revista brasileira de reumatologia - Sociedade Brasileira de ...

ISSN 0482-5004

REVISTA BRASILEIRA DE REUMATOLOGIA BRAZILIAN JOURNAL OF RHEUMATOLOGY MARCH/APRILt7PMVNFt/VNCFS ."3±0"#3*-t7PMVNFt/ÞNFSP

www.reumatologia.com.br

REVISTA BRASILEIRA DE REUMATOLOGIA BRAZILIAN JOURNAL OF RHEUMATOLOGY Official Organ of Brazilian Society of Rheumatology

Órgão Oficial da Sociedade Brasileira de Reumatologia Bimonthly Edition (Publicação Bimestral)

Editors (Editores)

Coeditors (Coeditores)

Max Victor Carioca Freitas

Eloísa Silva Dutra de Oliveira Bonfá

Mittermayer Barreto Santiago

Roberto Ezequiel Heymann

Hilton Seda

Paulo Louzada-Junior

Universidade Federal do Ceará, Fotaleza, CE, Brazil Universidade Federal de São Paulo, São Paulo, SP, Brazil

Universidade de São Paulo, São Paulo, SP, Brazil

Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil

Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Universidade de São Paulo, Ribeirão Preto, SP, Brazil

João Carlos Tavares Brenol


Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

Ricardo Fuller

Simone Appenzeller

Universidade Estadual de Campinas, Campinas, SP, Brazil

Editorial Board (Conselho Editorial) Acir Rachid

Geraldo da Rocha Castelar Pinheiro

Maurício Levy Neto

Universidade Federal do Paraná, Curitiba, PR, Brazil

Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil



Gilberto Santos Novaes

Universidade Federal de São Paulo, São Paulo, SP, Brazil

Alexandre Wagner S Souza

Natalino H. Yoshinari


Pontifícia Universidade Católica de São Paulo, São Paulo, SP, Brazil

Ari Stiel Radu

Isídio Calich

Nílzio Antônio da Silva

Adil Muhib Samara

Milton Helfenstein Jr. Universidade de São Paulo, São Paulo, SP, Brazil



Carlos Alberto von Muhlen

Ivânio Alves Pereira

Percival Degrava Sampaio-Barros

Faculdade de Medicina da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil


Claudia Goldenstein-Schainberg

Jamil Natour



Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

Cláudio Arnaldo Len

João Francisco Marques Neto

Rina Dalva P. N. Giorgi


Clóvis Artur Almeida da Silva Universidade de São Paulo, São Paulo, SP, Brazil

Cristiano Augusto de Freitas Zerbini Hospital Heliópolis, São Paulo, SP, Brazil

Daniel Feldman Polak Universidade Federal de São Paulo, São Paulo, SP, Brazil

Durval Kraychete Escola Bahiana de Medicina e Universidade Federal da Bahia, Salvador, BA, Brazil

Eduardo de Souza Meireles Universidade de São Paulo, São Paulo, SP, Brazil

Eduardo Ferreira Borba Neto


José Goldenberg Universidade Federal de São Paulo, São Paulo, SP, Brazil

José Roberto Provenza Universidade Estadual de Campinas, Campinas, SP, Brazil

Jozélio Freire de Carvalho

Universidade Federal de Goiás, Goiânia, GO, Brazil

Ricardo M. Xavier

Hospital do Servidor Público Estadual de São Paulo "Francisco Morato de Oliveira", São Paulo, SP, Brazil

Roger A. Levy Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Rosa Maria Rodrigues Pereira Universidade de São Paulo, São Paulo, SP, Brazil

Centro Médico Aliança, Salvador, BA, Brazil

Rozana Mesquita Ciconelli

Lais V. Lage



Samuel Katsuyki Shinjo

Lilian Tereza Lavras Costallat



Sebastião Cézar Radominski

Luís Eduardo Coelho Andrade

Universidade Federal do Paraná, Curitiba, PR, Brazil



Sheila Knupp de Oliveira

Emília Inoue Sato

Luiz Fernando de Souza Passos

Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil


Universidade Federal do Amazonas, Manaus, AM, Brazil

Fernanda Rodrigues de Lima

Marcelo de Medeiros Pinheiro



Fernando Queiroz da Cunha

Maria Odete E. Hilário

Universidade de São Paulo, Ribeirão Preto, SP, Brazil


Francisco Airton Castro Rocha

Marta Maria das Chagas Medeiros

Universidade Federal do Ceará, Fortaleza, CE, Brazil

Universidade Federal do Ceará, Fortaleza, CE, Brazil

Simone Appenzeller Universidade de Campinas, Campinas, SP, Brazil

Vera Lúcia Szejnfeld 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

Université de Sherbrooke, Sherbrooke, Canada

Corporación de Investigaciones Biológicas, Medellín, Colômbia

St. Thomas´ Hospital, London, UK

Arthur Kavanaugh

Luis Javier Jara

H Ralph Schumacher Jr

University of California, San Diego, USA

Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

University of Pennsylvania, Philadelphia, USA

Bernardo Pons Estel

Mario Cardiel

Ricardo Cervera Segura

Universidad Nacional de Rosario, Rosario, Argentina

Instituto Nacional de la Nutrición "Salvador Zubiran", Morrelia, Mexico

Hospital Clinic, Barcelona, Spain

Hospital Monte Sinai, Cuenca, Equador

Mario Garcia-Carrasco

Chapel Allerton Hospital, Leeds, UK

Ernest Choy

Facultad de Medicina, BUAP, Puebla, Mexico

Claudio Galarza Maldonado King's College, London, UK

Mário Viana de Queiroz

Jordi Antón López

Universidade Clássica de Lisboa, Lisboa, Portugal

Hospital Sant Joan de Déu, Barcelona, Spain

Marvin Fritzler

José Antonio Melo Gomes

University of Calgary, Calgary, Canada

Instituto Português de Reumatologia, Lisboa, Portugal

Richard J Wakefield Thomas Dörner Charite Hospital, Berlin, Germany

Yehuda Shoenfeld Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel

BSR Office (Secretaria SBR) Rogério Quintiliano Amaral Av. Brigadeiro Luiz Antonio, 2.466 – conjs. 93-94 CEP 01402-000 São Paulo, SP Fone/fax: 55 (11) 3289-7165 E-mail: [email protected]; [email protected] website: www.reumatologia.com.br Brazilian Journal of Rheumatology is listed in Web of Science, MEDLINE, LILACS, SciELO, Scopus and Index Copernicus databases. BJR is affiliated to the International Committee of Medical Journal Editors. A Revista Brasileira de Reumatologia é indexada nas bases de dados Web of Science, MEDLINE, LILACS, SciELO, Scopus e Index Copernicus. A RBR é filiada ao International Committee of Medical Journal Editors. Brazilian Journal of Rheumatology (BJR) is an official publication of the Brazilian Society of Rheumatology (BSR) in partnership with Elsevier Editora Ltda. and is dedicated to the medical community in Brazil and Latin America. Edited by Brazilian Society of Rheumatology. Published by Elsevier Editora Ltda. © 2013. Tradução | Translation: Stela Maris Costalonga | American Journal Experts All rights reserved and protected by law 9.610 - 19/02/98. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission in writing from BSR and the Publisher. BJR receives finnancial support from Fundos Remanescentes da Sociedade Brasileira de Reumatologia. A Revista Brasileira de Reumatologia (RBR) é uma publicação oficial da Sociedade Brasileira de Reumatologia (SBR) em conjunto com Elsevier Editora Ltda., distribuída exclusivamente à classe médica do Brasil e da América Latina. Editada por Sociedade Brasileira de Reumatologia. Publicada por Elsevier Editora Ltda. © 2013. Todos os direitos reservados e protegidos pela lei 9.610 - 19/02/98. Nenhuma parte desta publicação poderá ser reproduzida, sem autorização prévia, por escrito, da Elsevier Editora Ltda. e da SBR, sejam quais forem os meios empregados: eletrônicos, mecânicos, fotográficos, gravação ou quaisquer outros. A RBR recebe auxílio financeiro de Fundos Remanescentes da Sociedade Brasileira de Reumatologia.

RJ: SP: Website: E-mail:

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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 their most important academic degree; c) the department and institution where the study was originated; d) the full address and e-mail of the corresponding author; e) conflict of interest and relevant financial agencies; f) a running title with no more than 60 characters.

Author Agreement It is the document where the authors declare that the manuscript is original, in addition to approve the manuscript object of the submission, the authorship and the order of authors listed. It must be signed by all authors. Below is presented an example. Dear Editor, We, the undersigned, declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We would like to draw the attention of the Editor to the following publications of one or more of us that refer to aspects of the manuscript presently being submitted. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. (Signature of all authors)

Original article The original article should contain: the title page, the abstract page with keywords, introduction, material and methods or patients and methods, results and discussion, acknowledgements, references, tables, figures and figure legends. Original articles should not exceed 5,000 words including references and excluding the title page, abstract, tables and legends. It is allowed up to six figures or tables and 50 references.

Abstract page The abstract page should contain: a) objective, methods, results and conclusions, with no more than 250 words; b) three to five keywords.

Introduction As the aim of this section is to define the purpose and the reasons for the accomplishment of the work, we do not recommend a large literature review.

Patients and methods or Material and methods This section should include enough information that allows the reproduction of the work and, when it is relevant, the approval by the institutional Committee of Ethics. The methods employed in the statistical analysis should always be quoted.

Results They should be clear and concise. Tables and graphics should not duplicate information.

Discussion It should be concise, interpreting the results in the context of the present literature. Please do not exceed the limit of half the number of pages of the complete work.

Acknowledgments Only to people who contributed; i.e., with techniques, discussion and sending patients. Financial help should be referred in the title page.

References They should be quoted in the text in Arabic numerals, superscript, with no brackets. Numbering should be sequencial, according to the quotation order in the text. Please quote all the authors in works with until six authors; after six authors, quote the first six followed by the expression et al. Reference Manager or Endnote programs are strongly recommended for use adopting the Vancouver style. Examples for reference citation are presented below. Authors should consult NLM’s Citing Medicine for additional information on the reference formats. Printed article 1. Rivero MG, Salvatore AJ, Gomez-Puerta JA, Mascaro JM, Jr., Canete JD, Munoz-Gomez J et al. Accelerated nodulosis during methotrexate therapy in a patient with systemic lupus erythematosus and Jaccoud’s arthropathy. Rheumatology (Oxford) 2004; 43(12):1587-8. Reference retrieved from electronic address 2. Cardozo JB, Andrade DMS, Santiago MB. The use of bisphosphonate in the treatment of avascular necrosis: a systematic review. Clin Rheumatol 2008. Available from: http://www.springerlink. com.w10069.dotlib.com. br/content/l05j4j3332041225/fulltext.pdf. [Accessed in February 24, 2008]. Book 3. Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.

Tables and figures Each Table or Figure should be numbered with Arabic numerals and sent in an individual file (.jpg, .tif, .png, .xls, .doc) with minimum of 300 dpi. Titles and legends should be in the same Table/Figure file to wich they refer. Tables and Figures should include enough information so the reader can understand them without going to the text. Photomicrographies should include the appropriated scale.

Review article Reviews, preferentially systematic, may be submitted to BJR. They should cover deeply any interesting theme for the rheumatologist. They do not present a standard structure, neither introduction or conclusion. Please send abstracts without subdivisions with three to five keywords. Review articles should not exceed 6,000 words including references and excluding the title page, abstract, tables and legends. It is allowed up to five figures or tables and 70 references.

Case report Must have six authors at most. They should include an abstract and keywords, without subdivisions. The text, however, should present the following sections: introduction, which should be concise; case report, containing the description and the evolution of the clinical case, laboratory exams, illustrations and tables (that substitute the sections material and methods and results); and discussion. It should not exceed 1,500 words including references and excluding the title page, abstract, tables and legends. It is allowed up to two figures or tables and 15 references.

Brief communication It covers a point or a specific detail. It should present an abstract with no more than 250 words and three to five keywords. The text does not include subdivisions, and should not exceed 2,500 words including references and excluding the title page, abstract, tables and legends. It is allowed up to three figures or tables and 25 references.

Rules for applying the appropriate tense in scientific writing Context or section

Appropriate verb tense

Abstract

Past tense

Introduction

Most present tense (established facts, previous published data)

Methods, materials used, and results

Past tense

Discussion/Conclusion

Mixture of past and present, sometimes future tense

Attribution

Past tense Ex.: Andrade et al. reported that...

Description of Tables and Figures

Present tense

Established knowledge, previous results etc.

Present tense

General rules to obtain a good scientific writing: 1. Use active voice. 2. Setences must be short, clear and objective. 3. Units of measurement are abbreviated when use with numerical values (e.g., 1 mg), but are not abbreviated if used without numerical values. Systeme International d'Únites (SI units) must be used. Remember to leave a space between the number and unit (e.g., 10 mg/dL), except for the percentage mark that follows the number without space (e.g., 70%). The plural form of units of measurement is the same as the singular form (e.g., 1 mL, 10 mL; 1 h, 10 h). Spell out numbers at the beginning of a sentence. 4. Define abbreviations the first time they appear. Avoid abbreviations in tittles and abstracts. 5. Do not use contractions (e.g., doesn't, can't etc.). Recommended book: Rogers SM. Mastering scientific and medical writing: a self-help guide. Berlin: Springer; 2007.

Legal and ethical considerations According to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (International Committee of Medical Journal Editors – February 2006).

Conflict of interest Public trust in the peer review process and the credibility of published articles depend in part on how well conflict of interest is handled during writing, peer review, and editorial decision making. Conflict of interest exists when an author (or the author’s institution), reviewer, or editor has financial or personal relationships that inappropriately influence (bias) his or her actions (such relationships are also known as dual commitments, competing interests, or competing loyalties). These relationships vary from those with negligible potential to those with great potential to influence judgment, and not all relationships represent true conflict of interest. The potential for conflict of interest can exist whether or not an individual believes that the relationship affects his or her scientific

judgment. Financial relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself. However, conflicts can occur for other reasons, such as personal relationships, academic competition, and intellectual passion.

Informed consent Patients have a right to privacy, that should not be infringed without informed consent. Identifying information, including patients’ names, initials, or hospital numbers, should not be published in written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that a patient who is identifiable be shown the manuscript to be published. Authors should identify Individuals who provide writing assistance and disclose the funding source for this assistance. Identifying details should be omitted if they are not essential. Complete anonymity is difficult to achieve. However, an informed consent should be obtained if there is any doubt. For example, masking the eye region in photographs of patients is inadequate protection of anonymity. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note. When informed consent has been obtained it should be indicated in the published article.

Ethical treatment When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. If doubt exists whether the research was conducted in accordance with the Helsinki Declaration, the authors must explain the rationale for their approach, and demonstrate that the institutional review body explicitly approved the doubtful aspects of the study. When reporting experiments on animals, authors should be asked to indicate whether the institutional and national guide for the care and use of laboratory animals was followed.

Clinical trials registry Clinical trials must be registered according to WHO recommendation at www. who.int/ictrp/en/. The definition of clinical trial include preliminary trials (phase I): any study with prospective recruiting of subjects to undergo any health-related intervention (drugs, surgical procedures, equipment, behavioral therapies, food regimen, changes in health care) to evaluate the effects on clinical outcomes (any biomedical or health-related parameter, including pharmacokinetics measurements and adverse reactions). The BJR has the right not to publish trials not complying with these and other legal and ethical standards determined by international guidelines.

Financing and support The authors should also inform if they received financing or support from institutions like CNPq, CAPES, SBR Remaining Funds, Graduated Institutions, Laboratories etc.

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

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

Epidemiology Commission Comissão de Epidemiologia

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

Editorial Council (Conselho Editorial) Kaline Medeiros Costa Pereira, SP Edgard Torres dos Reis Neto, SP

Editors (Editores) Tânia Carolina Monteiro de Castro, SP Frederico Augusto Gurgel Pinheiro, SP

Collaborator (Colaborador) Plínio José do Amaral, SP

Brazilian Journal of Rheumatology Revista Brasileira de Reumatologia Editors (Editores) Max Victor Carioca Freitas, CE Roberto Ezequiel Heymann, SP Eloísa Silva Dutra de Oliveira Bonfá, SP Hilton Seda, RJ João Carlos Tavares Brenol, RS Mittermayer Barreto Santiago, BA Paulo Louzada-Junior, SP Ricardo Fuller, SP Simone Appenzeller, SP

Representante junto ao Ministério da Saúde Ana Patrícia de Paula, DF Mário Soares Ferreira, DF

Representantes junto à AMB Eduardo de Souza Meirelles, SP Gustavo de Paiva Costa, DF Morton Aaron Scheinberg, SP

BSR Bulletin (Boletim SBR)

Coeditors (Coeditores)

Representatives of Ministry of Health

Representatives of AMB

Comissão de Comunicação Social

Comissão de Economia da Saúde Mirhelen Mendes de Abreu, SP Representantes junto à PANLAR Adil Muhib Samara, SP Antonio Carlos Ximenes, GO Fernando Neubarth, RS Maria Amazile Ferreira Toscano, SC

Media Commission

Health Economy Commission Coordinator (Coordenadora)

Representatives of PANLAR

Maria Teresa R. A. Terreri, SP Tania Caroline Castro, SP Teresa Cristina Robazzi, BA

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

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

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

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

Commission of Relations with Groups of Patients

Members (Membros)

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

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

Vasculopathies Commission

Osteomethabolic Diseases and Osteoporisis Commission

Comissão de Vasculopatias

Coordinator (Coordenador)

Comissão de Doenças Osteometabólicas e Osteoporose

Comissão de Relações com Grupos de Pacientes

Roger Abramino Levy, RJ

Members (Membros)

Sebastião Cezar Radominski, PR

Coordinators (Coordenadores)

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

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

Occupational Rheumatology Commission

Image Commission

Spondiloarthropathies Commission

Comissão de Reumatologia Ocupacional

Comissão de Imagem

Comissão de Espondiloartropatias


Coordinator (Ccoordenador)


Helenice Alves Teixeira Gonçalves, DF

Members (Membros)

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


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

Rheumatoid Arthritis Commission

Célio Roberto Gonçalves, SP

Members (Membros)

RBE Coordinator (Coordenador RBE)

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

Coordinator (Ccoordenador) 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 Artrite Reumatoide

Lupus Commission

Coordinator (Coordenadora)

Comissão de Lúpus

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

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

José Alexandre Mendonça, SP

David Cezar Titton, PR

Members (Membros)


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

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

Spinal Commission

Comissão de Osteoartrose

Comissão de Coluna Vertebral

Comissão de Documentação e Registro Histórico




Ibsen Bellini Coimbra, SP

Marcos Renato de Assis, SP

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

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

Professional Defense Commission

Endemic and Infectious Diseases Commission (Comissão de Doenças Endêmicas e Infecciosas)

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

Assisted Therapy Immunobiological Centers Commission (Comissão de Centros de Terapia Imunobiológica Assistida)

Coordinator (Coordenador) Reno Martins Coelho, RJ

Members (Membros) Adrian Nogueira Bueno, MG Ana Teresa Amoedo Medrado, BA Antonio Carlos Scafutto, MG Claudio Goldenstein Schainberg, SP Eliezer Rushansky, PE Evelin D. Goldenberg M. M. da Costa, SP José Eyorand Castelo B Andrade, CE José Roberto Silva Miranda, SP Manoel Barros Bertolo, SP Rafael de Oliveira Fraga, MG Ricardo Jorge de Percia Name, RJ Vander Fernandes, MT

Supervisory Board (Conselho Fiscal) Fernando Neubarth, RS Iêda Maria Magalhães Laurindo, SP Geraldo da Rocha Castelar Pinheiro, RJ

(Comissão de Defesa Proﬁssional)

Coordinators (Coordenadores)

BSR – Regionals

Francisco Deoclécio D. Rocha, RN Vander Fernandes, MT

Regionais – SBR

Members (Membros)

Sociedade Alagoana de Reumatologia Dra. Inês Cristina de Mello

Francisco Alves Bezerra Neto, RN Matheus Staufackar Carlos, RN Inês Cristina de Mello Lima, AL Mauro Furtado Cavalcante, PI

Gout Commission (Comissão de Gota)


Rheumatology Society of Alagoas

Rheumatology Society of Amazonas

Rheumatology Society of Ceará Sociedade Cearense de Reumatologia Dr. José Eyorand Castelo Branco de Andrade

Rheumatology Society of Goiânia Sociedade Goiana de Reumatologia Dra. Ana Carolina Oliveira e Silva Montandon

Rheumatology Society of Maranhão Sociedade Maranhense de Reumatologia Dra. Raquel Moraes da Rocha Nogueira

Rheumatology Society Mato Grosso Associação Mato-Grossense de Reumatologia Dr. Vander Fernandes

Rheumatology Society of Minas Gerais Sociedade Mineira de Reumatologia Dr. Rafael de Oliveira Fraga

Rheumatology Society of São Paulo Sociedade Paulista de Reumatologia Dr. Paulo Louzada-Junior

Rheumatology Society of Pará Sociedade Paraense de Reumatologia Dr. Otávio Augusto Gomes da Paz

Rheumatology Society of Paraíba Sociedade Paraibana de Reumatologia Dra. Danielle Christinne Soares Egypto de Brito

Rheumatology Society of Paraná Sociedade Paranaense de Reumatologia Dr. Eduardo Santos Paiva

Rheumatology Society of Pernambuco Sociedade Pernambucana de Reumatologia Dra. Lílian David de Azevedo Valadares

Rheumatology Society of Piauí Sociedade Piauiense de Reumatologia Dra. Aline do Socorro Miranda Ribeiro

Rheumatology Society of Espírito Santo Sociedade de Reumatologia do Espírito Santo Dr. José Roberto Pereira Santos

Rheumatology Society of Mato Grosso do Sul Sociedade de Reumatologia do Mato Grosso do Sul Dr. Marcelo Cruz Rezende

Rheumatology Society of Rio de Janeiro Sociedade de Reumatologia do Rio de Janeiro Dr. Evandro Mendes Klumb

Sociedade Amazonense de Reumatologia Dra. Maria do Socorro A. de Souza

Rheumatology Society of Rio Grande do Norte

Rheumatology Society of Bahia

Sociedade de Reumatologia do Rio Grande do Norte Dr. Francisco Deoclécio Damasceno Rocha

Sociedade Baiana de Reumatologia Dr. Mittermayer Barreto Santiago

Rheumatology Society of Rio Grande do Sul

Geraldo da Rocha Castelar Pinheiro, RJ

Rheumatology Society of Brasília

Members (Membros)

Sociedade de Reumatologia de Brasília Dr. Cleandro Pires de Albuquerque

Sociedade de Reumatologia do Rio Grande do Sul Dr. Marco Aurélio Goldenfum

Rheumatology Society of Santa Catarina

Rheumatology Society of Sergipe

Sociedade Catarinense de Reumatologia Dr. Gláucio Ricardo Werner de Castro

Sociedade Sergipana de Reumatologia Dra. Regina Adalva de Lucena Couto Ocea

Adil Muhib Samara, SP Antonio José Lopes Ferrari, SP Ana Beatriz Vargas dos Santos, RJ Hellen Mary da Silveira de Carvalho, DF

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 53. Number 2. March/April 2013 Volume 53. Número 2. Março/Abril 2013

CONTENTS | SUMÁRIO Editorial | Editorial Alexander and the Guidelines – the importance of strategy and the guidelines for the diagnosis and medicamentous treatment of rheumatoid arthritis Alexandre e as Diretrizes – a importância da estratégia e as Diretrizes para diagnóstico e tratamento medicamentoso da artrite reumatoide Licia Maria Henrique da Mota, Geraldo da Rocha Castelar Pinheiro .................................................

137

Antiphospholipid syndrome Síndrome do anticorpo antifosfolipídeo Adriana Danowski, Roger A. Levy .....................................................................................................

139

Guidelines | Documentos de Diretrizes Guidelines for the diagnosis of rheumatoid arthritis Diretrizes para o diagnóstico da artrite reumatoide Sociedade Brasileira de Reumatologia, Sociedade Brasileira de Pneumologia e Tisiologia, Colégio Brasileiro de Radiologia .........................................................................................................

141

Guidelines for the drug treatment of rheumatoid arthritis Diretrizes para o tratamento da artrite reumatoide Sociedade Brasileira de Reumatologia ................................................................................................

158

Guidelines for the treatment of antiphospholipid syndrome Diretrizes para o tratamento da síndrome do anticorpo antifosfolipídeo Adriana Danowski, Jozelia Rego, Adriana M. Kakehasi, Andreas Funke, Jozelio Freire de Carvalho, Isabella V. S. Lima, Alexandre Wagner Silva de Souza, Roger A. Levy ...............................................

184

Original Articles | Artigos Originais Resistance training versus weight-bearing aquatic exercise: a cross-sectional analysis of bone mineral density in postmenopausal women Treinamento de força versus hidroginástica: uma análise transversal comparativa da densidade mineral óssea em mulheres na pós-menopausa Sandor Balsamo, Licia Maria Henrique da Mota, Frederico dos Santos de Santana, Dahan da Cunha Nascimento, Lídia Mara Aguiar Bezerra, Denise Osti Coscrato Balsamo, João Lindolfo Cunha Borges, Ana Patrícia de Paula, Martim Bottaro .................................................

193

Lack of association between interleukin-18 polymorphisms and rheumatoid arthritis Ausência de associação entre os polimorfismos do gene interleucina-18 e artrite reumatoide Ticiana Della Justina Farias, Luisa Matos do Canto, Mayara Delagnelo Medeiros, Aline Fernanda Rodrigues Sereia, Lia Kubelka Fernandes de Carlos Back, Filipe Martins de Mello, Adriana Fontes Zimmermann, Ivânio Alves Pereira, Yara Costa Netto Muniz, Andrea Rita Marrero, Ilíada Rainha de Souza.......................................................................................................................

199

Review Articles | Artigos de Revisão What a rheumatologist needs to know about yellow fever vaccine O que o reumatologista deve saber sobre a vacina contra febre amarela Ana Cristina Vanderley Oliveira, Licia Maria Henrique da Mota, Leopoldo Luís dos Santos-Neto, Pedro Luiz Tauil ..................................................................................................................................

206

Update on the treatment of calcinosis in dermatomyositis Atualização na terapêutica da calcinose em dermatomiosite Samuel Katsuyuki Shinjo, Fernando Henrique Carlos de Souza ........................................................

211

Case Reports | Relatos de Caso Chondrolysis of the hip in an adolescent: clinical and radiological outcomes Condrólise de quadril em uma adolescente: evolução clínica e radiológica Ana Paula Sakamoto, Larissa Lucati Ramos, Artur da Rocha Corrêa Fernandes, Maria Teresa Terreri

215

Mesenteric vasculitis in a juvenile systemic lupus erythematosus patient Vasculite mesentérica em paciente com lúpus eritematoso sistêmico juvenil Adão F. Albuquerque-Netto, Erica G. Cavalcante, Adriana M. E. Sallum, Nádia E. Aikawa, Uenis Tannuri, Clovis Artur Almeida da Silva ...................................................................................

219

Erratum | Errata The quality of life of patients with lúpus erythematosus influences cardiovascular capacity in 6-minute walk test Qualidade de vida de pacientes com lúpus eritematoso influencia a capacidade cardiovascular em teste de caminhada de 6 minutos [Rev Bras Reumatol 2013;53(1):75-87] Sandor Balsamo, Dahan da Cunha Nascimento, Ramires Alsamir Tibana, Frederico Santos de Santana, Licia Maria Henrique da Mota, Leopoldo Luiz dos Santos-Neto..........

223

R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 3 7 – 1 3 8


Editorial

Alexander and the Guidelines – the importance of strategy and the guidelines for the diagnosis and medicamentous treatment of rheumatoid arthritis Alexander and the Guidelines – the importance of strategy and the guidelines for the diagnosis and medicamentous treatment of rheumatoid arthritis Alexander III, who would enter History as “the Great”, son of Philip II and Olympias, was born in Pella, the capital of the Ancient Greek Kingdom of Macedon, in the year 356 b.C. When he died, at the age of 33 years, somewhere in Babylon, he had conquered all the world then known – and had the following titles King of Macedon, King of Greece, Lord of Asia, Shahanshah of Persia, Pharaoh of Egypt and Hegemon of the Hellenic League. As his greatest legacy, Alexander had fused the Greek culture to the Eastern culture, forming the base of the later called Hellenistic Civilization, which influenced profoundly several aspects of the current Western culture.1 But why are we writing about Alexander, the Great, in a scientific editorial on the guidelines for rheumatoid arthritis (RA)? Because Alexander was, more than a great conqueror, a brilliant strategist, maybe the greatest in entire History. The word ‘strategy’ comes from the ancient Greek (stratos, “army”, and ago, “leadership” or “command”), and designated the military commander at the time of Athenian democracy. Currently, the term ‘strategy’ can be understood as a way to plan the future, integrated in the decision making process and based on a formalized procedure that articulates results. Using the figure of a great strategist to illustrate the elaboration and publication of guidelines is part of the strategy of the Brazilian Society of Rheumatology (SBR) to spread and implant knowledge based on scientific evidence for the diagnosis and treatment of RA in Brazil. Rheumatoid arthritis is a chronic systemic disease, usually progressive, that affects 0.5%–1% of the world population, characterized by inflammatory involvement of the synovial membrane, mainly in peripheral joints. The daily fight of rheumatologists against that disease comprises treating the pain and preventing or delaying both structural joint damage and functional and labor disability, in addition to preventing early mortality of the patients. Success in this

battle depends mainly on the adoption of proper strategies, including early diagnosis and adequate treatment as soon as possible in the RA natural history. The SBR, through its Rheumatoid Arthritis Committee, has elaborated over the past two years four consensual documents guiding the diagnosis and treatment of RA in Brazil, including peculiarities such as management of comorbidities and vaccination of patients immunosuppressed by the disease and its treatment.2–5 Consensus documents are educational instruments, rather than normative guidelines, that allow their authors to add information originating from experience and experts’ opinion to scientific evidence. If, as a publication, the consensus loses in grade of recommendation and level of evidence, it gains as an educational tool to prize the experience of those who deal with daily practice difficulties in managing the disease.6,7 The Guidelines Project of the Brazilian Medical Association (AMB) and the Federal Board of Medicine (CFM), was aimed at producing diagnostic, therapeutic and, when applicable, preventive guidance, based on scientific evidence, conciliating information of the medical area to standardize management that helps physician’s reasoning and decision making. The documents present the grade of recommendation and level of scientific evidence published, preserving in its elaboration the autonomy of the authors, medical experts, of the texts.8 Thus, that was the strategy of the Rheumatoid Arthritis Committee when elaborating both documents presented in this issue of the Revista Brasileira de Reumatologia – the Guidelines for the Diagnosis of RA9 and the Guidelines for the Medicamentous Treatment of RA.10 The elaboration of the texts carefully followed the recommendations of the AMB and the CFM, the result being evidence-based responses to the following questions: Are the new 2010 ACR/EULAR classification criteria for RA superior to the 1987 classification criteria of the early phase of disease? Are genetic markers (search for HLA-DRB1 alleles – shared epitope and PTPN22 genes)

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useful to characterize patients with poorer prognosis of RA? Is it feasible to treat the disease to achieve remission? Does the use of corticosteroids in the early phase of disease improve the patient’s prognosis? Although the personality and some actions of Alexander the Great might be questioned, studying how he managed his armies and his actions to conquer Persia and Asia, including the historical battles of Gaugamela, Issus, Granicus and Hydaspes, leads us to conclude that there is a close relationship between the success achieved by Alexander and the proper use of the entire management process, formally conceived and used to a specific purpose, i.e., the implementation of strategies.11 We hope that, by reading and applying the strategies proposed by the guidelines currently published, rheumatologists, and, to a lesser extent, their patients, can be as victorious in their fight against RA as was the magnificent strategist Alexander in his many battles. “And it happened afterwards that Alexander, the son of Philip the Macedonian, who first reigned in Greece having come from the land of Kittim, struck Darius the king of the Persians and the Medes. He appointed many battles, and took hold of all the fortifications and he executed the kings of the earth. And he passed through even to the ends of the earth. And he received the spoils of many nations. And the earth was silenced in his sight.” Maccabees 1, 1-3 Licia Maria Henrique da Mota Medical School, Universidade de Brasília (UnB), Brasília, DF, Brazil Brazilian Society of Rheumatology Rheumatoid Arthritis Committee E-mail: [email protected] Geraldo da Rocha Castelar Pinheiro Discipline of Rheumatology, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil

REFERENCES

1. Bose P. Alexander the Great’s Art of Strategy. Crows Nest, N.S.W: Allen & Unwin; 2003. 2. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Fronza LS, Bertolo MB, et al. 2011 Consensus of the Brazilian Society of Rheumatology for diagnosis and earlyassessment of rheumatoid arthritis. Rev Bras Reumatol. 2011;51(3):199219. 3. da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo MB, et al.; Brazilian Society of Rheumatology. 2012 Brazilian Society of Rheumatology Consensus for the treatment of rheumatoid arthritis. Rev Bras Reumatol. 2012;52(2):152-74. 4. Pereira IA, Mota LM, Cruz BA, Brenol CV, Fronza LS, Bertolo MB, et al.; Brazilian Society of Rheumatology. 2012 Brazilian Society of Rheumatology Consensus on the management of comorbidities in patients with rheumatoid arthritis. Rev Bras Reumatol. 2012;52(4):474-95. 5. Brenol CV, Mota LCH, Cruz BA, Pileggi GS, Pereira IA, Rezende LS, et al. Consenso 2012 da Sociedade Brasileira de Reumatologia sobre vacinação em pacientes com artrite reumatoide. Rev Bras Reumatol. 2013;53(1):4-23. 6. da Mota LM. Considerations about the 2011 consensus of the Brazilian Society of Rheumatology for diagnosis and early assessment of rheumatoid arthritis. Rev Bras Reumatol. 2011;51(3):197-8. 7. Mota LM. On mosaics and consensus: Gaudí, Brazil and rheumatoid arthritis. Rev Bras Reumatol. 2012;52(2):133-4. 8. Projeto Diretrizes. [Accessed on: 22 fevereiro 2013] Available from: http://www.projetodiretrizes.org.br. 9. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo MB, et al., Sociedade Brasileira de Reumatologia, Sociedade Brasileira de Pneumologia e Tisiologia, Colégio Brasileiro de Radiologia. Diretrizes para o diagnóstico da artrite reumatoide. Rev Bras Reumatol. 2013;53(2):141-57. 10. Mota LMH, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo MB, et al., Sociedade Brasileira de Reumatologia. Diretrizes para o tratamento da artrite reumatoide. Rev Bras Reumatol. 2013;53(2):158-83. 11. Rodrigues RC. Alexandre, “o Grande”, e a informação para o planejamento estratégico. Inf Soc. 2007;17(2):74-85.



Editorial

Antiphospholipid syndrome The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis, gestational morbidity and presence of elevated and persistently positive levels of antiphospholipid antibodies.1 The treatment of APS is controversial, especially because of the absence of good quality clinical studies. In the primary prevention of thrombosis, clinical studies report different results.2,3 The association of risk factors with thrombotic events and the type and number of positive antiphospholipid antibodies are current concepts and should be considered in the therapeutic decision, be it medicamentous or a change in lifestyle. Full anticoagulation for undetermined time is indicated for secondary prevention, but the therapeutic target is still discussed. Although retrospective studies have suggested a lower number of recurrences with an elevated international normalized ratio (INR), prospective studies do not corroborate such findings.4,5 However, the inclusion of patients with arterial thrombosis in those protocols was small, making the definitive conclusion about the target INR in APS difficult. The obstetric questions have also generated discussion: teratogenicity associated with warfarin6 and the dosing of heparin in patients with vascular APS have little scientific evidence.7 International efforts aimed at designing and conducting good quality prospective studies for patients with antiphospholipid antibodies, such as the creation of a multicenter data bank, have been observed.8 Thus, new perspectives arise and, in the near future, we will have answers based on better evidence regarding the treatment of APS, including the use of hydroxychloroquine for primary prevention, the use of new anticoagulants, and biologic therapy. In face of the need to improve understanding and treatment, and to establish recommendations for rheumatologists and other specialists about the management of APS, the Committee of Vasculopathies and APS of the Brazilian Society of Rheumatology (SBR), with the support of the Brazilian Medical Association (AMB), publishes this guideline, elaborated from nine relevant and controversial clinical questions related to the treatment of APS, based on the best scientific evidence available. Once finished this first publication, our committee proceeds to the objectives established for the next two years:

elaboration and publication of guidelines for the diagnosis of APS and elaboration and publication of guidelines and manuals for patients with Granulomatosis with Polyangiitis and Takayasu’s Artheritis. In addition, the committee has been working along with AMB to include the following tests in the table of procedures: IgM/IgG anti-beta 2-glycoprotein I test; IgA anticardiolipin test; antiproteinase 3 test; and antimyeloperoxidase test. Adriana Danowski Hospital Federal dos Servidores do Estado (HFSE), Rio de Janeiro, RJ, Brazil E-mail: [email protected] Roger A. Levy Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil REFERENCES

1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update to the classification for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306. 2. Tarr T, Lakos G, Bhattoa HP, Shoenfeld Y, Szegedi G, Kiss E. Analysis of risk factors for the development of thrombotic complications in antiphospholipid antibody positive lupus patients. Lupus. 2007;16:39-45. 3. Erkan D, Harrison MJ, Levy RA, Peterson M, Petri M, Sammaritano L, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibodypositive individuals. Arthritis Rheum. 2007;56:2382-91. 4. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3:848-53. 5. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133-8.

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6. Levy RA, Jesús GR, Jesús NR. Obstetric antiphospholipid syndrome: still a challenge. Lupus. 2010;19:457-9. 7. Hunt BJ, Gattens M, Khamashta M, Nelson-Piercy C, Almeida A. Thromboprophylaxis with unmonitored intermediate-dose low molecular weight heparin in pregnancies with a previous

arterial or venous thrombotic event. Blood Coagul Fibrinolysis. 2003;14:735-9. 8. APS ACTION – AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking. D Erkan, MD Lockshin on behalf of APS ACTION members. Lupus. 2012;21:695-8.



Guidelines

Guidelines for the diagnosis of rheumatoid arthritis Diretrizes para o diagnóstico da artrite reumatoide Sociedade Brasileira de Reumatologia, Sociedade Brasileira de Pneumologia e Tisiologia, Colégio Brasileiro de Radiologia (Brazilian Society of Rheumatology, Brazilian Society of Pneumology and Tuberculosis, Brazilian College of Radiology) Projeto Diretrizes da Associação Médica Brasileira, São Paulo, SP, Brazil

Participants Licia Maria Henrique da Mota*, Bóris Afonso Cruz, Claiton Viegas Brenol, Ivânio Alves Pereira, Lucila Stange Rezende-Fronza, Manoel Barros Bertolo, Max Vitor Carioca Freitas, Nilzio Antônio da Silva, Paulo Louzada-Junior, Rina Dalva Neubarth Giorgio, Rodrigo Aires Corrêa Lima, Ronaldo Adib Kairalla, Alexandre de Melo Kawassaki, Wanderley Marques Bernardo, Geraldo da Rocha Castelar Pinheiro

Final elaboration

D: Opinion that is not substantiated by critical evaluation, based on consensus, physiological studies or animal models.

Objective To formulate guidelines for the management of rheumatoid arthritis (RA) in Brazil, with a focus on diagnosis. The aim of the present document is to summarise the current position of the Brazilian Society of Rheumatology on this topic to orient Brazilian doctors, particularly rheumatologists, to RA diagnosis in our country.

12 April 2012

Description of the evidence collection method A review of the scientific literature was performed with the Medline database. The search for evidence was based on actual clinical scenarios and used the following Medical Subject Headings (MeSH) terms: Arthritis, Rheumatoid, Diagnosis (Delayed Diagnosis OR Delay OR Early Rheumatoid Arthritis OR VERA), Prognosis, Criteria (American College of Rheumatology/European League Against Rheumatism OR ACR/EULAR OR classification), Comparative Study, Smoking (OR tobacco use disorder), Rheumatoid Factor, Anti-cyclic Citrullinated Peptide (or anti-CCP), HLA-DRB1 OR PTPN22 OR EPITOPE, extra-articular OR extraarticular OR systemic OR ExRA, Disease Progression, Radiography OR X RAY, ULTRASONOGRAPHY, and MAGNETIC RESONANCE

Grades of recommendation and strength of evidence A: Most consistent experimental and observational studies. B: Less consistent experimental and observational studies. C: Case reports (uncontrolled studies).

Introduction Rheumatoid arthritis (RA) is a chronic, progressive, and systemic inflammatory disease that preferentially affects the synovial membranes of joints and eventually leads to bone and cartilage destruction1(D). RA affects 0.5%–1% of the adult population worldwide; the disease targets patients from every ethnic background2(D) and predominately affects females (2- or 3-fold more often than males). Although RA can occur at any age, it is more frequent among individuals in the fourth to sixth decades of life3(D). A Brazilian multicentre study conducted with samples from the various macro-regions found a prevalence of up to 1% in Brazil’s adult population4(B), which corresponds to 1,300,000 people. As a chronic disease that causes irreversible joint damage, RA exacts high costs from both the patients and society at large 5(B) 6,7(D).

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In recent years, significant advances have been achieved in understanding the physiopathogenesis, diagnostic methods, and therapeutic management of RA. Among these advances, the recently attributed significance of the early disease stages or so-called early RA (first 12 months with RA symptoms) stands out as an acknowledged “window of therapeutic opportunity”8(B)9,10(D). However, despite all advances, the currently available (clinical, laboratory, and radiological) diagnostic and prognostic indicators are of limited value to early diagnoses and individual prognoses11(B). The demographic and clinical features of RA vary as a function of the affected population12(B). Most available data correspond to populations in Europe and the United States13,14(D). Few studies have been conducted on the Brazilian population15,16(B). RA affects mostly individuals within the economically productive age range, and the disease eventually imposes significant limitations on their functional ability that result in the loss of work abilities. For these reasons, the indirect costs associated with RA must be included in pharmacoeconomic studies17(B). In Brazil and industrialised countries, the costs associated with RA are high18(B). The impact of the expenses associated with RA is more remarkable in developing countries in which the financial resources allocated to healthcare are less robust. This situation points to the relevance of studies adapted to Brazilian conditions that assess the costs and allocation of resources for the diagnosis and treatment of RA19(B). RA diagnosis is based on clinical findings and complementary diagnostic tests. No single laboratory, imaging, or histopathological test alone can confirm a diagnosis. Several illnesses that present with arthritis must be considered in the differential diagnosis of RA20-22(D), as described in Table 1. Diagnosis is easier when RA presents with the well-known pattern and the full range of typical symptoms. Diagnosis might be difficult in the early stages of disease because the characteristic serologic and radiological alterations are often absent23(D). The clinical manifestations of RA can be classified as articular and extra-articular. As RA is a systemic disease, general symptoms such as fever, asthenia, fatigue, myalgia, and weight loss can appear before or concomitantly with the onset of the articular manifestations24(D).

The characteristic features of arthritis in RA are as follows24(D): a) Polyarticular affection: usually involving more than four joints. Nevertheless, RA might begin and eventually remain as mono- or oligoarthritis. b) Hand and wrist arthritis: affections of the wrist, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints are frequent from the very early disease stages. The distal interphalangeal (DIP) joints are seldom affected, a feature that distinguishes RA from other conditions such as osteoarthritis and psoriatic arthritis. c) Symmetric arthritis: symmetric affection of joints is a common finding, although not mandatorily absolute in cases of the PIP, MCP, and metatarsophalangeal (MTP) joints. d) Cumulative or additive arthritis: arthritis usually exhibits a cumulative pattern (progressive affection of new joints concomitant to inflammation of the previously affected ones). e) Morning stiffness: prolonged stiffness that appears in the morning, which is accompanied by a sensation of swelling, is near-universal feature of synovial inflammation. Unlike the short-lasting (5–10 minutes, as a rule) variety observed in osteoarthritis, in inflammatory diseases, stiffness tends to last for more than 1 hour. This phenomenon is associated with immobility that occurs concomitantly to the state of sleep or rest, rather than to a particular time of the day. The duration of stiffness tends to correlate with the degree of inflammation and is an important parameter in follow-up evaluations25(B)26(C).

Extra-articular manifestations Although the articular manifestations are the most characteristic, other organs and systems can also be affected by RA. The most common extra-articular manifestations of

Table 1 – Differential diagnoses of arthritis. Classes of diseases Infections

Articular manifestations Although the articular manifestations of RA might be reversible in the early stages, persistent and uncontrolled synovitis leads to bone and cartilage destruction and irreversible tendon and ligament injuries. The basic factor behind RA articular manifestations is synovial inflammation (synovitis), which can affect any diarthrodial joint in the body. The clinical complaints include pain, swelling, and motion limitations of the affected joints. A physical examination will disclose the presence of pain, increased joint volume, intraarticular effusion, heat, and eventual redness. Those findings might not be evident in deep joints such as the hips and shoulders24(D).

Spondyloarthritis

Systemic rheumatic diseases

Microcrystalline arthritis Endocrine diseases Neoplastic diseases Others

Diseases Viral (e.g. dengue, human immunodeficiency virus – HIV, parvovirus, cytomegalovirus, hepatitis), bacterial (e.g. N. gonorrhoeae, S. aureus), microbacterial, fungal, and others Reactive arthritis (Chlamydia, Salmonella, Shigella, Yersinia), ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis Systemic lupus erythematosus, polymyositis/dermatomyositis, systemic sclerosis, Sjögren’s syndrome, Behçet’s disease, rheumatic polymyalgia, systemic vasculitis, and others Gout, calcium pyrophosphate deposition disease, and others Hypothyroidism, hyperthyroidism Metastatic neoplastic disease, lymphoma, paraneoplastic syndromes, and others Osteoarthritis, haemochromatosis, amyloidosis, sarcoidosis, serum sickness


RA include skin, eye, pleuropulmonary, heart, blood, neurological, and osteo-metabolic conditions. These occur more often in patients with severe and polyarticular disease, positive serology for the rheumatoid factor (RF) or cyclic citrullinated peptide antibodies (anti-CCP), and rheumatoid nodules27(B)28(D). Brazilian studies confirmed that the initial manifestations of RA include polyarticular affection with persistent synovitis in the hands, long-lasting morning stiffness, a large number of painful and swollen joints, and fatigue15,16(B).

1. Is diagnosis of RA within the first 12 months of symptoms (early RA) associated with better radiological and functional prognosis, compared to later diagnosis? The modern differentiation of RA from other joint diseases dates from 1907. As no pathognomonic traits allow a distinction among the various types of arthritis in their early stages, the exact moment at which RA begins to progress as a separate entity from other articular illnesses is unknown12(B). The definition of early RA is important from both the theoretical and practical perspectives, although the terms “early” and “RA” might be addressed independently, particularly because the criteria applied to these classifications are based on established RA13(D). Although controversial, early RA might be defined as the initial stage of disease or a “window of therapeutic opportunity” in which adequate therapy might modify the disease progression; the prognosis in this stage is better than that of later stages14(D). The required symptom duration for the definition of early RA varies widely in the specialised literature. Historically, any RA of a duration less than five years has been characterised as “early”15(B). However, together with the notion of a “window of opportunity”, the original length of early RA needed to be restricted. Starting in the early 90’s, early RA was consistently defined as the presence of symptoms for less than 24 months, with the main emphasis on the first 12 months of clinical manifestations16(B). The current indications are to assess patients with articular symptoms as soon as possible and to limit the early stage of RA to the first weeks or months of symptoms (as a rule, less than 12 months). In particular, the first 12 weeks are a critical period known as “very early” RA (VERA), while patients with more than 12 weeks but fewer than 12 months of articular symptoms are classified as so-called “late early RA” (LERA)17(B). The proportion of rheumatologists with opportunities to assess patients within the first six weeks of symptoms increased from 9% in 1997 to 17% in 2003; however, not every case is liable to such early assessment18(B). Even while admitting imprecisions in the definition of early RA, several authors have suggested that a substantial proportion of the cases with short-lasting (less than eight weeks) inflammatory arthritis exhibit spontaneous resolution, while only the few patients with persistent clinical manifestations progress into proper RA19(B)20-22(D). Thus, the

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establishment of clinical, serologic, or genetic markers that can identify patients who will progress to RA at the earliest stages and consequently will need appropriate treatments to reduce the odds of developing persistent disease and articular damage is of paramount importance. The average time for the first visit of RA patients with a rheumatologist is 17 months, and 19 months usually elapse before the first administration of disease-modifying antirheumatic drugs (DMARDs). Factors such as education, the number of swollen joints, age, and occupation are associated with such delays29(B). Arthritis is characterised by articular swelling that is associated with pain or stiffness. Cases that involve more than one articulation should be referred to a rheumatologist, ideally within the first six weeks following the onset of symptoms30(D). For cases in which articular swelling was present only during the first year of disease, the risk of articular erosion was reduced by five years (NNT: 4), compared to those patients with joint swelling throughout the follow-up period31(B). RA diagnosis within the first three months of VERA was predictive of clinical (American College of Rheumatology – ACR) and radiological (Sharp score) remission32(B). The early identification of some factors allows clinicians to predict whether the RA lesions will exhibit radiological progression in the following 12 months. These factors include the Sharp score and modified Total Sharp Score (mTSS), the presence of autoantibodies such as RF and anti-CCP, and increased acute-phase reactants such as an erythrocyte sedimentation rate (ESR) greater than 28 mm and an average Creactive protein (CRP) level of 10 mg/L33(B). The higher the erosion score at the onset of treatment, the worse the 10-year radiological prognosis (Sharp score)34(B). Early (within the first year) calculations of the Sharp, erosion, and reduced joint space scores permitted predictions of the radiological progression of RA patients who were followed-up for three years35(B). In spite of the early (three to six months from the beginning of symptoms) administration of DMARD treatment, 63.6% of the patients exhibited erosion three years later due to constitutional factors such as the presence of autoantibodies (e.g. RF or anti-CCP) and the length of disease activity (CRP, joint swelling, and response to treatment)36(B). The duration of RA interferes with the functional prognosis, which is measured by means of the Health Assessment Questionnaire (HAQ) and is independent of the baseline values37(B). When DMARD treatment was initiated within the first year of disease (average symptom duration, six months), the radiological progression (Ratingen score) was reduced at the 5-year follow-up38(B). In patients with symptom durations less than 12 weeks who were treated for RA, the radiological progression (Sharpvan der Heijde score, SHS) was reduced after six years of follow-up. Sustained DMARD-induced remission was 8% higher (NNT: 13) in patients with symptom durations less than 12 weeks39(B). DMARD treatment of RA patients within the first year of disease induced better functional (Keitel Functional Test – KFT) and clinical (joint swelling) progression at a 10-year

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follow-up, compared to those who were treated one to five years after disease onset40(B).

Recommendation Diagnosis of RA with a symptom duration of less than 12 months (early RA) is of paramount importance because early diagnosis exerts beneficial effects on radiological and functional prognoses compared to later diagnosis.

2. Are the new 2010 ACR/European league against rheumatism (EULAR) classification criteria for RA superior to the 1987 classification criteria for the early disease stage? RA classifications were essentially based on the criteria formulated by the ACR in 198741(B), which are described in Table 2. However, those criteria did not perform well in early RA cases42(B). The ACR classification criteria for RA were based on individuals with long-standing disease and, until then, were considered to be the standard for the selection of patients for clinical studies. These criteria exhibit 91%–94% sensitivity and 89% specificity for established RA. However, some of the items, such as radiological changes (erosions) and rheumatoid nodules, do not occur often in early RA. Thus, such criteria are suboptimal for the identification of individuals with early RA (40%–90% sensitivity, and 50%–90% specificity)43(B).

Table 2 – 1987 American College of Rheumatology classification criteria for rheumatoid arthritis. Criteria

Definition

1.Morning stiffness

Morning stiffness lasting at least 1 hour before maximal improvement 2.Arthritis of 3 or more At least three joint areas simultaneously joint areas affected and observed by a physician. The possible areas include the right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints. 3.Arthritis of hand joints Arthritis in wrist, MCP, or PIP joint 4.Symmetric arthritis Simultaneous involvement of the same joint areas on both sides of the body. 5.Rheumatoid nodules Subcutaneous nodules over bony prominences, extensor surfaces, or in juxta-articular regions as observed by a physician 6.Serum rheumatoid Demonstration of abnormal amounts of factor serum rheumatoid factor. 7.Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs showing juxta-articular bone thinning or erosions For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least four or these seven criteria. Criteria 1 through 4 must have been present for at least six weeks. Modified from: Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-24.

As a result, new RA classification criteria were needed, with a special focus on the early disease stages14(D). The new ACR/EULAR classification criteria can be applied to any patient, provided that two basic requirements are met as follows: 1) Evidence of active clinical synovitis in at least one joint at the time of examination. 2) Synovitis cannot be better explained by another disease. The new criteria (Table 3) are based on a score system that is calculated by direct addition. The clinical manifestations are grouped into the following four domains: joint involvement, serology, duration of symptoms, and acute-phase reactants. In questionable cases, the number of involved joints can be calculated by the use of imaging methods such as ultrasound (US) and magnetic resonance (MRI). A score > 6 is needed to classify a patient as having definite RA44(B). These criteria can be applied both prospectively and retrospectively, provided that the data were properly recorded. It is worth observing that whenever a patient exhibits typical erosions upon radiological examination and a clinical history compatible with RA (albeit non-documented), RA diagnosis can be directly established in a manner independent of the applicability of the classification criteria14(D). The new 2010 criteria were not developed for the purpose of diagnosis but rather of classification. The criteria basically serve to select homogeneous populations for studies. Clinical RA diagnoses are extremely complex and includes multiple features that are hard to reconcile with a single scoring system14(D). Eventually, the formal criteria might serve to guide clinical diagnoses. Several features of the new criteria must be subjected to careful analysis before they can be universally accepted. In particular, the criteria must be validated in different populations, including Brazilian early RA cohorts. In patients who use methotrexate and those with persistent RA, the discriminatory powers of the 2010 ACR/EULAR criteria were 76% and 87%, respectively, when the score was at least 6, and 63% and 46%, respectively, when it was < 645(B). Assuming the need for methotrexate, a diagnostic gold standard, during the first year of follow-up, the 2010 ACR/EULAR criteria were able to diagnose 86% of the cases for which the score was at least 6 and 49% when it was < 645, compared to 87% and 41%, respectively, when the 1987 ACR criteria were used46(B). A comparison of the 2010 ACR/EULAR (score of at least 6) and 1987 ACR (score > 4) criteria relative to the diagnosis of patients with a disease duration of less than 12 months showed positive predictive values of 70.7% and 65.3%, respectively, and negative predictive values of 76.1% and 79.1%, respectively47(B). The discriminatory powers of the 2010 ACR/EULAR and 1987 ACR criteria during an 18-month follow-up period were compared and are shown in Table 4. The application of the 2010 ACR/EULAR criteria at disease onset detected more patients who required DMARD treatment than did the 1987 ACR criteria; the values were 62% and 38%, respectively, and more particularly with regard to the use of methotrexate during the 18-month follow-up, the values were 68% versus 42%, respectively. However, the 2010 ACR/EULAR criteria were associated with a higher rate of false-positive cases (8% versus 2% for the 1987 ACR criteria)48(B).

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Table 3 – 2010 ACR/EULAR classification criteria for rheumatoid arthritis. Target population (Who should be tested?) Patients who meet the following criteria: 1) Have at least 1 joint with definite clinical synovitis (swelling)* 2) Present with synovitis that is not better explained by another disease *Differential diagnoses might include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If the relevant differential diagnoses to consider are unclear, an expert rheumatologist should be consulted.

Joint involvement (0–5)

Serology (0–3)

1 large joint

0

2–10 large joints

1

1–3 small joints (large joints are not taking into account) 4–10 small joints (large joints are not taking into account ) > 10 joints (at least 1 small joint)

2

Negative RF AND negative ACPA Low-positive RF OR lowpositive ACPA High-positive RF OR highpositive ACPA

Duration of symptoms (0–1) 0

< 6 weeks

0

2

≥ 6 weeks

1

Acute-phase reactants (0–1) Normal CRP AND normal ERS Abnormal CRP OR abnormal ERS

0 1

3

3

5

A score ≥ 6 is needed for the classification of a patient with definite RA. “Joint involvement” refers to any swollen or tender joint on examination, which might be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. “Large joints” refers to the shoulders, elbows, knees, and ankles. In the category “> 10 joints” at least one of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as joints that are not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular). In “Serology”, negative refers to IU values of the rheumatoid factor or anti-citrullinated protein antibody that are less than equal to the upper limit of normal (ULN) for the laboratory and assay, low-positive refers to IU values that are higher than the ULN, but ≤ 3 times the ULN for the laboratory and assay, and high-positive refers to IU values that are ≥ 3 times the ULN for the laboratory and assay. “Duration of symptoms” refers to patient self-reports of the duration of signs or symptoms of joint synovitis that are clinically involved at the time of assessment. “Acute-phase reactants” (erythrocyte sedimentation rate, and C-reactive protein) are considered to be normal/abnormal according to the local laboratory standards. Modified from: Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010; 69(9):1580-8.

Table 4 – Positive and negative predictive values from the 1987 ACR and 2010 ACR/EULAR criteria for patients with rheumatoid arthritis who are using disease-modifying anti-rheumatic drugs at the onset of disease and 18 months later. Measurement

Cohort onset 2010 ACR/EULAR

+ predictive value - predictive value

75% 66%

18 months later 1987 ACR

85% 59%

In cases for which the 1987 ACR criteria had been used to define RA (without radiological aid), the 2010 ACR/EULAR criteria were diagnostic of disease in 59% of the cases (positive predictive value), and ruled out the diagnosis in 93% (negative predictive value). The rate of false-positive results for the 2010 ACR/EULAR criteria was 17%. If RA was considered a chronic disease (five years of follow-up), the discriminatory power of the 2010 ACR/EULAR criteria fell to 68% when the score was at least 6 and to 61% when the score was < 6. Nevertheless, the 1987 ACR criteria identified 11.3% fewer cases as RA than did the 2010 ACR/EULAR criteria49(B).

Recommendation The 2010 CR/EULAR criteria identify more patients with early RA than do the 1987 ACR criteria. However, the rate of

2010 ACR/EULAR 73% 69%

1987 ACR 81% 79%

false-positive cases is higher with the newer criteria. When follow-up criteria such as use of DMARDs or disease persistence are used, the discriminatory powers of the 2010 CR/ EULAR and the 1987 ACR criteria are similar.

3. Is smoking associated with a poorer prognosis for articular disease in RA patients? Smoking was found to increase the risk of non-response (ACR50) by 18.3% [number needed to harm (NNH): 6] in patients with early RA (24 weeks of symptom duration)50(B). According to the EULAR criteria, RA patients who were smokers were less likely to achieve a good response at three months of treatment, compared to the non-smokers (NNH: 11). The patients who continued to smoke exhibited lower odds

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of good treatment responses during a 5-year follow up period. That difference in good treatment responses was somewhat higher in patients who were treated with anti-tumour necrosis factor (TNF) (14%; NNH: 7)51(B). Smokers tend to exhibit more extra-articular manifestations of RA (pleuritic, pericarditis, interstitial lung disease, neuropathy, glomerulonephritis, vasculitis), compared to nonsmokers, as well as higher average Disease Activity Score (DAS28), and Health Assessment Questionnaire (HAQ) values 52(B). Smoking increased the use of DMARDs in RA patients and reduced their clinical responses (ACR50) by 16% (NNH: 6), particularly in smokers of more than 20 packages/year53(B). The radiological progression of RA was similar in smokers and non-smokers after three years, which did not agree with the poorer clinical responses exhibited by the former54(B). RA patients who were smokers exhibited greater disease activity (joint pain and swelling) when compared to non-smokers after 24 months of treatment. The pain scores [(on a visual analogue scale – VAS) were also higher among the smokers. However, radiological progression did not differ between smokers and non-smokers55(B). Disease activity (measured as joint swelling, pain, and DAS28) was greater in patients with an average symptom duration of seven months who were smokers when compared to nonsmokers after a 5-year follow-up56(B).

Recommendation Smoking increases the disease activity of RA and reduces clinical and functional responses over time. However, there is no sufficient evidence regarding its influence on radiological disease progression.

4. Is measurement of the rheumatoid factor a reliable test for diagnosis and prognostic stratification in RA? RF is an antibody that targets the Fc fragment of IgG57(D). RF is classically associated with RA, is found in the serum of approximately 70% of RA patients, and is significantly correlated with a poorer prognosis. High RF levels are associated with aggressive disease, the presence of rheumatoid nodules, and extra-articular manifestations58(D). The diagnostic value of RF alone is limited because 30%– 50% of patients might be seronegative during the early stage of RA57(D). In addition to its low sensitivity, its specificity is limited. Individuals without RA might test positive for RF, and its prevalence increases with age59(B). Patients with other medical conditions, both rheumatologic and not, might also test positive for RF44,60(B). Therefore, negative RF serology does not rule out a diagnosis of RA, whereas the interpretation of positive results must be carefully checked against the clinical findings. Brazilian data (incident early RA cohort) indicate a RF prevalence of approximately 50% in patients 61(B). RF-positive patients with RA exhibited a 17% increase of mortality (NNH: 6) and cardiovascular mortality (NNH: 6) after 20 years of follow-up62(A). The mortality of RA patients with RF-positive serology did not differ from that of seronegative patients after 14 years of

follow-up. However, when the results were analysed according to the number of expected events in the population, the mortality, and more specifically the cardiovascular mortality, was elevated in the RF-positive patients 63(B). A 10-year follow-up study of RA patients, in which 24% of the cases tested positive for RF of the IgM and IgA isotypes, found that radiological progression was associated with and could be predicted by the serological findings (e.g. IgM or IgA)64(B). In a population of RA patients, 51% of whom were RF-positive, the presence of RF was predictive of radiological progression in 69% of the cases, whereas its absence ruled out progression in 83%. RF was predictive of radiological progression (Larsen score) in RA patients after 5 years of follow-up65(B). RF was predictive of radiological progression (Sharp or Larsen scores)35,66(B) and the need for biological therapy67(B) in RA patients after three years of follow-up. The risk of radiological progression was 24.3% (NNH: 4) higher among RF-positive patients versus RF-negative patients68(A). With a pre-test RA probability rate of 35%, positive RF (IgM, IgA, and IgG isotypes), measured by ELISA, increased the diagnostic probability rate to 94%, while negative serology ruled out RA with an 85% certainty rate69(B). In a population of patients with a 35% probability rate of RA, RF (IgM, IgA, and IgG isotypes) increased the post-test probability to 96%70(B).

Recommendation RF measurement contributes estimations of prognosis for RA patients, particularly with regard to radiological progression and mortality. Positive RF serology, particularly in populations with a pre-test probability rate of 35%, increased the diagnostic probability to 94%–96%, whereas negative RF serology ruled RA out with a post-test probability of 85%.

5. Is anti-CCP investigation superior to rheumatoid factor investigation for RA diagnosis? Recently, several anti-citrullinated protein antibodies (ACPA) were shown to behave as important diagnostic tools for RA; these had a similar sensitivity and superior specificity to RF, in addition to their possible participation in disease physiopathogenesis71(B). Their possible roles as markers of RA activity are controversial72(B).

Cyclic citrullinated peptide antibodies Among the investigated antibodies that target filaggrin-citrulline system antigens, anti-CCP exhibits the widest clinical applicability, with 70%–75% sensitivity and approximately 95% specificity. Anti-CCP analyses are particularly useful for patients with early RA and negative RF serology73(B). Anti-CCP measurements are also valid in investigations of undifferentiated arthritis. These antibodies are detected very early in the course of RA, and thus might be used as markers for progression and disease prognosis41-43,7478 (B)21,79(D).


Other antibodies Other antibodies are also used to investigate RA. The aim is to develop methods with sensitivities and specificities satisfactory for early disease diagnosis, as well as more reliable markers for activity and prognosis. These antibodies include anti-mutated citrullinated vimentin (anti-MCV)8082 (B), anti-keratin (AKA), anti-perinuclear factor (APF)83(B), anti-filaggrin84(B), anti-citrullinated fibrinogen (ACF)85(B), antiprotein A2 of the heterogeneous nuclear ribonucleoprotein complex (anti-RA33)83(B), anti-interleukin 1 (anti-IL1)86(B), anti-1-α-enolase87(B), and anti-advanced glycation end-product (AGE)88(B). The specificities of these antibodies are generally satisfactory for RA diagnosis, but their sensitivities is generally lower than that of anti-CCP. The 2010 ACR/EULAR criteria14(D) include only RF and ACPA under the heading “autoantibodies”, and the values of these antibodies are described as negative, low, or high titres. As the values of both RF and anti-CCP are expressed as international units (IU), the results are rated negative when they are equal to or higher than the upper limit of normal (ULN) in the corresponding laboratory; low-positive when they are higher than the ULN, but equal to or lower than 3 times the ULN; and high-positive when they are higher than three times the ULN. Positive anti-CCP correlated with the MRI swelling and erosion score at a 4-year follow-up, whereas negative anti-CCP correlated with the synovitis score89(B). Anti-CCP was superior to RF for predictions of the progression of undifferentiated arthritis into RA (diagnostic certainties of 93% and 68%, respectively). The former also permitted better estimates of the severity of disease at a 7-year followup90(B). The risk of positive anti-CCP serology in patients with active RA is 23% higher than that of patients in the period before disease. The anti-CCP alterations did not change after seven years of follow-up91(B). With regard to the use of anti-CCP (second generation, anti-CCP2) and data from 15 recent RA cohorts, it was concluded that a single positive result permits a diagnosis of RA (likelihood ratio, LR+ 12.7), but that a single negative result does not rule out RA (LR− 0.45). Upon comparing RF and antiCCP2, we found that their sensitivities are similar (56% and 58%, respectively), but the specificity of anti-CCP2 is superior (96% versus 86% for RF). The sensitivity and specificity of antiCCP2 are higher than those of anti-CCP1. The combination of positive RF and anti-CCP2 only slightly increases the diagnostic certainty, compared to anti-CCP2 alone (LR+ 27 versus 22, respectively). An analysis of global evidence allows us to estimate the sensitivity of anti-CPP2 a 67%, and the specificity as 96%. Assuming a prevalence of 42% in RA patients according to the 1987 ACR criteria, positive anti-CCP2 serology increases the diagnostic certainty to 90%, and negative serology rules out RA with a certainty of 75%92(B).

Recommendation The sensitivity of anti-CCP is similar to that of RF, but the specificity of the former is superior, especially in the early disease stages. Anti-CCP evaluations are recommended in patients with a clinical suspicion of RA and negative RF test serology.

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6. Are genetic markers (evaluations of HLA-DRB1 shared epitope alleles and PTPN22 genes) useful for characterisations of RA patients with poorer prognosis? Although countless genetic markers have been described in association with RA, only the HLA-DRB1 shared epitope (SE) 10The presence of SE (HLA-DRB1) in RA patients did not correlate with radiological disease progression105,107(B). However, according to some data, SE alleles and anti-CCP antibody levels might be associated with the severity of joint damage (erosion and radiological damage score) in RA patients108(B). The HLA SE had no predictive value relative to radiological RA progression109(B). The frequency of HLA-DRB1 alleles with SE was found to be high in Latin American RA patients110(B). The presence of SE alleles (DRB1) might be predictive of mortality, including cardiovascular mortality, in RA patients with RA111,112(B). An association was found between the DRB1 genotype and RF-positive RA patients with a 3.0%–3.7% (NNH: 30) risk increase113(B).

Recommendation The PTPN22 gene polymorphism is associated with RA. Although it is not predictive of specific therapeutic responses to biological therapy, it is predictive of remission when associated with anti-CCP. Alone or in combination with HLADRB1 (SE), the PTPN22 polymorphism permits estimations of radiological progression or disease activity. The HLA-DRB1 allele seems to play a more important role in the prediction of poor prognosis relative to the progression, activity, severity, and mortality of RA.

7. Does the occurrence of extra-articular manifestations denote a more aggressive disease progression? Although articular manifestations are the most characteristic, RA can also affect other organs and systems. The most frequent extra-articular manifestations include skin, eye, pleuropulmonary, heart, blood, neurological, and osteo-metabolic conditions. These occur more often in patients with severe and polyarticular disease, positive RF or anti-CCP serology, and rheumatoid nodules27(B)28(D). The incidence of extra-articular manifestations in RA is 47.5%, which includes cardiovascular, blood, eye, and lung affections. Such manifestations are associated with a greater likelihood of the use of biological agents114(B). Clinically significant lung interstitial disease occurs in 10% of RA patients115(B). Patient mortality depends on the type of lung affection and is greater when the affection is diffuse116(B). Pulmonary fibrosis-related mortality is approximately 6%115(B). The average survival of patients with interstitial pneumonia is 3.2 years, and thus is generally lower compared to that of other varieties of interstitial disease (6.6 years)116(B). In RA patients with lung interstitial disease, anti-TNF drugs must be used cautiously due to the risk of increased mortality117(B).

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The mortality rate of RA patients with lung interstitial disease is 7%, and the average survival duration after diagnosis is three years. In spite of the association between interstitial lung disease and RA activity, the latter was only denoted by increased ESR in that study118(B). The presence of kidney dysfunction in RA patients is not associated with the activity, progression, dysfunction, or severity of the disease119(B). RA patients with extra-articular manifestations exhibit a 20% increase in the risk of cardiovascular events (including acute myocardial infarction, angina, coronary disease, and stroke) (NNH: 5)120(B). The survival of patients with extra-articular manifestations of RA (18% of cases) is lower than that of patients with exclusive articular manifestations, and the relative risk of death in the former increases by 27% after seven years of follow-up. Similar to the extra-articular manifestations, comorbidities also increase mortality, particularly cardiovascular conditions because these cause 31% of patient deaths. Increased mortality correlates with greater disease activity (RF), worse function (HAQ), and increased radiological progression121(B). In RA patients with extra-articular manifestations, the scores that assess disease activity, such as DAS28 and HAQ, and the Larsen radiological score tend to be poorer, thus denoting a greater disease severity. Only 4.1% of such patients achieved remission122(B). After 15 years of follow-up, mortality increased only in the patients with extra-articular manifestations (relative risk increase: 51%), compared to those without such conditions; pericarditis was the most significant of the manifestations123(B). The mortality rate of RA patients with extra-articular manifestations (7.9% prevalence) was one death per 4.3 patients per year, whereas the rate of patients without articular manifestations was one death per 11.4 patients per year124(B). The risk of severe gastrointestinal diseases is elevated in RA patients with extra-articular manifestations (4.6% prevalence). In such patients, the disease intensity (ACR criteria) and the signs of radiological progression are also greater125(B).

Recommendation RA progression is more severe in patients with extra-articular manifestations. These patients have more intense disease activity with reduced functional capacities, responses to treatment (less occurrence of remission), and life expectancies, compared to those with exclusive articular manifestations.

8. Is conventional radiography an appropriate test for RA diagnosis? Conventional radiography is the most widely used imaging method for assessments of structural joint damage in RA. In addition to its diagnostic utility, conventional radiography plays an important role in the monitoring of disease progression, provided that it is performed at regular intervals126(D). The initial radiographic signs include increased amounts of soft tissues and juxta-articular osteopenia. More characteristic signs of RA, such as reduced joint space and bone erosion, appear later in the disease course.

The presence of bone erosion during the early stages of RA represents a risk factor for the development of persistent arthritis127(B). This factor is associated with functional limitation and thus with poorer prognosis128(B). When erosions are identified by radiography (15% prevalence), the diagnostic probability increases to 100%. However, as negative findings do not reduce the probability (18%), they do not rule out a RA diagnosis129(B). In patients with strong clinical suspicion of RA but negative RF serology and radiography, the presence of anti-CCP antibodies and erosions on MRI are highly specific for RA diagnosis130(B). In RA patients, the sensitivity of MRI for the detection of erosions is greater than that of conventional radiography. Conventional radiography detected 89% of erosions in the MCP joint bones and 15.8% in the wrist bones; these were lower than the MRI detection rates of 100% and 69%, respectively131(B). The diagnostic accuracy of conventional radiography in the detection of wrist bone erosions in RA patients was 63%, whereas the accuracy of MRI was 77%132(B). The diagnostic sensitivity of radiography for the detection of MCP joint bone erosions in RA patients was 14%, compared to 66% with MRI133(B). In RA patients who were followed-up for two years, radiography identified damage progression in 40% of the cases (total Larsen score) and 15% of the MCP joint bones (Larsen score). The accuracy of plain radiography in the identification of damage progression was similar to that of MRI134(B). Detection of erosions by means of the E score in RA patients was lower on radiographic assessment (13.1 ± 8.3) than on MRI (28.8 ± 10.0)135(B). In a population of RA patients with joint erosions (95% prevalence), radiography identified 59% of the cases, compared to 95% by MRI136(B). Radiography of the hands of RA patients identified 50% fewer erosions than MRI, although the identification of radiological progression was similar with both methods137(B). In a population of RA patients with a 43% prevalence of erosions, radiography increased the diagnostic probability to 80% for cases with positive findings, and ruled out a diagnosis in 85% for those with negative findings. After a 3-year followup period, the identification of erosions on radiography decreased to 81% and 60%, respectively138(B). In a population of patients with arthritis, 36% of whom were diagnosed with RA, diagnostic radiography increased the probability of RA to 50%, but when the results were negative, the probability decreased to 33%139(B). Radiographic assessment of RA patients only slightly increased the probability of distinguishing between RF seropositive and seronegative cases. In a population with a 59% prevalence of RF seropositive cases, positive radiographic findings (destruction) increased the probability to 66%, and a lack of radiographic findings decreased it to 47%140(B).

Recommendation Conventional radiography must be used in diagnostic and prognostic assessments of RA. When needed and available, US and MRI should also be used.


9. Is ultrasound superior to conventional radiography in the diagnosis and establishment of prognosis of RA? The sensitivity of musculoskeletal US and MRI for the detection of structural damage was superior to that of conventional radiography141(D). US is useful for early detection, as well as the monitoring of inflammatory activity and signs of joint destruction when performed by an operator with significant experience in musculoskeletal diseases135(B). Compared to MRI, the cost of US is lower, and it is not contraindicated for patients with metallic implants or claustrophobia. Additionally, US permits dynamic assessments of the joints and bilateral comparisons, as well as evaluations of other anatomical structures134(B)141,143(D). The use of power and colour Doppler might provide complementary information and thus contribute to characterisations of inflammatory activity144(D). Positive and negative US findings, when used to identify joint inflammation in RA patients, permits definite diagnoses in 79% and 55% of the cases, respectively. These results are similar those of radiography (Sharp score) when it exhibits positive findings (74%), but superior when the radiographic findings are negative (38%)145(B). Using MRI as the gold-standard (as in the present study), US was superior to radiography in the detection of bone erosions in patients with recent RA, whereby the LR+ values were 31 and 20, respectively. Based on a lesion prevalence of 50%, in cases with positive findings, the diagnostic probabilities of US and radiography increase to 99% and 97%, respectively. Therefore, the utility of both methods is similar135(B). Relative to the detection of erosions in RA patients, when US exhibits positive findings, it achieves a diagnostic certainty of 82% and for negative findings, a certainty rate of 61%, compared to 95% and 55%, respectively, for radiography146(B). The sensitivity and specificity of US in the detection of inflammatory signs and interphalangeal joint destruction in RA patients were 59% and 98%, respectively, compared to 42% and 99% for radiography, respectively. The diagnostic certainties relative to US and conventional radiography were 97% and 98%, respectively, when those results were positive and 71% and 63%, respectively, when they were negative147(B). The sensitivity and specificity of US in the detection of MCP joint erosions in the of RA patients were 79% and 97%, respectively, compared to 32% and 98% for conventional radiography, respectively. The diagnostic certainties relative to US and conventional radiography were 96% and 94%, respectively, when those results were positive and 82% and 46%, respectively, when they were negative148(B). The sensitivity and specificity of US in the detection of glenohumeral joint erosions in RA patients were 74% and 75%, respectively, compared to 67% and 100% for radiography, respectively. The diagnostic certainties relative to US and conventional radiography were 75% and 100%, respectively, when those results were positive and 74% and 75%, respectively, when they were negative149(B). The diagnostic accuracy of US in the identification of erosions in RA patients was 84% and was thus superior to that

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of radiography (73%). However, when only the tests with positive findings were considered for analysis, the LR of US was lower (5 versus 13), which indicates less diagnostic certainty150(B). In patients with early RA, US found erosions that were not identified by radiography in 19.3% of the cases, but failed to diagnose 8.8% of the cases that were identified by radiography. The combination of both methods permitted the diagnosis of 45.6% of the lesions in that patient population151(B). In patients with early RA, US correlated with disease activity (DAS28) and functional capacity (HAQ) scores at 12 months of follow-up152(B). In patients with early RA, US increased the detection of erosions in 42.0% of the cases at the time of diagnosis and after 9 months of follow-up, compared to radiography153(B). The detection of joint lesions in RA patients was greater with US versus radiography; specifically, US detection was 5% greater at the time of diagnosis, and 23% greater after seven years of follow-up154(B). However, in another study, radiography identified a larger number of erosions in RA patients, compared to US (37% and 30%, respectively). After six months, the rates were 48% and 41%, respectively155(B). After accounting for the number of humeral erosions (greater tuberosity, anteromedial, and posterolateral) in RA patients, the diagnostic certainties of US and radiography were 90% and 40%, respectively, when the findings were positive and 96% and 39%, respectively, when the findings were negative152(B).

Recommendation US might contribute to the diagnosis of joint erosions in RA patients, as well to the monitoring of disease progression.

10. Is magnetic resonance superior to conventional radiography and ultrasound for the diagnosis and establishment of prognosis of RA? MRI is the most sensitive method with which to detect the changes associated with the early stages of RA. It permits the assessment of structural alterations of the soft tissues, bone, and cartilage, in addition to erosions at an earlier stage than conventional radiography138(B). In addition to the features identified by conventional radiography, MRI is further able to detect bone swelling, which was shown to be a predictor of bone erosion135(B). In Brazil, factors such as the high cost and lack of standardisation limit the use of MRI in clinical practice. The results of MRI relative to RA diagnosis vary widely as a function of the applied criteria and the investigated population. Thus, the sensitivity varies from 20% to 100%, and the specificity from 0% to 100%136,156-158(B). Additionally, the results of MRI relative to RA progression vary widely, with a sensitivity range from 18% to 100% and a specificity range from 6% to 97%156,159-161(B). Furthermore, the use of MRI in the management of patients with recent RA does not seem to be cost-effective when compared to standard diagnostic and prognostic assessments162(B).

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In RA patients, MRI (Outcome Measures in Rheumatology – OMERACT - definition) permits the diagnosis of erosions (hands or wrists) with 35%–90% sensitivity and 35%–90% specificity, bone swelling (hands, wrists, or MCP joints) with 32.5%–65% sensitivity and 82.5%–100% specificity, and synovitis (hands or wrists) with 40-80% sensitivity and 57.7%–92.5% specificity163(B). Compared to MRI, when the findings were positive, conventional radiography could diagnose MCP and PIP joint erosions with certainty in 98%–100% of the cases, and US in 86%– 7% of the cases. When the findings were negative, the rates were 84% and 93%, respectively 135,155(B). The diagnostic accuracy of Doppler US for the identification of joint inflammation in RA patients was 75%, compared to MRI164(B). Using computed tomography (CT) as the gold-standard for the diagnosis of erosions in the wrists of RA patients, when the findings were positive, MRI accurately diagnosed 90% of the cases, compared to conventional radiography138,154(B). Using high-field MRI as the gold-standard for the diagnosis of erosions in the wrists and MCP joints of RA patients, when the findings were positive, limb MRI accurately diagnosed 88% to 93% of the cases, compared to conventional radiography (94%–98%) and US (82%)165,166(B). A combination of MRI synovitis, swelling, and erosion scores permitted the identification of RA patient responses to TNF-α inhibitor treatment at a 12-month follow-up167(B). As a method for long-term functional assessments in RA patients, MRI identified improvements only in 29% of the cases, compared to the functional status (assessed by doctors and patients)168(B). MRI (bone swelling) and US (inflammation) exhibited similar abilities to identify the progression of erosion in RA patients (using the Rheumatoid Arthritis MRI Scoring System – RAMRIS – as the gold standard) over a 12-month follow-up period152(B). The progression of erosion was identified by MRI (OMERACT) in 23% of patients with RA over a 5-year period, compared with 40% by conventional radiography (Larsen score)140(B).

Recommendation MRI is the most sensitive method with which to detect the changes associated with the early stages of RA. It permits the assessment of structural alterations of the soft tissues, bone, and cartilage, in addition to erosions at an earlier stage than conventional radiography. In Brazil, factors such as the high cost and lack of standardisation have limited the use of MRI in clinical practice. Table 5 summarises the advantages and disadvantages of the imaging methods used to assess RA patients.

Conclusion The present guidelines were elaborated by the Commission of Rheumatoid Arthritis of the Brazilian Society of Rheumatology to formulate recommendations for the diagnosis and initial assessment of RA in Brazil. Due to the country’s territorial extension and the diversity of its macro-regions, local differences relative to differential diagnoses and access to some (laboratory or imaging) technologies might occur. RA diagnosis is of paramount importance, especially in the earliest stages. Lack of diagnosis means a lack of appropriate treatment and, consequently, an increased risk of the development of persistent inflammation and progressive joint damage. Rheumatologists must be included as early as possible in assessments of patients with arthritis due to their wider experience and familiarity with the possible differential diagnoses and investigational approaches. Despite the recent publication of guidelines for the diagnosis of RA, a revision of this subject that accounts for particular Brazilian features is relevant. Therefore, the establishment of recommendations for RA ultimately seeks to define and provide a solid basis for Brazilian rheumatologists with data from controlled trials to promote a homogeneous approach to diagnosis within the Brazilian socioeconomic context.

Table 5 – Advantages and disadvantages of the imaging methods used to assess patients with rheumatoid arthritis. Methods

Advantages

Conventional radiography

- Low cost - Easy access

Ultrasound

- Intermediate cost - No ionising radiation - Allows assessing several joints - Guides diagnostic and therapeutic interventions - Early detection of cartilage and bone structural damage - Detection of inflammatory activity by means of power Doppler - High sensitivity - No ionising radiation - Complementation using contrast agents - Early detection of bone swelling, cartilage and bone structural damage

Magnetic resonance

Disadvantages - Two-dimensional representation of 3-D lesions - Exposure to ionising radiation - Low sensitivity for early bone damage - Operator-dependent test - Poor sensitivity to detect changes in deep joints (hips)

- High cost - Limited equipment availability - Long testing time - Limited to one joint per exam (e.g., knee, hand)


Because the knowledge relative to RA increases rapidly, the corresponding recommendations should be updated on a periodic and regular basis.

Conflicts of interest Mota LMH: Participated in clinical and/or experimental studies sponsored by Roche and Mantecorp; was given personal or institutional grants by Abbott, AstraZeneca, MSD, Roche, and Pfizer; and was a guest lecturer at meetings and other activities sponsored by Abbott, MSD, Novartis, Roche, and Wyeth. Cruz BA: Participated in clinical and/or experimental studies sponsored by Roche; was given personal or institutional grants by Abbott, Bristol-Myers Squibb, Mantecorp, MSD, Novartis, Roche, Wyeth, and Pfizer; and was a guest lecturer at meetings and other activities sponsored by Abbott, MSD, Mantecorp, Novartis, Roche, and Wyeth. Brenol CV: Participated in clinical and/or experimental studies sponsored by Bristol-Myers Squibb, Pfizer, Roche, and Wyeth; was given personal or institutional grants by Abbott, Bristol-Myers Squibb, Mantecorp, MSD, Roche, and Wyeth; and was a guest lecturer at meetings and other activities sponsored by Abbott and Roche. Pereira IA: Participated in clinical and/or experimental studies sponsored by Roche; was given personal or institutional grants by Abbott, MSD, Roche, BMS, Jansen, and Pfizer; was a guest lecturer at meetings and other activities sponsored by Abbott, MSD, BMS, Pfizer, Roche, and Janssen; is a member of the consultant or executive boards of pharmaceutical companies or the normative committees of scientific studies sponsored by Abbott, BMS, Janssen, Roche, Pfizer, and MSD. Rezende-Fronza LS: Participated in clinical and/or experimental studies sponsored by Bristol-Myers Squibb, Pfizer, and Roche; and wrote scientific papers for journals sponsored by Pfizer. Bertolo MB: Was a guest lecturer at meetings and other activities sponsored by Abbott, Pfizer, and Sanofi Aventis. Freitas MVC: Was given personal or institutional grants by Abbott, MSD, Pfizer, Roche, and Wyeth; was a guest lecturer at meetings and other activities sponsored by Abbott, MSD, Pfizer, Roche, and Wyeth; is a member of the consultant or executive boards of pharmaceutical companies or the normative committees of scientific studies sponsored by AstraZeneca, MSD, and Wyeth; and wrote scientific papers for journals sponsored by Abbott, AstraZeneca, Bristol-Myers Squibb, and Wyeth. Silva NA: Participated in clinical and/or experimental studies sponsored by Bristol-Myers Squibb and Roche; was given personal or institutional grants by Abbott, MSD, Pfizer, Roche, and Wyeth; and was a guest lecturer at meetings and other activities sponsored by Janssen, Mantecorp, MSD, and Roche. Louzada-Junior P: Participated in clinical and/or experimental studies sponsored by Merck and Roche; was given personal or institutional grants by Abbott; and was a guest lecturer at meetings and other activities sponsored by Bristol-MeyersSquibb, Pfizer, and Roche. Giorgi RD: Was given personal or institutional grants by Bristol-Myers Squibb and Roche; and was a guest lecturer at meetings and other activities sponsored by Bristol-Myers Squibb and Roche.

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Lima RAC: Participated in clinical and/or experimental studies sponsored by Mantecorp and Roche; was given personal or institutional grants by Acteion, Lilly, and Pfizer; and was a guest lecturer at meetings and other activities sponsored by Acteion, Lilly, and Pfizer. Pinheiro GRC: Was given personal or institutional grants by Janssen and Roche.

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assessment of joint inflammatory activity in early rheumatoid arthritis: predictive value in disease activity and radiologic progression. Arthritis Rheum. 2007;57: 116-24. Bajaj S, Lopez-Ben R, Oster R, Alarcón GS. Ultrasound detects rapid progression of erosive disease in early rheumatoid arthritis: a prospective longitudinal study. Skeletal Radiol. 2007;36:123-8. Scheel AK, Hermann KG, Ohrndorf S, Werner C, Schirmer C, Detert J, et al. Prospective 7 year follow up imaging study comparing radiography, ultrasonography, and magnetic resonance imaging in rheumatoid arthritis finger joints. Ann Rheum Dis. 2006;65:595-600. Alasaarela E, Suramo I, Tervonen O, Lähde S, Takalo R, Hakala M. Evaluation of humeral head erosions in rheumatoid arthritis: a comparison of ultrasonography, magnetic resonance imaging, computed tomography and plain radiography. Br J Rheumatol. 1998;37:1152-6. Suter LG, Fraenkel L, Braithwaite RS. Role of magnetic resonance imaging in the diagnosis and prognosis of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011;63:675-88. Eshed I, Feist E, Althoff CE, Hamm B, Konen E, Burmester GR, et al. Tenosynovitis of the flexor tendons of the hand detected by MRI: an early indicator of rheumatoid arthritis. Rheumatology (Oxford). 2009;48:887-91. Tamai M, Kawakami A, Uetani M, Takao S, Arima K, Iwamoto N, et al. A prediction rule for disease outcome in patients with undifferentiated arthritis using magnetic resonance imaging of the wrists and finger joints and serologic autoantibodies. Arthritis Rheum. 2009;61:772-8. Mundwiler ML, Maranian P, Brown DH,Silverman JM, Wallace D, Khanna D, et al. The utility of MRI in predicting radiographic erosions in the metatarsophalangeal joints of the rheumatoid foot: a prospective longitudinal cohort study. Arthritis Res Ther. 2009;11:R94. McQueen FM, Benton N, Perry D, Crabbe J, Robinson E, Yeoman S, et al. Bone edema scored on magnetic resonance imaging scans of the dominant carpus at presentation predicts radiographic joint damage of the hands and feet six years later in patients with rheumatoid arthritis. Arthritis Rheum. 2003;48:1814-27. McQueen FM, Benton N, Crabbe J, Robinson E, Yeoman S, McLean L, et al. What is the fate of erosions in early rheumatoid arthritis? Tracking individual lesions using x rays and magnetic resonance imaging over the first two years of disease. Ann Rheum Dis. 2001;60:859-68. Suter LG, Fraenkel L, Braithwaite RS. Cost-effectiveness of adding magnetic resonance imaging to rheumatoid arthritis management. Arch Intern Med. 2011;171:657-67. Olech E, Crues JV 3rd, Yocum DE, Merrill JT. Bone marrow edema is the most specific finding for rheumatoid arthritis (RA) on noncontrast magnetic resonance imaging of the hands and wrists: a comparison of patients with RA and healthy controls. J Rheumatol. 2010;37:265-74. Horikoshi M, Suzuki T, Sugihara M, Kondo Y, Tsuboi H, Uehara T, et al. Comparison of low-field dedicated extremity magnetic resonance imaging with articular ultrasonography in patients with rheumatoid arthritis. Mod Rheumatol. 2010;20:556-60. Freeston JE, Conaghan PG, Dass S, Vital E, Hensor EM, Stewart SP, et al. Does extremity-MRI improve erosion detection in severely damaged joints? A study of longstanding rheumatoid arthritis using three imaging modalities. Ann Rheum Dis. 2007;66:1538-40. Ejbjerg BJ, Narvestad E, Jacobsen S, Thomsen HS, Østergaard M. Optimised, low cost, low field dedicated extremity MRI is highly specific and sensitive for synovitis and bone erosions in rheumatoid arthritis wrist


and finger joints: comparison with conventional high field MRI and radiography. Ann Rheum Dis. 2005;64:1280-7. 167. Haavardsholm EA , Østergaard M, Hammer HB, Bøyesen P, Boonen A, van der Heijde D, et al. Monitoring anti-TNFalpha treatment in rheumatoid arthritis: responsiveness of magnetic resonance imaging and ultrasonography of the dominant wrist joint compared with conventional

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Guidelines

Guidelines for the drug treatment of rheumatoid arthritis Diretrizes para o tratamento da artrite reumatoide Sociedade Brasileira de Reumatologia (Brazilian Society of Rheumatology) Projeto Diretrizes da Associação Médica Brasileira, São Paulo, SP, Brazil

Participants

Objective

Licia Maria Henrique da Mota*, Bóris Afonso Cruz, Claiton Viegas Brenol, Ivânio Alves Pereira, Lucila Stange Rezende-Fronza, Manoel Barros Bertolo, Max Vitor Carioca Freitas, Nilzio Antônio da Silva, Paulo Louzada-Junior, Rina Dalva Neubarth Giorgio, Rodrigo Aires Corrêa Lima, Wanderley Marques Bernardo, Geraldo da Rocha Castelar Pinheiro

These guidelines aim to provide recommendations for the treatment of rheumatoid arthritis in Brazil. Although North American and European guidelines for the treatment of rheumatoid arthritis have been recently published, it is important to review the subject with regard to specific aspects of Brazilian reality. Thus, the ultimate purpose of the establishment of consensus guidelines for the treatment of rheumatoid arthritis in Brazil is to provide an orientation and foundation for Brazilian rheumatologists with evidence from scientific studies and the experience of a committee of experts on the subject. Thus, therapeutic approaches to rheumatoid arthritis within the Brazilian socioeconomic context will be standardized, while physician autonomy will be maintained with regard to the indication/selection of available treatment options. As knowledge in this scientific field progresses rapidly, we suggest biannual updates to these guidelines.

Final elaboration 12 April, 2012

Description of evidence collection method A literature review of the scientific articles referenced in these guidelines was conducted with the MEDLINE database. The evidence search was based on real clinical scenarios, and the following keywords (MeSH terms) were used: Arthritis, Rheumatoid, Therapy (early OR late OR later OR time factors OR delay), Prognosis, Remission, Steroids, AntiInflammatory Agents, Non-Steroidal, NSAIDs, Diclofenac, Ibuprofen, Indomethacin, Piroxicam, COX-2, Celecoxib, Etoricoxib, Disease-modifying antirheumatic drug OR DMARD, Methotrexate, Gold sodium, Leflunomide, Sulfasalazine, Hydroxychloroquine, Tumor Necrosis Factor-alpha, Adalimumab, Certolizumab, Etanercept, Infliximab, Golimumab, Rituximab, Tocilizumab and Abatacept.

Grade of recommendation and strength of evidence A: Most consistent experimental and observational studies. B: Less consistent experimental and observational studies. C: Case reports (uncontrolled studies). D: Opinion that is not substantiated by critical evaluation, based on consensus, physiological studies or animal models.

Introduction Rheumatoid arthritis (RA) is a systemic and inflammatory autoimmune disease that is characterized by the preferential impairment of the synovial membranes of peripheral joints. The RA prevalence varies between 0.5% and 1% of the population, and RA affects predominantly women and adults in the 30- to 50-year age group1,2(B). The generally symmetrical involvement of small and large joints is the main feature of RA, and involvement of the hands and feet is common. The chronic and destructive nature of the disease can lead to significant functional limitations, including the loss of ability to work and an impaired quality of life, unless a diagnosis is made at an early stage of the disease and treatment leads to clinical improvements3(B). In addition to the irreversible deformity and functional limitations, patients with

* Corresponding author. E-mail: [email protected] (L.M.H Mota) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.


advanced-stage RA might have lower survival rates, a finding that highlights the severity of this disease4(B) 5(D). RA-related costs are high as the result of both direct (spending on various medications, such as expensive biologic drugs, and medical and hospital expenses) and indirect (loss of personal productivity, absenteeism, payment of disability pensions and a total loss of working capacity) factors6(B). In the last two decades, there have been significant advances in an understanding of RA physiopathology, accompanied by the development of new therapeutic categories and the implementation of different treatment strategies, patient monitoring and intensive intervention and disease control at early symptomatic stages7(D). The initial period of the disease, particularly the first 12 months, is known as early RA5(D) and is considered to be a window of therapeutic opportunity, a time during which rapid and effective pharmaceutical intervention can change the long-term disease course. These interventions result in better disease control and the possibility of sustained RA remission7,8(D).

Treatment of RA RA treatment includes patient and family education, drug therapy, physiotherapy, psychosocial support, occupational therapy and surgical approaches. Drug therapies that will be addressed in this document include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, biologic and synthetic diseasemodifying anti-rheumatic drugs (DMARDs) and immunosuppressive drugs. DMARDs should be indicated for all patients once a diagnosis of RA9(B) has been established. The use of DMARDs can be considered for patients with undifferentiated arthritis and positive test levels for RA predictive biomarkers such as anticyclic citrullinated peptides (anti-CCPs) and/or rheumatoid factors (RFs)10(B). Table 111-44(A) 45-64(B) 65-80(D) summarizes the DMARDs that are most frequently used in Brazil along with their presentations, doses and monitoring considerations.

1. Is disease treatment with the intent to achieve remission a feasible goal? Once a diagnosis of RA has been established, an initial disease assessment is important and should include the adequate monitoring of disease activity by assessing not only articular but also extra-articular manifestations and the presence of comorbidities. Some of the parameters that have been found to correlate with RA activity include patient visual pain scales, patient and physician-reported disease activity, the number of tender and swollen joints, instruments for functional capacity assessments (e.g., the Health Assessment Questionnaire – HAQ), inflammatory markers (e.g., erythrocyte sedimentation rate – ESR and/or C-reactive protein – CRP), fatigue, duration of morning stiffness, radiography of the hands, wrists and feet and quality of life indices (e.g., the Short Form – SF-36)81-83(A) 84(B) 85,86(C). Composite indices of disease activity (CIDAs) have been created and validated with these parameters. The main indices

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are the one based on 28 joint count (Disease Activity Score 28 – DAS-28), the simplified disease activity index (SDAI) and the clinical disease activity index (CDAI). These indices use a more simplified count of 28 joints (bilateral proximal interphalangeal, metacarpophalangeal (MCP), wrist, elbow, shoulder and knee joints) and determine a numerical value for RA activity. Tables 2, 3 and 4 detail the calculations and uses for these indices87-95(A) 96(B). There are good correlations between the CIDAs (CDAI, SDAI and DAS-28), and any of these indices can be used alone. Patients who are in remission or have low disease activity according to any index also have reduced radiographic progression and improved functional outcomes. Therefore, the aim should always be to keep the patient in clinical remission or, if this outcome is not possible, in a state of low disease activity87(A). The use of methotrexate (MTX), especially in combination with other DMARDs (gold, chloroquine or sulfasalazine), led to clinical remission in 14.0%97(B), 33.3%98(A), 38.0%3(B) and 95%99(A) of adult patients with active RA of a duration ranging between four months and five years (mostly between one and two years), according to the American College of Rheumatology (ACR) criteria. The best results were observed in the first 6 months after treatment. According to DAS-28 criteria, the remission rate at 24 months is 76%100(B). A combination of MTX and infliximab led to remission in 70% (ACR criteria)101(A) and 21.3% (SDAI criteria)102(A) of patients with RA of a duration less than 36 months who were evaluated between 54 weeks and 24 months. Similarly, MTX and etanercept combinations have achieved remission rates in a period of 12 to 36 months in 37% (DAS-44 ≤ 1.6)103(A), 50% (DAS-28 ≤ 2.6)43,45,104(A) and 50% (DAS-28 ≤ 3.2) of patients105(A). Remission, as measured by the DAS-28 ≤ 2.6 parameter, was achieved in 43% to 45% of patients with active RA (12 months) within four to nine years with a combination of adalimumab and MTX28,106(A). The remission rate, as measured by SDAI criteria, was 15% at 24 months107(B). The rates of early (in the first 12 months) remission in these patients, according to different criteria, were 47.7%, 50.8% and 32.3% for EULAR (European League against Rheumatism; DAS-28), ACR70 and DAS-28, respectively108(B). Responses to recent RA treatments (less than 24 months of illness) with combinations of DMARDs (MTX, gold, chloroquine or sulfasalazine) have also been measured according to several criteria or parameters during remission periods ranging from 2–11 years; the different criteria included ACR (14%–48%)109-113(B), DAS ≤ 2.4 (39%–43%)114,115(B) and DAS-28 ≤ 2.6 (23%–51%)116,117(B).

Recommendation RA patient remission, as measured by any of the objective parameters of disease activity (DAS, DAS-28, SDAI and CDAI), should be considered as central objective of patient treatment.

2. Does the early initiation of RA treatment offer benefits over a later initiation with respect to clinical and radiographic prognosis? In patients who began treatment with non-biologic DMARDs, the remission rate at 12 months, defined as a CDAI score
5 and ≤ 20 > 20 and ≤ 40 > 40 ≤ 2.8 ≤ 10 > 10 and ≤ 22 > 22 ≤≤ 2.6 > 2.6 and ≤ 3.2 > 3.2 and ≤ 5.1 > 5.1

SDAI, simplified disease activity index; CDAI, clinical disease activity index; DAS-28, disease activity index (28 joints). Modified from Aletaha D, Smolen JS. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): A review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005; 23(39):S100–8.

joint damage progression per year than patients who were treated after less than one year of symptoms118(B). Early administration of DMARD treatment (less than nine months from symptom onset) produced a 33% relative reduction in radiographic disease progression during the following three years119(B). It was also found that for patients whose treatment began with 3 g/day of sulfasalazine or more than 15 mg/week of MTX in the first three months after symptom onset, the following results were observed in comparison to patients whose treatment began after 12 months: a 40% increase in the number of patients with responses within 32 months (as measured by DAS-28 < 3.2; NNT: 2); a 4-fold reduction in joint damage progression (measured by the Larsen radiographic score) and a 35% increase (NNT: 3) in the number of patients who achieved 50% and 70% ICR120(B). However, in patients with symptom durations of less than 24 months, no differences in the ACR (20 or 50) or DAS-44 < 1.6 response rates were found between patients who began non-biologic DMARD therapy after less than five months of

Table 4 – Responses according to variations in the Composite Indices of Disease Activity points. Index Response EULAR-DAS2887,88(A)

SDAI response90 (A) CDAI response90 (A)

Response Type Good: down > 1.2 points and patients achieve DAS-28 with low activity (≤ 3.2). Moderate: down 1.2 points on DAS-28; down between 0.6 and 1.2 points with a decline in disease activity from high to moderate activity or moderate to low activity. Good: down 17 points. Moderate: down 7 points. BGood: down 14 points. Moderate: down 6 points.

SDAI, simplified disease activity index; CDAI, clinical disease activity index, DAS-28; disease activity index (28 joints). Modification of: Aletaha D, Funovits J, Wards MM, Smolen JS, Kvie TK. Perception of improvement in patients with rheumatoid arthritis varies with disease activity levels at baseline. Arthritis Rheum. 2009;61:313–20.

symptoms and those who started treatment after more than five months 121(B). If four months after symptom onset is set as the cutoff for delayed or retarded treatment with 1.0 g of sulfasalazine (monotherapy) or 500 mg of sulfasalazine twice per day, 7.5 mg of methotrexate per week, 300 mg of hydroxychloroquine and 5 mg of prednisone per day (combination therapy), the disease remission rate in response to earlier treatment (< 4 months) is 24% greater (NNT: 4) in patients who underwent monotherapy, despite the similar time course for those who underwent combination therapy110(B). In patients with early RA who were treated for two years with DMARDs (MTX, combined or not with adalimumab), the additional time to achieve remission (SDAI) in the first year of treatment was accompanied by an increase in joint damage progression, as evaluated by imaging, in the second year107(B).

Recommendation Treatment introduction for patients with early RA should be early (in the first few months after symptom onset) to increase the clinical response rate (NNT: 2–4) and reduce


radiological joint damage progression in the early years of treatment.

3. Does corticosteroid use in early-stage disease improve patient outcomes? Improvements in inflammation and pain are the bestknown and expected effects of corticosteroids in RA. However, some studies have indicated that corticosteroids, when combined with DMARDs, can modify the course of the disease14(A) 66(D). Most studies on the use of corticosteroids in RA treatment suggest the use of prednisone or prednisolone at low doses (≤ 15 mg/day). There are no comparative studies that have preferentially indicated higher doses at the beginning of treatment14(A) 66(D). Because corticosteroids have many side effects, their usage should be kept to a minimum. If corticosteroid use for three or more months is foreseen, calcium and vitamin D supplements should be taken. The use of antiresorptive drugs such as bisphosphonates could be considered in patients with risk factors as determined by fractures or bone densitometry results50(B). Gastric protection via proton pump inhibitors is recommended for patients who concomitantly use corticosteroids and NSAIDs67(D). The use of intra-articular corticosteroids can be considered at any treatment stage during which the disease remains active in a small number of joints67(D). In patients with early RA (less than 12 months of symptoms) and involvement of the MCP joints, the use of MTX in combination with intra-articular methylprednisolone infiltration can reduce bone loss in the inflamed joints122(B). Prednisone (12.5 mg/day for two weeks and 6.25 mg/day for 12 months), when combined with MTX (15 mg/month), led to an increase of 43.4% (NNT: 2) in the 6-month remission rate (according to DAS) in patients with early RA (less than 12 months of disease)115(B). In patients with early-stage arthritis (less than 16 weeks of symptoms), the use of an intramuscular glucocorticoid (single injection of 120 mg methylprednisolone) offered no benefit with respect to symptom remission or RA development at 52 weeks123(B). The use of 1–4 mg of prednisone per day for 24 weeks reduced the risk of loss of treatment adherence due to a lack of efficacy by 31% (NNT: 3) in RA patients124(A). In RA patients, combined treatment with MTX (15 mg weekly) and prednisone (60 mg per day with gradual reduction) for 24 months reduced radiological progression and improved functional responses (HAQ) but increased the number of patients with a loss of treatment adherence by 7% (number needed to harm – NNH: 14)125(A). The combination of MTX (15 mg/week) and prednisone (60 mg/day) led to an increase in the 24-month remission rate (DAS ≤ 2.4) of 18% (NNT: 6), increases in clinical responses (ICR) and functional capacity (HAQ), and reductions in radiographic progression in RA patients, compared to treatment without prednisone56(B) 126(A). However, de-

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spite the lack of increased adverse events, patients reported greater intolerance to this combination127(B). The combination of DMARDs and prednisolone (7.5 mg/ day) over 24 months reduced radiological joint damage progression (Sharp score) and increased disease remission (DAS-28) by 22.7% (NNT: 4), with few adverse events in patients with early RA (less than 12 months of symptoms)128(A). The use of budesonide (9 mg/day) or prednisone (7.5 mg/ day) in RA patients (less than 12 months of disease) for 12 weeks caused improvements in disease activity (number of involved joints) and function (HAQ)129(B). There was no increased clinical benefit from the use of prednisone at 10 mg/day for 24 months in patients with early-stage RA. However, there is evidence for reduced radiographic joint damage progression, and no increases in the rates of bone fractures have been reported130,131(A). The combination of prednisolone (initial dose of 30 mg/ day and maintenance of 4.5 mg/day) and DMARDs only caused a reduction in radiographic injury progression (Larsen score) at 12 months in patients with early RA132(B).

Recommendation The use of corticosteroids, particularly daily prednisone, in combination with drugs that modify the disease course, especially MTX, for 12 to 24 months offers radiological and clinical benefits to patients with early RA. Because corticosteroids have many side effects, their usage should be kept to a minimum, and their dose should be the smallest possible.

4. Does the prescription of anti-inflammatory drugs alter the disease prognosis with regard to clinical and radiographic progression? NSAIDs are useful because they decrease inflammation and pain, especially early in the disease, as DMARDs are not immediately effective. NSAIDs can also be used when disease activity is not completely controlled and when disease flareups occur47(B)65(D). Patients who were diagnosed with RA within the past 12 months and who initially received NSAID treatment (12 months) alone or, if necessary, with DMARDs, had worse clinical responses within five years than those who initially received DMARDs (gold sodium, chloroquine, MTX or sulfasalazine), as measured by ESR (in mm/hour), mean pain score (visual analogue scale – VAS-100 mm), articular score (Thompson articular index of edema and joint pain, 0–534), general well-being (VAS-100 mm), duration of morning stiffness (maximum, 720 minutes), grip strength (kPa; measured with a vigorimeter), and functional disability (HAQ) (0–3)133(B). Of the patients who used NSAIDs for the first 14 months (on average), 86% discontinued the treatment due to ineffectiveness and were subsequently treated with DMARDs for an average of 42 months. Patients who remained on NSAIDs for five years had worse clinical and radiological progressions in comparison to those who discontinued treatment133(B). Furthermore, adult patients who had RA for at least six months and had previous clinical responses to NSAIDs had varying lower discontinuance rates due to ineffectiveness

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of 12%–20% and 10%–50% after 12-week treatments with 90 mg/day of etoricoxib or 500 mg of naproxen twice daily, respectively. However, there were measurable benefits for patients who remained on the treatment, according to the patient global assessment scores (PGA), Investigator of Global Assessment of Disease Activity scores and the number of joints with edema134,135(A). Patients who had been diagnosed with RA in the previous 12 months were treated with either 1.2 g/day of sulfasalazine or 100 mg/day of diclofenac; 11% and 20%, respectively, did not complete the 12-month treatment course due to ineffectiveness. The number of radiographic erosions was significantly higher in patients treated with diclofenac. Furthermore, with regard to the disease activity scores (ESR and DAS), swollen joints, patient global assessments and HAQ, the patients treated with sulfasalazine had 65% to 82% better responses than those treated with NSAIDs136(B). Despite a discontinuation rate of 15%, the use of diclofenac for active RA treatment produced significant responses at 12 weeks according to the ACR20 criteria, patient global assessments, VAS for pain, functional HAQ scores and joint swelling. CRP and ESR outcomes did not show significant benefits137(A). RA patients (duration of more than three months) who used different doses of celecoxib (100 mg, 200 mg or 400 mg) or a dose of naproxen (500 mg twice daily) showed functional (HAQ) and quality of life (SF-36) improvements at 12 weeks according to the ACR20 and also the number of involved joints, VAS for pain, HAQ and PGA, with no differences in response between these medications. However, naproxen produced adverse gastrointestinal events in a number of patients138,139(A). Patients with RA for at least six months who used 200 mg of celecoxib or 75 mg of diclofenac twice daily for 24 weeks were found to have reduced edema, joint stiffness and PGA score indices with no differences between the treatments. However, adverse gastrointestinal events were significantly more frequent in patients treated with diclofenac140(A). There are indications that the combination of NSAIDs and DMARDs is a favorable prognostic factor for RA remission141(B). The chosen NSAID should be personalized, as there is no known superiority of any drug in this class. Greater control, replacement, suspension, shorter usage time and lower dose should be considered if there are any medical conditions that might be aggravated by NSAIDs such as previous NSAID hypersensitivity, hypertension, heart failure, renal failure, gastrointestinal disease, arterial failure, liver disease or clotting disorders48(B). For patients with a history of gastrointestinal disease, the selective cyclooxygenase 2 (COXIB) inhibitors present a lower risk than other NSAIDs49(B). For those with a higher risk of cardiovascular disease, anti-inflammatory drugs should generally be used with caution13(A).

Recommendation The use of NSAIDs alone as an early treatment in patients with active RA produces a worse clinical response in the first 24 months than combined treatment with DMARDs and also suffers from a high rate of treatment discontinuation due to

inefficacy. The rate of adverse gastrointestinal events associated with treatment discontinuation, the short treatment response evaluation time, as well as the worse radiological clinical prognosis means that RA treatment with NSAIDs alone is not recommended. Apparently, the use of NSAIDs in combination with DMARDs during early-stage disease is a favorable prognostic factor for RA remission.

5. Should methotrexate be the first treatment option? MTX is an immunomodulatory agent that acts by inhibiting the synthesis of DNA, RNA, thymidylate and proteins. In RA, the anti-inflammatory effects of MTX appear to be at least partly related to the modulation of adenosine metabolism and to possible effects on tumor necrosis factor (TNF) activity. The immunosuppressive and toxic effects of MTX are due to the inhibition of dihydrofolate reductase, an enzyme involved in folic acid metabolism that prevents the reduction of dihydrofolate to active tetrahydrofolate. The time to maximum concentration is 1–5 hours orally (OR) and 30–60 minutes intramuscularly (IM) or subcutaneously (SC). After administration, 40% - 90% is eliminated renally in an unaltered form68(D). MTX is currently considered the standard drug for RA treatment69(D). Its abilities to reduce the signs and symptoms of RA activity and improve patient functionality have been demonstrated15(A). Additionally, MTX reduces the progression of radiographic lesions. An initial dose of 10–15 mg/week MTX, administered orally or parenterally (IM or SC), is recommended. If disease improvement or control is not observed in response to the initial dose, the dose should be gradually increased every 2–4 weeks to a final dose of 20–30 mg/week, preferably within the first 12 weeks. Parenteral presentation may be indicated in patients with gastrointestinal intolerances or inadequate responses to the oral form70(D). The adverse events most frequently reported in response to MTX are anemia, neutropenia, nausea and vomiting, mucositis, and elevated liver enzyme levels. Less frequent manifestations include interstitial pneumonia. It is contraindicated in patients with renal failure, liver disease, alcoholism, bone marrow suppression and in women of childbearing potential who are not using contraception. Pregnancy and breastfeeding are formally contraindicated in MTX-treated patients. MTX should be used with caution in patients with mild lung disease and avoided in patients with moderate or severe pulmonary disorders70(D). It has been suggested that MTX administration should be combined with folic acid at doses of 5–10 mg/week, given 24–48 hours after MTX, to minimize adverse events70(D).

Recommendation The efficacy of MTX for the treatment of active and early RA is well established. MTX is currently considered the standard drug for RA treatment. Its abilities to reduce the signs and symptoms of RA activity and improve patient functionality have been demonstrated. MTX also reduces the progression of radiographic lesions.


6. Are other DMARDs such as leflunomide, sulfasalazine and gold sodium equivalent to MTX in terms of safety and efficacy for disease treatment? Leflunomide Leflunomide is an immunomodulatory agent that inhibits the enzyme dihydroorotate dehydrogenase, which is involved in pyrimidine synthesis, and thus presents with antiproliferative activity. It is absorbed via the gastrointestinal tract, and biotransformation most likely occurs in the liver and gastrointestinal wall, where leflunomide is mainly transformed into M1, the active metabolite responsible for all leflunomide-associated actions. The time to maximum concentration (peak) of M1 is 6-12 hours, and elimination is renal and intestinal71(D). Leflunomide improves disease activity and patient quality of life and reduces radiographic progression18(A) 53(B). Leflunomide is prescribed at a dose of 20 mg/day (OR)18(A) 53 (B) 71(D), although a dose of 20 mg on alternate days may be used. Adverse events in response to leflunomide include nausea, vomiting, abdominal pain and diarrhea, abnormal liver enzyme levels, rash and hypertension71(D). It is contraindicated in women of childbearing potential who are not using contraception, as well as in patients with renal and hepatic disease. Pregnancy and breastfeeding are formally contraindicated in leflunomide-treated patients, and its suspension is recommended for two years before a possible pregnancy. In cases of complications, especially in pregnancy, leflunomide can be eliminated by the administration of cholestyramine, given in 8-g doses three times daily for 11 days71(D). A comparison between MTX (25 mg/day) and leflunomide (20 mg/day) combined with prednisone, given for 24 weeks, showed no difference in clinical response in patients with RA for more than 2.4 years as measured by DAS-28142(B). In a systematic review of randomized controlled trials (RCTs) that studied the use of leflunomide in patients with active RA, it was concluded that there was no difference in clinical outcomes compared to MTX143(A) . In patients with active RA, the use of leflunomide (20 mg/ day) for four months showed no differences in clinical (ICR and VAS) or functional (HAQ) responses compared with MTX (15 mg/week) but showed better results according to MR imaging criteria144(A). However, this comparison was performed with submaximal doses of MTX. There was no difference between leflunomide (20 mg/day) and MTX (15 mg/week) with respect to clinical response (ICR) in RA patients after a 24-month treatment, but functional responses (HAQ) were higher in response to leflunomide145(A). In a 24-month RA treatment with leflunomide (20 mg/ day) or MTX (15 mg/week), the results were similar for the two forms of treatment with regard to ICR, joint swelling, overall evaluations and radiological responses146(A). The functional response (HAQ) was also similar for the two forms of treatment146(A). Leflunomide treatment (20 mg/day) in patients with active RA produced similar effects to MTX (15 mg/week) with regard to radiological disease progression147(B).

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The clinical (ICR) and radiological responses in patients with RA for more than 6 months were similar when the patients were treated for 52 weeks with leflunomide (20 mg/day) or MTX (7.5 mg/week)148(A). However, the functional results in some components of the HAQ and SF-36 were better in the leflunomide-treated patients149(A). Again, we must emphasize that the dose of methotrexate used in this study was lower than the doses typically used for RA treatment. Patients with active RA showed a greater tolerance to MTX treatment (15 mg/week) than to leflunomide treatment (20 mg/day), but the clinical and radiological efficacies over 12 months were similar150,151(A) 152(B).

Sulfasalazine Sulfasalazine belongs to the group of salicylates and sulfonamides. It is produced by intestinal bacteria from sulfapyridine and 5-aminosalicylic acid. Sulfapyridine has multiple immunomodulatory effects, including the inhibition of prostaglandin production, various neutrophilic and lymphocytic functions and chemotaxis. It also inhibits folate-dependent enzymes. The peak serum concentration of sulfasalazine is approximately 1.5–6 hours, and it has an elimination half-life of 5–10 hours. The drug is metabolized in the gastrointestinal tract (via the intestinal flora), and its excretion is renal (75%–91%)16(A). Sulfasalazine is considered to be more effective than a placebo with regard to disease activity reduction, pain control and global clinical assessments. Its clinical efficacy and interference with radiographic progression have been confirmed16(A). Sulfasalazine is usually prescribed at a dose of 1-3 g/day (OR)16,17(A). Side effects include gastrointestinal intolerance (anorexia, nausea, vomiting), rash, elevated liver enzyme levels, oral ulcers and myelosuppression (leukopenia with neutropenia). Hypersensitivity pneumonitis, neurological manifestations and changes in male fertility are rarely observed. Most effects are benign and reversible with drug withdrawal17(A). Salicylates or any components of the sulfasalazine formula are contraindicated in patients with known sulfonamide hypersensitivity and individuals with porphyria16,17(A). There was no difference in the clinical responses (DAS ≤ 2.4) of RA patients who received MTX monotherapy (15 mg/week) or sulfasalazine (40 mg/kg/day), although the combination of the two forms of treatment produced better outcomes at 18 months14(A). In patients with RA for less than 12 months, sulfasalazine treatment (2 g/day) produced similar results (DAS, EULAR and ACR) as MTX treatment (15 mg/week) over 52 weeks; however the combined therapies appeared to increase the treatment benefits, according to DAS measurements66(D).

Gold sodium Gold sodium, specifically in injectable forms (aurothioglucose and aurothiomalate), is able to reduce both the constitutional and articular symptoms and slow the radiographic evolution of RA22(A). It can be used alone or in combination with other agents23(A).

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The usual dose of gold sodium is 50 mg/week; the treatment is usually initiated at 25 mg/week, and it is possible to increase the application interval to biweekly and monthly doses after the symptoms are controlled. The cumulative dose should not exceed 3 g22,23(A). Its toxicity profile includes myelotoxicity (particularly thrombocytopenia), oral ulcers, skin reactions (exfoliative dermatitis), nephropathy (possibly including involving proteinuria) and interstitial lung disease22,23(A). Although it has been recommended in recent international reports66(D), gold sodium is currently used very rarely in Brazil due to its adverse effects and the difficulty of drug acquisition in this area. A comparison between MTX (15 mg/week) and gold sodium (50 mg/week) for the treatment of RA patients (duration > 4 months) demonstrated improved clinical outcomes (swelling and stiffness) in the first year for patients treated with gold sodium but similar outcomes in the third year of follow up. There was greater toxicity in the first and third year (increased risk of 38%; NNH: 3)98,153(A) and similar results with regard to radiological progression in one154(A) and three years22(A). Gold sodium (50 mg/week) has a similar treatment efficacy (clinical and functional) as MTX (20 mg/week) for RA patients but also has an increase in toxicity of 24% (NNH: 4 )154(A).

Recommendation Leflunomide, sulfasalazine and gold sodium appear to have similar efficacies to that of MTX for the treatment of active RA; however, there is a greater risk of intolerance and toxicity and discontinuation with these drugs relative to MTX.

7. Are antimalarial drugs effective in RA treatment? Antimalarials have been used in RA treatment for more than 50 years. These drugs are safe and effective, especially for early and mild forms of RA. The action mechanism is still unclear, although it appears to involve multiple factors, including anti-inflammatory activity (stabilization of lysosomal membranes, inhibition of lysosomal enzymes and chemotaxis and polymorphonuclear phagocytosis) and interference in prostaglandin production, among others19,20(A). The two available forms are chloroquine diphosphate and hydroxychloroquine sulfate; the latter is preferred due to its better safety profile, especially with regard to ophthalmologic factors. The maximum daily doses of chloroquine phosphate and hydroxychloroquine sulfate are 4 mg/kg/day and 6 mg/ kg/day orally, respectively, depending on the ideal weight of the patient. The onset of action is slow and requires three to four months to achieve peak efficiency in approximately 50% of patients. The side effects are diverse and include gastrointestinal intolerance (nausea, vomiting, abdominal pain), skin hyperpigmentation, headache, dizziness, myopathy and retinopathy. The latter is infrequent, but regular ophthalmologic monitoring is indicated (baseline and annually after five years, or annually from the outset in patients with risk factors such

as those with renal or hepatic impairment or maculopathy, those who are elderly or those with a cumulative dose greater than 1,000 g of hydroxychloroquine sulfate or 460 g of chloroquine diphosphate)72(D). Hydroxychloroquine was more effective than a placebo in reducing the analyzed clinical and laboratory parameters (ESR), although in isolation it did not alter radiographic progression19-21(A). Similar results were observed with chloroquine, which is less expensive. These drugs are contraindicated in patients with retinal and visual field abnormalities21(A)72(D). Although these drugs are traditionally used in Brazil, often in combination with other DMARDs, antimalarials are currently considered less potent drugs and should only be used in early cases of RA or undifferentiated arthritis with a low erosion potential. Several therapeutic regimen studies have included hydroxychloroquine; however, these studies did not permit a specific and individualized analysis of the effects of hydroxychloroquine in early-stage RA treatment. In RA patients who did not respond to NSAID use, hydroxychloroquine treatment (200-400 mg/day) for 12 weeks led to reduced swelling, stiffness and joint pain (20%, 23% and 26%, respectively) and increased clinical responses (ICR)(ACR20) of 20% (NNT: 5). There was no increase in adverse events155(A). Hydroxychloroquine treatment (7 mg/kg/day) in RA patients (disease duration less than 24 months) for 36 weeks reduced joint involvement and pain and improved functional responses20(A). A follow-up after 36 months showed better outcomes for these patients than for those who were treated later (after nine months)156(B). There were no differences in treatment responses and numbers of adverse events between three different doses of hydroxychloroquine (400 mg/day, 800 mg/day or 1.2 g/day) during a 24-week period in patients with early-stage RA157(B). Patients (more than six months of RA) who were previously treated with a combination of MTX (15 mg/week) and hydroxychloroquine (400 mg/day) for 24 weeks have benefited from a 12-week maintenance regimen of hydroxychloroquine158(B). In early-stage RA patients, hydroxychloroquine treatment (400 mg/day for 24 weeks) reduced joint involvement by 10% (NNT: 10) and pain by 19% (NNT: 5), while overall patient and physician evaluations improved by 16% (NNT: 6) and 12% (NNT: 8), respectively. There was an increase in adverse events in 13% of patients (NNT: 8)19(A). The combination of MTX (15 mg/week) and hydroxychloroquine (200 mg/day) for six months for the treatment of early-stage RA patients increased clinical responses and reduced pain and joint impairment when compared with hydroxychloroquine treatment alone159(B). The addition of hydroxychloroquine (400 mg/day) to the treatment regimens of patients with partial responses to gold sodium (six months) added no benefits with respect to pain and joint involvement160(B).

Recommendation The treatment of early-stage RA with hydroxychloroquine at doses of 200–400 mg/day provides benefits related to pain, joint involvement and clinical responses, although the evi-


dence for these benefits is weak, whether due to improper measures used to demonstrate the benefits, the reduced size of the benefits or weak supporting evidence. Although these drugs are traditionally used in Brazil, often in combination with other DMARDs, antimalarials are currently considered less potent drugs and should be used in early cases of RA or undifferentiated arthritis with low erosion potential.

Biologic DMARDs One of the most important advances in RA therapy has been the development of biologic DMARDs. While these medications effectively control RA, studies are needed to determine their long-term safety. The following biologic DMARDs are approved by the National Agency for Sanitary Surveillance (Agência Nacional de Vigilância Sanitária (ANVISA)) for use in Brazil: • TNF blockers: adalimumab, certolizumab, etanercept, infliximab and golimumab; • B lymphocyte depletion: rituximab; • Costimulatory blocker: abatacept; • Interleukin-6 (IL-6) receptor blocker: tocilizumab. These drugs are indicated for patients with persistent disease activity despite treatment with at least two synthetic DMARD regimens (at least one in combination with DMARDs). Biologic agents must be combined with a DMARD, preferably MTX. However, one biologic DMARD may be prescribed earlier in the course of RA treatment, especially in cases of disease with signs of poor prognosis (a high number of involved joints, radiographic erosions in early-stage disease, high rheumatoid factor and/or anti-CCP levels); this exception is described below. Social, educational and demographic characteristics of different macro-regions of Brazil, including difficulties in the administration of SC medications for certain patients and their families, as well as the absence of infusion centers for the administration of IV medications in certain places, may determine the choice of biologic DMARDs. Public or private drug dispensing and infusion centers should inform patients and families about the appropriate conditions for each medication or send them directly to the infusion sites to avoid losses in treatment efficacy. It is recommended that these drugs be used as indicated and monitored by a rheumatologist78(D). Biologic DMARDs should not be combined due to the potential risk of serious infection.

8. Is the introduction of biologic therapy with anti-TNF drugs such as adalimumab, certolizumab, etanercept, infliximab and golimumab effective and safe for RA patients? Currently, the most commonly used biologic DMARDs are TNF blockers. TNF is a potent inflammatory cytokine that is expressed in large amounts in the serum and synovial fluid of RA patients. TNF promotes the release of other cytokines, particularly IL-1, IL-6 and IL-8, and stimulates protease pro-

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duction. TNF inhibition has been shown to be an effective and rapid method of controlling disease activity79(D). In terms of effectiveness, no evidence suggests the superiority of any of the 5 anti-TNF agents approved in Brazil for RA treatment55,56 (B). Anti-TNFs should be used in combination with MTX or other DMARDs because the combined use of these drugs is safe and effective and provides rapid control of disease activity, compared to anti-TNF monotherapy. In patients who have contraindications to the use of synthetic DMARDs, anti-TNF may eventually be prescribed as a monotherapy77(D) 26-31,43,44(A) 45,57,58(B).

Adalimumab Adalimumab is a human monoclonal anti-TNF antibody prescribed for SC use at a biweekly dose of 40 mg28,33-37,45(A). A 52-week follow-up of RA patients who were treated with MTX and adalimumab (40 mg or 20 mg biweekly) showed increased clinical responses (ACR50) of 32% (NNT: 3) and 28.2% (NNT: 4), respectively, with combination therapy compared to MTX monotherapy. There was also a reduction in radiographic progression and functional improvement (HAQ) with the combination therapy, with no increase in adverse events161(A) 162(B). Treatment of RA patients with a combination of biweekly 40 mg adalimumab and MTX (20 mg weekly) increased clinical responses (ACR50) by 21% (NNT: 5) and 16% (NNT: 6) compared to adalimumab and MTX monotherapies, respectively. There was also a reduction in radiographic progression, as well as an increase in clinical remission (DAS-28 ≤ 2.6) of 20% (NNT: 5) and of 22% (NNT: 5) compared to adalimumab and MTX monotherapy, respectively57(B). The clinical response (ACR50) obtained with biweekly 40 mg adalimumab for 24 weeks in RA treatment concomitantly with the use of synthetic DMARDs increased clinical responses (ACR50) by 17.6% (NNT: 6) and did not increase the risk of adverse events or serious adverse events34(A). The combination of adalimumab in doses of 20 mg, 40 mg or 80 mg and MTX (15 mg/week) for 24 weeks produced increases in clinical response (ACR50) of 23.8% (NNT: 4), 47.1% (NNT: 2) and 30.4% (NNT: 3), respectively, compared to MTX monotherapy, with no difference in adverse events163(A).

Certolizumab Certolizumab pegol is a Fab fragment of a humanized, highaffinity anti-TNF antibody linked to two polyethylene glycol molecules. It is prescribed for SC use at a biweekly dose of 400 mg during weeks 0, 2 and 4 and at a dose of 200 mg every two weeks or 400 mg every four weeks thereafter30,31,37(A). Certolizumab treatment at 200 mg or 400 mg biweekly for 52 weeks, combined with MTX (15 mg/week), increased clinical responses (ACR50) by 29.5% (NNT: 3), reduced the progression of radiological lesions and increased functional responses (HAQ) when compared to MTX monotherapy. There was a 35% increase in serious adverse events (NNH: 3) with both certolizumab regimens. There were no differences in response or adverse events between the certolizumab doses164(A). There was also evidence of a positive impact on patient quality of life 30(A). According to RAPID3 criteria, there was an increase in remission of 32% (NNT: 3) in patients treated with

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certolizumab165(B), and clinical responses were also higher than the hybrid ICR score166(B).

Etanercept Etanercept is a fusion protein composed of the TNF soluble receptor that binds more strongly to the Fc region than to the IgG. This therapy is prescribed at a weekly dose of 50 mg SC36(A) 43,45,59 (B). At a 52-week follow-up of RA patients, it was concluded that a combined treatment of etanercept (50 mg/week) and MTX (15 mg/week) increased remission by 22.5% (NNT: 5) and reduced radiographic lesion progression when compared to MTX monotherapy105(A). This effect was maintained after 24 months of follow-up45(B). The use of etanercept (50 mg/week) for 24 weeks in patients with active RA, with or without sulfasalazine (2–3 g/day), demonstrated superior clinical responses (ACR50) of 32% to 38% (NNT: 3); however there was a 19.6% increase in the number of infections (NNH: 5), as well as infusion reactions167(A). At a 24-month follow-up, there was less treatment discontinuation due to lack of efficacy in patients undergoing etanercept treatment (NNT: 2), and the benefits were permanently sustained. There was, however, an increase in infectious adverse events and adverse events from local application168(B). An ACR-N analysis of the clinical responses of RA patients after 24 weeks of treatment with etanercept (50 mg/week) combined with MTX (15 mg/week) showed a 6.1% increase (NNT: 17)169(A). After 52 weeks, remission remained evident in 18.2% (NNT: 6) and 12.4% (NNT: 8) of patients who received etanercept alone or combined with MTX, respectively170(B). Additionally, after 52 weeks, there was a reduction in radiological lesion progression in these patients171(B). Of the RA patients who were treated with etanercept (50 mg/week), 51% showed a clinical response (ACR50) after three years, and this response was maintained after five years. There was a reduction in disease activity (DAS < 2.4) in 44% of the patients. However, 44% of the patients experienced episodes of infection, which can induce cancer and treatment-related death172,173(C). After a 12-month treatment, the use of 50 mg etanercept per week conferred greater benefits to RA patients than a dose of 20 mg/week. When compared with MTX (15 mg/week), the clinical responses (ACR50) was similar, although there were greater radiological lesion progression and more adverse events in MTX-treated patients174(A). These results were maintained at a 24-month follow-up, and the functional responses (HAQ) were better in 18% (NNT: 6) of the etanercept-treated patients59(B). In patients with inadequate responses to a combination of MTX (15 mg/week) and etanercept (50 mg/week), an increased dose of etanercept (100 mg/week) did not improve the patient clinical responses175(A).

Infliximab Infliximab is a monoclonal mouse-human chimeric anti-TNF antibody that is prescribed at an initial dose of 3 mg/kg, given IV, followed by the same dose (3 mg/kg) in the second and sixth weeks and every eight weeks thereafter76(D). In patients with insufficient responses, the dose can be increased to 5

mg/kg by infusion, or the dose interval can be reduced. Larger doses add little therapeutic benefit and increase the risk of infectious complications; thus, this approach should be avoided in RA treatment27,58(B) 36,38,44(A). In RA patients who are nonresponsive to MTX (15 mg/week), when combined with infliximab (3 mg/kg initially at weeks 0, 2 and 6 and every 8 weeks thereafter), there were increases in clinical response according to the EULAR and ACR50 criteria of 14% (NNT: 7) and 10% (NNT: 10), respectively, compared to a combination of sulfasalazine and hydroxychloroquine58(B). Treatment of RA patients with a combination of infliximab (3 mg/kg or 10 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter) and MTX (15 mg/week) for 22 weeks increased clinical responses by 22.4% (NNT: 5) and 25.7% (NNT: 4) and remission (DAS-28 < 2.6) by 17.0% (NNT: 6) and 18.0 % (NNT: 6), respectively. There was no difference in response between the two infliximab dose regimens. There was no difference in adverse events related to infliximab treatment, regardless of the dose176(A). Treatment of RA patients with a combination of 3 mg/kg or 6 mg/kg infliximab (initially at weeks 0, 2 and 6, and every 8 weeks thereafter) and MTX (15 mg/week) for 54 weeks increased ACR-N clinical responses by 12.5% (NNT: 8) and 20.3% (NNT: 5), respectively, ACR50 clinical responses by 13.5% (NNT: 7) and 18.3% (NNT: 6), reduced the progression of radiological damage (Sharp score) and increased functional responses by 6.2% (NNT: 16) and 16.0% (NNT: 6), respectively. No difference in efficacy was observed between the two treatment regimens. There were increases in the rates of serious adverse events of 3.5% (NNH: 30) and 2.9% (NNH: 33) with the doses of 3 mg/kg and 6 mg/kg, respectively177(A).

Golimumab Golimumab is a human monoclonal anti-TNF antibody that is administered at a dose of 50 mg/month SC44,60(B). Treatment of RA patients with a combination of MTX (15 mg/week) and golimumab (50 mg every 4 weeks) for 24 weeks increased remission rates (ACR50) by 10.9% (NNT: 10) and 13.9% (NNT: 7) (DAS-28 ≤ 2.6) compared to MTX monotherapy. There were no increases in adverse events for this combination over monotherapy44(B). The radiological response (Sharp score) was also higher in response to golimumab (50 mg) plus MTX178(B). In RA patients, a 14-week treatment with a combination of MTX (15 mg/week) and golimumab (50 mg or 100 mg every four weeks) yielded increases of 25.0% (NNT: 4) and 19.4% (NNT: 5), respectively, in clinical responses and of 14.2% (NNT: 7) and 16.5% (NNT: 6), respectively, in remission (DAS-28). However, there was an increase in adverse events and serious adverse events with the 100 mg dose of golimumab compared to the 50 mg dose179(A). After a 52-week follow-up, there were no differences with respect to monotherapy, although the clinical response and remission rates were maintained43(B). After a 24-week treatment with a combination of golimumab (2 mg/kg or 4 mg/kg) and MTX, the proportion of patients who achieved clinical responses (ACR50) increased by 9.3% (NNT: 10) and 17.7% (NNT: 6), respectively, compared to MTX monotherapy. Remission (DAS-29 ≤ 2.6) over the same period was greater only with a golimumab dose of 4 mg/kg. There were no differences in adverse events and serious ad-


verse events between the combination of MTX and golimumab and MTX monotherapy180(A). RA treatment with a combination of MTX and golimumab (50 mg or 100 mg every two or four weeks for 16 weeks) resulted in similarly increased clinical response rates (ACR50) and remission rates (DAS-28 ≤ 2.6) with all regimens; the only treatment regimen that showed no benefit compared to MTX monotherapy was a 50-mg dose every four weeks. There were no differences in adverse events between the various forms of treatment181(A).

Adverse events and contraindications of TNF blockers Adverse events include infusion reactions to IV drugs (fever, chills, chest pain, blood pressure fluctuation, dyspnea, rash and/or hives) and manifestations at SC drug injection sites (erythema, itching, local pain and/or hives). These drugs increase the risk of infections, especially in the first year of use (including serious infections and those caused by intracellular pathogens such as tuberculosis bacillus, listeria, histoplasma, atypical mycobacteria, legionella) cardiac dysfunction, demyelinating diseases, autoimmune phenomena (autoantibody production), cutaneous vasculitis, interstitial lung disease and a possible increased risk of lymphoma37,39(A) 61,62(B). Human anti-chimeric antibodies (HACA) can occur in response to all drugs in this class, but their effects on treatment efficacy are uncertain63,64(B). Anti-TNF drugs are contraindicated in women who are pregnant or breastfeeding; in patients with class III and IV congestive heart failure, according to the New York Heart Association classification; in patients with infection; or in those who have a high risk of infection development (chronic ulcers of the lower limbs, septic arthritis in the past 12 months), recurrent pulmonary infections, multiple sclerosis, or current or previous cancer diagnoses (less than five years). Patients should be carefully monitored for the possible emergence of signs of infection, which should be treated promptly and immediately39(A) 61,62(B).

Recommendation RA patients can be treated with anti-TNF biologic DMARDs, including adalimumab (40 mg SC every two weeks), certolizumab (400 mg SC every two weeks at weeks 0, 2 and 4 and 200 mg every two weeks thereafter or 400 mg every four weeks, or monthly), etarnecept (50 mg SC every two weeks), golimumab (50 SC every four weeks or monthly), or infliximab (3 mg/kg IV at weeks 0, 2 and 6 and every 8 weeks thereafter). All anti-TNF biologic DMARDs should be preferentially prescribed in combination with MTX (15 mg weekly) or another synthetic DMARD to achieve clinical, radiological and functional benefits and remission. There may be an increased risk of serious adverse events and local reactions to treatment administration.

9. Is rituximab a safe and effective alternative treatment for RA patients? Rituximab is a chimeric monoclonal antibody directed against CD20+ lymphocytes. It is indicated for patients with moderate

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to severe active RA who failed to respond to anti-TNF agents. Rituximab is administered at a dose of 1,000 mg in two IV infusions at 14-day intervals. Each infusion is preceded by a dose of 100 mg of IV methylprednisolone 60 minutes before the rituximab, as well as 1 g of paracetamol and antihistamine to decrease the severity and frequency of infusion reactions81-83(A) 86(C). Given the severity of the condition, it should be noted that reports have linked the occurrence of progressive multifocal leukoencephalopathy to rituximab use182(C). Rituximab is preferentially used in combination with MTX and can be prescribed in combination with other DMARDs. It is important to stress that there might be a delay of 3–4 months before the onset of symptomatic improvement81-83(A). Rituximab induces better therapeutic responses in individuals who are seropositive for RF and/or anti-CCP84(B). Should the disease reactivate, individuals with good treatment responses can be subjected to new courses of rituximab at intervals of no less than six months81-83(A) 86(C). The most frequent adverse events are infusion reactions, which occur in 35% of patients during the first infusion and approximately 10% during the second infusion. Infectious complications may occur, as well as interstitial pneumonia, neutropenia and thrombocytopenia81-83(A) 86(C). In RA patients, treatment with rituximab (two IV 500 g doses at 15 day intervals) combined with MTX (10–25 mg/week) and etanercept (50 mg/week) or adalimumab (40 mg every 15 days) for 24 weeks did not cause an increase in adverse events, including serious adverse events, relative to the placebo combined with MTX. There were increased risks of 22% (NNH: 5) for infusion reactions and of 15% (NNH: 7) for grade three infections. There were no differences in the clinical response (ACR50) or remission rates (DAS-28 < 2.6)183(A). Treatment of RA patients (disease duration of 8 weeks to 4 years) over 52 weeks with 1 g or 2 g of rituximab combined with MTX increased clinical responses (ACR50) by 17% and 23%, respectively, and remission rates (DAS-28 ≤ 2.6) by 20% and 23%, respectively. There were also increases in functional response (HAQ), and there were no increases in adverse events184(A). Treatment of RA patients whose conditions were nonresponsive to MTX treatment with 1 g or 2 g rituximab increased the clinical response rate (ACR50) by 17% (NNT: 6) after 24 weeks. There was no increase in adverse events82(A). A comparison of 1-g, 1-g escalated to 2-g after 24 weeks and 2-g rituximab doses for the treatment of RA patients (with inadequate responses to MTX) after 48 weeks demonstrated similar clinical responses between the treatments (ACR50), a higher EULAR clinical response to the 2-g dose, compared to the 1-g dose and a higher remission rate (DAS-28 < 2.6) with the 1-g dose, compared to the escalated dose. There were no differences in adverse events185(A). The treatment of anti-TNF-α and MTX-nonresponsive RA patients with 1 g rituximab led to reduced radiological disease progression, decreased pain (FACIT-F) and improved functional responses (HAQ) and quality of life (SF-36) after 24 weeks83,186(A). The clinical responses (ACR50 and EULAR) increased by 22% (NNT: 5) and 43% (NNT: 2), respectively81(A). Treatment of RF-positive RA patients with a combination of rituximab and MTX for 24 weeks resulted in increased clin-

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ical response rates that (ACR50) ranged from 10%–20%, compared to monotherapy. A greater number of patients did not require additional treatment for 48 months, due to the positive effects on functional capacity (NNT: 4)187(A). In patients who were nonresponsive to synthetic DMARD treatment, the use of 1 g or 2 g rituximab for 24 weeks increased the proportion of patients with clinical responses (ACR50 or EULAR) by 20% and reduced disease activity (DAS28)188(A). The combination of rituximab (1 g) and MTX (10 mg/week) for the treatment of RA patients produced better results after 24 weeks than monotherapy with either of these drugs, increased the clinical response rates (ACR50) by 10%–30%, and increased clinical responses (EULAR) and rates of disease remission (DAS-28). There were no differences in the numbers of adverse events189(A).

Recommendation In RA patients with inadequate responses to MTX or other synthetic DMARDs and anti-TNF, the use of rituximab (1-g and 2-g doses), primarily in combination with MTX, improved clinical, radiological and functional progress while increasing the risk of adverse events.

10. Is tocilizumab proven for use in RA treatment? Tocilizumab is a humanized monoclonal antibody that binds to the IL-6 receptor, thus inhibiting the biological effects of IL6. It can be used alone or in combination with MTX or other DMARDs. The incidence of infections and serious infections with tocilizumab is equivalent to that of other biologic agents. It is prescribed at a dose of 8 mg/kg IV every four weeks87,88(A) 96(B). Tocilizumab can cause dose-dependent adverse events such as neutropenia, thrombocytopenia and elevated transaminase levels. There may even be elevated levels of total and low-density lipoprotein (LDL) cholesterol, as well as an increased risk of infections87,88(A) 96(B). Tocilizumab should be avoided in patients who have a greater risk of bowel perforation and those with diverticular disease of the colon89(A). RA patients with inadequate responses to MTX have shown positive results in response to tocilizumab (4 mg/kg or 8 mg/kg every four weeks for 52 weeks) with respect to clinical response (ACR70), remission (DAS < 2.6), and functional (HAQ) and radiological (Sharp score) responses. Radiological disease progression was reduced by 74% and 70%, respectively, compared to MTX monotherapy. There were significant functional improvements of 15.4% (NNT: 6) and 9.9% (NNT: 10), respectively, and a functional response of > 0.3 units was maintained. The clinical response rates were 6.0% (NNT: 16) and 3.5% (NNT: 30), respectively. Disease remission rates were 39.3% (NNT: 2) and 22.3% (NNT: 5), respectively. There was a 2% incidence of neoplasias in patients who received tocilizumab, a 2.5% incidence of severe anaphylactic reactions (4 mg/kg), and a 5% increase in the risk of severe adverse events (NNH: 20)190(A). In RA patients between six months and five years, the administration of 8 mg/kg tocilizumab every four weeks for 52 weeks led to a reduction in radiographic disease progression

of 15% (NNT: 7) compared to synthetic DMARDs, and this effect was greater in patients at a high risk for progression191(A). The clinical efficacy (ACR50) was 51% (NNT: 2). The remission rate was 56% higher (NNT: 2), and the functional response rate improved by 28% (NNT: 4). There was an increase of 5% in the occurrence of serious adverse events in response to tocilizumab (NNH: 20) and 2% and 7% increases in cancer incidence and infusion reaction rates, respectively. There were no differences in mild to moderate adverse events between the two forms of treatment191(A). A comparison between 8 mg/kg tocilizumab, given every four weeks, and 15 mg/week MTX for a 24-week treatment of RA patients provided results in favor of tocilizumab. Tocilizumab was found to increase the clinical response rate (ACR50) by 10.6% (NNT: 9) and the remission rate (DAS-28 < 2.6) by 21.5% (NNT: 5). The most common adverse reactions were infections, although no difference was observed between the two forms of treatment. There was an increase of 3.8% in the infusion reaction rate with tocilizumab (NNH: 30)96(A). In RA patients (more than six months), treatment with 8 mg/kg tocilizumab every four weeks in combination with DMARDs (MTX, chloroquine, gold sodium, sulfasalazine, azathioprine or leflunomide) produced an increased clinical response rate (ACR50) of 29% (NNT: 3), an increase in remission (DAS-28 < 2.6) and a functional response rate of (HAQ) of 26% after 24 weeks (NNT: 4) compared to monotherapy with these drugs. There was an increase of 11.7% in the risk of adverse events (NNH: 9)192(A). RA patients with inadequate responses to MTX showed positive results after treatment with tocilizumab (4 mg/kg or 8 mg/kg every four weeks for 24 weeks) with respect to clinical response (ACR50), remission (DAS < 2.6), and functional (HAQ) response. There were significant functional improvements with both doses. The clinical response rates were 20.0% (NNT: 5) and 33% (NNT: 3), respectively. Disease remission rates were 12.2% (NNT: 8) and 26.2% (NNT: 4), respectively. There were no differences in the various adverse events, of which infection was the most frequent193(A).

Recommendation Tocilizumab treatment of RA patients, especially those with inadequate responses to MTX, when combined with MTX or synthetic DMARDs or as a monotherapy, produces effective clinical, functional, radiological and remission responses. Tocilizumab is also effective in patients who are nonresponsive to anti-TNFs. There may be an increased risk of adverse events.

11. Is abatacept a treatment option for patients with RA, considering its safety and efficacy profile? Abatacept is a CTLA-4-IgG fusion protein that acts as an inhibitor of T lymphocyte costimulation. It is indicated for patients with active RA who have experienced DMARD or anti-TNF agent treatment failure. Abatacept can be used in combination with DMARDs or as a monotherapy. Abatacept should be administered as an IV infusion over a 30-minute period and


should be administered at a dose of 500 mg to patients with a body weight less than 60 kg, 750 mg to patients between 60–100 kg and 1,000 mg to patients greater than 100 kg. The next dose should be administered 2 to 4 weeks after the initial dose and every four weeks thereafter40-42(A). Abatacept is associated with a greater risk of infectious complications than a placebo, similarly to other biologic DMARDs. Infusion reactions to abatacept are uncommon and are mainly hypersensitivity reactions that manifest as a rash or bronchospasms. Abatacept is contraindicated in patients with symptoms of chronic obstructive pulmonary disease (COPD) due to its exacerbation of dyspnea and the increased risk of infections40(A) 85(C). Abatacept treatment (10 mg/kg every four weeks) produces benefits (ACR50) in 30% of patients with RA of an average 8.5-year duration. According to ACR50, for every three patients treated, one experiences no increase in adverse events194(A). RA patients (of at least a 12-month duration) who were nonresponsive to MTX yielded increases in clinical response rates of 12.1% (NNT: 9), 9.9% (NNT: 10) and 9.1% (NNT: 11) according to the EULAR, DAS-28 and ACR50 criteria, respectively, after treatment with 500–1000 mg abatacept every 30 days for 12 months. The functional improvement rate (HAQ) was 20.6% (NNT: 5). There was no increase in adverse events195(A). In RA patients who were nonresponsive to anti-TNF-α, treatment with 500-1000 mg abatacept for six months led to a clinical response rate of 16.5% (NNT: 6; ACR50 criteria) and a functional response rate of 24.0% (NNT: 4). There was no increase in adverse events196(A). At 24 months, there were improvements of 32.3% and 20.3% in the clinical response (ACR50) and remission rates (DAS-28), respectively. The functional response rate was 47.9% 197(B). After a year of treatment with 500–1,000 mg abatacept, RA patients who were nonresponsive to MTX had a clinical improvement rate (ACR50) of 30.1% (NNT: 3). Physical function improved by 24.7% (NNT: 4), with no difference in the rate of adverse events198(A). After 24 months of treatment, the patients had a clinical improvement rate (ACR50) of 55.6% and a remission rate (DAS-28) of 30.9%199(B).

Recommendation In RA patients who are nonresponsive to MTX or anti-TNF therapy, the use of abatacept at doses between 500–1,000 mg led to increased clinical responses (ACR50), remission (DAS28) and functional responses (HAQ) over 6–12 months, and these rates were maintained over a 24-month period. However, there may be an increased risk of adverse events.

12. Are there indications that some biologic treatment regimens are superior to others in the treatment of RA patients? Treatment of RA patients with a combination of MTX (15 mg/ week) and golimumab (50 mg every four weeks) for 24 weeks yielded increases (ACR50) of 10.9% (NNT: 10) and 13.9% (NNT: 7) in the remission rate (DAS-28 ≤ 2.6) compared to MTX monotherapy44(A).

171

A 52-week follow-up of RA patients who were treated with MTX and adalimumab (40 mg every other week) showed an increase (ACR50) of 32% (NNT: 3) in the clinical response rate compared with MTX monotherapy162(A). A decrease in radiographic progression and an increase in clinical remission (DAS-28 ≤ 2.6) of 23% (NNT: 5) were observed in comparison to MTX monotherapy74(D). At a 52-week follow-up of RA patients, it was concluded that treatment with etanercept (50 mg/week) in combination with MTX (15 mg/week) increased the remission rate (DAS-28) by 22.5% (NNT: 5) compared to MTX monotherapy. Additionally, the clinical response rate (ACR50) was 22% higher (NNT: 5)105(A). Treatment of RA patients with 3 mg/kg infliximab (initially at weeks 0, 2 and 6 and every eight weeks thereafter) in combination with MTX (15 mg/week) for 22 weeks increased the clinical response rate (ACR50) by 22.4% (NNT: 5) and the disease remission rate (DAS-28 < 2.6) by 17.0% (NNT: 6)176(A). Treatment with 200 mg or 400 mg of certolizumab (every two weeks for 52 weeks) in combination with MTX (15 mg/ week) increased the clinical response rate (ACR50) by 29.5% (NNT: 3), compared to MTX monotherapy. The remission rate (DAS-28) was 16% (NNT: 6). There was an increase of 35% in the rate of serious adverse events (NNH: 3)164(A) 165(B). Treatment of RA patients (disease duration between eight weeks and four years) for 52 weeks with rituximab (1.0 g IV infusion at intervals of 15 days) in combination with MTX increased the clinical response rate (ACR50) by 17% (NNT: 6) and the remission rate (DAS-28 ≤ 2.6) by 20% (NNT: 5)184(A). RA patients with inadequate responses to MTX who were treated with tocilizumab (8 mg/kg every four weeks for 24 weeks) in combination with MTX showed positive results with respect to clinical response (ACR50) and remission (DAS ≤ 2.6). There were significant functional improvements at both doses. The clinical response rate was 33% (NNT: 3). The remission rate was 26.2% (NNT: 4). There were no differences in the various adverse events, of which infection was the most frequent193(A). Patients with RA (duration of at least 12 months) who were nonresponsive to MTX had 9.9% (DAS-28; NNT: 10) and 9.1% (ACR50; NNT: 11) increases in the clinical response rate after treatment with 500-1000 mg of abatacept every 30 days for 12 months195(A). Table 5 summarizes the ACR50 and DAS-28 measures, which are expressed as the estimated benefits with the NNT.

Recommendation The various treatment regimens that use biologic DMARDs in combination with MTX in RA patients present similar results compared to MTX monotherapy, using ACR50 and DAS-28 as parameters with minor variations in the NNT (3–11 for ACR50 and 4–10 for DAS-28). There are no direct comparisons that enable an accurate estimate of the differences in benefits between the various biologics.

Strategies for RA treatment in Brazil DMARD treatment should be initiated immediately after diagnosis. The treatment should be adjusted as needed after frequent clinical evaluations within a period of 30–90 days.

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Treatment strategies based on specific goals produce better clinical outcomes and functional capacities as well as lower structural radiographic damage, compared to conventional treatments94(A). The goal is remission or at least low disease activity; this outcome can be evaluated by composite indices of disease activity (CIDAs) while taking into consideration the role of treatment responses in reducing CIDA values, as established in the 2011 Consensus of the SBR for the Diagnosis and Initial Assessment of Rheumatoid Arthritis5(D).

First line – synthetic drugs that alter the course of the disease MTX should be the first choice for DMARD treatment95(A) 66,200 (D). In cases with contraindications, sulfasalazine201(A) or leflunomide143(A) can be used as a first option202(B). Antimalarial drugs (chloroquine diphosphate and hydroxychloroquine)203(B) might be indicated only for patients with mild disease or undifferentiated arthritis with low erosion potential. In exceptional cases, such as patients with hypersensitivity to other DMARDs or those with viral hepatitis, gold sodium can be used. MTX should preferentially be prescribed as a monotherapy during early treatment128(A). In the absence of an objectified clinical response (remission or lower disease activity) to the maximum tolerated MTX dose or in the presence of adverse events, it is recommended that MTX be exchanged for another DMARD monotherapy or DMARD combinations. The most frequently used combinations are MTX with chloroquine, sulfasalazine, a combination of these three drugs15(A) and MTX combined with leflunomide204(A). Therapy progression should be rapid, with monthly patient evaluations during the first 6 months of treatment, and the doses and schedules should be adjusted as required. A maximum of six months should be allowed to define an absence of response to the first-line treatment66(D). Low doses of corticosteroids (up to 15 mg/day of prednisone or equivalent) and anti-inflammatories may be used at the beginning of the treatment regimen, although caution and usage for the shortest time possible are recommended to minimize the occurrence of adverse events66(D).

Second line – biologic disease-modifying drugs Immunobiological RA treatment is indicated for patients who persist with moderate to high disease activity (according to

Table 5 – ACR50 and DAS-28 measures expressed as the estimated benefit using Number Needed to Treat (NNT). Biologic

Golimumab Adalimumab Etanercept Infliximab Certolizumab Rituximab Tocilizumab Abatacept

Dose

50 mg 40 mg 50 mg 3 mg/kg 200 mg 1,000 mg 8 mg/kg 500–1,000 mg

Time

24 weeks 52 weeks 52 weeks 22 weeks 52 weeks 52 weeks 24 weeks 52 weeks

CIDAs) despite treatment with at least two of the regimens proposed for the first line of treatment. In Brazil, anti-TNF drugs are the first choice of biologic therapy after the failure of synthetic DMARD regimens. This approach is justified by the most comprehensive post-marketing experience, as well as the increased volume of safety information from clinical studies, registries and national205(B) and international66(D) recommendations. However, other drugs such as abatacept and tocilizumab may be prescribed at the discretion of the attending physician after a failure with synthetic DMARDs, given the publication of randomized controlled trials that support this indication40,88(A). Rituximab should be avoided as a first-line biologic66(D) except in specific cases (e.g., patients with contraindications to other biologics, preferably those who are positive for RF and/or anti-CCP or those who present with a diagnosis associated with lymphoma). In exceptional situations, biologic DMARDs may be indicated after a failure of the first regimen of synthetic DMARDs in patients with associated poor prognostic factors, including very high disease activity, a high number of painful/inflamed joints, high RF and/or anti-CCP levels and the early occurrence of radiographic erosions66(D). Poor prognosis factors are better detailed in the 2011 Consensus of the SBR Diagnosis and Initial Assessment of Rheumatoid Arthritis5(D). The use of biologic drugs as a first-line RA treatment is not indicated in Brazil because there is no evidence of costeffectiveness in this country.

Third line – failure or intolerance to modifying drugs in the course of biological disease In clinical scenarios where there is no response to the initial biologic treatment, a progression to loss of response, or major adverse events, one biologic agent may be exchanged for another. The biologics that have presented benefits in randomized clinical trials in patients for whom anti-TNF treatment failed are abatacept, rituximab and tocilizumab206(B). Patients for whom the first anti-TNF agent failed have also derived benefits from the use of a second drug from the same class, including adalimumab, certolizumab, etanercept, golimumab or infliximab, in prospective observational studies and randomized controlled double-blind trials (golimumab), but uncertainties persist about the magnitude of the therapeutic effects and the cost-effectiveness of this strategy207(B). The choice of the employed treatment sequence remains at the discretion of the physician, depending on the particularities of each case. A minimum of three months and a maximum of six months of clinical evaluation are recommended before proceeding to a change in regimen (switching between biologic DMARDs).

NNT ACR50

DAS-28

10 3 5 5 3 6 3 11

7 5 5 6 6 5 4 10

Withdrawal of medications and eventual suspension of therapy There are no data that allow us to define the RA treatment duration, and currently the medication to which the patient has an adequate response should be maintained for an indefinite period at the physician’s discretion. In cases of complete (remission) and sustained (more than 6–12 months) responses, a gradual and careful withdrawal can be attempted according to the following sequence: first NSAIDs, then corticosteroids

173


and biologic DMARDs, while maintaining the use of synthetic DMARDs208(B). In exceptional situations, if remission is maintained, the physician may very cautiously attempt to withdraw synthetic DMARDs66(D). Sustained drug-free remission is uncommon, especially in patients with biomarkers such as anti-CCP and/or RF. Fig. 1 summarizes RA drug treatment in Brazil as a flowchart, as proposed by the RA SBR Commission.

Treatment monitoring In patients with active early-stage disease and symptoms of a 12-month duration or less, intensive monitoring with monthly visits is recommended with rapid medication progression when necessary209(B) 210(D). The treatment regimens and their possible adverse events have been discussed in previous sections. At each visit, physicians should evaluate the efficacy and safety of the therapeutic interventions while considering patient comorbidities and preferentially targeting remission or the lowest disease activity possible, as well as an improved functional status and quality of life. In patients with established disease, especially in those with controlled disease, visits can occur every three months108,109,209(B) 210(D).

Table 6 summarizes in schematic form the monitoring frequencies for the main parameters considered appropriate for evaluations of a patient undergoing RA treatment.

Conflicts of interest Mota LMH participated in clinical and/or experimental studies sponsored by the companies Roche and Mantecorp; received personal or institutional assistance from the companies Abbott, AstraZeneca, Merck, Pfizer and Roche; and was a speaker at events or activities sponsored by the companies Abbott, MSD, Novartis, Roche and Wyeth. Cruz BA participated in clinical and/or experimental studies sponsored by Roche; received personal or institutional assistance from the companies Abbott, Bristol-Myers Squibb, Mantecorp, MSD, Novartis, Roche, Wyeth and Pfizer; and was a speaker at events or activities sponsored by the companies Abbott, MSD, Mantecorp, Novartis, Roche and Wyeth. Brenol CV participated in clinical and/or experimental studies sponsored by the companies Bristol-Myers Squibb, Pfizer, Roche and Wyeth; received personal or institutional assistance from the companies Abbott, Bristol-Myers Squibb, Mantecorp,

At all phases:

Monotherapy (preferably MTX) Q

Failure ĂŌĞƌ 3 months

Prednisone up to 15 mg/day or equivalent (for the ƐŚŽƌƚĞƐƚƟŵĞ possible) ŝŶƚƌĂĂƌƟĐƵlar ĐorƟĐoid and/or NSAIDs and painkillers

First line

Q

ParƟĂůresponse to MTX

IntoleranĐe to MTX

Failure ĂŌĞƌ 3 months

CombinaƟon of ƐǇŶƚŚĞƟĐDZDs

ǆĐŚĂŶŐĞďĞƚǁĞĞŶ ƐǇŶƚŚĞƟĐDZƐ

^ĞĐond line

Failure aŌer 3 months

SyntheƟĐMARD (preferably MTX) + BioloŐŝĐDZ (anƟ-TNF ĂƐĮrst ĐŚŽŝĐĞor ABAT or TOCI)

Third line

Failure aŌer 3-6 months

Failure of or intolerĂŶĐĞ to bioůŽŐŝĐ DMARD: To maintain ƐǇŶƚŚĞƟĐDZD (preferably MTX) and ĐŚĂŶŐĞ biologiĐ DMARD to another ĂŶƟ-TNF or ABAT or RTX or TOCI Failure aŌer 3-6 months

ĐƟǀĞĚŝƐĞĂƐĞ͗ Consider CIDA aiming at remission or at least lower disease ĂĐƟǀŝƚǇ

Fig. 1 – RA drug treatment flowchart for Brazil, as proposed by the RA SBR Commission. ABAT, abatacept; CIDA, compound indices of disease activity; DMARD, diseasemodifying antirheumatic drug; MTX, methotrexate; NSAIDs, nonsteroidal anti-infl ammatory drugs; RTX, rituximab; TOCI, tocilizumab.

X

Evaluation and education regarding emergency situations*****

X

X

X

X

X

X

X

X

X X X X

X

X

X

X

X X X X

X

X

X

X

CIDA, compound indices of disease activity (SDAI – simple disease activity index; CDAI – clinical disease activity index; DAS28 – disease activity score - 28 joints); +, for CIDA goals, see the 2011 BSR Consensus for diagnosis and early assessment of RA; mHAQ, modified health assessment questionnaire; HAQ-DI, health assessment questionnaire - disability index; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PPD, tuberculin skin test; IGRA, interferon gamma release assays. * Extra-articular manifestations: rheumatoid nodules, interstitial lung disease, serositis, ocular inflammation, and vasculitides. **Comorbidities: arterial hypertension, cardiovascular ischemia, diabetes mellitus, atherosclerosis, low bone mass, depression, fibromyalgia, etc. ***Laboratory exams: blood count, liver function, lipid profile, and renal function; depending on the comorbidities, consider additional exams. ****Medication for RA: consider the efficacy and safety issues of each medication detailed throughout the text. *****Urgencies on RA: scleromalacia perforans, myelopathies, multiple mononeuritis and vasculitis, pregnant patients on teratogenic drugs.

X Serologies (hepatitis B and hepatitis C at the beginning of the investigation, HIV in selected situations)

X

Gestational counseling

Evaluation of infections (clinical assessment and occasional complementary exams)

X

Coordination of the multidisciplinary team

X X X X

X X

X X X X

X X X X

X X

X X

X X X X

X X X X X X X

X X X X

X X X X X X X X X X X X X

X

X

X X X (minimum reduction desired: 0.22 points) X (if negative at the first assessment, they can be repeated in the two initial years)

Annual assessment

Conventional radiography (hands and wrists, feet and ankles, other joints affected) Joint resonance or ultrasound (in doubt regarding the synovitis) Assessment of extra-articular manifestations * Assessment of comorbidities** Inflammatory activity tests (ESR and CRP) Laboratory assessment*** Vaccination assessment Specific medicamentous treatment for RA**** Medicamentous treatment of comorbidities PPD (or IGRA) and chest radiography (if a biologic DMARD, specially anti-TNF, is prescribed) Occupational therapy Rehabilitation Evaluation of orthotic indication Evaluation of surgical indication

X X X

Assessment every three months (established RA)

X

X X X

Extra consultations

RF/anti-CCP

X X

Monthly assessment (early RA)

X X X

Initial assessment

Education of patients and families CIDA+ mHAQ or HAQ-DI (0–3 points)

Parameter

Table 6 – Monitoring the treatment of rheumatoid arthritis (continued).

174 R E V B R A S R E U M AT O L . 2 0 1 3 ; 5 3 ( 2 ) : 1 5 8 – 1 8 3


MSD, Roche and Wyeth; and was a speaker at events or activities sponsored by the companies Abbott and Roche. Rezende-Fronza LS participated in clinical and/or experimental studies sponsored by the companies Bristol-Myers Squibb, Pfizer, and Roche; and elaborated scientific papers in journals sponsored by Pfizer. Bertolo MB was a speaker at events or activities sponsored by the companies Abbott, Pfizer and Sanofi Aventis. Freitas MVC received personal or institutional assistance from the companies Abbott, MSD, Pfizer, Roche and Wyeth; was a speaker at events or activities sponsored by the companies Abbott, MSD, Pfizer, Roche Wyeth; is an advisory board member or director of pharmaceutical industry or advisory committees of scientific studies sponsored by the companies AstraZeneca, MSD and Wyeth; and elaborated scientific papers in journals sponsored by the companies Abbott, AstraZeneca, Bristol-Myers Squibb, Wyeth. Silva NA participated in clinical and/or experimental studies sponsored by the companies Bristol-Myers Squibb and Roche; received personal or institutional assistance from the companies Abbott, MSD, Roche and Wyeth; and was a speaker at events or activities sponsored by the companies Janssen, Mantecorp, MSD and Roche. Louzada-Junior P participated in clinical and/or experimental studies sponsored by the companies Merck and Roche; received personal or institutional assistance from Abbott; and was a speaker at events or activities sponsored by the companies Bristol-Meyers Squibb, Pfizer and Roche. Giorgi RD received personal or institutional assistance from the companies Bristol-Myers Squibb and Roche; was a speaker at events or activities sponsored by the companies Bristol-Myers Squibb and Roche; and was a speaker at events or activities sponsored by the companies Bristol-Myers Squibb and Roche. Lima RAC participated in clinical and/or experimental studies sponsored by the companies Mantecorp and Roche; received personal or institutional assistance from the companies Acteion, Lilly and Pfizer; and was a speaker at events or activities sponsored by the companies Acteion, Lilly and Pfizer. Pinheiro GRC received personal or institutional assistance from the companies Janssen and Roche.

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Guidelines

Guidelines for the treatment of antiphospholipid syndrome Adriana Danowskia,*, Jozelia Regob, Adriana M. Kakehasic, Andreas Funked, Jozelio Freire de Carvalhoe, Isabella V. S. Limaf, Alexandre Wagner Silva de Souzag, Roger A. Levyh a

Hospital Federal dos Servidores do Estado (HFSE), Rio de Janeiro, RJ, Brazil Medical School, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil c Locomotor Department, Medical School, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil d Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil e Centro Médico Aliança, Salvador, BA, Brazil f Universidade Federal da Bahia (UFBA), Salvador, BA, Brazil g Discipline of Rheumatology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/Unifesp), São Paulo, SP, Brazil h Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil b

article info

abstract

Article history:

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized

Received on 11 December 2012

by arterial and venous thrombosis, gestational morbidity and presence of elevated and

Accepted on 13 December 2012

persistently positive serum titers of antiphospholipid antibodies. The treatment of APS is still controversial, because any therapeutic decision potentially faces the risk of an insuf-

Keywords:

ficient or excessive antithrombotic coverage associated with anticoagulation and its major

Antiphospholipid syndrome

adverse effects. This guideline was elaborated from nine relevant clinical questions related

Treatment

to the treatment of APS by the Committee of Vasculopathies of the Brazilian Society of

Pregnancy

Rheumatology. Thus, this study aimed at establishing a guideline that included the most

Anticoagulation

relevant and controversial questions in APS treatment, based on the best scientific evi-

Thrombosis

dence available. The questions were structured by use of the PICO (patient, intervention or indicator, comparison and outcome) process, enabling the generation of search strategies for evidence in the major primary scientific databases (MEDLINE/PubMed, Embase, Lilacs, Scielo, Cochrane Library, Premedline via OVID). A manual search for evidence and theses was also conducted (BDTD and IBICT). The evidence retrieved was selected based on critical assessment by using discriminatory instruments (scores) according to the category of the therapeutic question (JADAD scale for randomized clinical trials and Newcastle-Ottawa scale for non-randomized studies). After defining the potential studies to support the recommendations, they were selected according to level of evidence and grade of recommendation, according to the Oxford classification. © 2013 Elsevier Editora Ltda. All rights reserved.

* Corresponding author. E-mail: [email protected] (A. Danowski) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.


185

Diretrizes para o tratamento da síndrome do anticorpo antifosfolipídeo resumo Palavras-chave:

A síndrome do anticorpo antifosfolipídeo (SAF) é uma doença sistêmica autoimune carac-

Síndrome do anticorpo antifosfo-

terizada por trombose arterial e venosa, morbidade gestacional e presença de níveis séricos

lipídeo

de anticorpos antifosfolipídeos elevados e persistentemente positivos. O tratamento da SAF

Tratamento

ainda é sujeito a controvérsias, já que qualquer decisão terapêutica potencialmente irá con-

Gestação

frontar-se com o risco de uma cobertura antitrombótica insuficiente ou com o risco excessivo

Anticoagulação

associado à anticoagulação e seus principais efeitos adversos. Esta diretriz foi elaborada a

Trombose

partir de nove questões clínicas relevantes e relacionadas ao tratamento da SAF pela Comissão de Vasculopatias da Sociedade Brasileira de Reumatologia. O objetivo deste trabalho foi criar uma diretriz que incluísse as questões mais relevantes e controversas no tratamento da SAF, com base na melhor evidência científica disponível. As questões foram estruturadas por meio do P.I.C.O. (paciente, intervenção ou indicador, comparação e outcome/desfecho), o que possibilitou a geração de estratégias de busca da evidência nas principais bases primárias de informação científica (MEDLINE/Pubmed, Embase, Lilacs/ Scielo, Cochrane Library, Premedline via OVID). Também realizou-se busca manual da evidência e de teses (BDTD e IBICT). A evidência recuperada foi selecionada a partir da avaliação crítica, utilizando instrumentos (escores) discriminatórios de acordo com a categoria da questão terapêutica (JADAD para ensaios clínicos randomizados e New Castle Ottawa Scale para estudos não randomizados). Após definir os estudos potenciais para sustento das recomendações, eles foram selecionados pela força da evidência e pelo grau de recomendação, segundo a classificação de Oxford. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

Introduction The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis, gestational morbidity and presence of elevated and persistently positive serum titers of antiphospholipid antibodies. It is currently recognized as the most frequent cause of acquired thrombophilia associated with venous and arterial thrombosis. The current classification meant for inclusion in clinical research protocols, but often used in daily practice to establish the diagnosis of APS1(D) and indicate a treatment, was reviewed in 2006 and includes clinical and laboratory criteria.

Clinical criteria • Vascular thrombosis: one or more episodes of arterial or venous thrombosis or thrombosis of small vessels of any organ or tissue, confirmed on Doppler or histopathology, vasculitis excluded; • Gestational morbidity: - One or more deaths of a morphologically normal fetus after the 10th gestational week, confirmed on ultrasound or by examining the fetus; - One or more premature births of a morphologically normal fetus before the 34th gestational week due to eclampsia, preeclampsia or causes of placental insufficiency; - Three or more spontaneous abortions before the 10th gestational week, with neither maternal hormonal nor anatomical abnormalities, paternal and maternal chromosomal causes excluded.

Laboratory criteria • Presence of lupus anticoagulant antibody (LA) in the plasma on two or more occasions at a minimum 12-week interval, detected according to the recommendations of the International Society on Thrombosis and Hemostasis (ISTH); • Moderate (> 40) to high (> 80) titers of IgG or IgM anticardiolipin antibodies (ACL) on two or more occasions at a minimum 12-week interval, detected by using standard ELISA test; • IgG or IgM anti-beta 2-GPI antibodies in the plasma on two or more occasions at a minimum 12-week interval, detected by using standard ELISA test. The presence of arterial or venous thrombosis or thrombosis of small vessels is the major characteristic of the disease and the major cause of death in those patients. The disease can affect vessels of any caliber and from any place. The most frequently reported events are deep venous thrombosis, pulmonary embolism, and encephalic vascular accident (EVA). Untreated patients with APS have been reported to be at high risk for recurrence (B).2 The treatment of APS is still controversial, because any therapeutic decision potentially faces the risk of an insufficient or excessive antithrombotic coverage associated with anticoagulation and its major adverse effects. Currently, the indication of lifelong oral anticoagulation in cases of arterial, venous or microcirculatory thrombosis is consensual, but its intensity and possibility of interruption are still discussed. The new anticoagulants (rivaroxaban and dabigatran), indicated to prevent EVA and systemic embolism in patients with non-valvular atrial fibrillation after hip or knee arthroplasty, are still being studied in patients with APS, and the short- and medium-term study results are awaited. New anticoagulants that do not require

186


monitoring and bearing a lower risk of bleeding are certainly of interest. Once confirmed their efficacy and safety, they will have a solid place in the arsenal of APS treatment. However, the current objective of the research in the area is to improve the therapeutic management of APS, aiming at acting on the pathogenic process triggered by antiphospholipid antibodies. The candidates are as follows: agents potentially used in primary prophylaxis, such as hydroxychloroquine and clopidogrel; agents used in more severe situations, such as intravenous gamma globulin and rituximab; and others more recently introduced that can reduce antibody production, such as tocilizumab and belimumab. The management of individuals with antiphospholipid antibodies and no previous thrombotic events, such as primary thromboprophylaxis, is still a matter of concern and debate. Thus, this study aimed at establishing a guideline that included the most relevant and controversial questions in APS treatment, based on the best scientific evidence available.

Material and methods This guideline was elaborated from nine relevant clinical questions related to the treatment of APS by the Committee of Vasculopathies of the Brazilian Society of Rheumatology. The questions were structured by use of the PICO (patient, intervention or indicator, comparison and outcome) process, enabling the generation of search strategies (Appendix 1) for evidence in the major primary scientific databases (MEDLINE/PubMed, Embase, Lilacs, Scielo, Cochrane Library, Premedline via OVID). A manual search for evidence and theses was also conducted (BDTD and IBICT). The evidence retrieved was selected based on critical assessment by using discriminatory instruments (scores) according to the category of the therapeutic question (JADAD scale for randomized clinical trials and Newcastle-Ottawa scale for non-randomized studies). After defining the potential studies to support the recommendations, they were selected according to level of evidence and grade of recommendation, based on the Oxford classification. Grade of recommendation and level of evidence: A: data derived from more consistent experimental and observational studies. B: data derived from less consistent experimental and observational studies. C: case reports (uncontrolled studies). D: expert opinion without explicit critical appraisal, or based on consensus, physiological studies or animal models.

Results

1. Do asymptomatic individuals positive for antiphospholipid antibodies (moderate or high IgG or IgM LA+ or ACL or anti-beta 2-GP) and with no history of thrombosis benefit from anticoagulation? And from antiplatelet agents? Adult patients with antiphospholipid antibodies on a mean 36-month follow-up and undergoing continuous thromboprophylaxis (aspirin) show no difference in the risk of thromboem-

bolic events. However, patients undergoing thromboprophylaxis and at risky situations (surgery/immobilization, pregnancy/ puerperal period) show a 31% reduction in the risk of thrombotic events (NNT:3) (B).3 The primary prevention of thrombosis in patients positive for antiphospholipid antibodies either with low doses of aspirin (75 mg/day) or with aspirin associated with warfarin shows 5% of thrombotic events for both forms of prophylaxis, and, in one to five years, there is an incidence of 4.9 events per 100 patientyears in both groups (B).4 A 5% reduction in the risk of thrombotic events (NNT:20) is observed in patients with antiphospholipid antibodies on primary prevention with aspirin and/or coumarins (B).5 Thrombosis prophylaxis (low dose of aspirin, long-term warfarin or heparin) in patients with antiphospholipid antibodies (medium/high titers of ACL) and arterial hypertension can reduce the risk of events by 51.2% (NNT:2) (B).6 In populations positive for antiphospholipid antibody, the prophylactic use of aspirin can reduce the risk of thrombotic events in 17% of the cases over 120 months (NNT:6) (B).7 However, there is evidence of no difference between using aspirin or not to prevent thrombotic events in those patients; in addition, there is even a 6% increase in the risk of thrombotic events (NNH:16) in patients on aspirin (B).8 The benefit of thromboprophylaxis (primary prevention) is controversial in patients with antiphospholipid antibodies and no clinical symptoms (B).9 In pregnant women with consecutive spontaneous abortions, with neither antiphospholipid antibodies nor any apparent cause, the use of aspirin or enoxaparin does not reduce the risk of new events (A).10

Recommendation Because of the controversial results of thromboprophylaxis (primary prevention) in patients positive for antiphospholipid antibodies, the continuous administration of aspirin and/or coumarins cannot be recommended to those patients, their use being reserved to situations with an elevated risk of thrombosis.

2. Is anticoagulation for undetermined time indicated to patients positive for antiphospholipid antibodies and with a history of venous thrombosis? What should the target INR be? In patients with a history of venous thrombosis and moderate to high titers of ACL and/or LA, anticoagulation with a target range for INR of 2.0 to 3.0 reduces the risk of recurrence similarly to anticoagulation with a target range for INR of 3.0 to 4.0, as compared to no anticoagulation (B).2 In patients with antiphospholipid antibodies, the use of moderate intensity anticoagulation with warfarin (target range for INR of 2.0 to 3.0) as compared to no treatment reduces the risk of venous thrombosis by 80% to 90% (B).9 Intensive regimens of anticoagulation (INR between 3.5 and 4.5) as compared to conventional regimens (INR between 2.0 and 3.0) for the treatment of patients with APS reduce the risk of thrombosis recurrence at similar rates, but intensive anticoagulation increases the risk of mild bleeding (B).11,12


187

In the treatment of patients with APS and a history of venous thrombosis with warfarin, the following target ranges for INR yielded similar recurrence indices: INR between 3.0 and 4.0, 7.1%; and INR between 2.0 and 3.0, 2.2% (A).13 The recurrence risk of thrombosis in patients with APS and no treatment for one year is 29%. Anticoagulation with warfarin (INR between 2.0 and 3.0) reduces the risk by 19% (NNT:5), and when the goal is an INR > 3.0, either associated or not with aspirin, the risk is reduced by 27.5% (NNT:4). After six months of treatment cessation, the risk is increased by 100% (NNH:1) (B).14 In patients with a history of venous or arterial thrombosis and positive for antiphospholipid antibody, treatment with warfarin (INR between 2.0 and 2.9) and aspirin (75 mg/ day) leads to a 21% increase in the risk of recurrence within 24 months as compared to warfarin (INR > 2.9) and aspirin (75 mg/day) (B).15 Patients positive for antiphospholipid antibodies and previous venous thrombosis, when treated with anticoagulation, have an increase in the likelihood of thrombosis-free survival of 50% and 78% within two and eight years, respectively (B).16 The thromboprophylaxis of patients with APS and previous venous thrombosis recommends maintaining long-term anticoagulation with oral anticoagulants, aiming at an INR between 2.0 and 3.0 (B).17

There is a 56% reduction in the risk of recurrence of arterial events in anticoagulated patients with antiphospholipid antibody as compared to untreated ones. Patients on highintensity warfarin (INR > 3.0) either with or without aspirin have a 90% probability of not experiencing a new thrombotic event within five years (B).14 Regarding the thromboprophylaxis of arterial events in patients with antiphospholipid antibodies, treatment with warfarin (INR > 2.9) and aspirin (75 mg/day) reduces the risk of events by 50% as compared to aspirin alone at the same dosage. The recurrence risk of thrombotic events does not differ between warfarin with an INR greater than or lower than 2.9 (B).15 Triple-positive APS patients (with three positive antiphospholipid tests) have a high recurrence rate, more frequently arterial. Warfarin with a target INR between 2.0 and 3.0 is more effective than low-dose aspirin or no therapy; however, in patients on warfarin (target INR between 2.0 and 3.0) for six years, the recurrence rate is 30% (B).17 Over a five-year treatment with oral anticoagulants, patients with APS have an 11% reduction in the recurrence risk of arterial events as compared to untreated patients (B).19

Recommendation

The treatment of patients with antiphospholipid antibody and history of arterial thrombosis should be long and performed with warfarin (INR between 2.0 and 3.0 or INR > 3.0) either associated or not with antiplatelet agents. The prospective studies that found no difference between high-intensity warfarin and standard INR included a small group of patients with arterial thrombosis, hindering, thus, definitive conclusions. The authors suggest long-term anticoagulation with high-intensity warfarin.

Patients with APS and previous venous thrombosis should remain on anticoagulants for undetermined time, aiming at an INR between 2.0 and 3.0.

3. Is anticoagulation for undetermined time indicated for patients with APS and previous arterial thrombosis? Which should the target INR be? The recurrence rate of thrombotic events in patients with APS and previous arterial thrombosis is greater in untreated patients and lower in those on warfarin and INR between 3.0 and 4.0, as compared to low-intensity warfarin (INR between 2.0 and 3.0) or aspirin alone. Patients with arterial events are at a greater risk of recurrence than those with venous events (B).2 Warfarin and aspirin seem to be equivalent in preventing thromboembolic complications in patients with their first ischemic EVA and positive for antiphospholipid antibodies. The use of warfarin (INR 1.4–2.8) or aspirin (325 mg/day) does not differ regarding the risk for cerebral arterial thrombotic events (recurrence) (A).18 The number of arterial events (transient cerebral ischemia, EVA or death due to EVA) occurring in patients with antiphospholipid antibodies and history of arterial thrombotic events during thromboprophylaxis with high-intensity warfarin (INR between 3.5 and 4.5) or standard warfarin (INR between 2.0 and 3.0) is similar (B).11 The risk of recurrence of thrombotic events in patients with antiphospholipid antibody and history of arterial thrombosis in a three-year follow-up on warfarin (target INR between 3.1 and 4.0) or aspirin (target INR between 2.0 and 3.0) is 21.4% and 7.6%, respectively (A).12

Recommendation

4. Is anticoagulation for undetermined time indicated for patients with APS who have only obstetric events? And antiplatelet therapy? In patients with obstetric APS on aspirin (75,100 mg/day) having used low-weight heparin during pregnancy and six weeks after delivery, the number of thrombotic events in 36 months can be 3.3/100 patient-years. The determinant factor for events, independently of anticoagulation or antiplatelet therapy, is the presence of at least two antibodies, when the rate of events is 4.6/100 patient-years (C).20 The five-year incidence of thrombotic events in pregnant patients with obstetric manifestations of APS can be 2.5%, being even reported in one patient on aspirin. Approximately 7.4% of the patients on anticoagulants can have hemorrhagic manifestations (B).21 Treating women with APS and obstetric manifestations by using low-dose aspirin reduces the risk of thrombotic event by 49% over an eight-year follow-up (B).22 The nine-year follow-up of patients with obstetric APS (obstetric events) treated with low-dose aspirin (100 mg/day), as compared to patients with no antiphospholipid antibody, shows an increased risk for pulmonary embolism of 31%, for deep venous thrombosis of 103%, and for EVA of 13% (B).23

188


Recommendation Patients diagnosed with APS and exclusive presence of obstetric events should undergo long-term thromboprophylaxis with low-dose aspirin, aiming at reducing thrombotic events, especially the arterial ones.

5. Should a primipara positive for antiphospholipid antibodies with no history of thrombosis undergo any intervention? In female patients positive for antiphospholipid antibodies, considered at low-risk due to the lack of associated morbidities (none or one spontaneous abortion or no previous thrombosis), low-dose aspirin reduces the risk of neither events nor complications (B).24 The risk of venous thromboembolism in pregnant patients positive for antiphospholipid antibody and with no history of thrombotic events is similar to that of pregnant patients with no antiphospholipid antibody (B).25,26 The risk of thrombotic events in patients with antiphospholipid antibodies and history of obstetric events is 19% in 12 months, but the risk of patients with antiphospholipid antibody and no history of obstetric events is 0% (zero) (B);27 thus, pharmacological treatment (thromboprophylaxis) is not justified in those patients (B).28

Recommendation Patients with antiphospholipid antibodies and no history of thrombotic events should not receive pharmacological treatment during pregnancy.

6. Is oral anticoagulation indicated for pregnant women (between 14 and 35 weeks) with APS and previous thrombosis? Which should the target INR be? Oral anticoagulants are recommended during pregnancy (16th to 36th week), or even for six weeks after delivery (D),29 to patients with antiphospholipid antibody and history of thrombosis, mainly arterial thrombosis, based on extrapolation of the use of oral anticoagulants in similar, but not pregnant, patients and on the fact of the lower teratogenic risk of those medications at that phase of pregnancy (D).30 Events can recur in 20% of patients with APS, even when on oral anticoagulants (80% with INR between 2.0 and 3.0, and 20% with INR > 3.0) (B).21 The use of oral anticoagulants (INR between 2.0 and 3.0) in 80% of patients with APS reduces the recurrence risk of thromboembolism within five years by 22% (NNT:5) (B).19 However, their specific use in pregnant women has not been properly studied.

Recommendation Pregnant patients with APS and history of thromboembolic events should not receive oral anticoagulants, because their use in that population has not been properly studied.

7. Is heparin indicated to pregnant women with APS and previous thrombosis? Which dosing should be used for unfractionated and low molecular weight heparin? Treating pregnant women with APS and history of thromboembolic events (venous or arterial) with dalteparin (5,000 IU/day, subcutaneously, once a day, increasing to twice a day between the 16th and 20th gestational week) can cause a 100% reduction in thrombotic events over a 35-week follow-up (B).31 In pregnant women with APS and history of thromboembolic events, treatment with full dose low molecular weight heparin associated with aspirin during pregnancy and for six weeks after delivery can reduce the recurrence risk of thrombotic events by 100% (NNT:1) (B).32 Comparing the use of low molecular weight heparin (enoxaparin, 1 mg/kg/day) associated with 100 mg of aspirin and warfarin (INR between 2 and 2.5) from the 14th to the 34th gestational week to patients with APS and one previous thrombotic episode shows a 28.9% increase in the risk of thrombosis in those receiving warfarin (NNH: 4) (B).33 Pregnant patients with APS and previous episodes of thrombosis have a high recurrence rate of thrombosis, and the antithrombotic treatment should be maintained during pregnancy and post-partum. The standard regimen combines low-dose aspirin and heparin (unfractionated or low molecular weight). Warfarin, except between the 6th and 12th week, might be an alternative to heparin, and should be reinitiated after delivery (D).34

Recommendation The use of low molecular weight heparin subcutaneously (dalteparin, 5,000 IU/day or enoxaparins, 1 mg/kg/day, doubling one or the other after the 16th week) associated with aspirin (100 mg/day) during pregnancy and after delivery reduces the occurrence of maternal thrombosis and fetal loss. Warfarin is the option after the 13th gestational week. Despite the lack of good quality scientific evidence, the authors recommend, based on case series, case reports and personal experience, that pregnant patients with APS and previous thrombosis maintain full dose and nonprophylactic low molecular weight heparin associated with aspirin during pregnancy due to the high risk of new thromboembolic events in that period.

8. Is there any difference in the management of pregnant women with history of late fetal loss or early abortions? Are there advantages in using aspirin? Pregnant patients with APS and history of either early abortions or late fetal loss can be managed with low-dose aspirin and low molecular weight heparin. However, under the same treatment, the outcomes of patients with history of early abortions as compared to those of patients with history of late fetal loss differ, a higher number of premature deliveries and small for gestational age newborns being observed in patients with history of late fetal loss (B).35


Comparison of low molecular weight heparin and aspirin in isolation for the treatment of pregnant women with APS and history of repeated abortions shows a 14% increase (NNT:7) in fetal survival and in newborn weight in patients medicated with heparin (B).36 The use of aspirin to treat pregnant patients with APS and repeated abortions has no benefits regarding prenatal complications (for example, premature delivery) and neonatal outcomes (for example, weight) (B).37 Neonatal and obstetric outcomes occur at similar numbers in pregnant patients with antiphospholipid antibody and history of repeated abortions treated with aspirin and low molecular weight heparin as compared to those treated only with aspirin (A).38,39 However, when aspirin is associated with unfractionated heparin, a 29% increase (NNT:3) in newborn survival is observed (A).40

Recommendation Pregnant patients with antiphospholipid antibody and history of early or late abortions should be treated with heparin (unfractionated or low molecular weight) and aspirin.

9. Is the association of other medications (corticosteroid, immune globulin, rituximab) with anticoagulants in the catastrophic antiphospholipid syndrome (CAPS) advantageous? Considering the presence or absence of one single treatment, improvement occurs in 63.1% of the episodes of CAPS treated with anticoagulants versus 22.2% of episodes not treated with anticoagulants (NNT:2). In addition, there is no difference in improvement between presence and absence of individual treatment with other agents, such as corticosteroids, plasmapheresis, immune globulin or antiplatelet agents. The individual use of corticosteroids produces the poorest recovery (B).41,42 When treatments are associated, the most common combination is anticoagulants and corticosteroids, followed by anticoagulants, corticosteroids, plasmapheresis and/or immune globulin. The recovery rate showed no difference between the several combinations, and no difference between combining with anticoagulants or not (B).41,42

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Acknowledgements The authors thank Dr. Wanderley Marques Bernardo, from the Brazilian Medical Association, for his valuable collaboration in this project.

Appendix 1: Search strategies and words used in the search for the clinical questions. PICO 1 Do asymptomatic individuals positive for antiphospholipid antibodies (moderate or high IgG or IgM LA+ or ACL or antibeta 2-GP) and with no history of thrombosis benefit from anticoagulation? And from antiplatelet agents? (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND (Platelet Aggregation Inhibitors OR Anticoagulants OR Coumarins OR Heparin or Aspirin) AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract]) OR random*[Title/Abstract] OR random allocation[MeSH Terms])

PICO 2 Is anticoagulation for undetermined time indicated to patients positive for antiphospholipid antibodies and with a history of venous thrombosis? What should the target INR be? (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND (Anticoagulants OR Coumarins OR Heparin) AND Embolism and Thrombosis AND ((clinical[Title/ Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/ Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

PICO 3 Recommendation There are no good quality studies confirming the benefit of the association of other medications with anticoagulants in the treatment of patients with CAPS. Despite the limited good quality scientific evidence, the authors recommend, based on case series, case reports and personal experience, the association of corticosteroid, plasmapheresis and/or rituximab with anticoagulant therapy, because of the high mortality of that condition.

Conflicts of interest The authors declare no conflicts of interest.

Is anticoagulation for undetermined time indicated for patients with APS and previous arterial thrombosis? Which should the target INR be? (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND (Anticoagulants OR Coumarins OR Heparin OR INR) AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/ Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

190


PICO 4 Is anticoagulation for undetermined time indicated for patients with APS who have only obstetric events? And antiplatelet therapy? Pregnancy Complications AND (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND (Platelet Aggregation Inhibitors OR Anticoagulants OR Coumarins OR Heparin OR Aspirin) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/ Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

PICO 8 Is there any difference in the management of pregnant women with history of late fetal loss or early abortions? Are there advantages in using aspirin? Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND heparin AND ((clinical[Title/ Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/ Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

PICO 5 PICO 9 Should a primipara positive for antiphospholipid antibodies with no history of thrombosis undergo any intervention? Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading])

PICO 6 Is oral anticoagulation indicated for pregnant women (between 14 and 35 weeks) with APS and previous thrombosis? Which should the target INR be? Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

PICO 7 Is heparin indicated to pregnant women with APS and previous thrombosis? Which dosing should be used for unfractionated and low molecular weight heparin? Pregnancy AND (Antiphospholipid Syndrome OR AntiPhospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid) AND heparin AND (Embolism and Thrombosis OR Arterial Occlusive Diseases) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms]

Is the association of other medications (corticosteroid, immune globulin, rituximab) with anticoagulants in the catastrophic antiphospholipid syndrome (CAPS) advantageous? (Antiphospholipid Syndrome OR Anti-Phospholipid Antibody Syndrome OR Antiphospholipid Antibody Syndrome OR Anti-Phospholipid Syndrome OR Antibodies, Antiphospholipid ) AND Catastrophic AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading] OR Comparative study OR Epidemiologic methods)

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retrospective follow-up study. Ann Rheum Dis. 2009;68(3):397-9. Hereng T, Lambert M, Hachulla E, Samor M, Dubucquoi S, Caron C, et al. Influence of aspirin on the clinical outcomes of 103 anti-phospholipid antibodies-positive patients. Lupus. 2008;17(1):11-5. Erkan D, Harrison MJ, Levy RA, Peterson M, Petri M, Sammaritano L, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibodypositive individuals. Arthritis Rheum. 2007;56(7):2382-91. Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA. 2006;295(9):1050-7. Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev. 2009;(1):CD004734. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3(5):848-53. Crowther MA, Wisloff F. Evidence based treatment of the antiphospholipid syndrome II. Optimal anticoagulant therapy for thrombosis. Thromb Res. 2005;115(1-2):3-8. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349(12):1133-8. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332(15):993-7. Rivier G, Herranz MT, Khamashta MA, Hughes GR. Thrombosis and antiphospholipid syndrome: a preliminary assessment of three antithrombotic treatments. Lupus. 1994;3(2):85-90. Derksen RH, de Groot PG, Kater L, Nieuwenhuis HK. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulant treatment. Ann Rheum Dis. 1993;52(9):689-92. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibodypositive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011;20:206-18. Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR, et al. Antiphospholipid antibodies and subsequent thromboocclusive events in patients with ischemic stroke. JAMA. 2004;291(5):576-84. Pengo V, Ruffatti A,Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8(2):237-42. Lefèvre G, Lambert M, Bacri JL, Dubucquoi S, Quemeneur T, Caron C, et al. Thrombotic events during long-term followup of obstetric antiphospholipid syndrome patients. Lupus. 2011;20(8):861-5. Cervera R, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Kiss E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2009;68(9):1428-32.

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22. Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 2001;44(6):1466-7. 23. Gris JC, Bouvier S, Molinari N, Galanaud JP, CocheryNouvellon E, Mercier E, et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood. 2012;119(11):2624-32. 24. Cowchock S, Reece EA. Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Organizing Group of the Antiphospholipid Antibody Treatment Trial. Am J Obstet Gynecol. 1997;176(5):1099-100. 25. Bergrem A, Jacobsen EM, Skjeldestad FE, Jacobsen AF, Skogstad M, Sandset PM. The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis – a populationbased case-control study. Thromb Res. 2010;125(5):e222-7. 26. Quenby S, Farquharson RG, Dawood F, Hughes AM, Topping J. Recurrent miscarriage and long-term thrombosis risk: a case-control study. Hum Reprod. 2005;20(6):1729-32. 27. Martinez-Zamora MA, Peralta S, Creus M, Tassies D, Reverter JC, Espinosa G, et al. Risk of thromboembolic events after recurrent spontaneous abortion in antiphospholipid syndrome: a case-control study. Ann Rheum Dis. 2012;71(1):61-6. 28. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis. 9. Ed. American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-736S. 29. Levy RA, Jesús GR, Jesús NR. Obstetric antiphospholipid syndrome: still a challenge. Lupus. 201019(4):457-9. 30. Derksen RH, De Groot PG, Nieuwenhuis HK, Christiaens GC. How to treat women with antiphospholipid antibodies in pregnancy? Ann Rheum Dis. 2001;60:1-3. 31. Hunt BJ, Gattens M, Khamashta M, Nelson-Piercy C, Almeida A. Thromboprophylaxis with unmonitored intermediate- dose low molecular weight heparin in pregnancies with a previous arterial or venous thrombotic event. Blood Coagul Fibrinolysis. 2003;14:735-9. 32. Hunt BJ, Khamashta M, Lakasing L, Williams FM, Nelson Piercy C, Bewley S, et al. Thromboprophylaxis in antiphospholipid syndrome pregnancies with previous cerebral arterial thrombotic events: is warfarin preferable? Thromb Haemost. 1998;79(5):1060-1. 33. Pauzner R, Dulitzki M, Langevitz P, Livneh A, Kenett R, Many A. Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy. Thromb Haemost. 2001;86(6):1379-84. 34. Jesus GR, Santos FC, Oliveira CS, Mendes-Silva W, Jesus NR, Levy RA. Management of obstetric antiphospholipid syndrome. Curr Rheumatol Rep. 2012;14(1):79-86. 35. Bramham K, Hunt BJ, Germain S, Calatayud I, Khamashta M, Bewley S, et al. Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus. 2010;19(1):58-64. 36. Alalaf S. Bemiparin versus low dose aspirin for management of recurrent early pregnancy losses due to antiphospholipd antibody syndrome. Arch Gynecol Obstet. 2012;285(3):641-7. 37. Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol. 2000;183(4):1008-12. 38. Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, et al. Low molecular weight heparin

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and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol. 2009;36(2):279-87. 39. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100(3):408-13. 40. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314(7076):253-7.

41. Bucciarelli S, Espinosa G, Cervera R, Erkan D, Gómez-Puerta JA, Ramos-Casals M, et al. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum. 2006;54(8):2568-76. 42. Cervera R, Bucciarelli S, Plasín MA, Gómez-Puerta JA, Plaza J, Pons-Estel G, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun. 2009;32(3– 4):240-5.



Original article

Resistance training versus weight-bearing aquatic exercise: a cross-sectional analysis of bone mineral density in postmenopausal women Sandor Balsamoa,b,c,*, Licia Maria Henrique da Motaa, Frederico Santos de Santana a,b,c, Dahan da Cunha Nascimentoc,d, Lídia Mara Aguiar Bezerrae, Denise Osti Coscrato Balsamoc, João Lindolfo Cunha Borgesf, Ana Patrícia de Paulag, Martim Bottaroe a

Postgraduate Program in Medical Sciences, Medical School, Universidade de Brasília (UnB), Brasília, DF, Brazil Department of Physical Education, Centro Universitário Euro-Americano (UNIEURO), Brasília, DF, Brazil c Research group of strength training and Health (GEPEEFS), Brasília, DF, Brazil d Postgraduate Program in Physical Education, School of Physical Education, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil e School of Physical Education, Universidade de Brasília (UnB), Brasília, DF, Brazil f Department of Medicine, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil g Postgraduate Program in Sciences for Health, Health Sciences Teaching and Research Foundation, Secretary of State of Health (FEPECS/ SESDF), Ministry of Health, Brasilia, DF, Brazil b

article info

abstract

Article history:

Introduction: Many studies have shown that resistance training has a positive effect on bone

Received on 7 January 2012

mineral density (BMD). However, few studies have compared the BMD of individuals undergo-


ing resistance training and those training aquatic weight-bearing exercises. Objective: To compare, in a cross-sectional study, the BMD of postmenopausal women undergo-

Keywords:

ing resistance training and postmenopausal women training aquatic weight-bearing exercises.

Strength training

Methods: The sample comprised 63 women divided into the following three groups: resistance

Aquatic weight-bearing exercises

training (STRENGTH: n = 15; 51.4 ± 2.7 years); aquatic weight-bearing exercises (WATER: n =

Bone density

22; 54.5 ± 3.3 years); and non-trained controls (CONTROL: n = 26; 52.0 ± 3.3 years). All volun-

Postmenopause

teers were on hormone replacement therapy for at least one year. The STRENGTH and WATER groups were training for at least one year prior to study beginning (mean years of training – STRENGTH: 4.5 ± 2.0; WATER: 4.2 ± 2.2). Results: The STRENGTH group had higher BMD of total body, femoral neck, lumbar spine L2L4 as compared with the CONTROL group (all P < 0.05). The WATER group had higher BMD of total body, total hip, lumbar spine L2-L4 as compared with the CONTROL group (all P < 0.05). However, no difference was observed between the STRENGTH and WATER groups regarding the sites assessed. Conclusions: Those findings suggest that not only the resistance training, but also aquatic weight-bearing exercises might be a non-pharmacological strategy to prevent BMD loss in postmenopausal women. © 2013 Elsevier Editora Ltda. All rights reserved.

* Corresponding author. E-mail: [email protected] (S. Balsamo) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.

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Treinamento de força versus hidroginástica: uma análise transversal comparativa da densidade mineral óssea em mulheres na pós-menopausa resumo Palavras-chave:

Introdução: Há um grande número de estudos mostrando que o treinamento de força tem

Treinamento de força

um efeito positivo sobre a densidade mineral óssea (DMO). Porém, existem poucos estudos

Hidroginástica

comparando a DMO entre praticantes de hidroginástica e treinamento de força.

Densidade óssea

Objetivo: Comparar, em uma análise transversal, a DMO de mulheres praticantes de treina-

Pós-menopausa

mento de força com mulheres praticantes de hidroginástica, na pós-menopausa. Métodos: A amostra foi composta de 63 mulheres, divididas em três grupos: treinamento de força (FORÇA: n = 15; 51,4 ± 2,7 anos), hidroginástica (HIDRO: n = 22; 54,5 ± 3,3 anos) e controles não treinadas (CONTROLE: n = 26; 52,0 ± 3,3 anos). Todas as voluntárias estavam em terapia de reposição hormonal há no mínimo um ano. Os grupos FORÇA e HIDRO treinavam há pelo menos um ano antes do início do estudo (média de anos de treinamento – FORÇA: 4,5 ± 2,0; HIDRO: 4,2 ± 2,2). Resultados: O grupo FORÇA apresentou maior DMO de corpo total, colo femoral e coluna lombar L2-L4 quando comparado ao grupo-controle (todos P < 0,05). O grupo HIDRO apresentou maior DMO no corpo total, quadril total e coluna lombar L2-L4 quando comparado ao grupo-controle (todos P < 0,05). Entretanto, não foram observadas diferenças entre os grupos FORÇA e HIDRO em nenhum dos sítios avaliados. Conclusões: Estes achados sugerem que não apenas o treinamento de força, mas também a hidroginástica podem ser estratégias não farmacológicas para prevenção da perda de DMO em mulheres na pós-menopausa. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

Introduction There is growing evidence that exercise contributes to the prevention and treatment of osteoporosis due to the osteogenic effect of mechanical stimulus on bone tissue.1-3 It has been suggested that activities that require heavy loading with few repetitions, resulting in high strain rates, may be optimal for increasing bone mineral density (BMD).4 Cross-sectional studies have shown that resistance-trained individuals showed more BMD than inactive5,6. Some experts recommendations,7 prospective8 or meta-analysis9 studies have shown increases or maintenance of BMD on those individuals. On the other hand, water weight bearing exercises has been associated with improve in neuromuscular and functional fitness10 and cardiometabolic health,11 and also is highly recommended for old people with disability, because of security.10,12 Although, in the last 20 years, only a few studies have investigated BMD and water weight bearing exercises.13-16 Nevertheless, the literature is not clear whether there is an association between water weight bearing exercises and BMD. Most studies have yielded conflicting results ranging from worsening14 to improve bone health.15 Additionally, to date, no studies have compared, in a cross-sectional analysis, BMD in postmenopausal women resistance-trained versus postmenopausal women who are practicing aquatic weight bearing exercise, which is a novel approach. The purpose of this study was to compare BMD in postmenopausal women resistance-trained with postmenopausal women aquatic-trained with weight bearing exercises, and both with untrained controls. It was hypothesized that postmenopausal women aquatic-trained with weight bearing ex-

ercises would have similar BMD as postmenopausal women resistance-trained, and they would have higher BMD than untrained controls.

Materials and methods Subjects The research project was approved by the Research Ethics Committee of the Universidade Católica de Brasília (UCB) according to the institutional policies and the Declaration of Helsinki.17 All the participants were from Brasília and were recruited by means of electronic mail and leaflets and posters distributed in the city of Brasília. During the study, a single blinded rheumatologist analyzed the medical records and conducted the structured interviews with 95 women. The volunteers were composed by three groups: resistance-trained (STRENGTH), aquatic-trained with weight bearing exercises (WATER) and untrained controls (CONTROL).

Inclusion criteria All participants should be: a) at the minimum of one year in menopause; b) in exclusive estrogen hormone replacement therapy (HRT); c) into the STRENGTH and WATER groups required that the subject had been training at least one year before the study; d) into the CONTROL group the participants should not be engaged in regular physical activities programs for at least six months prior to the study. We used a questionnaire consisting of three questions to identify type of exercise, its regularity, frequency, intensity, and duration: 1) What


type of exercise do you practice regularly during one week?; 2) How often do you do this exercise during one week?; and 3) Which is the average duration in minutes of a single session of physical exercises?

Exclusion criteria All the participants with the following characteristics were excluded: a) using drugs or treatment that affects bone metabolism, except for calcium supplementation and HRT; b) smoking; c) with the body mass index (BMI) 30 kg/m2 (obesity); d) have any disease that affects the bone metabolism or strength (hypothyroidism/fibromyalgia/rheumatoid arthritis).

The resistance-trained and aquatic-trained with weight bearing exercises group The STRENGTH group had traditional resistance training at least three nonconsecutive days per week with supervision with a physical education teacher, each session lasting approximately 60 minutes, and the program consisted in a zone of 10 to 15 repetitions each exercise (included leg press, knee extension, knee flexion, seated bench press, seated row/lat pull down, biceps curls and core exercise). The WATER group had classes through at least three nonconsecutive days per week (one hour each session) with a physical education teacher certified by the Aquatic Exercise Association (AEA). The goal was to reach a heart rate of 60%–80% of maximum during the session, being exercised the major muscle groups with movements of pushing and pulling, jumping and displacements. We could not control exactly how many training sessions the trained groups (STRENGTH/WATER) did in last year(s).

Procedures Participants eligible for the study attended to the laboratory at the same time (8 am to 12 pm). Participants had to attend the following procedures prior to the laboratory visits: avoid practicing intense activities, caffeine use or alcohol derivatives 24 hours before the test, and have their last meal (including water) at least two hours before the test. All the tests were evaluated by a single blinded examiner.

Anthropometric measurements For height, weight, BMI, individuals were asked to remove shoes and any weight that might interfere in the measurements. For measuring the height, the individual should be barefoot with heels and trunk against the wall, head in the Frankfurt plane. The subject’s body weight in minimal clothing was measured to the nearest 100 g with a precision scale weight (Filizola ID-1500, Brazil), and height was measured to the nearest 5 mm with a wall-mounted stadiometer (Sanny Standard ES 2030, Brazil).

Bone densitometry The BMD of the total body, lumbar spine L2-L4, femur neck, total hip and forearm – 33% radius, ultradistal radius, and

195

total radius were measured using a dual-energy X-ray absorptiometry (DPX-L; Lunar Radiation Corporation, Madison, Wisconsin, U.S.A) and the scan were analyzed using software version 3.6. Before the tests, the devices were calibrated according to manufacturers recommendations and the same examiner performed all examinations.

Statistical analysis Values are presented as mean and standard error. We used a model analysis of covariance (ANCOVA) by a factor, with the measure of BMD as the dependent variable and measures of age, total muscle mass, fat mass and body fat percentage as covariates. The Bonferroni correction was used to adjust the pre-specified comparisons and it was considered, in the analysis, a significance level of 5%. Coefficient of variation (CV) was used to calculate within-participant variation (CV% = [SD/mean] x 100). To identify the differences among groups of the percentage of voluntaries with osteoporosis, osteopenia and normal scores, according ISCD (2005), the Kruskal-Wallis test was applied using the Mann-Whitney test with Bonferroni correction, considering in this test a significance level of P 0.05). However, the WATER group was older then the STRENGTH and CONTROL groups. The results of dependent variable BMD in the STRENGTH group was significantly higher compared to the CONTROL in total body (5.73%), in the sites lumbar spine, L2-L4 (16.40%) and femoral neck (8.73%), all P 0.05). In addition, more smokers were found among patients with RA as compared with controls (OR = 1.691; P = 0.088), and the CRP levels were slightly higher in patients who smoked than in patients who did not (OR = 2.673; P = 0.061). Conclusions: In this sample of patients with RA in the South of Brazil, association of the polymorphisms of the IL-18 gene was observed with neither RA nor risk factors for CVD. © 2013 Elsevier Editora Ltda. All rights reserved.

&

Both authors contributed equally to this manuscript.

* Corresponding author. E-mail: [email protected] (I. R. de Souza) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.

200


Ausência de associação entre os polimorfismos do gene interleucina-18 e artrite reumatoide resumo Palavras-chave:

Objetivo: Analisar a associação dos polimorfismos do gene interleucina-18 (IL-18) com

Interleucina-18

artrite reumatoide (AR) e com fatores de risco de doenças cardiovasculares (DCV).

Artrite reumatoide

Métodos: A amostra foi constituída por 97 pacientes com AR e 151 controles saudáveis. Nos

Doenças cardiovasculares

primeiros, foram analisados fatores de risco de DCV, tais como níveis do colesterol, hi-

Polimorfismo genético

pertensão arterial, tabagismo e fator reumatoide, bem como o nível da proteína C-reativa

Brasil

(CRP). O DNA foi extraído e foram analisados os polimorfismos de nucleotídeo único (SNP) nas posições -607C/A e -137G/C do gene IL-18 em ambos os grupos. O equilíbrio de Hardy-Weinberg (EHW) e o odds ratio (OR) foram realizados, considerando IC 95% e P < 0,05. Resultados: As frequências do alelo -607A nos pacientes com AR e nos controles foram de 0,443 e 0,424 e do alelo -137C foram de 0,304 e 0,291, respectivamente. As frequências do genótipo estavam em EHW, exceto em controles no locus -137 (P = 0,006). Não foi encontrada associação dos polimorfismos do gene IL-18 com AR, nem com fatores de risco de DCV, incluindo o nível do colesterol e de CRP (P > 0,05). Além disso, observaram-se mais indivíduos fumantes entre pacientes com AR em comparação aos controles (OR = 1,691; P = 0,088), e os níveis de CRP eram ligeiramente mais elevados em pacientes fumantes quando comparados aos de pacientes não fumantes (OR = 2,673; P = 0,061). Conclusões: Ao analisar uma amostra de pacientes com AR no sul do Brasil, não foi encontrada associação dos polimorfismos do gene IL-18 com AR, nem com os fatores de risco de DCV. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

Introduction Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation, leading to joint destruction and systemic complications which increase morbidity and mortality.1,2 This disease affects 0.5%–1% of the general population worldwide, with a higher incidence in women than in men.3 Although the incidence and clinical manifestations of RA have been shown to vary in many different geographical regions, in Latin America, especially in Brazil, this information is scarce.4,5 Therefore, it is very important to enlighten RA pathogenesis in heterogeneous population such as in Brazil. The RA has a complex and unclear etiology, but in genetically susceptible individuals, specific environmental factors can potentially activate pathogenic immune reactions, including autoantibody formation and autoreactivity response.1-3,6 The onset of RA can be indicated by the development of antibodies against citrullinated protein antigens (ACPA) and rheumatoid factor (RF) related to the self-tolerance loss.7 Recently, it has been recognized two RA subsets based on presence or absence of ACPA. Patients with ACPA positive have more extra-articular manifestations, smoking habit, and worse prognosis.2 The main cause of mortality in RA patients is cardiovascular diseases (CVD). Once the risk of CVD in RA patients is 50% higher when compared with the general population, it is believed that other risk factors are present in RA disease.8,9 Thus, the pathogenesis of accelerated cardiovascular damage is caused by traditional cardiovascular risk factors in combination to disease-related inflammatory and autoimmune mechanisms.10,11

Inflammation has an important role in atherosclerotic lesion and RA patients have a higher prevalence of atherosclerosis.12 In immune-mediated diseases such as RA, the accelerated and early atherosclerotic vascular damage may partially be explained by humoral and cellular autoimmune response against antigens expressed on the endothelium.8,13 Cytokines are also implicated in many immune processes associated with the pathogenesis of RA, especially in maintaining the active chronic inflammatory response. Because cytokines are involved in immune-regulatory and tissuedestructive events, it is likely that they would influence the severity of RA manifestations.7 Interleukin-18 (IL-18), a proinflammatory cytokine produced in RA by several synovium cells such as macrophages, chondrocytes and osteoblasts, induces signaling pathways common to other IL-1 family members, such as activation of nuclear factor-κB (NF-κB) and interferon-γ expression.7,14–16 Administration of IL-18 to mice caused development of erosive, inflammatory arthritis, suggesting that this cytokine can play a pro-inflammatory role in vivo.14 Furthermore, IL-18 mRNA and its protein were detected in RA synovial tissues in higher levels than in osteoarthritic controls.14 The structure, levels and regulation of IL-18 can be due to genetic differences on IL-18 gene expression.16 The chronic inflammatory condition seen in RA increase the levels and expression of C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukins-1, -6, and also -18, which are relevant as CVD risk factors.11,13,19 IL-18 is considered pro-atherogenic, presumably as a mediator of vascular inflammation itself, leading to augmentation and vulnerability of atherosclerotic plaque and finally, to its rupture.18 Human adipocytes are also capable of producing IL-18, con-

201


tributing to systemic IL-18 concentrations and development of the increased risk of diabetes and CVD that are associated with obesity and insulin resistance states.19 Plasma IL-18 concentration has shown to be increased in post myocardial infarction patients and was associated with coronary atherosclerosis.20 Indeed, variations in the IL18 gene were associated with raised IL-18 serum concentrations and higher cardiovascular mortality among coronary artery disease (CAD) patients.21 Other studies showed that IL-18 gene polymorphisms are involved in the development of ischemic stroke,22 myocardial infarction (MI),23 and higher cardiovascular mortality risk.24 Moreover, IL-18 serum levels were associated with traditional risk factors such as LDL- and HDL-cholesterol abnormal values, obesity, insulin resistance and cell dysfunction.20 Even though the endogenous production of IL-18 is affected by multiple factors, individual differences could also be determined by genetic polymorphisms, potentially affecting the balance between Th1 and Th2 cytokine responses. This mechanism could be responsible for an increased resistance to microbial infections, but also for a higher susceptibility to autoimmune disorders in individuals carrying more active IL-18 alleles.15 The IL-18 gene is regulated by its promoter region polymorphisms, which variability could lead to differences in transcription factor binding. Two single nucleotide polymorphisms (SNPs) in the promoter region at -607C/A and -137G/C position have been studied, and those changes disrupts a potential binding site of the cAMP-responsive element binding (CREB) protein and the H4TF-1 nuclear factor, respectively.15,25 In RA patients, the higher frequency of -607A allele and/ or higher frequency of -137C allele are related to deficiency in gene transcription; that would be beneficial for the individual, protecting against the development of RA. Accordingly, one study demonstrates that the -607AA genotype is associated with lower prevalence of RA in a Chinese population.25 On the other hand, the homozygous for C at position -607 and G at position -137 promote higher levels of IL-18 mRNA compared to the other genotypes, and the resulting elevated levels of the pro-inflammatory IL-18 protein mediate many acute and chronic inflammatory processes.15,25 The aim of this study was to analyze the influence of the IL-18 polymorphisms on RA pathogenesis, as well as in CVD risk factors (dyslipidemia, blood pressure, smoking).

Methods Ninety seven RA patients diagnosed according to 1987 ACR classification criteria, from the outpatient clinic of the Rheumatology Division at the University Hospital of the Federal University of Santa Catarina, Florianópolis, Brazil, were enrolled. Control group was composed by 151 healthy volunteers without personal or family history of autoimmune diseases. The study was approved by the local Ethics Committee (CEP/UFSC – case number 172/06). All participants gave their written informed consent. Familial and epidemiologic data were collected using structured questionnaires. Clinical data were obtained from medical records.

As traditional CVD risk factors, we considered: high total (> 200 mg/dL) and LDL (> 100 mg/dL) cholesterol levels, systemic arterial hypertension (systolic arterial pressure (AP) ≥ 140 mmHg and/or dyastolic AP ≥ 90 mmHg), current smoking habit, RF positivity (> 20 IU/mL), and levels of CRP above the reference value (> 5mg/L). Peripheral blood samples were collected for DNA extraction.26 The SNP -607C/A (rs1946518) of IL-18 gene was detected by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique, amplifying a 301 base pair (bp) segment covering the polymorphic site by using the primers sequences on Table 1.27 To detect the polymorphism, the PCR products were followed by MseI restriction enzyme (BioLabs Inc., New England) digestion, at 37°C for 12 hours, then subjected to electrophoresis in a 3% agarose gel and stained with ethidium bromide (1%). The digested PCR products were identified as CC homozygous individuals when cut into 199 and 73bp fragments, and as AA homozygous individuals when cut into 101, 98 and 73 bp fragments. Thus, the CA heterozygous individuals were identified when showing the expected fragments: 199, 101, 98 and 73 bp (Fig. 1a). The SNP -137G/C (rs187238) of the same gene was detected by sequence specific PCR (PCR-SSP) method, according to Takada et al. (2002).27 In this method were used a common reverse primer (R) and two sequence-specific forwards primers, specific F1 for C allele and specific F2 for G allele, amplifying a product of 261 bp (Table 1). As an internal positive amplification control, a control forward primer (F) was used to amplify a 446 bp fragment which covers the polymorphic site (Table 1) (Fig. 1b). For confirmation of typing, we used negative and positive controls for each genotype in all experiments in both SNP detection methods. The frequencies of alleles and genotypes in RA patients and controls of both SNPs -607 and -137 was performed by direct counting. To verify the genotype distribution, the Hardy-Weinberg Equilibrium (HWE) test was calculated using GENEPOP software.28 Since both SNPs are located in the same gene, we have verified if they were inherited together due to linkage disequilibrium (LD) using GENEPOP software. Once both SNPs are linked, they can be considered as one haplotype, and frequency of its combination was calculated by PHASE software.29 The odds ratio (OR) with 95% confidence interval was obtained for association analysis30 of the polymorphisms (alleles, genotypes and haplotypes). The analysis was performed

Table 1 – Primers sequences used to amplify the -607 and -137 single polymorphisms nucleotide (SNP) in promoter site of interleukin (IL)-18 gene by polymerase chain reaction (PCR). Position -607 -137 Allele C Allele G

Primers sequences* F: 5-CTTTGCTATCATTCCAGGAA-3 R: 5-TAACCTCATTCAGGACTTCC-3 control F: 5-CCAATAGGACTGATTATTCCGCA-3 control R: 5-AGGAGGGCAAAATGCACTGG-3 specific F1: 5-CCCCAACTTTTACGGAAGAAAAG-3 specific F2: 5-CCCCAACTTTTACGGAAGAAAAC-3

*F, forward primer; R, reverse primer. G and C denote alleles.

202


Fig. 1 – Genotyping for the IL-18 position -607 (a) and -137 (b) polymorphisms. (a) Genotyping SNP -607 C/A locus in IL-18 gene by PCR-RFLP technique, whose PCR products were followed by MseI (Biolabs, New England) digestion at 37°C for 12 hours, then subjected to electrophoresis 3% agarose gel and stained with ethidium bromide (1%).27 (b) Genotyping SNP -137 G/C locus in IL-18 gene by PCR-SSP technique, whose PCR products are allele specific, subjected to electrophoresis 1.5% agarose gel and stained with ethidium bromide (1%).27 In the picture, each lane represents an individual. In (1) the PCR products were amplified with specific primer to G allele (arrow). In (2) the PCR products were amplified with specific primer to C allele (arrowhead). The fragment that was amplified by specific primers had 261 bp, while an intern control is present in both assays and amplified a fragment with 446 bp. Thus, if both bands are present in the gel it means that the specific allele is present (e.g. lane 2 represents the genotype GC). L, 50bp ladder; 1, PCR product (301bp) without digestion; samples 2 and 4 were genotype as CA (199bp. 101bp. 98bp and 73bp); sample 3 was genotyped as AA (101bp. 98bp and 73bp) and sample 5 was considered as CC genotype (199 bp and 73 bp).

separately for clinical and epidemiological data as well as for RA susceptibility and further confirmed using the HDS EpiMax Calculator.31 The -607A and -137G alleles were considered as risk alleles to RA susceptibility. A P value below 0.05 was considered significant.

Results Women were 88.66% of the RA patients and 96.40% of the controls (P > 0.05). Mean age was 54.63 (± 12.48) in patients and 48.00 (± 15.56) years old in controls (P > 0.05). Although in RA and controls the predominant ethnicity was Euro-Brazilian, frequency of Afro-Brazilians and Amerindian-Brazilians was higher in RA patients than in controls (P = 0.027) (Table 2). The allele, genotype and haplotypes frequencies of IL-18 gene polymorphisms were estimated in case and controls. The allele frequencies were showed in Table 3. The genotype frequencies distribution for both SNPs were in HWE in RA patients and controls, except for the genotype frequencies for -137 SNP in controls (P = 0.006) (Table 4). Furthermore, because we found that the polymorphisms -607 and -137 were in linkage disequilibrium in RA patients and controls (P < 0.001), both SNPs were analyzed as haplotypes (Table 5). We showed that the allele, genotype and haplotype frequencies of IL-18 gene were similar in RA patients and controls, and the IL-18 polymorphisms were not associated with the development of RA (P > 0.05). Among the prevalence of CVD risk factors in RA patients, it was observed the presence of hypercholesterolemia (54.95%), arterial hypertension (56.99%), smoking habit (41.76%), positive RF (66.27%), and high CRP levels (52.38%) (Table 2). High cholesterol levels and arterial hypertension were not associated with IL-18 gene polymorphisms. Also, we observed that smok-

ing habit in RA patients have a tendency to be associated with levels of positive RF (OR = 2.199; 0.739–6.677 95 CI%; P = 0.182), and CRP high levels (OR = 2.673; 0.961–7.546 95% CI; P = 0.061). The frequency of smokers was higher among RA patients than in controls (OR = 1.691; 0.930–3.079 95% CI; P = 0.088), however not statistically significant. Furthermore, neither RF nor smoking was associated with -607 or -137 polymorphisms.

Discussion This is an important study that analyses for the first time in a Brazilian population the genetic features of the pro-inflammatory cytokine IL-18, and its role in RA. This cytokine can be involved in the characteristic inflammatory condition that causes so many injuries in RA patients. The genotype frequencies of both -607 and -137 SNPs found in the present study resemble to other case-control studies including Caucasian RA patients, such as Polish,32 and Spanish.33 On the other hand, the genotype frequencies found in Asian studies differ from ours.25,34 Thus, the similarity to the European population regarding genotype frequencies could be explained by the high prevalence of Euro-descendants in our sample, since many immigrants from Europe were settled in Southern Brazil.35 A Chinese study found that the AA genotype of -607 SNP confers protection against RA development.25 However, this study showed no association between both -607 and -137 SNPs of IL-18 gene and susceptibility for RA development. In the same way, a recent meta-analysis on autoimmune diseases36 concluded that these polymorphisms were not related to RA development, similar to other studies done in Poland,32 Spain,33 and China.34 The latter study also showed that -607 SNP did not change IL-18 serum levels.34

203


Table 2 – Clinical and epidemiological characterization of rheumatoid arthritis patients and controls from Southern Brazil. Patients, n (%)

Total, n *

Controls, n (%)

Total, n *

86 (88.65) 54.63 (± 12.48) 69 (75.82) 20 (21.98) 2 (2.20) 38 (41.76)

97 97 91 91 91 91

146 (96.40) 48.00 (± 15.56) 121 (88.32) 15 (10.94) 1 (7.29) 39 (29.77)

151 151 137 137 137 131

50 (54.95) 53 (56.99) 55 (66.27) 44 (52.38)

91 93 83 84

MD MD MD MD

Epidemiological data Female Mean age Euro-Brazilian Afro-Brazilian Amerindian-Brazilian Smoking habit

Clinical data Hypercholesterolemia Arterial hypertension Positive RF High CRP levels

MD, missing data. * The n value differs because of data availability.

Table 3 – Allele frequencies of promoter IL-18 polymorphisms (-607C/A and -137G/C) in rheumatoid arthritis patients and controls.

SNP-607 Allele A SNP-137 Allele C

RA patients, n = 97(%)

Controls, n = 151(%)

OR (95% CI)

P

43 (44.3)

64 (42.4)

1.064 (0.732–1.547)

0.80

30 (30.4)

44 (29.1)

1.063 (0.703–1.606)

0.84

IL-18,interleukin-18; RA, rheumatoid arthritis; OR, odds ratio; CI, confidence interval. P < 0.05 was considered significant.

Table 4 – Genotypes frequencies of promoter IL-18 polymorphisms (-607C/A and -137G/C) in rheumatoid arthritis patients and controls.

-607 Genotypes CC CA AA (CA+AA) versus CC HWE -137 Genotypes GG GC CC (GC+CC) versus GG HWE

RA patients n = 97 (%)

Controls n = 151 (%)

OR (95% CI)

P

31 (32) 46 (47) 20 (21) —

48 (32) 78 (52) 25 (16) — — χ2 = 0.502

1.0 (Ref.) 0.914 (0.497-1.681) 1.164 (0.522-2.593) 0.947 (0.550-1.729) — —

— 0.86 0.83 1.00 0.83 0.33

70 (46) 74 (49) 7 (5) — — χ2 = 5.264

1.0 (Ref.) 0.946 (0.540-1.658) 1.556 (0.452-5.365) 0.999 (0.580-1.720) — —

— 0.94 0.62 1.00 0.34 0.006

χ2 = 0.149 — 45 (46) 45 (46) 7 (8) — χ2 = 0.599 —

IL-18,interleukin-18; RA, rheumatoid arthritis; OR, odds ratio; χ2, chi-square value; CI, confidence interval. P < 0.05 was considered significant. The -607CC and -137GG genotypes were considered as reference (OR = 1.0).

Although RA is a disease of complex etiology, it is believed to be caused by the combination of genetic susceptibility and several environmental factors such as infections and lifestyle characteristics, the exact contribution of each of these factors for RA development in distinct populations are not well understood and need further investigation.3,37 We demonstrated that the IL-18 SNPs were in linkage disequilibrium in RA patients, as it was ever previously shown

by other studies.25,32,33 Also, we found no association of haplotypes with RA susceptibility, in agreement to results from Spanish34 and Chinese studies.25 Nevertheless, a study from Poland found a significant decreased number of subjects with AC/AC and AG/AG diplotypes among RA patients as compared with controls, suggesting these diplotypes are related to RA development.32 The polymorphisms in the IL-18 promoter gene affect its activity, but this effect depends on

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Table 5 – Haplotypes frequencies of promoter IL-18 polymorphisms (-607C/A and -137G/C) in rheumatoid arthritis patients and controls.

Haplotype (-607/-137) C/G C/C A/G A/C

RA patients 2n = 194(%)

Controls 2n = 302 (%)

OR (95% CI)

P

103 (53) 5 (3) 32 (16) 54 (28)

159 (53) 15 (5) 55 (18) 73 (24)

1.018 (0.698–1.485) 0.512 (0.160–1.534) 0.898 (0.541–1.260) 1.228 (0.798–1.888)

0.99 0.28 0.75 0.38

IL-18,interleukin-18; RA, rheumatoid arthritis; OR, odds ratio; CI, confidence interval. P < 0.05 was considered significant.

cell types and local cytokine environment. Thus, the interaction between genotype and cellular environment remains to be evaluated.15 Although dyslipidemia is a controversial factor of CVD in RA, studies showed that low levels of HDL-cholesterol are common and could contribute for increased CV morbidity in these patients.8,17,38,39 Dyslipidemia has been associated with high levels of IL-18.20 However, our study showed that high levels of total cholesterol were not associated with the presence of the IL18 SNPs analyzed, which was found by other studies as well.24,40 Arterial hypertension is common among RA patients, but the cause of this increased prevalence compared with controls is unclear. There are multiple factors that influence blood pressure, such as obesity, physical inactivity, specific genetic polymorphisms, and some antirheumatic medications.8,37 Arterial hypertension is associated with increased IL-18 serum levels,20 and the expression of mRNA of this cytokine in atherosclerotic tissue samples was augmented when the -137GC polymorphisms and arterial hypertension were both present.41 Furthermore, a study about metabolic risk factors for CVD found that -137GC genotype confers increased risk of arterial hypertension development to African women when compared with -137GG subjects.41 In our study, however, arterial hypertension was not associated with IL-18 polymorphisms, as also demonstrated by Szeto et al.24 Smoking is a known risk factor for development of RA, and smokers with RA appear to have higher RF titers and worse prognosis in terms of disability, radiographic damage, and treatment response.38 We found no association between smoking habit and the IL-18 polymorphisms, nor between smoking habit and RF in RA patients (OR = 2.2; P > 0.05), which differs from data of a recent meta-analysis.38 In the same way, the presence of RF was not associated with the polymorphisms of IL-18 gene, as showed by other studies in RA.15,33 High levels of CRP were more frequent in RA patients who smoke, but this association was not statistically significant (OR = 2.67; P = 0.061). CRP levels were not associated with IL-18 gene polymorphisms, similarly to the results of another study.24 Although other studies have demonstrated that expression of IL-18 gene is higher in RA patients and that this cytokine might be relevant in the pathogenesis of the disease, we found that the polymorphisms -607 and -137 of IL-18 gene do not play a major role in RA susceptibility in our population. In addition, these polymorphisms are not associated with CVD risk factors in our RA patients. IL-18 exhibits pleiotropic activities in RA, with a wide variety of effects that are influenced by the overall cytokine network. Future studies considering novel genetic markers

within IL-18 or other genes involved in the cytokine network should be performed to evaluate their relevance in the context of RA and other inflammatory diseases.

Financial support Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento Pessoal de Ensino Superior (CAPES) and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC).

Conflicts of interest The authors declare no conflicts of interest.

Acknowledgements This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento Pessoal de Ensino Superior (CAPES) and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC). The authors wish to thank the patients and volunteers for their cooperation, and the colleagues that helped in this work. REFERENCES

1. Firestein GS. Envolving concepts or rheumatoid arthritis. Nature. 2003;423:356-61. 2. Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373(9664):659-72. 3. Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev. 2005;4(3):130-6. 4. Harney S, Wordsworth BP. Genetic epidemiology of rheumatoid arthritis. Tissue Antigens. 2002;60(6):465-73. 5. Coenen MJ, Grefersen PK. Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun. 2009;10(2):101-11. 6. de Souza AW, Mesquita Júnior D, Araújo JA, Catelan TT, Cruvinel W de M, Andrade LE, et al. Immune system: part III. The delicate balance of the immune system between tolerance and autoimmunity. Rev Bras Reumatol. 2010;50(6):665-79. 7. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-42. 8. Gabriel SE, Crowson CS. Risk factors for cardiovascular disease in rheumatoid arthritis. Curr Opin Rheumatol. 2012;24(2):171-6.


9. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59(12):1690-7. 10. Boyer JF, Gourraud PA, Cantagrel A, Davignon JL, Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: A meta-analysis. Jt, Bone Spine. 2011;78(2):179-83. 11. Bartoloni E, Alunno A, Bistoni O, Gerli R. Cardiovascular Risk in Rheumatoid Arthritis and Systemic Autoimmune Rheumatic Disorders: a Suggested Model of Preventive Strategy. Clin Rev Allergy Immunol. 2013;44(1):14-22. 12. Gonzalez-Juanatey C, Llorca J, Testa A, Revuelta J, GarciaPorrua C, Gonzalez-Gay MA. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine (Baltimore). 2003;82(6):40713. 13. Pereira IA, Borba EF. The role of inflammation, humoral and cell mediated autoimmunity in the pathogenesis of atherosclerosis. Swiss Med Wkly. 2008;138(37-38):534-9. 14. Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999;104(10):1393-401. 15. Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol. 2001;112(1-2):146-52. 16. Thompson SR, Humphries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun. 2007; 8(2):91-9. 17. Nurmohamed MT. Cardiovascular risk in rheumatoid arthritis. Autoimmun Rev. 2009;8(8):663-7. 18. Blankenberg S, Tiret L, Bickel C, Peetz D, Cambien F, Meyer J, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002;106:24-30. 19. Skurk T, Kolb H, Müller-Scholze S, Röhrig K, Hauner H, Herder C. The proatherogenic cytokine interleukin-18 is secreted by human adipocytes. Eur J Endocrinol. 2005;152:863-8. 20. Hulthe J, McPheat W, Samnegård A, Tornvall P, Hamsten A, Eriksson P. Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6. Atherosclerosis. 2006;188(2):450-4. 21. Hernesniemi JA, Karhunen PJ, Oksala N, Kähönen M, Levula M, Rontu R, et al. Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study. Eur Heart J. 2009;30(23):2939-46. 22. Zhang N, Yu JT, Yu NN, Lu RC, Ma T, Wang ND, et al. Interleukin-18 promoter polymorphisms and risk of ischemic stroke. Brain Res Bull. 2010;81(6):590-4. 23. Bis JC, Heckbert SR, Smith NL, Reiner AP, Rice K, Lumley T, et al. Variation in inflammation-related genes and risk of incident nonfatal myocardial infarction or ischemic stroke. Atherosclerosis. 2008;198(1):166-73. 24. Szeto CC, Chow KM, Poon PY, Kwan BC, Li PK. Association of interleukin-18 promoter polymorphism and atherosclerotic

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diseases in Chinese patients with diabetic nephropathy. Nephrology. 2009;14(6):606-12. Sivalingam SP, Yoon KH, Koh DR, Fong KY. Single-nucleotide polymorphisms of the interleukin-18 gene promoter region in rheumatoid arthritis patients: protective effect of AA genotype. Tissue Antigens. 2003;62(2):498-504. Sambrook J, Russel DW. Molecular cloning: a laboratory manual. 3.ed. New York: Cold Spring Harbour Laboratory Press; 2001. Takada T, Suzuki E, Morohashi K, Gejyo F. Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens. 2002;60(1):36-42. Raymond M, Rousset F. GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Hered 1995; 86(3):248-9. Available from: http://genepop.curtin.edu.au/ [Access in May 2011]. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68(4):978-89. Woolf B. On estimating the relation between blood groups and disease. Ann Hum Genet 1955;19(4):251-3. HDS EpiMax Table Calculator. Available from: http://www. healthstrategy.com/epiperl/epiperl.htm [Access in May 2011]. Pawlik A, Kurzawski M, Czerny B, Gawronska-Szklarz B, Drozdzik M, Herczynska M. Interleukin-18 promoter polymorphism in patients with rheumatoid arthritis. Tissue Antigens. 2006;67(5):415-8. Rueda B, González-Gay MA, Mataran L, López-Nevot MA, Martín J. Interleukin-18-promoter polymorphisms are not relevant in rheumatoid arthritis. Tissue Antigens. 2005;65(6):544-8. Ying B, Shi Y, Pan X, Song X, Huang Z, Niu Q, et al. Association of polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis. Mol Biol Rep. 2011;38(1):379-58. Salzano FM, Freire-Maia SM. Problems in Human Biology. A Study of Brazilian Populations. Detroit: Wayne State University Press; 1970. Pan HF, Leng RX, Ye DQ. Lack of association of interleukin-18 gene promoter -607 A/C polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Lupus. 2011;20(9):945-51. 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(2):152-74. Boyer JF, Gourraud PA, Cantagrel A, Davignon JL, Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: A meta-analysis. Jt, Bone Spine. 2011;78(2):179-83. Torigoe, DY, Laurindo, IMM. Artrite Reumatoide e Doenças Cardiovasculares. Rev Bras Reumatol. 2006;46(1):60-6. Evans J, Collins M, Jennings C, van der Merwe L, Söderström I, Olsson T, et al. The association of interleukin-18 genotype and serum levels with metabolic risk factors for cardiovascular disease. Eur J Endocrinol. 2007;157(5):633-40. Hernesniemi JA, Anttila K, Nieminen T, Kähönen M, Mononen N, Nikus K, et al. IL-18 gene polymorphism, cardiovascular mortality and coronary artery disease. Eur J Clin Invest. 2010;40(11):994-1001.



Review article

What a rheumatologist needs to know about yellow fever vaccine Ana Cristina Vanderley Oliveiraa, Licia Maria Henrique da Motaa,b,*, Leopoldo Luiz dos Santos-Netob, Pedro Luiz Tauilc a

Medical Sciences Program, Medical School, Universidade de Brasília (FMUnB), Brasília, DF, Brazil Department of Internal Medicine, Hospital das Forças Armadas, Brasília, DF, Brazil c Tropical Medicine Program, Medical School, Universidade de Brasília (FMUnB), Brasília, DF, Brazil b

article info

abstract

Article history:

Patients with rheumatic diseases are more susceptible to infection, due to the underlying

Received 2nd December 2011

disease itself or to its treatment. The rheumatologist should prevent infections in those

Accepted 13 December 2012

patients, vaccination being one preventive measure to be adopted. Yellow fever is one of such infectious diseases that can be avoided. The yellow fever vaccine is safe and effective

Keywords:

for the general population, but, being an attenuated live virus vaccine, it should be avoided

Yellow fever

whenever possible in rheumatic patients on immunosuppressive drugs. Considering that

Yellow fever vaccine

yellow fever is endemic in a large area of Brazil, and that vaccination against that disease

Rheumatic diseases

is indicated for those living in such area or travelling there, rheumatologists need to know

Immunosuppressive agents

that disease, as well as the indications for the yellow fever vaccine and contraindications to it. Our paper was aimed at highlighting the major aspects rheumatologists need to know about the yellow fever vaccine to decide about its indication or contraindication in specific situations. © 2013 Elsevier Editora Ltda. All rights reserved.

O que o reumatologista deve saber sobre a vacina contra febre amarela resumo Palavras-chave:

Os pacientes portadores de doenças reumáticas são mais suscetíveis à infecção, quer seja

Febre amarela

pela própria doença de base ou pelo tratamento empregado. É papel do reumatologista pre-

Vacina contra febre amarela

venir as infecções nesse grupo de pacientes e, dentre as estratégias empregadas, encontra-

Doenças reumáticas

-se a vacinação. No grupo das doenças infecciosas que podem ser prevenidas está a febre

Agentes imunossupressores

amarela. Sua vacina é segura e eficaz na população em geral, mas, assim como as vacinas contendo organismos vivos atenuados, deve ser evitada sempre que possível em portadores de doenças reumáticas em uso de medicamentos imunossupressores. Sendo a febre amarela endêmica em grande parte do Brasil, e estando a vacinação contra essa doença indicada para a população residente em extensa parte do território nacional (além dos viajantes para essas regiões), torna-se essencial que o reumatologista tenha conhecimento da doença, das indicações e contraindicações da vacina contra a febre amarela. Nosso artigo tem o objetivo de destacar os principais aspectos que o reumatologista precisa conhecer

* Corresponding author. E-mail: [email protected] (L.M.H. Mota) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.


207

sobre a vacina contra a febre amarela, para decidir por sua indicação ou contraindicação após avaliação do risco-benefício em situações específicas. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

Introduction The treatment of rheumatic diseases has improved over the years.1 The prescription of immunosuppressive drugs, usually early or even aggressive, is aimed at reducing and eventually eliminating disease activity.2 That immune system manipulation inherent to therapy in association with the autoimmune disease dysfunction can increase the risk for infections in that group of patients.2,3 The risk for severe infections in that population is two times greater than that in the general population.1 Vaccination is one of the most effective measures to prevent infectious diseases.2,4 However, the vaccination of rheumatic patients on immunosuppressive therapy requires some special considerations. Its efficacy can be jeopardized due to the immune system changes characteristic of those patients.4 In addition, there is the risk of disease activation following immunization.4,5 Vaccines containing attenuated live organisms should be avoided whenever possible in rheumatic patients on immunosuppressive drugs.2,4 These vaccines represent an increased risk to patients who cannot fight infections; in addition, vaccines can lead to manifestations similar to those of primary disease.2 The yellow fever vaccine is one of such vaccines.2,4 Yellow fever is endemic in a large area of Brazil, the yellow fever vaccine being indicated for the population living in that area and for travelers to that area; therefore, rheumatologists need to know that disease, as well as the indications for the yellow fever vaccine and contraindications to it. Our paper was aimed at highlighting the major aspects rheumatologists need to know about the yellow fever vaccine to decide about its indication or contraindication in specific situations.

Yellow fever Yellow fever is an infectious, hemorrhagic, febrile, viral disease, which is noncontagious (it is not transmitted through contact) and endemic in regions of the Africa and South America, being caused by a single-stranded RNA virus.6 In Brazil, since 2009, the Ministry of Health, based on epizootics occurring in 2008 and 2009, divided the regions according to their potential of yellow fever transmission into areas with recommendation for vaccination, previously called endemic and of transition, and areas without recommendation for vaccination, previously called disease-free areas. The areas with recommendation for vaccination are as follows: the North and West-Central Brazilian regions; the states of Maranhão and Minas Gerais; and part of the states of São Paulo, Piauí, Bahia, Paraná, Rio Grande do Sul and Santa Catarina.7,8 The disease is transmitted by the bite of hematophagous mosquitoes of the Culicidae family, especially of the Aedes and Hae-

magogus genera.6 Its transmission comprises two cycles: the urban and the sylvatic.6 In Brazil, the last urban cases were identified in 1942. Since then, the disease cases reported have been of sylvatic transmission.6 Susceptibility to yellow fever is general and neither a race nor an age group more or less susceptible to the virus is known.6 The most affected individuals are young males, because of greater exposure.6 The mean incubation period ranges from 3–6 days.6 The clinical findings vary from lack of symptoms or shortduration mild fever to a severe and fulminant infection.6,9 In moderate and severe forms, the following can occur: kidney and liver failures; heart disorders; hemorrhage; and shock.9 The overall fatality rate ranges from 5%–10%.6 Only 10% of the cases are estimated to be severe forms, associated with high fatality rate, ranging from 40%–60% of the cases.6 According to the Ministry of Health, the mean fatality rate is 52.8%, ranging from 23%–100%.7 Yellow fever cannot be eradicated because it is a zoonosis.10 Disease outbreaks occur every 5 to 7 years.7 There is no specific treatment for the disease.6 Regarding the general measures to be taken, the fight against the Aedes aegypiti mosquito is one of the major aspects to consider in combating the urban form. Appropriate garbage collection and water supply, use of larvicides, health education provided by government institutions, and population awareness to reduce transmission should prevent water stagnation, such as in flowerpots, gutters or untreated swimming pools. Regarding the urban form, wild areas should be avoided in regions with recommendation for vaccination if no immunization was performed in the period from 10 days and 10 years from the trip.6–8,10 The yellow fever vaccine is the major way to prevent that disease.6

Yellow fever vaccine The yellow fever 17D vaccine has been available in Brazil since 1937.10,11 Over 500 million doses have been used worldwide.12 It is considered to be one of the most effective and safe vaccines in the world.12 It provides protection for at least 10 years, and even lifelong protection.6,13 Within 30 days from vaccination, more than 90% of the individuals develop antibodies against yellow fever.9 About 98%–100% of the individuals vaccinated become immunized.13,14 Nevertheless, the World Health Organization recommends a booster shot every 10 years.13 Vaccination should be performed from the age of 9 months in areas with recommendation for vaccination according to the Ministry of Health. In situations of epidemic or outbreak, it should be performed from the age of 6 months.7 The original 17D strain has been developed from 176 passages of the wild Asabi strain in murine and gallinaceous tissues.13 The vaccines currently used derive from two sub-

208


strains, 17DD and 17D204,11,13 which are obtained from 287– 289 and from 235–240 passages, respectively.13 The passages are aimed at attenuating the virulence of the virus.11 In Brazil, the vaccine used is the 17DD, produced in Biomanguinhos, an agency of the Fundação Oswaldo Cruz.6 After immunization, low viremia is detected in half of the individuals vaccinated.13 There is rapid induction of humoral response and immunoglobulin M (IgM) can be detected in 7 to 10 days.13 Neutralizing antibody titers as low as 1:10 are sufficient to provide protection.13 The 17D strain is a potent inducer of CD4+ and CD8+ cytotoxic T responses.13 The innate immune system is also involved, because the 17D strain replicates minimally in dendritic cells, and can lead to their apoptosis.13 The toll-like receptors (TLR) 2, 3, 7, 8 and 9 are stimulated and the IFNα/β/γ, TNF-α and IL-1β levels increase.13,15

Adverse effects Although safe, the 17DD vaccine still has adverse effects, usually well tolerated. The following effects are considered mild and usually occur between 2 and 11 days after vaccination: local pain; inflammation; mild headache; myalgia; back pain; and transient elevation in transaminases.13,16 Anaphylaxis secondary to yellow fever vaccine is another relevant effect that occurs at the frequency of 0.9 to 1.8 per 100,000 doses, being attributed to allergy to egg or vaccinerelated gelatin allergy.12,16,17 The most relevant serious adverse effects (SAEs) are the yellow fever vaccine-associated neurotropic disease (YELAND) and the yellow fever vaccine-associated viscerotropic disease (YEL-AVD).6,13,18 According to data of the Information System of the National Immunization Program of the Brazilian Ministry of Health, 1994 adverse effects were reported from 2000 to 2008, when 101,564,083 doses of the 17DD vaccine were administered.17 The SAEs occurred more frequently after the administration of the first dose than after revaccination. There were 0.023 cases of anaphylactic shock, 9 cases of hypersensitivity, and 0.84 episodes of YEL-AND for every 1,000,000 doses. Twenty-six cases of viscerotropic disease were identified. During that period, there was an increase in publications on SAEs in Brazil.17

Yellow fever vaccine-associated neurotropic disease (YEL-AND) The incidence of YEL-AND worldwide is estimated to be between 0.4 and 9.9 for every 100,000 doses.12 It is more frequent under the age of 6 months, whose incidence varies from 0.5 to 4 cases for every 1,000 vaccines.19 The occurrence of YEL-AND decreased after suspending vaccination to that age group.20 YEL-AND might manifest as encephalitis, meningitis, neuropathy, myelitis or Guillain-Barré syndrome.12,16,19 Its clinical findings are typically mild, with complete recovery.19

Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) In 2001, the first cases of YEL-AVD were reported,18,21,22 although a retrospective analysis indicates its occurrence in the 1970s.13 In Brazil, the expected frequency is 0.006 to 1.32 cases per 100,000 doses.13 The risk of YEL-AVD increases with

age. The risk for patients aged 60 to 69 years is 4.2 per 100,000 doses, and it might reach 12.6 per 100,000 doses in those over the age of 75 years.16 It is a severe condition, whose expected fatality rate is about 60%.13 On average, the symptoms begin four days after vaccination, the findings being identical to those of the infection by the wild virus.6,23 Studies on YEL-AVD are scarce, because of the small number of cases.13 Most cases reported, except for the outbreak in Ica, Peru, have been related to different vaccine lots.13,23 Thomas et al.,24 in a systematic review, have estimated between 11.1 and 15.6 SAEs per million doses administered. The gene sequencing obtained from individuals with YELAVD is identical to that of corresponding vaccine strains.12,23 This suggests that YEL-AVD is more related to host conditions, who cannot control vaccine replication, than to mutations of the vaccine virus.12 Considering those findings, some risk factors for SAEs have already been identified: advanced age (over 60 years); male gender; thymectomy; and use of immunosuppressive drugs.13

Yellow fever vaccine and rheumatic patients Chronic rheumatic patients on immunosuppressive drugs are more often exposed to infection, and, thus, their immunization has been increasingly studied and recommended.1,4 However, according to current recommendations, the yellow fever vaccine should be avoided or even contraindicated to that group of patients, because it is an attenuated live virus vaccine with risk for uncontrolled vaccine viral replication.4,13,25,26 The European League Against Rheumatism (EULAR) recommends that live virus vaccines should be avoided and their risk should be weighed.4 According to the British Pediatric Rheumatology Group, live virus vaccines are contraindicated to all patients on cytotoxic drugs.27 However, the Brazilian Immunization Consensus for Children and Adolescents With Rheumatic Diseases recommends that children and adolescents with rheumatic diseases on immunosuppressive agents should not receive live virus vaccines, referring specifically to yellow fever.26 Da Luz states that the vaccine should not be administered to immunocompromised patients, because of their high risk of encephalitis.3 Hayes has contraindicated vaccination to those patients and encouraged the creation of new vaccines.12 However, there is no specific recommendation regarding rheumatic patients at risky areas, temporarily or not, and who are susceptible to the disease. Still regarding rheumatic patients, cases of YEL-AVD have been reported in patients with systemic lupus erythematosus and rheumatic polymyalgia.17,22,23 Thus, analysis of the risk of infection and possible SAEs associated with vaccine in that population is required. The immunosuppression degree should be assessed and varies according to the disease, the immunosuppressive drugs used, their dose and use duration.26 The disease influences the intensity of immunodeficiency because it also defines the dose and duration of treatment.28 There is no consensus about the minimum dose that causes clinical immunosuppression, and there is little evidence about the immunodeficiency caused by cytotoxic drugs at doses used for rheumatic diseases.27 Regarding corticosteroids, the use of prednisone at


equivalent doses of 10 mg/day has not been associated with an increase in infection.28 Prednisone doses at equivalent doses of 2 mg/kg/day for more than one week or 1 mg/kg/day for more than one month are contraindication to live virus vaccines in those patients.27 The British Pediatric Rheumatology Group admits immunization with live virus in patients with juvenile idiopathic arthritis who are not on immunosuppressive drugs,27 indicating that immunosuppression can be more related to therapy than to the underlying disease. Another factor to be considered is the seroconversion capacity of those patients, which is inversely proportional to their immunosuppression degree.25 Regarding the immune response of rheumatic patients, a study has assessed 17 patients with rheumatoid arthritis on biologics, who received the yellow fever vaccine. Their pre- and post-vaccine IgG and IgM titers were measured by using a method with sensitivity and specificity similar to those of the plaque reduction assay to determine neutralizing antibody titers (gold standard to assess protective immune response). Comparing the antibody titers of patients and controls, a tendency towards a reduced response in the group studied was observed, although a statistical analysis could not be performed because of the small number of patients.29 The only study about the adverse effects in that population has assessed 70 patients with several rheumatic diseases, with a mean age of 46 years, who inadvertently received the yellow fever vaccine. Of those patients, 16 (22.5%) reported minor adverse effects, which is in accordance with that expected for the healthy population.30 It is worth noting that, in general, vaccines can be related to the development of autoimmune diseases. Viral molecular structures can induce the immune activation of cells of the innate defense system and lead to self-sustained chronic inflammation.31 The time interval between vaccination and the occurrence of autoimmunity can vary from days to years, making its identification difficult.5 There have been reports of cases in which the yellow fever vaccine has triggered autoimmune diseases, such as multiple sclerosis, transverse myelitis and Kawasaki disease.32–34 Cases of autoimmune hepatitis and of multiple evanescent white dot syndrome have been reported in association with hepatitis A vaccination.35,36 Infections and immunizations can also promote immunomodulation, leading to a reduction in the exacerbated inflammatory activity.31 Regulatory T cells activated in that process can be investigated in the control of inflammation and autoimmunity.31 Similarly to that which happens with allergic diseases, the “hygiene hypothesis” suggests that the relative absence of infections would account for the increasing incidence of autoimmune diseases.31

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So what to do with patients living in endemic areas, close to the wilderness or who are exposed during work? There are no other studies assessing the response to yellow fever vaccination or its adverse effects in rheumatic patients on immunosuppressive drugs. Due to ethical reasons, that vaccine cannot be administered to those patients for scientific research purposes. In addition, conclusive results can only be yielded after assessing a large number of patients, because adverse effects seem to be rare, even in that population. To assess the cost-benefit ratio, the risk of contracting the infection should be compared with the risk of contracting the disease.25 The immunosuppressive dose used is fundamental to support the physician’s decision. According to the American Academy of Pediatrics, prednisone at equivalent doses of 2 mg/kg/day or 20 mg/day or greater doses contraindicate vaccination with live virus vaccines (Varicella Zoster).38 The Brazilian Immunization Consensus for Children and Adolescents With Rheumatic Diseases of the Brazilian Society of Rheumatology, when considering the yellow fever vaccine, states that rheumatic patients should not receive live virus vaccines, a type of vaccine that is usually contraindicated in immunosuppressed individuals.26 In specific cases, a window of opportunity can exist before starting the immunosuppressive drugs, when the live virus vaccines can be administered.27 According to the British Society of Rheumatology, vaccination should occur two weeks before beginning the treatment.27 According to that same group, at least three months should be waited for immunization with those vaccines.27 Specialists advocate the risk/benefit analysis for patients on corticosteroids and/or cytotoxic drugs. The EULAR specialists state that those vaccines should be avoided, but the risks and benefits should be considered. It is up to the assistant physician to instruct patients about the areas with recommendation for vaccination, epidemics and outbreaks, as well as to assess the individualized risk of infection and the immunosuppression degree of each patient so that the yellow fever vaccine can be properly indicated.

Financial support The author Ana Cristina Vanderley Oliveira has a CAPES-CNPq grant.

Conflicts of interest The authors declare no conflicts of interest. REFERENCES

Final considerations The current recommendation is that patients on immunosuppressive drugs should not be vaccinated against yellow fever.2,4 The vaccine with the inactivated virus is being developed and has shown good protective immune response in murines.37 However, the occurrence of periodical outbreaks enables the appearance of new cases before the vaccine is available for the population.

1. Glück T, Müller-Ladner U. Vaccination in patients with chronic rheumatic or autoimmune diseases. Clin Infect Dis. 2008;46(9):1459-65. 2. Kavanaugh A. Infection prophylaxis in antirheumatic therapy: emphasis on vaccination. Curr Opin Rheumatol. 2009;21(4):419-24. 3. da Luz KR, de Souza DCC, Ciconelli RM. Vacinação em Pacientes Imunossuprimidos e com Doenças Reumatológicas Autoimunes. Revis Bras Reumatol. 2007;47(2):106-13.

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4. van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2011;70(3):414-22. 5. Dell’Era L, Esposito S, Corona F, Principi N. Vaccination of children and adolescents with rheumatic diseases. Rheumatology (Oxford). 2011;50(8):1358-65. 6. Vasconcelos PF. Yellow Fever. Rev Soc Bras Med Trop. 2003;36(2):275-93. 7. Ministério da Saúde. Doenças infecciosas e parasitárias: guia de bolso. 8 ed. Brasília: Ministério da Saúde; 2010. 8. Ministério da Saúde. 2008 [cited 2011 3 de fevereiro]; Available from: http://portal.saude.gov.br/portal/arquivos/pdf/nota_fa.pdf. 9. Vellozzi C, Mitchell T, Miller E, Casey CG, Eidex RB, Hayes EB. Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and corticosteroid therapy: eleven United States cases, 19962004. Am J Trop Med Hyg. 2006;75(2):333-6. 10. Tauil PL. Critical aspects of yellow fever control in Brazil. Rev Saude Publica. 2010;44(3):555-8. 11. Frierson JG. The yellow fever vaccine: a history. Yale J Biol Med. 2010;83(2):77-85. 12. Hayes EB. Is it time for a new yellow fever vaccine? Vaccine. 2010;28(51):8073-6. 13. Barrett AD, Teuwen DE. Yellow fever vaccine – how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol. 2009;21(3):308-13. 14. Monath TP, Cetron MS, McCarthy K, Nichols R, Archambault WT, Weld L, et al. Yellow fever 17D vaccine safety and immunogenicity in the elderly. Hum Vaccin. 2005;1(5):207-14. 15. Neves PC, Matos DC, Marcovistz R, Galler R. TLR expression and NK cell activation after human yellow fever vaccination. Vaccine. 2009;27(41):5543-9. 16. Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF, Marano N, et al. Adverse event reports following yellow fever vaccination. Vaccine. 2008;26(48):6077-82. 17. Martins RM, Maia MLS, Santos EM, Cruz RLS, Santos PG, Carvalho SMD, et al. Yellow Fever Vaccine Post-marketing Surveillance in Brazil. Procedia in Vaccinology. 2010;2:178-83. 18. Vasconcelos PF, Luna EJ, Galler R, Silva LJ, Coimbra TL, Barros VL, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet. 2001;358(9276):91-7. 19. Fernandes GC, Camacho LA, Sa Carvalho M, Batista M, de Almeida SM. Neurological adverse events temporally associated to mass vaccination against yellow fever in Juiz de Fora, Brazil, 1999-2005. Vaccine. 2007;25(16):3124-8. 20. McMahon AW, Eidex RB, Marfin AA, Russell M, Sejvar JJ, Markoff L, et al. Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine. 2007;25(10):1727-34. 21. Chan RC, Penney DJ, Little D, Carter IW, Roberts JA, Rawlinson WD. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet. 2001;358(9276):121-2. 22. Martin M, Tsai TF, Cropp B, Chang GJ, Holmes DA, Tseng J, et al. Fever and multisystem organ failure associated with 17D204 yellow fever vaccination: a report of four cases. Lancet. 2001;358(9276):98-104.

23. Whittembury A, Ramirez G, Hernández H, Ropero AM, Waterman S, Ticona M, et al. Viscerotropic disease following yellow fever vaccination in Peru. Vaccine. 2009;27(43):5974-81. 24. Thomas RE, Lorenzetti DL, Spragins W, Jackson D, Williamson T. Active and passive surveillance of yellow fever vaccine 17D or 17DD-associated serious adverse events: systematic review. Vaccine. 2011;29(28):4544-55. 25. Bruyand M, Receveur MC, Pistone T, Verdière CH, Thiebaut R, Malvy D. Yellow fever vaccination in non-immunocompetent patients. Med Mal Infect. 2008;38(10):524-32. 26. Silva CAA, Terreri MTRA, Barbosa CMPL, Hilário MOE, Pileggi GCS, Ferriani VPL, et al. Consenso de imunização para crianças e adolescentes com doenças reumatológicas. Rev Bras Reumatol. 2009;49(5):562-89. 27. Davies K, Woo P. Immunization in rheumatic diseases of childhood: an audit of the clinical practice of British Paediatric Rheumatology Group members and a review of the evidence. Rheumatology (Oxford). 2002;41(8):937-41. 28. Cutolo M, Seriolo B, Pizzorni C, Secchi ME, Soldano S, Paolino S, et al. Use of glucocorticoids and risk of infections. Autoimmun Rev. 2008;8(2):153-5. 29. Scheinberg M, Guedes-Barbosa LS, Mangueira C, Rosseto EA, Mota L, Oliveira AC, et al. Yellow fever revaccination during infliximab therapy. Arthritis Care Res (Hoboken). 2010;62(6):896-8. 30. Mota LM, Oliveira AC, Lima RA, Santos-Neto LL, Tauil PL. Vaccination against yellow fever among patients on immunosuppressors with diagnoses of rheumatic diseases. Rev Soc Bras Med Trop. 2009;42(1):23-7. 31. Cooke A, Ferraccioli GF, Herrmann M, Romani L, Schulze C, Zampieri S, et al. Induction and protection of autoimmune rheumatic diseases. The role of infections. Clin Exp Rheumatol. 2008;26(1 Suppl 48):S1-7. 32. Schmöeller D, Keiserman MW, Staub HL, Velho FP, de Fatima Grohe M. Yellow fever vaccination and Kawasaki disease. Pediatr Infect Dis J. 2009;28(11):1037-8. 33. Gout O. Vaccinations and multiple sclerosis. Neurol Sci. 2001;22(2):151-4. 34. Chaves M, Riccio P, Patrucco L, Rojas JI, Cristiano E. Longitudinal myelitis associated with yellow fever vaccination. J Neurovirol. 2009;15(4):348-50. 35. Stangos A, Zaninetti M, Petropoulos I, Baglivo E, Pournaras C. Multiple evanescent white dot syndrome following simultaneous hepatitis-A and yellow fever vaccination. Ocul Immunol Inflamm. 2006;14(5):301-4. 36. Perumalswami P, Peng L, Odin JA. Vaccination as a triggering event for autoimmune hepatitis. Semin Liver Dis. 2009;29(3):331-4. 37. Monath TP, Lee CK, Julander JG, Brown A, Beasley DW, Watts DM, et al. Inactivated yellow fever 17D vaccine: development and nonclinical safety, immunogenicity and protective activity. Vaccine. 2010;28(22):3827-40. 38. American Academy of Pediatrics. Committee of Infectious Diseases. Red Book. 28.ed. Elk Groove Village, IL; 2009. p. 72–86.



Review article

Update on the treatment of calcinosis in dermatomyositis Samuel Katsuyuki Shinjo*, Fernando Henrique Carlos de Souza Service of Rheumatology, Hospital das Clínicas, Medical School, Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil

article info

abstract

Article history:

Calcinosis is a connective tissue disorder classified into the following four types: metastat-

Received 2nd February 2012

ic; idiopathic; iatrogenic and dystrophic. Dystrophic calcinosis can occur, for example, in


dermatomyositis, mainly in juvenile dermatomyositis, and is characterized by an abnormal deposition of calcium salts in affected skin, subcutaneous tissues, and muscles or tendons,

Keywords:

with normal serum levels of calcium and phosphate. The treatment of calcinosis in der-

Review

matomyositis remains a challenge, with few descriptions in the literature of low scientific

Calcinosis

evidence. So far, no therapy has proved to be highly effective in the combat and resolution

Dermatomyositis

of that comorbidity. The present study discusses the concept of calcinosis, particularly in

Therapy

dermatomyositis, as well as its treatment described in the literature. © 2013 Elsevier Editora Ltda. All rights reserved.

Atualização na terapêutica da calcinose em dermatomiosite informações

resumo

Palavras-chave:

Calcinose é uma afecção do tecido conjuntivo classificada em quatro tipos: metastática,

Revisão

idiopática, iatrogênica e distrófica. Esta última é o que acontece, por exemplo, em derma-

Calcinose

tomiosite, principalmente na forma juvenil, e é caracterizada por uma deposição anormal

Dermatomiosite

de sais de cálcio em pele afetada, tecidos subcutâneos, músculos ou tendões, sendo os

Terapêutica

níveis séricos de cálcio e fósforo normais. O tratamento da calcinose em dermatomiosite continua sendo um desafio, havendo poucas descrições na literatura, de pouca evidência científica. Não se apresenta, até o momento, nenhuma terapia altamente eficaz no combate e resolução dessa comorbidade. No presente trabalho, abordamos o conceito de calcinose, particularmente em dermatomiosite, assim como o seu tratamento descrito na literatura. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

Concept of calcinosis Calcinosis is a connective tissue disorder classified into the four following types: metastatic; idiopathic; iatrogenic and dystrophic.1,2 Metastatic calcinosis refers to the deposition

of calcium salts in normal tissues, with increased serum levels of calcium and/or phosphate, whose product is ≥ 70.1,2 Idiopathic calcification occurs in normal tissues, with normal serum levels of calcium and phosphate.1,2 Iatrogenic calcinosis includes the hypersensitivity reaction, which usually begins with livedo reticularis rapidly progressing to

* Corresponding author. E-mail: [email protected] (S.K. Shinjo) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.

212


the formation of skin ulcers and necrosis; it is more commonly reported in patients with chronic renal failure on hemodialysis.1 Dystrophic calcinosis is the abnormal deposition of calcium salts in affected skin, subcutaneous tissue, and muscles or tendons, with normal serum levels of calcium and phosphate.2,3 Dystrophic calcinosis can occur, for example, in dermatomyositis (DM).

Calcinosis in dermatomyositis In patients with DM, calcinosis is much more frequent in the pediatric age group, being present in 10%–70% of the cases.4–9 In adults, it is reported in about 20% of the patients,10,11 and can precede the diagnosis of DM or even appear years after that. Usually, calcinosis appears between the first and third years of the disease.6 In DM, calcinosis can present as follows: (a) hard nodules or plaques in subcutaneous or periarticular regions; (b) tumors; (c) deposits in the intermuscular fascia, leading to mobility limitation of the affected muscles; (d) severe dystrophic calcification similar to an exoskeleton; and (e) mixed form.4 Calcinosis can have a negative impact on the patients’ quality of life, causing weakness, functional disability, joint contractures, muscle atrophy, skin ulcers, and, consequently, local pains and secondary infections.

Pathogenesis and risk factors The etiopathogenesis of calcinosis in DM is unknown. Based on case reports, calcinosis is believed to result from the intracellular accumulation of calcium secondary to a change in cell membrane. It can be triggered by trauma and/or chronic inflammation,12,14–31 such as in cases nonresponsive to corticotherapy, in the presence of generalized cutaneous vasculitis, important muscle weakness, and persistent elevation in muscle enzymes.4–6,13–15 The hypothesis of inflammation at the calcinosis site is plausible, because several authors have shown the presence of cells and pro-inflammatory cytokines, such as IL-116 and TNF-alpha,17 and a variety of proteins related to mineralization, such as osteopontin, osteonectin, bone sialoprotein and hydroxyapatite,18 at the calcinosis site.17 It has also been associated with the presence of antibodies against the 140 kDa protein19 and with TNF-alpha-308A polymorphism.16 Fisler et al.20 have studied 35 cases and reported an association between calcinosis and a delay in the diagnosis and/or beginning of treatment, increased muscle enzymes, and prolonged disease duration. Similarly, Pachman et al.13 have observed calcinosis and a delay in disease diagnosis. However, Sallum et al.6 have reported the association of the development of calcified nodules, systemic involvement of the myopathy and aggressive use of medicaments. Bowyer et al.4 have shown that inadequate initial therapy plays an important role in the development of calcinosis. In addition, as previously mentioned, calcinosis is less frequent in adults with DM, raising the possibility that age-dependent factors could influence the risk of developing ectopic calcifications.21

Treatment of calcinosis in dermatomyositis The present study systematically review the treatments reported for calcinosis in DM. A literature search was conducted in the MEDLINE database by using the following terms: calcinosis and dermatomyositis. Except for 14 cases reported as having spontaneous resolution,1–4,9,22–24 calcinosis in DM tends to increase with disease progression. An early and aggressive therapeutic intervention against DM activity has been suggested to possibly reduce the musculocutaneous sequelae of the disease, including calcinosis itself.20 However, so far, no consensus has been achieved about the effective treatment for calcinosis in DM, and the data available in the literature are based only on reports and/or case series, particularly in juvenile DM. The use of the following medications has been mentioned: bisphosphonates; probenecid; warfarin; aluminum hydroxide; colchicine; diltiazem; and infliximab. Ambler et al.25 have reported the case of an 8-year-old child with chronic juvenile DM, whose calcinosis was completely resolved after using alendronate (10 mg/day) for 12 months. The patient had previously received diltiazem (15 mg, 2x/day) and probenecid (500 mg, 2x/day), with no resolution of the calcinosis. Similarly, Mukamel et al.26 have reported an improvement in calcinosis in a 6-year-old patient with juvenile DM by introducing alendronate (10 mg/day) for 12 months. Mori et al.27 have reported the use of etidronate (800 mg/ day) in a 26-year-old patient with DM, who, in addition to calcinosis, had osteoporosis. Those authors have reported the regression of calcinosis three months after beginning drug therapy. In addition, a significant improvement was observed in densitometric values after a three-year follow-up. Nevertheless, Metzger et al.28 have assessed the effect of etidronate in three patients with DM and calcinosis for 12 months, no satisfactory effect being observed. The use of pamidronate has also been described.29,30 Three patients with juvenile DM received pamidronate at the dosage of 1 mg/kg/day for three consecutive days, repeated every month. A satisfactory response was observed in all cases, including one complete resolution of the calcinosis. Based on the principle that probenecid might reduce the local inflammatory process, it has been used, but the results are controversial.8,9,31–33 Fuchs et al.34 have described a case of juvenile DM with calcinosis in the prepatellar region, accompanied by inflammation and localized cutaneous ulcer. An improvement in the cutaneous lesions was observed two months after using colchicine at the dosage of 1 mg/day. Based on the theory of having an inhibitory effect on the calcium channels of the cell membrane, diltiazem has proved to be, mainly in cases of juvenile DM, a therapeutic alternative.35–39 Its dosages have varied from 30–180 mg/day, and that drug was introduced to patients whose treatments with bisphosphonate and aluminum hydroxide did not succeed. All cases described35–39 showed an excellent response in follow-ups ranging from 6–10 months. Miyamae et al.40 have assessed the beneficial effect of thalidomide in one 14-year-old female patient with juvenile DM


for ten years, who had previously undergone pulse therapy with methylprednisolone, cyclophosphamide, cyclosporine, azathioprine, probenecid, magnesium hydroxide, aluminum hydroxide, in addition to infliximab (suspended due to adverse effects) and etanercept for disease activity and calcinosis progression. Later, at the age of 12 years, thalidomide was introduced (1.3 mg/kg/day, orally, in the first month, and, then, 2 mg/ kg/day), the response being satisfactory. Older descriptions have evidenced good results with aluminum hydroxide for patients with juvenile DM, no adverse effects being reported.41–44 Nakagawa et al.42 have reported a case with an almost complete resolution of calcinosis after eight months of treatment. Vitamin K plays an important role in calcium binding with bones and tissues.23 Based on this concept, Berger et al.45 and Matsuoka et al.46 have used low doses of warfarin to patients with juvenile DM and nodular calcinosis. Those authors have reported a reduction in the size of the lesions after using warfarin for three years. Regression of cutaneous calcinosis following intralesional infiltration of corticosteroid has been described by Al-Mayouf et al.47 in a 10.5-year-old patient, preceded by use of methotrexate and corticosteroid for disease activity. For the calcinosis located in one of the elbows, colchicine and pamidronate infusion every three months (total of five doses) were unsuccessfully used. Corticosteroid infiltration using the barbotage technique was performed, with consequent regression of the calcinosis. Surgical procedures have been reserved to extensive areas of calcification,48,49 with incision and local drainage, and have shown satisfactory results. In the era of biological therapy, infliximabe has been used at the dosage of 3 mg/kg (same schedule for rheumatoid arthritis) to treat five patients with juvenile DM refractory to previously proposed treatments; all cases had a positive response, with calcinosis regression in periods ranging from 8–30 months after beginning treatment.50 Arabshahi et al.51 have reported the use of abatacept (10 mg/kg, monthly, after fortnightly application in the first month) and sodium thiosulfate (topic, initially at 3%, and, then, at 10%, fortnightly) to a 14-year-old patient with juvenile DM for three years, refractory to corticosteroid, tacrolimus and intravenous human immunoglobulin, who had progressive calcinosis and ulcerated cutaneous lesions. The therapy instituted determined a reduction in musculocutaneous inflammation and calcinosis regression. In conclusion, the treatment of calcinosis in both adult and juvenile DM remains a challenge, with few descriptions in the literature of low scientific evidence. So far, no therapy has proved to be highly effective in the combat and resolution of that comorbidity.


1. Walsh JS, Fairley JA. Calcifying disorders of skin. J Am Acad Dermatol. 1995;33(5Pt1):693–706.

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2. Touart DM, Sau P. Cutaneous deposition diseases. Part II. J Am Acad Dermatol. 1998;39(4 Pt1):527–44. 3. Paul H, Reginato AJ, Schumacher HR. Alizarin red S staining as a screening test to detect calcium compounds in synovial fluid. Arthritis Rheum. 1983;26(2):191–200. 4. Bowyer SL, Blane CE, Sullivan DB, Cassidy JT. Childhood dermatomyositis: factors predicting functional outcome and development of dystrophic calcification. J Pediatr. 1983;103(6):882–8. 5. Sogabe T, Silva CA, Kiss MHB. Clinical and laboratory characteristics of 50 children with dermato/polymyositis. Rev Bras Reumatol. 1996;36:351–9. 6. Sallum AM, Kiss MH, Sachetti S, Resende MB, Moutinho KC, Carvalho M de S, et al. Juvenile dermatomyositis: clinical, laboratorial, histological, therapeutical and evoluative parameters of 35 patients. Arq Neuropsiquiatr. 2002;60(4):889–99. 7. Ravelli A, Trail L, Ferrari C, Ruperto N, Pistorio A, Pilkington C, et al. Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res. 2010;62(1):63–72. 8. Eddy MC, Leelawattana R, McAlister WH, Whyte MP. Calcinosis universalis complicating juvenile dermatomyositis: resolution during probenecid therapy. J Clin Endocrinol Metab. 1997;82(11):3536–42. 9. Sewell JR, Liyanage B, Ansell BM. 1978 Calcinosis in juvenile dermatomyositis. Skeletal Radiol. 1978;3:137–43. 10. Muller DA, Winkelmann RK, Brunstig LA. Calcinosis in dermatomyositis. Arch Dermatol. 1959;79(6):669–73. 11. Weinel S, Callen JP. Calcinosis cutis complicating adult-onset dermatomyositis. Arch Dermatol. 2004;140(3):365–6. 12. Crowe WE. Dermatomyositis and polymyositis In: Gershwin ME, Robbins DL. Musculoskeletal diseases of children. New York: Grune & Stratton; 1983. p.113–37. 13. Pachman LM, Boskey AL. Clinical manifestations and pathogenesis of hydroxyapatite crystal deposition in juvenile dermatomyositis. Curr Rheumatol Rep. 2006;8(3):236–43. 14. Burgos-Vargas R, Vázquez-Mellado J, Gómez-Gordillo Y, Katona G. Clinical study of dermato/polymyositis with onset in childhood . Bol Med Hosp Infant Mex. 1987;44(8):463–70. 15. Miller LC, Michael AF, Kim Y. Childhood dermatomyositis. Clinical course and long-term follow-up. Clin Pediatr. 1987;26(11):561–6. 16. Pachman LM, Liotta-Davis MR, Hong DK, Kinsella TR, Mendez EP, Kinder JM, et al. TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications. Arthritis Rheum. 2000;43(10):2368–77. 17. Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr. 2001;138(5):763–6. 18. Pachman LM, Veis A, Stock S, Abbott K, Vicari F, Patel P, et al. Composition of calcifications in children with juvenile dermatomyositis: association with chronic cutaneous inflammation. Arthritis Rheum. 2006;54(10):3345–50. 19. Gunawardena H, Wedderbun LR, Chinoy H, Betteridge ZE, North J, Ollier WER, et al. Juvenile dermatomyositis research group, UK and Ireland Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheumatism. 2009;60(6):1807–14. 20. Fisler RE, Liang MG, Fuhlbrigge RC, Yalcindag A, Sundel RP. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol. 2002;47(4):505–11. 21. Callen JP. Dermatomyositis. Lancet 2000; 355 (9197):53–7. 22. Cassidy JT, Petty RE. Dermatomyositis. In: Pediatric rheumatology, 3rd ed. Philadelphia: W.B. Saunders Co. 1995; 323–64.

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23. Wilsher ML, Holdaway IM, North JD. Hypercalcemia during resolution of calcinosis in juvenile dermatomyositis. Brit Med J (Clin Res Ed). 1984;288(6427):1345. 24. Ostrov BE, Goldsmith DP, Eichenfield AH, Athreya BH. Hypercalcemia during the resolution of calcinosis universalis in juvenile dermatomyositis. J Rheumatol. 1991;18(11):1730–4. 25. Ambler GR, Chaitow J, Rogers M, McDonald DW, Ouvrier RA. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. J Rheumatol. 2005;32(9):1837–9. 26. Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr. 2001;138(5):763–6. 27. Mori H, Okada Y, Yamaoka K, Saito K, Tanaka Y. Marked improvement of calcinosis in adult dermatomyositis with etidronate therapy. J Bone Miner Metab. 2012;30(1):114–8. 28. Metzger AL, Singer FR, Bluestone R, Pearson CM. Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. N Engl J Med. 1974;291(24):1294–6. 29. Marco Puche A, Calvo Penades I, Lopez Montesinos B. Effectiveness of the treatment with intravenous pamidronate in calcinosis in juvenile dermatomyositis. Clin Exp Rheumatol. 2010;28(1):135–40. 30. Slimani S, Abdessemed A, Haddouche A, Ladjouze-Rezig A. Complete resolution of universal calcinosis in a patient with juvenile dermatomyositis using pamidronate. Jt, Bone Spine. 2010;77(1):70–2. 31. Skuterud E, Sydnes OA, Haavik TK. 1981 Calcinosis in dermatomyositis treated with probenecid. Scand J Rheumatol. 1981;10(2):92–4. 32. Ansell BM. Treatment of dermatomyositis. Arthritis Rheum. 1977;20:341. 33. Ansell BM. Management of polymyositis and dermatomyositis. Clin Rheum Dis. 1984;10(1):205–13. 34. Fuchs D, Fruchter L, Fishel B, Holtzman M, Yaron M. Colchicine suppression of local inflammation due to calcinosis in dermatomyositis and progressive systemic sclerosis. Clin Rheumatol. 1986;5(4):527–30. 35. Downey EC, Woolley MM, Hanson V. Required surgical therapy in the pediatric patient with dermatomyositis. Arch Surg. 1988;123(9):1117–20. 36. Ichiki Y, Akiyama T, Shimozawa N, Suzuki Y, Kondo N, Kitajima Y. An extremely severe case of cutaneous calcinosis with juvenile dermatomyositis, and successful treatment with diltiazem. Br J Dermatol. 2001;144(4):894–7. 37. Jiang X, Yi Q, Liu D, Wang S, Li L. A case of juvenile dermatomyositis with severe calcinosis and successful treatment with prednisone and diltiazem Int J Dermatol. 2011;50(1):74–7.

38. Oliveri MB, Palermo R, Mautalen C, Hübscher O. Regression of calcinosis during diltiazem treatment in juvenile dermatomyositis. J Rheumatol. 1996;23(12):2152–5. 39. Vinen CS, Patel S, Bruckner FE. Regression of calcinosis associated with adult dermatomyositis following diltiazem therapy. Rheumatology (Oxford). 2000;39(3):333–4. 40. Miyamae T, Sano F, Ozawa R, Imagawa T, Inayama Y, Yokota S. Efficacy of thalidomide in a girl with inflammatory calcinosis, a severe complication of juvenile dermatomyositis. Pediatr Rheumatol Online J. 2010;8(1):6. 41. Aihara Y, Mori M, Ibe M, Kuriyama T, Takahashi Y, Shimizu C, et al. A case of juvenile dermatomyositis with calcinosis universalis-remarkable improvement with aluminum hydroxide therapy. Ryumachi. 1994;34(5):879–84. 42. Nakagawa T, Takaiwa T. Calcinosis cutis in juvenile dermatomyositis responsive to aluminum hydroxide treatment. J Dermatol. 1993;20(9):558–60. 43. Wang WJ, Lo WL, Wong CK. Calcinosis cutis in juvenile dermatomyositis: remarkable response to aluminum hydroxide therapy. Arch Dermatol. 1988;124(11):1721–2. 44. Nassim JR, Connolly CK. Treatment of calcinosis universalis with aluminium hydroxide. Arch Dis Child. 1970;45(239):118–21. 45. Berger RG, Featherstone GL, Raasch RH, McCartney WH, Hadler NM. Treatment of calcinosis universalis with low-dose warfarin. Am J Med. 1998;83(1):72–6. 46. Matsuoka Y, Miyajima S, Okada N. A case of calcinosis universalis successfully treated with low-dose warfarin. J Dermatol. 1998;25(11):716–20. 47. Al-Mayouf SM, Alsonbul A, Alismail K. Localized calcinosis in juvenile dermatomyositis: successful treatment with intralesional corticosteroids injection. Int J Rheumatic Dis. 2010;13(3):e26–e28. 48. Jashin J, Bradie J, Metz MD. Calcinosis Cutis of Juvenile Dermatomyositis Treated with Incision and Drainage Dermatol Surg. 2008;34(4):575–7. 49. Vitale A, Delia G, La Torre F, Calcagno G, D Alcontres FS. Massive gluteal calcinosis in a 10-year-old girl with juvenile dermatomyositis: successful surgical management. Plast Reconstr Surg. 2009;124(6):456e–8e. 50. Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ, Pilkington CA. Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology (Oxford). 2008;47(6):877–80. 51. Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. J Pediatr. 2012;160(3):520–2.



Case report

Chondrolysis of the hip in an adolescent: clinical and radiological outcomes Ana Paula Sakamotoa, Larissa Lucati Ramosb, Artur da Rocha Corrêa Fernandesc, Maria Teresa Terreria,* a

Pediatric Rheumatology Sector, Department of Pediatrics, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil Department of Pediatrics, Santa Casa de Misericórdia de São Paulo (SCMSP), São Paulo, SP, Brazil c Imaging Diagnosis Department, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil b

article info

abstract

Article history:

Idiopathic chondrolysis of the hip is a rare condition of unknown etiology characterized by

Received 26 April 2011

progressive destruction of the hyaline cartilage that covers the femoral head and acetabu-


lum. Idiopathic chondrolysis of the hip has an insidious beginning and affects more often female adolescents. Patients report severe hip pain, mobility limitation, and even claudi-

Keywords:

cation. This study aimed at reporting one case of that rare disease: an 11-year-old female

Hip

adolescent with chondrolysis, followed up for three years. Inflammatory activity tests were

Adolescent

normal. Imaging tests (radiography, ultrasonography and magnetic resonance) were essen-

Child

tial for the diagnosis. The treatment was based on pain control and preservation of the

Idiopathic chondrolysis of the hip

joint mobility, and included low-impact physical activity, non-steroidal anti-inflammatory drugs, and disease-modifying antirheumatic drugs, with good response after 12 months of treatment. Surgery was not necessary. © 2013 Elsevier Editora Ltda. All rights reserved.

Condrólise de quadril em uma adolescente: evolução clínica e radiológica resumo Palavras-chave:

A condrólise idiopática de quadril é uma condição rara, caracterizada por destruição pro-

Quadril

gressiva da cartilagem articular da cabeça do fêmur e do acetábulo, sem etiologia conheci-

Adolescente

da. A CIQ tem início insidioso e acomete com maior frequência meninas na adolescência.

Criança

Os pacientes apresentam dor intensa em quadril, restrição de movimentação e até claudi-

Condrólise idiopática de quadril

cação. O objetivo do trabalho foi demonstrar um caso dessa doença rara: uma adolescente de 11 anos de idade, com condrólise, em acompanhamento por três anos. As provas de atividade inflamatória eram normais. Os exames de imagem (radiografia, ultrassonografia e ressonância magnética) foram essenciais para o diagnóstico. O tratamento baseou-se no controle da dor e preservação da mobilidade articular, incluindo atividades físicas de baixo impacto, anti-inflamatórios não hormonais e droga modificadora de doença, com boa resposta após um ano de tratamento. Intervenção cirúrgica não foi necessária. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

* Corresponding author. E-mail: [email protected] (M. T. Terreri) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.

216


Introduction Idiopathic chondrolysis of the hip (ICH) is a rare condition of unknown etiology characterized by narrowing of the joint space caused by the progressive destruction of the hyaline cartilage that covers the femoral head and acetabulum.1 In the literature, the description of ICH in the pediatric age group is rare, being mostly restricted to case reports.2–6 Chondrolysis can occur as an apparently idiopathic event or be secondary to other hip pathologies.7 The most common causes of secondary chondrolysis are as follows: prolonged immobilization; neoplasias; Legg-CalvéPerthes disease (avascular necrosis of the femoral head); trauma; septic arthritis; juvenile idiopathic arthritis (JIA); Stickler syndrome; and slipped upper femoral epiphysis. Idiopathic chondrolysis of the hip most frequently affects female adolescents (80%) of Asian or African ethnicity, and is more commonly monoarticular (60% affects the right side).3,8 Bilateral ICH occurs in 5% of the cases.3,8 It is clinically characterized by severe pain in the hip, knee or the entire lower limb, mobility limitation, and claudication. Shortening of the limb might result. The differential diagnosis of ICH is difficult to be made, mainly with JIA. However, ICH lacks systemic symptoms and has normal laboratory findings (hematological, microbiological, immunological, and acute phase markers).7 In addition, the sole involvement of the hip joint is not frequent in JIA. In juvenile ICH, the radiological images are useful to exclude secondary causes.3 Magnetic resonance imaging plays an important role in the diagnosis and follow-up of that disease.8,9 Some authors have speculated on a genetic and hormonal (girls) etiology, but such hypotheses have not yet been confirmed.10,11 Morrissy et al.12 have suggested that ICH, similarly to slipped upper femoral epiphysis, could represent a seronegative type of immune response, because its joint space narrowing is similar to that of JIA.12 Other authors have demonstrated that antibodies and immune complexes in the synovial fluid could play an important role in the development of chondrolysis.13–16 Thus, although the treatment is still

Fig. 1 – Initial frontal radiography of the pelvis (Lauenstein, frog view). Osteopenia of the left hip and mild joint space narrowing can be seen.

debated and literature evidence lacks, non-steroidal antiinflammatory drugs and disease-modifying antirheumatic drugs are used. The use of biologics, such as anti-TNF-alpha agents, has been limited to a case report.10 In severe cases, when there is no response to clinical treatment, cutaneous traction can be used, in addition to surgery. The major indications of those procedures are improvement of pain and of the hip range of motion, and correction of the deformity.10 The surgical treatment includes capsulectomy with or without psoas and/or adductor tenotomy, hip arthrodesis and arthroplasty, but the results are not promising.11,17 Physical therapy is an important measure in the treatment. According to the literature, remission occurs in 54% of the cases.9 Because of the scarcity of reports on ICH in the pediatric age group, we describe the case of an 11-year-old female adolescent.

Case report The patient is an 11-year-old white female, complaining of pain in the left hip and claudication after physical exercise for one month and a half. She denied infections and/or trauma. She used a non-steroidal anti-inflammatory drug for one month with no improvement. She also denied involvement of other joints. The osteoarticular exam revealed pain and limitation to external and internal rotation of the left hip joint and limping gait. Her laboratory tests showed normal complete blood count, erythrocyte sedimentation rate of 10 mm in the first hour, normal C-reactive protein, and a negative antinuclear antibody result. The diagnostic hypothesis of chronic arthritis of the left hip was suggested. Naproxen (500 mg/day – 12 mg/ kg/day) was introduced and slit lamp examination performed, resulting normal. The tuberculin skin test was negative. The hip radiography (postero-anterior and Lauenstein views) showed mild joint space narrowing and mild osteopenia to the left (Fig. 1). Ultrasonography of the hip showed synovial thickening and joint effusion to the left. On scintigraphy, increased enhancement of the left hip was observed. Magnetic resonance imaging showed joint effusion in the left hip, a small area of 8 mm of hyposignal in T1 and hypersignal in T2 compatible with subchondral edema related to inflammatory process, with no cartilaginous lesion (Fig. 2). The diagnostic hypotheses were as follows: JIA; avascular necrosis; and chondrolysis. There was no response to naproxen, which was replaced with indomethacin (50 mg/ day – 1.2 mg/kg/day). After one month with no improvement, oral methotrexate (15 mg/week – 0.25 mg/kg/week) was introduced. Indomethacin was maintained, and motor physical therapy and swimming were initiated. After five months, the patient returned to consultation with persistent pain, and reported not using methotrexate for two months. The physical therapy and swimming were maintained. Her physical exam was unaltered. Three months after reintroducing methotrexate, the patient returned to consultation reporting pain on physical exertion and claudication after that. The methotrexate dose was increased to 20 mg, once a week, subcutaneously (0.4 mg/kg/week), the physical therapy and swimming were maintained, and new tests requested. Six months after reintroducing methotrexate, the patient was


217

Fig. 2 – Initial magnetic resonance imaging of the left hip. Coronal plane, T1- and T2-weighed fast spin-echo sequence showing moderate joint effusion and a small area with hyposignal in T1 and hypersignal in T2 (arrow), compatible with subchondral edema.

asymptomatic, with no claudication. On physical exam, mild limitation of her left hip mobility was observed. Twelve months later and 24 months of disease progression, the patient, on regular use of methotrexate, remained asymptomatic with no limitation of her left hip mobility. Her hip ultrasonography was normal. Her left hip magnetic resonance imaging showed mild lateral subchondral thinning, with no edema, and small effusion to the left in T2, showing an improvement as compared with the previous exam. Slow and progressive reduction in the methotrexate dose was initiated. After three months, the patient returned to consultation, with no complaints and denying claudication; her physical exam showed no changes. After four more months with no complaints, methotrexate was suspended. The patient is well. After a 12-month follow-up with no medication, her left hip magnetic resonance imaging showed a small amount of synovial fluid and subchondral and coxofemoral thinning in the posterosuperior portion of her hip (burden area), in addition to mild subchondral edema.

Discussion We report the case of a female adolescent with chondrolysis, whose initial complaint was chronic pain in the left hip with claudication. She reported no history of trauma, and had limitation of her hip mobility and normal laboratory tests. After receiving methotrexate and undergoing physical therapy, she improved. Her disease is currently under remission with no medication. According to the literature, ICH usually manifests as hip pain and/or radiated pain to the knees.2 The diagnosis is clinical and radiographic.1 Our patient had monoarticular involvement of the hip, as frequently described in the literature.6 In addition, hers is the most frequently reported joint impairment in a female adolescent.3 Functional limitation and limb shortening might lead to claudication, if the diagnosis and treatment are delayed, which was not the case of our patient.4,12

The patient’s radiological findings were joint space narrowing and osteopenia. The following radiographic changes of ICH are described in the literature: joint space narrowing; acetabular protrusion; subchondral cysts; joint erosion; premature closure of the growth plate; and lateral increase of the femoral head.3,6,8,9,12 The patient’s ultrasonography of the hip showed synovial thickening and joint effusion. The magnetic resonance imaging findings of ICH included early subchondral edema, joint effusion and bone marrow edema; on the progression, focal loss of the cartilage, muscle mass loss and acetabular and femoral remodeling occur.7–9 The diagnosis of ICH is difficult, requiring the exclusion of inflammatory diseases that progress with monoarthritis.4,8 The most important differential diagnosis is with JIA, the most frequent chronic arthritis of childhood. However, JIA is hardly ever restricted to the hip, usually affecting other joints.18 In addition, the patient had neither laboratory test changes (acute phase markers or presence of autoantibodies) nor extra-articular manifestations, such as iridocyclitis. In JIA, the magnetic resonance imaging shows hypervascular synovial thickening (synovial enhancement), reflecting intense inflammatory activity.8 Avascular necrosis of the femoral head, epiphysiolysis and neoplasia were excluded based on imaging tests. Trauma as a cause of chondrolysis was also ruled out because of the long duration of the symptoms and progression of the findings. Infectious causes, such as tuberculosis, should also be excluded. Van der Hoeven et al.4 have reported the presence of antinuclear antibodies, immune complex deposition and immune disorders in some patients, physiopathological factors of ICH similar to those of JIA. That fact can justify the treatment with drugs usually used to treat JIA, although the literature lacks evidence of good response. The treatment is based on controlling the progression of the disease and its symptoms, for whose relief non-steroidal anti-inflammatory drugs are recommended. Disease-modifying antirheumatic drugs, such as methotrexate, are used in

218


the absence of response to anti-inflammatory drugs, as was the case of our patient.10 Physical therapy and low-impact physical activities are additional measures that should be associated to drug treatment. Despite the poor adhesion to treatment initially, our patient had a good response in the nine months following methotrexate reintroduction. Increasing the methotrexate dose was necessary to achieve that good response. There was complete reversion of the findings, similarly to that reported in other studies.2,10 We believe that the early diagnosis and treatment, and the rapid institution of physical therapy were important factors for success. In addition, the favorable clinical and radiological outcomes prevented the need for surgery. In a case series of 14 adolescents with chondrolysis, about 70% required surgery.19 Of the 14 adolescents assessed, 4 (28%) had a poor outcome.19 Idiopathic chondrolysis of the hip should be considered in the differential diagnosis of the monoarticular involvement of the hip. Sequelae, such as an expressive reduction in the joint cartilage or changes in limb size, can be prevented with early treatment.3


1. Bruschini S. Ortopedia Pediátrica. 2.ed. São Paulo: Atheneu; 1998. 2. François J, Mulier M. Idiopathic chondrolysis of the hip: a case report. Acta Orthop Belg. 2007;73(5):653–7. 3. Hughes AW. Idiopathic chondrolysis of the hip: a case report and review of the literature. Ann Rheum Dis. 1985;44(44):268–72. 4. Van der Hoeven H, Keessen W, Kuis W. Idiopathic chondrolysis of the hip - a distinct clinical entity? Acta Orthop Scand. 1989;60(6):661–3.

5. Rachinsky I, Boguslavsky L, Cohen E, Hertzanu Y, Lantsberg S. Bilateral idiopathic chondrolysis of the hip: a case report. Clin Nucl Med. 2000;25(12):1007–9. 6. Mounach A, Nouijai A, Ghozlani I, Ghazi M, Bezza A, Achemlal L, et al. Idiopathic chondrolysis of the hip – case report. Jt, Bone Spine 2007;74(6):656–8. 7. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of Pediatric Rheumatology. 6.ed. Philadelphia: Elsevier; 2011. 8. Johnson K, Haigh SF, Ehtisham S, Ryder C, Gardner-Medwin J. Childhood idiopathic chondrolysis of the hip: MRI features. Pediatr Radiol. 2003;33(3):194–9. 9. Laor T, Crawford AH. Idiopathic chondrolysis of the hip in children: early MRI findings. Am J Roentgenol. 2009;192(2):526–33. 10. Appleyard DV, Schiller JR, Eberson CP, Ehrlich MG. Idiopathic chondrolysis treated with etanercept. Orthopedics. 2009;32(3):214–7. 11. Korula RJ, Jebaraj I, David KS. Idiopathic chondrolysis of the hip: medium to long-term results. ANZ J Surg. 2005;75(9):750–3. 12. Morrissy RT, Steele RW, Gerdes MH. Localized immune complexes and slipped upper femoral epiphysis. J Bone Joint Surg Br. 1983;65(5):574–9. 13. Eisenstein A, Rothschild S. Biochemical abnormalities in patients with slipped capital femoral epiphysis and chondrolysis. J Bone Joint Surg Am. 1976;58(4):459–67. 14. Herman JH, Herzig EB, Crissman JD, Dennis MV, Hess EV. Idiopathic chondrolysis – an immunopathological study. J Rheumatol. 1980;7(5):694–705. 15. Joseph B, Pydisetty RK, Chondrolysis and the stiff hip in Perthes´disease: an immunological study. J Pediatr Orthop. 1996;16(1):15–9. 16. Yoshioka Y, Shichikawa K. Autoimmunity and chondrolysis of the hip. A report of two cases. Int Orthop. 1987;11(3):289–93. 17. Abril JC, Ferrer A, Castillo F, Ferrer-Torrelles M. An intraarticular hip process with chondrolysis simulating Perthes disease: a report of five cases. J Pediatr Orthop. 2000;20(6):729–35. 18. Houghton KM. Review for the generalist: evaluation of pediatric hip pain. Pediatr Rheumatol Online J. 2009;7:10–9. 19. Bilski P, Snela S. Difficulties in treating chondrolysis and avascular necrosis of the hip in adolescent patients. Ortop Traumatol Rehabil. 2006;8(1):34–40.



Case report

Mesenteric vasculitis in a juvenile systemic lupus erythematosus patient Adão F. Albuquerque-Nettoa, Erica G. Cavalcanteb, Adriana M. E. Sallumc, Nádia E. Aikawab, Uenis Tannurid, Clovis Artur Almeida da Silvab,* a

Faculdade de Ciências Médicas e da Saúde, Pontifícia Universidade Católica de São Paulo (FCMS-PUC-SP), São Paulo, SP, Brazil Pediatric Rheumatology Unit, Department of Clinical Medicine, Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (ICr-HC-FMUSP), São Paulo, SP, Brazil c Department of Pediatrics, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil d Pediatric Surgery Unit, Department of Surgery, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil b

article info

abstract

Article history:

Lupus mesenteric vasculitis (LMV) is a rare cause of acute abdominal pain. Few cases of

Received on 16 May 2011

LMV have been reported in adults, children and adolescents. However, to our knowledge,


the prevalence of that severe vasculitis in a pediatric population with lupus is yet to be studied. This study reviewed data from 28 consecutive years and included 5,508 patients

Keywords:

being followed up at the hospital of the Faculdade de Medicina of the Univesidade de São

Vasculitis

Paulo (FMUSP). We identified 279 (5.1%) patients meeting the American College of Rheuma-

Adolescent

tology classification criteria for the diagnosis of systemic lupus erythematosus (SLE), one

Cutaneous lupus erythematosus

of whom (0.4%) had LMV. That male patient was diagnosed with SLE at the age of 11 years. At the age of 13 years, he was hospitalized with diffuse and acute abdominal pain, nausea, bilious vomiting, abdominal distension, rebound tenderness, and abdominal muscle guarding. The patient underwent laparotomy immediately, and segmentary intestinal ischemia with intestinal wall edema and adhesions were identified. Partial small bowel resection with lysis of the adhesions was performed, as were pulses of intravenous methylprednisolone. The histopathologic analysis evidenced mesenteric arteritis. After 13 days, the diffuse and intense abdominal pain recurred, and the patient underwent a new laparotomy, during which adhesive small bowel obstruction with intestinal gangrene was identified. New intestinal resection was performed, and the patient received pulses of intravenous methylprednisolone and infusion of immunoglobulin. Thus, LMV is a rare and severe abdominal manifestation of the pediatric population with lupus, and can be the only manifestation of disease activity. In addition, this study stresses the importance of the early diagnosis and immediate treatment. © 2013 Elsevier Editora Ltda. All rights reserved.

* Corresponding author. E-mail: [email protected] (C.A.A. da Silva) 0482-5004/$ - see front matter. © 2013 Elsevier Editora Ltda. All rights reserved.

220


Vasculite mesentérica em paciente com lúpus eritematoso sistêmico juvenil resumo Palavras-chave:

A vasculite mesentérica lúpica (VML) é uma rara causa de dor abdominal aguda. Há poucos

Vasculite

relatos de caso demonstrando VML em adultos e, particularmente, em crianças e adoles-

Adolescente

centes. No entanto, para o nosso conhecimento, a prevalência dessa grave vasculite em uma

Lúpus eritematoso cutâneo

população pediátrica com lúpus ainda não foi estudada. Portanto, dados de 28 anos consecutivos foram revisados e incluídos 5.508 pacientes em seguimento no Hospital da Faculdade de Medicina da Univesidade de São Paulo (FMUSP). Identificamos 279 (5,1%) casos que preencheram critérios de classificação diagnóstica do American College of Rheumatology para lúpus eritematoso sistêmico (LES) e um (0,4%) desses apresentou VML. Este paciente recebeu diagnóstico de LES aos 11 anos de idade. Aos 13 anos foi hospitalizado com dor abdominal difusa e aguda, náuseas, vômitos biliosos, distensão e rigidez abdominal, com descompressão brusca positiva. O paciente foi prontamente submetido à laparotomia exploradora, identificando isquemia intestinal segmentar, com edema de parede intestinal e aderências. Foi realizada ressecção parcial de intestino delgado, com lise das aderências e pulsoterapia com metilprednisolona. A análise histopatológica identificou arterite de vasos mesentéricos. Após 13 dias, apresentou recorrência de dor abdominal difusa intensa, sendo novamente submetido à laparotomia exploradora, identificando obstrução em intestino delgado por aderências, com gangrena intestinal. Nova ressecção intestinal foi realizada, além de pulsoterapia com metilprednisolona e infusão de imunoglobulina. Portanto, VML é uma rara e grave manifestação abdominal na população com lúpus pediátrico, e pode ser a única manifestação de atividade da doença. Além disso, este estudo reforça a importância do diagnóstico precoce e do tratamento imediato. © 2013 Elsevier Editora Ltda. Todos os direitos reservados.

Introduction

Case report

Systemic lupus erythematosus (SLE) may affect multiple organs and systems, such as gastrointestinal involvement.1,2 Digestive tract manifestations in SLE patients are generally caused by treatment related to adverse events, infections,3 and disease activity.2,4 Of note, lupus mesenteric vasculitis (LMV) is a cause of acute abdominal pain, associated with nausea, vomiting, diarrhea in SLE patients usually with disease activity.4 The diagnosis of LMV requires the evaluation of bowel wall and the abdominal vasculature by image examination,4 such as abdominal ultrasound,3,5,6 computer tomography scan,3,7,8 magnetic resonance image,6 digital arteriography,8 and/or particularly histopathological findings.4 A few case reports have demonstrated LMV in adult SLE7,8,10 and particularly in juvenile SLE (JSLE) patients.5,6,9,10 However, to our knowledge, the prevalence of this severe vasculitis in paediatric lupus population has not been studied. Therefore, from January 1983 to December 2010, 5,508 patients were followed-up at the Paediatric Rheumatology Unit of the Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (ICr-HC-FMUSP) and 279 (5%) of them were acquainted to the American College of Rheumatology (ACR)11 classification criteria for SLE. Only one (0.4%) of our JSLE patients had LMV, confirmed by the description of histopathological findings and required intestinal resections. This study was approved by the Local Ethics Committee of FMUSP.

An 11-year old boy was diagnosed with JSLE based on malar rash, arthritis, pericarditis, psychosis, lymphopenia, and thrombocytopenia, and positivity of the following autoantibodies: antinuclear antibodies (ANA) 1:1280 (speckled pattern), anti-Sm, and anti-double stranded DNA (anti-dsDNA) antibodies. At that moment, the SLE Disease Activity Index 2000 (SLEDAI-2K)12 was 19 and he received three pulses of intravenous methylprednisolone, intravenous cyclophosphamide (500–1,000 mg/m2/month for 24 months) and prednisone (2.0 mg/kg/day), with progressive dose decrease to 7.5 mg/day. At the age of 13, he was hospitalized due to an acute diffuse abdominal pain, nausea and bilious vomiting. On physical examination, he had abdominal distension, rebound tenderness and abdominal muscle guarding, compatible with acute surgical abdomen. At that moment, he was under 7.5 mg/day of prednisone and abdominal ultra-sound examination showed mild ascites, diffuse distension and bowel-wall thickening. Laboratory tests showed hemoglobin 13.5 g/L, hematocrit 40%, white blood cell count 5,400/mm3 (72% neutrophils, 21% lymphocytes, 4% eosinophils and 3% monocyte), platelets 265,000/mm3, proteinuria (0.02 g/24h), urinalysis – leukocytes 500 high-power field, and erythrocytes 250 high-power field, urea 19 mg/dL (normal range 10– 42), creatinine 0.5 mg/dL (normal range 0.5–0.9), C3 0.86 mg/ dL (normal range 0.5–1.8), C4 0.13 mg/dL (normal range 0.1– 0.4), and amylases 46 U/L (normal