects (C).67
There is only one randomized controlled trial specifically
designed to include cases of severe NL (GFR 25–80 mL/min
or with crescent cells/necrosis in more than 25% of the
glomeruli), in which high doses of CY IV associated with
pulsed methylprednisolone (MP) were effective (C).68 Thus,
8
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
there are virtually no studies designed to evaluate the efficacy of MMF in these patients with severely impaired renal
function.
The use of AZA as induction therapy in PGN is not recommended, because studies showed less effectiveness versus CY
in this phase of treatment.52,69 One study with repeated renal
biopsy also showed that AZA was less effective in preventing
the evolution to glomerular fibrosis.69 However, AZA may be
a therapeutic option in LN for Euro-descendants without predictors of severity and who do not tolerate CY or MMF, despite
the higher risk of nephritis reactivation when comparing this
agent to CY (C).69
In women with LN who still wish to become pregnant, it
is recommended preferably the use of MMF, as CY is associated with an increased risk of infertility, particularly in those
women over 30 years and that had a prolonged use of this
agent (approximate risk: 60%). However, MMF is formally contraindicated during pregnancy because its teratogenicity; and
it must be emphasized the need for an effective contraception
during its use. The use of CY for shorter periods (6 months) in
young women, even at high doses, is associated with lower
rates of infertility (4.3–10%),7,54 a percentage similar to the
Eurotrial scheme (4.5%).7 Given the greater number of side
effects with MMF use in Asians, doses ≤2 g/day are recommended in these patients. Given that some studies showed
a worse response of CY in African-descendant and Hispanic
patients, it may be advantageous the use of MMF in these
cases. However, we should point out that a study specifically
targeted to the Brazilian population with the use of this agent
has not yet been published (Table 3).
Corticosteroids
Although in most studies CS were administered PO at doses
of 0.5–1 mg/kg/day with gradual reduction, pulse therapy IV
with MP for three days at the beginning of treatment could
allow the subsequent use of lower doses of CS PO, as shown
by Houssiau.70 In order to reduce the side effects of high doses
of CS, and also to allow a more rapid control of the inflammatory process, the use of MP at a dose of 0.5–1.0 g/day IV
(or 10–30 mg/kg/day for pediatric patients) for 3 days is recommended, keeping the prednisone dose in 0.5–1.0 mg/kg/day
for 3–4 weeks, followed by a progressive reduction, aiming to
achieve doses of 5–10 mg/day after six months. Some extrarenal manifestations may require maintaining higher doses
for longer periods, but due to the high frequency of adverse
effects of CS, every effort should be made for reducing the daily
dose. Patients with worse prognosis factors, e.g., presence of
cellular crescents and of necrosis, as well as those with higher
creatinine levels, should receive higher doses of prednisone
(1.0 mg/kg/day).20
In the case of achieving only PR after 6 months of an appropriate treatment, the induction phase may be extended from
7 to 9 months, according to clinical judgment.
After six months of induction treatment, if CR or PR
has not been achieved, the patient is considered with
refractory LN and a new induction therapy with MP and
replacement of CY by MMF or MMF by CY is recommended
(Table 3).
Proliferative glomerulonephritis – maintenance
treatment
Although there is no evidence to establish the duration of
the induction phase, most authors and international consensuses consider the period of six months.20,71 At the same time,
changing the therapeutic regimen for that of maintenance
phase depends on CR or PR achievement. In some instances,
even after the first six months of induction, a second scheme
will be required until CR or PR is reached. Controlled studies that have addressed the duration of this phase are also
lacking, but most authors agree that it should last 24–48
months. For patients with PGN, there are two major acknowledged alternatives for patient maintenance: AZA or MMF,
both associated with low-dose prednisone (5–10 mg/day). The
maintenance with CY IV every 3–4 months has not been used
anymore, due to its side effects and also because the available
options (AZA or MMF) have proven reasonably safe, with few
side effects in the long term.
These two immunosuppressive agents were compared in
two studies, MAINTAIN72 and Aspreva Lupus Management
Study – ALMS.71 The designs of these studies were different
and did not show the same outcomes. The MAINTAIN study
included European Caucasian patients and did not show significant differences between drugs. On the other hand, the
ALMS study, which selected only patients who had achieved
good responses in the induction phase with CY IV or MMF for
six months and that occurred in little more than 50% of those
patients included, showed superiority of MMF versus AZA in
preventing new episodes of renal activity.
EULAR recommends that patients with good responses to
induction therapy for LN should use MMF (2 g/day) or AZA
(2 mg/kg/day) for at least three years, while other authors recommend at least five years, with discontinuation of the drug in
a very gradual manner and under monitoring.73,74 The discontinuation of this medication should be gradual and initiated
always by CS.21
ACR also recommends that patients who responded to
induction therapy have a maintenance treatment with AZA
2 mg/kg/day or MMF 2 g/day, combined with low doses of CS.
According to ACR, the existing data are insufficient to recommend the time to dose reduction or discontinuation of
medication (A).20
In summary, in the maintenance therapy of patients with
PGN with complete or partial response in the induction phase,
they should be treated with AZA or MMF, and the choice should
be evaluated case by case. Mycophenolate sodium may also be
an option to mycophenolate mofetil, if there is intolerance to
this latter drug.
Facing the possibility of pregnancy, it is preferable to
administer AZA, considering the teratogenicity of MMF. Due to
the high cost of MMF and the favorable results for those milder
forms of LN, patients without markers of severity of LN and
who have had a complete response can be treated with AZA
as first choice in their maintenance phase.
Results of some studies and, especially, the opinion of
some authors suggest that AZA could be administered preferably in Euro-descendants,75 and MMF in African descendants
(Table 3).66
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
Membranous glomerulonephritis – induction
treatment
Membranous GN (MGN) is present in 10–20% of cases undergoing biopsy. This disease can occur alone or in association
with other histological classes.76 The usual expression of MGN
is the presence of proteinuria and edema without concomitant systemic manifestations, complement consumption or
presence of anti-ds-DNA (D).77 the classic features of GN, as
hematuria (dysmorphic), cellular casts, HBP and early elevation of serum creatinine, are infrequent. As with other
classes, MGN can also progress from a “silent” type, including
a slightly elevated proteinuria.78 On the other hand, nephrotic
syndrome (NS) occurs in up to 75% of patients,79 representing a greater risk of venous thrombosis (3–22%), including
renal veins (a still greater risk in patients with aPl),80,81 coronary artery disease (RR = 2.8) and acute myocardial infarction
(RR = 5.5).82 The association of MGN with proliferative forms
determines a worse prognosis and, even in isolated forms,
7–53% of patients progress to ERF in 10 years (C).80.82 Thus,
it is understood that despite MGN not being the most aggressive histological class in LN patients, we should not consider
it as a mild form of renal involvement.
Nonetheless, there are few studies available in the literature, and most of them evaluating small series, with
short periods of observation and varied treatment regimens with respect to doses of CS, concomitant use of MP,
use of angiotensin-converting enzyme inhibitors (ACEI) or
angiotensin receptor blockers (ARBs) and especially with heterogeneity of response criteria (reduction in proteinuria versus
CR/PR rates).
AZA is one of the more often used immunosuppressants
in the treatment of SLE patients and, by having a better safety
profile than other agents, this drug has been long used as a
CS-sparing agent and even in the treatment of milder GNs.
However, few prospective studies with this drug were published. In an open-label, prospective, multicenter study with
38 Asian patients on AZA associated with prednisone (without
pulse therapy with MP, or ACE inhibitors or ARBs), the results
were analyzed at 12 months with respect to CR (whose criterion was: stable or improved serum creatinine and proteinuria
<1.0 g/24 h) or PR (reduction in proteinuria of at least 50% with
sub-nephrotic level) rates. CR was achieved in 67% and PR in
22% of patients (refractoriness in 11%). The authors concluded
that the results with AZA were similar to, or better than, those
obtained with other regimens.83
Evidence of response to cyclosporine (CsA) was obtained
in a few studies, each with a small number of patients. One
open-label study followed 10 patients treated with CsA associated with prednisone for 24 months. The only response
criterion was the intensity of proteinuria decrease, but in
some patients, an increase in creatinine, secondary to this
agent, was observed. Thus, CsA does not seem to be a suitable option, except for refractory cases, with its use as an
alternative therapy.84
In some studies, CY has been used for induction in cases
of MGN. One of these studies prospectively followed 20
patients with MGN and NS; the induction was done with
oral CY (2.0–2.5 mg/kg/day) for 6 months in combination with
9
prednisone, with sequential reduction and maintenance
with AZA (without adjuvant therapy with ACEI and/or ARB
or pulse therapy with MP). The response was based on the
achievement of CR (proteinuria <0.3 g/24 h, stable serum
creatinine and a normal urinalysis) or PR (proteinuria >0.3
and <3.0 g/day, a stable creatinine). In 12 months, CR and PR
were achieved in 55% and 35% of patients, respectively.79
Cyclophosphamide was also evaluated in a randomized
controlled study comparing this drug with CsA and with
prednisone alone for induction of remission in GNM patients
with NS. CY IV was administered every two months for one
year (0.5–1.0 g/m2 BSA) and CsA daily (5 mg/kg/day) for 11
months; both medications were associated with prednisone
and ACE inhibitors, as decided by the assistant physician. CR
and PR rates obtained in 12 months with CY were 40% and
20%, respectively, compared with 50% for CR and 30% for PR
obtained for CsA and 13% for CR and 23% for PR with prednisone alone. Both immunosuppressants were superior to CS
used alone (p = 0.002); however, throughout the observation
period (12 months), there were more relapses with CsA versus
CY (p = 0.02) (B).85
MMF was used for induction of remission in GNM, although
in a few studies with a small number of cases, most of them
with no more than 20 patients. In 2010, a study gathered data
from two multicentric randomized controlled trials, with similar protocols previously published which evaluated responses
of the induction of remission in 6 months with regimens
including CY or MMF in patients suffering only MGN (n = 84).
Patients were treated with CY IV (0.5–1.0 g/m2 BSA monthly);
MMF was administered at a dose of 2–3 g/day, both for 6
months. No pulse therapy with MP was used. The majority
of patients were treated with ACE inhibitors. There was no
difference between groups regarding the percentage change
in proteinuria and serum creatinine, and CR was achieved by
only 1 (2.5%) patient, while PR was achieved by 60% of patients
in both groups. The analysis was limited to patients who completed treatment (analysis per protocol); furthermore, 23% of
cases were lost to follow up during the observation period after
six months (induction); nevertheless, the authors assumed
that the induction treatment for GNM with MMF have been as
effective as with CY,86 although in both groups (CY and MMF)
the rates of complete/partial remission were low (B).
MMF was also used for induction of remission in patients
with MGN as compared to tacrolimus (TAC). Yap et al. studied 16 patients with GNM and NS whose treatment was done
with MMF (7 cases) or TAC (9 cases), both associated with
prednisone, whose initial dose was 0.8 mg/kg/day (without
association of ACEI or ARB). In both groups an improvement
in proteinuria was observed, but remission rates were only
determined at 24 months (CR for MMF and TAC, 57% and 11%,
respectively, and PR for MMF and TAC, 11% and 44%, respectively). The authors demonstrated that the time to reach a
(complete) response to treatment was 15.3 months for MMF
and 21.7 months for TAC.6
It is also likely that, in cases of MGN, the concomitant
use of hydroxychloroquine (HCLQ) during induction treatment
is valid, as suggested by evaluation data from a prospective cohort that included 29 patients with a recent diagnosis
of this histologic class (34.5%) or in combination with PGN
(65.5%). Immunosuppressive treatment was done with MMF;
10
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
Table 4 – SBR recommendations for the treatment of membranous nephritis.
Recommendations
Agreement
Protocol for induction in membranous GN (class V)
CR or PR are the targets to be achieved in six months.
Immunosuppressants are recommended for all patients, because they are more effective than CS as
monotherapy.
Attention should be given to the exclusion of thromboses, including into renal veins, which are frequently
present with positivity for aPl.
The treatment should begin with MP pulse therapy [0.5–1.0 g IV (or 10–30 mg/kg/day in PSLE patients) for 3
days] followed by prednisone (0.5–1.0 mg/kg/day) for 3–4 weeks, with subsequent reduction and with the goal
to achieve a dose of 5–10 mg/day within six months.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
In conjunction with CS, CY IV 0.5–1.0 g/m2 BSA monthly for 6 months, or CY IV 0.5 g every 15 days for 3
months, or MMF (2–3 g/day) and AZA (2 mg/day) should be included.
a) 0.9; b) 0.1
Lack of response after 3 months of an appropriate therapy indicates the need to consider an early change of
induction protocol.
a) 0.9; b) 0.1
After 6 months of induction treatment, if CR or PR have not been achieved, LN is considered refractory, and a
new induction therapy with MP and an exchange of the immunosuppressive agent (CY, MMF or AZA) are
recommended.
a) 1.0
Protocol for maintenance in membranous GN (class V)
The modification of the treatment regimen for that of the maintenance phase depends on achieving CR or PR.
AZA or MMF are indicated for patients who have achieved CR or PR in the induction phase.
For patients who have not achieved a favorable response with AZA or MMF, switching to one another, or the
substitution by a calcineurin inhibitor or rituximab, should be considered.
These medications must be used for at least 36 months, but they can be kept for longer periods. Their
suspension should only be performed after achieving and maintaining a complete and continuous remission.
The doses of corticosteroids should be reduced progressively and, if possible, discontinued, ideally after
achieving and maintaining a complete and sustained remission.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 0.9; b) 0.1
Agreement: the numbers in each recommendation express the percentages of agreement among the members, according to the classification
used.
aPl, antiphospholipid antibodies; AZA, azathioprine; CY, cyclophosphamide; CS, corticosteroids; GN, glomerulonephritis; MMF, mycophenolate
mofetil; MP, methylprednisolone; LN, lupus nephritis; CR, complete remission; PR, partial remission; BSA, body surface area.
and among the 11 patients (38%) achieving complete renal
remission in 12 months, seven had been treated with HCLQ
compared with four patients without HCLQ (p = 0.036) (C).87
In summary, we can admit that, in relation to MGN, there
exists little scientific evidence to guide our clinical decisions,
but it is likely that we should not regard them as mild forms
of LN (Table 4).
Membranous glomerulonephritis –
maintenance treatment
Just as in PGN, the maintenance treatment in cases of MGN
also includes an immunosuppressive agent such as AZA or
MMF, in combination with prednisone at progressively lower
doses. Except for the ALMS study, there are no other randomized controlled trials examining AZA in the maintenance
of remission in patients with MGN. Nevertheless, this agent
has been widely used in most centers and Mok, in 2009, published the results of an open-label study with an observation
period of 12 ± 6 years, in which all patients received induction
with AZA and prednisolone. At the end of this long observation period, 35% had suffered relapses, and despite the need
for the use of other immunosuppressants and for increasing
doses of CS, 79% of patients had reached proteinuria values
lower than 1.0 g/24 h with preservation of renal function, and
21% had a proteinuria higher than 1.0 g/24 h, although still in
a subnephrotic level. The doubling of serum creatinine was
observed in 8% and no patient progressed to ERF.80 The study
design was not ideal and, furthermore, only included Chinese
patients; however, longer observation period and the favorable
results allow us to admit that AZA has potential for use in the
maintenance period (C).
In the ALMS study,71 which evaluated the maintenance
phase with MMF or AZA, only patients who had achieved a
favorable response in the induction phase were included. Most
patients presented PGN, but about 15% exhibited pure MGN
(18 cases in MMF group and 17 in AZA group), and for these
patients, there are no specific response data.
The recommendations of EULAR and ACR suggest the use
of either of the two medications (D).20,21 However, there is no
publication or consensus establishing the maximum time of
therapy, as well as how fast should be the reduction of the
selected medication.
CsA has been evaluated in a randomized controlled study
of induction and maintenance in the short-term (12 months)
and, when compared to the isolated use of prednisone, the
drug was more effective as regards the achievement of CR
(B).85 However, the period of one year does not allow us to
generalize the long-term response to this agent, especially if
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
one considers the high frequency of relapses during followup.
Some case series suggest the use of TAC, with less nephrotoxic potential in the patient’s maintenance.73,86 TAC could be
used in special cases, such as in patients with normal renal
function, negativity for aPl and persistently elevated proteinuria (D).
Although the results with CY for the maintenance phase
are not favorable compared with AZA or MMF, this medication
can also be considered as an alternative of exception for maintenance in patients with known poor adherence to treatment
(D).54,88
Although the existing data in the literature are inconsistent, we understand that, for the maintenance phase,
in addition to low doses of prednisone (ideally less than
10 mg/day), the most suitable agents are AZA (2 mg/kg/day) or
MMF (2–3 g/day) in combination with HCLQ and an adjuvant
therapy, as discussed below. In cases of MGN refractoriness,
one can consider the use of calcineurin inhibitors, especially
TAC and even RTX (Table 4).21
Renal involvement in the antiphospholipid
antibody syndrome – diagnosis and treatment
Renal involvement can occur in primary or secondary APS, but
the impact on prognosis in NL patients is still controversial.89
aPl (anti-cardiolipins, anti-␤2-glycoprotein I and lupus anticoagulant) may trigger intrarenal vascular lesions, determining
the development of an APS associated nephropathy (APSN).90
The clinical picture is characterized by HBP, nondysmorphic hematuria, proteinuria and worsening of renal
function, which may be acute, with rapid progression to dialysis; or chronic, with slow and progressive evolution.34,91–93
Acute renal artery thrombosis evolves mainly with an acute,
severe, difficult-to-control hypertension, with or without low
back pain, hematuria and acute renal failure.90 On the other
hand, renal vein thrombosis evolves mainly with proteinuria,
which can reach nephrotic levels and, if it occurs in a complete and acute form, may be associated with a sudden low
back pain and loss of renal function.90
Histopathological findings of APSN occur in 4–40% of
SLE patients, being more frequent in patients with a previous diagnosis of APS.34,89,91–94 Thrombotic microangiopathy
is the most important acute injury; it is characterized by
the presence of fibrin thrombi in glomerular capillaries and
arterioles.95 However, this injury is hardly found alone in
patients with SLE, given the frequent overlapping with the
histopathological changes of lupus nephritis.34 The following
chronic injuries are frequently found, although they have less
specificity for the diagnosis of APSN: fibrous intimal hyperplasia and the presence of organized thrombi with or without
recanalization, fibrous or fibrocellular occlusion of arteries
and arterioles, tubular tireoidization characterized by atrophy
of tubules with eosinophilic casts, and focal cortical atrophy with or without depression in the contour of the renal
capsule.95 The association of at least one acute or chronic
histopathological finding with the presence of aPl defines
APSN.95,96
11
The main differential diagnoses involve clinical conditions associated with clotting disorder or endothelial injury,
such as thrombotic thrombocytopenic purpura, hemolytic
uremic syndrome, malignant hypertension, diabetes, scleroderma renal crisis, pre-eclampsia (PE), drug toxicity (CsA and
chemotherapics) and renal transplant rejection.34,91–96
APSN was associated with lupus anticoagulant, ACL IgG
and beta 2 GPI, and even more often when two or more of these
aPl are present. However, during the vasoocclusive event these
antibodies may be temporarily absent.89,94,96
Echography with color Doppler, scintigraphy with 99m
Tc-DMSA and renal-vessel angiography assist in the identification of vascular involvement,97 but the histopathological
changes necessary for the diagnosis of APSN are identified by
renal biopsy.90
All patients with SLE and aPl must control the risk factors
for thrombosis: obesity, HBP, smoking, diabetes and dyslipidemia. Furthermore, these patients should avoid using
estrogen contraceptives and hormone replacement therapy
(D).98 In cases of venous thrombosis, anticoagulation is indicated indefinitely with an INR between 2.0 and 3.0 (B).99 In
cases of arterial thrombosis, although with this same recommendation, some authors advocate the combination of
anticoagulation with an antiplatelet agent or maintaining an
INR above 3.0 in recurrent cases (C).98 The use of statins could
also play an adjuvant role in the treatment of patients with
APS (C)98 and in patients with APSN, one should take into
account the use of HCLQ and an antiplatelet agent, or anticoagulation (B).21,100
Adjuvant therapy in lupus nephritis
In addition to the judicious use of immunosuppressive agents,
both in induction of remission as in the maintenance phase,
several other measures can also contribute positively, not only
to obtain a better control of the inflammatory process, but also
for the preservation of renal function in the long term. These
measures consist of non-pharmacological and pharmacological recommendations listed below:
(a) Provide dietary counseling for the prevention and control
of dyslipidemia, diabetes, obesity, HBP and osteoporosis.
Encourage a balanced diet with proteins, lipids and carbohydrates, with low levels of salt (D).101
(b) Consider vitamin D supplementation for all patients, with
doses 800–4000 IU/day, with sequential adjustments; the
serum levels of 25 (OH) vitamin D should remain above
30 ng/mL, although the clinical benefits are still negligible (B).102,103 Encourage a calcium-rich diet and consider
its supplementation in cases where there is a need, especially in patients treated with CS and in postmenopausal
women (C).101
(c) Avoid the use of nephrotoxic drugs, particularly nonsteroid anti-inflammatory drugs (NSAIDs) (C).104
(d) Strongly encourage smoking cessation (C).101
(e) Establish a strict control of blood pressure, targeting levels at or below 130/80 mmHg, in which there is a greater
chance of preservation of renal function (A).105 There is a
preference for the use of ACEI or ARB, whose efficacies
12
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are already well established for chronic kidney disease
from other etiologies, (a)106 and by their renoprotector and antiproteinuric effects. For that reason, these
agents should be used even in patients with normal blood
pressure levels. These drugs should be used with caution in cases of renal failure, since they can both cause
hyperkalemia, but can also reduce the filtration pressure,
with a subsequent decline in glomerular filtration rates
(A).107–110 The association of these classes of antihypertensive drugs appears to have an even greater antiproteinuric
effect; however, their impact on renal function in the
long term has not yet defined.110 The dose should be
adequate for a maximum antihypertensive and antiproteinuric effect, with monitoring of potassium levels and
renal function.21
(f) HCLQ is associated with higher rates of response to
treatment, lower frequency of relapses, less severe kidney damage, reduction of thromboembolic events and
increased survival; for all that, this medication is indicated for all patients with LN, both in their induction
and in maintenance phases, unless contraindicated
(B).20,21,87,111–114 An ophthalmologic evaluation should be
performed before starting the treatment and should be
repeated annually after five years of continuous use,
except in cases with increased risk for development of retinal toxicity: elderly patients; renal or hepatic dysfunction;
HCLQ >400 mg/day (>6.5 mg/kg/day); cumulative dose of
HCLQ >1000 g; or presence of prior retinal disease or maculopathy. In these cases, it is recommended an interval of
one year after starting the treatment with HCLQ.115
(g) Contraceptives containing estrogens should be avoided,
especially during the active phase of the disease, or if
the patient has a prior history of cardiovascular event
or of increased risk of occurrence of thromboembolic
events (B).116 The use of hormone replacement therapy
also should be avoided (B).117
(h) The treatment of dyslipidemia with statins should
be recommended for patients with LDL cholesterol
>100 mg/dL,20 despite the small number of studies involving patients with SLE (C).118,119
Refractory lupus nephritis
Despite the significant improvement in survival and in the
preservation of renal function in most patients with LN,
about 10–29% progress to ERF.16,120 This progression can occur
silently,78 or may be evident through the evolution, being more
common in patients who develop proliferative forms. In most
studies, at the end of the induction period, less than 50% of
the individuals achieve CR74 ; in clinical practice, a more realistic goal seems to be the achievement of PR or CR in a period
from 6 to 12 months. Cases that do not achieve CR or PR after
this time with an appropriate treatment could be classified as
refractory to the regimen instituted.
There are various clinical and/or laboratory aspects related
to refractoriness, and among these, the most common are:
LN appearance in adolescence, male gender, low blood levels
of complement, thrombocytopenia, elevated serum creatinine
and massive proteinuria at diagnosis of LN.11,121 Some factors
are directly related to the aggressiveness of glomerular inflammatory events, such as new episodes of renal reactivation,
particularly in the first 18 months of the disease, massive presence of crescents and/or vascular necrosis, histological transformation, or overlapping of lesions secondary to APS.122–128
On the other hand, the refractoriness to LN may be related to
other variables, such as delaying the start of an effective treatment, besides an impossibility of compliance with the treatment protocol, either by infection and/or temporary suspension of medicines, or by poor adherence to treatment.29,129–131
Patients with treatment-refractory lupus nephritis (RLN)
should be further evaluated for the presence of other possible causes of persistent proteinuria or renal function loss,
for example, use of nephrotoxic drugs, thrombosis of renal
veins/arteries, infections, and decompensated hypertension
or diabetes mellitus.20,21,29 Another condition that deserves
to be investigated is the overlapping of injury secondary to
tubulointerstitial nephritis (TIN) related, in most cases, to
the use of antimicrobial agents, too common in phases of
increased immunosuppression. The most suggestive findings
are hyperuricemia, hypokalemia, isosthenuria and renal tubular acidosis, as well as findings in the urinary sediment, which
may be the presence of a greater quantity of kidney tubule cells
in association with absence of findings indicative of active GN.
In isolated cases, other causes of proteinuria (glomerulopathy secondary to diabetes, syphilis, or to HIV or HCV infection)
can also co-exist, or may arise during the evolution, giving the
impression of refractoriness. In the case of RLN, a new renal
biopsy may be indicated, because this procedure may allow
the identification of lesions (like some of those above) or the
characterization of the presence of exclusively chronic lesions
– or characterization of the presence of pure chronic lesions –
and in the latter case, further immunosuppression would not
benefit the patient (A).131,132
After identifying a non-treatment responsive, persistent
inflammatory activity, RTX, an anti-CD20 monoclonal antibody, has been considered as therapeutic option. Published
studies of case series involving patients classified as refractory to treatment have shown good response in 47–89% of
cases.132,133 In a prospective controlled trial with RTX (LUNAR),
which included patients with LN, no superiority of RTX was
demonstrated, when this drug was used in combination with
MMF and CS versus placebo. But it is likely that these negative results were more due to the study design than the lack
of efficacy of the drug.134 Despite the lack of controlled studies demonstrating efficacy of RTX for treatment of LN, this
drug has been used with good results in most reference centers, and currently its use is recommended in the consensuses
of EULAR and ACR for patients considered refractory, both in
cases of PGN and MGN.20,21 The administration regimen and
doses used are similar to the recommendations for rheumatoid arthritis (two doses of 1000 mg, with an interval of 15 days)
(C).
Calcineurin inhibitors, including CsA, TAC and sirolimus,
are targeted to T cells. Among these agents, TAC in particular has been used alone or in combination with MMF in
the treatment of patients with RLN, mainly in small series
with patients of Asian origin. The results show a reduction
in proteinuria and benefits in relation to extra-renal manifestations, in addition to the possibility of its use during
13
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
Table 5 – SBR recommendations for the treatment of refractory lupus nephritis, APSN, LN in pregnancy, pediatric LN and
management in ERF.
Recommendations
Agreement
Refractory LN
LN should be considered refractory when CR or PR is not achieved after 12 months of an appropriate
treatment.
a) 1.0
Consider a new kidney biopsy to assist in identifying the cause of refractoriness and in therapeutic decision.
a) 0.9; b) 0.1
Rituximab is indicated, including cases with renal insufficiency.
Tacrolimus (alone or in combination with MMF) may be used as an alternative.
a) 1.0
a) 1.0
APSN associated to LN
Search aPl in patients with LN, due to the possibility of an association with APSN.
Maintain control of risk factors associated with vasoocclusive events in patients with aPl.
In patients with APSN, maintain INR close to 3 and consider the concomitant use of antiplatelet agents.
LN and pregnancy
SLE female patients should be advised not to become pregnant until disease remission for at least six months
and with a normal renal function.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
Pregnancy should be planned, including discontinuation of teratogenic medications (ARB, CY, coumarin, ACE
inhibitors, leflunomide, MMF and MTX).
a) 0.75; b) 0.25
Monitoring should be done by a multidisciplinary team throughout pregnancy and puerperium.
a) 0.9; b) 0.1
HCLQ should be used throughout pregnancy.
CS and AZA can be used during pregnancy.
a) 1.0
a) 1.0
LN in PSLE patients
The treatment of nephritis in PSLE patients is similar to that of adults, with dose adjustment of drugs
(AZA = 2.0–3.0 mg/kg/day, MP = 20–30; MMF = 30 mg/kg/day or 600 mg/m2 BSA/day); reinforce adherence at every
visit.
LN and ERF
Maintain the treatment by a rheumatologist even after RRT, including the use of HCLQ with adjustment of its
doses.
Extrarenal recurrences can be treated with CS, AZA and MMF (with adjusted doses).
Consider renal transplantation in patients with ERF (living or cadaver donor).
Special consideration should be given to patients with aPl, because of the risk of thrombosis in arteriovenous
fistula and vasoocclusive lesions with potential graft loss.
a) 1.0
a) 1.0
a) 1.0
a) 1.0
a) 1.0
Agreement: the numbers in each recommendation express the percentages of agreement among the members, according to the classification
used.
aPl, antiphospholipid antibodies; AZA, azathioprine; ARB, angiotensin receptor blockers; CY, cyclophosphamide; CS, corticosteroids; ERF, established chronic kidney disease; ACEI, angiotensin-converting enzyme inhibitors; SLE, systemic lupus erythematosus; PSLE, pediatric SLE; MMF,
mycophenolate mofetil; MP, methylprednisolone; MTX, methotrexate; LN, lupus nephritis; APSN, nephropathy of APS; CR, complete remission;
PR, partial remission; INR, international normalized ratio; RRT, renal replacement therapy.
pregnancy (class C). However, its known diabetogenic effect
should be taken into account, especially in patients with
metabolic syndrome, in addition to the thrombotic risk in
aPl positive patients (C).135–138 Belimumab, an anti-Blys antibody, was not specifically evaluated in patients with LN, but
in the two main studies with this agent approximately 10%
of patients had GN with proteinuria of up to 6 g/day. In the
analysis of this subgroup, the drug was effective in reducing the levels of proteinuria139,140 ; however, more studies are
needed to determine the efficacy of belimumab in this condition (Table 5).141
Nephritis in pediatric systemic lupus
erythematosus (PSLE)
In about 10–20% of patients with SLE, the onset of the disease occurs before reaching the age of 18, when the condition
is classified as PSLE,142,143 characteristically showing greater
activity, cumulative damage and disease severity compared to
the adults. Additionally, these patients show high frequency
of nephritis (in up to 80% of patients), neurological and hematological involvement and pulmonary hemorrhage.143–147
The treatment of nephritis in patients with PSLE is similar to the treatment of adults, but the severity and poor
adherence determine a higher annual cost.148 For this reason, in most centers of reference the current concept is that
one should emphasize adherence across all visits, particularly in the case of adolescents.147 A consensus document
published in 2012 for induction therapy of lupus PGN in children and adolescents suggested three regimens with CS: oral,
MP pulse therapy, or a combination of these two. However,
studies are lacking to determine which of these schemes
with CS is the most suitable for LN in the pediatric age
group.149 Prolonged exposure to corticosteroids should always
be avoided, reducing doses of prednisone to ≤10 mg/day
14
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
between 4 and 6 months21 and discontinuation of this drug,
whenever possible. As is recommended for adult patients,
HCLQ (5.0–6.0 mg/kg/day) is indicated in all cases of PSLE
nephritis.21 NL class I or II is generally controlled by CS
and HCLQ. For class III or IV, induction therapy is indicated
with a combination of HCLQ, CS and an immunosuppressive
agent: CY IV (0.5–1.0 g/m2 BSA/month for 6 months) or MMF
(30 mg/kg/day or 600 mg/m2 BSA/day). Maintenance therapy
is suggested with AZA (2.0–3.0 mg/kg/day) or MMF.150 A controlled study of LN in patients with PSLE suggests a therapeutic
response similar to that obtained in studies of adults with CY
or MMF.151 CY seems to have a better risk-benefit profile in
children and adolescents compared with adults,150 with rare
occurrences of primary ovarian failure (early menopause),152
besides facilitating adherence.149 The scheme with low doses
of CY (ET) has not been evaluated in the pediatric population.21
In cases of LN class V, drugs to reduce proteinuria – HCLQ, CS
and immunosuppressants (CY, MMF or AZA) – are indicated,153
despite the absence of adequate prospective studies evaluating these agents in pediatric populations.
Therapy with RTX (375 mg/m2 BSA/week for 4 doses) has
been used in refractory nephritis in PSLE patients,154 but this
scheme still requires studies with a larger number of patients.
To date, there is still no study of belimumab in children and
adolescents with lupus (Table 5).
Both CS and HCLQ can be employed for RRT, but myelotoxic
drugs such as methotrexate and CY should be avoided. Other
drugs such as AZA and MMF should be evaluated individually. Doses of immunomodulatory medications should not be
corrected and do not require an additional dose after dialysis
of the drugs already mentioned. There is no evidence on the
safety of the use of immunobiologicals in SLE patients on dialysis, but it is likely that in the event of such drugs are used,
there is no need of dosage readjustment, for these are high
molecular weight compounds not removable by dialysis membranes (D). All things considered, all SLE patients in RRT should
be monitored by the rheumatologist.
Renal transplantation (TxR) from cadaveric source has
proved a successful option since the 1950s, but its use
in patients with LN was questioned by the potential risk
of recurrence in the transplanted kidney. However, since
1975 it has been demonstrated that patients with SLE have
a behavior similar to other patients (Advisory Committee,
1975); and since that time, TxR procedures have been performed with a very low frequency of recurrence.173–175 Factors
such as an association with APS or high aPl titles176,177 and
donor type178 contribute to worse results, but these are not
hindering factors to this procedure in these patients (C)
(Table 5).
Lupus nephritis and pregnancy
Established chronic kidney disease in lupus
nephritis
Currently, about 10–29% of patients with NL develop ERF,
requiring renal replacement therapy (RRT).16 Data from the
United States Renal Data System (USRDS) show an increased
prevalence of LN as a cause of ERF, from 1.13 to 3.2% in the age
group 20–44 years, possibly related to an earlier definition of
diagnosis (USRDS 2011). As with in other countries, in Brazil
the mean age of patients with SLE at the onset of RRT is 38
years, much lower than that of patients with HBP (70 years),
diabetes mellitus type 1 (51 years) and DM type 2 (64 years)
(SBR 2014 census) (A).
Complication rates of ERF in SLE patients are similar to
other etiologies, but with higher frequency of fistula loss.155
There is also the possibility of renal function recovery, which
may occur after the implementation of dialysis in up to 28%
of patients, usually in the first 6 months of dialysis.156–158
Most patients remain in remission, but outbreaks of activity may occur.159–163 In fact, many symptoms of ERF may be
confused with manifestations of SLE, such as fever, arthralgia,
arthritis, alopecia, retinal changes, headache, serositis, hematological changes and reduced levels of complement fractions.
In this sense, non-renal SLEDAI score (SLEDAInr) which is
derived from SLEDAI, was validated as a useful instrument for
assessing activity in patients on RRT160,163,164 ; this tool can be
used in approaching those patients (B). The survival of patients
with SLE in RRT at 5 years ranges from 50 to 89% and the
mortality is typically multifactorial.157,158,162,164–172 Recently,
a prospective study showed an independent association of
disease activity at the start of RRT (with SLEDAInr >8) with
increased mortality at 5 years (B).9
The fertility rate in patients with SLE is considered normal;
however, severe renal failure and high doses of CS can cause
menstrual irregularities and amenorrhea.179 At the same time,
some immunosuppressants such as CY can induce ovarian
failure, and this complication depends on the patient’s age at
onset of medication, duration of treatment and, additionally,
the accumulated dose (D).180
Pregnancy in patients with SLE should be considered as
being a high-risk event; a multidisciplinary approach up to
puerperium is recommended. Studies report a two to threefold
increase in the frequency of disease activity during pregnancy
(C)181,182 and the occurrence of complications, especially in
women with moderate to severe disease (C).183
Women with SLE should be advised to avoid pregnancy
until the disease is in remission for at least six months
(D)184–186 and that GFR >50 mL/min.21 (D) Furthermore, the use
of improper medication for the period is avoided.187
The risk of obstetric and neonatal complication is higher in
women with SLE compared to the general population (A).188,189
However, in the last decades there has been a reduction from
43% (between 1965 and 1969) to 17% (between 2000 and 2003) in
fetal loss (D).190 The frequency of miscarriage is increased and
intrauterine fetal death is five times greater. Pre-eclampsia (PE)
occurs in over 20% versus 7.6% in the population without lupus;
on the other hand, intrauterine growth restriction (IUGR) is
also common, especially with pre-existing renal disease. Prematurity affects up to 33% of pregnancies and is associated
with HBP, use of CS at the time of conception and during pregnancy, disease activity, and presence of nephrotic proteinuria
and aPl (C).188,191
The independent risk factors for pregnancy loss in the
cohort at Johns Hopkins Hospital were: proteinuria in 1st
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):1–21
trimester, thrombocytopenia, APS and HBP (C).192 A systematic
review on the outcome of pregnancy in patients with SLE,
which included 1842 patients and 2751 pregnancies, identified
as main maternal complications: lupus activity (25.6%), HBP
(16.3%), nephritis (16.1%), PE (7.6%) and eclampsia (0.8%). Fetal
complications included abortion (16.0%), fetal death (3.6%),
neonatal death (2.5%) and IUGR (12.7%). The pregnancy failure rate was 23.4% and that of preterm babies, 39.4%. The
meta-analysis showed a positive association between active
nephritis and prematurity, HBP and PE (D).193
The main risk factors for PE are current or previous LN,
PE, lupus active at the time of conception, presence of native
anti-ds-DNA, low blood levels of complement, obesity and HBP
(A).188,191,194–196
It is mandatory to differentiate activity of lupus from physiologic changes of pregnancy, and activity of PE from activity of
NL, since the therapeutic approach will be absolutely distinct:
immunosuppression or interruption (D).196,197 This challenge
is even greater when these conditions coexist.
During pregnancy, the risk of LN reactivation goes from 20
to 30%186 and a multicenter study identified that LN increases
the risk of miscarriage, premature birth, PE and IUGR, but this
disease is not a contraindication for pregnancy, provided that
a careful planning of conception, monitoring and multidisciplinary treatment occur (C).198 In a series of Brazilian female
patients with SLE, the frequency of fetal loss was significantly
higher in those patients with LN and aPl (37%) and also in
those with LN but without aPl (26.6%) compared to patients
both without LN and aPl (12.2%) (C).199
A literature review conducted between 1962 and 2009 identified that all maternal deaths during pregnancy in patients
with LN occurred during disease activity and showed a correlation with infection (41.2%) or lupus complications (29.4%) (D)
(Table 5).200
SLE therapy in pregnancy
Pregnancy in a patient with SLE does not require any specific
treatment (D)20,21 ; however, if the woman is being treated with
HCLQ before conception, this agent should be continued during pregnancy, because it reduces the chance of reactivation
and possibly also the incidence of neonatal lupus. NSAIDs
should not be used in female patients with LN; these drugs
increase the risk of miscarriage, premature ductus arteriosus
closure and prolonged labor (D).196,201
Given that prednisone suffers placental inactivation, this
is the preferred CS for use in this period (D).202 Fluorinated
CS, as dexamethasone and betamethasone, cross the placental barrier and should be used to induce fetal lung maturation
in premature births (D).203
Prednisone should be used according to the seriousness of
symptoms (D),204 but in doses >20 mg/day this medication is
associated with gestational diabetes, HBP, PE and premature
rupture of membranes.191 When CS are used in the periconception period, these drugs are associated with a 1.7-fold
increase in the risk of cleft lip and palate (D).205
AZA (≤2 mg/kg/day) is considered safe during pregnancy,
although this drug has been associated with IUGR and with
higher rates of pregnancy loss (D).201
15
Due to the increased risk of thrombosis in women with
NS, the use of low-dose aspirin (100 mg/day) is indicated
throughout pregnancy, regardless of the presence of aPl.188
Methotrexate, CY, MMF, leflunomide, ACEI, ARB and coumarin
are considered drugs with proven teratogenic risk (D)201,202,205 ;
thus, ideally these agents should be discontinued at least 3
months before conception (Table 5).
Conflicts of interest
The authors declare that they have not received any kind
of advantage that resulted in influence on the concepts presented in this consensus and introduce the support received
for work done, related to the topic as potential conflicts of
interest. EM Klumb participated in clinical trials or received
personal/institutional aid sponsored by the pharmaceutical
industry [PI (Aspreva Pharm., BMS, GSK, Roche)]. CCD Lanna
participated in clinical trials or received personal/institutional
aid sponsored by PI (GSK and Roche). JCT Brenol participated in
clinical trials or received personal/institutional aid sponsored
by PI (Abbott, Astra Zeneca, BMS, GSK, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Wyeth). EMN Albuquerque
participated in clinical trials or received personal/institutional
aid sponsored by PI (Aspreva Pharm., BMS, GSK, Roche).
OA Monticielo participated in clinical trials or received personal/institutional aid sponsored by PI (Abbott, Anthera,
Aspreva Pharm., BMS, GSK, Pfizer, Roche). LTL Costallat participated in clinical trials or received personal/institutional
aid sponsored by PI (GSK). LC Latorre participated in clinical trials or received personal/institutional aid sponsored by
PI (Aspreva, GSK and Roche). FM Ribeiro participated in clinical trials or received personal/institutional aid sponsored by
PI (Aspreva Pharm., GSK). CAA Silva; EI Sato; EF Borba Neto;
MFLC Sauma and ESDO Bonfá declare no potential conflicts of
interest.
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r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Assessing the magnitude of osteoarthritis
disadvantage on people’s lives: the MOVES study
Luís Cunha-Miranda a,∗ , Augusto Faustino a , Catarina Alves b ,
Vera Vicente b , Sandra Barbosa c
a
b
c
Instituto Português de Reumatologia, Lisboa, Portugal
Eurotrials, Scientific Consultants, Lisboa, Portugal
AstraZeneca, Produtos Farmacêuticos Lda., Barcarena, Portugal
a r t i c l e
i n f o
a b s t r a c t
Article history:
Introduction: Osteoarthritis (OA) is one of the ten most disabling diseases in developed
Received 27 March 2014
countries and one of the leading causes of pain and disability over the world. Early diagnosis
Accepted 28 July 2014
increases the likelihood of preventing disease progression.
Available online 8 January 2015
Objectives: To estimate the prevalence of self-reported osteoarthritis and quality of life in
Portuguese adults with 45 or more years old.
Keywords:
Methods: Observational, cross-sectional study, implemented in households by face-to-face
Osteoarthritis
interview.
Quality of life
Results: 1039 subjects with mean age of 62 years and 54.2% female were included. The preva-
Self-report
lence of self-reported osteoarthritis was 9.9%. Knees and hands were the most frequent site
of disease. The prevalence of OA was higher in women and in participants without professional activity. Presence of OA was higher in participants with comorbidities. Most subjects
have done some treatment at some point in time for this disease: 94.5% had drug therapy, 49.5% physiotherapy, and 19.8% physical activity. Pain was associated with height, with
some disease locations specifically neck, lower spine and shoulders, SF12 scores of quality
of life, and measurements of impact in daily living, severity of disease and disability. The
impact of OA in daily living was greater in subjects that had been on sick leave or stopped
working due to OA, had worse physical and mental health, and with more severe of disease.
Conclusion: This study confirmed that osteoarthritis is a very relevant disease with a high
potential impact on quality of life, function and work ability and because of its prevalence
with a very high growing social impact.
© 2014 Elsevier Editora Ltda. All rights reserved.
∗
Corresponding author.
E-mail: [email protected] (L. Cunha-Miranda).
http://dx.doi.org/10.1016/j.rbre.2014.07.009
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
23
Avaliação da magnitude da desvantagem da osteoartrite na vida das
pessoas: estudo MOVES
r e s u m o
Palavras-chave:
Introdução: A osteoartrite (OA) é uma das dez doenças mais incapacitantes nos países desen-
Osteoartrite
volvidos e uma das principais causas de dor e incapacitação no mundo. O diagnóstico
Qualidade de vida
precoce aumenta a probabilidade de prevenção da progressão da doença.
Auto-relato
Objetivos: Estimar a prevalência de osteoartrite auto-referida e a qualidade de vida em
adultos portugueses com 45 ou mais anos de idade.
Métodos: Estudo observacional, transversal, implementado em domicílios por entrevista
interpessoal.
Resultados: Foram incluídos no estudo 1039 indivíduos com idade média de 62 anos, sendo
54,2% do gênero feminino. A prevalência de osteoartrite auto-referida foi de 9,9%. Os joelhos e as mãos foram o local mais freqüente da doença. A prevalência de OA foi maior em
mulheres e em participantes sem atividade profissional. A presença de OA foi maior em
participantes com comorbidades. A maioria dos indivíduos já tinham passado por algum
tratamento em alguma ocasião de suas vidas para esta doença: 94,5% tiveram tratamento
farmacológico, 49,5% fisioterapia, e 19,8% atividade física. A dor estava associada com a
estatura, com alguns locais da doença, especificamente pescoço, coluna lombar e ombros,
pontuação do SF12 para qualidade de vida, e medidas de impacto no cotidiano dos participantes, gravidade da doença e incapacitação. O impacto da OA no dia-a-dia foi maior em
indivíduos que tinham gozado licença por doença ou que pararam de trabalhar por causa da
OA, apresentavam-se com pior saúde física e mental, e exibiam maior gravidade da doença.
Conclusão: Este estudo confirmou que a osteoartrite é uma doença muito relevante, com
impacto potencial elevado na qualidade de vida, no funcionamento e na capacidade para
o trabalho e, por causa de sua prevalência, exerce um impacto social muito elevado e crescente.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Osteoarthritis (OA) is the most important rheumatic disease,
which affects all the components of joints, mainly the articular cartilage.1 OA is one of the ten most disabling diseases in
developed countries,1 and is thought to be the most prevalent
chronic joint disease.2 It is, by far, the most common form of
arthritis and one of the leading causes of pain and disability
worldwide.1,3
Pain is the main symptom of patients with OA,4 with significant impact on functional ability, causing severe disability
in activities of daily living, and being associated with considerable loss in productivity and decreased quality of life.4–7
Considered an age-related disease, it is most likely to affect
joints that have been continually stressed throughout the
years, including knees, hips, small hand joints, and lower
spine region.1,4,8
Worldwide, it has been estimated that 9.6% of men and
18.0% of women aged over 60 years have symptomatic
osteoarthritis.1 The main risk factors associated to OA are
age, gender (more frequent in women), obesity, metabolic or
endocrine diseases, trauma or joint overload, and also genetic
factors.8–10 However, the importance of individual risk factors
varies, and even differs, between joint sites.8 Many lifestyle
risk factors, however, are reversible or avoidable which has
important implications for its prevention. Early diagnosis
increases the likelihood of preventing disease progression to
situations of greater disability.
Because patients frequently disregard pain and symptoms,
OA tends to progress almost silently. Patients should know
their disease and have a prevention plan, avoiding mechanisms that may intensify progression of disease and using
pharmacological treatments that may prevent the structural
degradation of the joint.
The MOVES study aimed to estimate the prevalence of selfreported osteoarthritis and its impact on the quality of life, in
Portuguese adults with 45 or more years old. In this study, we
attempted to compare subjects with and without self-reported
OA in some of the parameters that may contribute to a worse
quality of life and loss of functionality.
Methods
This observational cross-sectional study took place in 17
municipalities of mainland Portugal between September 27th
and October 26th, 2011. To ensure representativity of the population, the sample was stratified by region (Norte, Centro,
Lisboa, Alentejo and Algarve, age and gender, according to
estimates of National Statistics Institute (Demographic Statistics 2008). The study was implemented in households, with
street selection by random procedure. Questionnaires were
administered by face-to-face interview, by specifically trained
24
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
interviewers. Subjects from the households selected were
invited to participate if they were aged >45 years and agreed
to participate in the study.
A sample size of 1039 participants was estimated to allow
the calculation of 95% confidence intervals (95%CI) for selfreported prevalence of osteoarthritis with a precision error of
1.8%.
Collected data included, for all responders, sociodemographic variables, professional activity and working
conditions, comorbidities, and self-reported aspects of the
disease. For subjects reporting OA, specific data was further
collected, including OA characterization (date of diagnosis,
symptoms, site of disease), working abilities and sick leave,
treatment and therapeutic characterization, and quality of
life and functionality (SF-12 v2.0). Additionally, subjects were
asked to answer to five visual analog scales (VAS) to measure
pain intensity, impact of OA in daily living, severity of disease,
disability level and patient’s perception of the importance that
the doctor gives to the disease.
Statistical analysis
Self-reported osteoarthritis prevalence estimates were calculated for the Portuguese population, stratified by region, age
and gender. Results were subdivided in two groups, subjects
with self-reported OA and subjects without self-reported OA.
The scores of SF-12 v2.0 were obtained with Health Outcomes
Scoring Software 4.5 and range between 0 and 100 (higher values
indicate better quality of life/health status).
Chi-square (CS) and Fisher exact tests (FS), for small
cell counts, were used to identify associations between
osteoarthritis and qualitative variables. The non-parametric
test of Mann–Whitney U was used to compare participants with and without osteoarthritis and quantitative
variables, since the assumption of normality was not
accepted (Kolmogorov–Smirnov). Association between quantitative variables was confirmed with Spearman correlation
coefficient. Multiple logistic regression analysis results for
the presence of self-reported OA are presented by odds ratio
(OR) and 95% confidence intervals. All tests were two-sided
considering a significance level of 5%. Statistical analyses were
carried out using IBM® SPSS® Statistics 18.
This observational study was registered in ClinicalTrials.gov, under the number NCT01423097.
Results
This study included 1039 participants with average age of 62
years (45–99 years old) and 54.2% female. Table 1 summarizes
the sociodemographic and anthropometric characteristics of
the total sample and by group (with or without OA).
Overall, approximately 72% of the sample lived with spouse
and/or children. Overweight was observed in almost half of
the subjects (47.0%), and obesity was present in 18.0%. 65% of
participants did not have professional activity, most of them
(76.2%) by retirement, not due to OA. The mean age of onset
of labor was 15.2 years (SD = 5.7).
Hypertension was the most frequent comorbidity (32.2%),
followed by diabetes (15.4%) and cardiovascular disorders
(14.2%). Approximately 30% of participants reported no illness.
The prevalence of self-reported osteoarthritis, in this study,
was 9.9% (95% CI: 8.1–11.7%).
The prevalence of OA was higher in women (13.3% versus 5.9%; p < 0.001), in subjects from Norte and in participants
without professional activity, as shown in Table 1. The participants with OA were older (median age = 64) and had less years
of education.
For the overall sample, the self-reported prevalence of OA
was 6.3% in the knees, and 5.5% and 3.1% in hands and feet,
respectively. Spine had a prevalence of 2.7%, and ankles and
hips, 2.2%. Fists, shoulders, elbows, neck and thoracic spine
all had prevalence’s under 2%.
Presence of OA was higher in participants with comorbidities (13.5% versus 1.6% without; p < 0.001). Subjects with OA
presented higher median number of comorbidities (2 versus 1
in subjects without OA; p < 0.001).
The prevalence of OA was associated with some of
the comorbidities: rheumatoid arthritis, depression, kidney
problems, intestinal disorders, osteoporosis, cardiovascular
disorders, diabetes and hypertension (Fig. 1).
The results of multiple logistic regressions for the presence
of self-reported osteoarthritis (Table 2) showed that the risk of
OA is 2 times higher for women, 2.6 times higher for subjects
with rheumatoid arthritis, and 1.8 times higher for those with
more comorbidities.
For the subgroup of subjects with self-reported OA, further data was collected in order to understand which variables
could have had some impact on the disease. Table 3 summarizes the evaluation variables of subjects with OA.
In this group of subjects, the average age at diagnosis was
52 years old (20–85 years), and the mean time between complaint and diagnosis was 3 years, ranging from 1 month to
35 years. The mean duration of disease was 13 years (1–56
years). In most cases, the general practitioner diagnosed the
disease (63.0%) and is the one who follows the patient (58.4%).
Approximately 92% of self-reported prevalent subjects had Xray confirmed diagnosis.
Among subjects with OA, knees and hands were the most
frequent site of disease (63.1% and 55.3% respectively), and the
thoracic spine the less frequent site registered (8.7%).
Approximately 30% of OA subjects have been on sick leave
at some moment in time or stopped working due to this condition. Absenteeism ranged between 3 days and 3 years. From
these, 41.4% changed their type of work, 34.5% change the
way of working for reasons related to OA, and 10.3% stopped
working completely because of the disease.
Most of OA prevalent subjects (88.3%) have done some
treatment for this disease at some moment in time: 94.5% had
drug therapy, 49.5% physiotherapy, and 19.8% physical activity; surgery and special diet were also referred. Approximately
84% of patients took NSAIDs to treat OA (42.0% used only
NSAIDs), 46.9% took analgesics (3.7% used only analgesics),
and 34.6% were on disease modifying drugs (6.2% used only
disease modifying drugs) (Table 3).
Most of the subjects reported the intake of analgesics
(52.4%) or anti-inflammatory drugs (86.9%) in the 3 months
previous to the study. On average, intake of analgesics
Table 1 – Sample characteristics.
Age (years)
Total (n = 1039)
Without self-reported OA (n = 936)
With self-reported OA (n = 103)
62.0 (45–99)
61.0 (45–99)
64.0 (45–87)
p-value
MW:0.002
Gender†
Female
Male
563
476
54.2%
45.8%
488
448
86.7%
94.1%
75
28
13.3%
5.9%
CS:<0.001
Region†
Norte
Centro
Lisboa
Alentejo
Algarve
355
262
284
94
44
34.2%
25.2%
27.3%
9.0%
4.2%
309
243
253
88
43
87.0%
92.7%
89.1%
93.6%
97.7%
46
19
31
6
1
13.0%
7.3%
10.9%
6.4%
2.3%
CS:0.036
Scholarship (years)
5.0 (0–26)
183
105
749
1
BMI (kg/m2 )†
Underweight
Normal weight
Overweight
Obesity
17.6%
10.1%
72.2%
0.1%
166
101
667
1
6
356
486
186
0.6%
34.4%
47.0%
18.0%
5
329
435
162
Professional activity†
369
35.5%
Comorbidities†
Hypertension
Cardiovascular disorders
Diabetes
Osteoporosis
Depression
Kidney problems
Intestinal disorders
Rheumatoid arthritis
Lung problems
Cancer
Liver problems
Gastric ulcer
Fibromyalgia
Other
334
147
160
100
87
51
43
25
29
52
16
19
5
197
32.2%
14.2%
15.4%
9.6%
8.4%
4.9%
4.1%
2.4%
2.8%
5.0%
1.5%
1.8%
0.5%
19.0%
No. of comorbidities
90.7%
96.2%
89.1%
100.0%
MW:0.020
17
4
82
0
9.3%
3.8%
10.9%
0.0%
83.3%
92.4%
89.5%
87.1%
26.7 (16.9–40.1)
1
27
51
24
16.7%
7.6%
10.5%
12.9%
342
92.7%
27
7.3%
CS:0.038
289
121
137
80
67
40
34
16
23
47
12
17
4
163
30.9%
12.9%
14.7%
8.6%
7.2%
4.3%
3.6%
1.7%
2.5%
5.0%
1.3%
1.8%
0.4%
17.4%
45
26
23
20
20
11
9
9
6
5
4
2
1
34
43.7%
25.2%
22.3%
19.4%
19.4%
10.7%
8.7%
8.7%
5.8%
4.9%
3.9%
1.9%
1.0%
33.0%
CS:0.008
CS:0.001
CS:0.041
CS:<0.001
CS:<0.001
CS:0.004
FS: 0.031
FS:<0.001
FS:0.059
CS:0.939
FS:0.065
FS:>0.999
FS:0.408
–
22.2 (15.2–42.2)
1.0 (0–8)
4.0 (0–19)
26.2 (15.2–42.2)
1.1 (0–6)
MW:0.068
CS:0.213
MW:<0.001
25
MW, Mann–Whitney; CS, Chi-square; FS, Fisher exact test; NA, Not applicable.
Values presented in median (minimum–maximum) except in categorical variables (†), presented n (%).
For comorbidities, the percentages were calculated within groups (with and without self-reported OA).
2.1(0–8)
NA
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
Living with†
Alone
With family/friends
Spouse/children
Retirement home
6.0 (0–26)
26
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
Rheumatoid arthritis**
Liver problems
Depression*
Kidney problems*
Intestinal disorders**
Lung problems
Osteoporosis*
Fibromyalgia
Cardiovascular disorders*
Diabetes*
No
Yes
Hypertension*
Gastric ulcer
Cancer
0%
5%
10%
15%
20%
25%
30%
35%
40%
% participants with self-reported osteoarthritis
* p < 0.050, Chi-square test.
** p < 0.050, Fisher exact test.
Fig. 1 – Association between comorbidities and osteoarthritis.
Table 2 – Logistic regression for the presence of
self-reported osteoarthritis.
OR
95% CI for OR
Gender
Male
Female
Ref.
2.017
[1.263;3.223]
Rheumatoid arthritis
No
Yes
Ref.
2.585
[1.027; 6.506]
No. of comorbidities
1.780
[1.499; 2.113]
of disease (rs = 0.557; p < 0.001) and disability level (rs = 0.587;
p < 0001).
Furthermore, we evaluated the parameters to which the
impact of OA in daily living (VAS) was related. Statistically
higher scores for the impact of OA in daily living were shown
by subjects that had been on sick leave or stopped working
due to OA (8.1 points versus 6.0 points; p = 0.001). In addition,
a higher impact of OA on daily living was associated with
worse physical health (rs = −0.582; p < 0.001), mental health
(rs = −0.460; p < 0.001), and with higher severity of disease
(rs = 0.506; p < 0.001).
Ref.: Category versus the one is making comparisons.
Discussion
occurred 4 days/week (1–7 days per week) during 6 weeks. The
intake of anti-inflammatory drugs occurred on average for 5
days/week during 7 weeks.
Results from VAS evaluation are shown in Table 3. On average, pain intensity adds up to 4.5 points while severity of
disease adds up to 5.9 points, considering a mean disability
level of 5.3. Impact on daily living scores 6.1 points on VAS,
being the most important parameter associated to this disease
from the patient’s perspective. Subject’s perception of doctor’s
importance to disease is scored with 6.4 points.
Analysis of SF-12 v2.0 demonstrated that overall score for
mental health registered a higher value than overall score for
physical health, suggesting that patients have a better quality
of mental life than physical (45.9 points [SD = 12.7] and 38.5
points [SD = 9.3], respectively) (Fig. 2).
Association tests have been done to understand which
variables relate to pain in OA. In the present study, pain was
associated with stature (rs = −0.221; p = 0.025) and some sites
of disease [neck (7.9 versus 4.2 points in OA of other sites;
p = 0.008); hands (5.0 versus 3.1 points in OA of other sites;
p = 0.029); spine (7.3 versus 4.1 points in OA in other sites;
p = 0.020); and shoulders (7.2 versus 4.1 points in OA in other
sites; p = 0.025)]. Pain was also associated with SF12 scores
of quality of life (physical health: rs = −0.479; p < 0.001 and
mental health: rs = −0.414; p < 0.001), and VAS measurements
of impact of OA in daily living (rs = 0.524; p < 0.001), severity
This epidemiological study aimed to evaluate osteoarthritis in
adult individuals over 45 years of age in Portugal. The results
suggest that the prevalence of self-reported OA in the Portuguese population with 45 or more years of age is between
8.1% and 11.7%. This result is similar to the prevalence results
reported in countries like Canada, United States, UK, Australia,
New Zealand, Belgium, and the Netherlands.11,12 The overall
prevalence of OA among Norwegian inhabitants was 12.8%,
being significantly higher among women than men.13,14 In
Dutch population with OA, the prevalence of knee osteoarthritis was higher than hip one, which is also reported in other
countries,12,14 as well as in our study in Portugal.15 In Poland,
OA was diagnosed in 14.7% of participants. The occurrence
of OA increased with age, being highest in the group aged
more than 50 years, and more frequent in women.14 Spain
has shown an estimated prevalence of symptomatic knee OA
of 10.2% in general adult population over 20 years old, and
6.2% for symptomatic hand OA. These results were mainly
related to a high rate of knee pain in women aged more than
55 years.14,16–18
However, most of the published studies11,13–15 report prevalence data from knees, hands and hip symptomatic OA.
Information about other sites of disease is very scarce.
This study uses self-reported information, which has some
limitations, once it did not require medical confirmation of
the diagnosis. As such, it is possible that some subjects report
as diagnosed when they were not, and, on the contrary, some
27
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
Table 3 – Characterization of subjects with OA.
With self-reported OA (n = 103)
Age at diagnosis, years (SD)
52.3 (12.0)
Time from complaint to diagnosis, years (SD)
2.9 (4.8)
Duration of disease, years (SD)
12.7 (10.4)
Site of disease
Knees
Hands
Feet
Lumbar spine
Hips
Ankles
Fists
Shoulders
Elbows
Neck
Thoracic spine
N
65
57
32
28
23
23
20
19
16
12
9
%
63.1%
55.3%
31.1%
27.2%
22.3%
22.3%
19.4%
18.4%
15.5%
11.7%
8.7%
Working abilities and sick leave (last year)
Changed the type of work due to OA
Changed the way of working due to OA
Reduced nr. of working hours due to OA
Did not work some days due to OA
Stopped working completely due to OA
Other
N
12
10
1
2
3
1
%
41.4%
34.5%
3.4%
6.9%
10.3%
3.4%
Have done any treatment (ever) for OA
Drug therapy
Physiotherapy
Physical activity
Surgery
Special diet
Other
91
86
45
18
9
1
7
88.3%
94.5%
49.5%
19.8%
9.9%
1.1%
7.7%
Drug therapy for OA over the last 3 months
NSAIDs
NSAIDs + Analgesics
NSAIDs + Analgesics + Disease modifying
Disease modifying
Analgesics + Disease modifying
NSAIDs + Disease modifying
Analgesics
Total
N
34
16
14
5
5
4
3
81
%
42.0%
19.8%
17.3%
6.2%
6.2%
4.9%
3.7%
100.0%
Visual Analog Scales – VAS (SD)
Pain intensity
Impact of OA in daily living
Severity of disease
Disability level
Subject’s perception of doctor’s importance to disease
4.5 (3.3)
6.1 (2.8)
5.9 (2.4)
5.3 (2.7)
6.4 (3.0)
Values presented in mean (SD) except in categorical variables (†), presented n (%).
Vitality
Social function
Mental health
Role physical
Pain
Role emotional
Physical function
General health
Mental health summary
Physical health summary
0
Worst state
10
20
30
Mean
40
50
60
Best state
Fig. 2 – Scores of quality of life and functionality (SF-12 v2.0).
28
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
might think they have been diagnosed with another condition
but were diagnosed with OA, implying a risk of false-positive or
false-negative diagnosis. In summary, assessment of disease
through self-report information can lead to some misdiagnoses, nevertheless self-reported information is considered
an important indicator of a person’s condition, even though
it is dependent on how one perceives and acknowledges his
or her disease.
Not surprisingly, in our study the most common sites for OA
were also knees and hands. However, despite high evidence
of hip OA reported in other countries,13,19–21 this has not been
demonstrated in this population.
Age, gender, obesity, injuries, occupation and physical
activity are some of the risk factors associated with OA
that have been extensively discussed previously on published
literature.14,22–24
The oxidative damage that occurs with age is one of
the main responsible for the development of OA. Women
are more likely to have OA than men and also to develop
more severe forms of disease. The results from this study
confirm these findings with prevalence of OA being higher
in women than in men, in line with results reported
from other countries.11,13,16,18,25,26 Also in line with other
studies,2,11,13,16,18,25,27 age was associated with OA, with a
higher median age in subjects with OA.
Some studies have shown that risk factors for OA of different localization may vary. In Italy, hip OA results showed
correlations with weight, genetic factors, gender, previous
traumas, occupational factors, and age, while knee OA had
great correlation with weight, lifestyle, and physical activity.14
Obesity and overweight have long been recognized a potent
risk factor for OA, especially OA of the knee.2,7,22,27 Also, BMI
appears to play important roles in determining disability of
individuals.28 In the present study, however, OA was not associated with BMI, as opposed to data from a population survey
in Norway,13 where BMI was significantly associated with hip
and knee OA.
It has been shown that, in OA patients, comorbid conditions may affect not only disease progression, but also
their psychological well-being, independently of the extent of
disease.29,30 In our study, the prevalence of OA was higher in
subjects with hypertension, cardiovascular disorders and diabetes. These comorbidities have also been reported by other
authors, along with depression, dyslipidemia or other musculoskeletal conditions.31–33 Our findings showed a risk of OA
higher for subjects with more comorbidities which result in
an increased need for attention, investigate and treat those
comorbidities in order to try to diminish the associated disability and decrease in QoL in patients with those conditions.
Our results showed that OA was associated with less years
of education and absenteeism, which was also one of the findings from the Norwegian13 and Spanish16,18 studies, in which
an increased occurrence of OA was observed in people with
less than 12 years of education and in those out of work.
Concerning absenteeism or working conditions associated
to OA, the results of the present study were in line with
those reported in the US,4 with similar percentage of subjects, changing type or way of working due to OA in our
study compared to overall work and activity impairment registered in US. Employment reduction due to OA might also be
dependent on the site affected by OA.34 In the US study,4 workers with OA pain reported significantly lower SF-12 health
status when compared to workers without OA pain. Likewise,
we also found lower scores on physical components which,
not surprisingly, have been proved to be associated to pain,
since OA and pain affect physical functioning.4,13,30
In our study, pain measured by VAS was also associated
with impact on daily living, severity of disease and disability
level. According to literature, pain relief is the main motivator in patients with OA seeking medical attention.14 Given the
relationship between pain and quality of life, it is important
to seek proper ways to provide patient’s with better quality of
life. It is important to understand the relationship between OA,
self-reported pain and disability measures, to develop a better
knowledge of the effect that OA has on a patient’s life, progression of disease, and effective pathways for intervention.29,30
For some authors,22,30 pain and function are assumed as
symptomatic outcomes of OA that may frequently be considered by patients as part of the pharmacologic efficacy
evaluation, associated with one’s perceptions of severity and
improvement. In our study, the results point out to a relationship between impact on daily living, severity and disability,
which were the outcomes most considered as being associated
to this disease, from the patients’ perspective. Statistically,
neck has been the most painful site of disease for the subjects in this study, which is quite uncommon in other similar
studies already published. Along with neck, also lumbar spine
and shoulders were statistically significant for pain and overall these pain levels might be responsible for the results, from
the patients’ perspective for impact on daily living and disability. Some studies5,14,28,29 reported that the presence of pain in
osteoarthritis of the hip and knees were strongly associated
with perceptions of disability in basic activities of daily living.
Associations between self-reported OA, severity and other
patient-reported outcomes indicate the clinical relevance
of asking patients to self-evaluate their condition.14 This
approach may represent an additional way to assess OA in
clinical practice, although further data is needed to confirm
the utility of this method.
Conclusion
There are a few studies assessing self-reported OA and its
impact on daily life. With this study we attempted to understand how patients are affected by this disease.
Our study confirms that the prevalence of osteoarthritis
was higher in women and is associated with age. Among subjects with OA, knees and hands were the most frequent site
of self-reported disease. OA was associated with fewer years
of education and absenteeism. Impact on daily living was
patients’ most important parameter associated to this disease,
which was also associated with worse physical and mental
health, and with higher severity of disease.
Overall, our study confirms that the impact of OA is very
significant on patients over 45 years old and that is also
present in patients with several other diseases. That might
indicate a profile of patient with lower global health status in
whom OA contributes for a diminished quality of life.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):22–30
In a growing-old population, that has to work for more
years, OA has to be considered in terms of prevention and
treatment in order to control the global impact of the disease
not only on patients, but also on society.
Financial support
This study was sponsored by Astrazeneca Produtos Farmacêuticos, Lda., Portugal.
Conflicts of interest
The authors declare no conflicts of interest.
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16. Carmona L, Ballina J, Gabriel R, Laon A, EPISER Study Group.
The burden of musculoskeletal diseases in the general
population of Spain: results from a national survey. Ann
Rheum Dis. 2001;60:1040–5.
17. Pueyo MJ, Surís X, Larrosa M, Auleda J, Mompart A, Brugulat P,
et al. Importancia de los problemas reumáticos en la
población de Cataluña: prevalencia y repercusión en la salud
percibida, restricción de actividades y utilización de recursos
sanitarios. Gac Sanit. 2012;26:30–6.
18. Fernandez-Lopez JC, Laffon A, Blanco FJ, Carmona L, EPISER
Study Group. Prevalence, risk factors, and impact of knee
pain suggesting osteoarthritis in Spain. Clin Exp Rheumatol.
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[internet]. Musculoskeletal health in Europe: Summary
report. Available from: http://eumusc.net/ [accessed
22.02.13].
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Lafuente I. Prevalence of knee and hip osteoarthritis and the
appropriateness of joint replacement in an older population.
Arch Intern Med. 2008;168:1576–84.
21. Thiem U, Schumacher J, Zacher J, Burmester GR, Pientka L.
Prevalence of musculoskeletal complaints and self-reported
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survey. Z Rheumatol. 2008;67:432–9.
22. Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin
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K, Cupps T, et al. Knee pain and radiographic osteoarthritis
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r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):31–36
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Comparison of the Disease Activity Score (DAS-28)
and Juvenile Arthritis Disease Activity Score
(JADAS) in the juvenile idiopathic arthritis
Renata Campos Capela, José Eduardo Corrente, Claudia Saad Magalhães ∗
Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, SP, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history:
Introduction: The assessment of the activity of rheumatoid arthritis and juvenile idiopathic
Received 20 February 2014
arthritis is made by means of the tools DAS-28 and JADAS, respectively.
Accepted 17 August 2014
Objective: To compare DAS-28 and JADAS with scores of 71, 27 and 10 joint counts in juvenile
Available online 27 November 2014
idiopathic arthritis.
Keywords:
cacy of abatacept was conducted in 8 patients with 178 assessment visits. Joint count scores
Method: A secondary analysis of a phase III placebo-controlled trial, testing safety and effiDAS-28
for active and limited joints, physician’s and parents’ global assessment by 0–10 cm Visual
JADAS
Analog Scale, and erythrocyte sedimentation rate normalized to 0–10 scale, in all visits. The
Juvenile idiopathic arthritis
comparison among the activity indices in different observations was made through Anova
Rheumatoid arthritis
or adjusted gamma model. The paired observations between DAS-28 and JADAS 71, 27 and
10, respectively, were analyzed by linear regression.
Results: There were significant differences among individual measures, except for ESR, in
the first 4 months of biological treatment, when five of the eight patients reached ACRPedi 30, with improvement. The indices of DAS-28, JADAS 71, 27 and 10 also showed
significant difference during follow-up. Linear regression adjusted model between DAS28 and JADAS resulted in mathematical formulas for conversion: [DAS-28 = 0.0709 (JADAS
71) + 1.267] (R2 = 0.49); [DAS-28 = 0.084 (JADAS 27) + 1.7404] (R2 = 0.47) and [DAS-28 = 0.1129
(JADAS-10) + 1.5748] (R2 = 0.50).
Conclusion: The conversion of scores of DAS-28 and JADAS 71, 27 and 10 for this mathematical
model would allow equivalent application of both in adolescents with arthritis.
© 2014 Elsevier Editora Ltda. All rights reserved.
∗
Corresponding author.
E-mail: [email protected] (C.S. Magalhães).
http://dx.doi.org/10.1016/j.rbre.2014.08.009
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
32
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):31–36
Comparação entre o Disease Activity Score (DAS-28) e o Juvenile Arthritis
Disease Activity Score (Jadas) na artrite idiopática juvenil
r e s u m o
Palavras-chave:
Introdução: A avaliação de atividade da artrite reumatoide e da artrite idiopática juvenil é
Artrite idiopática juvenil
feita por meio de instrumentos distintos, respectivamente pelo DAS-28 e pelo JADAS.
Artrite reumatoide
Objetivo: Comparar o DAS-28 e o JADAS com a pontuação de 71, 27 e 10 articulações, na
DAS-28
artrite idiopática juvenil.
Jadas
Método: Foram avaliadas 178 visitas em oito pacientes com artrite idiopática juvenil, participantes de um ensaio clínico controlado de fase III, testando eficácia e segurança do
abatacepte. Pontuaram-se as articulações ativas e limitadas, a avaliação global pelo médico
e pelos pais em escala analógica visual de 0-10 cm e a velocidade de hemossedimentação
convertida em escala de 0-10, em todas as visitas. A comparação entre os índices de atividade entre diferentes observações foi por Anova ou modelo ajustado Gama. As observações
pareadas entre o DAS-28 e o JADAS 71, 27 e 10, respectivamente, foram analisadas por meio
de regressão linear.
Resultados: Houve diferença significativa entre as medidas individuais, exceto a VHS, nos
primeiros quatro meses de tratamento com biológico, quando cinco entre os oito pacientes
atingiram a resposta ACR-Pedi 30, com melhoria. Os índices DAS-28, JADAS 71, 27 e 10 também apresentaram diferença relevante durante o período de observação. O ajustamento por
meio de regressão linear entre o DAS-28 e o JADAS resultou em fórmulas matemáticas para
conversão: [DAS-28 = 0,0709 (JADAS 71) + 1,267] (R2 = 0,49); [DAS-28 = 0,084 (JADAS 27) + 1,7404]
(R2 = 0,47) e [DAS-28 = 0,1129 (JADAS-10) + 1,5748] (R2 = 0,50).
Conclusão: A conversão da pontuação do DAS-28 e do Jadas 71, 27 e 10 por esse modelo
matemático permitiria a aplicação equivalente de ambos em adolescentes com artrite.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Juvenile idiopathic arthritis (JIA) has a chronic course and great
variability of outcomes, it may progress to spontaneous remission or be refractory to available treatments.1 JIA subtypes
represent different phenotypes, classified as oligoarticular (<5
joints), polyarticular (≥5 joints), systemic, arthritis related to
enthesitis, psoriatic arthritis, and undifferentiated or unclassified arthritis.2
In order to assess arthritis activity, it is essential to measure
the response to treatment, and early treatment is crucial to the
outcome. In children, the response to treatment, evaluated in
clinical trials, involves six primary outcome measures: physician’s global assessment, global assessment by the parents or
by the patient, joint count in absolute numbers of inflamed
joints and joints with limited range of motion, erythrocyte
sedimentation rate (ESR), and functional capacity index. The
minimum criteria for response (ACR Pedi 30) are defined as
improvement of at least 30% in three of six measures, with
not more than 30% of worsening in no more than one of these
parameters, representing a cutoff of response differentiation
in the treated group and in the placebo group in clinical trials.3
Currently, the improvements that are considered clinically significant are those in excess of 50, 70, 90%, or even the inactive
state of arthritis.4 However, these measures are related to the
response to treatment, and are not suitable as absolute measures of arthritis activity, because nature of calculation does
not allow absolute comparison of response between groups of
patients.
The most commonly used in rheumatoid arthritis (RA) are
the DAS5 (Disease Activity Score) and DAS286 in its simplified
version. JADAS7 (Juvenile Arthritis Disease Activity Score), with
three versions of joint scoring, was developed for JIA. Both
use the same components for the absolute assessment of
arthritis activity, including “active” joint count, physician’s
and patient’s or his/her parents’ global assessment, and laboratory tests, which may be ESR or C-reactive protein (CRP), and
is useful in clinical trials and in daily practice.8
DAS286 combines information on the number of painful
and swollen joints, with 28 joints being selected, as well as
ESR or CRP and patient’s global assessment measured on a
visual analog scale (VAS) from zero to 10 cm. DAS28 score is
calculated using a mathematical formula, and the activity of
arthritis can be interpreted in categorical scale.
JADAS score7 is performed by adding the four individual measurements: global assessment of arthritis activity by
the physician, in 10-cm VAS, global evaluation by the parents/patients as measured in the same 10-cm VAS, where 0
indicates no activity and 10, maximum activity, ESR and joint
count. There are three versions, scoring from 0 to 71, 0 to 27
or 0 to 10 joints.
Functional capacity is often assessed through a health
questionnaire, the Childhood Health Assessment Questionnaire (CHAQ),9,10 the corresponding version of the Health
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):31–36
Assessment Questionnaire (HAQ). Both evaluate the degree
of difficulty and independence in activities of daily life in
eight domains of functional capacity, also considering the pain
and discomfort through aggregated VAS (0–10 cm). Functional
capacity is included among the response measures of ACR Pedi
30.
The present study is a secondary analysis of a placebocontrolled, phase III clinical trial, to evaluate the efficacy
and safety of intravenous abatacept in patients with
active polyarticular JIA and unresponsive to treatment with
antirheumatic therapy with methotrexate (MTX).11,12 Patients
selected for clinical trials have more intense activity and are
resistant to conventional treatment, showing more enhanced
differences of clinical response. Thus, this sample was considered optimal to compare different continuous measures of
activity.
The aim was to explore score equivalence of the tool DAS28
and JADAS with scores of 71, 27 and 10 joints, respectively, in
children and adolescents with JIA.
Subjects and method
One hundred and seventy-eight visits were assessed of eight
patients with JIA who participated in a controlled clinical
phase III trial testing the efficacy and safety of abatacept11,12
and using the same evaluations at intervals of four to 12 weeks
of the original trial, a withdrawal study design,11,12 which
included an open-label phase of 4 months, double-blind phase
trial open-label extension phase of up to 5 years. In the doubleblind period, assessments were monthly performed, and in
other periods, complete assessments, including measures of
activity, were performed every 3 months. The same clinical,
laboratory and functional parameters of the clinical trial for
the calculation of activity rates of DAS28 and JADAS-71, 27, 10
were used. The protocol of secondary study was approved by
the Ethics Committee in Institutional Research (no. 345/2009)
of 14 September 2009.
Data were collected from first to last visit with complete
joint assessment. Of the eight subjects included, five completed the open phase of induction and the double-blind
phase, extension open-label phase. Of the five who concluded
the double-blind period, two were given placebo and three
were given the study medication. Three subjects concluded
the open period, but were not approved for the double-blind
since they did not reach ACR-Pedi 30 response, staying in the
open-label extension indicated by the protocol. Four subjects
left the study in the extension phase in different periods, due
to lack of medication efficacy, with change of treatment being
necessary. Three subjects concluded the 5 years of extension
phase.
Standardized joint assessment (it is more specific for the
technical procedure) was performed by the same observer
throughout the study. Within the same joint assessment of
each valid visit, JADAS-71, 27 and 10 were scored alongside
DAS28. To calculate JADAS 71, the score includes 71 joints, with
more comprehensive examination including the joints of the
lower and upper extremities, spine, and temporomandibular
joint. In JADAS-27, the following joints are scored: cervical spine, elbows, wrists, metacarpophalangeal from 1 to 3,
33
proximal interphalangeal, hips, knees and ankles. Regarding
JADAS-10, the upper score is 10, that is, if a patient has 15 or
20 active joints, the maximum score to be assigned will be
10.
JADAS final score is calculated by the sum of four components: global assessment of arthritis activity by a physician,
measured in a 10-cm VAS, where zero indicates no activity and
10, maximum activity; global assessment by parents/patients
also measured on a 10-cm VAS, where zero indicates no activity and 10, the maximum activity perceived by parents or
by the patient; active joints count of zero-71 joints and ESR
converted to a scale from zero-10 = [VHS mm/h − 20)/10] with
values over 120 mm/h being converted to 120.
The following joints were assessed for scoring DAS 28:
shoulders (2), elbows (2), wrists (2), metacarpophalangeal (10),
proximal interphalangeal (10) and knees (2). The joints with
pain and edema are independently scored, in addition to the
global assessment of activity by the patient, which in this
study was performed either by the parents or by the patient
him/herself, according to age, being measured on a 10-cm VAS
in which zero indicates no disease activity and 10, maximum
activity, according to the patient’s perception. In this study,
scales scores were performed by the parents regardless of age.
DAS28 score was calculated using the following formula in
Microsoft Excel:
√
DAS28 = 0.56 number of joints with pain(28)
√
+ 0.28 number of joints with swelling + 0.70 log n(ESR)
+ 0.014 global VAS.
Functional capacity, as an integral parameter for the calculation of ACR-Pedi-30 response, was assessed by the CHAQ score
with values of zero-3, with 3 meaning the maximum disability
scale.
Statistics analysis
A descriptive analysis was carried out of baseline variables
obtained during patient selection and with calculation of average, standard deviation, median and quartiles for quantitative
variables, as well as frequencies and percentages for qualitative variables.
A longitudinal analysis of variables was performed using
a repeated measure model through analysis of variance
(ANOVA) followed by Tukey’s multiple comparisons test for
data showing symmetrical distribution. The adjustment of a
generalized linear model for repeated measures, with Gamma
distribution, was performed for the data that showed an asymmetric distribution.
For comparative evaluation between DAS28 and JADAS in
three versions (71, 27 and 10), a linear regression was performed by applying the ANOVA test for data with normal
distribution. As for the comparison between JADAS-71, JADAS27 and JADAS-10, a model with Gamma distribution was
adjusted.
All analyses were performed using SAS for Windows, v.9.2.
In all tests, we used a significance level of 5% or the corresponding p-value.
34
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):31–36
Table 1 – Clinical, anthropometric, laboratorial, activity and functional parameters in eight patients during the first
evaluation of selection for the clinical trial.
Variables
Average
Age (months)
Weight (kg)
Height (cm)
No. of active joints
No. of limited joints
No. of joints with edema
No. of joints with pain
Physician’s VAS (0–10 cm)
Parents’ VAS (0–10 cm)
Pain VAS (0–10 cm)
CHAQ DI (0–3)
JADAS-71 (0–101)
JADAS-27 (0–57)
JADAS-10 (0–40)
DAS-28 (0–7.8)
ESR (mm/h)
137.6
31.9
135.5
24
20.3
19.6
12
5.5
3.6
3.2
1.2
10.1
8.7
7.9
4.8
36.2
Standard deviation
39.5
11.4
18.6
10.5
11.6
10
13.3
1.3
2.2
2.1
0.5
12
10
7.6
1
10.3
Median
Q1
136.2
32.4
139.7
20.5
16.5
20
8.5
5.8
3.1
2.4
1.2
6.1
5.7
6.1
4.8
35
110.8
23.4
124
18
15
12.5
4.5
5.3
1.8
2.2
0.8
0.4
0.4
3.9
3.9
30
Q3
162.3
39.4
149.5
30.5
26
28
11.5
6.3
5.6
5.3
1.8
14.1
11.5
13
5.2
45
Q1, first quartile; Q3, third quartile; VAS, visual analogical scale; CHAQ-DI, Childhood Health Assessment Questionnaire Disability Index; JADAS,
Juvenile Arthritis Disease Activity Score; DAS-28, Disease Activity Score; ESR, erythrocyte sedimentation rate.
Results
Three boys and five girls were assessed, all diagnosed with JIA
and aged 7–17 years, with a case classified as systemic and
seven as polyarticular, with two being positive for rheumatoid
factor (latex test). Clinical, anthropometric, laboratory and
activity variables of arthritis, including the functional indices
in the first evaluation, are presented in Table 1.
With the use of ANOVA a significant difference was found
in the visits which took place for selection and those after 4
months of treatment for all indices, when five patients met the
criteria of ACR Pedi 30 response, that is, there was improvement in 30% of at least three of the six key variables.
Longitudinal comparison showed that there was asymmetric distribution of CHAQ, DAS28, JADAS-71, 27 and 10 variables,
and the adjustment of the model with Gamma distribution
showed statistically significant difference within the assessments (p < 0.05), with the highest rates being in the first and in
the second evaluation, respectively, at the selection and after
4 months of biological treatment in open phase. The other
visits included a total of 30 serial evaluations, monthly, within
6 months of the double-blind phase, and quarterly in the evaluations that followed during the open-label extension. These
evaluations were compared, but no significant difference was
found in all the individual parameters for the calculation of
the indices and items of DAS28 and JADAS-71, 27 and 10. No
significant difference was observed within the respective versions of JADAS-71, 27 and 10. For this comparison, we also
adjusted a model with Gamma (p = 0.5) distribution.
The linear regression analysis of JADAS-71, 27 and 10 and
DAS 28 resulted in conversion formulas among the scales, the
regression analysis of which is shown in Fig. 1:
[DAS 28 = 0.0709 (JADAS-71) + 1.267] (R2 = 0.49).
[DAS 28 = 0.084 (JADAS-27) + 1.7404] (R2 = 0.47).
[DAS 28 = 0.1129 (JADAS-10) + 1.5748] (R2 = 0.50).
Discussion
The presented results support the equivalence between the
DAS-28 and JADAS in three versions, with joint counts of 71,
27 or 10, respectively, through longitudinal observation made
during a controlled clinical trial in polyarticular JIA. Besides
DAS28, there are other instruments used for RA, such as the
Clinical Disease Activity Index (CDAI), among others,13 but of
limited use in pediatric patients.
Continuous measures such as DAS28 and JADAS have the
advantage of establishing absolute values, identifying changes
in clinical status by a number on a continuous scale.13 The
straightforward calculation makes the method feasible in
daily practice, just as in clinical trials. However, there are few
publications reporting the use of DAS28 in JIA.7,8
Measures in absolute values provide better consistency of
assessment among physicians and allow patients to understand the significance of their disease activity via an absolute
number. The corresponding measures for JIA were recently
developed,7 and three versions of the tool JADAS allowed to
equate the different presentations of JIA according to the ILAR
classification.2
One must also consider that the joint counts of the DAS28
omit the lower limb joints,14 but in the JIA the involvement of
the lower extremities is predominant. Measures of perceived
activity of arthritis by the physician, the patient him/herself or
their parents, as well as ESR or CRP, implement the composite measures, weighing up several competing factors for the
activity status.
In JADAS validation study,7 as well as in a recent study,
which used CRP to replace ESR,15 results of JADAS-71, 27 and
10 kept the correlation among them and with the other activity
parameters. Also, McErlane et al.16 recently calculated JADAS
with only three variables, excluding ESR for broader applicability, and reported a correlation of measures and their metric
equivalence.
One must consider, however, that in this study VAS scores
by the patient him/herself as conceived in DAS28 was replaced
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):31–36
a
years and another diagnosed with RA at 17 could be evaluated
by calculating the equivalence of the instruments used.
8
y=0.0709x + 1.7546
R2=0.4913
7
35
6
DAS28
5
Conflicts of interest
4
3
The authors declare no conflicts of interest.
2
1
0
0
10
20
30
40
50
60
70
references
JADAS71
b
8
y=0.084x + 1.7404
R2=0.4745
7
6
DAS28
5
4
3
2
1
0
20
10
0
30
40
50
60
JADAS27
c
8
y=0.1129x + 1.5748
R2=0.5043
7
6
DAS28
5
4
3
2
1
0
0
5
10
15
20
25
30
35
JADAS10
Fig. 1 – Linear regression plots within values of DAS28 and
JADAS-71 (a), JADAS-27 (b) and JADAS-10 (c) and their
respective conversion equations (plots a, b, c).
by the score of the scale performed by the parents. It is also
known that, regardless of age, caregiver’s perception may substantially differ from the perception of the patient at any age.
Among the other limitations of this analysis we find the
small sample that limits the power of the study, and the selection of children enrolled in clinical trials. If, on one hand,
the population sample would provide greater variability of
activity, strict control of all measures and standardized joint
examination, by the same observer at regular intervals, in
addition to the parallel evaluation of response measures (ACRPedi-30) to establish responders, the response pattern in the
period of greatest activity when selecting for testing, were the
favorable points to test this equivalence.17
There is practical applicability of the results to patients
with JIA, because, besides the simple and direct score, the individual measures of clinical parameters can be conducted in
daily practice. The use of metric conversion may also be useful in specific situations of transition from adolescent to adult
condition. As an example, a patient diagnosed with JIA at 15
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et al. Long-term safety and efficacy of abatacept in children
with juvenile idiopathic arthritis. Arthritis Rheum.
2010;62:1792–802.
13. Fransen J, Van Riel PL. The disease activity score and the
EULAR response criteria. Rheum Dis Clin N Am.
2009;35:745–57.
14. Landewé R, Van der Hayde, Van der Linden, Boers M. 28-joint
counts invalidate the DAS-28 remission definition owing to
the omission of the lower extremity joints: a comparison with
the original DAS remission. Ann Rheum Dis. 2006;65:
637–41.
36
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):31–36
15. Nordal EB, Zak M, Aalto K, Bernston L, Fasth A, Herlin T, et al.
Validity and predictive ability of the juvenile arthritis disease
activity score based on CRP versus ESR in a Nordic
population-based setting. Ann Rheum Dis. 2012;71:1122–7.
16. McErlane F, Beresford ME, Baildam EM, Chieng A, Davidson J,
Foster HE, et al. Validity of three-variable Juvenile Arthritis
Disease Activity Score in children with new onset-juvenile
idiopathic arthritis. Ann Rheum Dis. 2013;72:1983–8.
17. Ringold S, Bittner R, Neogi T, Wallace CA, Singer NG.
Performance of rheumatoid arthritis disease activity
measures and juvenile arthritis disease activity scores in
polyarticular-course juvenile idiopathic arthritis: analysis of
their ability to classify the American College of Rheumatology
Pediatric measures of response and the preliminary criteria
for flare and inactive disease. Arhtritis Care Res.
2010;62:1095–102.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):37–42
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
The association of fibromyalgia and systemic lupus
erythematosus changes the presentation and
severity of both diseases?
Ana Luiza P. Kasemodel de Araújo, Isabella Cristina Paliares,
Maria Izabel P. Kasemodel de Araújo, Neil Ferreira Novo, Ricardo Augusto M. Cadaval,
José Eduardo Martinez ∗
Hospital Complex of Sorocaba and Pontifícia Universidade Católica de São Paulo (PUC-SP), Sorocaba, SP, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history:
Introduction: The association of fibromyalgia (FM) and systemic lupus erythematosus (SLE)
Received 19 August 2013
has been investigated, with conflicting results regarding the impact of a condition on the
Accepted 26 August 2014
other.
Available online 28 November 2014
Objectives: To determine the frequency of FM in a sample of patients with SLE treated at the
Hospital Complex of Sorocaba (CHS) and the impact of FM in SLE activity and quality of life,
Keywords:
as well as of SLE in FM.
Fibromyalgia
Materials and Methods: Descriptive and correlational study. Patients who met the American
Systemic lupus erythematosus
College of Rheumatology (ACR) criteria for SLE and/or FM were included. The total sample
Clinical activity
was divided into three groups: FM/SLE (patients with association of SLE and FM), SLE (SLE
Quality of life
patients only) and FM (FM patients only). The following variables were used: Fibromyalgia
Association
Impact Questionnaire (FIQ), activity index of SLE (SLEDAI), Indices of Diagnostic Criteria for
Fibromyalgia 2010 (SSI end GPI) and SF-36.
Results: The prevalence of patients with FM among SLE patients was 12%. FIQ showed no
difference between groups, indicating that SLE did not affect the impact caused by FM alone.
The presence of FM in SLE patients did not influence the clinical activity of this disease. A
strong impact of FM on the quality of life in patients with SLE was observed; the opposite
was not observed.
Conclusions: The prevalence of FM observed in SLE patients is 12%. The presence of FM
adversely affects the quality of life of patients with SLE.
© 2014 Elsevier Editora Ltda. All rights reserved.
∗
Corresponding author.
E-mail: [email protected] (J.E. Martinez).
http://dx.doi.org/10.1016/j.rbre.2014.08.003
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
38
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):37–42
A associação fibromialgia e lúpus eritematoso sistêmico altera a
apresentação e a gravidade de ambas as doenças?
r e s u m o
Palavras-chave:
Introdução: A associação da fibromialgia (FM) e de lúpus eritematoso sistêmico (LES) tem
Fibromialgia
sido investigada com resultados conflitantes em relação ao impacto de uma condição na
Lúpus eritematoso sistêmico
outra.
Atividade clínica
Objetivos: Determinar a frequência de FM em uma amostra de pacientes com LES atendidos
Qualidade de vida
no Conjunto Hospitalar de Sorocaba (CHS) e o impacto da FM na atividade do LES e na
Associação
qualidade de vida, bem como do LES na FM.
Material e métodos: Estudo descritivo e transversal. Incluíram-se pacientes que preenchem
os critérios de classificação para LES e/ou de FM do Colégio Americano de Reumatologia
(ACR). A amostra total foi dividida em três grupos: FM/LES (pacientes com associação LES
e FM), LES (somente pacientes com LES) e FM (somente pacientes com FM). As seguintes
variáveis foram Questionário de Impacto da Fibromialgia (FIQ), Índice de Atividade do Lúpus
Eritematoso Sistêmico (Sledai), Índices dos Critérios Diagnósticos de Fibromialgia de 2010
(IGS E IDG) e o SF-36.
Resultados: A prevalência de pacientes com FM entre os pacientes com LES foi de 12%. O
FIQ não apontou diferença entre os grupos e indicou que o LES não interferiu no impacto
causado pela FM isoladamente. A presença da FM em pacientes com LES não influenciou a
atividade clínica dessa doença. Observou-se um forte impacto da FM na qualidade de vida
nos pacientes com LES e não foi observado o contrário.
Conclusões: A prevalência de FM observada nos pacientes com LES é de 12%. A presença de
FM afeta adversamente a qualidade de vida dos pacientes com LES.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Fibromyalgia (FM) is a rheumatic condition that has as main
features a diffuse chronic pain, hyperalgesia and allodynia.
Fatigue, sleep disturbances, morning stiffness, headache and
paresthesia are symptoms often present.1 Comorbidities like
depression, anxiety, irritable bowel syndrome, myofascial
pain syndrome and nonspecific urethral syndrome are also
associated.2
This syndrome, whose etiology and pathogenesis have not
been fully elucidated yet, has as its most important mechanism the amplification of the transmission of painful stimuli,
with changes in the perception of pain.1 An imbalance in neurotransmitters involved in the physiology of pain was also
observed. Among other abnormalities, na increase of substance P and nerve growth factor in the cerebrospinal fluid
(CSF) of individuals with fibromyalgia was found.3
Although few Brazilian epidemiological data have been
published, some studies show a prevalence of about 2.5% in
the general population; mostly they are women aged 35–44
years old.4 The mean age of patients is around 29.8 years old.
A relationship with low family income was also noted.5
The clinical assessment can be done through scales of
intensity of symptoms, by specific instruments to assess the
disease like the Fibromyalgia Impact Questionnaire (FIQ),6 and
by generic questionnaires on quality of life.7
Systemic lupus erythematosus (SLE) is an inflammatory
autoimmune disease involving multiple organs, especially the
skin, joints, kidneys, blood vessels, heart and lungs. It is a rare
disease, with more frequent incidence in young women, i.e., in
the reproductive phase, in a ratio of nine to ten women to one
man, and with its prevalence ranging from 14 to 50/100,000
inhabitants.8–12
SLE causes significant morbidity and mortality due to
inflammatory disease activity, infectious processes secondary
to the disease-induced immunosuppression and its treatment, and to cardiovascular complications.13
The disease assessment can be made by clinical observation, laboratory tests and imaging studies of the organs
involved, evidence of inflammatory activity, evidence relating
to autoimmunity, specific questionnaires for the assessment
of disease activity such as the Systemic Lupus Erythematosus
Disease Activity Index (SLEDAI)14 and generic questionnaires
to assess quality of life.15
The association of FM and SLE has been investigated by several authors, with conflicting results regarding the impact of a
condition on the other.16–22 The prevalence of a concomitant
association between the two diseases is around 20%.16 Thus,
the presence of FM in SLE patients is much greater than in the
general population. No study of this association was held in
the Brazilian population; and taking into account the personal
and cultural nature of the impact of chronic diseases on the
quality of life, we believe that knowing the nature of this association in a Brazilian sample can contribute to this discussion.
The objectives of this study are to determine the presence of
FM in a sample of patients with SLE treated at the Hospital
Complex of Sorocaba (CHS) and the impact of FM on SLE clinical activity and on the quality of life of these patients, as well
as of SLE in FM.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):37–42
Materials and methods
This is a descriptive cross-sectional study involving patients
from the Rheumatology outpatient clinic, Sorocaba Hospital
Complex (CHS). Female patients who met the American College of Rheumatology (ACR) criteria for SLE and/or FM were
included.23,24
The patients were assessed by a rheumatologist who
checked the fulfillment of ACR criteria. The total sample was
divided into three groups: FM/SLE (patients with an association of SLE and FM), SLE (SLE patients only) and FM (FM
patients only).
Data were obtained from medical records and through
interviews conducted for the questionnaires’ administration,
since the medical records of patients with SLE did not present
specific tools for FM; and the medical records of patients with
FM had no specific tools for LES. Besides these, the following
data were obtained through questionnaires: disease duration,
clinical activity and severity of the disease, and the impact
on the patients’ quality of life. The instruments used in this
assessment are described below.
The number of patients in each group was determined
by the number of patients with the association of SLE and
FM in the outpatient clinic of CHS. Twenty patients were
selected for each group. During the study, patients who were
lost to follow-up with the rheumatologist for unknown reasons were excluded, as well as patients whose data on their
medical records were incomplete and patients whose questionnaires were not fully answered. There was no refusal by
any patient to answer the questionnaires. Although the number of subjects in this research can be considered small, the
study design aimed to show the reality of a particular service and, therefore, a number compatible with the size of the
outpatient clinic where the study was conducted was used.
Despite the exclusions, a number of 20 for each group was
reached.
The impact of SLE on FM was evaluated using FIQ,25
which proved to be a valid and reliable instrument to measure functional capacity and health status of these patients.
FIQ consists of questions that evaluate the difficulty that FM
imposes on day-to-day activities, the occupational impact and
the intensity of the main features of the syndrome. The FIQ
total score ranges from 0 to 100, 0 being the milder impact
and 100 being the worst impact. This is a specific instrument;
therefore, it should only be used in groups with patients who
meet the classification criteria for FM and not in the SLE-only
group.
SLEDAI16 was used to evaluate the activity index of SLE
and the impact that FM may have on this condition, using
clinical parameters present in SLE. SLEDAI is a scale that
assesses 24 variables associated with SLE activity and grouped
into nine systems, wherein the presence of each commitment receives different weights; thus, weight 8 to lesions of
the central nervous system and vascular injuries; weight 4 for
renal, musculoskeletal and osteoarticular disorders; weight 2
for skin, serous and immunological changes; and weight 1 for
constitutional and hematological symptoms. The scores were
obtained from the medical records on the day the questionnaire was administered. SLEDAI is a specific instrument; thus,
39
it should only be used in groups with patients who meet the
classification criteria for SLE and not in the FM-only group.
Through the Symptom Severity Index (SSI),26 the severity of
the main symptoms in patients with FM, except for the pain,
was verified. This questionnaire has a range from 0 to 12, 0
being the lowest and 12 the highest intensity of symptoms.
Generalized Pain Index (GPI)26 was used to evaluate the
extent of pain. GPI shows the number of areas of the body
having pain. This index varies between 0 and 19.
Both GPI and SSI are indexes that comprise the Preliminary
Diagnostic Criteria for Fibromyalgia, 2010.26 By being specific,
GPI and SSI are instruments that should only be used in groups
of patients who fulfill the criteria of classification for FM and
not in SLE-only groups.
SF-3627 is a generic questionnaire for assessing the quality of life, consisting of eight domains: functioning capacity,
physical limitations, general health, vitality, mental health,
and social and emotional aspects. Each scale has a score ranging from 0 to 100, where zero is the worst possible quality of
life and 100 the best QoL scenario.
For the analysis of the results, the following tests were
used: Mann–Whitney test with the aim of comparing the FM
and FM/SLE groups in relation to the FIQ and SSI values; analysis of variance of Kruskal–Wallis for the purpose of comparing
SLE, FM and FM/SLE groups with respect to the values of VAS,
GPI and the eight domains of SF-36; and the chi-squared test
with the aim of comparing SLE, FM and FM/SLE groups with
respect to percentages of presence of hypertension, diabetes
mellitus and osteoarticular diseases.
Results
Sixty patients with FM, SLE and FM associated with SLE
were studied from September 2011 until August 2012, being
distributed equally into three groups, namely, FM, LES and
FM/LES. The prevalence of patients with FM among patients
with SLE followed at CHS was 12%. The average age of the interviewed patients was 44 years for FM group, 40 for SLE group
and 43.5 for FM/LES group.
Similarly, the presence of co-morbidities – diabetes mellitus (DM) and systemic arterial hypertension (SAH) – showed
no significant difference. The variables “diagnosis of depression prior to the study” and “other osteoarticular diseases
(OAD)” were more present in FM-presenting groups (Table 1).
Regarding OAD, patients with FM referred myofascial pain
(5 patients), low back pain (4 patients) and tendinopathy (6
patients). Patients with SLE reported tendinopathy (7 patients)
and low back pain (4 patients). On the other hand, patients of
FM/SLE group mentioned arthritis (1 patient), tendinopathy (7
patients) and low back pain (10 patients).
Table 2 shows the clinical characteristics and impact on
quality of life. The comparison of the impact of fibromyalgia
by FIQ showed no statistically significant difference between
FM and FM/SLE groups, indicating that LES did not affect
the impact of FM alone. Although no level of significance
(p = 0.0881) was observed, there is a tendency that, in this sample, patients with FM in association with SLE present a minor
impact on quality of life than those only with FM.
40
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):37–42
Table 1 – Clinical data of patients evaluated.
Variables/groups
Age of disease onset (median)
Presence of DM (n, %)
SAH (n, %)
Presence of OAD (n, %)
Presence of previous depression (n, %)
FM
SLE
SLE/FM
P
36
2 (10%)
6 (30%)
15 (75%)
16 (80%)
28
0
12 (60%)
11 (55%)
3 (15%)
31.5/35.5
1 (5%)
8 (40%)
18 (90%)
12 (60%)
0.0638
0.3499
0.1496
0.0426a
0.0001a
n, number; DM, diabetes mellitus; SAH, systemic arterial hypertension; OAD, osteoarticular diseases; p < or > 0.05.
a
FM and SLE/FM > SLE.
Considering that the patients were studied in the tertiary
sector of health care, in the case of patients with fibromyalgia we expect an important participation of emotional issues
such as depression. In the present study it was not possible to
conclude what is the influence of depression on the quality of
life of the two groups, since this variable has not been studied
with specific instruments.
Through GPI and SSI, we observed a greater intensity of
symptoms of fibromyalgia in patients who only had this
syndrome, in comparison with those FM patients with an
association with SLE. This finding may explain the tendency
for a lower impact, cited above, observed with the use of FIQ.
The presence of FM in SLE patients did not influence the clinical activity of this disease, when assessed by SLEDAI.
Regarding the quality of life measured by SF-36, it can be
seen that the groups with FM had a more negative physical,
social, emotional and mental impact, when compared to the
SLE-only group in all its scales. The domains most affected
by fibromyalgia were physical aspects, pain and emotional
aspects. In SLE patients, this analysis did not detect differences between domains. On the other hand, in the group
FM/LES the most altered scales were also physical and emotional aspects – thus, a finding similar to the FM group, again
suggesting a strong influence of FM in SLE, and not otherwise.
Discussion
SLE is an autoimmune disease that can affect various organs,
especially the skin, musculoskeletal system and kidney,
among others.10 The literature has pointed to a higher
prevalence of FM in patients with SLE, than in the general
population. The prevalence identified of FM in SLE patients
in this study was 12%, slightly lower than that found in the
literature,16–22 ranging from 17 to 22%.
In the evaluation of the characteristics of pain and symptom intensity through VAS, GPI and SSI questionnaires, the
worst performances occurred in the groups presenting FM
alone or in association with SLE. Thus, the presence of FM has
a significant negative impact on the quality of life of patients
with SLE. It should be emphasized, however, that most of the
patients pertaining to the group of SLE in this study presented
no disease activity (SLEDAI = zero).
These findings are in agreement with the literature, since
studies have shown that FM, besides being common in SLE
patients, is the primary determinant of the frequency and
severity of symptoms. In addition, FM causes incapacity for
daily activities.17 Therefore, it is likely that a better control
of FM would result in improvement in the quality of life of
patients with SLE.
In most SF-36 domains, we observed a worse outcome in
the FM-only group. The FM/SLE group showed intermediate
values, which may indicate that FM contributes to the worsening of health status. These patients are more symptomatic and
dysfunctional than patients exclusively with LES. Fibromyalgia causes a significant negative impact on the quality of life of
patients, showing a strong correlation with intensity of pain,
fatigue and decreased functional capacity.18,28,29
According to a Canadian study, the presence of FM in SLE
patients was not related to an increase of the parameters that
Table 2 – Data from clinical activity and impact on quality of life.
Variables/groups
FIQ
SLEDAI
GPI
SSI
SF-36 functional capacity
limitations due to
physical aspects
Pain
General health
Vitality
Social aspects
Limitation due to emotional
aspects
Mental health
Variables/groups
FM
SLE
SLE/FM
P
71.3
–
15.05
10.4
30.75
–
0.1
–
–
70.25
59.89
0.3
11.75
8.2
48.25
0.0881
0.9892
0.0001
0.0152
0.0008
87.5
17.9
45.5
21.25
44.43
35
73.68
63.25
59.75
76.25
71.25
37.6
37.85
33
55.63
0.0004
<0.0001
0.0067
0.0009
0.0023
88.23
33.15
33.3
70.8
73.3
38
0.0014
0.0003
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):37–42
make up SLEDAI; however, the presence of FM has a strong
correlation with the eight domains of SF-36.29 Thus, FM is not
related to disease activity in SLE, but can generate a misinterpretation of its activity, due to the clinical features of FM,
besides contributing to worsening the quality of life in patients
with SLE.29
Despite the contribution of FM to the worsening of the
health status of patients with SLE, it has been shown in the
literature that FM causes little or no impact on the activity of
SLE,19,29 which corroborates the findings of our study, where
no change in SLEDAI of respective groups (SLE, FM and SLE/FM)
was noted.
In our study, patients with SLE presented with a stable clinical picture; thus, our results may not reflect the reality in the
acute phases of SLE.
The sample of patients with both FM and SLE differs in
relation to what is observed in the community. Patients with
FM are those individuals refractory to a standard treatment,
since they are seen at a tertiary level center, while SLE patients
are generally treated at tertiary centers. Therefore, our sample may not reflect the general population of patients with
fibromyalgia. A complement to this study intends to propose
the assessment of patients seen at primary and secondary
sectors.
Conclusion
The frequency of FM observed in patients with SLE treated
at CHS is 12%. The patients had a mean age of 40–44 years
in the three groups. The presence of SLE has not determined
a greater impact on quality of life of patients with SLE/FM,
when assessed by FIQ. FM, in turn, also did not result in higher
levels of LSE activity measured by SLEDAI. A higher intensity of
symptoms in the FM-only group, in relation to the association
SLE/FM, was noted. The presence of FM adversely affects the
quality of life of patients with SLE.
Funding
Grant PIBIC-CNPq for Medicine students.
Conflicts of interest
The authors declare no conflicts of interest.
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r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):43–47
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Evaluation of grip strength in normal and obese
Wistar rats submitted to swimming with overload
after median nerve compression夽
Josinéia Gresele Coradini a , Camila Mayumi Martin Kakihata a , Regina Inês Kunz a ,
Tatiane Kamada Errero a , Maria Lúcia Bonfleur a,b , Gladson Ricardo Flor Bertolini a,c,∗
a
Universidade Estadual do Oeste do Paraná, Cascavel, PR, Brazil
Universidade Estadual de Campinas, Campinas, SP, Brazil
c Health Sciences Applied to the Locomotor Apparatus, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão
Preto, SP, Brazil
b
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To verify the functionality through muscle grip strength in animals with obesity
Received 16 September 2013
induced by monosodium glutamate (MSG) and in control animals, which suffered compres-
Accepted 26 August 2014
sion of the right median nerve, and treated with swimming with overload.
Available online 26 November 2014
Methods: During the first five days of life, neonatal Wistar rats received subcutaneous injec-
Keywords:
divided into six groups: G1 (control); G2 (control + injury); G3 (control + injury + swimming);
tions of MSG. The control group received a hypertonic saline solution. Forty-eight rats were
Muscle strength
G4 (obese); G5 (obese + injury); and G6 (obese + injury + swimming). The animals in groups
Nerve compression
G2, G3, G5 and G6 were submitted to compression of the median nerve and G3 and G6
Obesity
groups were treated, after injury, with swimming exercise with load for three weeks. The
Swimming
swimming exercise had a progressive duration, according to the week, of 20, 30 and 40 min.
Muscle strength was assessed using a grip strength meter preoperatively and on the 3rd, 7th,
14th and 21st days after surgery. The results were expressed and analyzed using descriptive
and inferential statistics.
Results: When the grip strength was compared among assessments regardless of group, in
the second assessment the animals exhibited lower grip strength. G1 and G4 groups had
greater grip strength, compared to G2, G3, G4 and G6.
Conclusion: The swimming exercise with overload has not been effective in promoting
improvement in muscle grip strength after compression injury of the right median nerve in
control and in obese-MSG rats.
© 2014 Elsevier Editora Ltda. All rights reserved.
夽
Laboratory of Endocrine Physiology and Metabolism; Laboratory for the Study of Injuries and Physical Therapy Resources, Universidade
Estadual do Oeste do Paraná.
∗
Corresponding author.
E-mail: gladson [email protected] (G.R.F. Bertolini).
http://dx.doi.org/10.1016/j.rbre.2014.08.002
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
44
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):43–47
Avaliação da força de preensão em ratos Wistar, normais e obesos,
submetidos à natação com sobrecarga após compressão do nervo
mediano
r e s u m o
Palavras-chave:
Objetivo: Verificar a funcionalidade por meio da força muscular de preensão em animais com
Força muscular
obesidade induzida por glutamato monossódico (MSG) e animais controle, que sofreram
Compressão nervosa
compressão do nervo mediano direito, tendo como tratamento a natação com carga.
Obesidade
Métodos: Ratos Wistar neonatos durante os primeiros cinco dias de vida receberam injeções
Natação
subcutâneas de MSG. O grupo controle recebeu solução salina hiperosmótica. Quarenta e
oito ratos foram divididos em seis grupos: G1(controle); G2 (controle com lesão); G3 (controle
com lesão + natação); G4 (obesos); G5 (obesos com lesão); G6 (obesos com lesão + natação).
Os animais dos grupos G2, G3, G5 e G6 foram submetidos à compressão do nervo mediano
e os dos grupos G3 e G6 foram tratados, após a lesão, com exercício de natação com carga
durante três semanas. A natação teve duração progressiva conforme as semanas, de 20, 30
e 40 minutos. A força muscular foi avaliada por meio de um medidor de força de preensão
no pré-operatório, no terceiro, sétimo, 14◦ e 21◦ dia pós-operatório. Os resultados foram
expressos e analisados por estatística descritiva e inferencial.
Resultados: Quando comparada a força de preensão entre as avaliações, indiferentemente
de grupos, na segunda avaliação os animais apresentaram menor força de preensão. Os
grupos G1 e G4 apresentaram força de preensão maior, em comparação com os grupos G2,
G3, G4 e G6.
Conclusão: O exercício de natação com sobrecarga não foi eficaz em promover melhoria na
força muscular de preensão após lesão de compressão do nervo mediano direito em ratos
controle e obesos-MSG.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Peripheral nerve lesions are commonly encountered in
the clinical practice of physiotherapy, especially traumatic
injuries such as crushing, compression or stretching, resulting in functional impairment, caused by the interruption in
the proper transmission of nerve impulse.1,2 The interruption
of the nerve supply leads to a decreased muscle activity, causing muscular atrophy, and the main effect of this atrophy is the
reduction of the area and diameter of the muscle fiber and consequent reduction in its strength.1 Axons of injured peripheral
nerves have the capacity to regenerate; however, this process
is slow and the functional recovery is usually not complete.3
Studies involving disorders in peripheral nerves and obesity
can be found in the literature;4,5 however, the approach of
conservative treatment for peripheral nerve injury in obese
subjects is still scarce.
Physical therapy seeks to repair the consequences of
peripheral nerve injury, restoring functionality to the individual. The treatment can be performed by various therapeutic
approaches, such as passive and active cinesiotherapy, electrotherapy, functional skills training, specific proprioceptive
neuromuscular facilitation techniques and therapeutic exercise.
Animal studies demonstrate the efficacy of exercise
on peripheral nerve regeneration.6,7 The exercise practice
promotes recovery of contractile and metabolic properties
of muscle after denervation,8 helps removing degenerated
myelin and subsequent synthesis,9 aids in axonal diameter
recovery10 and axonal sprouting, favors the regeneration of
injured nerves and functional recovery11 and also increases
the expression of nerve growth factors such as BDNF and NGF,
stimulating the growth and development of new cells.12 The
physiological effects of exercise in the aquatic environment
provide benefits to the cardiovascular, skeletal, muscular and
nervous systems, increasing the tissue repair process.13 However, Oliveira et al.,10 despite observing improvements in
axonal diameter, report that the swimming practice did not
affect the maturation of regenerated nerve fibers or their
functionality, and when associated with electrical stimulation, delayed functional recovery. These findings disagree with
what was observed by Teodori et al.,7 who observed a significant effect of swimming exercise, with acceleration of nerve
regeneration in post-axonotmesis of sciatic nerves of rats.
One way to evaluate the functionality of the individual
is by the measurement of muscle strength, which enables
a functional diagnosis by an evaluation of improvement or
worsening during treatment, and as a predictive or prognostic
measure.14 In this context, the aim of this study was to assess
the muscle grip strength in MSG-obese and in control animals,
which suffered compression of the right median nerve and
underwent swimming with load.
Materials and methods
Characterization of the study and sample
This is an experimental research approved by the Ethics
Committee on Animal Experimentation and Practical
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):43–47
Classes – CEEAAP, Universidade Estadual do Oeste do Paraná,
under protocol number 01712.
Neonatal Wistar rats during the first five days of age
received subcutaneous injections of monosodium glutamate
(MSG) in a concentration of 4 g/kg body weight/day, forming
the obese group. The control group received a hyperosmotic saline solution at a concentration of 1.25 g/kg body
weight/day.15 The animals were kept in a light/dark photoperiod of 12 h and at a temperature of 23 ± 2 ◦ C, with food and
water ad libitum.
At 68 days of life, 48 rats were divided into six
experimental groups: G1 (control); G2 (control + injury); G3
(control + injury + swimming); G4 (MSG); G5 (MSG + injury); and
G6 (MSG + injury + swimming). At 73 ± 4 days of life, the animals in groups G2, G3, G5 and G6 underwent surgery for
median nerve compression.
Nerve compression
The compression of the right median nerve was based on the
model presented by Chen et al.,16 with nerve tie-down using
4.0 chromic catgut in 4 points, with an approximate distance of
1 mm in the median nerve, proximal to the elbow. To perform
the surgical procedure for compression of the median nerve,
the animals were anesthetized with ketamine hydrochloride
solution (50 mg/kg) and xylazine (10 mg/kg).
Swimming
Five days prior to the surgery, the animals were adapted and
trained in a gradual manner to swim, wherein in the first three
days the rats swam for 15 min with an overload of 5% of body
weight; in the following two days, they swam 20 min with an
overload of 10% of body weight. The swimming exercise was
held in an oval tank made of strong plastic material (200 l
capacity, 60 cm deep) and containing water maintained at a
controlled temperature of 32 ± 1 ◦ C. The treatment began on
the third day postoperatively; the exercises were performed
once a day, five times a week, totaling 15 days of swimming.
The animals were weighed every day for weight control and
adjustment of their loads for the swimming exercise. In the
first week, G3 and G6 groups started with 20 min of exercise;
during the second week, 30 min; and in the third week, 40 min.
In all practices, the animals supported a load of 10% of body
weight. The other groups of animals were placed in water for
1 min.
Muscle strength
For muscle strength assessment, one grip strength meter
described by Bertelli and Mira17 was used. This assessment
is a useful tool for analyzing the recovery of median nerve
lesions, through the function of the flexor digitorum muscle.
To perform the evaluation, the animal was pulled by the tail
with increasing force. The rat could seize a grid attached to
a force transducer, till the animal lost its grip. The anterior
left limb was temporarily immobilized by wrapping with
tape. Five days prior to surgery, the animals were adapted
and trained on the equipment. The first evaluation (AV1) was
performed before the compression of the median nerve, to
45
obtain baseline values, i.e., preoperatively, followed by a second assessment on the 3rd postoperative day (AV2). The other
assessments were carried out at the end of each week of treatment, i.e., the 7th (AV3), 14th (AV4) and 21st (AV5) day, with
the aim to observe the evolution of the lesion and the type
of treatment used. In each evaluation the test was repeated
three times, and the mean value of repetitions was used.
Statistical analysis
The results were expressed and analyzed using descriptive
and inferential statistics. To compare groups and times, oneway ANOVA with Tukey post-test was used, with a significance
level of 5%.
Results
Both G1 and G4 showed no intragroup variations (P > 0.05),
which was expected, since in these groups injuries were not
inflicted. For the other groups, the values of AV1 were superior
to the other assessments (P < 0.05), whereas G2 and G6 showed
significant increases in AV4, when compared to AV2 (P < 0.05);
the same was observed for G2, G3 and G6, when comparing
AV5 versus AV2 (P < 0.05) (Table 1).
As for the comparison among groups, in AV1 (the pre-injury
time) there were no significant differences (P > 0.05). However,
from AV2 to AV5, differences between G1 versus G2, G3, G5
and G6 (P < 0.05) groups were observed, occurring the same
with respect to G4 (Table 1), i.e., the values found revealed
that the lesion reduced the grip strength, when comparing
control groups (G1 and G4) with those which only underwent
injury (G2 and G5), or those which underwent injury associated
with swimming (G3 and G6). No significant differences were
noted among groups of obese animals compared to eutrophic
animals.
Discussion
Peripheral nerve injuries are responsible for high morbidity and functional loss, requiring therapeutic interventions18
to assist in the morphological and functional tissue repair,
hence the importance of controlled experiments to evaluate the effectiveness of therapies. Most of the experimental
studies in rats are carried out on models of sciatic nerve
injury/compression. However, the most common injuries in
humans occur in the upper limbs.19 Thus, in the present study,
we sought to find a model that could produce a compressive
lesion in the median nerve. The nerve compression model
used was presented by Bennett and Xie20 for compressing
the sciatic nerve; subsequently, the procedure was modified
for the median nerve by Chen et al.,16 which causes, besides
hypernociception, muscle activity dysfunction. These changes
begin from the 2nd day postoperatively (PO), reaching its maximum around the 10th to 14th PO day, disappearing after the
2nd month. Thus, in the present study, we began the treatment with swimming exercise in the 3rd PO, during which
the changes arising from nerve compression had already been
established. It was realized that the aquatic exercise could be
important in recovering from paresis, both by decreasing the
46
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):43–47
Table 1 – Values found for handgrip of Wistar rats (mean and standard deviation), in grams, for different time points
(AV1–AV5) in the different groups (G1–G6).
AV1
G1
G2
G3
G4
G5
G6
a
b
c
d
265.8
284.6
329.8
212.9
247.5
226.6
±
±
±
±
±
±
106.3
60.2
113.9
55.3
72.9
49.2
AV2
330.9
32.1
39.5
270.5
34.0
42.7
±
±
±
±
±
±
AV3
87.6
19.6a,b,c
26.1a,b,c
54.7
27.8a,b,c
35.3a,b,c
327.8
83.1
79.6
277.8
62.0
81.1
±
±
±
±
±
±
AV4
99.6
48.2a,b,c
31.3a,b,c
79.6
49.3a,b,c
26.1a,b,c
303.7
95.4
93.3
268.3
74.5
109.4
±
±
±
±
±
±
124.3
26.7a,b,c,d
25.5a,b,c
88.8
18.9a,b,c
42.4a,b,c,d
AV5
332.1
103.5
124.0
294.3
83.7
107.3
±
±
±
±
±
±
121.3
21.1a,b,c,d
46.9a,b,c,d
127.6
33.5a,b,c
57.5a,b,c,d
Significant difference when comparing with G1.
Significant difference when comparing with G4.
Significant difference when comparing with AV1, within the same group.
Significant difference when comparing with AV2, within the same group.
protein degradation21 and by functioning as a possible analgesia mediated by endogenous opioids,22 which could reduce
the immobility of the limb due to pain.
When a peripheral nerve suffers compression (inducing
local ischemia), some electrophysiological nerve conduction
change occurs,23 leading to muscle weakness.24,25 The results
show that, at the first assessment (when the nerve compression had not yet been performed), the animals showed a
significantly higher strength compared with the other results
– which is consistent with normal standards. A reduction in
muscle strength may be related to the hypernociception generated by nerve compression, producing muscle inhibition.26
Silva et al.27 warned that, after the surgical compression of
the median nerve, a painful condition settles down, lasting
at least until the 8th postoperative day, not decreasing in its
intensity.
The results also revealed that there was no increase in
grip strength in injured/swimming-treated animals versus
injured/sedentary animals, suggesting that the swimming
exercise was not efficient to produce an increase in muscle
strength, after the injury by compression of the median nerve.
In a study by Possamai, Siepko and Andrew,28 40 Wistar rats
were functional and histologically evaluated, being divided
into four groups according to the day the treatment would
begin after an axonotmesis-type sciatic nerve injury. The animals were submitted to freestyle swimming for 30 min/day.
The results show that there was no interference of physical
exercise on peripheral nerve regeneration. Additionally, the
treated groups showed no histological changes compared to
sedentary rats. Accordingly, Oliveira et al.10 noted that daily
swimming exercise for 30 min, 5 times a week for 22 days, was
ineffective with respect to nerve recovery in rats subjected to
axonotmesis; when this was combined with electrical stimulation, the functional recovery was delayed. On the other
hand, Teodori et al.,7 evaluating functional and morphological characteristics of rats with sciatic axonotmesis, found
that 30 min/day of swimming for two weeks accelerated nerve
regeneration. Thus, a disagreement regarding the effects of
exercise on aquatic recovery from nerve injury becomes evident.
This divergence is also found in the case of exercise
outside the aquatic environment. Sobral et al.29 performed
histomorphometric and functional analyses to evaluate the
influence of exercise on a treadmill, applied in early and
late stages of sciatic nerve regeneration in rats following
axonotmesis. The authors concluded that the treadmill exercise protocol applied to the immediate and late phases did
not influence axonal sprouting, degree of maturation of the
regenerated fibers, nor the functionality of the reinnervated
muscles. Conversely, Seo et al.11 reported that 30 min of
walking on a treadmill between the 3rd and 14th day postinjury and with a speed of 18 m/min, played an important
role in axonal regeneration. Ilha et al.6 reported that, after
two weeks of compression of the sciatic nerve in rats, the
animals performed exercises during five weeks, namely: progressive treadmill exercises (about 9 m/min) in the first week
and, in the remaining four weeks, 60 min/day. These authors
noted improvement in nerve regeneration. However, animals that performed climbing-stair exercises (training against
resistance) with body overload, with or without swimming,
exhibited a delayed functional recovery.
The obesity model used in this study was the neonatal
administration of MSG. Animals exposed to this substance
undergo a neural reorganization that is reflected in a
new metabolic structure, which predisposes to obesity in
adulthood,30 and that also causes changes in the animal by
application of MSG, such as a reduction in lean body mass.31
These animals have lower levels of growth hormone (GH),
hence lower body weight and length, but with increased fat
deposition.15 In the results found at the end of the experiment, despite the MSG animals have presented lower means
for grip strength, there were no significant differences in control and obese-MSG animals (independent of having been
injured/treated, or not) with swimming – a fact that may be
related to the nociception due to injury.
Because of the discrepancy in the literature regarding the
optimal exercise time and about what is the better stage
to start the practice, it is believed that swimming has been
ineffective with respect to increasing grip strength as a result
of some of these parameters, considering that the exercises
were implemented in the immediate phase after injury,
with progressive duration along the weeks. Additionally, an
excessive load may have been generated in animals which
swam, by virtue of the load of 10% of their body weight during
the treatment – a factor identified as an important cause of
delay in nerve regeneration.32 We wish to emphasize, as a
limitation of the present study, the absence of correlations
with morphological findings of the median nerve and flexor
carpi radialis muscle. This issue is suggested as a topic for
future studies. Additionally, we also postponed the onset
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):43–47
of physical exercise, with different protocols (i.e., with the
addition of different overloads).
The swimming exercise with overload has not been effective in promoting improvement in muscle grip strength after
compression injury of the right median nerve in control and
obese-MSG rats.
Conflicts of interest
The authors declare no conflicts of interest.
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r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):48–54
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Original article
Evaluation of performance of BASDAI (Bath
Ankylosing Spondylitis Disease Activity Index) in a
Brazilian cohort of 1492 patients with
spondyloarthritis: data from the Brazilian Registry
of Spondyloarthritides (RBE)
Izaias Pereira da Costa a,∗ , Adriana B. Bortoluzzo b , Célio R. Gonçalves c ,
José Antonio Braga da Silva d , Antonio Carlos Ximenes e , Manoel B. Bértolo f ,
Sandra L.E. Ribeiro g , Mauro Keiserman h , Rita Menin i , Thelma L. Skare j ,
Sueli Carneiro k , Valderílio F. Azevedo l , Walber P. Vieira m , Elisa N. Albuquerque n ,
Washington A. Bianchi o , Rubens Bonfiglioli p , Cristiano Campanholo q ,
Hellen M.S. Carvalho r , Angela L.B. Pinto Duarte s , Charles L. Kohem t , Nocy H. Leite u ,
Sonia A.L. Lima v , Eduardo S. Meirelles w , Ivânio A. Pereira x , Marcelo M. Pinheiro y ,
Elizandra Polito z , Gustavo G. Resende aa , Francisco Airton C. Rocha bb ,
Mittermayer B. Santiago cc , Maria de Fátima L.C. Sauma dd , Valéria Valim ee ,
Percival D. Sampaio-Barros c
a
Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brazil
Instituto Insper de Educação e Pesquisa, São Paulo, SP, Brazil
c Rheumatology Discipline, 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 Universidade Federal do Paraná, Curitiba, PR, Brazil
m Hospital Geral de Fortaleza, Fortaleza, CE, Brazil
n Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
b
∗
Corresponding author.
E-mail: [email protected] (I.P.d. Costa).
http://dx.doi.org/10.1016/j.rbre.2014.05.005
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
49
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):48–54
o
Santa Casa do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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 de Pernambuco, Recife, PE, Brazil
t Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
u Faculdade de Medicina Souza Marques, Rio de Janeiro, RJ, Brazil
v Hospital do Servidor Público Estadual, São Paulo, SP, Brazil
w Institute of Orthopedy and Traumatology, Universidade de São Paulo, São Paulo, SP, Brazil
x Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
y Universidade Federal de São Paulo, São Paulo, SP, Brazil
z Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
aa Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
bb Universidade Federal do Ceará, Fortaleza, CE, Brazil
cc Escola de Medicina e Saúde Pública, Salvador, BA, Brazil
dd Universidade Federal do Pará, Belém, PA, Brazil
ee Universidade Federal do Espírito Santo, Vitória, ES, Brazil
p
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To analyze the results of the application of the Bath Ankylosing Spondylitis Dis-
Received 13 February 2013
ease Activity Index (BASDAI) in a large series of Brazilian patients with the diagnosis of SpA
Accepted 19 May 2014
and establish its correlations with specific variables into the group.
Available online 20 December 2014
Methods: A common protocol of investigation was prospectively applied to 1492 Brazilian
Keywords:
(ESSG), attended at 29 referral centers of Rheumatology in Brazil. Clinical and demographic
Spondyloarthritis
variables, and disease indices (BASDAI, Basfi, Basri, Mases, ASQol) were applied. The total
patients classified as SpA according to the European Spondyoarthropathies Study Group
Disease activity
BASDAI
Epidemiology
values of BASDAI were compared to the presence of the different variables.
Results: The mean score of BASDAI was 4.20 ± 2.38. The mean scores of BASDAI were higher
in patients with the combined (axial + peripheral + entheseal) (4.54 ± 2.38) clinical presentation, compared to the pure axial (3.78 ± 2.27) or pure peripheral (4.00 ± 2.38) clinical
presentations (P < 0.001). BASDAI also presented higher scores associated with the female
gender (P < 0.001) and patients who did not practice exercises (P < 0.001). Regarding the axial
component, higher values of BASDAI were significantly associated with inflammatory low
back pain (P < 0.049), alternating buttock pain (P < 0.001), cervical pain (P < 0.001) and hip
involvement (P < 0.001). There was also statistical association between BASDAI scores and
the peripheral involvement, related to the lower (P = 0.004) and upper limbs (P = 0.025). The
presence of enthesitis was also associated to higher scores of BASDAI (P = 0.040). Positive
HLA-B27 and the presence of cutaneous psoriasis, inflammatory bowel disease, uveitis and
urethritis were not correlated with the mean scores of BASDAI. Lower scores of BASDAI were
associated with the use of biologic agents (P < 0.001).
Conclusion: In this heterogeneous Brazilian series of SpA patients, BASDAI was able to
demonstrate “disease activity” in patients with axial as well as peripheral disease.
© 2014 Elsevier Editora Ltda. All rights reserved.
Avaliação do desempenho do BASDAI (Bath Ankylosing Spondylitis
Disease Activity Index) numa coorte brasileira de 1.492 pacientes com
espondiloartrites: dados do Registro Brasileiro de Espondiloartrites (RBE)
a b s t r a c t
Palavras-chave:
Objetivo: Avaliar os resultados da aplicação do Índice de Atividade de Doença da Espondilite
Espondiloartrites
Anquilosante de Bath (BASDAI) numa série de pacientes brasileiros com EpA e estabelecer
Atividade de doença
suas correlações com as variáveis específicas do grupo.
50
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):48–54
Métodos: Um protocolo comum de investigação foi prospectivamente aplicado em 1.492
BASDAI
Epidemiologia
pacientes brasileiros classificados como EpA pelos critérios do Grupo Europeu de Estudo das
Espondiloartropatias (ESSG), acompanhados em 29 centros de referência em reumatologia
no Brasil. Variáveis clínicas, demográficas e índices de doença foram colhidos. Os valores
totais do BASDAI foram comparados com a presença das diferentes variáveis.
Resultados: O valor médio do BASDAI foi de 4,20 ± 2,38. Os escores médios do BASDAI foram
mais elevados nos pacientes com forma clínica combinada, comparado às formas axiais
e periféricas isoladas, nos pacientes do sexo feminino e nos sedentários. Com relação ao
componente axial, valores mais altos do BASDAI estiveram significativamente associados
à lombalgia inflamatória, à dor alternante em nádegas, à dor cervical e ao acometimento
de coxofemorais. Houve associação estatística entre os valores do BASDAI e o comprometimento periférico, relacionado ao número de articulações inflamadas, tanto dos membros
inferiores quanto dos membros superiores, e às entesites. A positividade do HLA-B27 e a
presença de manifestações extra-articulares não estiveram correlacionadas com os valores
médios do BASDAI. Valores mais baixos do BASDAI estiveram associados ao uso de agentes
biológicos (p < 0,001).
Conclusão: Nesta série heterogênea de pacientes brasileiros com EpA, o BASDAI conseguiu
demonstrar “atividade de doença” tanto nos pacientes com acometimento axial quanto
naqueles com envolvimento periférico.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
The denomination spondyloarthritis (SpA) defines a heterogeneous group of diseases that share genetic and clinical
characteristics, as well as structural changes in imaging studies. The positivity of HLA-B27 and the absence of rheumatoid
factor are common to this group of diseases, and the high
frequency of inflammatory processes of the spine, sacroiliac
joints and enthesis is considered the main clinical criteria for
the diagnosis of SpA.1 Other clinical manifestations occur in
varying degrees of involvement in the group of SpA; more
often, skin, ocular, intestinal and urogenital injuries and,
less frequently, pulmonary, cardiac, renal and neurological
involvement.1
This group of diseases consists of ankylosing spondylitis
(AS), psoriatic arthritis (PA), reactive arthritis (ReA), arthritis associated with inflammatory bowel diseases (also known
as enterophatic arthritis – EA) and undifferentiated spondyloarthritis (USpA).1
With the advent of new therapeutic modalities for the
group of SpA, the elaboration of measures of disease activity that could be used in long-term follow-up was necessary.2
Currently, to evaluate and monitor clinical disease activity in
SpA, the Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI) has been used. This index is obtained by summing
the values of a visual analog scale (VAS) that evaluates six
items, namely: fatigue, axial pain, peripheral pain, enthesitis, duration and intensity of morning stiffness.3 BASDAI does
not use any marker of inflammatory activity in its calculation, since these tests were not standardized at the time of
its proposition.3 BASDAI values are internationally used (BASDAI ≥ 4 is deemed as “high disease activity”) for the indication
of biological agents in the treatment of SpA, when there was
no response to conventional treatment with nonsteroidal antiinflammatory drugs or with conventional remissive drugs.4,5
When the patient reaches BASDAI 50 (improvement in the
BASDAI score of ≥50%) in the first 12 weeks of treatment,
this can be considered as a very good clinical response.6 Due
to its importance, BASDAI has been translated and validated
in several languages, including French,7 Swedish,8 German,9
Spanish,10 Turkish,11 Arabic12 and Portuguese.13 Recently, the
Ankylosing Spondylitis Disease Activity Score (ASDAS) was
created14 ; this index associates the presence of a marker of
inflammatory activity, erythrocyte sedimentation rate (ESR)
or C-reactive protein (CRP); nowadays, ASDAS has its cutoff scores to differentiate “moderate”, “high” and “very high”
activity.15
This paper analyzes the application of BASDAI in a heterogeneous Brazilian cohort of 1492 patients with SpA.
Methods
This is a prospective, observational, multicenter study,
conducted with 1492 patients from 29 referral centers participating in the Brazilian Registry of Spondyloarthritides
(Registro Brasileiro de Espondiloartrites – RBE). All patients
fulfilled the criteria of the European Spondyloarthropathy
Study Group (ESSG).16 Data were collected from June 2006 to
December 2009. RBE participates in the RESPONDIA group
(Registro Iberoamericano de Espondiloartrites), consisting of nine
Latin American countries (Argentina, Brazil, Costa Rica, Chile,
Ecuador, Mexico, Peru, Uruguay and Venezuela) and the two
countries of the Iberian peninsula (Spain and Portugal).
The joint investigation protocol included demographic
variables (gender, race, family history, HLA-B27, exercise),
osteoarticular (inflammatory low back pain, buttock pain,
neck pain, hip pain, lower limb arthritis, upper limb arthritis,
enthesitis, dactylitis) and extra-articular (uveitis, inflammatory bowel disease [IBD], psoriasis, urethritis) disorders, and
laboratory data (erythrocyte sedimentation rate – ESR and
51
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):48–54
C-reactive protein – CRP), as well as the treatment (nonsteroid anti-inflammatory drugs – NSAIDs, corticosteroids and
conventional and biological remissive drugs).
For the diagnosis of AS, the New York criteria were used17 ;
for psoriatic arthritis, the participants had to meet the criteria of Moll and Wright.18 The diagnosis of reactive arthritis
was considered if asymmetric oligoarthritis of the lower limbs
were present, with enthesopathy and/or inflammatory low
back pain arousing after an enteric or urogenital infection,19
and spondyloarthritis/arthritis associated with inflammatory
bowel disease, if the patient had an inflammatory axial disorder and/or peripheral joint involvement, associated with
confirmed Crohn’s disease or ulcerative colitis.
BASDAI is a tool for evaluation of disease activity that
contains six questions.3 The responses were marked on a
horizontal line measuring 10 cm (from 0 to 10 cm), where the
patient evaluates how he feels in relation to each item in the
last week, marking on the scale: if the patient is fine (“very
well”), he/she marks zero cm, gradually increasing until “very
poor”, corresponding to a 10-cm mark. The six questions comprising BASDAI are as follows: (1) How would you describe the
degree of fatigue or tiredness you have had?; (2) How would
you describe the overall level of neck, back and hip pain related
to your illness?; (3) How would you describe the overall level
of pain and edema (swelling) in other joints, apart from neck,
back and hip?; (4) How would you describe the overall level of
discomfort you felt to the touch or compression in the painful
regions of your body?; (5) How would you describe the intensity of morning stiffness you have had, from the time you wake
up?; (6) How long does your morning stiffness take, from the
time you wake up?
Table 2 – Results of BASDAI according to specific SpA.
Primary AS
Psoriatic AS
Enteropathic AS
Psoriatic Arthritis
USpA
Reactive Arthritis
Enteropathic Arthritis
%
Mean
SD
P
67.6
4.6
2.6
14.2
6.8
3.4
0.8
4.21
4.38
4.70
4.13
4.35
4.12
4.37
2.36
2.32
2.41
2.47
2.28
2.57
3.05
0.305
There was no significant difference between the mean values of BASDAI and any specific disease within the SpA group.
The mean values of BASDAI for each disease within the group
are shown in Table 2. As to the clinical presentation, the
mean values of BASDAI were significantly higher in enthesitic
(4.96 ± 2.22) and combined (axial and peripheral; 4.50 ± 2.38)
forms, compared to pure forms, both axial (3.78 ± 2.28) and
peripheral (3.87 ± 2.23) (Table 3).
With regard to demographic variables, BASDAI was significantly higher in females (P < 0.001) and in those patients who
did not exercise regularly (P < 0.001). Ethnicity, HLA-B27 and
family history of SpA did not influence the results of BASDAI
(Table 4).
Numerous clinical variables influenced BASDAI scores.
Inflammatory low back pain (P = 0.039), buttock pain (P < 0.001),
neck pain (P < 0.001), hip pain (P < 0.001), arthritis of lower
(P = 0.004) and upper (P = 0.025) limbs, and enthesitis (P = 0.040)
were significantly associated with higher mean values of BASDAI. Extra-articular manifestations such as uveitis, psoriasis,
Statistical analysis
The variable categories were compared using2 and Fisher’s
exact tests, and continuous variables were compared using
ANOVA. A value of P < 0.05 was considered significant; and
0.05 > P > 0.10 was considered as a statistical trend.
Table 3 – Results of BASDAI according to clinical form.
%
Mixed
Axial
Peripheral
Enthesitic
48.5
34.5
11.0
6.0
Mean
SD
4.50
3.78
3.87
4.96
2.38
2.28
2.23
2.22
P
<0.001
Results
The mean score of total BASDAI was 4.20 ± 2.38. Among the
six items that make up the final value of BASDAI, the item 2
(related to axial pain; 5.05 ± 3.20) had the highest mean, and
the item 3 (related to peripheral component; 3.28 ± 3.18) was
that with the lowest value. The mean values of BASDAI to all
the questions that make up the index are described in Table 1.
Table 1 – Results of BASDAI per item.
BASDAI
Mean
Standard
deviation
Total
Question 1
Question 2
Question 3
Question 4
Question 5
Question 6
4.20
4.21
5.05
3.28
4.28
4.59
3.85
2.38
2.99
3.20
3.18
3.34
3.29
3.36
Table 4 – Results of BASDAI according to epidemiological
data.
%
Mean
SD
P
Gender
Male
Female
72.3
27.7
3.97
4.84
2.95
3.05
<0.001
Race
White
Non-white
67.4
32.6
4.03
4.30
2.38
2.40
0.057
Exercise
Yes
No
40.8
59.2
3.89
4.42
2.35
2.38
<0.001
Family history
Yes
No
18.0
82.0
4.32
4.18
2.49
2.36
0.413
HLA-B27
Positive
Negative
69.0
31.0
4.16
4.33
2.33
0.391
2.50
52
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):48–54
Table 5 – Results of BASDAI according to clinical data.
Inflammatory low back pain
Yes
No
Buttock pain
Yes
No
Neck pain
Yes
No
Hip pain
Yes
No
Arthritis, lower limb
Yes
No
Arthritis, upper limb
Yes
No
Enthesitis
Yes
No
Dactylitis
Yes
No
Uveitis
Yes
No
Skin psoriasis
Yes
No
Inflammatory bowel disease
Yes
No
Urethritis
Yes
No
%
Mean
SD
67.6
32.4
4.29
4.02
2.31
2.53
33.1
66.9
4.59
4.01
2.39
2.36
30.8
69.2
4.64
4.01
2.32
2.39
25.1
74.9
4.63
4.06
2.35
2.38
48.9
51.1
4.38
4.03
2.35
2.30
22.1
77.9
4.46
4.13
2.40
27.1
72.9
4.41
4.13
2.41
2.37
9.1
90.9
4.04
4.22
2.48
2.37
19.1
80.9
4.22
4.20
2.53
2.35
17.8
82.2
4.23
4.20
2.42
2.38
4.7
95.3
4.67
4.18
2.46
2.38
4.4
95.6
4.51
4.19
2.57
2.37
Table 6 – Results of BASDAI according to treatment.
P
0.049
<0.001
<0.001
<0.001
0.004
0.025
2.37
0.040
0.423
0.926
NSAID
Yes
No
NSAID on-demand
Yes
No
Corticosteroid
Yes
No
Methotrexate
Yes
No
Sulfasalazine
Yes
No
Biologicals
Yes
No
Infliximab
Yes
No
Etanercept
Yes
No
Adalimumab
Yes
No
%
Mean
SD
67.6
32.4
4.21
4.19
2.35
2.45
24.9
75.1
4.16
4.22
2.40
2.38
35.3
64.7
4.29
4.16
2.37
2.39
51.7
48.3
4.21
4.19
2.32
2.45
44.7
55.3
4.21
4.19
2.44
2.34
20.4
79.6
3.73
4.32
2.47
2.35
15.3
84.7
3.58
4.32
2.50
2.35
2.8
97.2
4.78
4.19
2.30
2.38
2.3
97.7
3.70
4.22
2.06
2.39
P
0.888
0.713
0.297
0.866
0.934
<0.001
<0.001
0.104
0.164
0.849
0.106
0.326
inflammatory bowel disease and urethritis did not influence
BASDAI scores (Table 5).
With regard to treatment, only the use of anti-TNF biological agents was significantly associated with lower scores of
BASDAI (P < 0.001), while the use of NSAIDs, corticosteroids,
methotrexate and sulfasalazine did not influence the values
of BASDAI (Table 6).
Discussion
This study aimed to evaluate the activity of SpA using BASDAI as a clinical activity index; this is a tool traditionally
used in patients with SpA. The results showed that BASDAI
could demonstrate “disease activity”, both in patients with
an axial component as in those with peripheral involvement,
even in patients with SpA but with no diagnosis of AS. In
view of the fact that BASDAI evaluate “axial” (question 2)
and “peripheral” (questions 3 and 4) components, an important finding in this study was represented by the highest
mean scores in patients who had an involvement described as
“combined” (where the “axial” and “peripheral” components
are observed in the same patient) – a common characteristic of Brazilian patients.20 Similarly, an European multicenter
study evaluating 214 patients with SpA found higher values
of BASDAI in those participants with a peripheral component
(4.4 ± 2.3) compared to patients with an isolated axial component (3.1 ± 1.9) (P < 0.001).21 Also important was the fact that
the mean values of BASDAI were significantly elevated, both in
presence of axial (inflammatory low back pain, buttock pain,
neck pain and hip pain) and peripheral (lower and upper joints)
clinical variables, in addition to enthesitis.
In the spectrum of SpA, psoriatic arthritis is that disease
where the peripheral component is most striking. Our study
showed that BASDAI can also be effective in the evaluation of
patients with PA, as shown in recent studies,22,23 even when
compared to ASDAS.24
With the proposition of ASDAS as a valid method of
assessing disease activity in cases of AS,14,15 it will be important to apply this tool to patients with SpA in the second phase
of RBE, to compare its effectiveness versus BASDAI. There is
no established consensus about what is the best method for
assessment of disease activity in patients with AS (if ASDAS
is better than BASDAI). Meanwhile, BASDAI has been shown
as an efficient index in the therapeutic follow-up of patients
with AS.6,25,26 The combination of BASDAI with the functional
index BASFI (Bath Ankylosing Spondylitis Disease Activity
Index)27 made it possible to obtain important characteristics
of patients in the Brazilian Registry of Spondyloarthritides.28
Although representing only 27.7% of the patients, women
had higher mean BASDAI scores, when compared to men.
These results certainly may vary with the population
evaluated.29
Regarding the skin color of the patients, there was no significant difference, as previously described,30 and no significant
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):48–54
difference in BASDAI scores in relation to HLA-B27, family history and extra-articular manifestations was found.
In short, BASDAI showed to be an efficient method of
assessing disease activity in a heterogeneous population of
Brazilian patients with SpA.
Conflicts of interest
The electronic version of the Brazilian Registry of Spondyloarthritides is supported by a grant from Wyeth/Pfizer Brazil,
which has no influence on the capture and analysis of data,
as well as in the writing and publication of articles. Dr. Percival Sampaio-Barros received a research grant from Federico
Foundation.
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Espondiloartrites: análise de uma série brasileira comparada
a uma grande casuística ibero-americana (estudo Respondia).
Rev Bras Reumatol. 2010;50:581–9.
21. Heuft-Dorenbosch L, Van Tubergen A, Spoorenberg A,
Landewé R, Dougados M, Mielants H, et al. The influence of
peripheral arthritis on disease activity in ankylosing
spondylitis patients as measured with Bath Ankylosing
Spondylitis Disease Activity Index. Arthritis Rheum.
2004;51:154–9.
22. Taylor WJ, Harrison AA. Could the Bath Ankylosing
Spondylitis Disease Activity Index (Basdai) be a valid measure
of disease activity in patients with psoriatic arthritis?
Arthritis Rheum. 2004;51:311–5.
23. Fernandez-Sueiro JL, Willisch A, Pertega-Diaz S, Tasende JA,
Fernández-López JC, Villar NO, et al. Validity of the Bath
Ankylosing Spondylitis Disease Activity Index for the
evaluation of disease activity in axial psoriatic arthritis.
Arthritis Care Res. 2010;62:78–85.
24. Eder L, Chandran V, Shen H, Cook RJ, Gladman DD. Is Asdas
better than Basdai as a measure of disease activity in axial
psoriatic arthritis? Ann Rheum Dis. 2010;69:2160–4.
25. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL,
Hetland ML. Predictors of treatment response and drug
continuation in 842 patients with ankylosing spondylitis
treated with anti-tumour necrosis factor: results from 8
years’ surveillance in the Danish nationwide Danbio registry.
Ann Rheum Dis. 2010;69:2002–8.
26. Arends S, Brower E, Van der Veer E, Groen H, Leijsma MK,
Houtman PM, et al. Baseline predictors of response and
discontinuation of tumor necrosis factor-alpha blocking
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therapy in ankylosing spondylitis: a prospective longitudinal
observational cohort study. Arthritis Res Ther. 2011;13:R94.
27. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Malorie
P, et al. A new approach to defining functional ability in
ankylosing spondylitis: the development of the Bath
Ankylosing Functional Index. J Rheumatol. 1994;21:2281–5.
28. Valim V, Marianelli BF, Bortoluzzo AB, Gonçalves CR, Braga da
Silva JA, Ximenes AC, et al. Aplicação do Basfi (Bath
Ankylosing Spondylitis Functional Index) numa coorte de
pacientes do Registro Brasileiro de Espondiloartrites (RBE).
Rev Bras Reumatol. 1492 (submetido).
29. Roussou E, Sultana S. Spondyloarthritis in women:
differences in disease onset, clinical presentation, and Bath
Ankylosing Spondylitis Disease Activity and Functional
indices (Basdai and Basfi) between men and women with
spondyloarthritides. Clin Rheumatol. 2011;30:
121–7.
30. Roussou E, Sultana S. Early spondyloarthritis in multiracial
society: differences between gender, race, and disease
subgroups with regard to first symptom at presentation, main
problem that the disease is causing to patients, and
employment status. Rheumatol Int. 2012;32:604–1597.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):55–61
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Review article
Possible changes in energy-minimizer
mechanisms of locomotion due to chronic
low back pain - a literature review
Alberito Rodrigo de Carvalho a,b,∗ , Alexandro Andrade c ,
Leonardo Alexandre Peyré-Tartaruga a
a
b
c
Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Universidade Estadual do Oeste do Paraná, Cascavel, PR, Brazil
Universidade do Estado de Santa Catarina, Florianópolis, SC, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history:
One goal of the locomotion is to move the body in the space at the most economical way
Received 23 November 2013
possible. However, little is known about the mechanical and energetic aspects of locomotion
Accepted 28 January 2014
that are affected by low back pain. And in case of occurring some damage, little is known
Available online 5 January 2015
about how the mechanical and energetic characteristics of the locomotion are manifested in
functional activities, especially with respect to the energy-minimizer mechanisms during
Keywords:
locomotion. This study aimed: a) to describe the main energy-minimizer mechanisms of
Lower back pain
locomotion; b) to check if there are signs of damage on the mechanical and energetic char-
Human locomotion
acteristics of the locomotion due to chronic low back pain (CLBP) which may endanger the
Walk
energy-minimizer mechanisms. This study is characterized as a narrative literature review.
Biomechanics
The main theory that explains the minimization of energy expenditure during the loco-
Energy consumption
motion is the inverted pendulum mechanism, by which the energy-minimizer mechanism
converts kinetic energy into potential energy of the center of mass and vice-versa during the
step. This mechanism is strongly influenced by spatio-temporal gait (locomotion) parameters such as step length and preferred walking speed, which, in turn, may be severely altered
in patients with chronic low back pain. However, much remains to be understood about the
effects of chronic low back pain on the individual’s ability to practice an economic locomotion, because functional impairment may compromise the mechanical and energetic
characteristics of this type of gait, making it more costly. Thus, there are indications that
such changes may compromise the functional energy-minimizer mechanisms.
© 2014 Elsevier Editora Ltda. All rights reserved.
∗
Corresponding author.
E-mail: [email protected] (A.R.d. Carvalho).
http://dx.doi.org/10.1016/j.rbre.2014.01.005
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
56
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):55–61
Possíveis alterações no mecanismo minimizador de energia da
caminhada em decorrência da dor lombar crônica - revisão de literatura
r e s u m o
Palavras-chave:
Um dos objetivos da marcha é deslocar o corpo no espaço da forma mais econômica pos-
Dor lombar
sível. Porém, pouco se sabe como os aspectos mecânicos e energéticos da caminhada são
Locomoção humana
afetados pela dor lombar. Ainda, caso haja prejuízos, é pequeno o conhecimento de como
Caminhada
as características mecânicas e energéticas da caminhada se manifestam nas atividades
Biomecânica
funcionais, principalmente nos mecanismos minimizadores de energia da locomoção. Este
Consumo de energia
estudo teve por objetivos: a) descrever os principais mecanismos minimizadores de energia
da locomoção; e b) verificar se há indicativos de prejuízos nas características mecânicas
e energéticas da caminhada decorrentes da dor lombar crônica (DLC) que possam comprometer os mecanismos minimizadores. Estudo caracterizado como revisão narrativa de
literatura. A principal teoria que explica a minimização do dispêndio energético durante a
caminhada é a do pêndulo invertido pelo qual o mecanismo minimizador converte energia cinética em energia potencial do centro de massa e vice-versa durante a passada. Esse
mecanismo é fortemente influenciado por parâmetros espaços-temporais da marcha, tais
como comprimento de passo e velocidade preferida da caminhada, que, por sua vez, podem
estar severamente alterados em pacientes com dor lombar crônica. Contudo ainda há muito
que se entender sobre os efeitos da dor lombar crônica sobre a capacidade do indivíduo de
praticar uma marcha econômica, pois os prejuízos funcionais podem comprometer características mecânicas e energéticas dessa modalidade de marcha e torná-la mais dispendiosa.
Desta forma, há indicativos de que tais mudanças funcionais possam comprometer os
mecanismos minimizadores de energia.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
The adoption of locomotion on two legs as an exclusive form
of march was an important marker of human evolution, and
energy saving, in this type of locomotion, is one of the main
reasons for the establishment of bipedalism.1–3 However, the
bipedal locomotion cannot always be considered as a simple
task. The trunk, essentially unstable for its multijoint characteristics, maintains its stability by muscular action that
constantly modifies itself to ensure the needed posture to
movements.4
Walking is a form of locomotion that stands out by influencing multiple aspects in the physical, social and evolutionary
spheres of human existence.6 An anthropological and evolutionary vision makes us think that, if the modern man
can walk quietly and use this ability to perform his daily
activities, in the past perhaps this was not so simple for
our ancestors - probably bipedal locomotion was used for
escape, producing tiredness and fatigue. Therefore, the ability
of locomotion depends on a complex interaction of patterns of
coordinated movements of the hip, pelvis and lumbar spine,
which, when harmonic, determine the normal biomechanical gait pattern.1,5 Bipedal locomotion was used to permit
man’s flight, causing greater exhaustion and fatigue. Throughout the evolutionary period, certain anatomical changes were
occurring slowly over thousands of years, to allow the fixation of this mode of march and promoting adaptations of
human locomotor system that provide us with perspectives
on musculoskeletal disorders found in the current clinical
scenario.7
The biped march encompasses many aspects that go
beyond a simple act of placing one leg in front of the other.
It can be understood as a cyclic movement with loss and
recovery of the balance, due to the constant change of position of the body center of mass promoting body instability.
Such instability is compensated by leg movements, ranging
from a stance phase, which can be single-leg or bipedal, and
a swing phase, in which the leg is free in the air. Thus, at
the end of the swing phase, the center of mass lies in a
posterior relation to the anteriorly extended leg and begins
to rise, due to the kinetic energy, at the beginning of the
stance phase, after the heel contact with the ground (i.e.,
heel-strike). During the first half of the step, the kinetic
energy decreases as the center of mass gains height, with
consequent increase of potential energy which reaches its
peak in the middle of the one-leg support phase. In the
second half of the step, the opposite occurs; the center of
mass loses height and the potential energy is converted into
kinetic energy. The reconversion between the mechanical
energies connected to the center of mass during walking
plays a crucial role in the individual’s ability to walk as
economically as possible, and is influenced by a number of
spatio-temporal gait variables, such as step length and gait
speed.8–11
The impairment of the normal gait cycle and the loss of
characteristics of energy conservation between trunk and limb
movements result in greater energy expenditure. Patients with
diseases that compromise the ability to walk tend to develop
compensatory gait patterns to minimize the additional energy
expenditure.9
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):55–61
Low back pain is a common syndrome worldwide, generating relevant socioeconomic costs. According to estimates, 80%
of people will experience an episode of this kind of pain at
some point in their life. Low back disorders are multifactorial;
and pathologic, physical, neurophysiological, psychological
and social factors have a different impact on each individual, and in about 90% of cases it is not possible to pinpoint
the cause of the dysfunction, which characterizes the nonspecific low back pain picture. Despite the limitations to
establish the relationship among clinical characteristics and
the conditions causing low back pain with the effectiveness
of treatment procedures, it is observed that biomechanical
and physiological losses tend to follow chronic cases of low
back pain. Many of these losses are identified in the literature, such as decreased speed of a comfortable gait, decreased
step length and swing time,12,13 decreased maximal aerobic
capacity,14 decreased resistance of the lumbar extensors with
consequent anterior displacement of the center of mass, poor
postural control,15,16 incoordination of the pelvic and thoracic
rotations,17 delay in the planned activation of the transversus abdominis, and impaired relaxation phenomenon during
trunk anteflexion.18,19
In a study that identified the main activities performed
with difficulty in the perception of patients with chronic low
back pain, it was observed that 56% of 101 volunteers reported
low tolerance to walking as one of the five activities more
poorly performed, this being the most prevalent item in that
sample.20 However, our knowledge it is still limited about how
the mechanical and energetic aspects of locomotion, especially with respect to gait, are affected by low back pain and
how the damages resulting from its occurrence are manifested
in functional activities, mainly with regard to the energyminimizer mechanisms of locomotion. The understanding
of these issues would be an improvement to explain if the
changes observed during walking in this population are due
to the inability of the body to provide an economical gait, or if
they exist precisely to preserve these energy-minimizer mechanisms.
Thus, this study aimed: a) to describe the main energyminimizer mechanisms of locomotion; b) to check if there are
signs of damage for mechanical and energetic characteristics
of gait due to chronic low back pain, which may endanger the
energy-minimizer mechanisms.
Method
This study was characterized as a narrative review of literature. We conducted a literature search in electronic databases:
Capes, PubMed and SciELO articles, written in English, Portuguese and Spanish languages, listed from the intersection
of the following keywords in English (low back pain, human
locomotion, walking, biomechanics, gait, energy consumption) and their equivalents in Portuguese idiom (dor lombar;
locomoção humana; caminhada, biomecânica, marcha, consumo de
energia) in a search period delimited from 1998 to March
2013; as well as classic articles related to the subject,
cited in the references of those previously selected articles.
57
Energy-minimizer mechanisms of human
locomotion
The normal human gait can be defined as the march modality
that humans use to move at low speeds. The gait cycle can be
understood as the time period between two identical events
in the walking process, and this full cycle is divided into two
phases: stance and swing phases.21
The stance phase begins with the first contact of a foot
(usually the heel) with the ground, ending with the last contact of the same foot with the ground, corresponding to hallux
take-off. The swing phase begins with the last contact of the
foot with the ground, ending with the first contralateral foot
contact with the ground. During the first half of the stance
phase, there is a decrease in the velocity of the center of mass
until the midpoint is reached; on the other hand, in the second half the center of mass increases its speed again. During
the stance phase, the leg remains extended and the midpoint
of this phase coincides with the highest point of the trajectory
of the center of mass.8–10
Complex phenomena, such as gait, in which many variables contribute to their occurrence (some of them difficult to
quantify), may not always be amenable to studies in real conditions. However, in some fields such as biomechanics, these
phenomena are simplified in the form of models, which can be
mathematical, physical or conceptual ones; and such models
allow us to understand the phenomenon more broadly.22,23
Although contradictory, there are two theories (models)
reported in studies with respect to march that seek to explain
the mechanisms by which this phenomenon can be more economical: the theory of six determinants of gait and the theory
of inverted pendulum. The main difference between the two
theories resides in the trajectory of the center of mass.23
The less accepted is the theory of six determinants, which
proposes that a set of kinematic features, such as knee flexion
at the time of stance and pelvic rotations, among others, are
used strategically to permit that the center of mass of the body
describe a straight trajectory during walking. The argument
for such behavior is that the vertical oscillations of the center
of mass generate an additional energy expenditure, due to the
need for muscle contraction to speed it up and lift it against
gravity. The main criticism of this model is that, to minimize
the energy expenditure associated with the oscillations of the
center of mass, it creates a need for the legs remaining bent
in the most part of the step, and that this has more costly
energetic consequences, in comparison with the oscillations
of the center of mass.23
On the other hand, the theory of inverted pendulum is
the more accepted, being used in the studies. The human
march, on level ground and under a biomechanical perspective, resembles a “rolling egg” or an inverted pendulum; these
analogies describe the behavior of the energy changes related
to the center of mass of the body. Mechanical models that represent the behavior of the body center of mass, understood as
the external work done to raise/lover and accelerate/delay the
center of mass in relation to the environment, have been used
to explain how each type of gait employs and saves mechanical energy. According to the inverted pendulum model (that
58
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):55–61
can also be seen as a rigid segment model), when applied
to gait, the kinetic and potential energies change in terms
of phase opposition (while one of them reaches a minimum
value, the other reaches a maximum value) during contact
with the ground in the unipodal phase, allowing an interchange between the two energies. This model proposes that
the mass center describes a curvilinear trajectory during the
step (similar to a pendulum positioned upside down) and that
the lower limb that supports the weight behaves as a rigid
segment. In addition, this mechanism of energy fluctuation
reduces the mechanical work imposed by the muscular system, thanks to the energy conservation; and this reduction
is proportional to the body’s ability to reconvert one energy
type into another (i.e., kinetic energy into potential energy, and
vice-versa) – a mechanical feature known as recovery.8,10,24,25
Thus, the act of walking with the knee extended in the
stance phase appears to result in two advantages: in addition
to providing the vertical displacement of the center of mass,
facilitating energy conservation through exchanges between
kinetic and potential energy, also allows that the action line
(vector) of the body weight pass near the lower limb joints, so
that there is little need for muscle action to prevent that these
joints suffer from their imposed loads. These two conditions
favor energy conservation.26
The pendulum transduction between kinetic and potential energies reduces the expenditure of chemical energy from
both the positive muscle work (that required to increase
potential and kinetic energy) and negative muscle work (that
required to reduce potential and kinetic energy). The fraction
of reconverted mechanical energy due to pendular transduction (recovery – %R) is defined mathematically as: %
R = 100 (W+ f + W+ v – W+ ext ) / (W+ f + W+ v ) where W+ f is the
positive work calculated from the sum, throughout the step
cycle, of the positive increments promoted by the previous displacement due to horizontal kinetic energy (CEh = 0,5
MVh 2 , where M = mass of the body and Vh = the instantaneous
horizontal velocity of the center of mass); W+ v represents
the positive work calculated from the sum, throughout the
step cycle, of the positive increments promoted by the
vertical displacement due to gravitational potential energy
(PE = Mgh, where M = body mass, g = the acceleration due to
gravity and h = the instantaneous height of the center of
mass); + W ext is the positive external work calculated from
the sum, throughout the step cycle, of the positive increments promoted by the total mechanical energy of the center
of mass (Emtot = PE + CEh + CEv , where PE = potential energy,
CEh = horizontal kinetic energy, and CEv = vertical kinetic
energy). CEv (CEv = 0,5 MVv 2 , where Mv = instantaneous vertical speed) has been neglected in this calculation, because it
does not influence W+ v , since the vertical velocity is zero at the
top and at the valley of the potential energy curve. Thus, the
recovery represents the maximum fraction of positive energy
increments linked to the center of mass that are reconverted
by the pendulum mechanism throughout the step cycle.10,27
In an ideal pendulum, the energy exchange is complete
(energy recovery = 100%). Nevertheless, in the human gait, the
energy recovery is moderately high (up to 60%) and depends on
the step length and walking speed. Recent literature suggests
some contribution of elastic energy to the march mechanisms,
by storing this energy and its releasing in the Achilles tendon
and possibly through the arch of the foot. The participation
of elastic energy during gait is accepted by some authors,
although this kind of energy has an apparently more decisive
participation in the race activity.10,28,29
During the locomotion, the gait parameters are adjusted
so that the force, work, power and/or energy expenditure are
minimized. Thus, during gait the average mechanical power
is minimal, when the subject is walking on a step frequency
close to that freely chosen (self-selected speed). Correspondingly, the oxygen consumption is also minimized at the same
frequency.30
Under normal conditions, the power consumption of gait
(metabolic power – consumption of oxygen per kilogram of
body weight during a given time) is related to the intensity of
effort, and can be affected by changes in speed. Thus, speed
is a crucial measure, being determinant to energy expenditure in walking tests. The influence of speed is so relevant to
energy consumption that the oxygen cost per meter walked
(a concept called the transportation cost) is obtained by the
ratio between metabolic power and speed of walking, being
indicative of the quality of the walk.9,31
Transportation cost is a measure of the economy of locomotion and represents the amount of metabolic energy
consumed to move one kilogram of body mass per unit of
distance, being expressed as J.kg-1 .m-1 10,32 and provides a
metabolic information of gait quality. Put more simply, transportation cost can be defined as the force required to move a
unit of mass by a unit of distance.
The transportation cost varies depending on the speed with
which the march is held, being usually lower in self-selected
speeds for each gait type. Based on this, Margaria, in the late
1930s, proposed that the curves of transportation cost in terms
of speed took the form of “U”, because the farther the studied speed with respect to that self-selected speed, the greater
the transportation cost.10,33 In fact, the optimal walking speed
has been defined in some studies as that speed in which,
simultaneously, there is optimization of the contribution of
mechanical parameters characteristic of this type of gait and
a lower metabolic cost.34
walking at higher speeds than the self-selected one
requires an increase in the activity of those muscles involved
in propelling the body forward, being also associated with a
greater step length, which increases the activity both of the
muscles that contribute to leg swing as of those that contribute
to the vertical control, since the vertical excursion of the center of mass of the body also increases. Conversely, walking
at lower speeds becomes mechanically less efficient, because
there is greater need for stabilization, and one can rely less on
the elastic energy of the muscle and tendon units.35
Consequently, one might think that there is a parallelism
between energetic and mechanic aspects of human locomotion. However, because of its complexity, many factors must be
taken into consideration. Taylor and Heglund36 showed that
observed changes in metabolic power, due to the variation
of speed and body weight, did not result in parallel changes
in the mechanical work done by muscles. These authors also
suggest that the metabolic cost of generating muscular force
during the foot-and-ground contact, regardless of whether
the mechanical work (product of force by displacement) is
produced (e.g., concentric contractions) or not (e.g., isometric
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):55–61
concentrations), is what determines the rate at which energy
is consumed. Shi and Stuhmiller37 concluded that, for many
activities, there is a relationship between metabolic cost and
the magnitude and frequency of force application, linked to
the effective contact time of the foot with the ground.
Very different changes in step frequency, in comparison
with that considered natural, can induce significant changes
in energy-minimizer mechanisms in walking. At a given
speed, the recovery percentage tends to increase when the
step length is greater than that observed in the natural gait
and, conversely, tends to decrease when the step length is
smaller than that freely chosen.38
The trunk coordination during the human march has also
been a focus of study. In normal subjects, the increase in
walking speed changes the phasic relationship between the
rotations of the trunk and pelvis in the horizontal plane,
so that at lower speeds these two segments tend to have a
more synchronous behavior (in phase), that becomes more
and more asynchronous (out of phase) as the speed increases.
Thus, in a brisk march, the oscillatory movements of the trunk
in relation to the pelvis become more evident. Although the
mechanisms that govern such coordination are still not completely understood, even in normal subjects, in some disease
conditions – such as in low back pain – there is a loss of this
coordinative movement in a way that, even for higher walking speeds, both segments (trunk and pelvis) tend to move
synchronously, forcing a more “en bloc” style of walking.39,40
Mechanical and energy losses during gait arising from low
back pain
While normal subjects select their length and frequency of
steps in order to make the most economical gait from the
point of view of energy, those with diseases involving the locomotor system change that strategy. Large step lengths induce
changes in the system of coordination between trunk and
pelvis, implying larger rotations between these segments during walking. In pathological marches, there is a trend to avoid
large oscillations of the column, and these individuals can do
this in several ways; as to chronic low back pain patients, they
tend to walk more slowly, decreasing the length and increasing, to a lesser extent, the frequency of their steps.40
Subjects with low back pain exhibit several adaptations
during walking as a result of pain, such as: alteration of proprioceptive postural control; stiffer trunk and body strategy,
leading to the adoption of the ankle strategy; increased activity of lumbar muscles during all step periods and, secondarily,
less relative relaxation during swing periods, compared with
double-stance periods; a decrease of the vertical component
of ground reaction forces in those individuals whose pain is
radiating to the lower limbs; a decrease in preferred walking
speed; a decreased thorax-pelvic coordination in the transverse plane, inducing a more rigid behavior between these
segments; a shorter step length, among others. Moreover,
patients with nonspecific chronic low back pain, when asked
to increase their walking speed, tend to increase more the
cadence, rather than the length, of the steps, unlike individuals free of pain.15,41-45
Lamoth et al.44 observed that individuals with low back
pain who walked in the same relative speed (110% of preferred
59
speed) of subjects without low back pain showed step length,
walking speed and step length variability significantly lower,
but this was not observed when the step frequency was evaluated. Elbaz et al.46 observed that patients with nonspecific
chronic low back pain showed asymmetry in their one-foot
support and in swing and stance phases, in addition to a lower
walking speed. These authors suggest that, in these patients,
the decrease in walking speed can be understood as a protective mechanism attributed to an attempt to reduce the ground
reaction forces and to minimize the overload in the column
and avoid pain.
The pain, at least when it comes to walking, seems to play
a more important role in acute episodes. Moe-Nilssen, Ljunggren and Torebjork47 tried to find out if the measurement of
the lumbar spine acceleration, quantified by an accelerometer,
could indicate changes in motor behavior during walking, as
a result of a transient low back pain experimentally induced
by an injection of hypertonic saline into the longissimus dorsi
muscle. These authors found a dynamic interaction between
pain and adaptation in motor performance, when observing reduction of lumbar acceleration during the period of
maintenance of induced pain, assuming that this change was
processed by the vegetative nervous system.
Taylor, Evans and Goldie48 compared a group of volunteer
subjects with acute low back pain seven days after the onset of
pain and six weeks later, when the pain had disappeared, and
also evaluated subjects without low back pain. In each assessment all participants walked at the self-selected speed and
at an intensity 40% faster than the self-selected speed. These
authors observed that, at higher speeds, during the period of
exacerbation the lumbar group exhibited significant adjustments in the way of walking, such as increases in pelvic tilt,
in lateral flexion of the lumbar spine and in the step length versus post-test evaluation. However, no differences in relation to
the control group were found. These findings suggest that the
pain can cause changes in walking style.
In chronic pain conditions, an understanding of the
adaptative processes becomes a much more complex task.
Accordingly, other studies also shift the focus of pain as a
determinant variable in the population of chronic low back
pain patients, at the expense of the functional picture. The
evidence suggesting that supraspinal changes (neurodegeneration of dorsolateral portion of prefrontal cortex; gradual
decrease in neocortical, prefrontal cortex and thalamus
gray matter volume, among others) present in patients with
chronic nonspecific low back pain may contain the mechanisms that justify the clinical findings is increasing, although
still without consensus about this supposition. Thus, it is
believed that this reorganization within the brain is capable of
generating a picture of persistent pain, even in the absence of
physical change, and this includes the cortical neurodegeneration and descending inhibition, producing an abnormal state
of sensitivity; memory of pain; and generation of central pain
as a result of sensorimotor incongruence, when the patient
is moving. Therefore, the motor changes observed in these
individuals would have a central, rather than peripheral, origin, and this knowledge imposes the need to rethink both the
nature of the problem as the best way to approach it, because,
by all accounts, the physical changes cease to be the cause
and become a result of a significant change in the central
60
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):55–61
representation and in the attempts of the patient to maintain
the same functionality, even in the presence of a changed
body image.49
Other studies have also confirmed the changes in volume
and density of the cortex as well as of the white matter among
patients with chronic low back pain.50-52 These changes were
observed in several cortical areas, including those related with
the speed of gait processing, as the corpus callosum, which
also seems to be associated with poor physical fitness and
duration of pain.51 The structural and functional changes that
occur in the brain of low back pain patients, suggested by
these studies, give due credit to the hypothesis that these
individuals are less able to adapt their spatio-temporal gait
parameters, in comparison with pain-free individuals. Consequently, as the gait kinematics plays an important role
in energy-minimizer mechanisms, the hypothesis proposing
that these patients are also less economical becomes more
robust.
Thus, it is important to identify whether the changes during gait, observed in this population, arise also from the
inability of the body to provide an economical gait, or if they
exist precisely to preserve the economy of gait.
At least with respect to the scope of this literature review,
no studies correlating the motor losses in locomotion (widely
described among chronic low back pain patients) with energyminimizer mechanisms of walking were found. Therefore, this
suggests the need for studies that seek to understand whether
or not there is a loss of these mechanisms in this population.
Final considerations
The main theory explaining the minimization of energy
expenditure during walking is the inverted pendulum mechanism, and the energy-minimizer mechanism of this theory
would be the reconversion that occurs during the march,
among the mechanical energies linked to the body center of mass (kinetic and potential energies). However, this
energy-minimizer mechanism is strongly influenced by
spatio-temporal parameters of gait which, in turn, may be
severely altered in those individuals with chronic back pain.
Thus, there is evidence that such functional changes may
compromise the energy-minimizer mechanisms.
Conflict of interests
The authors declare no conflict of interests.
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r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):62–67
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Review article
Monitoring the functional capacity of patients with
rheumatoid arthritis for three years
Leda M. de Oliveira, Jamil Natour ∗ , Suely Roizenblatt, Pola M. Poli de Araujo,
Marcos B. Ferraz
Discipline of Rheumatology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To quantify modification of functional capacity in a three-year period in a group
Received 17 October 2013
of patients with rheumatoid arthritis (RA) using HAQ and EPM-ROM inventories.
Accepted 12 June 2014
Methods: Forty patients with RA on methotrexate (MTX) as disease-modifying antirheumatic
Available online 3 December 2014
drug (DMARD) were followed for up to three years. The functional status was assessed at
the beginning and end of the period by HAQ and EPM-ROM.
Keywords:
Results: Thirty-two patients were retrieved, with initial HAQ score of 1.14 ± 0.49 (mean ± SD)
Rheumatoid arthritis
and EPM-ROM score of 5.8 ± 2.75. After an average period of three years, the HAQ score was
Functional capacity
1.13 ± 0.49 and EPM-ROM score, 6.81 ± 3.66. In the subgroup of seven patients submitted to
HAQ
orthopedic surgery, HAQ score decreased from 0.84 ± 0.72 to 1.64 ± 0.56 and the EPM-ROM
EPM-ROM
score, from 5.8 ± 1.80 to 8.3 ± 0.74. In the subgroup of non-operated patients, HAQ score
varied from 1.2 ± 0.45 to 1.07 ± 0.70 and EPM-ROM score, from 5.7 ± 3.06 to 6.4 ± 3.90.
Conclusion: In a group of RA patients in use of only MTX as DMARD, there was little change on
HAQ score and EPM-ROM scores over the average period of three years. Worsening functional
capacity was observed in the group of operated patients in comparison to the not operated
ones. This fact alerts us to the need for use of broader therapeutic regimens availability of
musculoskeletal surgeries in a timely manner in patients with RA.
© 2014 Elsevier Editora Ltda. All rights reserved.
Acompanhamento da capacidade funcional de pacientes com artrite
reumatoide por três anos
r e s u m o
Palavras-chave:
Objetivo: Quantificar a modificação da capacidade funcional em um período de três anos
Rheumatoid arthritis
em um grupo de pacientes com artrite reumatoide (AR), utilizando os inventários HAQ e
Functional capacity
EPM-ROM.
HAQ
Métodos: Quarenta pacientes com AR em tratamento com metotrexato (MTX) como fármaco
EPM-ROM
antirreumático modificador da doença (DMARD) foram acompanhados por até três anos. O
estado funcional foi avaliado no início e no final do período por HAQ e EPM-ROM.
∗
Corresponding author.
E-mail: [email protected] (J. Natour).
http://dx.doi.org/10.1016/j.rbre.2014.06.007
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):62–67
63
Resultados: Trinta e dois pacientes foram recuperados, com escore HAQ inicial de 1,14 ± 0,49
(média ± DP) e EPM-ROM de 5,8 ± 2,75. Após um período médio de três anos, o HAQ foi de
1,13 ± 0,49 e EPM-ROM em 6,81 ± 3,66. No subgrupo de sete pacientes submetidos a cirurgia ortopédica, o HAQ diminuiu de 0,84 ± 0,72 para 1,64 ± 0,56; e o EPM-ROM, de 5,8 ± 1,80
para 8,3 ± 0,74. No subgrupo de pacientes não operados, o HAQ variou de 1,2 ± 0,45 para
1,07 ± 0,70; e o EPM-ROM, de 5,7 ± 3,06 para 6,4 ± 3,90.
Conclusão: Em um grupo de pacientes com AR medicados apenas com MTX como DMARD,
houve pouca mudança nas pontuações HAQ e EPM-ROM durante o período médio de três
anos. Observou-se agravamento da capacidade funcional no grupo de pacientes operados,
em comparação com os não operados. Este fato nos alerta para a necessidade do uso de
esquemas terapêuticos mais abrangentes e de maior disponibilidade de cirurgias musculoesqueléticas, em tempo hábil, em pacientes com AR.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease
in which the joint inflammation presents as synovitis. The
inflammation causes joint pain, swelling, and stiffness, as
well as systemic symptoms such as fatigue, weight loss and
anemia. The synovitis is the main factor that leads to joint
destruction and, if untreated, may progress to serious joint
damage, with loss of functional capacity.1
RA is a condition that affects approximately 0.5–1% of the
adult population worldwide, and its occurrence is observed in
all ethnic groups. There is a predominance of females (two to
three times, compared to males), occurring mainly in patients
between the fourth and sixth decades of life, although there
are occurrences of RA in all age groups.2
The negative consequences for physical functioning in RA
patients are multidimensional, with loss of muscle strength
and endurance, besides the loss of range of motion (ROM)
of joints, due to changes caused by the disease. For a proper
understanding of the situation of the patient, a multifaceted
view is required, because the only use of laboratory tests will
not allow a comprehensive assessment of his/her functional
capacity.3
Functional capacity is a key factor of morbidity and a predictor of mortality4 in RA patients. The Health Assessment
Questionnaire (HAQ) is a commonly used tool to assess the
functional status in RA patients, but some studies have shown
an inverse relationship between sensitivity to change in HAQ
and disease duration, so that the duration of the disease influences the degree of functional improvement.5
HAQ was developed by Fries et al. (1980)6 to assess functional capacity in RA; and the dysfunction occurs early in the
disease, due to factors that are not entirely clear.
The pain per se can lead to functional loss, even in the
absence of radiological changes, which only become evident
with the persistence of synovitis.7 HAQ has been translated
and validated into many languages, including Brazilian Portuguese by Ferraz et al. in 1990.8
Functional capacity in RA can also be assessed by EPMROM, which is a standardized measure of the potential range
of motion of joints in upper and lower limbs.9 The scale
assesses ROM of 10 large-and-small, right-and-left joints by
using a goniometer.10
The progression of joint dysfunction occurs in a subclinical,
slow and progressive way in the different stages of the disease,
which complicates the acceptance of surgical indication by
RA patients. However, the indication of surgery must be done
early, in order to avoid the onset of joint deformities.11
In our environment, there are no studies on the long-term
outcome of functional capacity in RA patients who were not
treated with biologicals. This study portrays the situation of
availability of musculoskeletal surgeries performed in a timely
fashion in patients seen in the Public Health Service.
“In our country there are no studies on the long-term outcome of functional capacity of patients with RA taking
biologic medication. This study portrays the situation of
availability of musculoskeletal surgeries in a timely fashion
in patients seen in the Public Health Service. Considering that HAQ and EPM-ROM may reflect the changes in
functional capacity over time,12 this study assessed the
modification of the indices in question as a result parameter of indication of orthopedic surgery within a 3-year
period in RA patients.”
Objectives
This study aims to quantify the change in the functional
capacity of RA patients treated routinely at our Service of
Rheumatology, Universidade Federal de São Paulo.
Methods
This prospective study involved 40 RA patients according to
American College of Rheumatology criteria,13 all aged over 18
years at disease onset. All patients were informed on the content of the research and agreed to participate in the study
by signing a consent form. RA patients in functional classes
2 and 314 treated with corticosteroids, nonsteroidal antiinflammatory drugs, and methotrexate as disease-modifying
antirheumatic drug (DMARD) were included in this study.
Patients who used other DMARDs, or those with some pathology that would interfere with their movement, e.g., other
musculoskeletal or neurological disorders, fractures with joint
deformity, or with congenital malformation were excluded.
Patients with diabetes mellitus and alcohol or illegal drug
64
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):62–67
users were also excluded. Our patients were selected sequentially, being inquired about duration of the disease, presence
of morning stiffness (in minutes) and medications used at the
time of enrollment. The overall clinical assessment and the
counting of inflamed joints were performed by a rheumatologist, and HAQ and EPM-ROM tools were applied by one of
the authors of this study (Oliveira LM). After an average 3-year
period, 32 of those patients still being monitored at the outpatient service of Rheumatology, Universidade Federal de São
Paulo, were reassessed.
Considering the occurrence of a 10% loss of functional
capacity even in healthy individuals after the age of 50,15 we
set the rate of loss of functional capacity expected by HAQ in
RA in 20%. Thus, we compared baseline and final assessment
data with respect to the loss of function, using HAQ (greater or
lesser than 20%) and with respect to whether or not perform
a surgery.
Continuous data were presented as mean (standard deviation – SD) and minimum and maximum values. Categorical
data were expressed as absolute number and percentage. For
the comparison between baseline and final assessments of
variables (e.g., medications in use and function loss greater or
lesser than 20% measured by HAQ), the chi-square or Fisher’s
exact test was used.
Comparisons between continuous variables, such as HAQ
and EPM-ROM scores and HAQ and EPM-ROM score changes,
were only descriptive, due to the limitation imposed by the
sample size. The correlation between variables was performed
using the Spearman test.
The statistical package SPSS, version 15.0, was used, and
significance was set at 5%.
Results
After a 3-year period, of those 40 patients included in the study
we could reassess 32 subjects. Thus, eight patients were not
reassessed: three had died and five failed to visit the service
of Rheumatology. The characteristics of the group are shown
in Table 1.
Seven patients underwent orthopedic surgery during the
time period of this study and their data are described in
Table 2. Table 3 shows the values for HAQ and EPM-ROM for
patients submitted or not to surgery. Of the seven patients
surgically treated, four underwent more than one procedure.
The operations performed in the upper limbs (n = 5) were: synovectomy in three patients, wrist fixation in one patient, and
metacarpophalangeal prosthesis application in one patient.
The surgeries performed in the lower limbs (n = 9) were: synovectomy in the foot of a patient, a talocalcaneal fixation on
another and knee prosthesis application in three patients.
Table 4 shows the comparison of patients stratified with
respect to loss of function by HAQ and whether or not a surgery
was performed.
With respect to surgery procedures, although the frequency
of patients who had greater than 20% loss of functional capacity was not significant (Fisher, P = 0.16), those patients who
underwent surgery had a three times greater risk of suffering loss of functional capacity greater than 20% during the
Table 1 – Clinical and demographic characteristics.
Gender (women/men)
Average age (years)
Min/Max
29:3
53.8 (13)
28–75 years
Race, n (%)
White
Mixed race (“pardos”)
Black
Oriental
15 (46.9)
12 (37.5)
3 (9.4)
2 (6.3)
Duration of illness
Min/Max
12.2 (7.4)
4–33 years
Number of inflamed joints
HAQ, baseline
HAQ, final
EPM-ROM (DP), baseline
EPM-ROM (DP), final
Methotrexate (%)
5 (7.1)
1.14 (0.49)
1.13 (0.49)
5.8 (2.75)
6.81 (3.66)
23 (73.6)
Continuous data expressed as mean (SD), minimum and maximum
values.
Categorical data in absolute numbers, n (percentage).
study period (hazard ratio = 3.42) compared with patients not
operated.
A correlation was noted between number of inflamed joints
and baseline EPM-ROM score (0.46); between baseline EPMROM and baseline HAQ (0.46); between final EPM-ROM score
and disease duration (0.45); and between disease duration
and EPM-ROM change (difference between baseline and final
scores). A strong correlation was noted between final HAQ
score and HAQ change (0.74), influenced by the subgroup of
patients who underwent surgery (Table 5).
Discussion
This prospective study involved 32 RA patients aged over
18 years at disease onset and with moderate functional
impairment according to HAQ and EPM-ROM scores. After
a mean follow-up of three years, the frequency of patients
who had greater than 20% loss of functional capacity was
Table 2 – Characteristics of RA patients who underwent
surgery during the study period.
Conservative
treatment
Surgery
Gender (women/men)
Age (years)
Min/Max
22:3
50.0
28–75
7:0
49.7
31–69
Disease duration (years)
Min/Max
11.3
4–33
14.2
8–23
Morning stiffness (minutes)
Min/Max
29.2
0–360
23.5
0–120
Number of inflamed joints
Min/Max
5.2
0–26
7
0–30
Average, minimum and maximum values.
Categorical data in absolute numbers, n.
65
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):62–67
Table 3 – HAQ and EPM-ROM scores for patients who were or not submitted to orthopedic surgery.
Surgery
n=7
Without surgery
n = 25
Baseline
Final
HAQ 0.84 (0.72)
EPM-ROM 5.8 (1.80)
HAQ 1.20 (0.45)
EPM-ROM 5.7 (3.06)
HAQ 1.64 (0.56)
EPM-ROM 8.3 (0.74)
HAQ 1.07 (0.70)
EPM-ROM 6.4 (3.90)
Methotrexate use
4 (57%)
21 (84%)
Data expressed as mean (SD).
Table 4 – Loss of function as measured by HAQ after
three years of progression.
Loss of function
>20%
<20%
Surgery
Without surgery
4 (57%)
7 (28%)
3 (43%)
18 (72%)
Data in absolute numbers and percentages.
not significant. Patients who underwent surgery had a three
times greater risk of functional capacity loss greater than 20%
during the study period compared with not surgically treated
patients.
Our data indicate a relative score stability, not only for
HAQ,16 but also for EPM-ROM over time. Although extensively
used, the exclusive use of HAQ has proven more suitable to
evaluate RA activity,17 while EPM-ROM is a more sensitive tool
to changes in functional capacity.10 The use of EPM-ROM in
this study has provided objective data about the ROM needed
to performing activities of daily living. In fact, the EPM-ROM
score is sensitive to the modification of functional status,
translating the goniometry required to perform the basic activities of life.17
Even in healthy individuals, there is loss of functional
capacity throughout life;18 and in RA patients, such a loss is
more significant.19 In our sample of RA patients with a mean
age of 58 years, an HAQ score of 1.1 is equivalent to the score
for people aged 85 years.18 Sokka et al., assessing functional
capacity in RA patients, established that HAQ values smaller
than 1 would mean a milder disease, while values above 2
would suggest a severe illness.12 The annual increase in HAQ
score found by these authors was confirmed by Scott et al.
These authors found an annual increase of 1% in HAQ score.20
Although the literature considers a 0.24-change in HAQ as clinically relevant,21 reductions of 0.19 can already considered as
minimal improvement in function.20
The functional capacity measured by HAQ is influenced not
only by age or duration of disease, but also by levels of pain
and medications used. In Brazilian patients, there was a faster
progression in HAQ scores compared to Spanish patients. This
finding was attributed to the difference in the pain assessment
and medications used.21 At that time, there was scarce access
to biologic drugs in several centers in Brazil, while in Spain
these medications were already widely available.
HAQ can predict the severity and dysfunction caused by
RA during the progression of the disease – which is not evident with the use of other clinical measures. The functional
loss after five years is related to female gender, older age at
disease onset, HAQ >1 in the first assessment, comorbidities
and depression.16 In addition to a positive correlation with disease duration, HAQ presents also a negative correlation with
socioeconomic status.20
In the present study, we observed a slight improvement
in functional capacity measured by HAQ in the group of
patients who did not undergo surgery and a significant worsening in the operated group. One can interpret this finding
as a difference in disease severity between groups. Allegedly,
the group not operated would suffer a less aggressive disease, although with a disease duration similar to that of the
operated group. Thus, the more favorable progression of the
non-operated group may reflect a condition more susceptible to control by medication. A worsening of both HAQ and
EPM-ROM scores was observed in the RA group who underwent orthopedic surgery, denoting that their surgery may
have occurred late, when the anatomical deformities (e.g.,
musculoskeletal impairment) already installed would prevent
functional improvement of the joint.
Back when the patients in this study showed the first symptoms of RA, biologicals were not available in the Public Health
Service. Currently the importance of the early use of DMARDs
and biologicals in controlling the course of the disease in
its first years has already been established. This window of
opportunity may have been lost by the patients in this study,
who had only methotrexate available as DMARD. Our findings
agree with Sokka et al.’s, which emphasize the positive impact
of an early use of DMARDs in functional capacity measured
Table 5 – Correlations found among clinical data.
Baseline EPM-ROM scoring
Inflamed joints (n)
Duration of disease
HAQ, baseline
Final HAQ scoring
EPM-ROM, baseline
0.46
NS
0.46
NS
NS
Spearman correlation, NS, not significant.
Final EPM-ROM scoring
NS
0.45
NS
NS
0.53
EPM-ROM change
NS
0.48
NS
NS
NS
HAQ change
NS
NS
NS
0.74
NS
66
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):62–67
by HAQ. We can add to this the finding that functional disability was a predictor factor of mortality in RA.12 Pain and
joint mobility are considered as important factors limiting
the functional capacity of RA patients.3,22,23 The loss of functional capacity occurs early in the disease, with the presence of
acute inflammation.24 With the early use of DMARDs and after
controlling the disease activity, a functional recovery occurs,
followed by structural lesions that settle slowly and cumulatively. Thus, the functional deterioration may occur even
before the radiographic changes, which become relevant after
a lapse of five years from the onset of the disease.7,20
An inverse correlation between HAQ score and ROM of
some joints, e.g. wrists, shoulders and knees, was observed.24
EPM-ROM takes into account the ROM ranges needed to
perform wide-ranging functions, and not just a percentage
of amplitude loss caused by the disease, which can differ
depending on the joint.8 Our data show the expected correlation between the baseline evaluation by EPM-ROM and the
number of inflamed joints. We also noted an EPM-ROM variation with the duration of disease, showing worsening in joint
mobilization capacity after a 3-year period.
In subjects with joint impairment consolidated by a disease
duration longer than 12 years, EPM-ROM remains stable, while
HAQ varies depending on the degree of disease activity.22
These questionnaires are complementary, to the extent that
HAQ is influenced by the subject’s adaptation to dysfunction
over time, while EPM-ROM reflects the capacity of the movement itself.
Although the dysfunction due to pain and inflammation
can be modified by clinical and rehabilitative approaches, this
strategy may not be sufficient in the context of the sum of
structural joint injuries, regardless of the surgical approach.25
The best time for surgery indication in RA remains to be
defined, being hampered by the availability of surgical services and the patient’s motivation.7,11,25 We must add to this
the fact that, even when indicated early, the surgery acts in
an indirect manner in function improvement, i.e., through
improvement of pain, rather than through regaining functional capacity.19 Few studies have evaluated the long-term
effect of surgical interventions. Benoni et al. demonstrated
improvement in pain in RA patients who underwent surgery
of lower limb joints after one year of follow-up. The improvement in HAQ score of at least 0.2 occurred only in cases of
knee and hip surgery, but not in ankle and feet surgery.26 On
the other hand, March et al. observed a reduction in HAQ only
in patients undergoing knee arthroplasty, and stability in HAQ
in those undergoing hip arthroplasty.19 Therefore, total HAQ
does not reflect the potentially expected functional improvement after an orthopedic surgery in RA patients; and clinical
practice shows that the modification of HAQ has value as
a measure of the effect of other therapeutic modalities in
RA.27
In our study, we observed a positive correlation between
the final score of the HAQ and its changes over the 3-year
period, influenced by the subgroup of patients undergoing
surgery. This finding highlights the deterioration of functional
capacity in the group of operated patients, which is in agreement with other authors that the effect of arthroplasty in
RA is more prominent in relieving pain than in the recovery
of function.19,26,27 Considering that disease activity is a key
determinant factor to explain the loss of functional capacity, patients treated by rheumatologists have a more favorable
progression of AR versus those treated by physicians from
other specialties.12
Furthermore, we observed lower baseline HAQ scores in
the surgery group compared to the conservatively treated
group. No statistical analysis could be performed between the
two groups, in view of the diversity in the group of patients
operated and the small sample size. In four patients, more
than one type of surgery was performed, and three patients
underwent surgery both in their upper and lower limb. Two
patients underwent ankle surgery which, according to Benoni
et al., evolves unfavorably, with reduction of HAQ.27 As for
metacarpophalangeal arthroplasty, it is known that, although
the patient demonstrates satisfaction with improved pinch
and grip strength, the functional capacity shows modest
gains.28
Some of the limitations of this study reflect the deficiencies in tertiary care of Public Health Services in our midst.
Among them, we can mention the difficulty in establishing
the diagnosis of RA within the window of opportunity that
would allow the preservation of joint function, as well as to
getting the surgery needed in a timely manner. In our country,
there are long waiting lines for treatment in the Public Health
Service, and this can contribute to the deterioration of functional capacity to the point that, when finally the surgery is
performed, the preservation of function is no longer possible.
In this context, the heterogeneity with respect to disease duration and the small number of patients undergoing surgery are
included.
This study was limited to a baseline evaluation and to
another, after approximately three years of progression. The
fulfillment of interim evaluations, and in particular a preoperative assessment for the surgical group, could shed light
on the worst course of operated patients. These patients may
present a more aggressive disease, and perhaps their functional capacity was very poor at the time of surgery, justifying
their unfavorable outcome.
Finally, patients taking biologic medications were not
included in this study. It is not yet clear whether the biologicals are responsible for a reduction in surgical indications
in RA patients.24,25,29 In general, it is known that the early
use of DMARDs in RA tends to decrease the disease progression, improve quality of life and also reduce the costs of
hospitalization, surgical procedures, and the long periods of
rehabilitation.11,30
Our data demonstrate that HAQ and EPM-ROM scores in a
group of RA patients seen in the Public Health Service have
not changed over an average 3-year period. The group of
patients undergoing orthopedic surgery experienced worsening of functional capacity versus the group of patients who
were not operated. This fact serves as a warning of the need to
use broader therapeutic regimens and also of the need for the
availability of musculoskeletal surgeries in a timely manner
for RA patients.
Conflicts of interest
The authors declare no conflicts of interest.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):62–67
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Chary-Valckenaere I, et al. Improving agreement in
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2. Mota LM, Cruz BA, Brenol CV, Pereira IA, Fronza LS, Bertolo
MB, et al. Guidelines for the diagnosis of rheumatoid arthritis.
Rev Bras Reumatol. 2013;53:141–57.
3. Hakkinen A, Kautiainen H, Hannonen P, Ylinen J,
Arkela-Kautiainen M, Sokka T. Pain and joint mobility explain
individual subdimensions of the health assessment
questionnaire (HAQ) disability index in patients with
rheumatoid arthritis. Ann Rheum Dis. 2005;64:59–63.
4. Pincus T, Sokka T. Quantitative target values of predictors of
mortality in rheumatoid arthritis as possible goals for
therapeutic interventions: an alternative approach to
remission or ACR20 responses? J Rheumatol. 2001;28:1723–34.
5. Aletaha D, Ward MM. Duration of rheumatoid arthritis
influences the degree of functional improvement in clinical
trials. Ann Rheum Dis. 2006;65:227–33.
6. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of
patient outcome in arthritis. Arthritis Rheum. 1980;23:
137–45.
7. Plant MJ, O’Sullivan MM, Lewis PA, Camilleri JP, Coles EC,
Jessop JD. What factors influence functional ability in
patients with rheumatoid arthritis. Do they alter over time?
Rheumatology (Oxford). 2005;44:1181–5.
8. Ferraz MB, Oliveira LM, Araujo PM, Atra E, Tugwell P.
Crosscultural reliability of the physical ability dimension of
the health assessment questionnaire. J Rheumatol.
1990;17:813–7.
9. Kuhlow H, Fransen J, Ewert T, Stucki G, Forster A, Langenegger
T, et al. Factors explaining limitations in activities and
restrictions in participation in rheumatoid arthritis. Eur J
Phys Rehabil Med. 2010;46:169–77.
10. Ferraz MB, Oliveira LM, Araujo PM, Atra E, Walter SD.
EPM-ROM scale: an evaluative instrument to be used in
rheumatoid arthritis trials. Clin Exp Rheumatol. 1990;8:491–4.
11. Arija SM, Lasanta ML, Nunez FG, Ureña I, Espiño-Lorenzo P,
Barco CM, et al. Annual trends in knee and hip arthroplasty in
rheumatoid arthritis 1998–2007. Rheumatol Clin. 2011;7:
380–4.
12. Sokka T, Mottonen T, Hannonen P. Disease-modifying
anti-rheumatic drug use according to the ‘sawtooth’
treatment strategy improves the functional outcome in
rheumatoid arthritis: results of a long-term follow-up study
with review of the literature. Rheumatology (Oxford).
2000;39:34–42.
13. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid
arthritis. Arthritis Rheum. 1988;31:315–24.
14. Escalante A, Del Rincón I, Cornell JE. Latent variable approach
to the measurement of physical disability in rheumatoid
arthritis. Arthritis Rheum. 2004;51:399–407. PubMed PMID:
15188325.
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15. Bendtsen P, Bjurulf P, Trell E, Lindstrom F, Larsson JE.
Cross-sectional assessment and subgroup comparison of
functional disability in patients with rheumatoid arthritis in
a Swedish health-care district. Disabil Rehabil. 1995;17:94–9.
16. Schneeberger EE, Citera G, Maldonado Cocco JA, Salcedo M,
Chiardola F, Rosemffet MG, et al. Factors associated with
disability in patients with rheumatoid arthritis. J Clin
Rheumatol. 2010;16:215–8.
17. Vliet Vlieland TP, van den Ende CH, Breedveld FC, Hazes JM.
Evaluation of joint mobility in rheumatoid arthritis trials: the
value of the EPM-range of motion scale. J Rheumatol.
1993;20:2010–4.
18. March LM, Brnabic AJ, Skinner JC, Schwarz JM, Finnegan T,
Druce J, et al. Musculoskeletal disability among elderly people
in the community. Med J Aust. 1998;168:439–42.
19. March LM, Barcenilla AL, Cross MJ, Lapsley HM, Parker D,
Brooks PM. Costs and outcomes of total hip and knee joint
replacement for rheumatoid arthritis. Clin Rheumatol.
2008;27:1235–42.
20. Scott DL, Strand V. The effects of disease-modifying
anti-rheumatic drugs on the Health Assessment
Questionnaire score. Lessons from the leflunomide clinical
trials database. Rheumatology (Oxford). 2002;41:899–909.
21. Ide MR, Gonzalez-Gay MA, Yano KC, Imai MJ, de Andrade MC
Jr, Llorca J. Functional capacity in rheumatoid arthritis
patients: comparison between Spanish and Brazilian sample.
Rheumatol Int. 2011;31:221–6.
22. Bulthuis Y, Drossaers-Bakker KW, Taal E, Rasker J, Oostveen J,
van’t Pad Bosch P, et al. Arthritis patients show long-term
benefits from 3 weeks intensive exercise training directly
following hospital discharge. Rheumatology (Oxford).
2007;46:1712–7.
23. Fitzcharles MA, DaCosta D, Ware MA, Shir Y. Patient barriers
to pain management may contribute to poor pain control in
rheumatoid arthritis. J Pain. 2009;10:300–5.
24. Marcos J, Waimann C, Dal Pra F, Hogrefe J, Retamozo S, Caeiro
F, et al. General characteristics of an early arthritis cohort in
Argentina. Rheumatology (Oxford). 2011;50:110–6.
25. Lee JK, Choi CH. Total knee arthroplasty in rheumatoid
arthritis. Knee Surg Relat Res. 2012;24:1–6.
26. Sokka T. Long-term outcomes of rheumatoid arthritis. Curr
Opin Rheumatol. 2009;21:284–90.
27. Benoni AC, Bremander A, Nilsdotter A. Patient-reported
outcome after rheumatoid arthritis-related surgery in the
lower extremities: a report from the Swedish National
Register of Rheuma Surgery (RAKIR). Acta Orthop.
2012;83:179–84.
28. Waljee JF, Chung KC. Objective functional outcomes and
patient satisfaction after silicone metacarpophalangeal
arthroplasty for rheumatoid arthritis. J Hand Surg Am.
2012;37:47–54.
29. Aaltonen KJ, Virkki LM, Jämsen E, Sokka T, Konttinen YT,
Peltomaa R, et al. Do biologic drugs affect the need for and
outcome of joint replacements in patients with rheumatoid
arthritis? A register-based study. Semin Arthritis Rheum.
2013;43:55–62.
30. Rat AC, Boissier MC. Rheumatoid arthritis: direct and indirect
costs. Joint Bone Spine. 2004;71:518–24.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):68–74
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Case report
Coexisting systemic lupus erythematosus and
sickle cell disease: Case report and literature review
Teresa Cristina Martins Vicente Robazzi a,∗ , Crésio Alves b , Laís Abreu b , Gabriela Lemos b
a
b
Reumatologia pediátrica, Universidade Federal da Bahia, Salvador, BA, Brasil
Universidade Federal da Bahia, Salvador, BA, Brasil
a r t i c l e
i n f o
a b s t r a c t
Article history:
Objective: To report a case of coexisting systemic lupus erythematosus (SLE) and sickle cell
Received 8 May 2012
disease (SCD) with a review of the literature on the topic.
Accepted 14 May 2013
Methodology: Case report and literature review of the association between SLE and SCD
Available online 28 November 2014
through scientific articles in health sciences databases, such as LILACS, MEDLINE/Pubmed
Keywords:
Systemic lupus erythematosus; 4. Hemoglobinopathies.
and Scielo, until May 2012. Descriptors used: 1. Sickle cell anemia; 2. Sickle cell disease; 3.
Sickle cell anemia
Results: The authors describe an association between SLE and SS hemoglobinopathy in an
Sickle cell disease
eight-year-old female patient presentingarticular, hematologic and neuropsychiatric mani-
Systemic lupus erythematosus
festations during clinical evolution. Forty-five cases of association between SLE and SCD are
Hemoglobinopathies
described in literature, mostly adults (62.2%), women (78%) and with the SS phenotype in
78% of the cases, and diverse clinical manifestations. Compared with our patient, articular,
hematologic and neuropsychiatric manifestations were present in 76%, 36% and 27% of the
cases, respectively.
Conclusion: SLE and SCD are chronic diseases that have several clinical and laboratory findings in common, meaning difficult diagnosis and difficulty in finding the correct treatment.
Although the association between these diseases is not common, it is described in literature,
so it is imperative that physicians who treat such diseases be alert to this possibility.
© 2014 Elsevier Editora Ltda. All rights reserved.
Coexistência de lúpus eritematoso sistêmico e doença falciforme: relato
de caso e revisão da literatura
r e s u m o
Palavras-chave:
Objetivo: relatar um caso de coexistência de lúpus eritematoso sistêmico (LES) e doença
Anemia falciforme
falciforme (DF) com revisão da literatura sobre o tema.
Doença falciforme
Metodologia: relato de caso e pesquisa da associação entre LES e DF na literatura, através de
artigos científicos nas bases de dados de ciências da saúde, como LILACS, MEDLINE/Pubmed
∗
Corresponding author.
E-mail: [email protected] (T.C.M.V. Robazzi).
http://dx.doi.org/10.1016/j.rbre.2013.05.004
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):68–74
69
Lúpus eritematoso sistêmico
e Scielo, até maio de 2012. Descritores utilizados: 1. anemia falciforme; 2. doença falciforme;
Hemoglobinopatias
3. lúpus eritematoso sistêmico; 4. hemoglobinopatias.
Resultados: os autores descrevem a associação de LES e hemoglobinopatia SS em paciente
do sexo feminino, oito anos, apresentando manifestações articulares, hematológicas e neuropsiquiátricas durante a sua evolução clínica. Na literatura são descritos 45 casos de
associação entre LES e DF, sendo a maioria em mulheres (78%) adultas (62,2%), apresentando
fenótipo SS em 78% dos casos e com manifestações clínicas variadas. Comparando com a
nossa paciente, manifestações articulares, hematológicas e neuropsiquiátricas, estiveram
presentes em 76%, 36% e 27% dos casos, respectivamente.
Conclusões: LES e DF são doenças crônicas que apresentam diversos achados clínicos e
laboratoriais em comum, implicando em dificuldades diagnósticas e na correta condução
terapêutica dessas doenças. A associação entre essas enfermidades não é comum, mas está
descrita na literatura, por isso é importante que médicos que cuidam dessas enfermidades
estejam atentos para tal possibilidade.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Case report
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with an incidence of 1.9 to 5.6 per 100,000
inhabitants,1 while sickle cell disease (SCD) is one of
the most common hereditary diseases, affecting mainly
black individuals.2 SCD is characterized by a mutation
in the hemoglobin beta chain with formation of abnormal hemoglobin (HbS), responsible for microcirculation
obstruction, ischemia, tissue necrosis and systemic organ
dysfunction.2
The coexistence of SCD and SLE is rarely described in literature, even in predominantly black populations, in which
the prevalence of both conditions is higher.3 Wilson et al.
were the first to report this association.4 Perhaps the defective
activation of the alternative complement pathway in sickle
cell patients and the increased risk of infections caused by
encapsulated bacteria predispose this group to develop an
autoimmune disease.5
The clinical features of SCD and SLE may show similar
manifestations, such as the presence of fever, anemia, articular, renal, neurological and cardiopulmonary involvements
and, consequently, diagnostic difficulties. Sickle cell patients
showing atypical symptoms or refractory response to conventional treatment should be investigated for the possibility of
coexistence of diseases.6
In view of the uncommon occurrence of this association,
the authors describe an early childhood case and review the
previously reported cases until May 2012.
Female patient diagnosed with SS hemoglobinopathy since
birth, showing recurring, mild painful vaso-occlusive crises
responsive to traditional hydration and analgesia. She has
never received blood transfusions. At the age of nine, pain
symptoms intensified, mainly characterized by repeated
crises of acute and asymmetric polyarthritis of the knees,
wrists, elbows and ankles, initially attributed to SCD. The
clinical picture evolved with the development of photosensitivity, asthenia and intermittent fever, with an episode of
generalized tonic-clonic seizure associated with transient left
hemiparesis. Laboratory tests: hemoglobin, 7.9 g/dL; hematocrit, 25%; WBC, 12.000/mm3 ; platelet count, 374.000 mm3
(160-400.000); hemoglobin electrophoresis HbS 98.7% and
HbA2 1.26%; positive antinuclear antibody (ANA) 1:320 (homogeneous pattern); positive anti-dsDNA antibody; erythrocyte
sedimentation rate, 68 mm (<20); C-reactive protein, 71 units
(< 6); rheumatoid factor, anti-Sm, anti-SSA, anti-SSB, were all
negative as were viral serology. Serum C3 , C4 and CH50 levels
were normal as were renal and liverfunctions. Cranial magnetic resonance imaging revealed an area of hypoperfusion in
the right temporal lobe. The study of the cerebrospinal fluid
was normal. The patient had a sibling with sickle cell anemia
who died at the age of two from acute myocardial infarction, and has two maternal aunts diagnosed with cutaneous
lupus. She was diagnosed with SLE according to American
College of Rheumatology (ACR) criteria,7 and the possibility
of involvement of the central nervous system (CNS) by both
diseases (SLE and SCD) was discussed. The patient received
prednisone 2 mg/kg/day, hydroxychloroquine 5 mg/kg/day and
blood transfusions in order to reduce HbS < 30%. Due to the
possibility that the neurological manifestation was secondary
to SCD we chose not to associate another immunosuppressive agent. There was significant reduction in joint pain, no
progression of the neurological condition and improvement of
hematological indices (HbS 60%; Hb 8.5 g/dL). Patient remains
asymptomatic, taking hydroxychloroquine and prednisone
5 mg/day.
Methodology
Case report and literature review of the association between
SLE and SCD through scientific articles in health sciences
databases, such as LILACS, MEDLINE/Pubmed and Scielo
until May 2012. Descriptors used: 1. Sickle cell anemia;
2. Sickle cell disease; 3. Systemic lupus erythematosus; 4.
Hemoglobinopathies.
70
Table 1 – Coexisting systemic lupus erythematosus and sickle cell disease – literature review.
Age/Sex
Hb Type
Articular
involvement
Serositis
Renal
involvement
Neuropsychiatric
involvement
Malar
rash
Oralulcer
Photosensitivity
Discoid
lupus
Hematological
alterations
ANA
Current report
8/F
28/F
55/F
8/M
63/F
21/M
16/F
35/F
30/F
40/M
32/F
35/F
27/F
25/F
26/M
28/F
32/F
27/F
40/F
38/F
17/F
28/F
23/M
16/F
24/F
17/M
14/F
11/F
7/F
9/M
18/F
29/M
10/F
15/M
16/F
SS
SS
SS
SS
SS
SS
SS
AS
SS
SS
SC
SS
SS
SS
SC
SS
SS
SS
SS
SS
SC
SC
SS
SS
SS
SS
SS
S␤
SS
SS
SS
S ␤0SS
SS
SS
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
-
+
+
-
+
+
+
-
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
21
22
5
14
15
16
17
31
9
33
19
6
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):68–74
Reference
+
+
+
-
+
+
+
+
+
+
10
13
23
11
20
3
SS
SC
SS
SS
SC
SS
SS
SS
SS
SS
SS
15/F
11/F
14/M
8/F
23/F
50/F
16/F
27/F
24/F
10/F
4/F
12
F, female; M, male; Hb, hemoglobin; SS, homozygous sickle cell disease; S␤, beta-thalassemia sickle cell disease; SC, Sickle-Hemoglobin C Disease; ANA, antinuclear antibodies; + , present; -, absent.
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
+
+
+
+
-
Oralulcer
Renal
involvement
Hb Type
Age/Sex
Reference
Table 1 – (Continued)
Articular
involvement
Serositis
Neuropsychiatric
involvement
Malar
rash
Photosensitivity
Discoid
lupus
Hematological
alterations
ANA
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):68–74
71
Discussion
Epidemiology of SLE and SCD
The coexistence of SCD and SLE is rarely described in the literature, probably due to the small number of cases. Because
of the overlapping of symptoms of both diseases, particularly
those related to the CNS, establishing a differential diagnosis
between the diseases is unquestionably difficult. Until April
2012, 45 patients with SCD and SLE had been reported in
the MEDLINE database (Table 1). Thirty-five (78%) of these
patients were female, while 10 (22%) were male. The majority
of patients are adults (62.2%), with a mean age of 23 yearsold at diagnosis (variation: 4 to 63). This resembles the age
group of SLE patients proposed by Manzi, in which the disease developed during the ages of 15 to 45.8 SLE developed in
patients aged ≤16 in only 37.7% of the cases described. Among
patients with SCD and SLE, 33 (78%) had the SS phenotype. Due
to the coexistence of severe complications, life expectancy
of these individuals can potentially be reduced when compared to that of individuals who are diagnosed with one of the
diseases.9 Treatment has also become a great challenge, since
there are no controlled and randomized trials (that address
the impact of SCD) of immunosuppressive drugs often used in
SLE.
Probable etiology for coexistence of SCD and SLE
The infectious complications of SCD patients have a multifactorial etiology: splenic atrophy, reduced phagocytic capacity,
defective opsonization, reduced production of antibodies and
alternative complement pathway components. Some authors
have proposed that the deficiency of factors of the alternative pathway complement and recurring infections caused
by encapsulated bacteria could be the link between the
immune complex disease and hemoglobin S.10–12 However,
there had been no reduction of alternative complement pathway components in this report or in others described in the
literature.6,13
Articular manifestations
Articular disease were present in 35 patients (76%)
with SLE and SCD, corresponding to the most common
manifestation.5,6,9–11,13–22 The difficulty in diagnosing the
coexistence of these two diseases is due to the fact both have
articular manifestations. Hence, SCD patients’ joint complaints are interpreted as vaso-occlusive crises, delaying the
diagnosis of SLE.6,17 In this study, the patient presented with
a clinical picture of an asymmetric, additive, non-deforming
polyarthritis unresponsive to analgesia and with prolonged
evolution. Such characteristics diverge from standard SCD
arthritis, which is usually short-term, monoarticular, acute
and recurrent.16 Thus, general practitioners, pediatricians,
hematologists and rheumatologists should be alert to the SCD
patients with unsatisfactory response to hydration, analgesia
and articular involvement pattern change in relation to the
initial picture, and consider the possibility of association with
other diseases, including SLE.3,6,17
72
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):68–74
Hematological manifestations
Hematological disorders are common in both SCD and SLE.
Table 1 shows patients with anemia, leukopenia or thrombocytopenia. In this review, 16 patients (36%) met at least one
of these criteria.3,5,6,9,10,12,15,17–19,21–24 However, hematological
laboratory evaluation is not very specific and, separately, it
does not contribute to the clinical suspicion of coexistence of
both diseases.
In most cases, SLE anemia is initially normocytic and normochromic and, if persistent, evolves into microcytosis and
hypochromia.1 Hemolytic anemia is only found in 13% of
the cases.25 On the other hand, the decreased hemoglobin in
SCD is more important, reaching levels that range from 6 g
to 9 g/dL,25 particularly in cases of sickle cell anemia (HbSS).
Therefore, patients suffering from both diseases may show
more severe anemia due to the overlapping of pathophysiological disorders.
Leukopenia is identified in 20% to 40% of cases of isolate SLE,1 including granulocytopenia andlymphopenia. These
findingsare caused by autoantibodies and by the systemic
involvement of the disease. In SCD, predominantly leukocytosis and thrombocytosis are observed due to functional
asplenia around the age of five.16
Neuropsychiatric manifestations
Cerebral infarction, intracranial hemorrhage, cognitive dysfunction and seizures are neuropsychiatric disorders common
to both SLE and SCD. The prevalence of neurological disorders
in SLE patients is estimated to be 50%, with large variation
among studies,26 while in SCD it occurs in 25% of patients.27,28
In SLE, hemorrhage, thrombosis associated with antiphospholipid antibodies, hypertension and thrombocytopenia relate
to cerebrovascular accident,29 while in SCD the formation of
aneurysms and the accumulation of drepanocytes in brain
vessels promote increased adhesion, intimal hyperplasia and
limited endoluminal flow.30 In Table 1, one can see that 12
patients (27%) with SLE and SCD had neuropsychiatric disorders, including seizures, psychosis, cognitive disorders and
cerebrovascular accident, and only two patients did not have
the SS phenotype.10–12,14,16,17,22,23,31 Presumably, individuals
with both diseases, particularly of SS phenotype, are more
likely to develop cerebrovascular disease. However, identifying
its etiology is imperative for an effective treatment. Additional
tests are critical for this differentiation. Transcranial Doppler
ultrasonography is a valuable tool for assessing cerebral blood
flow dynamic.30 The presence of antiphospholipid antibodies
associated with the increase of inflammatory markers may
suggest lupus etiology, requiring high doses of corticosteroids
and additional immunosuppressive agents.1
Renal manifestations
Both SCD and SLE can cause progressive renal failure, particularly juvenile SLE. Lupus nephritis is reported in 29% to 80% of
juvenile cases, depending on the specialty of the researchers,
if rheumatologists or nephrologists.1 The diagnosis of SLE in
sickle cell individuals could be neglected due to the overlapping of signals that suggest renal disorder. Proteinuria,
hematuria, hyperfiltration, glomerulopathy, nephrotic syndrome and chronic renal failure occur in both diseases.
However, nephrotic syndrome is particularly interesting since
it occurs much more often in SLE than in SCD.4 In Table 1, 21
patients (47%) developed renal disease attributed to the development of the SLE.3,5,6,10,11,13–17,19,21,23 Sickle cell nephropathy
has a broad spectrum of pathological presentations. Glomerular hyperfiltration, hemosiderin deposits, papillary necrosis,
cortical infarction, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis with or without deposition of immune complexes, tubular atrophy and interstitial
fibrosis may occur.30 Due to the wide renal involvement variety in SCD, renal biopsy becomes a useful diagnostic method
for sickle cell patients with suspected coexistence of SLE.
Lupus renal involvement targets glomeruli in most cases,
with subendothelial immune deposits and proliferation of
mesangial cells.1 The definition of the etiology of the renal
involvement in patients with both SCD and SLE has different
implication with regard to morbidity, mortality and treatment
options.16
Immunologic manifestations
Both SCD and SLE show important immunologic manifestations. Such involvement is mentioned in all case reports of
coexistence of both diseases. The ANA may be present in the
two diseases, being positive in almost 100% of SLE patients.1
Approximately 20% of SCD patients have positive ANA with
titers greater than 1:160;32 however, mechanisms related
to the development of antibodies in such patients remain
unknown.16 Nonetheless, in the case of the association of both
diseases, more specific autoantibodies, e.g. anti-dsDNA, antiSM, anti-SSA and anti-SSB, should be ordered to support the
diagnosis. Testing for antiphospholipid antibodies and lupus
anticoagulant are also suggested, although these are also more
commonly found in SLE than in SDC patients.23 Our patient
presented with a positive ANA and anti-dsDNA. Anti-Sm, antiSSA, anti-SSB were negative and C3 , C4 and CH50 were within
normal levels.
Serositis
Serositis is a clinical manifestation observed in both SCD
(as a consequence of vaso-occlusive crises) and SLE patients,
present in 18 patients (42.8%) of this review.3,5,6,9–11,15–19,23 The
clinical similarities of these two diseases may delay the diagnosis of an underlying connective tissue disorder; pericarditis
in sickle cell patients is a possible evidence of an active systemic autoimmune disease and/or an infectious process.33
Skin manifestations
Cutaneous involvement is reported in 50% to 80% of SLE
patients at diagnosis and in 85% of patients during the
course of the disease.1 Skin manifestations may include malar
rash, photosensitivity, vascular skin lesions with nodules
and ulceration, palmar/plantar erythema, Raynaud’s phenomenon, annular erythema, alopecia and, less often, discoid
lupus or lupus profundus.1 The characteristic cutaneous manifestation in SCD is the presence of lower-limb ulceration. The
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):68–74
most common manifestation in patients with both SLE and
SCD has not been reported yet.
The following cutaneous manifestations are described in
Table 1: malar rash (26%), discoid lesions (21%), photosensitivity (9.3%) and oral ulcers (6.9%).5,9,10,12,16,17,19–23 These
features are uncommon in SCD patients and may facilitate
the diagnosis of association of the two diseases.5
Conclusion
There is consensus among authors that physicians may face
diagnostic difficulties when treating a SCD patient who develops SLE. These are different diseases, both with greater
prevalence among blacks and sharing similar clinical manifestations during the course of the disease, delaying the diagnosis
of a systemic autoimmune disease in these patients. Another
confounding factor is that approximately 20% of SCD patients
have a positive ANA at higher titers.32
Due to microvascular occlusion and hemolytic anemia at
variable levels, SCD patients will have clinical manifestations,
such as severe localized or diffuse pain that may be associated
with edema and erythema, as well as chest pain, pulmonary
infiltrates, cardiomegaly, congestive heart failure, abdominal
pain and other vaso-occlusive manifestations.2
The limited number of cases published in the literature on
the coexistence of SLE and SCD in the same individual does
not allow stating if SCD patients are more likely to develop
SLE.
According to the findings shown in this review, the
presence of certain clinical features in SCD should alert
pediatricians, hematologists and rheumatologists to the
possibility of SLE diagnosis, particularly articular manifestations unresponsive to usual supportive measures, recurrent
and refractory neuropsychiatric manifestations (especially
if associated to the presence of antiphospholipid antibodies), presence of nephrotic proteinuria and, also, presence
of leukopenia and/or thrombocytopenia. Renal biopsy and
assessment of the specific antibodies for SLE could be very
useful in these cases, just as positivity for other clinical manifestations, such as malar rash, photosensitivity, oral ulcers,
alopecia and discoid lupus.
Prospective studies are required to clarify which mechanisms lead SCD individuals to develop SLE or if the coexistence
of these two diseases is a mere coincidence.
Conflicts of interest
The authors declare no conflicts of interest.
references
1. Benseler SM, Silverman ED. Systhemic lupus erythematosus.
Pediatr Clin N Am. 2005;52:443–67.
2. Loureiro MM, Rozenfeld S, Portugal RD. Acute clinical events
in patients with sickle cell disease: epidemiology and
treatment. Rev Bras Hematol. Hemoter. 2008;30:95–100.
3. Luban NL, Boeckx RL, Barr O. Sickle cell anemia and SLE. J
Pediatr. 1980;96:1120.
73
4. Wilson FM, Clifford GO, Wolf PL. Lupus erythematosus
associated with sickle cell anemia. Arthritis Rheum.
1964;7:443–9.
5. Appenzeller S, Fattori A, Saad ST, Costallat LT. Systemic lupus
erythematosus in patients with sickle cell disease. Clin
Rheumatol. 2008;27:359–64.
6. Katsanis E, Hsu E, Luke K, McKee JA. Systemic lupus
erythematosus and sickle hemoglinopathies: a report of two
cases and review of the literature. Am J Hematol.
1987;25:211–4.
7. Hochberg MC. Updating the American College of
Rheumatology revised criteria for the classification of
systemic lupus erythematosus. Arthritis Rheum.
1997;40:1725.
8. Manzi S. Lupus update: perspective and clinical pearls. Cleve
Clin J Med. 2009;76:137–42.
9. Kaloterakis A, Filiotou A, Haziyannis S. Sickle
cell/␤◦ -thalassemia and systemic lupus erythematosus.
Lupus. 1999;8:778–81.
10. Wilson WA, Nicholson GD, Hughes GR, Amin S, Alleyne G,
Serjeant GR. Systemic lupus erythematosus and sickle-cell
anaemia. Br Med J. 1976;1:813.
11. Wilson WA, Decelauer K, Morgan AG. Sickle cell anemia,
complement, and systemic lupus erythematosus. Arthritis
Rheum. 1979;22:803.
12. Warrier RP, Sahney S, Walker H. Hemoglobin sickle cell
disease and systemic lupus erythematosus. J Natl Med Assoc.
1984;76:1030–1.
13. Karthikeyan G, Wallace SL, Blum L. SLE and sickle cell
disease. Arthritis Rheum. 1978;21:862–3.
14. Kanodia KV, Vanikar AV, Goplani KR, Gupta SB, Trivedi HL.
Sickle cell nephropathy with diffuse proliferative lupus
nephritis: a case report. Diagn Pathol. 2008;3:9.
15. Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros
F, et al. Characteristics and outcome of connective tissue
diseases in patients with sickle-cell disease: Report of 30
Cases. Semin Arthritis Rheum. 2008;38:228–40.
16. Khalidi NA, Ajmani H, Varga J. Coexisting systemic lupus
erythematosus and sickle cell disease: a diagnostic and
therapeutic challenge. J Clin Rheumatol. 2005;11:86–92.
17. Saxena VR, Mina R, Moallem HJ, Rao SP, Miller ST. Systemic
lupus erythematosus in children with sickle cell disease. J
Pediatr Hematol Oncol. 2003;25:668–71.
18. Shetty AK, Baliga MR, Gedalia A, Warrier RP. Systemic lupus
erythematosus and sickle cell disease. Indian J Pediatr.
1998;65:618–21.
19. Eissa MM, Lawrence 3rd JM, McKenzie L, Little FM, Mankad
VN, Yang YM. Systemic lupus erythematosus in a child with
sickle cell disease. South Med J. 1995;88:1176–8.
20. Shaw HE, Osher RH, Smith JL. Amaurosis fugax associated
with SC hemoglobinopathy and lupus erythematosus. Am J
Ophthalmol. 1979;87:281–5.
21. Cherner M, Isenberg D. The overlap of systemic lupus
erythematosus and sickle cell disease: report of two cases
and a review of the literature. Lupus. 2010;19:
875–83.
22. Oqunbiyi AO, George AO, Brown O, Okafor BO. Diagnostic and
treatment difficulties in systemic lupus erythematosus
coexisting with sickle cell disease. West Afr J Med.
2007;26:152–5.
23. White LE, Reeves JD. Polyarthritis and positive LE preparation
in sickle hemoglobinopathies: a report of two cases. J Pediatr.
1979;95:1003–4.
24. Nossent JC, Swaak AJC. Prevalence and significance of
haematological abnormalities in patients with systemic
lupus erythematosus. Q J Med. 1991;80:605–12.
25. Di Nuzzo DVP, Fonseca SF. Anemia falciforme e infecções. J
Pediatr (Rio J). 2004;80:347–54.
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26. Bruns A, Meyer O. Neuropsychiatric manifestations of
systemic lupus erythematosus. Joint Bone Spine.
2006;73:639–45.
27. Adams RJ, Mckie VC, Hsu L, Files B, Vichinsky E, Pegelow C.
Prevention of a firs stroke by transfusions in children with
sickle cell anemia and abnormal results on transcranial
doppler ultrasonography. N Engl J Med. 1998;339:5–11.
28. Preul MC, Cendes F, Just N, Mohr G. Intracranial aneurysms
and sickle cell anemia: multiplicity and propensity for the
vertebrobasilar territory. Neurosurgery. 1998;42:971–7.
29. Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The
prevalence of neuropsychiatric syndromes in systemic lupus
erythematosus. Neurology. 2001;57:496–500.
30. Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia.
Radiographics. 2001;21:971–94.
31. Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal
abnormalities in sickle cell disease. Kidney Int. 2000;57:
1–8.
32. Baethge BA, Bordelon TR, Mills GM, Bowen LM, Wolf RE,
Bairnsfather L. Antinuclear antibodies in sickle cell disease.
Acta Haematol. 1990;84:186–9.
33. Shetty AK, Kumar SR, Gedalia A, Warrier RP. Sickle cell
anemia with systemic lupus erythematosus: response to
hydroxyurea therapy. J Pediatr Hematol Oncol. 1998;20:
335–7.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):75–78
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Case report
Two pairs of brothers with juvenile idiopathic
arthritis (JIA): case reports
Teresa Cristina M.V. Robazzi a,b,∗ , Gabriela Rios b , Catarina Castro c
a
b
c
Department of Pediatric Rheumatology, Universidade Federal da Bahia, Salvador, BA, Brazil
Department of Pediatrics, Medical School, Universidade Federal da Bahia, Salvador, BA, Brazil
Medicine School, Universidade Federal da Bahia, Salvador, BA, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history:
This is a case report of juvenile idiopathic arthritis in two pairs of brothers followed in
Received 21 July 2012
the Department of Pediatric Rheumatology, Universidade Federal da Bahia. Genetic involve-
Accepted 21 May 2013
ment in juvenile idiopathic arthritis pathogenesis is clear and the risk of recurrence among
Available online 26 November 2014
siblings supports this contribution. An important landmark of this discovery involves the
acknowledgment of major histocompatibility complex polymorphism contribution to juve-
Keywords:
nile idiopathic arthritis development susceptibility. Despite many advances, the numerous
Juvenile idiopathic arthritis
available studies cannot explain several implicit mechanisms in juvenile idiopathic arthritis
Siblings
pathogenesis yet.
© 2014 Elsevier Editora Ltda. All rights reserved.
Children
Dois pares de irmãos com artrite idiopática juvenil (AIJ): relato de casos
r e s u m o
Palavras-chave:
Relato de casos de ocorrência de Artrite Idiopática Juvenil (AIJ) em dois pares de irmãos
Artrite idiopática juvenil
acompanhados no serviço de reumatologia pediátrica da Universidade Federal da Bahia. O
Irmãos
envolvimento genético na patogênese da AIJ está claro e o risco de recorrência entre irmãos
Crianças
corrobora esta contribuição. Um importante marco dessa descoberta envolve a confirmação
da contribuição dos polimorfismos do complexo principal de histocompatibilidade (MHC)
na susceptibilidade ao desenvolvimento da AIJ. Apesar de muitos progressos, os inúmeros
estudos existentes ainda não são capazes de explicar diversos mecanismos implícitos na
patogênese da AIJ.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
∗
Corresponding author.
E-mail: [email protected] (T.C.M.V. Robazzi).
http://dx.doi.org/10.1016/j.rbre.2013.05.005
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
76
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):75–78
Introduction
Juvenile idiopathic arthritis (JIA) refers to a collection of
chronic arthropathies in children with an onset before the age
of 16 and a yet unknown etiology, but with a multifactorial
influence linked to immune, infectious and genetic factors.1
The literature shows higher disease prevalence in siblings, as well as in first-degree relatives with other rheumatic
diseases, thus demonstrating the magnitude of genetic contribution to disease susceptibility.2 Several genetic studies have
focused the understanding of major histocompatibility complex (MHC) polymorphism contribution to JIA development
susceptibility. The results of these studies demonstrate associations between JIA and genes encoding HLA and non-HLA.3
However, identifying genetic factors involved in JIA pathogenesis has been difficult for several reasons, including a low
prevalence of familial cases and a lack of population studies estimating their risk of recurrence. Thus, few studies have
been conducted and they are often based on a low number of
cases.4
The authors describe JIA occurrence in two pairs of nontwin brothers.
Case reports
First report
NSF, an 11 years and 8 months old boy, presented with proximal interphalangeal joints (PIP) of the fingers, knee and
ankle polyarthritis associated with an intermittent fever since
8 months of age. On physical examination, he had bilateral 4th finger PIP, knee, and ankle synovial thickening and
swelling with preserved range of movement. Antinuclear antibodies (ANA) and rheumatoid factor (RF) were negative. The
patient failed to adhere to treatment for socioeconomic reasons and was lost to follow up, but returned to the clinic
with a clinically active disease 9 years later and was then
accompanied by a younger brother, JPSF, a patient aged 5
years and 10 months with intermittent fever and arthritis of metatarsophalangeal, knee, and ankle joints since 9
months of age. Claudication, wrist and knee synovial thickening, bilateral knee arthritis, and a 5th-finger boutonniere
deformity were noted on physical examination. ANA and RF
were negative. After ruling out infectious diseases, malignancies, and other systemic autoimmune diseases, the diagnosis
of polyarticular JIA (ILAR) was made for both brothers. They
are currently taking naproxen, methotrexate, and etanercept
(Fig. 1).
Second report
IJS, an 8 year old boy, presented with a history of daily fever
(100.4–102.2 ◦ F), evanescent skin rash, and additive polyarthritis involving the wrists, elbows, knees, ankles, and proximal
interphalangeal joints since 11 months of age. On physical examination, hepatosplenomegaly, bilateral arthritis of
the knee, ankle, distal and proximal interphalangeal joints
and a nodule in the 3rd left PIP were noted. ANA and RF
Fig. 1 – Siblings with polyarticular JIA; case report 1.
were negative, and infections, malignancies and other systemic autoimmune diseases were ruled out, thus leading to
a diagnosis of systemic JIA (ILAR). The treatment started with
methotrexate, naproxen, prednisolone, folic acid, and etanercept with improvement of the fever, rash, morning stiffness
and articular manifestations. Three years later than the abovementioned diagnosis, his younger brother aged 5 years was
seen with a complaint of generalized joint pain for 5 months
associated with right wrist and knee swelling and high evening
fever with an onset two months earlier than joint features.
He had anorexia and weight loss. Hepatomegaly, right wrist
and knee swelling with local heat and pain on active and passive movement were noted on physical examination. ANA and
RF were negative. Following the exclusion of other diseases,
the diagnosis of a systemic JIA was made and treatment with
indomethacin, methotrexate, and folic acid was initiated. He
showed good clinical and laboratory response to treatment.
They evolved to polyarticular and pauciarticular JIA, respectively (Fig. 2).
Discussion
Despite genetic studies not being performed in those patients
described, evidence suggests that JIA is a complex disorder
influenced by multiple genetic and environmental factors.
JIA prevalence among individuals having siblings affected by
the disease is 15- to 30-fold higher than in general population and the risk of recurrence among siblings supports
the genetic contribution to the disease. In addition, studies demonstrate pairs of siblings affected by JIA have similar
human leukocyte antigens (HLA) and clinical features, with
a concordance rate in monozygotic twins of 25%, thus suggesting a 250-fold higher prevalence than in the general
population.4
There are literature reports on the effects of genetics
on pairs of affected siblings or, less frequently, on twins.
Baum et al. firstly described dizygotic twins concurrently
having JIA with a confirmed degree of genome identity.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):75–78
77
patients with familial JIA versus sporadic JIA regarding clinical
and laboratory variables, observed results that were similar to
previous results regarding age of onset: patients with familial
JIA were significantly younger at the disease onset and were
diagnosed earlier than patients in the sporadic group. However, the high degree of concordance regarding the onset type
seen in that group of cases was not consistent with previous
reports. The fact that data were collected from a hospital that
is the main tertiary center in the country, which could represent a cohort of patients with more severe JIA cases, would be
a reasonable explanation for the results.10
Recently, Prahalad et al. performed an analysis of the
largest available database and found that siblings and firstdegree cousins of subjects with JIA have a higher risk to
develop the disease. The relative risks (RRs) for each class of
kinship were calculated through conditional logistic regression: RR in siblings and first-degree cousins was elevated
compared with controls; the same fact did not occur with
second-degree cousins.11
In summary, genetic involvement in JIA pathogenesis is
clear; however, the ability to list the genes involved and understand the contribution of gene products to the pathogenesis
will depend on large-scale well planned studies, as well as the
understanding of environmental contribution to the disease
triggering and perpetuation.
Fig. 2 – Siblings aged 8 and 5 years (from left to right) with
pauciarticular and polyarticular JIA; case report 2.
Conflicts of interest
The authors declare no conflicts of interest.
Thereafter, other studies reported JIA in pairs of twins and
a number of them highlighted the disease onset within
a shorter time in twins than in other pairs of affected
siblings.5 Studies have further shown the same disease
onset and course subtype among siblings, as well as different onset patterns, but a similar subsequent course,
emphasizing the influence and complexity of genetic effects
on JIA; however, the implicit mechanisms could not be
explained.5,6
In a review study by Prahalad et al., the genetic influence
on JIA development is pointed out either within or out of HLA
region.7
Säilä et al. studied patients from multiplex families of JIA
and observed that the only significant difference between
familial and sporadic cases was an earlier onset of the disease in familial cases, with no essential difference in the
disease clinical features being seen between patients from
both groups.8
Maroldo et al. investigated clinical phenotypes and demographic characteristics in 183 pairs of siblings affected by JIA to
determine whether differences between clinical phenotypes
in the familial disease cohort compared with patients in the
sporadic disease cohort existed. The results confirmed the
conclusions from other studies showing a high concordance
rate for the disease onset type between pairs of siblings, except
for the subgroup of patients with systemic disease.9 Regarding
the current study, there was a concordance for the onset type
only in the first case report.
A fact that stands out in the current reports is the disease
onset at early ages. Al-Mayouf et al., by aiming to compare
references
1. Berent P, Salvatore A, Alberrto M. Juvenile idiopathic arthritis.
Lancet. 2011;377:2138–49.
2. Bukulmez H, Fife M, Tsoras M, Thompson SD, Twine NA, Woo
P, et al. Tapasin gene polymorphism in systemic onset
juvenile rheumatoid arthritis: a family-based case–control
study. Arthritis Res Ther. 2005;7:R285–90,
http://dx.doi.org/10.1186/ar1480. Published online 2005
January 11.
3. Prahalad S. Genetics of juvenile idiopathic arthritis: an
update. Curr Opin Rheumatol. 2004;16:588–94.
4. Prahalad S, O’brien E, Fraser AM, Kerber RA, Mineau GP, Pratt
D, et al. Familial aggregation of juvenile idiopathic arthritis.
Arthritis Rheum. 2004;50:4022–7.
5. Prahalad S, Ryan MH, Shear ES, Thompson SD, Glass DN,
Giannini EH. Twins concordant for juvenile rheumatoid
arthritis. Arthritis Rheum. 2000;43:2611–2.
6. Ozçakar L, Dinçer F, Ozçakar ZB. Juvenile chronic arthritis in a
monozygotic twin couple. Rheumatol Int. 2003;23:149–50.
7. Prahalad S, Glass DN. A comprehensive review of the genetics
of juvenile idiopathic arthritis. Pediatr Rheumatol Online J.
2008;21:6–11.
8. Säilä HM, Savolainen HA, Kotaniemi KM,
Kaipiainen-Seppänen OA, Leirisalo-Repo MT, Aho KV. Juvenile
idiopathic arthritis in multicase families. Clin Exp Rheumatol.
2001;19:218–20.
9. Moroldo MB, Chaudhari M, Shear E, Thompson SD, Glass DN,
Giannini EH. Juvenile rheumatoid arthritis affected sibpairs:
extent of clinical phenotype concordance. Arthritis Rheum.
2004;50:1928–34.
78
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):75–78
10. Al-Mayouf SM, Madi SM, AlMane K, Al Jummah S.
Comparison of clinical and laboratory variables in familial
versus sporadic systemic onset juvenile idiopathic arthritis. J
Rheumatol. 2006;33:597–600.
11. Prahalad S, Zeft AS, Pimentel R, Clifford B, McNally B, Mineau
GP, et al. Quantification of the familial contribution to
juvenile idiopathic arthritis. Arthritis Rheum. 2010;62:
2525–9.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):79–82
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Case report
Macrophage activation syndrome in a patient with
systemic juvenile idiopathic arthritis
Anna Carolina Faria Moreira Gomes Tavares a,∗ , Gilda Aparecida Ferreira b ,
Luciano Junqueira Guimarães c , Raquel Rosa Guimarães a ,
Flávia Patrícia Sena Teixeira Santos a
a
b
c
Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Department of the Locomotor System, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Service of Reumathology, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history:
Machrophage activation syndrome (MAS) is a rare and potentially fatal disease, com-
Received 25 October 2012
monly associated with chronic rheumatic diseases, mainly juvenile idiopathic arthritis.
Accepted 10 February 2014
It is included in the group of secondary forms of haemophagocytic syndrome, and other
Available online 28 November 2014
causes are lymphoproliferative diseases and infections. Its most important clinical and
laboratorial manifestations are non-remitting fever, splenomegaly, bleeding, impairment
Keywords:
of liver function, cytopenias, hypoalbuminemia, hypertriglyceridemia, hypofibrinogenemia
Hemophagocytic
and hyperferritinemia. The treatment needs to be started quickly, and the majority of
lymphohistiocytosis
cases have a good response with corticosteroids and cyclosporine. The Epstein–Barr virus is
Epstein–Barr virus
described as a possible trigger for many cases of MAS, especially in these patients in treat-
Systemic-onset juvenile idiopathic
ment with tumor necrosis factor (TNF) blockers. In these refractory cases, etoposide (VP16)
arthritis
should be administered, associated with corticosteroids and cyclosporine. Our objective is
HLH-04 treatment protocol
to describe a rare case of MAS probably due to EBV infection in a subject with systemiconset juvenile idiopathic arthritis, which achieved complete remission of the disease after
therapy guided by 2004-HLH protocol.
© 2014 Elsevier Editora Ltda. All rights reserved.
Síndrome de ativação macrofágica em paciente com artrite idiopática
juvenil sistêmica
r e s u m o
Palavras-chave:
A síndrome de ativação macrofágica (SAM) é uma doença rara e potencialmente fatal,
Síndrome hematofagocítica
normalmente associada às doenças reumáticas crônicas, em especial a artrite idiopática
Vírus Epstein-Barr
juvenil. É incluída no grupo das formas secundárias de síndrome hemofagocítica, cujas
∗
Corresponding author.
E-mail: [email protected] (A.C.F.M.G. Tavares).
http://dx.doi.org/10.1016/j.rbre.2014.02.020
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
80
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):79–82
Artrite idiopática juvenil forma
outras causas podem ser as doenças linfoproliferativas e infecções. As manifestações
sistêmica
clínicas e laboratoriais mais importantes são a febre não remitente, esplenomegalia,
Protocolo de tratamento HLH-04
hemorragias, disfunção hepática, citopenias, hipoalbuminemia, hipertrigliceridemia e
hiperferritinemia. O tratamento deve ser iniciado rapidamente, e a maioria dos casos
responde bem aos corticosteroides e à ciclosporina (CSA). O vírus Epstein-Barr (EBV) é
descrito como possível gatilho para muitos casos de SAM, especialmente naqueles em
tratamento com bloqueadores do fator de necrose tumoral (TNF). Nos casos refratários ao
tratamento convencional, etoposide (VP16) deve ser administrado, em associação com corticosteroides e CSA. Nosso objetivo foi descrever um caso raro de síndrome hematofagocítica
provavelmente secundária à infecção pelo vírus Epstein-Barr (EBV), em paciente com artrite
idiopática juvenil sistêmica, confirmada pelas manifestações clínicas e laboratoriais típicas,
mielograma e sorologia positiva contra o EBV, que atingiu remissão completa após inclusão
no protocolo de tratamento HLH-04.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a rare and
potentially fatal disease. Its annual incidence is 1:50,000 liveborn infants. It can be divided into two groups: primary and
secondary.
Macrophage activation syndrome (MAS) is a severe
complication of rheumatic diseases that occurs much
more frequently in patients with systemic juvenile idiopathic arthritis (SJIA). It is characterized by fever, hepatosplenomegaly, cytopenias, liver dysfunction, bleeding
diathesis and neurological symptoms, revealing a heterogeneous syndrome, which makes its detection harder. The
presence of macrophages actively phagocytosing hematopoietic cells in the liver, spleen, bone marrow or lymph node
confirms the diagnosis.1,2 The criteria formulated for HLH
diagnosis (Table 1) may not be useful to define MAS.2 The
great challenge is to differentiate it from the exacerbation
of the underlying disease.1,3,4 The clinical manifestations of
Table 1 – Diagnostic criteria for hemophagocytic
lymphohistiocytosis (HLH).
A. Molecular diagnosis compatible with HLH: pathological mutations
of PRF1, UNC13D, Munc 18-2, Rab27a, STX11, SH2D1A, or BIRC 4
OR
B. 5 of the 8 criteria listed below:
1. Fever (temperature greater than 38.3 ◦ C);
2. Splenomegaly;
3. Cytopenias (involvement of at least 2 lineages)
3.1. Hemoglobin < 9 g/dL or <10 g/dL in newborns
3.2. Platelets < 100,000 mL
3.3. Neutrophils < 1000 mL;
4. Hypertriglyceridemia (>265 mg/dL) or hypofibrinogenemia
(<150 mg/dL);
5. Hemophagocytosis in the bone marrow, spleen, lymph nodes or
liver – no evidence of malignancy;
6. Reduced or absent activity of NK cells;
7. Serum ferritin > 500 ng/dL;
8. Increase soluble CD25 (>2.400 U/mL)
Source: Histiocyte Society – Treatment Protocol of The Second International HLH Study 2004.
both showed 40% similarity.5 The pathogenesis of MAS consists of cytokine overproduction and exuberant inflammation,
leading to uncontrolled macrophage phagocytosis, antigen
presentation and persistent activation of T lymphocytes.6,7
Prevalence is more often studied in SJIA patients, estimated
to be between 7% and 13%.3
MAS is included in the group of secondary forms of HLH,
whose causes are lymphoproliferative diseases, infections
(viral, bacterial, parasitic and fungal) and rheumatic diseases.
Genetic mutations, which compromise secretion of perforins,
are the main trigger in the primary form.
Our objective was to describe a case of MAS probably due
to Epstein–Barr virus (EBV) infection and show how the appropriate treatment was essential for a favorable outcome.
Case report
The patient is a 9-year-old girl diagnosed with SJIA since 2007,
taking prednisolone 9 mg/day (0.3 mg/kg/day), methotrexate
(MTX) 20 mg/week (0.6 mg/kg/week) and etanercept (ETN)
25 mg/week (0.8 mg/kg/week), with partially controlled disease. In December 2011, she presented fever, vomit, abdominal
pain, diarrhea and jaundice, evolving with impairment of
liver function, mucocutaneous bleeding, bicytopenia and hepatosplenomegaly. Upon hospital admission, she presented
anemia (Hb 8.1 g/dL), thrombocytopenia (57 × 103 /␮L), elevated
serum liver enzyme levels (aspartate aminotransferase – AST
– 518 U/L and alanine aminotransferase – ALT – 121 U/L),
hypoalbuminemia (2.8 g/dL), coagulopathy (RNI 1,29), reduced
serum levels of fibrinogen (94 mg/dL), increased triglycerides
(353 mg/dL) and ferritin (>1000 ng/mL). Serology for viral and
autoimmune hepatitis was negative. She received transfusions of fresh frozen plasma that controlled the bleeding. A
bone marrow examination revealed hemophagocytosis (Fig. 1).
She was diagnosed with MAS and treated with 3 pulses
of methylprednisolone 30 mg/kg/day, followed by oral prednisone (PDN) 2 mg/kg/day and cyclosporine (CSA) 2 mg/kg/day.
MTX and ETN were suspended. Her symptoms and clinical
signs did not improve despite the increase in CSA dose to
6 mg/kg/day. Fever was sustained and she maintained abnormal laboratory findings: bicytopenia (Hb 7.8 g/dL and platelets
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):79–82
Fig. 1 – Hemophagocytosis in the bone marrow.
Credit: Dr. Paulo do Val Rezende (Department of Pediatric
Hematology of Hospital das Clínicas of Universidade
Federal de Minas Gerais).
94 × 103 /␮L), increased serum ferritin levels (>1.000 ng/mL),
elevated triglycerides (445 mg/dL) and reduced fibrinogen
(96 mg/mL).
She developed sepsis after the initial treatment, worsening
her clinical and laboratory condition. In addition to antibiotics, intravenous human immunoglobulin (IVIG) 2 g/kg was
administered, with no improvement.
After cytomegalovirus (CMV) and EBV serology results,
the latter positive IgM and IgG, and a lumbar puncture,
to rule out central nervous system (CNS) involvement, we
decided in conjunction with the Hematology team, to start
HLH-04 treatment protocol: dexamethasone, etoposide (VP
16), in addition to CSA, for eight weeks. After the fourth
week of treatment protocol, there was febrile neutropenia
(total leukocyte count 0.87 × 103 /␮L), and hair rarefaction,
both complications that were already expected with this
treatment.
The disease remitted after eight weeks. Her last laboratory assessment showed normalization of ferritin (270 ng/mL),
triglycerides (78 mg/dL), hemoglobin (13.7 g/dL), fibrinogen
(250 mg/mL), AST (23 U/L) and ALT (34 U/L). The patient is currently taking PDN 5 mg/day and CSA 6 mg/kg/day.
Discussion and conclusion
The purpose of this case report is motivating rheumatologists to consider MAS when faced with patients with
fever, hepatosplenomegaly, impairment of liver function
and cytopenias, so treatment can be quickly initiated. It
81
is important to emphasize that the diagnosis of MAS is
often a challenge as it may mimic a flare of the underlying disease. There are no validated criteria for diagnosis
of MAS.6 Ravelli et al.2 proposed diagnostic guidelines
for MAS complicating SJIA, based on expert consensus.
Clinical and laboratory findings that were more sensitive to MAS differentiation from flares of the underlying
disease were selected. The most frequent findings were
thrombocytopenia, hyperferritinemia, elevated liver enzymes,
leukopenia, bone marrow hemophagocytosis, persistent fever,
drop in the erythrocyte sedimentation rate, hypofibrinogenemia and hypertriglyceridemia.2 In our patient, the
presence of bleeding, daily and non-remitting fever, pancytopenia and reduced fibrinogen serum levels stood out,
which led us to consider a diagnosis other than SJIA
activation.
We consider that there was a combination of triggers.
Immunosuppression with synthetic and biological drugs, persistent disease activity, and EBV infection has contributed to a
severe and life-threatening disease. The SJIA therapy, mainly
MTX but also ETN,5,6 might have been the trigger. Biological
drugs have been described not only as a possible treatment
for MAS, but also as syndrome triggering factors.6
Currently, the treatment for macrophage activation syndrome is based on corticosteroids and CSA. CSA has proved
effective in patients with severe disease and corticosteroid
resistant,6,7 that is why it was introduced early in the treatment. Human intravenous immunoglobulin is an alternative
therapy,6,8 also ineffective in our patient. There are a few
reports of effectiveness of interleukin-1 antagonists, particularly anakinra9 (unavailable in our country) in those patients
refractory to conventional treatment. Since the disease was
refractory to the initial therapy, we were motivated to look
for other causes, like the possible association with EBV infection, considered to be one of the major etiological agents and
responsible for the most severe cases.8,10,11 So we chose the
treatment guided by the HLH-04 protocol. VP16 is important,
mainly, in refractory cases,6,8,11–13 and should be promptly initiated since it confers the most favorable prognosis in these
situations.11
The HLH treatment protocol was proposed in 1994 and
revised in 2004 for treatment of primary and secondary forms,
related to infections and malignancies. The specific infectious treatment appears to have a result in cases of visceral
leishmaniasis, cytomegalovirus and bacterial infections, but
there is no benefit described in disease associated with EBV
infection.9,10 The treatment was based on the dexamethasone
and VP16 association, in an eight-week induction period. In
case of remission, treatment should be suspended after eight
weeks.1,3,12 Otherwise, these patients should be referred to
stem cell transplantation.6,12
In summary, the importance of this report is, in addition
to the extensive discussion of possible triggers, the successful
treatment with etoposide, which was essential for induction of
remission of MAS. We also emphasize how often MAS has been
diagnosed nowadays and question whether the immunobiological therapy has implied an increase in the number of cases,
since it makes our patients more vulnerable to opportunistic infections of any etiology that is also considered to be a
predisposing factor for the disease.
82
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):79–82
Conflict of interest
The authors declare no conflicts of interest.
references
1. Ravelli A, Magni-Manzoni A, Pistorio A, Besana C, Foti T,
Ruperto N, et al. Preliminary diagnostic guidelines for
macrophage activation syndrome complicating systemic
juvenile idiopathic arthritis. J Pediatr. 2005;146:
598–604.
2. Davi S, Consolaro A, Guseinova D, Pistorio A, Ruperto N,
Martini A, et al. An international consensus survey of
diagnostic criteria for macrophage activation syndrome in
systemic juvenile idiopathic arthritis. J Rheumatol.
2011;38:764–8.
3. Deane S, Selmi C, Teuber SS, Gershwin ME. Macrophage
activation syndrome in autoimmune disease. Int Arch
Immunol. 2010;153:109–20.
4. Canna SW, Behrens EM. Not all hemophagocytes are created
equally: appreciating the heterogeneity of the
hemophagocytic syndromes. Curr Opin Rheumatol.
2012;24:113–8.
5. Filho AXC, Correa FO, Schuman I. Síndrome de ativação
macrofágica secundária à infecção aguda pelo vírus
Epstein-Barr. Rev Bras Reumatol. 2008;48:
179–83.
6. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of
pediatric rheumatology: macrophage activation syndrome,
45, 6th ed. Elsevier Saunders; 2011. p. 674–81.
7. Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N,
Magni-Manzoni S, et al. Macrophage activation syndrome in
juvenile systemic lupus erythematosus: a multinational
multicenter study of thirty-eight patients. Arthr Rheumat.
2009;60:3388–99.
8. Weitzman S. Approach to hemophagocytic syndromes. Am
Soc Hematol. 2011;1:178–83.
9. Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron
RQ. Successful treatment of severe paediatric rheumatic
disease-associated macrophage activation syndrome with
interleukin-1 inhibition therapy: case series with 12 patients.
Rheumatology. 2011;50:417–9.
10. Henter JI, Horne AC, Aricó M, Egeler RM, Filipovich AH,
Imashuku S, et al. Review HLH-2004: diagnostic and
therapeutic guidelines for hemophagocytic
lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.
11. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL.
How I treat hemophagocytic lymphohistiocytosis. Blood.
2011;118:4041–52.
12. Shiraishi A, Ohga S, Doi T, Ishimura M, Takimoto T, Takada H,
et al. Treatment choice of immunotherapy or further
chemotherapy for Epstein–Barr virus-associated
hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer.
2011;59:265–70.
13. Henter JI, Samuelsson-Horne AC, Aricó M, Egeler RM, Elinder
G, Filipovich AH, et al. Treatment of hemophagocytic
lymphohistiocytosis with HLH-94. Blood. 2002;100:2367–71.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):83–88
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Brief communication
Analysis of the influence of pharmacotherapy on
the quality of life of seniors with osteoarthritis
Katia F. Salvato a , João Paulo M. Santos a , Deise A.A. Pires-Oliveira a , Viviane S.P. Costa a ,
Mario Molari a , Marcos T.P. Fernandes a , Regina C. Poli-Frederico a ,
Karen B.P. Fernandes a,b,∗
a
b
Universidade Norte do Paraná, Londrina, PR, Brazil
Pontifícia Universidade Católica do Paraná, Londrina, PR, Brazil
a r t i c l e
i n f o
a b s t r a c t
Keywords:
Aims: This study aimed to assess the influence of pharmacotherapy on health-related qual-
Osteoarthritis
ity of life of elderly with ostheoarthritis.
Elderly
Methods: Longitudinal study involving 91 older adults from both genders (Age: 70.36 ± 5.57
Functional status
years) from EELO project with self-reported knee or hip ostheoartritis, confirmed by
Functional disability
radiographic analysis. Data regarding pharmacotherapy was assessed by a structured ques-
Quality of life
tionnaire and the quality of life was analyzed by SF-36 questionnaire at the initial moment
and two years thereafter. All domains from quality of life were grouped in physical and
mental components for further data analysis.
Results: A statistically significant decline in both physical and mental components of quality
of life was observed (Wilcoxon test, p < 0.05). However, it was observed a slighted decline in
physical components in group treated with chondroitin/glucosamine when compared to
other groups, according to Kruskal–Wallis test (p = 0.007). On the other hand, it was not
observed any influence of pharmacological treatment on mental components of healthrelated quality of life (p > 0.05).
Conclusions: Treatment with condroitin/glucosamin contributes to a lower decline in physical component while it had no influence on mental component of health-related quality of
life in older adults with ostheoartritis.
© 2014 Elsevier Editora Ltda. All rights reserved.
∗
Corresponding author.
E-mail: [email protected] (K.B.P. Fernandes).
http://dx.doi.org/10.1016/j.rbre.2014.08.005
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
84
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):83–88
Análise da influência da farmacoterapia sobre a qualidade de vida em
idosos com osteoartrite
r e s u m o
Palavras-chave:
Objetivos: Analisar a influência da farmacoterapia da osteoartrite na qualidade de vida de
Osteoartrite
idosos.
Idoso
Métodos: Estudo longitudinal, do qual participaram 91 idosos de ambos os gêneros (idade:
Funcionalidade
70,36 ± 5,57 anos), integrantes do projeto Estudo sobre Envelhecimento e Longevidade
Incapacidade funcional
(EELO), portadores de osteoartrite de quadril e/ou joelho, confirmada por análise radiográ-
Qualidade de vida
fica. Foram levantados dados sobre a farmacoterapia da osteoartrite mediante o uso de
questionários estruturados e a qualidade de vida foi analisada pelo questionário SF-36, no
momento inicial e dois anos após a coleta de dados. Os diferentes domínios da qualidade
de vida foram agrupados em domínios físicos e mentais para posterior análise dos dados.
Resultados: Foi observado um declínio estatisticamente significativo tanto nos componentes
físicos quanto mentais da qualidade de vida dos indivíduos (teste de Wilcoxon, p < 0,05). Foi
observado menor declínio no componente físico da qualidade de vida para os usuários de
condroitina/glicosamina em comparação com o grupo tratado com anti-inflamatórios ou
não tratado, segundo o teste de Kruskal–Wallis (p = 0,007). Por outro lado, não foi observada
influência do tratamento farmacológico sobre o componente mental da qualidade de vida
(p > 0,05).
Conclusão: O tratamento com condroitina/glicosamina contribuiu para menor declínio do
componente físico e não influenciou os componentes mentais da qualidade de vida de
idosos com osteoartrite.
© 2014 Elsevier Editora Ltda. Todos os direitos reservados.
Introduction
Osteoarthritis (OA), also known as arthrosis and osteoarthrosis, is a chronic degenerative disease caused by the
deterioration of the cartilage and the formation of marginal
osteophyte, with bone outgrowths on the surfaces and at the
margins of the joints.1 It is characterized by pain and functional limitations, it has slow evolution, as a result of the
imbalance between the formation and elimination of the main
elements of the cartilage.2
OA is age-related,1 being the rheumatic disorder more
prevalent among the elderly,3 affecting approximately 10% of
the world’s elderly population.4 Despite there is no accurate
data in Brazil, Backer study5 shows prevalence of 26.3%. In this
context, it represents one of the most frequent causes of disability and pain in the musculoskeletal system.3 Knee OA is
the most common manifestation, affecting 23% of the elderly
population, although these numbers are even higher among
elderly women.6 However, the prevalence of OA can reach 40%
among individuals aged 74 or older.6
The cartilage lesion may be caused by a mechanical aggression or due to inflammatory joint disease, and it has strong
genetic predisposition.1,2
Its pathophysiology is characterized by severe changes
in the joint surface (loss of articular cartilage, ulceration,
remodeling and sclerosis of the subchondral bone), with sudden biochemical changes in the proteoglycans, resulting in
catabolic and anabolic processes in the cartilage metabolism,
with reduced levels of chondroitin and glucosamine sulfates.1
Its symptoms are basically constant: localized articular
pain, which accentuates with increasing load and movement (worse at the beginning of the movement and at rest),
reduced range of motion, muscle weakness, joint stiffness
after rest, crepitus and increased articular volume, with consequent progressive inability to perform usual activities, such as
gait.1
OA is initially treated with physical measures, analgesics,
steroidal and nonsteroidal anti-inflammatories (NSAIDs), and
surgical treatment is indicated for the most severe cases
only. However, based on the actual knowledge of the disease
pathophysiology, disease modifying drugs, such as chondroitin and glucosamine seems to be able to abolish or
reduce its symptoms, increasing functional status of the
patients.2,7
Quality of life is an important item in the health of the
individual that should be considered in the study of OA.8
According to the World Health Organization (WHO), quality
of life is the individual’s perception of their position in life,
in the context of culture and in the value systems in which
they live and in relation to their goals, their expectations,
their standards and concerns.9 The instruments that assess
quality of life may be influenced by the impact of the health
condition in life, including the physical, emotional and social
domains.10
Considering the concern over the use of medications in
elderly patients with OA, the aim of this study was to analyze
the effect of pharmacotherapy on the quality of life of these
individuals.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):83–88
Patients and methods
Ethical procedures
This study was approved by the Research Ethics Committee
(protocol no. 0063/09). Before any procedure was undertaken,
patients were briefed on the nature of the work and signed
a free and informed consent form in which they agreed to
participate in the study.
Outline and study population
Ninety-one elderly patients with OA from a subsample of EELO
project were included in this longitudinal, observational study.
EELO was a thematic project developed in the city of
Londrina, Paraná, which aimed to examine the social and
demographic conditions and health indicators of elderly individuals of this city. The project had a total sample of 508
seniors, who were selected in a random and stratified manner
from the records of Basic Health Units from this city.
The criteria for inclusion were patients of both genders,
aged 60 years or older and diagnosis of hip and knee OA, either
receiving clinically prescribed drug treatment or not and who
had signed a free and informed consent.
The criteria for exclusion were individuals with full or
partial prosthetics in any of the joints being evaluated, with
concomitant diagnosis of other osteoarticular/muscle diseases, such as rheumatoid arthritis, fibromyalgia, systemic
lupus erythematosus and other rheumatic diseases with
severe cognitive impairment or those who have not agreed
to sign the free and informed consent form.
Instrumentation
A structured interview guide with questions about gender, age,
weight, height, race, previous occupation and occupational
status was used to characterize the profile of senior patients
with OA. The formula: weight (kg)/height2 (m2 ) was used to
calculate the body mass index (BMI).
A structured questionnaire with information about drug
type, dosage and duration of the treatment of patients with OA
was used to evaluate the drug treatment adopted by the individuals. Then the patients were divided into three subgroups
according to the treatment, for further statistical comparison:
control group (individuals who are not making use of medication for OA), anti-inflammatory group (individuals being
treated with steroidal anti-inflammatories and NSAIDs) or
the chondroitin/glucosamine group (individuals being treated
with the chondroitin + glucosamine association).
The Medical Outcomes Study 36 Short-Form Health
Survey (SF-36) questionnaire, translated and validated into
Portuguese and currently recommended by the American College of Rheumatology, was used to assess the quality of life.
The SF-36 questionnaire is an instrument that covers the following domains: functional capacity, physical aspects, bodily
pain, general health condition, vitality, social aspects, emotional aspects and mental health.
The first four domains (functional capacity, physical
aspects, bodily pain, general health condition) assess the
85
physical health or physical component, while the last four
(vitality, social aspects, emotional aspects and mental health),
the mental health or mental component. The score of each
domain varies from zero to 100, in which zero corresponds to
the worst health condition and 100, to the best. Each domain
is analyzed separately, and there is no overall score.11
Procedures
Data collection procedures were carried out in two stages.
With the objective of evaluating the variation in the quality
of life of these elderly patients over time and with pharmacotherapy, these were reevaluated two years after the initial
collection, i.e., the first evaluation was made in 2010 and the
second in 2012.
Statistical analysis
A database was prepared in the Statistical Package for Social
Sciences (SPSS) program, version 15.0, from the data collected.
A confidence interval (CI) of 95% was established for all tests
applied (p < 0.05).
Initially, the Shapiro–Wilk normality test was used and,
as the data did not display a normal distribution, descriptive data, such as median and interquartile range (median;
Q1–Q3) and nonparametric tests were applied to compare the
groups.
The Wilcoxon test was used to compare the difference in
the physical and mental components of the life quality of
each group between evaluations (initial evaluation and final
evaluation, carried out two years after the initial analysis).
In order to analyze if any pharmacological treatment would
be related to a smaller decline of functional capacity, the
variation of physical and mental components of the quality
of life () was calculated, and the Kruskal–Wallis test was
used to compare groups under drug treatment (control × antiinflammatory × chondroitin/glucosamine).
Results
Ninety-one elderly patients with OA, predominantly female
(71.4% of the sample), participated in the study. The age
of the individuals was 70.4 ± 5.6 years, and it was observed
that the study population presented high BMI (29 ± 5.2). The
descriptive data of the study population are presented in
Table 1. Table 2 lists the results of the groups in the first
and second evaluations, with a statistically significant decline
of the physical and mental components of quality of life
(p < 0.05, Table 2) in all groups, according to the Wilcoxon
test. It was observed that users of chondroitin/glucosamine
had a smaller decline in the physical component of quality
of life when compared to the group being treated with antiinflammatories, or untreated, according to the Kruskal–Wallis
test (p = 0.007, Table 2, Fig. 1A). On the other hand, the influence
of the pharmacological treatment on the mental component of quality of life (p > 0.05, Table 2, Fig. 1B) was not
observed.
86
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):83–88
B
Mental Comp.
50
0
–50
∇
Physical Comp.
A
50
0
–50
∇
–100
e
in
y
ro
An
iti
ti-
n/
in
G
lu
fla
C
m
co
m
sa
at
m
or
l
tro
on
m
sa
C
C
ho
ho
nd
nd
ro
An
iti
ti-
n/
in
G
lu
fla
C
m
co
m
on
at
tro
l
or
in
y
e
–100
Fig. 1 – Variation of physical ( Physical Comp., A) and mental ( Mental Comp., B) components of quality of life in relation
to pharmacological treatment.
Table 1 – Characterization of the variables of the study
population.
Discussion
Variables
Average
Age
BMI
70.36
28.99
OA is the most common joint disease in the world,6 which justifies the importance of the study of this disorder on quality of
life of senior patients. Moreover, OA is closely related to aging,
causing pain and functional disability, with major social, psychological and economic losses, triggering the worsening of
quality of life of these individuals.5
As the individual ages, the disease tends to progress as a
result of the biomechanical aspects, causing deficit in functionality and quality of life,10 since there is a process inversely
proportional between disease progression and the quality of
life of patients,12 as demonstrated in the results of this study.
The BMI average was 28.99, corroborating other studies that
show an association between OA and overweight, since obesity is the most significant factor for the onset of the disease.13
In addition to that, obesity is associated with lower social
classes.14
This sample was composed mostly by women and, according to evidence observed in other studies, women tend to have
greater joint involvement as the quality of life declines,10 facilitating the explanation of the negative variation perceived
in all groups. This result could be explained by greater joint
Gender
Standard
Deviation
5.57
5.25
Relative
frequency (%)
Absolute
frequency (n)
Male
Female
Total
26
65
91
Pharmacological treatment
Control
Anti-inflammatory drugs
Chondroitin/Glucosamine
28.6
71.4
100.0
Absolute
frequency (n)
50
27
14
Relative
frequency (%)
54.9
29.7
15.4
BMI, body mass index.
Table 2 – Comparison of groups in of the 1st and 2nd evaluations and with regard to variation of physical and mental
components of quality of life.
Life quality
1st evaluation
Life quality 2nd
evaluation
Physical components
Control
Anti-inflammatory drugs
Chondroitin/glucosamine
77.500
78.667
80.417
48.375
48.000
56.375
<0.001
<0.001
0.003
Mental components
Control
Anti-inflammatory drugs
Chondroitin/glucosamine
87.625
82.275
82.875
65.437
55.662
59.662
<0.001
0.037
0.01
Groups
p
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):83–88
involvement, probably associated to clinical and functional
changes.15 OA is much more frequent among women above
the age of 55,16 especially among women from lower social
classes.14
Thus, one can infer that poorer quality of life is associated with a worse functional capacity of patients with OA,17
since the main problems of OA are pain and discomfort, which
in turn cause functional limitations and changes in social
behavior.18
While several advances have been made in trying to elucidate the pathogenesis of the OA, focusing on joint damage
and changes in the joint’s synovial fluid,19 there is still no cure
for this disease,12 another factor that helps us understanding
the worsening of the quality of life of the patients observed in
this study.12
Although there is no cure, treatments can be divided into
conventional (drug and physiotherapy) and surgical, and the
choice of treatment will depend largely on the severity of the
joint damage.12
The pharmacological treatment aims to relieve the signs
and symptoms of the disease and whenever it is possible,
reduce its progression. Thus, the goals of this treatment are
pain relief, improving the quality of life, increasing mobility,
increasing the ability to walk and reducing the progression of
the disease.12
It was observed that the group treated with the chondroitin/glucosamine association showed a statistically less
significant variation, leading to the assumption that this class
would have better clinical efficacy. The glucosamine sulfate
associated with chondroitin hydrochloride belongs to the
group of OA-modifying drugs. It is known that the drug blocks
a potential change of the viscoelastic properties of the cartilaginous tissue.12
The variation observed in the group treated with antiinflammatory drugs did not show a statistically significant
difference, probably due to mode of action of this drug type
that act on the general treatment of symptoms (pain, fever and
inflammation). However, there is still controversy over their
effectiveness in pain from musculoskeletal conditions, with
significant variation in the response of these drugs according
to each individual.20 According to several random clinical trials, NSAIDs produced better results with regard to pain when
compared to placebo, but with worse results when compared
to patients treated with painkillers.21
NSAIDs operate by inhibiting the synthesis of
prostaglandins, which is known as a primary antiinflammatory mechanism; prostaglandins are inflammatory
mediators that contribute to pain and inflammation in a
process mediated by cyclooxygenase enzymes (COX-1 and
COX-2),19 i.e., they inhibit COX-1 and COX-2. Despite the
biomechanical characteristics of the disease, its pathophysiology is caused by an imbalance between the mechanisms
of formation and degeneration of the cartilage matrix, being
this process regulated by proinflammatory cytokines, such
as the interleukin-1 (IL-1), the tumor necrosis factor alpha
(TNF-alpha) and proteinases. Despite being widely used, the
efficiency and safety of NSAIDs as a method of treatment of
OA have not yet been elucidated.12 The size of the sample and
the lack of evaluation of drugs effects in the sense of being or
not being dose-dependent were limiting factors for this study.
87
Therefore, we suggest subsequent population-based studies
to confirm these results.
Conflicts of interest
The authors declare no conflict of interest.
references
1. Herbert S. Ortopedia e traumatologia: princípios e prática. 4th
ed. Porto Alegre: Artmed; 2009.
2. Rezende UM, Gobbi RG. Tratamento medicamentoso da
osteoartrose do joelho. Rev Bras Ortop. 2009;44:14–9.
3. Alexandre TS, Cordeiro RC, Ramos LR. Fatores associados à
qualidade de vida em idosos com osteoartrite de joelho.
Fisioter Pesq. 2008;15:326–32.
4. Brandt KD, Kovalov-St. John K. Osteoarthritis. In: Wilson JD,
Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci
AS, et al., editors. Harrison’s principles of internal medicine.
12th ed. New York: McGraw-Hill; 1991. p. 1475–9.
5. Backer RC. Prevalência da osteoartrite de joelho na população
acima de 50 anos usuária da unidade local de saúde Saco
Grande [monografia]. Florianópolis: Universidade Federal de
Santa Catarina; 2006.
6. Felson DT, Couropmitree NN, Chaisson CE, Hannan MT,
Zhang Y, McAlindon TE, et al. Evidence for a Mendelian gene
in a segregation analysis of generalized radio – Graphic
osteoarthritis. The Framingham Study. Arthr Rheum.
1998;41:1064–71.
7. Nguyen US, Zhang Y, Zhu Y, Niu J, Zhang B, Aliabadi P, et al.
Increasing prevalence of knee pain and symptomatic knee
osteoarthritis. Ann Intern Med. 2011;155:725–32.
8. Ebrahim S. Clinical and public health perspectives and
applications of healthrelated quality of life measurement. Soc
Sci Med. 1995;41:1383–94.
9. WHOQOL Group. The World Health Organization Quality of
Life assessment (WHOQOL): position paper from the World
Health Organization. Soc Sci Med. 1995;41:1403–9.
10. Ackerman IN, Busija L, Tacey MA, Bohensky MA, Ademi Z,
Brand CA. Performance of the Assessment of Quality of Life
measure in people with hip and knee joint disease and
implications for research and clinical use. Arthritis Care Res.
2013, doi:10.1002/acr.22129. [Epub ahead of print].
11. Ciconelli RM, Ferraz MB, Santos W, Meinão I, Quaresma MR.
Tradução para a língua portuguesa e validação do
questionário genérico de avaliação de qualidade de vida
SF-36 (Brasil SF-36). Rev Bras Reumatol. 1999;39:143–50.
12. Michael JW, Schlüter-Brust KU, Eysel P. The epidemiology,
etiology, diagnosis, and treatment of osteoarthritis of the
knee. Dtsch Arztebl Int. 2010;107:152–62.
13. Woolf AD, Pfleger B. Burden of major musculoskeletal
conditions. Bull World Health Organ. 2003;81:646–56.
14. Ostor JKA, Conaghan PG. Is there a relationship between
running osteoarthritis. ISMJ. 2006;7:75–84.
15. National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institutes of Health Osteoarthritis; July
2010. Available in: http://www.niams.nih.gov/Health Info/
Osteoarthritis/default.asp#2.
16. Srikanth VK, Fryer JL, Zhai G, Winzenberg TM, Hosmer D,
Jones G. A meta-analysis of sex differences prevalence,
incidence and severity of osteoarthritis. Osteoarthr Cartil.
2005;13:769–81.
17. Berger A, Bozic K, Stacey B, Edelsberg J, Sadosky A, Oster G.
Patterns of pharmacotherapy and health care utilization and
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costs prior to total hip or total knee replacement in patients
with osteoarthritis. Arthritis Rheum. 2011;63:2268–75.
18. Dieppe PA, Lohmander LS. Pathogenesis and management of
pain in osteoarthritis. Lancet. 2005;365:965–73.
19. Adatia A, Rainsford KD, Kean WF. Osteoarthritis of the knee
and hip. Part II: therapy with ibuprofen and a review of
clinical trials. J Pharm Pharmacol. 2012;64:626–36.
20. Patrono C, Rocca B. Nonsteroidal antiinflammatory drugs:
past, present and future. Pharmacol Res. 2009;59:285–9.
21. Puopolo A, Boice JA, Fidelholtz JL, Littlejohn TW, Miranda P,
Berrocal A, et al. A randomized placebo-controlled trial
comparing the efficacy of etoricoxib 30 mg and ibuprofen
2400 mg for the treatment of patients with osteoarthritis.
Osteoarthr Cartil. 2007;15:1348–56.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):89–90
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Letter to the editors
Efficacy and safety of intra- and periarticular
corticosteroid injections in treatment of lupus
arthritis
Eficácia e segurança das injeções intra-articulares e periarticulares
de corticosteroides no tratamento da artrite lúpica
Arthritis in systemic lupus erythematosus (SLE) is one of
the most common disease manifestation.1 In daily clinical
practice, intra- and periarticular corticosteroid injections are
frequently used as they provide rapid reduction of symptoms
in clinically inflamed joints.2,3
Although there are no studies to prove the efficacy and
safety of intra- and periarticular corticosteroids, they may also
be helpful in the management of lupus arthritis. The aim of
this paper is to assess the efficacy and safety of intra- and periarticular corticosteroids’ injection in treatment of arthritis on
patients with SLE.
Retrospective analysis of medical records of all patients
with a SLE diagnosis observed in our department, with record
of demographic data, clinical data and therapeutic interventions and their results, was conducted. All patients included
fulfilled the ACR criteria.
We studied 94 patients, 91 female (96.8%) and 3 male (3.2%),
with a mean age of 30 ± 12 years at the time of the diagnosis
and 40 ± 12 years in the follow-up.
Sixty-three patients (67%) had articular involvement. Of
these, 49% (n = 31) underwent intra- and/or periarticular corticosteroids’ injection.
Sixty-five intra- and/or periarticular corticosteroid injections were carried out on 31 patients.
Treatments had been unguided before 2009, after that
they were performed mostly under ultrasound guidance. On
average, 2.1 procedures were carried out per patient. The
most frequent local treatments were intra-articular injections (n = 54), usually with triamcinolone hexacetonide (dose
depended on the treated joint). Knees (n = 23), wrists (n = 15)
and proximal interphalangeal joints (n = 11) were the most
frequently treated joints. The periarticular corticosteroid
injections were always performed with methylprednisolone,
and the most common injection was in the extensor tendon
sheath of the wrist. A single treatment injection was sufficient
to control symptoms in 29 patients. There were no complications observed.
Effective control of arthritis with the local treatment precluded the need for oral corticoids in the majority of patients.
Methotrexate was used in 13 of 63 patients (21%) to further
control arthritis.
In our experience the local treatments with steroids are
effective and safe for treatment of lupus arthritis as for
rheumatoid arthritis, and may be used as first-line therapy.
Effective control of arthritis with this local treatment may
also preclude the need for systemic corticosteroids, with their
consequent adverse effects.
Conflicts of interest
The authors declare no conflicts of interest.
references
1. Grossman JM. Lupus arthritis. Best Pract Res Clin Rheumatol.
2009;23:495–506.
2. Konai MS, Vilar Furtado RN, Dos Santos MF, Natour J.
Monoarticular corticosteroid injection versus systemic
administration in the treatment of rheumatoid arthritis
patients: a randomized double-blind controlled study. Clin Exp
Rheumatol. 2009;27:214–21.
3. Furtado RN, Oliveira LM, Natour J. Polyarticular corticosteroid
injection versus systemic administration in treatment of
rheumatoid arthritis patients: a randomized controlled study.
J Rheumatol. 2005;32:1691–8.
90
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):89–90
Filipa Teixeira ∗ , Daniela Peixoto, Carmo Afonso,
Domingos Araújo
Departamento de Reumatologia, Unidade Local de Saúde do Alto
Minho (ULSAM), Ponte de Lima, Portugal
∗ Corresponding author.
E-mail: fi[email protected] (F. Teixeira).
2255-5021/© 2014 Elsevier Editora Ltda. All rights reserved.
http://dx.doi.org/10.1016/j.rbre.2014.09.002
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):91–92
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Erratum
Erratum on “Epidemiologic profile of
juvenile-onset compared to adult-onset
spondyloarthritis in a large Brazilian cohort”
Errata de “Perfil epidemiológico da espondiloartrite de início juvenil
comparada com a espondiloartrite de início na vida adulta em uma
grande coorte brasileira”
Angela P. Duarte a , Cláudia D.L. Marques a , Adriana B. Bortoluzzo b , Célio R. Gonçalves c ,
José Antonio Braga da Silva d , Antonio Carlos Ximenes e , Manoel B. Bértolo f ,
Sandra Lúcia E. Ribeiro g , Mauro Keiserman h , Thelma L. Skare i , Sueli Carneiro j,k ,
Rita Menin l , Valderilio F. Azevedo m , Walber P. Vieira n , Elisa N. Albuquerque k ,
Washington A. Bianchi o , Rubens Bonfiglioli p , Cristiano Campanholo q ,
Hellen M.S. Carvalho r , Izaias P. Costa s , Charles L. Kohem t , Nocy Leite u ,
Sonia A.L. Lima v , Eduardo S. Meirelles w , Ivânio A. Pereira x , Marcelo M. Pinheiro y ,
Elizandra Polito z , Gustavo G. Resende aa , Francisco Airton C. Rocha bb ,
Mittermayer B. Santiago cc , Maria de Fátima L.C. Sauma dd ,
Valéria Valim ee , Percival D. Sampaio-Barros c,∗
a
Universidade Federal de Pernambuco, Recife, PE, Brazil
Insper Institute of Education and Research, São Paulo, SP, Brazil
c Division of Rheumatology, 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 Hospital Evangélico de Curitiba, Curitiba, PR, Brazil
j Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
k Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
l Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil
m Universidade Federal do Paraná, Curitiba, PR, Brazil
n Hospital Geral de Fortaleza, Fortaleza, CE, Brazil
b
DOI of original article: http://dx.doi.org/10.1016/j.rbre.2014.06.001.
Corresponding author.
E-mail: [email protected] (P.D. Sampaio-Barros).
http://dx.doi.org/10.1016/j.rbre.2015.01.001
2255-5021/© 2015 Elsevier Editora Ltda. All rights reserved.
∗
92
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):91–92
o
Santa Casa do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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 do Rio Grande do Sul, Porto Alegre, RS, Brazil
u Faculdade de Medicina Souza Marques, Rio de Janeiro, RJ, Brazil
v Hospital do Servidor Público Estadual, São Paulo, SP, Brazil
w Instituto de Ortopedia e Traumatologia, Universidade de São Paulo, São Paulo, SP, Brazil
x Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
y Universidade Federal de São Paulo, São Paulo, SP, Brazil
z Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
aa Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
bb Universidade Federal do Ceará, Fortaleza, CE, Brazil
cc Escola de Medicina e Saúde Pública, Salvador, BA, Brazil
dd Universidade Federal do Pará, Belém, PA, Brazil
ee Universidade Federal do Espírito Santo, Vitória, ES, Brazil
p
In the list of authors of the original article “Epidemiologic profile of juvenile-onset compared to adult-onset spondyloarthritis
in a large Brazilian cohort” (Rev Bras Reumatol 2013;54(6):424-430), where it reads:
Percival D. Sampaio Barros
It should read:
Percival D. Sampaio-Barros
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(1):93
REVISTA BRASILEIRA DE
REUMATOLOGIA
www.reumatologia.com.br
Erratum
Erratum of supplement 54, number 1, of Revista
Brasileira de Reumatologia
Errata do suplemento 54, número 1, da Revista Brasileira de
Reumatologia
Diego da Silva Lima, Kamila Abtibol Alves, Renan Danilo Lima da Rocha,
Fernanda de Sá Barreto Lócio, Caroline Pamponet da Fonseca Oliveira,
Domingos Sávio Nunes de Lima, Luiz Fernando de Souza Passos
On page 114, work 330, “Perfil do paciente com lúpus eritematoso sistêmico e suas comorbidades atendidos no ambulatório
Araújo Lima HUGV/UFAM em Manaus”, where it reads
Diego da Silva Limaa , Kamila Abtibol Alvesa , Renan Danilo Lima da Rochab , Fernanda de Sá Barreto Lóciob , Caroline Pamponet
da Fonseca Oliveiraa , Domingos Sávio Nunes de Limaa , Luiz Fernando de Souza Passosa ,
it should read
Diego da Silva Limaa , Diogo da Silva Limaa , Kamila Abtibol Alvesa , Renan Danilo Lima da Rochab , Fernanda de Sá Barreto
Lóciob , Caroline Pamponet da Fonseca Oliveiraa , Domingos Sávio Nunes de Limaa , Luiz Fernando de Souza Passosa
http://dx.doi.org/10.1016/j.rbre.2015.01.002
2255-5021/