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ISSN 0482-5004 Impact Factor 2012: 0.864 © Thomson Reuters Journal Citation Reports, Science Edition (2012) REVISTA BRASILEIRA DE REUMATOLOGIA BRAZILIAN JOURNAL OF RHEUMATOLOGY MAY/JUNE 2014 • Volume 54 • Number 3 MAIO/JUNHO 2014 • Volume 54 • Número 3 www.reumatologia.com.br REVISTA BRASILEIRA DE REUMATOLOGIA BRAZILIAN JOURNAL OF RHEUMATOLOGY Official Organ of Brazilian Society of Rheumatology Órgão Oficial da Sociedade Brasileira de Reumatologia Bimonthly Edition (Publicação Bimestral) Editors (Editores) Coeditors (Coeditores) Max Victor Carioca Freitas Eloísa Silva Dutra de Oliveira Bonfá Mittermayer Barreto Santiago Roberto Ezequiel Heymann Hilton Seda Paulo Louzada-Junior Universidade Federal do Ceará, Fotaleza, CE, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, Brazil João Carlos Tavares Brenol Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil Universidade de São Paulo, Ribeirão Preto, SP, Brazil Ricardo Fuller Universidade de São Paulo, São Paulo, SP, Brazil Simone Appenzeller Universidade Estadual de Campinas, Campinas, SP, Brazil Editorial Board (Conselho Editorial) Acir Rachid Universidade Federal do Paraná, Curitiba, PR, Brazil Adil Muhib Samara Universidade Estadual de Campinas, Campinas, SP, Brazil Geraldo da Rocha Castelar Pinheiro Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil Gilberto Santos Novaes Maurício Levy Neto Universidade de São Paulo, São Paulo, SP, Brazil Milton Helfenstein Jr. Universidade Federal de São Paulo, São Paulo, SP, Brazil Pontifícia Universidade Católica de São Paulo, São Paulo, SP, Brazil Natalino H. Yoshinari Ari Stiel Radu Isídio Calich Universidade de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Nílzio Antônio da Silva Carlos Alberto von Muhlen Ivânio Alves Pereira Percival Degrava Sampaio-Barros Claudia Goldenstein-Schainberg Jamil Natour Cláudio Arnaldo Len João Francisco Marques Neto Clóvis Artur Almeida da Silva José Goldenberg Alexandre Wagner S Souza Universidade Federal de São Paulo, São Paulo, SP, Brazil Faculdade de Medicina da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Cristiano Augusto de Freitas Zerbini Hospital Heliópolis, São Paulo, SP, Brazil Daniel Feldman Polak Universidade Federal de São Paulo, São Paulo, SP, Brazil Durval Kraychete Escola Bahiana de Medicina e Universidade Federal da Bahia, Salvador, BA, Brazil Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade Estadual de Campinas, Campinas, SP, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil José Roberto Provenza Universidade Estadual de Campinas, Campinas, SP, Brazil Jozélio Freire de Carvalho Centro Médico Aliança, Salvador, BA, Brazil Lais V. Lage Universidade de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Universidade Federal de Goiás, Goiânia, GO, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Ricardo M. Xavier Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Rina Dalva P. N. Giorgi Hospital do Servidor Público Estadual de São Paulo "Francisco Morato de Oliveira", São Paulo, SP, Brazil Roger A. Levy Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil Rosa Maria Rodrigues Pereira Universidade de São Paulo, São Paulo, SP, Brazil Rozana Mesquita Ciconelli Universidade Federal de São Paulo, São Paulo, SP, Brazil Samuel Katsuyuki Shinjo Universidade de São Paulo, São Paulo, SP, Brazil Eduardo de Souza Meirelles Lilian Tereza Lavras Costallat Eduardo Ferreira Borba Neto Luís Eduardo Coelho Andrade Universidade Federal do Paraná, Curitiba, PR, Brazil Emília Inoue Sato Luiz Fernando de Souza Passos Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil Fernanda Rodrigues de Lima Marcelo de Medeiros Pinheiro Universidade de São Paulo, São Paulo, SP, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Fernando Queiroz da Cunha Maria Odete E. Hilário Francisco Airton Castro Rocha Marta Maria das Chagas Medeiros Universidade de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, São Paulo, SP, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade de São Paulo, Ribeirão Preto, SP, Brazil Universidade Federal do Ceará, Fortaleza, CE, Brazil Universidade Estadual de Campinas, Campinas, SP, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade Federal do Amazonas, Manaus, AM, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil Universidade Federal do Ceará, Fortaleza, CE, Brazil Sebastião Cézar Radominski Sheila Knupp de Oliveira Simone Appenzeller Universidade de Campinas, Campinas, SP, Brazil Vera Lúcia Szejnfeld Universidade Federal de São Paulo, São Paulo, SP, Brazil Wiliam H. Chahade Hospital do Servidor Público Estadual de São Paulo "Francisco Morato de Oliveira", São Paulo, SP, Brazil International Editorial Board (Conselho Editorial Internacional) Ariel Masetto Juan Manuel Anaya Munther Khamashta Arthur Kavanaugh Luis Javier Jara H Ralph Schumacher Jr Bernardo Pons Estel Mario Cardiel Ricardo Cervera Segura Université de Sherbrooke, Sherbrooke, Canada University of California, San Diego, USA Universidad Nacional de Rosario, Rosario, Argentina Claudio Galarza Maldonado Hospital Monte Sinai, Cuenca, Equador Corporación de Investigaciones Biológicas, Medellín, Colômbia Universidad Nacional Autonoma de Mexico, Mexico City, Mexico Instituto Nacional de la Nutrición "Salvador Zubiran", Morrelia, Mexico Mario Garcia-Carrasco Ernest Choy Facultad de Medicina, BUAP, Puebla, Mexico Jordi Antón López Universidade Clássica de Lisboa, Lisboa, Portugal José Antonio Melo Gomes University of Calgary, Calgary, Canada King's College, London, UK Hospital Sant Joan de Déu, Barcelona, Spain Instituto Português de Reumatologia, Lisboa, Portugal Mário Viana de Queiroz Marvin Fritzler St. Thomas´ Hospital, London, UK University of Pennsylvania, Philadelphia, USA Hospital Clinic, Barcelona, Spain Richard J Wakefield Chapel Allerton Hospital, Leeds, UK Thomas Dörner Charite Hospital, Berlin, Germany Yehuda Shoenfeld Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel BSR Office (Secretaria SBR) Rogério Quintiliano Amaral Av. Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 CEP 01402-000 São Paulo, SP Fone/fax: 55 (11) 3289-7165 E-mail: [email protected]; [email protected] website: www.reumatologia.com.br Brazilian Journal of Rheumatology is listed in Web of Science, MEDLINE, LILACS, SciELO, Scopus and Index Copernicus databases. BJR is affiliated to the International Committee of Medical Journal Editors. A Revista Brasileira de Reumatologia é indexada nas bases de dados Web of Science, MEDLINE, LILACS, SciELO, Scopus e Index Copernicus. A RBR é filiada ao International Committee of Medical Journal Editors. Brazilian Journal of Rheumatology (BJR) is an official publication of the Brazilian Society of Rheumatology (BSR) in partnership with Elsevier Editora Ltda. and is dedicated to the medical community in Brazil and Latin America. Edited by Brazilian Society of Rheumatology. Published by Elsevier Editora Ltda. © 2014. All rights reserved and protected by law 9.610 - 19/02/98. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission in writing from BSR and the Publisher. BJR receives finnancial support from Fundos Remanescentes da Sociedade Brasileira de Reumatologia. A Revista Brasileira de Reumatologia (RBR) é uma publicação oficial da Sociedade Brasileira de Reumatologia (SBR) em conjunto com Elsevier Editora Ltda., distribuída exclusivamente à classe médica do Brasil e da América Latina. Editada por Sociedade Brasileira de Reumatologia. Publicada por Elsevier Editora Ltda. © 2014. Todos os direitos reservados e protegidos pela lei 9.610 - 19/02/98. Nenhuma parte desta publicação poderá ser reproduzida, sem autorização prévia, por escrito, da Elsevier Editora Ltda. e da SBR, sejam quais forem os meios empregados: eletrônicos, mecânicos, fotográficos, gravação ou quaisquer outros. A RBR recebe auxílio financeiro de Fundos Remanescentes da Sociedade Brasileira de Reumatologia. Revista Brasileira de Reumatologia – $ISSN 0482-5004 Revista Brasileira de Reumatologia (English Edition – Brazilian Journal of Rheumatology) – ISSN 2255-5021 Revistas produzidas em Elsevier España, SL Travessera de Gràcia, 17-21 08021 Barcelona, España RJ: Tel.: 21 3970-9300 Fax: 21 2507-1991 SP: Tel.: 11 5105-8555 Fax: 11 5505-8908 Website:www.elsevier.com E-mail:[email protected] No responsibility is assumed by Elsevier or BSI for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. A Elsevier não assume nenhuma responsabilidade por qualquer injúria e/ou danos a pessoas ou bens como questões de responsabilidade civil do fabricante do produto, de negligência ou de outros motivos, ou por qualquer uso ou exploração de métodos, produtos, instruções ou ideias contidas no material incluso. Devido ao rápido avanço no campo das ciências médicas, em especial, uma verificação independente dos diagnósticos e dosagens de drogas deve ser realizada. Embora todo o material de publicidade deva estar em conformidade com os padrões éticos (médicos), a inclusão nesta publicação não constitui uma garantia ou endosso da qualidade ou valor de tal produto ou das alegações feitas pelo seu fabricante. Content dedicated to the medical community. Material de distribuição exclusiva à classe médica. INSTRUCTIONS TO AUTHORS The Brazilian Journal of Rheumatology (BJR), an official organ of Sociedade Brasileira de Reumatologia (Brazilian Society of Rheumatology), was founded in 1957 and is published bimonthly. The journal publishes original articles, review articles, brief communications, case reports and letters to the editors. To submit a manuscript, please access the site http://ees.elsevier.com/bjr. Format of the manuscript The manuscript can be submitted in Portuguese or English, double spaced, with 2.5 cm margins. Unconventional abbreviations, medical jargon and telegraphic style should not be used in the text. Citation of drugs and pharmaceutical products must be done using pharmacological nomenclature, without any mention to commercial names. Manuscript structure Manuscript*, Title Page*, Cover Letter, and Author Agreement* must be submitted in separate files. Tables and Figures should be numbered as cited in the text and sent in separate files with corresponding titles and legends. (*required files) Title page The title page should contain: a) the full title; b) the full name of the authors and institutional affiliation; c) the department and institution where the study was originated; d) the full e-mail of the corresponding author; e) conflict of interest and relevant financial agencies; f) a running title with no more than 60 characters. Author Agreement It is the document where the authors declare that the manuscript is original, in addition to approve the manuscript object of the submission, the authorship and the order of authors listed. It must be signed by all authors. Below is presented an example. Dear Editor, We, the undersigned, declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We would like to draw the attention of the Editor to the following publications of one or more of us that refer to aspects of the manuscript presently being submitted. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. (Signature of all authors) Original article The original article should contain: the title page, the abstract page with keywords, introduction, material and methods or patients and methods, results and discussion, acknowledgements, references, tables, figures and figure legends. Original articles should not exceed 5,000 words including references and excluding the title page, abstract, tables and legends. It is allowed up to six figures or tables and 50 references. Abstract page The abstract page should contain: a) objective, methods, results and conclusions, with no more than 250 words; b) three to five keywords. Introduction As the aim of this section is to define the purpose and the reasons for the accomplishment of the work, we do not recommend a large literature review. Patients and methods or Material and methods This section should include enough information that allows the reproduction of the work and, when it is relevant, the approval by the institutional Committee of Ethics. The methods employed in the statistical analysis should always be quoted. Results They should be clear and concise. Tables and graphics should not duplicate information. Discussion It should be concise, interpreting the results in the context of the present literature. Please do not exceed the limit of half the number of pages of the complete work. Acknowledgments Only to people who contributed; i.e., with techniques, discussion and sending patients. Financial help should be referred in the title page. References They should be quoted in the text in Arabic numerals, superscript, with no brackets. Numbering should be sequencial, according to the quotation order in the text. Please quote all the authors in works with until six authors; after six authors, quote the first six followed by the expression et al. Reference Manager or Endnote programs are strongly recommended for use adopting the Vancouver style. Examples for reference citation are presented below. Authors should consult NLM’s Citing Medicine for additional information on the reference formats. Printed article 1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD, Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy. Rheumatology (Oxford) 2004; 43(12):1587-8. Reference retrieved from electronic address 2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in the treatment of avascular necrosis: a systematic review. Clin Rheumatol 2008. Available from: http://www.springerlink. com.w10069.dotlib.com. br/content/l05j4j3332041225/fulltext.pdf. [Accessed in February 24, 2008]. Book 3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002. Tables and figures Each Table or Figure should be numbered with Arabic numerals and sent in an individual file (.jpg, .tif, .png, .xls, .doc) with minimum of 300 dpi. Titles and legends should be in the same Table/Figure file to wich they refer. Tables and Figures should include enough information so the reader can understand them without going to the text. Photomicrographies should include the appropriated scale. Review article Reviews, preferentially systematic, may be submitted to BJR. They should cover deeply any interesting theme for the rheumatologist. They do not present a standard structure, neither introduction or conclusion. Please send abstracts without subdivisions with three to five keywords. Review articles should not exceed 6,000 words including references and excluding the title page, abstract, tables and legends. It is allowed up to five figures or tables and 70 references. Case report Must have six authors at most. They should include an abstract and keywords, without subdivisions. The text, however, should present the following sections: introduction, which should be concise; case report, containing the description and the evolution of the clinical case, laboratory exams, illustrations and tables (that substitute the sections material and methods and results); and discussion. It should not exceed 1,500 words including references and excluding the title page, abstract, tables and legends. It is allowed up to two figures or tables and 15 references. Brief communication It covers a point or a specific detail. It should present an abstract with no more than 250 words and three to five keywords. The text does not include subdivisions, and should not exceed 2,500 words including references and excluding the title page, abstract, tables and legends. It is allowed up to three figures or tables and 25 references. Rules for applying the appropriate tense in scientific writing Context or section Appropriate verb tense Abstract Past tense Introduction Most present tense (established facts, previous published data) Methods, materials used, and results Past tense Discussion/Conclusion Mixture of past and present, sometimes future tense Attribution Past tense Ex.: Andrade et al. reported that... Description of Tables and Figures Present tense Established knowledge, previous results etc. Present tense General rules to obtain a good scientific writing: 1. Use active voice. 2. Setences must be short, clear and objective. 3. Units of measurement are abbreviated when use with numerical values (e.g., 1 mg), but are not abbreviated if used without numerical values. Systeme International d'Únites (SI units) must be used. Remember to leave a space between the number and unit (e.g., 10 mg/dL), except for the percentage mark that follows the number without space (e.g., 70%). The plural form of units of measurement is the same as the singular form (e.g., 1 mL, 10 mL; 1 h, 10 h). Spell out numbers at the beginning of a sentence. 4. Define abbreviations the first time they appear. Avoid abbreviations in tittles and abstracts. 5. Do not use contractions (e.g., doesn't, can't etc.). Recommended book: Rogers SM. Mastering scientific and medical writing: a self-help guide. Berlin: Springer; 2007. Legal and ethical considerations According to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (International Committee of Medical Journal Editors – February 2006). Conflict of interest Public trust in the peer review process and the credibility of published articles depend in part on how well conflict of interest is handled during writing, peer review, and editorial decision making. Conflict of interest exists when an author (or the author’s institution), reviewer, or editor has financial or personal relationships that inappropriately influence (bias) his or her actions (such relationships are also known as dual commitments, competing interests, or competing loyalties). These relationships vary from those with negligible potential to those with great potential to influence judgment, and not all relationships represent true conflict of interest. The potential for conflict of interest can exist whether or not an individual believes that the relationship affects his or her scientific judgment. Financial relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself. However, conflicts can occur for other reasons, such as personal relationships, academic competition, and intellectual passion. Informed consent Patients have a right to privacy, that should not be infringed without informed consent. Identifying information, including patients’ names, initials, or hospital numbers, should not be published in written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that a patient who is identifiable be shown the manuscript to be published. Authors should identify Individuals who provide writing assistance and disclose the funding source for this assistance. Identifying details should be omitted if they are not essential. Complete anonymity is difficult to achieve. However, an informed consent should be obtained if there is any doubt. For example, masking the eye region in photographs of patients is inadequate protection of anonymity. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note. When informed consent has been obtained it should be indicated in the published article. Ethical treatment When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. If doubt exists whether the research was conducted in accordance with the Helsinki Declaration, the authors must explain the rationale for their approach, and demonstrate that the institutional review body explicitly approved the doubtful aspects of the study. When reporting experiments on animals, authors should be asked to indicate whether the institutional and national guide for the care and use of laboratory animals was followed. Clinical trials registry Clinical trials must be registered according to WHO recommendation at www. who.int/ictrp/en/. The definition of clinical trial include preliminary trials (phase I): any study with prospective recruiting of subjects to undergo any health-related intervention (drugs, surgical procedures, equipment, behavioral therapies, food regimen, changes in health care) to evaluate the effects on clinical outcomes (any biomedical or health-related parameter, including pharmacokinetics measurements and adverse reactions). The BJR has the right not to publish trials not complying with these and other legal and ethical standards determined by international guidelines. Financing and support The authors should also inform if they received financing or support from institutions like CNPq, CAPES, SBR Remaining Funds, Graduated Institutions, Laboratories etc. INSTRUÇÕES PARA OS AUTORES A Revista Brasileira de Reumatologia (RBR), órgão oficial da Sociedade Brasileira de Reumatologia, foi fundada em 1957 e é publicada bimestralmente. A revista publica artigos originais, artigos de revisão, comunicações breves, relatos de casos e cartas aos editores. Resultados Devem ser claros e concisos. Tabelas e gráficos não devem duplicar informações. Discussão O manuscrito deve ser submetido online através do site http://ees.elsevier.com/bjr. Deve ser concisa, interpretando os resultados no contexto da literatura atual. É conveniente não ultrapassar a metade do número de páginas do trabalho completo. Apresentação do manuscrito Agradecimentos O manuscrito pode ser submetido em português ou inglês, em espaço duplo, com margens de 2,5 cm. No texto não devem ser empregadas abreviaturas não convencionais, gírias (jargões) médicas ou redação tipo telegráfica. A citação de medicamentos e produtos farmacêuticos deve ser feita utilizando-se apenas a nomenclatura farmacológica, sem menção do nome comercial. Estrutura do manuscrito Manuscript*, Title Page*, Cover Letter e Author Agreement* devem ser enviados em arquivos individuais. Tabelas e figuras devem ser numeradas conforme citadas no texto e enviadas em arquivos separados, com títulos e legendas correspondentes. (*arquivos obrigatórios) Página do título Deve conter: a) título do artigo; b) nome completo dos autores e sua afiliação institucional; c) departamento(s) e instituição(ões) onde se originou o trabalho; d) nome e e-mail válido do autor responsável para correspondência; e) conflito de interesse e agências financiadoras relevantes; f) título resumido com no máximo 60 caracteres. Author Agreement É o documento no qual os autores declaram a originalidade do manuscrito, além de aprovarem o artigo objeto da submissão, a autoria e a ordem da lista de autores. Deve ser assinado por todos os autores. A seguir é apresentado um modelo. Caro Editor, Os autores, abaixo assinados, declaram que este manuscrito é original, não foi publicado antes e não se encontra submetido para qualquer outra publicação. Gostaríamos de pedir a atenção do Editor para a presente publicação de nós autores, referente a aspectos do presente manuscrito submetido. Confirmamos que o manuscrito foi lido e aprovado por todos os autores signatários e que não há nenhum outro autor a fazer parte senão os listados. Confirmamos também que a ordem dos autores listada no manuscrito foi aprovada por todos. Entendemos que o Autor para Correspondência será o único contato para o processo editorial. Ele será o único responsável pela comunicação com os demais autores acerca do progresso da submissão, da revisão do manuscrito e de sua aprovação final. (Assinatura de todos os autores) Artigo Original Deve conter: página do título, página de resumo com palavras-chave, introdução, material e métodos ou pacientes e métodos, resultados e discussão, agradecimentos, referências, tabelas, figuras e legendas das figuras. Não deve exceder 5.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até seis figuras ou tabelas e até 50 referências. Página de resumo Deve conter: a) objetivo, métodos, resultados e conclusões, não excedendo 250 palavras; b) três a cinco palavras-chave. Introdução A finalidade dessa seção é definir o propósito e as razões para a realização do trabalho. Não se recomenda extensa revisão da literatura. Pacientes e métodos ou Material e métodos Deve incluir informações suficientes que permitam a reprodução do trabalho e, quando pertinente, a aprovação pelo Comitê de Ética institucional. Os métodos empregados na análise estatística devem sempre ser citados. Apenas às pessoas que contribuíram, por exemplo, com técnicas, discussão e envio de pacientes. Auxílio financeiro deve ser referido na página do título. Referências Devem ser citadas no texto em algarismos arábicos, sobrescritos e depois da pontuação, sem parênteses ou colchetes. A numeração deve ser sequencial, de acordo com a ordem de citação no texto. Nas referências com mais de seis autores, devem ser citados os seis primeiros, seguidos pela expressão et al. Sugere-se a utilização dos programas Reference Manager ou Endnote, seguindo-se o estilo Vancouver. Exemplos de referência para diferentes formatos são apresentados a seguir. Os autores devem consultar o NLM’s Citing Medicine para mais informações sobre os formatos das referências. Artigo de revista 1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD, Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy. Rheumatology (Oxford) 2004; 43(12):1587-8. Artigo extraído de endereço eletrônico 2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in the treatment of avascular necrosis: a systematic review. Clin Rheumatol 2008. Available from: http://www.springerlink.com.w10069.dotlib.com.br/ content/l05j4j3332041225/fulltext. pdf. [Accessed in February 24, 2008]. Livro 3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002. Tabelas e Figuras Cada tabela ou figura deverá ser numerada em algarismo arábico e enviada em arquivo separado (.jpg, .tif, .png, .xls, .doc) com 300 dpi no mínimo. Título e legenda devem estar no mesmo arquivo da figura ou tabela a que se referem. Tabelas e ilustrações devem ser autoexplicativas, com informações suficientes para sua compreensão sem que se tenha de recorrer ao trabalho. Fotomicrografias devem incluir a escala apropriada. Artigo de Revisão Revisões, preferencialmente sistemáticas, podem ser submetidas à RBR, devendo abordar com profundidade um tema de interesse para o reumatologista. Não apresentam estruturação padronizada, prescindindo de introdução ou discussão. Devem apresentar resumo sem subdivisões, com três a cinco palavras-chave, e não devem exceder 6.000 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Podem exibir até cinco figuras ou tabelas e até 70 referências. Relato de Caso Deve incluir resumo e palavras-chave, sem necessidade de subdivisões. O texto, porém, apresenta as seguintes seções: introdução, que deve ser concisa; relato de caso, contendo a descrição e a evolução do quadro clínico, exames laboratoriais, ilustrações e tabelas (que substituem as seções material e métodos e resultados); e discussão. Deve conter no máximo seis autores, e não deve exceder 1.500 palavras, incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até duas figuras ou tabelas e até 15 referências. Comunicação breve Aborda um ponto ou detalhe específico de um tema. Deve incluir resumo com no máximo 250 palavras, e três a cinco palavras-chave. O texto não necessita subdivisões, deve ter até 2.500 palavras incluindo-se as referências e excluindo-se a página do título, resumo, tabelas e legendas. Pode exibir até três figuras ou tabelas e até 25 referências. Regras para aplicar tempos verbais apropriados de acordo com o contexto ou seção Contexto ou seção Resumo Introdução Métodos, materiais e resultados Discussão/Conclusão Atribuições Descrição de Tabelas e Figuras Conhecimento estabelecido e resultados prévios Tempo verbal apropriado Passado Presente, quando se referir a fatos estabelecidos e conhecimento prévio Passado Combinado de passado (quando se referir a resultados obtidos no trabalho) e presente (quando se referir a fatos estabelecidos e conhecimento prévio); às vezes pode ser utilizado o futuro (especialmente quando se referir a perspectivas de trabalhos a serem realizados) Passado Ex.: Andrade et al. relataram... Presente Presente Regras gerais para se obter uma boa escrita em um artigo científico: 1. Prefira a voz ativa. 2. As sentenças devem ser curtas, claras e objetivas. 3. A unidade de medida deve ser abreviada quando empregada com valores numéricos (p. ex., 1 mg), mas escrita por extenso quando separada de valor numérico. Utilize o Sistema Internacional de Unidades (SI units) para definir as unidades de medida. Lembre-se de deixar um espaço entre o número e a unidade (p. ex., 10 mg/dL), exceto quando for porcentagem, que deve estar junto (p. ex., 70%). O plural das unidades de medida é a mesma forma do singular (p. ex., 1 mL, 10 mL; 1 h, 10 h). Quando iniciarem a frase, os números devem estar por extenso, e não em algarismo arábico. 4. Defina a abreviação na primeira vez que aparecer no texto principal. Após a definição, use sempre a abreviação em vez da forma por extenso. Evite o uso de abreviações no título e no resumo. 5. Ao escrever em inglês, não utilize contrações (p. ex., prefira does not em vez de doesn't). Livro recomendado: Rogers SM. Mastering scientific and medical writing: a self-help guide. Berlin: Springer; 2007. Considerações éticas e legais A RBR segue as normas do Uniform Requirements for Manuscripts (URM) Submitted to Biomedical Journals desenvolvidas pelo The International Committee of Medical Journal Editors (ICMJE) – fevereiro de 2006. Conflito de interesse A confiança pública no processo de revisão por pares e a credibilidade dos artigos publicados dependem, em parte, de como o conflito de interesse é administrado durante a redação, a revisão por pares e a decisão editorial. O conflito de interesse existe quando um autor (ou instituição do autor), revisor ou editor tem relações financeiras ou pessoais que influenciem de forma inadequada (viés) suas ações (tais relações são também conhecidas como duplo compromisso, interesses conflitantes ou fidelidades conflitantes). Essas relações variam entre aquelas com potencial insignificante até as com grande potencial para influenciar o julgamento, e nem todas as relações representam verdadeiro conflito de interesse. O potencial conflito de interesse pode existir dependendo se o indivíduo acredita ou não que a relação afete seu julgamento científico. Relações financeiras (tais como emprego, consultorias, posse de ações, testemunho de especialista pago) são os conflitos de interesse mais facilmente identificáveis e os mais suscetíveis de minar a credibilidade da revista, dos autores e da própria ciência. No entanto, podem ocorrer conflitos por outras razões, tais como relações pessoais, competição acadêmica e paixão intelectual. Consentimento informado Os pacientes têm o direito à privacidade, que não deve ser infringida sem o consentimento informado. A identificação de informações, incluindo os nomes dos pacientes, iniciais ou números no hospital, não devem ser publicadas em descrições, fotografias e genealogias, a menos que a informação seja essencial para os propósitos científicos e o paciente (ou responsável) dê o consentimento livre e esclarecido para a publicação. O consentimento informado para este propósito requer que o manuscrito a ser publicado seja mostrado ao paciente. Os autores devem identificar os indivíduos que prestam assistência a escrever e divulgar a fonte de financiamento para essa assistência. Detalhes identificadores devem ser omitidos se não são essenciais. O anonimato completo é difícil de se conseguir; no entanto, no caso de qualquer dúvida, o consentimento deve ser obtido. Por exemplo, mascarar a região ocular em fotografias de pacientes é uma proteção de anonimato inadequada. Se as características de identificação são alteradas para proteger o anonimato, como na linhagem genética, os autores devem garantir que as alterações não distorçam o significado científico. Quando o consentimento informado foi obtido, ele deve ser indicado no artigo publicado. Princípios éticos Ao relatar experimentos em seres humanos, os autores devem indicar se os procedimentos seguidos estiveram de acordo com os padrões éticos do comitê responsável por experimentação humana (institucional e nacional) e com a Declaração de Helsinki de 1975, revisado em 2000. Se houver dúvida se a pesquisa foi realizada em conformidade com a Declaração de Helsinki, os autores devem explicar a razão para sua abordagem e demonstrar que o corpo de revisão institucional aprovou explicitamente os aspectos duvidosos do estudo. Ao relatar experimentos com animais, os autores devem indicar se as orientações institucionais e nacionais para o cuidado e a utilização de animais de laboratório foram seguidas. Registro de ensaios clínicos Os ensaios clínicos devem ser registrados segundo recomendação da OMS em www.who.int/ictrp/en/. A definição de ensaios clínicos incluem ensaios preliminares (fase I): um estudo prospectivo com o recrutamento de indivíduos submetidos a qualquer intervenção relacionada à saúde (medicamentos, procedimentos cirúrgicos, aparelhos, terapias comportamentais, regime alimentar, mudanças nos cuidados de saúde) para avaliar os efeitos em desfechos clínicos (qualquer parâmetro biomédico e de saúde, inclusive medidas farmacocinéticas e reações adversas). A RBR tem o direito de não publicar trabalhos que não cumpram estas e outras normas legais e éticas explicitadas nas diretrizes internacionais. Financiamento e apoio Os autores devem, também, informar se receberam financiamento ou apoio de instituições como CNPq, CAPES, Fundos Remanescentes da SBR, instituições universitárias, laboratórios etc. Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia) Founded on July 15, 1948 (Fundada em 15 de julho de 1948) Executive Board of Directors for the 2012–2014 Biennium Diretoria Executiva para o Biênio 2012–2014 President (Presidente) Walber Pinto Vieira, CE General secretary (Secretário geral) Francisco José Fernandes Vieira, CE 1st secretary (1º secretário) Lauredo Ventura Bandeira, SP 2nd secretary (2ª secretária) Rosa Maria Rodrigues Pereira, SP Treasurer (Tesoureiro) José Eyorand Castelo B. Andrade, CE Vice-treasurer (Vice-tesoureiro) José Roberto Provenza, SP Scientific director (Diretor científico) Mittermayer Barreto Santiago, BA Elected president (Presidente eleito) Cesar Emile Baaklini, SP Rheumatology Aid Fund to Rheumatology Research and Teaching Conselho do Fundo de Auxílio a Pesquisa e Ensino em Reumatologia Acir Rachid, PR Adil Muhib Samara, SP Antônio Carlos Ximenes, GO Caio Moreira, MG Cesar Emile Baaklini, SP Emília Inoue Sato, SP Fernando de Souza Cavalcanti, PE Fernando Neubarth, RS Geraldo da Rocha Castelar Pinheiro, RJ Geraldo Gomes de Freitas, PE Hilton Seda, RJ Iêda Maria Magalhães Laurindo, SP João Carlos Tavares Brenol, RS João Francisco Marques Neto, SP Nílzio Antônio da Silva, GO Sebastião Cezar Radominski, PR Walber Pinto Vieira, CE Wiliam Habib Chahade, SP Health Economy Commission Comissão de Economia da Saúde Coordinator (Coordenadora) Representatives of PANLAR Representantes junto à PANLAR Adil Muhib Samara, SP Antonio Carlos Ximenes, GO Fernando Neubarth, RS Maria Amazile Ferreira Toscano, SC Mirhelen Mendes de Abreu, SP Members (Membros) Ana Cristina de Medeiros Ribeiro, SP Claiton Viegas Brenol, RS Eduardo de Souza Meirelles, SP Jussara de Almeida L. Kochen, SP Rafael Mendonça da Silva Chakr, RS Representatives of Ministry of Health Epidemiology Commission Representante junto ao Ministério da Saúde Ana Patrícia de Paula, DF Mário Soares Ferreira, DF Comissão de Epidemiologia Representatives of AMB Representantes junto à AMB Eduardo de Souza Meirelles, SP Gustavo de Paiva Costa, DF Morton Aaron Scheinberg, SP Specialist Title Commission Comissão de Título de Especialista Coordinator (Coordenadora) Emília Inoue Sato, SP Members (Membros) Fernanda Rodrigues Lima, SP Gilda Aparecida Ferreira, MG Ines Guimarães Silveira, RS José Tupinambá Souza Vasconcelos, PI Marcelo de Medeiros Pinheiro, SP Mauro Goldfarb, RJ Nafice Costa Araujo, SP Rafael Navarrete, GO Valeria Valim Cristo, ES Wilton Silva dos Santos, DF Coordinator (Coordenadora) Eutilia Andrade Medeiros Freire, PB Members (Membros) Alessandra Souza Braz C. Andrade, PB Bernardo Matos da Cunha, DF Camila Cruz Leijoto, RJ Carlos Augusto F. de Andrade, RJ Jussara de Almeida L. Kochen, SP Mirhelen Mendes de Abreu, SP Pediatric Rheumatology Commission Comissão de Reumatologia Pediátrica Coordinator (Coordenador) Cláudio Arnaldo Len, SP Members (Membros) Adriana Maluf Elias Sallum, SP Ana Paula Vecchi, GO Andre de Souza Cavalcanti, PE Blanca Elene Rios Gomes Bica, RJ Carlos Nobre Rabelo Jr., CE Claudia Saad Magalhães, SP Clovis Artur Almeida da Silva, SP Cynthia Torres Franca da Silva, RJ Luciana Brandão Paim Marques, CE Marcia Bandeira, PR Maria Teresa R. A. Terreri, SP Tania Caroline Castro, SP Teresa Cristina Robazzi, BA Media Commission Comissão de Comunicação Social BSR Bulletin (Boletim SBR) Editorial Council (Conselho Editorial) Kaline Medeiros Costa Pereira, SP Edgard Torres dos Reis Neto, SP Editors (Editores) Tânia Carolina Monteiro de Castro, SP Frederico Augusto Gurgel Pinheiro, SP Collaborator (Colaborador) Plínio José do Amaral, SP Brazilian Journal of Rheumatology Revista Brasileira de Reumatologia Editors (Editores) Max Victor Carioca Freitas, CE Roberto Ezequiel Heymann, SP Coeditors (Coeditores) Eloísa Silva Dutra de Oliveira Bonfá, SP Hilton Seda, RJ João Carlos Tavares Brenol, RS Mittermayer Barreto Santiago, BA Paulo Louzada-Junior, SP Ricardo Fuller, SP Simone Appenzeller, SP BSR Website (Site SBR) Coordinators (Coordenadores) Marcelo Cruz Rezende, MS Maria Roseli Monteiro Callado, CE Ethics and Discipline Commission Comissão de Ética e Disciplina Coordinator (Coordenador) José Marques Filho, SP Members (Membros) Adriana Maria Kakehasi, MG Antonio Carlos Althoff, SC Henrique Josef, SP João Elias Moura Jr., SC José Geraldo Araújo Paiva, CE José Roberto Pereira Santos, ES Teaching and Medical Education Commission Comissão de Ensino e Educação Médica Coordinator (Coordenador) Francisco Airton Castro da Rocha, CE Members (Membros) Cesar Emile Baaklini, SP Charles Lubianca Kohem, RS Claudia Diniz Lopes Marques, PE Elaine Lira Medeiros de Bezerra, RN Elisa Martins das N. de Albuquerque, RJ Jozélia Rego, GO Marcelo Pimenta, GO Maria José Pereira Vilar, RN Ricardo Machado Xavier, RS Congresses, Journeys, and Events Commission Comissão de Congressos, Jornadas e Eventos Coordinators (Coordenadores) Fernando Neubarth, RS Georges Basile Christopoulos, AL José Roberto Provenza, SP Members (Membros) Antônio Carlos dos Santos Novaes, SP Claudia Diniz Lopes Marques, PE Elda Matilde Hirose Pastor, SP Francisco Saraiva da Silva Júnior, CE Hilton Seda, RJ José Caetano Macieira, SE Reno Martins Coelho, RJ Ricardo Fuller, SP Vasculopathies Commission Comissão de Vasculopatias Commission of Relations with Groups of Patients Coordinator (Coordenador) Comissão de Relações com Grupos de Pacientes Members (Membros) Coordinators (Coordenadores) Helenice Alves Teixeira Gonçalves, DF Members (Membros) Ana Maria Camargo Gallo, SC Ana Paula Espinula Gianordoli, ES Eduardo de Souza Meirelles, SP Luis Piva Junior, DF Valderílio Feijó Azevedo, PR Wanda Heloisa Rodrigues Ferreira, RJ Occupational Rheumatology Commission Comissão de Reumatologia Ocupacional Coordinator (Coordenador) Milton Helfenstein Junior, SP Members (Membros) Anna Beatriz Assad Maia, DF Antônio Techy, PR César Augusto Fávaro Siena, SP Marco Aurélio Goldenfum, RS BiobadaBrasil Comission Comissão do BiobadaBrasil Coordinator (Coordenador) David Cezar Titton, PR Members (Membros) Roger Abramino Levy, RJ Adriana Danowski, RJ Adriana Maria Kakehasi, MG Alexandre Wagner S. de Souza, SP Ana Beatriz S. Bacchiega de Freitas, RJ Andreas Funke, PR Carlos Ewerton Maia Rodrigues, CE Danieli Castro Oliveira de Andrade, SP Isabella Vargas de Souza Lima, BA Jozélia Rego, GO Manuella Lima Gomes Ochtrop, RJ Image Commission Comissão de Imagem Coordinator (Ccoordenador) José Alexandre Mendonça, SP Members (Membros) Andrea B. Vannucci Lomonte, SP Cristiane Kayser Veiga da Silva, SP Iêda Maria Magalhães Laurindo, SP Inês Guimarães Silveira, RS Jamil Natour, SP Karine Rodrigues da Luz, SP Laura Maria C. Mendonça, RJ Simone Appenzeller, SP Verônica Silva Vilela, RJ Procedures Commission Comissão de Procedimentos Aline Ranzolin, PE André Luiz Shinji Hayata, SP Ines Guimarães da Silveira, RS Mirhelen Mendes de Abreu, SP Paulo Louzada-Junior, SP Roberto Ranza, MG Valéria Cristo Valim, ES Coordinator (Ccoordenador) Rheumatoid Arthritis Commission Lupus Commission Comissão de Artrite Reumatoide Coordinator (Coordenadora) Licia Maria Henrique da Mota , DF Members (Membros) Bóris Afonso Cruz, MG Claiton Viegas Brenol, RS Geraldo da Rocha Castelar Pinheiro, RJ Ieda Maria Magalhães Laurindo, SP Jozélio Freire de Carvalho, BA Manoel Barros Bertolo, SP Max Victor Carioca Freitas, CE Nilzio Antônio da Silva, GO Paulo Louzada-Junior, SP Rina Dalva Neubarth Giorgi, SP Rodrigo Aires Corrêa Lima, DF Jamil Natour, SP Members (Membros) Geraldo da Rocha Castelar Pinheiro, RJ Luiza Helena Coutinho Ribeiro, SP Monique Sayuri Konai, SP Rita Nely Vilar Furtado, SP Comissão de Lúpus Coordinator (Coordenador) Evandro Mendes Klumb, RJ Members (Membros) Cristina Costa Duarte Lanna, MG Eduardo Ferreira Borba Neto, SP Eloisa Silva Dutra de Oliveira Bonfá, SP Emília Inoue Sato, SP Francinne Machado Ribeiro, RJ João Carlos Tavares Brenol, RS Lilian Tereza Lavras Costallat, SP Luiz Carlos Latorre, SP Maria de Fátima Lobato da Cunha, PA Odirlei Andre Monticielo, RS Spinal Commission Ari Stiel Radu Halpern, SP Carlos Appel da Silva, RS Jamil Natour, SP Jose Gerardo de Araújo Paiva, CE Luíza Helena Coutinho Ribeiro, SP Maria Amazile Ferreira Toscano, SC Renê Donizeti Ribeiro de Oliveira, SP Silvio Figueira Antonio, SP Osteomethabolic Diseases and Osteoporisis Commission Comissão de Doenças Osteometabólicas e Osteoporose Coordinator (Coordenador) Sebastião Cezar Radominski, PR Members (Membros) Ana Patricia de Paula, DF Caio Moreira, MG Charlles Heldan de Moura Castro, SP Cristiano Augusto de F. Zerbini, SP Elaine de Azevedo, SP Laura Maria C. de Mendonça, RJ Mailze Campos Bezerra, CE Marco Antonio Rocha Loures, PR Vera Lúcia Szejnfeld, SP Spondiloarthropathies Commission Comissão de Espondiloartropatias Coordinator (Coordenador) Célio Roberto Gonçalves, SP RBE Coordinator (Coordenador RBE) Percival Degrava Sampaio Barros, SP Members (Membros) Antonio Carlos Ximenes, GO Eduardo de Souza Meirelles, SP Gustavo Gomes Rezende, MG Ivânio Alves Pereira, SC Marcelo Medeiros Pinheiro, SP Mauro Waldemar Keisermann, RS Thelma Larocca Skare, PR Walber Pinto Vieira, CE Washington Alves Bianchi, RJ Psoriatic Arthritis Subcommission (Sub-Comissão de Artrite Psoriásica) Claudia Goldenstein-Schainberg, SP Roberto Ranza, MG Rubens Bonfiglioli, SP Sueli Coelho da Silva Carneiro, RJ Valderilio Feijó Azevedo, PR Pain, Fibromyalgia and Other Painful Syndromes of the Soft Parts Commission Comissão de Dor, Fibromialgia e Outras Síndromes Dolorosas de Partes Moles Coordinator (Coordenador) Marcelo Cruz Rezende, MS Members (Membros) Aline Ranzolin, PE Daniel Feldman Pollak, SP Eduardo dos Santos Paiva, PR José Eduardo Martinez, SP José Roberto Provenza, SP Marcos Aurélio Freitas Machado, SP Nilton Salles Rosa Neto, SP Rafael Mendonça da Silva Chakr, RS Roberto Ezequiel Heymann, SP Documentation and Historical Registry Commission Osteoarthrosis Commission Comissão de Coluna Vertebral Comissão de Documentação e Registro Histórico Comissão de Osteoartrose Coordinator (Coordenador) Coordinator (Coordenador) Coordinator (Coordenador) Ibsen Bellini Coimbra, SP Marcos Renato de Assis, SP Members (Membros) Joaquim Jaguaribe Nava Ribeiro, RJ Members (Membros) Célio Roberto Gonçalves, SP Henrique Josef, SP José Eduardo Gonçalves, CE José Knoplich, SP José Marques Filho, SP Lauredo Ventura Bandeira, SP Lipe Goldenstein, BA Plínio José Amaral, SP Systemic Sclerosis Commission Comissão de Esclerose Sistêmica Coordinators (Coordenadores) Izaias Pereira da Costa, MS Sandra Lucia Euzébio Ribeiro, AM Members (Membros) Ana Carolina de Oliveira S. Montandon, GO Helena Lucia A. Pereira, AM Luiz Sergio Guedes Barbosa, MT Mauro Furtado Cavalcanti, PI Natalino Hajime Yoshinari, SP Rejane Maria R. de Abreu, CE Roberta de Almeida Pernambuco, SP Coordinator (Coordenador) Percival Degrava Sampaio-Barros, SP Members (Membros) Adriana Fontes Zimmermann, SC Carolina de Souza Muller, PR Cláudia Tereza Lobato Borges, MA Cristiane Kayser Veiga da Silva, SP Eutília Andrade Medeiros Freire, PB Giselle Baptista Maretti, RJ João Francisco Marques Neto, SP Maria Cecília Fonseca Salgado, RJ Maria de Fátima Lobato da Cunha Sauma, PA Mário Newton Leitão de Azevedo, RJ Sheila Marcia de A. Fontenele, CE Sjögren Syndrome Commission (Comissão de Síndrome de Sjögren) Coordinator (Coordenadora) Valéria Valim Cristo, ES Members (Membros) Érica Vieira Serrano, ES Leandro Augusto Tanure, MG Sandra Gofinet Pasoto, SP Sandra Lucia Euzébio Ribeiro, AM Virginia Fernandes Moça Trevisani, SP Rheumatology Society of Mato Grosso do Sul Sociedade de Reumatologia do Rio de Janeiro Dr. Evandro Mendes Klumb Members (Membros) Rheumatology Society of Rio Grande do Norte Reno Martins Coelho, RJ Adrian Nogueira Bueno, MG Ana Teresa Amoedo Medrado, BA Antonio Carlos Scafutto, MG Claudio Goldenstein Schainberg, SP Eliezer Rushansky, PE Evelin D. Goldenberg M. M. da Costa, SP José Eyorand Castelo B Andrade, CE José Roberto Silva Miranda, SP Manoel Barros Bertolo, SP Rafael de Oliveira Fraga, MG Ricardo Jorge de Percia Name, RJ Vander Fernandes, MT Supervisory Board (Conselho Fiscal) Fernando Neubarth, RS Iêda Maria Magalhães Laurindo, SP Geraldo da Rocha Castelar Pinheiro, RJ Rheumatology Society Mato Grosso Associação Mato-Grossense de Reumatologia Dr. Eduardo Benevides Lindote Filho Rheumatology Society of Alagoas Sociedade Alagoana de Reumatologia Dra. Inês Cristina de Mello Rheumatology Society of Amapá Gout Commission Sociedade Amapaense de Reumatologia Dr. Alessandro Marcus Pinheiro Melo (Comissão de Gota) Rheumatology Society of Amazonas Coordinator (Coordenador) Geraldo da Rocha Castelar Pinheiro, RJ Sociedade Amazonense de Reumatologia Dra. Maria do Socorro A. de Souza Members (Membros) Rheumatology Society of Bahia (Comissão de Doenças Endêmicas e Infecciosas) Sociedade de Reumatologia do Espírito Santo Dr. José Roberto Pereira Santos Coordinator (Coordenador) Coordinators (Coordenadores) Endemic and Infectious Diseases Commission Rheumatology Society of Espírito Santo Rheumatology Society of Rio de Janeiro Regionais – SBR Adil Muhib Samara, SP Antonio José Lopes Ferrari, SP Ana Beatriz Vargas dos Santos, RJ Hellen Mary da Silveira de Carvalho, DF Sociedade de Reumatologia de Rondônia Dr. Liszt Jonney Silva dos Santos (Comissão de Centros de Terapia Imunobiológica Assistida) BSR – Regionals Francisco Alves Bezerra Neto, RN Matheus Staufackar Carlos, RN Inês Cristina de Mello Lima, AL Mauro Furtado Cavalcante, PI Rheumatology Society of Rondônia Sociedade de Reumatologia do Mato Grosso do Sul Dr. Izaias Pereira da Costa (Comissão de Defesa Profissional) Members (Membros) Sociedade de Reumatologia de Brasília Dr. Cleandro Pires de Albuquerque Assisted Therapy Immunobiological Centers Commission Professional Defense Commission Francisco Deoclécio D. Rocha, RN Vander Fernandes, MT Rheumatology Society of Brasília Sociedade Baiana de Reumatologia Dr. Mittermayer Barreto Santiago Rheumatology Society of Santa Catarina Sociedade Catarinense de Reumatologia Sonia Cristina de Magalhães Souza Fialho Rheumatology Society of Ceará Sociedade Cearense de Reumatologia Dr. José Eyorand Castelo Branco de Andrade Sociedade de Reumatologia do Rio Grande do Norte Dr. Francisco Deoclécio Damasceno Rocha Rheumatology Society of Rio Grande do Sul Sociedade de Reumatologia do Rio Grande do Sul Dr. Marco Aurélio Goldenfum Rheumatology Society of Tocantis Sociedade de Reumatologia do Tocantins Dra. Daniela Edilma Japiassu Custódio Rheumatology Society of Goiânia Sociedade Goiana de Reumatologia Dra. Rosane Gouveia Vilela Machado Rheumatology Society of Maranhão Sociedade Maranhense de Reumatologia Dra. Raquel Moraes da Rocha Nogueira Rheumatology Society of Minas Gerais Sociedade Mineira de Reumatologia Dr. Boris Afonso Cruz Rheumatology Society of Pará Sociedade Paraense de Reumatologia Dr. Rosana de Britto Pereira Cruz Rheumatology Society of Paraíba Sociedade Paraibana de Reumatologia Dra. Danielle Christinne Soares Egypto de Brito Rheumatology Society of Paraná Sociedade Paranaense de Reumatologia Dr. Eduardo Santos Paiva Rheumatology Society of São Paulo Sociedade Paulista de Reumatologia Dr. Dawton Torigoe Rheumatology Society of Pernambuco Sociedade Pernambucana de Reumatologia Dra. Lílian David de Azevedo Valadares Rheumatology Society of Piauí Sociedade Piauiense de Reumatologia Dra. Aline do Socorro Miranda Ribeiro Rheumatology Society of Sergipe Sociedade Sergipana de Reumatologia Dra. Regina Adalva de Lucena Couto Ocea Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia) Avenida Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 – CEP: 01402-000 – São Paulo, SP, Brasil Phone/Fax: 55 11 3289-7165 E-mail: [email protected], [email protected] Website: www.reumatologia.com.br REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Volume 54. Number 3. May/June 2014 Volume 54. Número 3. Maio/Junho 2014 CONTENTS | SUMÁRIO Editorial ScienceDirect: The indexation which RBR lacked ScienceDirect: a indexação que faltava à RBR Paulo Louzada-Junior.................................................................................................................................. 165 Original articles | Artigos originais Inequality in the distribution of rheumatologists in Brazil: correlation with local of medical residency, Gross Domestic Product and Human Development Index Inequalidade na distribuição de reumatologistas no Brasil: correlação com local de residência médica, Produto Interno Bruto e Índice de Desenvolvimento Humano Cleandro Pires de Albuquerque................................................................................................................... 166 Otorhinolaryngological findings in a group of patients with rheumatic diseases Achados otorrinolaringológicos em um grupo de pacientes com doenças reumatológicas Reinaldo Jordão Gusmão, Fernando Laffitte Fernandes, Alexandre Caixeta Guimarães, Lutiane Scaramussa, Zoraida Sachetto, Henrique Furlan Pauna, Guilherme Machado de Carvalho......... 172 Randomized controlled trial of a therapeutic intervention group in patients with fibromyalgia syndrome Estudo randomizado e controlado de uma intervenção terapêutica grupal em pacientes com síndrome fibromiálgica Marielza R. Ismael Martins, Cristiane Carnaval Gritti, Randolfo dos Santos Junior, Maria Carolina Luizetto de Araújo, Lilian Chessa Dias, Marcos Henrique D’all Aglio Foss, Larissa Batista de Andrade, Carlos Eduardo D’all Aglio Rocha.................................................................. 179 Construction of a manual of work processes and techniques from Centro de Dispensação de Medicamentos de Alto Custo (CEDMAC), Hospital de Clínicas, Unicamp Construção do manual de processos de trabalho e técnicas do Centro de Dispensação de Medicamentos de Alto Custo (CEDMAC) do Hospital de Clínicas da Unicamp Manoel Barros Bertolo, Bruno Silva de Araújo Ferreira, Adriana G. Mucke Marchiore, Glaucia Pereira do Amaral Carvalho, Débora Pessoa de Souza, Eliane Molina Psaltikidis......................... 185 Evaluation of respiratory impairment in patients with systemic lupus erythematosus with the six-minute walk test Avaliação do comprometimento respiratório em pacientes com lúpus eritematoso sistêmico com o teste de caminhada de seis minutos Marivone Arruda Leite, Mônica Corso Pereira, Lílian Tereza Lavras Costallat, Wander de Oliveira Villalba, Marcos Mello Moreira, Ilma Aparecida Paschoal.......................................... 192 Analysis of the association of fatigue with clinical and psychological variables in a series of 371 Brazilian patients with rheumatoid arthritis Análise da associação da fadiga com variáveis clínicas e psicológicas em uma série de 371 pacientes brasileiros com artrite reumatoide Washington A. Bianchi, Fernanda R. Elias, Geraldo da Rocha Castelar Pinheiro, Carlos Roberto Machado Gayer, Claudio Carneiro, Rachel Grynzpan, Paulo Hamdan, Sueli Carneiro............ 200 Evaluation of postural control and quality of life in elderly women with knee osteoarthritis Avaliação do controle postural e da qualidade de vida em idosas com osteoartrite de joelho Júlia Guimarães Reis, Matheus Machado Gomes, Thamires Máximo Neves, Marina Petrella, Renê Donizeti Ribeiro de Oliveira, Daniela Cristina Carvalho de Abreu..................................................... 208 Review articles | Artigos de revisão Pre-operative anesthetic assessment of patients with rheumatoid arthritis Avaliação anestésica pré-operatória de pacientes com artrite reumatoide Rodrigo Barbosa Aires, Jozélio Freire de Carvalho, Licia Maria Henrique da Mota.................................... 213 Rituximab for rheumatoid arthritis treatment: a systematic review Rituximabe para o tratamento da artrite reumatoide: revisão sistemática Lívia Lovato Pires de Lemos, Juliana de Oliveira Costa, Marina Amaral de Ávila Machado, Alessandra Maciel Almeida, Mariana Michel Barbosa, Adriana Maria Kakehasi, Vânia Eloísa de Araújo, Augusto Afonso Guerra Júnior, Francisco de Assis Acurcio.................................. 220 Case report | Relato de caso IgA nephropathy and polymyositis: a rare association Nefropatia por IgA e polimiosite: uma rara associação Thiago Bitar Moraes Barros, Fernando Henrique Carlos de Souza, Denise Maria Avancini Costa Malheiros, Mauricio Levy-Neto, Samuel Katsuyuki Shinjo......................... 231 Spondyloptosis in athlete Espondiloptose em atleta Ana Paula Luppino Assad, Andressa Silva Abreu, Luciana Parente Costa Seguro, Lissiane Karine Noronha Guedes, Fernanda Rodrigues Lima, Ana Lucia de Sá Pinto................................ 234 First report of mild Brazilian spotted fever associated to arthritis Primeiro caso de febre maculosa brasileira branda associada à artrite Virgínia Lucia Nazario Bonoldi, Roberta Gonçalves Marangoni, Giancarla Gauditano, Jonas Moraes-Filho, Marcelo Bahia Labruna, Natalino Hajime Yoshinari.................................................................................. 237 Brief communication | Comunicação breve Patients with systemic lupus erythematosus and secondary antiphospholipid syndrome have decreased numbers of circulating CD4+CD25+Foxp3+ Treg and CD3–CD19+ B cells Pacientes com lúpus eritematoso sistêmico e síndrome antifosfolípide secundária possuem números reduzidos de células B CD4+ CD25+ Foxp3+ (células Treg) e células B CD3– CD19+ circulantes Ester Rosári Raphaelli Dal Ben, Carine Hartmann do Prado, Talita Siara Almeida Baptista, Moisés Evandro Bauer, Henrique Luiz Staub.............................................................................................. 241 When anti-TNF fails, anti-IL12-23 is an alternate option in psoriasis and psoriatic arthritis Quando anti-TNF não obtém sucesso, anti-IL-12-23 é opção alternativa na psoríase e na artrite psoriásica Ricardo Prado Golmia, Ayk Helena Barbosa Martins, Morton Scheinberg.................................................. 247 Articular ultrasonography: interobserver reliability in rheumatoid arthritis Ultrassonografia articular: confiabilidade interobservadores em artrite reumatoide Melissa Cláudia Bisi, Aline Defaveri do Prado, Cristina Rabelo, Flávia Brollo, Inês Guimarães da Silveira, José Alexandre de Mendonça, Henrique Luiz Staub....................................... 250 Retraction | Retratação Retraction of Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection Retratação de Anticorpos antipeptídeos citrulinados e o fator reumatoide em pacientes sudaneses com infecção Leishmania donovani Erik Ahlin, Amir Elshafei, Musa Nur, Sayda Hassan El Safi, Johan Ronnelid, Gehad Elghazali................. 255 Erratum | Errata Erratum of volume 54, issue 1 Errata do volume 54, número 1............................................................................................................................ 256 2oanos de experiência1 MAIS LONGO HISTÓRICO DE DADOS DE SEGURANÇA E EFICÁCIA1-10 NOS TRATAMENTOS DE: Artrite Reumatoide1, Espondilite Anquilosante1 e Artrite Idiopática Juvenil1 – resposta clínica rápida e sustentada em estudo de até 4 anos.1,11-13 Psoríase1* e Artrite Psoriásica1 – tratamento eficaz e seguro.14,15 Referências bibliográficas: 1) Bula de Enbrel® PFS. 2) Bula de Remicade®. 3) Bula de Humira®. 4) Bula de Stelara®. 5) Bula de Simponi®. 6) Bula de Cimzia®. 7) Bula de Actemra®. 8) Bula de Mabthera®. 9) Bula de Orencia®. 10) Yamauchi PS, Gindi V, Lowe NJ. The treatment of psoriasis and psoriatic arthritis with etanercept: practical considerations on monotherapy, combination therapy, and safety. Dermatol Clin. 2004 Oct;22(4):449-59. 11) Davis J C, et al. Efficacy and safety of up to 192 weeks of etanercepte therapy in patients with ankylosing spondylitis. Ann Rheum Dis, 2008; 67:346–352. 12) Davis J C, et al. Reduction in health related quality of life in patients with ankylosing spondylitis and improvements with etanercept therapy. Arthritis Rheum 2005;53:494–501. 13) Gorman J D, et al. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor. N Engl J Med, 2002; 346: 1349-56. 14) Siegfried EC, et al. Intermittent etanercept therapy in pediatric patients with psoriasis. J Am Acad Dermatol. 2010 Nov;63(5):769-74. 15) Sterry W, et al. Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomised double blind multicentre trial. BMJ. 2010 Feb 2;340:c147. Enbrel®/Enbrel® PFS (etanercepte). Indicações: adulto: artrite reumatoide, espondilite anquilosante, artrite psoriásica e psoríase em placas. Pediátrico: artrite idiopática juvenil (AIJ) poliarticular (4-17 anos) e psoríase em placas (8-17 anos). Contraindicações: hipersensibilidade ao etanercepte ou a qualquer componente da fórmula do produto. Pacientes com infecção localizada ou generalizada, crônica ou ativa, ou em risco de desenvolvê-la. Advertências e Precauções: foram relatadas reações alérgicas associadas ao Enbrel®/ Enbrel® PFS. Caso ocorra, descontinuar imediatamente a medicação. Imunossupressão: terapia anti-TNF pode comprometer a defesa do hospedeiro contra infecções e doenças malignas. No período pós-comercialização há relatos de doenças malignas em diversos órgãos, mas ainda não se sabe qual o impacto do tratamento com etanercepte sobre o desenvolvimento e a progressão das malignidades e infecções ativas e/ou crônicas. Há relatos de câncer de pele melanoma e não melanoma com antagonistas de TNF. Exame de pele periódico recomendado. Reações hematológicas: casos incomuns de trombocitopenia, raros de pancitopenia e muito raros de anemia aplástica, alguns evoluindo para óbito. Cautela em pacientes com história pregressa de discrasia sanguínea. Procurar aconselhamento médico imediato caso desenvolva sinais e sintomas sugestivos de discrasias sanguíneas ou infecções durante o tratamento. Discrasias confirmadas, etanercepte deve ser descontinuado. Enbrel®/Enbrel® PFS pode estar associado à formação de anticorpos autoimunes. Não administrar concomitantemente vacinas com microrganismos vivos. Atualizar cartão vacinal de acordo com normas locais antes do início da terapia. Eventos neurológicos: relatos raros de distúrbios desmielinizantes, porém não se sabe qual a relação causal com etanercepte. Recomendase avaliação da relação risco/benefício ao prescrever este medicamento a pacientes com doença desmielinizante ou com risco aumentado de desenvolvê-la. Distúrbios cardíacos: relatos pós-comercialização de piora da insuficiência cardíaca congestiva (ICC), com e sem a identificação dos fatores precipitantes. Embora não conclusivos, dados de estudo clínico sugerem possível tendência à piora da ICC com etanercepte. Recomenda-se cautela nesses pacientes. Infecções: avaliar pacientes para infecções antes, durante e depois do tratamento com Enbrel®/Enbrel® PFS. Tuberculose (TB): antes do início da terapia com Enbrel®/Enbrel® PFS, o paciente deve ser avaliado para infecção ativa ou latente. A profilaxia de TB latente deve ser iniciada antes da terapia com Enbrel®/Enbrel® PFS seguindo diretrizes locais. Havendo TB ativa, o Enbrel®/Enbrel® PFS não deve ser iniciado. Não se sabe se a terapia com Enbrel®/Enbrel® PFS aumenta esse risco. Reativação da Hepatite B: relatada reativação do vírus da hepatite B (HBV) em portadores crônicos usando terapia anti-TNF. Cautela no uso do etanercepte em portadores do HBV. Monitorar sinais e sintomas de infecção ativa pelo HBV. Hepatite C: relatos de piora embora sem estabelecer relação causal com o etanercepte. Não recomendado em conjunto com tratamento de hepatite alcoólica. Hipoglicemia: relatada em associação com tratamento para diabetes. Gravidez: ainda não se estabeleceu o uso seguro de Enbrel® durante a gravidez. Lactação: optar entre descontinuar a amamentação ou descontinuar Enbrel® durante lactação. Pediátrico: não usar em menores de 4 anos. Idosos: não necessita ajuste posológico específico. Dirigir veículos e operar máquinas: não há estudos sobre este tipo de efeito. Gravidez: categoria de Risco B: este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista. Reações adversas: adulto: reação no local da injeção com eritema, prurido, dor, edema, hemorragia e hematoma. Infecção do trato respiratório superior, infecções por bactérias, microbactérias, vírus, fungos e parasitas (incluindo protozoários). Infecções oportunistas também foram relatadas (incluindo a listeriose e legionelose). Doenças malignas. Reações muito comuns: infecções (incluindo infecções do trato respiratório superior, bronquite, cistite, infecções da pele). Comuns: reações alérgicas, autoanticorpos, febre, prurido. Incomuns: infecções sérias (incluindo pneumonia, celulite, artrite séptica, sepse e infecção parasitária), urticária, rash cutâneo, psoríase, vasculite sistêmica (incluindo vasculite ANCA positiva), uveíte, esclerite, trombocitopenia, doença pulmonar intersticial, câncer de pele não melanoma. Raras: tuberculose, infecções oportunistas (incluindo fúngica invasiva, infecções bacterianas e microbacterianas atípicas e Legionela), reação anafilática, convulsões, evento desmielinizante do SNC, neurite óptica, mielite transversa, vasculite cutânea, síndrome de Stevens-Johnson, eritema multiforme, lúpus cutâneo, lúpus discoide, síndrome do tipo lúpus, anemia, leucopenia, neutropenia, pancitopenia, elevação de enzimas hepáticas, hepatite autoimune, melanoma, piora da ICC. Muito raras: anemia aplástica, necrólise epidérmica tóxica. Não conhecidas: listeria, reativação da hepatite B, carcinoma de célula de Merkel, síndrome de ativação de macrófagos. Presença de anticorpo antinuclear, anti-DNA e anticardiolipina. Pediatria: eventos semelhantes aos observados em adultos. Relato de dois casos de varicela e quatro casos de síndrome de ativação de macrófagos na AIJ. Interações: não recomendado uso de Enbrel®/Enbrel® PFS com anakinra e abatacepte. Uso concomitante de sulfassalazina pode se associar a leucopenia de significância clínica não conhecida. Não há interações de Enbrel®/ Enbrel® PFS com glicocorticoides, salicilatos, anti-inflamatórios não esteroides (AINEs), analgésicos ou metotrexato. Não há interações farmacocinéticas com digoxina e varfarina. Posologia: uso em adultos (≥ 18 anos): artrite reumatoide, espondilite anquilosante e artrite psoriásica: 50 mg por semana (uma injeção subcutânea utilizando uma seringa de 50 mg, em duas injeções de 25 mg administradas praticamente simultâneas ou 25 mg de Enbrel® duas vezes por semana, com 3 ou 4 dias de intervalo). Psoríase em Placas: 50 mg por semana (uma injeção subcutânea utilizando uma seringa de 50 mg, em duas injeções de 25 mg administradas praticamente simultâneas ou 25 mg de Enbrel® duas vezes por semana, com 3 ou 4 dias de intervalo). Respostas maiores podem ser obtidas com tratamento inicial por até 12 semanas com 50 mg duas vezes por semana. Pacientes adultos podem ser tratados intermitente ou continuamente, baseados no julgamento do médico e nas necessidades individuais do paciente. Mesma posologia no retratamento. Uso pediátrico: AIJ (≥ 4 e < 18 anos): 0,4 mg/kg (máximo 25 mg por dose) administrada 2 vezes por semana em injeção subcutânea com intervalo de 3-4 dias entre as doses. Pacientes com 31 kg ou menos: a dose deve ser administrada em uma única injeção subcutânea uma vez por semana. Psoríase em placas (≥ 8 e < 18 anos): 0,8 mg/kg por semana (máximo 50 mg por dose) administrada 1 vez por semana durante período máximo de 24 semanas. Descontinuar caso paciente não responda após 12 semanas. Mesma dose no retratamento. A cada nova aplicação, usar local diferente a, pelo menos, 3 cm do local anterior. NÃO aplicar a injeção em áreas com pele sensível, hematoma, avermelhada ou endurecida. VENDA SOB PRESCRIÇÃO MÉDICA. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. MS – 1.2110.0206 (Enbrel®) e MS – 1.2110.0274 (Enbrel® PFS). Para informações completas, consulte as bulas dos produtos (ENBPOI_14 e ENBPFS_12). Documentação científica e informações adicionais estão à disposição da classe médica mediante solicitação. Wyeth Indústria Farmacêutica Ltda. Rua Alexandre Dumas, 1.860, São Paulo – SP – CEP 04717-904. Tel.: 08000-160625. www.wyeth.com.br. INTERAÇÃO MEDICAMENTOSA: NÃO UTILIZAR O PRODUTO EM ASSOCIAÇÃO A ANAKINRA E ABATACEPTE. CONTRAINDICAÇÃO: ENBREL® PFS (ETANERCEPTE) É CONTRAINDICADO EM PACIENTES COM SEPTICEMIA OU EM RISCO DE DESENVOLVER UMA SEPTICEMIA. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. * Único aprovado para psoríase pediátrica (a partir de 8 anos de idade).1-9 Material para ser entregue exclusivamente a profissionais prescritores ou dispensadores de medicamentos. Maio/2014. Wyeth uma empresa do grupo Pfizer. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 5 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Editorial ScienceDirect: The indexation which RBR lacked ScienceDirect: a indexação que faltava à RBR Since 2014, the Brazilian Journal of Rheumatology became indexed to ScienceDirect, which is responsible for nearly a quarter of the world’s peer-reviewed scientific content. It is estimated that this indexer receives 15 million views per year. Its target audience is composed by researchers, health professionals, teachers, and students. At its base, ScienceDirect has about 12 million scientific articles, 2,200 journals and 26,000 books, and its data are indexed in Scopus. Thus, I believe we are closing a cycle that began in 2010 with the indexation in PubMed,1 followed by the inclusion of RBR in the Web of Science database in 2012,2,3 with its first impact factor at JCR measured in 2013 (IF=0.864). RBR is maturing in its scientific content; it represents the only journal in Latin America in the field of Rheumatology, and is also the only one included in the three main international scientific publications’ indexers.1-3 RBR is becoming the main portal of scientific rheumatological divulgation for all our vast continent. In addition to this, the indexation in ScienceDirect will allow the publication of articles in the online first system, allowing the already accepted articles to have a DOI and remain available for consultation in PubMed. I urge everyone to access the following link for checking out this new indexation: http://www.journals.elsevier.com/revistabrasileira-de-reumatologia/ In conclusion, the indexation in ScienceDirect is one more reason for celebration by the Brazilian Society of Rheumatology, which should be congratulated. This achievement is nothing but the result of a hard and persistent work pioneered decades ago. Now we are seeing the fruits of a small seed planted so long ago. I have no doubt that this legacy of our generation will be acknowledged in the future; I also know that much work lies ahead, always aiming to improve our Brazilian Journal of Rheumatology. Paulo Louzada-Junior Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo E-mail: [email protected] R eferences 1. Santiago MB,FullerR. RBR indexada no MEDLINE. (Editorial). Rev Bras Reumatol.2010;50:613-15. 2. Louzada-Junior P, Freitas MV. The Brazilian Journal of Rheumatology over the last ten years: a scientometrics-based view. Rev Bras Reumatol. 2011;51:1-4. 3. Freitas MV; Heymann RE. O Fator de Impacto. Rev Bras Reumatol 2013;53:321. 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2014.05.001 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Inequality in the distribution of rheumatologists in Brazil: correlation with local of medical residency, Gross Domestic Product and Human Development Index Cleandro Pires de Albuquerque* Service of Rheumatology, Medicine Faculty, Universidade de Brasília, Brasília, DF, Brazil article info abstract Article history: Objective: To assess the distribution of rheumatologists in Brazil and their correlation with Received on 15 April 2013 Medical Residency specialization offer, Gross Domestic Product (Gdp) And Municipal Hu- Accepted on 23 August 2013 man Development Index (HDI-M) of units of the federation (UFs). Methods: Query to various official databases, data summarization by techniques for de- Keywords: scriptive statistics and cross-referenced information. For correlation analysis, we used the Rheumatology Spearman correlation coefficient (r). Physician’s distribution Results: There were 1229 rheumatologists regularly registered in the country. The North- Health policy ern region had only 3.6% of the total (n = 44), while the Southeast had 42.2% (n = 519). The Epidemiology State capitals, added to the five largest municipalities in each UF, concentrated 75.8% of these specialists (n = 931). In total, 49.9% of rheumatologists offered treatment at SUS. A general ratio of 157,809 inhabitants per rheumatologist in Brazil was determined, but with wide variation among UFs with respect to this ratio. In the years 2000-2012, there were 593 Rheumatology Residency graduated physicians in Brazil. We observed a positive correlation among number of rheumatologists compared with GDP (r = 0.94), HDI-M of the State capitals (r = 0.77) and number of Rheumatology Residency graduated physicians (r = 0.79) in UFs. Conclusions: We noted a strong concentration of rheumatologists in State capitals and larger municipalities, with noticeable inequalities also between UFs and country regions. The distribution of these professionals accompanied GDP, HDI-M of the State capital and number of Rheumatology Residency graduated physicians, suggesting that factors related to income opportunities and human development and the place of speciality training may influence the geographical fixation of rheumatologists. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (C.P. Albuquerque). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.08.001 167 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1 Inequalidade na distribuição de reumatologistas no Brasil: correlação com local de residência médica, Produto Interno Bruto e Índice de Desenvolvimento Humano resumo Palavras-chave: Objetivo: Avaliar a distribuição dos reumatologistas no Brasil e sua correlação com oferta de Reumatologia residência médica (RM) especializada, Produto Interno Bruto (PIB) e Índice de Desenvolvim- Distribuição de médicos ento Humano Municipal (IDH-M) das unidades da federação (UFs). Política de saúde Métodos: Consulta a várias bases de dados oficiais, sumarização de dados por técnicas es- Epidemiologia tatísticas descritivas e cruzamento de informações. Para análise de correlação, utilizou-se o coeficiente de Spearman (r). Resultados: Foram encontrados 1.229 reumatologistas registrados regularmente no país. A região Norte reunia apenas 3,6% desse contingente (n = 44), enquanto o Sudeste, 42,2% (n = 519). As capitais somadas aos cinco maiores municípios de cada UF concentraram 75,8% desses especialistas (n = 931). No total, 49,9% dos reumatologistas prestavam atendimento pelo Sistema Único de Saúde (SUS). Achou-se razão geral de 157.809 habitantes para cada reumatologista no Brasil, porém com grande variação entre as UF quanto a essa proporção. Entre 2000 e 2012, houve 593 concluintes de RM em reumatologia no Brasil. Achou-se correlação positiva do número de reumatologistas ante o PIB (r = 0,94), o IDH-M da capital (r = 0,77) e o número de concluintes de RM em reumatologia (r = 0,79) das UF. Conclusões: Observou-se forte concentração de reumatologistas nas capitais e maiores municípios brasileiros, com inequalidades perceptíveis também entre as UF e as regiões do país. A distribuição desses profissionais acompanhou o PIB, o IDH-M da capital e o número de concluintes de RM em reumatologia das UF, sugerindo que fatores relacionados a oportunidades de renda e desenvolvimento humano e ao local de formação especializada podem influir na fixação geográfica dos reumatologistas. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction A recently published study by the Federal Council of Medicine (Conselho Federal de Medicina, CFM) and the Regional Council of Medicine of São Paulo (Conselho Regional de Medicina do Estado de São Paulo, CREMESP) demonstrates poor distribution of physicians in the country, not considering any absolute deficiency in the number of these professionals. This inequality is observed both in relation to doctors in general as to specialists, who concentrate their activity on State capitals and larger municipalities, resulting in a shortage of physicians in the periphery and in the hinterland.1 The Brazilian government has sought strategies to achieve greater internalization of physicians, some of them questionable, as the liberal authorization for opening medical schools, which multiply without strict criteria of geographical necessity, and the proposal of compulsory civil service, which does not attack the bases of the problem and imposes on this particular profession a social obligation not uniformly distributed to the other ones.2 Historically, it has been easier to attract physicians (temporarily) for the poorest and remote areas than to fix the professionals in these regions, with consequent turnover of professionals working in the hinterland and in the periphery, particularly in the case of primary care. The determinants of the geographical fixation process of the physician are complex and include factors such as the region where the pro- fessional was born, his/her alma mater, formative content and experiences during graduation, job/chief satisfaction, adequacy of resources for the professional performance, quality and safety in the workplace, opportunities for development/ updating of her/his career, personal respect and professional prestige, opportunities for cultural development, nature of employment relationship, besides the perception of a remuneration consonant with the investment in training and the responsibilities of profession, among others.3-5 Studies suggest that the existence of Medical Residency (MR) programs in a particular locality may have attractive effect, functioning as a “medical fixator”; furthermore, the regions holding the higher gross domestic product (GDP) – and therefore with a greater generation of wealth – also bear the greatest numbers of these professionals.6-8 Although the priority in the search for better distribution in the provision of medical services should be the primary care, we must not lose sight that the access to specialists continue to be essential in more complex cases, and this need cannot be fully supplied by telemedicine capabilities. In the particular case of rheumatology, there is a current perception, among physicians and users (patients), of a relative scarcity of these specialists, possibly even in State capitals, resulting in difficulties in accessing their services. In the UK, the Royal College of Physicians postulated as ideal a ratio of 1 full-time-available rheumatologist (40 hours per week) for each 86,000 inhabitants.9 Although an universally recognized methodology to estimate the ideal physician/popula- 168 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1 tion ratio is lacking, and although the needs certainly may differ between regions and countries, this number gives us a starting point for comparisons. This study adopts the premise that the same determinants of the geographical fixation process of physicians in general apply to rheumatologists. If this is the case, and if the factors related to the institution where the MR was obtained and to opportunities for income generation and human development are determinant for the choice of the fixation local by the physician, then the distribution of rheumatologists in the country should accompany the levels of indicators that measure (even partially) such constructs. The objective of this study is to evaluate the distribution of rheumatologists in Brazil, as well as its correlation with the number of Rheumatology Residency graduated physicians, GDP and municipal human development index (HDI-M) from federal units (UFs). Materials e methods We conducted a direct research (online) in databases of Conselho Federal de Medicina (CFM), Instituto Brasileiro de Geografia e Estatística (IBGE), Cadastro Nacional de Estabelecimentos de Saúde (CNES) of the Ministry of Health, Comissão Nacional de Residência Médica (CNRM) of the Ministry of Education and the United Nations Program for Development (UNDP).10-15 These databases provide public access via World Wide Web (Internet). All searches were conducted between March 1st and March 20th, 2013. The variables analyzed with their respective original bases were: from CFM, number of rheumatologists with active registration, by UF and municipalities; IBGE’s residents’ population and GDP by UF and municipalities; from CNES, number of rheumatologists providing attendance to SUS by UF; from CNRM, number of certificates of Rheumatology Residency issued by UF; from UNDP, the HDI-M by UF. The research methodology did not include pediatric rheumatologists, whose CFM registration takes place nowadays under the designation of area of activity, and not of specialty. GDP is defined as the total of goods and services produced, with the purpose of final consumption, equivalent to the sum of values added by the various economic activities plus taxes (free of subsidies) on products.16 GDP represents the sum of the wealth generated by the different economically active sectors in a particular region/time period. HDI aims to be a general, synthetic, measure of human development, calculated from three pillars: (i) health, as measured by life expectancy; (ii) access to knowledge, measured by average years of adult education and expected years of schooling for children at early school age; and (iii) income.17 The query to CNES by number of rheumatologists attending at SUS used the option of search by individuals; this technique computes the professional only once, even in the case of multiple links. We used the number of certificates issued for Rheumatology Residency as an estimator of the number of trainees in the specialty, by MR modality, in the UF. All certificates of Rheumatology Residency completion registered at CNRM from 2000 to 2012 were included. The choice of this inclusion period was based on two criteria: (a) the registration data of the CNRM prior to 2000 have greater likelihood of inconsistencies; and (b) the searches aimed to comprise the latest consolidated information. Information from CFM, CNES and CNRM was up-to-date with reference to the time of access.10-12 The GDP used refers to the year 2010, and population data are estimates for the year 2012.13,14 HDI-M was calculated by UNDP, based on information from the 2000 Brazilian census; the UF’s HDI-M corresponds to the average of its municipalities.15 The Federal District was considered as an equivalent of a single municipality. Considering the small number of rheumatologists in the country compared to the number of inhabitants, with the aim to avoid notations of the type 1/x or an excessive number of decimals, in this paper the commonly reported rates in form of physician/habitants are reported in its inverse form (inhabitants/physician). UFs are referred to by their usual abbreviations (ex: DF, GO, PB, RJ, SP, etc.). Data were summarized by descriptive statistics techniques. In the correlation analysis, we used the correlation coefficient of Spearman (r), with a two-tailed significance level of 0.01. The analyses were performed using SPSS software for Windows. Results Table 1 summarizes the results by UF. At the time of the survey, there were 1,229 rheumatologists with active registries in databases from CFM throughout our country. The Northern region had only 3.6% of the contingent (n = 44); Midwest, 12.1% (n = 149); Northeast, 17.5% (n = 215); South, 24.6% (n = 302); and Southeast, 42.2% (n = 519). The 27 State capitals concentrated 64% of registered rheumatologists (n = 787), 93% of the rheumatologists in the Northern Region lived in its capitals; in the Midwest, 85%; in the Northeast, 80%; in the South, 52%; and in the Southeast, 56%. Taking the five largest municipalities in each state, a concentration of 75.8% of all registered rheumatologists (n = 931) was reached. There was only one rheumatologist with active registry in Acre, while the State of São Paulo showed 241 active registries. In our country, 49.9% (n = 614) of the rheumatologists offered their services to SUS, with heterogeneity noted between the regions: in the Northern Region, this proportion was 70.5% (n = 31); Midwest, 37.6% (n = 56); Northeast, 58.1% (n = 125); South, 19.2% (n = 58); and Southeast, 68.2% (n = 354). A general rate of 157,809 inhabitants/rheumatologist was observed. By region, the rate was 370,867 inhabitants/rheumatologist in the Northern Region; 250,731 in Northeast; 157,160 in Southeast; 120,819 in Midwest; and 91,827 in South. But UFs differed considerably in this respect, with a median of 192,624 inhabitants/rheumatologist (interquartile range = 175,981) and extremes of 41,383 in DF and 758,786 in AC. If we consider only the specialists who offer their services to SUS, the median was 413,692 inhabitants/rheumatologist (interquartile range = 338,273), with extremes of 156,071 in RJ and 1,053,583 in PI. From 2000 to 2012, Brazil has certified 593 Rheumatology Residency graduated physicians, of whom 66.9% were graduated in the Southeast (n = 397), 12.5% in the Midwest (n = 74), 11.1% in the South (n = 66), 8.4% in the Northeast (n = 50), and 1% in the North (n = 6) region. A strong positive correlation among number of rheumatologists with respect to GDP (r = 0.94), HDI-M for the capital (r = 0.77) and number of Rheu- 169 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1 Table 1 – Population, number of rheumatologists, GDP, HDI-M, medical resident finishers in rheumatology and habitants/ rheumatologist ratio per state Region North AC AM AP PA RO RR TO Northeast AL BA CE MA PB PE PI RN SE Midwest DF GO MS MT Southeast ES MG RJ SP South PR RS SC Brazil Population Rheumatologist GDP† State Capital SUS 758.786 3.590.985 698.602 7.792.561 1.590.011 469.524 1.417.694 1 10 4 19 3 1 6 1 10 4 18 2 1 5 0 10 4 12 2 1 2 3.165.472 14.175.341 8.606.005 6.714.314 3.815.171 8.931.028 3.160.748 3.228.198 2.110.867 22 47 38 12 29 30 10 16 11 18 32 33 10 18 26 10 14 11 2.648.532 6.154.996 2.505.088 3.115.336 64 44 26 15 3.578.067 19.855.332 16.231.365 41.901.219 10.577.755 10.770.603 6.383.286 193.946.886 HDI-M†† State Capital 8.477 59.779 8.266 77.848 23.561 6.341 17.240 0,697 0,753 0,713 0,723 0,735 0,746 0,710 0,754 0,774 0,772 0,806 0,763 0,779 0,800 19 16 17 7 23 24 3 11 5 24.575 154.340 77.865 45.256 31.947 95.187 22.060 32.339 23.932 0,649 0,688 0,700 0,636 0,661 0,705 0,656 0,705 0,682 64 35 19 9 15 20 4 7 149.906 97.576 43.514 59.600 34 148 96 241 17 71 72 130 10 49 104 191 131 114 57 1.229 77 61 19 787 19 29 10 614 RM‡ Hab/Rheum.# General SUS 0 6 0 0 0 0 0 758.786 359.099 174.651 410.135 530.004 469.524 236.282 dna 359.099 174.651 649.380 795.006 469.524 708.847 0,739 0,805 0,786 0,778 0,783 0,797 0,766 0,788 0,794 0 11 19 0 0 18 2 0 0 143.885 301.603 226.474 559.526 131.558 297.701 316.075 201.762 191.897 166.604 885.959 506.236 959.188 165.877 372.126 1.053.583 293.473 422.173 0,844 0,776 0,773 0,778 0,844 0,832 0,814 0,821 47 16 11 0 41.383 139.886 96.350 207.689 176.569 307.750 626.272 445.048 82.122 351.381 407.123 1.247.596 0,765 0,773 0,807 0,820 0,856 0,839 0,842 0,841 5 55 63 274 105.237 134.158 169.077 173.864 357.807 405.211 156.071 219.378 217.290 252.483 152.482 3.770.086 0,787 0,814 0,822 dna 0,856 0,865 0,875 dna 37 29 0 593 80.746 94.479 111.987 157.809 556.724 371.400 638.329 315.874 † GDP is the gross domestic product, in millions of reais; †† HDI-M is the human development index per municipality; ‡ RM is the number of concluders of medical residence in rheumatology between 2000 and 2012; # Hab/Rheum. is the ratio between the number of habitants and the number of rheumatologists in a given region.; dna = does not apply. matology Residency graduated physicians in the UF (r = 0.79), respectively, was found. A moderate correlation between number of rheumatologists and HDI-M of the UF (r = 0.56) was observed. Discussion We found imbalances in the distribution of rheumatologists in this country, who were concentrated in State capitals and larger municipalities, following a similar pattern to that reported by CFM/CREMESP for physicians in general.1 Inequalities were also observed between regions: the seven UFs of South and Southeast regions gathered about two-thirds of rheumatologists, with the remainder distributed among the remaining twenty UFs. North, Northeast and Midwest regions had the highest concentrations of rheumatologists in the State capitals, which housed 80% or more of these professionals. In South and Southeast regions, although this phenomenon of concentration also had been observed, it is less intense, with slightly more than half of rheumatologists in the capitals. The Northern region exhibited the lowest presence of rheumatologists, both in absolute (number of professionals, n = 44) and relative (370,867 inhabitants/rheumatologist) terms. Some UFs reached levels close to or even exceeding the ideals proposed by the British Royal College of Physicians,9 of about 86,000 inhabitants/rheumatologist (e.g., DF, 41,383; PR, 80,746; RS, 94,479; MS, 96,350), while still others fell far short of this level (e.g., AC, 758,786; RO 530,004; MA 559,526; RR 469,524). Considering only the number of rheumatologists offering their services to SUS, all UFs were far from optimal levels of provision, and the best positioned UF was RJ with 156,071 inhabitants/rheumatologist. Data on SUS rheumatologists were generated from CNES, whose records are used in the calculation of financial transfers for service providers, with mandatory periodic updating of the system by its administrators.18 In general, CNES is a good indicator of human resources at SUS, but there is an overestimation bias: the reduction of registered human resources can result in reduced financial transfer to the management unit. Thus, despite the requirement for periodic updating, not always a physician 170 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1 who leaves SUS will have his/her registration status at CNES immediately modified by the administrator. Therefore, the situation of rheumatologists’ provision to SUS can be even worse than the picture reported here. About two-thirds of Rheumatology Residency graduated physicians attended specialization in the Southeast, and the state of São Paulo alone accounted for 46.2% (n = 274) of all graduates. At the other extreme, the entire Northern region accounted for only 1% (n = 6) of these graduates. In 13 UFs, there was no active program and/or any physician who finished their Rheumatology Residency in the years 2000-2012. Among these UFs, four presented general rates larger than 400,000 inhabitants/rheumatologist, namely AC, PA, RO, RR, and MA. Despite these numbers, the rheumatology specialty is not contemplated as a priority specialty by the national program for supporting the training of medical specialists in strategic areas (Pró-Residência).19,20 The results presented here argue in favor of the reconsideration of that position by the officials of Public Administration. The Brazilian Society of Rheumatology can exercise a preponderant role in this subject. We observed a strong positive correlation between the number of rheumatologists and GDP, HDI-M of State capitals and the number of Rheumatology Residency graduated physicians in each UF, suggesting that some elements related to income opportunities and human development elements, besides the place where the specialized training was offered, may influence the geographical fixation of these specialists. Póvoa and Andrade observed a greater likelihood of finding non-native physicians,7 i.e., those coming from other regions, in UFs with a highest number of MR vacancies, and thus also in those UFs with the highest GDP per capita, suggesting that these two factors function as local physician concentrators. Other studies show that physicians tend to stay in the place where they did their MR, and that there are more physicians in UFs with greater GDP.6,8 The only moderate correlation with HDI-M of the UF (average of the municipalities) is not surprising, given the concentration of rheumatologists in the States’ capitals. Moreover, it seems reasonable to assume that factors operating at local (municipal) level exert greater influence on the individual’s choice as to where to fix his/her living, because the local problems and opportunities will occur mainly at this level. The study published by CFM/CREMESP, previously cited, adopted different methodology for its counting of physicians.1 This study used other sources, in addition to the CFM records, performing data cross-checking with the goal of identifying specialists. For that research, 1,631 rheumatologists were operating in Brazil in 2012, different from the 1,229 professionals reported here. The system of administrative and notary record of CFM is integrated with those of the Conselhos Regionais de Medicina (CRMs), so that all specialist qualification titles registered in CRM are automatically also included in CFM basis. Thus, a specialists’ underreporting CRM/CFM system was noted. That is, there were physicians with a rheumatologist title, obtained either through completion of medical residency or by approval at Brazilian Society of Rheumatology specific scrutiny; but these entities do not register titles in CRM/CFM system. This underreporting leads to curious situations, as in Table 1, where it can be seen that the total rheumatologists registered at CRM/CFM in Rio de Janeiro was inferior to the number of rheumatologists who worked in the SUS in that UF. Therefore, the present work, in considering rheumatologists from CFM records, underestimates by approximately 24.6% the total number of rheumatologists in the country. For the calculation of inhabitants/rheumatologist rate, the CFM system search was not restricted to primary enrollments, considering that a rheumatologist with active registration in more than one UF will be available to each of them (unevenly, or not). If only the primary registrations were considered, then 1,187 registered rheumatologists across the country would be computed, bringing the sub-registry in CFM to 27.2%, compared with the study of CFM/CREMESP. Given this limitation, we must evaluate to what extent this difference impacts the results presented here. First, data on number of rheumatologists in the SUS and its relationship versus number of inhabitants do not change, because, at that point, the sources of both studies (CNES and IBGE) are identical. As for the correlation analysis, we recalculated the tests using the data published by CFM/CREMESP for number of rheumatologists versus GDP, HDI-M of State capital and number of MR graduates in rheumatology in each state, and the coefficients (r) were 0.94, 0.74 and 0.82, respectively – very similar to our original coefficients. Thus, here the findings also do not change. However, when relating data from CNES (rheumatologists in SUS) with those published by CFM/CREMESP (total of rheumatologists), we conclude that only 37.6% of rheumatologists in the country are available to SUS, compared to those 49.9% reported here. There are also differences in the inhabitants/ rheumatologist general rates by UF. Fig. 1 associates the results obtained here (from databases of CFM) with those published by CFM/CREMESP. The main differences were seen in SP and RJ, where – by the methodology of CFM/CREMESP – more 283 and 76 rheumatologists were respectively computed, compared with our data in this study. As for MG and PE, more 12 and 11 rheumatologists, respectively, were noted. For all remaining states, the differences in absolute numbers between Fig. 1 – Distribution of rheumatologists by UF by two counting procedures. Note: In the figure, only the numbers of CFM/CREMESP study are indicated; the values obtained from databases of CFM are listed in Table 1. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 6 6 – 1 7 1 forms of counting ranged from 0 to 5 rheumatologists by UF (either more or less). Data of CFM/CREMESP imply that Brazil has an overall ratio of 118,913 inhabitants/rheumatologist. When analyzed by UF, the median of this ratio is 174,651 inhabitants/rheumatologist (interquartile range = 144,670), with extremes of 38,385 in DF and 758,786 in AC. These numbers show a better scenario for the inhabitants/rheumatologist rate, compared to that obtained from CFM registry data, but do not modify the pattern of poor distribution of rheumatologists among UFs, as noted in Fig. 1. Even using CFM/CREMESP data, several UFs still present inhabitants/rheumatologist general rates distant from the levels postulated as ideal (e.g., AC, 758,786; MA, 559,526; RO, 530,004; PA, 432,920; TO, 283,539; BA, 277,948; AM, 276,230), while others exhibit proper proportions or even an excess of rheumatologists (e.g., DF, 38,385; SP, 79,964; PR, 81,998; RS, 91,276; MS, 92,781; RJ, 94,368). So, no matter which data set used, whether CFM’s (methodology adopted for this study) or CFM/CREMESP’s – the general conclusions of this paper do not change. In short, we observed imbalance in the distribution of rheumatologists in our country, with a concentration of these specialists in Brazilian State capitals and larger municipalities. The South and Southeast gathered about two-thirds of rheumatologists, the remaining third being distributed by North, Northeast and Midwest regions. Some units of the federation reached levels postulated as ideal for the inhabitants/rheumatologist rates (particularly in Southeast, South and Midwest), while others exhibited severe shortage of these professionals (especially in North and Northeast). Half or less of the total number of rheumatologists in Brazil were available to SUS. The distribution of rheumatologists in our country paralleled the GDP, the HDI-M from the state capital and the number of Rheumatology Residency graduates of UFs, suggesting that factors related to income opportunities and human development, besides the site where the specialized training occurred, may influence the choice of their geographical settlement. Conflicts of interest The author declares no conflicts of interest. REFERENCES 1. Conselho Federal de Medicina, Conselho Regional de Medicina do Estado de São Paulo. Demografia Médica no Brasil, v. 2. São Paulo: CFM, CREMESP; 2013. 2. Brasil, Ministério da Saúde, Secretaria de Gestão do Trabalho e da Educação na Saúde. Seminário nacional sobre escassez, provimento e fixação de profissionais de saúde em áreas remotas e de maior vulnerabilidade. Relatório síntese. Brasília: Ministério da Saúde, 2012. 171 3. Ney MS, Rodrigues PH de A. Fatores críticos para a fixação do médico na Estratégia Saúde da Família. Physis. 2012;22:1293-311. 4. Campos CV de A, Malik AM. Satisfação no trabalho e rotatividade dos médicos do Programa de Saúde da Família. Rev Adm Pública. 2008;42:347-68. 5. Perpetuo IHO, De Oliveira AC, Ribeiro MM, Rodrigues RB. A categoria profissional dos médicos: fatores condicionantes da sua atração e fixação na Atenção Primária à Saúde em Minas Gerais. Belo Horizonte: Observatório de Recursos Humanos em Saúde do Nig. One / UFMG; 2009. 6. Pinto LF da S, Machado MH. Médicos migrantes e a formação profissional: um retrato brasileiro. Rev Bras Educ Med. 2000;24:53-64. 7. Póvoa L, Andrade MV. Distribuição geográfica dos médicos no Brasil: uma análise a partir de um modelo de escolha locacional. Cad Saúde Pública. 2006;22:1.555-64. 8. Bittar OJNV. O mercado médico no Brasil. Rev Adm Pública. 1999;33:55-66. 9. Royal College of Physicians. Consultant physicians working with patients – rheumatology. London: RCP, 2011. 10. Conselho Federal de Medicina. Busca de Médicos. Disponível em: http://portal.cfm.org.br/index.php?option=com_ medicos&Itemid=59. Acesso em: 13 mar. 2013. 11. Cadastro Nacional de Estabelecimentos de Saúde. Disponível em: http://tabnet.datasus.gov.br/cgi/deftohtm.exe?cnes/cnv/ prid02br.def. Acesso em: 20 mar. 2013. 12. Comissão Nacional de Residência Médica. Consulta de certificados. Disponível em: http://siscnrm.mec.gov.br/ consulta/consultaresidente. Acesso em: 11 mar. 2013. 13. Instituto Brasileiro de Geografia e Estatística. Contas Regionais 2010. Disponível em: http://www.ibge.gov.br/home/ estatistica/economia/contasregionais/2010/default.shtm. Acesso em: 12 mar. 2013 14. Instituto Brasileiro de Geografia e Estatística. População residente enviada ao Tribunal de Contas da União 2001-2012. Disponível em: http://www.ibge.gov.br/home/estatistica/ populacao/estimativa2012/default.shtm. Acesso em 12 mar. 2013. 15. Organização das Nações Unidas, Programa das Nações Unidas para o Desenvolvimento. Atlas de Desenvolvimento Humano 2003. Disponível em: http://www.pnud.org.br/IDH/ Atlas2003.aspx?indiceAccordion=1&li=li_Atlas2003. Acesso em: 15 mar. 2013. 16. Brasil, Ministério do Planejamento, Orçamento e Gestão, Instituto Brasileiro de Geografia e Estatística. Contas Regionais do Brasil 2010. Rio de Janeiro: IBGE, 2012. 17. Organização das Nações Unidas, Programa das Nações Unidas para o Desenvolvimento. O que é IDH. Disponível em: http://www.pnud.org.br/IDH/IDH. aspx?indiceAccordion=0&li=li_IDH. Acesso em: 20 mar. 2013. 18. Brasil, Ministério da Saúde. Portaria N° 3.462, de 11 de novembro de 2010. Estabelece critérios para alimentação dos Bancos de Dados Nacionais dos Sistemas de Informação da Atenção à Saúde. Diário Oficial da União. 12 nov. 2010; Seção 1:50. 19. Brasil, Ministério da Educação. Portaria Interministerial N° 1.001, de 22 de outubro de 2009. Institui o Programa Nacional de Apoio à Formação de Médicos Especialistas em Áreas Estratégicas — PRÓ-RESIDÊNCIA. Diário Oficial da União. 23 oct 2009; Seção 1:9. 20. Brasil, Ministério da Saúde, Secretaria de Gestão do Trabalho e da Educação na Saúde. Edital convocatório N° 19, de 21 de julho de 2010. Diário Oficial da União. 22 jul. 2010; Seção 3:95-8. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Otorhinolaryngological findings in a group of patients with rheumatic diseases Reinaldo Jordão Gusmãoa, Fernando Laffitte Fernandesa, Alexandre Caixeta Guimarãesa, Lutiane Scaramussaa, Zoraida Sachettob, Henrique Furlan Paunaa,*, Guilherme Machado de Carvalhoa Otorhinolaryngology, Head and Neck Discipline, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil Rheumatology Discipline, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil a b article info abstract Article history: Introduction: Otorhinolaryngological manifestations of rheumatologic diseases represent a Received on 26 July 2013 great challenge not only to the generalistphysician but also to the ENT doctor andrheu- Accepted on 13 October 2013 matologist. They often represent early manifestations of an autoimmune disorder which requires prompt and aggressive immunosuppressive treatment. Auditory, nasal, laryngeal Keywords: and eye symptoms can be the first manifestation of rheumatic diseases and their proper Autoimmune diseases assessment helps the doctor to identify signs of disease activity. The objective of this study Otorhinolaringology is to identify the ENT manifestations in patients with rheumatic diseases in a high comple- Rheumatology xity hospital, regarding facilitating an early diagnosis and treatment. Methods: We performed clinical and complete otorhinolaryngological evaluations in patients selected from the outpatient rheumatology in a standardized manner by the use of a standardized form filling during the secondhalf of 2010. Results: In the study group, systemic lupus erythematosus (SLE) patients had predominantly laryngeal manifestations, while patients with Sjögren’s syndrome showed a higher prevalence of otologic manifestations. Changes in audiometric tests were found in 53% of Wegener’s granulomatosis (WG) patients, 80% of relapsing polychondritis (RP), 33% of systemic lupus erythematosus (SLE) and 50% of Churg-Strauss syndrome (SCS). Regarding nasal alterations, these were found so prevalent in all conditions, especially Churg-Strauss syndrome. Discussion and conclusion: This study demonstrated that most patients treated in our hospital has the ENT signs and symptoms commonly associated in previous studies on rheumatic diseases, but further studies with a larger number of patients must be made to establish such relations. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (H.F. Pauna). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.10.001 173 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8 Achados otorrinolaringológicos em um grupo de pacientes com doenças reumatológicas resumo Palavras-chave: Introdução: As manifestações otorrinolaringológicas de doenças reumáticas representam Reumatologia um grande desafio não só ao médico generalista, mas também ao otorrinolaringologista Otorrinolaringologia e ao reumatologista. Frequentemente representam manifestações iniciais de uma desor- Doenças autoimunes dem autoimune que exige um tratamento imunossupressor imediato e agressivo. Sintomas auditivos, nasais, laríngeos e oculares podem ser a primeira manifestação de doenças reumáticas, e sua correta avaliação auxilia o médico a identificar sinais de atividade da doença. O objetivo deste trabalho foi identificar as manifestações otorrinolaringológicas em pacientes com doenças reumáticas em um hospital de alta complexidade, no que se refere a facilitar diagnóstico e tratamento precoces. Métodos: Foram realizadas avaliações clínicas e otorrinolaringológicas completas em pacientes selecionados no ambulatório de reumatologia, no segundo semestre do ano de 2010, de forma padronizada e com utilização de um formulário de preenchimento normatizado. Resultados: No grupo estudado, pacientes com LES apresentaram predominantemente manifestações laríngeas, enquanto pacientes com síndrome de Sjögren apresentaram predomínio das manifestações otológicas (100% dos casos). As alterações de exames audiométricos são encontradas em 53% dos casos portadores de GW, 80% de PR, 33% de LES e 50% de SCS. Quanto às alterações nasais, estas foram encontradas de forma prevalente em todas as patologias, principalmente a síndrome de Churg-Strauss. Discussão e conclusão: Este estudo demonstrou que a maioria dos pacientes em seguimento em nosso serviço apresenta os sinais e sintomas otorrinolaringológicos comumente relacionados em trabalhos prévios sobre doenças reumáticas, porém novos estudos com um número maior de pacientes devem ser feitos para comprovar tais relações © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Rheumatic diseases have a high prevalence rate worldwide and a representative functional disability index.1 These conditions comprise a heterogeneous group of entities that produce systemic changes involving the connective tissue throughout the body. For this reason they may involve blood vessels and serous and mucous membranes of all the aerodigestive tract.2 The treatment itself of such diseases with non-steroidal anti-inflammatory drugs can cause symptoms in many patients.3 In this sense, much has been discussed about the current ENT manifestations in patients with rheumatic diseases.4 Ear, nasal, laryngeal and ocular symptoms may be the first manifestations of various rheumatic diseases, as relapsing polychondritis (RP), systemic lupus erythematosus (SLE), Wegener’s granulomatosis (WG), Sjögren’s syndrome (SS) and Churg-Strauss syndrome (CSS),5,6 and this combination is described in several trials. As an example, there are some case reports of patients with RP in which changes in pinna, nasal cartilage, nasal septum, larynx and trachea were found, causing dysphonia, dyspnea and cosmetic deformities.7,8 Allergic rhinitis, chronic sinusitis and serous otitis media are commonly found in patients with CSS,9 while immunological abnormalities are frequently found in patients with Menière’s disease.10 Sensorineural hearing loss may be the first manifestation of polyarteritis nodosa,11 as well as recurrent parotitis for SS12 and chronic otitis media for ankylosing spondylitis.13 Given the global growth of rheumatic diseases, driven by population ageing and exposure to a larger number of inducers of autoimmune changes,14 the identification of ENT symptoms in these patients can become an important tool for the diagnosis and, consequently, for the early treatment of such diseases. The correct evaluation of rheumatic conditions, particularly in SLE, helps the physician to identify signs of disease activity, which directly affects the patients’ quality of life and their prognosis.15-17 Thus, the objective of this work is to identify ENT manifestations in patients with rheumatic diseases in a hospital of high complexity. As this trial was conducted in 2010 and considering the fact that the old nomenclature for rheumatologic diseases is more widespread in our environment, we used this nomenclature in the present trial. In the new nomenclature established by the Chapel Hill Consensus in 2012, Wegener’s granulomatosis became known as granulomatous with polyangiitis, and Churg-Strauss syndrome became known as eosinophilic granulomatous with polyangiitis.18 Materials e methods In all patients, complete clinical and ENT evaluations consisting of a detailed history, a thorough ENT physical examination and audiometry, imitanciometry (acoustic impedance) and 174 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8 nasofiberlaryngoscopy were performed. Sensorineural hearing loss or sound discrimination impairment with bilateral and symmetrical occurrence and with subacute evolution were considered as audiometric alterations. The assessment was fully standardized, and a normatized filling form was used during the second half of 2010. For the selection of patients, we requested from the Department of Rheumatology a random referral of patients for specialized ENT evaluation, but some specific outpatient services contributed more to the project (such as vasculitis and Wegener’s granulomatosis outpatient services). The first five patients in each outpatient rheumatology should have been referred for a period of 15 days. Every patient evaluation was performed at the otorhinolaryngology ambulatory of our national reference, tertiary care, university hospital. The patients were attended and evaluated by two otolaryngologists randomly selected among the professionals who participated in this trial. The criteria used were those of the Otorhinolaryngologist available at the time and who would perform the patient’s assessment. This trial was evaluated and approved by the Research Ethics Committee from our institution (Opinion CEP/FCM nº 1187/2011). Results Thirty-two selected patients of Rheumatology Discipline Outpatient Clinic (HC/FCM/UNICAMP) were evaluated. In the evaluated sample , the patients were diagnosed as defined by the criteria of Medical Guidelines of the Brazilian Society of Rheumatology19 for SLE and by the American College of Rheumatology20,21,22,23 for other diseases, with a diagnosis established for one from five rheumatic diseases: Wegener’s granulomatosis (WG), Churg-Strauss syndrome (CSS), relapsing polychondritis (RP), Sjögren’s syndrome (SS) and systemic lupus erythematosus (SLE). The mean age of the participants was 41.7 years (range 2270 years) and the mean disease duration was 9.12 years (range 1-40 years). 1 – Wegener’s granulomatosis (n = 17) Among WG patients, nine (53.1%) reported hearing loss and had low tone threshold results at audiometry. The most fre- quent type of reduction was that of a bilateral sensorineural pattern, present in five patients (55.6%). In the context of rhinologic symptoms, nasal obstruction in 11 (64.8%) and rhinorrhea in ten (58.8%) patients were the most prevalent symptoms, with compatible changes present in the rhinoscopic exam in 12 (70.2 %) of these patients, and the most frequent symptoms were coryza, septal perforations, mucosal oedema and turbinate hypertrophy. Complaints related to the larynx, dyspnea and raucousness were found in six (35.2%) and seven (41.2%) patients, respectively, being the most prevalent complaints. Of these, seven (41.2%) patients had an abnormal physical examination, for instance, hyperaemia of posterior pharynx, inter-arytenoidal oedema and relative degrees of subglottic stenosis (Table 1). 2 – Recidivant polychondritis (n = 5) In patients with RP, among the otologic symptoms, the most frequent complaint was ear itching in three patients (60%), followed by tinnitus, hearing loss and ear fullness in two (40%). The changes more often found during the physical examination were pinna oedema and opacity of the tympanic membrane. The main nasosinusal symptoms were: presence of nasal obstruction, rhinorrhea and sneezing, reported by two patients (40%), and coryza, mucosal oedema, pale mucosa, granulation of the turbinates and turbinate hypertrophy were the primary findings. As to laryngeal complaints, cough, foreign body sensation, raucousness and choking were present in two cases (40%). The changes found on physical examination were inter-arytenoidal oedema, paresis of vocal folds and laryngeal hyperaemia (Table 2). 3 – Sjögren’s syndrome (n = 5) For patients with SS, tinnitus and ear fullness were present in three and four of the five patients, respectively; the most frequent changes were in conductive hearing loss and presence of a large amount of desquamation in the external auditory canal. Nasal obstruction was present in all patients. In the rhinoscopic examination, hyperaemia and oedema of mucosa were the observed findings. Dysphonia and raucousness were the only reported laryngeal symptoms; and the signs found were salivary gland hypertrophy, dry mouth and inter-arytenoidal oedema (Table 3). Table 1 – Presence of otological signs and symptoms Otalgia Otorrhea Tinnitus Ear fullness Hearing loss Hyperacusis Ear pruritus Dizziness Wegener’s granulomatosis n = 17 Relapsing Polychondritis n = 5 Syndrome of Sjögren n = 5 8 (47%) 4 (23%) 7 (41%) 3 (18%) 9 (53%) 0 3 (18%) 1 (6%) 1 (20%) 0 2 (40%) 2 (40%) 2 (40%) 0 3 (60%) 0 0 1 (20%) 3 (60%) 4 (80%) 2 (40%) 0 5 (100%) 1(20%) Systemic Lupus Syndrome of Erythematosus n = 3 Churg-Strauss n = 2 0 0 1 (33%) 0 1 (33%) 0 0 0 0 0 1 (50%) 1 (50%) 1 (50%) 0 0 0 175 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8 Table 2 – Presence of nasal signs and symptoms Relapsing polychondritis Nasal obstruction Rhinorrhea Nasal itching Hyposmia Anosmia Cacosmia Postnasal drip Wegener’s granulomatosis n = 17 Relapsing Polychondritis n = 5 Syndrome of Sjögren n = 5 Systemic Lupus Syndrome of Erythematosus n = 3 Churg-Strauss n = 2 11 (65%) 2 (40%) 5 (100%) 1 (33%) 1 (50%) 10 (59%) 2 (40%) 2 (40%) 1 (33%) 1 (50%) 6 (35%) 6 (35%) 2 (12%) 1 (6%) 5 (29%) 7 (41%) 0 0 0 0 0 2 (40%) 4 (80%) 2 (40%) 0 0 1 (20%) 1 (20%) 0 0 0 0 0 0 1 (50%) 1 (50%) 0 0 1 (50%) 2 (100%) Table 3 – Aerodigestive pathways/pharyngal symptoms Dysphonia Cough Snoring Foreign body sensation Dysphagia Odynophagia Dyspnea Hemoptysis Hawk Heartburn Gagging Wegener’s granulomatosis n = 17 Relapsing Polychondritis n = 5 Syndrome of Sjögren n = 5 3 (14%) 4 (23%) 0 1 (6%) 1 (20%) 2 (40%) 0 2 (40%) 2 (40%) 0 0 0 2 (67%) 0 0 0 1 (50%) 1 (50%) 0 0 0 0 6 (35%) 1 (6%) 7 (41%) 1 (6%) 1 (6%) 0 0 1 (20%) 0 2 (40%) 1 (20%) 2 (40%) 0 0 0 0 3 (60%) 2 (40%) 0 0 0 1 (33%) 0 0 0 0 0 0 1 (50%) 1 (50%) 1 (50%) 0 0 4 – Systemic Lupus Erythematosus (n = 3) Among SLE patients, tinnitus and hearing loss were reported by one patient (33%), with presence of left ear sensorineural hearing loss and right ear conducive hearing loss. Among nasal symptoms, nasal obstruction and rhinorrhea were also present in one patient, and edema and coryza were the signs most often found . Dysphonia was present in two cases (67%), and the presence of glottic cleft during phonation and inter-arytenoidal oedema were the changes observed. 5 – Churg-Strauss syndrome (n = 2) One patient (50%) with Churg-Strauss reported tinnitus, ear fullness and hearing loss, with conductive hearing loss at audiometry. At rhinoscopy, pale mucosa, turbinate hypertrophy and coryza were observed in patients. The complaints of dysphonia, cough, dyspnea, haemoptysis, and raucousness were compatible with the presence of oedema of laryngeal mucosa, glottic cleft and secretion, observed during the examination of the larynx. In the evaluation of all the symptoms studied by region, all SS patients reported the presence of at least one otologic or nasal symptom, and also had audiometric change. Laryngeal symptoms were more frequent in patients with SLE, being present in two patients (66%) (Table 4); however, patients with SLE were those with fewer ear and nasal symptoms, or with Systemic Lupus Syndrome of Erythematosus n = 3 Churg-Strauss n = 2 audiometric changes. These conditions were present in only one patient (33%) (Tables 5 and 6). The audiometric changes (indicated in Table 6) found were described as sensorineural hearing loss (SNHL), conductive hearing loss (CHL) or mixed hearing loss (MHL). In the case of SNHL, the following distribution was observed: 29% of WG, 60% of PR, 20% of SJ, 33% of SLE and 0% of CSS. With MHL, no cases were observed. On the other hand, for CHL another distribution was observed: 23% of WG, 20% of PR, 80% of SJ, 33% of SLE and 50% of CSS. Discussion ENT manifestations in autoimmune diseases represent a diagnostic challenge for the rheumatologist, otolaryngologist and clinician.1,5,15,24,25 Generally, ENT symptoms may represent an early sign of an undiagnosed autoimmune disorder that often requires an immediate and aggressive immunosuppressive treatment.25-29 There are diseases of systemic action that present themselves with localized manifestations, and the region of the head and neck is an important site of these manifestations.5 Ear damage have been occasionally reported as a complication in the course of several rheumatic diseases.8,30 It is common, for example, to find sensorineural hearing loss with decreased hearing acuity or discrimination of sounds. Uni- or bilateral sensorineural hearing loss affecting medium and high frequencies have been reported in patients with SLE, and there is evidence of a strong association between hearing loss and 176 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8 Table 4 – Other head and neck signs and symptoms Wegener’s granulomatosis n = 17 Relapsing Polychondritis n = 5 Syndrome of Sjögren n = 5 0 3 (18%) 0 1 (20%) 1 (20%) 0 2 (40%) 0 0 Wegener’s granulomatosis n = 17 Relapsing Polychondritis n = 5 Syndrome of Sjögren n = 5 Rhinoscopy, change in Otoscopy, change in 12 (70%) 3 (60%) 5 (100%) 1 (33%) 2 (100%) 7 (41%) 0 0 0 0 Nasofibroscopy, 7 (41%) 3 (60%) 4 (80%) 2 (67%) 2 (100%) 7 (41%) 2 (40%) 5 (100%) 1 (33%) 0 Conjunctivitis Headache Facial paralysis Systemic Lupus Syndrome of Erythematosus n = 3 Churg-Strauss n = 2 0 0 0 1 (50%) 1 (50%) 0 Table 5 – Findings of ENT physical examination Systemic Lupus Syndrome of Erythematosus n = 3 Churg-Strauss n = 2 change in Otoscopy, change in Table 6 – Otologic, nasal, and laryngal symptoms and audiometric change in the studied diseases Wegener’s Granulomatosis Relapsing Polychondritis Sjögren’s Syndrome Systemic Lupus Erythematosus Churg-Strauss Syndrome Otologic symptoms Nasal symptoms Laryngeal symptoms Audiometric change 9 (53%) 3 (60%) 11 (65%) 2 (40%) 7 (41%) 2 (40%) 9 (53%) 4 (80%) 5 (100%) 1 (33%) 5 (100%) 1 (33%) 3 (60%) 2 (67%) 5 (100%) 1 (33%) 1 (50%) 2 (100%) 1 (50%) 1 (50%) elevated titres of anticardiolipin antibodies. A sensorineural hearing loss in the course of Sjögren’s syndrome (SS) is partly attributed to the presence of high titres of those antibodies.4 A sudden or gradual hearing loss may occur in about 50% of patients with recidivant polychondritis, and both in these as in patients with WG, a conductive hearing loss is the main otologic damage. According to literature, audiovestibular deficits are uncommon in patients with CSS.4 According to the findings of this trial, ear manifestations in the patients studied confirm the literature data, maintaining statistical similarity. In literature we find data on vestibulocochlear system involvement by vascular lesions in the internal auditory artery, causing sensorineural dysacusis in addition to symptoms such as dizziness and tinnitus. According to the authors, the little mention of vestibular symptoms is due to the fact that the gradual involvement of the vestibular system promotes labirynthic compensation.31 Laryngeal involvement is extremely rare and the symptoms can range from hoarseness to respiratory distress.32 Smith et al. published two cases with cricoarytenoid ulceration, stenosis and oedema. Kraus and Guerra-Bautista published a case with complete vocal fold paralysis in 1990. Tietel et al. published, in 1997, a review of cases of laryngeal involvement in SLE, in which laryngeal oedema occurred in 28% of cases and vocal paralysis in 11%.32 Allergic rhinitis is often present in patients with ChurgStrauss syndrome.4 Symptoms such as nasal itching, airflow obstruction, coryza and recurrent sinusitis are common manifestations in CSS, GW and PR.9,33 In general, Churg-Strauss syndrome is characterized by asthma, eosinophilia, and extravascular eosinophilic granulomata. Also, as part of the clinical manifestations of CSS, the first phase of this syndrome is characterized by asthma possibly associated with allergic rhinitis, and often complicated by nasal polyposis and recurrent rhinosinusitis.9 The other phases are manifestations of eosinophilia and/or eosinophilic infiltrates in the tissues (lungs, gastrointestinal tract) or of systemic vasculitis. In the available literature, three stages of the natural history of CSS are described: (1) prodromal stage, characterized by asthma and allergy for several years, (2) eosinophilic stage with peripheral blood eosinophilia and an organic infiltrate that can decrease or increase over several years, and (3) systemic vasculitis stage, that can be life threatening.30 Still, the main feature of ENT manifestations in this disease is an allergic rhinitis associated with nasal polyposis.30,33 According to Bacciu et al., allergic rhinitis is present in 42.8% of CSS patients studied.9 According to literature, in patients with GW, the respiratory tract is involved in 70-100 % of cases, with nasal and paranasal involvement in 80-90 % of cases.4,25,33,34 Chronic nasal obstruction with a clear rhinorrhea, nasal ulceration and oedema of the mucosa, besides perforation, erosion of the vomer and nasal deformity with “saddle nose” are classic signs of the disease. We can also observe cases of chronic secretory otitis media and tympanic membrane perforation, in addition to the cases described of sensorineural dysacusis, vertigo and tinnitus.4,25,33,34 The prevalence of otologic involvement is around 35 %, being related to vasculitis and blockage of the R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 2 – 1 7 8 Eustachian tube due to the involvement of nasopharynx.4,25,33,34 Facial palsy is found in 8-10% of cases and results from vasculitis of facial nerve vasa-vasorum, granulomatous invasion of middle ear tissue, primary granulomatous lesion of the nerve, or a combination of these factors.4,25,33,34 Dysphonia, larynx stridor, wheezing, oral ulceration and oedema and gingivitis complement the picture of ENT manifestations.4,25,33,34 It is also worth remembering the important complications and cardiovascular events in SLE, with risk of fatal complications.35 In a transversal trial conducted at Hospital Universitário Barros Barreto (HUJBB/UFPA) during 1997-2006, the main complication in SLE patients was the infectious syndrome (76.4%), followed by renal (33.8%) and thromboembolic (4.2%) events.36 The main sites of infection were pleura and lungs (45.4%). The middle ear infection represented 1.8% of the cases.36 On the other hand, as a well-documented complication, we can find nasal septum perforation (which can manifest with nasal obstruction , epistaxis, posterior nasal discharge or crust formation into the nasal cavity), being attributed to local inflammation or ischemia.1 Upper airway obstruction due to laryngeal involvement is a rare, but well documented, complication of SLE, which usually occurs in association with other signs and symptoms that indicate active disease.1 Data from the literature show auricular chondritis as the most frequent and characteristic finding of the disease, present in 85% of cases, and in 40% of them as the initial manifestation.8 This condition may be uni- or bilateral, causing phlogistic signs, with swelling of the external ear canal, and that may lead to conductive hearing loss. Vasculitis of the internal auditory artery may cause cochlear and/or vestibular involvement by cochlear infarct or ischemia, resulting in sensorineural dysacusis.8 Moreover, among the seven diagnostic criteria established by McAdam et al., four of them involve the presence of symptoms that affect the upper respiratory tract or vestibulocochlear system.37 Nasal compromise, arising from nasal chondritis, can result in a “saddle nose” in up to 50% of patients. The diagnosis of laryngo-tracheo-bronchial chondritis is also crucial due to its high morbidity and mortality.8 Xerostomia is a common feature of Sjögren’s syndrome, being usual in patients with primary and secondary syndrome.38 It is the most obvious symptom of this syndrome.36 Patients often exhibit dryness of lips, tongue and pharynx and consequent painful burning sensation and of mucosa, accompanied by speech, chewing, swallowing and digesting food difficulty.32 More than one third of patients present systemic manifestations that can include vasculitis, cryoglobulinemia, autoimmune hepatitis, pulmonary fibrosis, central nervous system involvement, renal tubular acidosis, B-cell lymphomas and multiple myeloma.33 Other trials showed oral symptoms of dry mouth in 86% and eye symptoms in 53% of patients.39 In the same trial, 46% of patients exhibited ocular involvement, demonstrated by Schirmer test or by Rose Bengal staining; and in 85.7% of studied cases an involvement of the salivary gland (by scintigraphy, sialography or sialometry) was evidenced.39 The literature review shows that the most obvious oral symptom is xerostomia, with dryness of lips, tongue and pharynx and with chewing, swallowing and speech difficulty, as well 177 as increased susceptibility to dental caries and periodontal disease.36 About a third to half of patients display an usually symmetrical and recurrent parotid gland hypertrophy.40 Finally, we must consider the large time lag between complaints of rheumatology patients and the correct diagnosis, already described. The vasculitis involving the airways, for example, is a common presentation of a vascular disease involving ANCA (anti-neutrophil cytoplasmic antibody) and can precede by several years the diagnosis of the disease.33 One should keep in mind that the referral of patients for this trial occurred unevenly among specific rheumatology outpatient clinics, according to the aforementioned rheumatologic diseases; then, the patients’ distribution does not represent the overall distribution of patients with rheumatic diseases. Conclusion This trial demonstrated the various ENT manifestations of a group of patients with rheumatologic diseases that commonly can be related to rheumatic diseases, according to other trials. The early identification of these symptoms as a manifestation of such diseases, both by the otolaryngologist as by the rheumatologist, is critical to the early implementation of an immunosuppressive treatment, thereby reducing the morbidity and mortality of these conditions. Conflicts of interest The authors declare no conflicts of interest. Acknowledgements We thank all who contributed to the development of our project at the Rheumatology and Otorhinolaryngology, Head and Neck disciplines at HC/FCM/UNICAMP. REFERENCES 1. Riera R, Ciconelli RM, Ferraz MB. COPCORD studies. Acta Reumatol Port. 2006;31:119-23. 2. Gonzalez-Gay MA, García-Porrua C. Etiopatogenia y clasificación e las vasculitis sistémicas. In: Alonso Ruiz A, Alvaro-Gracia Alvaro JM, Blanch i Rubio J et al. (Ed.) Manual SER de enfermedades reumáticas. 3 ed., Madrid: Médica Panamericana. 2000. p. 349-54. 3. Bogas M, Afonso MC, Araújo D. Non-steroidal antiinflammatory drugs and lower intestinal tract toxicity.Acta Reumatol Port. 2006;31:227-35. 4. Pereira DB, Amaral JLA, Szajubok JCM, Lima SMAL, Chahade WH. Otorhinolaryngologic manifestations of autoimmune rheumatic diseases. Rev Bras Reumatol. 2006;46:118-25. 5. Papadimitraki ED, Kyrmizakis DE, Kritikos I, Boumpas DT. 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Aspectos do diagnóstico da Síndrome de Sjögren. Rev. Bras. Otorrinolaringol. 2002;68:363-67. 40. Freitas TMC, Medeiros AMC, Oliveira PT, Lima KC. Síndrome de Sjögren: revisão de literatura e acompanhamento de um caso clínico. Rev Bras Otorrinolaringol. 2004;70283-88. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Randomized controlled trial of a therapeutic intervention group in patients with fibromyalgia syndrome Marielza R. Ismael Martinsa,*, Cristiane Carnaval Grittib, Randolfo dos Santos Juniorb, Maria Carolina Luizetto de Araújob, Lilian Chessa Diasb, Marcos Henrique D’all Aglio Fossa, Larissa Batista de Andradeb, Carlos Eduardo D’all Aglio Rochaa Department of Neurological Sciences, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil Service of Pain Clinics, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brazil a b article info abstract Article history: Objective: To evaluate the efficacy of a weekly interdisciplinary program (WIP) consisted Received on 6 February 2013 of educational activities, physical therapy, stretching, ergonomics, posture guidance com- Accepted on 15 October 2013 bined with cognitive behavioral strategies and approaches to psychosocial and occupational factors in order to determine whether this intervention would be effective to short Keywords: and medium-term improvement of symptoms in these patients. Fibromyalgia Methods: This was a single-center study, randomized single blind controlled trial with a Controlled study sample test group (T), with a diagnosis of FMS (n = 12), and a control group (C) subjected to Group intervention Pain Clinic referral (n = 15). The instruments used at two different times were the Fibromyalgia Impact Questionnaire (FIQ), Visual Analogue Scale (VAS) and Post-Sleep Protocol (PSI). To assess quality of life, we used the SF-12. Results: In samples, both groups were predominantly female, mean age of 42.5 ± 9.8 years, 43% married, average schooling of 8.3 ± 4.5 years. It was reported a mean of 4.2 years pain and an average of two years for the diagnosis of SFM from the group T. There was statistical difference between the groups in terms of efficacy post intervention WIP, in almost all outcome measures. Conclusion: It was found that weekly interdisciplinary program (WIP) has contributed to improving the quality of life of patients with fibromyalgia. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (M.R.I. Martins). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.10.002 180 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4 Estudo randomizado e controlado de uma intervenção terapêutica grupal em pacientes com síndrome fibromiálgica resumo Palavras-chave: Objetivo: Avaliar a eficácia de um programa interdisciplinar semanal (PIS) composto de ati- Fibromialgia vidades educativas, terapias físicas, alongamento, ergonomia, orientações posturais com- Estudo controlado binado com estratégias cognitivas e comportamentais e abordagens de aspectos psicosso- Intervenção grupal ciais e ocupacionais, a fim de determinar se esta intervenção seria efetiva em curto e médio prazos para melhora dos sintomas destes pacientes. Casuística e métodos: Trata-se de um estudo unicêntrico, randomizado, simples cego e controlado com amostra de um grupo-teste (T), com diagnóstico de SFM (n = 12), e de um grupo-controle (C) submetido a interconsulta na Clínica da Dor (n = 15). Os instrumentos utilizados em dois momentos distintos foram: Questionário de Impacto de Fibromialgia (FIQ), Escala Visual Analógica (EVA) e Protocolo Pós-Sono (PSI). Para avaliar a qualidade de vida, foi utilizado o Questionário SF-12. Resultados: Na amostra dos dois grupos houve predomínio do gênero feminino, média de idade de 42,5±9,8 anos, 43% casados e média de escolaridade de 8,3±4,5 anos. Foi relatado um tempo médio de dor de 4,2 anos e uma média de dois anos para o diagnóstico de SFM no grupo T. Houve diferença estatística entre os grupos, em relação à eficácia pós-intervenção do PIS, em quase todos os desfechos analisados. Conclusão: Verificou-se que o programa interdisciplinar semanal (PIS) contribuiu para melhora da qualidade de vida dos pacientes fibromiálgicos. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction The fibromyalgia syndrome (FMS) is a rheumatic syndrome of unknown etiology that predominantly affects women. It is characterized by diffuse and chronic musculoskeletal pain, in addition to specific anatomical sites with pain elicited by palpation, called tender points. Other symptoms such as fatigue, sleep disturbances, morning stiffness and psychological disorders such as anxiety and depression are often associated.1-3 Statistic data shows that FMS affects 3-5% of general population, occurring in all ages with chronic symptoms that can fluctuate throughout the day and with inactivity, compromising about a quarter of those affected.3 The clinical picture of FMS is complex, and several works4,5 propose multidisciplinary teams to perform interventions, highlighting programs with exercise sessions,4 relaxation,5 stress management and compartmental cognitive therapy6 that consist in extending the adherence to treatment and motivating patients to remain active.7 The mean duration of interdisciplinary programs varies from one to six months, usually performed with groups of 10 and 25 individuals. The justification for choosing this type of intervention proves itself by improving the quality of life and health status of patients with FMS.8,9 Regarding the pathogenesis of FMS, it is not well defined yet, although psychosomatic phenomena occur in most patients.10 In addition to this possible effect, some areas of the nervous system functioning may represent a role in the pathogenesis of FMS, which include: changes in pain sensitivity,11,12 and also on autonomic and neuroendocrine systems.13-15 Bacterial and viral agents may also be related to the origin of this syndrome,16 and there is some association between the disease and infection by hepatitis virus C.11 Considering that SFM probably has multifactorial etiology that still remains unclear, recent trials17,18 reported that the reorientation of attention for the treatment of the patients to this combination of factors and the education of these patients (so that they can control their symptoms) are measures that could promote changes in behavior and improve their functional capacity. Given this context, the objective of this trial was to evaluate the efficacy of a weekly interdisciplinary program (WIP) consisting of educational activities, physical therapy, stretching, ergonomics and postural orientations combined with cognitive-behavioral strategies and approaches to psychosocial and occupational features, in order to determine whether this intervention would be effective in the short and medium terms to improve the symptoms of these patients. Patients and Methods After approval by the Ethics and Research Committee from FAMERP (2384/2010) and with the Free and Informed Consent Form (FICF) already signed, we conducted this single-center, randomized, single-blind, controlled trial. The trial was conducted in two groups, with a duration of three months, comparing the weekly interdisciplinary program (WIP) to a control intervention consisting of educational guidelines for the prevention of pain, relaxation techniques, muscle stretching and body awareness. The sessions lasted 60 minutes each and happened once a week for 12 weeks for each of the study groups, being conducted by a physician, occupational thera- R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4 pist, physiotherapist, psychologist and social worker. After participating in this program, a revaluation was performed using the same instruments. To perform WIP, 12 patients diagnosed with FMS (test group – TG) were recruited according to criteria of the American College of Rheumatology,1 of both genders, with enough cognitive level to understand the procedures and follow the directions given. Patients with psychiatric disease and no clinical follow-up in the Pain Clinic, Hospital de Base, were excluded. The control group (CG) consisted of patients who were in interconsultation in the Pain Clinic and without diagnosis of musculoskeletal and neurological disorders, or with disabling complaints in these systems, with a recommendation for walking (pelvic pain, migraine, inflammatory bowel pain post-herpetic neuralgia). CG consisted of subjects matched for age and educational level in relation to TG (n = 15). The evaluation of the subjects in both groups was performed using the Fibromyalgia Impact Questionnaire (FIQ),19 involving 20 questions divided into 10 items (functional capacity, feeling good, work absenteeism, interference of symptoms at work, pain, fatigue, morning stiffness, morning tiredness, anxiety and depression), in which nine of them have a higher score as the worst condition, with the exception of the item “feeling good”. Seven of the nine items (4th to 10th) are scored using a visual analogue scale, i.e., between 0 and 10. Functional capacity is estimated by answering 10 questions, with answers from 0 to 3, which are added at the end of the questionnaire, ranging between 0 and 30. The “work absenteeism” and “feeling good” questions are scored on weekdays, originally ranging from 0 to 5; the Visual Analogue Scale (VAS),20 which consists of measuring the intensity of pain in the patient and is an important tool to verify more reliably the evolution of the patient during treatment and even at every visit, consists of a limited strip of 10 cm in length, representing a continuum of the painful experience; this strip has in her ends anchor-words: “no pain” and “worst pain possible”. The participants are instructed to report the intensity of pain sensation to a point of this line, and the scores can range from zero to 10 and are obtained by measuring, in millimeters, the distance between the end anchored by the words “without pain” and the point marked by the participant; the Post-Sleep Protocol (PSP),21 which assesses the sleep quality and features 30 items divided into three categories: pre-sleeping (at bedtime), during sleep and post-sleeping (awakening) (30-390; higher scores are related to better quality of sleep). To assess the quality of life, the Generic Quality of Life SF-1222 questionnaire was used. It consists of 12 questions that address the physical component (functional capacity and limitation by physical aspects) and the mental component (pain, vitality, social functioning, limitations due to emotional problems and mental health), and their results are expressed by a score in a scale of zero to 100 by researched component (worst – best general health, cutoff score ≤ 50). To assess depressive and anxiety symptoms, we used the Hospital Anxiety and Depression (HAD) scale,23 translated and validated in Brazil, which consists of a self-report instrument containing 14 multiple choice questions, composed of two interleaved sub-scales: one for anxiety-state (7 questions) and another for depression-state (7 questions). HAD scores range 181 from 0 to 21 points, and the subjects with scores < 7 are considered without significant clinical symptoms for anxiety and/or depression; scores ≥ 8 and ≤ 10, with mild symptoms; scores ≥ 11 and ≤ 14, with moderate symptoms; and scores ≥ 15 and ≤ 21, with severe symptoms of anxiety and/or depression. During the sessions, exercises to strengthen the muscle and to improve cardiovascular fitness were conducted, consisting of stretching exercises of muscle groups of the shoulder and pelvic girdle, lower limb muscles, gluteus, abdominals and quadriceps, as well as body correction and awareness, and ergonomics. The sessions were initiated with relaxation techniques to combat muscle tension. Educational, psychosocial and occupational programs were also developed to help understand and manage fibromyalgia, with the monitoring of vital signs at the beginning and end of each treatment session and the questioning on the use of drugs by patients. All the participants were instructed and taught to practice a series of daily exercises at home. It emphasized the need to maintain the home exercise program, and guidelines were given on the correct way to perform ADLs and AVPs. Analyses were performed using ANOVA. This descriptive parametric statistical test was selected for inferential analyses, because the dependent variables of this trial were quantitative (interval scale). The significance level used for the tests was 0.05. Results The twenty-seven subjects enrolled in both groups adhered totally to the program, with no occurrence of sample loss. The mean age was 42.5 ± 9.8 years, ranging from 28-67 years; most of the participants were female (64%). The mean duration of pain was 4.2 years, with an average of two years for the clinical diagnosis of FMS in TG. Table 1 lists the characterization of the sample for the two groups (T and C). During the experimental phase, all patients in the T group maintained their pharmacological routine. Significant difference was observed between the groups regarding the functional capacity and work absenteeism, observed in the FIQ questionnaire. As for the other questionnaires used in this trial, data of mean and standard deviation (SD) can be obtained from Table 2. It is important to notice, in Fig. 1, the frequency of depressive and anxiety symptoms. It is noteworthy that 50% of patients with FMS in T group had depressive symptoms, and 33% had moderate to severe symptoms. 78% of these individuals had symptoms of anxiety, and in 43% of them the symptoms were severe. Discussion The actions performed in this trial by the weekly interdisciplinary program (WIP) demonstrated that the approach to individuals with FMS showed statistically significant clinical effects, as the increase of functional capacity and motivation, as well as greater control of symptoms such as sleep, anxiety and depression. 182 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4 With regard to functional capacity, it was found that in group T the activities in WIP improved the energy that comes from the symptoms of chronic fatigue and stiffness, corroborating other trials.23,24 Other work on the impairment of muscle contractility in a group of fibromyalgia patients is associated with a higher Table 1 – Data on sociodemographic variables for T (n = 12) and C groups (n = 15) Variable Age Gender Marital status Education Group n Mean ± SD Test Control Test Control Test 12 15 12 15 12 39,5±7,8 45,5±8,3 Control 15 Test 12 % Female 62 Female 55 Married 52 Single 28 Divorced 20 Married 43 Single 37 Divorced 13 Widowed 7 Fundamental 32 Secondary 48 Superior 20 Fundamental 37 Secondary 45 Superior 18 Formal work 12 Sick-leave aid 58 Retired 4 Informal work 26 Formal work 20 Sick-leave aid 48 Retired 6 Informal work 26 8,3 ± 4,5 years 15 Employment situation Test Control 12 15 perception of effort and reduced maximal exercise capacity. Due to this fact, the inclusion of physical activity in the treatment of these patients would improve their functional responses, with decreased fatigue and increased functional capacity.25 Firestone et al.26 evaluated the impact of a program of group therapy for patients with fibromyalgia. The sessions consisted of behavioral modifications, stress reduction techniques, strategies to improve flexibility and physical performance, in addition to sessions for familial help. The sessions were held weekly for a period of six months. The authors report promising results obtained in the short and long terms. There was also a decrease in symptoms of depression and anxiety in WIP participants. Among the various factors affecting the QoL of fibromyalgia patients, Aliciati et al.27 suggest that the presence of depression predisposes patients to impaired social functioning, and Clark et al.23 reported that the inclusion of these patients in multidisciplinary groups favors the practice of daily living activities, mobility and quality of body movements and of physical fitness, thereby improving their quality of life. Título do Gráfico 80% 70% 60% 50% DEPRESSION 40% ANXIETY 30% 20% 10% 0% GT GC Fig. 1 – Distribution of fibromalgics according to the calculated mean of depression and anxiety symptoms Table 2 – Change in mean values of FIQ, SF-12 and Post-Sleep Protocol (SIP) questionnaire domains throughout the follow-up period, expressed as mean ± standard deviation and variation Instruments applied FIQ functional capacity Feeling good Work absences Ability to work Pain Fatigue Sleep Morning stiffness Anxiety Depression Total FIQ SF-12 Physical component Mental component PSP At bedtime Overnight 1st review Mean and SD TG GC 2nd review Mean and SD TG GC p value 12.4±7.7 9.3±5.9 2.0±2.6 4.8±2.7 0.0±0.0 0.0±0.1 6.6±2.8 5.1±3.1 7.7±1.8 5.7±3.0 7.5±2.3 5.7±2.0 6.6±3.0 4.1±3.1 7.5±2.5 5.3±7.9 7.6±2.5 4.3±3.3 7.0±2.5 3.4±3.1 64.9±27.7 47.7±37.2 10.8±5.4 8.2±5.8 2.5±2.5 3.7±2.8 0.1±0.6 0.2±0.9 5.7±3.0 2.4±2.8 6.3±2.5 2.2±2.8 6.9±2.5 3.1±3.1 5.8±2.8 2.3±2.3 5.9±3.0 1.8±2.3 6.6±2.3 6.3±2.9 6.2±2.8 5.4±3.2 56.8±27.4 35.6±28.9 0.04* 0.06 0.20 0.03* 0.04* 0.04* 0.06 0.03* 0.03* 0.04* 0.03* 48.5 52.3 38.5 48.5 59.5 62.3 67.5 78.5 0.03* 0.001* 38.6±13.6 51.4±8.6 72.2±8.6 91.2±6.4 53.4±5.6 68.3±7.8 92.3±8.4 98.3±7.4 0.04* 0.03* * statistically significant difference, p < 0.05. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4 Regarding the prescription of activities and exercises to patients with FMS, orientations, as well as pharmacological prescriptions with dose, duration and specific intervals, were performed. The concern in relation to the intensity and execution of the proposed and previously trained activities in WIP began gradually, considering the preferences of patients, their comorbidities, medication use, and functional capacity. Corroborating this procedure, the trial by Miró et al.28 involved different areas in action groups with expertise on fibromyalgia patients, showing that they are promoters of pain relief, generating well-being and contributing significantly to the quality of the patients’ life. Regarding the sleep, some trials29,30 relate a worst sleeping period to a greater number of tender points in patients with fibromyalgia. Sleep disturbances were also associated with chronicity of pain complaints. It is known that individuals with chronic pain, such as those with FMS, have a persistent health condition that changes their life. The goal of their treatment is to control FMS and not to seek its elimination; therefore, the sleep pattern assessment becomes a sensitive indicator that should be considered. In this trial, after the intervention of WIP (with approaches focused on body biomechanics, kinesiology, ergonomics, psychosocial aspects and improvement of cardiorespiratory capacity), a better sleep pattern was noted in these individuals. Follow-up studies with FMS patients are scarce, as well as those on the health care, that should have an interdisciplinary planning, but they have been performed separately by each professional. The actions resultant of WIP revealed that the approach to patients with FMS should be multifactorial; this strategy enables the understanding of this syndrome as a summation of disorders that end up manifesting itself by the association of a variety of symptoms. Conclusion The treatment of fibromyalgia patients should follow multifactorial models; this will allow a systematic development of the necessary abilities to the transition from rehabilitation in the maintenance of an active and independent lifestyle. Conflicts of interest The authors declare no conflicts of interest. REFERENCES 1. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL et al. The American College of Rheumatology 1990 Criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990; 33:160-72. 2. Martins MRI, Polvero L, Rocha CE, Foss MH, Santos Junior R. Uso de questionários para avaliar a multidimensionalidade e a qualidade de vida do fibromiálgico. Rev Bras Reumatol. 2012;52:21-26. 183 3. Mease PJ et al. Identifying the clinical domains of fibromyalgia: Contributions from clinician and patient Delphi exercises. Arthritis Care Res. 2008;39:952-60. 4. Da Costa D, Abrahamowicz M, Lowensteyn I et al. A randomized clinical trial of an individualized homebased exercise programme for women with fibromyalgia. Rheumatology (Oxford). 2005;44:1422-7. 5. Boomershine CS, Emir B, Wang Y, Zlateva G. Simplifying Fibromyalgia Assessment: The VASFIQ Brief Symptom Scale. Ther Adv Musculoskelet Dis. 2011;3:215-26. 6. Veldhuijzen DS, Sondaal SF, Oosterman JM. Intact cognitive inhibition in patients with fibromyalgia but evidence of declined processing speed. J Pain. 2012;13:507-15. 7. Persson E, Lexell J, Eklund M, Rivano-Fischer M. Positive effects of a musculoskeletal pain rehabilitation program regardless of pain duration or diagnosis. PM R. 2012;4:355-66. 8. Ayan C, Alvarez MJ, Alonso-Cortés B, Barrientos MJ, Valencia M, Martín V. Health education home-based program in females with fibromyalgia: a pilot study. J Back Musculoskelet Rehabil. 2009;22:99-105. 9. Mannerkorpi K, Henriksson C. Non-pharmacological treatment of chronic widespread musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007;21:513-34. 10. Orlandi AC, Ventura C, Gallinaro AL, Costa RA, Lage LV. Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia. Rev Bras Reumatol. 2012;52:672-678. 11. Endresen GK. Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes. Rheumatol Int. 2003;23:211-5. 12. Buskila D, Atzeni F, Sarzi-Puttini P. Etiology of fibromyalgia: the possible role of infection and vaccination. Autoimmun Rev. 2008;8:41-3. 13. Suleı̆manova GP, Grekhov RA, Kharchenko SA, Aleksandrov AV, Zborovskiı̆ AB. Psychosomatic relationships in patients with primary fibromyalgia syndrome. Klin Med. 2009;87:55-9. 14. Riberto M, Pato TR. Fisiopatologia da fibromialgia. Acta Fisiatr. 2004;11:78-81. 15. Bellometti S, Galzigna L. Function of the hypothalamic adrenal axis in patients with fibromyalgia syndrome undergoing mudpack treatment. Int J Clin Pharmacol Res. 1999;19:27-33. 16. Sarzi-Puttini P, Atzeni F, Cazzola M. Neuroendocrine therapy of fibromyalgia syndrome: an update. Ann N Y Acad Sci. 2010;1193:91-7. 17. Torma LM, Houck GM, Wagnild GM, Messecar D, Jones KD. Growing old with fibromyalgia: factors that predict physical function. Nurs Res. 2012;3:212-8 18. Jahan F, Nanji K, Qidwai W, Qasim R. Fibromyalgia syndrome: an overview of pathophysiology, diagnosis and management. Oman Med J. 2012;27:192-5. 19. Marques AP, Santos AMB, Assumpção A, Matsutani LA, Lage LV, Pereira CAB. Validação da versão brasileira do Fibromyalgia Impact Questionnaire (FIQ). Rev Bras Reumatol. 2006;46:24-31. 20. Pimenta CAM. Escalas de avaliação de dor. In: Teixeira MD (ed). Dor: conceitos gerais. São Paulo: Limay, 1994 pp. 46-56. 21. Webb WB, Bonnet M, Blume G. A post-sleep inventory. Percept Motor Skills. 1976;43:987-93. 22. Camelier A. Avaliação da qualidade de vida relacionada à saúde em pacientes com DPOC: estudo de base populacional com o SF-12 na cidade de São Paulo-SP. [tese]. São Paulo: Universidade Federal de São Paulo, 2004. 23. Clark P, Paiva ES, Ginovker A, PA. A patient and physician survey of fibromyalgia across Latin America and Europe. BMC Musculoskelet Disord. 2013;14:188. 24. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361-370. 25. Bachasson D, Guinot M, Wiyam B, Favre-Juvin A, Millet GY, Levy P et al. Neuromuscular fatigue and exercise capacity in fibromyalgia syndrome. Arthritis Care Res. 2013;65:432-40. 184 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 7 9 – 1 8 4 26. Firestone KA, Holton KF, Mist SD, Wright CL, Jones KD. Optimizing fibromyalgia management. Nurse Pract. 2012;37:12-21. 27. Aliciati A, Sgiarovello P, Atzeni F, Sarzi-Puttini P. Psychiatric problems in fibromyalgia: clinical and neurobiological links between mood disorders and fibromyalgia. Reumatismo. 2012;64:268-74. 28. Miró E, Martínez MP, Sánchez AI, Prados G, Medina A. When is pain related to emotional distress and daily functioning in fibromyalgia syndrome? The mediating roles of selfefficacy and sleep quality. Br J Health Psychol. 2011;16:799814. 29. Consoli G, Marazziti D, Ciapparelli A, Bazzichi L, Massimetti G, Giacomelli C et al. The impact of mood, anxiety, and sleep disorders on fibromyalgia. Compr Psychiatry. 2012; 53:962-7. 30. Gui M, Pedroni CR, Rossini S, Reimão R, Barbosa CMR. Distúrbios do Sono em Pacientes com Fibromialgia. Neurobiologia. 2010;73:175-182. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Construction of a manual of work processes and techniques from Centro de Dispensação de Medicamentos de Alto Custo (CEDMAC), Hospital de Clínicas, Unicamp Manoel Barros Bertolo a, Bruno Silva de Araújo Ferreirab, Adriana G. Mucke Marchiore b, Glaucia Pereira do Amaral Carvalho b, Débora Pessoa de Souzab, Eliane Molina Psaltikidis b,* Discipline of Rheumatology, School of Medical Sciences, University of Campinas, Campinas, SP, Brazil Clinical Hospital, University of Campinas, Campinas, SP, Brazil a b article info abstract Article history: The Centers for High Cost Medication (Centros de Medicação de Alto Custo, CEDMAC), Received on 27 August 2013 Health Department, São Paulo were instituted by project in partnership with the Clini- Accepted on 28 October 2013 cal Hospital of the Faculty of Medicine, USP, sponsored by the Foundation for Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Keywords: Paulo, FAPESP) aimed at the formation of a statewide network for comprehensive care of Rheumatology patients referred for use of immunobiological agents in rheumatological diseases. The Biological Therapy CEDMAC of Hospital de Clínicas, Universidade Estadual de Campinas (HC-Unicamp), im- Hospital Administration plemented by the Division of Rheumatology, Faculty of Medical Sciences, identified the Quality Assurance, Health Care need for standardization of the multidisciplinary team conducts, in face of the specificity of care conducts, verifying the importance of describing, in manual format, their operational and technical processes. The aim of this study is to present the methodology applied to the elaboration of the CEDMAC/HC-Unicamp Manual as an institutional tool, with the aim of offering the best assistance and administrative quality. In the methodology for preparing the manuals at HC-Unicamp since 2008, the premise was to obtain a document that is participatory, multidisciplinary, focused on work processes integrated with institutional rules, with objective and didactic descriptions, in a standardized format and with electronic dissemination. The CEDMAC/HC-Unicamp Manual was elaborated in 10 months, with involvement of the entire multidisciplinary team, with 19 chapters on work processes and techniques, in addition to those concerning the organizational structure and its annexes. Published in the electronic portal of HC Manuals in July 2012 as an e -Book (ISBN 978-85-63274-17-5), the manual has been a valuable instrument in guiding professionals in healthcare, teaching and research activities. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (E.M. Psaltikidis). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.10.003 186 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 Construção do manual de processos de trabalho e técnicas do Centro de Dispensação de Medicamentos de Alto Custo (CEDMAC) do Hospital de Clínicas da Unicamp resumo Palavras-chave: Os Centros de Medicação de Alto Custo (CEDMAC) da Secretaria de Saúde do Estado de São Reumatologia Paulo foram instituídos por projeto em parceria com Hospital das Clínicas da Faculdade de Terapia biológica Medicina da USP, patrocinado pela Fundação de Amparo à Pesquisa do Estado de São Paulo Administração hospitalar (FAPESP), visando à formação de rede estadual para atendimento integral dos pacientes Garantia da qualidade dos cuidados indicados ao uso de agentes imunobiológicos nas doenças reumatológicas. O CEDMAC do de Saúde Hospital de Clínicas da Universidade Estadual de Campinas (HC-Unicamp), implementado pela Disciplina de Reumatologia da Faculdade de Ciências Médicas, identificou a necessidade de padronização das condutas da equipe multidisciplinar, frente à especificidade da assistência, verificando a importância da descrição, em formato de manual, dos seus processos de trabalho e técnicas. O objetivo do estudo foi apresentar a metodologia de construção do manual do CEDMAC/HC-Unicamp como ferramenta institucional, visando à qualidade assistencial e administrativa. A metodologia para elaboração dos manuais no HC-Unicamp, desde 2008, tem como premissas ser participativo, multidisciplinar, focado em processos de trabalho, integrado às normas institucionais, com descrição objetiva e didática, formato padronizado e divulgação eletrônica. O Manual do CEDMAC/HC-Unicamp foi construído em dez meses, com o envolvimento de toda equipe multidisciplinar, tendo 19 capítulos sobre processos de trabalho e técnicas, além dos relativos à estrutura organizacional e anexos. Publicado no portal eletrônico dos Manuais HC, em julho de 2012, como e-book, com registro ISBN 978-85-63274-17-5. O Manual tem sido valioso instrumento na orientação dos profissionais da área nas atividades assistenciais, de ensino e pesquisa. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction The treatment of rheumatic diseases has changed markedly in the last 10 to 15 years, with the emergence of new drugs, the so-called biological therapies.1 Disease-modifying drugs (DMDs) are conventional therapies that can control about 20% of symptoms in approximately 55%-60% of patients; only 10%-20% attain a response of 70% of development of arthritis.2-4 However, there is a niche of patients who, even in association with conventional DMARDs,5 do not achieve a good response or are intolerant (e.g., nausea with methotrexate, diarrhoea with leflunomide, maculopathy to antimalarials), requiring another pharmacological agent to improve symptoms and return to their productive lives. Biologic therapies are so named because they are organic molecules of high molecular weight and have biological origin, i.e., produced by living beings and containing carbon atoms in their molecular structure. In general, the organic molecules used as substrates are immunoglobulins or antibodies. However, their greater efficacy with greater specificity justifies the high cost, since the patient will be again a productive member of society. This will be possible after research on the physiopathogenesis, with biomolecular foundation, and on the activity in specific and critical points for a particular disease.6-10 In general, patients are lay people in the medical field, or even have a low level of education; thus, most of them are not equipped to handle (storage, application and disposal) self- administered subcutaneous drugs or would not have a proper place for infusion of intravenous medications, and also do not have proper supervision. Being organic molecules, these drugs are very exquisite, requiring special care in their handling or transport. This can be observed in medical consultations, considering that it is the responsibility of the rheumatologist to evaluate the patient response to the prescribed medication. It is known that a closer monitoring of patients with rheumatologic disease results in a better response to treatment, compared with patients in routine visits every 3 to 6 months, as that strategy enables an earlier intervention.3-5,11 Initially, this conduct of a more rigorous and closer followup may seem more difficult and costly. However, in the study TICORA, a survey on costs was also done, showing no increase in financial costs and a better quality of care and improved response.5 This strategy is practiced at CEDMAC, Health Department, São Paulo, considering that the visits take place with a shorter time interval and with the possibility of extra visits to check for effects and adverse events. CEDMAC was established from a project developed in partnership between Hospital das Clínicas, Faculty of Medicine, USP, and Health Department of the State of São Paulo, and is sponsored by the Foundation for Research Support of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP), aimed at the formation of a statewide network for dispensing costly medication. CEDMAC serves patients with an indication for use of immunobiological agents R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 in rheumatological diseases, and accompanies the indication, dispensing and application of these medications. Another important function of the Centers is the registration of users for reporting side effects; thus, CEDMAC can feed data into Brazilian Registry of Biological Rheumatology (BiobadaBrasil). The role of specialist nurses is also crucial, because in addition to being familiar with terms and conditions, these professionals are also aware of the conventional drugs and, in the case of CEDMAC, of this new class of antirheumatic drugs. Thus, the specialist nurses interfere in the patients’ education – on what is the disease, treatment options, the proper use of medication, and improvement in the degree of fidelity to its use. Thus, these professionals help increase the response to therapy. In some countries, these professionals even count joints and advice on contraception. Another important role of CEDMAC is to establish innovative conduct protocols on biologicals, following the most current recommendations. By being in the public university scenario, the scientific knowledge is considered an essential factor, together with the reduction of costs. One of the main terms that enter into discussion in the context of biological drugs, particularly in the use of infusion drugs, is how to reduce the infusion time for each patient, increasing vacancies and obtaining full efficiency of the service with the highest quality possible.9,10 Since this is a statewide network of centers for dispensing and infusion of high-cost drugs (especially biologicals) in the field of rheumatology, there is the possibility of exchanging information with other centers, with the aim of standardizing the care in the State of São Paulo, with sharing of experiences. The CEDMAC/HC-Unicamp was implemented by the Department of Rheumatology, Faculty of Medical Sciences. Its main goal is to benefit rheumatological patients with the use of biological drugs, with respect to guidance on this type of medication, its proper use and supervision as to their doubts and responses to therapy. Thereby, the CEDMAC also interferes to avoid the improper use or misuse of medications, as well as their loss. Moreover, CEDMAC also must train specialized teams that will deal with this type of patient and drug, offering appropriate multidisciplinary care and providing more welfare to the rheumatic patient. In addition, data are generated from standardized consultations, with production of clinical research and exchange of information and experiences with other CEDMACs of São Paulo. Considering the specificity of the assistance offered and the need for a clear standardization of conducts for the multidisciplinary team, it became important to develop and describe, in manual format, the work processes and techniques of CEDMAC/HC-Unicamp. In the literature and in all certification programs adopted by healthcare institutions, there is consensus on the need of elaboration of operational manuals, even if the nomenclature of these documents may vary according to the source consulted: manuals of routines, norms, procedures, techniques, processes, or of standardized operating procedures.12,13 The manual is an administrative instrument that allow the organization and standardization of service guidelines in a health care institution, systematizing activities and their execution by different professionals; moreover, this document 187 establish points of process control and of measurement of results.14 Manuals give subsidies for training and supervision of procedures, reducing the risk of adverse events, facilitating the revision of processes, meeting the requirements of regulatory agencies and offering protection against lawsuits generated by patients or labourers. It is known that people produce better when following a standardized routine. This standardization reduces the variability of offered products or services, and this translates into predictable and reliable processes. The manual should serve as a reference document, being used for training teams to operate the work process. Moreover, the manual can function as a tool which facilitates the dissemination of institutional knowledge, as a benefit within reach of all interested.12,15 A discussion that still occurs in the healthcare scenario relates to the supposed difficulty in developing manuals for this sector, in which every patient is an unique being, with an absolutely peculiar clinical picture. In reality, what are intended to standardize are the processes likely to be used, and not the assistance to be provided.16 A good standardization must demonstrate essential characteristics: it must arise from those professionals who perform the tasks, be the result of consensus, be simple and based on institutional practice, should address more frequent and higher risk/complexity situations, be consistent with the recommendations and literature, follow a standard format and be accessible to all members of the institution. No single model exists for a manual elaboration. These documents may vary as to content, level of detail and format, according to the needs of each institution. Manuals are flexible, never complete or finished works, and depend on constant review and updating.17 Objective To present the methodology of elaboration of the manual of work processes and techniques for CEDMAC/HC-Unicamp as an institutional tool, aiming to the best care and administrative quality. Material and methods The HC-Unicamp develops, since 2008, a program of institutional elaboration of manuals, entailed to and supported by, Hospital Superintendence, with clearly defined premises and logistical support for elaborating and formatting manuals, favoring the adhesion of multidisciplinary teams and the project success.18 The premises of HC-Unicamp Manuals are: • Participative elaboration – to involve professionals from different hierarchical levels in the processes’ description in the area. • Description by processes, where possible, with multiprofessional, interareas and multidisciplinary approaches – to involve all professional categories in the preparation of the manual, and to describe the processes, allowing the dem- 188 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 onstration of the interrelationship of the multidisciplinary team and the different areas of the institution. • Address liability processes of the area – to describe only proper and specific processes of the area. • To reflect the reality and current practice – the manual must not describe idealized processes, but those that, in fact, are practiced; thus, in practice the motto prevails: Write what you do and do what is written!. • Depth and detail are determined by demand and interest in the area – due to its specificity, each area determines what are the important processes to be described and what level of detail is necessary to their reality. • Objective, didactic and attractive description, with a focus on target audience – to avoid excessively detailed descriptions that make the reading process a tiresome thing. Use simple and direct language, favouring clarity. • A standardized format – operational help for manual formatting and configuration of an institutional document, in accordance with the recommendations of certification programs and literature: standardized header and footer containing institutional logos, authors, implantation date, revision date, revision number, author and signature of the professional in charge of the area in question; use of documents and descriptive papers of activities already existing in the area, with its conversion to standard format. • Compatibility and integration with manuals from other areas – to avoid repetitions and contradictions among manuals of different areas. • Priority in dissemination and electronic use – to create, in the community, the habit of searching for information in the manuals in electronic format, avoiding the use of printed copies.18 prepares technical recommendations for occupational safety. Regarding the use of individual protection, collective protection and protection barriers’ equipment, as prescribed by legislation, in particular the Regulatory Standards of the Ministry of Labor and Employment and those issued by the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, ANVISA) and the Brazilian Association of Technical Standards (Associação Brasileira de Normas Técnicas, ABNT). After the analyses, utterance of technical recommendations, and alignment of occupational safety conducts, the manual is signed by the labor safety technician in charge.18 With the final approval and signature of the professional in charge of the area in question, the document is converted to pdf, using a security system that prevents changing contents, printing and text fragments copying. This measure aims to prevent misuse of the document, especially unnecessary copies and plagiarism. Moreover, in order to improve the institutional control of all manuals issued, these are registered in the International Standard Book Number (ISBN) in e-Book format.18 Subsequently, the manual is forwarded to the Division of Informatics for allocation to a specific directory on the hospital’s central server. In this directory, all books available for consultation can be found at a portal accessed by care network and intranet (Fig. 1). The access is free throughout HCUNICAMP in more than 1.700 computers. Currently, there are 79 manuals of support, care areas, and management available for consultation. Although each area has a printed copy of its manual, the electronic access is highly encouraged because of its advan- The content of the manual covers: • Mission and/or objectives of the area; • Area relationship map – consists in a model that represents the relationship between supplier, input, process, output and customers; • Macroflow of operational process of the area; • Description of the various processes of the areas, highlighted in the analytical index; • Description of the standards of occupational safety in each specific operational process; • Annexes relevant to each area, such as: regulatory standards, bibliographies, used documents and guidance booklets. After all processes were described in a certain area, the manual is referred to the Committee on Hospital Infection Control, that will analyze all procedures and techniques with which this document interfaces, assessing its compliance to standards and guidelines established for the infection control in the institution. If there is any non-compliance, a meeting is scheduled with the participation of members of the area of the manual in question and the HC-Manuals project coordinator, besides professionals of CCIH, for the needed conducts’ agreement. After the arrangements, the president of CCIH signs the processes with which he/she has interface.18 In parallel, the manual is also forwarded to the Labor Safety Service that performs the analysis of the activities and Fig. 1 – Images from the manual’s Portal, HC-Unicamp. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 tages: less paperwork, continuous and simultaneous access to manuals, frequent updating of content, access to all manuals and not only to that of a specific area, quick identification of the desired process and easy consultation. Results The manual of work processes for CEDMAC-HC-Unicamp was elaborated in a period of 10 months, in a participative manner with involvement of the entire multidisciplinary team, and published in the electronic portal of HC-Manuals in July 2012 in form of e-Book (ISBN 978-85-63274-17-5). The organizational structure of CEDMAC was addressed through: • Description of the objectives of the area in question, encompassing the intervention in care, teaching and research. • Map of supplier/process/client relationship that presents the interrelationships of the area with its key suppliers and internal and external customers (Fig. 2). • Macroflow of the operational process that summarizes, in graphic presentation, the care process (Fig. 2). In order to provide a basic technical knowledge indispensable to a good care practice by non-specialist professionals 189 of major and secondary levels, a chapter has been prepared addressing the biological drugs used in CEDMAC (Fig. 3) with respect to: • Differences between traditional and biological medicines. • Classes of biologicals used in rheumatology. • Major biological drugs used; their characteristics, indications, contraindications and usual dosage. The structure and operating rules of CEDMAC were described, as well as the duties of the professionals involved, specifying their accountability for tasks and hierarchical bonds. The profile of patients and their flow of access to the service were detailed. The origin of the administered medications, acquisition routine, control and care for their preservation were also described. Chapters on the technique of preparation and administration for each biological medicine used in CEDMAC were elaborated: infliximab, adalimumab, etanercept, abatacept, rituximab, tocilizumab (Fig. 3). Chapters were also prepared for zoledronic acid and cyclophosphamide that, although not biologicals, are eventually prescribed and require special care in their preparation and administration. The most frequent adverse events in the administration of these drugs and the recommended actions were also highlighted. Specific chapters detailed medical procedures and the systematization of nursing care performed in CEDMAC, as well as for administrative, teaching and research activities. A total of 19 chapters describing the work process and techniques were elaborated, besides those relating to the organizational structure and annexes (references, documents used in the area, a chronological table of educational documents and folders). Discussion Fig. 2 – Map of relationship and macro flow of the operational process of CEDMAC HC-Unicamp. Despite the hard work represented by the elaboration of the manual and of the required dedication of the multidisciplinary team, the results clearly justify it. Throughout the preparation process, care practices can be revised according to the literature and manufacturers’ guidelines for their own drugs, in relation to precautions in storage, preparation, application and user assistance. Small variations in practice between practitioners of CEDMAC regarding the handling of products were observed; this way, there is opportunity for adjustments of conduct. The possession of work processes and of described and accredited techniques facilitates the dissemination of specific technical knowledge of the area, the integration of new professionals, a continuing education for the multidisciplinary team and supervision of procedures. Due to its teaching and research activities (characteristics of HC-UNICAMP), the manual can also function as a guidance tool for trainees, including medical residents and graduate students. In addition to these benefits, with the manual of work processes and techniques from CEDMAC HC-Unicamp, there is a possibility of exchanging of information and experiences with other centers of infusion of biologic medicines in the area of rheumatology. 190 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 Fig. 3 – Content images of the work manual processes, CEDMAC HC-Unicamp. Conflicts of interest The authors declare no conflicts of interest. REFERENCES 1. McInnes IB, Sousa E, Fonseca JE. Treatment of rheumatoid arthritis. EULAR Course. 2010. p. 1-34. 2. Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med. 2012;159:2542-50. 3. Almoallim H, Kamil A. Rheumatoid arthritis: should we shift the focus from “Treat to Target” to “Treat to Work?” Clinical rheumatology [Internet]. 6 jan. 2013 [cited 14 February 2013];168. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23292522. 4. Smolen JS, Aletaha D, Bijlsma JWJ, Breedveld FC, Boumpas D, Burmester G et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Annals of the rheumatic diseases [Internet]. Abril 2010 [cited 10 February 2013];69:631-7. Available at: http://www.pubmedcentral.nih. gov/articlerender.fcgi?artid=3015099&tool=pmcentrez&render type=abstract. 5. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet [Internet]. 2004;364:263-9. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/15262104. 6. Firth J, Critchley S. Treating to target in rheumatoid arthritis: biologic therapies. British Journal of Nursing. 2011;20:1284-91. 7. Firth J. Rheumatoid arthritis: treating to target with diseasemodifying drugs. British Journal of Nursing. 2011;20:1240-5. 8. Corominas H, Sánchez-Eslava L, García G, Padró I, Aimarich C, Gonzàlez J et al. Safety profile of biological intravenous therapy in a rheumatoid arthritis patients cohort. Clinical nursing monitoring (Sebiol study). Reumatologia clinica [Internet]. SEGO; 22 October 2012 [cited 11 February 2013];1-5. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/23099285. 9. EMA – European Medicines Agency. Resumo das Características do Medicamento – Remicade. 2009. p. 1-56. 10. FDA – US Food and Drug Administration. Highlights of Prescribing Information – Infliximab. 2011. p. 1-47. 11. Verstappen SMM, Jacobs JWG, Van der Veen MJ, Heurkens HM, Schenk Y, Ter Borg EJ et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 8 5 – 1 9 1 Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Annals of the rheumatic diseases [Internet]. November 2007 [cited 11 February 2013];66:1443-9. Available at: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2111604&tool =pmcentrez&rendertype=abstract 12. Cavalcanti M, Gomes E, Pereira A. Gestão de empresas na sociedade do conhecimento: um roteiro para a ação. Rio de Janeiro, Campus, 2001. 13. Organização Nacional de Acreditação. Manual Brasileiro de Acreditação. Brasília, ONA, 2006. 3ª revisão. 14. Bork, AMT. Enfermagem de excelência: da visão à ação. Rio de Janeiro, Guanabara-Koogan, 2003. 191 15. Campos ER, Lima MBBPB, Martinez MHSL, Monticelli NAM. Metodologia de gestão por processos. Campinas, UNICAMP, 2003. 16. Nogueira LCL. Gerenciando pela qualidade total na saúde. Belo Horizonte, Desenvolvimento Gerencial, 1999. 17. Porfírio RBM, Munhoz S, Pinter MG. Gerenciamento de enfermagem em Centro Cirúrgico. In: Enfermagem em centro cirúrgico e recuperação. São Paulo, Manole, 2007. 18. Psaltikidis EM, Oliveira MA, Kitaka EL, Leichsenring ML, Fagnani R, Gama J et al. Portal de Manuais do Hospital de Clínicas da Unicamp: amplo acesso às informações institucionais. Boletim do Instituto de Saúde. 2013;14:247-253. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Evaluation of respiratory impairment in patients with systemic lupus erythematosus with the six-minute walk test Marivone Arruda Leite, Mônica Corso Pereira, Lílian Tereza Lavras Costallat, Wander de Oliveira Villalba, Marcos Mello Moreira, Ilma Aparecida Paschoal* Department of Internal Medicine, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil article info abstract Article history: Objective: Evaluate SLE stable patients, without overt respiratory compromise, by means of Received on 24 April 2013 6MWT. Accepted on 10 February 2014 Casuistic and methods: Forty-five stable SLE patients were enrolled. The ATS/ERS protocol for 6MWT, was used and two parameters with cut-off points were chosen. Keywords: Results: Forty-two patients were women. The mean age was 39 ± 11.4 years; mean duration Systemic lupus erythematosus of disease, 121 ± 93.1 months; mean value of MRC, 2 ± 0; mean FVC, 85.9 ± 34.2%; mean Six-minute walk test FEV1, 67.5 ± 21.6%; mean MIP, 82 ± 58.4%; mean MEP, 78 ± 37.3%; mean heart rate at rest, Oxygen saturation 75 ± 12.8 bpm; mean respiratory rate at rest, 19 ± 5.3 bpm; mean 6MWD, 478 ± 82 m; mean Respiratory function test SpO2 at rest was 98 ± 0.8%; mean fall in SpO2, 4 ± 6 points. When the study population was Questionnaires divided according to the 400-m walk distance cut-off value, the heart rate immediately before the test was significant lower in those participants who walked less than 400 m (p = 0.0043), just like the value of Borg scale (p = 0.0036); according to the presence of saturation ≥ 4, heart rate at the end of the test was significantly higher in those participants who were showing desaturation (p = 0.0170); MEP (p = 0.0282) and 6MWD (p = 0.0291) were significantly lower, and MIP showed a tendency towards being smaller (p = 0.0504). FVC < normal inferior limit was significantly associated with the group with desaturation (p = 0.0274). Conclusion: Compared to 6MWD, desaturation was better suited to find the patients with the most compromised indexes in respiratory function tests. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (I.A. Paschoal). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2014.02.017 193 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 Avaliação do comprometimento respiratório em pacientes com lúpus eritematoso sistêmico com o teste de caminhada de seis minutos resumo Palavras-chave: Objetivo: Avaliar pacientes com LES estável, sem comprometimento respiratório evidente, Lúpus eritematoso sistêmico (LES) por meio do TC6M. Teste de caminhada de seis Casuística e métodos: Foram recrutados 45 pacientes com LES estável. Foi utilizado o protoco- minutos lo ATS/ERS para TC6M, tendo sido escolhidos dois parâmetros com pontos de corte. Saturação de oxigênio Resultados: Quarenta e dois dos pacientes eram mulheres. A média de idade foi 39 ± 11,4 anos; Teste de função respiratória a duração média da doença, 121 ± 93,1 meses; valor médio de MRC 2 ± 0; CVF média 85,9 ± Questionários 34,2%; VEF1 médio 67,5 ± 21,6%; PIM média 82 ± 58,4%; PEM média 78 ± 37,3%; frequência cardíaca média em repouso 75 ± 12,8 bpm; frequência respiratória média em repouso 19 ± 5,3 bpm; Distância média no TC6M 478 ± 82 m; SpO2 média em repouso 98 ± 0,8%; queda média em SpO2 4 ± 6 pontos. Quando a população em estudo foi dividida de acordo com o valor de corte de 400 m de distância caminhada, a frequência cardíaca imediatamente antes do teste foi significativamente menor naqueles participantes que caminharam menos de 400 m (p = 0,0043), da mesma forma que o valor da escala de Borg (p = 0,0036). De acordo com a presença de saturação ≥ 4, a frequência cardíaca ao final do teste estava significativamente mais elevada naqueles participantes exibindo dessaturação (p = 0,0170); PEM (p = 0,0282) e TC6M (p = 0,0291) estavam significativamente menores e PIM revelou uma tendência para diminuir (p = 0,0504). CVF < limite inferior do normal foi achado significativamente associado com o grupo com dessaturação (p = 0,0274). Conclusão: Comparado com TC6M, a dessaturação foi o indicador mais apropriado para localizar os pacientes com os índices mais comprometidos nos testes de função respiratória. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Systemic lupus erythematosus (SLE) is a progressive autoimmune disease of unknown etiology and a broad spectrum of clinical manifestations, that has a chronic course with periods of exacerbation and remission. According to American studies, the disease most frequently affects young women (9-10:1), with its prevalence ranging from 14 to 50/100.000 inhabitants.1 A study involving Brazilian population observed a higher incidence in Caucasian patients2 and also in young women.3 In pulmonary manifestations, we have, by frequency, pleural involvement (pleural effusion, pleuritis). However, there may be vascular manifestations (pulmonary hypertension, alveolar hemorrhage), interstitial disease (interstitial pneumonia with possible progression to pulmonary fibrosis), neurological involvement (phrenic neuropathy and diaphragmatic paralysis), among other problems.4,5 The activation of the endothelial cells and the immunological deregulation, which leads to the production of many different autoantibodies, are the central pathological disturbances of the disease.5 The endothelial cells produce substances that control vascular tone and activate the immune and coagulation systems which, in their turn, have the same endothelial cells as targets of the inflammation generated by the immune processes and the coagulation cascade. Vascular injury is probably the primary site of lesion in lupus pathogenesis.5 The activation and damage of the endothelial cells of the immune system are capable of explaining the involvement of the renal, central nervous, cardiovascular and respiratory systems in patients with SLE.6 Apart from serositis, no other pulmonary or respiratory involvement appears in the list of diagnostic criteria proposed by the American College of Rheumatology (ACR).7 The diagnosis of SLE is not simple and requires the fulfillment of a minimum number of criteria from a set developed by the ACR.8 Various respiratory manifestations of SLE can provoke acute respiratory symptoms such as pleural thickening, pleural effusion and alveolar hemorrhage; however, some may be insidious and difficult to diagnose, such as interstitial lung disease or vascular disease, which are often silent for quite a long time. Early diagnosis of respiratory involvement in patients with lupus is fundamental because it allows the therapeutic management established in the earliest stages of the disease, which can prevent the progression to a more dramatic functional impairment. Therefore, it is essential to actively search for symptoms and to perform tests – preferably little or minimally invasive – which indicate involvement in early disease. Thus, 6MWT is a submaximal exercise test that has already been validated in the evaluation of several lung diseases.9-13 This test is easy to be performed, low cost and has a good correlation with other more sophisticated tests such as the diffusion test for carbon monoxide (DLCO) or cardiorespiratory.11,14 This study aimed to evaluate a patient group with stable SLE, without overt respiratory compromise, by six-minute walk test (6MWT), a self-paced and submaximal exercise test, in order to investigate the possibility of an unnoticed respiratory involvement. 194 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 Methods This was a cross-sectional study that enrolled stable SLE patients, diagnosed according to the updated and revised American College of Rheumatology (ACR) criteria,7 who attended the SLE outpatient clinic of the Teaching Hospital of the University of Campinas, between November 2007 and August 2009. All patients were evaluated in order to check if there was presence of any respiratory symptom. The patients were clinically stable – during the prior three months – using one or a combination of the following drugs: hydroxychloroquine, chloroquine, prednisone, azathioprine, and/or mycophenolate mofetil. None of them had recently changed their therapeuthic regimen. Six months before the study, all patients were radiographically evaluated by a radiologist and, if it had been noticed the presence of pleural thickening or pleural abnormalities suggestive of interstitial involvement or increased cardiac area in some of these patients, they would not have been included in the study. Patients would not be considered eligible for the 6MWT if they had a recent chest X-Ray showing any abnormality, hemoglobin concentration below normal values, complaints that could interfere with the walk, if the oxygen saturation (SpO2) levels in rest were under 90% on ambient air, or the pulse signal on a pulse oximeter was inadequate due to Raynaud’s phenomenon. Aiming to ensure an accurate assessment of SpO2, the respiratory therapist checked if the pulse oximeter showed an acceptable pulse signal and if the oximeter light was green and pulsing in synchrony with the heart rate before beginning all tests. The study was approved by the Research Ethics Committee of the Faculty of Medical Sciences of the University of Campinas, and an informed consent was signed by each patient. The protocol used for the 6MWT was designed to ensure an accurate assessment of the walking distance and the oxygen desaturation, as proposed by the American Thoracic Society.8 All patients were tested under standardized conditions by the same technician (ML). Baseline blood pressure and heart rate were measured and SpO2 was determined with a Nonin® pulse oximeter (finger probe) (Nonin Medical, Inc; MN, USA). The walking course had 30 m of length. The patients walked on a level surface and were gently encouraged periodically. Assessment of dyspnea by the Borg index was performed at the beginning and at end of the test. SpO2 was measured at rest and immediately after the end of the 6-minute period, and the patients were carefully observed to avoid dangerously exceeding their exercise limits. For the purpose of data analysis, desaturation was defined as a decrease in SpO2 of 4 points or more (Δsat = resting saturation – saturation immediately after the 6-minute period), in comparison with the initial values. Maximal distance was defined as the maximal achieved walking distance on room air 6MWT. Spirometric maneuvers were performed as recommended by Brazilian guidelines,15 and the curves for forced vital capacity (FVC) and slow vital capacity (VC) were performed using a flow spirometer (microQuark model; COSMED Srl, Rome, Italy). The measured values were compared with those predicted for age, sex and height for each patient, and the inferior limit of the normal value for FVC was used to diagnose the reduction in FVC.16 British MRC (Medical Research Council) questionnaire modified and translated to Portuguese was used to assess the degree of shortness of breath (0=o shortness of breath, except with strenuous exercise; 1=troubled by shortness of breath when hurrying or walking up a slight hill; 2=walks slower than people of the same age due to shortness of breath; need to stop for catch their breath when walking at their own pace; 3=stops to breath after walking for approximately 100 m or after a few minutes; 4=show themselves with an excessive shortness of breath; breathless when dressing or undressing).17 The static maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were determined using a digital manuvacuometer (MVD30-Globalmed). The maneuvers were performed as recommended in ATS/ERS statement about respiratory muscle testing18, and the normal values were expressed as percentage of expected values predicted for Brazilians.19 The quantitative variables measured in these groups were submitted to the Anderson-Darling test to define their distribution. Variables with normal distribution were analyzed using the Student t test. Variables identified as not having a normal distribution were studied with the Wilcoxon test. The categorical data were compared using chi-square test or Fisher’s exact test when necessary. The statistical software used was SAS, version 8®. Differences were considered significant in the face of a p-value < 0.05. Results There were forty-five consecutive patients enrolled who agreed to participate in the study and fulfilled the inclusion criteria. There were 42 women with 39 ± 11.4 years, in total. None of the patients were smokers. The duration of the disease was 121 ± 93.1 months in the occasion. The characteristics of the patients and their functional measurements are detailed in Table 1. The 6MWD was 478 ± 82 m and the SpO2 at rest was 98 ± 0.8%. The fall in SpO2 at the end of the 6MWT was 4 ± 6 points. The spirometric evaluation showed FVC of 85.9 ± 34.2 (% of predicted value) and 21 patients with FVC below the limit of normality. The MIP was 82 ± 58.4 and MEP was 78 ± 37.3 (% of predicted value). For the purpose of data analysis, two main variables were defined and used to separate the study population in groups: a fall in saturation (Δsat) ≥ 4% and walking distance < 400 m. Considering the cut-off value of 400 m of walking distance, no differences were found between the groups concerning age, disease duration, height, MIP, MEP, FVC, FEV1, FEV1/FVC, initial SpO2, Δsat, increase in heart rate, initial respiratory rate, increase in respiratory rate, and increase in the Borg scale value. In addition, no association was found for the groups regarding sex, MRC value and the finding of a FVC inferior to the low limit of predicted value. The heart rate obtained immediately before the test was significantly smaller in those participants who walked less than 400 m (p = 0.004) when considering the R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 Table 1 – Study population characteristics and functional measurements (n = 45) Variables Age (years) Height (cm) Duration of disease (months) MRC questionnaire FVC (% of predicted value) FEV1 (% of predicted value) MIP (% of predicted value) MEP (% of predicted value) Heart rate (bpm) Respiratory rate (cpm) SpO2 (%) 6MWD (m) Δ SpO2(%) Mean±SD Median (Min–Max) 39±11.4 161±7.5 121±93.1 2±0.5 85.9±34.2 67.5±21.6 82±58.4 78±37.3 75±12.8 19±5.3 98±0.8 478±82 4±6 39 (17-70) 162 (145-179) 96 (12-373) 2 (0-4) 81(31.6-247.7) 62.3 (30.4-113) 73(13-316) 75 (30-163) 70 (57-99) 18 (12-32) 98 (94-99) 500 (180-600) 1 (0-22) Mean ± SD, mean ± standard deviation; Median (Min-Max), Median (minimum and maximum); MRC, Medical Research Council; FVC, Forced Capacity Value; FEV1, Forced Expired Volume in one second; MIP, Maximal Inspiratory Pressure; MEP, Maximal Expiratory Pressure; 6MWD, Six minute walk distance; cpm, cycles per minute; bpm, beat per minute. Borg scale value (p = 0.004). The distance walked by the patients in the two groups was also significantly different (p < 0.001): the value in the group ≥ 400 m was 505.3 ± 53.7 m; and in the group < 400 m was 350.8 ± 70.4 m (Table 2). When the population studied was divided in two groups, according to the presence of desaturation ≥ 4 by the end of the 6MWT, no differences were found between the groups concerning age, disease duration, height, FEV1/FVC, initial SpO2, initial heart rate, initial respiratory rate, increase in respiratory rate, initial value and increase in Borg scale. The heart rate at the end of the test was significantly higher in those participants who showed desaturation (p = 0.017). MEP was significantly lower in the group with desaturation (p = 0.028) and MIP as well, but it did not reach significance (p = 0.050). The distance walked by the patients in the two groups was also significantly different (p = 0.029): the value in the group with desaturation was 443.1 ± 94.6 m and in the group without desaturation was 497 ± 68.5 m. The ΔSat was also significantly different in the two groups: the value in the group with desaturation was 11.6 ± 4.6 points; and in the one without desaturation, the fall was of 0.5 ± 0.9 points. The finding of a FVC below the limit of the normal expected value was significantly associated with the group with desaturation (p = 0.027) (Table 2). Discussion One finding that seems quite relevant in this study is that, within a population of SLE patients without relevant respiratory symptoms, the 6MWT can give useful information about respiratory compromise, especially if there is a reduction in SpO2 by the end of the test. It was considered a reduction equal to or greater than 4 points as significant, based on the findings by Prefaut et al., who validated this cut-off value in a study of exercise-induced hypoxemia during maximal exercise tests in 195 athletes.20 This 4% fall was defined as accounted for potential inaccuracy of oximetry plus the effects of metabolic acidosis on the hemoglobin saturation curve (a right shift).9 Subjects in this study with ΔSat ≥ 4% showed a significant reduction in walking distance (443 m versus 497 m, p = 0.029), although both values were way above the accepted inferior limit for 6MWD. Furthermore, these patients, when compared to those who did not desaturate had a higher heart rate at the end of the 6MWT (p = 0.017), lower MEP (p=0.028), lower MIP (p = 0.050) and a spirometry restrictive defect (FVC below the lower limit of predicted value, p = 0.027, with a normal FEV1/ FVC ratio). Conversely, those who walked less than 400 m showed no significant differences regarding initial saturation or ΔSat ≥ 4%. In addition, there were no significant differences between the groups with 6MWD < 400 m and MWD ≥ 400 m in spirometric values, heart rate, static pressures or severity of dyspnea, either. These findings suggest the hypothesis that desaturation during the 6MWT may be a useful tool to evaluate SLE patients without respiratory symptoms – perhaps more sensitive than the 6MWD. The 6MWT is a standardized submaximal test of exercise capacity that is self-paced, simple, reproducible and inexpensive. The measured variables are distance walked in 6 minutes (6MWD), symptoms and SpO2 at rest and at the end of the test.8 Because of its safety profile, physician attendance is not required, but a health professional, such as physiotherapist or a nurse, with clinical experience should supervise the patient during the test. Age, sex, height, weight and ethnicity are important determinants of an individual’s 6MWD. In general, men walk further than women; and the distance walked declines with increasing age.21 Equations are available to predict expected normal values of 6MWD, with some variation in the expected distances.21,22 A walking distance of less than 350 m has predictive value of increased mortality in a number of cardiopulmonary disorders, such as COPD, interstitial lung disease, pulmonary arterial hypertension, cystic fibrosis, congestive heart failure.10,11,14,22-24 Although the 6MWD is a sensitive measurement of walking ability for patients with moderate to severe disease, it is likely that its sensitivity in patients with better preserved exercise tolerance may not be so good. A ceiling effect was reported in patients with pulmonary arterial hypertension whose 6MWD is greater than 450 m, and this observation may be true for patients with other conditions.25 From the studies mentioned above, it can be seen that the cut-off value for the walking distance is not well established; apparently, it is between 350 m and 450 m. In this study, only 8 patients walked less than 400 m, with median value of 367.5 m and mean value of 350.8 ± 70 m. For the groups separated by the walking distance, the only statistically significant differences were initial heart rate (slower for those who walked less) and degree of dyspnea in Borg scale (smaller for those who walked less). There were no significant differences for these variables at the end of the 6MWT. It is hard to have an explanation for these findings, perhaps because of the small number of patients in one of the groups. 37.7±10.9 118.7±98.5 160.7±8.0 83.5±61.6 78.9±37.1 85.7±35.9 68.5±22.8 0.7±0.2 76.8±12.9 24.3±13.7 19.2±5.2 9±4.8 98.1±0.8 3.7±5.4 8.5±1.7 4.3±2.7 505.3±53.7 39 (17-62) 84 (12-373) 160 (145-179) 73 (29-316) 75 (31-163) 80.4 (31.6-247.7) 67.1 (30.4-113) 0.7 (0.39-0.99) 73 (57-99) 19 (4-60) 18 (12-32) 8 (0-20) 98 (94-99) 1 (0-16) 8 (6-13) 4 (0-10) 510 (401-600) Median (Min-Max) 43.1±13.3 129±67.2 163.4±4.1 73.5±42.8 76.3±40.4 87±26.4 62.6±13.9 0.7±0.2 64±4.9 23.9±12.8 19±6.0 8.1±4.2 97.9±0.8 8±7.8 6.8±1.0 5.5±3.2 350.8±70.4 Mean ± SD 40.5(26-70) 126(24-240) 163(157-169) 65(13-137) 71(30-123) 89.7(53-127.3) 58.5(47.5-83.6) 0.6(0.42-0.89) 64(57-70) 18(12-49) 18(12-32) 8(4-16) 98(96-99) 8(0-22) 6.5(6-9) 5.5(1-10) 367.5(180-397) Median (Min-Max) < 400 m (n= 8) 0.307 0.502 0.185 0.835 0.867 0.523 0.352 0.355 0.004 0.917 0.856 0.610 0.369 0.127 0.003 0.330 0.000 p value 38.9±9.2 117±95.8 158.9±5.5 61±33 63.9±35.4 70.1±27.9 57.5±18 0.7±0.1 76±15.8 29.4±12.2 21.4±6.3 10.6±5.1 97.8±1.2 11.6±4.6 7.8±1.4 5.4±3.1 443.1±94.6 Mean ± SD 38.5(17-51) 90(12-312) 160(150-169) 53.5(13-137) 56.5(30-150) 68.2(31.6-127.6) 55.8(30.4-91.3) 0.7(0.49-0.94) 69.5(57-99) 28(15-51) 20(12-32) 10(3-20) 98(94-99) 12(4-22) 8(6-10) 5.5(1-10) 450(180-600) Median (Min-Max) With desaturation (fall in SpO2 ≥ 4%) (n=16) 38.5±12.6 122.5±93.2 162.4±8.2 93.1±66.3 86.5±36.4 94.7±34.5 73±21.7 0.7±0.2 73.7±11.1 21.3±13.3 17.9±4.2 7.9±4.2 98.2±0.5 0.5±0.9 8.4±1.9 4±2.4 497±68.5 Mean ± SD 39(18-70) 120(12-373) 163(145-179) 84(30-316) 81(32-163) 93(53.4-247.7) 74.7(39.8-113) 0.7(0.39-0.99) 70(57-96) 17(4-60) 18(12-28) 8(0-16) 98(97-99) 0(0-3) 8(6-13) 4(0-9) 512(360-600) Median (Min-Max) Without desaturation (n=29) Δ Sat 0.914 0.830 0.091 0.050 0.028 0.015 0.015 0.231 0.952 0.017 0.080 0.080 0.139 0.000 0.396 0.132 0.029 p value Mean ± SD, mean ± standard deviation; Median (Min-Max), Median (minimum and maximum); 6MWD, 6 minutes walked distance; Δ Sat, Final SpO2 – Initial SpO2; MIP, Maximal inspiratory pressure; MEP, Maximal expiratory pressure; FVC, Forced Capacity Value; FEV1, Forced Expired Volume in one second; HR, Heart rate; ∆ HR, Final HR – Initial HR; cpm, cycles per minute; ∆ RR, Final RR – Initial RR; ∆ Borg, Final Borg – Initial Borg. Differences were considered significant with a p < 0.05. a Values expressed as % of predicted value. Age (years) Duration of disease (months) Height (cm) MIP * MEP * FVC * FEV1* FEV1/FVC Heart rate (bpm) ∆ HR (bpm) Respiratory rate (cpm) ∆ RR (cpm) Initial SpO2 % ∆ SpO2 (in % points) Initial Borg ∆ Borg 6MWD (m) Mean ± SD ≥ 400 m (n=37) 6MWD Table 2 – Comparison of functional variables and 6MWT parameters between the groups separated by distance and desaturation (n = 45) 196 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 The relation between walking distance and mortality is not seen in patients suffering from untreated pulmonary arterial hypertension, in whom desaturation during the 6MWT was a better predictor of mortality than walking distance: for every percent decrease in SpO2 there was a 26% increase in the risk of death.12 The desaturation during 6MWT has demonstrated its value as an index of severity of disease and prognostic factor. Lama et al. showed that, in patients with interstitial pulmonary fibrosis without resting hypoxemia, desaturation up to 88% at any point during the 6MWT was associated to an increased hazard of death; however, no associations between 6MWD and survival were observed.26 In this study, FVC values below the lower limit of normality, simultaneously reduced FEV1 and normal FEV1/FVC indexes, indicating the presence of a restrictive defect, were significantly more frequent among patients who showed desaturation. In addition, patients with desaturation had significantly lower MEPs and showed a trend towards significantly lower MIPs. The 6MWD was not able to detect the patients who had reductions in FVC, and not even the ones with reduced expiratory pressures. In this study, desaturation was associated with lower 6MWD, although the mean walking distance in the group that showed desaturation was much greater than 350 m. In our patients, an association between the presence of desaturation (Δsat ≥ 4%) with the values of MIP (p = 0.050) and MEP (p = 0.028) was observed, suggesting that some impairment of respiratory muscles, not only the diaphragm, was present. The presence of unexplained dyspnea, especially in the supine position, small lung volumes on chest radiographs, dysfunction and elevation of the diaphragm and pulmonary function tests displaying patterns of restrictive disease in the absence of parenchymal involvement prompt the diagnosis of shrinking lung syndrome. Some authors found that the ability of the diaphragm to generate pressure is impaired in patients with the shrinking lung syndrome;27 however, other authors28 were unable to show a reduced diaphragmatic strength in a cohort of 12 patients. In a comparison to the 6MWD, desaturation revealed itself as better suited to find patients with the most impaired indexes in respiratory function tests. A previous published study, carried out by our group, showed that desaturation during a 6MWT provides additional information regarding severity of disease in patients with scleroderma presenting pulmonary manifestations.13 Inter-test variation is high in cases of oxygen desaturation. This fact implies that therapeutic decisions should not be based on a single measurement of exertional desaturation recorded on a 6MWT. This inter-test variation is expressed by the finding of different values of SpO2 at the end of various tests performed by the same patient. In the study by Eaton et al., the value of hemoglobin desaturation upon pulse oximetry was found to be non-reproducible, with unacceptable measurement variation. However, instead of using the hemoglobin desaturation as a categorical variable, they computed the values of desaturation in two 6MWTs.29 We believe that the important information here is 197 the occurrence of desaturation per se, a fact that is not observed in normal subjects.21 We surely expect the value of desaturation to vary because of different homeostatic situations at different moments in individuals with pulmonary diseases and in whom gas exchange abnormalities are probably present. Except for the involvement of the pleura, the most common pulmonary manifestation of SLE, all other pulmonary manifestations are infrequent, and many of them may cause decrease oxygenation during exercise, by different pathogenic mechanisms. Those less common respiratory disorders in patients with SLE include: interstitial lung disease, acute lupus pneumonitis, diffuse alveolar hemorrhage, pulmonary arterial hypertension, thromboembolic disease, acute reversible hypoxemia and shrinking lung syndrome. It is worth reminding that the prevalence of respiratory symptoms and signs in patients with SLE vary depending on several factors, most importantly the methods used for diagnosing respiratory tract compromise. In athletes, the exercise-induced arterial hypoxemia is defined as a reduction in the arterial O2 pressure (PaO2) by more than 1kPa and/or hemoglobin O2 saturation (SaO2) below 95%, both determined by blood gas analysis. Desaturation is consistently found during maximal rowing ergometer and is most pronounced at the end of an exercise bout.30 Exercise-induced hypoxemia is explained by the interplay of many different factors. Alveolar PO2 must be maintained at a high level, so ventilation becomes a critical issue. A widening of the PAO2-PaO2 difference frequently occurs, indicating that diffusion limitation or a ventilation-perfusion mismatch or shunt may be influencing the transport of oxygen from the alveoli to the pulmonary capillaries. Cardiac output increases greatly, leading to a fast transit time of red cells in the lungs and further limiting O2 uptake. It is well known that a post-exercise reduction in pulmonary diffusion capacity really occurs, and this suggests damage to the alveolar-capillary membrane.31 All these factors have been proposed to be involved in exercise- induced hypoxemia, but the six-minute walk test is a submaximal exercise. Disease states may facilitate the occurrence of desaturation by all these mechanisms. Vascular injury with endothelial cell activation and damage play a central role in the pathogenesis of SLE.5 The vascular endothelial growth factor (VEGF) is the main mediator of angiogenesis, and increased levels of VEGF were found in serum from patients with rheumatoid arthritis, dermatomyositis/polymyositis, sclerodermapolymyositis, scleroderma complicated by interstitial lung disease,32 and SLE.33 The mitogen is connected to vascular hypertrophy, inflammation, tissue remodeling, extracellular matrix synthesis and fibrosis.34 Increased levels of endothelin-1, a potent vasoconstrictor, were observed in many collagen-vascular diseases including SLE. The combination of inflammatory vascular lesion, slightly elevated arterial pulmonary pressures and initial fibrotic interstitial disease impaired function of diaphragm with exercise stress, although submaximal, may explain the occurrence of desaturation during the 6MWT in SLE patients. Only the follow-up of these patients will be able to clarify the relevance of this desaturation during 6MWT; however, given the available data from studies that used other diseases, such as idiopathic pulmonary fibrosis and pulmonary arte- 198 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 1 9 2 – 1 9 9 rial hypertension, associated with a poor prognosis, a close monitoring of the patients with SLE who presented desaturation during the 6MWT is advisable. A recently published study assesses the association between quality of life and distance walked during the 6MWT in Brazilian premenopausal patients with SLE and compared with a healthy control group. The authors of this study concluded that patients with SLE walked a shorter distance during the 6MWT, which was associated with poorer quality of life.35 In addition to that, the finding of desaturation justifies the indication of a more thorough cardiorespiratory evaluation using echocardiogram, CT scans, measurements of diffusion capacity and total lung capacity. Conflicts of interest The authors declare no conflicts of interest. R eferences 1. Rus V, Maury EE, Hochberg MC: The epidemiology of systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois lupus erythematosus. 7th ed. Filadélfia: Lippincott Williams & Wilkins; 2007:34-44. 2. Sato EI, Natour J, Martinelli VPL, Assis LSS, Farão SR, Medeiros EL et al. Seguimento clínico e laboratorial de 132 pacientes com lúpus eritematoso sistêmico. Rev Bras Reumatol. 1991,31:57-62. 3. Costallat LTL & Coimbra AMV. 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Balsamo S, Nascimento Dda C, Tibana RA, de Santana FS, da Mota LM, Dos Santos-Neto LL. The quality of life of patients with lupus erythematosus influences cardiovascular capacity in 6-minute walk test. Rev Bras Reumatol. 2013;53:75-87. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Analysis of the association of fatigue with clinical and psychological variables in a series of 371 Brazilian patients with rheumatoid arthritis Washington A. Bianchi a,*, Fernanda R. Elias a, Geraldo da Rocha Castelar Pinheiro b, Carlos Roberto Machado Gayer c, Claudio Carneiro d, Rachel Grynzpan e, Paulo Hamdan f, Sueli Carneiro f Department of Rheumatology, Universidade Gama Filho, Rio de Janeiro, RJ, Brazil Department of Rheumatology, Universidade e Escola de Ciências Médicas, Rio de Janeiro, RJ, Brazil c Department of Biochemistry, Biologic Institute Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil d School of Medical Sciences and University Hospital, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil e Department of Dermatology, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil f Department of Internal Medicine, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil a b article info abstract Article history: Objectives: Fatigue is a highly subjective and extremely common symptom in patients with Received on 15 November 2013 rheumatoid arthritis although it is difficult to characterize and define. The aim of this study Accepted on 29 November 2013 was to assess fatigue in a cohort of Brazilian patients, and to analyze the relationship between fatigue and disease-specific variables. Keywords: Methods: 371 Brazilian patients diagnosed with rheumatoid arthritis according to the 1987 Rheumatoid Arthritis American College of Rheumatology classification criteria were prospectively investigated. Fatigue Demographic, clinical and laboratorial data were obtained from hospitals records. The Disease Activity number of painful joints, bone mass index, disease duration, quality of life, functional ca- Quality of Life pacity, anxiety and depression were recorded. Fatigue was evaluated using the subscale of Pain Fatigue Assessment of Chronic Illness Therapy (FACIT-FATIGUE scale). Results: The median fatigue score was 42.0 (10.0), negatively correlated with functional capacity (-0.507; P < 0.001), anxiety and depression (-0.542 and -0.545; P < 0.001 respectively), and predominantly with physical domain of Short Form 36-item quality of life questionnaire (SF-36P: 0.584; P < 0.001). The scores were not associated with the erythrocyte sedimentation rate (-0.118; P < 0.05), C-reactive protein (-0.089; P < 0.05), disease activity (-0.250; P < 0.001) or the number of painful joints (-0.135; P < 0.01). Confidence interval of 95% was applied for all measures. Conclusions: In this series of Brazilian patients with rheumatoid arthritis, we suggest a new significance for fatigue complains as an independent parameter not related with number of painful joints, disease or inflammatory activity scores. Psychological and functional im- * Corresponding author. E-mail: [email protected] (W.A. Bianchi). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.11.002 201 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 pairments appear to be more related to fatigue. Additional studies and inclusion of standard measures for monitoring fatigue complains are required. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. Análise da associação da fadiga com variáveis clínicas e psicológicas em uma série de 371 pacientes brasileiros com artrite reumatoide resumo Palavras-chave: Objetivos: A fadiga é um sintoma altamente subjetivo e extremamente comum em pacien- Artrite reumatoide tes com artrite reumatoide, embora seja difícil de caracterizar e definir. O objetivo desse Fadiga estudo foi avaliar a fadiga em uma coorte de pacientes brasileiros e analisar a relação entre Atividade da doença fadiga e variáveis específicas da doença. Qualidade de vida Métodos: Foram prospectivamente investigados 371 pacientes brasileiros diagnosticados Dor com artrite reumatoide, de acordo com os critérios de classificação do Colégio Americano de Reumatologia de 1987. Dados demográficos, clínicos e laboratoriais foram obtidos dos registros clínicos. Foram registrados o número de articulações dolorosas, índice de massa corporal, duração da doença, qualidade de vida, capacidade funcional, ansiedade e depressão. A fadiga foi avaliada com o uso da subescala específica da escala Fatigue Assessment of Chronic Illness Therapy (FACIT-FATIGUE). Resultados: O escore mediano para fadiga foi 42 (10), negativamente correlacionado com a capacidade funcional (-0,507; p < 0,001), ansiedade e depressão (-0,542 e -0,545; p < 0,001, respectivamente) e predominantemente com o domínio físico do questionário Short Form36 para qualidade de vida (SF-36P: 0,584; p < 0,001). Não houve correlação entre os escores e a velocidade de sedimentação das hemácias (-0,118; p <0,05), proteína C reativa (-0,089; p < 0,05), atividade da doença (-0,250;p < 0,001) ou número de articulações dolorosas (-0,135; p < 0,01). Para todas as medidas foi aplicado um intervalo de confiança de 95%. Conclusões: Nesta série de pacientes brasileiros com artrite reumatoide, sugerimos um novo significado para as queixas de fadiga como um parâmetro independente não relacionado com o número de articulações dolorosas ou escores de atividade inflamatória. Parece haver maior relação entre transtornos psicológicos e funcionais com a fadiga. Seriam importantes novos estudos e uso rotineiro de medidas padronizadas para a monitorização das queixas de fadiga. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to significant morbidity, joint deformity and an impaired quality of life (QoL). This disease affects approximately 0.5%-1% of the general population, with considerable variations being observed among different populations.1-3 Although the joints are the major loci of disease activity, fatigue is a notably common and disabling symptom experienced almost universally by patients with RA (88%98%), who consider the effect and importance of fatigue similar to pain.4-9 There is no universally accepted definition of fatigue. It can be either defined as a progressive impairment of capacity to generate muscle or a lessened capacity to work, with reduced efficiency of accomplishment, that are usually accompanied by feelings of weariness, sleepiness or irritability.10 Belza et al. described fatigue as an “enduring the subjective sensation of generalized tiredness or exhaustion”.11 In the general population, 20% of men and 30% of women complain about frequent tiredness.12 Fatigue often accompanies various illnesses, and has been increasingly recognized and studied in a number of chronic diseases, such as liver disorders, infections and hematological diseases.12 Hewlett et al. observed that RA fatigue is a different phenomenon from normal tiredness because it is extreme, endless and unresolved described as an important and overwhelming complaint.4 Studies examining the predictive factors of fatigue in RA reported not only physical but also psychological and social aspects related to fatigue.4,13,14 Pain, physical disability, inactivity and poorer sleep quality and psychosocial factors, such as depressive symptoms, anxiety and social stress (as long-term symptoms or associated conditions) are predictive of fatigue in RA.13,14 During the chronic course of RA, continuing inflammatory activity with periods of prolonged physical inactivity leads to muscle atrophy and instability of the periarticular structures with reduced strength and muscular endurance 202 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 that contribute to the onset of fatigue. Ekdahl et al. demonstrated that 80% of patients with RA exhibited changes in muscle strength and coordination of the lower extremities and decreased aerobic activity. These results were confirmed by Semble et al.15,16 In 1996, Rall et al. evaluated the effect of an exercise program to improve the muscle strength in patients with RA and observed a significant reduction in fatigue (38%).17 Due to fatigue’s multifactorial and multidimensional nature, this condition is difficult to assess. Little is known concerning the correlations, adequate measurements or the clinical management and interventions for fatigue.4,18 Persistent fatigue is one of the most significant obstacles to optimizing function in these patients.19 The aim of this study was to analyze aspects of fatigue in 371 Brazilian RA patients, and the association of fatigue with disease-specific variables, such as inflammatory activity, pain, QoL, physical function, and psychological complains, such as anxiety and depression. Methods A total of 371 patients with RA were recruited at the Department of Rheumatology of Hospital da Santa Casa da Misericórdia do Rio de Janeiro (HSCMRJ) and Hospital Universitário Pedro Ernesto (HUPE) into this cross-sectional prospective study from 2010-2011. Patients were between the ages of 18 and 65 years, diagnosed with RA according to the 1987 American College of Rheumatology (ACR) RA classification criteria.20 For all of the patients invited and included in the study written informed consents were provided. The research was conducted with approval by and in accordance with the Ethics Committee of both hospitals. The patients who were unable to understand and respond the questionnaires or who had any comorbidities that might interfere with the assessment of fatigue, such as anemia (hemoglobin > 9.0 mg/dl), endocrine diseases (diabetes type I and II, thyroid diseases), renal failure (creatinine < 2.0mg/dl), liver diseases including cirrhosis, pulmonary (Chronic Obstructive Pulmonary Disease) or cardiovascular disorders, were excluded. Demographic and clinical data were collected including duration of disease, number of painful peripheral joints and body mass index (BMI). Disease activity was clinically measured, using the 28 joint count Disease Activity Score (DAS 28), and biologically, using the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Physical function was assessed by the Health Assessment Questionnaire-Disability Index (HAQ DI), where scores range from 0 to 3, and higher scores indicate lower levels of physical functioning.21,22 The health-related quality of life (HRQol) was assessed using physical and mental scores of the Short-Form 36-Items Health Survey (SF-36P and SF-36M) generic questionnaire.23 The Hospital Anxiety and Depression Scale (HAD a/d) was used to evaluate the depression and anxiety symptoms. This questionnaire has 14 interlaced questions: one-half of the questions were related to anxiety, and one-half to depression. For each question, a value from 0 to 3 is added to each domain separately, building the two sub-scales. Patients with results greater than 8 are considered at risk of anxiety and/or depression independently.12 All questionnaires used were validated and culturally adapted to the Portuguese language.12,21–23 Fatigue was evaluated using a subscale of the Functional Assessment of Chronic Illness Therapy (FACIT), which was initially validated to assess QoL in patients with cancer or other chronic illnesses. The scale was used for RA patients, who only scores the fatigue complains (FACIT-Fatigue). The total score ranges from 0 to 52, and higher scores represent less fatigue.24 The FACIT-Fatigue was validated for Portuguese version through an authorization from the site http:// www.facit.org. Statistical analysis Calculating the minimum patient number with precision measurements estimated under parameters of 90% with confidence interval of 0.20 and α = 0.05, we got a minimum sample size of 258 patients. Considering that both departments of Rheumatology treat approximately 800 patients with RA per year, 30%-40% of which fulfill the inclusion/exclusion criteria, the sample size could be about 240 to 320 patients. Taking into account also that the fatigue complains could be present in 25% to 60% of RA patients,4,5,10,18,20,25,26,27 we found a sample size of 200 to 480 of those hospital’s populations. We decided to establish a final sample size between 320 to 480 patients. After two years of recruitment, 371 patients with useful data were finely included in this study. All data were tested for normality by applying the Shapiro-Wilk Test. As all variables showed non-normal distribution, the variables were presented by median (interquartile range). Spearman’s rank correlation coefficient (rs) was calculated to determine correlations between fatigue and clinical or psychological measures. All tests were 2-sided, and P values ≤ 0.05 were considered statistically significant. Statistical analysis was performed using Statistica software, version 8.0 (Statsoft. Inc. Tulsa, USA). Results A total number of 371 patients were evaluated. The group studied included 335 women (90.3%) and 36 men (9.7%). The demographic and clinical data, which are summarized in Table 1, indicated the majority of our patients were white (66.8%), followed by mixed-race patients (20.5%), and black patients (12.7%). The median age was 51 (13) years and the BMI was 25.0 (3.6). The mean score of fatigue (FACIT–Fatigue) was 42.0 (10), and the mean number of painful joints was 6 (6). The median disease duration was 6 (6) years. The median disease activity, as assessed by DAS 28, was 4.7 (2). The median ESR was 33 (27) mm, and the median of CRP level was 0.8 (1.7). When the DAS 28 cut-off values for measuring inflammatory disease activity were applied, 7.0% of the patients were 203 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 Table 1 – Baseline characteristics of RA patients (n = 371) Characteristics Women Ethnic group White Mixed-race Black Age BMI Disease duration (year) Laboratory assessment of disease activity ESR CRP Clinical assessments DAS 28 HAQ DI SF-36 Physical domain Mental domain HAD a HAD d FACIT-Fatigue Number of Painfull joints Mean (sd) or n (%) Median Min Max - CI 95% + CI 95% 248 (66.8) 76 (20.5) 47 (1.7) 49.5 (10.2) 25.2 (3,9) 7.8 (5,8) 51.0 25.0 6.0 18.0 16.3 1.0 65.0 43.9 43.0 48.6 24.8 7.2 50.7 25.6 8.4 36.2 (22.7) 1.8 (3.2) 33.0 0.8 2.0 0.1 118.0 33.5 33.9 1.5 38.5 2.2 4.6 (1.4) 1.0 (0.7) 86.9 (8.5) 39.1 (10.5) 47.6 (11.0) 7.0 (3.4) 5.4 (3.6) 39.9 (8.6) 6.83(4.78) 4.7 0.8 87.5 39.5 50.1 7.0 5.0 42.0 6.0 0.0 0.0 51.0 12.1 12.4 0.0 0.0 4.0 0.0 8.1 2.8 99.6 68.3 96.1 20.0 20.0 52.0 28.0 4.4 0.9 86.0 38.1 46.5 6.7 5.0 39.0 6.4 4.7 1.0 87.7 40.2 48.8 7.4 5.7 40.8 7.3 335 (90.3) in remission (DAS 28 < 2.6), 7.8% had lower disease activity (DAS 28 ≥ 2.6 ≤ 3.2), 9.7% had moderate disease activity (DAS 28 ≥ 3.2 ≤ 5.1), and 75.5% of the sample had high disease activity (DAS 28 > 5.1). The median score of the SF-36 was 87.5 (12.2). The means of the physical and mental subscales were 39.1 (10.5) and 47.6 (11.0), respectively. The mean of the HAQ DI was 1.0 (0.7). The anxiety and depression questionnaire (HAD a/d) showed means of 7.0 (3.4) for anxiety, and 5.4 (3.6) for depression, respectively. The distribution of disease activity (DAS 28) and duration of illness (years) in this sample of RA patients are shown in Fig. 1. The correlations between fatigue (FACIT-Fatigue), quality of life (SF-36), functional capacity (HAQ DI), painful joints, anxiety and depression (HAD a/d), DAS 28, ESR and CRP are shown in Table 2. The correlations of fatigue with QoL, anxiety and depression or functional capacity are shown in the graphs of Figs. 2 and 3. Table 3 presents the correlations of fatigue with disease activity measured by ESR, CRP and DAS 28 and the QoL by the physical and mental domains of SF-36 (SF-36P and SF36M), functional capacity by HAQ DI, the number of painful joints, and anxiety or depression as measured by HAD a/d in patients with moderate and high disease activity (DAS 28 ≥ 3.2). Discussion This study was the first in our country to analyze a sample of 371 Brazilian patients with RA, assessing fatigue by FACIT-Fatigue, a 13-items measure of fatigue that previously showed good internal consistency in patients with RA. Number of patients BMI: Bone Mass Index, ESR: Erythrocyte Sedimentation Rate, CRP: C Reactive Protein, DAS 28: 28 Disease Activity Index, HAQ DI: Health Assessment Questionnaire Disability Index, SF-36: Short-Form 36-item, HAD a/d: Hospital Anxiety and Depression Scale, FACIT-Fatigue: Fatigue Assessment of Chronic Illness Therapy. High Moderate Low Remission Disease duration (years) Fig. 1 – Distribution of disease duration with disease activity by DAS28 and number of patients. In recent years, fatigue has emerged as an important outcome in RA,4,8,13,14 although the symptoms are largely ignored in terms of clinical care and educational and research endeavours. The multifactorial and multidimensional characteristics of fatigue demand a broad analysis that takes into consideration the clinical, cultural and social aspects of fatigue complaints and includes the patient’s perspective. In Rio de Janeiro, a cosmopolitan coastal city, the mixed population and the tropical climate with a majority of sunny days could modify the perception of fatigue and its correlation to the indices of disease activity, QoL, functional capacity, pain, anxiety and depression. Cella D et al. validated the FACIT-Fatigue, comparing it to other scales such as the Multidimensional Assessment of Fatigue (MAF) and the SF-36 in 636 patients with RA for 24 weeks in a double blind, randomized trial using anti-TNF 204 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 alpha monoclonal antibody and placebo, where the psychometric performance of the FACIT-Fatigue scale for assessment of fatigue was comparable to the other scales.24 The demographic findings of gender and ethnicity are similar to previous reports, which indicate a female and white predominance, reflecting the typical incidence of RA Table 2 – Analysis of Spearman’s correlations coefficient of all patients ESR ESR CRP SF-36P SF-36M HAD a HAD d DAS 28 HAQ DI Facit fatigue Painful joints 0.467* -0.203* -0.161* 0.101 0.130* 0.472* 0.190* -0.118* 0.220* CRP SF36-P SF36-M HAD-a HAD-d DAS28 HAQ-DI Facit fatigue Painful joints 0.467* -0.203* -0.191* -0.161* -0.024 0.121* 0.101 0.072 -0.328* -0.477* 0.130* 0.103* -0.406* -0.437* 0.648* 0.472* 0.356* -0.439* -0.131* 0.169* 0.244* 0.190* 0.189* -0.672* -0.175* 0.294* 0.347* 0.356* -0.118* -0.089 0.584* 0.405* -0.542* -0.545* -0.250* -0.507* 0.220* 0.203* -0.293* -0.019 0.060 0.101* 0.725* 0.219* -0.135* -0.191* -0.024 0.072 0.103* 0.356* 0.189* -0.089 0.203* 0.121* -0.328* -0.406* -0.439* -0.672* 0.584* -0.293* -0.477* -0.437* -0.131* -0.175* 0.405* -0.019 0.648* 0.169* 0.294* -0.542* 0.060 0.244* 0.347* -0.545* 0.101* 0.356* -0.250* 0.725* -0.507* 0.219* -0.135* ESR: Erythrocyte Sedimentation Rate, CRP: C-Reactive protein, SF-36: Short-Form 36-item, SF-36P: Short-Form 36-item Physical domain, SF-36M: Short-Form 36-item Mental domain, HAD a: Hospital Anxiety Scale, HAD d: Hospital Depression Scale, DAS28: Disease Activity Score, HAQ DI: Health Assessment Questionnaire – Disability Index, and FACIT fatigue: Fatigue Assessment of Chronic Illness Therapy. *Statistically significant (p < 0.05). A A 70 22 20 60 18 16 50 12 40 HAD-a SF-36F 14 30 10 8 6 20 4 2 10 0 0 95% confidence 0 10 20 30 40 50 -2 60 95% confidence 0 10 20 30 40 50 60 40 50 60 Facit-fatigue Facit-fatigue B B 3,0 22 20 2,5 18 16 2,0 12 1,5 HAD-d HAQ DI 14 1,0 10 8 6 0,5 4 2 0,0 0 -0,5 95% confidence 0 10 20 30 40 50 Facit-fatigue Fig. 2 – Spearman’s correlations coefficient between FACIT fatigue and SF-36 (A) and HAQ DI (B). 60 -2 95% confidence 0 10 20 30 Facit-fatigue Fig. 3 – Spearman’s correlations coefficient between FACIT fatigue and HAD a (A) and HAD d (B). 205 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 Table 3 – Analysis of Spearman’s correlations coefficient of patients with high and moderate disease activity (n = 316) n = 316 Facit-fatigue ESR CRP SF-36P SF36M HAD a HAD d DAS 28 HAQ DI Painful joints -0.108 -0.065 0.577* 0.456* -0.539* -0.528* -0.218* -0.489* -0.080 ESR: Erythrocyte Sedimentation Rate, CRP: C Reactive Protein, SF36P: Short-Form 36-Item Physical domain, SF-36M: Short-Form 36-Item Mental domain, HAD a: Hospital Anxiety and Depression Scale-anxiety domain, HAD d: Hospital Anxiety and Depression Scale-depression domain, DAS 28: Disease Activity Score, HAQ DI: Health Assessment Questionnaire Disability Index, and FACIT fatigue: Fatigue Assessment of Chronic Illness Therapy. *Statistically significant (p < 0.001). patients. These results differ in ethnic characteristics of Brazilian population, in which 47.7% are white according to data from the Brazilian Institute of Geography and Statistics (IBGE).28 The disease duration was under 10 years, and for the largest number of patients there had been less than 5 years since symptoms onset and diagnosis confirmation. The mean disease activity quantified by DAS 28 score of 4.6, shown in Table 1, confirms that most of our cohort exhibit moderate or high disease activity. Based on our findings, fatigue did not correlate with disease activity. As shown in Table 2, the FACIT-Fatigue has not demonstrated correlation with CRP, ESR and DAS 28, which are routinely evaluated as inflammatory disease activity indexes. The FACIT- Fatigue demonstrated a moderate correlation with functional capacity (HAQ DI), as shown in Fig. 2B, Table 2; anxiety and depression (HAD a/d), shown in Fig. 3, and predominantly with the physical domain of quality of life (SF-36P), shown in Fig. 2A. A similar analysis with moderate and high disease activity (DAS 28 > 3.2) subgroups of this sample confirmed the absence of a correlation between fatigue and disease activity, shown in Table 3. This finding is in accordance with Huyser et al., who suggested that fatigue in RA is not related to disease activity and showed that many of the variables that were significantly correlated with fatigue had a psychosocial basis.25 Such factors, as anxiety and higher depressive symptoms, were significantly associated with increased fatigue, as was seen in this study (Fig. 3). The best predictors of fatigue were higher levels of pain, more depressive symptoms and female gender, which were independent of disease activity.25 Our study showed that the number of painful joints, measured by the first item of DAS 28, did not correlate with fatigue independently of the level of pain or the patient global assessment. Bergman et al. showed that fatigue is not an inflammatory variable and has virtually no correlation with the number of swollen or tender joints. These researchers showed a moderate association of fatigue with DAS 28, and 79% of the complaints could be explained by the patient global assessment.29 Yacoub et al. assessed fatigue in 248 patients with RA, finding a prevalence of fatigue in approximately 90% and, in contrast to our results, a significant association with disease activity.30 Thyberg et al. suggested that disease activity is among the factors closely related to fatigue.31 This study, using the HAD a/d scale, determined a correlation between fatigue and emotional aspects, such as depression and anxiety, shown in Fig. 3 and Table 2, which was reported by Huyser et al. Depression is a frequent complaint associated with fatigue in RA patients with a prevalence of 13%-20%, which is 2 to 3 times higher than observed in healthy people.25,32,33 The presence of pain, joint swelling and deformities, as well as functional disabilities and work or leisure restrictions in RA patients, could explain the higher number of depression cases. Functional disabilities result in reduction of self-confidence and QoL, leading to a depressive mood. Several authors attempted to correlate depression, anxiety and fatigue.25,34-36 Tack et al. found that in the RA population, higher fatigue was strongly associated with depressive symptoms, pain, and poorer overall mood.36 A recent study by Munsterman et al. confirms earlier results that depressive symptoms are associated with fatigue.27 We observed a moderate correlation of fatigue with QoL (SF-36) and functional capacity (HAQ DI), as presented in Fig. 2. Yacoub et al. report that fatigue was significantly associated with functional disability.30 Pollard et al. found similar results with a significant relationship between fatigue and functional disability, suggesting that severe fatigue had a negative impact on patients QoL.37 Thyberg et al. suggest that fatigue is related to physical aspects of disability such as pain, activity limitation and mental aspects, which may be a psychological reaction to physical disability.31 Each of these studies measures fatigue by different questionnaires, scales and methods, achieving results that are not directly comparable. Regarding the application of FACIT–Fatigue as a specific instrument of fatigue evaluation in RA patients, these data showed consistency and significant correlation with other protocols (SF-36, HAD a/d, HAQ DI) demonstrated in Figs. 2 and 3, with significant values being observed in Table 2. These findings indicate that patient’s complaint of fatigue is an independent data in the analysis of disease evolution. We suggest a new significance for fatigue complaints in RA patients, which is an independent parameter that is not related to inflammatory activity. Fatigue appears to be related to the physical capacity and emotional symptoms associated with the negative effect of disability on the quality of life of some patients. Reports in the literature are conflicting, most likely because of the multifactorial etiology of fatigue and its correlation with physiological, psychological, social, personal and individual disease aspects, as well as the non-existence of a standardized evaluation method. These results emphasize the need for a better understanding of fatigue in RA patients with additional studies and an inclusion of standard measures for monitoring the symptoms and clinical management of fatigue. As recently recommended by OMERACT, psychological and psychosocial interventions, taking into account considerations that the 206 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 0 – 2 0 7 patient’s perspective should be considered in studies and clinical practice to improve the results of treatment of fatigue.38 Conflicts of interest The authors declare no conflicts of interest. REFERENCES 1. Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006;36:182-8. 2. Lee DM, Michael L. Weinblatt rheumatoid arthritis. The Lancet. 2001;358:903-9. 3. Symmons DP, Barrett EM, Bankhead CR, Scott DG, Silman AJ. The incidence of rheumatoid arthritis in the United Kingdom: results of the Norfolk Arthritis Register. Br J Rheumatol. 1994;33:735-9. 4. Hewlett S, Cockshott Z, Byron M, Kitchen K, Tipler S, Pope D et al. 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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Original article Evaluation of postural control and quality of life in elderly women with knee osteoarthritis Júlia Guimarães Reisa,*, Matheus Machado Gomesa, Thamires Máximo Nevesa, Marina Petrellaa, Renê Donizeti Ribeiro de Oliveirab, Daniela Cristina Carvalho de Abreua Department of Biomechanics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil Department of Clinical Medicine, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil a b article info abstract Article history: Objective: To assess the balance in dynamic tasks and in the quality of life in elderly women Received on 8 May 2013 with and without knee osteoarthritis. Accepted on 12 November 2013 Methods: Elderly women were divided into Group 1 (n = 12), consisting of participants with bilateral knee osteoarthritis (Kellgreen-Lawrence grade 1 and 2), and Group 2 (n = 12), con- Keywords: sisting of controls. A force plate (EMG System do Brazil) was used to assess postural sway in Osteoarthritis dynamic tasks, whereas the quality of life was assessed by using the WHOQOL-Bref ques- Knee tionnaire. Elderly Results: Student’s t-test showed no statistical difference during sitting down and standing Quality of Life up from the chair (p > 0.05). However, stair ascent revealed difference in displacement speed (p < 0.05), whereas stair descent showed differences in both displacement speed and amplitude (p < 0.05). In the questionnaire, Group 1 showed values lower than those in the control group regarding physical domain (p < 0.05). Conclusion: Elderly women with knee osteoarthritis seemed to have more difficulty on stair descent task and had perception of worst physical domain. These findings were observed in OA group, even in the early stages of the disease, which shows the importance of even earlier interventions. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (J.G. Reis). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.11.001 209 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2 Avaliação do controle postural e da qualidade de vida em idosas com osteoartrite de joelho resumo Palavras-chave: Objetivo: Avaliar o equilíbrio em tarefas dinâmicas e a qualidade de vida em idosas com e Osteoartrite sem osteoartrite no joelho. Joelho Métodos: As idosas foram divididas em: Grupo 1 (n = 12), consistindo de idosas com osteo- Idosos artrite bilateral no joelho (Grau Kellgreen-Lawrence 1 e 2); e Grupo 2 (n = 12), consistindo Qualidade de vida de controles. Foi empregada uma plataforma de força (EMG System do Brasil) para avaliar a oscilação postural em tarefas dinâmicas; já a qualidade de vida foi avaliada mediante a aplicação do questionário WHOQOL-Bref. Resultados: O teste t de Student não demonstrou diferença estatística durante as ações de ficar de pé e sentar em uma cadeira (p > 0,05). Contudo, a tarefa de subir escadas revelou diferença na velocidade de deslocamento (p < 0,05), enquanto a tarefa de descer escadas demonstrou diferenças tanto na velocidade como na amplitude do deslocamento (p < 0,05). No questionário, o Grupo 1 demonstrou valores mais baixos do que os obtidos no Grupo de controle, no que diz respeito ao domínio físico (p < 0,05). Conclusão: Aparentemente, idosas com osteoartrite no joelho tiveram mais dificuldade na tarefa de descer escadas e pior percepção de domínio físico. Esses achados foram observados no grupo com OA, mesmo nos estágios iniciais da doença, o que demonstra a importância de intervenções ainda mais precoces. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Methods The aging process causes changes in several organ systems, which may result in alterations in people’s lifestyle and in their quality of life as well. Together with these alterations, some chronic-degenerative joint diseases like osteoarthritis (OA) can manifest themselves in elderly individuals.1 OA is one of the most common musculoskeletal complaints worldwide.2 According to the World Health Organisation (WHO), this is the fourth leading cause of disability among women.3 Individuals with OA are more likely to have pain, decrease in range of movement (ROM), decline in muscle function4 and balance, thus resulting in functional limitation and decreased capacity to perform activities of daily living.5-7 About 18% of elderly have difficulty performing one or more activities of daily living, mainly those requiring muscle force, mobility and balance such as standing up and sitting down from a chair, stair ascent and descent.7,8 Limitations in these tasks can lead to both loss of functional capacity and reduction in quality of life.4,9 Based on the muscle-joint dysfunctions individuals with knee OA have, one can question whether the early stages of this disease interferes with postural control during performance activities of daily living and people’s quality of life, since there are very few studies on this theme.10-12 Therefore, the objectives of the present study were to evaluate the balance in dynamic tasks as well as the quality of life regarding physical, social, psychological, environmental and global domains in elderly individuals with and without knee OA. The subjects, all female, taking part in the study were divided into two groups: Group 1 (n = 12), consisting of elderly individuals with bilateral knee OA and mean ± SD age of 67.25 ± 4.65 years, mean weight of 72.09 ± 10.13kg and mean height of 1.54 ± 0.06m; and Group 2 (n = 12), consisting of elderly individuals without OA (controls) whose mean age, mean weight, and mean height were, respectively, 65.58 ± 4.23years, 64.51 ± 8.59kg, and 1.55 ± 0.05m. Group 1 had knee OA Kellgreen-Lawrence (K/L) grade 1 and 213 diagnosed by a rheumatologist in accordance with the American College of Rheumatology criteria.14 X-ray radiographs involved antero-posterior and lateral aspects. The Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) was used to measure pain, with Group 1 having mean score of 0.77 (value ranging from 0 to 1, that is, no pain to little pain).15 Group 2 was not submitted to X-ray examination for ethical reasons, with the controls exhibiting no symptom in lower limbs that could characterize OA. Those individuals, in both groups, having neurological diseases, vestibulopathies, neuropathies, history of fracture and lesions in lower limbs in the last 6 months or other complications that could affect their balance were excluded from study. The volunteers were recruited from the Outpatient Rheumatology Center of the Ribeirão Preto School of Medicine (CSE-FMRP-USP) as well as from the community. The study was approved by the ethics research committee (protocol number 291), with all the volunteers signing a free informed consent before participating in the study. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2 Results Fig. 1a and 1b show, respectively, amplitude and speed of the CoP displacement in antero-posterior (AP) direction of subjects from both groups during the tasks of standing up and sitting down. Student’s t-test showed no difference in the variables between both groups (p > 0.05). This means that women with OA exhibited a balance similar to that of controls performing such activities. Fig. 2a and 2b show, respectively, amplitude and Fig. 2b of the CoP displacement in antero-posterior (AP) direction of subjects during stair ascent and descent task. During stair ascent the Student’s t test revealed difference for displacement speed (p < 0.05), whereas displacement amplitude was found to be similar between both groups (p > 0.05). On the other hand, differences were found in both displacement speed and b) a) 14.0 COP Displacement (cm/s) 2.5 OA Control COP Speed (cm/s) 12.0 10.0 8.0 6.0 4.0 2.0 0.0 2.0 1.5 1.0 0.5 0.0 Fig. 1 – Values of both amplitude (a) and speed (b) of the CoP displacement in antero-posterior (AP) direction from both groups during standing up and sitting down task. a) 20.0 Ascent Descent 15.0 10.0 * 5.0 0.0 OA 4.0 COP Speed (cm/s) To evaluate postural sway in dynamic situations (standing up and sitting down from a chair, stair ascent and descent), a force platform (EMG System do Brasil) was used to quantify both antero-posterior (AP) displacement amplitude and speed of the center of pressure (CoP). Data were analyzed by using Matlab software. During the tasks of standing up and sitting down, elderly women were asked to stand up from the chair with their arms crossed over the chest and remain in standing position for 30 seconds, looking at a marker positioned at 1.5 m from the chair and then sitting down again. The subjects were initially positioned on the chair with knees and hips flexed at 90 degrees. With regard to task on stairs, the subjects were instructed to go up and go down 3 steps, each one measuring 17.8 cm height, 80 cm width, and 30.5 cm depth, using one foot at once. The platform was placed on the first step of the stairs. All the tasks were repeated three times.16 The Brazilian version of the validated WHOQOL-Bref questionnaire, which is the condensed version of the World Health Organisation Quality of Life Instrument 100 (WHOQOL-100), was used to assess the quality of life. This instrument consists of 26 questions, where 24 encompass four domains of quality of life (physical capacity, psychological well-being, social relations, and environmental in which the subject is inserted), whereas two questions (questions 1 and 2) are on global quality of life.17 Each question has answers ranging from 1 to 5. The final scores of each domain are those regarding the mean scores of each question multiplied by 4, thus resulting in final scores within a scale ranging from 4 to 20 that is proportional to that from WHOQOL-100 instrument (scale from 0 to 100). Questions 3, 4 and 26 were re-coded as (1 = 5), (2 = 4), (3 = 3), (4 = 2), (5 = 1), and the higher the score the better the quality of life. By using the Shapiro-Wilks normality and the Levene’s variance homogeneity tests, it was observed that the mean values of the subjects had normality and variance homogeneity. As a result, the Student’s t test for independent samples was employed for comparison between Groups 1 and 2. Analyses were performed by using the SPSS software (SPSS for Windows, Version 16.0, SPSS Inc.) The alpha value was set at 0.05. COP Displacement (cm) 210 b) 3.0 * 1.0 0.0 Control * 2.0 OA Control Fig. 2 – Values of both amplitude (a) and speed (b) of the CoP displacement in antero-posterior (AP) direction from both groups during stair ascent and descent task. amplitude during stair descent task (p < 0.05). Women with OA showed higher speed and greater amplitude of CoP displacement compared to controls. Table 1 lists the results for questions 1 and 2 as well as for the four domains of WHOQOL-Bref instrument regarding both groups. Women with OA had lower scores for physical domain compared to controls. Discussion During the activities in which there are postural changes (dynamic tasks), it is needed to control the movement of center of pressure in relation to the support base. The balance control is crucial for performing daily life activities involving maintenance of static posture as well as complex dynamic movements.6 Subjects suffering from knee OA have joint and muscle changes, most frequently associated with local pain that can, in turn, impair the ability to perform dynamic tasks and consequently interfere with the quality of life. Table 1 – Values (mean ± SD) obtained in the Questionnaire WHOQOL-bref of Osteoarthritis (OA) and control group Groups Question 1 Question 2 Physical Domain Psychological Domain Social Domain Environmental Domain * Significant T Test OA Control 14.5 ± 4.1 13.1 ± 4.0 13.2 ± 2.6 15.0 ± 3.2 16.2 ± 3.0 14.4 ± 1.3 16.0 ± 4.2 16.3 ± 3.6 17.2 ± 1.6 14.4 ± 2.2 17.0 ± 1.4 15.2 ± 2.9 p value 0.41 0.06 0.001* 0.62 0.44 0.44 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2 211 The present study evaluated the balance in elderly individuals with and without knee OA during functional tasks such as standing up and sitting down from a chair and stair ascent and descent. Additionally, quality of life was also evaluated in both groups. According to Hinman18 (2002), because several daily activities require balance, understanding the impact of knee OA on the postural sway can help clarify the poor mechanisms in this population in addition to allowing a more effective treatment to be established. It is important to use tests that reflect the dynamism of motion tasks during evaluation of the balance.19 It was expected that the subjects with knee OA exhibited changes in their balance while performing the experimental tasks because of pain, muscular, proprioceptive and ROM alterations, resulting from such a disease. However, the degree of OA can influence differently in the individuals’ physical capacity. The results of this study showed no difference in the speed, and amplitude of CoP displacement was found between the groups in this study for the tasks of standing up and sitting down, probably because the subjects with OA were in the initial stages of the disease. It is also possible that the task of standing up and sitting down was not difficult enough to affect the postural control of subjects with OA (K/L grade 1 and 2). Alencar et al.10 (2007) have evaluated the shift in the center of gravity in faller and non-faller individuals with knee OA by using the stand-up test and no difference in the displacement speed was observed. It is important to keep the control of the center of gravity while performing a movement in order to avoid excessive forward or backward displacement. With regard to stair ascent and descent tasks, it was observed significant differences in AP displacement amplitude of CoP during stair descent only, and AP displacement speed of CoP during stair ascent and descent task. The results of the present study showed that individuals with OA had alterations in postural control during stair ascent and descent, although such changes were greater in the latter task probably. For some authors, the ability to walk stairs may require much effort by elderly subjects whose motor function is impaired due to the presence of diseases like osteoarthritis.20,21 In the present study, despite the presence of little or no pain it was possible to observe changes in postural control at Group 1. Other studies have reported that the decrease in muscle strength over time can impair the capacity to reduce CoP sway during stair descent, with elderly individuals having more difficulty in keeping their balance while descending stairs rather than ascending stairs.16,22 In fact, this finding is corroborated by our results. On the other hand, Mian et al.23 (2007) observed no difference in the AP displacement between healthy young and elderly men during the task of stair ascent and descent. important to evaluate the quality of life of individuals suffering from OA as this information helps determine adequate interventions as well as their efficacy. An increasingly used approach is the use of questionnaires containing questions on the individual’s perception on his or her health.25 The present study has used the WHOQOL-Bref instrument to assess the perception on the global quality of life of individuals with and without knee OA regarding physical, psychological, social and environmental domains. It was observed a difference in perception physical domain only, which involves questions such as: How much does your pain (physical) prevent you from doing what you need to do? How much medical treatment do you need to function in your daily life? Do you have enough energy for your daily tasks? How well do you move? How well do you sleep? How well are you performing your daily activities? How well are you performing at your job? Subjects with knee OA had lower scores than that of controls, thus demonstrating that even the early stages of OA have negatively influenced the perception of them on quality of life. Alves and Bassitt26 (2013) reported that worse functional capacity was associated with lower quality of life scores after correlation between WOMAC and WHOQOL-OLD in elderly women with knee OA. Alexandre et al.27 (2008) observed a negative correlation between functionality domain assessed by questionnaire WOMAC and functional capacity, physical aspect, pain and general health assessed by SF-36. They suggest that elderly with knee OA that have more difficulty in performing activities of daily living (ADL) also have worse perception of important domains of quality of life. The present study corroborates these findings since subjects with OA had alterations in the postural control during stair descent and also worse perception of physical domain in the WHOQOL-OLD. The decline in physical performance has become an increasing major public health problem because of the higher number of elderly people.28 Together, pain and functional disability often account for a significant reduction in the quality of life.27 The present study may have some limitations regarding small sample size and lack to evaluate variables reflecting the questions addressed in the WHOQOL-Bref instrument, such as time spent for performing the tasks and quality of gait. Although consisting of a small sample size, the present study evaluated balance and quality of life in women with initial stages of OA and some significant differences were observed between groups. Elderly women with knee OA may have had more difficulty in stair descent task as they exhibited more AP displacement and speed CoP, which is a risky situation for them. Furthermore, subjects with knee OA showed a lower score in physical domain than that of controls, confirming that the physical changes possibly caused by OA were perceived by them. Quality of Life Conclusion The evaluation of the functional capacity plays an important role in understanding the effects of OA on physical deficit and disability in elderly individuals.24 For Moskowitz12 (2009), it is Therefore, the worst postural control during stair descent stairs and lower scores in the physical domain were observed in OA group, even in the early stages of the disease, which 212 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 0 8 – 2 1 2 shows the importance of interventions ever earlier to maintain or improve balance in dynamic tasks and physical capacity, since functional deficits due to knee OA could negatively affect the quality of life. It is expected that the improvement of physical aspects, provided by physiotherapy treatment, reflects positively on their quality of life. Further studies with a larger sample should be conducted to confirm these results. Conflicts of interest The authors declare no conflicts of interest. REFERENCES 1. Huang MH, Lin YS, Yang RC, Lee CL. A comparison of various therapeutic exercises on the functional status of patients with knee osteoarthritis. Semin Arthritis Rheum. 2003;32:398-406. 2. Badley EM, Tennant A. Impact of disablement due to rheumatic disorders in a British population: estimates of severity and prevalence from the Calderdale Rheumatic Disablement Survey. Ann Rheum Dis. 1993;52:6-13. 3. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145-55. 4. Kaufman KR, Hughes C, Morrey BF, Morrey M, Ann KN. Gait characteristics of patients with knee osteoarthritis. J Biomech. 2001;34:907-15. 5. Felson DT, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention [review]. Arthritis Rheum. 1998;41:1343-55. 6. Guccione A, Felson DT, Anderson JJ, Anthony MJ, Zhang Y, Wilson PW et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham study. Am J Public Health. 1994;84:351-8. 7. Landers KA, Hunter GR, Wetzstein CJ, Bamman MM, Weinsier RL. The interrelationship among muscle mass, strength, and the ability to perform physical tasks of daily living in younger and older women. J Gerontol A Biol Sci Med Sci. 2001;56A:B443-8. 8. Gornick ME, Warren JL, Eggers PW, Lubitz JD, De Lew N, Davis MH et al. Thirty years of Medicare: Impact on the covered population. Health Care Financ Rev. 1996;18:179-237. 9. Bennell KL, Hinman RS, Metcalf BR, Crossley KM, Buchbinder R, Smith M et al. Relationship of knee joint proprioception to pain and disability in individuals with knee osteoarthritis. J Orthop Res. 2003;21:792-7. 10. Alencar MA, Arantes PMM, Dias JMD, Kirkwood RN, Pereira LSM, Dias RC. Muscular function and functional mobility of faller and non-faller elderly women with osteoarthritis of the knee. Braz J Med Biol Res. 2007;40:A277-83. 11. Moskowitz RW. The burden of osteoarthritis: clinical and quality-of-life issues. The Am J Manag Care. 2009;12:S223-8. 12. Salaffi F, Carotti M, Stancati A, Grassi W. Health-related quality of life in older adults with symptomatic hip and knee osteoarthritis: a comparison with matched healthy controls. Aging Clinical and Experimental Research. 2005;17:255-63. 13. Park HJ, Ko S, Hong HM, Ok E, MD, Lee JI. Factors related to standing balance in patients with knee osteoarthritis. Ann Rehabil Med. 2013;37:373-8. 14. Altman R, Asch E, Bloch D, Bole D, Borenstein K, Brandt K et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Arthritis Rheum. 1986;29:1039-49. 15. Bellamy N, Watson-Buchanan W, Goldsmith CH, Campbell J. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833-40. 16. Lee HJ, Choub LS. Balance control during stair negotiation in older adults. J Biomech. 2007;40:2530-6. 17. Fleck MPA, Louzada S, Xavier M, Chachamovich E, Vieira G, Santos L et al. Aplicação da versão em português do instrumento abreviado de avaliação da qualidade de vida “WHOQOL-Bref”. Rev Saúde Pública. 2000;34:178-83. 18. Hinman RS, Bennell KL, Metcalf BR, Crossley KM. Balance impairments in individuals with symptomatic knee osteoarthritis: a comparison with matched controls using clinical tests. Rheumatology. 2002;41:1388-94. 19. Shumway-Cook A, Brauer S, Woollacott M. Predicting the probability for falls in community-dwelling older adults using the timed up & go test. Phys Ther. 2000;80:896-903. 20. Brechter JH, Powers CM. Patellofemoral joint stress during stair ascent and descent in persons with and without patellofemoral pain. Gait Posture. 2002;16:115-23. 21. Costigan PA, Deluzio KJ, Wyss UP. Knee and hip kinetics during normal stair climbing. Gait Posture. 2002;16:31-7. 22. Hamel KA, Cavanagh PR. Stair performance in people aged 75 and older. J Am Geriatr Soc. 2004:52:563-7. 23. Mian OS, Narici MV, Minetti AE, Baltzopoulos V. Centre of mass motion during stair negotiation in young and older men. Gait Posture. 2007;26:463-9. 24. Lin YC, Davey RC, Cochrane T. Tests for physical function of the elderly with knee and hip osteoarthritis. Scand J Med Sci Sports. 2001;11:280-6. 25. Meenan RF, Mason JH, Anderson JJ, Guccione AA, Kazis LE. AIMS2: The content and properties of a revised and expanded arthritis impact measurement scales health status questionnaire. Arthritis Rheum. 1992;35:1-10. 26. Alves JC, Bassitt DP. Qualidade de vida e capacidade funcional de idosas com osteoartrite de joelho. Einstein. 2013;11:209-15. 27. Alexandre TS, Cordeiro RC, Ramos LR. Fatores associados à qualidade de vida em idosos com osteoartrite de joelho. Fisioter Pesqui. 2008;15:326-32. 28. Hammerman D. Clinical implications osteoarthritis and ageing. Ann Rheum Dis. 1995;54:82-5. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Review article Pre-operative anesthetic assessment of patients with rheumatoid arthritis Rodrigo Barbosa Airesa, Jozélio Freire de Carvalhob, Licia Maria Henrique da Motac,* Anestesiology Service, Instituto de Cardiologia do Distrito Federal, Brasília, DF, Brazil Centro Médico do Hospital Aliança, Salvador, BA, Brazil c Rheumatology Service, Hospital Universitário de Brasília, Universidade de Brasília, Brasília, DF, Brazil a b article info abstract Article history: The management and surgical interventions of problems directly or indirectly arising from Received on 25 January 2013 rheumatoid arthritis vary drastically. Anesthesiologists and rheumatologists should be aware Accepted on 15 August 2013 of the peculiarities of the anesthetic preoperative assessment of these patients, including the assessment of possible disorders of the airways, in addition to the intra-operative manage- Keywords: ment and analysis of relevant pharmacological parameters. It is critical that the anesthetist Rheumatoid arthritis is familiar with the peculiarities of the disease and the specific characteristics of drugs used Anesthesia in its treatment: thus, he/she will be able to plan the best possible anesthetic technique for Preoperatory evaluation the surgery in question, offering safety and comfort to his/her patient. It is up to the rheu- Surgery matologist to know the procedure to which the patient will be submitted to and be aware of the most appropriate anesthetic technique in each case. This will allow a better interaction between the rheumatologist and the anesthesiologist in the pre-anesthetic evaluation, through the sharing of relevant information on the articular and systemic involvement by the disease that might interfere with preoperative and intraoperative management. Furthermore, the information on the pre-anesthetic assessment and the choice of anesthetic technique will enable the rheumatologist to clarify any doubts that his/her patient and family may have, as well as to guide them as to whether or not the medications in use should be maintained, and eventually about the need for a supplemental dose of corticosteroid. The objective of this review is to acquaint the rheumatologist with key concepts related to the anesthetic preoperative assessment of patients diagnosed with RA, mainly including general notions that dictate the choice of the anesthetic technique. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (L.M.H. da Mota). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.08.002 214 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 Avaliação anestésica pré-operatória de pacientes com artrite reumatoide resumo Palavras-chave: O manejo e as intervenções cirúrgicas de problemas decorrentes direta ou indiretamente Artrite reumatoide da artrite reumatoide variam drasticamente. O anestesiologista e o reumatologista devem Anestesia estar atentos às peculiaridades da avaliação anestésica pré-operatória desses pacientes, Avaliação pré-operatória incluindo a avaliação de possíveis distúrbios das vias aéreas, além do manejo intraope- Cirurgia ratório e da análise dos parâmetros farmacológicos pertinentes. É essencial que o médico anestesiologista esteja familiarizado com as peculiaridades da doença e com as características específicas das drogas utilizadas no seu tratamento, pois, assim, ele poderá planejar da melhor forma possível a técnica anestésica para o ato cirúrgico em questão, oferecendo segurança e conforto ao paciente. Ao reumatologista, cabe conhecer o procedimento a que o paciente será submetido e ter noção da técnica anestésica mais indicada em cada caso. Isso permitirá melhor interação entre o reumatologista e o anestesiologista na avaliação pré-anestésica, através do compartilhamento de informações relevantes sobre o acometimento articular e sistêmico pela doença que possam interferir com o manejo pré e intraoperatório. Além disso, as informações sobre a avaliação pré-anestésica e a escolha da técnica de anestesia contribuirão para que o reumatologista possa esclarecer dúvidas que o paciente e seus familiares porventura apresentem, bem como orientá-los quanto à manutenção ou não das medicações em uso e, eventualmente, da necessidade de suplementação da dose do corticosteroide. O objetivo desta revisão é familiarizar o reumatolostia com os principais conceitos relacionados à avaliação anestésica pré-operatória de pacientes com diagnóstico de AR, incluindo, principalmente, as noções gerais que ditam a escolha da técnica anestésica. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Rheumatoid arthritis (RA) is a systemic, chronic, progressive inflammatory disease, which mainly affects the synovial membrane, and which can lead to bone and cartilaginous destruction. The management and surgical interventions of conditions directly or indirectly arising from RA vary drastically.1,2 Anesthesiologists and rheumatologists should be aware of the peculiarities of the anesthetic preoperative assessment of these patients, including the assessment of possible disorders of the airways, in addition to the intra-operative management and analysis of relevant pharmacological parameters.3 The objective of this review is to acquaint the rheumatologist with key concepts related to the anesthetic preoperative assessment of patients diagnosed with RA, mainly including general notions that dictate the choice of the anesthetic technique. Methodology From June to December 2012, a literature review was performed, including searches using the following databases: Medline (1990-2012), Cochrane Library, Lilacs, Pubmed (1990-2012) and Scopus, in English, Portuguese and Spanish languages. The key words used were “artrite reumatoide” (rheumatoid arthritis), “avaliação pré-operatória” (preoperative evaluation), “propofol” (propofol), “etomidato” (etomidate), “anestesia venosa total” (total intra-venous anesthesia), “anestesia geral” (general anesthesia), “anestesia regional” (regional anesthesia) and “controle das vias aéreas” (airway control). Preoperative evaluation The goals of a preoperative assessment of patients with RA are assessing the extent of disease involvement, its systemic consequences and possible adverse effects of therapies in use, to minimize the risk of anesthetic and surgical procedures.4 In the preoperative evaluation of patients with RA, in addition to a routine history and physical examination applicable to all patients (a record of the surgical procedure that will be performed, systemic medical evaluation, a history of drug use, prior surgeries, allergies, a detailed physical examination and relevant ancillary tests), an evaluation of the extent of involvement of the disease and its possible implications regarding the anesthetic technique should be performed. We list the affections (divided by topics) of the sites most commonly involved by RA which entail special considerations for the anesthetic procedure. Cervical spine Regarding the involvement of peripheral joints, especially the hands, RA may affect the axial skeleton in the neck.5 This involvement may occur both in an early as in a late stage of the disease. Most patients are asymptomatic, but about 4085% may have neck pain associated with the radiographic R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 presence of instabilities (atlanto-axial subluxation and superior migration of the odontoid process).6,7 An interesting prospective observational trial that included 100 patients with early RA (<1 year of symptoms) showed atlanto-axial subluxation in 12% of the cases within the first 5 years of the disease.8 A radiological evaluation of the cervical region in a neutral profile, with maximum flexion and extension, prior to elective surgical and endoscopic procedures, can be performed in patients with RA.6,9 Trials that show the actual cost-effectiveness of this routine assessment in the management of anesthesia and surgery are still lacking.9 Fiber optic laryngoscopes can be employed in the management of patients with RA when general anesthesia with intubation is considered necessary.10 In this situation, it is important that efforts are employed to prevent hyperextension of the neck, a common occurrence in airways manoeuvres. Temporomandibular joint RA can also affect the temporomandibular joints. For the anesthesia, the implication will be the reduction of mouth opening and a commonly occurring cervical stiffness that make difficult both the intubation procedures and the positioning of head and neck in surgeries performed in this region.11 Some authors recommend the use of the Mallampati score, mouth opening and mandible protrusion as preoperative predictors of temporomandibular dysfunction.12 215 Cardiovascular system Patients with RA may present early atherosclerosis secondary to dyslipidemia (particularly a reduction in HDL-cholesterol), presence of systemic hypertension and smoking.20 The activity of inflammatory disease is also a factor to be considered.21 Heart failure is a major cause of mortality in RA. Thus, a story addressed to atherosclerotic disease is mandatory in patients with RA who will be submitted to anesthetic procedures. In those patients with symptoms or risk factors, an assessment of cardiovascular situation through non-invasive methods such as ECG, echocardiography and myocardial scintigraphy is recommended. If ischemic lesions are detected, catheterization and possible corrections (i.e., angioplasty or CABG) are mandatory. Impairment of the conduction system and valvular involvement are also possible.22 The risk for developing cardiovascular disease appears to be underestimated by the current methods employed; thus, an even greater attention to this group of patients is necessary.23 Renal system The use of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclosporine may lead to a risk of kidney damage in patients with RA.2,24 Gastrointestinal system Cricoarytenoid dysfunction The larynx may be affected in approximately 80% of patients with RA.13 Generally, patients are asymptomatic, but in those cases with symptoms, these can be represented by a foreign body sensation in the oropharynx, dysphagia, dyspnea, hoarseness, stridor, and also by an airway obstruction.5,14,15 The direct visualization of the larynx may reveal cricoarytenoid and vocal cords dysfunction during inspiration.16 In patients in whom this disorder is suspected , nasoendoscopy with visualization of the larynx is recommended, besides the use of the tracheal tube with a smaller diameter, a quiet intubation without trauma on the laryngeal structures, administration of oxygen by catheter after extubation, removal of the tracheal tube in an appropriate environment prepared for emergencies and, in severe cases, the possibility of a preventive preoperative tracheostomy.15,17 In the postoperative phase of RA patients, after the tracheal extubation the patient should be observed closely for signs of laryngeal dysfunction and airway obstruction. Respiratory system Another important aspect to be considered is the presence of lung injury. In fact, trials have shown a reduction in vital capacity and total lung volume in patients with RA, even in the absence of pulmonary fibrosis.18,19 The presence of rheumatoid nodules is another possible injury that can lead to inflammation with possible dyspnea and accumulation of lung fluid.18,19 The use of medications such as methotrexate brings a potential risk of lung disease.19 The almost universal use of NSAIDs in patients with RA carries the risk of gastrointestinal tract injury.24 In fact, trials show a higher prevalence of gastritis and ulceration with possible risk of bleeding in the digestive tract of these patients.25,26 The prophylaxis of peptic ulcer and gastrointestinal bleeding should be performed, especially in NSAIDs users. Patients using glucocorticoids and with diverticulitis should be considered at high risk for perforation of the gastrointestinal tract.27 Endocrine system The Cushing's syndrome characteristic effects of the glucocorticoids are well known. For those patients who are under prednisone or who used this drug within an year, there is a need to perform an intravenous injection of hydrocortisone 100 mg at the time of anesthesia induction.28,29 General measures such as prophylaxis of venous thrombosis should also be considered in patients with RA, such as the use of elastic stockings, adequate hydration and prophylactic use of heparin. One must bear in mind that these patients have limited mobility and some of them will have a longer post-operative recovery than patients not affected by this condition (50).25 Difficulties may emerge while handling catheters used for continuous blockages in patients on immunosuppressive therapy, corticosteroids and biologic drugs, due to an increased risk of infections. Some joint deformities resulting from RA can impact the conduct of anesthesia and the choice of the anesthetic technique, because they compromise the patient positioning during surgery and hinder the access to 216 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 the techniques of regional blockade, causing difficulties associated with nervous plexus blocks.4 Choice of the anesthetic technique The choice of anesthetic technique generally depends on the general condition of the patient and on the type of proposed surgical procedure; there is not one specific optimal technique for patients with RA.5,30 One should take into account the risks inherent to each technique, the possible side effects of the anesthetics used and the experience of the anesthesiologist. Table 1 summarizes the main anesthetic techniques used, including a brief description of the technique, its indications and absolute and relative contraindications, in addition to considerations on the appropriate choice for patients diagnosed with RA. The use of general, inhalatory, total venous or balanced anesthesia may provide better control of the cardiovascular and respiratory systems, without imposing a time limit for the duration of surgery,30 as it occurs with the use of non-continuous techniques of regional anesthesia. The use of general anesthesia is also useful in situations where there is a need to keep the patient in unusual or uncomfortable positions, as it occurs in some orthopedic and neurosurgical procedures.5 Special attention should be paid to a proper protection of the limbs and neck in order to avoid worsening of pre-existing injury or the onset of a new lesion.28,31 Another very important aspect in general anesthesia procedures refers to the maintenance of airway patency. In this situation, the risk is due to pathological changes caused by RA, which are atlanto-axial subluxation and temporomandibular ankylosis.30 During the manoeuvres of airway instrumentation, one incurs in the risk of worsening the situation and of possible permanent neurological injury.28,31 Thus, a careful assessment of the presence and intensity of subluxation is required in the pre-anesthetic evaluation. In suspected or proven cases, the tracheal intubation manoeuvres should be gentle, avoiding sudden or exaggerated manoeuvres. As previously mentioned, the use of fiber optic bronchoscopy is of great help in such cases, because it allows an adequate access to the airways with minimal cervical mobilization.30,32 In extreme cases, intubation with the patient awake can be easily achieved by a suitably trained anesthesiologist, with minimal sedation.30,32 Also with regard to the airways, the occurrence of ankylosis of the temporomandibular joint can bring additional risk during anesthesia, since the occurrence of small mouth openings to less than 2 cm is possible. Such cases will also benefit from the use of a flexible fiber optic bronchoscope.32,33 An alternative to endotracheal intubation would be the use of a laryngeal mask, which provides a clear airway with less airway trauma.34 Even so, the anesthesiologist must be careful, since there are reports that its use can worsen the symptoms of cricoarytenoid involvement of RA.35 Another aspect to be considered is the effect, on pharmacokinetics, of psychotropic drugs by the organic changes caused by the disease, or by its treatment. Cardiac changes could imply in the need of changes in hypnotic inducing drugs, with an option by less cardiodepressant medications such as etomidate or midazolam.34,36,37 Hepatic or renal impairment may require drugs with less dependence on its exception, e.g., cisatracurium, the neuromuscular blocker of choice in cases of these organ dysfunctions (metabolism by plasma esterases)38,39 and propofol or etomidate as hypnotic drugs and remifentanil as an opioid with plasma metabolism.40 All these procedures are important in order to reduce the risk of drug recirculation, with possible deleterious effects such as respiratory depression and the eventual risk of an emergency approach to airways.41,42 An alternative to general anesthesia would be the use of one of the several techniques of regional anesthesia, in which sodium channel blocking drugs, the local anesthetics, are applied near peripheral nerves or nerve trunks, with no need for airway instrumentation.43 The most common contraindications for the use of regional techniques are the use of anticoagulant drugs or of potent antiplatelet agents, patient objections, hemodynamic instability (in neuraxial techniques, because of the extensive sympathetic blockade) and infection at the puncture site. The most common type of anesthesia for procedures on the lower limbs is the spinal anesthesia with the application of local anesthetics administered alone or in combination with opioids for the provision of an effective postoperative analgesia. The addition of clonidine or soluble opioids (e.g., sufentanil) to intratecal bupivacain significantly improves the duration and quality of spinal anesthesia and provides an extended perioperative analgesia, without significant side effects.40,42 There is evidence of increased extent of subarachnoid blockade in patients with rheumatoid arthritis, and this may justify a reduction of the doses of anesthetics in these individuals.44 Prolonged postoperative analgesia can be achieved through a combination of peripheral nerve blocks (e.g., femoral nerve, lumbosacral plexus, and tibial, saphenous or fibular nerves); this strategy yields an excellent analgesia with minimal side effects and less need for systemic opioids.5 Likewise, the anesthesiologist can choose the peridural use of local anesthetics as the selected technique; in this case he can recur to continuous techniques with peridural catheters, which ensures an extension of the anesthetic effect and the possibility of an efficient post-operative analgesia, contributing to less risk of thromboembolism, facilitating early ambulation and reducing the risk of pulmonary complications such as atelectasis and pneumonia.45-48 For the upper limbs, the brachial plexus anesthetic blockades fulfil a similar function, providing high quality anesthesia to the surgeon for prolonged periods and also allowing the option in favour of a continuous technique for the postoperative analgesia.49,50 Also with regard to the choice of drugs, attention should be paid to the use of drugs to treat the disease or to control the symptoms. NSAIDs can lead to gastrointestinal haemorrhages, and the steroids may predispose to adrenal insufficiency in stress situations, such as the surgical procedure, imposing the need for supplementation in the perioperative period.29 Disease modifying drugs, such as methotrexate and leflunomide, may trigger peripheral neuropathies; their previous documentation is important in those cases in which the anesthesiologist favoured a regional technique, which use of the risk of nerve trauma can always be questioned.3 The unconsciousness and analgesia remain by continuous inhalation of a halogenated anesthetic. Widely used in children without orotracheal intubation or with laryngeal mask. Description Surgical procedures with less painful potential, as very high inhaled fractions are required to achieve surgical anesthesia for major surgery, with the emergence of side effects such as myocardial depression and vasodilatation. Any surgical procedure. Indications The analgesia, loss of consciousness and muscle relaxation are maintained through the use of various drugs. Currently there are infusion pumps that allow a controlled target infusion of medication (with the objective of achieving a certain plasma concentration) with rapid awakening. Intubation and controlled ventilation are required. Balanced general Association of intravenous drugs and Any surgical procedure. anesthesia inhaled agents, seeking lower doses of each class, and minimizing the side effects. Intubation and controlled ventilation required. Regional anesthesia Administration of local anesthetics near Surgical procedure restricted nerve trunks or plexuses, or at cauda to the area of coverage of the equina. Provides analgesia in great anesthetized nerve trunk or regions of the body, with consciousness plexus. The duration of the and spontaneous ventilation maintained. surgical act limited to the duration of the chosen local anesthetic agent. General intravenous anesthesia Inhalational anesthesia Anesthetic technique Hypovolemia, coagulopathy, use of potent antiplatelet agents, anticoagulants, sepsis, infection at the puncture site. Past or suspected malignant Need for airway manipulation; hyperthermia, which allows maintenance of the patient can be triggered by the even in awkward positions. halogenated agent. Allergy to any of the drugs used. No agreement by the patient. Provides long-lasting analgesia; can be difficult to implement due to improper body positioning; obviate the manipulation of the airways. Possible difficulty in airway control. Need for airway manipulation; allows maintenance of the patient even in awkward positions. Need for airway manipulation; allows maintenance of the patient even in awkward positions. Considerations for use in patients with RA If propofol was the chosen drug, allergy to any of the drugs used, mainly to egg and soy. Past or suspected malignant hyperthermia, which can be triggered by the halogenated agent. Absolute contraindications Possible difficulty in airway control. Possible difficulty in airway control. Relative contraindications Table 1 – General characteristics of the most commonly used anesthetic techniques and considerations for their indications and contraindications in patients with RA R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 217 218 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 Conclusion With the evolution of RA treatment, the consequent increase in patients’ life expectancy and reduction of morbidity and mortality, it will be increasingly common that these people have a need for any surgical procedure throughout their lives. It is therefore critical that the anesthetist is familiar with the peculiarities of the disease and the specific characteristics of the pharmacological agents used in its treatment. Thus, this professional can plan in the best possible way the anesthetic technique for the surgery in question, offering safety and comfort to his/her patient. It is up to the rheumatologist to know the procedure that his/her patient will be submitted to and be aware of the most appropriate anesthetic technique in each case. This will allow better interaction between the rheumatologist and the anesthesiologist in the pre-anesthetic assessment, through the sharing of relevant information on the articular and systemic involvement by the disease that might interfere with the preoperative and intraoperative management. Furthermore, the information on the pre-anesthetic assessment and the choice of anesthetic technique will enable the rheumatologist to clarify any doubts that his/her patient and family may have, as well as to guide them as to whether or not the medications in use should be maintained and eventually about the need for a supplemental dose of corticosteroid. Conflicts of interest The authors declare no conflicts of interest. REFERENCES 1. Timmermann A. Supraglottic airways in difficult airway management: successes, failures, use and misuse. Anaesthesia. 2011;66:45-57. 2. da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo MB et al. 2012 Brazilian Society of Rheumatology consensus for the treatment of rheumatoid arthritis. Rev Bras Reumatol. 2012;52:152-175. 3. Reddy D, Trost LW, Lee T, Baluch AR, Kaye AD. Rheumatoid arthritis: current pharmacologic treatment and anesthetic considerations. Middle East J Anesthesiol. 2007;19:311-344. 4. Skues MA, Welchew EA. Anaesthesia and rheumatoid arthritis. Anaesthesia. 1993;48:989-999. 5. Lisowska B, Rutkowska-Sak L, Maldyk P, Cwiek R. Anaesthesiological problems in patients with rheumatoid arthritis undergoing orthopaedic surgeries. Clin Rheumatol 2008;27:553-559. 6. Kwek TK, Lew TW, Thoo FL. The role of preoperative cervical spine X-rays in rheumatoid arthritis. 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AANA J 2006;74:133-142. 30. Vieira EM, Goodman S, Tanaka PP. Anesthesia and rheumatoid arthritis. Rev Bras Anestesiol. 2011;61:367-376. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 1 3 – 2 1 9 31. Tokunaga D, Hase H, Mikami Y, Hojo T, Ikoma K, Hatta Y et al. Atlantoaxial subluxation in different intraoperative head positions in patients with rheumatoid arthritis. Anesthesiology. 2006;104:675-684. 32. Rosenstock CV, Thøgersen B, Afshari A, Christensen AL, Eriksen C, Gätke MR. Awake fiberoptic or awake video laryngoscopic tracheal intubation in patients with anticipated difficult airway management: a randomized clinical trial. Anesthesiology. 2012;116:1210-1216. 33. Iseli TA, Golden JB, Jones VL, Boudreaux AM, Boyce JR, Weeks DM et al. Outcomes of intubation in difficult airways due to head and neck pathology. Ear Nose Throat J. 2012;91:1-6. 34. Lim YS, Kim SH, Jang TH, Kim KH, Ryu SJ, Yu SB et al. The cardiovascular effects of midazolam co-induction to propofol for induction in aged patients. Korean J Anesthesiol. 2012;62:536-543. 35. Miyanohara T, Igarashi T, Suzuki H, Hirabayashi Y, Seo N. Aggravation of laryngeal rheumatoid arthritis after use of a laryngeal mask airway. J Clin Rheumatol. 2006;12:142-146. 36. Stephan H, Sonntag H, Schenk HD, Kettler D, Khambatta HJ. Effects of propofol on cardiovascular dynamics, myocardial blood flow and myocardial metabolism in patients with coronary artery disease. Br J Anaesth. 1986;58:969-976. 37. Ulsamer B, Doenicke A, Laschat M. Propofol in comparison with etomidate for the induction of anesthesia. Anaesthesist. 1986;35:535-543. 38. Kisor DF, Schmith VD, Wargin WA, Lien CA, Ornstein E, Cook DR. Importance of the organ-independent elimination of cisatracurium. Anesth Analg. 1996;83:1065-1072. 39. Mellinghoff H, Radbruch L, Diefenbach C, Buzello W. A comparison of cisatracurium and atracurium: onset of neuromuscular block after bolus injection and recovery after subsequent infusion. Anesth Analg. 1996;83:1072-1077. 40. Glass PS, Hardman D, Kamiyama Y, Quill TJ, Marton G, Donn KH et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg. 1993;77:1031-1041. 41. Somri M, Coran AG, Mattar I, Teszler C, Shaoul R, Tomkins O et al. The postoperative occurrence of cardio-respiratory 219 adverse events in small infants undergoing gastrointestinal surgery: a prospective comparison of general anesthesia and combined spinal-epidural anesthesia. Pediatr Surg Int. 2011;27:1173-1181. 42. Yoo YC, Na S, Jeong JJ, Choi EM, Moon BE, Lee JR. Dosedependent attenuation by fentanyl on cough during emergence from general anesthesia. Acta Anaesthesiol Scand. 2011;55:1215-1221. 43. Seller Losada JM, Sifre Julio C, Ruiz García V. Combined general-epidural anesthesia compared to general anesthesia: a systematic review and meta-analysis of morbidity and mortality and analgesic efficacy in thoracoabdominal surgery. Rev Esp Anestesiol Reanim. 2008;55:360-366. 44. Leino KA, Kuusniemi KS, Pälve HK, Korpelainen JT, Tiusanen HT, Tuppurainen TT. Spread of spinal block in patients with rheumatoid arthritis. Acta Anaesthesiol Scand. 2010;54:65-74. 45. Gurlit S, Reinhardt S, Möllmann M. Continuous spinal analgesia or opioid-added continuous epidural analgesia for postoperative pain control after hip replacement. Eur J Anaesthesiol. 2004;21:708-715. 46. Kettner SC, Willschke H, Marhofer P. Does regional anaesthesia really improve outcome? Br J Anaesth. 2011;107:90-95. 47. Sitsen E, van Poorten F, van Alphen W, Rose L, Dahan A, Stienstra R et al. Postoperative epidural analgesia after total knee arthroplasty with sufentanil 1 microg/ ml combined with ropivacaine 0.2%, ropivacaine 0.125%, or levobupivacaine 0.125%: a randomized, double-blind comparison. Reg Anesth Pain Med. 2007;32:475-481. 48. Tziavrangos E, Schug SA. Regional anaesthesia and perioperative outcome. Curr Opin Anaesthesiol. 2006;19:521-526. 49. Bruce BG, Green A, Blaine TA, Wesner LV. Brachial plexus blocks for upper extremity orthopaedic surgery. J Am Acad Orthop Surg. 2012;20:38-48. 50. Sripada R, Bowens C Jr. Regional anesthesia procedures for shoulder and upper arm surgery upper extremity update — 2005 to present. Int Anesthesiol Clin. 2012;50:26-47. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Review article Rituximab for rheumatoid arthrits treatment: a systematic review Lívia Lovato Pires de Lemosa,*, Juliana de Oliveira Costab, Marina Amaral de Ávila Machadob, Alessandra Maciel Almeidab, Mariana Michel Barbosac, Adriana Maria Kakehasid, Vânia Eloísa de Araújoa, Augusto Afonso Guerra Júniora, Francisco de Assis Acurcioa Department of Social Pharmaceutics, Pharmacy Faculty, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil Department of Preventive and Social Medicine, Medicine Faculty, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil c Center of Research René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil d Department of Locomotor Apparatus, Medicine Faculty, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil a b article info abstract Article history: Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by Received on 22 March 2013 systemic joint inflammation that often leads to significant disability. Several effective anti- Accepted on 23 August 2013 TNF agents have been used, but some patients have shown an inadequate response. Rituximab is a therapeutic monoclonal antibody indicated in such cases. Keywords: Methods: We conducted a systematic review to access efficacy and safety of rituximab in Rheumatoid arthritis patients with active RA which have or have not been treated with anti-TNF agents before, Rituximab and to relate outcome with RF and anti-CCP serology. We searched major electronics data- Systematic review bases, grey literature and searched for references manually. We used Review Manager®5.1 Safety for meta-analysis. Efficacy Results: We included six RCTs comparing rituximab 1000 mg with placebo. Methotrexate was used by both groups. Treatment with rituximab was more effective in naïve and in anti-TNF treatment failure patients - ACR20/50/70 and EULAR response. We observed lower changes in Total Genant-modified Sharp score, erosion score and joint narrowing scores in the rituximab group, and SF-36, FACIT-T and HAQ-DI scores were also better in this group. There were no differences between groups regarding safety outcomes, with exception of acute injection reactions, which were more common on rituximab group. More RF/anti-CCP seropositive patients achieved ACR20 than RF/anti-CP negative patients in rituximab group. Conclusion: Available data support the use of rituximab for the treatment of RA, as it is an effective and safe option for naïve and anti-TNF treatment failure patients. RF and anti-CCP seam to influence treatment results, but this inference needs further research. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (L.L.P. Lemos). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.08.003 221 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 Rituximabe para o tratamento da artrite reumatoide: revisão sistemática resumo Palavras-chave: Introdução: A artrite reumatoide (AR) é uma doença autoimune crônica caracterizada por Artrite reumatoide inflamação articular sistêmica que, com frequência, leva a significativa incapacitação. Vá- Rituximabe rios agentes anti-TNF têm sido usados efetivamente, mas alguns pacientes demonstraram Revisão sistemática resposta inadequada. Rituximabe é um anticorpo monoclonal terapêutico indicado em tais Segurança casos. Eficácia Métodos: Realizou-se uma revisão sistemática para avaliar a eficácia e a segurança de rituximabe em pacientes com AR ativa previamente tratados ou não com agentes anti-TNF e para relacionar o desfecho com a sorologia para FR e anti-CCP. Pesquisaram-se importantes bancos de dados eletrônicos e a literatura não convencional, além de se fazer uma busca manual de referências. Para a meta-análise, utilizou-se o programa Review Manager® 5.1. Resultados: Consideramos seis ERCs comparando rituximabe 1000 mg com placebo. Em ambos os grupos usou-se Metotrexato. O tratamento com rituximabe foi mais efetivo em pacientes jamais tratados e nos que não obtiveram sucesso com a terapia anti-TNF – critérios ACR 20/50/70 e EULAR. No grupo de rituximabe, observaram-se mudanças menos expressivas nos escores de Sharp/Genant, de erosão e de estreitamento do espaço articular; nesse grupo, os escores SF-36, FACIT-T e HAQ-DI também foram melhores. Não foram notadas diferenças entre grupos com relação aos desfechos de segurança, com exceção das reações agudas à infusão, que foram mais comuns no grupo de rituximabe. Ainda no grupo de rituximabe, um número maior de pacientes soropositivos para FR/anti-CCP alcançou ACR20, em comparação com pacientes negativos para RF/anti-CCP. Conclusão: Os dados disponíveis falam em favor do uso de rituximabe para o tratamento da AR, como opção efetiva e segura para pacientes jamais tratados ou que não obtiveram sucesso com o tratamento anti-TNF. FR e anti-CCP parecem influenciar os resultados do tratamento, mas essa inferência ainda está à espera de futuras pesquisas. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by symmetrical joint inflammation that often evolves into erosive joint damage.1-3 Its prevalence and incidence vary among countries, affecting 2% of Argentina’s population and over 10% of the U.S. population.4 In addition to the articular manifestations, which can lead to damage and functional disability, the disease is related to systemic manifestations and an increase in cardiovascular mortality.5 The development of anti-TNF monoclonal antibodies shed light on the treatment of those patients who have failed the first-line therapy, in which synthetic disease modifying drugs (DMD) such as methotrexate (MTX), sulfasalazine and leflunomide are used.6-8 However, after one year of treatment, approximately 20% of patients abandoned treatment with antiTNF due to its ineffectiveness.9 To work around this situation, the use of a different therapeutic target is an interesting alternative. Rituximab is a monoclonal antibody that selectively depletes peripheral CD20+ B cells. Evidence supports its use in combination with MTX in patients who have failed anti-TNF therapy and in those naïve to treatment with these agents.10-13 However, the patients’ response may be incomplete, indicating the necessity to investigate biomarkers that have predic- tive or prognostic value, to assist in choosing the best treatment strategy. Rheumatoid factor (RF) is an IgM antibody targeted to the constant region of IgG. The anti-cyclic citrullinated peptide (anti-CCP) antibody has more specificity for RA, relating to a more aggressive disease. Both markers are used for the diagnosis of RA and its titration corresponds to the disease activity.14 The objectives of this review were to evaluate the safety and efficacy data of rituximab, as well as to illustrate the influence of RF and anti-CCP in the outcome of treatment of patients with active RA. Methods This systematic review (SR) is part of a larger trial that also includes infliximab, adalimumab and etanercept, designed to evaluate the efficacy and safety of these agents in the treatment of RA. We conducted this trial according to the Cochrane handbook15 and prepared the manuscript using PRISMA Statement as reporting guidance.16 Eligibility criteria Randomized controlled trials (RCTs) comparing a scheme with rituximab versus without rituximab in the treatment of RA in patients over 18 years of age were eligible. We excluded 222 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 trials with less than a total of 30 participants, pilot trials and dosage comparison. Search for trials We investigated the databases EMBASE (until April 2012), Cochrane Register of Controlled Trials (CENTRAL; until June 2012), MEDLINE (via PubMed; until July 2012) and LILACS (until October 2012) in order to to identify potentially eligible articles in English, Spanish or Portuguese languages. For manual search we investigated meetings’ annals (American College of Rheumatology, 2010 and 2011; European League Against Rheumatism, 2010, 2011 and 2012) dissertations and theses’ banks (OpenThesis, National Library of Australia – Trove, Biblioteca Digital Brasileira de Teses e Dissertações from USP, Theses Database of Capes, Pro Quest Dissertation & Theses Database) and reference lists of articles included in other SRs. We searched ongoing trials and unpublished trials in the databases of ClinicalTrials.gov and EUClinical Trials Register records. deviation as a measure of association. Continuous outcomes were qualitatively evaluated and presented as mean ± SD. We planned subgroup analyses considering seropositivity for RF and anti-CCP and developed a sensitivity analysis using participant type for primary outcomes. We assessed metaanalyses’ publication bias by funnel chart. Results Results of the Search After review by title and abstract, 249 references for rituximab, infliximab, adalimumab and etanercept were considered eligible. Six RCTs were enrolled on rituximab, comprising 15 published articles (Fig. 1). Result of Search: 5782 Manual Search: 9 PubMed: 3620 Lilacs: 98 Outcome measurements Embase: 1577 Central: 487 We considered as primary outcome measures: ACR20, ACR50 and ACR70.17 The secondary outcome measures were EULAR responses,18 individual components of ACR, disease activity measured by baseline DAS28-ESR change, SF-36 scores,19,20 fatigue assessed by FACIT-F21 and adverse events (AE) . Total of included articles in searchs: 5791 Duplicates: 92 Total of excluded articles by title: 2648 Reason for exclusion: Study selection and data extraction Excluded by trial type: 1123 Excluded by participant type: 283 We performed the assessment of the eligibility of the trial and data collection, in a standard form, in duplicate and, when necessary, a third reviewer solved disagreements. Authors of the papers were contacted when there was any difficulty in extracting data. We organized the trials according to the previous use of DMD. Total of included articles after removal of duplicates: 5699 Statistical analysis We used the Review Manager® 5.1 software to conduct the meta-analyses using the random effects model and considered those analyses with I2 > 40% and P value of chi-squared test < 0.10 with substantial heterogeneity.25 The causes of heterogeneity were investigated by the exclusion of one trial at a time and subsequent verification of the change in the values of I2 and P. For dichotomous outcomes, we used the relative risk (RR) with confidence interval (CI) of 95% and standard Excluded by outcome type: 1107 Total of articles excluded by abstract: 1912 Reason for exclusion: Excluded by trial type: 1366 Excluded by participant type: 79 Quality assessment and risk of bias of included trials We assessed the methodological quality using the modified Jadad scale22 and the risk of bias by Cochrane Collaboration tool.23 The trial was considered high risk if presented a possibility of high risk of bias in at least one of the criteria evaluated. We calculated the interobserver agreement using Kappa statistics24 using SPSS® 17 software, which we considered excellent for Jadad scale; Kappa = 0.83 ± 0.60 (SD), and substantial for assessing risk bias; Kappa = 0.71 ± 0.69. We also checked conflicts of interest declared by authors of the included articles. Excluded by intervention type: 135 Excluded by intervention type: 83 Total of articles included by title: 3051 Total of articles included by abstract: 1139 Excluded by outcome type: 384 Articles of observational trials that will be analysed in a subsequent phase: 890 Total of articles excluded by complete text: 175 Reason for exclusion: Excluded by trial type: 96 Excluded by participant type: 02 Excluded by intervention type: 13 Total of RCT articles included by abstract: 249 Excluded by outcome type: 24 Not found: 40 Total of included articles by complete text: 74 Adalimumab: 17 Infliximab: 17 Etanercept: 31 Rituximab: 15 Fig. 1 – Flowchart of selection of trials. 223 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 We included 15 trials in progress, and one of them was terminated prematurely in some research centres without stated justification (2008-002381-55). A trial was completed, but we could not find the publication of the results (NCT01117129). We did not include any dissertation or thesis. an open phase. After 24 weeks of follow-up, those patients who did not achieve remission were randomized to receive re-treatment with rituximab or placebo and were followed for another 24 weeks. We considered the results of this part of the trial in the meta-analyses. Trial characteristics Assessment of methodological quality and risk of bias The characteristics of RCTs included are shown in Table 1. We evaluated a total of 2,139 patients with active disease, of which 1,198 used rituximab 1,000 mg twice with an interval of 15 days. MTX was used as co-treatment for all patients. The participants averaged 50 years of age, and 80% were female. The inclusion criteria of the trials were similar in terms of the diagnostic criteria – all followed the classification criteria of the American College of Rheumatology (ACR).26 One trial evaluated outcomes in 52 and 104 weeks of MTX naïve participants who had, on average, less than one year of diagnosis.27-29 The baseline data of participants in this trial were similar to those in the other trials, with the exception of the radiographic score, much lower in those newly diagnosed patients. In the other five trials, the participants had active disease despite MTX use and averaged more than seven years of disease evolution. In two trials, the participants were naïve for anti-TNF, while the outcomes were presented for 24,30 48 and 104 weeks.31-34 In the other three trials, the participants exhibited treatment failure with anti-TNF agent, while the outcomes were presented after 24 weeks of follow-up (Table 1).35-41 One trial evaluated the effectiveness of the second administration of rituximab in patients in whom the first application cycle was not sufficient to achieve remission, i.e., DAS28ESR < 2.6.41 In this trial, all participants received rituximab in All included trials had high methodological quality (Jadad score, modified = 5). The risk of bias assessment showed that the methods of generation of allocation sequence and of ensuring allocation confidentiality were considered adequate in only one RCT.27-29 For the remaining domains, all trials had low risk of bias (Fig. 2). Conflicts of interest and publication bias All included trials were funded by the pharmaceutical industry and only one report36 did not declare a conflict of interests. The funnel plot suggested publication bias, but this analysis could not be considered robust, considering that the number of included trials was small. Primary outcomes The meta-analyses that evaluated ACR measures after 24 weeks of treatment included studies whose participants were naïve or had failed with anti-TNF treatment (n = 1,640). In general, more patients in rituximab group achieved ACR20, ACR50 and ACR70 compared to placebo. However, these analyses showed substantial heterogeneity, and the subset of patients naïve to anti-TNF displayed a robust result. But it is notewor- Table 1 – Summary of characteristics of included trials Study N MTX virgins IMAGE [29-31] placebo 249 rituximab 250 Anti-TNF virgins Edwards [33-36] placebo 40 rituximab 40 SERENE [32] placebo 172 rituximab 170 Failure with Anti-TNF DANCER [37,38] placebo 122 rituximab 122 REFLEX [39-42] placebo 201 rituximab 298 SUNRISE [43] placebo 157 rituximab 318 Women (%) Age (years ± DP) Disease duration (years ± DP) Previous use of MMCD (others than MTX; no. ± DP) 77 85 48,1 (12,7) 47,9 (13,3) 0,91 (1,1) 0,92 (1,3) 30 31 - 80 75 54 (11) 54 (12) 11 (7) 12 (7) 2,6 (1,3) 2,5 (1,4) - 85,5 81,2 52,16 (12,390) 51,30 (12,644) 7,48 (7,642) 6,61 (7,294) 1,1 (1,10) 1,1 (1,11) - 79,5 76,2 50,8 (11,7) 52,1 (10,9) 9,6 (7,7) 11,3 (8,5) 2,2 2,5 27 31,1 82 81 52,89 (12,31) 52,24 (12,20) 11,74 (7,68) 12,15 (8,4) 2,4 (1,8) 2,6 (1,8) IFX: 81; ADA: 18; ETA: 50 IFX: 71; ADA: 23; ETA: 55 79 81 54 (11) 54 (11) 11 (8,5) 12 (9,2) 4,1 (1,9)* 4,1 (2,0)* ADA adalimumab, ETA etanercepte, IFX infliximab * Including anti-TNF, † 1, 2, 3 mean one, two and three agents anti-TNF, respectively. Previous use of anti-TNF N (%) 1: 53; 2: 35; 3: 12† 1: 57; 2: 32; 3: 11 No. (DP) 224 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 Fig. 2 – Assessment of risk of bias using the Cochrane Collaboration tool. A. Graph of risk of bias of all trials included in this review, presented by author names of each trial and their respective percentages in each item of the assessment. B. Summary of risk of bias of the trials (represented by trial names) with their respective result in each item of assessment. thy that this subgroup is small, n = 22; then, more studies are needed to confirm the result (Fig. 3). In the analyses of heterogeneity, it was noted that one trial reported favourable results with the use of rituximab, a statistically significant result, but less expressive than the other RCTs.41 After its exclusion of the meta-analyses, the results favouring the use of rituximab persisted, and the heterogeneity decreased to ACR20, ACR50 and ACR70, respectively RR (95% IC) = 2.24 (1.86-2.69; I2 = 15 %; P = 0.32) , RR = 2.86 ( 2.07-3.94; I2 = 0%; P = 0.90) and RR = 3.91 (1.84-8.31; I2 = 50%; P = 0.11). In the pooled analysis of two trials (n = 579), we did not perceive any benefits from the use of the biological agent compared to placebo for ACR20 until 48-52 weeks and 104 weeks of follow-up.27-29,31-34 The ACR50 and ACR70 results did not favour the use of rituximab until 48-52 weeks, although they have favoured its use till 104 weeks. This fluctuation of the presence or absence of benefit may be related to the small number of participants. Furthermore, the type of patients in these two trials was different: one trial evaluated MTX-naïve patients with less than one year of disease evolution,29-31 and the other evaluated patients naïve to anti-TNF with more than ten years of diagnosis.31-34 Secondary outcomes In general, the group of patients who used rituximab achieved a statistically significant improvement compared to placebo in all individual components of the ACR, including in relation to the average change in HAQ-DI score. The meta-analysis of the number of participants who showed a change in HAQ-DI score ≥ 0.22 after 24 weeks from baseline (n = 1,161) pointed to the benefit of rituximab use with substantial heterogeneity, probably due to the SERENE trial.30 The joint analysis of two trials (n = 562) showed no statistically significant difference between groups after 48-52 weeks. After 72 weeks, there was no difference between intervention and control groups of patients with more than ten years of diagnosis.31 But after 104 weeks there was a difference which benefited the use of rituximab in patients with less than one year of disease progression (Table 2).27-29 After 24 weeks of follow-up, more patients in rituximab group compared to placebo achieved good (n = 1,637) and moderate (n = 1,393) EULAR responses, but with substantial heterogeneity (data not shown). Regarding good EULAR response, in the analysis of heterogeneity (and after removal of the SERENE trial)30 the outcome continued favouring rituximab. The analysis of the trial that evaluated recently diagnosed patients showed that the benefit of rituximab remained after 52 and 104 weeks of follow up.27-29 The heterogeneity of good and moderate EULAR responses diminished with the exclusion of those participants with therapeutic failure with anti-TNF,35,39 and with the exclusion of participants naïve to anti-TNF, respectively.30-34 The change of baseline DAS28-ESR was generally higher in rituximab group compared to placebo after 24, 52 and 104 weeks of follow-up. A pooled analysis of two trials showed no difference between groups in relation to the outcomes of low activity of the disease and remission till 24 weeks of follow-up;30,41 however, more patients in rituximab group compared to placebo achieved these targets after 52 and 104 weeks in the trial that evaluated patients with less diagnosis time (Table 2).27-29 The summarized physical component (SPC) change of SF-36 was superior and statistically significant in rituximab group compared to placebo after 24 and 52 weeks of followup. On the other hand, the results of the summarized mental component (SMC) change were divergent: two trials showed no difference between groups and other two showed a statistically significant difference. In joint analyses, the chances of achieving a mean change of SPC > approx. 5 and SMC > approx. 5 after 24 weeks of treatment were higher and statistically significant in participants who used rituximab. The heterogeneity of the first analysis was substantial, but the individual reports favoured rituximab (Table 2). The group using rituximab had benefits with respect to the fatigue measured by FACIT-F, as compared to placebo after 24 and 52 weeks of treatment. Likewise, the chance of achieving a clinically significant lower change after 24 weeks of treatment, i.e., a mean change in FACIT-F score ≥ approx. 3.5, was higher in participants who used the biological agent (Table 2). Two trials reported that the participants using rituximab achieved better results in radiological outcomes than those in placebo.35-40 A joint analysis (n = 934) showed that the participants treated with the biological agent had lower probability of progression by the Sharp score (modified) compared to placebo + MTX after 104 weeks of treatment (Table 2). Regarding safety, there was no difference between intervention and control groups regarding the incidence of severe AEs, malignancies and death. Infection was the most common AE in the trials. In any case, the rate of occurrence of serious infections was low, about 2% after 24 months of treatment in both groups, increasing to approximately 6% after this pe- 225 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 Subgroup analysis – RF and anti-CCP riod. Acute reaction to the first infusion was more common in rituximab group compared to placebo. In the second infusion, we could observe an opposite association; more patients in placebo group exhibited a reaction. There were no deaths related to this outcome in the RCTs included (Table 2). The loss for total follow-up was higher in placebo group compared to rituximab. Individually, the trials were different as the magnitude of the loss, ranging from 2.5% to 14% in rituximab group and from 5% to 35% in placebo group. The losses due to lack of efficacy were more frequent in placebo group and the rates of loss due to AEs were not different between groups (Table 2). A. Rituximabe Placebo Events Total Events Total Weight Study or subgroup Anti-TNF virgins With the exception of one trial that included only rheumatoid factor-positive (RF+) participants, the groups of other trials were balanced with regard to the inclusion of positive and negative participants.31-34 These latter were always minority and were not included in the overall analysis of a trial.35,36 The distribution of patients in relation to anti-CCP was reported by a trial, with homogeneity between groups.41 With respect to ACR20, we could observe a smaller proportion of responders in the FR- group when compared to FR+. We could also observe that in the group FR+ the number Risk Ratio M-H, Random, 95% Cl Year 29 40 15 40 17.4% Edwards [33] 86 170 40 172 20.3% SERENE [32] 210 212 37.7% Subtotal (95% CI) Total events 115 55 Heterogeneity: Tau2 = 0.00; Chi2 = 0.19, df = 1 (P = 0.67); I2 = 0% Test for overall effect Z = 5.70 (P < 0.00001) Risk Ratio M-H, Random, 95% Cl 1.93 [1.24, 3.01] 2004 2.18 [1.60, 2.96] 2010 2.09 [1.62, 2.70] Failure with Anti-TNF DANCER [37] 66 122 1.94 [1.40, 2.70] 2006 34 122 19.9% REFLEX [39] 152 298 2.85 [2.08, 3.91] 2006 36 201 20.1% SUNRISE [43] 172 318 1.20 [0.98, 1.46] 2010 71 157 22.3% Subtotal (95% CI) 738 480 62.3% 1.86 [1.07, 3.22] Total events 390 141 Heterogeneity: Tau2 = 0.22; Chi2 = 23.54, df = 2 (P = 0.00001); I2 = 92% Test for overall effect Z = 2.20 (P = 0.03) Total (95% CI) 948 692 100.0% 1.92 [1.36, 2.73] Total events 505 196 2 2 2 Heterogeneity: Tau = 0.13; Chi = 26.49, df = 4 (P = 0.00001); I = 85% Test for overall effect Z = 3.66 (P = 0.0003) Teste for subgroup differences: Chi2 = 0.15, de = 1 (P = 0.70). I2 = 0% B. Rituximabe Placebo Study or subgroup Events Total Events Total Weight Anti-TNF virgins Risk Ratio M-H, Random, 95% Cl Year Edwards [33] 17 40 5 40 15,8% SERENE [32] 44 170 16 172 21,8% Subtotal (95% CI) 210 212 37,6% Total events 61 21 Heterogeneity: Tau2 = 0.00; Chi2 = 0.14, df = 1 (P = 0.71); I2 = 0% Test for overall effect Z = 4.61 (P < 0.00001) 0.1 0.2 0.5 Favours placebo 1 2 5 10 Favours Rituximab Risk Ratio M-H, Random, 95% Cl 3.40 [1.39, 8.33] 2004 2.78 [1.64, 4.73] 2010 2.93 [1.86, 4.63] Anti-TNF failure REFLEX [39] 27 298 3.64 [1.43, 9.30] 2006 5 201 15.1% DANCER [37] 41 122 2.56 [1.52, 4.31] 2006 16 122 22.0% SUNRISE [43] 92 318 1.11 [0.81, 1.52] 2010 41 157 25.3% Subtotal (95% CI) 738 480 62.4% 2.01 [0.95, 4.26] Total events 160 62 Heterogeneity: Tau2 = 0.34; Chi2 = 11.39, df = 2 (P = 0.003); I2 = 82% Test for overall effect Z = 1.83 (P = 0.07) Total (95% CI) 948 692 100.0% 2.33 [1.35, 4.01] Total events 221 83 2 2 2 Heterogeneity: Tau = 0.28; Chi = 17.97, df = 4 (P = 0.001); I = 78% Test for overall effect Z = 3.05 (P = 0.002) Test for subgroup differences: Chi2 = 0.70, de = 1 (P = 0.40). I2 = 0% C. Rituximabe Placebo Study or subgroup Events Total Events Total Weight Anti-TNF virgins Risk Ratio M-H, Random, 95% Cl Year Edwards [33] 9 40 2 40 14.8% SERENE [32] 17 170 9 172 22.5% Subtotal (95% CI) 210 212 37.3% Total events 26 11 Heterogeneitye: Tau2 = 0.01; Chi2 = 1.03, df = 1 (P = 0.31); I2 = 3% Test for overall effect Z = 2.34 (P = 0.02) 0.1 0.2 0.5 Favours placebo 1 2 5 10 Favours Rituximab Risk Ratio M-H, Random, 95% Cl 4.50 [1.04, 19.54] 2004 1.91 [0.88, 4.17] 2010 2.32 [1.15, 4.71] Anti-TNF failure DANCER [37] 24 122 4.00 [1.69, 9.44] 2006 6 122 21.6% REFLEX [39] 36 298 12.14 [2.96, 49.86] 2006 2 201 15.4% SUNRISE [43] 45 318 1.11 [0.68, 1.81] 2010 20 157 25.7% Subtotal (95% CI) 738 480 62.7% 3.37 [0.84, 13.52] Total events 105 28 Heterogeneity: Tau2 = 1.27; Chi2= 15.63, df = 2 (P = 0.003); I2 = 82% Test for overall effect Z = 1.72 (P = 0.09) Total (95% CI) 948 692 100.0% 2.94 [1.30, 6.66] Total events 131 39 2 2 2 Heterogeneity: Tau = 0.61; Chi = 16.70, df = 4 (P = 0.002); I = 76% Test for overall effect Z = 2.58 (P < 0.010) Test for subgroup differences: Chi2 = 0.22, de = 1 (P = 0.64). I2 = 0% 0.1 0.2 0.5 Favours placebo 1 2 5 10 Favours Rituximab Fig. 3 – Forest plot depicting the statistically significant difference between rituximab and placebo in response criteria of the American College of Rheumatology (ACR) after 24 weeks of treatment. A. ACR20 (20% of improvement). B. ACR50. C. ACR70. 226 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 Table 2 – Joint analysis of the secondary outcomes of efficacy, adverse events e loss of follow-up Outcome HAQ-DI < 0,22 24 weeks [32, 36, 37, 40] 48-52 weeks [29, 36] 72 weeks [36] 104 weeks [31] Good EULAR response 24 weeks [32, 35, 37, 39, 43] 52 weeks [29] 104 weeks [31] Moderate EULAR response 24 weeks [32, 33, 39, 43] Low DAS 28 activity 24 weeks [32, 43] 52 weeks [29] 104 weeks [31] DAS 28 remission 24 weeks [32, 43] 52 weeks [29] 104 weeks [31] PCS (SF-36) ≥ ~5 24 weeks [32, 40] 52 weeks [29] MCS (SF-36) ≥ ~5 24 weeks [32, 40] 52 weeks [29] FACIT-F ≥ ~3.5 24 weeks [37, 40] 52 weeks [29] No progression at mTSS 24 weeks [29] 52 weeks [29] 96-104 weeks [31,42] No progression at erosion score 24 weeks [40] 96-104 weeks [31,42] Serious adverse events 24 weeks [32, 33, 37, 39, 43] 48-52 weeks [29, 33] 104 weeks [31] Serious infections 24 weeks [32, 33, 37, 43] 48-52 weeks [29, 33] 104 weeks [31] Reaction at the infusion site 1° infusion [29, 32, 33, 37, 39, 43] 2° infusion [29, 32, 37, 39, 43] Losses of follow-up 24 weeks [32, 33, 37, 39, 43] 48-52 weeks [29, 33] 72 weeks [36] 104 weeks [31, 36] Losses by lack of efficacy 24 weeks [33, 37] 48-52 weeks [29, 33] 72 weeks [37] 104 weeks [36] Losses by AE 24 weeks [32, 33, 37, 39, 43] 48-52 weeks [29, 33] 72 weeks [36] 104 weeks [31, 36] Rituximab n Placebo n RR (95% IC) P Value I2 (%) 629 288 40 250 532 274 40 249 1,61 (1,22, 2,12) 1,57 (0,71, 3,44) 4,33 (1,34, 14,05) 1,12 (1,03, 1,21) 0,004 0,02 - 77 82 - 946 250 250 619 249 249 3,37 (1,35, 8,43) 2,32 (1,72, 3,14) 2,10 (1,61, 2,72) <0,0001 - 84 - 824 569 1,62 (1,10, 2,37) 0,0001 86 488 250 250 329 249 249 1,61 (0,70, 3,72) 2,13 (1,60, 2,84) 1,93 (1,50, 2,48) 0,05 - 73 - 488 250 250 329 249 249 2,05 (0,64, 6,53) 2,40 (1,65, 3,48) 2,49 (1,72, 3,61) 0,06 - 73 - 468 250 373 249 2.48 (1.13, 5.46) 1.21 (1.08, 1.36) 0,0009 - 91 - 468 250 373 249 1,71 (1,36, 2,16) 1,16 (0,98, 1,37) 0,53 - 0 - 420 250 322 249 1,90 (1,60, 2,25) 1,11 (1,00, 1,25) 0,41 - 0 - 244 244 252 232 232 420 1,19 (1,04, 1,36) 1,21 (1,03, 1,41) 1,53 (1,29, 1,81) 0,84 0 268 514 177 420 1,10 (0,95, 1,28) 1,50 (1,26, 1,78) 0,20 39 1028 290 250 727 289 249 0,98 (0,70, 1,38) 0,93 (0,57, 1,52) 0,78 (0,51, 1,19) 0,44 0,91 - 0 0 - 720 290 250 518 289 249 0,86 (0,36, 2,04) 0,68 (0,30, 1,57) 0,63 (0,31, 1,27) 0,74 0,34 - 0 0 - 1280 1238 976 936 1,55 (1,30, 1,86) 0,79 (0,63, 0,99) 0,42 0,83 0 0 1030 290 40 290 727 289 40 289 0,47 (0,29, 0,76) 0,54 (0,04, 7,56) 0,48 (0,28, 0,82) 0,48 (0,28, 0,82) 0,18 0,0004 - 36 92 - 232 290 40 40 189 289 40 40 0,27 (0,16, 0,45) 0,19 (0,08, 0,50) 0,44 (0,15, 1,33) 0,24 (0,09, 0,64) 0,85 0,74 - 0 0 - 1028 290 40 290 727 289 40 289 1,47 (0,53, 4,09) 0,95 (0,17, 5,34) 0,33 (0,04, 3,07) 0,38 (0,17, 0,85) 0,15 0,21 0,67 41 37 0 AE Adverse events, DAS 28 Disease Activity Score 28-joint assessment for swelling and tenderness, EULAR European league Against Rheumatism, FACIT-F Functional Assessment of Chronic Illness Therapy – Fatigue, HAQ-DI Health Assessment Questionnaire – Disability Index, MCS Mental Component Summary, mTSS Mean change in Genant-modified Sharp radiographic score, PCS Physical Component Summary, SF-36 Medical Study Short-Form Health Survey. 227 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 of participants treated with rituximab achieved ACR20 that was statistically significant compared to placebo, but with substantial heterogeneity; RR = 1.71 (1.19-2.48; I2 = 90%; P < 0.00001), and this was explained by the exclusion of any trial. In FR- group, there was no difference between experimental and control groups; however, the analysis also showed substantial heterogeneity; RR = 1.16 (0.73-1.85; I2 = 71%; P = 0.02), with no explanation (Fig. 4). The IMAGE trial also assessed ACR50, ACR70, good EULAR response, low activity, and remission of disease according to DAS28-ESR, percentage of participants without radiological progression and mean change in modified Sharp score in relation to seropositivity for RF and anti-CCP.27 After 52 weeks of follow-up, only the mean change in modified Sharp score was statistically different between rituximab and placebo in the analysis of participants FR+. In this trial, all participants FR- were anti-CCP-. According to Tak et al.,29 after 104 weeks of follow-up the participants FR+ and/or anti-CCP+ in rituximab group had a higher probability of not showing radiological progression compared to placebo; odds ratio (OR, 95% CI) = 2.228 (1.5133.281).29 In the analyses of the participants FR- and anti-CCP-, rituximab group showed a tendency to higher probability of non-progression compared to placebo, but without statistical significance; OD = 1.833 (0.558-6.027). Regarding ACR50, the group differences were statistically significant in the subgroup FR+ and/or anti-CCP+. The participants FR- and antiCCP- that used placebo achieved ACR50 in greater proportion A. versus intervention group; however, these analyses were not statistically significant. In SERENE trial,30 after 24 weeks of treatment (the controlled trial phase) there was no difference in relation to the change in DAS28-ESR among patients FR+ and FR- who used rituximab. In the open phase of the trial (24 to 48 weeks of treatment), the patients who had not achieved remission were re-treated with the biological agent; more patients FR+ achieved ACR50 and ACR70, compared to patients FR-. Discussion The results of efficacy and safety of this RS point to the benefit of rituximab 1000 mg applied twice at 15-day intervals associated with weekly MTX for the treatment of RA. Regarding the primary outcomes, greater number of patients achieved ACR20, ACR50 and ACR70 in rituximab group versus placebo. This result was obtained for up to 24 weeks of follow-up in patients naïve and in those patients who have failed with antiTNF and with more than seven years of the disease; and for up to 52 weeks for patients naïve to MTX and anti-TNF and newly diagnosed. These results can also be applied to good and moderate EULAR responses. In comparison to individual components of ACR response criteria, summarized physical and mental components of SF36, fatigue measured by FACIT-F and in relation to the change in baseline DAS28-ESR, we noted better results with ritux- Rituximabe Placebo Risk Ratio Events Total Events Total Weight M-H, Random, 95% Cl Year Study or subgroup 24 weeks 122 23.8% 134 245 DANCER [37] 34 1.96 [1.44, 2.67] 165 23.0% 131 242 REFLEX [39] 31 2.88 [2.08, 4.04] 118 25.6% 139 244 SUNRISE [43] 51 1.32 [0.98, 1.67] 405 72.3% 731 Subtotal (95% CI) 1.93 [1.07, 3.07] Total events 404 116 Heterogeneity: Tau2 = 0.14; Chi2 = 15.21, df = 2 (P = 0.0005); I2 = 87% Test for overall effect Z = 2.78 (P < 0.005) 52 weeks IMAGE [29] 181 224 145 Subtotal (95% CI) 224 Total events 181 145 Heterogeneity: does not apply Test for overall effect Z = 3.94 (P < 0.0001) 227 227 27.7% 27.7% Risk Ratio M-H, Random, 95% Cl 1.26 [1.13, 1.42] 1.26 [1.13, 1.42] Total (95% CI) 955 632 100.0% 1.71 (1.19, 2.48] Total events 585 261 2 2 2 Heterogeneity: Tau = 0.12; Chi = 30.69, df = 3 (P = 0.00001); I = 90% 0.1 0.2 0.5 Test for overall effect Z = 2.86 (P < 0.004) Favours placebo+MTX Test for subgroup differences: Ch2 = 3.00, df = 1 (P = 0.08), I2 = 66.7% Rituximabe Placebo Risk Ratio Events Total Events Total Weight M-H, Random, 95% Cl 24 weeks 21 27.2% 30 63 DANCER [37] 12 0.83 [0.53, 1.31] 44 15.9% 27 66 REFLEX [39] 5 3.60 [1.50, 8.63] 39 28.4% 32 74 SUNRISE [43] 19 0.89 [0.59, 1.34] 104 71.4% 203 Subtotal (95% CI) 1.25 [0.61, 2.57] Total events 89 36 Heterogeneity: Tau2 = 0.32; Chi2 = 10.61, df = 2 (P = 0.005); I2 = 81% Test for overall effect Z = 0.61 (P < 0.54) B. Study or subgroup 52 weeks IMAGE [29] 17 24 14 Subtotal (95% CI) 24 Total events 17 14 Heterogeneity: does not apply Test for overall effect Z = 0.52 (P = 0.061) 22 22 28.6% 28.6% Year 1 2 5 10 Favours rituximab+MTX Risk Ratio M-H, Random, 95% Cl 2006 2006 2010 1.11 [0.71, 1.67] 2010 1.11 [0.71, 1.67] Total (95% CI) 227 126 100.0% 1.16 [0.73, 1.85] Total events 106 50 2 2 2 Heterogeneity: Tau = 0.15; Chi = 10.42, df = 3 (P = 0.02); I = 71% Test for overall effect Z = 0.64 (P < 0.52) Test for subgroup differences: Ch2 = 0.08, df = 1 (P = 0.78), I2 = 0% 0.1 0.2 0.5 Favours placebo+MTX 1 5 10 2 Favours rituximab+MTX Fig. 4 – Forest-plot depicting the responses of the American College of Rheumatology ACR20 (20% improvement) of rituximab versus placebo. A. RF-positive patients. B. RF-negative patients. 228 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 imab. Remission and low disease activity were reported by three trials, despite all other trials also measured disease activity by DAS28-ESR.27,30,41 These measures were achieved after 52 weeks of treatment for newly diagnosed patients.27 The prevention or minimization of the progression of joint damage is a mainstay RA treatment; however, only IMAGE27 and REFLEX39 performed an analysis of radiographic progression, and in both trials the participants who used rituximab achieved better results versus placebo after 104 weeks. We need more trials to strengthen the results of radiographic progression. In this review we observed that the favourable results with rituximab according to ACR were more expressive in the trial that studied patients with less than one year of diagnosis,27 which confirms the recommendations of ACR7 and EULAR8 current guidelines, pointing to the fact that the treatment of RA will be more effective if started early. SUNRISE41 was responsible for high heterogeneity in various analyses. In this trial, patients who did not achieve remission with an application of rituximab were randomized to re-treatment from 24th week. This trial showed benefits of rituximab versus placebo in all parameters measured, but the results were less significant than those shown by the other included trials. The authors reported that patients who achieved ACR20, ACR50 and ACR70 after the first application of rituximab were more likely to maintain its gains or improve with re-treatment with rituximab. On the other hand, patients who did not achieve such measures were not benefited with the second drug application. Emery et al.42 conducted a joint analysis of three RCTs and its extensions – SERENE30 and MIRROR,43 with 43 participants re-treated to achieve clinical remission (Treat to Target – TT) (n = 236), and DANCER,35 and patients re-treated when necessary (RWN) (n = 257). The groups were homogeneous with respect to basal data, with the exception of disease duration, that was 3.6 and 8.5 years, respectively. Both groups have evolved to improve at every application of rituximab; however, patients in TT group achieved better results than participants RWN, regarding HAQ-DI and DAS-28. In addition, during the first four applications of rituximab, more patients discontinued the trial in RWN group compared to TT group, mainly due to an insufficient therapeutic response. In general, rituximab in association with MTX proved to be as safe as MTX. Acute infusion reaction was the most common event and was more frequent in rituximab group compared to placebo, but only in the first infusion. Van Vollenhoven et al.44 conducted a joint analysis of six RCTs (SERENE,30 DANCER,35 REFLEX,37 SUNRISE,41 MIRROR43 and SIERRA45), including extensions of open phase DANCER and REFLEX trials, and demonstrated that the overall incidence was 359.6 adverse events per 100 patients-year (95% CI 354.4-364.9). The AE rate was higher after the first application, falling to 329.44 events per 100 patient-years (320.59-338.53) after the second application, remaining stable until the subsequent five years of monitoring. The most common event detected was an acute infusion reaction, occurring in 25% of participants. Other AEs occurring in ≥ 10 % of the assessed population were infections, not including RA exacerbations. In this review, the mortality rate was 0.6 per 100 patient-years, and there were no deaths due to infusion reactions. Loss of participants is critical in epidemiological trials, since the analysis, even if done by intention to treat, may be compromised. In the included RCTs, generally the losses did not exceed 20% and total loss and loss due to lack of efficacy were higher in placebo group compared to rituximab. The loss rates for EA were not different between groups. Finckh et al.46 conducted a prospective cohort trial to assess which subset of patients with RA and with anti-TNF failure obtain benefit with the exchange for rituximab versus exchange for another anti-TNF agent. Blom et al.47 evaluated a retrospective cohort of patients who had failed with two antiTNF agents and who were treated with a third anti-TNF drug (n = 64), or with rituximab (n = 90). These authors concluded that patients using rituximab obtained better results with respect to disease activity versus patients using anti-TNF agent.46,47 Both trials concluded that in case of failure with an anti-TNF treatment, the introduction of a biological agent with different mechanism of action, such as rituximab, would be the best conduct, increasing the efficacy of rituximab as third-line treatment. Current guidelines from ACR for RA have established, as an alternative, the use of rituximab if the patient exhibits low activity associated with a poor prognosis, or moderate/ high activity.7 Current guidelines from EULAR recommend the use of rituximab only after a failure with anti-TNF, despite reiterating that the approval of rituximab for use as a second line option has been discussed in Europe.8 The results of this trial point to a possible benefit of rituximab for patients naïve to anti-TNF. However, these findings should be evaluated with caution, since we could not find any RCT to evaluate the exchange by an anti-TNF, after failure of rituximab. The possibility of use of rituximab as a second line drug and of an anti-TNF as a third drug needs to be more deeply evaluated. Data from IMAGE,27 DANCER,35 REFLEX,37 and SUNRISE41 were used in subgroup analysis for seropositivity; we observed a trend towards greater efficacy of rituximab, compared to placebo, in the subgroup FR+ and/or anti-CCP+; however, the observed heterogeneity was high. In any case, we used the method of random effects, which may have underestimated differences between groups. The predictive value of assessment of seropositivity needs to be further explored in future clinical trials, as well as the role of other biomarkers that may be useful for deciding on the best treatment to be used for each specific type of patient. This RS has some limitations. The possibility of selection bias could not be excluded from most trials. Moreover, all included trials were funded by pharmaceutical industry, which may have led to an overestimation of the results. Systematic reviews showed that industry-funded trials tend to show favourable results for its products, compared to not funded trials.48,49 An inherent limitation of clinical trials, which is reflected in this RS, is the fact that they were conducted in carefully selected populations. Thus, the profile of patients does not reflect the reality, especially in relation to treatment adherence (since these patients are followed more strictly) and to comorbidities, since they exclude patients with multiple comorbidities. Depression, hypertension and diabetes, for example, negatively influence the quality of life, functionality, results and prognosis of subjects with RA.50 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 2 0 – 2 3 0 Moreover, the analysis of which type of participant would be more benefited with the use of rituximab is not conclusive, since few trials within each group (MTX-naïve and anti-NPTnaïve) were included. In general, the efficacy analyses were heterogeneous. Nevertheless, it was possible to assess the direction of the effect that showed benefit with the use of rituximab in all outcomes assessed. Conclusion The trials included in this RS showed that rituximab is effective and safe compared to placebo for the treatment of RA, particularly in patients with a recent diagnosis. The effectiveness was also observed both in naïve patients to anti-TNF as in those whose treatment with these agents had failed. The use of rituximab was well tolerated by all patient subtypes. More trials are needed to evaluate the role of RF and anti-CCP antibody in predicting success in the treatment of RA with rituximab, but there is indication that RF+ and anti-CCP+ patients exhibit a better response to this biological agent. Conflicts of Interest Coauthor Adriana Maria Kakehasi declares conflict of interest, as she received education grant from Abbott. REFERENCES 1. McInnes IB and Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205-2219. 2. Minaur NJ, Jacoby RK, Cosh JA, Taylor G, Rasker JJ. Outcome after 40 years with rheumatoid arthritis: A prospective study of function, disease activity, and mortality. J Rheumatol. 2004;31; Suppl 69:3-8. 3. Scott DL, Pugner K, Kaarela K, Doyle DV, Woolf A, Holmes J, Hiek K. The links between joint damage and disability in rheumatoid arthritis. Rheumatology. 2000;39:122-132. 4. Alamanos Y, Voulgari PV, Drosos AA. 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Best Pract. Res. Clin. Rheumatol. 2007;21:885-906. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 1 – 2 3 3 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Case report IgA nephropathy and polymyositis: a rare association Thiago Bitar Moraes Barrosa, Fernando Henrique Carlos de Souzaa, Denise Maria Avancini Costa Malheirosb, Mauricio Levy-Netoa, Samuel Katsuyuki Shinjoa,* Service of Rheumatology, Hospital das Clínicas, Medicine Faculty, Universidade de São Paulo, São Paulo, SP, Brazil Service of Pathology, Hospital das Clínicas, Medicine Faculty, Universidade de São Paulo, São Paulo, SP, Brazil a b article info abstract Article history: Polymyositis is a systemic and idiopathic inflammatory myopathy that, besides muscle Received on 30 November 2012 manifestation, may occur with respiratory involvement, gastrointestinal tract and rarely Accepted on 30 November 2012 renal involvement. In this latter, there are only two cases of IgA nephropathy, but both in dermatomyositis. On the other hand, we reported, for the first time, a case of IgA nephro- Keywords: pathy in polymyositis. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. Inflammatory myopathy All rights reserved. IgA nephropathy Polymyositis Case report Nefropatia por IgA e polimiosite: uma rara associação resumo Palavras-chave: A polimiosite é uma miopatia inflamatória idiopática sistêmica que, além da manifestação Miopatia inflamatória muscular, pode eventualmente cursar com acometimento respiratório, do trato gastrintes- Nefropatia por IgA tinal e, raramente, renal. Neste último caso, há descrição de apenas dois casos de nefro- Polimiosite patia por IgA em pacientes com miopatia, ambos em dermatomiosite. Em contrapartida, Relato de caso relatamos pela primeira vez esta rara associação em polimiosite. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Polymyositis is classified within the spectrum of idiopathic inflammatory myopathies, together with dermatomyositis. It is clinically characterized by progressive proximal muscle weakness of the limbs, leading to high morbidity and functional disability. Among the extramuscular manifestations found, the most common are the respiratory and gastrointestinal involvement respiratory and of gastrointestinal tract involvement.1,2 Renal involvement in polymyositis is uncommon, with rare descriptions of nephropathy associated with acute tubular necrosis secondary to rhabdomyolysis and chronic glomerulonephritis.3-9 IgA nephropathy is a primary glomerulonephritis characterized by IgA deposits in the mesangial area of glomeruli. * Corresponding author. E-mail: [email protected] (S.K. Shinjo). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2012.11.001 232 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 1 – 2 3 3 Approximately one-third of patients with this type of renal manifestation progresses to chronic renal failure after 20-25 years of disease.10 Among the systemic diseases, IgA nephropathy is most commonly associated with Henoch-Schönlein purpura.11 However, its association with idiopathic inflammatory myopathies is extremely rare, with only two cases described, both in dermatomyositis,12,13 which motivated us to present this case. Clinical case Male patient, 35 years-old, white, trader, born in São Paulo. Previously healthy, presented six months ago with progressive proximal muscle weakness of all four limbs without apparent cause and without constitutional symptoms. When the patient came to our hospital service, the physical examination showed grade III proximal muscle strength in all four limbs without skin lesions and/or involvement of other organs, such as lung or kidney. Laboratory tests showed serum creatine kinase (CK) = 3,545 IU/L (normal range: 24-204 IU/L), aldolase = 33 IU/L (reference value: 7.5 < IU/L), antinuclear factor and anti-Jo-1 negative, C-reactive protein = 7.8 µg/mL (reference value: < 5 µg/mL), erythrocyte sedimentation rate = 17 mm/1st hour (reference value: < 10 mm/1st hour), electroneuromyography suggestive of proximal inflammatory myopathy of all limbs without evidence of associated neuropathy. The muscle biopsy (biceps brachii) revealed the presence of an endomysial and perimysial inflammatory infiltrate and also necrosis of the muscle fibers and macrophage invasion, thus suggesting inflammatory myopathy. During the clinical investigation, neoplastic and metabolic causes were ruled out. With the presumptive diagnosis of polymyositis, according to the criteria of Bohan and Peter,14 corticosteroids (prednisne 0,5mg/kg/day) and methotrexate (maximum dose 20 mg/week) were initiated. After six months of treatment, the patient developed acute lung injury secondary to pneumopathy requiring endotracheal intubation and mechanical ventilation for three weeks. Infection and/or disease activity were discarded. In face of the possibility of lung disease secondary to methotrexate, this medication was discontinued, and the prednisone dose was optimized. The patient developed progressive pulmonary improvement without sequelae. Subsequently, as a steroid sparing drug, azathioprine was introduced (maximum dose of 3 mg/kg/day). Due to the stability of the disease and to the pulmonary improvement, the dose of prednisone (which at that time was 0.2 mg/kg/day) was gradually reduced. However, with no apparent cause the patient began to show macroscopic hematuria, edema of lower limbs (2+/4+) without hemodynamic and pressure repercussion. The laboratory examination showed: urinalysis with pyuria (> 100 leukocytes/field), hematuria (> 100 erythrocytes/field), moderate erythrocyte dysmorphism and lipoid casts; 24h-proteinuria = 1.76 g, serum albumin = 3.6 g/dL, serum creatinine = 0.9 mg/dL and negative urine culture. There was no sign of clinical-laboratorial activity of PM at that time. We decided then to perform a renal biopsy which showed 14 glomeruli with diffuse segmental endocapillar cell proliferation. One glomerulus showed one cellular crescent and two fibroblastic crescents. Moreover, the glomerulus exhib- ited mild tubulointerstitial change, focal tubular atrophy and interstitial fibrosis. An interlobular artery showed intimal fibrosis. Immunofluorescence showed diffuse deposits of only IgA in the mesangial region and in the peripheral capillary wall of the glomerulus (fig. 1), suggestive of IgA nephropathy. The dose of prednisone (0.2 mg/kg/day) was maintained, azathioprine was discontinued, and monthly cyclophosphamide (0.75 mg/m2, IV) was initiated for 12 months; with the patient achieving complete remission of the renal disease. disease. Subsequently, as a maintenance drug, azathioprine was reintroduced (maximum dose of 2.5 mg/kg/day). Currently, the patient denotes stability, both from the point of view of polymyositis as of nephropathy, and without corticosteroid therapy. Discussion To our knowledge, this is the first case in the literature that reports an IgA nephropathy in idiopathic inflammatory myopathy, particularly polymyositis. A B Fig. 1 – Renal biopsy (A) Optical microscopy. A glomerulus with diffuse proliferative glomerulonephritis. PAS staining, (B) Immunofluorescence demonstrating diffuse IgA deposit in mesangial region and the peripheral capillary wall of the glomerulus. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 1 – 2 3 3 Renal involvement in idiopathic inflammatory myopathy is uncommon, including acute tubular necrosis and glomerulonephritis.3-9 In the latter case, Takizawa et al.4 demonstrated by renal biopsy in a series of 21 cases of dermatomyositis/ polymyositis, that the presence of nephritis was associated with membranous and proliferative mesangial glomerulonephritis, respectively, in polymyositis and dermatomyositis. The relationship between IgA nephropathy and idiopathic inflammatory myopathies is extremely rare. To date, there are only two case reports, both occuring in dermatomyositis.12,13 Civilibal et al.13 reported a case of newly diagnosed juvenile dermatomyositis, with hematuria and nephrotic proteinuria in course, without loss of kidney function. A percutaneous renal biopsy allowed the diagnosis of IgA nephropathy. There was a favourable response both from the point of view of inflammatory myopathy as of nephropathy, with the maintenance of methotrexate associated with oral corticosteroids. On the other hand, Yen et al.12 described a young woman who developed IgA nephropathy after 1.5 years of an established diagnosis of dermatomyositis while using both azathioprine and corticosteroids. Unlike these two cases, in the present trial we present a male patient with confirmed diagnosis of polymyositis. However, like the case reported by Yen et al.,12 the patient had been using corticosteroids and immunosuppressive medication, when evolved with renal dysfunction after 1.5 years, being subsequently diagnosed with IgA nephropathy. The association between dermatomyositis and IgA nephropathy is plausible, since both diseases share the involvement of humoral immunity (immunecomplexes).3,15 On the other hand, the relationship with polymyositis is remote, because in the latter case there is a predominance of cellular immunity. Thus, in the present clinical case, we strongly suggest the existence of two distinct morbidities. In short, to our knowledge, we reported for the first time a case of IgA nephropathy in a patient with polymyositis. Conflicts of interest The authors declare no conflicts of interest. 233 REFERENCES 1. Marie I, Hachulla E, Cherin P, Dominique S, Hatron PY, Devulder B et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum. 2002;47:614-22. 2. de Merieux P, Verity MA, Clements PJ, Paulus HE. Esophageal abnormalities and dysphagia in polymyositis and dermatomyositis. Arthritis Rheum. 1983;26:961-8. 3. Yen TH, Lai PC, Chen CC, Hsueh S, Huang JY. Renal involvement in patient with polymyositis and dermatomyositis. Int J Clin Pract. 2005;59:188-93. 4. Takizawa Y, Kanda H, Sato K, Kawahata K, Yamaguchi A, Uozaki H et al. Polymyositis associated with focal mesangial proliferative glomerulonephritis with depositions of immune complexes. Clin Rheumatol. 2007;26:792-6. 5. Dyck RF, Katz A, Gordon DA, Johnson M, Shainhouse Z, Cardella CJ et al. Glomerulonephritis associated with polymyositis. J Rheumatol. 1979;6:336-44. 6. Pirovino M, Neff MS, Sharon E. Myoglobulinuria and acute renal failure with acute polymyositis. NY State J Med. 1979;79:764-7. 7. Tsunemi M, Ishimura E, Tsumura K, Shoji S, Sugimura T, Nishizawa Y et al. A case of crescentic glomerulonephritis associated with polymyositis. Nephron. 1993;64:488-9. 8. Valenzuela OF, Reiser IW, Porush JG. Idiopathic polymyositis and glomerulonephritis. J Nephrol. 2001;14:120-4. 9. Makino H, Hirata K, Matsuda M, Amano T, Ota Z. Membranous nephropathy developing during the course of dermatomyositis. J Rheumatol. 1994;21:1377-8. 10. D’Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis. 2000;36:227-37. 11. Sanders JT, Wyatt RJ. IgA nephropathy and Henoch-Schönlein purpura nephritis. Curr Opin Pediatr 2008;20:163-70. 12. Yen TH, Huang JY, Chen CY. Unexpected IgA nephropathy during the treatment of a young woman with idiopathic dermatomyositis: case report and review of the literature. J Nephrol. 2003;16:148-53. 13. Civilibal M, Selcuk Duru N, Ozagari A, Durali K, Elevli M. Immunoglobulin A nephropathy associated with juvenile dermatomyositis. Pediatr Nephrol. 2009;24:2073-5. 14. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344-7. 15. Yen TH, Huang JY, Chen CY. Unexpected IgA nephropathy during the treatment of a young lady with idiopathic dermatomyositis. Case report and review of the literature. J Nephrol. 2002;16):148-53. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 4 – 2 3 6 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Case report Spondyloptosis in athlete Ana Paula Luppino Assad*, Andressa Silva Abreu, Luciana Parente Costa Seguro, Lissiane Karine Noronha Guedes, Fernanda Rodrigues Lima, Ana Lucia de Sá Pinto Rheumatology, Hospital das Clínicas, Medicine School, Universidade de São Paulo, São Paulo, SP, Brazil article info abstract Article history: The adolescent athletes are at greater risk of low back pain and structural spine injuries. Received on 20 May 2012 Spondylolysis is responsible for the majority of back pain cases in young athletes, rarely Accepted on 30 November 2012 occurring in adults. We report a case of a 13-year-old judo female athlete, who came to our service with 5 months of progressive low back pain during training which was initially Keywords: attributed to mechanical causes, without any further investigation by imaging methods. Spondyloptosis At admission, the patient had lumbar deformity, antalgic posture and bilaterally positive Spondylolysis unipodalic lumbar hyperextension maneuver. After a research which showed spondylopto- Low back pain sis, the patient underwent surgery. In this article, we discuss, based on this case report, the Teenager diagnostic approach to low back pain in young athletes, since the complaint of chronic back Ahtlete pain can be a marker of a structural lesion that may be permanent and bring irreversible functional loss. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. Espondiloptose em atleta resumo Palavras-chave: Os atletas adolescentes estão sob maior risco de lombalgia e lesões estruturais da coluna. Espondiloptose A espondilólise é responsável pela maioria das lombalgias em jovens esportistas e rara- Espondilólise mente ocorre em adultos. Relatamos o caso de uma paciente de 13 anos, atleta de judô, que Lombalgia chegou a nosso serviço com quadro de cinco meses de lombalgia progressiva durante os Adolescente treinos, sendo inicialmente atribuída a causas mecânicas, sem que houvesse uma investi- Atleta gação mais detalhada por métodos de imagem. Na admissão já apresentava deformidade lombar, postura antálgica e manobra de hiperextensão lombar em unipodálico positiva bilateralmente. Realizou-se investigação, que evidenciou espondiloptose, sendo, então, submetida a tratamento cirúrgico. Com base neste relato de caso, discutimos a abordagem diagnóstica de lombalgia em atletas jovens, uma vez que a queixa de lombalgia crônica pode ser marcador de uma lesão estrutural, a qual pode ser definitiva e trazer perda funcional irreversível. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. * Corresponding author. E-mail: [email protected] (A.P.L. Assad). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2012.11.002 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 4 – 2 3 6 Introduction Low back pain is a very common complaint among adolescents. Among the athletes, there is a higher prevalence of pain and an increased risk of structural damage.1 The sports gesture is related to the development of joint lesions, for example, repetitive movements of extension and rotation are associated with lesions of the posterior column, such as spondylolysis.2 There is a tendency to associate low back pain of the athlete to mechanical factors.3 Among differential diagnoses, disc disease, muscle contracture, and constitutional deformities like scoliosis and lumbar lordosis should be considered. Furthermore, it is important to rule out inflammatory diseases that may go unnoticed when there are no other peripheral symptoms.3,4 In children and teen athletes, the aetiology of low back pain is different from the causes of adult low back pain.5 Spondylolysis is responsible for the majority of back pain cases in young athletes, and rarely occurs in the adult ones.6 The patient’s complaint must be taken into consideration. The history and physical examination are important to establish the underlying cause of low back pain; but imaging studies may be crucial for an early diagnosis and treatment, preventing irreversible structural damage and disadvantage to the daily activities and sports practice.6,7 Case report JCT, 13, female, born and raised in Mogi das Cruzes city, student and judo athlete for seven years. The patient came to the Outpatient Sports Medicine Service, Discipline of Rheumatology, HC-FMUSP, complaining of back pain for five months. She referred back pain associated with local tumor five months ago. In the beginning of the clinical manifestation, the pain appeared only during her training activities and had no irradiation, but evolved with pain during resting periods and radiating to the posterior aspect of the right leg. The patient had no improvement of the picture with use of nonsteroidal anti-inflammatory agents, as well as with analgesic measures (thermotherapy and electrotherapy) performed in the Physical Therapy Department. However, the girl did not stop her practice, despite the pain. There was no history of trauma, night pain, fever, asthenia, weight loss, sensory or motor changes in lower limbs or sphincter alterations, use of supplements or steroids, or any other morbidity. She practiced judo competitively for seven years, was an orange belt, performed physical conditioning with strength exercises and stretching for an hour, and specific training for two hours, four times a week. On physical examination, the patient was in good general condition, with weight of 45 kg and height of 155 cm, with cardiovascular, pulmonary and abdominal examinations without changes. At musculoskeletal examination, the patient had an antalgic posture while sitting, wore her arms as support for the weight of the trunk, with postural deviation in antalgic scoliosis, accentuation of physiological lumbar lordosis 235 and with a bone tumour at L5 (Fig. 1). At palpation, we found painful contracture of the paraspinal musculature. The pain was triggered by lateralization movement of the trunk, and lumbar rotation and hyperextension. The unipodalic lumbar hyperextension maneuver was positive bilaterally. After a diagnostic hypothesis of spondylolisthesis, we requested imaging studies (Fig. 2) which showed high-grade spondylolisthesis, or also classified as spondyloptosis. The patient was symptomatically treated, instructed to rest and referred to the care of Neurosurgery, which indicated reduction and fixation of L5-S1. Discussion Low back pain is very common in athletes, with an estimated prevalence of up to 45%, while in non-athletes the prevalence is 18%.2 Numerous athletes exhibit mechanical low back pain secondary to muscle spasm and ligament injuries. In adults, the main causes of pain are disc herniation, vertebral body fracture, spinal canal stenosis and degenerative diseases.3 In young patients, although the major cause of low back pain has muscle origin, some clinical aspects must be considered, as night pain, pain after trauma, hyperextension pain, presence of a specific painful spot, or any neurologic finding.8 In adolescents, muscle imbalance, incomplete ossification of the pars articularis, and inadequate training are the risk factors involved in the development of spinal lesions.9 In these Fig. 1 – Bone tumor topography of L5. Fig. 2 – Plain radiography with total slippage of L5 on S1, not reducible with the position (A: neutral, B: in flexion, C: in extension, D: MRI of vertebral column with spondyloptosis of L5 on S1, with stenosis of the spinal canal). 236 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 4 – 2 3 6 young athletes, the most common structural change is spondylolysis, i.e., a pars articularis fracture.3,5,8 Spondylolysis is responsible for 47% of all back pain in this population, while in adults the diagnosis appears in only 5% of cases.10 The athletes with higher risk of developing spondylolysis and spondylolisthesis are those who practice repetitive spine extension, flexion and rotation movements, for instance, practitioners of artistic gymnastics, skating, hockey and soccer players.2 The present case report patient practiced judo, which involves performing such movements. The spondylolysis may be asymptomatic, except in the acute phase of fracture. The patient can present with hyperlordotic posture, and his/her back pain can be reproduced by hyperextension and rotation of the spine, a maneuver easily reproducible and that was positive in the present case.6 After spondylolysis, there is an increased risk of an anterior vertebral slip over another – this is called spondylolisthesis. The greatest instability phase occurs during the growth spurt in adolescence.11 The spondylolisthesis is classified into five grades, with grade I occurring when there is 25% slippage; grade II, 50 %; grade III, 75 %; grade IV, 100%; and grade V, also called spondyloptosis, when a total slippage of L5 on S1 occurs. The symptoms depend on the degree of slip, and can range from an asymptomatic patient to back pain, with neurological symptoms associated. The prevention of injury in young athletes is crucial. This prevention must be taken with the reversal of risk factors, such as muscle shortening and imbalance, and the use of incorrect techniques during training. An abrupt change in training volume during the growth spurt should also be considered as a risk factor.9 In our case, the patient already had pain with five-month length during workouts, without further investigation by imaging methods that could rule out a possible structural damage or even a recommendation of cessation of training. This combination of factors certainly contributed to delay in the diagnosis of spondylolysis, and resulted in the evolution of the injury to spondyloptosis. The investigation of spondylolysis by imaging studies should be done with a request of plain radiography in three positions, showing the defect in the pars interarticularis (Scotty dog sign), but with low sensitivity. Computed tomography (CT) is the gold standard for diagnosis. SPECT can be used to evaluate the activity of the lesion.6 Bone scintigraphy is recommended for patients with low back pain, because of its high sensitivity. A CT-scan may be indicated, when the scintigraphy results positive, to define if the hypercaptation aetiology represents pars articularis fracture or bone stress reaction, and helps define the degree and chronicity of the fracture.11,12 MRI is less sensitive than CT for assessing bone injury, but it can help to assess whether the injury is acute, when it identifies a local oedema.1,12 When there is suspicion of spondylolisthesis, magnetic resonance imaging (MRI) or computed tomography (CT) for evaluating stenosis of the spinal canal and foramina is indicated.6 In our case, we chose to perform MRI due to signs of neurological involvement and the time course of the complaint. The treatment of spondylolisthesis is controversial. Therapeutic modalities include rest and sometimes orthopaedic corsets, aiming to avoid hyperextension of the spine. Surgical arthrodesis is indicated for pain refractory to conservative treatment, or in high-grade spondylolisthesis (slippage greater than 50%), especially in children or adolescents during the growth spurt, due to the risk of progression and neurological injury.13 It is expected that young athletes can return to sports activity after successful treatment, even in cases in which surgical treatment was necessary, with the exception of collision sports,8 as in the case in question. Therefore, in a teen athlete, it is always important to recognize and investigate the complaint of chronic low back pain because this symptom may be a marker of a structural lesion that may be permanent and bring irreversible functional loss. Conflicts of interest The authors declare no conflicts of interest. REFERENCES 1. Standaert JC. Low back pain in the adolescent athlete. Phys Med Rehabil Clin N Am. 2008;19:287-304 2. Kujala UM, Taimela S, Erkintalo M, Salminen JJ, Kaprio J. Low back pain in adolescent athletes. Med Sci Sports Exerc. 1996;28:165-70 3. Jennings F, Lambert E, Fredericson M. Rheumatic diseases presenting as sports-related injuries. Sports Med. 2008;38:917-30 4. Carlson C. Axial back pain in the athlete: pathophysiology and approach to rehabilitation. Curr Rev Musculoskelet Med. 2009;2:88-93 5. Baker RJ, Patel D. Lower back pain in the athlete: common conditions and treatment. Prim Care. 2005;32:201-29 6. Melenger AL, Krivickas LS. Neck and back pain: Musculoskeletal Disorders. Neurol Clin, 2007;25:419-38 7. Gurd DP. Back pain in the young athlete. Sports Med Arthrosc. 2011;19:7-16 8. Sucato DJ, Micheli LJ, Estes AR, Tolo VT. Spine problems in young athletes. Instr Course Lect.2012; 61:499-511 9. Purcell L. Causes and prevention of low back pain in young athletes. Paediatr Child Health. 2009;14:533-8 10. Mohriack R, Silva PDV, Trandafilov MJ, Martins DE, Wajchenberg M, Cohen M et al. Espondilólise e espondilolistese em ginastas jovens. Rev Bras Ortop. 2010;45:79-83 11. Zoner CS, Amaral DK, Natour J, Fernandes ARC. Contribuição dos métodos de diagnóstico por imagem na avaliação da espondilólise. Rev Bras Reumatol. 2006;46:287-91 12. Masci L, Pike J, Malara F, Phillips B, Bennell K, Brukner P. Use of the onelegged hyperextension test and magnetic resonance imaging in the diagnosis of active spondylolysis. Br J Sports Med. 2006;40:940-6 13. Lonstein JE. Spondylolisthesis in children. Cause, natural history, and management. Spine. 1999;24:2640 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Case report First report of mild Brazilian spotted fever associated to arthritis Virgínia Lucia Nazario Bonoldia, Roberta Gonçalves Marangonia, Giancarla Gauditanoa, Jonas Moraes-Filhob, Marcelo Bahia Labrunab, Natalino Hajime Yoshinaria,* Department of Rheumatology, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil Faculty of Veterinary Medicine, Universidade de São Paulo, São Paulo, SP, Brazil a b article info abstract Article history: We describe the first Brazilian case of mild Rickettsiosis, complicated by knee monoarthri- Received on 15 February 2012 tis, in young adult bitten by a tick on his left leg in Camburi zone, located in São Sebastião Accepted on 18 February 2013 municipality, southern coastal region of the State of São Paulo, in the Atlantic rainforest region, Brazil. The patient developed inoculation eschar at the tick bite site associated with Keywords: enlarged lymph nodes in the left groin, fever, polyarthralgia, headache and macular rash. Brazilian spotted fever Twenty days after tick bite episode, he displayed monoarthritis in his right knee. The diag- Mild rickettsiosis nosis of mild Rickettsiosis was established by sequential immunological analysis in serum Arthritis and synovial fluid, using the indirect immunofluorescence (IF) assay for antibodies reactive Infectious arthritis with Rickettsia parkeri and Rickettsia rickettsii. The mild Rickettsiosis is an emerging zoonosis, that must be investigated by physicians, including rheumatologists, in patients that present macular rash, fever and eventually arthritis, after visiting the southern coastal Atlantic rainforest region in Brazil. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. Primeiro caso de branda maculosa brasileira branda associada à artrite resumo Palavras-chave: Descrevemos o primeiro caso brasileiro de Riquetsiose branda, agravada por monoartrite em Febre maculosa brasileira joelho, em adulto jovem picado por carrapato na perna esquerda na região de Camburi, lo- Riquetsiose branda calizada no município de São Sebastião, sul da região costeira do estado de São Paulo, Mata Artrite Atlântica, Brasil. O paciente apresentou uma escara de inoculação no local da picada do car- Artrite infecciosa rapato, associada ao aumento ganglionar em virilha esquerda, febre, poliartralgia, cefaleia e erupção macular. Vinte dias após o episódio da picada de carrapato, o paciente apresentou monoartrite em joelho direito. O diagnóstico de Riquetsiose branda foi estabelecido pela análise imunológica sequencial em amostras de soro e líquido sinovial, tendo sido empregada a técnica de imunofluorescência (IF) indireta para anticorpos reativos contra Rickettsia parkeri e Rickettsia rickettsii. A Riquetsiose branda é uma zoonose emergente, que deve ser investigada * Corresponding author. E-mail: [email protected] (N.H. Yoshinari). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.02.002 238 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0 pelos médicos, incluindo reumatologistas, em pacientes que apresentem erupção macular, febre e, eventualmente, artrite, após visita ao sul da região costeira da Mata Atlântica no Brasil. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Spotted fever caused by Rickettsia rickettsii is a serious zoonosis transmitted by ticks described in Americas, including in Brazil.1 The disease can lead to death if not diagnosed and treated at the onset of clinical symptoms. Laboratory diagnosis is based on seroconversion of consecutive samples from acute and convalescent phases of the disease using R rickettsii antigen. The clinical manifestations of BSF begin about a week after the tick bite with fever, headache, abdominal pain and maculopapular rash. The disease can progress to respiratory and renal complications, coagulation disorders and encephalitis. Due to the severity of the illness, antibiotic treatment should be started quickly despite laboratory analysis.1,2 Paddock et al. identified a new tick-borne Rickettsia of the spotted fever group that causes disease. Patients exhibited characteristic skin ulceration at the tick bite site (eschar), followed by maculopapular rash, fever, headache, myalgia and arthralgia. However, the clinical picture is milder due to the absence of coagulopathy.3 The etiologic agent was identified as Rickettsia parkeri, which has a lot of genetic similarity with R. conorii, R. africae and R. sibirica, species that cause similar clinical symptoms in the Mediterranean region.4 In Brazil, the etiologic agent of the mild rickettsiosis was identified in the skin lesion biopsy (eschar) of two patients. The molecular studies demonstrated that this agent is genetically similar to R. parkeri, R. africae and R. sibirica.5,6 The present study reports the discovery of the third case of mild rickettsiosis in Brazil, and importantly, for the first time, related to occurrence of monoarthritis following this rickettsial infection. In Brazil, all three cases were described in the Atlantic Forest, ecological complex with the occurrence of the Amblyomma ovale tick infected with the etiologic agent.7 In the fourth week of therapy, prednisone (10 mg/day) was prescribed associated with doxycycline due to the persistence of arthritis. After 7 days of therapy, the arthritis worsened with physical exercise and the prednisone was replaced by sulfasalazine (1g/ 12/12h). After 3 months of therapy with sulfasalazine, the right knee monoarthritis remitted. Two samples of blood and synovial fluid were collected (March 1st, 2011, and March 15th, 2011); the first, after 10 days of antibiotic therapy, the other, 15 days after this. Additional laboratory tests showed alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatinine phosphokinase, gamma glutamyl transferase, lactic dehydrogenase, glucose, hemogram with platelets counting, protein electrophoresis, urea, creatinine, sodium, potassium and anti-streptolisin O levels within reference ranges. Tests for hepatitis B and C, cytomegalovirus, HIV 1 and 2, syphilis, Brazilian borreliosis and bartonellosis were negative. IgE and C-Reactive Protein were increased, but levels became normal with treatment. Two serum samples revealed A Case report In February 2011, a 30-year-old man was bitten by a tick on his left leg while walking on an ecological trail within Atlantic rainforest area in Camburi, São Sebastião city, southern coastal region of the State of São Paulo. After 7 days, he presented erythematous skin lesions with central ulceration (eschar) at the tick bite site (Fig. 1a). After 10 days of the tick bite, he developed fever not measured, polyarthralgia (hands, elbows, wrists, ankles), myalgia, neck pain, headache, nausea, enlarged lymph nodes on the left groin and chills, followed by generalized rash on the trunk and limbs. The patient sought medical care and, based on suspicion of rickettsial disease, the physician prescribed doxycycline even before the laboratorial tests. After 10 days of treatment, general symptoms had improved, but the doxycycline was continued due to the emergence of right knee monoarthritis (Fig. 1b). B Fig. 1 – (A) Inoculation eschar on the left leg of a patient with mild Brazilian spotted fever and acute knee monoarthritis. (B) Acute monoarthritis in right knee of a patient with mild Brazilian spotted fever, after a tick bite episode occurred in the Atlantic rainforest, São Sebastião, São Paulo State, Brazil. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0 presence of anti-nuclear antibodies (ANA), exhibiting a dense fine speckled pattern on HEp-2 cells analysis (Table 1). Paired samples of acute-phase and convalescent-phase of blood sera and synovial fluids were evaluated under the same conditions by IF assay for antibodies to R. parkeri and R. rickettsia. The samples were tested with a goat anti-human immunoglobulin (Ig) G for the first and second serum and synovial fluid samples or a goat anti-human IgM fluorescein isothiocyanate conjugate (Sigma Diagnostics, St. Louis, MO, USA) for samples of acute-phase and convalescent-phase of synovial fluids and a single convalescent-phase sample of serum. In Table 1, we can see that the titles of the IgM to R. parkeri and to R. rickettsii in synovial fluid showed increased antibody reactivity between the first and second samples. Titers of IgG to R. parkeri and R. rickettsii were always high in synovial fluid. The IgG titles to rickettsial antigens were high in both sequential samples of blood serum, but the IgG to R. parkeri showed an increase in antibody title in blood serum samples. Discussion and conclusions We described the third Brazilian case of mild rickettsiosis, at this time complicated with knee monoarthritis, which appeared nearly twenty days after tick bite episode. Like the previously described two cases of mild rickettsiosis,5,6 the patient caught the disease walking on ecological trail, within Atlantic rain Forest. The specific serologic diagnostic tests for rickettsiosis, performed in serum and synovial fluid samples at acute and convalescent phases of disease confirmed the diagnosis. Moreover, laboratorial investigations for other infectious diseases were negative, including the possibility of co-infection with Lyme like,8 which is transmitted by ticks and causes arthritis. Antinuclear antibodies positivity was not correlated with clinical findings, and therefore, interpreted as an isolated phenomenon Table 1 – Sequential Immunofluorescent (IF*) assays (IgM and IgG) to detect antibodies against R. parkeri and R. rickettsii in serum and synovial fluid samples. C-Reactive protein, IgE and antinuclear antibodies (ANA**) in serum samples of a patient with mild Brazilian spotted fever and acute knee monoarthritis in Brazil, 2011. Serum IF IgG R. parkeri IF IgM R. parkeri IF IgG R. rickettsii IF IgM R. rickettsii IgE (IU/ml) PCR (mg/L) ANA Synovial fluid March 1 March 15 March 1 March 15 1/1024 1/2048 1/2048 1/2048 - - 1/256 1/512 1/1024 1/1024 1/2048 1/2048 - - 1/128 1/256 1240 1,5 783 0,5 - - > 1/320 > 1/320 - - 239 or related to rickettsial infection. The increased level of IgE was understood as mast cell-dependent allergic response to the tick bite. This hypothesis is plausible, since the IgE levels decreased as the disease improved. In patients with Mediterranean Spotted Fever disease, caused by R. conorii, arthritis in large joints with joint effusion in the hips, knees and ankles is described.9 Sundy et al. reported knee acute monoarthritis in patient with RMSF.10 Ding et al. reported polyarthritis in the wrists, metacarpal phalangeal and proximal interphalangeal joints in patient who acquired the illness in travel to Africa, where the disease is caused by R. parkeri or R. conorii.11 In the present case, the pathogenesis of knee monoarthritis following mild rickettsiosis infection is uncertain. The joint effusion can result of direct articular infection by rickettsial microorganisms (infectious arthritis) or can reflect synovial inflammation triggered by immune complexes depositions (reactive arthritis). The identification of rickettsial infection by molecular procedures in the synovial fluid and eschar biopsy was inconclusive, because PCR was done lately when patient was treated with doxycycline. We believe that arthritis viewed in this patient is of reactive origin, since arthritis appeared late, nearly 20 days from bacteria inoculation. Additionally, this period of time was enough to produce specific antibodies to rickettsial components. Outbreak of arthritis in the opposite leg of tick bite and uprising of antinuclear antibodies are further evidences to suggest occurrence of immunological inflammatory arthritis. In Rickettsia infection, the IgM and IgG serum levels increase by the second week of illness, IgM antibodies wane after 3 or 4 months and IgG titers persist for 7 or 8 months.12 We noted that despite the existence of cross-reactivity between rickettsial species,2 the IgG titer to R. parkeri increased, at least, 1-fold higher in the serum, although it was a low increase in title, which did not occur to R. rickettsii. We can see an increase in R. parkeri IgM titer of paired synovial fluid specimens taken early and later in the disease course, unlike in R. rickettsii, suggesting more IgM specificity to R. parkeri. In addition, the R. parkeri rickettsiosis can be associated with the presence of an eschar at the site of tick bite.3 High titers of IgM antibodies to rickettsial antigens in synovial fluid confirmed the etiology of knee acute arthritis. We conclude that Brazilian spotted fever is not a single disease, because at least two pathogenic species of Rickettsia are present in Brazil causing similar symptoms. The mild form of the disease is reported in the region that attends the Atlantic Forest and, as described in this current case report, may be associated to arthritis as a complication of systemic disease. Conflicts of interest The authors declare no conflicts of interest. *IF Cut off = 1/64 **Dense fine speckled ANA pattern on HEp-2 cells analysis. -: not evaluated. REFERENCES 1. Labruna MB. Ecology of rickettsia in South America. Ann N Y Acad Sci. 2009 May;1166:156-66. 2. Paddock CD, Finley RW, Wright CS, Robinson HN, Schrodt BJ, Lane CC et al. Rickettsia parkeri rickettsiosis and its clinical 240 3. 4. 5. 6. 7. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 3 7 – 2 4 0 distinction from Rocky Mountain spotted fever. Clin Infect Dis. 2008;47:1188-96. Paddock CD, Sumner JW, Comer JA, Zaki SR, Goldsmith CS, Goddard J et al. Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis. 2004 Mar 15;38:805-11. Goddard J. Historical and recent evidence for close relationships among Rickettsia parkeri, R. conorii, R. africae, and R. sibirica: implications for rickettsial taxonomy. J Vector Ecol. 2009 Dez;34:238-42. Spolidorio MG, Labruna MB, Mantovani E, Brandao PE, Richtzenhain LJ, Yoshinari NH. Novel spotted fever group rickettsiosis, Brazil. Emerg Infect Dis. 2010 Mar;16:521-3. Silva N, Eremeeva ME, Rozental T, Ribeiro GS, Paddock CD, Ramos EA, Favacho AR, Reis MG, Dasch GA, de Lemos ER, Ko AI. Eschar-associated spotted fever rickettsiosis, Bahia, Brazil. Emerg Infect Dis. 2011 Fev;17:275-8. Sabatini GS, Pinter A, Nieri-Bastos FA, Marcili A, Labruna MB. Survey of ticks (Acari: Ixodidae) and their rickettsia in an Atlantic rain forest reserve in the State of São Paulo, Brazil. J Med Entomol. 2010 Set;47:913-6. 8. Yoshinari NH, Mantovani E, Bonoldi VLN, Marangoni RG, Gauditano G. Doença de Lyme-símile brasileira ou Síndrome Baggio-Yoshinari: Zoonose exótica e emergente brasileira transmitida por carrapatos. Rev Assoc Med Bras. 2010;56:3639. 9. Pedro-Botet J, Auguet T, Pallás O, Gimeno JL. Arthritis in Mediterranean spotted fever. Infection. 1991 Set-Out;19:346-7. 10. Sundy JS, Allen NB, Sexton DJ. Rocky Mountain spotted fever presenting with acute monoarticular arthritis. Arthritis Rheum. 1996 Jan;39:175-6. 11. Ding T, Lloyd G, Tolley H, Bradlow A. Tick bite fever and arthritis associated with travel to Africa. Ann Rheum Dis. 2004 Dez;63:1703-4. 12. Clements ML, Dumler JS, Fiset P, Wisseman CL Jr, Snyder MJ, Levine MM. Serodiagnosis of Rocky Mountain spotted fever: comparison of IgM and IgG enzyme-linked immunosorbent assays and indirect fluorescent antibody test. J Infect Dis. 1983;148:876-80. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Brief communication Patients with systemic lupus erythematosus and secondary antiphospholipid syndrome have decreased numbers of circulating CD4+CD25+Foxp3+ Treg and CD3– CD19+ B cells Ester Rosári Raphaelli Dal Bena,*, Carine Hartmann do Pradoa, Talita Siara Almeida Baptistaa, Moisés Evandro Bauer a, Henrique Luiz Staubb a Laboratory of Immunosenescence, Institute of Biomedical Research, Faculty of Biosciences, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil b Rheumatology Department, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil article info abstract Article history: Introduction: CD4+CD25+Foxp3+ regulatory T (Treg) cell depletion has been reported in sys- Received on 20 May 2013 temic lupus erythematosus (SLE) and, recently, in primary antiphospholipid syndrome Accepted on 16 September 2013 (APS); the issue has not been studied in SLE patients with secondary APS (SLE/APS) so far. Objective: To quantify total lymphocytes, Treg cells, CD3+CD19– T cells and CD3–CD19+ B cells Keywords: in SLE/APS patients and healthy controls. Systemic lupus erythematosus Methods: Cell subtypes underwent immunophenotyping using specific monoclonal antibod- Secondary antiphospholipid ies (anti-CD3 CY5, anti-CD4 FITC, anti-CD25, anti-Foxp3, anti-CD19 PE) and flow cytometry. syndrome Results: Twenty-five patients with SLE/APS (mean age 43.5 years, 96% females, 96% cauca- Treg cells sians, mean duration of disease 9.87 years, mean SLEDAI 10 ± 5.77) and 25 age and sex- CD3–CD19+ B cells matched controls entered the study. It was realized that the numbers of Treg and CD3– CD19+ B cells were significantly lower in SLE/APS patients than in controls (all p < 0.05). Treg and CD3–CD19+ B cells remained numerically low after controlling (ANCOVA) for percentage of total lymphocytes (p < 0.05). Decreasing levels of circulating Treg and CD3–CD19+ B cells correlated to higher scores of lupus activity (rs = -0.75, p < 0.0001; rs = -0.46, p = 0.021, respectively). Number of Treg cells and CD3–CD19+ B lymphocytes did not significantly differ in users or nonusers of chloroquine, azathioprine and corticosteroids (all p > 0.05). Conclusions: In this preliminary study, patients with SLE and secondary APS showed depletion of Treg and CD3–CD19+ B cells; decreasing numbers of both subtypes correlated to a higher SLEDAI. Treg cells depletion might contribute to the autoimmune lesion seen in patients with SLE/APS. The reduced number of CD3–CD19+ B cells seen in these patients deserves more studies in order to get further elucidation. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. * Corresponding author. E-mail: [email protected] (E.R.R. Dal Ben). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.09.001 242 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6 Pacientes com lúpus eritematoso sistêmico e síndrome antifosfolípide secundária possuem números reduzidos de células B CD4+ CD25+ Foxp3+ (células Treg) e células B CD3– CD19+ circulantes resumo Palavras-chave: Introdução: A depleção de células T CD4+ CD25+ Foxp3+ regulatórias (células Treg) foi descrita Lúpus eritematoso sistêmico (LES) em pacientes com lúpus eritematoso sistêmico (LES) e, recentemente, na síndrome antifosfo- Síndrome antifosfolípide lípide (SAF) primária; até o momento, o tópico não tinha sido estudado em pacientes com LES secundária (SAFS) e com SAF secundária (LES/SAFS). Células Treg Objetivo: Quantificar linfócitos totais, células Treg, células T CD3+ CD19– e células B CD3– CD19+ Células B CD3– CD19+ em pacientes com LES/SAF e em controles saudáveis. Métodos: Subtipos celulares foram imunofenotipados utilizando anticorpos monoclonais específicos (anti-CD3CY5, anti-CD4FITC, anti-CD25, anti-Foxp3, anti-CD19PE) e citometria de fluxo. Resultados: Participaram do estudo 25 pacientes com LES/SAF (média de idade 43,5 anos, 96% mulheres, 96% da raça branca, duração média da doença 9,87 anos, SLEDAI médio 10±5,77) e 25 controles compatibilizados para idade e gênero. Foi constatado que os números de células Treg e de células B CD3– CD19+ estavam significativamente mais baixos em pacientes com LES/ SAF, em comparação com controles (todos p<0,05). As células Treg e as células B CD3- CD19+ permaneceram numericamente baixas em seguida ao controle (ANCOVA) para percentual de linfócitos totais (p<0,05). Níveis decrescentes de células Treg e células B CD3- CD19+ circulantes tiveram correlação com escores mais elevados de atividade lúpica (rs=-0,75, p<0,0001; rs=-0,46, p=0,021, respectivamente). Os números de células Treg e de células B CD3- CD19+ não diferiam significativamente em usuários ou não usuários de cloroquina, azatioprina e corticosteroides (todos p>0,05). Conclusões: Nesse estudo preliminar, pacientes com LES e com SAF secundária demonstraram depleção de células Treg e de células B CD3- CD19+; a redução numérica dos dois subtipos teve correlação com aumento de SLEDAI. A depleção de células Treg pode contribuir para a lesão autoimune observada em pacientes com LES/SAFS. O número reduzido de células B CD3- CD19+ observado nesses pacientes está a merecer estudos objetivando um aprofundamento em sua elucidação. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Systemic lupus erythematosus (SLE) is a multiorganic disease characterized by immune dysregulation; loss of tolerance to self-antigens leads to formation of immune complexes.1 Recent data in both human SLE and mouse models have highlighted the role of type I interferon’s (α/β) in the initiation and perpetuation of the disease.2 Individuals with SLE are more susceptible to thrombosis than the general population, and the antiphospholipid syndrome (APS) is a well-known risk factor for vascular obstruction in such patients.3 The reason why patients with SLE and APS produce pathogenic antiphospholipid (aPL) antibodies has been a matter of intense debate. CD4+CD25+Foxp3+ regulatory T (Treg) cells are a distinct thymically derived or inducible subset of T cells with unique immunosuppressive abilities. Quantitative or functional impairment of Treg lymphocytes seems to direct the immune system toward autoimmunity.4 It is frequently observed an imbalance between IL-17 producing T helper (Th17) and Treg cells during the course of SLE, with marked impairment of the Treg subset.5 It is noteworthy that the blockage of Treg cells by interferon-α-producing antigen presenting cells may contribute to loss of peripheral tolerance in SLE.6 A CD4+CD25+Foxp3+ Treg cell dysfunction has been documented in a number of autoimmune disorders.7 In SLE cases, most studies have shown decreased number of circulating Tregs in active disease, but data are still conflicting.8 B lymphocytes, in turn, are pivotal cells in SLE; they are linked to antigen-presentation, autoantibody synthesis and cytokine production. It is noteworthy that a distinct subset of B cells shown to exert immunosuppressive effects;9 these IL-10-producers and regulatory-B cells, knowingly able to suppress T helper cells differentiation, appear to be functionally impaired in SLE patients.10 Considering the importance of the interplay of T, Treg cells and B lymphocytes in the immunopathogenesis of SLE (5-7; 9,10) we set up to originally quantify total lymphocytes, Treg cells, CD3+CD19– T cells and CD3–CD19+ B cells in a Brazilian survey of patients with SLE/ secondary APS (SLE/APS) and healthy controls. Material and methods This cross-sectional study included patients with SLE and history of secondary APS from our Outpatient Lupus Clinic. Clinical and laboratory diagnosis of SLE were based on the American College of Rheumatology 1997 criteria,11 while the 243 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6 Sidney 2006 criteria was utilized to diagnose APS.12 Lupus activity was assessed by the systemic lupus erythematosus disease activity index, SLEDAI.13 The exclusion criteria were as follows: 1) age below 16 years; 2) infective endocarditis or other current infections; 3) diabetes mellitus; 4) neoplasms (current or past); and 5) infection by human immunodeficiency virus or Treponema pallidum. The control group comprised healthy individuals aged more than 16 years-old, matched by age and sex, and with no APS, connective tissue disorders, neoplasms or current infections. Clinical and demographic data were obtained from a chart review and interview with patients or family after informed consent. The study was approved by the local ethics committee. Cell subtypes underwent immunophenotyping using the specific monoclonal antibodies anti-CD3CY5, anti-CD4 FITC, anti-CD25, anti-Foxp3 and anti-CD19 PE (Biosciences, San Jose, CA, USA) and identified by multicolor flow cytometry.14 Quantitative statistical analysis was performed using SPSS 17.0 software (SPSS Inc, Chicago, IL, USA). The significance level was set at a = 0.05 (two-tailed). The results were shown as means and standard deviation or by absolute and relative frequencies. The statistical analysis was performed by Student’s t test and the Mann-Whitney test for the continuous variables, and chi-square or Fisher’s exact test for categorical variables. The Pearson test was utilized to correlate circulating cell subtypes with the SLEDAI. An analysis of covariance (ANCOVA) was performed to evaluate relationships between variables. Results Twenty-five patients with SLE/APS and 25 healthy controls entered the study. Middle-aged (mean age 43.5 years) females (96%) highly predominated in our SLE/APS survey. Twenty-four patients (96%) were caucasians. Mean duration of the disease was 9.87 years, and the average SLEDAI score was 10 ± 5.77. At the moment of evaluation, arthritis (36%), oral ulcers (32%), malar rash (24%), seizures (16%), nephritis (12%), and leukopenia (8%) were the most frequent SLE manifestations. All patients had antinuclear antibodies, and 40% were positive for anti-dsDNA. Low complement levels were seen in 8% of patients. Regarding the APS clinical features, deep vein thrombosis (DVT) was seen in 15 patients (60%), while fetal losses (so considered after 12 weeks of pregnancy) occurred in 6 patients (24%). Optic neuritis was seen in 4 cases (16%). Stroke and miscarriages were each diagnosed in 3 cases (12%). Moderate or high levels of anticardiolipin (aCL) antibodies were detected in 21 patients (84%), whereas lupus anticoagulant was present in 9 patients (36%). Fourteen patients (56%) were on oral anticoagulation regime with warfarin, and the remaining was being treated with low-dose aspirin. Chloroquine, azathioprine and corticosteroids were being utilized by 9 patients (36%), 5 patients (20%) and 16 patients (64%), respectively. Table 1 compares demographic aspects and lymphocyte subsets of SLE/APS patients and controls. Both groups were homogenous regarding age, gender and race. The mean number of CD4+CD25+Foxp3+ Treg cells and CD3–CD19+ B cells were significantly lower in patients with SLE/APS when compared to controls. The mean number of total lymphocytes, CD3+CD19– T cells and CD4+CD25+ lymphocytes did not significantly differ between groups. The SLE/APS patients were maintaining a significantly lower number of Treg cells after the control (ANCOVA) for percentage of total lymphocytes (F = 28.50, p < 0.0001). The FoxP3 expression in CD4+CD25+ cells, as estimated by mean fluorescence intensity, did not differ in SLE/APS patients and controls (2660.55 ± 1044.06 vs 2470,65 ± 1732.87; p = 0.67; respectively). Patients with SLE/APS persisted with significantly lower percentage of CD3–CD19+ B cells after controlling for total lymphocytes (F = 13.17; p = 0.002). Fig. 1 shows the distribution of total lymphocytes, CD4+CD25+Foxp3+ Treg cells and CD3–CD19+ B lymphocytes in SLE/APS patients as compared to controls. The Pearson test for correlation of circulating Treg and CD3–CD19+ B lymphocytes with the SLEDAI is shown in Fig. 2. A significant negative correlation of both cell subtypes with the SLEDAI was obtained, indicating that a lower number of Treg and CD3–CD19+ B cells were linked to increasing scores of lupus activity. Table 1 – Demographic data and lymphocyte subset in 25 patients with systemic lupus erythematosus/secondary antiphospholipid syndrome (SLE/APS) and 25 healthy controls Mean age (years ±SD) Females Caucasians Total lymphocytes CD3+CD19– T lymphocytes CD4+CD25+ T lymphocytes CD4+CD25+Foxp3+ T lymphocytes CD3–CD19+ B lymphocytes SD, standard deviation. a Chi-square test. b Students t test. 29.42 ± 4.57% 73.72 ± 8.34% 1.28 ± 0.89% 0.74 ± 0.34% 5.71 ± 2.66 % SLE/APS Controls (n = 25) (n = 25) 43.5 ± 12.84 24 (96%) 24 (96%) 2227.86±528.83 cells/μL 1522.52±527.20 cells/μL 20.50±9.35 cells/μL 21.61±12.70 cells/μL 136.34±92.68 cells/μL 43.80 ± 8,45 24 (96%) 24 (96%) 32.2 ± 2.49% 2523.60±528.83 cells/μL 73.64 ± 7.70% 858.38±194.32 cells/μL 1.81 ± 0.80% 45.68±20.19 cells/μL 1.83 ± 0.77% 46.18±19.43 cells/μL 9.25 ± 3.00% 233.43±75.71 cells/μL p 0.93a 1.00a 1,00a 0.13b 0,100b 0,81b <0.0001b 0.006b 244 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6 A) rs=-0.75, p<0.0001* %CD4+CD25+FOXP3+ 2,00 1,50 1,00 0,50 0,00 0 10 SLEDAI 15 20 25 B) Fig. 1 – Graphical distribution of total lymphocytes (A), CD4+CD25+Foxp3+ Treg cells (B) and CD3–CD19+ B cells (C) in controls and patients with systemic lupus erythematosus/secondary antiphospholipid syndrome (SLE/APS).*Students t-test. rs=-0.46, p=0.021* 20,00 15,00 %CD3-CD19+ Levels of circulating Treg cells did not significantly vary among users or nonusers of chloroquine, azathioprine and corticosteroids (p = 0.90; p = 0.76 and p = 0.29 in the chi-square test, respectively). Similarly, the number of CD3–CD19+ B cells did not significantly differ in users on nonusers of these medicines (p = 0.462; p = 0.512 and p = 0.341 in the chi-square test, respectively). When we compared cell subtypes selectively in 5 patients with inactive SLE/APS (SLEDAI < 4) and 25 healthy controls, only the CD3–CD19+ B population remained diminished in the first group (5.37 ± 1.95% × 9.25 ± 3.00%; p = 0.003; Student’s t test). 5 10,00 5,00 0,00 0 5 10 15 20 25 SLEDAI Fig. 2 – Pearson correlation of circulating Treg cells (A) and CD3–CD19+ B cells (B) with lupus activity assessed by the systemic lupus erythematosus disease activity index (SLEDAI). *Student’s t test Discussion A number of reports have accounted for a decrease of Treg cells in patients with SLE.15-17 As far as we are aware, this study is the first to approach circulating Treg cells and B lymphocytes in Brazilian patients with SLE and secondary APS. Our survey included predominantly middle-aged white females with high SLEDAI, and mean disease duration of approximately a decade. Arthritis and oral ulcers were the prominent SLE findings, while DVT and aCL antibodies were cardinal APS features. We have found a decreased number of circulating CD3– CD19+ B cells in our SLE/APS patients when compared to controls. It is important to say that there was no association of CD3–CD19+ B cell count with intake of chloroquine, azathioprine and steroids. The reasons for this B cell decrease in SLE/ APS patients are nebulous, but an explanation could be autoantibodies directed to B lymphocytes or intrinsic defects of B cell subsets. The fact that B cell depletion was confirmed even in the 5 patients with inactive SLE might support the latter. We could only suppose the hypothesis that the population with B cells depletion is the IL-10 producer subset with immunosuppressive properties. It is noteworthy that competent B cells seem to be important to trigger Treg activity, as shown in patients with common variable immunodeficiency18. Reduced numbers of circulating CD4+CD25+Foxp3+ Treg cells were seen in our SLE/APS patients as compared to controls. As occurred the with the B cell subtype, Treg cells depletion was confirmed after controlling (ANCOVA) for total lymphocyte count. Decreasing levels of circulating Treg cells, just as seen with the CD3–CD19+ B subset, were correlated with higher scores of disease activity. Diminished levels of Treg cells have been associated with active SLE19,20, but other reports21,22 questioned this finding. In our study, Treg cells depletion could be representative of an intrinsic defect related to previous SLE/ APS, or current SLE activity. Patients with inactive SLE did not show Treg reduction, which favors the second hypothesis. It is worthy of note that there was no association between Treg R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6 cells decrease and the intake of chloroquine, azathioprine or steroids in our patients either. Our group recently reported low levels of circulating Treg and also of CD3–CD19+ B cells in patients with primary APS23. These data, combined with the current study, imply that depletion of both subsets occurs in APS populations as a whole. If this assumption will be confirmed, the Treg cells decrease may comprise one of the immune mechanisms leading to pathogenic aPL responses in primary or secondary APS. Nevertheless, it should be considered that Treg cells decrease in our SLE/APS patients seemed to relate more to SLE activity than any other particular factor. Recent data disclosed that any quantitative analysis of Tregs in patients with autoimmune disorders have to be seen with some caution. The reg cells show formidable plasticity and comprise a heterogeneous population of suppressive cells, non-functional Treg cells and IL-17A-producing Treg cells acting as effector T lymphocytes. Thus, the simple numeric count of Tregs might not be truly representative of their functional status.24 Some other limitations of our study must be mentioned. Even though the majority of our patients showed active SLE, the APS thrombotic manifestations were not current; newer studies should investigate the biological function of Treg cells and B lymphocytes during the thrombotic event and also in a longitudinal analysis. Given the small sample, we could not subgroup patients by SLE/APS features or drug dosage. The small number of patients with inactive SLE restricted the statistical power of the article. The same way, the lack of comparison between patients with SLE and without APS limited our conclusions. Up to date, the treatments of SLE and APS have been reasoned in immunosuppression and anticoagulation, respectively. A direct immunomodulatory approach shifting the balance to favor Treg cells is being tried with autologous Treg cell therapy in type-1 diabetes,25 and such intervention might be promising for SLE and APS as well. Recently, it was noticed that Treg cells were able to prolong the interval of remission induced by conventional cytostatic drugs in (NZB × NZW) F1 lupus mice.26 Although many questions concerning the pathogenesis of SLE and APS remain undefined, it is possible that the progression of the disease results from a breakdown in Treg-dependent peripheral self-tolerance. In this context, Treg-based immunotherapy might have a place in the maintenance of disease remission in this group of patients. In summary, this preliminary study demonstrated impaired numbers of CD4+CD25+Foxp3+ Treg cells and CD3–CD19+ B lymphocytes in Brazilian patients with SLE and secondary APS. Lower cell counts were seen in patients with higher SLE activity. Future studies shall confirm if the decrease of Treg cell levels is connected to the abnormal immune response seen in SLE/APS. The decrease of CD3–CD19+ B cells seen in these patients, and potentially linked to Treg dysfunction, also justifies new studies in order to search for more clarifications. Conflicts of interest The authors declare no conflicts of interest. 245 REFERENCES 1. Buc M, Rovenský J. Systemic lupus erythematosus – a contemporary view of its genetic determination, immunopathogenesis and therapy. Epidemiol Mikrobiol Imunol. 2009;58:3-14. 2. Jorgensen TN, Gubbels MR, Kotzin BL. Links between type I interferons and the genetic basis of disease in mouse lupus. Autoimmunity. 2003;36:491-502. 3. Burgos PI, Alarcón GS. Thrombosis in systemic lupus erythematosus: risk and protection. Expert Rev Cardiovasc Ther. 2009;7:1541-9. 4. Tang Q, Bluestone JA. 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Nihon Rinsho Meneki Gakkai Kaishi. 2012;35:495-502. 10. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, Mauri C. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010;32:129-40. 11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. 12. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306. 13. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee of Prognosis Studies in SLE. Arthritis Rheum. 1992;35:630-40. 14. Moon HW, Kim BH, Park CM, Hur M, Yun YM, Kim SY, Lee MH. CD4+CD25highFoxP3+ regulatory T-cells in hematologic diseases. Korean J Lab Med. 2011;31:231-7. 15. Fathy A, Mohamed RW, Tawfik GA, Omar AS. Diminished CD4+CD25+ T-lymphocytes in peripheral blood of patients with systemic lupus erythematosus. Egypt J Immunol. 2005;12:25-31. 16. Mellor-Pita S, Citores MJ, Castejon R, Tutor-Ureta P, YebraBango M, Andreu JL et al. Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis. 2006;65:553-4. 17. Barreto M, Ferreira RC, Lourenco L, Moraes-Fontes MF, Santos E, Alves M et al. Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFbeta gene variants. BMC Immunol. 2009;10:5. 246 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 1 – 2 4 6 18. Genre J, Errante PR, Kokron CM, Toledo-Barros M, Câmara NO, Rizzo LV. Reduced frequency of CD4(+)CD25(HIGH) FOXP3(+) cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132:215-21. 19. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523-32. 20. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol. 2005;175:8392-400. 21. Yates J, Whittington A, Mitchell P, Lechler RI, Lightstone L, Lombardi G. Natural regulatory T cells: number and function are normal in the majority of patients with lupus nephritis. Clin Exp Immunol. 2008;153:44-55. 22. Zhang B, Zhang X, Tang FL, L.P. Z, Liu Y, Lipsky PE. Clinical significance of increased CD4+CD25-Foxp3+ T cells in patients with new-onset systemic lupus erythematosus. Ann Rheum Dis. 2008;67:1037–40. 23. Dal Ben ERR, do Prado CH, Baptista TSA, Bauer ME, Staub HL. Decreased levels of circulating CD4+CD25+Foxp3+ regulatory T cells in patients with primary antiphospholipid syndrome. J Clin Immunol (In Press). 24. Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. Nat Rev Immunol. 2013;13:461-7. 25. Thompson JA, Perry D, Brusko TM. Autologous regulatory T cells for the treatment of type 1 diabetes. Curr Diab Rep. 2012;12:623-32. 26. Weigert O, von Spee C, Undeutsch R, Kloke L, Humrich JY, Riemekasten G. CD4+Foxp3+ regulatory T cells prolong druginduced disease remission in (NZBxNZW) F1 lupus mice. Arthritis Res Ther. 2013;15:R35. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 7 – 2 4 9 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Brief communication When anti-TNF fails, anti-IL12-23 is an alternate option in psoriasis and psoriatic arthritis Ricardo Prado Golmia, Ayk Helena Barbosa Martins, Morton Scheinberg* Hospital Israelita Albert Einstein and Clinical Research Center Hospital Abreu Sodré, São Paulo, SP, Brazil article info abstract Article history: Patients with psoriasis and psoriatic arthritis respond to anti-TNF therapy, but not all pa- Received on 12 April 2013 tients maintain effective response, and some do not respond. In this article, we demon- Accepted on 16 October 2013 strate the role of a new pathogenetic pathway to some extent TNF-independent in these patients. Anti-IL12-23 is a new and alternate mode of therapy for patients with recalcitrant Keywords: response to anti-TNF. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. Psoriasis All rights reserved. Psoriatic arthrits Biologic therapy Quando anti-TNF não obtém sucesso, anti-IL-12-23 é opção alternativa na psoríase e na artrite psoriásica resumo Palavras-chave: Pacientes com psoríase e artrite psoriásica respondem à terapia anti-TNF, mas nem todos Psoríase os pacientes mantêm uma resposta efetiva e alguns não respondem. Nesse artigo, demons- Artrite psoriásica tramos o papel de uma nova via patogenética que, até certo ponto, independe de TNF nes- Terapia biológica ses pacientes. Anti-IL-12-23 é um modo terapêutico novo e alternativo para pacientes com resposta recalcitrante à medicação com anti-TNF. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine involved in inflammation of the skin and synovium, making it a logical target for the treatment of psoriasis (Ps) and psoriatic arthritis (Psa). It has been demonstrated that this cytokine plays a fundamental role in the pathogenesis of both Ps and Psa through several pathogenetic mechanisms, including the expression of adhesion molecules to the surface of endothelial cells, keratinocytes, and dendritic cells promoting leukocyte migration.1 In the joints, it triggers the production of a variety of cytokines, which in turn increase the inflammatory cascade. In the skin, TNF-alpha * Corresponding author. E-mail: [email protected] (M. Scheinberg). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.10.004 248 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 7 – 2 4 9 also leads to a decrease in the apoptosis of keratinocytes, thus contributing to a hyperproliferative epidermis. AntiTNF-alpha has the potential to provide symptomatic relief and help prevent disease progression in Ps and Psa by decreasing joint and skin inflammation.2 Guidelines derived from evidence based clinical trials and from clinical practice has established the clinical usefulness of all the three anti-TNF agents for the treatment of axial and peripheral P and Psa. These agents selectively block the role of TNF-alpha and proved to be effective in clinical trials and also in clinical practice.3 All the three agents – infliximab, etanercept, and adalimumab – have shown marked improvements in disease activity in the PASI-75 of the skin and in disease activity indexes ACR20, ACR50, ACR70 when compared to patients treated with placebo. However, in our and others’ experience, not all patients respond to these agents, and in some of them, the initial response is lost after variable periods of time.4,5 Although switching to another anti-TNF can boost a secondary response, this may also be variable, and, in some patients, no response at all can be observed. Currently, two new anti-TNFs are being evaluated for the treatment of Psa a humanized form of infliximab by subcutaneous route, golimumab and a pegylated form of anti-TNF, certolizumab pegol. Phase-2 preliminary studies indicate efficacy similar to the conventional antiTNFs.6,7 Surprise as it may be, a few patients develop Ps after the treatment with anti-TNFs, and several explanations are being developed for this enigmatic observation. One of the most attractive is the switch to another inflammatory pathway after prolonged blockade of TNF.8-10 Ustekinumab is an immunoglobulin, a human monoclonal antibody that binds with great affinity to the shared p40 subunit of human interleukin 12 and 23.11,12 Increased production of IL-23 (but not of IL-12 mRNA) production can be observed in the skin of Ps patients. IL-23 is essential for the survival and proliferation of Th17 cells. Previous published data have shown CD4 and CD8 cells in Ps lesions, and Ps is considered a Th1 disease. However, it has been demonstrated that the CD4 cells secrete excessive amounts of IL17; they are Th17 cells, therefore, and one scenario consists in considering Ps as a Th1/Th17-mixed disease.13 Two clinical studies known as PHOENIX 1 and 2 evaluated patients with moderate to severe Ps. PHOENIX 1 studied 66 patients randomized to receive 45 mg or 90 mg at the weeks zero, four, and every 12 weeks. In PHOENIX 2, a similar study was performed, but in this time with adjustable doses in case of partial responses, totaling 70% of the patients in both studies against 3% in the group treated with placebo. After 52 weeks, besides a good index of response, no serious adverse events happened, except minor symptoms at upper respiratory tract (apparently common with the use of any immunobiological agents), neither anaphylaxis nor presence of tuberculosis, being these symptoms still associated with a very convenient way of administration subcutaneously every two to three months. When compared with etanercept, it was demonstrated that the response observed with ustekinumab was superior in efficacy and side effects (Figs. 1, 2, and 3).14-17 Studies with ustekinumab in Psa are underway. The superiority of this agent has been demonstrated versus placebo in controlled trials, reducing signs Fig. 1 – Phoenix 1 & 2: study design. Fig. 2 – Ustekinumab pasi 75 responses at week 12 (after doses at weeks 0, 4). Fig. 3 – Significant efficacy after two injections. and symptoms in the joints and also in the skin. Phase-3 results are still pending.18,19 Briakinumab (ABT-974) is another fully human monoclonal antibody against the p40 subunit of IL12-23, that is currently under evaluation for Ps.20 Preliminary results are similar to those observed with ustekinumab. Finally, as the activation of IL-23 depends on Th17,future biological agents for Ps and Psa might be directed at Th17 and their secreted product IL-17, a pathway still not taken in Psoriasis.21 In summary, the current status on the therapy of Ps and Psa should now include new medications despite the fact that after TNF failure, we still lack proper guidelines.22,23 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 4 7 – 2 4 9 Conclusions It is conceivable that we are not ready to replace anti-TNF as an alternative for the treatment of Ps, but it is a possibility, in case of Psa, until the ongoing phase-3 studies are available, it may also become a possibility in reducing articular signs and symptoms. So, what is the alternative if anti-TNF fails in patients suffering from Ps and Psa? Our understanding is that until comparative studies be performed, inhibition of new pathogenetic pathways should be considered and evaluated at the individual level; moreover, blocking IL12-23 is an alternative pathway initially indicated for the skin, although it also seems to be helpful in alleviating symptoms of arthritis.24,25 Conflicts of interest The authors declare no conflicts of interest. R eferences 1. Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149-60. 2. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-79. 3. Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: lessons learned unresolved issues and future directions. Curr Dir Autoimmun. 2010;11:180-210. 4. Papagoras C, Voulgari PV, Drosos AA. Strategies after the failure of the first anti-tumor necrosis factor alpha agent in rheumatoid arthritis. Autoimmu Rev.2010;9:574-82. 5. Scheinberg M, Goldenberg J, Feldman DP, Nóbrega JL. Retrospective study evaluating dose standards for infliximab in patients with rheumatoid arthritis at Hospital Israelita Albert Einstein, São Paulo, Brazil. Clin Rheumatol. 2008;27:1049-52. 6. Voulgari PV. Golimumab: a new anti-TNF-alpha agent for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Expert Rev Clin Immunol. 2010;6:721-33. 7. Patel AM, Moreland LW. Certolizumab pegol: a new biologic targeting rheumatoid arthritis. Expert Rev Clin Immunol. 2010;6:855-66. 8. Grinblat B, Scheinberg M. Unexpected onset of psoriasis during infliximab treatment: comment on the article by Beuthien et al. Arthritis Rheum. 2005;52:1333-4. 9. Grinblat B, Scheinberg M. The enigmatic development of psoriasis and psoriasiform lesions during anti-TNF therapy: a review. Semin Arthritis Rheum. 2008;37:251-5. 249 10. Laurindo IM, Scheinberg M. Why do some biologic agents induce psoriasis or psoriasiform lesions? Nat Clin Pract Rheumatol. 2008;4:168-9. 11. Gandhi M, Alwawi E, Gordon KB. Anti-p40 antibodies ustekinumab and briakinumab: blockade of interleukin-12 and interleukin-23 in the treatment of psoriasis. Semin Cutan Med Surg. 2010;29:48-52. 12. Elliott M, Benson J, Blank M, Brodmerkel C, Baker D, Sharples KR, Szapary P. 13. Ann N Y. Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Acad Sci. 2009;1182:97-110. 14. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9:461-7. 15. Leonardi CL, Kimball AB, Papp KA, Yeildin N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;37:1665-74. 16. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich K; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371:1675-84. 17. Young MS, Horn EJ, Cather JC. The ACCEPT study: ustekinumab versus etanercept in moderate-to-severe psoriasis patients. Expert Rev Clin Immunol. 2011;7:9-13. 18. Farhi D. Ustekinumab for the treatment of psoriasis: review of three multicenter clinical trials. Drugs Today (Barc). 2010;46:259-64. 19. Kavanaugh A, Menter A, Mendelsohn A, Shen YK, Lee S, Gottlieb AB. Effect of ustekinumab on physical function and health-related quality of life in patients with psoriatic arthritis: a randomized, placebo-controlled, phase II trial. Curr Med Res Opin. 2010;26:2385-92. 20. Cuchacovich R, Espinoza LR.: Ustekinumab for Psa.The Lancet. 2009;373:605-606. 21. Lima XT, Abuabara K, Limball AB, Lima HC. Briakinumab. Expert Opin Biol Ther. 2009;9:1107-13. 22. Weinberg JM. The path not taken. Cutis. 2010;86:115-116. 23. Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol. 2010;160:810-20. 24. Deighton C. Therapy: what should we do after the failure of a first anti-TNF? Nat Rev Rheumatol. 2009;5:596-7. 25. Mease P. Update on treatment of psoriatic arthritis. Bull NYU Hosp Jt Dis. 2012;70:167-71. 26. Wallis DE, Waldron NM, Korendowych E. Ustekinumab for resistant psoriatic arthritis. J Rheumatol. 2013 Feb;40:207. doi: 10.3899/jrheum.121152. R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Brief communication Articular ultrasonography: interobserver reliability in rheumatoid arthritis☆ Melissa Cláudia Bisi a,*, Aline Defaveri do Prado a, Cristina Rabelo b, Flávia Brollo b, Inês Guimarães da Silveira b, José Alexandre de Mendonça c, Henrique Luiz Staub b Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil Faculty of Medicine, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil c Pontifícia Universidade Católica de Campinas, Campinas, SP, Brazil a b article info abstract Article history: Introduction: Ultrasonography (US) has a recent use in Rheumatology, and the reliability of Received on 17 May 2013 the method in rheumatoid arthritis (RA) patients has yet to be clarified. Accepted on 27 September 2013 Objective: To test, in a RA survey, the reproducibility of musculoskeletal US performed by rheumatologists with one-year training through re-analysis by a Rheumatologist experien- Keywords: ced in the method. Rheumatoid arthritis Patients and methods: This cross-sectional study included consecutive RA patients from our Ultrasonography tertiary center. US exam was performed in metacarpophalangeal joints, proximal interpha- Reproducibility, kappa langeal joints, and wrists. Presence of synovitis, power Doppler (PD) signal, bone erosions, and cartilage changes comprised the US parameters evaluated. A kappa value in-between 0.20 and 0.40 was considered fair; in-between 0.41 and 0.60 was moderate; in-between 0.61 and 0.80 was good; and above 0.81 was excellent. Results: We analyzed 1,380 joints of 60 RA patients (78% females, 78% caucasoids). Mean age was 58 ± 11.56 years, mean disease duration was 9.98 ± 7.79 years, mean DAS28 was 3.82 ± 1.53, and mean HAQ was 0.91 ± 0.67. Kappa agreement for synovitis ranged from 0.30 to 0.70; for PD signal, from 0.53 to absolute agreement; for erosions, from 0.70 to 0.97; for cartilage changes, from 0.28 to 0.63. Conclusion: Although good, moderate and excellent interobserver agreement were obtained for erosions and PD, concordance for synovitis and cartilage changes were less impressive in our patients with active RA. Further studies on standardization of scanning technique are necessary to improve musculoskeletal US reproducibility. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. ☆ Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil. * Corresponding author. E-mail: [email protected] (M.C. Bisi). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2013.09.002 251 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4 Ultrassonografia articular: confiabilidade interobservadores em artrite reumatoide resumo Palavras-chave: Introdução: A ultrassonografia (US) tem uso recente na reumatologia, e a confiabilidade do Artrite reumatoide (AR) método em pacientes com artrite reumatoide (AR) ainda está por ser definida. Ultrassonografia (US) Objetivo: Testar, em uma pesquisa de AR, a reprodutibilidade da US musculosquelética re- Reprodutibilidade Kappa alizada por reumatologistas com treinamento de um ano por meio da reanálise por um reumatologista com experiência no método. Pacientes e métodos: Esse estudo transversal incluiu pacientes de AR consecutivos de nosso centro terciário. O exame US foi realizado nas articulações metacarpofalângicas, articulações interfalângicas proximais e pulsos. Os parâmetros avaliados foram: presença de sinovite, sinal de power Doppler (PD), erosões ósseas e alterações cartilaginosas. Um valor Kappa entre 0,20 e 0,40 foi considerado razoável; entre 0,41 e 0,60, moderado; entre 0,61 e 0,80, bom; e acima de 0,81, excelente. Resultados: Analisamos 1380 articulações de pacientes com AR (78% mulheres, 78% caucasoides). Média de idade = 58 ± 11,56 anos, duração média da doença = 9,98 ± 7,79 anos, DAS28 média = 3,82 ± 1,53 e HAQ média = 0,91 ± 0,67. A concordância de Kappa para sinovite variou de 0,30-0,70; para sinal PD, de 0,53 até a concordância absoluta; para erosões, de 0,70-0,97; para alterações cartilaginosas, de 0,28-0,63. Conclusão: Embora tenha sido obtida concordância interobservadores boa, moderada e excelente para erosões e PD, a concordância para sinovite e alterações cartilaginosas foi menos substancial em nossos pacientes com AR ativa. Há necessidade de novos estudos sobre a padronização da técnica de análise, objetivando a melhora da reprodutibilidade da US musculosquelética. © 2014 Sociedade Brasileira de Reumatologia. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction Materials and methods Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting mostly peripheral joints. Radiologically, articular involvement is characterized by cortical bone erosions, culminating with deformities.1 Currently, musculoskeletal ultrasonography (US) has become an important tool in the diagnosis and monitoring of rheumatic diseases, especially in RA. This method has shown better sensitivity than clinical evaluation and radiography for detection of rheumatoid synovitis and joint erosion.2 US have some advantages when compared to other imaging techniques, such as: it is noninvasive, fast, low-cost, and can display various joints in motion, in addition, can be repeated without major risks, and is well accepted by the patient.3 Despite these significant advantages, sonographic findings remain highly operator-dependent requiring professional knowledge in Anatomy, Pathology and techniques allowed by the US machine.4 This is partly due to the subjective image’s assessment and the low degree of standardization of the technique, due to the small number of multicenter studies evaluating the interobserver concordance.5 The current study aims to analyze the interobserver agreement of data obtained by two rheumatologists with one yeartraining in US, in comparison with those ones of an expert on US. This interobserver concordance among rheumatologists of different experiences in US has not been detailed in Brazilian RA patients to date. Patients Patients with RA according to criteria of the American College of Rheumatology 1987 were recruited at Saint Lucas Hospital, 6 Pontifical University Catholic of Rio Grande do Sul (PUC-RS), Porto Alegre, Brazil; for this cross-sectional study, we excluded patients with a prior history of fracture or surgery in the dominant hand. The study was approved by the local ethics committee, and all patients signed a free consent. Patients screened were submitted blindly to US examination by a rheumatologist. Another rheumatologist carried out the disease activity score (DAS28) calculation. This score defines remission when it is below 2.6; low activity from 2.6 to 3.2; moderate activity from 3.2 to 5.1; and severe activity > 5.1.7 Patients also responded to the health assessment questionnaire (HAQ); in-between 0 and 1: mild limitation; greater than 1 to 2: moderate limitation; and greater than 2 to 3: severe limitation.8 Methods US examination of wrist, second and third proximal interphalangeal and metacarpophalangeal joints were proceeded with high-resolution machine My Lab 60 (ESAOTE, Genoa, Italy) with high-frequency linear transducer (18 MHz).The PD frequency was from 8.0 to 10.0 MHZ, pulse 252 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4 repetition frequency (PRF) from 0.5 to 1.0. The examination was performed on the dominant side dorsal and ventral in longitudinal and transverse scan, to evaluate the following parameters: presence of synovitis (qualitative and semiquantitative), signal of power Doppler (PD, qualitative and semi-quantitative), presence of erosions (qualitative) and cartilage assessment (qualitative and semi-quantitative scores). Images were recorded and archived in Dropbox site, so that all investigators obtained remote access. The examination was carried out by two rheumatologists with the same one-year level of US training (EULAR basic and intermediate courses), one of them the main author of this study. Each rheumatologist examined independently, at different times, 30 different patients (total database of 60 patients). In addition, each of the two played their own images and recorded separately assessments to be re-analyzed by a rheumatologist expert on musculoskeletal US. This PhD expert has over five years of experience in musculoskeletal US and is a national reference in the field. None of the three involved in the evaluations knew the interpretation of the other. Statistical testing was proceeded using the total data from the two rheumatologists and re-analysis by the expert. In the US analysis, synovitis was scored by gray scale US as: 0 = absence; 1 = mild (discrete hypoechoic image/ anechoic in the joint capsule); 2 = moderate (the joint capsule is elevated parallel to the joint area); and 3 = severe (important distention of the joint capsule).9 Quantitative evaluation of synovial inflammatory activity through the PD was classified as: 0 = absence (no signal PD, no intra-articular color signal); 1 = mild (up to 3 color signals or 2 single and 1 confluent signal in the intra-articular area); 2 = moderate (greater than grade 1 to < 50% of the intra-articular area filled with color signals); and 3 = severe (> 50% flow intra-articular area filled with color signals).10 The presence of erosions was evaluated in the transverse and longitudinal plane and rated as follows: 0 = no erosion; 1 = very small (< 1mm); 2 = small (1-2 mm); 3=moderate (2-4 mm); and 4 = large (> 4 mm). 11 Cartilage assessment was divided in: 0 = normal hyaline cartilage; 1 = loss of sharpness of the superficial margin of the hyaline cartilage; 2 = partial thickness defect of cartilage layer; 3 = thickness defect of cartilage with normal subchondral bone; and 4 = complete loss of cartilage layer and subchondral bone involvement.12 Statistics Kappa values were utilized to assess interobserver concordance of variables. The weight kappa was calculated when the linear correlation was below 50%. The PABAK (prevalenceadjusted bias-adjusted kappa) was utilized for linear correlations above 50%.13 Confidence intervals were obtained using the standard error (SE) of weight kappa (wk) (nonzero) as follows: [interval lower kappa = -1.96 *SE (wk)] and [high range kappa = + 1.96 * SE (wk)].13 Kappa values were divided in: < 0.20: poor concordance; between 0.21 and 0.40: fair; between 0.41 and 0.60: moderate; between 0.61 and 0.80: good; and between 0.81 and 1: excellent.13 The significance level for statistical tests was 5%. Statistical programs used were SPSS 12.1 and WinPepi for different kappa calculation. Results Out of the 60 RA patients, 47 (78%) were females, and also 78% were caucasian. Mean age was 58 ± 11.56 years, while the mean disease duration was 9.98 ± 7.79 years. Forty-two patients (70%) tested positive for rheumatoid factor. The mean DAS28 was 3.8, pointing to moderate disease activity, while the mean HAQ (0.91) indicated mild limitations to our patients. A total of 1,380 images of the 60 patients were scanned by the two investigators. Tables 1 and 2 show the agreement rates of data from the two rheumatologists and the expert. The kappa values disclosed good to excellent agreement for erosion (0.70-0.97); moderate to excellent to PD (0.53-1), here including absolute agreement in the third metacarpophalangeal ventral; and fair to good concordance for synovitis (0.300.70) and cartilage changes (0.28-0.63). Table 1 – Agreement and kappa values for synovitis and power Doppler Synovitis Wrist dorsal Wrist ventral 2 MCP dorsal 2 MCP ventral 2 MCP radial 3 MCP dorsal 3 MCP ventral 2 PIP dorsal 2 PIP ventral 3 PIP dorsal 3 PIP ventral Power Doppler Agreement (%) Kappa 95% CI Agreement (%) Kappa 95% CI 58 64 63 45 66 55 65 81 73 80 0.44 0.47a 0.51a 0.30b 0.56a 0.33a 0.53a 0.63a 0.64a 0.70a 0.27 - 0.61 0.25 - 0.69 0.35 - 0.67 0.13 - 0.47 0.38 - 0.74 0.10 - 0.56 0.31 - 0.75 0.35 - 0.91 0.41 - 0.87 0.38 - 1.02 68 90 91 91 95 100 85 97 84 98 0.53 0.87a 0.89a 0.83a 0.93a 1a 0.77a 0.93a 0.77a 0.97a 0.32 - 0.74 0.84 - 0.90 0.76 - 1.02 0.46 - 1.20 0.75 - 1.11 NC 0.52 - 1.02 0.91 - 0.95 0.55 - 0.99 0.97 - 0.98 a MCP, metacarpophalangeal joints; PIP, proximal interphalangeal; CI, confidence interval; NC, not calculated. When agreement > 50%, considered PABAK. b When agreement < 50%, considered weighted kappa. a a 253 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4 Table 2 – Agreement and kappa values for erosions and cartilage changes Erosion 2 MCP dorsal 2 MCP ventral 2 MCP radial 3 MCP dorsal 3 MCP ventral 2 PIP dorsal 2 PIP ventral 3 PIP dorsal 3 PIP ventral Cartilage Agreement (%) Kappa 95% CI Agreement (%) Kappa 95% CI 93 95 88 85 98 95 93 95 97 0.87 0.90a 0.77a 0.70a 0.97a 0.90a 0.87a 0.90a 0.93a 0.73 - 1.01 0.90 - 0.90 0.60 - 0.94 0.46 - 0.94 0.35 - 1.59 0.36 - 1.44 0.37 - 1.37 0.36 - 1.44 0.32 - 1.54 67 70 - 0.58 0.63a - 0.37 - 0.79 0.45 - 0.81 - a a MCP, metacarpophalangeal joints; PIP, proximal interphalangeal; CI, confidence interval; NC, not calculated. When agreement > 50%, considered PABAK. a Discussion The usefulness of US in monitoring structural changes of rheumatoid joints has been previously reported.14,15 Technological advances have improved the definition of US images, expanding the spectrum of the method in Rheumatology and other areas.16,17 The main objective of our study was to evaluate the interobserver concordance of musculoskeletal US in RA patients, an issue yet to be explored. The central idea was to analyze data from two rheumatologists trained in basic and intermediate US courses with re-analysis by a rheumatologist expert in musculoskeletal US. The great majority (about three quarter) of our survey of 60 RA patients was of caucasian women. The ratio femalemale was similar to that described in Europe and United States.18 Mean age of our patients was around 60 years, with mean disease duration of approximately 10 years. Age of disease onset, in our survey by 50 years, was higher than previously reported.18 As a whole, our RA population showed active disease (mean DAS28 3.8, configuring moderate activity). In fact, only two patients were in remission (DAS28 ≤ 2.6). As for the HAQ (mean value 0.91) our survey showed mild functional limitation; only four patients had severe limitations (HAQ > 2.0). We analyzed a total of 1380 images as to the presence of synovitis, PD signal, bone erosion and cartilage changes. The usual Cohen kappa coefficient was not appropriate for our study, since we dealt with ordered semiquantitative variables and great heterogeneity in the prevalence of such variables.19 We then set up to use the weight kappa when the linear correlation was below 50%, and PABAK for concordances above 50%.20 The highest concordance in our study (good to excellent kappas; 0.70 to 0.97) concerned the presence of bone erosions. Kappas for PD were moderate to excellent (0.53 to 1.00), including absolute agreement in the third MCP. By looking at the pictures, however, we noticed that no patient had positive PD at this location. As to synovitis, data were well less impressive, with kappas varying from fair to good at the most (0.30 to 0.70). Worthy of note, synovitis and PD are variables that must be analyzed dynamically in the US examination; a subtle change in the transducer angle may spoil the interpretation of these parameters. The interobserver agreement for musculoskeletal US was evaluated by Naredo et al. in 2006.21 This project (“Teach the Teachers”) included 22 rheumatologists and one experienced radiologist. In hands and wrists, mean kappa value for synovitis was 0.73, just higher than ours; as to erosions, their kappa value (0.64), although conceptually moderate, was lower than the one we obtained. Iagnocco et al. reported kappa values for synovitis, tenosynovitis and erosions between 0.73 and 0.89; again, concordance for synovitis, but not for erosions, was higher than in our study.22 According to Gutierrez et al., 4-week training for rheumatologists with no experience in US was enough to achieve moderate to excellent concordance for bone erosions.23 Kappas for cartilage changes can also be interpreted as a negative surprise in our study (performance fair to good at the maximum, 0.28 to 0.63). In theory, images of cartilage should have been more reproducible, since their interpretation is static. Cartilage evaluation was only recently standardized;24 this implies difficulties in training professionals for this parameter. Knowingly, basic and intermediate US courses tend to emphasize training for the synovitis and erosion parameters. Slightly differently from our data, Filippucci et al. reported moderate to good interobserver concordance for cartilage changes (0.56 to 0.76).24 The US has been considered an operator-dependent test. For this reason, US studies of interobserver reliability are of great importance. European rheumatologists highly experienced in musculoskeletal US formatted the EULAR Standing Committee for Education and Training in US, in order to spread US knowledge in Rheumatology to different countries.25 As long as the US standardization takes place, the amount of evidence-based multicenter studies will naturally grow. Despite the overall good concordance obtained for the majority of variables herein evaluated, we recognize that the knowledge of musculoskeletal US has a learning curve that is dependent on the increasing experience of the examiner and parameters standardization. The US, an emerging extension of physical exam for the rheumatologist, stands not only as a diagnostic tool, but also as a parameter of disease monitoring. Our study presents logistical limitations that should be mentioned. The RA sample could be larger, for a more reliable statistics. The US procedures were not carried out simultane- 254 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 0 – 2 5 4 ously. Lastly, we were not able, for the moment, to compare US variables with scores of activity and functional impairment. In summary, in our survey of active RA patients, the majority of the US variables proved reproducible. There was fair to good interobserver reliability for synovitis and cartilage changes, moderate to excellent for PD and good to excellent for bone erosions. Newer studies should better define the usefulness and reproducibility of musculoskeletal US in RA and other related rheumatic disorders. Conflicts of interest The authors declare no conflicts of interest. 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R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 5 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Retraction Retraction: “Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection” Erik Ahlina, Amir Elshafeib, Musa Nurc, Sayda Hassan El Safid, Johan Ronnelide, Gehad Elghazalif,* Msc - Immunobiology, Clinical Immunology Unit, Uppsala University, Uppsala, Sweden Bachelor of Medicine - Hematology Laboratory of Pathology and Microbiology, Alribat Hospital, Khartoum, Sudan c Rheumatologist - Consultant, Unit of Rheumatology, Alribat University Hospital, Khartoum, Sudan d Professor of Immunology - Consultant, Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Sudan e Associate Professor of Immunology - Consultant, Clinical Immunology Unit, Uppsala University, Uppsala, Sweden. f Professor of Immunology - Senior Consultant, University of Shendi, Shendi, Sudan; and King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia a b Retracted article: Ahlin E, Elshafei A, Nur M, El Safi SH, Johan R, Elghazali G. Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection. Rev Bras Reumatol. 2011 Dec;51(6):579-86. DOI: http://dx.doi. org/10.1590/S0482-50042011000600005 RETRACTION: Ahlin E, Elshafei A, Nur M, El Safi SH, Johan R, Elghazali G. Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection. Rev Bras Reumatol. 2011 Dec;51(6):579-86. English, Portuguese. PubMed PMID: 22124592 has been retracted. ABSTRACT: The paper entitled Ahlin E, Elshafei A, Nur M, El Safi SH, Johan R, Elghazali G. Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection. Rev Bras Reumatol. 2011 Dec;51(6):579-86. English, Portuguese. PubMed PMID: 22124592 has been retracted. This is due to plagiarism. The reasons pointed out were: 1) Author Elghazali G did not take part in the production of the data for the paper and has never been a co-author on any version of the manuscript. 2) A paper with very similar content, which was part of the PhD thesis of author Ahlin E (first author), was accepted for another journal. 3) The figures in the paper published in this journal were identical to the figures in author Ahlin E’s PhD thesis. 4) The name of author Johan Ronnelid was misspelt in the paper published in our journal (RBR). * Corresponding author. E-mail: [email protected] (G. Elghazali). 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2014.05.002 R E V B R A S R E U M AT O L . 2 0 1 4 ; 5 4 ( 3 ) : 2 5 6 REVISTA BRASILEIRA DE REUMATOLOGIA www.reumatologia.com.br Erratum Erratum of volume 54, issue 1 Errata do volume 54, número 1 On the headings of the pages of the Brazilian Journal of Rheumatology, v. 54, n. 1, where it reads: REV BRAS REUMATOL 2013;54(1): and the number of the pages comprehending the article, it should read: REV BRAS REUMATOL 2014;54(1): and the number of the pages comprehending the article. 0482-5004/$ - see front matter. © 2014 Sociedade Brasileira de Reumatologia. Published by Elsevier Editora Ltda. All rights reserved. http://dx.doi.org/10.1016/j.rbre.2014.05.002