Acta Reumatológica Portuguesa Rahman (UK) Bernard Mazières (França) Carmo Afonso (Portugal) Clovis Silva (Brasil) Dafna Gladman (Canada) ... A Tabela I resume as prevalências en

Publicação Trimestral • ISS

N: 0303-464X

• 10

€

Vol 36 • Nº 3Julho/Setembro 2011

Acta

Reumatológica

Portuguesa

Acta Reumatológica Portuguesa

e d i t o r e s / e d i t o r s

Editor Chefe (Chief Editor)Lúcia Costa

Editores Associados (Associated Editors)António Albino José Carlos RomeuFilipa Mourão José Melo GomesFilipa Ramos Luís GraçaHelena Canhão Maria José LeandroJoão Eurico Fonseca Maria José SantosJosé António Pereira da Silva Mónica Bogas

Alfonse Masi (USA)Anisur Rahman (UK)Bernard Mazières (França)Carmo Afonso (Portugal)Clovis Silva (Brasil)Dafna Gladman (Canada)Emília Sato (Brasil)Evrim Karadag-Saygi (Turquia)Francisco Airton Rocha (Brasil)Gabriel Herero-Beaumont (Espanha)

Gomez Reino (Espanha)Graciela Alarcon (USA)Ivânio Alves Pereira (Brasil)Jaime Branco (Portugal)Johannes Bijlsma (Holanda)John Isacs (UK)José Alberto Pereira da Silva (Portugal)José Canas da Silva (Portugal)José Vaz Patto (Portugal)Loreto Carmona (Espanha)

Marcos Ferraz (Brasil)Mário Viana Queiroz (Portugal)Maurizio Cutolo (Itália)Patrícia Nero (Portugal)Paul Peter Tak (Holanda)Piet Van Riel (Holanda)Ralph Schumacher (USA)Raquel Lucas (Portugal)Yrjo Konttinen (Finlândia)

Administração, Direcção Comercial e Serviços de PublicidadePublisaúde - Edições Médicas, LdaAlameda António Sérgio 22, 4º BEdif. Amadeo de Souza-Cardoso1495-132 AlgésTel: 214 135 032 • Fax: 214 135 007Website: www.publisaude.pai.pt

RedacçãoSociedade Portuguesa de ReumatologiaAvenida de Berlim, Nº 33B1800-033 Lisboa

RegistoIsenta de inscrição no I.C.S. nos termos daalínea a) do n.o 1 do artigo 12.0 do Decreto Regulamentar n.o 8/99, de 9 de Junho.

Assinaturas Anuais (4 Números)Yearly Subscriptions (4 Issues)Individual/Personal Rate

Portugal ..........................45 €Outside Portugal ..........65 €

Instituições/Institutional RatePortugal ..........................55 €Outside Portugal ..........75 €

Depósito Legal: 86.955/95

Tiragem: 6.500 exemplares

Impressão e AcabamentoDilazo – Artes Gráficas, Lda.R. Cidade de Aveiro, 7-A – Frielas

Produção GráficaRita Correia

PeriodicidadePublicação Trimestral

c o n s e l h o e d i t o r i a l / e d i t o r i a l b o a r d

Revista referenciada no Index Medicus, Medline, Pubmed desde Janeiro 2006.

Journal referred in Index Medicus, Medline, Pubmed since January 2006.

Revista incluída nos produtos e serviços disponibilizados pela Thomson Reuters, com indexação e publicação de resumos desde Janeiro de 2007 em: • Science Citation Index Expanded (also known as SciSearch®)• Journal Citation Reports/Science Edition

Journal selected for coverage in Thomson Reuters products and custom information services. This publication is indexed and abstracted since January 2007 in the following:

• Science Citation Index Expanded (also known as SciSearch®)• Journal Citation Reports/Science Edition

Proibida a reprodução, mesmo parcial, de artigos e ilustrações, sem prévia autorização da Acta Reumatológica Portuguesa. Exceptua-se a citação ou transcrição de pequenos excertos desde que se faça menção da fonte.

O papel utilizado nesta publicação cumpre os requisitos da ANSI/NISO Z39.48-1992 (Permanence of Paper).The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper).

e d i t o r t é c n i c o / t e c h n i c a l e d i t o r

J. Cavaleiro

Presidente Dr. Luís Maurício Santos

Vice-Presidente Dr. José Carlos Romeu

Vice-Presidente Prof. Dr. João Eurico Cabral Fonseca

Sec. Geral Dr. Luís Cunha-Miranda

Sec. Geral Adjunto Dra. Maria Lúcia Carvalho Dias Costa

Tesoureiro Dra. Anabela Barcelos

Vogal Região Norte Dr. José Miguel Andrade Oliveira Bernardes

Vogal Região Centro Dra. Margarida Alexandre Oliveira

Vogal Região Sul Dra. Sandra Isabel Salvador Falcão

Vogal Ilhas Dr. Herberto Rúben C. Teixeira Jesus

Presidente-Eleito Dra. Viviana Tavares

D I R E C C A O

Ó R G Ã O S S O C I A I S D A S P R

B I É N I O 2 0 1 1 - 2 0 1 2

Presidente Dr. Rui André Santos

Secretário Dra. Maria Cristina Nobre Catita

Secretário Dra. Ana Filipa Lopes Oliveira Ramos

M E S A D A A S S E M B L E I A G E R A L

Presidente Dr. José Maria Gonçalves Vaz Patto

Relator Dr. Jorge Silva

Vogal Dra. Cláudia Margarida M. O. Crespo da Cruz

C O N S E L H O F I S C A L

A Acta Reumatológica Portuguesa é o órgão oficial da Sociedade Portuguesa de Reumatologia

órgão of ic ial da soc iedade portuguesa de reumatologia

200


Vol 36 • Nº3 Julho/Setembro 2011

s u m á r i o / c o n t e n t s

e d i t o r i a i s / e d i t o r i a l s

Estudo Epidemiológico das Doenças Reumáticas em Portugal – EpiReumaPt 203Epidemiological Study of Rheumatic Diseases in Portugal – EpiReumaPtJaime C. Branco, Helena Canhão

Biologicals and switch in rheumatoid arthritis throughout time – are we being more aggressive? 234Sofia Ramiro, Raquel Roque, Filipe Vinagre, Ana Cordeiro, Viviana Tavares, Astrid Van Tubergen, J. Canas da Silva, Robert Landewé, M. José Santos

Interobserver reliability in ultrasound assessment of rheumatoid wrist joints 245Karine R. Luz, Rita N.V. Furtado, Sonia V. Mitraud, Jorge Porglhof, Conceição Nunes, Artur R. C. Fernandes, Jamil Natour

Biologic therapy and pregnancy. A systematic literature review 219Bogas M, Leandro MJ

ACPA (Anti-Citrullinated Protein Antibodies) and rheumatoid arthritis 205Rene E. M. Toes, Diane van der Woude

Muscular kinetics and fatigue evaluation of knee using by isokinetic dynamometer 252in patients with ankylosing spondylitisNilay Sahin, Emel Ozcan, Akin Baskent, Ayse Karan, Erdem Kasikcioglu

Psychometric properties of the portuguese version of the Pain Self-Efficacy Questionnaire 260M. Alexandra Ferreira-Valente, José L. Pais-Ribeiro, Mark P. Jensen

a r t i g o s o r i g i n a i s / o r i g i n a l pa p e r s

RANK/RANKL/OPG: literature review 209Silva I, Branco JC

a r t i g o s d e r e v i s ã o / r e v i e w s


201



Paget’s disease of bone and its complications due to delay in diagnosis 288Lorena Penha de Almeida, Juliana Alves Scrignoli, Kelly Simone Castro dos Santos, Luiz Fernando de Souza Passos, Sandra Lúcia Euzébio Ribeiro

Policondrite recidivante, dermatite intersticial granulomatosa e síndrome antifosfolípido: 292uma associação clínica invulgarRelapsing polychondritis, interstitial granulomatous dermatitis and antiphospholipid syndrome: an unusual clinical associationS Serra, P Monteiro, E Pires, R Vieira, O Telechea, L Inês, M J Salvador, A Malcata

Crioglobulinémia mista 298Mixed cryoglobulinemiaRoque R, Ramiro S, Vinagre F, Cordeiro A, Godinho F, Santos MJ, Gonçalves P, Canas da Silva J

Schwannoma of the posterior tibial nerve in leprosy patient: imaging features 309Erilane Leite Guedes, Sandra Lúcia Euzébio Ribeiro, Paula Frassinetti Bessa Rebello, Denis Esteves Raid, Ernani Júnior Guedes de Freitas

i m a g e n s e m r e u m at o l o g i a / i m a g e s i n r h e u m at o l o g y

Kawasaki disease in a young infant: diagnostic challenges 304Marta Cabral, Paula Correia, Maria João Brito, Marta Conde, Helena Carreiro


Endocardite com hemoculturas negativas e alterações imunológicas: um grande desafio 282Endocarditis with negative blood cultures and immunological alterations: a grand challengeHerval de Lacerda Bonfante, Heloína Lamha Machado Bonfante, Carolina Bassoli de Azevedo, Lena Márcia de Carvalho Valle, José Resende de Castro Júnior

c a s o s c l í n i c o s / c l i n i c a l c a s e s

Physiotherapy in hip and knee osteoarthritis: development of a practice guideline concerning 268initial assessment, treatment and evaluationW.F.H. Peter, M.J. Jansen, E.J. Hurkmans, H. Bloo, L.M.M.C.J. Dekker-Bakker, R.G. Dilling, W.K.H.A. Hilberdink, C. Kersten-Smit, M. de Rooij, C. Veenhof, H.M. Vermeulen, I. de Vos, J.W. Schoones, T.P.M. Vliet Vlieland

p r át i c a c l í n i c a / c l i n i c a l p r a c t i c e


202



Neuropatia periférica e leflunomida 313Peripheral neuropathy and leflunomideSantiago T, Rovisco J, Silva J, Malcata A


a g e n d a

n o r m a s d e p u b l i c a ç ã o / i n s t r u c t i o n s t o a u t h o r s

316

317

Olanzapine treatment improved quality of life in a patient with fibromyalgia syndrome: 311a psychological evaluationCorallo F, Italiano D, Bonanno L, Baglieri A, Marino S, Bramanti P

c a r ta s a o e d i t o r / l e t t e r s t o t h e e d i t o r

órgão of ic ial da soc iedade portuguesa de reumatologia - acta reumatol port. 2011;36:203-204

203

e d i t o r i a l

e s t u d o e p i d e m i o l ó g i c o d a s d o e n ç a s

r e u m át i c a s e m p o r t u g a l – e p i r e u m a p t

Jaime C. Branco*, Helena Canhão**

As doenças reumáticas (DR) são, nos países desen-volvidos, o grupo de doenças mais frequentes daraça humana e representam um importante pro-blema médico, social e económico.

As DR, no seu conjunto, têm um enorme im-pacto quer no indivíduo doente e sua família, querao nível social e representam uma avultada factu-ra económica para os países.

As DR são o primeiro motivo de consulta noscuidados de saúde primários e são também a prin-cipal causa de incapacidade temporária para o tra-balho e de reformas antecipadas por doença/inva-lidez. Assim, as DR têm um importante impactonegativo em termos de saúde pública, com tendên -cia crescente, tendo em conta os actuais estilos devida e o aumento de longevidade das populações.

As queixas clínicas referidas ao sistema músculo--esquelético (SM-E) atingem, em média e em cadamomento, cerca de 1/3 da população adulta, 1/4 daspessoas maiores de 18 anos padecem de alguma for-ma de doença M-E que, tem um carácter crónico em1/5 de todos os indivíduos adultos. As DR constituementre 70% e 85% de todas estas situações1.

No 4º Inquérito Nacional de Saúde 2005/06 a pre-valência, das DR auto-declaradas, ao longo da vida,foi de 16,3% para a população continental. Este va-lor só foi ultrapassado pela HTA com 20% de pre-valência. A frequência das DR nas Regiões Autóno-mas (RA) foi menor (6% para a Madeira e 12,9% paraos Açores). Quer no Continente quer nas RA, as DRforam mais prevalentes nas idades mais avançadase nas mulheres, para todos os grupos etários2.

Num estudo do Observatório Nacional de Saúde,

de 2005, a prevalência auto-declarada das DR foiainda mais elevada (24%) mas continuou a ser maisfrequente nas mulheres (29,1%) do que nos ho mens(18,3%) e também aumentava com a idade3.

Os estudos realizados em Portugal no início domilénio mostraram números homogéneos e coin-cidentes, apresentando as DR como a patologia clí-nica mais prevalente (entre 28% e 37% da popula-ção) e principal motivo de consulta de clínica ge-ral/medicina familiar (i.e., 20% do total)4,5.

O Observatório Nacional das Doenças reumáti-cas (ONDOR), utilizando a coorte EpiPorto (n=2485indivíduos) identificou pelo menos um diagnósti-co de DR (entre as doenças mais frequentes e/oumais importantes) em 23% dessa população. Denovo, as mulheres (28,7%) apresentavam pelo me-nos uma destas doenças mais frequentemente doque os homens (13,1%)6.

As queixas dolorosas músculo-esqueléticas sãotambém muito frequentes nas crianças e adoles-centes. Num estudo realizado, em 2002, pelo nos-so grupo de trabalho, que incluiu 762 indivíduosentre 6 e 17 anos, a prevalência da dor músculo-es-quelética nos 3 meses anteriores à avaliação foi de28,4%. Estas dores foram muito mais mencionadaspelos indivíduos do sexo feminino (62,8%) e foramsobretudo referidas aos membros inferiores7.

O programa CINDI (Countrywide Noncommu-nicable Disease Intervention),patrocinado pela Or-ganização Mundial de Saúde, realizado em Portu-gal, nos anos 80, incluiu a avaliação da prevalênciadas DR. Neste estudo, efectuado na península deSetúbal, foi observada, por reumatologistas, umapopulação aleatorizada de 1381 indivíduos de am-bos os sexos8. A Tabela I resume as prevalências en-contradas neste trabalho para algumas DR.

Este trabalho realizado há mais de 20 anos, foi oque, até hoje, envolveu a maior amostra popula-cional com o objectivo de estudar a prevalência devárias doenças reumáticas no nosso país.

Muitos outros trabalhos de natureza epidemio-lógica foram efectuados entre nós. Uns destina-vam-se a caracterizar apenas uma patologia espe-

*Investigador Principal do EpiReumaPt; Professor Associado com

Agregação da Faculdade de Ciências Médicas (FCM) da

Universidade Nova de Lisboa (UNL); Investigador Principal do

CEDOC da FCM da UNL; Director do Serviço de Reumatologia

do CHLO, EPE/Hospital Egas Moniz, Lisboa; Coordenador do

Programa Nacional Contra as Doenças Reumáticas

** Investigadora EpiReumaPt; Investigadora Principal, Unidade de

Investigação em Reumatologia, Instituto de Medicina Molecular:

Professora Auxiliar de Reumatologia, Faculdade de Medicina da

Universidade de Lisboa; Reumatologista, Hospital de Santa Maria,

CHLN, Lisboa


204

cífica; outros, ou foram levados a cabo em áreasgeográficas menores, ou não conseguiram reunirpopulações mais amplas.

Os estudos que foram realizados nos últimosdez anos foram objecto de extensa e profunda re-visão. As conclusões deste trabalho apontam paravárias e importantes lacunas no conhecimentoepidemiológico das DR em Portugal9.

A falta de dados epidemiológicos nacionais,confiáveis e actualizados sobre as DR em geral e al-gumas das mais importantes em particular, é umarealidade há muito identificada.

Por isso, o Programa Nacional Contra as Doen-ças Reumáticas (PNCDR), aprovado por despachoministerial de 26 de Março de 2004, apontava, comoprimeiro dos cinco objectivos específicos identifi-cados, a necessidade de «conhecer a prevalênciadas DR abrangidas pelo presente Programa»10.

Três dos outros quatro objectivos definiam aprecisão de «conhecer a incidência, respectiva-mente, das doenças reumáticas periarticulares,lombalgias e fracturas osteoporóticas»10.

Em consequência, o EpiReumaPt começou aser desenhado e planeado logo no fim de 2004.Contudo, por vicissitudes várias, só a partir de 2010se foram sucessivamente reunindo os meios ma-teriais, os recursos humanos, a capacidade orga-nizativa e os apoios financeiros para o concretizar.

Neste sentido, foi publicado o protocolo do es-tudo e foram criadas as condições julgadas neces-sárias e suficientes para que ele se possa iniciar noúltimo trimestre de 201111.

A extensa e árdua recolha de dados (isto é, in-quérito do entrevistador e consulta do reumatolo-gista) vão durar, pelos menos, 2 anos. Seguir-se-á ademorada e complexa fase de tratamento estatísti-co da enorme quantidade de elementos recolhidos.

Assim, será possível que os primeiros resultadospossam começar a ser libertados durante a pri-

meira metade do ano de 2014.Exactamente nesse momento, em que cessa a vi-

gência do PNCDR, estaremos na posse dos resulta-dos necessários para elaborar o próximo Programa,que se espera poder servir como guia para o pla-neamento e roteiro para a administração dos recur-sos do Sistema Nacional de Saúde, tendo em vista aresolução das necessidades e carências identifica-das, sempre com o intuito de melhorar a assistênciamédica aos doentes reumáticos no nosso País.

Correspondência paraJaime C. BrancoServiço de Reumatologia CHLO, EPE/Hospital Egas MonizRua da Junqueira, 1261349-019, Lisboa, PortugalTelef / Fax +351213629353E-mail: [email protected]

Referências1. Badley EM, Webster GK, Rasooly I. The impact of mus-

culoskeletal disorders in the population: are they justaches and pains? Findings from the 1990 OntarioHealth Survey. J Rheumatol 1995; 22: 733-739

2. Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA) eInstituto Nacional de Estatística (INE). Indicadoresadicionais do 4º Inquérito Nacional de Saúde [Inter-net]. INE, Lisboa, 2009

3. Instituto Nacional de Saúde Dr. Ricardo Jorge – Obser-vatório Nacional de Saúde (ONSA). Uma observação so-bre a prevalência de algumas doenças crónicas em Portu-gal Continental. Instituto Nacional de Saúde Dr. Ricar doJorge. Observatório Nacional de Saúde, Lisboa, 2005

4. Faustino A. Aspectos da reumatologia em Portugal:relevân cia epidemiológica das doenças reumáticas emPortugal. Rev Port Reumatol Patol Osteo Art 2003; 13:4-5

5. Faustino A. Epidemiologia e importância económica esocial das doenças reumáticas: estudos nacionais. Acta Reumatol Port 2002; 27: 21-36

6. Costa L, Gal D, Barros H. Prevalência auto-declaradade doenças reumáticas numa população urbana. ActaReumatol Port 2004; 29: 169-174

7. Costa MM, Nero P, Branco E, Branco JC. Dor músculo-esquelética na criança e adolescente. Acta ReumatolPort 2002; 27: 165-174

8. Matos AA, Branco JC, Silva JC, Queiroz MV, Pádua F.Inquérito epidemiológico das doenças reumáticasnuma amostra da população portuguesa (ResultadosPreliminares). Acta Reumatol Port 1991; 16 (1): 98

9. Monjardino T, Lucas R, Barros H. Frequency of rheu -matic diseases in Portugal: a systematic review. ActaReumatol Port 2011 (submetido para publicação)

10. Marques A, Branco JC, Costa JT, Miranda LC, AlmeidaM, Reis P, Santos RA, Tavares V, Diniz A, Queiroz VM.Programa Nacional Contra as Doenças Reumáticas.Direcção Geral da Saúde, Lisboa, 2005: 1-92

11. Ramiro S, Canhão H, Branco JC. EpiReumaPt Protocol– Portuguese Epidemiologic Study of the Rheu ma ticDiseases. Acta Reumatol Port 2010; 35: 384-390

Tabela I. Frequência de algumas (DR)*

DR Prevalência

Gota úrica 1,5%

Artrite reumatóide 0,36%

Espondilite anquilosante 0,22%

Artrite psoriática 0,14%

Artrite idiopática juvenil 0,07%

*Nesta população de 1.381 indivíduos não foi encontrado qualquer caso de lúpus eritematoso sistémico


205

e d i t o r i a l

a c p a ( a n t i - c i t r u l l i n at e d p r o t e i n a n t i b o d i e s )

a n d r h e u m at o i d a r t h r i t i s

Rene E. M. Toes*, Diane van der Woude*

Abstract

It has recently been discovered that anti-citrulli-nated protein antibodies (ACPA) are present in 50%of patients with early rheumatoid arthritis (RA). As-says for detecting ACPA have been shown to havevery good diagnostic and predictive characteristics,and they may facilitate the identification of patientswith early arthritis who need aggressive treatment.

In addition to their diagnostic and predictiveproperties, ACPA have also provided new insightsinto the pathophysiology of RA. The specific asso-ciation of certain genetic and environmental riskfactors with ACPA-positive but not with ACPA-ne -ga tive RA, has led to new concepts of the underly-ing pathogenetic mechanisms. The fact that ACPA--positive patients have a more severe diseasecourse with greater joint destruction has also fueledthe hypothesis that ACPA themselves may bepathogenic. Although there is no direct proof forthis intriguing theory so far, it is clear that ACPA al-low the classification of RA patients into two dif-ferent disease subsets that are associated with dis-tinct pathophysiological mechanisms and clinicaloutcomes.

Rheumatoid arthritis (RA) is a chronic, poten-tially destructive, arthritis which has a large impacton patients’ quality of life1. It has become clear thatin order to be able to prevent disease progressionand joint destruction, RA needs to be diagnosedearly, which requires diagnostic markers which canreliably predict disease development and progres-sion2. Some of the most attractive diagnostic mar -kers are autoantibodies.

Rheumatoid factor (RF) has long been known tobe a marker of future RA development3, but morerecently, a better diagnostic and predictive markerhas emerged in the form of anti-citrullinated pro-tein antibodies (ACPA).

Development of anti-citrullinated protein immunity

ACPA were first described as anti-perinuclear fac-tor over 45 years ago, but it was not until severalyears later that recognition of this antigen wasfound to be exclusively dependent on the presenceof citrulline-residues4,5. Based on these findings,several commercial assays that test for the pre senceof antibodies to cyclic citrullinated proteins (CCP)have been developed and successfully introducedin clinical practice6.

Several studies have investigated at what pointin time individuals develop ACPA. Using pre-disea -se samples from blood bank donors who later de-veloped RA, it was shown that ACPA can be detec -ted years before disease manifestation7,8. Further-more, ACPA titers were found to increase up to thepoint of disease onset. However, once present,ACPA almost never disappear, but tend to persist inthe vast majority of patients in whom they have de-veloped. Likewise, ACPA-negative RA-patientshardly ever sero-convert, indicating that ACPA area stable biomarker that does not demand re-tes tingonce ACPA-status is known.

The fact that ACPA appear in the pre-clinicalphase of RA, together with the finding that ACPAcan exacerbate arthritis in mice, suggest that anti--citrulline immunity may play a role in the patho-genesis of the disease9. This notion is further sup-ported by investigations into the risk factors that areassociated with RA.

Genetic risk factors for RA

The risk of developing rheumatoid arthritis isknown to be influenced by several genetic risk fac-tors, of which the HLA-DRB1 shared epitope (SE)al leles confer the highest risk10. After the first des -criptions of ACPA, it soon became clear that the SEalleles were only associated with ACPA-positive RAand thus only predisposed to ACPA-positive di -

*Department of Rheumatology, Leiden University Medical Center,

The Netherlands


206

sease11. Intriguingly, no apparent contribution ofthe SE alleles to the progression towards RA or theprogression of RA is found when the analyses arestratified for the presence of ACPA in a patient--population with early arthritis12,13. Thus, the SE al-leles do not independently contribute to the pro-gression to or of RA, but rather predispose to thedevelopment of ACPA. The latter is also reflectedby the observation that the presence of HLA-SE-al-leles influences the profile of the antigens recog-nized by ACPA, indicating that they are a risk fac-tor for ACPA-development14.

Conversely, there are other genetic risk factors,which have been described to be exclusively asso-ciated with ACPA-negative RA, such as HLA-DR315.Because there are no markers available that arespecific for this disease subset, it is currently notfeasible to determine if this genetic risk factor pre-disposes to specific immunological alterations inthese patients.

Not only genetic, but also environmental riskfactors are known to contribute to the etiology ofRA. Many epidemiological studies have shown anassociation between cigarette smoking. Smokingwas found to interact with the HLA SE alleles in thepredisposition for RA16,17. Interestingly, this associa -tion is also predominantly associated with ACPA--positive RA, mainly in the context of the presenceof the HLA-SE-alleles18,19. Together, as distinct ge-netic-and environmental factors associated withACPA-positive and negative disease, these findingsindicate that ACPA-positive- and negative RA aredistinct disease entities. Nonetheless, at first clini -cal presentation, no apparent clinical differencesseem to be present, although it is clear that ACPA--positive patients will suffer from a more progres-sive disease course as compared to ACPA-negativesubjects20.

Conclusion

The discovery of the RA-specific anti-citrullinatedprotein immune response has had great implica-tions, not only for diagnosis and disease predic-tion, but also for the way we think about the patho-physiology of the disease. Recognition of the dis-tinct genetic and environmental risk factors in-volved in ACPA-positive versus ACPA-negativedisease, has allowed us to view rheumatoid arthri-tis in a more differentiated way. Even though thereis no conclusive proof as yet that ACPA themselves

are pathogenic, they allow a useful distinction ofdisease subsets, each with associated risk factorsand prognosis. For the ability to serologically con-firm the diagnosis of RA, as well as with regards tothe pathophysiologic understanding of the disease,the identification of ACPA has been a great stepforward.

Correspondence toDiane van der Woude M.D.Department of RheumatologyLeiden University Medical CenterP.O.Box 96002300 RC Leiden, The NetherlandsTel: +31 71 5263265, Fax: + 31 71 5266752E-mail: [email protected]

References1. Suurmeijer TP, Waltz M, Moum T, et al. Quality of life

profiles in the first years of rheumatoid arthritis: re-sults from the EURIDISS longitudinal study. ArthritisRheum 2001;45:111-121.

2. Lard LR, Visser H, Speyer I, et al. Early versus delayedtreatment in patients with recent-onset rheumatoidarthritis: comparison of two cohorts who receiveddifferent treatment strategies. Am J Med 2001;111:446-451.

3. Visser H, Gelinck LB, Kampfraath AH, et al. Diagnos-tic and prognostic characteristics of the enzymelinked immunosorbent rheumatoid factor assays inrheumatoid arthritis. Ann Rheum Dis 1996;55:157--161.

4. Nienhuis RL, Mandema E. A new serum factor in pa-tients with rheumatoid arthritis; the antiperinuclearfactor. Ann Rheum Dis;23:302-305.

5. Schellekens GA, de Jong BA, van den Hoogen FH, etal. Citrulline is an essential constituent of antigenicdeterminants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest;101:273-281.

6. Coenen D, Verschueren P, Westhovens R, et al. Tech-nical and diagnostic performance of 6 assays for themeasurement of citrullinated protein/peptide anti-bodies in the diagnosis of rheumatoid arthritis. ClinChem 2007;53:498-504.

7. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al.Antibodies against cyclic citrullinated peptide andIgA rheumatoid factor predict the development ofrheumatoid arthritis. Arthritis Rheum 2003;48:2741--2749.

8. Nielen MM, van Schaardenburg D, Reesink HW, et al.Specific autoantibodies precede the symptoms ofrheumatoid arthritis: a study of serial measurementsin blood donors. Arthritis Rheum 2004;50:380-386.

9. Kuhn KA, Kulik L, Tomooka B, et al. Antibodiesagainst citrullinated proteins enhance tissue injuryin experimental autoimmune arthritis. J Clin Invest2006;116:961-973.

10. Gregersen PK, Silver J, Winchester RJ. The shared epi-


207

tope hypothesis. An approach to understanding themolecular genetics of susceptibility to rheumatoidarthritis. Arthritis Rheum;11:1205-1213.

11. Huizinga TW, Amos CI, van der Helm-van Mil HA, etal. Refining the complex rheumatoid arthritis pheno-type based on specificity of the HLA-DRB1 sharedepitope for antibodies to citrullinated proteins.Arthritis & Rheum 2005;52:3433-3438.

12. van der Helm-van Mil AH, Verpoort KN, BreedveldFC, et al. The HLA-DRB1 shared epitope alleles areprimarily a risk factor for anti-cyclic citrullinatedpeptide antibodies and are not an independent riskfactor for development of rheumatoid arthritis.Arthritis Rheum 2006;54:1117-1121.

13. Scherer HU, van der Woude D, Willemze A, et al. Dis-tinct fine-specificities, formed under the influence ofHLA shared-epitopes, have no effect on radiographicjoint damage in rheumatoid arthritis. Ann RheumDis 2011;70:1461-1464.

14. Verpoort KN, van Gaalen FA, van der Helm-van MilAH, et al. Association of HLA-DR3 with anti-cycliccitrullinated peptide antibody-negative rheumatoidarthritis. Arthritis Rheum 2005;52:3058-3062.

15. Verpoort KN, Cheung K, Ioan-Facsinay A, et al. Finespecificity of the anti-citrullinated protein antibodyresponse is influenced by the shared epitope alleles.Arthritis & Rheum 2007;56:3949-3952.

16. Hazes JM, Dijkmans BA, Vandenbroucke JP, et al.Lifestyle and the risk of rheumatoid arthritis:cigarette smoking and alcohol consumption. AnnRheum Dis 1990;49:980-982.

17. Symmons DP, Bankhead CR, Harrison BJ, et al. Bloodtransfusion, smoking, and obesity as risk factors forthe development of rheumatoid arthritis: resultsfrom a primary care-based incident case-controlstudy in Norfolk, England. Arthritis Rheum 1997;40:1955-1961.

18. Klareskog L, Stolt P, Lundberg K, et al. A new modelfor an etiology of rheumatoid arthritis: smoking maytrigger HLA-DR (shared epitope)-restricted immunereactions to autoantigens modified by citrullination.Arthritis Rheum 2006;54:38-46.

19. Linn-Rasker SP, van der Helm-van Mil AH, vanGaalen FA, et al. Smoking is a risk factor for anti-CCPantibodies only in rheumatoid arthritis patients whocarry HLA-DRB1 shared epitope alleles. Ann RheumDis 2006;65:366-371.

20. van der Helm-van Mil AH, Verpoort KN, BreedveldFC, et al. Antibodies to citrullinated proteins and dif-ferences in clinical progression of rheumatoid arthri-tis. Arthritis Res Ther 2005;7:R949-R958.


209

a r t i g o d e r e v i s ã o

r a n k / r a n k l / o p g : l i t e r at u r e r e v i e w

Silva I*, Branco JC**,*

*Serviço de Reumatologia do Centro Hospitalar de Lisboa

Ocidental, Hospital de Egas Moniz, EPE

** Faculdade de Ciências Médicas, Universidade Nova de Lisboa

This work was sponsored by AMGEN

trix of proteoglycans and collagen mineralized bythe deposition of calcium hydroxyapatite1. Boneremodeling results from the balance between os-teoblast and osteoclast activity, through four pha -ses: activation, resorption, reversal and formation.This includes removal of trenches or tunnels ofbone from the surfaces of trabecular and corticalbone, respectively, by osteoclasts, while osteoblastssubsequently fill in these trenches by laying downnew bone matrix2.

Formation matches resorption during normalbone remodeling. This remodeling becomes dis-turbed in a variety of pathologic conditions that af-fect the skeleton (osteoporosis, glucocorticoid-in -du ced bone loss, multiple myeloma, and rheuma-toid arthritis)2,3. Discovery of the receptor activatorof nuclear factor-kB (RANK)/RANK ligand (RANKL)//osteoprotegerin (OPG) signaling pathway as a major regulatory system for osteoclast formationand action, showed the major role of the tumor ne -crosis factor (TNF) superfamily in bone meta -bolism1,5.

Studies also revealed new functions of this triadin other pathologies and tissues, and suggest thatin response to mechanical forces osteocytes regu-late the osteoclasts recruitment to sites of bone re-sorption, by inducing the RANKL expression by os-teoblastic cells in the local micro-environment2-4.Emerging treatments have been explored accord-ing to new molecules and mechanisms discoveries.

Osteoblasts differentiation and proliferation de-pends on Wingless (Wnt)/β-catenin pathway andmutations on some of their proteins lead to bone di -seases (eg. loss-of-function mutation in the Wnt co-receptor low-density lipoprotein receptor-rela-ted protein 5 (LRP5) is associated with osteoporo-sis)6,7.

In this article, we will review RANK/RANKL/OPGtriad, its role in the bone, and recent concepts.

RANK, RANKL and OPG signaling pathway

Ostoblasts are mononuclear cells responsible for

Abstract

The discovery of the receptor activator of nuclearfactor-kB (RANK)/RANK Ligand (RANKL)/osteo-protegerin (OPG) pathway contributed to the un-derstanding of how bone formation and resorptionwere processed and regulated. RANKL and OPG aremembers of the tumor necrosis factor (TNF) andTNF receptor (TNFr) superfamilies, respectively,and binding to receptor activator of NF-kB (RANK)not only regulate osteoclast formation, activationand survival in normal bone modeling and remode -ling, but also in several other pathologic conditionscharacterized by increased bone turnover. There isaccumulating evidence of the potential role of OPGand RANKL in other tissues.

Looking beyond the RANK/RANKL/OPG axis,Wingless (Wnt) pathway emerged as the osteoblastdifferentiation way, and also as a bone mass regulator.

Researchers have been discovering newmolecules and cytokines interactions. Altogether,data suggest that RANK/RANKL/OPG system couldbe targeted as a new treatment strategy in boneconditions. FREEDOM is the more recently pub-lished clinical trial about a RANKL-specific recom-binant fully human monoclonal antibody (deno-sumab). OPG is also a potential innovative thera-peutic option to be investigated.

Keywords: RANK; RANKL; Osteoprotegerin; Os-teoclast; Bone Formation.

Introduction

Bone is a connective tissue made up of specificcells, osteoblasts (bone-forming), osteocytes (os-teoblasts entrapped within lacunae) and osteo-clasts (bone-reabsorbing), and an extracellular ma-


210

the deposition of bone matrix and for osteoclastsregulation. They originate from mesenchymalstem cells (MSC) by the action of transcription fac-tors like core binding factor α1 (Cbfa-1) also knownas Runx2, osterix (Osx), activating transcriptionfactor 4 (ATF4), and bone morphogenic proteins(BMP) as BMP46. Osteoclasts are derived frommononuclear precursors in the myeloid lineage ofhematopoietic cells that also originate macro pha -ges2. Macrophage-colony stimulating factor (M--CSF) expression by osteoblastic stromal cells isrequired for progenitor cells to differentiate intoosteo clasts, but is unable to complete this processby its own. In a 1997 publication OPG was identi-fied, and its gene encoded a member of the TNF re-ceptor family. In a 1998 publication RANKL was re-ported as a new member of the TNF family thatcould bind to OPG and RANK8. RANK/RANKL//OPG are closely linked with each other.

RANKL is synthesized in membranous or solu-ble form by the osteoblastic lineage cells, the immune cells, and some cancer cells. This factorlinks to the osteoclasts surface receptor, RANK, and stimulates bone resorption through osteo-clastogenesis and the activation of multinuclea-ted mature osteoclasts. OPG that is secreted by osteoblasts as a decoy receptor for RANKL, pre-vents RANKL from binding to RANK and bone re-sorption1-6.

In the immune system RANKL in activated Tcells binds to RANK expressed by the dendriticcells, regu lating the function and survival of thosecells. OPG is produced by B-lymphocytes and den-dritic cells, maintaining an equilibrium in this sys-tem1.

OPG

OPG belongs to the TNF receptor superfamily (TNFRS), preventing the biological effects of RANKL.Also known as TNFRS member 11B (TNFRS11B),osteoclastogenesis inhibitory factor (OCIF) andtropine reductase 1 (TR1), is highly expressed as asoluble protein, closely related to CD40 and ableto bind to CD40 ligand (CD40L). Is produced in theadult lung, heart, kidney, liver, thymus, lymphnodes, bone marrow, osteoblasts, vascular smoothmuscle cells, B-lymphocytes, and articular chon-drocytes1-3,6. Over expression of OPG in the mice re-sulted in osteopetrosis and its deficiency deter-mined osteoporosis6. The osteoprotective role of

OPG is supported by the report of homozygousdeletions of 100 kilobases of OPG in juvenile Paget’sdisease, and the inactivating deletion in exon 3 ofOPG in idiopathic hyperphosphatasia3.

When RANKL expression is up-regulated OPGexpression is down-regulated or not induced to thesame degree as RANKL, and the RANKL/OPG ra-tio favors osteoclastogenesis2. OPG expression inosteoblasts is increased by vitamin D3, interleukin(IL)-1α, IL-1β, TNFα, TNFβ, BMP2, transforminggrowth factor β (TGFβ) and 17�-estradiol and Wntsignaling pathway. Its expression is decreased byprostaglandin E2 (PGE2), parathyroid hormone(PTH), glucocorticoids and insulin-like growth fac-tor-1 (IGF-1) (Figure 1)4.

Furthermore, the RANKL/OPG ratio expressedby pre-osteoblasts cells is higher than in mature osteoblasts, favoring osteoclasts maturation andaction. Jagged1/Notch1 signaling negatively regu-lates osteoclast formation directly and indirectly by changing RANKL/OPG ratio in stromal cells. So, bone mass is regulated by osteoblasts throughthree signaling pathways: RANKL/RANK, Wnt//β-catenin and Jagged1/Notch12. Jagged 1 is a 180kDa type I transmembrane glycoprotein with an extracellular DSL (delta, serrate, lag-2 consen-sus sequence) domain that is necessary for bin-

rank/rankl/opg: literature review

Figure1.Regulatory mechanisms of bone remodeling:role of RANK, RANKL and OPG in osteoclast activation.OPG expression in osteoblasts is increased by vitamin D3, interleukin (IL) -1α, IL-1β, TNFα, TNFβ, BMP2, transforming growth factor β (TGFβ) and 17β-estradiol,and Wnt signaling pathway. Its expression is decreased byprostaglandin E2 (PGE2), parathyroid hormone (PTH), glucocorticoids and insulin-like growth factor-1 (IGF-1). From: Vega D, Maalouf NM, Sakhaee K. The role of receptor activator of nuclear factor-kB (RANK)/RANKligand/Osteoprotegerin: clinical implications. The journal of clinical endocrinology and metabolism. 2007; 92:4514-4521.


211

ding to Notch receptors. Jagged-Notch signalingspecifies cell fate, modulates cell proliferation anddifferentiation, especially during hematopoiesis,myoge nesis, neurogenesis and development of thevasculature. Direct cell-cell interactions arethought to be necessary for functional Notch sig-naling2,6.

In mammals there are four Notch receptors(Notch 1-4). The canonical Notch signaling inskeletal biology is evolving while the non-canoni-cal is poorly understood9. Suppression of Notchsignaling by a selective g-secretase inhibitor orNotch2 short hairpin RNA suppressed RANKL-in-duced osteoclastogenesis. Induction of Notch sig-naling by Jagged1 or by ectopic expression of in-tracellular Notch2 enhanced nuclear factor of acti -vated T cells 1 (NFATc1) promoter activity leadingto the increase of osteoclastogenesis10. In a patho-logical context, aberration of Notch signaling is as-sociated with osteosarcoma9,10.

RANKL

RANKL belongs to the TNF superfamily, is ex-pressed in bone, lung, bone marrow and lymphoidtissues, and exists as 3 isoforms: RANKL 1, 2 and 3.These three isoforms of this type II homotrimerictransmembrane protein can differentially regulateosteoclastogenesis and exists as a soluble and amembranous form. Soluble form has low capacityto generate osteoclasts11. Typically is expressed ina membrane-bound form in osteoblasts and acti-vated T cells, and after a proteolytic cleavage bymatrix metalloproteases (MMP3 or 7) or a disinte-grin and metallopeptidase (ADAM) is secreted. Itsexpression by synovial cells and activated T cells in patients with rheumatoid arthritis contributes,with TNF, to joint destruction1,2,8. RANKL sti-mulates the release of immature osteoclasts progenitors into the circulation. Analysis of RAN-KL promoter revealed the presence of binding sites for vitamin D and glucocorticoids (stimula-tors)6. Clinical studies in mice showed RANKL ex-pression in mammary epithelial cells during preg-nancy and its effect in lactational hyperplasia ofmammary epithelial cells and milk production.RANKL is also expressed by some malignant tu-mors cells, thus regulating tumor cell proliferationand probably migration1,2. Recently, the first reportof a mutation in the RANKL gene was described in Canada. The affected individuals had osteope -

trosis, without obvious defect in immunologic system2.

MicroRNAs (miRs) are small non-coding RNAsthat function in the spatiotemporal regulation ofprotein translation in animal cells. MiR-21 wasidentified as a miR expression signature of RANKL--induced osteoclastogenesis that down-regulatesprogrammed cell death 4 (PDCD4) protein level,and RANKL-induced c-Fos up-regulates miR-21gene expression12.

RANK

RANK belongs to the TNFR superfamily, is synthe-sized as a type I homotrimeric transmembraneprotein, and is expressed by different tissues suchas skeletal muscle, thymus, liver, colon, mamma-ry glands, prostate, pancreas, and cells of themonocyte/macrophage lineage (precursors andmature osteoclasts, B and T cells, dendritic cells, fi-broblasts, and articular chondrocytes). RANKLproduced by osteoblasts binds to RANK in the sur-face of osteoclasts, recruits the tumor necrosis fac-tor receptor associated factor (TRAF) 2,5 and 6 thatbind to RANK cytoplasmic domain (only TRAF6seems to be essential in osteoclasts), leading to NF-kB activation and translocation to the nucleus.NF-kB increases c-Fos expression and c-Fos inte -racts with NFATc1 to trigger the osteoclastogenicgenes transcription (Figure 2). At least seven signa -ling pathways are activated by RANK-mediatedprotein kinase signaling: four mediate osteoclas-togenesis (inhibitor of NF-kB kinase/NF-kB, c-Junamino-terminal kinase/activator protein-1, c-myc,and calcineurin/NFATc1) and three mediate osteo -clast activation [Rous sarcoma oncogene (src) andmi togen-activated protein kinase kinase 6(MKK6)/p38/microphthalmia-associated trans -cription factor (MITF)] and survival (src and ex-tracellular signal-regulated kinase)1,2,6,8.

On the basis of mice studies, NFATc1 was des -cribed as the master regulator of osteoclastogene-sis (Figure 3). It is activated by a calcium-depen-dent calcineurin dephosphorylation. Howeversome patients treated with cyclosporine A (NFATc1inhibition) presented bone loss, what brought an-other explanation: NFATc1 also positively regulatesexpression of osterix, an essential transcriptionfactor in osteoblast function, and the result of thisnet effect is reduced bone formation and osteo-porosis3.

silva i. e col.


212

OPG/RANKL complex

The OPG/RANKL ratio is considered to better re-flect the bone remodeling environment signs. Ahigh ratio represents bone formation while a lowratio favors bone resorptio1,4.

After OPG/RANKL complex formation, its in-ternalization can be either through lipid rafts bymembranous syndecan-1 or by the clathrin coatformation pathway. These two mechanisms con-trol the bioavailability of extracellular OPG. In addition, glycosami noglycans (GAGs) such ashepa rin, heparin sulfate, chondroitin sulfate anddermatan sulfate binds OPG via the heparin bin -ding domains and compete with OPG/RANKL in-teraction, thus preventing OPG internalizationthrough membranous RANKL. This internalizationprocess is of particular importance for futurethera peutic involvement of OPG1.

The anti-resorptive effect of OPG can be ex-plained by its properties of a decoy receptor and asa modulator of RANKL half-life. As RANKL andOPG controls each other bioavailability, the ba -lance between RANKL and soluble OPG will be im-portant for a curative application of OPG1.

RANK/RANKL/OPG pathway in rheumatologicalconditions

Bone diseases are related to increased bone re-sorption, disturbed coupling between bone for-mation and resorption, and bone destruction2.

GENETIC DISORDERS: familiar expansile osteolysis[activating 18-bp tandem duplication in the genecoding RANK (TNFRSF11A)]; familiar form of ear-ly-onset Paget disease of bone (similar 27-bp dupli-cation of the previous gene); expansile skeletal hy-perphosphatasia (15-bp tandem duplication inRANK); idiopathic hyperphosphatasia or juvenilePaget disease [homozygous complete deletion ofOPG gene (TNFRSF11B)]5. Sabacchi et al13, repor -ted mutations in the gene encoding RANKL in 6 pa-tients with autossomal recessive osteopetrosis.

RHEUMATOID ARTHRITIS (RA):RANKL has been im-plicated as an important mediator of bone ero-sion14. Synovial T cells express RANKL and there isan over expression of RANKL messenger RNA(mRNA) and OPG in the RA patients synovium atthe site of bone resorption, which contributes toosteoclast differentiation and activity14-16. OPGbinding to soluble RANKL can better prevent os-teoclast activation in non erosive arthritis than inRA17. Elevated serum levels of soluble RANKL nor-malize after anti-TNF therapy4,8,14. Assmann et al,


Figure2.The essential signaling pathway for normal osteoclastogenesis. RANKL produced by osteoblasts bindsto RANK in the surface of osteoclasts, recruits the tumornecrosis factor receptor associated factor (TRAF) 2,5 and6 that bind to RANK cytoplasmic domain (only TRAF6seems to be essential in osteoclasts), leading to NF-kB activation and translocation to the nucleus. NF-kB increases c-Fos expression and c-Fos interacts with FATc1to trigger the osteoclastogenic genes transcription. From: Boyce BF, Xing L. Biology of RANK, RANKL, an osteoprotegerin. Arthritis research and therapy. 2007;9:1-7.

Figure3.Signaling pathways involved osteoclastogenesisin diseases states with the activation of NFATc1. On thebasis of mice studies, NFATc1 was described as the master regulator of osteoclastogenesis. From: Boyce BF,Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Archives of biochemistry andbiophysics. 2008; 473:139-146.


213

studied genetic variations of this pathway in thesusceptibility to RA and showed the minor allele ofthe RANK SNP rs35211496 might be protectiveagainst RA18. Haynes et al, confirmed the hypo -thesis that successful treatment with modifyinganti-rheumatic drugs (DMARDs) reduce RAN-KL/OPG ratio, suppressing osteoclast formation inthe RA synovial tissue19,20.

SPONDYLOARTHROPATHIES (SPA): the pattern ofparaarticular bone tissue damage is different be-tween different forms of peripheral arthritis. In SpAthere is limited degradation of the paraarticularbone with new bone formation that can result inankylosis21. In human SpA are described osteo-clastic foci in the subchondral bone marrow of hipjoints, which suggests a relation with cartilage-in-duced inflammation (the osteoclasts number isnot increased at axial inflammation sites). TheRANK/RANKL/OPG pathway contribute to boneerosions was demonstrated in RA, and also psoria -tic arthritis (PsA), but only scarcely in peripheraljoint inflammation in SpA21. Vandooren et al22,demonstrated that both RANKL (mostly by ca -dherin 11-expressing synovial fibroblasts and CD3T cells) and OPG were expressed in the inflamedsynovium; the presence of osteoclasts precursorsin the inflamed synovial tissue and that the factorsneeded to local osteoclastogenesis are present inthe SpA synovium. There were no qualitative orquantitative differences in the expression of RAN-KL, OPG, and RANK between nonpsoriatic SpA,psoriatic SpA and RA synovium with the same de-gree of inflammation. They conclude that the rela -tive protection against bone erosion in SpA cannotbe explained by differences of RANK/RANKL/OPGsynovial expression, and that these factors expres-sion is disconnected from systemic and local in-flammation22.

OSTEOPOROSIS: in human osteoblastic cell lineshave been shown a dose and time-dependent in-crease in OPG mRNA in response to 17-estradiol,which probably decreases the RANK-RANKL bind-ing and osteoclastic bone resorption. Human bonemarrow cells from untreated early postmeno -pausal women showed a greater expression ofRANKL compared to the estrogen-treated group4,8.Ominsky et al, showed that ovariectomy in rats wasassociated with high levels of serum RANKL andosteoclast surface and reduced areal and volu-metric BMD23. It was also showed that OPG re-duced osteoclast surface and prevented ovaritec-tomy-associated bone loss in the lumbar vertebrae,

distal femur and femur neck23. In the glucocorti-coid-induced osteoporosis the RANK/RANKL//OPG role was described: glucocorticoids stimu-late RANKL expression by osteoclasts and inhibitOPG synthesis, favoring osteoclasts differentiationand proliferation (increased RANKL/OPG ratio andurinary and serum markers of bone resorption)4,8.

OSTEOARTHRITIS (OA): OPG and RANKL havebeen found to be expressed and modulated in hu-man OA subchondral bone, and by other articularchondrocytes. The OPG/RANKL ratio in the syno -vial fluid is greater in OA compared to RA. There aretwo different phenotypes of subchondral bone os-teoblasts, L-OA (low endogenous levels of PGE2)and H-OA (high endogenous levels of PGE2). L-OApresents low PGE2 level, low OPG/RANKL ratio,high osteoclastogenesis and a decreased sub-chondral bone thickness; while H-OA shows highPGE2 level, high OPG/RANKL ratio, low osteoclas-togenesis, and an increased subchondral bonethickness1,24. A recent in vitro study with human L-OA subchondral bone osteoblasts showed thatthe combination of glucosamine and chondroitinsulfate modulated OPG/RANKL ratio, decreasingbone resorption25. The addition of OPG or the inhi -bition of RANKL would be beneficial on the sub-chondral bone of the L-OA (resorptive phase), whi -le in the H-OA patients the anti-resorptive agentsare less effective as the subchondral bone seems tobe in a formation phase1. Moreno-Rubio et al24,sho wed that in patients with OA celecoxib de-creased RANKL synthesis in the cartilage by in-creasing the OPG:RANKL ratio; in vitro, PGE2 regu -lated the expression and release of the mediatorsof bone metabolism by articular chondrocytes.

POLYMIALGIA RHEUMATIC (PMR): Pusatelli et al26,found no significant differences in circulating OPGlevels in PMR patients in the active phase of the di -sease or the follow-up compared to normal con-trols; the systemic RANKL (sRANKL) production isincreased, is not modulated by corticosteroid treat-ment, and can be related to bone osteoporosis.

SYSTEMIC SCLEROSIS (SS): microvascular damageis an early pathogenetic event in SS and RANK//RANKL/OPG system is involved in vascular biolo -gy. Dovio et al27, showed that higher sRANKL levelsand sRANKL/OPG ratio in patients with SS are aconsequence of altered bone microenvironment,and showed dissociation between the well esta -blished activation/injury endothelial marker, so -luble vascular cell adhesion molecule (sVAM), andOPG, as another vascular damage marker.

silva i. e col.


214

JUVENILE DERMATOMYOSITIS ( JDM): Rouster--Stevens et al28, documented that at the time ofdiag nosis of JDM untreated patients have an eleva -ted RANKL/OPG ratio compared to normal con-trols, and this ratio is related to lower bone mine -ral density (BMD)29,30.

RANK/RANKL/OPG pathway in non-rheumatologic conditions

There is accumulating evidence of the potentialrole of OPG and RANKL in other tissues (Figure 4)1.

BONE TUMORS: osteoclastic activating factors areproduced by myeloma cells in response to IL-1, IL--6 and TNF-α. IL-7 may increase RANKL produc-tion in T cells, and there is also an increased lyso-somal degradation of OPG. Although serum OPGlevels correlated with World Health Organizationmultiple myeloma performance status, it have notbe found to be associated with clinical stage or sur-vival4,29.Myeloma cells release not only RANKL, butalso dickkopff-1 (DKK-1), which suppresses boneformation, enhancing tumor growth. In metasta -tic bone diseases, tumor cells increase RANKL:OPGratio directly and by T cells, osteoblast/stromalcells and endothelial cells, together with PTH re-lated peptide, increasing bone removal and tumorgrowth8.

VASCULAR CALCIFICATION: there are two main typesof vascular calcification, depending if the calciumdeposits are located in the intima (intimal calcifi-cation, related to atherosclerotic plaques) or in themedial layer (medial calcification, related to chro -nic kidney disease). An imbalance in the RANK//RANKL/OPG system was suggested as responsi-

ble for the calcification process of atheroscleroticplaques4. The identification of tissue-specific iso-forms could increase the importance of sRANKLand OPG in predicting calcified plaque rupture31,32.However, direct evidence of a role of RANKL onvascular calcification is missing33. Panizo et al33,showed that RANKL is able to induce vascularsmooth muscle cells (VSMCs) calcification in vit-ro by binding to RANK; RANK activation will in-crease BMP4 expression by stimulating alternativeNF-kB pathway. The inhibition of RANKL maybe isa possible target to treat vascular calcification33,34.

INFLAMMATORY BOWEL DISEASE (IBD): Moschen etal35, demonstrated that IBD is related to alterationsin the RANKL/OPG system, and elevated RANKL//OPG ratio is associated to bone loss.

DIABETES MELLITUS (DM): Secchiero et al36, sho -wed that OPG but not the RANKL is significantly in-creased in type 2 DM patients compared to con-trols; serum OPG increases early after DM induc-tion in mice, and showed a positive correlationwith blood glucose levels and inverse correlationwith free RANKL levels. Thus, increased OPG pro-duction represents an early event in DM and pos-sibly is related to endothelial cell dysfunction.

CHRONIC ALCOHOLIC LIVER DISEASE: OPG is raised inalcoholics, especially in cirrhotics without relationwith decreased BMD. Raised TNF and IL-6 levelswere related with increased OPG levels, which sup-port the protective effect of OPG in bone loss37.

THYROID TUMORS: the role of RANK/RANKL/OPGin thyroid pathophysiology remains unclear. Hey-mann et al38, showed that RANK/RANKL/OPG isexpressed in the pathological thyroid gland by fol-licular cells, by malignant parafollicular cells, andin metastatic lymph node microenvironment.Thus this system might have a role in the patho-genesis of these tumors.

CHRONIC RENAL FAILURE: Fahrleitner-Pammer etal39, demonstrated that RANK/RANKL/OPG sys-tem is associated with BMD in predialysis chronicrenal failure. Serum OPG concentrations are lo werin patients with adynamic bone disease, in contrastto those with increased bone turnover due to se -condary hyperparathyroidism. It is possible thatincreased serum OPG in chronic kidney diseasepatients is an adaptative mechanism to attenuatePTH-induced bone loss4.

BREAST AND PROSTATE CANCER: OPG production bybreast cancer cells is a possible survival mecha-nism of the tumoral cells, because OPG inhibitsTNF-related apoptosis-inducing ligand (TRAIL).


Figure4.The role of the RANKL/RANK system in boneand other tissues. From: Boyce BF, Xing L. Biology ofRANK, RANKL, an osteoprotegerin. Arthritis research andtherapy. 2007;9:1-7.


215

OPG is also a potential indicator for the diagnosisand early progression of prostate cancer (elevatedlevels)4.

Wnt signaling pathway: interaction withRANK/RANKL/OPG

The Wnt proteins are a family of secreted growthfactors found in all animal species that bind to cell--surface receptors and regulate cellular activitieslike cell fate, determination, proliferation, migra-tion, polarity, and gene expression6. Genes enco -ding for Wnt proteins are highly conserved. At leastfour signaling pathways are described: Wnt//β-catenin; planar cell polarity; Wnt/Ca2+; and pro-tein kinase A.

The main biologic functions of the Wnt pathwayin bone metabolism are: mesenchymal cell diffe -rentiation, implications in multiple myeloma andmetastatic bone disease, bone mass regulation andbone response to mechanical loading.

The Wnt/β-catenin pathway involves the bin -ding of Wnt proteins to LRP5 or 6 and a member offrizzled (Fz) family of proteins, increasing intra-cellular β-catenin levels which promote the tran-scription of target genes inside the nucleus. Its rolein bone biology, RA and OA, has been highlighted.Wnt/receptor Fz is inhibited by members of thesecreted frizzled-related protein family (sFRP) andWnt inhibitory factor (WIF-1). Sclerostin (enco dedby SOST gene) blocks LRP5 activity6. Inactivatingmutation of Wnt co-receptor LRP5 and the lack ofβ-catenin, blocks the expression of transcriptionfactors that determine osteoblastic phenotype andthe mesenchymal cell achieves another phenotype(chondrocyte or adipocyte)6,8, which results in re-duced OPG expression and bone loss.

The Wnt signaling in osteoprogenitors promotesnew bone formation by functioning as a positiveregulator and upregulating OPG and down-regu-lating RANKL. Kamiya et al7, found that osteoblastsrespond to BMP signaling to support differentia-tion of osteoclasts through RANKL/OPG pathway,possibly by downregulating Opg gene and upre gu -lating Rankl. It was also showed in mice that BMPsignaling via BMP1A receptor directs osteoblasts toreduce bone mass by upregulating sclerostin ex-pression as a Wnt inhibitor, and supporting osteo-clastogenesis through the RANKL/OPG pathway.

Dkk-1 is a soluble inhibitor of Wnt pathway anda negative regulator of osteoblastogenesis in vivo

(in mice)40. Diarra et al41, proposed that Dkk-1 is amaster regulator of joint remodeling, shifting thebalance from bone resorption (increased Dkk-1 ex-pression) to bone formation (decreased Dkk-1 ex-pression). Wnt inhibitors Dkk-1 and 2 can induceosteoclastogenesis by changing the RANKL/OPGpathway in vitro42 (Figure 5).

Wnt system activation seems to be responsiblefor syndesmophyts growth in SpA.

New hypothesisIL-6 is a mechano-sensitive cytocine and probablya key factor to the biomechanical control of boneremodeling in OA, possibly decreasing OPG/RAN-KL ratio43,44.

TGFβ inducible early gene-1 (TIEG) directlybinds to and inhibits OPG promoter activity in os-teoblasts, explaining the possible inability of TIEGknockout osteoblasts to support osteoclast diffe -rentiation45.

Leukotriene B4 is capable of inducing osteoclastdifferentiation by a RANKL-dependent mecha-nism46

.

Pigment epithelium-derived factor (PEDF), themost potent inhibitor of angiogenesis, up-regu-lates OPG and thus inhibits osteoclast function byregulating OPG expression47.

MSCs can differentiate into adipocytes, osteo -blasts, and other cells. There are a reciprocal rela-tion between adipogenesis and osteogenesis. Der-Chih et al48, identified cAMP/PKA signaling, that

silva i. e col.

Figure5.A model of the relationship between BMPR1Aand canonical Wnt signaling in mouse bone. Wnt inhibitorsDkk-1 and 2 can induce osteoclastogenesis by changingthe RANKL/OPG pathway in vitro. From: Kamiya N, Ye L, Kobayashi T, Mochida Y, Yamauchi M,e tal. BMP signaling negatively regulates bone massthrough sclerostin by inhibiting the canonical Wnt pathway. Development 2008;135:3801-3811.


216

regulates bone homeostasis, as a via controllingcyto-differentiation of MSCs (adipocytogenesis,osteogenesis, osteoclastogenesis) by controllingthe release of leptin and altering RANKL/OPG geneexpression.

The leucine-rich repeat-containing 17 (LRRc17)is a member of the LRR superfamily that acts as anegative regulator of RANKL-induced osteoclastdifferentiation (by decreasing NFATc1 expressiondepending on phospholipase C signaling), andthus, is a specific inhibitory molecule for osteo-clastogenesis. Recombinant LRRc17 did not affectthe differentiation of other myeloid precursors. Theregulation of LRRc17 expression in oteoblasts by1,25(OH)2D3 suggests that this molecule is pro-duced by osteoblasts and regulates its interactionwith osteoclasts49.

Emerging treatmentsRANKL-SPECIFIC RECOMBINANT FULLY HUMAN MONO-CLONAL ANTIBODY (DENOSUMAB): clinical trials showedits effectiveness in suppressing bone resorption,with an increase in BMD in postmenopausal wo -men with osteoporotic low BMD50, and have thepotential to prevent progression of erosions in RAand metastatic bone disease. The recently pub-lished FREEDOM study51 assessed the effects onfracture reduction in postmenopausal osteoporo-sis, and achieved a reduction of vertebral and hipfractures to 2,3% and 0,7% respectively, comparedto 7,2% and 1,2% in the placebo group. As in theother trials, adverse events (infections or neo-plasm) were similar to placebo4,8.

OPG:beside its ability to inhibit osteoclastic ac-tivity, OPG can promote cell survival by inhibitingTRAIL-induced apoptosis52. A randomized con-trolled trial was conducted in postmenopausalwomen to determine the effect of a single subcu-taneous dose of OPG on bone resorption (by uri-nary N-telopeptide and seric alkaline phospha -tase). It concluded that OPG acted primarily on os-teoclasts to decrease bone resorption and that asingle OPG subcutaneous dose (3mg/Kg) was ef-fective to reduce the bone turnover for a sustainedperiod52,53. However, OPG has also been reported asa potential survival factor for several different celltypes, through the TRAIL activity inhibition. Breastcancer cells produce OPG in order to be protectedfrom the TRAIL effects in vitro54. Holen et al,demonstrated that OPG can act as an endocrinesurvival factor for breast cancer cells55. This newunexpected role of OPG discouraged investigators

to further studies of the OPG administration boneeffects. OPG might be a therapeutic option forbone lysis in metastatic breast cancer and in mul-tiple myeloma. OPG is a potential marker ofprostate cancer progression or relapse, and a po-tential marker of bone disease in renal osteodys-trophy52.

Conclusion

The RANK/RANKL/OPG pathway mediates the ef-fects of the calciotropic hormones in different tis-sues and their imbalance contribute to several cli -ni cal rheumatologic and non-rheumatologic con-ditions. Multiple molecular discoveries gave riseto different mechanisms of interaction betweensignaling pathways that tried to explain bone for-mation/resorption. According to this develop-ment, new emerging treatments have been stu -died, like denosumab already approved by theFood and Drug Administration (FDA) and the Eu-ropean Medicines Agency (EMA) for the treatmentof postmenopausal osteoporosis and the potentialrole of OPG as an osteoclastic inhibitor and a cellsurvival promoter.

Correspondence toInês Maria Crispim Gomes da Silva Serviço de Reumatologia do Centro Hospitalar de Lisboa Ocidental, Hospital de Egas Moniz, EPE Rua da Junqueira, 126, LisboaE-mail: [email protected]

References1. Tat ST, Pelletier JP, Velasco CR, Padrines M, Pelletier

JM. New perspective in osteoarthritis: the OPG andRANKL system as a potential therapeutic target? KeioJ Med 2009;58:29-40.

2. Boyce BF, Xing L. Functions of RANKL/RANK/OPG inbone modeling and remodeling. Archives of bio-chemistry and biophysics 2008;473:139-146.

3. Boyce BF, Xing L. Biology of RANK, RANKL, an osteo-protegerin. Arthritis research and therapy 2007:1-7.

4. Vega D, Maalouf NM, Sakhaee K. The role of receptoractivator of nuclear factor-kB (RANK)/RANK li -gand/Osteoprotegerin: clinical implications. TheJournal of Clinical Endocrinology and Metabolism2007;92:4514-4521.

5. Whyte MP, Mumm S. Heritable disorders of the RAN-KL/OPG/RANK signaling pathway. J MusculoskelNeuron Interact 2004;4:254-267.

6. Caetano-Lopes J, Canhão H, Fonseca JE. Osteoblastsand bone formation. Acta Reumatológica Portuguesa2007;32:103-110.



217

7. Kamiya N, Ye L, Kobayashi T et al. BMP signaling ne -ga tively regulates bone mass through sclerostin byinhibiting the canonical Wnt pathway. Development2008;135:3801-3811.

8. Geusens P. Emerging treatments for postmenopausalosteoporosis – focus on denosumab. Clinical inter-vention in aging 2009;4:241-250.

9. Tao J, Chen S, Lee B. Alteration of Notch signaling inskeletal development and disease. Ann N Y Acad Sci2010;1192:257-268.

10. Engin F, Lee B. NOTCHing the bone: Insights intomulti-functionality. Bone 2010; 46:274-280.

11. Nakashima T, Kobayashi Y, Yamasaki S, et al. Proteinexpression and functional difference of membrane-bound and soluble receptor activator of NF-kappaBligand: modulation of the expression by osteotropicfactors and cytokines. Biochem Biophys Res Com-mun 2000;275:768-775.

12. Sugatani T, Vacher J, Hruska KA. A microRNA expres-sion signature of osteoclastogenesis. Blood 2011;117:3648-3657.

13. Sabacchi C, Frattini A, Guerrini MM, et al. Osteoclast--poor human osteopetrosis due to mutations in thegene encoding RANKL. Nat Genet 2007;39:960-962.

14. Pettit AR, Walsh NC, Manning C, Goldring SR,GRavallese EM. RANKL protein is expressed at thepannus-bone interface at sites of articular bone ero-sion in rheumatoid arthritis. Rheumatology2006;45:1068-1076.

15. Ainola M, Mandelin J, Liljeström M, Konttinen YT, Sa-lo J. Imbalanced expression of RANKL and osteopro-tegerin mRNA in pannus tissue of rheumatoid arthri-tis. Clin Exp Rheumatol 2008;26:240-246.

16. Kim YG, Lee CK, Oh JS et al. Effect of interleukin-32gamma on differentiation of osteoclasts from CD14+monocytes. Arthritis Rheum 2010; 62:515-23.

17. Hein GE, Meister M, Oelzner P, Franke S. sRANKLand OPG in serum and synovial fluid of patients withrheumatoid arthritis in comparision to non-destruc-tive chronic arthritis. Rheumatol Int 2008;28:765--769.

18. Assmann G, Koenig J, Pfreundschuh M, et al. Geneticvariations in genes encoding RANK, RANKL, andOPG in rheumatoid arthritis: a case-control study. JRheumatol 2010;37:900-904.

19. Haynes D, Crotti T, Weedon H et al. Modulation ofRANKL and Osteoprotegerin expression in synovialtissue from patients with rheumatoid arthritis in res -ponse to disease-modifying antirheumatic drugtreatment and correlation with radiologic outcome.Arthritis and Rheumatism 2008;59:911-920.

20. Haynes DR, Barg E, Crotti TN et al. Osteoprotegerinexpression in synovial tissue from patients withrheumatoid arthritis, spondyloarthropathies and os-teoarthritis and normal controls. Rheumatology2003;42:123-134.

21. Walsh NC, Gravallese EM. Bone remodeling inrheumatic diseases: a question of balance. ImmunolRev 2010;233:301-312.

22. Vandooren B, Cantaert T, Noordenbos T, Tak PP,Baeten D. The abundant synovial expression of theRANK/RANKL/Osteoprotegerin system in peripheralspondylarthritis is partially disconnected from in-flammation. Arthritis and Rheumatism 2008;58:718--729.

23. Ominsky MS, Li X, Asuncion FJ et al. RANKL inhibi-tion with osteoprotegerin increases bone strength byimproving cortical and trabecular bone architecturein ovariectomized rats. Journal of Bone and MineralResearch 2008;23:672-682.

24. Moreno-Rubio J, Herrero-Beaumont G, Tardio L, Al-varez-Soria MA, Largo R. Nonsteroidal antiinflamma-tory drugs and prostaglandin E(2) modulate the syn-thesis of osteoprotegerin and RANKL in the cartilageof patients with Sever knee osteoarthritis. ArthritisRheum 2010;62:478-488.

25. Tat K, Pelletier JP, Vergés J et al. Chondroitin and glu-cosamine sulfate in combination decrease the pro-resorptive properties of human osteoarthritis sub-chondral bone osteoblasts. Arthritis Res Ther 2007;9:R117.

26. Pulsatelli L, Dolzani P, Silvestri T et al. CirculatingRANKL/OPG in polymyalgia rheumatic. Clin ExpRheumatol 2007;25:621-623.

27. Dovio A, Data V, Carignola R et al. Circulating osteo-protegerin and soluble RANK ligand in systemic scle-rosis. J Rheumatol 2008;35:2206-2213.

28. Rouster-Stevens KA, Langman CB, Price HE et al.RANKL:Osteoprotegerin ratio and bone mineral den-sity in children with untreated juvenile dermato-myositis. Arthritis and Rheumatism 2007;56:977-983.

29. Zdzisinnska B, Bjoarska-Junak A, Walter-Croneck A,Kandefer-Szerszen M. Dysregulation of the receptoractivator of NF-kappaB ligand and osteoprotegerinproduction influence the apoptosis of multiplemyeloma patients’ bone marrow stromal cells co-cultured with myeloma cells. Arch Immunol TherExp 2010;58:153-163.

30. Spelling P, Bonfá E, Caparbo VF, Pereira RM. Osteo-protegerin/RANKL system imbalance in active po -lyarticular-onset juvenile idiopathic arthritis: a bonedamage biomarker? Scand J Rheumatol 2008;37:439--444.

31. Montecucco F, Steffens S, Mach F. The immune res -ponse is involved in atherosclerotic plaque calcifica-tion: could the RANKL/RANK/OPG system be amarker of plaque instability? Clin Dev Immunol2007;2007:75805.

32. D’Amelio P, Isaia G, Isaia GC. The osteo prote -gerin/RANK/RANKL system: a bone key to vasculardisease. J Endocrinol Invest 2009;32:6-9.

33. Panizo S, Cardus A, Encinas M et al. RANKL increasesvascular smooth muscle cell calcification through aRANK-BMP4 dependent pathway. Journal of theAmerican Heart Association- Circulation Research2009; 104:1041-1048.

34. Bakhireva LN, Laughlin GA, Bettencourt R, Barrett--Connor E. Does Osteoprotegerin or receptor activa-

silva i. e col.


218

tor of nuclear factor-kappa B ligand mediate the as-sociation between and coronary artery calcification?The J of Clin Endocrin and Metabolism 2008;93:2009--2012.

35. Moschen AR, Kaser A, Enrich B et al. The RANKL//OPG system is activated in inflammatory bowel di -sease and relates to the state of bone loss. Gut 2005;54:479-487.

36. Secchiero P, Corallini F, Pandolfi A et al. An increasedosteoprotegerin serum release characterizes the earlyonset of diabetes mellitus and may contribute to en-dothelial cell dysfunction. Am J Pathol 2006;169:2236-2244.

37. Garcia-Valdecasas-Campelo E, González-Reimers E,Santolaria-Fernández F et al. Serum osteoprotegerinand RANKL levels in chronic alcoholic liver disease.Alcohol 2006;41:261-266.

38. Heymann MF, Riet A, Le Goff B et al. OPG, RANK andRANK ligand expression in thyroid lesions. REgulPept 2008;148:46-53.

39. Fahrleitner-Pammer A, Dobnig H, Dimai HP et al.The effect of RANKL and OPG on bone mineral den-sity in predialysis chronic renal failure. Clin Nephrol2009;71:652-659.

40. Daoussi D, Andonopoulos AP, Liossis SNC. Wnt path-way and Il-17: novel regulators of joint remodeling inrheumatic diseases. Looking beyond the RANK-RAN-KL-OPG axis. Semin Arthritis Rheum 2010;39:369--383.

41. Diarra D, Stolina M, Polzer K et al. Dickkopf-1 is amaster regulator of joint remodeling. Nat Med2007;13:156-163.

42. Fujita KK; Janz S. Attenuation of WNT signaling byDKK-1 and -2 regulates BMP2-induced osteoblastdifferentiation and expression of OPG, RANKL andM-CSF. Molecular Cancer 2007;6:71:1-13.

43. Sanchez C, Gabay O, Salvat C, Henrotin YE, Beren-baum F. Mechanical loading highly increases IL-6production and decreases OPG expression by os-teoblasts. Osteoarthritis Cartilage 2009;17:473-481.

44. Kim CH, Kim KH, Jacobs CR. Effects of high frequen-cy loading on RANKL and OPG mRNA expression inST-2 murine stromal cells. BMC musculoskeletal di -sorders 2009;109:1-7.

45. Subramaniam M, Hawse JR, Bruinsma ES et al. TGF--beta inducible early gene-1 directly binds to, and re-presses, the OPG promoter in osteoblasts. BiochemBiophys Res Commun 2010;392:72-76.

46. Chen ZK, Lv HS, Jiang J. LTB4 can stimulate humanosteoclast differentiation dependent of RANKL. ArtifCells Blood Substit Immobil Biotechnol 2010;38:52--56.

47. Akiyama T, Dass Cr, Shinoda Y et al. PEDF regulatesosteoclasts via osteoprotegerin and RANKL. BiochemBiophys Re Commun 2010; 391:789-794.

48. Yang DC, Tsay HJ, Lin SY et al. cAMP/PKA regulatesosteogenesis, adipogenesis and ratio of RANKL/OPGmRNA expression in mesenchymal stem cells bysuppressing leptin. PLoS ONE 2008;3:1-10.

49. Kim T, Kim K, Lee SH et al. Identification of LRRc17as a negative regulator of receptor activator of NF-kBligand (RANKL)-induced osteoclast differentiation.Journal of Biological Chemistry 2009;284:15308--15316.

50. Moen MD, Kean SJ. Denosumab: a review of its use inthe treatment of postmenopausal osteoporosis.Drugs Aging 2011;28:63-82.

51. Cumming SR, Martin JS, McClung MR et al. Deno-sumab for prevention of fractures in post-menopausal women with osteoporosis. NEJM2009;361:756-765.

52. Fili S, Karalaki M, Schaller B. Therapeutic implica-tions of osteroprotegerin. Cancer cell international2009;26:1-8.

53. Bekker PJ, Holloway D, Nakanishi A, et al. The effectof a single dose of osteoprotegerin in postme no -pausal women. J Bone Miner Res 2001;16:348-360.

54. Van Poznak C, Cross SS, Saggese M, et al. Expressionof osteoprotegerin (OPG), TNF related apoptosis in-ducing ligand (TRAIL), and receptor activator of nu-clear factor kappaB ligand (RANKL) in human breasttumours. J Clin Patholog 2006;59:56-63.

55. Holen I, Cross SS, Neville-Webbe HL, Cross NA, Bala-subramaniam SP, et al. Osteoprotegerin (OPG) ex-pression by breast cancer cells in vitro and breast tu-mours in vivo – a role in tumours cell survival? BreastCancer Res Treat 2005;92:207-215.



219

a r t i g o d e r e v i s ã o

b i o l o g i c t h e r a p y a n d p r e g n a n c y .

a s y s t e m at i c l i t e r at u r e r e v i e w

Bogas M*, Leandro MJ**

*Serviço de Reumatologia, Hospital de Ponte de Lima, ULSAM, EPE

**Centre for Rheumatology, University College London, London,

UK

bowel diseases which disproportionately affect fe-males during reproductive years. Choosing appro-priate treatment for pregnant patients may be chal-lenging and important issues emerge addressing therisk of adverse fetal outcomes or adverse pregnancy. All biological manufacturers recommend that

these drugs should be avoided during pregnancyand lactation. Indeed, none of the biologic thera-pies are described as safe to use during humanpregnancy either by the US Food and Drug Ad-ministration (FDA) or the European MedicinesAgency (EMA)1-3. All approved anti-tumor necrosisfactor (anti-TNF) agents and anakinra are classifiedas Pregnancy FDA Category B. This category indi-cates that although no risk is apparent from animalstudies, there are no controlled studies of womenreceiving these agents during pregnancy, and there-fore, it is not known if they can cause fetal harm. Ri -tuximab, abatacept and tocilizumab are classifiedas Pregnancy FDA Category C, which means that nocontrolled studies in humans have been performedand that animal studies have either shown adverseevents or are not available. For ethical reasons, ran-domized trials cannot be designed to evaluate thesafety of these drugs during pregnancy. It is nearlyinevitable though that there will be some patientsexposed to these drugs during pregnancy, typical-ly during the early stages of an unplanned or un-known pregnancy and that difficult decisions willhave to be made in the individual clinical settings.To provide further information on this topic and

because biological agents may represent an im-portant therapeutic alternative in pregnant wo menexperiencing persistent or increased disease acti -vity, we decided to perform a systematic literaturereview of the relevant data available focusing onagents used in rheumatology.

Methods

A systematic literature search for articles published

Abstract

Aim: To review available data regarding the safetyof biological therapies during pregnancy, focusingon agents used in rheumatology.Methods: A systematic literature search was car-ried out to identify all studies with human data onfetal and/or child outcomes following exposure tobiologic agents during pregnancy.Results: A total of 65 publications out of 745 iden-tified references were included in the review.Conclusions:Experience with pregnancy exposureto anti-TNF agents has been slowly accumulating.Although the numbers are small and with few con-trolled studies the reviewed data suggest that theoverall risk of TNF antagonists is relatively low andbenefits may outweigh the risks of drug exposureto the fetus. Information on other biologic agentsis still very limited. Large controlled studies withlonger follow-up periods will be necessary beforefirm conclusions about the safety of biologics du -ring conception and pregnancy can be drawn.

Keywords: Biologics; anti-TNF; Pregnancy; Sys-tematic literature review

Introduction

The use of medications during the conception pe-riod or throughout pregnancy is a cause of greatconcern and anxiety for patients and the physicianscaring for them.In the past 15 years, several biologic therapeutic

agents have been approved for the treatment andhave significantly improved outcomes among pa-tients with various immune-mediated inflammato-ry disorders such as rheumatic and inflammatory


220

up to October 20th of 2010 was carried out to iden-tify all studies with human data on fetal and/orchild outcomes following exposure to biologicagents during pregnancy. The search strategy forPubMed was restricted to articles published in En-glish, French, German, Portuguese or Spanish andincluded the following medical subject headings(MeSH) terms: “infliximab”, “adalimumab”, “aba -tacept”, “rituximab”, “tocilizumab”, “golimumab”,“certolizumab”, “pregnancy”, and the non-MeSHterms “etanercept”, “anakinra” and “teratogenicity”.A hand-search of relevant references not capturedby the electronic searches was also made lookingfor the reference lists of the retrieved articles. Other references, including the product mono-graphs, data provided by the Organization of Tera -tology Information Specialists (OTIS) studies andthe European League Against Rheumatism (EU-LAR), American College of Rheumatology (ACR)and the European Crohn’s and Colitis Organisa-tion (ECCO) congress abstracts were also reviewed. Articles were selected in a systematic two-step

approach. First, titles and abstracts of all identifiedreferences were screened, excluding articles thatclearly did not address the topic of interest. Second,retrieved articles, including case reports, case se-ries, letters, registries reports, and narrative re-views, were selected for full paper review, applyingthe following inclusion criteria: 1) data on womenwith any disease exposed to infliximab (INF), eta -ner cept (ETA), adalimumab (ADA), rituximab(RTX), anakinra (ANAk), abatacept (ABAt), toci lizu -mab (TCZ), golimumab (GOL) and certolizumab(CTZ) during pregnancy; 2) reported outcome onpregnancy length, health condition of live births,neonatal complications, fetal development, con-genital defects/malformations, miscarriages orelective terminations. Papers were included only ifrelated to patients exposed to the biologic duringpregnancy. Reports of patients exposed to treat-ment before conceptionwere excluded, except forrituximab for which data will be presented sepa-rately.

Results

The systematic review search identified a total of745 references, of which 65 met the inclusion cri-teria and were selected for detailed analysis. Dataretrieved will be presented the most accuratelypossible avoiding duplication of reported cases.

Nevertheless, it is difficult to be sure that indivi dualcases were not reported in the registries. For stu -dies with more than one publication describing re-sults among overlapping groups of participantsand with the same outcome measure, we consi -dered only the dataset with the largest number ofpatients and the longest follow-up. In a first sec-tion, we will present the number of pregnanciesand outcomes definitely known for each biologic.Afterwards and separately, we will show data des -cribing the number of pregnancies and/or thenumber of live births and/or their outcomes for awhole group of patients where results cannot be in-dividualized by anti-TNF agent or other biologic.As it is understandable, the exact number of preg-nancies exposed to each biologic is therefore dif-ficult to assess. Additional information on reports of pregnan-

cies exposed to biologic therapies may be seen inTable I.

TNF antagonists

Infliximab – FDA Pregnancy category BInfliximab is a chimaeric human-murine mono-clonal antibody that binds with high affinity toboth soluble and transmembrane forms of TNF. It’sapproved for the treatment of severe rheumatoidarthritis, ankylosing spondylitis, adult and paedia -tric Crohn’s disease, ulcerative colitis, psoriaticarthritis and adult plaque psoriasis, when the res -ponse to conventional treatment has been inade-quate.Advised period of discontinuation of infliximab

before conception based on the summary of theproduct characteristics (SPC) is 6 months4. How-ever, according to other recommendations a preg-nancy appears acceptable 2 months after inter-rupting infliximab, respecting a time interval offive half-lives and using the highest half-life valuesreported5,6. Experience with pregnancy exposure to inflixi -

mab has been slowly accumulating and this is re-flected in the number of reports found in the litera -ture search. Twenty-four references where the safe-ty of infliximab during pregnancy was evalua tedwere selected for detailed analysis: data from fourregistries, three case series and individual case re-ports7-30.According to information from the selected ar-

ticles, there were 156 patients treated with inflixi -

biologic therapy and pregnancy


221

bogas m e col.

Tabl

e I.

Sum

mar

y of

pre

gnan

cies

exp

osed

to

anti-

TNF

ther

apie

s

Live

Spon

t. The

rap.

Birth

Stud

y Other

Pregn

ancies,

births,

Abo

rtions,

Abo

rtion,

defects/

Autho

r, ye

arinfo

Biologic

drug

sno

.no

.Exp

osition

no.

no.

Com

plications

Com

men

tOther

Disea

seG

raci

a, 2

006

BIO

BA

DA

SER

INF

yes

43

T1

10

Rheu

mD

is

Kat

z, 2

004

INF

Safe

ty

INF

som

e:

96

64

32bC

; 58T

1;

14

18

5 (

all in

pat

ients

1 p

rem

at w

ith intr

acer

ebra

l 8R

A, 8

2 C

D,

Dat

abas

eM

TX

8%

;6 N

Dex

p. t

o IN

F an

d intr

apulm

onar

y ble

edin

g 2JIA

, 1 U

C;

AZ

A 3

3%

, duri

ng

die

d; 1

IRD

S; 1

inte

stin

al

3N

R

MT

NZ

14%

pre

gnan

cy)

mal

rota

tion (

exp.

LFN

);

1 T

etra

logy

Fal

lot;

del

ayed

dev

elopm

ent

and

hypoth

yroid

ism

Mah

adev

an,

Inte

ntional

Tx

INF

som

e10

10

2T

1; 8

T2-3

00

11 r

espir

atory

dis

tres

s 3 p

rem

atC

D

2005

(IC

U)

Schnitzl

er,

Inte

ntional

Tx

INF

12

10

T1T

21

02 p

rem

atIB

D

2007

Ber

thel

ot,

CR

IIN

F3

31T

1; 2

T1-2

00

0

1JIA

, 1R

A,

2009

1Sp

A

Cham

ber

s,

OT

ISIN

Fno

43

T1

10

2 p

rem

atR

A

2004

Turs

i, 2006

INF

yes

11

T1-3

00

0C

D

Ange

lucc

i, 2008

INF

yes

11

T1

00

0C

D

Burt

, 2003

INF

no

11

T1

00

0C

D

Kin

der

, 2004

INF

MT

X1

0T

11 (

MT

X)

00

RA

Vas

iliau

skas

, 200

6IN

Fno

11

T1

00

0C

D

Sten

gel,

2008

INF

mes

alaz

ine

11

T1-3

00

0C

D

Chap

arro

, 2010

INF

ND

11

T1-3

00

0C

D

Aki

nci

, 2008

INF

ND

11

T2-3

00

0Sp

A

Pal

mer

, 2008

INF

no

10

T1

11

del

ayed

U

C

dev

elopm

ent

Anto

ni,

2002

INF

11

T1

0

PsA

Srin

ivas

an, 2

001

INF

11

T1

0

dea

th o

nC

D

day

3

Jam

es, 2

001

INF

11

T2 (

singl

e 0

CD

dose

)

Ner

om

e, 2

008

INF

MT

X

11

T1-2

0

pre

mat

JIA

Corr

eia, 2

010

INF

22

T3

0

IBD

Puig

, 2009

INF

11

T1

0Pso

rias

is

Ost

ense

n, 2

008

INF

51

T1

4R

A, P

sA,

Olig

oar

t

Rosn

er, 2

007

INF

AZ

A3

3T

1-3

00

01 p

rem

at1JIA

and

2R

A

Kan

e, 2

009

INF

33

T1-2

00

0C

D

cont

inue

on

next

pag

e


222


Tabl

e I.

Sum

mar

y of

pre

gnan

cies

exp

osed

to

anti-

TNF

ther

apie

s (c

ontin

uatio

n)

Live

Spon

t. The

rap.

Birth

Stud

y Other

Pregn

ancies,

births,

Abo

rtions,

Abo

rtion,

defects/

Autho

r, ye

arinfo

Biologic

drug

sno

.no

.Exp

osition

no.

no.

Com

plications

Com

men

tOther

Disea

seB

erth

elot,

CR

IETA

1M

TX

10

76T

1; 2

T1-2

21 (

MT

X)

02R

A; 6

SpA

;

2009

1PsA

; 1JIA

Gar

cía, 2

006

BIO

BA

DA

SER

ETA

NR

84

T1

2R

heu

mD

is

Chak

rava

rty,

ETA

som

e7

6"d

uri

ng

10

0R

A

2003

pre

gnan

cy"

Kosv

ik, 2

005

ETA

no

53

T1

20

0IJA

and R

A

Roux, 2

007

ETA

yes

32

T1

01

1U

TI +

CA

HR

A

Rum

p, 2

004

ETA

no

11

T1

00

0R

A

Feye

rtag

, 2004

ETA

no

11

T1-3

00

0R

A

Car

ter,

2006

ETA

no

11

T1-3

0

01

VA

CT

ER

L a

ssoc

PsA

(hig

h d

ose

)

Sinha, 2

006

ETA

no

11

00

0R

A

Mic

hel

oud, 2

006

ETA

no

11

T2-3

00

0SL

E (

LN

)

Ote

rmin

, 2007

ETA

no

11

T1-3

00

0JIA

Rosn

er, 2

007

ETA

MFM

11

T1-3

00

0SL

E

Um

eda, 2

010

ETA

11

T1, T

2 a

nd T

30

00

RA

Mura

shim

a, 2

009

ETA

PD

N1

1T

1-T

30

00

pre

mat

RA

Rum

p, 2

010

ETA

86

C a

nd

11

Meg

acolo

n c

onge

nitum

RA

and A

S

"duri

ng

pre

gnan

cy"

Borr

ego, 2

010

ETA

NSA

IDs

11

T1

00

0PsA

Ost

ense

n, 2

008

ETA

95

6T

1; 3

T3

13 o

utc

om

e

unko

wn

RA

and A

S

Johnso

n, 2

008

OT

ISETA

yes

139

130

T1

6 (

1

2 (

1

11

1 a

tria

l se

pta

l def

ect

+ p

aten

t R

heu

mD

is

Tris

som

y unsp

ecifi

ed

duct

us

arte

riosu

s, e

sotr

opia

,

18)

hea

rt

and in

guin

al h

erni

a; 1

tra

nsve

rse

def

ect)

stom

ach w

ith e

pis

pad

ias

+

conge

nital

eye

def

ect

in a

tw

in

whose

co-t

win

had

dis

pla

ced

stom

ach; 1

ven

tric

ula

r se

pta

l

def

ect

+ p

aten

t fo

ram

en o

vale

+ p

aten

t duct

us

arte

riosu

s;

1 v

entr

icula

r se

pta

l def

ect

+

pulm

onic

ste

nosi

s; 1

pyl

ori

c

sten

osi

s; 1

cys

tic

aden

om

atoid

mal

form

atio

n; 1

hyp

osp

adia

s +

ingu

inal

her

nia

; 1 v

olv

ulu

s; 1

mic

roce

phal

y; 1

conge

nital

hypoth

yroid

ism

; 1 T

riss

om

y 21

cont

inue

on

next

pag

e


223

bogas m e col.

Tabl

e I.

Sum

mar

y of

pre

gnan

cies

exp

osed

to

anti-

TNF

ther

apie

s (c

ontin

uatio

n)

Live

Spon

t. The

rap.

Birth

Stud

y Other

Pregn

ancies,

births,

Abo

rtions,

Abo

rtion,

defects/

Autho

r, ye

arinfo

Biologic

drug

sno

.no

.Exp

osition

no.

no.

Com

plications

Com

men

tOther

Disea

seJo

hnso

n, 2

009

OT

ISA

DA

94

80

T1

13

17

1 u

ndes

cended

tes

ticl

e, 1

C

D a

nd R

A

mic

roce

phal

y, 1 v

entr

icula

r

septa

l def

ect,

1 c

onge

nital

hip

dys

pla

sia, 1

conge

nital

hypoth

yroid

, 1 b

icusp

id a

ort

ic

valv

e an

d a

genes

is o

f th

e

corp

us

callo

sum

, 1 c

onge

nital

hydro

nep

hro

sis

Gar

cía, 2

006

BIO

BA

DA

SER

AD

A2

?T

11

0R

heu

mD

is

Ber

thel

ot,

2009

CR

IA

DA

22

1T

1; 1

T1-3

0

1R

A; 1

SpA

Ves

ga, 2

005

AD

Ano

11

T1-3

00

0C

D

Sanch

ez, 2

005

AD

A1

1T

10

0C

D

Kra

emer

, 2008

AD

ALF

N u

ntil W

81

1T

1-3

00

0Ta

kaya

su

Mis

hki

n, 2

006

AD

Ano

11

T1-3

00

0C

D

Coburn

, 2006

AD

Aye

s1

1T

2T

30

00

CD

Car

ter,

2007

AD

A1

1T

10

01

VA

CT

ER

L a

ssoc

?

Jurg

ens, 2

009

AD

A1

1T

10

00

CD

Des

sinio

ti, 2

010

AD

A1

1T

10

low

wei

ght

Pso

rias

is

Kin

g, 2

008

BSR

BR

7IN

F+29M

TX

58

30

55T

1; 3

T1-3

18

64 +

23 intr

aute

rine

dea

th a

nd 1

R

heu

mD

is

40ETA

+(3

ETA

: T1-

T3

neo

nat

al d

eath

; 1 c

onge

nital

(m

ost

ly R

A)

11A

DA

"all

hea

lthy

")

hip

dys

pla

sia

and 1

pyl

ori

c

sten

osi

s

Stra

ngf

eld, 2

007

RA

BB

ITIN

F+ETA

2 M

TX

/LFN

22

20

most

ly T

1;

20

0R

heu

mD

is

+A

DA

3T

2 /

T3

Cush

, 2005

On-lin

e quer

y IN

F+ETA

454

378

"duri

ng

25

50

9 p

rem

atR

A

(USA

)+

AD

Apre

gnan

cy"

Ouss

alah

, 2009

CT

Z1

1T

1 a

nd T

30

CD

NF

- in

flixim

ab, E

TA

- e

taner

cept,

AD

A -

adal

imum

ab, R

TX

- r

ituxim

ab, A

NA

k -

anak

inra

, AB

At

- ab

atac

ept,

TC

Z-

toci

lizum

ab, C

TZ

- c

erto

lizum

ab, M

TX

- m

ethotr

exat

e, A

ZA

- a

zath

iopri

ne, M

FM -

myc

ophen

ola

te

mofe

til,

MT

NZ

- m

etro

nid

azole

, PD

N -

pre

dnis

olo

ne, N

D -

not

des

crib

ed, T

1 -

1st

tri

mes

ter,

T2 -

2nd t

rim

este

r, T

3 -

3rd

tri

mes

ter,

RA

- r

heu

mat

oid

art

hri

tis, P

sA -

pso

riat

hic

art

hri

tis, JIA

- juve

nile

idio

phat

ic

arth

ritis, A

S -

anky

losi

ng

spondyl

itis

, Rheu

mD

is -

rheu

mat

ic d

isea

ses, C

D -

Cro

hn's

dis

ease

, IB

D -

infla

mm

atory

bow

el d

isea

se, U

C -

ulc

erat

ive

colit

is, S

LE (

LN

) -

syst

emic

lupus

eryt

hem

atosu

s (lupus

nep

hri

tis)

;

for

oth

er a

cronym

s ple

ase

see

text.


224


mab duringpregnancy. Of these women, about 70%were exposed in the first trimester, around 5 to 10%throughout pregnancy and the remaining on thefirst two trimesters or punctually to control flares. Congenital malformations and other complica-

tions occurred in 8 infants one intestinal malrota-tion (concomitant leflunomide), one tetralogy ofFallot, one child experienced intracerebral and in-trapulmonary hemorrhage and died at 24 weeks,another died on day 3 (reason not known), 2 hadrespiratory distress (1 in an infant with seizures)and 2 delayed development (1 with hypothy-roidism)9,10,20,22.

Etanercept – FDA Pregnancy category BEtanercept is a TNF receptor-IgG fusion proteinthat binds TNF molecules preventing these frombinding TNF receptors on the cell surface. It is ap-proved for the treatment of severe rheumatoidarthritis, polyarticular juvenile idiopathic arthritis,psoriatic arthritis, ankylosing spondylitis, adult andpaediatric plaque psoriasis, in patients who failedto respond to conventional therapies.In the SPC, the safety interval between the last

treatment and conception is not referred31. Recom -mendations vary advocating different safety inter-vals from 3 weeks to 2 months5,6. Eighteen papers were selected for their report of

etanercept exposure in pregnant women: data fromthree registries, five small case series and indivi -dual case reports7,8,27,28,32-45. Overall, taking into ac-count the included studies, exposure to etanerceptwas reported in 199 pregnancies. Exposure oc-curred in the first trimester in about 70% of the pa-tients and in other trimesters or throughout preg-nancy in the remainder. Congenital malformations or other complica-

tions in confirmed pregnancies exposed to etaner -cept were noticed in 14 cases: 1 VACTERL syndro -me (Vertebral defects [V], Anal atresia [A], Cardiacabnormalities [C], Tracheoesophageal fistula or tra-cheal atresia/stenosis [T], Esophageal atresia [E],Renal and/or Radial abnormalities [R], and pre--a xial Limb abnormalities [L]), 1 megacolon con-genitum, 1 atrial septal defect with patent ductusarteriosus, esotropia and inguinal hernia, 1 trans-verse stomach with epispadias and congenital eyedefect in a twin whose co-twin had displaced sto -mach, 1 ventricular septal defect with patent fora-men ovale and patent ductus arteriosus, 1 ventri -cular septal defect with pulmonary stenosis, 1 py-loric stenosis, 1 cystic adenomatoid malformation,

1 hypospadias with inguinal hernia, 1 volvulus, 1microcephaly, 1 congenital hypothyroidism and 1Trissomy 21. Another case with trissomy 18 resul -ted in abortion37,38,44. There was another case des -cribed as a congenital abnormality but that mightbe interpreted as hereditary adrenal hyperplasiawith 21 hydroxilase inheritated from the father 34.

Adalimumab – FDA Pregnancy category BAdalimumab is a fully human monoclonal antibodythat binds to TNF±, preventing it from activatingTNF receptors. It is approved for the treatment ofsevere rheumatoid arthritis, ankylosing spondyli-tis, idiopathic juvenile arthritis, adult and paedi-atric Crohn’s disease, ulcerative colitis, psoriaticarthritis and adult plaque psoriasis, when the re-sponse to conventional treatment has been inade-quate.The SPC advises a safety interval between the

last treatment of adalimumab and the conceptionof 5 months46. Again, other recommendations exis tbased on half-lives of the product, stating shorterperiods of 8 weeks and 3 months as possibly safe5,6.Existing data on adalimumab use during preg-

nancy is more limited than for the previous agentsand based on the information from three registriesand individual case reports. Overall, eleven paperswere selected for the information on adalimumabexposure during pregnancy7,27,47-55. According to in-formation from the selected articles, exposure toadalimumab during pregnancy occurred in 106 pa-tients. Exposure occurred in the first trimester inapproximately 90% and throughout pregnancy injust about 10% of patients. Overall there were 8 reported malformations: 1

VACTERL syndrome, 1 undescended testicle, 1 mi-crocephaly, 1 ventricular septal defect, 1 congeni-tal hip dysplasia with inguinal hernia, 1 congenitalhypothyroidism, 1 bicuspid aortic valve and agene -sis of the corpus callosum (twin pregnancy in which2nd twin had patent ductus arteriosus) and 1 con-genital hydronephrosis (twin pregnancy in which2nd twin was spontaneously aborted)51,52.

Other data on pregnancy exposure to anti-TNF As referred before, further data come from studiesdescribing the number of pregnancies and/or thenumber of live births and/or their outcomes for awhole group of patients that cannot be individua -lized by anti-TNF or other biologic. These data isdiscussed here, separately.One of the largest descriptions on anti-TNF ex-


225

posure during pregnancy comes from an internetsurvey based on practicing US rheumatologists re-call on the use of biological agents published byCush in 200556. This study describes 454 pregnan-cies exposed to anti-TNF agents (81% to etaner-cept) with 378 normal deliveries, 9 premature ba-bies, 5 therapeutic abortions, and 25 miscarriagesin this group. TNF antagonists were used throu -ghout the pregnancy in 31.3% of the patients. Therewere no birth defects, fetal malformations, orneonatal deaths reported. However, detailed in-formation could only be retrieved on part of the pa-tients and therefore, there is some uncertainty asto the exactitude of the data57. In 2006, Hyrich et al published the outcomes of

23 pregnant patients exposed to anti-TNF treat-ment (ETA, n=17; INF, n=3; ADA, n=3) at the timeof conception and/or during pregnancy identifiedfrom the British Society for Rheumatology Bio -logics Registry (BSRBR) database58. In 2008, the BSRBR updated the previous publication and re-ported 58 women directly exposed (DE) to an anti--TNF drug (INF, n=7; ETA, n=40; ADA, n=11; andMTX, n=29), during pregnancy59. Data from theBSRBR were described in patients receiving anti--TNF therapy for rheumatic diseases alongside aparallel DMARD control group: 41 women pre -viously exposed (PE) to anti-TNF therapy (INF,n=14; ETA, n=21; ADA, n=6; MTX, n=1 at concep-tion) and 6 pregnancies in the DMARD only con-trol group. Anti-TNF therapy was discontinued inall but 2 pregnancies in the DE group (3 babies - 1twin pregnancy). A trend towards a higher miscar-riage rate was seen in the DE group compared tothe PE group and DMARD group: 18/58 (31%) ver-sus 7/41(17%) and 1/6 (16%). There were 30/58,32/41, and 5/6 live births in the DE group, PEgroup, and DMARD control group, respectively.Two congenital abnormalities were reported ineach DE (1 congenital hip dysplasia and 1 pyloricstenosis) and PE (1 strawberry naevus and 1 “win -king jaw syndrome”) groups. Additionally, 3 in-trauterine deaths, 1 neonatal death, and 6 electiveterminations were reported in the DE group. Oneintrauterine death and one elective terminationwere reported in the PE group. Strangfeld et al collected data from the German

biologics register (RABBIT), a study evaluating pa-tients with Rheumatoid Arthritis (RA) who initia -ted therapy with a biologic agent60. Analysis wasperformed of 37 pregnancies in 29 women whowere exposed to anti-TNF agents during concep-

tion or at least the first trimester of pregnancy: INF(n=2), ADA (n=5), ETA (n=20), DMARDs (n=8).Comparison was made to those who stopped ei-ther biologic and/or other DMARDs before con-ception. Mean birth weight was similar in infantsexposed to biologic therapy (3.1 kg) compared toinfants exposed to non-biologic therapy (3.1 kg).There were no congenital malformations reported.Three patients re-initiated treatment with the bio -logic after week 20 and continued the therapy un-til delivery. Mothers and newborns were reportedto be well post-partum (ETA, n=2; INF, n=1). See additional information on Table I.

Golimumab and Certolizumab – FDA Pregnancycategory BGolimumab (a human monoclonal anti-TNF-αan-tibody) and certolizumab (a PEGylated Fab frag-ment of humanized monoclonal TNF-α antibody)are the two latest anti-TNF biologics. Golimumabis indicated for the treatment of severe rheumatoidarthritis, ankylosing spondylitis and psoriaticarthritis and certolizumab is indicated for rheuma-toid arthritis, in both cases, in patients who haveresponded inadequately to conventional therapy.According to the SPC, women of childbearing

potential should use adequate contraception toprevent pregnancy and continue its use for at least5 and 6 months after the last certolizumab andgolimumab administration, respectively61,62.As both of these therapies are relatively new,

there are no published data regarding their use inhuman pregnancy apart from a report in abstractform of a woman treated with certolizumab du -ring the first and third trimesters delivering a nor-mal baby63.

Rituximab – FDA Pregnancy category CRituximab is a monoclonal chimaeric human--mouse antibody that binding specifically to atransmembrane antigen, CD20, located on pre-Band mature B lymphocytes, mediates B cell death.This drug is indicated for the treatment of non--Hodgkin’s lymphoma (NHL) and chronic lym-phocytic leukaemia (CLL) in combination withche mo therapy, and for severe, refractory rheuma-toid arthritis.Since rituximab is an IgG-based antibody, it is

likely to cross the placental barrier and interferewith fetal and neonatal B-cell development andgiven its pharmacokinetic properties and its long-term effects it may cause some concern even when

bogas m e col.


226

the mother is exposed to treatment before con-ception64,65. Due to the long retention time of ritu -ximab in B-cell-depleted patients, the SPC men-tions that women of child-bearing potential shoulduse effective contraceptive methods for 12 monthsfollowing the last infusion before conception65.However, the elimination half-life of rituximab sug-gests that a 6-month wait may be adequate, as sta -ted by some published recommendations5,6.Published experiences on the use of rituximab

during pregnancy consist of a limited number ofcase reports. Our literature search found 16 wo -men exposed to rituximab at least 6 months beforeconception, at conception or during pregnan-cy28,64,66-76. Some of them were also exposed to other treatments, potentially harmful, for lifethreatening si tuations as lymphomas69,71,74-76. Treat-ment with ri tuximab was administered in the firsttrimester in three, in the second and/or third ineight pregnancies. There were 15 live healthyneonates and 1 elective termination. There were noserious infectious complications documented. Ad-ditional information on reports of pregnancies ex-posed to rituximab may be seen in Table II.

Anakinra – FDA Pregnancy category BAnakinra is a human interleukin-1 receptorantago nist approved for the treatment of severerheumatoid arthritis in patients who have not res -ponded adequately to convencional therapy. Al-though without a formal indication it has also beenused to treat the systemic form of juvenile idio-pathic arthritis.The safety interval between the last adminis-

tered dose and conception is not referred in theSPC77. Information regarding ANAk during pregnancy

is limited to data from the German Register60. Twopregnancies exposed to ANAk during the concep-tion/first trimester have had good outcome withno malformations described.

Abatacept – FDA Pregnancy category CAbatacept is a fusion protein that selectively modu -lates a key costimulatory signal required for fullactivation of T lymphocytes. It is approved for thetreatment of refractory rheumatoid arthritis andpolyarticular juvenile idiopathic arthritis.The elimination half-life of abatacept suggests

that an 18 week wait between the last abatacept in-fusion and conception may be adequate5. The SPCadvises effective contraceptive methods for at least

14 weeks following the last infusion until attemptsto conceive78. In the double blind and open-label periods of

the 5 core studies and in another phase II trial, 10pregnancies that involved women treated withabatacept were reported79. Of these 8 women, 7 received MTX and 1 leflu -

no mide as concomitant medication. Three sub-jects experienced a spontaneous abortion duringthe first trimester (two had a history of previousspontaneous abortions). Two subjects had theirpregnancy terminated. Three pregnancies wereongoing at the time of the report. In a phase II trial of abatacept for multiple scle-

rosis (IM101200), 2 women became pregnant. Onesubject delivered a healthy baby 10 months afterdiscontinuation from the study (was not exposedduring pregnancy) and the other subject had anelective abortion at 4 weeks gestation79.

Tocilizumab – FDA Pregnancy category CTocilizumab binds specifically to both soluble andmembrane-bound IL-6 receptors. It is indicatedfor the treatment of refractory rheumatoid arthri-tis. According to SPC, pregnancy appears accepta -ble 3 months after stopping tocilizumab80.No data on exposure to tocilizumab during hu-

man pregnancy have been published.

Discussion

Although currently available data are sparse andlimited in number, experience with pregnancy ex-posure to biological therapies is slowly accumu-lating. Interpretation of the results must be cau-tious and some important issues need to be con-sidered:Many women had active disease and were con-

comitantly exposed to potential teratogenic drugssuch as MTX, leflunomide and metronidazole.Exposure may be divided into two groups: a) un-

planned pregnancies – exposure occurred at thetime of conception and 1st trimester; b) pregnantwomen who were treated intentionally because ofactive refractory disease. The duration and time ofexposure during pregnancy to these agents maylead to different outcomes; in most of the reports,women have suspended the biologic treatment assoon as the pregnancy was confirmed, usually inthe first trimester.Doses of anti-TNF vary depending on the di -



227

bogas m e col.

Tabl

e II

. Sum

mar

y of

pre

gnan

cies

exp

osed

to

othe

r bi

olog

ics

(non

-ant

i-TN

F)

Live

Spon

t. The

rap.

Birth

Stud

y Other

Pregn

ancies,

births,

Abo

rtions,

Abo

rtion,

defects/

Autho

r, ye

arinfo

Biologic

drug

sno

.no

.Exp

osition

no.

no.

Com

plications

Com

men

tOther

Disea

seN

g, 2

009

RT

XA

AS+

Igs+

11

>=

6m

onth

s 0

00

APPS

PD

Nbef

C

Ponte

, 2010

RT

X2

2T

10

0

Ato

pic

Der

mat

itis

Pel

lkofe

r, 2009

RT

X1

1C

00

Optic

Neu

-

rom

yelit

is

Ost

ense

n, 2

008

RT

X3

23 m

o b

C

01

0

SLE

e T

1-T

2

Her

old

, 2001

RT

XH

OP

11

T2 e

T3

00

0

pre

mat

Lym

phom

a

Kim

by,

2004

RT

X1

1T

10

0

Lym

phom

a

Frie

dri

chs, 2

006

RT

XC

HO

P1

1T

2 e

T3

00

0

Lym

phom

a

Scully

, 2006

RT

X1

1T

2 e

T3

00

0

pre

mat

TT

P

Oje

da-

Uri

be,

RT

X1

1T

10

0

AI H

emolA

n

2006

Mag

lori

e, 2

006

RT

XC

HO

P1

1T

20

00

Lym

phom

a

Dec

ker,

2006

RT

XC

HO

P1

1T

20

00

pre

mat

Lym

phom

a

Klin

k, 2

008

RT

XIg

s1

1T

30

00

ITP

Rey

, 2009

RT

XC

HO

P1

1T

2 e

T3

00

0

pre

mat

Lym

phom

a

Stre

ngf

eld, 2

007

RA

BB

ITA

NA

k2

2>

T1; 2

T2-3

0

Rheu

mD

is

Abat

acep

t_EM

AA

BA

tM

TX

or

LFN

83?

T1 (

3

32 (

MT

X o

r LFN

)?

RA

2007

ongo

ing

pre

gnan

cies

when

report

ed)

Abat

acep

t_EM

AA

BA

t1

0T

1

1M

ultip

le

2007

Scle

rosi

s


228

sease being treated; in some reports a high dosewas used to obtain disease control (ex. the patientwho delivered a baby diagnosed with a VACTERLassocia tion was being treated with 100 mg weeklyof etanercept for severe psoriatic arthritis).The outcome of each pregnancy may be de-

pendent on several other factors including the in-dividual women herself, the disease, the activitystate and the presence of other co-morbidities81.This information is lacking in most of the reports. Congenital anomalies are seen in 3 to 5% of live

births and some are relatively more common likethose that involve the nervous system, the heart,the limbs and the urinary system (with a preva-lence of more than 20 cases per 10,000 births)82.VACTERL is a nonrandom association of birth de-fects that occurs in 1.6/10,000 live births83. The fre-quency of preterm births varies from 5 to 13% inmost of developed countries84. The risk forcongeni tal anomalies or prematurity is describedto be higher in RA when compared to women wi -thout RA81. It is obvious that the lack of a nontrea -ted control group in most of the reports includedin this systematic review may lead to some biasbut, importantly, no specific pattern of congenitaldefects has been noted in infants prenatally ex-posed to bio logics.The Otis (Organization of Teratology Informa-

tion Specialists) Collaborative Research Group, anot-for-profit organization in United States andCanada, has been prospectively following preg-nant women exposed to anti-TNF during pregnan -cy. They provide the some of the few controlled in-formation included in this systematic review basedon data from pregnancy outcomes in expo-sed group compared with those in a disease--matched non-treated control and healthy controlgroups29,37,52. The preliminary data of the informa-tion published suggest that the rate of major struc-tural defects in the TNF treated group is similar tothe general population rates52. Preterm deliveryand poor growth are increased in the exposedgroup and diseased non exposed group suggestingthat it might be attributable to the underlying ma-ternal disease37,52. Aside from the current systematic review, three

other publications have to be mentioned and in-troduced in the discussion. A recently publishedpaper raised concerns of a possible causative effectof the TNF antagonists in some congenital anoma-lies that are part of the VACTERL spectrum51. Thisstudy based on a voluntary post-marketing adverse

event database of FDA was not included in the sys-tematic review because it is not possible to knowthe total number of pregnant women exposed toTNF-antagonists and it reports only those with badpregnancy outcomes. The information providedmay still, nevertheless, be important. The reviewreported 41 children with 61 congenital anomaliesborn to 40 mothers receiving a TNF antagonist.The TNF antagonist was considered the “primarysuspect” as the cause of the birth defect in all ca -ses (22 ETA and 19 INF). The most commonly re-ported anomaly was a form of heart defect. A totalof 24 children (59%) had ≥1 congenital anomalyconsidered part of VACTERL association. Conversely, Snoeckx et al conducted a search of

the Benefit Risk Management Worldwide SafetyDatabase (SCEPTRE) of Johnson & Johnson for allmedically confirmed cases of pregnancy reportedin patients who have ever received INF (before orafter conception) in order to identify any cases ofVACTERL association85. Pregnancy outcome datawere available for 627 cases. The number of pa-tients directly exposed to INF during pregnancy isnot specified and the report included women thathad been treated with INF years before concep-tion. There were 14 cases with ≥1 congenitalanomalies/malformations but none of the repor -ted cases met the criteria for VACTERL association. Also the TREAT registry was designed to assess

the long-term safety of infliximab in patients withCrohn’s disease. A total of 114 pregnancy knownoutcome reports in patients treated with infliximabhave been collected as of June 200886. Again, thenumber of patients directly exposed to INF duringpregnancy is not known and many women trea tedwith INF years before conception were included.A total of 9 neonatal problems were reported (5premature infants, 1 jaundice, 1 hypoxia, 1 ven-tricular defect and 1 with congenital ectrodactyly).None of the reports with neonatal problems metthe criteria for VACTERL association.As it is the predominant route of communica-

tion between the mother and the fetus, under-standing the process of placental transfer of somedrugs would help us to better evaluate the risk oftheir exposure during pregnancy. Theoretically, thestructure of several of the molecules, which con-tain a human immunoglobulin G1 (IgG1) constantregion, allows little placental transfer of the mo -lecule during the first trimester87. However, IgGsubclasses are readily passed into the foetus du ringthe second and third trimesters, which specifical-



229

ly raises questions regarding safety of administra-tion of these drugs beyond the 2nd trimester of pre -gnancy. There are studies that prospectively analy -zed INF serum levels in newborns exposed in uteroto INF during 2nd and/or 3rd trimesters15,30,88. Data issomewhat contradictory. In one study, levels of INFwere not detectable in the newborn, sugges tingthat INF was not transferred from mother to child30.In the other studies, the authors found detectablelevels of INF in the newborn and until 2 to 6months of age15,88.Rituximab was also evaluated in similar studies

describing women treated with the drug duringthe 2nd and 3rd trimester of pregnancy. Serum le velsof the drug and B lymphocytes in the neonate andin the mother were measured64,71,75. At birth, RTXserum levels were detectable and neonates hadvery low or no detectable B-cells. Time of ritu ximabadministration during gestation did not appear toinfluence this outcome. A decline in RTX levelsseemed consistent with the known half-life of ri -tuximab and at the age of 6 months, the numberof B-cells was in the normal range. In addition, nor-mal immunoglobulin levels and normal vaccina-tion responses could be demonstrated.Despite the persistence of some doubts and the

insufficient data on the safety of these agents, someimportant organizations have already stated theirposition on the use of biologics during pregnancy.The official recommendations of the American So-ciety of Gastroenterology published in 2006 de-clared that “there is growing body of evidence sug-gesting low risk of infliximab during pregnancy”89.The reference centre for teratogenicity of France(CRAT) has implied that infliximab might be usedfor the treatment of a refractory disease if this is theonly way for controlling active disease, warninghowever to avoid the final weeks of the thirdtrimester5.We may conclude that the true implications of

biologic exposure during pregnancy are yet un-known. The existing evidence suggests that theoverall risk of TNF antagonists is relatively low andbenefits may outweigh the risks of drug exposureto the fetus. At least we may say that although thenumbers are small and there is little informationfrom controlled studies the reviewed data suggestthat women who inadvertently become pregnantwhile taking anti-TNF agents may be reassuredthat stopping the treatment and continuation ofpregnancy does not appear to hold a real increasedrisk of congenital malformations. Information on

other biologic agents (not TNF blockers) is still verylimited. The decision to treat with a biologic agentin pregnancy should be made on a case-by-casebasis. What remains for the patient, the rheuma-tologist and the obstetrician to do is to balance therisk between the importance of remaining in re-mission or with partial control of the disease withthe potential risk of these drugs to cause any harm.Patients with inflammatory rheumatic disorders

and the physicians caring for them should keep inmind that disease activity at the time of conceptionor during the course of pregnancy may be associa -ted with a risk of low birth weight, premature birthsand spontaneous abortions. In women with a se-vere, refractory disease course, in whom biologicaltherapies have been the only agents to induce andmaintain remission, therapy may probably be con-tinued at least until conception.

Conflict of Interest StatementBogas M has received speaking fees from Pfizer.Leandro MJ has received consultancy and speaking feesfrom Roche and GSK.

Correspondence toMónica BogasPraça Linha Vale do Lima, nº2 Bl.3 Edif. 2 – 4ºMeadela - 4900-296 Viana do CasteloE-mail: [email protected]

References1. US Food and Drug Administration. United States FDA

pharmaceutical pregnancy categories. Fed Regist 1980;44: 37434–37467.

2. European Medicines Agency. http://www.ema.eu-ropa.eu/ema. 2010. Accessed in October 20th

3. US Food and Drug Administration. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ Develop-mentResources/Labeling/ucm093307.htm. Accessedin October 20th

4. European Medicines Agency. European Public Assess-ment report (EPAR) for Remicade® http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Product_Information/human/000240/ WC50005 -0888. pdf. Accessed in October 20th

5. Centre de référence sur les agents tératogènes. www.le-crat.org. Accessed in October 20th

6. Fonseca JE, Silva C JA, Canhão H, et al. Guia prático deutilização de terapêuticas de biotecnologia na artritereumatóide. Acta Reumatol Port. 2009: 34: 395-399.

7. Garcia-Gonzalez AJ, Joven BE, Ruiz T, et al. Pregnancyin women receiving anti-TNF-alpha therapy, expe -rience in Spain. Ann Rheum Dis 2006; 65: S317.

8. Rosner I, Haddad A, Boulman N, et al. Pregnancy inrheumatology patients exposed to anti-tumour necro-sis factor (TNF) therapy., Rheumatol 2007; 46:1508.

9. Katz JA, Antoni C, Keenan GF. Outcome of pregnancy

bogas m e col.


230

in women receiving infliximab for the treatment ofCrohn’s disease and rheumatoid arthritis. Am J Gas-troenterol 2004; 99:2385–2392.

10. Mahadevan U, Kane S, Sandborn WJ, el al. Intentionalinfliximab use during pregnancy for induction or main-tenance of remission in Crohn’s disease. Aliment Phar-macol Ther 2005; 21: 733–738.

11. Tursi A. Effect of intentional infliximab use throughoutpregnancy in inducing and maintaining remission inCrohn’s disease. Dig Liver Dis 2006; 38:439–40.

12. Angelucci E, Cocco A, Viscido A, Caprilli R. Safe use ofinfliximab for the treatment of fistulizing Crohn’s di -sease during pregnancy within 3 months of concep-tion. Inflamm Bowel Dis 2008; 14:435–436.

13. Burt MJ, Frizelle FA, Barbezat GQ. Pregnancy and ex-posure to infliximab (anti tumor necrosis factor anti-body). J Gastroenterol Hepatol 2003; 18:465–466.

14. Kinder AJ, Edwardes J, Samanta A, Nichol F. Pregnan-cy in a rheumatoid arthritis patient on infliximab andmethotrexate. Rheumatology (Oxford) 2004; 43:1196–1197.

15. Vasiliauskas EA, Church JA, Silverman N, Barry M, Tar-gan SR, Dubinsky MC. Case report: evidence fortransplacental transfer of maternally administered in-fliximab to the newborn. Clin Gastroenterol Hepatol2006; 4:1255–1258.

16. Stengel JZ, Arnold HL. Is infliximab safe to use whilebreastfeeding? World J Gastroenterol 2008; 14:3085– -3087.

17. Chaparro M, Gisbert JP. Successful Use of infliximab forperinatal Crohn's disease in pregnancy. Inflamm Bo -wel Dis 2010; 17:868-9.

18. Akıncı A, Özçakar L. Infliximab use during pregnancyrevisited. Acta Reum Port 2008; 33:374-375.

19. Schnitzler F, Fidder HH, Ferrante M, et al. Intentionaltreatment with infliximab during pregnancy in wo menwith inflammatory bowel disease. Gastroenterology2007; 142:A144.

20. Palmer RB, Poullis AP, Pollok RCG. Acute severe colitisin pregnancy treated with infliximab. GastroHep.com;8Th June 2008.

21. Antoni C, Dechant C, Hanns-Martin Lorenz PD, et al.Open-Label Study of Infliximab Treatment for psoria -tic arthritis: clinical and magnetic resonance imagingmeasurements of reduction of inflammation. ArthritisRheum 2002;47:506-512.

22. Srinivasan R. Infliximab treatment and pregnancy out-come in active Crohn’s disease. Am J Gastroenterol2001; 96:2274-2275.

23. James RL, Pearson LL. Successful treatment of preg-nancy-triggered Crohn’s disease complicated by severerecurrent life-threatening gastrointestinal bleeding.Am J Gastroenterol 2001; 96:S295.

24. Nerome Y, Imanaka H, Nonaka Y, et al. A case of plannedpregnancy with an interruption in infliximab admin-istration in a 27-year-old female patient with rheuma-toid-factor-positive polyarthritis juvenile idiopathicarthritis which improved after restarting infliximab andmethotrexate. Mod Rheumatol 2008;18:189-192.

25. Correia LM, Bonilha DQ, Ramos JD, Ambrogini O, Mis-zputen SJ. Inflammatory bowel disease and pregnan-cy: report of two cases treated with infliximab and a re-view of the literature. Eur J Gastroenterol Hepatol2010;22: 1260-4.

26. Puig L, Barco D, Alomar A. Treatment of psoriasis withanti-TNF drugs during pregnancy: case report and re-view of the literature. Dermatology 2010;220:71-76.

27. Berthelot J. De Bandt M, Goupille P. Exposition to anti-TNF drugs during pregnancy: Outcome of 15 cases andreview of the literature. Joint Bone Spine 2009; 76:28--34.

28. Østensen M, Lockshin M, Doria A, et al. Update onsafety during pregnancy of biological agents and someimmunosuppressive anti-rheumatic drugs. Rheuma-tol 2008;47:28–31.

29. Chambers CD, Johnson DL, Jones KL. Pregnancy out-come in women exposed to anti-TNF medications: theOTIS Rheumatoid Arthritis in Pregnancy Study. Arthri-tis Rheum 2004;50:S479

30. Kane S, Ford J, Cohen R, et al. Absence of infliximab ininfants and breast milk from nursing mothers recei vingtherapy for Crohn’s disease before and after delivery. JClin Gastroenterol 2009; 43:613–616.

31. European Medicines Agency. European Public As-sessment report (EPAR) for Enbrel® http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000262/ WC500027361.pdf Accessed in October 20th

32. Chakravarty EF, Sanchez-Yamamoto D, Bush TM. Theuse of disease modifying antirheumatic drugs in wo -men with rheumatoid arthritis of childbearing age: asurvey of practice patterns and pregnancy outcomes.J Rheumatol 2003; 30:241-246.

33. Koskvik HS, Magnussen AM, Skomsvoll JF. One yearfollow-up of etanercept exposed pregnancies. AnnRheum Dis 2005;64:S449.

34. Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L.Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-therapy. Rheumatol2007;46:695–698.

35. Rump JA, Schönborn H. Conception and course ofeight pregnancies in five women on TNF blocker eta -nercept treatment. Z Rheumatol 2010; 69:903-909.

36. Feyertag J, Dinhof G, Salzer H, Dunky A. Pregnancy ina rheumatoid arthritis patient treated with etanercept.Ann Rheum 2004; 63:S198.

37. Johnson DL, Jones KL, Chambers CD. Pregnancy out-come in women exposed to etanercept: the OTIS au-toimmune diseases in pregnancy project. www.otispregnancy.org/readResource.php?r=108642. Ac-cessed in October 20th 2010.

38. Carter JD, Valeriano J, Vasey FB. Tumor necrosis factorinhibition and VATER association: a causal relation-ship? J Rheumatol 2006;33:1014-1017.

39. Sinha A, Patient C. Rheumatoid arthritis in pregnancy:successful outcome with anti-TNF agent (etanercept).J Obstet Gynaecol 2006; 26:689–691.

40. Micheloud D, Nuno L, Rodriguez-Mahou M, et al. Ef-



231

ficacy and safety of etanercept, high-dose intravenousgammaglobulin and plasmapheresis combined thera -py for lupus diffuse proliferative nephritis complica tingpregnancy. Lupus 2006; 15:881–885.

41. Otermin I, Elizondo G, Zabaleta J, Amigot A. Etanerceptand pregnancy. An Sist Sanit Navar 2007;30:491–493.

42. Umeda N, Ito S, Hayashi T, Goto D, Matsumoto I, Sumi -da T. A Patient with Rheumatoid Arthritis Who Had aNormal Delivery under Etanercept Treatment. InterMed 2010; 49:187-189.

43. Murashima A, Watanabe N, Ozawa N, et al. Etanerceptduring pregnancy and lactation in a patient withrheumatoid arthritis: drug levels in maternal serum,cord blood, breast milk and the infant's serum. AnnRheum Dis 2009;68:1793-1794.

44. Rump JA, Usadel S, Schonborn H. Pregnancy and eta -nercept: two cases and follow-up. Ann Rheum Dis 2004;63:S182.

45. Borrego L. Etanercept en el embarazo y lactancia. Ac-tas Dermo-Sifiliogr 2010; 101:97-101.

46. European Medicines Agency. European Public Assess-ment report (EPAR) for Humira® http://www.ema.eu-ropa.eu/docs/en_GB/document_library/EPAR_-_P roduc t _ In f o rma t i on /human/000 4 8 1 /WC500050870.pdf. Accessed in October 20th

47. Vesga L, Terdiman JP, Mahadevan U. Adalimumab usein pregnancy. Gut 2005; 54:890.

48. Kraemer B, Abele H, Hahn M, et al. A Successful Preg-nancy in a Patient with Takayasu’s Arteritis. Hyperten-sion in Pregnancy 2008, 27:247–252.

49. Mishkin DS, Deinse WV, Becker JM, Farraye FA. Suc-cessful Use of Adalimumab (Humira) for Crohn's Di -sease in Pregnancy. Inflamm Bowel Dis 2006; 12:827--828.

50. Coburn LA, Wise PE, Schwartz DA. The Successful Useof Adalimumab to Treat Active Crohn’s Disease of anIleoanal Pouch During Pregnancy. Dig Dis Sci 2006;51:2045–2047.

51. Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. ASafety Assessment of TNF antagonists during preg-nancy: A review of the FDA database. J Rheumatol 2009;36:635-641.

52. Johnson DL, Jones KL, Jimenez J, Mirrasoul N, Salas E,Chambers CD. Pregnancy outcomes in women ex-posed to adalimumab: the OTIS autoimmune diseasesin pregnancy project. http://www.otispregnancy.org/readResource.php?r=108643. Accessed in October 20th-2010

53. Dessinioti C, Stefanaki I, Stratigos AJ, Kostaki M, Kat-sambas A, Antoniou C. Pregnancy during adalimu mabuse for psoriasis. J Eur Acad Dermatol Venereol 2010.Epub ahead of print DOI: 10.1111/j.1468-3083.2010.03756.

54. Sánchez MD, Hoyas PE, Ramírez MC, Núñez HD, Guer-rero JP. Term pregnancy in a patient with Crohn's di -sease under treatment with adalimumab. Gastroen-terol Hepatol 2005; 28:435.

55. Jürgens M, Brand S, Filik L, Hübener C, Hasbargen U,Beigel F, Tillack C, Göke B, Ochsenkühn T, Seiderer J.

Safety of Adalimumab in Crohn’s Disease During Preg-nancy: Case Report and Review of the Literature. In-flamm Bowel Dis 2009;16:1634-1636.

56. Cush JJ. Biological drug use: US perspectives on indi-cations and monitoring. Ann Rheum Dis 2005;64:18–23.

57. Orozco C, Dao K, Cush JJ, Kavanaugh A. Safety of TNFinhibitors during pregnancy in patients with inflam-matory arthritis. Arthritis Rheum 2005;48:S22-S23.

58. Hyrich KL, Symmons DP, Watson KD, Silman AJ; BritishSociety, for Rheumatology Biologics Register. Preg-nancy outcome in women who were exposed toanti–tumor necrosis factor agents: results from a na-tional population register. Arthritis Rheum 2006;54:2701–2702.

59. King YE, Watson KD, Symmons DP, et al. Pregnancyoutcome in women exposed to Anti-TNF agents: Anupdate from the British Society for Rheumatology Bio -logics Register (BSRBR). Arthritis & Rheum 2008;58:S542.

60. Strangfeld A. Pregnancy outcome after exposure to bi-ologics: results from the german biologics register RAB-BIT. Arthritis Rheum 2007;56:S311.

61. European Medicines Agency. European Public Assess-ment report (EPAR) for Cimzia® http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_P roduc t _ In f o rma t i on /human/001 0 3 7 /WC500069763.pdf. Accessed in October 20th

62. European Medicines Agency. European Public Assess-ment report (EPAR) for Simponi® http://www.ema.eu-ropa.eu/docs/en_GB/document_library/EPAR_-_P roduc t _ In f o rma t i on /human/000 9 9 2 /WC500052368.pdf. Accessed in October 20th

63. Oussalah A, Bigard MA, Peyrin-Biroulet L. Certolizum-ab use in pregnancy. Gut 2009;58: 608.

64. Klink DT, van Elburg RM, Schreurs MW, van Well GT.Rituximab Administration in Third Trimester of Preg-nancy Suppresses Neonatal B-Cell Development. ClinDev Immunol 2008; article ID: 271363.

65. European Medicines Agency. European Public Assess-ment report (EPAR) for Mabthera® http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_ Informat ion/human/000165/WC500025821.pdf. Accessed in October 20th

66. Ng CT, O'Neil M, Walsh D, Walsh T, Veale DJ. Success-ful pregnancy after rituximab in a women with recur-rent in vitro fertilisation failures and anti-phospholipidantibody positive. Ir J Med Sci 2008; 178:531–533.

67. Ponte P, Lopes MJ. Apparent safe use of single doseritu ximab for recalcitrant atopic dermatitis in the firsttrimester of a twin pregnancy. J Am Acad Dermatol2010;63:355-356.

68. Pellkofer HL, Suessmair C, Schulze A, Hohlfeld R,Kuempfel T. Course of neuromyelitis optica during in-advertent pregnancy in a patient treated with rituxi -mab. Mult Scler 2009;15: 1006-1008.

69. Herold M, Schnohr S, Bittrich H. Efficacy and safety ofa combined rituximab chemotherapy during preg-nancy. J Clin Oncol 2001;19:3439.

bogas m e col.


232

70. Kimby E, Sverrisdottir A, Elinder G.Safety of rituximabtherapy during the first trimester of pregnancy: a casehistory. Eur J Haematol 2004;72:292-295.

71. Friedrichs B, Tiemann M, Salwender H, Verpoort K,Wenger MK, Schmitz N. The effects of rituximab treat-ment during pregnancy on a neonate. Haematologica2006;91:1426-1427.

72. Scully M, Starke R, Lee R, Mackie I, Machin S, CohenH. Successful management of pregnancy in womenwith a history of thrombotic thrombocytopaenic pur-pura. Blood Coagul Fibrinolysis 2006;17:459-463.

73. Ojeda-Uribe M, Gilliot C, Jung G, Drenou B, Brunot A.Administration of rituximab during the first trimesterof pregnancy without consequences for the newborn.J Perinatol 2006;26: 252-255.

74. Magloire LK, Pettker CM, Buhimschi CS, Funai EF.Burkitt’s lymphoma of the ovary in pregnancy. ObstetGynecol 2006; 108:743–745.

75. Decker M, Rothermundt C, Holländer G, Tichelli A,Rochlitz C. Rituximab plus CHOP for treatment of dif-fuse large B-cell lymphoma during second trimester ofpregnancy. Lancet Oncol 2006; 7:693-694.

76. Rey J, Coso D, Roger V, Bouayed N, Belmecheri N,Ivanov V, Gastaut JA, Bouabdallah R. Rituximab com-bined with chemotherapy for lymphoma during preg-nancy. Leuk Res 2009;33:8-9.

77. European Medicines Agency. European Public Assess-ment report (EPAR) for Kineret® http://www.ema.eu-ropa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000363/ WC500042310.pdf. Accessed in October 20th

78. European Medicines Agency. European Public Assess-ment report (EPAR) for Orencia® http://www.ema.eu-ropa.eu/docs/en_GB/document_library/EPAR_-_P roduc t _ In f o rma t i on /human/000 7 0 1 /WC500048935.pdf. Accessed in October 20th

79. Orencia: EPAR – Scientific Discussion. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Scientific_Discussion/human/000701/WC500048938.pdf. Accessed in October 20th 2010.

80. European Medicines Agency. European Public Assess-ment report (EPAR) for RoActemra®. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000955/WC500054890. pdf. Accessed in October 20th

81. Nørgaard M, Larsson H, Pedersen L, et al. Rheumatoidarthritis and birth outcomes: a Danish and Swedishnationwide prevalence study. J Intern Med 2010;268:329-337.

82. European Surveillance of Congenital Anomalies HomePage. http://www.eurocat-network.eu. Accessed in Oc-tober 20th 2010.

83. Barnes JC, Smith WL. The VATER association. Radiolo-gy 1978;126:445-449.

84. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epi-demiology and causes of preterm birth. Lancet2008;371:75-84.

85. Snoeckx Y, Keenan G, Sanders M, Gardiner M. Preg-nancy outcomes in women taking infliximab: the in-fliximab safety database. Arthritis Rheum 2008;58:S286.

86. Lichtenstein GR, Cohen RD, Feagan BG, et al. Safety ofinfliximab in Crohn’s disease: data from the 5000 pa-tient TREAT registry. Gastroenterology 2004;126:A54.

87. Simister NE. Placental transport of immunoglobulin G.Vaccine 2003;21:3365–3369.

88. Mahadevan U, Terdiman JP, Church J, et al. Infliximablevels in infants born to women with inflammatorybowel disease. Gastroenterology 2007;4:A144.

89. Mahadevan U, Kane S. American gastroenterologicalassociation institute medical position statement onthe use of gastrointestinal medications in pregnancy.Gastroenterology 2006;131:278 – 282.


Jornadas de Outono SPR 2011

Viseu, Portugal30 de Setembro a 2 de Outubro 2011


234

a r t i g o o r i g i n a l

b i o l o g i c a l s a n d s w i t c h i n r h e u m at o i d

a r t h r i t i s t h r o u g h o u t t i m e – a r e w e

b e i n g m o r e a g g r e s s i v e ?

Sofia Ramiro*,**†, Raquel Roque*†, Filipe Vinagre*, Ana Cordeiro*, Viviana Tavares*, Astrid Van Tubergen***,

J. Canas da Silva*, Robert Landewé**, M. José Santos*

*Department of Rheumatology, Hospital Garcia de Orta, Almada,

Portugal

**Department of Clinical Immunology & Rheumatology, Academic

Medical Center, Amsterdam, Netherlands

***Department of Rheumatology, Maastricht University Medical

Center, Maastricht, Netherlands

†These authors contributed equally to this paper.

switches 461.9 ± 293.2 days vs older switches 773.7± 475.8 days, p=0.03). No further significant diffe -rences were found, including the disease activity.The survival of the first biological was shorter inpatients starting biological therapy after 2007 (2949days for biological onset before 2007 and 818 daysfor onset after 2007, p <0.001). A good EULAR res -ponse was achieved by 19% and 30% of the patients,before and after 2007, respectively (p = 0.23). Re-mission was achieved by 14% and 22% of the pa-tients, before and after 2007, respectively (p = 0.30).Conclusions: Switches were more frequently per-formed in more recent years, in older patients andwith a shorter duration of biological therapy. Atrend towards a better and more targeted control ofthe disease could be discussed in light of our results.Although switches were more frequently per-formed in more recent years, in older patients andwith a shorter duration of biological therapy, thereis still room for improvement when aiming at re-mission, for example by applying a tighter therapystrategy like the “treat to target model”.

Keywords: Rheumatoid Arthritis; Biological The -rapy; Drug Switching; Registries; Portugal.

Introduction

In the last decade, biological therapies have dra-matically changed the treatment of rheumatoidarthritis (RA) in such a way that remission is cur-rently an achievable goal. This goal has been advo-cated by recent initiatives, namely the Treat to Tar-get1 and the EULAR recommendations for the ma -na gement of RA2, as attaining a state of remissionor low disease activity leads to better structural andfunctional outcomes than allowing residual diseaseactivity3,4, and the earlier the remission state isachie ved the better it is1. Both initiatives recom-

Abstract

Objectives: To investigate the switches performedin patients with rheumatoid arthritis under biolo -gical therapy and specifically comparing the swi -tches from earlier days with more recent switches.Patients and methods: Patients with rheumatoidarthritis under biological therapy followed atHospi tal Garcia de Orta, Almada, and included inthe Rheumatic Diseases Portuguese Register(Reuma.Pt) were included in this study. Switchesoccurring before and after January 2007 were com-pared with respect to patients’ demographic andclinical characteristics, such as disease activity andduration of biological therapy. The survival of thefirst biological agent was compared between pa-tients starting biological therapy before and after2007. EULAR response and remission rate at thelast evaluation were calculated. Comparisons be-tween groups were established using a t-test or chi--square, as appropriate. Survival curves of the firstbiological were compared through the logrank test.Results: In total, 123 patients were included in theanalysis (mean age 57.0 ± 13.1 years and mean di -sease duration 11.7 ± 8.0 years). A total of 85 swi -tches were documented, 20% of which took placebefore 2007. Comparing the switches before andafter 2007, the latter were registered among olderpatients (recent switches 56.2 ± 12.9 years vs olderswitches 48.9 ± 11.0 years, p=0.04) and with a shor -ter duration of the first biological agent (recent


235

sofia ramiro e col.

mend that patients should be followed meticu-lously and existing therapy should be intensified orultimately changed for another one until the tar-get is achieved: remission1,2. With respect to biolo -gical therapy in RA, a “cycling for remission” approach has recently been proposed: start with aneffective agent; move to another effective agentunless persistent remission is achieved with ac-ceptable toxicity; consider going back to the mosteffective agent if none of the biological diseasemodifying anti-rheumatic drugs (DMARDs) resultsin remission5. This proposal is presented in light ofthe evidence reflected in the EULAR recommen-dations for the management of RA2, and the pro-cess can develop at a relatively fast pace, as a pa-tient’s response to treatment during the first 3months of biological therapy is known to deter-mine the level of disease activity at 1 year6. For several years, inhibitors of TNF (etanercept,

infliximab, and adalimumab) and anakinra havebeen the only option available for patients failingsynthetic DMARDs. Recently, biological agentswith novel mechanisms of action (rituximab, aba -ta cept, and tocilizumab) have been approved foruse in patients with RA and, even more recently, thearmamentarium of biological agents has been en-riched through the approval of new TNF inhibitors,golimumab and certolizumab pegol. The diversityof biological agents increases the possibilities ofswitching therapies and consequently of achievingsuccessful treatment response. Patients may fail toachieve the target with one medication, for ins -tance, a TNF inhibitor, but then may respond verywell to another medication with an identical7, 8 ordifferent mechanism of action9-11. Consequently,rheumatologists’ clinical practice is expected tohave been adapted, throughout this decade, to amore intensified treatment strategy and to a bet-ter and more targeted control of the disease. Amore aggressive attitude towards RA therapy, morespecifically involving biological therapy, is there-fore expected. Hence, it is interesting to reflectupon our daily clinical practice and to analyze howwe are dealing with switches. The aims of the pre-sent study were to investigate the switches per-formed in patients with RA under biological thera -py and to compare older switches (i.e. performedin earlier days) versus more recent switches and thecircumstances in which these took place, as well asto evaluate the survival of the first biological. Aim-ing at higher response levels as we currently do, wewould expect to identify, comparing to earlier days,

a higher number of switches currently being per-formed, a lower disease activity value before aswitch and a shorter survival of the first biologicalagent.

Patients and methods

Study populationData from the Rheumatic Diseases PortugueseRegister, Reuma.pt, more specifically the register ofpatients with RA receiving biological therapies(BioRePortAR) and the subset from Hospital Gar-cia de Orta, Almada, has been used. Reuma.pt hasbeen described in detail elsewhere12. In summary,this electronic register was launched in 2008 andcontinuously includes patients from several Por-tuguese Rheumatology departments. Inclusion cri-teria are RA, diagnosed according to the AmericanCollege of Rheumatology (ACR; formerly, theAmerican Rheumatism Association) criteria13 andstart of biological therapy. Data from the previousyears, from the introduction of biologicals in 2000until 2008, have been collected on paper and laterwere entered into the electronic register; these datahave been systematically collected according to astandardized, published protocol, which con-tained the same items as the ones included in theelectronic register14. Reuma.pt is also used as anelectronic patient chart and, therefore, the fre-quency of observations of the patients is not pre--determined. Assessments are made by rheumato -logists, in general every 3-4 months, and includeclinical information, such as the monitoring of di -sease activity (Disease Activity Score with 28-jointassessment – DAS2815), medication, adverseevents, and comorbidities. Function is monitoredthrough the Health Assessment Questionnaire(HAQ) once a year16. Demographic and other clini -cal characteristics, including health habits and pre-vious medication, are collected at the onset of bio -logical therapy. Data from all patients exposed tobiologicals from 2001 to 2011 were used. Data re-fer to usual clinical practice, without any inter-vention on the decisions of the rheumatologists.Patients with missing information at baseline, i.e. evaluation corresponding to the start of the first bio logical, were not included in the analysis,in order to require all the patients to have a com-plete follow-up while on biological therapy and to assure completeness of the information onswitches.


236

biologicals and switch in rheumatoid arthritis throughout time

Switch assessment and subcohortsA switch of biologicals was defined as the start ofa subsequent biological, independently of the rea-son of discontinuation of the previous one. In or-der to investigate the current practice with respectto switches and to compare our earlier practice interms of switches with our more recent clinicalpractice, a time cut-off was necessary. We decidedto establish the cut-off as of January 1st 2007, withthe following reasoning: 1) it divided the total pe-riod (2001-2011) in approximately balanced partsin terms of number of patients starting a first bio-logical therapy in each of them; 2) in 2007, the Por-tuguese guidelines for the use of biologicals in RAwere updated by the RA Study Group (GEAR) ofthe Portuguese Society of Rheumatology17. In theseguidelines, the criteria for introduction and main-tenance of biologicals were discussed, as well as thecontraindications and procedures in case of inade -quate response. Taking the cutoff of 2007 into account, three

subcohorts of patients could be identified: subco-hort 1 – patients starting the first biological in theperiod of 2001-2006 and being followed-up duringthe same period (2001-2006); subcohort 2 – pa-tients starting the first biological in the period of2001-2006 and being followed-up in the period of2007-2011, actually including the same patients assubcohort 1, but in a later follow-up period, andonly excluding patients with a definitive discon-tinuation of biological therapy in the follow-up pe-riod of 2001-2006; subcohort 3 – patients startingthe first biological in the period of 2007-2011 andbeing followed-up in this period. Each of these sub-cohorts was analyzed in terms of demographic andclinical characteristics of the patients, includinginitial and final levels of DAS28 (calculated withthe erythrocyte sedimentation rate) and HAQ,number of switches, ratio of switches per numberof patients on biologicals, number of first swi tches,disease duration and time under biological expo-sition. Switches before 2007 were designated as older

switches and switches after 2007 as recent swi t -ches. Older and recent switches were comparedwith respect to demographic and clinical charac-teristics of the patients at the evaluation immedia -tely before the switch, as this was considered theevaluation where the rheumatologist actuallymade the decision about the switch. Clinical cha -rac teristics compared were disease duration, timeunder biological exposition, disease activity (as

measured by the DAS28), function (as measured bythe HAQ), concomitant therapy with corticos-teroids, concomitant therapy with methotrexate,and duration of first biological at first switch. Be-cause recent switches included both switches inpatients who started biological therapy before andafter 2007, a more pure comparison between ol derand recent switches was also performed, in whichonly the recent switches of patients who had star -ted their first biological after 2007 (i.e. belongingto the subcohort 3) where compared to olderswitches (subcohort 1).Furthermore, the survival of the first biological

was evaluated through means of assessing its sur-vival time for half of the patients and comparingthe survival between patients starting their firstbio logical before and after 2007.

Disease activity controlA possible way to assess the effectiveness of opti-mal and targeted disease activity control and ofthe approach to switches throughout time is toevaluate its effect, more specifically the diseaseacti vity control achieved at the last evaluation ofthe total population and stratified by each subco-hort. Disease activity control was considered to beevaluable when the DAS28 was available at the lastevaluation of each subcohort. For the purpose ofthis assessment, patients starting a new biologicalor awaiting a switch at their last evaluation, or whohad discontinued biological therapy permanentlywere not included, as the disease activity controlcould not be properly evaluated in these cases. Re-mission achieved at the last assessment, as definedby a DAS28<2.618, was also determined.For all the patients with an available DAS28 both

at baseline and at the last evaluation, the EULARresponse was calculated19, both for the total popu -lation and also split by each subcohort.

Statistical analysisContinuous variables are presented as means ±standard deviations, and categorical variables asfrequencies.Comparisons were established between diffe -

rent groups. Continuous variables were comparedusing an independent two-samples t-test adjus tedfor heterogeneity of variances, as appropriate.Cate gorical variables were compared using the chi--square test.The survival of the first biological was assessed

through means of a survival analysis and the sur-


237

sofia ramiro e col.

vival curves for patients starting their first biologi -cal before and after 2007 were compared by a lo-grank test. Statistical analysis was performed assuming a

5% significance level and using STATA SE 10.

Results

A total of 123 out of 159 patients with RA who havebeen treated with biological therapy at the Hospi-tal Garcia de Orta were included in this analysis.Eight patients were not included because informa-tion was only available from recent evaluations andnot from the first years of follow-up. The remaining28 patients have been on biological the rapy at somepoint throughout the follow-up pe riod (16 pertai -ning to the 1st subcohort, 5 to the 2nd, and 7 to the3rd subcohort), but have been definitely disconti -nued, mainly due to adverse events, others due toloss to follow-up or transfer to another hospital,and their information was no longer available.The demographic and clinical characteristics of

the included population are summarized in TableI. The majority of the patients were on a TNF in-hibitor as a first biological (33% infliximab, 32%etanercept, 20% adalimumab), followed bytocilizumab (7%) and anakinra (2%).Table II shows the characteristics of each of the

subcohorts stratified according to the date of on-set of biological therapy and the follow-up period.A total of 56 patients started their first biological inthe period of 2001-2006 and the same patients werefollowed-up in both periods (2001-2006 and 2007--2011). A total of 67 patients were started on a bio -logical in the period 2007-2011. Patients from thesubcohorts 1 and 3, starting a biological before andafter 2007, respectively, had similar demographicand clinical characteristics, except for the age atonset of first biological, which was higher in thegroup of patients who started their first biologicalin the period of 2007-2011 (55 years old vs 50 yearsold). With respect to the switches, fifty-eight patients

(47%) had their biological therapy switched at leastonce (Table I). A total of 85 switches were regis-tered, of which 17 (20%) in the 1st subcohort (TableII). In total, 68 switches were of recent onset (i.e.taking place after January 2007), of which 32 (47%)in patients who had started their first biologicalbefore 2007. Comparing subcohorts 1 and 3 (i.e.starting their first biological before and after 2007),

there was an increase in the number of switches,with a ratio of switches per number of patients un-der biologicals of 30% in subcohort 1 and of 54%in subcohort 3 (p = 0.02). A tendency towards alower disease activity level at baseline and at the fi-nal evaluation was found throughout time, but thedifference between subcohorts 1 and 3 was not sta-tistically significant.Table III shows the comparison between swi -

tches of older and recent onset. Patients with re-cent switches were found to be statistically signifi -cantly older. This difference was also found whenthe comparison was refined to patients from sub-cohort 3 only (i.e. starting their first biological inthe period of 2007-2011) compared with subco-hort 1. Comparing all the recent and older swit -ches, a longer time under biological exposition wasfound in patients with a recent switch (3.0 years inrecent switches vs 1.6 in older switches, p <0.01).In patients from subcohort 3, a trend towardsshorter biological exposition was found comparedwith subcohort 1 (1.2 years vs 3.0, p = 0.16). Pa-tients with a recent switch and who had started thefirst biological in the period 2007-2011 had a shor -ter duration on their first biological at the time oftheir first switch (461.9 ± 293.2 in recent switches

Table I. Demographic and clinical characteristicsof the population

Mean ± SD

or n (%)

(N = 123)

Current age (years) 57.0 ± 13.1

Female gender (%) 106 (86%)

Disease duration (years) 11.7 ± 8.0

Time under biological exposition 4.4 ± 2.8

(years)

Rheumatoid factor positivity (%) 81 (66%)

ACPA positivity (%) 86 (70%)

Number of patients with at least 58 (47%)

one switch (%)

Number of biologicals per patient 1.72 ± 0.95

Frequency of number of biologicals

per patient (%):

• 1 63 (51%)

• 2 40 (33%)

• 3 15 (12%)

• 4 4 (3%)

• 7 1 (1%)


238


vs 773.7 ± 475.8 days in older switches, p = 0.03).No further significant differences were found be-tween older and recent switches. Interestingly, aslight tendency towards a lower level of DAS28 wasnoted in recent switches.The survival of the first biological was shorter in

patients who started biological therapy in the pe-riod of 2007-2011. The time to 50% discontinuationof the first biological was 2949 days when the firstbiological was started before 2007, compared to818 days when the first biological was started in theperiod of 2007-2011 (p < 0.001) (Figure 1).

One hundred and eleven patients were conside -red evaluable for analysis of disease control, as as-sessed at the last observation (Table IV). Only pa-tients that had not recently started a new bio lo -gical, had not been proposed for a switch and hadnot definitely discontinued biological therapy wereincluded for this analysis. In terms of EULAR res -ponse, 53% had a moderate response, 35% a goodresponse and 12% none. A total of 24 patients (22%)were in remission (DAS28 < 2.6). Dividing the population in the three subcohorts

and considering the last evaluation of each of

Table II. Demographic and clinical characteristics of the subcohorts stratified by onset of biological therapy and follow-up period

Cohort 2001-2006 Cohort 2007-2011Follow-up period Follow-up period

2001-2006 2007 – March 2011Subcohort 1 Subcohort 2 Subcohort 3 Mean ± SD Mean ± SD Mean ± SD

or n (%) or n (%) or n (%) p value N = 56 N = 56 N = 67 §

Age at onset of 1st biologic (years) 49.8 ± 12.3 54.7 ± 13.7 0.04*

Female gender (%) 50 (89%) 56 (84%) 0.36

Rheumatoid factor positivity (%) 35 (64%) 46 (69%) 0.10

Disease duration at onset of 1st 6.6 ± 7.2 7.6 ± 8.0 0.46

biologic (years)

Number of switches 17 32 36 –

Ratio number of switches/number 17/56 32/56 36/670.02*

of patients under biologic (%) (30%) (57%) (54%)

Number of first switches 15 14 280.08

(15/17 = 88%) (14/32 = 44%) (28/36 = 78%)

Ratio number of first switches/ 15/56 (27%) 14/56 (25%) 28/67 (42%) 0.12

/number of patients under first

biologic

Initial DAS28 5.8 ± 1.2 4.0 ± 1.4 5.7 ± 1.20.67

(n = 50) (n = 48) (n = 66)

Final DAS28 4.0 ± 1.4 3.7 ± 1.2 3.7 ± 1.30.07

(n = 48) (n = 52) (n = 62)

Initial HAQ (0-3) 1.6 ± 0.7 1.0 ± 0.7 1.5 ± 0.60.67

(n = 41) (n = 47) (n = 52)

Final HAQ (0-3) 1.0 ± 0.7 1.0 ± 0.8 1.0 ± 0.60.70

(n = 47) (n = 42) (n = 48)

Time under biological exposition 2.9 ± 1.8 4.2 ± 0.3 4.2 ± 0.1<0.01*

(years) (n = 56) (n = 56) (n = 67)

Definitive discontinuation of 0 3 (5%) 2 (3%) –

biologics

§Comparison between subcohort 3 and subcohort 1*Statistically significant difference (p-value <0.05)


239

sofia ramiro e col.

Table III. Comparison of the disease activity between older and recent switches

Recent switch, Recent switch only Older switch all considered from subcohort 3¶(before 2007) (after 2007) (after 2007)

N = 17+ N = 68 N = 36Mean ± SD Mean ± SD Mean ± SD

or n (%) or n (%) p value§ or n (%) p value¤Age (years) 48.9 ± 11.0 56.2 ± 12.9

0.04*56.6 ± 14.1

0.049*(n = 17) (n = 68) (n = 36)

Disease duration (years) 7.4 ± 4.5 9.2 ± 7.50.22

7.5 ± 8.6

(n = 17) (n = 66) (n = 34)0.98

Time under biological 1.6 ± 1.3 3.0 ± 2.7 1.2 ± 0.9

exposition (years) (n = 17) (n = 68)<0.01*

(n = 36)0.16

Duration of first biological 773.7 ± 475.8 918.6 ± 932.0 461.9 ± 293.2

at first switch (days) (n = 15) (n = 42)0.45

(n = 28)0.03*

DAS28 before the switch 5.7 ± 1.3 5.2 ± 1.6 5.7 ± 1.8

(n = 14) (n = 64)0.28

(n = 34)0.91

HAQ (0-3) 1.3 ± 0.5 1.1 ± 0.8 1.2 ± 0.80.65

(n = 8) (n = 26)0.53

(n = 14)

Corticosteroids (%) 15 (88.2%) 46 (67.7%) 0.09 28 (77.8%) 0.36

Methotrexate (%) 15 (88.2%) 56 (82.4%) 0.60 29 (80.6%) 0.49

+n refers to number of observations/switches; some patients had more than one switch§Comparison of older vs recent switches, all considered¤Comparison of older vs recent switches in subcohort 3 (i.e. patients started on biological in the period of 2007-2011) ¶Subcohort 3 means that patients were started on a first biologic in the period of 2007-2011*Statistically significant (p < 0.05)

them, a trend towards a higher achievement of re-mission and a better profile of EULAR responseswas found in subcohort 2 (i.e. patients starting bio -logical the rapy in the period of 2001-2006 and be-ing followed--up in the period of 2007-2011) andsubcohort 3 (i.e. patients starting biological thera -py in the period of 2007-2011).

Discussion

This study showed a clear increase in the numberof switches in patients with RA under biologicaltherapy throughout time, specifically when com-paring patients who started biological therapy be-fore and after 2007. Patients with a recent switchwere found to be older and had a shorter durationof the first biological compared with patients witha switch before 2007. No significant differences withrespect to disease activity before the switch couldbe demonstrated. The survival of the first bio logicalwas shorter in patients who started bio logical the -ra py in the period of 2007-2011. A trend towards a

better disease activity control, as assessed by themean final DAS28 score and the EULAR response,was also manifest in the more recent follow-up pe-riod (i.e. 2007-2011), when compared to the ear lierfollow-up period of 2001-2006. These results suggest a trend towards a better and

more targeted disease control of patients with RAunder biological therapy throughout time. This goesalong with what we expected, with the improve-ments we have witnessed in RA during the lastdecade and with the consequent increasing level ofdemand we have with respect to the disease control.In more recent years, switches were performed at anearlier stage, in terms of the duration of biologicaltherapy, suggesting that rheumatologists were re-ducing the time to evaluate the effectiveness of atherapy before switching if they were not satisfiedwith the results. This is also in line with the largeravailability of biologicals in recent years, includingdrugs with a different mode of action. However, di -sease activity was still considera bly high before aswitch, and has not decreased signi ficantly through-out time, as one may have expec ted. One potential


240


explanation for this is that rheumatologists may bereluctant to switch and still wait a long period be-fore actually changing the biological. This periodwas on average of 467 days in more recent years,which is around 15 months. There seems to beroom for improvement in this aspect. Another finding was that recent switches were

performed in older patients. We would instead ex-pect that patients were started on biological thera -py earlier in their disease course and, consequen -tly, in their life. However, this would also be de-

pendent on an earlier referral of patients from theirgeneral practitioners to rheumatologists, and ac-tually no difference was demonstrated in the di -sease duration before a switch. The fact thatswitches were performed in older patients poten-tially reflects the increased occurrence of swi tchesthat can take place and to a less restrictive groupof patients, being in fact generalizable to older pa-tients as well. Remission was achieved in appro -ximately one fifth of the patients. This number isin line with remission achievements in other ob-servational studies. The German registry, RABBIT,showed a remission rate achieved in 16% of the pa-tients under biological therapy20. In the Italian re -gistry, MonitorNet, 36% of the patients were repor -ted to be in remission21. The data from the Germanregistry are from a publication from 2006, whichcan justify a lower value. The data from the Italianregistry are from 2009 and only included patientswho were started on biological therapy after 2007,which can partially explain the higher achievementof remission. Interpreting our findings in light ofthese other publications, we can conclude that ourpatients’ disease activity control was in line withother observational studies and potentially withsome room for improvement in this aspect. To ourknowledge, no previous studies focused on thesame aspect as we did, meaning that no studiesspecifically addressed the circumstances in which

Table IV. Comparison of the disease activity between older and recent switches

p value Subcohort 1§ Subcohort 2¶ Subcohort 3¤ subcohort 3 vs

n (%) (n = 56) (n = 56) (n = 67) subcohort 1Disease activity control 111 (90%) 56 (100%) 51 (91%) 60 (90%) –

evaluable at last

observation*

EULAR response 99 (89%) 43 (77%) 41 (80%) 56 (84%) –

evaluable

• Good 35 (35%) 8 (19%) 18 (42%) 17 (30%)

• Moderate 52 (53%) 25 (58%) 20 (46%) 32 (57%) 0.23

• None 12 (12%) 10 (23%) 5 (12%) 7 (13%)

Remission 24 (22%) 8 (14%) 11 (22%) 13 (22%) 0.30

§Subcohort 1: start of first biologic before 2007, follow-up period before 2007. For this cohort, the last observation is the first observation in thenext follow-up period (beginning of 2007)¶Subcohort 2: start of first biologic before 2007, follow-up period after 2007¤Subcohort 3: start of first biologic after 2007, follow-up period after 2007*By disease activity control evaluable at last observation is meant that the patient did not start a new biologic at the last evaluation, was not proposed to switch at the last evaluation and did not discontinue a biologic definitely, as these cases compromise the evaluation of disease activitycontrol

Analysis time (days)

Survival of first biological agent

400030002000100000.00

0.25

0.50

0.75

1.00 Biological onset 2001-2006Biological onset 2007-2011

Analysis time (days)

Survival of first biological agent

40003000200010000

0.00

0.25

0.50

0.75

1.00 Biological onset 2001-2006

Biological onset 2007-2011

Fi gu re 1. Time to discontinuation of the first biologicagent, stratified by the period for onset of biological therapy


241

sofia ramiro e col.

switches take place or compared switches fromearlier years with switches from more recent years. The main limitation of the present study is the

relatively small population. Some of the differencesbetween the groups did not reach statistical si -gnificance and only remained as a trend. A secondpotential limitation is that not all patients thatstarted biological therapy were included in thedataset, and therefore selection bias may have oc-curred. Nevertheless, all the efforts were done to in-clude the maximum number of patients possibleand we are confident that they are a good repre-sentation of the total population. We strongly believe that this type of analyses

provides clinicians with insight to their behavior inclinical practice. Clinicians might have the slight-ly deviated perception they are being interventiveenough in their medical decisions, for instance ofkeeping or changing a therapy, and only when thereality is put into numbers can the misperceptionsbe understood. A parallelism can probably be es-tablished with situations when a tight control of RAis compared to routine clinical care, just as forexam ple was illustrated in the TICORA trial, whereit was demonstrated that a tight control led tosigni ficantly better outcomes22. This parallelismcan at the moment only remain as an image to bet-ter illustrate the idea and, if deemed to be true,then a scientific demonstration will be required.

ConclusionIn summary, this study demonstrated that swi tchesin biological therapy were more frequently perfor -med in more recent years, compared to the periodbefore 2007. Patients with switches in biologicaltherapy performed in more recent years were ol -der and had a shorter duration of biological the -rapy compared to switches in biological therapybefore 2007. A trend could be shown towards a bet-ter and more targeted control of the disease. Ne -vertheless, there is still room for improvement, es-pecially when aiming at remission and followingthe current EULAR recommendations for the treat-ment of RA2, for example, applying a tighter the -rapy strategy, like the “treat to target model”1.

Correspondence toSofia RamiroHospital Garcia de Orta, EPEAv. Prof. Torrado da Silva2801- 951 Almada – PortugalE-mail: [email protected]

References1. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating

rheumatoid arthritis to target: recommendations of aninternational task force. Ann Rheum Dis 2010;69:631--637.

2. Smolen JS, Landewe R, Breedveld FC, et al. EULAR re -commendations for the management of rheumatoidarthritis with synthetic and biological disease-modi -fying antirheumatic drugs. Ann Rheum Dis 2010;69:964-975.

3. Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD,Boers M, Dijkmans BA. Progression of radiologic dama -ge in patients with rheumatoid arthritis in clinical re-mission. Arthritis Rheum 2004;50:36-42.

4. Aletaha D, Funovits J, Smolen JS. The importance of re-porting disease activity states in rheumatoid arthritisclinical trials. Arthritis Rheum 2008;58:2622-2631.

5. Ramiro S, Machado P, Singh JA, Landewe RB, da SilvaJA. Applying science in practice: the optimization ofbio logical therapy in rheumatoid arthritis. Arthritis ResTher 2010;12:220.

6. Aletaha D, Funovits J, Keystone EC, Smolen JS. Diseaseactivity early in the course of treatment predicts res -ponse to therapy after one year in rheumatoid arthri-tis patients. Arthritis Rheum 2007;56:3226-3235.

7. van Vollenhoven R, Harju A, Brannemark S, KlareskogL. Treatment with infliximab (Remicade) when etaner -cept (Enbrel) has failed or vice versa: data from theSTURE registry showing that switching tumour necro-sis factor alpha blockers can make sense. Ann RheumDis 2003;62:1195-1198.

8. Hyrich KL, Lunt M, Watson KD, Symmons DP, SilmanAJ. Outcomes after switching from one anti-tumornecrosis factor alpha agent to a second anti-tumornecrosis factor alpha agent in patients with rheuma-toid arthritis: results from a large UK national cohortstudy. Arthritis Rheum 2007;56:13-20.

9. Finckh A, Ciurea A, Brulhart L, et al. B cell depletionmay be more effective than switching to an alternativeanti-tumor necrosis factor agent in rheumatoid arthri-tis patients with inadequate response to anti-tumornecrosis factor agents. Arthritis Rheum 2007;56:1417--1423.

10. Genovese MC, Becker JC, Schiff M, et al. Abatacept forrheumatoid arthritis refractory to tumor necrosis fac-tor alpha inhibition. N Engl J Med 2005;353:1114-1123.

11. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhi-bition with tocilizumab improves treatment outcomesin patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24--week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67:1516-1523.

12. Canhao H, Faustino A, Martins F, et al. Reuma.pt - therheumatic diseases portuguese register. Acta Reuma-tol Port 2011:45-56.

13. Arnett FC, Edworthy SM, Bloch DA, et al. The Ameri-can Rheumatism Association 1987 revised criteria forthe classification of rheumatoid arthritis. ArthritisRheum 1988;31:315-324.


242


14. Fonseca JE, Canhao H, Reis P, et al. [Protocol for clini-cal monitoring of rheumatoid arthritis [PMAR]—De-cember 2007 update.]. Acta Reumatol Port 2007;32:367--374.

15. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA,van de Putte LB, van Riel PL. Modified disease activityscores that include twenty-eight-joint counts. Deve -lopment and validation in a prospective longitudinalstudy of patients with rheumatoid arthritis. ArthritisRheum 1995;38:44-48.

16. Fries JF, Spitz P, Kraines RG, Holman HR. Measurementof patient outcome in arthritis. Arthritis Rheum1980;23:137-145.

17. Fonseca JE, Canhão H, Reis P. Portuguese guidelines forthe use of biological agents in rheumatoid arthritis—December 2007 update. Acta Reumatol Port 2007;32:363-366.

18. Fransen J, Creemers MC, Van Riel PL. Remission inrheumatoid arthritis: agreement of the disease activi-ty score (DAS28) with the ARA preliminary remissioncriteria. Rheumatology (Oxford) 2004;43:1252-1255.

19. van Gestel AM, Prevoo ML, van ‘t Hof MA, van Rijswi-jk MH, van de Putte LB, van Riel PL. Development andvalidation of the European League Against Rheuma-tism response criteria for rheumatoid arthritis. Com-parison with the preliminary American College ofRheumatology and the World Health Organization/In-ternational League Against Rheumatism Criteria.Arthritis Rheum 1996;39:34-40.

20. Listing J, Strangfeld A, Rau R, et al. Clinical and func-tional remission: even though biologics are superior toconventional DMARDs overall success rates remainlow—results from RABBIT, the German biologics re -gister. Arthritis Res Ther 2006;8:R66.

21. Sfriso P, Salaffi F, Montecucco CM, Bombardieri S, Tode-sco S. MonitorNet: the Italian multi-centre observa-tional study aimed at estimating the risk/benefit pro-file of biologic agents in real-world rheumatology prac-tice. Reumatismo 2009;61:132-139.

22. Grigor C, Capell H, Stirling A, et al. Effect of a treatmentstrategy of tight control for rheumatoid arthritis (theTICORA study): a single-blind randomised controlledtrial. Lancet 2004;364:263-269.

I Curso Básico de Ecografia Músculo-Esquelética

Castelo Branco, Portugal14 a 16 Outubro 2011

75th Annual Meeting of the American College ofRheumatology

Chicago, EUA5 a 9 Novembro 2011


245


i n t e r o b s e r v e r r e l i a b i l i t y i n u lt r a s o u n d

a s s e s s m e n t o f r h e u m at o i d w r i s t j o i n t s

Karine R. Luz*, Rita N.V. Furtado*, Sonia V. Mitraud**, Jorge Porglhof**,

Conceição Nunes*, Artur R. C. Fernandes**, Jamil Natour*

*Rheumatology Division, Universidade Federal de São Paulo –

Escola Paulista de Medicina, São Paulo, Brazil.

** Department of Radiology, Universidade Federal de São Paulo –

Escola Paulista de Medicina, São Paulo, Brazil.

Introduction

In recent years, musculoskeletal ultrasound has be-come an important diagnostic tool for rheumaticdisease, as it allows the detection of the inflamma-tory process in intra-articular and periarticularstructures as well as the identification of bone ero-sion1,2. This exam has a number of advantages overother imaging methods, including its non-invasivenature, good visualization of the joint cavity, ab-sence of radiation, and wide acceptance by pa-tients. The exam’s dynamic and rapid executionena bles it to assess multiple joints at low cost,thereby making it is a “bedside exam”3,4. Despitethese significant advantages, ultrasound findingsremain highly dependent on the individual exami -ner’s findings. This occurs partially due to the sub-jective assessment of the images and the low degreeof standardization of the technique due to the smallnumber of multi-center studies involving themethod5-9.

In cases of rheumatoid arthritis (RA), the wrist isaffected in 90% of patients in the first 10 years of thedisease10. The wrist is an anatomical complex madeup of various articular recesses and inter-bone liga -ments. The three main recesses in the wrist are theradiocarpal (RC), midcarpal (MC) and ulnocarpal(UC)11,12. Ultrasound has proven useful in the as-sessment of these articular recesses as well as inthe distinction between healthy individuals and pa-tients with chronic inflammatory arthropathy ofthe wrist13-16. It is a helpful tool for guiding proce-dures, assessing sub-clinical findings and moni-toring treatment16,17.

There are few studies investigating interobser verreliability in the ultrasound assessment of muscu-loskeletal conditions6-9,18-21. The majority of thesestudies have analyzed ultrasound reliability for thejoints of the hands and feet, knees and periarticu-lar structures, such as in cases of rotary cuff inju -ry7-9,14-16. The reliability of ultrasound assessment of

Abstract

Objective: To evaluate interobserver reliability inthe ultrasound assessment of synovitis in the ra-diocarpal (RC), midcarpal (MC) and ulnocarpal(UC) joints in RA.Methods:Ultrasound examinations of 295 rheuma-toid wrist joints were performed over a three monthperiod. The RC, MC and UC joints were examinedusing dorsal longitudinal ultrasound scans. Syno -vial thickening was assessed by quantitative mea-surement and a previously established semi-quan-titative scoring system (Grades 0 to 3). Interobser -ver reliability was determined by the comparingthe findings of two radiologists who were unawareof each other findings.Results: The intraclass correlation coefficient (ICC)between examiners for the quantitative measure-ment of synovitis in the RC, MC and UC recesseswere 0.508, 0.346 and 0.240 (p<0.001), respectively.Weighted kappa values using the semi-quantita-tive scoring system were 0.308, 0.312 and 0.153 forthe RC, MC and UC joints, respectively.Conclusion: Interobserver reliability of the ultra-sound assessment in rheumatoid wrists provedgood for the quantitative measurement of synovi-tis in the RC joint, but poor agreement was foundfor the MC and UC joints. Using the semi-quanti-tative scoring system, interobserver agreement waspoor for all three joints (RC, MC and UC).

Keywords: Ultrasonography; Reliability; Wrist;Rheumatoid Arthritis.


246

were performed from the radial and ulnar sides aswell as midline to assess the RC, MC and UC re-cesses in accordance with the standards establi -shed by the European League Against Rheumato -logy24.

Both quantitative and semi-quantitative mea-surements were performed in each recess for syno -vial thickening13,19. The quantitative measurementwas obtained from the distance between the jointcapsule and subchondral bone (Figure 1). For thesemi-quantitative assessment, a modified versionof a previously established semi-quantitative sco -ring system to evaluate metacarpophalangeal(MCP), proximal interphalangeal and metatar-sophalangeal joints were used19. A single score wasused for effusion and synovitis, ranging from 0 to3: 0- no synovial thickening; 1- minimal synovialthickening up to the joint capsule; 2- synovialthickening causing curvature of the joint capsule,but without extending to the bone diaphysis; 3- synovial thickening with curvature of the jointcapsule and extending to at least one bone diaphy -sis. Figure 2 displays the semi-quantitative mea-surement at radiocarpal joint and respectivescores.

Interobserver ReliabilityInterobserver reliability was determined by com-paring the mean quantitative and semi-quantita-tive scores obtained by two radiologists who wereunaware of clinical assessments. Each operatorperformed the ultrasound exams sequentially andindependently. The assessments were performedin different rooms, using the same machine andsettings, and the measurements were recorded onseparate charts. Therefore, each evaluator wasblinded to the measurements of the other.

interobserver reliability in ultrasound assessment of rheumatoid wrist joints

the wrist has only been evaluated regarding thepresence or absence of synovitis in a small num-ber of patients with different chronic inflammato-ry conditions8-9,22. There is no evidence of any studyinvestigating interobserver reliability in the ultra-sound assessment of the synovium in different ar-ticular recesses of the wrist.

The aim of the present study was to determineinterobserver reliability in the ultrasound assess-ment of the radiocarpal (RC), midcarpal (MC) andulnocarpal (UC) recesses of the wrist in patientswith RA and clinical synovitis.

Methods

A cross-sectional study was carried out involvingpatients with RA based on the classification crite-ria of the American College of Rheumatology23 pre-senting clinical synovitis in at least one of thewrists. The patients included had no diagnosticcriteria for any other collagen disease

Ultrasound Assessment Assessments were carried out by two radiologistswith experience in musculoskeletal ultrasound.Two hundred and ninety five wrists of RA patientswith clinical synovitis were examined by ultra-sound over a three-month period. The ultrasoundexaminations were performed using a Sonosite 180Plus (SonoSite. Inc – United States) device equip -ped with a linear probe (5 to 10 MHz).

All patients were instructed to stay seated in acomfortable position in front of the examiner withtheir hand in a pronated position on top of the deskto take dorsal scans in neutral position of the wrist.

The ultrasound examinations were performedfrom the dorsal aspect of the wrist with the trans-ducer in a longitudinal position. The examinations

Figure1.B-mode US synovial thickness measurementsin the wrist joint, scanned in a longitudinal plane of thedorsal central and ulnar surface of radiocarpal (RC), midcarpal (MC) and ulnocarpal (UC) recess. Synovial measurements were performed perpendicular to thegreat axis and at the point of greatest thickness

Figure2.Ilustration of semi-quantitative scoring systemat radiocarpal joint: L – lunate; R- radius; RCJ – radiocarpaljoint; JC – joint capsule; BD – bone diaphysis; * – synovialthickening


247

karine r. luz e col.

of 1 in 147 and 164 assessments, a score of 2 in 121and 115 measurements, and a score of 3 in 27 and16 measurements. In the semi-quantitative mea-surements of the MC recess, Operators A and B de-termined a score of 1 in 28 and 103 assessments,respectively; a score of 2 in 164 and 126 measure-ments, respectively; and a score of 3 in 27 and 16measurements, respectively. In the semi-quanti-tative measurements of the UC recess, OperatorsA and B determined a score of 1 in 97 and 118 as-sessments, respectively; a score of 2 in 152 and 117measurements, respectively; and a score of 3 in 46and 60 measurements, respectively (Table III).

The absolute agreement for semiquantitativescoring for both observers was 58,3% for RC, 47,5%for MC and 46,4% for UC recess.

Interobserver reliabilityThe ICC between the two evaluators for the quan-titative measurements of the RC, MC and UC re-cesses was 0.508, 0.3463 and 0.240 (p<0.001), res -pectively. Weighted Weighed kappa values forsemi-quantitative assessments of the RC, MC andUC recesses were 0.308, 0.312 and 0.153, respec-tively (Tables II and III).

Discussion

The present study assessed the interobserver relia -bility ultrasonography for quantitative and semi--quantitative measurements of wrist in patientswith long-standing RA. The wrist is one of the mostaffected joints in RA and is a complex anatomicalstructure made up of various joint recesses and pe-

Statistical AnalysisThe intra-class correlation coefficient (ICC) wasused for the quantitative measurements andweighted Kappa test (κ) was used for the semi--quan titative measurements. For the ICC, inte -robser ver reliability was considered excellent if R > 0.75, good to optimal if R was 0.4 to 0.75 andpoor if R < 0.425. With the Kappa test, interobser verrelia bility was considered excellent if κ> 0.81, subs -tantial when values were 0.61 to 0.80, moderatewhen values were 0.41 to 0.60, good when valueswere 0.21 to 0.40, minimal when values were 0.20to 0 and poor when the value was 026.

Results

Fifty-nine patients with RA were analyzed. Table I dis-plays the demographic data and clinical parameters.

Ultrasound AssessmentA total of 295 assessments were performed on therheumatoid wrists over a three-month period. Themean quantitative measurement of synovium inthe RC, MC and UC recesses according to Opera-tor A was 5.09 ± 1.83 (1.2 – 10.12) mm, 4.82 ±1.83(0 –11.66) mm and 5.34 ± 1.68 (1.16 – 12.23) mm,respectively. According to Operator B, these mea-surements were 4.53 ± 1.41 (1.7 – 9.9) mm, 4.40±1.34 (0.66 – 8.3) mm and 7.03 ± 1.74 (1.16 – 11.56)mm, respectively (Table II).

In the semi-quantitative measurements of theRC recess, Operators A and B determined a score

Table I. Demographic parameters, disease relatedvariables in 59 RA patients

Age, years (Mean ± SD) 48.7 (± 9.25)

Gender (Women/ Men) 55/4

Race (White/ Black) 52/7

Disease Duration, years 11.33 (± 9.61)

Functional ClassII (46)

III (13)

Rheumatoid Factor (positive) (%) 59

Prednisone, mg/day (Mean ± SD) 6.65 (± 5.22)

Diphosphate Cloroquine (%) 7

Methotrexate (%) 89

Sulfassalazine (%) 13

Leflunomide (%) 42

SD – standard desviation

Table II. The mean quantitative measurement(mm) of synovial in the RC, MC and UC recessaccording to Operator A and Operator B

Recesses Operator A Operator B ICC (Mean ± SD) (n-295) (n-295) (R)RC recess 5.09 mm 4.82 mm 0.482

(Mean ± SD) (± 1.83) (± 1.41)

MC recess 4.53 mm 4.40 mm 0.509

(Mean ± SD) (±1.83) (±1.34)

UC recess 5.34 mm 7.03 mm 0.240

(Mean ± SD) (± 1.68) (± 1.74)

RC – radiocarpal; MC – mediocarpal; UC – ulnocarpal; SD – standard

desviation; ICC – intra-class correlation coefficient


248

moderate reliability (k = 0.49) for the presence ofsynovitis in the RC recess of the wrist27.

Few studies on ultrasound have employed aquantitative measurement of the synovia as an as-sessment instrument. Schmidt et al., determinedreference values for the measurement of the syno -vium in different joints in healthy individuals; inthe wrist, the mean distance between the jointcapsu le and scaphoid bone profile was < 1.5 mm28.Koski (2003) established the measurement of thesynovium in the recesses of rheumatoid joints andconsidered unequivocal synovitis to be a mea-surement greater than 2 mm in the RC recess andthe presence of any area of synovial proliferationin the MC recess13. However, interobserver reliabi -lity was not determined in either of these studies.

The poor interobserver reliability (ICC = 0.346)for the quantitative measurement of synovitis in the MC recess in the present study may have occurred due to the fact that the patients had long--standing RA, in which erosion is common and the possible destruction of the carpal bones, such as the lunate and capitate, has occurred,which would hamper the visualization of the subchondral bone profile for the quantitative mea-surement. In the UC recess, there is a presence ofthe triangular fibrocartilage and the styloid pro-cess, which may have impaired the exact posi-tioning of the transdu cer, thereby causing ananisotropic effect and lea ding to the poor reliabili -ty in the measurement of the synovium in this re-cess. Moreover, a portable ultrasound device oflesser resolution was used in the present study,which may have compromised the adequate lo-calization of the joint capsule and hampered thequantitative measurement.

A semi-qualitative assessment of synovitis in the


riarticular structures, which makes the physicalexam of this joint a difficult task that requires theuse of imaging methods11,14,15. A number of studieshave demonstrated the ultrasound is capable ofrevealing inflammatory alterations in this joint.However, there are no previous studies that haveevaluated the interobserver reliability of thismethod for joint recesses of the wrist1-4.

In the present study, good reliability (ICC = 0.5081) was found for the RC recess, whereas poorcorrelations were found for the MC (ICC = 0.3463)and UC (ICC = 0.240) recesses. Likewise, poor inter-observer reliability was found for the semi-quanti-tative assessment for all three recesses ana lyzed (RC,MC and UC), with Kappa values of k = 0.308, k = 0.312and k = 0.153, respectively. Two previous studies in-volving experts in musculoskeletal ultrasound andthe assessment of different joints found moderate in-terobserver reliability (k = 0.59 to 0.61) regarding thepresence or absence of synovitis in the wrist; thesestudies report interobserver reliability similar to thatfound in the present study in the quantitative mea-surement of synovia in the RC recess8,9. Unlike thepresent study, however, these studies only performeda qualitative assessment (presence or absence of syn-ovitis) and did not perform a quantitative measure-ment of synovitis. Moreover, no systematic exami-nations of rheumatoid wrists were carried out, butrather the evaluation of different joints and degene -rative inflammatory conditions8,9.

Iagnocco et al., investigated the presence orabsen ce of synovitis in the wrists of patients withsystemic lupus erythematosus and found optimalinterobserver reliability for the RC recess (k = 0.73to 0.89)22. A recent study investigated interobser -ver reliability in the ultrasound assessment of syno -vitis in 28 joints in patients with RA and found

Table III. Interobserver agreement for the semi-quantitative scores of the RC, MCand UC recesses according to Operator A and Operator B

Recess (n = 295) Operator Semi-quantitative scores (N) kappa1 2 3 k

RC recess A 147 121 27 0.308

B 164 115 16

MC recess A 103 164 28 0.312

B 66 126 103

UC recess A 97 152 46 0.153

B 118 117 60

RC – radiocarpal; MC – mediocarpal; UC – ulnocarpal; A – operator A; B – operator B


249

RC, MC and UC recesses was employed in the pre-sent study, as this method is the most common formof measuring synovial thickening. For this assess-ment, a semi-quantitative scoring system which waspreviously estabilished by Szkularek et al., for smalljoints of the hand and feet (proximal metacar-pophalangeal, interphalangeal and metatarsopha-langeal) was used19. In this study the sco ring systemfor synovitis and joint effusion showed moderate tooptimal interobserver reliability (ICC of 0.61 and0.78, respectively) for all evaluations19. In the presentstudy, the scoring system was mo dified to deter-mine the presence of synovitis and joint effusion inthe same assessment. This decision was made dueto the fact that both alterations occur simultane-ously in the chronic inflammatory process. Howe -ver, there was poor interobserver reliability in the as-sessment of the recesses. The MCP joints used bySkzudlarek et al., are consi dered joints with a sim-ple anatomical model, in which the subchondralbone and cartilage may be assessed and detectionof synovitis is easy26. An explanation for differentlevels of agreement between studies may be thatthe wrist is a more elaborate joint with diverse re-cesses and multiple ligament structures11,12.

The assessment of synovial proliferation in thepresent study was not carried out with the aid of apower Doppler signal. This decision was made dueto the low resolution of the ultrasound device in theassessment of a power Doppler, which could havecompromised the results.

In conclusion, there was moderate interobser verreliability for the quantitative measurement of thesynovium in the RC recess and poor reliability re-garding the MC and UC recesses. The semi-quanti-tative assessment of the synovium using a pre -viously established scoring system for small jointsdemonstrated poor interobserver correlations forthe RC, MC and UC recesses of rheumatoid wrists.Further studies are needed for the standar dizationof a quantitative measurement of the synovium injoint recesses of the wrist as well as the va lidation ofsemi-quantitative scoring systems for this fre-quently affected joint in patients with RA.

Correspondence toJamil NatourDisciplina de Reumatologia, Universidade Federal de São PauloRua Botucatu, 740 São Paulo, SP – Brazil 04023-900Phone/Fax: 55 11 5576 4239E-mail: [email protected]

References1. Canoso JJ. Ultrasound Imaging: A Rheumatologist’s

Dream. J Rheumatoi 2000; 27:2063-2064. 2. Kane D, Ballin PV, Sturrock R, Grassi W. Muscu-

loskeletal Ultrasound – a state of the art review ofmusculoskeletal ultrasound in rheumatology.Rheumatology (Oxford) 2004; 43:823028.

3. Manger B, Kalden JR. Joint and Connective Tissue Ul-trasonography – a Rheumatologic Bedside Proce-dure? A German Experience. Arthritis and Rheuma-tism 1995; 38:736-742.

4. Grassi W, Cervini C. Ultrasonography in Rheumatolo-gy: an evolving technique. Ann Rheum Dis1998;57:268-271.

5. Joshua F, Lassere M, Bruyn GA, et al. Summary find-ings of a systematic review of the ultrasound assess-ment of synovitis: proceedings of OMERACT 8. JRheumatol 2007;34:839–847.

6. Naredo E, Rodriguez M, Campos C, et al, and the Ul-trasound Group of The Spanish Society of Rheuma-tology. Validity, reproducibility and responsiveness ofa twelve-joint simplified power Doppler ultraso -nographic assessment of joint inflammation inrheumatoid arthritis. Arthritis Rheum 2008;59:515–522.

7. D’Agostino MA, Maillefert JF, Said-Nahal R, BrebanM, Ravaud P, Dougados M. Detection of small jointsynovitis by ultrasonography: the learning curve ofrheumatologists. Ann Rheum Dis 2004;63:1284–1287.

8. Scheel AK, Schmidt WA, Hermann K-GA, et al. Inter-observer reliability of rheumatologistis performingmusculoskeletal ultrasonography; results from a EU-LAR “Train the trainers” course. Ann Rheum Dis2005;64:1043-1049.

9. Naredo E, Moller I, Moragues C, de Agustin JJ, ScheelAK, Grassi W. Interobserver reliability in muscu-loskeletal ultrasonography: results from a “Teach andTeachers” rheumatologist course. Ann Rheum Dis2006;65:14-19.

10. Hamalainen M, Kamoonen M, Lethimaki M. Epi-demiology of wrist involvement of rheumatoidarthritis. Rheumatol 1992;17:1-7.

11. Harrison MO, Freiberger RH, Ranawat CS. Arthrogra-phy of the wrist joint. Am J Roentgenol Radium TheNucl Med 1971;112:480-486.

12. Hastings DE, Evans JA. Rheumatoid wrist deformitiesand their relation to ulnar drift. J Bone Joint Surg1975;57:930-934.

13. Koski JM. Ultrasonography in detection of effusion inthe radiocarpal and midcarpal joints. Scand JRheumatol 1992;21:79-81.

14. van Vugt RM, van Dallen A, Bijlsma JW. The currentrole of high-resolution ultrasonography of the handand wrist in rheumatic disases. Clin Exp Rheumatol1998;16:454-458.

15. van Vugt RM, van Jaarsveld CH, Hofman DM, HeldersPJ, Bijlsman JW. Patterns of disease progression inthe rheumatoid wrist; a long term followup. JRheumatol 1992;26:1467-1473.

karine r. luz e col.

16. Koski JM, Hermunen H. Intra-articular glucocorticoidtreatment of the rheumatoid wrist. An ultrasono-graphic study. Scan J Rheumatol2001;30:268-270.

17. Luz KR, Furtado RN, Nunes CC, Rosenfeld A, Fernan-der AR, Natour J. Ultrasound guided intra-articularinjections in the wrist in patients with rheumatoidarthritis: a Double –blind, randomized controlledstudy. Ann Rheum Dis 2008;67:1198-2000.

18. Balint OV, Sturrock RD. Intraobserver repeatabilityand interobserver reproductibility in musculoskeletalultrasound imaging measurements. Clin Exp Rheu -matol 2001;19:89-92.

19. Szkudlarek M, Court-Payen M, Jacobsen S, KlarlundM, Thomsen HS, Ostergaard M. Interobserver agree-ment in ultrasonography of the fingers and toe jointsin rheumatoid arthritis. Arhritis and Rheum 2003;48:995-962.

20. Middleton WD, Teefey SA, Yamaguchi K. Sonographyof the rotator cuff: analysis of interobserver variabili-ty. AJR Am J Roentgenol 2004;183:1465-1458.

21. O�Connor PJ, Rankine J, Gibbon WW, Richardson A,Winter F, Miller JH. Interobserver variation in sonog-raphy of the painful shoulder. J Clin Ultrasound2005;33:53-56.

22. Iagnocco A, Ossandon A, Coari G, et al. Wrist joint in-volvement in systemic lúpus erythematosus. An ul-trasonographic study. Clin Exp Rheumatol2004;22:621-624.

23. Arnett FC, Edworthy SM, Bloch DA, et al. The Ameri-can Rheumatism Association 1987 revised criteria forthe classification of rheumatoid arthritis. ArthritisRheum 1988;31:315-324.

24. Backhaus M, Burmester GR, Gerber T, et al. Guide-lines for musculoskeletal ultrasound in rheumatolo-gy. Ann Rheum Dis 2001;60:641-649.

25. Shourt PE, Fleiss JL. Intraclass correlation: use in as-sessing rater reliability. Psychol Bull 1979;86:420-428.

26. Landis JR, Koch GG. The measurement of observeragreement for categorical data. Biometrics 1977;33:159-174.

27. Salaffi F, Filippucci E, Carotti M, et al. Interobserveragreement of standard joint couts in early rheuma-toid arthritis; a comparasion with grey scale ultra-sonography – a preliminary study. Rheumatology(Oxford) 2008;47:54-58.

28. Schmidt WA, Schmidt H, Schicke B, Gromnica-lhle E.Standard reference values for musculoskeletal ultra-sonography. Ann Rheum Dis 2004;63:988-994.

29. Conaghan PG, Green M. Emery P. Established rheu -matoid arthritis. Bailliere’s Best Prac Res Clin Rheu -matol 1999;13:561-575.


250


XIX Jornadas Internacionais do Instituto Português de Reumatologia

Lisboa, Portugal24 a 25 Novembro 2011


252


m u s c u l a r k i n e t i c s a n d f at i g u e e va l u at i o n

o f k n e e u s i n g b y i s o k i n e t i c d y n a m o m e t e r

i n p at i e n t s w i t h a n k y l o s i n g s p o n d y l i t i s

Nilay Sahin*, Emel Ozcan**, Akin Baskent***, Ayse Karan****, Erdem Kasikcioglu*****

*Assistant Professor, Selcuk University, Meram Faculty of Medicine,

Physical Medicine and Rehabilitation Department, Meram/Konya

**Professor, Istanbul University, Istanbul Faculty of Medicine,

Physical Medicine and Rehabilitation Department, Capa/Istanbul

***Istanbul University, Istanbul Faculty of Medicine, Physical

Medicine and Rehabilitation Department, Capa/Istanbul

****Professor, Istanbul University, Istanbul Faculty of Medicine,

Physical Medicine and Rehabilitation Department, Capa/Istanbul

*****Associate Professor, Istanbul University, Istanbul Faculty of

Medicine, Sports Medicine Department, Capa/Istanbul

sease of unknown etiology. Inflammation prima rilyaffects the joints and causes secondary changes inthese regions. The spine is the fundamentally af-fected region in AS1. In most of the patients, the pe-ripheral joints are mildly affected without showingany deformity. In time, impaired spinal mobilitymay cause articular instability and force the pa-tients to use their knee muscles more for posturalcontrol and for activities of daily living2,3. Further-more, changes in spine give rise to deformities inperipheral joints. Peripheral joint involvement mayalso affect posture and thus cause disability3. Pa-tients suffering from hip joint involvement rarelydevelop mild knee flexion pattern in knees duringwalking in order to make the walk more comfor -table2. Peripheral joint involvement can be presentin about 25% of patients as an asymmetricaloligoarthritis predominantly in lower extremities,particularly affecting the knees4. On the other hand,systemic inflammation may also affect the kneemuscles. Marcora et al., found reduced appendi -cular muscle mass in patients with long-standingAS compared to healthy controls. This muscle was-ting is significantly associated with reduced kneeextensors muscle strength and grip strength of thedominant hand5. Local inflammation (achilles ten-don enthesitis), frequently seen in seronegativespon dyloarthritis patients, may affect the kneemuscle6. Consequently, strength of knee musclesmay be affected due to some reasons in AS patientswho have a long-standing disease and impairedposture of spine. However, it is not yet clear whetherstrength of knee muscles may have an effect on ASpatients who have no postural disorders.

In addition, for the chance of success it can beimportant to know which muscle group is mostlyaffected during the rehabilitation of AS patient.When weakness is suspected in a muscle group, itis useful to evaluate the isokinetic performance inincreasing speed in every angle of that muscle7. Al-though isokinetic testing was used to different

Abstract

Objective: Ankylosing Spondylitis (AS) is an in-flammatory disease that is observed with arthritis,sacroiliitis and disability. The aim of the study wasto compare the strength and fatigue of knee exten-sor/flexor muscle group usage by isokinetic in pa-tients with AS with controls. Methods: Twenty-six AS diagnosed patients andtwenty-six healthy volunteers with similar age,height, body weight and gender were included inthis study. In both groups the isokinetic tests areconducted by isokinetic dynamometer for everysubject. Knee extension/flexion patterns;peaktorque, agonist/antagonist ratio and work fatigueisokinetic parameters were evaluated during theknee 60º/s,180º/s and 240º/s angular velocities.Results: Knee extension/flexion muscle strength inpatient group was significantly lower compared tothe control group in all angular velocities (p< 0.05). Conclusions:The study showed knee muscle weak-ness and fatigue in patients with AS compared tothe control group.

Keywords: Muscle strength; Dynamometer; Knee;Ankylosing spondylitis; fatigue

Introduction

Ankylosing Spondylitis (AS) is an inflammatory di -


253

joints in rheumatoid arthritis, fibromyalgia syn-drome and in some other rheumatologic baseddiseases as well, there is few knowledge about pe-ripheral weakness in patients with AS8-10. A studydetected muscle weakness and fatigue in ankleplantarflexor muscle groups in AS patients com-pared to the control group11.

The objective of this study was to measure thestrength and fatigue of the knee extensor/flexormuscle group using by isokinetic in AS patients,who do not have postural disorders or peripheraljoint involvement; to compare with healthy con-trols, and to determine the relation of these valueswith the functional situation.

Material and Methods

Twenty-six male patients between 18-54 years ofage diagnosed with AS and referred to PhysicalMedicine and Rehabilitation division AS unit, anda control group consisting of 26 healthy males be-tween 20-56 ages were enrolled for this study. Thepatient group was chosen according to ModifiedNew York diagnosing criteria, diagnosed with ASbut not in active period. Patients having seriousknee injury, having serious lumbar pain, hip painor knee pain, having some other systemic diseases,limitations in hip and knee joints, and havingsurgery in lower extremities were not included inthis study group. The control group was selectedfrom the hospital staff with similar age and gender.The control group with serious knee trauma, hip,knee and hip osteoarthritis demonstrated by X--rays, other comorbidities and ligament injurywere excluded from the study. Informed consent ofthe subjects was sought and the ethical committeeapproval was obtained prior to the initiation of thestudy.

Evaluation parametersKnee extensor/flexor muscle group isokinetic mus-cle strength (peak torque) of both groups was eva -luated by Biodex System 3PRO Multijoint Systemisokinetic dynamometer. Before testing AS patientsthe following evaluations were performed: Bodyweight-height, visual analog scale (VAS), modifiedlumbar Schober (MLS), lower extremity range ofmotion (ROM) as measured by goniometry, pre -sence of enthesitis as determined by Berlin Enthe-sitis Index (BEI), the activity of the disease as mea-sured by C-reactive protein (CRP), Bath Ankylo -

sing Spondylitis Disease Activity Index (BASDAI)score and functional status as determined by BathAnkyolosing Spondylitis Functional Index (BAS-FI)12.

PainPain was evaluated by VAS score between 0-10. Nopain corresponded to (0), whereas intolerable painwas expressed with (10) points. The severity of thepain was investigated separately if it occurred atnight and during resting. The higher points showthe severity of the pain13.

EnthesitisAccording to BEI, the patient is asked to evaluatepresence of pain during palpation to 12 enthesisareas in the lower extremities. The patient replieswith “yes” or “no” and score is determined between0-12. The score gives an idea about the activity ofthe disease12.

Activity of the DiseaseBASDAI gives information about the activity of thedisease. The evaluated activity is mostly about thepresence of inflammation in peripheral joints. Fa-tigue, axial pain, peripheral pain, morning stiff-ness and the presence of enthesopathy is evalua -ted by VAS between 0-10 points. It is accepted asthe activity period of the disease, when BASDAI is>412,14.

Functional StatusIn BASFI scale, 10 daily activities are evaluated. Thepatient is asked to evaluate each activity by VASbetween 0 and 10 according to the difficulty expe-rienced during each activity. The scores show 0= nodifficulty, 5= moderate difficulty, 10= maximumdifficulty, the total maximum score is determinedas 1015.

Muscle Testing Isokinetic tests with Biodex System 3PRO Multi-joint System isokinetic dynamometer were appliedto both groups The reliability of the dynamometerwas determined both in healthy group and the ASpatient group16-18. The tests were performed ac-cording to standardizations developed by Wilk etal10. Warm-up was accomplished on ergonomic bi-cycle for 10 min. at 60 rpm.

For knee extension/flexion pattern measure-ment the arms of the dynamometer were held pa -ral lel to the leg of the patient having pads fixed dis-

the isokinetic evaluation of knee muscles in ankylosing spondylitis patients


254

tally. Distal resistance pad was fixed. The stabilityof the patient on the dynamometer chair wasachieved by putting a belt covering the thorax, hipand thigh regions, and the procedure was ex-plained to the patient to ensure good coopera-tion10.

Muscle strength is measured better with testsperformed with low angular velocities, while highangular velocities are useful for the detection offunctional status and endurance of the muscle7,18,19.For this reason, slow, moderate and high angularvelocities such as 60º/s,180º/s, 240º/s were pre-ferred for the knee extension/flexion pattern19,21.The test was performed bilaterally, starting withthe dominant side first. Four repetitions were per-formed at the first two angular velocities in exten-sion/flexion and at the third angular velocity, 20repetitions were performed. Peak torque (New-tonmetre-Nm) (PT), peak torque/body weight (%)(PT/BW), maximal repetition total work (Joule-J)(MRTW), work/body weight (%) (W/BW), ago-nist/antagonist ratio (%) (Ag/An) and work fatigue(%) (WF) isokinetic parameters were evaluated atall angular velocities. In order to decrease the oc-currence of strain in the muscles, 60 sec. resting pe-riod was maintained between each angular veloci -ty22. In order to motivate the patients during thetest maximal, strength was maintained by verbalinstructions. The test was carried out in a quiet andappropriate physical environment with air condi-tioner.

PT is the highest torque value measured with allvelocities in one angular velocity and is expressedin terms of newtonmeter. PT is the most conve-nient and the most used parameter in isometrictest parameters20. PT/BW ratio is used to persona -lize, standardize and interpret isokinetic scores23.MRTW is one of the parameters where the rela-tionship between flexion and extension is inter-preted and is expressed as Joules21,24,25. W/BW is themaximum work (force x distance) produced in asingle repetition. This could be a better represen-tation of the functional ability (over PT), becausethe muscle must maintain the force throughoutthe range of motion, as opposed to the force at oneinstant24. Ag/An ratio evaluates the balance be-tween the knee extensor/flexor muscles. With thisratio, the weakest muscle in the muscle group canbe determined. The ag/an ratio is calculated as theratio between the peak values of the concentrictorque of the flexor muscles, and the concentricpeak torque of the extensor of the knee. The hams-

nilay sahin e col.

tring action as antagonist is directly proportionalto its ability to generate concentric strength26-28. WFtest measures the weariness of the muscle after anexcess number of repetitions. This is calculated asthe percentage of the difference between the pro-duction of work between the first 1/3 and the last1/3 repetitions at the 240º/sec. velocity. There is nostandardized test to evaluate fatigue. The numberof trials to evaluate fatigue is between 20-100. Inthis study, we used 20 trials. This parameter acts asa dependent variable used to evaluate the strengthof the muscle and shows the endurance capacityof the muscle29,30.

Statistical AnalysisThe comparison demographic data of both groupswere assessed using Mann–Whitney U tests. Twoway ANOVA was used in the group evaluations forcomparisons between the groups for PT, PT/BW,MRTW, W/BW, AG/AN and dominant versus non--dominant leg isokinetic parameters. The compa-rison WF of both groups was assessed usingMann–Whitney U tests. The correlation betweenPT parameter and BASFI, VAS and ROM was as-sessed by Pearson correlation test. p<0.05 valueswere accepted as statistically significant.

Results

Age, gender, height, weight, MLS, VAS, CRP, BASFI,BASDAI, and BEI values are presented in Table I.There was no statistically significant difference be-tween the two groups for age, gender, height andweight. The test group was not in the active stage;BASDAI values were <4, BEI 0-2 and CRP was <511.Resting and night VAS values were below 5. Hipflexion and knee extension and flexion ROM mea-surements for isokinetic tests performed with thegoniometer’s dynamometer revealed no statisti-cally significant difference between the two groups.In both groups, the right side was the dominantside.

Significantly lower values than the healthy con-trol group were observed in AS patients for the kneePT, PT/BW, MRTW and W/BW parameters evalua -ted with bilateral extension and flexion performedat the angular velocities of 60º/s, 180º/s and 240º/s(p<0.001) (Tables II, III). There was no significantdifference between the groups in dominant versusnon-dominant leg for bilateral knee movementtested at 60º/s, 180º/s and 240º/s. Statistical eva -


255

luation for the Ag/An parameter revealed a signifi -cant difference in AS patients compared to thehealthy controls for bilateral knee movements tes -ted at 60º/s (p<0.05). There was no statisticallysigni ficant difference in Ag/An scores for bilateralknee movement tested at 180º/s and 240º/s. Therewas no significant difference for Ag/An values be-tween the dominant and non-dominant side in ASpatients (Table IV).

A significant decrease of work fatigue in AS pa-tients was determined for knee extensors at 240º/safter 20 repetitions (P<0.05) (Table V).

There was no statistical correlation betweenmuscle strength measurements and BASFI, VASand ROM (p>0.05).

Discussion

Isokinetic dynamometer is an instrument whichhelps us to measure the joint movements in all an-gles, in constant angle speed, allowing maximalmuscle contraction along with the measurementof the contraction and muscle capacity objective-ly8. In isokinetic measurements for painful chro nicdiseases like osteoarthritis, rheumatoid arthritis, fi-bromyalgia syndrome and chronic low back painangular velocities such as 60º/s 180º/s, 240º/s and300º/s angular velocities were used and many rep-etitions were employed8,9,18-22,25,31. There is no stan-dardized model for isokinetic measurement in ASpatients, so we have used 60º/s 180º/s, 240º/s an-gular velocities in our study. The most valid pa-rameter in isokinetic evaluation is the PT whichmay be affected by body mass index and thePT/BW value is important in this issue as well asthe MRTW value that reflects the balance between

flexor and extensor muscle groups. The W/BW asone of the best indicator of PT values is also im-portant20,21,23-25. The parameters above at all angu-lar velocities showed significant lower scores forknee extensor and flexor muscles on both sides inAS patients as compared to the controls in thisstudy. Although 60º/s Ag/An ratio was significantlydecreased on both sides in the AS group, there wasno significant difference between the Ag/An ratiofor bilateral knee obtained at the angular velocitiesof 180º/s and 240º/s in the AS and the healthy con-trol groups. Also, higher velocities reflect the Ag/Anratio better than lower velocities8. Since the exten-sion and flexion losses for the knee joint are seentogether in AS patients, there was no statisticallysignificant difference in Ag/An scores. The low le -vel of the work fatigue showed that the work ofknee extensor is decreased in the first third and thelast third period of the work thus indica ting a de-crease in endurance capacity of the muscles. Themain finding of this study indicates that in AS pa-tients the tested knee muscles were significantlyweaker and the muscle endurance capacity de-creases compared to apparently healthy controls.Interestingly, the results of this study show that theforces at different angles and endurance of the tes -ted muscles related to non-involvement joints inpatients with AS are lower than those of controlsubjects.

The reason of the decrease in muscle strengthin AS patients is complicated32. The decreasedmuscle strength in inflammatory diseases is rela -ted to inflammation, pain, stiffness, inactivity, de-generation at the joints, fatigue and the primarysymptoms of AS patients are also pain, enthesisand stiffness1,33,34. Inactivity that is related to pain,inflammation and stiffness has a great role in theweakness of muscles in AS patients. Muscle wea k -ness develops in the first week of inactivation. Af-ter that, weakness increases rapidly. Decreasedphysical activity or inactivation results with atro-phy in the muscles, which further leads to wea k -ness in the muscles, causes a decrease in neuro-muscular performance and thus a decrease in thefunctional capacity ensues. But, this process doesnot have to be similar for all muscle groups1,32,35. Ina study on inflammatory disease, the decrease indynamic and isometric muscle strength was shownin early stages36. Inflammation raises catabolicstimulations including IL-6, IL-1 and TNF alphacytokine, each case causes muscle protein cata -bolism. Consequently, inflammatory conditions


Table I. Characteristics of patients with ankyolosingspondylitis (AS) and the control group (CG)

AS CG (n:26) (n:26) p

Age/mean 37.04±8.85 38.46±10.35 0.464

Height 172 174.31 0.139

Weight 75.19 73.42 0.288

Modified lumbar 18.72±2.62

Schober

BASFI 3.12±2.20

BASDAI 2.28±1.41


256

may affect muscle mass and cause loss of stren -gth37,38. The chronic inflammatory response is li-kely to be a major cause of muscle wasting in ASpatients. Marcoro et al., showed that patients withlong-standing AS have significant losses of leanmass in arms and legs. This muscle wasting is signi -ficantly associated with reduced knee extensormuscle strength and grip strength of the dominant

hand5. The other reason of the de-crease in muscle strength is fatiguein AS patients. There are a lot ofmechanisms res ponsible for thedevelopment of muscle fatigue19.An exceeding fatigue in AS patientsis acquainted with activity of thedisease, functional disability, andglobal wellness34. The fatigue inmuscles is res ponsible in motorcontrol deficit and in posture andbalance chan ges1,12,24,34. Conside -ring the relationship between thepostural changes and fatigue, fa-tigue may play an important role inpostural changes in AS patients. Inthis study, we determined that themuscle endurance capaci ty de-creases in the patient group, eventhough we used the least number oftrials recommen ded in the litera-ture. According to this result, themuscle weakness can be the causeof fatigue in AS patients, or fatigueseen in most of the AS patients canbe one of the cau ses of muscleweakness.

The other possible reasons formuscle strength decrease mecha-nism are local inflammation (en-thesitis) and proprioception dete -rio ration, which is related to it. En-thesitis, which is the basic me cha -nism of pathogenesis in AS pa tien ts,is an inflammation of en thesis, thelocation where the point at which atendon or ligament or muscle in-serts into bone. Enthesitis leads toinstable joint structure and thesechanges apparently cause muscleweakness in AS patients. Further-more, the attachment sites of theligamentous formations harbor theafferent nerve endings, which regu-

late the information about posture and are res -ponsible for joint motion; therefore, a pathology atthis site results with changes in proprioception inAS patients. Insufficiency of proprioce ption may acause to decrease in muscle stren gth32,35,39-41. Con-sequently, the muscle weakness detected in ourstudy may have correlation with the disorders inproprioceptors that is rela ted to enthesitis.

nilay sahin e col.

Tabl

e II. M

eans

of pa

ram

eter

s ev

alua

ted

by the

isok

inet

ic tes

t fo

r th

e kn

ee

Gro

up

AS

CG

ME

xten

sors

Fle

xors

Ext

enso

rsF

lexo

rsS

RL

RL

RL

RL

PT

(N

m)

60º/

s

1

39.5

6±

28.2

1139.6

7±

24.9

961.6

3±

13.5

260.2

0±

10.7

4174.2

9±

36.0

9171.8

2±

33.9

783.9

2±

22.7

883.2

7±

18.1

8

180º/

s

105.4

3±

21.6

4104.9

0±

16.9

158.1

9±

12.7

263.0

0±

14.8

7122.7

8±

25.3

7125.2

9±

27.3

675.5

5±

19.5

979.1

6±

16.0

6

240º/

s

9

6.6

1±

16.5

295.5

2±

12.4

067.2

5±

13.1

174.7

9±

15.4

6110.6

2±

23.2

1111.6

2±

25.3

182.2

1±

18.6

889.3

5±

17.7

3

PT

/BW

(%

)

60º/

s187.4

8±

42.1

0187.9

6±

38.3

782.5

0±

18.2

781.0

5±

16.9

7235.8

9±

36.5

3233.2

5±

36.0

7114.3

0±

29.6

7113.5

5±

24.3

3

180º/

s141.2

9±

29.4

5141.0

6±

25.3

878.3

3±

19.0

885.0

0±

22.3

4166.0

9±

24.1

9170.1

3±

29.1

2103.3

2±

27.4

4108.4

3±

23.2

3

240º/

s129.5

8±

23.9

7127.9

6±

17.1

690.7

0±

19.9

7101.0

8±

25.2

7147.8

0±

22.4

5149.8

8±

30.4

9110.5

4±

24.9

8120.3

5±

23.5

6

MRT

W (

J)

60º/

s147.2

1±

30.9

2147.3

4±

25.5

365.2

9±

18.0

964.7

9±

15.4

8187.8

8±

40.0

5183.0

4±

38.4

598.9

4±

29.3

097.6

1±

24.4

4

180º/

s117.6

1±

27.4

8117.1

9±

17.7

049.4

2±

18.4

247.2

2±

15.2

1141.0

6±

30.0

9141.4

7±

32.1

773.9

5±

23.2

970.1

5±

19.9

9

240º/

s100.8

4±

21.6

7100.6

1±

15.3

940.2

0±

15.9

038.7

8±

14.0

9119.8

9±

24.6

8121.5

6±

28.1

359.7

8±

18.7

856.8

8±

19.7

6

W/B

W(%

)

60º/

s191.6

0±

57.1

7198.1

9±

38.3

291.7

7±

30.0

894.0

0±

43.1

7254.5

8±

43.0

6248.0

1±

37.1

2134.7

2±

38.0

6132.9

8±

31.1

0

180º/

s157.5

6±

36.7

1157.4

5±

26.6

266.2

2±

24.2

363.7

5±

21.7

4190.5

1±

26.6

0191.6

5±

30.9

0100.6

3±

29.8

395.6

9±

25.0

1

240º/

s135.2

8±

30.1

7135.9

0±

22.3

054.2

7±

21.3

152.4

3±

20.0

9162.0

2±

21.6

6164.6

5±

28.7

181.0

2±

22.5

178.1

5±

23.4

9

R: r

ight,

L: l

eft.

AS:

anky

ols

ing

spondyl

itis

, CG

: contr

ol gr

oup.

M: m

usc

le, S

: sid

e.

Conclusions

In this study, we detected fatigue and muscleweakness in knee extensor and flexor musclegroups in AS patients compared to the controlgroup. Rehabilitation of the muscle weaknessand fatigue is important to delay the develop-ment of the posture disorder and thus preventthe development of ba lance problems in ASpatients. More studies are needed to be doneon this subject, in order to detect the effect ofexercises especially on the lower extremities,on the activity of the disease, on the posture ofthe patient and on the functional status in ear-ly stages of the disease before any posturalchange occurs in AS patients. The results ofthis study showed us how important the effectof muscle weakness in maintaining posture inAS patients is. As a conclusion, functional di -sability in patients with AS is not only develo -ped by axial deformities, but may also by mus-cular weakness and fatigue affect. Based onthis knowledge, it should be reminded that


257


Table IV. Means of agonist/antagonist parameters evaluated by isokinetictest (%)

AS CGGroup R (F/E) L (F/E) R (F/E) L (F/E) pKnee-AV 45.30±12.32 43.50± 6.56 48.28±8.77 48.68± 7.43 0.001

60°/s

180°/s 56.55±14.32 61.00±16.84 61.84±11.35 80.40±16.22 0.116

240°/s 72.37±18.91 80.05±17.49 75.31±14.65 82.01±17.28 0.312

R: right, L: left. AS: ankyolsing spondylitis, CG: control group. E:extensor, F: flexor.

Table V. Means of work fatique parameters evaluated by the isokinetic test (%)

Group AS CG pKnee

ExtensorR 35.35 (2.7-64.0) 27.50 (-9.0-47.8) 0.034

240º/s L 35.90 (3.2-65.2) 23.50 (-7.6-45.3) 0.030

FlexorR 38.75 (10.2-69.4) 24.30 (-8.3-79.7) 0.253

L 41.10 (16.6-68.8) 30.70 (-6.0-71.0) 0.249

R: right, L: left. AS: ankyolsing spondylitis, CG: control group. p<0.05

Table III. p values of isokinetic testing in AS versus CG

KneeAS-CG ND-D leg

Extensor Flexor Extensor FlexorPT (Nm)

60º/s <0.001 <0.001 0.603 0.755

180º/s <0.001 <0.001 0.829 0.183

240º/s <0.001 <0.001 0.990 0.055

PT/BW (%)

60º/s <0.001 <0.001 0.635 0.803

180º/s <0.001 <0.001 0.723 0.215

240º/s <0.001 <0.001 0.954 0.071

MRTW (J)

60º/s <0.001 <0.001 0.727 0.836

180º/s <0.001 <0.001 0.723 0.215

240º/s <0.001 <0.001 0.873 0.525

W/BW (%)

60º/s <0.001 <0.001 0.724 0.867

180º/s <0.001 <0.001 0.930 0.484

240º/s <0.001 <0.001 0.830 0.563

AS: ankylosing spondylitis, CG: control group.

ND: nondominant, D: dominant.


258

isokinetic evaluation is also important in the fol-low up of the efficacy of the scheduled effective re-habilitation in patients with AS.

Correspondence toNilay SahinSelcuk University, Meram Faculty of Medicine, Physical Medicine and Rehabilitation Department, Meram/Konya, TurkeyPhone: +90 5552332535E-mail: [email protected]

References1. Mengshoel AM, Jokstad K, Bjerkhoel F. Associations

between walking time, quadriceps muscle strengthand cardiovascular capacity in patients with rheuma-toid arthritis and ankylosing spondylitis. ClinRheumatol 2004;23:299-305.

2. Khan MA. Clinical features of ankylosing spondylitis.In: Hochberg MC, Silman AJ, Smolen JS, WeinblattME, Weisman MH, eds. Rheumatology, Vol 2. Pitts-burg: Mosby; 2003: 1161-78.

3. Gran JT, Skomsvoll JF. The outcome of ankylosingspondylitis: a study of 100 patients. Br J Rheumatol1997;36:766-771.

4. Carette S, Graham D, Little H, Rubenstein J, Rosen P.The natural disease course of ankylosing spondylitis.Arthritis Rheum 1983;26:186-190.

5. Marcoro S, Casanova F, Williams E, Jones J, Elaman -chi R, Lemmey A. Preliminary evidence for cachexiain patients with well-establihed ankylosing spon -dylitis. Rheumatology 2006;45:1385-1388.

6. Emad Y, Ragab Y, Bassyouni I, et al. Enthesitis and re-lated changes in the knees in seronegative spondy-loarthropathies and skin psoriasis: magnetic reso-nance imaging case-control study. J Rheumatol2010;37:1709-1717.

7. Kannus P, Beynnon B. Peak torque occurrence in therange of motion during isokinetic extension and fle -xion of the knee. Int J Sport Med 1993;14:422-426.

8. Meireles SM, Oliveira LM, Andrade MS, Silva AC, Na-tour J. Isokinetic evaluation of the knee in patientswith rheumatoid arthritis. Joint Bone Spine 2002;69:566-573.

9. Maqeut D, Croisier JL, Renard C, Crielaard JM. Mus-cle performance in patients with fibromyalgia. JointBone Spine 2002;69:293-299.

10. Wilk KE. Isokinetik testing and exercise for the knee.In: Mangine RE, ed. Physical therapy of the knee.New York: Churchill Livingstone; 1995: 263-88.

11. Sahin N, Ozcan E, Baskent A, Karan A, Ekmekci O,Kasikcioglu E. Isokinetic evaluation of musclestrenght and fatigue in patients with ankylosingspondylitis. Eur J Phys Rehabil Med 2011;2:Epubahead of print.

12. Zochling J, Braun J, Heijde D. Assessments in ankilos-ing spondylitis. Best Prac Research 2006;20:521-537.

13. Frank JM, Moll MH, Hort JF. A comparison of three

ways of measuring of pain. Rheum Rehab 1982;21:211-217.

14. Akkoc Y, Karatepe AG, Akar S, Kirazli Y, Akkoc N. ATurkish version of the Bath Ankylosing SpondylitisDisease Activity Index: reliability and validity.Rheumatol Int 2005;25:280-284.

15. Yanik B, Gursel YK, Kutlay S, Ay S, Elhan AH. Adapta-tion of the Bath Ankylosing Spondylitis functional In-dex to the Turkish population, its reliability andvalidi ty: functional assessment in AS. Clin Rheuma-tol 2005;24:41-47.

16. Drouin JM, Valovich-mcLeod TC, Shultz SJ, Gansned-er BM, Perrin DH. Reliability and validity of theBiodex system 3 pro isokinetic dynamometer veloci-ty, torque and position measurements. Eur J ApplPhysiol 2004;91:22-29.

17. Baskent A, Ozcan E, Dincer N, Karan A. Test-retest re-liability of isokinetic muscle strength of the knee inpatients ankylosing spondilitis. Ann Rheum Dis2004;63:409.

18. Holmbäck AM, Porter MM, Downham D, Lexell J. Re-liability of isokinetic ankle dorsiflexor strength mea-surements in healthy young men and women. ScandJ Rehabil Med 1999;31:229-239.

19. Hall C, Brody LT. Therapeutic Exercise Moving To-ward Function. Philadelphia: Williams and Wilkins;1999.

20. Kannus P. Isokinetic evaluation of muscular perfor-mance: implications for muscle testing and rehabili-tation. Int J Sports Med 1994;15:11-18.

21. Siqueira CM, Pelegrini FR, Fontana MF, Greve JM.Isokinetic dynamometry of knee flexors and exten-sors: comparative study among non-athletes, jumperathletes and runner athletes. Rev Hosp Clin Fac MedSao Paulo 2002;57:19-24.

22. Osternig LR. Isokinetic dynamometry: implicationsfor muscle testing and rehabilitation. Exerc Sport SciRev 1986;14:45-80.

23. Borges O. Isometric and isokinetic knee extensionand flexion torque in men and women aged 20-70.Scand J Rehabil Med 1989;21:45-53.

24. Prentice WE, Voight MI. Techniques in Musculoskele-tal Rehabilitation. New York: McGraw-Hill; 2001.

25. Pincivero DM, Lephart SM, Karunakara RG. Relationbetween open and closed kinematic chain assess-ment of knee strength and functional performance.Clin J Sport Med 1997;7:11-16.

26. Aagaard P, Simonsen EB, Magnusson SP, Larsson B,Dyhre-Poulsen P. A new concept for isokinetic ham-string: quadriceps muscle strength ratio. Am J SportsMed 1998;26:231-237.

27. Baratta R, Solomonow M, Zhou BH, Letson D,Chuinard R, D’ Ambrosia R. Muscular coactivation.The role of the antagonist musculature in maintai -ning knee stability. Am J Sports Med 1998;16:113-122.

28. Oberg B, Moller M, Gillquist J, Ekstrand J. Isokinetictorque levels for knee extensors and knee flexors insoccer players. Int J Sports Med 1986;7:50-53.

29. Cools AM, Geerooms E, Van den Berghe DFM, Cam-

nilay sahin e col.


259

bier DC, Witvrouw EE. Isokinetic scapular muscleperformance in young elite gymnasts. J Athl Train2007;42:458-463.

30. Ellenbecker TS, Davies GJ. The application of isoki-netics in testing and rehabilitation of the shouldercomplex. J Athl Train 2000;35:338-350.

31. Lesmes GR, Costill DL, Coyle EF, Fink WJ. Musclestrength and power changes during maximal isoki-netic training. Med Sci Sports 1978;10 266-269.

32. Carter R, Riantawan P, Banham SW, Sturrock RD. Aninvestigation of factors limiting aerobic capacity inpatients with ankylosing spondylitis. Respir Med1999;93:700-708.

33. Plasqui G. The role of physical activity in rheumatoidarthritis. Physiol Behav 2008;95:270-275.

34. Costa D, Dritsa M, Ring A, Fitzcharles MA. Mentalhealth status and leisure-time physical activity con-tribute to fatigue intensity in patients with spondy-larthropathy. Arthritis Rheum 2004;51:1004-1008.

35. Hakkinen A, Malkia E, Hakkinen K, Jappinen I, Laiti-nen L, Hannonen P. Effects of detraining subsequentto strength trainig on neuromuscular function in pa-

tients with inflammatory arthritis. British J Rheum1997;36:1075-1081.

36. Häkkinen A, Hannonen P, Häkkinen K. Musclestrength in healthy people and in patients sufferingfrom recent-onset inflammatory arthritis. Br JRheumatol 1995;34:355-360.

37. Stenholm S, Harris TB, Rantanen T, Visser M,Kritchevsky SB, Ferrucci L. Sarcopenic obesit-defini-tion, etiology and consequnces. Curr Opin Clin NutrMetabc Care 2008;11:693-700.

38. Adamo ML, Farrar RP. Resistance training, and IGFinvolvement in the maintenance of muscle massduring the aging process. Ageing Res Rev 2006;5:310--331.

39. Aydog E, Depedipi R, Bal A, Eksioglu E, Ünlü E, ÇakciA. Dynamic postural balance in ankylosing spondyli-tis patients. Rheumatology 2006;45:445-448.

40. Swinkels A, Dolan P. Spinal position sense in ankylos-ing spondylitis. Spine 2004;413-420.

41. Sharma L. Proprioceptive impairment in knee os-teoarthritis. Rheum Dis Clin North Am 1999;25:299--314.


24e Congrès Français de Rhumatologie

Paris, França11 a 14 Dezembro 2011

World Congress on Debates and Consensus on Bone, Muscle & Joint Diseases

Barcelona, Espanha19 a 22 Janeiro 2012


260


p s y c h o m e t r i c p r o p e r t i e s o f t h e

p o r t u g u e s e v e r s i o n o f t h e p a i n

s e l f - e f f i c a c y q u e s t i o n n a i r e

M. Alexandra Ferreira-Valente*,**,***, José L. Pais-Ribeiro*,***, Mark P. Jensen****

*Faculdade de Psicologia e Ciências da Educação da Universidade

do Porto, Porto, Portugal;

**Fundação para a Ciência e a Tecnologia, Portugal

***Unidade de Investigação em Psicologia e Saúde, ISPA, Lisboa,

Portugal

****University of Washington School of Medicine, Seattle, USA.

The present study was undertaken with the support of the first

author’s FCT PhD grant SFRH/BD/ 40956/2007.

the hypothesized directions, supporting its cons -truct validity. Additionally, the confirmatory factoranalysis supported a single factor solution, as hy-pothesized.Conclusions: The findings provide strong supportfor the reliability and validity of the P-PSEQ. Re-search is needed to determine the responsivity ofthe P-PSEQ and to establish the generalizability ofthe results in other samples of Portuguese patientswith chronic pain.

Keywords: Pain; Pain Assessment; Intractable Pain;Self-Efficacy.

Introduction

Biopsychosocial models of chronic pain hypothe-size that psychological and social factors play a keyrole in the adjustment to chronic pain. Pain self--effi cacy – that is, the belief or confidence in one’sabi lity to engage in a specific behaviour or other action to achieve desired goals despite pain1-4 – hasbeen one of the factors thought to mediate the im-pact of pain on disability and depression1,5-7. Thereis strong support for the importance of pain self-ef-ficacy across a broad range of pain populations andconditions, with patients endorsing higher levels ofself-efficacy reporting lower levels of pain intensi-ty, disability, depression and anxiety1,4,5,8-14, andhigher quality of life and general health12,15. Fur-thermore, self-efficacy is thought to influencethoughts and feelings, which in turn can affectfunctioning2,4,16-18. Self-efficacy may also influencethe use of pain coping strategies via its effects on readiness to engage in those coping respon -ses4,11,19-21, with patients endorsing lower levels ofself-efficacy being more likely to use passive co -ping responses and to catastrophize in response topain4,19. On the other hand, patients endorsinghigher levels of self-efficacy have been shown to

Abstract

Aims: This study sought to translate and evaluatethe psychometric properties of a European Por-tuguese version of the Pain Self-Efficacy Question-naire (P-PSEQ), in order to enable its use in clinicaland cross-cultural studies.Material and Methods: The Pain Self-Efficacy Ques-tionnaire was translated into European Portugueseand then back-translated into English. A consensusversion of the translated version was pre-tested witha pilot sample, followed by cognitive debriefing, re-sulting in a final version of the measure.

A convenience sample of 174 Portuguese adultswith chronic musculoskeletal pain completed thePortuguese Pain Self-Efficacy Questionnaire (P-PSEQ) and criterion measures of pain intensity(Numerical Ratings Scale), pain interference (Por-tuguese Brief Pain Inventory Interference Scale),quality of life and general health (SF-12), and psy-chological functioning (Hospital Anxiety and De-pression Scale). Cronbach’s alpha and compositereliability coefficients were computed as measuresof reliability, and confirmatory factor analysis wasperformed. Pearson correlation coefficients be-tween the P-PSEQ score and the criterion measureswere computed to evaluate the construct validity ofthe scale. Results: The P-PSEQ demonstrated good to excel-lent reliability (Cronbach’s alpha = 0.88 and Com-posite reliability = 0.92), and showed moderatelystrong associations with the criterion measures in


261

m. alexandra ferreira-valente e col.

use more adaptive coping responses2,11,19,22, evenafter controlling for demographic and medical sta-tus variables11. Given the importance of self-effi-cacy in the adaptive management of chronic pain,multidisciplinary treatment programs often aimto increase pain self-efficacy as a way to increasepatients’ quality of life and enhance positive phy -sical and psychological outcomes in response totreatment.

In order to determine the effects of treatment onpain self-efficacy as well as evaluate its potentialrole in adjustment to pain, a valid and reliable mea-sure of pain self-efficacy is needed. Moreover,translated measures of the construct are neededfor cross-cultural research to determine if the sametreatments have similar effects on outcomes acrosscultures. The Pain Self-Efficacy Questionnaire(PSEQ)4, which was developed from Bandura’s So-cial Learning theory2, is the only pain self-efficacymeasure developed specifically to assess confi-dence of patients to engage in a number of activi-ties of daily living, despite pain. The PSEQ was de-veloped to be applicable to patients with all chro -nic pain conditions and to be easy to understand.It assesses self-efficacy regarding a wide range offunctions such as household chores, social activi-ties, work, and coping with pain without medica-tion, yet takes less than two minutes to complete.Previous research shows the PSEQ to be reliableand to have both factorial and predictive validityacross a number of languages, cultures, and clini-cal settings4,9,12,14,23-33.

Although a Portuguese version of the PSEQ hasbeen developed, it was translated and validated tobe used in Brazilian populations14. However, a Eu-ropean Portuguese version of the PSEQ has not yetbeen translated and validated. A European Por-tuguese version of the PSEQ that is distinct fromthe Brazilian Portuguese version is needed becauseof the cultural and language differences betweenEuropean Portuguese (as spoken in Portugal) andBrazilian Portuguese.

The purpose of this study is to translate andevaluate the psychometric properties of a Euro-pean Portuguese version of the Pain Self-EfficacyQuestionnaire (P-PSEQ), to enable its use in clini-cal and cross-cultural studies. Based on previousresearch with the PSEQ in other samples, we hy-pothesized that: (1) the internal consistency (Cron-bach’s alpha) of the P-PSEQ would be good to ex-cellent (above 0.80)34; (2) the predictive validity ofthe P-PSEQ would be supported via a pattern of

significant negative associations with pain inten-sity (r between -0.12 and -0.39)4,5,9,12,14,30 and pain in-terference (r between -0.31 and -0.70)5,9,12,14,30, an -xiety (r between -0.49 and -0.56)4,12 and depression(r between -0.48 and -0.66)4,9,12,30 and moderate tostrong correlations (i.e., 0.30 or larger) with mea-sures of global physical functioning and psycho-logical functioning12; and (3) a factor analysis ofthe P-PSEQ items would yield one factor that ex-plains a substantial portion of the variance in theitems.

Materials and Methods

SubjectsOne-hundred and seventy four patients, all over18 years old, with chronic musculoskeletal painfrom seven health care institutions in northern andcentral Portugal completed the study protocol. In-clusion criteria included: (1) experiencing pain dueto a diagnosed musculoskeletal condition for atleast 3 months; (2) being at least 18 years old; (3)and being willing to participate in a research. Ex-clusion criteria included: (1) having a physical orcognitive disability which prevented participation,(2) known/diagnosed severe depression or othersevere mental health condition, and (3) pain due to fibromyalgia. As can be seen in Table I, the participants’ ages ranged from 23 to 90 years(M = 59.18, SD = 16.11), 60.2% were married or li -ving with a significant other, 26.3% were either sin-gle or divorced/separate and 8.8% of the partici-pants were widowed. The majority of the partici-pants were female (60.2%). Most participants hada history of chronic pain for at least two years(65.3%), and 38.8% reported having had pain formore than 10 years.

MeasuresAll participants were asked to provide basic de-mographic and pain history information (e.g. age,sex, marital status, level of education, professio nalstatus, duration of pain, pain location and cause ofpain). They were also asked to rate their pain in-tensity at its maximum, minimum and on averageduring the previous 24hours on a 0 to 10 Numeri-cal Rating Scale (NRS). Research supports the va-lidity of the NRS as a measure of pain intensity35.

The Portuguese BPI Pain Interference subscalewas used to assess pain interference across sevendaily life activities (general activity, mood, walking


262

portuguese pain self-efficacy questionnaire

-efficacy beliefs. The 10-item scale assesses confi-dence of patients to engage in a number of activi-ties of daily living despite pain on 0 - 6 numericalrating scales, where 0 = “not at all confident” and6 = “completely confident”. Higher scores (rangingfrom 0 to 60) reflect stronger self-efficacy beliefs.

ProcedureThe initial phase of the study involved translatingand back-translating the instructions and items ofthe PSEQ. Through expert discussion, we arrivedat a consensus version, and verified that its contentassessed the same construct as the ori gi nal. To en-sure that the individuals in our population under-stood the instructions and scale items, we thenperformed a pre-test of the P-PSEQ in a pilot sam-ple of 15 patients, followed by a cognitive debrie -fing. After making final modifications based on theresults of the cognitive testing, we invited a sam-ple of patients with chronic musculoskeletal painto complete all of the study measures. All patientswho agreed then signed an informed consent formand were administered the 0-10 NRS, P-BPI Inter-ference Scale, SF-12, HADS and P-PSEQ question-naires.

Data AnalysisMeans and standard deviations of the study varia -bles were computed for descriptive purposes. In-ternal consistency of the P-PSEQ was assessed bycomputing a Cronbach’s alpha. Composite relia-bility was also computed41,42. Then, to test a hy-pothesized one-factor model for the P-PSEQ items,we performed a confirmatory factor analysis (CFA).Model quality of fitness was evaluated using theChi Square (χ2/df), Comparative Fit Index (CFI),Parsimony Comparative Fit Index (PCFI), Good-ness of Fit Index (GFI), Parsimony Goodness of FitIndex (PGFI), and Root Mean Square Error of Ap-proximation (RMSEA). The model was consideredto have acceptable fit if χ2/df was less than 5 42-44,CFI and GFI higher than 0.842, the PCFI and PGFIwe re both higher than 0.642,45,46, the RMSEA was lo -wer than 0.1042,43. The model was considered to ha -ve a good fit it χ2/df was less than 242-44, the CFI andGFI were higher than 0.942, PCFI and PGFI higherthan 0.842,45, and the RMSEA was lower than 0.0843.Mo del adjustment was performed, step-by-step,via Modification Indices analysis (higher than 11;p<0.001)42,43 and based on theory. We also used theExpected Cross-Validation Index (ECVI), to com-pare fit after models’ adjustment, with lower ECVI

ability, normal work, relations with other people,sleep, and enjoyment of life) on 0 to 10 numericalrating scales. Research supports the validity and re-liability of BPI in several samples, cultures and lan-guages, including European Portuguese36-38. ThePortuguese SF-1239 was used as a measure of per-ceived Physical (Physical Component Summary,PCS) and Mental (Mental Component Summary,MCS) health status, with higher scores (rangingfrom 0 to 100) indicating better health. The Por-tuguese version has evidence supporting its relia-bility and validity39. The Portuguese version of theHospital Anxiety and Depression Scale (HADS)40

was used to assess psychological functioning. Itasks respondents to rate the severity of 14 depres-sive or anxiety symptoms on 4-point Likert scales,and has shown good reliability and validity40. Thepossible scores range from 0 to 21. Higher scoresreflect higher anxiety or depressive symptomatolo -gy. The Portuguese Pain Self-Efficacy Questionnai -re (P-PSEQ)4 was used to assess pain-related self-

Table I. Demographic Information

Portuguese sampleFrequency Mean

(%) (SD) Age – 59.18

(16.11)

Sex (female participants) 103 (60.2) –

Education Level

Primary education 76 (44.7) –

Incomplete High School 35 (20.6) –

High School 27 (15.9) –

College 32 (18.9) –

Marital Status

Single 31 (18.1) –

Married/Living with other 103 (60.2) –

Divorced 15 (8.8) –

Widow 22 (12.9) –

Professional Status

Employed 68 (39.8) –

Unemployed 19 (11.1) –

Retired (due to disability) 47 (27.5) –

Retired (normal age) 37 (21.6) –

Duration of Pain

3 months to 1 year 36 (21.2) –

1 to 2 years 23 (13.5) –

2 to 10 years 45 (26.5) –

More than 10 years 66 (38.8) –


263


Results

Descriptive informationAs can be seen in Table II, the study participants re-ported mild to moderate levels of pain severity(NRS) and pain-related disability (BPI Pain Inter-ference). Mean scores of SF-12 Physical Compo-nent Summary and SF-12 Mental ComponentSummary indicate significant dysfunction in theseareas, relative to published norms for healthy in-dividuals39. Overall, the mean scores on the HADSsuggested mild levels of anxiety, similar to indi-viduals with a variety of medical disorders, andnormal ratings of depressive symptoms40. Finally,the sample was characterized by relatively high le -vels of self-efficacy, on average, according to the cutoffs suggested by Tonkin47 (mean > 40), and whencompared to normative datasets for patients withchronic pain, as reported by Nicholas and col-leagues48 in a study of 6124 patients from across theAustralian state of New South Wales.

ReliabilityThe P-PSEQ’s internal consistencies (Cronbach’salphas) in our sample and in previous samples arelisted in Table III. The scale shows a very good le -vel of internal consistency in our sample that isconsistent with other samples, with an alpha coef -ficient of 0.8834. Values for alpha if single items aredeleted are comparable to the overall alpha, sug-

Table II. Descriptive Statistics Study Variables

Min-Mean (SD) Max

Pain Intensity (NRS)

Maximum (last 24 hours) 5.70 (2.49) 0-10

Minimum (last 24 hours) 2.97 (2.25) 0-9

Average Pain 4.59 (2.18) 0-10

Pain Interference (P-BPI) 4.03 (2.44) 0-9

Physical Component 39.07 (23.51) 0-100

Summary (SF-12)

Mental Component 57.02 (20.39) 10-100

Summary (SF-12)

Anxiety (HADS-A) 7.58 (3.91) 1-20

Depression (HADS-D) 6.07 (3.87) 0-17

Self Efficacy (P-PSEQ) 40.83 (11.31) 6-60

Note: NRS = Numerical Rating Scale of pain intensity; P-BPI = Portuguese Brief Pain Inventory – Interference scale; HADS-A = Hospital Anxiety and Depression Scale – Anxiety scale; HADS-D =Hospital Anxiety and Depression Scale – Depression scale; P-PSEQ =Portuguese Pain Self-Efficacy Questionnaire.

Table III. Reliability Analyses of Brief Pain Inventory Interference Scale

P-PSEQ Total scale or item Our sample Australia4 Brazil14 China12 Iran9

Cronbach's AlphaP-PSEQ Total scale 0.88 0.92 0.90 0.93 0.92

Cronbach's Alpha if item deleted (Item Total Correlation)P-PSEQ Items

Item 1 0.87 (0.48) - (0.70) - (0.79) 0.92 (0.72) –

Item 2 0.86 (0.56) - (0.72) - (0.73) 0.92 (0.71) –

Item 3 0.86 (0.61) - (0.71) - (0.67) 0.92 (0.66) –

Item 4 0.85 (0.70) - (0.83) - (0.71) 0.92 (0.66) –

Item 5 0.86 (0.61) - (0.74) - (0.76) 0.92 (0.71) –

Item 6 0.85 (0.67) - (0.79) - (0.77) 0.92 (0.81) –

Item 7 0.88 (0.43) - (0.67) - (0.50) 0.93 (0.62) –

Item 8 0.86 (0.62) - (0.79) - (0.82) 0.92 (0.80) –

Item 9 0.85 (0.72) - (0.84) - (0.80) 0.92 (0.78) –

Item 10 0.86 (0.63) - (0.84) - (0.79) 0.92 (0.75) –

Note: P-PSEQ = Portuguese Pain Self-Efficacy Questionnaire

reflecting better fit. Finally, Pearson correlation co-efficients between the P-PSEQ score (or scores) andthe criterion measures were computed to evaluatethe construct validity of the scale. Statistical ana -lyses were performed using software PASW Statis-tics (v.18, SPSS Inc. Chicago, IL) and AMOS (v.18,SPSS Inc. Chicago, IL).


264


gesting that no item detracts from the reliability ofthe measure. Additionally, the Composite Reliabi -lity coefficient41,42 of 0.92 indicates excellent relia-bility34,41,42,49.

Factor AnalysisA factor analysis of the PSEQ in the original scaledevelopment sample resulted in a single factor thataccounted for 59% of the variance. This result hasbeen replicated in other samples of patients fromBrazil14 and China12. We used a confirmatory factoranalysis, using maximum likelihood to estimatemodel parameters, to determine the fit of a singlefactor model. Four of the seven combined fit indices for the CFA supported a one-factor solutionwith acceptable fit. However, the fitness quality of the one-factor solution appeared somewhat

limi ted in our sample [χ2(35) = 155.58 (p<0.001);χ2/df = 4.44; CFI = 0.83; PCFI = 0.65; GFI = 0.84;PGFI = 0.54; RMSEA = 0.14 (p<0.001); ECVI = 1.15](Figure 1).

Inspection of P-PSEQ items suggests that someitems have very similar content, which could po-tentially explain the reduced fitness levels for theone-factor solution. For example, Item 2 (“I can domost household chores (e.g. tidying-up, washingdishes, etc.), despite the pain”) and Item 5 (“I cando some form of work, despite the pain. (“work” in-cludes housework, paid and unpaid work)”) ap-pear to assess a very similar domain, as do Item 8(“I can still accomplish most of my goals in life,des pite the pain”) and Item 9 (“I can live a normallifestyle, despite the pain”). Based on an inspectionof the modification indexes, specific error terms

Fi gu re 1. Confirmatory Factor Analysis: Initial Model χ2(35) = 155.58 (p<0.001); χ2/df = 4.44; CFI = 0.83; PCFI = 0.65; GFI = 0.84; PGFI = 0.54; RMSEA = 0.14(p<0.001); ECVI = 1.15

Fi gu re 2. Confirmatory Factor Analysis: Final Modelχ2(33) = 66.95 (p<0.001); χ2/df = 2.03; CFI = 0.95; PCFI = 0.70; GFI = 0.93; PGFI = 0.56; RMSEA = 0.08(p=0.05); ECVI = 0.65


265


were correlated sequentially, which resulted in anew model (Figure 2) that maintained all the itemsof the original P-PSEQ.

After taking into account the error term correla-tions, the combined fit indices for the CFA, supportthe one factor solution hypothesized [χ2(33) = 66.95(p<0.001); χ2/df = 2.03; CFI = 0.95; PCFI = 0.70; GFI = 0.93; PGFI = 0.56; RMSEA = 0.08 (p=0.05);ECVI = 0.65], with six of the seven combined fit in-dices for the CFA supporting this solutions, withacceptable to good fit. This new model revealed agoodness of fit significantly hi gher than the initialmodel [χ2(33) = 66.95 (p < 0.001), and ECVI conside -rably different: 1.15 vs. 0.65].

Correlational AnalysisTable IV presents the Pearson correlation coeffi-cients computed between the P-PSEQ score andthe criterion variables. As hypothesized, statisti-cally significant negative associations were foundbetween the self-efficacy score and pain intensity[ranging between -0.27 and -0.32, p < 0.01], pain in-terference [r = -0.41, p < 0.01], anxiety [r = -0.39, p < 0.01] and depression [r = -0.55, p < 0.01]. More-over, a statistically significant positive associationwas found between the P-PSEQ score and the SF-12Physical Health score [r = 0.51, p < 0.01] and SF-12Mental Health score [r = 0.46, p < 0.01]. All of the sig-nificant associations were in the hypothesized di-

rections and showed magnitudes that were withinthe anticipated ranges, with the exception of anxie -ty, which was slightly lower than expected, althougheven for this criterion a moderate association withself-efficacy in the hypothesized direction wasfound.

Discussion

Consistent with previous findings for other versionsof the PSEQ, our results provide strong support forthe reliability and validity of the Portuguese PSEQ.Its internal consistency (Cronbach’s alpha) isgreater than 0.80, indicating good reliability. More-over, its Composite Reliability coefficient of 0.92 in-dicates excellent reliability34,41,42,49. These values aresimilar to those found in the origi nal scale develop -ment sample and other transla ted versions of themeasure4,9,12,14. In addition, the results of a confir-matory factor analysis support a one factor solu-tion41-46,50 and provides further support for a highlevel of internal consistency. The correlation coef-ficients between P-PSEQ scale score and criterionmeasures are consistent with those found in previ-ous studies4,9,12,14,30, and support the validity of theP-PSEQ.

Consistent with previous research1,4,5,8-14, ourfindings support the importance of self-efficacy asa predictor of adjustment to chronic pain, given itssignificant associations with pain intensity, phy -sical and psychological functioning (pain interfe -rence, anxiety and depression), as well as with glo -bal quality of life and general health12,15. As a group,the findings from the current and pre vious studiessuggest that the concept and effects of pain self-ef-ficacy are similar across cultures, in line with thefindings available for the effects of self-efficacy be-liefs on performance17,51.

There are a number of study limitations thatshould be considered when interpreting the fin -dings. First, we employed a cross-sectional corre-lational design. As a result, we were unable to exa -mine the test-retest stability of the P-PSEQ. Also,such a design does not allow for an evaluation of thecausal effects of self-efficacy on functioning. Fur-ther research is needed to study the stability of P-PSEQ score over time, as well as to determine thepotential beneficial effects of interventions that in-crease pain self-efficacy beliefs. Second, the studysample was one of convenience. We were not ableto determine how representative the sample is of

Table IV. Correlations with Measures of Pain Intensity, Physical Dysfunction and PsychologicalFunctioning

Self-Efficacy Scale (P-PSEQ)Pain Intensity (NRS)

Maximum (last 24 hours) -0.27**

Minimum (last 24 hours) -0.32**

Average Pain -0.28**

Pain Interference (P-BPI) -0.41**

Physical Functioning (SF-12, PCS) 0.51**

Mental Health (SF-12, MCS) 0.46**

Anxiety (HADS-A) -0.39**

Depression (HADS-D) -0.55**

**p < 0.01 Note: P-PSEQ = Portuguese Pain Self-Efficacy Questionnaire; NRS = Numerical Rating Scale of pain intensity; P-BPI = PortugueseBrief Pain Inventory – Interference scale; HADS-A = Hospital Anxietyand Depression Scale – Anxiety scale; HADS-D = Hospital Anxietyand Depression Scale – Depression scale


266


the population of patients in Portugal with chro -nic musculoskeletal pain. Research is thereforeneeded to help establish the generalizability of thefindings. Third, we did not administer other mea-sures of self-efficacy to help establish the conver-gent validity of the P-PSEQ. Additional research isneeded to help determine the extent of overlap be-tween the P-PSEQ and other pain self-efficacymeasures.

Nevertheless, our findings provide support forthe reliability and validity of the Portuguese PSEQ,and suggest that the measure may be useful forunderstanding the importance of the self-efficacyconcept to pain and adjustment to pain in Por-tuguese patients with chronic pain, as well as forcross-cultural research examining similarities anddifferences in the role that self-efficacy plays in pa-tients from Portugal and patients from other coun-tries and cultures.

AcknowledgmentsM. Alexandra Ferreira-Valente has received PhD grantSFRH/BD/ 40956/2007 in the past year from the Por-tuguese Foundation for Science and Technology.

Correspondence toM. Alexandra Ferreira-Valente Rua 25 de Abril, n.º 5, Idanha – Belas 2605-119 Belas, Portugal Phone: (00351) 969082988 E-mail: [email protected]

References1. Arnstein P. The mediation of disability by self efficacy

in different samples of chronic pain patients. DisabilRehabil 2000;22:794-801.

2. Bandura A. Self-efficacy: toward a unifying theory ofbehavioural change. Psychol Rev 1977;84:191–215.

3. Geisser M, Robinson M, Miller Q, Bade S. Psychoso-cial factors and functional capacity evaluationamong persons with chronic pain. J Occup Rehabil2003;13:259-276.

4. Nicholas M. The pain self-efficacy questionnaire: Ta -king pain into account. Eur J Pain 2007;11:153-163.

5. Costa L, Maher C, McAuley J, Hancock M, Smeets R.Self-efficacy is more important than fear of move-ment in mediating the relationship between painand disability in chronic low back pain. Eur J Pain2011;15:213-219.

6. Denison E, Asenlöf P, Lindberg P. Self-efficacy, fearavoidance, and pain intensity as predictors of disabi -lity in subacute and chronic musculoskeletal pain pa-tients in primary health care. Pain 2004;111:245-252.

7. Saunders D. Coping with chronic pain: what can welearn from pain self-efficacy beliefs? J Rheumatol2004; 31:1032-1034.

8. Asenlöf P, Söderlund A. A further investigation of theimportance of pain cognition and behaviour in painrehabilitation: longitudinal data suggest disabilityand fear of movement are most important. Clin Re-habil 2010;24:422-430.

9. Asghari A, Nicholas M. An investigation of pain self--efficacy beliefs in Iranian chronic pain patients: apreliminary validation of a translated English-lan-guage scale. Pain Med 2009;10:619-632.

10. Denison E, Asenlöf P, Sandborgh M, Lindberg P. Mus-culoskeletal pain in primary health care: subgroupsbased on pain intensity, disability, self-efficacy, andfear-avoidance variables. J Pain 2007;8:67-74.

11. Keefe F, Rumble M, Scipio C, Giordano L, Perri L. Psy-chological aspects of persistent pain: current state ofthe science. J Pain 2004;5:195-211.

12. Lim H, Chen P, Wong T, et al. Validation of the Chi-nese version of pain self-efficacy questionnaire.Anesth Analg 2007;104:918-923.

13. Rahman A, Ambler G, Underwood M, Shipley M. Im-portant determinants of self-efficacy in patients withchronic musculoskeletal pain. J Rheumatol2004;31:1187-1192.

14. Sardá J, Nicholas MK, Pimenta CAM, Asghari A. Pain--related self-efficacy beliefs in a Brazilian chronicpain patient sample: A psychometric analysis. StressHealth 2007;23:185–190.

15. Börsbo B, Gerdle B, Peolsson M. Impact of the inte -raction between self-efficacy, symptoms and catas-trophising on disability, quality of life and health inwith chronic pain patients. Disabil Rehabil 2010;32:1387-1396.

16. Bandura A. Social foundations of thought and action:a social cognitive theory. New Jersey: EnglewoodCliffs, 1986.

17. Scholz U, Gutiérrez-Doña B, Sud S, Schwarzer R. Isgeneral self-efficacy a universal construct? Psycho-metric findings from 25 countries. Eur J Psychol As-sess 2002;18:242-251.

18. Turner J, Ersek M, Kemp C. Self-efficacy for mana -ging pain is associated with disability, depression,and pain coping among retirement community resi-dents with chronic pain. J Pain 2005;6:471-479.

19. Brown G, Nicassio P. The development of a question-naire for the assessment of active and passive copingstrategies in chronic pain patients. Pain 1987;31:53--65.

20. Kratz A, Molton I, Jensen M, Ehde D, Nielson W. Fur-ther evaluation of the motivational model of painself-management: coping with chronic pain in multi-ple sclerosis. Ann Behav Med 2011; 41:341-400.

21. Molton I, Jensen M, Nielson W, Cardenas D, Ehde D.A preliminary evaluation of the motivational modelof pain self-management in persons with spinal cordinjury-related pain. J Pain 2008;9:606-612.

22. Mueller A, Hartmann M, Mueller K, Eich W. Valida-tion of the arthritis self-efficacy short-form scale inGerman fibromyalgia patients. Eur J Pain 2003;7:163--171.


267


23. Adams J, Williams A. What affects return to work forgraduates of a pain management program withchronic upper limb pain? J Occ Rehab 2003;13:91–106.

24. Asghari A, Nicholas M. Pain self-efficacy beliefs andpain behaviour: a prospective study. Pain 2001;94:85–100.

25. Cohen M, Nicholas M, Blanch A. Medical assessmentand management ofwork-related low back or neck-arm pain: more questions than answers. J Occ HealthSafety, Aust New Zealand 2000;16:307–317

26. Dehghani M, Sharpe L, Nicholas M. Modification ofattentional biases in chronic pain patients: a prelimi-nary study. Eur J Pain 2004;8:585–594.

27. Estlander A, Vanharanta H, Moneta G, Kaivanto K.Anthropmetric variables, self-efficacy beliefs, andpain and disability ratings on the isokinetic perfor-mance of low back pain patients. Spine 1994;19:941–947.

28. Frost H, Klaber Moffett J, Moser J, Fairbank J. Evalua-tion of a fitness programme for patients with chroniclow back pain. Brit Med J 1993;310:151–154.

29. Gibson L, Strong J. The reliability and validity of ameasure of perceived functional capacity for work inchronic back pain. J Occ Rehab 1996;6:159–175.

30. Nicholas M, Asghari A. Investigating acceptance inadjustment to chronic pain: is acceptance broaderthan we thought? Pain 2006;124:269-279.

31. Watson P, Booker C, Main C. Evidence for the role ofpsychological factors in abnormal paraspinal activityin patients with chronic low back pain. J MusculoskelPain 1997;5:41–56.

32. Williams A, Nicholas M, Richardson P, Pither C,Justins D, Chamberlain J. Evaluation of a cognitivebehavioural programme for rehabilitating patientswith chronic pain. Brit J Gen Pract 1993;43:513–518.

33. Williams A, Richardson P, Nicholas M, Pither C, Har -ding V, Ralphs J. Inpatient versus outpatient painmanagement: results of a randomised controlled trial. Pain 1996;66:13–22.

34. Nunnally J, Bernstein I. Psychometric theory, 3rdedn. New York: Mcgraw-Hill;1994.

35. Jensen M. The validity and reliability of pain mea-sures in adults with cancer. J Pain 2003;4: 2-21.

36. Azevedo L, Pereira A, Dias C, et al. Tradução, adap-tação cultural e estudo multicêntrico de validação deinstrumentos para rastreio e avaliação do impacto dador crónica. Dor 2007;15:6-37.

37. Cleeland C, Ryan K. Pain assessment: global use ofthe Brief Pain Inventory. Ann Acad Med Singapore1994;23:129-138.

38. Ferreira-Valente M, Pais-Ribeiro J, Jensen M. Pain-re-lated interference in daily life: Validation of a Por-tuguese version of the Brief Pain Inventory Interfe -rence Scale. In: Cruz F, Petrus J, eds. Saúde, Cultura eSociedade: Actas do 5.º Congresso Internacional.Viseu: AGIR, 2010:164-181.

39. Pais-Ribeiro J. O importante é a saúde: estudo deadaptação de um instrumento para avaliar o estadode saúde. Lisboa: Fundação Merck Sharp & Dohme,2005.

40. Pais-Ribeiro J, Silva I, Ferreira T, Martins A, Meneses,R, Baltar M. Validations study of a Portuguese versionof the Hospital Anxiety and Depression Scale. Psy-chol Health Med 2007;12:225-237.

41. Fornell C, Larcker D. Evaluating SEM with unob-served variables and measurement error. J MarketingRes 1981;18:39-50.

42. Marôco J. Análise de equações estruturais: funda-mento teóricos, software e aplicações. Pêro Pinheiro:ReportNumber, 2010.

43. Arbuckle L. Amos 17 users’s guide. Chicago: IL: SPSS,2008.

44. Wheaton B. Assessment of fit in over-identified mo -dels with latent variables. Soc Methods Res 1987;16:118-154.

45. Blunch N. Introduction to structural equation mo -delling using SPSS and AMOS. London: SAGE, 2008.

46. Mulaik S, James L, Van Alstine J, Bennet N, Lind S,Stilwell C. Evaluation of goodness-of-fit indices forstructural equation models. Psychol Bull 1989;105:430-445.

47. Tonkin L. The pain self-efficay questionnaire. (App-saisal: Clinimetrics) Aust J Physiother 2008;54:77.

48. Nicholas M, Asghari A, Blyth F. What do the numbersmean? Normative data in chronic pain measures.Pain 2008;134:158-173.

49. Pais-Ribeiro J. Metodologia de investigação em psi-cologia e saúde, 2nd edn. Porto: Livpsic;2008.

50. Bentler P, Bonett, D. Significance tests and goodness-of-fit in the analysis of covariance structures. PsycholBull 1980;88:588-606.

51. Oettingen, G. Cross-cultural perspectives on self-effi-cacy. In Bandura A, ed. Self Efficacy in changingsocie ties. New York: Cambridge Univsersity Press,1995:149-176.


268

p r át i c a c l í n i c a

p h y s i o t h e r a p y i n h i p a n d k n e e

o s t e o a r t h r i t i s : d e v e l o p m e n t o f a

p r a c t i c e g u i d e l i n e c o n c e r n i n g i n i t i a l

a s s e s s m e n t , t r e at m e n t a n d e va l u at i o n

W.F.H. Peter1,2, M.J. Jansen3, E.J. Hurkmans4, H. Bloo5, L.M.M.C.J. Dekker-Bakker6, R.G. Dilling7, W.K.H.A. Hilberdink7,

C. Kersten-Smit8, M. de Rooij3, C. Veenhof9, H.M. Vermeulen10, I, de Vos11, J.W. Schoones12, T.P.M. Vliet Vlieland4,13

1. Department of Rheumatology, Leiden University Medical Cen-

ter (LUMC), Leiden, The Netherlands

2. Reade, center of rehabilitation and rheumatology (formerly Jan

van Breemen Institute), Amsterdam, The Netherlands

3. Center for Evidence Based Physiotherapy (CEBP), University of

Maastricht, Maastricht, The Netherlands

4. Dept of Rheumatology, LUMC, Leiden, The Netherlands

5. Veenendaal en Roessingh Research & Development, Enschede,

The Netherlands

6. Physiotherapy private practice, Amstelveen, The Netherlands

7. Paramedical Center for Rheumatology and Rehabilitation,

Groningen, The Netherlands

8. Department of Physiotherapy, St. Maartenskliniek, Nijmegen,

The Netherlands

9. Netherlands Institute for Health Services Research, Utrecht,

The Netherlands

10. Department of Physiotherapy, LUMC, Leiden, The Netherlands

11. Exercise therapy private practice, Leiden, The Netherlands

12. Walaeus Library, LUMC, Leiden, The Netherlands

13. Dept of Orthopaedics, LUMC, Leiden, The Netherlands

Funding: This study was financially supported by the Royal Dutch

Society of Physiotherapy (KNGF), Amersfoort, The Netherlands.

Results: In total 11 topics were selected. For the ini-tial assessment, three recommendations were for-mulated, pertaining to history taking, red flags, andformulating treatment goals. Concerning treatment,7 recommendations were formulated; (supervised)exercise therapy, education and self ma na gementinterventions, a combination of exercise and man-ual therapy, postoperative exercise therapy and tap-ing of the patella were recommended. Balneother-apy and hydrotherapy in HKOA, and thermothera-py, TENS, and Continuous Passive Motion in kneeOA were neither recommended nor discouraged.Massage therapy, ultrasound, electrotherapy, elec-tromagnetic field, Low Level Laser Therapy, preop-erative physiotherapy and education could not berecommended. For the evaluation of treatmentgoals the following measurement ins truments wererecommended: Lequesne index, Western Ontarioand McMaster Universities osteoarthritis index, Hipdisability and Osteoarthritis Outcome Score andKnee injury and Osteoarthritis Outcome Score, 6-minute walktest, Timed Up and Go test, PatientSpecific Complaint list, Visual Analoge Scale forpain, Intermittent and Constant OsteoArthritis PainQuestionnaire, goniometry, Medical ResearchCouncil for strength, handheld dynamometer. Conclusions: This update of a Dutch physiothera-py practice guideline on HKOA included 11 recom-mendations on the initial assessment, treatmentand evaluation. The implementation of the guide-line in clinical practice needs further evaluation.

Keywords: Guideline; Osteoarthritis; Physiothera-py; ICF.

Introduction

The physiotherapist plays an important role in thehealth care process of the patients with hip and

Abstract

Background: An update of a Dutch physiotherapypractice guideline in Hip and Knee Osteoarthritis(HKOA) was made, based on current evidence andbest practice.Methods: A guideline steering committee, com-prising 10 expert physiotherapists, selected topicsconcerning the guideline chapters: initial assess-ment, treatment and evaluation. With respect totreatment a systematic literature search was per-formed using various databases, and the evidencewas graded (1-4). For the initial assessment andevaluation mainly review papers and textbookswere used. Based on evidence and expert opinion,recommendations were formulated. A first draft ofthe guideline was reviewed by 17 experts from dif-ferent professional backgrounds. A second draftwas field-tested by 45 physiotherapists.


269

w.f.h. peter e col.

knee osteoarthritis and could be recommended,based on evidence in literature.

In 2001 theKNGF Guideline for physiotherapy inpatients with Hip and Knee Osteoarthritis (HKOA)of the Royal Dutch Society for Physiotherapy wasdeveloped.

A revision was desirable, as since 2001 there hasbeen a substantial increase of publications re-garding clinical studies and national1;2 and inter-national guidelines3-7 on HKOA. Moreover, the existing Dutch physiotherapyguideline did not in-clude recommendations on outcome measures,and did not provide recommendations on the pre-and postoperative management of patients un-dergoing hip or knee joint replacement. In addi-tion, the existing Dutch physiotherapy guidelinewas not using the International Classification ofFunctioning, Disability and Health (ICF)8 as aframework to systematically examine a patient’shealth status and to plan intervention strategiesand their evaluation by standardized outcomemeasures.

The aim of the current revision was to describeevidence-based physiotherapy for HKOA, inclu -ding initial assessment, interventions, and assess-ment of outcome, based on the ICF.

Methods

General methodology and Guideline Steering CommitteeThe revision of the guideline took place betweenSeptember 2008 and January 2010, following na-tional international methods for guideline deve -lopment and implementation9. The guideline wasdeveloped by a Guideline Steering Committeecomprising 10 expert physiotherapists. Based onthe existing Dutch physiotherapy guideline onHKOA and relevant umbrella reviews, systematicreviews and guidelines published since 2001, twomembers (WP and TVV) proposed a preliminarylist of topics to the Guideline Steering Committee.During a consensus meeting, 11 topics (3 for his-tory taking and examination, 7 for treatment (in-terventions) and 1 for outcome measures) were se-lected.

Step 1: Literature searchA literature search was performed up tot June 2009in the MEDLINE, EMBASE, CINAHL, PEDro, Webof Science and Cochrane Library databases to

identify systematic reviews, meta-analysis, andrandomized controlled trials (RCTs). The centralsearch strategy ‘Osteoarthritis’ (MESH) was com-bined with ‘Hip’ and “Knee’ and other MESH-hea -dings and/or free text words such as ‘physiothera-py’, ‘physical therapy’ (MESH), ‘physical therapymodalities’ (MESH), ‘exercise therapy’, ‘education’,and ‘self management’(MESH). Studies were se-lected if sufficient data were reported with regardto the physiotherapy treatment of HKOA patients.In case no systematic review or meta-analysis wasfound, RCTs were identified and selected for thetherapeutic process. The quality of the RCTs wasjudged by two independent evaluators (WP andMJ) by using Delphi criteria10. Textbooks, reviewarticles, umbrella review articles, and currentguidelines on other, related conditions.

With respect to the literature on examinationand assessment, in addition to the systematic lite -rature search, textbooks, review articles, and cur-rent guidelines on other, related conditions wereused.

Step 2: Categorizing evidence The selected literature was critically appraised byassessing the type and quality of the study design.Evidence was graded according to the EBRO (Evi-dence Based Recommendation Development) (seeTable I), which is in line with international classi-fication schemes11, such as the NICE (National Ins -titute of Clinical Effectiveness) approach. EBRO isan initiative of the Dutch Cochrane Center and theDutch Institute for Healthcare Improvement(CBO), a member of the Guidelines InternationalNetwork (GIN)12.

Step 3: Strength of recommendationsBy means of five consensus meetings and eightfeedback rounds of the Guideline Steering Com-mittee, recommendations were formulated andtheir strength graded A–D, based on the categoryof efficacy evidence (Table I).

Step 4: Guideline review processThe first draft of the guideline was reviewed by aGuideline Review Committee, comprising 17 per-sons from various professional backgrounds wasinstituted, including rheumatologists, an ortho-pedic surgeon, rehabilitation specialists, generalpractitioners, and representatives of the DutchArthritis Foundation and the Arthritis Patient Or-ganization. After adaptation, the second draft of


270

the dutch physiotherapy guideline on hip and knee osteoarthritis

the guideline was reviewed and pilot tested by 45physiotherapists. Among them 15 were specializedand members of an arthritis network. Almost all ofthe physiotherapists agree with the content. Someminor comments concerning the feasibility of themeasurement instruments, including lack of timeand space to perform are taken into account in theimplementation process after publication of theguideline.

Results

I. Initial assessmentIn the Netherlands, physiotherapy can be accessedwith or without a referral from a doctor (also called“direct access”).

The initial assessment comprises history ta king,physical examination and analysis. History takingand physical examination are performed to get acomprehensive overview of the patient’s healthstatus. This assessment includes screening for redflags. The doctor must be consulted in case of a redflag after deliberation with the patient. With theanalysis, the patient’s main limitations and im-pairments are prioritized, and treatment goals anda treatment plan are formulated, and in close col-laboration with the patient, treatment goals areset, with the focus on limitations of activity andres triction in participation.

The total initial assessment process is describedin Figure 1.

Clinical question 1: In which way the patient’shealth status can be assessed?RECOMMENDATION 1:• The physiotherapist should assess the patient’s

health status primarily in terms of activity limi -tations and participation restrictions (level 4).

• In addition, the therapist may also assess im-pairments of body function and structure, aswell as personal and environmental factors, in-sofar as these relate to the limitations and res -trictions (level 4). An overview of the most relevant health pro -

blems in HKOA patients was made, based on theshort version of the International Classification ofFunctioning, Disability and Health (ICF) Core Setfor Osteoarthritis8, supplemented with clinical re -le vant items, best practiced based, and completedwith a number of personal factors (Figure 2). Thisoverview is recommended to be used for the set-ting of treatment goals, the formulation of thetreatment plan and the evaluation.

Clinical question 2: Which contraindications forphysiotherapy should be taken into account inpatients with HKOA?RECOMMENDATION 2: PHYSIOTHERAPISTS SHOULD

EVA LUATE THE PRESENCE OF “RED FLAGS” (LEVEL 4).The following specific red flags in HKOA patientswere defined:• A warm, swollen (red) knee joint • A swelling in the groin• Severe blockade of the knee joint

Table I. From scientific evidence and expert opinion to recommendations according to the EBRO (Evidence Based Recommendation Development), which is in line with international classification schemes,such as the NICE approach.

Level of evidence 1 One A1 study or at least two A2 studies

2 One A2 study or at least two B studies

3 One B or multiple C studies

4 Expert opinion

Grades of A1 Meta-analyses (systematic reviews), which include at least two Randomized

recommendation Controlled Trials at quality level A2 that show consistent results between studies

A2 Randomized Controlled Trials of a good methodological quality (randomized

double blind controlled studies) with sufficient power and consistency

B Randomized Controlled Trials of a moderate methodological quality of with

insufficient power, or non- randomized, cohort of patient-control group study

involving intergroup comparisons

C Patient series

D Expert opinion


271

w.f.h. peter e col.

• (Extreme) pain at rest• And in the presence of one or more joint re-

placement prostheses: • Fever• Infection• And inexplicable extreme pain in hip or knee joint.

Clinical Question 3: How does the physiothera-pist set treatment goals?RECOMMENDATION3: BASEDONTHE INFORMATIONOBTAI -NED IN THE INITIAL ASSESSMENT, IN COOPERATION WITH

THE PATIENT AND ACCORDING THE ICF, THE PHYSIOTHE -RAPIST SHOULDDEFINETHETHERAPEUTICGOALS (LEVEL4).

Based on of the description ofthe health status and the pre -sence of barriers and facilita-tors, individual treatment goalsshould be defined. Goal settingis a shared process between thephysiotherapist and the patient.Treatment goals are set in termsof the ICF, with the focus on li -mi tations of activities and re-striction in participation.

Goals should be formulatedaccording to the SMART princi-ples (specific, measurable, achie -vable, realistic, and timed)13, forexample: being able to walk 800meters (from home to the super-market and back) two times aweek in six weeks.

II. InterventionsWith respect to the literaturesearch concerning the thera-peutic process, 22 systematic re-views and 74 RCTs (published af-ter these reviews) were selected.

Clinical question 4: Whichphysiotherapy interventionshould or should not be givenin HKOA?RECOMMENDATION4: (SUPERVISED)EXERCISE THERAPY AIMED AT REDU -CING PAIN AND IMPROVING PHYSICAL

FUNCTIONING SHOULD BE APPLIED

DURINGTHE PHYSIOTHERAPYTREAT-MENTOFHKOA PATIENTS (LEVEL1). Based on the literature exerci sesare recommen ded14-18, but no

specific intensity of exercises could be defined19.However, although there is a lack of evidence con-cerning the optimal type of exercises and their in-tensity, most research pertained to programs in-cluding aerobic and/or muscle strengthening exer -cises, and possible combined with ROM and func-tional exercises.

In previously published international multidis-ciplinary guidelines and a Dutch multidisciplinaryguideline in HKOA management exercise therapyis recommended1. There are no recommendationson intensity, specific exercise forms, number oftreatment or follow up sessions, and supervision.

Referralby GP orspecialist

(Supplementary)History taking

Examination

Measurementinstruments, atleast:Patient-SpecificComplaints(PSC)Timed Up and

Analysis

Directaccessscreening Expressed care requirement, pattern recognition, red flags, physiotherapy indicated?General information, incl.:• diagnosis• referral indication• patient’s care requirement• patient’s need for information Red flags:• unexplained raised temperature, swelling and redness of the knee joint (bacterial infection?)• unexplained (severe) pain in hip and/or knee joint• swelling in groin (malignancy?)• severe blocking of the knee joint• (severe) pain at rest and swelling without trauma (malignancy?)If patient has one or moreprosthetic joints:• fever• infection• unexplained severe pain in hip and/or kneeBody/functions/structures e.g.:proprioception pain,mobility, stability,muscle power,muscle endurance,alignement, muscularatrophy, hypertoniaEnvironmental factorse.g.:home adaptations and aidsfor ADL, work or sport,facilities, relatives, friends,care providers, clleagues

• presence of factors that may or may not be (directly or indirectly) modifiable by physiotherapy• presence of facilitators and barriers for functional recovery• Is a physiotherapy intervention an appropriate strategy to accomplish the intended therapeutic goals?

Personal factors e.g.:co morbidity, lifestyle,character, experiences, self-efficacy, age, sex, ethnicity,profession, socialbackground and diseaseperception

Activities e.g.:transferringoneself, walking,standing, sitting,moving about,washing oneself,dressing andtoileting

Participatione.g.:Remunerative ornon-remunerativeemployment,community life,recreation,

Relevant medical data, healthstatus, incl.• radiographic abnormalities of joints• co morbidity• medication use• prognosis, if applicable

ICF

Referralby GP orspecialist

(Supplementary)History taking

Examination

Measurementinstruments, atleast:Patient-SpecificComplaints(PSC)Timed Up and

Analysis

Directaccessscreening

Expressed care requirement, pattern recognition, red flags, physiotherapy indicated?

General information, incl.:• diagnosis• referral indication• patient’s care requirement• patient’s need for information

Red flags:• unexplained raised temperature, swelling and redness of the knee joint (bacterial infection?)• unexplained (severe) pain in hip and/or knee joint• swelling in groin (malignancy?)• severe blocking of the knee joint• (severe) pain at rest and swelling without trauma (malignancy?)

If patient has one or moreprosthetic joints:• fever• infection• unexplained severe pain in hip and/or knee

Body/functions/structures e.g.:

proprioception pain,mobility, stability,muscle power,muscle endurance,alignement, muscularatrophy, hypertonia

Environmental factorse.g.:home adaptations and aidsfor ADL, work or sport,facilities, relatives, friends,care providers, clleagues

• presence of factors that may or may not be (directly or indirectly) modifiable by physiotherapy• presence of facilitators and barriers for functional recovery• Is a physiotherapy intervention an appropriate strategy to accomplish the intended therapeutic goals?

Personal factors e.g.:co morbidity, lifestyle,character, experiences, self-efficacy, age, sex, ethnicity,profession, socialbackground and diseaseperception

Activities e.g.:

transferringoneself, walking,standing, sitting,moving about,washing oneself,dressing andtoileting

Participatione.g.:

Remunerative ornon-remunerativeemployment,community life,recreation,

Relevant medical data, healthstatus, incl.• radiographic abnormalities of joints• co morbidity• medication use• prognosis, if applicable

ICF

Fi gu re 1. Overview of the initial assessment process.


272


Body functions/structures• proprioception (b260)*• sensation of pain (b280)• mobility of joints (b710)• stability of joints (b715)• muscle power (b730)• muscle endurance (b740)• structure of lower extremity (s750) – e.g. alignment• additional musculoskeletal structures related to movement (s770) – e.g. muscular atrophy, hypertonia

Environmental factors• Products and technology for personal use in daily living (e115) – e.g. home adaptations and aids• Products and technology for employment (e135) – e.g. special chair at work• Products and technology for culture, recreation, and sport (e140)*• Design, construction, and building products and technology of buildings for public use (e150) – e.g. elevator• Immediate family (e310), friends, caregivers, social environment, employer,colleagues• Health services, systems, and policies (e580) – e.g. care providers, care institutions, health insurance

Personal factors*• age• sex• ethnicity• social background• profession• past and present experiences comorbidity (e.g. other articular disorders, heart and lung disorders, diabetes mellitus)• character• lifestyle• coping and self-efficacy• disease perception

Activities• transferring oneself (d420)* – bending down, squatting, kneeling• sitting down and getting up from bed or chair – getting in and out of a car – lying down, turning over in bed• walking (d450)• standing up or remaining seated for long period moving around (d455) – ascending and descending stairs – cycling, driving – traveling by bus/train/tram• washing oneself (d510)• toileting (d530)• dressing (d540)

Disease/disorderosteoarthritis of the hipand/or knee

Participating (social context) • remunerative employment (d850)• non-remunerative employment (d855)*• community life (d910)• recreation, leisure, and sport (d920)

Body functions/structures• proprioception (b260)*• sensation of pain (b280)• mobility of joints (b710)• stability of joints (b715)• muscle power (b730)• muscle endurance (b740)• structure of lower extremity (s750) – e.g. alignment• additional musculoskeletal structures related to movement (s770) – e.g. muscular atrophy, hypertonia

Environmental factors• Products and technology for personal use in daily living (e115) – e.g. home adaptations and aids• Products and technology for employment (e135) – e.g. special chair at work• Products and technology for culture, recreation, and sport (e140)*• Design, construction, and building products and technology of buildings for public use (e150) – e.g. elevator• Immediate family (e310), friends, caregivers, social environment, employer,colleagues• Health services, systems, and policies (e580) – e.g. care providers, care institutions, health insurance

Personal factors*• age• sex• ethnicity• social background• profession• past and present experiences comorbidity (e.g. other articular disorders, heart and lung disorders, diabetes mellitus)• character• lifestyle• coping and self-efficacy• disease perception

Activities• transferring oneself (d420)* – bending down, squatting, kneeling• sitting down and getting up from bed or chair – getting in and out of a car – lying down, turning over in bed• walking (d450)• standing up or remaining seated for long period moving around (d455) – ascending and descending stairs – cycling, driving – traveling by bus/train/tram• washing oneself (d510)• toileting (d530)• dressing (d540)

Disease/disorderosteoarthritis of the hipand/or knee

Participating (social context) • remunerative employment (d850)• non-remunerative employment (d855)*• community life (d910)• recreation, leisure, and sport (d920)

Fi gu re 2. Overview of the most relevant health problems in Hip and Knee Osteoarthritis according to the InternationalClassification of Functioning, Disability and Health (ICF) Core Set for Osteoarthritis (short version supplemented withclinically relevant items (*), based on expert opinion).

In addition to the abovementioned recommen-dation on exercise therapy, there was overall con-sensus within the Guideline Steering Committeethat exercises should comprise at least musclestrengthening exercises, exercises to improve aero -bic capacity, functional exercises, and gait training,either as a single treatment or combined with eachother, depending on treatment goals. The exerciseprogram must have a focus on limitations of acti -vities and restrictions in participation. In some ca -ses the exercise therapy could be adjusted to indi-vidual treatment goals. For example joint proprio-ception and balance training20 or a behavioral

graded activity strategy21. Decreasing the frequen-cy of treatment sessions at the end of the treat-ment is needed to help the patient to achieve anindependent adequate level of physical activity. Toimprove the transition to recreational or sport acti -vities the HKOA patient must be guided by thephysiotherapist.

RECOMMENDATION 5: PHYSIOTHERAPISTS SHOULD PRO-VIDE EDUCATION AND PROMOTE ADEQUATE SELF MANAGE-MENT IN PATIENTSWITH HKOA (LEVEL 2). Based on literature education and promotion ofade quate self management are recommended, pro-


273

w.f.h. peter e col.

vided in combination with exercise therapy (level2)22-27. Because of the variety of interventions in theliterature, it is unclear which content of edu cationor self management intervention is best in HKOA.

In international multidisciplinary guidelinesand a Dutch multidisciplinary guideline in HKOAmanagement education and self management isrecommended as an effective intervention as anadjunction to exercise therapy 1,3-5.

The Guideline Steering Committee recommendthat the content of the intervention comprise thefollowing items: knowledge and understanding ofHKOA; the consequences of HKOA on functions, ac-tivities and participation; the relation between themental and physical load and carrying capacity; theway to deal with complaints caused by HKOA; an ac-tive and healthy lifestyle (moving, nurturing, over-weight); change in moving behavior; joint protec-tion and the use of (walking) aids (le vel 4).

The physiotherapist needs to support the pa-tient in remaining a healthy physical activity level.

RECOMMENDATION 6: EXERCISE THERAPY SHOULD BE

COMBINED WITH MANUAL THERAPY IN CASES OF PAIN AND

REVERSIBLE LIMITATION IN JOINT MOBILITY (LEVEL 2).If there is pain in combination with a limitation injoint mobility it is recommended to add manualtherapy to exercise therapy (level 2)28-32. In interna-tional multidisciplinary guidelines and a Dutchmultidisciplinary guideline in HKOA management,manual therapy is not mentioned or classified byexercise therapy.

In the Netherlands it is common to use the com-bination of exercise therapy with manual therapy.Within the Guideline Steering Committee therewas consensus that manual therapy could be con-sidered as a preparation for exercise therapy inHKOA in case of pain and a reversible limitation injoint mobility. The manual therapy should com-prise manipulation, manual traction, and musclestretching exercises in Hip OA. In Knee OA ante -rior/posterior mobilizations of the tibia-femoraljoint and the patella, and muscle stretching exer-cises could be considered.

RECOMMENDATION7: EXERCISETHERAPYAIMEDAT IMPRO -VING PHYSICAL FUNCTIONING SHOULD BE APPLIED AFTER

HIP AND KNEE JOINT REPLACEMENT SURGERY (LE VEL 2).Postoperative exercises are recommended in hipand knee joint replacement surgery and shouldcomprise muscle strengthening exercises and exer-cises focusing on functional activities (level 2)33-36.

No recommendations on postoperative exer-cises are given in international guidelines in HKOAmanagement. In a Dutch multidisciplinary guide-line on hip and knee OA, postoperative exercisetherapy is recommended1.

RECOMMENDATION 8: TAPING THE PATELLA SHOULD BE

ADJUSTED TO MUSCLE STRENGTHENING EXERCISES AND

EXERCISES FOCUSING ON FUNCTIONAL ACTIVITIES TO IN-CREASE PAIN IN PATELLO-FEMORAL OA (LEVEL 2).There is evidence to recommend taping in patel-lo-femoral OA37,38. In international and Dutchguidelines included no recommendations on ta -ping and patello-femoral OA. In the Netherlandsoften taping is used as a support to make it morepossible to do exercises in patello-femoral OA.

RECOMMENDATION 9: THE PROVISION OF HYDROTHERA-PY, BALNEOTHERAPY, THERMOTHERAPY, PREOPERATIVEPHYSIOTHERAPY IN HKOA, AND TRANSCUTANE ELECTRI-CALNEUROSTIMULATION (TENS) INKNEEOA , ANDCON-TINUOUS PASSIVE MOTION (CPM) IN POSTOPERATIVE

KNEE OA, CAN NEITHER BE RECOMMENDED NOR DIS-COURAGED (LEVEL 1, 4). There is conflicting evidence that hydrotherapy iseffective in HKOA (level 1)39-44. An internationalguideline (OARSI) recommends hydrotherapy inpatient with hip OA5.

In daily practice in the Netherlands hydrothera -py is used and experienced as a pleasant interven-tion by the patient. There was overall consensuswithin the Guideline Steering Committee that hy-drotherapy could be applied in case of severe painand no effect of alternative interventions as exer-cise therapy on land, medication or surgery. Hy-drotherapy could also be used as preparation forexercise therapy on land in cases with severe pain.

There is also conflicting evidence that bal-neotherapy is effective in HKOA (level 1)45-47. Norecommendations are made in international andDutch guidelines. In the Netherland it is no com-mon intervention, but in some countries Spa the -ra py has a benefit in HKOA patient’s physical enmental wellbeing.

There is some evidence that ice massage is ef-fective as a cold application in knee OA48. An in-ternational guideline (OARSI) is mentioning that insome circumstances warmth or could applicationscould be beneficial in relieving pain5. There wasoverall consensus within the Guideline SteeringCommittee that an application of cold could beconsidered if there is severe pain in knee OA. The


274


application of warmth could be considered aspreparation for exercise therapy in patients withsevere joint stiffness or difficulty in relaxing themuscles. The Guideline Steering Committee advi -ses against the use of local heat application in caseof active joint inflammation which sometimes occurs in knee OA (level 4).

There is conflicting evidence that TENS is effec-tive to relieve pain in knee OA (level 1)49;50. An in-ternational guideline recommends TENS for theshort term (OARSI) and a Dutch multidisciplinaryguideline1,5 recommend TENS to decrease pain andstiffness as a second choice if medication and exer -cises turned out to be not effective.

The Guideline Steering Committee suggests thatTENS could be considered as a support for exercisetherapy in individual cases with severe pain butnot as a first choice (level 4).

Concerning physiotherapy around joint re-placement surgery there is conflicting evidencethat CPM is effective after total knee surgery51-54.CPM is a common intervention after knee surgeryto increase knee joint mobility. There is lack of evi -dence after knee surgery to recommend CPM according a Dutch multidisciplinary guideline1.

The Guideline Steering Committee could notrecommend or advise against CPM (level 1).

Preoperative exercises could not be recom-mended based on current evidence (level 3)55-58.There are no recommendations mentioned in in-ternational guidelines on HKOA management. ADutch multidisciplinary guideline could not re -commend preoperative exercises1. But literatureindicates that a good functional status beforesurgery is a important predictor on postoperativerecovery. Within the Guideline Steering Commit-tee there was an overall consensus that preopera-tive exercises could be considered in cases of poorpreope rative status in patients with multiple comorbidity and other affected joints (level 4).

Finally preoperative education could be con-sidered according the Guideline Steering Com-mittee if there is much anxiety for the operation(level 4). The education should then be focused oninformation about the operation and the periodthe patient stays in the hospital.

RECOMMENDATION 10: THE PROVISION OF MASSAGE, UL-TRASOUND, ELECTROTHERAPY, ELECTROMAGNETIC FIELD

AND LOW LEVEL LASER THERAPY (LLLT) CAN NOT BE RE -COMMENDED IN HKOA (LEVEL 1, 2, 4).There is little evidence that massage is effective in

knee OA (level 2)59. In the Netherlands massage wasa common physiotherapy intervention. Nowadaysthere is no place for massage in the active treat-ment strategy for HKOA.

There is conflicting evidence for the use of ul-trasound in knee OA (level 2)60,61. The Health Coun-cil of the Netherlands (Gezondheidsraad) has ad-vised against the use of ultrasound, except for theapplication in patients with a tennis elbow. There-fore the Guideline Steering Committee decided notto recommend ultrasound.

For electrotherapy there is conflicting evidencefor the effectiveness in knee OA (level 3)49,50. Elec-trotherapy is not common in the Netherlands astreatment for knee OA. Based on the current evi-denced and best practice electrotherapy can not berecommended.

No evidence can be found to support the use ofelectromagnetic field in de treatment of HKOA (le -vel1)50,62,63.

There is evidence that LLLT is effective in de-creasing pain (level 1)50, but it is a very uncommonintervention in the Netherlands. Further there areother interventions that can be recommended todecrease pain why the Guideline Steering Commit-tee did not recommend LLLT in knee OA (level 4).

In international and Dutch guidelines there areno recommendations for the use of massage, ul-trasound, electrotherapy, electromagnetic field enLLLT in the treatment of HKOA1,3-7.

III. Assessment of outcomeFor the evaluation of treatment goals in HKOA pa-tients several measurement instruments are avai -la ble. Recommended measurement instrumentspertained to ICF chapters activities and participa-tion and body functions and structures and werechosen based on their psychometric properties: va-lidity, reproducibility, responsiveness as well asthere practical applicability. The latter included theavailability of a Dutch version must be available, nospecial training should be necessary and the mea-surement should have a good applicability in dailyclinical practice. The measurement instrumentsclassified according the ICF are shown in Figure 3.

Clinical question 5: Which measurement instru-ment should be used to evaluate treatment?RECOMMENDATION11: A COMBINATIONOFQUESTIONNAI -RES (PREFERABLY THE PATIENT SPECIFIC COMPLAINT LIST

(PSK)) AND PERFORMANCE TESTING (PREFERABLY THE

TIMEDUPANDGOTEST (TUG)) IS RECOMMENDEDTOUSE


275

w.f.h. peter e col.

Body functions and structures:• Visual Analogue Scale for pain • ICOAP• Lequesne Index• WOMAC• HOOS• KOOS • Goniometry• Hand Held dynamometry• MRC scale for strenght

Activities:• PSK• Lequesne Index• WOMAC • HOOS• KOOS • 6-minute walk test• Timed up and Go test

Participation (social context) in:• PSK• HOOS• KOOS

Environmental factors:• History taking Personal factors:• History taking

Disease:Hip and Knee Osteoarthritis

Body functions and structures:

• Visual Analogue Scale for pain • ICOAP• Lequesne Index• WOMAC• HOOS• KOOS • Goniometry• Hand Held dynamometry• MRC scale for strenght

Activities:

• PSK• Lequesne Index• WOMAC • HOOS• KOOS • 6-minute walk test• Timed up and Go test

Participation (social context) in:

• PSK• HOOS• KOOS

Environmental factors:

• History taking

Personal factors:

• History taking

Disease:Hip and Knee Osteoarthritis

Fi gu re 3. Measurement instruments in Hip and Knee Osteoarthritis according a ICF classification (some measurementinstruments are suitable in more than one ICF component).

PSK = Patient Specific Complaint list, ICOAP = Intermittent and Constant OsteoArthrtis Pain, WOMAC = Western Ontario and

McMaster Universities Osteoarthritis index, HOOS = Hip disability and Osteoarthritis Outcome Score, KOOS = Knee injury and

Osteoarthritis Outcome Score, MRC = Medical Research Council

point that the patient marks.Timed Up and Go (TUG) test The TUG test65,66

measures the time in seconds in which the patientstand up from a chair, walk three meters, turnaround, walk back and sit down on the chair. Thetest must take place in comfortable speed.

Other measurement instruments that are re -com mended in HKOA patients are shown in Figu -re 2. In this figure the connections between themeasurement instruments to the different com-ponents of the ICF are clarified.

For measuring pain there is a choice to use twodifferent scales: A Visual Analogue Scale (VAS) forpain67 is usually a horizontal line of 100 millime-ters. The VAS is filled in by the patient as describedat the PSK. If the pain is intermittent, which occurin HKOA patient the Intermittent and Constant Os-teoArthritis Pain (ICOAP)68 could be used. Thisquestionnaire is taken into account intermittentpain experience by the patient, for example in using pain medication by the patient.

For measuring strength the use of a handhelddynamometer67 is recommended or if that is notavailable, the Medical Research Council (MRC) forstrength69 is recommended as an alternative.

IN THE INITIAL ASSESSMENT AND EVALUATING TREATMENT

GOALS AND SHOULD HAVE THE FOCUS ON THE ICF COM-PONENT INWHICHTHEPATIENTPRESENTSHISCOMPLAINTS. The physiotherapists in the field prefer a recom-mendation for one or two best measurement ins -truments. Despite more measurement instru-ments are useful in daily practice depending ontreatment goals, the Guideline Steering Commit-tee prefer to recommend one questionnaire andone performance test. They were chosen primari -ly for their good applicability in daily practice:

Patient Specific Complaint list In the Nether-lands the PSK (Patiënt Specifieke Klachten) is de-veloped64 as an instrument to record patient spe-cific complaints. The patient has to choose thethree most limited activities from a list of activitiesin which patients can be limited because of HKOA.On a 100 mm visual analogue scale the degree oflimitation can be outlined by the patient for eachactivity. With on the left end “no limitation in theactivity” and on the right end “the activity is notfeasible” the patient express how the degree of limi -tation of the activity is by means of a vertical line.The score is determined by measuring the distancein millimeters from the left end of the line to the


276


The Range Of Motion (ROM) should be mea-sured by using goniometry70. A Measurement ins -trument to measure walking and aerobic capacityis the 6 minute walk test65,66. During the 6-minuteswalk test the patients have to walk 6 minutes at aself chosen walking speed and they have to try toovercome as much distance as possible, withoutrunning. The accomplished distance is the totaldistance at the end of the 6 minutes.

Finally to measure limitation in activities andres trictions in participation four different ques-tionnaires are recommended. The choice betweenthose four depends on the joint and the treatmentgoals. The Western Ontario and McMaster Univer-sities osteoarthritis index (WOMAC)71,72 measureslimitations in activities as well as pain and stiff-ness in HKOA patients. The Lequesne index 73 hasits focus on limitations in walking distance and

pain during walking in HKOA. The HOOS 74and theKOOS 75 ask besides limitation in activities also forrestrictions in participation in sports and recrea -tional activities and quality of life, respectively inHip OA and Knee OA.

Table II shows an overview of all recommenda-tions.

Discussion

This study describes the development of a physio-therapy (PT) specific guideline for the manage-ment of HKOA. This guideline is based on recentresearch evidence and expert opinion. It was de-veloped according to standardised procedures forformulating recommendations. The guideline des -cribes the process of initial assessment, including

Table II. Summary of recommendations and level of evidence

Initial assessment1. The physiotherapist should assess the patient's health status primarily in terms of activity limitations and

participation restrictions. In addition, the therapist may also assess impairments of body function and structure,

as well as personal and environmental factors, insofar as these relate to the limitations and restrictions (level 4).

2. Physiotherapists should evaluate the presence of “red flags” (level 4).

3. Based on the information obtained in the initial assessment, in cooperation with the patient and according the

ICF, the physiotherapist should define the therapeutic goals (level 4).

Interventions4. (Supervised) exercise therapy aimed at reducing pain and improving physical functioning should be applied during

the physiotherapy treatment of hip and knee osteoarthritis patients (level 1).

5. Physiotherapists should provide hip and knee osteoarthritis patients education and must promote adequate self

management (level 2).

6. Exercise therapy should be combined with manual therapy in cases of pain and reversible limitation in joint

mobility (level 2).

7. Exercise therapy aimed at improving physical functioning should be applied after hip and knee joint replacement

surgery (level 2).

8. Taping the patella should be adjusted to muscle strengthening exercises and exercises focusing on functional

activities to increase pain in patellofemoral OA (level 2).

9. The provision of hydrotherapy, balneotherapy, thermotherapy, preoperative physiotherapy in hip and knee

osteoarthritis, and Transcutane Electrical Neuro Stimulation (TENS) in knee OA , and Continuous Passive Motion

(CPM) in postoperative knee OA, can neither be recommended nor discouraged (level 1, 4).

10. The provision of massage, ultrasound, electrotherapy, electromagnetic field and low level laser therapy (LLLT)

can not be recommended in hip and knee osteoarthritis (level 1, 2, 4).

Assessment of outcome11. A combination of questionnaires (preferably the Patient Specific Complaint list (PSK)) and performance testing

(preferably the Timed Up and Go test (TUG)) is recommended to use in the initial assessment and evaluating

treatment goals and should have the focus on the ICF component in which the patient presents his complaints

(level 4).


277

w.f.h. peter e col.

history taking, physical examination, analysis, PTinterventions and various measurement instru-ments that can be used to evaluate treatment.

In contrast with other guidelines, this guidelinegives recommendations on initial assessment enevaluation of treatment. The ICF framework8 has acentral place in this guideline. An overview isadded concerning the ICF linked health relatedproblems and measurement instruments. Thislinking on the ICF is also been used in two recent-ly developed PT guidelines on hip osteoarthritis76

and meniscal and articular cartilage lesions of theknee77.

Another difference between this guideline andother (multidisciplanairy) guidelines on HKOA isthat the recommendations are formulated not onlybased on literature but also considerations fromdaily practice are playing an important role in for-mulating recommendations. For example: al-though there is evidence that laser therapy couldbe effective in knee OA, it is not a common inter-vention in the Netherlands and furthermore theNational Health Counsel (Gezondheidsraad) is notrecommending the use of laser in knee OA patients.Concerning other interventions (hydrotherapy andthermotherapy ao.) in which the evidence is some-times weak, the guideline steering committee de-cided that the intervention only could be conside -red in specific individual cases after good clinicalreasoning.

Among multidisciplinary guidelines ICSI HealthCare78 is giving annotations in the initial assess-ment. But in treatment they have a more passiveapproach since recommendations on electricaltherapy and massage were given for pain relief,while this guideline has a clearly active approachwithout recommendations on passive modalitieslike massage, electrotherapy, laser, ultrasound andelectromagnetic field.

Exercise, education and self management in-terventions are overall recommended in nationaland international multidisciplinary guidelines onHKOA. For exercises and manual therapy the re -commendations are comparable with those fromthe Ottawa panel79. Also TENS in knee OA is ove -rall recommended. But this guideline is more cau-tious based on recent evidence 49.

In contrast with other national2 and interna-tional multidisciplinary guidelines on HKOA3-7 thisguideline gives recommendations concerningphysical therapy treatment before and after totalhip or knee replacement in osteoarthritis. Only the

Dutch multidisciplinary CBO guideline1 comprisesome individual exceptions for pre-operative exercises based on expert opinion for example incase of worse physical status of the patient beforesurgery.

The MOVE consensus7 mentions contra-indi-cators and barriers for exercise. The Dutch PTguideline pre-empt this by formulating general enspecific red flags for HKOA. But these red flags arenot only concerning exercises but also PT treat-ment in general. Besides barriers also facilitatorswhich can influence outcome of treatment, aredes cribed.

Guidelines, recommendations and protocols onhip and knee will be available in many differentcountries, published or not. Discrepancies existbased on date (of publication) or the different na-tional usual method of treatment. Internationalcooperation between PT societies may be a fol-lowing step in consensus on a guideline for thetreatment of HKOA patients.

To facilitate the use of guidelines in daily prac-tice it is important to apply an implementationstrategy. Implementation studies with regard toother PT guidelines have shown that didactic edu -cation and passive dissemination strategies wereineffective80. Multifaceted interventions, interacti -ve education and clinical reminder systems havebeen shown to be more effective to implement PTguidelines81. In a following study a more effectiveimplementation strategy will be researched.

Correspondence toW.F.H.Peter, PTLeiden University Medical Center, Department of Rheumatology (C1-R)P.O. box 9600, 2300 RC Leiden, The NetherlandsE-mail: [email protected]

References1. CBO. Richtlijn Diagnostiek en Behandeling van heu -

p- en knie artrose. http://www cbo nl/thema/Richtli-jnen/Overzicht-richtlijnen/Bewegingsapparaat/2007.

2. Belo JN, Bierma-Zeinstra SMA, Raaijmakers AJ, Vander Wissel F, Opstelten W. Huisarts Wet. NHG-Stan-daard Niet-traumatische knieproblemen bij vol-wassenen, NHG Standaarden voor de huisarts. 51 ed.Houten: Bohn Stafleu van Loghum; 2008.

3. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bi-jlsma JW, Dieppe P, et al. EULAR Recommendations2003: an evidence based approach to the manage-ment of knee osteoarthritis: Report of a Task Force of


278


the Standing Committee for International ClinicalStudies Including Therapeutic Trials (ESCISIT). AnnRheum Dis 2003 62:1145-1155.

4. Zhang W, Doherty M, Arden N, Bannwarth B, BijlsmaJ, Gunther KP, et al. EULAR evidence based recom-mendations for the management of hip osteoarthri-tis: report of a task force of the EULAR Standing Com-mittee for International Clinical Studies IncludingTherapeutics (ESCISIT). Ann Rheum Dis 2005;64:669--681.

5. Zhang W, Moskowitz RW, Nuki G, Abramson S, Alt-man RD, Arden N, et al. OARSI recommendations forthe management of hip and knee osteoarthritis, PartII: OARSI evidence-based, expert consensus guide-lines. Osteoarthritis Cartilage 2008;16:137-162.

6. Roddy E, Doherty M. Guidelines for management ofosteoarthritis published by the American College ofRheumatology and the European League AgainstRheumatism: why are they so different? Rheum DisClin North Am 2003;29:717-731.

7. Roddy E, Zhang W, Doherty M, Arden NK, Barlow J,Birrell F, et al. Evidence-based recommendations forthe role of exercise in the management of os-teoarthritis of the hip or knee—the MOVE consensus.Rheumatology (Oxford) 2005;44:67-73.

8. Dreinhofer K, Stucki G, Ewert T, Huber E, Ebenbich-ler G, Gutenbrunner C, et al. ICF Core Sets for os-teoarthritis. J Rehabil Med 2004;44 Suppl:75-80.

9. MacDermid JC, Brooks D, Solway S, Switzer-McIntyreS, Brosseau L, Graham ID. Reliability and validity ofthe AGREE instrument used by physical therapists inassessment of clinical practice guidelines. BMCHealth Serv Res 2005;5:18.

10. Verhagen AP, de Vet HC, de Bie RA, Kessels AG, BoersM, Bouter LM, et al. The Delphi list: a criteria list forquality assessment of randomized clinical trials forconducting systematic reviews developed by Delphiconsensus. J Clin Epidemiol 1998;51:1235-1241.

11. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clini-cal guidelines: developing guidelines. BMJ 1999;318:593-596.

12. Burgers JS, van Everdingen JJ. Evidence-based guide-line development in the Netherlands: the EBRO plat-form. Ned Tijdschr Geneeskd. Ned Tijdschr Genee -kunde 2004;16:2057-2059.

13. Bovend’Eerdt TJ, Botell RE, Wade DT. Writing SMARTrehabilitation goals and achieving goal attainmentscaling: a practical guide. Clin Rehabil 2009;23:352--361.

14. Lim BW, Hinman RS, Wrigley TV, Sharma L, BennellKL. Does knee malalignment mediate the effects ofquadriceps strengthening on knee adduction mo-ment, pain, and function in medial knee os-teoarthritis? A randomized controlled trial. ArthritisRheum 2008;59:943-951.

15. Fransen M, McConnell S. Exercise for osteoarthritis

of the knee. Cochrane Database Syst Rev 2008;(4):CD004376.

16. Hernandez-Molina G, Reichenbach S, Zhang B,Lavalley M, Felson DT. Effect of therapeutic exercisefor hip osteoarthritis pain: results of a meta-analysis.Arthritis Rheum 2008;59:1221-1228.

17. Jan MH, Tang PF, Lin JJ, Tseng SC, Lin YF, Lin DH. Ef-ficacy of a target-matching foot-stepping exercise onproprioception and function in patients with kneeosteoarthritis. J Orthop Sports Phys Ther 2008;38:19--25.

18. Jan MH, Lin JJ, Liau JJ, Lin YF, Lin DH. Investigationof clinical effects of high- and low-resistance trainingfor patients with knee osteoarthritis: a randomizedcontrolled trial. Phys Ther 2008;88:427-436.

19. Mangione KK, McCully K, Gloviak A, Lefebvre I, Hof-mann M, Craik R. The effects of high-intensity andlow-intensity cycle ergometry in older adults withknee osteoarthritis. J Gerontol A Biol Sci Med Sci1999;54: M184-M190.

20. Diracoglu D, Aydin R, Baskent A, Celik A. Effects ofkinesthesia and balance exercises in knee os-teoarthritis. J Clin Rheumatol 2005;11:303-310.

21. Veenhof C, Koke AJA, Dekker J, Oostendorp RA, Bijls-ma JWJ, van Tulder MW, et al. Effectiveness of be-havioral graded activity in patients with osteoarthri-tis of the hip and/or knee: A randomized clinical trial. Arthritis & Rheumatism-Arthritis Care & Re-search 2006;55:925-934.

22. Maurer BT, Stern AG, Kinossian B, Cook KD, Schu-macher HR, Jr. Osteoarthritis of the knee: isokineticquadriceps exercise versus an educational interven-tion. Arch Phys Med Rehabil 1999;80:1293-1299.

23. Devos-Comby L, Cronan T, Roesch SC. Do exerciseand self-management interventions benefit patientswith osteoarthritis of the knee? A metaanalytic re-view. J Rheumatol 2006;33:744-756.

24. Tak E, Staats P, Hespen van A, Hopman-Rock M. TheEffects of an Exercise Program for Older Adults withOsteoarthritis of the Hip. J Rheumatol 2005;32:1106--1113.

25. Hopman-Rock M, Westhoff MH. The effects of ahealth educational and exercise program for olderadults with osteoarthritis for the hip or knee. JRheumatol 2000;27:1947-1954.

26. Yip YB, Sit JW, Wong DY, Chong SY, Chung LH. A 1-yearfollow-up of an experimental study of a self-man-agement arthritis programme with an added exer-cise component of clients with osteoarthritis of theknee. Psychol Health Med 2008;13:402-414.

27. Heuts PH, de BR, Drietelaar M, Aretz K, Hopman-Rock M, Bastiaenen CH, et al. Self-management in os-teoarthritis of hip or knee: a randomized clinical trial in a primary healthcare setting. J Rheumatol2005;32:543-549.

28. Pollard H, Ward G, Hoskins W, Hardy K. The effect of


279

w.f.h. peter e col.

a manual therapy knee protocol on osteoarthriticknee pain: a randomised controlled trial. JCCA J CanChiropr Assoc 2008;52:229-242.

29. Deyle GD, Allison SC, Matekel RL, Ryder MG, StangJM, Gohdes DD, et al. Physical therapy treatment ef-fectiveness for osteoarthritis of the knee: a randomi -zed comparison of supervised clinical exercise andmanual therapy procedures versus a home exerciseprogram. Phys Ther 2005;85:1301-1317.

30. Hoeksma HL, Dekker J, Ronday HK, Heering A, vander LN, Vel C, et al. Comparison of manual therapyand exer cise therapy in osteoarthritis of the hip: arandomi zed clinical trial. Arthritis Rheum 2004;51:722-729.

31. Moss P, Sluka K, Wright A. The initial effects of kneejoint mobilization on osteoarthritic hyperalgesia.Man Ther 2007;12:109-118.

32. Vaarbakken K, Ljunggren AE. Superior effect of force-ful compared with standard traction mobilizations inhip disability? Adv Physiother 2007;9:117-128.

33. Minns Lowe CJ, Barker KL, Dewey M, Sackley CM. Ef-fectiveness of physiotherapy exercise after kneearthroplasty for osteoarthritis: Systematic review andmeta-analysis of randomised controlled trials. BritishMedical Journal, 2007;812-815.

34. Minns Lowe CJ, Barker KL, Dewey ME, Sackley CM.Effectiveness of physiotherapy exercise following hiparthroplasty for osteoarthritis: a systematic review ofclinical trials. BMC Musculoskelet Disord 2009;10:98.

35. Galea MP, Levinger P, Lythgo N, Cimoli C, Weller R,Tully E, et al. A targeted home- and center-based ex-ercise program for people after total hip replacement:A randomized clinical trial. Archives of PhysicalMedicine and Rehabilitation 89(8)()(pp 1442-1447),2008:1442-1447.

36. Gilbey HJ, Ackland TR, Tapper J. Perioperative exer-cise improves function following total hip arthro-plasty: A randomized controlled trial. Journal of Mus-culoskeletal Research 2003;7:111-123.

37. Warden SJ, Hinman RS, Watson MA, Jr., Avin KG,Bialocerkowski AE, Crossley KM. Patellar taping andbracing for the treatment of chronic knee pain: a sys-tematic review and meta-analysis. Arthritis Rheum2008;59:73-83.

38. Quilty B, Tucker M, Campbell R, Dieppe P. Phy -siothera py, including quadriceps exercises and patel-lar taping, for knee osteoarthritis with predominantpatello-femoral joint involvement: randomized con-trolled trial. J Rheumatol 2003 ;30:1311-1317.

39. Hinman RS, Heywood SE, Day AR. Aquatic physicaltherapy for hip and knee osteoarthritis: results of asingle-blind randomized controlled trial. Phys Ther2007;87:32-43.

40. Silva LE, Valim V, Pessanha AP, Oliveira LM, Myamo-to S, Jones A, et al. Hydrotherapy versus convention-al land-based exercise for the management of pa-

tients with osteoarthritis of the knee: a randomizedclinical trial. Phys Ther 2008;88:12-21.

41. Bartels EM, Lund H, Hagen KB, Dagfinrud H, Chris-tensen R, nneskiold-Samsoe B. Aquatic exercise forthe treatment of knee and hip osteoarthritis.Cochrane Database Syst Rev 2007;(4):CD005523.

42. Lund H, Weile U, Christensen R, Rostock B, DowneyA, Bartels EM, et al. A randomized controlled trial ofaquatic and land-based exercise in patients with kneeosteoarthritis. J Rehabil Med 2008;40:137-144.

43. Tsae-Jyy Wang, Basia Belza, F.Elaine Thompson,Joanne D.Whitney, Kim Bennett. Effects of aquaticexercise on flexibility, strength and aerobic fitness inadults with osteoarthritis of the hip or knee. Journalof Advanced Nursing 2006;57:141-152.

44. Fransen M, Nairn L, Winstanley J, Lam P, Edmonds J.Physical activity for osteoarthritis management: arandomized controlled clinical trial evaluating hydro -therapy or Tai Chi classes. Arthritis Rheum 2007;57:407-414.

45. Verhagen A, Bierma-Zeinstra S, Lambeck J, CardosoJR, de BR, Boers M, et al. Balneotherapy for os-teoarthritis. A cochrane review. J Rheumatol 2008;35:1118-1123.

46. Cantarini L, Leo G, Giannitti C, Cevenini G, Barberi-ni P, Fioravanti A. Therapeutic effect of spa therapyand short wave therapy in knee osteoarthritis: A ran-domized, single blind, controlled trial. Rheumatolo-gy International 27(6)()(pp 523-529), 2007;6:523-529.

47. Balint GP, Buchanan WW, Adam A, Ratko I, Poor L,Balint PV, et al. The effect of the thermal mineral wa-ter of Nagybaracska on patients with knee joint os-teoarthritis—a double blind study. Clin Rheumatol2007;26:890-894.

48. Brosseau L, Yonge KA, Robinson V, Marchand S, JuddM, Wells G, et al. Thermotherapy for treatment of os-teoarthritis. Cochrane Database Syst Rev 2003;(4):CD004522.

49. Rutjes AW, Nuesch E, Sterchi R, Kalichman L, Hen-driks E, Osiri M, et al. Transcutaneous electrostimu-lation for osteoarthritis of the knee. CochraneDatabase Syst Rev 2009;(4):CD002823.

50. Bjordal JM, Johnson MI, Lopes-Martins RA, Bogen B,Chow R, Ljunggren AE. Short-term efficacy of physi-cal interventions in osteoarthritic knee pain. Asystemati c review and meta-analysis of randomisedplacebo-controlled trials. BMC Musculoskelet Di sord2007;8:51.

51. Milne S, Brosseau L, Robinson V, Noel MJ, Davis J,Drouin H, et al. Continuous passive motion follo wingtotal knee arthroplasty. Cochrane Database Syst Rev2003;(2):CD004260.

52. Lenssen TA, van Steyn MJ, Crijns YH, Waltje EM, RooxGM, Geesink RJ, et al. Effectiveness of prolonged useof continuous passive motion (CPM), as an adjunctto physiotherapy, after total knee arthroplasty. BMC


280


Musculoskelet Disord 2008;9:60.53. Bruun-Olsen V, Heiberg KE, Mengshoel AM. Conti -

nuous passive motion as an adjunct to active exerci -ses in early rehabilitation following total knee arthro-plasty - a randomized controlled trial. Disabil Reha-bil 2009;31:277-283.

54. Denis M, Moffet H, Caron F, Ouellet D, Paquet J, No-let L. Effectiveness of continuous passive motion andconventional physical therapy after total knee arthro-plasty: a randomized clinical trial. Phys Ther2006;86:174-185.

55. Beaupre LA, Lier D, Davies DM, Johnston DB. The ef-fect of a preoperative exercise and education pro-gram on functional recovery, health related quality oflife, and health service utilization following primarytotal knee arthroplasty. J Rheumatol 2004;31:1166--1173.

56. Ackerman IN, Bennell KL. Does pre-operative phy -siotherapy improve outcomes from lower limb jointreplacement surgery? A systematic review. Aust J Phy -siother 2004;50:25-30.

57. Rooks DS, Huang J, Bierbaum BE, Bolus SA, RubanoJ, Connolly CE, et al. Effect of preoperative exerciseon measures of functional status in men and wo menundergoing total hip and knee arthroplasty. ArthritisRheum 2006;55:700-708.

58. Topp R, Swank AM, Quesada PM, Nyland J, MalkaniA. The effect of prehabilitation exercise on strengthand functioning after total knee arthroplasty. PM R2009;1:729-735.

59. Perlman AI, Sabina A, Williams AL, Njike VY, Katz DL.Massage therapy for osteoarthritis of the knee: a ran-domized controlled trial. Arch Intern Med 2006;166:2533-2538.

60. Welch V, Brosseau L, Peterson J, Shea B, Tugwell P,Wells G. Therapeutic ultrasound for osteoarthritis ofthe knee. Cochrane Database Syst Rev 2001;(3):CD003132.

61. Ozgonenel L, Aytekin E, Durmusoglu G. A double-blind trial of clinical effects of therapeutic ultrasoundin knee osteoarthritis. Ultrasound Med Biol 2009;35:44-49.

62. Ay S, Evcik D. The effects of pulsed electromagneticfields in the treatment of knee osteoarthritis: a ran-domized, placebo-controlled trial. Rheumatol Int2008.

63. Rattanachaiyanont M, Kuptniratsaikul V. No addi-tional benefit of shortwave diathermy over exerciseprogram for knee osteoarthritis in peri-/post-menopausal women: an equivalence trial. Os-teoarthritis Cartilage 2008;16:823-828.

64. Beurskens AJ, de Vet HC, Koke AJ, Lindeman E, vander Heijden GJ, Regtop W, et al. A patient-specific ap-proach for measuring functional status in low backpain. J Manipulative Physiol Ther 1999;22:144-148.

65. Steffen TM, Hacker TA, Mollinger L. Age- and gender-

related test performance in community-dwelling el-derly people: Six-Minute Walk Test, Berg BalanceScale, Timed Up & Go Test, and gait speeds. Phys Ther2002;82:128-137.

66. Stratford PW, Kennedy DM, Woodhouse LJ. Perfor-mance measures provide assessments of pain andfunction in people with advanced osteoarthritis ofthe hip or knee. Phys Ther 2006;86:1489-1496.

67. Swinkels RAHM. Measurement instruments for pa-tients with rheumatic disorders: a clinimatric ap-praisal. Datawyse boekprodukties Amsterdam, VrijeUniversiteit; 2005.

68. Maillefert JF, Kloppenburg M, Fernandes L, Punzi L,Gunther KP, Martin ME, et al. Multi-language trans-lation and cross-cultural adaptation of the OARSI//OMERACT measure of intermittent and constantosteoarthritis pain (ICOAP). Osteoarthritis Cartilage2009;17:1293-1296.

69. van der Ploeg RJ, Oosterhuis HJ. [Physical examina-tion—measurement of muscle strength]. Ned Tijd-schr Geneeskd 2001;145:19-23.

70. Steultjens MP, Dekker J, van Baar ME, OostendorpRA, Bijlsma JW. Range of joint motion and disabilityin patients with osteoarthritis of the knee or hip.Rheumatology (Oxford) 2000;39:955-961.

71. Veenhof C, Bijlsma JW, van den Ende CH, van DijkGM, Pisters MF, Dekker J. Psychometric evaluation ofosteoarthritis questionnaires: a systematic review ofthe literature. Arthritis Rheum 2006;55:480-492.

72. Roorda LD, Jones CA, Waltz M, Lankhorst GJ, BouterLM, van der Eijken JW, et al. Satisfactory cross culturalequivalence of the Dutch WOMAC in patients withhip osteoarthritis waiting for arthroplasty. AnnRheum Dis 2004;63:36-42.

73. Lequesne MG. The algofunctional indices for hip andknee osteoarthritis. J Rheumatol 1997;24:779-781.

74. de Groot I, Reijman M, Terwee CB, Bierma-ZeinstraSM, Favejee M, Roos EM, et al. Validation of the Dutchversion of the Hip disability and Osteoarthritis Out-come Score. Osteoarthritis Cartilage 2007;15:104-109.

75. de Groot I, Favejee MM, Reijman M, Verhaar JA, Ter-wee CB. The Dutch version of the Knee Injury and Os-teoarthritis Outcome Score: a validation study. HealthQual Life Outcomes 2008;6:16.

76. Cibulka MT, White DM, Woehrle J, Harris-Hayes M,Enseki K, Fagerson TL, et al. Hip pain and mobilitydeficits—hip osteoarthritis: clinical practice guide-lines linked to the international classification of func-tioning, disability, and health from the orthopaedicsection of the American Physical Therapy Associa-tion. J Orthop Sports Phys Ther 2009;39:A1-A25.

77. Logerstedt DS, Snyder-Mackler L, Ritter RC, Axe MJ.Knee pain and mobility impairments: meniscal andarticular cartilage lesions. J Orthop Sports Phys Ther2010;40:A1-A35.

78. Lee J, Thorson D, Jurisson M, Hunt A, Yokan N,


281

Ackerman S, et al. Health Care Guideline: Diagnosisand Treatment of Adult Degenerative Joint Disease(DJD)/Osteoarthritis (OA) of the Knee. 2007.

79. Ottawa panel memmbers et al. Ottawa panel evi-dence-based clinical practice guidelines for thera-peutic exercises and manual therapy in the manage-ment of osteoarthritis. Phys Ther 2005;85:907-971.

80. Prior M, Guerin M, Grimmer-Somers K. The effec-tiveness of clinical guideline implementation strate-gies—a synthesis of systematic review findings. J EvalClin Pract 2008;14:888-897.

81. van der Wees PJ, Jamtvedt G, Rebbeck T, de Bie RA,Dekker J, Hendriks EJ. Multifaceted strategies mayincrease implementation of physiotherapy clinicalguidelines: a systematic review. Aust J Physiother2008; 54:233-241.

w.f.h. peter e col.

2nd Systemic Sclerosis World Congress

Madrid, Espanha2 a 4 Fevereiro 2012

PANLAR

Punta Cana, República Dominicana18 a 21 Abril 2012


282

c a s o c l í n i c o

e n d o c a r d i t e c o m h e m o c u lt u r a s n e g at i va s e

a lt e r a ç õ e s i m u n o l ó g i c a s : u m g r a n d e d e s a f i o

Herval de Lacerda Bonfante*, Heloína Lamha Machado Bonfante**, Carolina Bassoli de Azevedo*,

Lena Márcia de Carvalho Valle**, José Resende de Castro Júnior*

Introdução

A endocardite infecciosa (EI) é uma doença graveque ocasiona grande morbidade e uma alta taxa demor talidade. Na maioria dos estudos, sua incidên-cia varia de 2 a 10 episódios por 100.000 pessoas--ano, alcançando cerca de 20 episódios por 100.000pessoas-ano na população idosa. Aproximada-mente 15.000 novos casos são diagnosticados nosEstados Unidos a cada ano. A mortalidade situa-seentre 15 a 20% e as principais complicações dadoença são: insuficiência cardíaca, formação deabscessos intra cardíacos e eventos embólicos1.A participação do sistema imunológico na EI é

importante e associada a muitas manifestações clí-nicas, como: mialgia, perda de peso, febre e glo-merulopatia, sintomas esses, que podem ser con-fundidos com polimialgia reumática, uma enfer-midade inflamatória caracterizada por dores pre-dominantemente em cintura escapular e pélvica,anemia e aumento da velocidade de sedimentação(VS)2,3.Várias condições clínicas, além da polimialgia

reumática, devem ser consideradas no diagnósticodiferencial da EI, entre elas a endocardite de Lib-man-Sacks (ELS) e a endocardite marantica (EM).A ELS pode ser manifestação do lúpus eritematososistémico e mais recentemente da síndrome anti-fosfolípidio, embora, tipicamente seja assintomáti-ca, pode ocasionar insuficiência valvular seve ra,eventos embólicos, EI e em alguns casos cursar comfebre e artrite4. A EM é definida como uma ou maisvegetações intracardíacas não infectadas, estan domais comumente associada com malignidade5.

Caso clínico

Paciente de 80 anos, sexo masculino, portador dediabetes mellitus e hipertensão arterial, com inícioda doença em abril de 2009, apresentando quadro

Re su mo

A endocardite infecciosa subaguda pode cursarcom fenómenos imunológicos e manifestações ex-tracardiacas como anemia e dores musculoesque-léticas que podem simular doenças reumatológi-cas. É relatado o caso de um paciente com endo-cardite infecciosa que apresentou sintomatologiasemelhante à polimialgia reumática, além de umquadro agudo de nefrite após início da antibioti-coterapia. São considerados aspectos do diagnos-tico diferencial entre endocardite de Libman-Sackse endocardite infecciosa.

Palavras-chave: Endocardite Bacteriana Subagu-da; Polimialgia Reumática; Fatores Imunológicos;Glomerulonefrites; Endocardite de Libman-Sacks.

Abstract

Subacute Infectious endocarditis can present im-munological phenomena and extracardiac mani-festations such as anemia and musculoskeletal painwhich can mimic rheumatological disease. It is re-lated a case on infectious endocarditis presen tingsymptomatology similar to Polymyalgia Rheu maticadespite acute nephritis after antibiotic. The diffe -rential diagnostic features of Libman-Sacks endo-carditis versus infective endocarditis are discussed.

Keywords: Endocarditis Subacute Bacterial; Poly -myalgia Rheumatica; Immunologic Factor; Glo -merulonephritis; Libman-Sacks Disease.

* Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora,

MG- Brasil.

** Faculdade de Ciências Médicas e da Saude de Juiz de Fora

(SUPREMA), Juiz de Fora, MG- Brasil.

Trabalho realizado no Serviço de Reumatologia e Cardiologia do

Hospital Monte Sinai


283

herval de lacerda bonfante e col.

álgico difuso predominando em cintura escapulare pélvica, além de dor abdominal em crises, prin-cipalmente noturna. Teve um emagrecimento de5 Kg em 4 meses e gradativa obstipação intestinal.Durante este período apresentava exame físicosem grandes alterações, a não ser dor nos sítios ci-tados e em região periumbilical e coluna lombar.No início da doença não havia febre, porém jáapresentava alterações laboratoriais: anemia comhemoglobina: 11g/dL (normal 13,5 a 16,5g/dL), VS:110 mm na primeira hora (normal até 20 mm), hi-poproteinemia com albumina: 2,3 g/dL (normal3,5 a 5,5 g/dL) e fosfatase alcalina: 425 U/L (nor-mal até 100 U/L). A contagem de leucócitos eranormal.Com a finalidade de esclarecer o quadro de dor

musculoesquelética e abdominal, foram solicita-dos: endoscopia digestiva alta, colonoscopia, RaioX de tórax, angiotomografia de artérias mesenté-ricas, tomografia computadorizada (TC) de abdó-men, cintilografia óssea e trânsito intestinalcom resultados normais. Após a investigação foidiagnosticado como polimialgia reumática e ini-ciada prednisona na dose de 10 mg por dia. A me-lhoria foi significativa nas 2 primeiras semanas,com redução da VS para metade do valor inicial;entretanto, após a 3ª semana, houve decréscimo daresposta terapêutica e nova elevação da VS, quan-do foi decidido a suspensão da corticoterapia eprosseguimento da investigação diagnóstica.Após 6 meses do início da doença e com uma

melhoria parcial da sintomatologia, embora per-sistissem dor na cintura escapular e pélvica e VSacelerada, evoluiu com edema nos membros infe-

riores e inicialmente com pequena elevação datemperatura axilar no período vespertino, varian-do de 37,5ºC a 38ºC de caráter diário e persisten-te. Após 1 semana houve elevação progressiva datemperatura atingindo 39°C. Foi solicitada uma TCde tórax que evidenciava um aumento discreto daárea cardíaca e a presença de um pequeno derra-me pleural bilateral. Devido à presença de febre eao surgimento de sopro diastólico no foco aórtico(+/4), foi realizado ecocardiograma transtorácicoque detectou a presença de uma vegetação de 6mm na válvula aórtica com regurgitação e ecocar-diograma transesofágicoque confirmou o diagnós -tico (Figura 1 e Figura 2).Foram realizadas colheitas de urina e sangue

para culturas, e iniciado esquema antimicrobianocom a associação de ampicilina/sulbactam e ci-profloxacina, visando a cobertura de Streptococ-cus viridans, Enterococcus, gram negativos e bac-térias do grupo HACEK (Haemomophilus sp, Acti-nobacillus actinomycetemcomitans, Cardiobacte-rium hominis, Eikenella corrodens e Kingella sp.).A cultura de urina e 5 amostras de hemoculturaapresentaram resultados negativos, apesar do pa-ciente não ter utilizado antibióticos previamente.Após uma semana de antibioticoterapia, não

havia febre, mas permanecia o quadro álgico difu-so com elevação da ureia e creatinina, que até aomomento apresentavam valores normais, e a pre-sença de proteinúria em níveis nefróticos, além dehematúria microscópica, caracterizando acometi-mento glomerular.Uma nova investigação laboratorial detectou os

seguintes resultados: Anticorpo antinuclear (ANA)

Fi gu ra 1. Ecocardiograma evidenciando vegetação naválvula aórtica

Fi gu ra 2. Ecocardiograma evidenciando regurgitação naválvula aórtica


284

endocardite com hemoculturas negativas e alterações imunológicas: um grande desafio

positivo em títulos 1:320, com padrão misto nu-clear pontilhado fino, citoplasmático e pontilhadoreticular. Imunocomplexos circulantes: 82mcg/mL (normal até 34 mcg/mL), fator reumatói-de negativo, consumo das frações do complemen-to C3: 75 mg/dL (normal de 77-152 mg/dL) e C4:3,8 mg/dL (normal de 16-38 mg/dL). VDRL positi-vo 1:32 , anticardiolipina IgG: 89,7 GPL e IgM: 97MPL (valores considerados de forte reatividade),Anticorpos anticitoplasma de neutrófilos (ANCA),P - ANCA negativo e C – ANCA positivo 1:20 (valo-res considerados normais= negativo), Anti Ro, AntiSm e Anti DNA negativos. A proteinúria de 24 ho-ras evidenciava valores de 8 g (normal até150mg/24h). A creatinina atingiu valores de 2,8mg/dL e a ureia de 98 mg/dl. Após 10 dias do início das manifestações renais,

houve melhoria gradual dos níveis de ureia e crea-tinina, com normalização em cerca de 30 dias, nãohavendo a necessidade da realização de biopsiarenal ou tratamento com imunossupressores.A sintomatologia de polimialgia reumática teve

regressão total após 4 semanas do início da anti-bioticoterapia, com queda significativa nos valo-res das provas inflamatórias, confirmando que asmanifestações reumatológicas eram secundárias aEI, pois não houve a introdução de qualquer outramedicação.Exames realizados após 6 meses da resolução do

processo indicaram negativação dos marcadoresimunológicos previamente positivos e normaliza-ção das provas inflamatórias e das frações do com-plemento, permanecendo positivo apenas o C--ANCA em título de 1:20. Um novo ecocardiogra-ma realizado evidenciava regressão da lesão na vál-vula aórtica.

Discussão

O diagnóstico de polimialgia reumática constituium desafio, pois baseia-se exclusivamente na pre-sença de dor proximal escapular e pélvica, anemiae VS acelerada na ausência de outra possível doen-ça . Não há teste específico que comprove o diag-nóstico. Em determinadas situações, pacientespresumivelmente com suspeita de polimialgia reu-mática, podem após semanas ou meses recebe-rem o diagnóstico correto de sua doença, como relatado por Mourão et al que ressaltam a impor-tância da história clínica para se estabelecer o diag-nóstico de polimialgia reumática, sendo funda-

mental excluir com segurança outras patologias,que possam apresentar sintomatologia seme -lhante6.A EI é uma infecção endovascular causada prin-

cipalmente por bactéria, que acomete não só asválvulas cardíacas como todo o organismo. As ma-nifestações reumatológicas ocorrem em 27% dosindivíduos, principalmente homens, em idadeavançada, de origem rural e com degeneração dasválvulas cardíacas, sendo a válvula aórtica a maisacometida. Esses sintomas podem retardar o cor-reto diagnóstico da doença3,7,8,9.Pacientes portadores de EI propensos a desen-

volver sintomas similares a polimialgia reumáticapossuem mais de 50 anos, sua mialgia está asso-ciada à rigidez matinal por mais de um mês e ocor-re em pelo menos duas das seguintes regiões: cer-vical, cintura escapular ou pélvica. A VS geralmenteestá acelerada9. O paciente não apresentou nenhum sinal clás-

sico da EI, entretanto as suas válvulas cardíacasestavam calcificadas devido à idade avançada. Oseu quadro álgico na cintura escapular e pélvica, aperda de peso, a VS acelerada e a ausência inicialde febre, simularam um quadro de polimialgia reu-mática, dificultando o diagnóstico7,10.O diagnóstico de EI foi firmado utilizando os

critérios modificados de Duke adaptados de Li etal, com a presença de 1 critério maior (ecocardio-grama positivo) e 3 menores (lesão prévia de cal-cificação em válvula aórtica, detectada em eco-cardiograma prévio, febre acima de 38º C e fenó-menos imunológicos, evidenciado pela glomeru-lonefrite)11. Quanto à etiologia da infecção, é provável que

o agente infeccioso tivesse acesso ao organismoatravés do uso de agulhas, por vezes reutilizadaspelo paciente para aplicação diária de insulina.Houve o relato da ocorrência de reação inflamató-ria em algumas das administrações. A negativida-de das 5 hemoculturas colhidas pode ser explica-da pela presença de patogéneos de difícil cultura.Num estudo realizado por Fournier et al, obser-vou-se que os pacientes com EI apresentaram 31%das hemoculturas negativas. Isso se deve a micro-organismos de colonização restrita como Coxiellaburnetti e Bartonella species12. Não foi possível nocaso relatado chegar ao diagnóstico etiológico.A participação do sistema imune é marcante no

caso relatado, evidenciado pelas várias alteraçõeslaboratoriais encontradas e que serão comentadasa seguir. As frações C3 e C4 do complemento en-


285

herval de lacerda bonfante e col.

contram-se diminuídas na EI, devido à ativaçãodas vias clássicas e alternativas do sistema com-plemento como meio de combater a infecção, oque é observado mais comumente quando há umavasculite associada9.Embora não houvesse positividade do fator reu-

matóide, esse pode ser encontrado em 35% á 50%na EI subaguda e correlaciona-se com a formaçãoconstante de anticorpos e consequentemente coma presença prolongada de antigénios microbia-nos2,9.

A positivação do anticorpo anticitoplasma deneutrófilo (C-ANCA) está associada às vasculitescomo a granulomatose de Wegener, mas tambémpode estar presente na EI subaguda, significandoenvolvimento cutâneo ou renal da doença. Em ge-ral é acompanhada da presença de outros anti-corpos, da elevação de imunocomplexos e da que-da de complemento, devido à ativação policlonaldo linfócito B. Os exames que mais comumente sealteram com o C-ANCA são: fator reumatóide, FAN,crioglobulinas e anticardiolipina. Os títulos, emgeral, se normalizam com a resolução da doença13.Os níveis de imunocomplexos circulantes pos-

suem relação direta com fenómenos extravalvula-res e com o tempo de duração da doença, atingin-do sua normalidade, assim como os demais mar-cadores sorológicos, com a instituição da antibio-ticoterapia e cura da doença. A permanência detítulos elevados significa ineficácia do tratamento2.A EI também está associada aos resultados fal-

so positivos de VRDL. Essa elevação ocorre namaioria dos casos, em conjunto com os anticorposantifosfolipídios, com fator reumatóide e com asqueixas de origem reumatológicas14.A elevação de anticorpos anticardiolipina IgM e

IgG que geralmente está associado a fenómenostrombóticos no lúpus eritematoso sistémico podeocorrer em 18% dos pacientes com EI, entretanto,não ocasiona patogenicidade14.As glomerulopatias são complicações possíveis

na EI e podem ser desencadeadas por fenómenosembólicos ou como no caso relatado por imuno-complexos. A glomerulonefrite de origem imune éprincipalmente de caráter subagudo e ocorre en-tre 28% a 68% dos casos, com a presença de he-matúria macro ou microscópica, edema, reduçãoda função renal, uremia e proteinúria em níveisnefróticos. Além disso, outros achados que indi-cam tal situação é a redução das frações de com-plemento, presença do fator reumatóide, crioglo-bulina, e elevação de imunocomplexos nos exa-

mes laboratoriais. O C-ANCA está intimamente re-lacionado ao diagnóstico da glomerulonefrite2,10.Embora alguns estudos, como o trabalho de

Koya et al, defenda o uso de corticosteróides, optou-se apenas por manter os antibióticos15. Coma instituição da antibioticoterapia os sintomas ten-dem a regredir na grande maioria dos casos8,10.Juanatey et al elaboraram um estudo avaliando

pacientes com manifestações reumatológicas econcluiram que em alguns casos não se pode di-ferenciá-los de outros portadores da forma clássi-ca da EI9.Alguns aspectos são relevantes no caso clínico

apresentado, entre eles: complexidade de apre-sentação clínica e laboratorial, semelhança dossintomas com polimialgia reumática e necessida-de do diagnóstico diferencial com ELS. Emborajulgamos tratar-se de EI, baseado na evolução clí-nica com remissão do quadro após início da an -tibio ticoterapia (desaparecimento da febre, re-missão do quadro álgico e normalização das pro-vas inflamatórias) não podemos deixar de consi-derar a possibilidade de ELS devido aos seguintesaspectos: contagem normal de leucócitos durantea evolução da doença, altos níveis de anticorposanticardiolipina e hemoculturas negativas. No tra-balho de Lee et al é considerada a grande dificul-dade do diagnóstico diferencial entre EI e ELS de-vido a semelhança de apresentação clínica em al-guns casos4.Conclui-se que o diagnostico de EI pode ser di-

fícil e manifestações reumatológicas devem ser in-cluídas como forma de apresentação clínica, re-tardando o correto diagnóstico. Na avaliação ini-cial deve-se incluir uma propedêutica cardíaca ena presença de altos títulos de anticorpos anticar-diolipina pensar na possibilidade de ELS.

Correspondência paraHerval de Lacerda BonfanteRua Capitão Arnaldo de Carvalho, 693, Apartamento 301 – Bairro Jardim GlóriaCEP: 36036-180 – Juiz de Fora Minas Gerais- BrasilE-mail: [email protected]

Referências1. McDonald JR. Acute infective endocarditis. Infect Dis

Clin North Am 2009; 23: 643-664.2. João SR, Bertim MR, Junior LM, Junior BNA, França

HH. Aspectos Patogênicos e Imunitários da Endo-cardite Infecciosa. Arq Bras Cardiol 1990; 54: 69-72.

3. Auzary C, Huong DLT, Delabre X, et al. Subacute bac-terial endocarditis presenting as polymyalgia


286

endocardite com hemoculturas negativas e alterações imunológicas: um grande desafio

rheumatic or giant cell arteritis. Clin Exp Rheumatol2006; 24: 38-40.

4. Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Re-visiting Libman-Sacks endocarditis: a historical re-view and update. Clin Rev Allergy Immunol 2009;36:126-130.

5. Durie NM, Eisenstein LE, Cunha BA, Plummer MM.Quadrivalvular Marantic Endocarditis MimickingAcute Bacterial Endocarditis. Heart Lung 2007; 36:154-158.

6. Mourão AF, Oliveira I, Pinheiro MN, Graça JP. Aci-dente vascular cerebral isquémico como apresen-tação dramática de Endocardite Infecciosa: a im-portância da história clínica. Acta Reum Port 2006;31: 342-347.

7. Habib G, Hoen B, Tornos P, et al. Guidelines on theprevention, diagnosis, and treatment of infective en-docarditis. Eur Heart J 2009; 30: 2369–2413.

8. Andrade JAM, Lugon JR. Revisão: Acometimento re-nal na endocardite infecciosa. J Bras Nefrol 2003; 25:25-33.

9. Juanatey CG, Gay MAG, Lorca JL, et al. RheumaticManifestations of Infective Endocarditis in Non-Ad-dicts a 12 Year Study. Medicine (Baltimore) 2001; 80:9-19.

10. Mansur AJ, Grinberg M, Gallucci SDD, Bellotti G,Jatene A, Pileggi F. Endocardite Infecciosa: Análise de300 episódios. Arq Bras Cardiol 1990; 54: 13-21.

11. Li JS, Sexton DJ, Mick N, et al. Proposed modifica-tions of the Duke criteria for the diagnosis of infec-tive endocarditis. Clin Infect Dis 2000; 30: 633-638.

12. Fournier PE, Thuny F, Richet H, et al. Comprehensivediagnostic strategy for blood culture-negative endo-carditis: a prospective study of 819 new cases. ClinInfect Dis 2010; 51: 131-140.

13. Chirinos JA, Medina VFC, Garcia S, Lichtstein DM,Bisno AL, Chakko S. Endocarditis associated with an-tineutrophil cytoplasmic antibodies: a case reportand review of the literature. Clin Rheumatol 2007;26: 590-595.

14. Arsheson RA, Tikly M, Staub H, et al. Infective endo-carditis, rheumatoid factor and anticardiolipin anti-bodies. Ann Rheum Dis 1990; 49: 107-108.

15. Koya D, Shibuya K, Kikkawa R, Haneda M. Successfulrecovery of infective endocarditis-induced rapidilyprogressive glomerulonephritis by steroid therapycombined with antibiotics: a case report. BMCNephrology. 2004; 5: 18.

XVI Congresso Português de Reumatologia

Algarve, Portugal1 a 5 Maio 2012


288


p a g e t ’ s d i s e a s e o f b o n e a n d i t s

c o m p l i c at i o n s d u e t o d e l ay i n d i a g n o s i s

Lorena Penha de Almeida*, Juliana Alves Scrignoli*, Kelly Simone Castro dos Santos**,

Luiz Fernando de Souza Passos***, Sandra Lúcia Euzébio Ribeiro***

gested. Long bones, pelvis, vertebral spine and skullare most often affected1.

Paget’s bone disease may run an asymptomaticcurse, but often manifests as skeletal pain whichmay be related to disease activity or complicationssuch as degenerative joint disease, fractures, os-teosarcoma and neural impingement2. Four to nineyears is the average lag time between the first symp-toms and diagnosis3,4, which is eventually made bythe clinical history along with image and laborato-rial finding5, Herein, the authors report a case of apatient with Paget’s bone disease with many com-plications related to delay in establishing the diag-nosis.

Case Report

Male patient, 74 years old, brown skin, native ofAmazon, retired driver, presented with a 30 yearshistory of mild skeletal pain that has begun at thesacroiliac region, not continuous, which worsenedwith physical effort, and, sometimes, relapsed atnight. Later, the skeletal pain has affected the lo werlimbs, diffusely, burning, associated with pares-thesias. Deformities developed progressively in theleft leg (arching) and in the vertebral spine. The pa-tient walks with difficulty due to functional im-pairment caused by deformity and pain, with limi -tation for daily activities and work capacity.

The patient complained of bilateral hearing lossand intestinal constipation but had no weight loss.Previous diagnosis of congestive heart failure, sys-temic arterial hypertension and ischemic heartdisea se had been made. He had never been sub-jected to transfusions or surgeries. There was nohistory of familiar osteoporosis with fractures orother metabolic bone disease. He denied the use ofcorticosteroids or other drugs related to osteope-nia. There was no personal history of renal failure,disease of the thyroid, hyperparathyroidism, hi-pogonadism or collagen-vascular disease. He

Abstract

Paget’s disease of bone is an osteometabolic focaldisease characterized by defects in bone remode -ling. It may be asymptomatic, but often is associa -ted with bone pain, deformity, pathological frac-ture, secondary osteoarthrosis and deafness. Thediagnosis is usually made by radiological and labo -ratory findings. This report describes a male pa-tient, 74 years old, native of Amazon, without Eu-ropean ancestry, with polyostotic Paget’s disease,with clinical, radiological and laboratory diagnosisafter 30 years of disease. The authors emphasizeseveral complications of Paget’s disease due to de-layed diagnosis and the rarity of the disease in thispopulation group.

Keywords: Osteitis Deformans; Paget; Fractures;Bone; Bone Diseases.

Introduction

Paget’s bone disease is a chronic focal non-inflam-matory osteometabolic disease with a strong ge-netic background, with defects in bone remodelingaffecting one (monostotic) or more points (polyos-totic) of the skeleton. Recognized and described bySir James Paget in 1877, it is typically found in peo-ple after the fourth decade of life, being slightlymore common in caucasoid men. Its etiology re-mains unknown, although an autoimmune disor-der associated with viral infections have been sug-

*Rheumatology Residency Program of Hospital Universitário

Getúlio Vargas (HUGV), Universidade Federal do Amazonas

(UFAM), Manaus/AM, Brazil.

**Internal Medicine Residency Program of Hospital Universitário

Getúlio Vargas (HUGV), Universidade Federal do Amazonas

(UFAM), Manaus/AM, Brazil.

***Departament of Rheumatology, Universidade Federal do

Amazonas (UFAM), Manaus/AM, Brazil.


289

lorena penha de almeida e col.

smoked cigarettes, 50 packets/year, and consumedalcoholic beverages socially.

At physical examination, there was a para-ver tebral protuberance at the thoracolumbar re-gion, warm bone deformities (bowing) at thelo wer limbs and an increased cranial circumfe -rence. He had small stature and walked with shortsteps and waddling gait. The range of motion waslimited at the hips and knees, which impaired theperformance of certain maneuvers, such as theevaluation of Lasegue sign. Patellar reflex was ab-sent and there was reduced strength in extensionand flexion of the hallux. The muscles of the lo werlimbs were hypotrophic, but proximal musclestrength and sensitivity were preserved.

Lab tests showed serum calcium: 9,0mg/dL (VR=8,8 –11); Phosphorus: 4,0mg/dL (VR= 2,5-4,5); glu-cose: 92mg/dL; urine calcium: 32,9mg/24hs(VR=60-180); urine protein: 75mg/24hs; serum al-kaline phosphatase: 1657U/L (VR= 644), C-Reactiveprotein: 12mg/dL; erythrocyte sedimentation rate:34mm; lactic dehidrogenase: 181UI; prosta tic spe-cific antigen: 0,5ng/mL; uric acid: 4,0mg/dL.

A magnetic resonance study of the lumbar spineshowed a partial collapse of the fourth vertebra,and low intensity lesions with T1 and heterogenicsignal with T2, which captures contrast medium,spreaded along lumbar vertebras and the sacrum.There was bone destruction with collapse and softtissues invasion at the twelfth vertebra, with back-

ward projection of the posterior borders of the ver-tebral bodies of D11, D12, L1 and L4, narrowing thevertebral channel and compression the dural sac.A tomografic study of the pelvis showed a coarsethickening of bone trabeculae with an insufflatedaspect, and sclerotic areas superposed on lytic le-sions in pelvic bones (Figures 1 and 2). A tomo-graphic study of the legs showed an expansive andinsufflated lesion all along the left tibia, with dif-fuse and irregular thickening of cortical bone anddisordered bone trabeculae (Figure 3). A tomo-graphic study of toraco-lumbar spine showed de-struction of vertebral bodies at D12, L1 and L2,with invasion of soft tissues, the medular channeland neural foramen at this level, and shrinking ofintervertebral spaces at L3-L4 and L4-L5, withtraces of air within the disks. Vertebral bone tra-beculae were diffusely disarranged and showed areactive zone (Figure 4). There was widespread in-ter-apophysary osteoarthritis. A radioisotope scan-ning showed excessive label capture at the abnor-mal bone, suggesting a metabolic disorder.

During the 30 years of disease, because of in-sidious mild pain, despite the major deformities,the patient was consulted only during periods ofpain exacerbation, in the emergency room, notpursuing a diagnosis. Difficulty of access to a pub-lic health specialist also contributed to delay indiag nosis. In 2005, he consulted an orthopedist,when the first radiographs were taken and Paget’s

Figure 1. Tomographic study of pelvic bones showing lytic images

Figure 2. Tomographic study of pelvic bones showing lytic images


290

paget’s disease of bone and its complications due to delay in diagnosis

disease was suspected. Subsequently, he was re-ferred to a rheumatologist, but he came to our De-partment of Rheumatology only in 2010. After athorough clinical and laboratory evaluation, thediagnosis of Paget disease of bone was established,and specific treatment with zolendronic acid wastried, but the patient still could not get the medi-cation because of financial reasons. Thus, alterna-tively, alendronate 40mg/day was used with gra -dually reduction of alcaline phosphatase: 1283 UI//L after three months and 1083 UI/L after sixmonths of starting treatment.

Discussion

Paget’s disease is the second most commonmetabolic bone disease, second only to osteo-porosis. It is difficult to estimate its impact be-cause, in most cases it is asymptomatic6, but ismore frequent in Countries of European and An-glo-Saxon extraction and is rare in the Americas5,7.In Latin America, 1149 cases were reported in thelast 30 years, and the fact common to these pa-tients is that the vast majority have European an-cestry8. In Brazil, most cases are found in the cityof Recife, owing to its peculiar mixed European co -lo nization over approximately four centuries9 andfor being a reference center for Paget’s disease inthe country. The patient reported is native of Ama-

zon, without European ancestry, which makes thecase interesting due to the rarity in this population.The axial skeleton is more often involved1, butproximal long bones may also be committed in 25to 35% of cases10. Appendicular involvement is usu-ally unilateral10. Polyostotic disease is found in 65to 90% of patients, representing the most commonform at diagnosis10,11.

Disease’s etiology remains uncertain8, but ge-netic, environmental 9,12 and viral factors13 are con-sidered. Typical manifestations of Paget’s diseaseare related to its complications2, which may beclassified according to the body system affected:ske letal (bone pain, bone deformities, osteoa -rthrosis, fractures and spinal channel stenosis),neural (deafness, cranial nerves dysfunction, highintracranial pressure), cardiovascular (ischemicheart disease, aortic valve stenosis, intracavitarycalcifications, widespread atherosclerosis, highoutput congestive heart failure), metabolic (hy-percalciuria, hypercalcemia, hyperuricemia,nephrolitiasis), and neoplasia (osteosarcoma, con-drosarcoma, fibrosarcoma, giant cell tumor)14. Atthe time of diagnosis, the patient already had seve -ral complications of the disease, such as fractures,bone deformities, deafness, and congestive car-diac failure, which reflects the delay in diagnostic.

Diagnosis is ultimately made through image andlaboratory findings. Radioisotope bone scanning isthe most sensible method to detect early lesions.

Figure 3. Tomographic study showing lytic images andthickening of cortical bone

Figure 4. Destruction of multiple vertebrae with lytic lesions and areas of repair (reactive zone).


291

lorena penha de almeida e col.

Most patients with Paget’s disease are identified byan elevation on the levels of alkaline phosphatasewhich cannot be explained by hepatobiliary patho -logy or another osteometabolic disorder. Altoge -ther, image findings rely on disease progression tobe classified in three distinct stages: lytic pha se,with initial reabsorption characterized by osteoly-sis,established by osteoclast activity; mixed phase,with vascular and osteoblastic repair, lea ding tothickening and distortion of cortical and trabecu-lar bone; and a blastic phase, which cur ses with ap-positional new bone, with an sclerosing scaringaspect5. The patient’s diagnostic was suspec ted bythe elevated levels of alkaline phosphatase and byradiological imaging characte ristics.

Drug treatment is made with bisphosphonates,which are shown to diminish bone pain and bio-chemical markers of bone remodeling in randomi -zed clinical trials, achieving restoration of histo-logical and radiographic patterns15. The first bis-phosphonate to be used was etidronate. However,more potent biphosphonates have proved to bemore effective, leading to more prolonged periodsof remission16. Oral alendronate, in a dose of 40mg/day, for 6 months, leads to a 77% decrease inalkaline phosphatase, compared with the 44% de-crease produced by etidronate17. Zoledronic acid is10.000 times more potent than etidronate in re-ducing the biochemical markers of bone remode -ling18 and patients with resistance to other bisphos -phonates usually respond to this drug19.As the onlybisphosphonate available in public services, thepatient has been treated with alendronate sodium40 mg/d, improving complaints of pain and redu cing gradually alkaline phosphatase levels. The apparent slow response to treatment may have been by the major bone involvement at diag-nosis, and the fact that the drug considered morepotent for the treatment of Paget’s disease (zolen-dronic acid) was not performed, due to financialreasons.

Paget’s disease diagnosis is rather difficult to bemade, as long as the disease runs a large and varia -ble clinical spectrum, involves many topographiesin the body with different degrees of metabolic in-tensity, a difficulty most marked in asymptomaticpatients. Nevertheless, in cases such as the one re-ported herein, with bone pain and deformities, thepossibility of Paget’s disease should always be con-cerned, considering the high impact of the com-plications brought forward by a delay in diseasediag nosis and treatment.

Correspondence toSandra Lúcia Euzébio RibeiroHospital Universitário Getúlio Vargas Av. Apurinã, nº4; Bairro Praça 14. CEP:69020-170; Manaus – AM, Brasil. Tel: +55 (92) 36334977. E-mail: [email protected]

References1. Schneider DE, Hofmann MT, Peterson JA. Diagnosis

and treatment of Paget’s disease of bone. Am FamPhysician 2002; 65: 2069-2072.

2. Bone HG. Nonmalignant complications of Paget’s di -sease. J Bone Miner Res 2006; 21: 64-68.

3. Selby PL, Davie MW, Ralston SH, Stone MDl. Guidelineson the management of Paget’s disease of bone. Bone.2002; 31: 366-373. Erratum in: Bone. 2002; 31: 437.

4. Langston AL, Ralston SH. Management of Paget’s di seaseof bone. Rheumatology (Oxford). 2004; 43: 955-959.

5. Terézhalmy GT. Paget’s disease (osteitis deformans).Quintessence Int 2002; 33: 82-83.

6. Cooper C, Harvey NC, Dennison EM, van Staa TP. Up-date on the epidemiology of Paget’s disease of bone. JBone Miner Res 2006;21:3-8.

7. Ankrom MA, Shapiro JR. Paget’s disease of bone (os-teitis deformans). J Am Geriatr Soc 1998; 46:1025--1033.

8. Rojas-Villarraga A, Patarroyo PA, Contreras AS, Restre-po JF, Iglesias-Gamarra A. Paget disease of bone inColombia and Latin America. J Clin Rheumatol2006;12:57-60.

9. Griz L, Caldas G, Bandeira C, Assunção V, Bandeira F.Paget’s disease of bone. Arq Bras Endocrinol Metabol2006;50:814-822.

10. Resnick D, Niwayama G. Paget disease. In: Resnick D,ed. Diagnosis of bone and joint disorders. Philadel-phia: Saunders, 2002: 1947–2000.

11. Gumà M, Rotés D, Holgado S et al. Paget’s disease ofbone: study of 314 patients. Med Clin 2002; 119: 537--540.

12. Josse RG, Hanley DA, Kendler D, Ste Marie LG, AdachiJD, Brown J. Diagnosis and treatment of Paget’s di -sease of bone. Clin Invest Med 2007; 30: 210-223.

13. Chaffins JA. Paget disease of bone. Radiol Technol2007; 79: 27-40.

14. Lyles KW, Siris ES, Singer FR, Meunier PJ. A clinicalapproach to diagnosis and management of Paget’sdisease of bone. J Bone Miner Res 2001; 16: 1379--1387.

15. Siris ES, Lyles KW, Singer FR, Meunier PJ. Medicalmanagement of Paget’s disease of bone: indicationsfor treatment and review of current therapies. J BoneMiner Res 2006; 21: 94-98.

16. Reid IR, Siris E. Alendronate in the treatment ofPaget’s disease of bone. Int Clin Pract 1999; 101:62-66.

17. Siris ES, Weinstein RS, Altman R et al. Comparativestudy of alendronate and etidronate for the treatmentof Paget’s disease of bone. J Clin Endocrinol Metab1996;81:961-967.


292


p o l i c o n d r i t e r e c i d i va n t e , d e r m at i t e i n t e r s t i c i a l

g r a n u l o m at o s a e s í n d r o m e a n t i f o s f o l í p i d o :u m a a s s o c i a ç ã o c l í n i c a i n v u l g a r

S Serra*, P Monteiro**, E Pires***, R Vieira****, O Telechea*****, L Inês******, M J Salvador******, A Malcata*******

patient with a 3-year history of antiphospholipidsyndrome, admitted after presenting in the emer-gency room with erythematous nodular skin le-sions, affecting the face and neck, with a week’s du-ration. Local biopsies were suggestive of interstitialgranulomatous dermatitis. The patient describedlesions compatible with bilateral auricular chon-dritis, two weeks prior to the appearance of thenodules, which resolved spontaneously after 3days. There was a previous episode of nasal chon-dritis, two years previously, and another episodestarting at the 7th day of hospitalization. Thesefindings, taken together with a diagnosis ofseronegative polyarthritis established 5 years be-fore the current events, lead to a diagnosis of re-lapsing polychondritis.

Keywords: Interstitial Granulomatous Dermatitis;Skin Biopsy; Relapsing Polychondritis; Antiphos-pholipid Syndrome.

Introdução

A Policondrite Recidivante é uma doença auto-imu-ne rara e de etiologia desconhecida, caracterizadapor episódios inflamatórios recorrentes, envolven-do estruturas cartilagíneas, com risco de destruição,atrofia e deformação das mesmas. Pode ocorrer iso-ladamente ou em associação a outras doenças.

A Dermatite Intersticial Granulomatosa (DIG) éuma afecção cutânea rara que ocorre em associa-ção com várias doenças sistémicas auto-imunes,fármacos ou neoplasias. A histologia das lesões cu-tâneas é típica, com infiltrado inflamatório difuso,e disposição celular em paliçada entre os feixes decolagénio na derme reticular profunda.

O Síndrome Antifosfolípido (SAF) é uma doen-ça auto-imune caracterizada por trombose vascu-lar recorrente e/ou morbilidade gestacional, asso-ciada à presença de títulos elevados de anticorpos

Resumo

Os autores apresentam o caso clínico de um doen-te do sexo masculino, de 49 anos de idade, com an-tecedentes de Síndrome antifosfolípido desde há 3anos, internado através do Serviço de Urgência paraesclarecimento de lesões cutâneas eritemato-nodu-lares na face e pescoço, com uma semana de evolu-ção. As biopsias das referidas lesões revelaram as-pectos sugestivos de Dermatite Intersticial granulo-matosa. O doente referiu quadro compatível comcondrite auricular bilateral duas semanas antes doaparecimento das lesões cutâneas, com resoluçãoespontânea ao fim de 3 dias. Tinha antecedentes decondrite nasal 2 anos antes, tendo surgido outro epi-sódio ao 7º dia de internamento. Estes achados, as-sociados a antecedentes pessoais de poliartrite se-ronegativa não erosiva há 5 anos, permitiram esta-belecer o diagnóstico de Policondrite Recidivante.

Palavras-chave: Dermatite Intersticial Granulo-matosa; Biopsia Cutânea; Policondrite Recidivan-te; Síndrome Antifosfolípido.

Abstract

The authors describe the case of a 49 year-old male

*Interna do Internato Complementar de Reumatologia, Serviço

de Reumatologia, Hospitais da Universidade de Coimbra

**Assistente Hospitalar de Reumatologia, Serviço de

Reumatologia, Hospital de S. Teotónio, Viseu

***Interna do Internato Complementar de Fisiatria, Hospital

Infante D. Pedro, Aveiro

****Assistente Hospitalar de Dermatologia, Serviço de

Dermatologia, Hospitais da Universidade de Coimbra

*****Chefe de Serviço, Serviço de Dermatologia dos Hospitais

da Universidade de Coimbra

******Assistente Hospitalar de Reumatologia, Serviço de

Reumatologia, Hospitais da Universidade de Coimbra

*******Chefe de Serviço, Serviço de Reumatologia dos Hospitais

da Universidade de Coimbra


293

sara serra e col.

antifosfolípidos.A associação SAF e DIG1 já foi reportada na litera-

tura, mas não a associação entre estas três entidades. Os autores revêem os aspectos importantes des-

te caso clínico, com particular destaque para asentidades mais raras, a Policondrite Recidivante ea Dermatite Intersticial Granulomatosa.

Caso Clínico

Doente do sexo masculino, 49 anos, raça branca,internado em Setembro de 2008 através do Servi-ço de Urgência para esclarecimento de lesões cu-tâneas eritemato-nodulares da face e pescoço evasculite das mãos, com uma semana de evolu-ção. Associadamente, referia astenia e anorexiacom o mesmo tempo de evolução. Negava febre,ou outras queixas sistémicas ou articulares.

Duas semanas antes do aparecimento das le-sões cutâneas referiu dor, edema e rubor de ambosos pavilhões auriculares, poupando os lobos, qua-dro esse que cessou espontaneamente ao fim de 3dias. Teve episódio semelhante, mas dessa vez comatingimento da cartilagem nasal, 2 anos antes.

O doente tinha antecedentes de Fenómeno deRaynaud desde há 20 anos, Síndrome Antifosfolí-pido desde há 4 anos (com 4 episódios de trombosevenosa profunda e um de tromboembolia pulmo-nar) e hipertensão arterial desde há 5 anos. Foi se-guido no hospital da sua área de residência, porquadro de poliartrite bilateral e simétrica envol-vendo punhos e pequenas articulações das mãos,seronegativa e não erosiva, diagnosticada 5 anos

Fi gu ra 1. Nódulos eritematosos na face e região cervicaldireita, um deles com componente purpúrico central

Fi gu ra 2. Máculas eritematosas nas polpas digitais e focosde hemorragia sub-ungueal

antes. Nessa altura foi medicado com corticoste-róides orais e metotrexato 10 mg/semana, com re-missão da doença ao fim de 5 meses. Manteve pormais dois anos a referida medicação, tendo depoissuspendido por completo.

Estava medicado em ambulatório com Varfari-na 5 mg (1 id), Diosmina 500 mg (2 id), e Amlodi-pina 5 mg (1 id).

Relativamente aos antecedentes profissionais,estava actualmente reformado devido ao elevadorisco trombótico, tendo exercido profissões de mi-neiro e trabalhador da construção civil.

Ao exame objectivo apresentava-se com bomestado geral, apirético, normotenso, sem adeno-megálias palpáveis ou alterações ao exame toraco--abdominal e membros inferiores. Na face e pes-coço, eram visíveis nódulos eritematosos, infla-matórios, de cerca de 0,5 cm de diâmetro, um de-les localizado na região cervical direita, comcomponente purpúrico central (Figura 1). As mãosevi den ciavam pequenas máculas eritematosas emalgumas polpas digitais, que não desapareciam àdigitopressão, e diversos focos de hemorragia sub -ungueal, lesões estas sugestivas de vasculite (Fi-gura 2). Sem outras alterações de relevo no examefísico.

Analiticamente apresentava hemograma nor-mal, com velocidade de eritrossedimentação de 56 mm/h, INR de 1,2, protrombinémia de 78%,proteína C reactiva de 1,9 mg/dL, com restantebioquímica normal. Sumária de urina, proteino-grama electroforético, fracções do complemento,C3 e C4, normais. Factor reumatóide, Ac anti-peptí- deo citrulinado 2 (Anti-CCP 2) e serologias para


294

policondrite recidivante e dermatite intersticial granulomatosa

hepatite B, C e HIV, negativas.Autoimunidade positiva para ANA�s (+++), pa-

drão granular fino denso, com ENA�s negativos;Anti-cardiolipinas IgM (> 150 U/mL) positivo, An-ticoagulante lúpico positivo, ANCAs e doseamen-to de crioglobulinas negativos. Estudo das trom-bofilias (proteínas C e S, factor V de Leiden, anti--trombina III, entre outros) sem alterações. Capi-laroscopia com várias tortuosidades capilares, al-terações sugestivas de doença do tecido conjunti-vo. A radiografia do tórax, mãos e pés, electrocar-diograma, ecocardiograma e ecografia abdominal,não apresentavam alterações.

Durante o internamento ocorreram 2 episódiosde rectorragias, sem dor abdominal, existindo con-texto de antecedentes de hemorróidas de longa

Fi gu ra 3. Biopsia de lesão cutânea – Vasculite Leucocitoclásica

Fi gu ra 4. Biopsia de lesão cutânea – disposição dos neutrófilos em paliçada, com formação focal de imagensdo tipo de granuloma de Churg-Strauss (seta)

Fi gu ra 5. Condrite nasal

data. No entanto, foi pedida Angio-TAC abdominalpara exclusão de vasculite sistémica, que não de-tectou alterações.

Realizou biopsia das lesões da face, que identi-ficou: «na derme média dilatação dos vasos san-guíneos com trombose luminal e marcado infiltra-do inflamatório neutrofílico, com carioclasia,acompanhado por necrose fibrinóide. Associada-mente e de particular interesse, é a disposição dosneutrófilos no interstício, entre os feixes de colagé-nio, com formação focal de imagens do tipo de gra-nuloma de Churg-Strauss. Trata-se, portanto, deuma vasculite leucocitoclásica, chamando-se aatenção para o aspecto intersticial, granulomato-so, focal do infiltrado neutrofílico, sugestivo de Der-matite Intersticial Granulomatosa» (Figuras 3 e 4).

As lesões cutâneas referidas resolveram espon-taneamente ao fim de 3 dias, sem sequelas.

Ao sétimo dia de internamento surgiu condritenasal, que resolveu com AINES (Naproxeno 500mg,2id) ao fim de 4 dias (Figura 5).

A existência de condrites recorrentes associa-das ao antecedente de poliartrite, permitiu esta-belecer o diagnóstico de Policondrite Recidivante.O doente esteve internado por um total de 15 dias,sem outras intercorrências. Teve alta com indica-ção de manter o INR entre 2,5 e 3, ficando orien-tado para a Consulta de Reumatologia. Até à data,não se registaram novos episódios de condrite oueventos trombóticos.

Discussão

A Policondrite Recidivante (PR) é uma doença sis-


295

sara serra e col.

témica rara, que se caracteriza por inflamação re-corrente das estruturas cartilagíneas, com risco dedestruição das mesmas. Afecta primariamente acartilagem auricular e nasal, as articulações peri-féricas e o tracto respiratório superior. As estrutu-ras ricas em proteoglicanos, como o olho, o ouvi-do interno, a pele, o coração, os vasos sanguíneose o rim, também podem ser afectadas2. A PR foi ini-cialmente descrita em 1923, por Jaksch-Warte-nhorst, como «policondropatia» e posteriormentedesignada de «condromalácia» ou «policondritecrónica atrófica». Foi finalmente reclassificadacomo Policondrite Recidivante, por Pearson et al.,em 1960. Estima-se uma incidência de 3,5/milhão2.Pode surgir em todas as raças, mas tem sido re-portada com mais frequência em caucasianos3. Aidade de diagnóstico oscila entre os 20 e os 60 anos,com pico de incidência aos 40 anos, e tem um ra-tio sexo feminino:masculino de 1:1 em algumasséries de casos, mas Trentham et al., reportaramum ratio de 3:13. Não existe predisposição heredi-tária, apesar de ter sido descrito uma maior asso-ciação ao HLA-DR43. A etiopatogenia é desconhe-cida, mas foram identificados anticorpos contra ocolagénio tipo II, em 33% dos casos de PR , o quefavorece a suposição do mecanismo fisiopatológi-co ser auto-imune2.

Os critérios de diagnóstico da PR foram inicial-mente estabelecidos por McAdam et al., em 1976,e incluíam pelo menos 3 de 6 características: con-drite auricular bilateral, condrite nasal, poliartritenão erosiva seronegativa, inflamação ocular, con-drite do tracto respiratório, ou alterações audio-vestibulares6. Mais tarde, Diamiani e Levine, revi-ram os critérios de McAdam e propuseram, para odiagnóstico, 3 dos critérios de McAdam ou, um cri-tério de McAdam e a histologia positiva ou 2 crité-rios de McAdam e resposta a corticóides ou dapso -na7. Mais recentemente, em 1986, Michet definiucomo critérios a existência de condrite em duas detrês localizações (auricular, nasal, laringo-tra-queal) ou condrite num desses locais e duas outrascaracterísticas, incluindo inflamação ocular, alte-rações audio-vestibulares ou artrite seronegativa,não sendo necessário que estas alterações ocorramem simultâneo.

A biopsia é geralmente desnecessária6. Não exis-tem marcadores bioquímicos de diagnóstico, sen-do a elevação da velocidade de eritrossedimenta-ção o achado laboratorial mais consistente, quege ralmen te se correlaciona com a actividade dadoença3.

A condrite auricular e a artrite são os sintomasde apresentação da doença mais frequentes. A con-drite auricular desenvolve-se em até 89% dosdoentes com PR e caracteriza-se pela existência desinais inflamatórios da cartilagem, com dor e ru-bor intensos, tipicamente poupando o lobo do pa-vilhão auricular. É bilateral em 95% dos casos, po-dendo persistir durante alguns dias a semanas,sendo geralmente recorrente. A inflamação repe-tida desta estrutura pode conduzir à destruição damesma, com deformações importantes e típicas,como o pavilhão em «couve-flor»3. Além do pavi-lhão auricular, o ouvido externo, médio e internopodem ser atingidos. O ouvido externo é envolvi-do pela extensão da inflamação ao canal auditivoexterno; o médio, pela obstrução tubárica; e o in-terno, por fenómenos de vasculite dos vasos co-cleo-vestibulares10. A condrite nasal ocorre em 54%dos casos, podendo conduzir ao colapso da carti-lagem, com deformação «em sela» do nariz8. A ar-trite, que surge em 50-80% dos casos, pode ser oli-go ou poliarticular, e envolve com frequência as ar-ticulações condro-costais, esterno-claviculares,membros superiores, coxofemorais ou joelhos. Ge-ralmente é migratória, não erosiva, não defor-mante e seronegativa, com duração de semanas ameses, podendo preceder em anos o aparecimen-to de condrite nasal ou auricular8. O envolvimen-to ocular surge em 60-70% dos casos, podendo in-cluir queratite, esclerite, episclerite, conjuntivite,uveíte ou irite. As alterações laringo-traqueais sur-gem em 50% dos casos, podendo este atingimen-to ser fatal por destruição e colapso da árvore tra-queo-brônquica8.

As manifestações dermatológicas podem ocor-rer em 35 a 50% dos casos. Podem preceder a doen-ça em 10 a 20 anos, sendo a primeira manifestaçãoda doença em 12% dos casos7. As alterações maisfrequentemente encontradas são a aftose oral, nó-dulos cutâneos «eritema nodoso-like» e púrpura,sendo a vasculite o achado histológico mais fre-quentemente identificado8. Outras alterações in-cluem urticária, angioedema, eritema multiforme,livedo reticularis, paniculite, dermatoses neutrofí-licas, pústulas estéreis e tromboflebite superficialmigratória. A inespecificidade das diversas mani-festações dermatológicas, explica porque não fo-ram incluidas nos critérios de diagnóstico pro-postos por Michet et al., em 19869.

Embora mais raramente, os sistemas cardíaco,neurológico e renal podem também ser atingidos3.

A PR pode ocorrer isolada ou associada a outras


296

policondrite recidivante e dermatite intersticial granulomatosa

doenças autoimunes, em 25 a 35% dos casos. A as-sociação mais frequentemente reportada foi a vas-culite, incluindo vasculite cutânea leucocitoclási-ca e outras vasculites sistémicas (Granulomatosede Wegener, Poliarterite Nodosa, Síndrome deChurg-Strauss, Doença de Behçet e Síndrome MA-GIC)8. Doenças reumáticas como a Artrite Reuma-tóide, o Lúpus Eritematoso Sistémico, Síndrome deSjögren e a Doença mista do tecido conjuntivo, po-dem coexistir em 20% dos casos. Associação comoutras doenças auto-imunes como o hipotiroidis-mo, anemia perniciosa, diabetes mellitus, miaste-nia gravis e colite ulcerosa foram também repor-tadas7.

As neoplasias mais frequentemente coexisten-tes com a PR são as Síndromes mielodisplásicos eoutras doenças hematológicas malignas7. Curio-samente, as manifestações cutâneas têm sido no-tadas com mais frequência em casos de PR asso-ciada a mielodisplasias8. Outros tumores sólidospodem também estar associados à PR, entre osquais, cancro da mama, pulmão, colo do útero, có-lon, recto, pâncreas, próstata, tiróide e testículo7.

O diagnóstico diferencial da PR varia consoan-te as manifestações clínicas, podendo incluir acondrite infecciosa, sarcoidose, tuberculose, lepra,granulomatose de Wegener, entre outras3.

O prognóstico é variável, desde remissões es-pontâneas a um curso crónico persistente3. A prin-cipal causa de morte é infecção pulmonar devidaquer à corticoterapia quer à obstrução das vias aé-reas; outras causas incluem falência respiratóriaaguda por colapso aéreo, vasculite sistémica e fa-lência renal7. São considerados factores de mauprognóstico, a anemia, o nariz «em sela», vasculi-te, artrite, atingimento laringo-traqueal e hema-túria à data do diagnóstico7.

Não existem protocolos standard para o trata-mento da PR. Nos casos mais ligeiros os anti-in-flamatórios não esteróides, a dapsona ou a colchi-cina podem ser usados, com alguma eficácia de-monstrada7. Nos casos mais graves a corticotera-pia é o gold standard, devendo ser usada na dosede 0,5 a 1 mg/Kg/dia. Tem bons resultados no con-trolo do episódio agudo e na redução da frequên-cia das crises. Em algumas séries de casos têm sidoreportados o uso de outros agentes imunossu-pressores como o metotrexato, azatioprina, hidro-xicloroquina, ciclosporina, ciclosfofamida, rituxi-mab, entre outros, com eficácia variável3.

No presente caso clínico o diagnóstico de PR foiefectuado com base na existência de condrite au-

ricular e nasal, e poliartrite. A resolução rápida eespontânea dos episódios de condrite, associadaà ausência de deformações cartilagíneas e de atin-gimento traqueobrônquico, permitiram presumirum melhor prognóstico a este caso, pelo que seoptou por não introduzir corticoterapia até à dataactual. A coexistência com o SAF evidencia um«terreno» auto-imune mais marcado, neste casocom manifestações trombóticas várias, a sugerirmaior gravidade. Quanto às manifestações der-matológicas, surgiram nódulos inflamatórios pur-púricos cuja histologia revelou, além de um com-ponente vasculítico, alterações que permitiram odiagnóstico de Dermatite Intersticial Granuloma-tosa. A sua evolução foi benigna, com resolução es-pontânea ao fim de alguns dias.

A dermatite Intersticial Granulomatosa é umaentidade histopatológica rara, inicialmente des-crita por Ackerman et al., em 199312. Já conhecidadesde 1983, quando Finan e Winkelmann descre-veram uma condição semelhante, que designaramde Granuloma de Churg-Strauss ou granuloma cu-tâneo extravascular necrotizante14. Outros termoslhe têm sido posteriormente atribuídos, tais comopápulas reumatóides, necrobiose reumatóide su-perficial ulcerada ou Dermatite granulomatosaneutrofílica em paliçada14. Tem sido descrita a suaassociação mais frequente a diversas doenças au-toimunes, entre as quais, a artrite reumatóide, o lú-pus eritematoso sistémico, o síndrome antifosfo-lípido primário, a tiroidite autoimune, vasculitessistémicas, hepatites auto-imunes e um caso as-sociado a Doença de Behçet13,14. Outras patologiasassociadas incluem silicose pulmonar, leucemiapromielocítica, uveíte crónica e carcinoma brôn-quico como manifestação paraneoplásica13. A etio-logia farmacológica também já foi reportada, sen-do os fármacos mais frequentemente envolvidos,os anti-hipertensores (inibidores da enzima deconversão da angiotensina, bloqueadores dos ca-nais de cálcio, beta-bloqueantes), hipolipemian-tes, inibidores do TNFα, anti-histamínicos, antide -pressivos e anticonvulsivantes11.

A apresentação clínica é variável, podendo in-cluir nódulos, pápulas ou placas, ou ainda, mais ra-ramente, petéquias, livedo reticularis ou urticária.Os nódulos são o tipo mais comum, raramente ex-cedendo os 2 cm de diâmetro, com consistência fir-me e coloração variando de vermelha a violácea13,14.A epiderme das lesões pode ser normal, mas estãodescritas úlceras. Na maioria dos casos são assin-tomáticas mas podem ser dolorosas ou prurigino-


297

sara serra e col.

sas. A localização mais frequente é nas extremida-des e no tronco, sendo a face raras vezes atingida14.

O diagnóstico é histológico, caracterizando-sepor infiltrado intersticial denso, difuso, na dermereticular, composto primariamente por histiócitoscom disposição em paliçada. Por vezes porções decolagénio necrobiótico são envolvidos por neu-trófilos e/ou eosinófilos, formando estruturas quelembram granulomas de Churg-Strauss. Pode exis-tir vasculite leucocitoclástica associada, sendo quecertos autores defendem que pode ser a alteraçãohistológica inicial deste processo11,15.

A fisiopatologia é desconhecida, sendo a deposi-ção de imunocomplexos nos vasos dérmicos a cau-sa mais consensual. Em muitos casos foram identi-ficados depósitos de IgM e C3 nos vasos dérmicos ena junção dermoepidérmica no estudo da imuno-fluorescência directa. O modelo patogénico maisaceite propõe que a deposição destes imunocom-plexos nos vasos dérmicos cause uma vasculite leu-cocitoclástica, degeneração das fibras colagénicas edermatite granulomatosa em paliçada, com even-tual fibrose dérmica em estágios terminais15.

A terapêutica de eleição não está bem definida,dada a inexistência de estudos.

Diferentes opções terapêuticas têm sido repor-tadas na literatura, com graus variados de suces-so, entre as quais, anti-inflamatórios não este -róides, corticosteróides tópicos ou orais (dose>30mg/dia), colchicina, ciclosporina, ciclofosfa-mida, hidroxicloroquina e dapsona14. Resoluçãoespontânea e formas resistentes também foramdescritas13. Com ou sem tratamento, as lesões ge-ralmente evoluem por semanas a meses. Na maio-ria dos casos não há recorrências, mas pode haverflares e remissões13.

Neste caso clínico, a localização das lesões e asua rápida e espontânea resolução, torna este casomenos habitual relativamente aos outros descritos.

Este é um caso que combina a existência de trêscondições auto-imunes, sendo duas delas raras, aPR e a DIG. Existem referências prévias a associa-ção do SAF e a DIG1, mas a associação desta últi-ma com a PR ainda não tinha sido reportada na li-teratura.

Correspondência paraSara SerraServiço de ReumatologiaHospitais da Universidade de CoimbraPraceta Mota Pinto3000 CoimbraE-mail: [email protected]

Referências1. Lee H, Chang SE, Lee MW et al. Intersticial granulo-

matous dermatitis with plaques associated withamtiphospholipid syndrome. Br J Dermatol 2005;152:814

2. Peebo BB, Peebo M, Frennesson C. Relapsing poly-chondritis: a rare disease with varying symptoms. Ac-ta Ophthalmol Scand 2004; 82: 472-475.

3. Rapini RP, Warner NB. Relapsing polychondritis.Clinics in Dermatology 2006; 24: 482-485.

4. Paudyal BP, Karki A, Zimmerman M. Relapsing poly-chondritis: a rare disease of multisystem involve-ment. J Nepal Med Assoc 2007; 46: 81-83.

5. Pinto P, Brito I, Brito J et al. Policondrite recidivante:estudo retrospectivo de seis casos. Acta Med Port2006; 19: 213-216.

6. Kent PD, Michet CJ, Luthra HS. Relapsing polychon-dritis. Curr Opin Rheumatol 2004; 16: 56-61.

7. Watkins S, Magill JM, Ramos-Caro FA. Annular erup-tion preceding relapsing polychondritis: case reportand review of the literature. International Journal ofDermatology 2009; 48: 356-362.

8. Letko E, Zafirakis P, Baltatzis S et al. Relapsing poly-chondritis: a clinical review. Semin Arthritis Rheum2002; 31: 384-395.

9. Francès C, El Rassi R, Laporte JL et al. DermatologicManifestations of Relapsing Polychondritis: a Studyof 200 Cases at a Single Center. Medicine 2001; 80:173-179.

10. Crovetto M, Solano D, Centeno J. Policondritis Re-cidivante: a Propósito de un Caso. Acta Otorrino-laringol Esp 2003; 54: 727-730.

11. Johnson H, Mengden S, Brancaccio RR. Interstitialgranulomatous dermatitis. Dermatology OnlineJournal 2008; 14: 18.

12. Swing DC, Sheehan DJ, Sangüeza OP, Woodruff RW.Interstitial Granulomatous Dermatitis Secondary toAcute Promyelocytic Leukemia. Am J Dermatopathol2008, 30: 197-199.

13. Jabbari A, Cheung W, Kamino H, Soter NA. InterstitialGranulomatous Dermatitis with Arthritis. Dermato -lo gy Online Journal 2009, 15: 22.

14. Heidary N, Mengden S, Pomeranz MK. PalisadedNeutrophilic and Granulomatous Dermatosis. Der-matology Online Journal 2008; 14: 17.

15. Misago N, Shinoda Y, Tago M, Narisawa Y. PalisadedNeutrophilic Granulomatous Dermatitis with Leuko-cytoclastic Vasculitis in a Patient Without any Under-lying Systemic Disease Detected to Date. J CutanPathol 2010; 37: 1092-1097.


298


c r i o g l o b u l i n é m i a m i s t a

Roque R*, Ramiro S*, Vinagre F*, Cordeiro A*, Godinho F*, Santos MJ*, Gonçalves P*, Canas da Silva J*

logical parameters of inflammation and amino-transferases, positive cryoglobulin and rheumatoidfactor in serum, and a severe reduction in C4 com-plement fraction. Hepatitis C virus (HCV) serologywas negative. Idiopathic mixed cryoglobulinemiawas diagnosed and corticosteroid therapy started.Given the lack of response, cyclophosphamide andplasmapheresis were added. Two weeks later thepatient died in septic shock. The second case refersto a 41 years old female, with untreated hepatitis Cwho developed over a 6 month period petechiaeand livedoid lesions on the lower limbs, periphe ralneuropathy, and constitutional symptoms and wasadmitted with intestinal necrosis. Exams were con-sistent with the diagnosis of mixed cryoglobuline-mia associated, with HCV. She started therapy withribavirin and pegylated interferon-alpha, with im-provement.

Keywords: Mixed Cryoglobulinemia; Cryoglobu-linemic Vasculitis; Clinical Features; HCV; Treatment.

Introdução

A crioglobulinémia mista (CM) é uma vasculite sis-témica que envolve vasos de pequeno e médio ca-libre por deposição de complexos imunes (crio-globulinas/factor reumatóide-FR) e fracções decomplemento1,2. Define-se pela presença de crio-globulinas (imunoglobulinas-Ig) no soro que pre-cipitam a temperaturas menores que 37º C e quese dissolvem novamente com o aquecimento3. ACM apresenta um largo espectro de manifestaçõesclínicas que varia desde uma síndrome crioglobu-linémica típica com púrpura, artralgias, astenia, atécasos de lesões mais graves com envolvimento re-nal, neurológico e intestinal. Está associada a in-fecção pelo vírus da hepatite C (VHC) em cerca de80 a 90 % dos casos, sendo nos restantes idiopáti-ca. Aproximadamente 15 a 20 % dos doentes apre-sentam uma vasculite sistémica grave que colocaem risco a vida1,2.

Os autores descrevem dois casos clínicos de crio-

Resumo

Os autores descrevem dois casos clínicos de crio-globulinémia. O primeiro, uma doente do sexo fe-minino de 70 anos, com úlceras cutâneas e pares-tesias dos membros inferiores, artralgias e sintomasconstitucionais com agravamento progressivo aolongo de 10 meses. Dos exames complementaresdestacava-se discreta anemia, elevação dos parâ-metros inflamatórios e transaminases, crioglobu-linas e factor reumatóide presentes no soro, e di-minuição acentuada de C4. A serologia para o ví-rus da hepatite C (VHC) foi negativa. Diagnosti-cou-se crioglobulinémia mista idiopática e iniciouterapêutica com prednisolona a que se associouposteriormente ciclofosfamida e plasmaférese porausência de resposta. Veio a falecer em choque sép-tico. O segundo caso, refere-se a uma doente dosexo feminino de 41 anos, com antecedentes de he-patite C não tratada, que apresentava desde há 6meses lesões petequiais e livedóides nos membrosinferiores, polineuropatia periférica e sintomasconstitucionais com agravamento progressivo aque se associou um quadro de necrose intestinal.Os exames complementares foram compatíveiscom crioglobulinémia mista associada a VHC. Ini-ciou terapêutica com ribavarina e alfa-interferãopegilado, com melhoria clínica e laboratorial.

Palavras-chave: Crioglobulinémia mista; Vasculi-te Crioglobulinemica; Manifestações Clínicas;VHC; Tratamento.

Abstract

The authors describe two clinical cases of cryo-globulinemia. A 70 years old woman, having skinulcers on lower limbs, arthralgias, paresthesias andconstitutional symptoms, for about 10 months.Exa ms revealed mild anemia, elevation of the bio-

*Serviço de Reumatologia, Hospital Garcia de Orta, Almada,

Portugal


299

roque r. e col.

globulinémia com envolvimento sistémico grave,um deles com desfecho fatal

Caso Clínico

Caso 1: Doente do sexo feminino de 70 anos, raçabranca, com antecedentes pessoais de hipertensãoarterial controlada com lercanidipina, infecçãopelo vírus de hepatite B (VHB) curada, insuficiên-cia venosa periférica e dislipidémia. Observada emconsulta de reumatologia 10 meses após inicio dequadro clínico caracterizado por lesões cutâneaspúrpuricas, não pruriginosas inicialmente inter-mitentes, posteriormente associadas a múltiplasúlceras necróticas muito dolorosas e de difícil ci-catrização a nível das pernas, edemas maleolaresbilaterais, astenia, perda ponderal de 20%, artral-gias difusas, mialgias e parestesias a nível da faceinferior do 5 º dedo dos pés bilateralmente. Tinhaefectuado tratamento sintomático com analgési-cos orais e anti-inflamatórios não esteróides (AI-NE’s) tópicos, mas com agravamento progressivodas queixas. Do exame objectivo, nesta fase, sa-lientava-se a existência de múltiplas lesões cutâ-neas purpúricas necróticas e ulceradas de diversostamanhos (de diâmetros compreendidos entre 1 e3 cm) a nível ambas as pernas, (Figuras 1, 2 e 3) as-

Fi gu ra 1. Lesao cutanea necrotica ulceradaFi gu ra 2. Multiplas lesoes cutaneas necroticas e ulceradas

sociadas a lesões petequiais do tipo vasculítico (Fi-gura 4) dispersas pela região anterior do tórax,abdó men, coxas e antebraço esquerdo. Apresen-tava discreta hipostesia a nível da face inferior dospés bilateralmente. Não apresentava sinais de ar-trite ou tenosinovite e a força muscular estavamantida. As alterações analíticas estão sumariza-das na Tabela I. O resultado histológico da biopsiade pele revelou necrose da epiderme, vasculite leu-cocitoclástica envolvendo os vasos dérmicos e hi-podérmicos com trombos intraluminais PAS + su-gestivo de crioglobulinémia mista. Realizou elec-tromiograma dos membros inferiores e ecocar-diograma que não apresentavam alterações. Feztomografia computorizada (TC) toraco-abdomi-no-pélvica que revelou hipotransparência paren-quimatosa bibasal pulmonar, aumento do lobo he-pático esquerdo de contornos irregulares, parên-quima heterogéneo e ligeira esplenomegalia ho-mogénea. Tendo em conta o quadro clínico eexames complementares chegou-se ao diagnósti-co definitivo de crioglobulinémia mista idiopáticado tipo II. A doente iniciou prednisolona na dosede (1mg/Kg/dia) oral associada a cálcio e vitami-na D, ibandronato 150 mg mensal, omeprazol 20mg/dia e irbesartan + hidroclorotiazida. Após 4meses de terapêutica a doente mantinha lesões ul-ceradas a nível das pernas, muito dolorosas e de di-fícil cicatrização, associadas a lesões vasculíticas denovo, a nível do tronco e abdómen. Pelo agrava-mento do quadro, apesar da terapêutica anteriorfoi administrado pulso de ciclofosfamida (500mg//m2) associado a plasmaférese e prednisolona 1mg/Kg/dia oral. No entanto, cerca de 2 semanas


300

crioglobulinémia mista

depois, a doente entrou em aplasia medular, com-plicada de choque séptico, sendo necessária atransferência para Unidade de Cuidados Intensi-vos. Da avaliação analítica nesta fase, destacava--se hemoglobina 7,7 g/dL, leucopenia (300 leucó-citos) com neutropenia (200 neutrófilos), plaque-tas 71.000; velocidade de sedimentação (VS) de 89mm 1ªh e proteína C reactiva (PCR) de 9 mg/dL.Foram isolados múltiplos microrganismos em cul-turas de sangue (Staphylococus aureus, Enterobac-ter cloacae, Citrobacter feudi) e ponta de catetercentral (Candida tropicalis). Necessitou de anti-bioterapia de largo espectro, entubação orotra-queal e ventilação mecânica, suporte vasoactivocom noradrenalina, factores de crescimento (G--CSF), corticoterapia em dose de choque séptico egamaglobulina humana endovenosa 400mg/Kg/

Fi gu ra 3. Lesao cutanea necrotica e ulcerada

Fi gu ra 4. Lesoes petequiais vasculíticas

/dia (5 dias). Apesar das medidas terapêuticas aci-ma referidas, verificou-se o óbito após 3 semanasnos cuidados intensivos.

Caso 2: Doente do sexo feminino, 41 anos, raçabranca, professora. Com antecedentes pessoais dehepatite C diagnosticada em 2003, sem terapêuti-ca, fumadora de 10 UMA. Apresentava quadro com6 meses de evolução de diarreia crónica com mucoe sangue, dor abdominal, anorexia, perda ponde-ral de 4 % e astenia. Foi observada em consulta deGastroenterologia por suspeita de doença infla-matória do intestino e foi medicada com azatio-prina 50 mg/dia (1mg/Kg/dia), prednisolona 5mg/dia, isoniazida 300mg/dia, suplementos deferro e ácido fólico. No entanto, verificou-se agra-vamento da dor abdominal, com empastamentodoloroso na fossa ilíaca esquerda (FIE) e hipogas-tro, e sinais de defesa abdominal com dor à des-

Tabela I. Avaliação laboratorial das doentes

Doente 1 Doente 2

Hemoglobina 11,8 g/dL 10,1 g/dL

Leucócitos 4700 6700

VS 42 96

PCR 1 mg/dL 2,2 mg/dL

Urina II Normal Normal

Creatinémia 0,9 mg/dL 0,2 mg/dL

AST 52 UI/l 19 UI/l

ALT 31 UI/l 29 UI/l

G-GT 139 UI/l 94 UI/l

ANA Negativo Negativo

Especificidades Negativo Negativo

ANA

VHC Negativo Positivo

(Genotipo Ia)

Ac HBs e HBc Positivos

1.773.700cópias

Ac HBe Negativo RNA/ml

Ag HBe e HBs Negativos Negativos

VIH1 e 2 Negativos Negativos

FR Positivo Negativo

Ac anti-citrulina Negativo Negativo

C3 89 mg/dl (90-180) 135 (90-150)

C4 2 mg/dl (10-40) 1.4 (10-40)

Criogloubulina Positiva (IgMk) Positiva (IgMk)

VS – Velocidade de sedimentação; PCR – Proteína C Reactiva; ANA –

Anticorpo antinuclear; AST – Aspartato Aminotransferase; ALT –

Alanina Aminotransferase; VHB – Vírus da Hepatite B; VHC – Vírus da

Hepatite C; VIH –Vírus da Imunodeficiência Humana; FR – Factor

Reumatóide; C3 e C4 – fracção de complemento 3 e 4


301

roque r. e col.

compressão. O quadro de abdómen agudo estavaassociado a leucocitose com neutrofilia e PCR de7 mg/dL. A TC abdominal e a colonoscopia reve-laram estenose do cólon sigmóideu e necrose in-testinal. Foi submetida a hemicolectomia esquer-da alargada e, posteriormente, a colectomia totale ileostomia terminal, devido a necrose isquémi-ca subsequente do restante cólon. Foi referencia-da a reumatologia, dois meses após a cirurgia in-testinal, devido ao aparecimento de dor na regiãogemelar e pés, parestesias e sensação de diminui-ção da força muscular distal dos membros infe-riores bilateralmente. Referia ainda algumas lesõespetequiais nas pernas e progressivo agravamentode lesões livedóides nos membros inferiores (MI).Ao exame objectivo salientava-se hipostesia dospés, disestesia do terço inferior das pernas, forçamuscular grau IV dos MI (distal) com reflexos os-teotendinosos mantidos. Dos exames comple-mentares destacavam-se, anemia normociticanormocrómica, aumento de VS, FR e crioglobuli-nas presentes no soro e infecção a VHC (Tabela I).A radiografia de tórax e a angiografia do tronco ce-líaco, artérias renais e mesentérica superior nãoapresentavam alterações. A ressonância magnéti-ca (RM) hepática revelou nódulo hepático de 3 cmsobreponível a exame anterior e sem relevânciaclínica. O electromiograma dos membros inferio-res revelou polineuropatia crural sensitiva e mo-tora (assimétrica e de predomínio sensitivo). O re-sultado histológico de biopsia intestinal (peça ope-ratória) mostrou microtrombos venosos e arteriais,infiltrado inflamatório e microaneurismas, acha-dos sugestivos de vasculite. Após o diagnóstico decrioglobulinémia mista associada a VHC, a doen-te iniciou tratamento com alfa-interferão pegiladoB na dose de 80 mcg/semana/sc, ribavarina 800mg/dia, gabapentina 900 mg/dia, amitriptilina 25mg/dia e paracetamol (até 3g/dia). Houve melho-ria laboratorial com descida da carga viral e parâ-metros biológicos de inflamação em cerca de 6 me-ses de seguimento em consulta, mas a doentemantém queixas neuropáticas exuberantes, semtradução objectiva, ou outras manifestações denovo.

Discussão

A característica patológica da CM é a existência deuma vasculite leucocitoclástica secundária à de-posição de complexos imunes circulantes (IgG e

IgM) e fracções de complemento a nível dos vasos,que é responsável pelo envolvimento cutâneo e deórgãos1,3,4.

Brouet et al., classificaram três tipos de crioglo-bulinémia: tipo I- com uma imunoglobulina (Ig)monoclonal; tipo II ou mista- com uma IgG poli-clonal combinada com uma IgM que mostra acti-vidade de factor reumatóide (FR); tipo III- comimunoglobulinas policlonais5.

A crioglobulinemia mista apresenta uma pato-genia complexa, estando associada em 90% doscasos à infecção pelo VHC e, nos restantes casos, éidiopática6,7. Vários estudos demonstraram a pre-sença de Antigénio (Ag) Hbs e/ou Anticorpo (Ac)Hbs em doentes com CM, mas mais tarde verifi-cou-se que a prevalência destes marcadores é se-melhante nos indivíduos com CM e na populaçãogeral3. Os casos clínicos descritos reflectem estascaracterísticas.

A CM é uma síndrome clínica muito heterogé-nea na sua forma de apresentação clínica, exten-são e gravidade de envolvimento de órgãos, alte-rações imunológicas e evolução clínica. Na apre-sentação clínica mais frequente existe uma tríadeclássica de púrpura, astenia e artralgias, podendohaver envolvimento multiorgânico sistémico, no-meadamente intestinal, com microaneurismas erisco de enfarte e necrose do intestino4,8. No pri-meiro caso descrito a forma de apresentação foiclássica, enquanto a segunda doente revelou en-volvimento de órgão alvo com necrose intestinalpor vasculite numa fase mais inicial do quadro.

A manifestação clínica mais típica da CM é aexistência de púrpura palpável, predominando nosmembros inferiores quando estão afectados os va-sos de pequeno calibre. Com o envolvimento dosvasos de médio calibre formam-se úlceras cutâ-neas. Cerca de 50 a 80 % dos doentes têm artral-gias difusas. Verifica-se envolvimento renal em25% dos doentes, que habitualmente, consiste naexistência de proteinúria que poderá ter agrava-mento progressivo e culminar em insuficiência re-nal nos casos não tratados. Histologicamente, a le-são renal mais frequente é a de glomerulonefritemembranosa proliferativa. A neuropatia periféri-ca varia entre 7 a 60 % dos casos, envolve, de for-ma preferencial, os nervos sensitivos e traduz-seem parestesias, dor ou perda de sensibilidade8,9.Ambas as doentes apresentaram queixas neuro-páticas, preferencialmente sensitivas, tal comodescrito na literatura. A CM está associada a algu-mas alterações laboratoriais, sendo mais caracte-


302

crioglobulinémia mista

rística a presença sérica de crioglobulinas, asso-ciadas a factor reumatóide e a diminuição da frac-ção de complemento C4. Nos dois casos descritosverificou-se a presença destas alterações labora-toriais descritas. Podem existir também alteraçõesinespecíficas, tais como discreta anemia normocí-tica normocrómica, elevação dos parâmetros bio-lógicos de inflamação, alterações da função renal,se existir glomerulonefrite, aumento discreto dastransaminases, presença no soro de anticorpos an-tinucleares e serologia para VHC positiva em 90 %dos casos8,10. Tendo em conta a maior frequênciade crioglobulinémia associada ao VHC, o caso daprimeira doente assume uma maior relevânciadado a sua raridade.

Devido ao seu pleiomorfismo, a crioglobuliné-mia mista pode confundir-se com várias doençasautoimunes, neoplasias, outras vasculites sistémi-cas, síndrome de Sjögren, hepatite autoimune edoenças linfoproliferativas de células B4.

O tratamento da CM deve ser individualizado deacordo com o doente e a gravidade das manifesta-ções. Nos casos em que há infecção a VHC, utiliza-se alfa-interferão pegilado associado a ribavari-na11. Os corticosteróides isolados ou em combina-ção com plasmaférese ou ciclofosfamida podemser utilizados como terapêutica de 1ª linha. A ci-clofosfamida oral (1mg/m2) diária durante 3 me-ses associada a corticosteróides em doses de 1-2mg/Kg/dia e/ou plasmaférese é a forma de trata-mento mais frequentemente preconizada nas for-mas graves de CM, nomeadamente quando há as-sociação a glomerulonefrite, neuropatia sensitivo--motora recente ou vasculite generalizada4.

Mais recentemente, tem sido utilizado o Rituxi-mab (anticorpo monoclonal anti-CD20) com su-cesso em doentes com CM sem efeitos secundáriossignificativos. No entanto, são necessários ensaiosclínicos controlados para verificar a sua eficácia esegurança a longo prazo12. A CM é uma doença rarae dado o seu pleomorfismo clínico é frequente ha-ver atraso no diagnóstico e no início da terapêuti-ca eficaz o que compromete o prognóstico dodoente13. Os doentes com CM têm maior taxa demortalidade que a população geral. Esta taxa pa-rece ser semelhante nos casos de CM essencial eassociada a VHC. Os factores de mau prognósticosão a idade superior a 60 anos na ocasião do diag-nóstico, o sexo masculino e o envolvimento renal1,8.As causas de morte mais frequentes são a insufi-ciência renal, a hepatite crónica com cirrose, a vas-culite sistémica disseminada, a infecção e o linfo-

ma não Hodgkin de células B1,3.A primeira doente apresentou uma complica-

ção menos frequentemente descrita, mas muitotípica, que foram as úlceras cutâneas nas pernas,refratárias ao tratamento com corticoesteróides,necessitando de tratamento com ciclofosfamida eplasmaférese. Estas duas modalidades terapêuti-cas estão indicadas e são eficazes nestes casos, talcomo descrito na literatura, mas a imunosupres-são tem riscos associados, e a infecção é um dosprincipais motivos de morte nesta patologia, talcomo se veio a verificar neste caso. A segundadoente apresentava CM associada a hepatite C, si-tuação mais frequente, contudo a forma de apre-sentação foi menos típica. Tal como referido na li-teratura, a CM é uma vasculite de difícil diagnós-tico dada a variedade de apresentações clínicas.Nesta doente, a principal manifestação foi a ne-crose intestinal por vasculite sistémica grave, as-sociada a neuropatia periférica e lesões cutâneas,não se verificando envolvimento renal nem art rite.

Em conclusão, a CM é uma vasculite sistémicaque apesar de rara é potencialmente fatal. A varie-dade de manifestações clínicas pode atrasar odiagnóstico e o tratamento atempado, que são es-senciais para a melhoria do prognóstico e da qua-lidade de vida do doente.

Correspondência paraRaquel Martins RoqueServiço de Reumatologia Hospital Garcia de Orta, Avenida Professor Torrado da Silva 2801-951 AlmadaE-mail: [email protected]

Referências1. Della Rosa A, Marchi F, Catarsi E, Tavoni A, Bom-

bardieri S. Mixed cryoglobulinemia and mortality: areview of the literature. Clin Exp Rheumatol 2008;26:105-108

2. Ferri C, Giuggioli D, Cazzato M, Sebastiani M, MasciaMT, Zignego AL. HCV-related cryoglobulinemic vas-culitis: an update on its etiopathogenesis and tera -peutic strategies. Clin Exp Rheumatol 2003; 21:578--584

3. Ramos-Casals M, Trejo O, Garcia-Carrasco M,Cervera, Font J. Mixed cryoglobulinemia: new con-cepts. Lupus 2000;9;83-91.

4. Ferri C, Mascia MT. Cryoglobulinemic vasculitis. CurrOpin Rheumatol 2006;18:54-63

5. Brouet JC, Clouvel JP, Danon F, Klein M, Seligman M.Biologic and clinical significance of cryoglobulins.Am J Med 1974;54:775-788

6. Ferri C, Zignego A. Relation between infection andautoimmunity in mixed cryoglobulinemia. Curr


303

roque r. e col.

Opin Rheumatol 2000;12:53-607. De Vita S, Quartucio L, Fabris M. Hepatitis C vírus in-

fection, mixed cyoglobulinemic and BLyS upregula-tion: targeting the infectious trigger, the autoimmuneresponse, or both. Autoimmun Rev 2008; 8:95-99

8. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed Cryo-globulinemia: demographic, clinical, and serologicalfeatures and survival in 231 patients. Semin ArthristisRheum 2004; 33:335-334

9. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J ClinPathol 2002;55:4-13

10. Sansonno D, Dammacco F. Hepatitis C virus, cryo-globulinemia, and vasculitis: immune complex rela-tions. Lanced Infect Dis 2005;5:227-236

11. Sansonno D, Carbone A, V. De Re, Dammacco F. He -pa titis C vírus infection, cryoglobulinemia, and be-yond. Rheumatology 2007; 46:572-578

12. Cacoub C, Delluc A, Saadoun D, Landau DA, Sene D.Anti-CD20 monoclonal antibody (rituximab) treat-ment for cryoglobulinemic vasculitis: where do westand? Ann Rheum Dis 2008; 67:283-287

13. Rieu V, Cohen P, André MH et al. Characteristics andoutcome of 49 patients with symptomatic cryoglobu-linemia. Rheumatology 2002;41:290-300

XXXVIII Congreso Nacional de la SER

Saragoça, Espanha16 a 18 Maio 2012

39th European Symposium on Calcified Tissues

Estocolmo, Suécia19 a 23 Maio 2012


304


k a w a s a k i d i s e a s e i n a y o u n g i n f a n t :

d i a g n o s t i c c h a l l e n g e s

Marta Cabral*,†, Paula Correia**,†, Maria João Brito**,†, Marta Conde***,†, Helena Carreiro****,†

infants and young children1. Since its first descrip-tion by Tomisaku Kawasaki in 1967, this enigmaticillness has surpassed acute rheumatic fever as theleading cause of acquired heart disease among chil-dren in developed countries1,2.

Incomplete KD is more common in young infantsthan in older children, making accurate diagnosis es-pecially important because of their higher risk for de-veloping coronary abnormalities6,7. Coronary arteryaneurysms occur in 20 to 25% of untreated children,predominantly in young children, with 80% of pa-tients being younger than 5 years old1.

Therapy with IVIG must be started within thefirst 10 days of illness because timely diagnosis andearly treatment are two crucial points for KD’s prog-nosis6,8,10. However, even when treated appropria -tely, 5% of children develop coronary artery dilata-tion and 1% develop giant aneurysms.

Case report

A previously healthy 3-month-old caucasian fe-male infant, born to non-consanguineous parents,with an unremarkable past medical history, pre-sented with a two-weeks high-grade (39ºC) con-tinuous fever with diarrhea during the first threedays. Before hospital admission, she was prescribedamoxicillin clavulanate for suspected urinary tractinfection. Physical examination revealed a febrile(38,7ºC), but “non-ill appearance” child. Bilateralcervical and inguinal lymph nodes were enlarged(<1cm in diameter), accompanied by a subtle hepa -tomegaly. Cardiopulmonary examination was nor-mal. There was no rash, conjunctival injection,changes in the lips or oral cavity or edema/erythe-ma of the hands.

Laboratory findings showed normocytic ane-mia (haemoglobin – 8.7 g/dL), leukocytosis of13,100/mm³ (44% neutrophils; 42.5% lympho-cytes), thrombocytosis of 891,000 platelets/mm³,C-reactive protein of 11.39 mg/dL, erythrocyte se -dimentation rate of 110mm/1st hr. Chest radiogra-

*Interna do Internato Complementar de Pediatria

**Assistente Hospitalar de Pediatria, Consulta de Infecciologia

pediátrica

***Assistente Hospitalar de Pediatria, Consulta de Reumatologia

pediátrica

****Directora do Departamento

†Departamento de Pediatria, Hospital Prof. Doutor Fernando

Fonseca E.P.E., Amadora, Portugal

Abstract

Kawasaki disease (KD) is a multisystem vasculitiscondition with a relatively unknown etiology. It hasa high prevalence in children ages 6 months to 5years, and patients often present with high fever,rash, cervical lymphadenopathy and mucocuta-neous abnormalities. Visceral manifestations canbe present, being coronary complications the mostfrequent. There is no diagnostic test for KD, its pre-sentation can be complete or incomplete and, insome cases, it can be atypical. We report a case ofa 3-month-old infant with 3-weeks of fever andaseptic meningitis. Infectious diseases were ex-cluded and there was no response to antibiotics.Echocardiography was normal in the second week.Genetic test for CINCA syndrome was negative. Inthe third week, dilatation of coronary arteries de-termined Kawasaki disease’s diagnosis. Prolongedfever, accompanied by nonspecific clinical symp-toms were the only manifestations, becoming achallenging diagnosis. KD must be consideredwhen prolonged fever is present, mainly in youngchildren in whom the incomplete forms of the di -sease are more frequent.

Keywords:Kawasaki Disease; Vasculitis; Incomplete;Coronary Artery Aneurysms; CINCA Syndrome.

Introduction

Kawasaki disease (KD) is an acute, multisystem andself-limited vasculitis of unknown etiology that hasa striking predilection for the coronary arteries of


305

kawasaki disease: diagnostic challenges

phy was normal. Examination of the cerebrospinal fluid (CSF)

was compatible with meningitis - white blood cellcount – 25/mm³ with polymorphonuclear pre-dominance, protein – 70.1 mg/dL, glucose – 52 mg/dL,and intravenous ceftriaxone was started. Trans-fontanelar ultrassonography was normal. CSFGram stain and culture were sterile and protein- -chain reaction for herpes simplex 1 and 2 wasnega tive. Additional analytic findings: hypoalbu-minemia (2.6g/dL), hyperferritinemia (360ng/mL)and mild elevation of hepatic aminotransferases. Abdominal ultrassonography showed an hete -rogenous hepatomegaly.

Echocardiography excluded cardiac involve-ment and ophthalmologic evaluation was normal.

The patient remained febrile until day 20 of ill-ness, with no response to antibiotics and persis-tently elevated acute phase reactants (Figure 1).Exhaustive laboratory searching for infectious andautoimmune diseases was negative (Table I). Con-sidering the association of persistent high feverwith aseptic meningitis, genetic test for chronicneurologic cutaneous and articular (CINCA) Syn-

Days

Temperature (ºC)

D19D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 D17 D16

4039.53938.53837.53736.53635.535

Day 22 of illnessIVIG2 g/kg

LP ApyrexiaCeftriaxone(10 days)

Periungual desquamationof fingers and toes+Diffuse maculopapularerythematous rash+Hepatomegaly

Day of illness D11 D14 D17 D20 D22 D28 D34 D49 D83 UnitsHemoglobin 8.7 8.7 8.0 7.9 8.9 9.4 10 11.2 10.8 g/dLWhite blood cell 9,300 11,900 12,400 6,700 10,900 12,700 8,200 8,900 7,400 X10³/µlPlatelets 891 987 891 891 891 891 588 413 421 X10³/µlC-reactive protein 11.39 11.24 10.84 6 6.7 2.55 2.37 1.51 0.53 mg/dLErythrocyte sedimentation rate 110 100 80 80 122 110 79 – 23 mm/1st h

IVIG Discharge

Days

Tem

pera

ture

(ºC

)

D19D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 D17 D16

40

39.5

39

38.5

38

37.5

37

36.5

36

35.5

35

Day 22 of illness

IVIG2 g/kg

LP Apyrexia

Ceftriaxone(10 days)

Periungual desquamationof fingers and toes

+Diffuse maculopapular

erythematous rash+

Hepatomegaly

Day of illness D11 D14 D17 D20 D22 D28 D34 D49 D83 Units

Hemoglobin 8.7 8.7 8.0 7.9 8.9 9.4 10 11.2 10.8 g/dL

White blood cell 9,300 11,900 12,400 6,700 10,900 12,700 8,200 8,900 7,400 X10³/µl

Platelets 891 987 891 891 891 891 588 413 421 X10³/µl

C-reactive protein 11.39 11.24 10.84 6 6.7 2.55 2.37 1.51 0.53 mg/dL

Erythrocyte sedimentation rate 110 100 80 80 122 110 79 – 23 mm/1st h

IVIG Discharge

Fi gu re 1. Clinical and laboratory evolution during hospitalization and after dischargeLegend: LP – lumbar punction; IVIG – Intravenous Immunoglobulin

drome was performed and it was negative.On day 22 of illness she developed a macu-

lopapular erythematous rash of the trunk, palmsand soles followed by periungual desquamation ofthe fingers and toes. At that time echocardiographyshowed right and left coronary arteries dilatation(3,4 and 4,2 mm in diameter respectively – Figures2 and 3). IVIG 2 g/kg and acetylsalicylic acid 100mg/kg/day were started, with significant clinicaland analytic improvement (Figure 1). On hospitalday 39 of illness, the patient was discharged homeon high-dose aspirin, which was reduced to5mg/kg/day two weeks later. Follow-up echocar-diography at week 4 of therapy showed persistentcoronary arteries dilatation (4mm) which was sub-sequently improved at week 8. Aspirin was dis-continued after complete resolution of coronaryinvolvement, demonstrated by coronary angio-computed tomography, at 4 months of treatment.

Discussion

Although KD primarily affects young children


306

marta cabral. e col.

(peak incidence - 2 years), it is uncommon in chil-dren younger than 6 months-old and quite moreunder 3 months-old, accounting for only 1.6% ofall patients with KD11-13.

Patients who do not fulfil classic criteria for KD’sdiagnosis, besides the presence of five or more daysof fever, should be referred as “incomplete” KDrather than the past designation of “atypical” KD,which should be reserved for patients who haveunusual manifestations3. KD under 6 months-oldis more likely to be incomplete and associated withcoronary artery aneurysms1,5,12. Remains unclearwhether young infants have a greater propensity todevelop coronary artery aneurysms or if this com-plication results from delayed diagnosis in incom-plete KD. Sometimes the presence of coronaryartery aneurysms may be the only definite meansto diagnose incomplete KD7. On the other hand,diag nosis may be delayed because signs and symp-toms are not present simultaneously, but appearsequentially, as it was seen in our patient5,14.

In fact, our patient had incomplete KD. Besidesthe 3-weeks long fever, she only had two diagnos-

tic criteria: the diffuse maculopapular erythema-tous rash and the periungual desquamation of fin-gers and toes, and those only appeared on the thirdweek of the disease. She had cervical lympha -denopathies, but they were bilateral and had lessthan 1.5cm in diameter. Other signs and symptomsoccasionally associated with KD include diarrheaand hepatitis1, which were present in this infant butalso common in other clinical situations.

No specific laboratory test exists for KD but uni-versal findings include leukocytosis, thrombocy-tosis and elevated acute phase reactants (erythro-cyte sedimentation rate and C-reactive protein),which were present in our patient (Figure 1). Mild--to-moderate normochromic anemia and hypoal-buminemia were also present and it is often rela -ted to a more severe and prolonged inflammatorydisease. During the subacute stage, platelet countelevation is the outstanding marker, and in theconvalescent stage platelets levels and other mar -

Table I. First laboratory searching for infectiousand autoimmune diseases

Infectious EtiologyAntistreptolysin O test (ASO); Normal;

anti-Dnase B <200 U/ml

Venereal Disease Research Negative

Laboratory (VDRL)

PCR for Enterovirus and Adenovirus (stool) Negative

and Human Herpesvirus type 6 (blood)

Serologic evaluation for Cytomegalovirus, Negative

Epstein-Barr virus, Parvovirus, Adenovirus, Respiratory syncytial virus (RSV), Influenza and Parainfluenza virus, Rickettsias, Mycoplasma pn, Chlamydia pn, Human immunodeficiency virus (HIV) 1 and 2,

Hepatitis B virus (HBV), Hepatitis C virus(HCV), Toxoplasma gondii, Brucella and

LeishmaniaTuberculin test Anergic

Cultures from blood (2), stool (3), Sterile

sputum and urine

Immunologic EvaluationAntinuclear, anti-DNAds, anti-sm, Negative

anti-RNP and anti-smoth muscle

antibodies

Figure2.Echocardiography image showing right coronary artery dilatation (3.4mm in diameter)

Figure3.Echocardiography image showing main leftcoronary artery dilatation (4.2mm in diameter)

kers begin to return to values within the referencerange, requiring 6-8 weeks to normalize, as it wasseen in our patient (Figure 1)9.

In the reported child, the presence of a “non-to -xic look” helped in the suspicion of KD. However,in a 3 month-old child disease’s clinical patternsare not specific and it was mandatory to excludeinfectious diseases.

Fever, rash, lymphadenopathy and hepato me -galy are common features in many childhood ill-nesses1. If those who have KD undergo lumbarpunc ture, approximately 50% have evidence ofaseptic meningitis1,2. Differential diagnosis withCINCA syndrome should be kept in mind when aninfant, in the first months of life, presents withfever, rash, lymphadenopathy, hepatomegaly,aseptic meningitis and high acute phase reac-tants¹�. CINCA syndrome, also known as neonatalonset multisystem inflammatory disease, is one ofthe CIAS1 syndromes characterized by fever and apersisting urticarial rash, often present at birth orin the first few months of life, accompanied byarthropathy with overgrowth (in about half ),chronic meningitis with neutrophilic pleocytosisand, later on, cerebral atrophy, sensorineural deaf-ness with developmental delay and growth delay15.Another differential diagnosis to be considered issystemic-onset juvenile idiopatic arthritis if arthri-tis was present1. However, her age (this autoim-mune disease is rare before six months-old, with amedian age of onset of 5 years old) make this hy-pothesis less probable.

The association of some infectious diseases withKD is well recognised, but rarely documented.Treatment with antibiotics doesn’t change thedisea se’s course, and fever persists unless IVIG isgiven, in responsive patients, as it was seen in ourpatient14. Considering delayed diagnosis and treat-ment in this child, it was expected a worse out-come then the observed, because 20% to 25% ofuntreated children develop coronary arteryaneurysms2,8.

Conclusion

KD should be considered in any infant or child,mainly if younger than 6 months-old, with persis-tent and unexplained fever and laboratory eviden -ce of systemic inflammation, even without moreclinical criteria suggestive of the disease, becauseearly recognition and treatment may prevent de-

velopment of coronary artery dilatation andaneurysm formation. On the other hand, this casereport showed that it’s important to perform se rialcardiac evaluations because complications can de-velop only some weeks later. The clinical challengelies in distinguishing cases of KD that do not fullymeet the diagnostic criteria from those that strong-ly resemble a variety of common childhood disor-ders.

Correspondence toMarta Cabral Hospital Prof. Doutor Fernando Fonseca E.P.E.Estrada da Venteira, IC192720-276 AmadoraPhone: +351 968 667 699E-mail: [email protected]

References1. Waseem M, Pinkert H. A febrile child who has red

eyes and a rash. Pediatr Rev 2003; 24:245-2482. Fimbres A, Shulman S. Kawasaki disease. Pediatrics

in Review 2008; 29:308-3163. Newburger J, Takahashi M, Gerber M, et al. Diagno-

sis, treatment and long-term management ofKawasaki Disease. Circulation 2004; 110:2747-2771

4. Sundel R, Petty R. Kawasaki disease. In: Cassidy JT,Petty R, Laxer R, Lindsley C. Textbook of pediatricrheumatology, 5th Ed. Elsevier Saunders, Philadel-phia. 2005, pp 521-538

5. Thapa R, Chakrabartty S. Atypical Kawasaki diseasewith remarkable paucity of signs and symptoms.Rheumatol Int 2009; 29:1095-1096

6. Juan C, Hwang B, Lee P, et al. The clinical manifesta-tions and risk factors of a delayed diagnosis ofKawasaki disease. J Chin Med Assoc 2007; 70:374-379

7. Sonobe T, Kiyosawa N, Tsuchiya K, et al. Prevalenceof coronary artery abnormality in incompleteKawasaki disease. Pediatr Int 2007; 49:421-426

8. De Rosa D, Pardeo M, Rigante D. Current recommen-dations for the pharmacologic therapy in Kawasakisyndrome and management of its cardiovascularcomplications. Eur Rev Med Pharmacol Sci 2007;11:301-308

9. Pinna G, Kafetzis D, Tselkas O, Skevaki C. Kawasakidisease: an overview. Curr Opin Infect Dis 2008;21:263-270

10. Barron KS. Kawasaki disease: etiology, pathogenesisand treatment. Clev Clin J Med 2002; 69:69-78

11. Taubert K, Rowley A, Shulman S. Seven-year nationalsurvey of Kawasaki disease and rheumatic fever. Pe-diatr Infect Dis J 1994; 13:704-708

12. Burns J, Wiggins J, Toews W, et al. Clinical spectrumof Kawasaki disease in infants younger than 6months of age. J Pediatr 1986; 109:759-763

13. Tsuchida S, Yamanaka T, Tsuchida R, Nakamura Y,Yashiro M, Yanagawa H. Epidemiology of infantKawasaki disease with report of the youngest neona-

kawasaki disease: diagnostic challenges

307



308

tal case ever reported in Japan. Acta Paediatr 1996;85:995-997

14. Simonini G, Rose C, Vierucci A, Falcini F, Athreya B.Diagnosing Kawasaki syndrome: the need for a newclinical tool. Rheumatology 2005; 44:959-961

15. Caroli F, Pontillo A, D’Osualdo A, et al. Clinical andgenetic characterization of Italian patients affectedby CINCA syndrome. Rheumatology (Oxford) 2007;46:473-478

marta cabral. e col.

13th Annual European Congress of Rheumatology

Berlim, Alemanha6 a 9 Junho 2012


309

i m a g e n s e m r e u m at o l o g i a

s c h w a n n o m a o f t h e p o s t e r i o r t i b i a l n e r v e

i n l e p r o s y p at i e n t : i m a g i n g f e at u r e s

Erilane Leite Guedes*, Sandra Lúcia Euzébio Ribeiro**, Paula Frassinetti Bessa Rebello***,

Denis Esteves Raid****, Ernani Júnior Guedes de Freitas*****

*Gastroenterology Resident, Base Hospital, Medicine Faculty of

São José do Rio Preto (FAMERP), São Paulo, Brazil

**Supervisor of Rheumatology Residence of Getúlio Vargas

University Hospital (HUGV)/ Amazon Federal University (UFAM),

Brazil

***Medical Dermatologist of the Foundation Alfredo da Matta

(FUAM), Amazon State University Brazil

****Medical of Neurosurgery Division Amazon Federal University

(UFAM), Brazil

*****Radiologist Medical of Getúlio Vargas University Hospital

(HUGV) Amazon Federal University (UFAM), Brazil

Schwannoma is a slow growing tumor, usually en-capsulated, which rarely undergo malignant trans-formation. Represents 5% of soft tissue tumors,most commonly found between the fourth to sixthdecades of life1-2. The tumor has a predilection forthe head, neck and flexor surfaces of the upper andlower extremities but posterior tibial nerve schwan-noma has also been described3. Man and womenare equally affected1,4.

Case Report

The author’s describe a 51 year old male, witharthralgia on the right elbow, and multiple painfulpurpuric macules and plaques with asymmetricdistribution in the trunk and in the extremities. Hehad pain and thickening in left ulnar and cubitalnerves course suggestive of neuritis. He was diag-nosed of lepromatous leprosy and started a mul-tidrug therapy for leprosy and prednisone 60mg/day to neuritis, with a clinical improvement af-ter 5 months of treatment. Subsequently developedsevere pain in right leg, first episode of neuritis inthe posterior tibial nerve and was submitted to neu-rolysis, but the pain in foot persisted. After 6months he had a palpable and painfull mass inpopliteal fossa and image studies were requested.Ultrasonography (US) showed a well-defined, hy-poechoic, heterogeneous and oval mass measuring

2.4 x 1.9 cm and 1.5 x 1.2 cm, along the tibial nerve(Figure 1). Magnetic resonance imaging (MRI) ofthe knee was performed. On spin-echo T1-weight-ed MR images, the lesion was homogeneous andisointense relative to skeletalmuscle (Figure 2A)and T2-weighted MR images demonstrated the le-sion to bemildly heterogeneous, with a signal in-tensity greater than thatof fat (Figure 2B), measur-ing 2.5 x 2.2 cm and 1.5 x 1.2 cm.

The diagnosis of schwannoma was made, basedon clinical and radiological findings. Clinical symp-

A B

Fi gu re 2. Sagital spin-echo T1-weighted MR image of theknee shows the mass to be homogeneous and isointenserelative to skeletal muscle (Figure 2A) and T2-weightedMR image shows a well-defined mass within the poplitealfossa. The mass is mildly heterogeneous with a signal intensity greater than that of fat (Figure 2B), measuring 2.5 x 2.2 cm and 1.5 x 1.2 cm.

Fi gu re 1. Longitudinal US - over the right popliteal fossashowed a well-defined, hypoechoic, heterogeneous andoval mass (2.4 x 1.9 cm and 1.5 x 1.2 cm), along the tibialnerve.


310

schwannoma of the posterior tibial nerve in leprosy patient

toms resulted from tumor location and size, withneurologic dysfunction from local mass effect4. USis a non-invasive convenient tool that can be usedto evaluate a soft-tissue mass as schwannoma, andimportant features include the presence of a cap-sule, the eccentric position of the nerve relative tothe mass, and a cystic lesion within it2. The MRimaging appearance of the schwannoma in thiscase is similar to that of others reported in the lite -rature5. Surgical resection of schwannoma is thetreatment of choice6. The recurrence on long termfollow up, after complete surgical excision, is rare6

.

Correspondence toSandra Lúcia Euzébio RibeiroRua Ramos Ferreira, nº 1280, Bairro CentroCEP:69020-080; Manaus – Amazonas State BRAZIL CEP:69020-080 Tel: (0XX92) 3633-4977, E-mail:[email protected]

References1. Kleihues P, Cavenee WK. Pathology and genetics of

tumours of the nervous system. Lyon: World HealthOrganization, 1997.

2. Lin HW, Shieh JY, Wang TG, Chen WS, Wang CL, WangYH. Ultrasonographic Features of Schwannoma ofthe Lower Limb: Two Case Reports. Tw J Phys MedRehabil 2008;36:169-175.

3. Maia M, Riobom F, Ferreira J, et al. Schwannoma ofthe Posterior Tibial Nerve: An Unusual Finding du -ring Arterial Ultrasound Examination of the LowerExtremities. J Vasc Ultrasound 2011;35:24-36.

4. Asthagiri AR, Helm GA, Sheehan JP. Current Conceptsin Management of Meningiomas and Schwannomas.Neurol Clin 2007;25:1209-1230.

5. Stull MA, Moser RP, Kransdorf MJ, Bogumill GP, Nel-son MC. Magnetic resonance appearance of periph-eral nerve sheath tumors. Skeletal Radiol 1991;20:9--14

6. Nievas MNC, Archavlis E, Unkel B. Delayed outcomefrom surgically treated patients with benign nerve as-sociated tumors of the extremities larger than 5 cm.Neurological Research 2010;32:563-571.


311

c a r ta a o e d i t o r

o l a n z a p i n e t r e at m e n t i m p r o v e d q u a l i t y o f

l i f e i n a p at i e n t w i t h f i b r o m y a l g i a

s y n d r o m e : a p s y c h o l o g i c a l e va l u at i o n

Corallo F*†, Italiano D*†, Bonanno L*, Baglieri A*, Marino S*, Bramanti P*

*IRCCS Centro Neurolesi “Bonino-Pulejo” Messina, Italy

†These authors equally contributed to this work.

increments were not needed. Indeed within a fewweeks patient referred an improvement of her dai-ly aching pain symptoms and an increased sense ofwell-being.

After three months OLZ-treatment, patient onlypresented slight muscular pain, so she strongly re-duced the use of non-steroidal anti-inflammatorydrugs, and she was able to discontinue pregabalinand to reduce prazepam to 20 mg/day. Patient isnow on duloxetine 60 mg/day, OLZ 2,5 mg/day andprazepam 20 mg/day, without any significant side--effect. The Fibromyalgia Impact Questionnaire,the Short-Form Health Survey and the CopingOrien tation to the Problems Experienced, wereadminis tered to assess the disease impact on dailyactivities and quality of life before OLZ introductionand at the three months follow-up7-9. Results aresummarized in the figure (Figure 1)

The only study evaluating OLZ influence on painand quality of life used uniquely the Brief Pain In-ventory to explore patient’s pain and functioning4.Another study on a series of 25 FMS patients fo-cused on OLZ effectiveness without exploring pa-tients’ quality of life5. To our knowledge the currentarticle is the first including a FMS symptom-spe-cific tool and a psychological evaluation to assesshow OLZ treatment influences the quality of life ina FMS patient.

Antagonism for 5HT-2 and 5HT-3 receptors wasproposed as a possible mechanism of action forOLZ-induced pain relief4,6. As OLZ plasma levels arenot modified by add-on duloxetine, we can rea-sonably exclude that pharmacokinetic interactionsbetween duloxetine and OLZ could account for theclinical and psychological improvement in thissubject10.

Our case provides further evidence that OLZ canbe a valuable therapeutic option in patients withFMS. Notably, just a very low OLZ dosage (2,5mg/day) was able to provide substantial benefits tothe patient, fact that is relevant because tolerabili-

Dear Editor,Fibromyalgia Syndrome (FMS) is a disabling

con dition characterized by widespread chronicmuscular pain, fatigue and a range of functionaldisorders, affecting 0.1% to 3.0% of the general po -pu lation. The etiology of FMS remain uncertain,involving somatic, psychological and social fac-tors1. Currently, no treatment has been demons -trated to be fully effective on all FMS symptoms, norany consensus on how to manage the conditionhas been reached. Treatment recommendationspropose palliating symptoms, along with a multi-modal approach1,3. Anecdotic evidences and fewstudies support the efficacy of olanzapine (OLZ) intreating FMS4-6. Nevertheless, benefits of OLZ onthe quality of life have not been investigatedexhaus tively.

We herein report a 56-years-old married whitefemale presenting with diffuse musculoskeletalpain, morning stiffness, headache and chronic fa-tigue for 2 years. Comorbidity for anxiety, depres-sion and dysphoric mood was also reported.

The diagnosis of FMS was based, according theAmerican College of Rheumatology criteria1,2, onthe presence of chronic (>3 months) pain in all fourquadrants of the body and tenderness in at least 11of 18 tender-points at pre-defined locations.

At the time of the initial evaluation, she was ta -king amitriptiline 50 mg/day at bedtime and pra -zepam 30 mg/day. Abuse of various non-steroidalanti-inflammatory drugs was also reported. Due tounsatisfactory response, treatment with amitripti-line was substituted by duloxetine 60 mg/day,obtai ning only partial efficacy in mood disordersbut no significant improvement in pain. Add-onpregabalin 150 mg/day did not significantly im-proved her disturbances. Therefore, OLZ was in-troduced at 2,5 mg/day at bedtime. Further dosage


312

ty appeared as the main limit to OLZ use in thispathology5. Therefore, association therapy of OLZand other pain-effective medication could be con-sidered as a feasible therapeutic choice for themanagement of pain and emotional symptoms inFMS patients. Obviously, these findings need to beexplored in controlled studies on a larger numberof patients.

Correspondence toDomenico Italiano, MDIRCCS Centro Neurolesi “Bonino-Pulejo”Tel. 09060128954E-mail: [email protected]

References1. Clauw DJ. Fibromyalgia: an overview. Am J Med 2009;

122:S3-S13.2. Wolfe F, Smythe HA, Yunus MB, et al. The American

College of Rheumatology 1990 Criteria for the Classi-fication of Fibromyalgia. Report of the MulticenterCriteria Committee. Arthritis Rheum 1990; 33:160--172.

3. Mease PJ. Fibromyalgia: key clinical domains, co-morbidities, assessment and treatment. CNS Spectr2009; 14:6-9.

4. Freedenfeld RN, Murray M, Fuchs PN, Kiser RS. De-creased pain and improved quality of life in fi-bromyalgia patients treated with olanzapine, anatypical neuroleptic. Pain Pract 2006; 6:112-118.

5. Rico-Villademoros F, Hidalgo J, Dominguez I, García-Leiva JM, Calandre EP. Atypical antipsychotics in thetreatment of fibromyalgia: a case series with olanza -pi ne. Prog Neuropsychopharmacol Biol Psychiatry2005; 29:161-164.

6. Kiser RS, Cohen HM, Freedenfeld RN, Jewell C, FuchsPN. Olanzapine for the treatment of fibromyalgiasymptoms. J Pain Symptom Manage 2001; 22:704--708.

7. Pagano T, Matsutani LA, Ferreira EA, Marques AP,Pereira CA. Assessment of anxiety and quality of lifein fibromyalgia patients. Sao Paulo Med J 2004;122:252-258.

8. Assumpção A, Pagano T, Matsutani LA, Ferreira EA,Pereira CA, Marques AP. Quality of life and discrimi-nating power of two questionnaires in fibromyalgiapatients: Fibromyalgia Impact Questionnaire andMedical Outcomes Study 36-Item Short-Form HealthSurvey. Rev Bras Fisioter 2010; 14:284-289.

9. Boehm A, Eisenberg E, Lampel S. The Contributionof social capital and coping strategies to functioningand quality of life of patients with fibromyalgia. Clin JPain 2010; 27:233-239.

10. Santoro V, D'Arrigo C, Spina E, Micò U, MuscatelloMR, Zoccali R. Effect of adjunctive duloxetine on theplasma concentrations of clozapine, olanzapine, andrisperidone in patients with psychotic disorders. JClin Psychopharmacol 2010; 30:634-636.

olanzapine and quality of life in fibromyalgia patients

PhysicalFunction

RoleLimitationPhysical

SF-36 test

RoleLimitationEmotional

PhysicalPain

GeneralHealth Energy

MentalHealth

SocialFunctioning

706050403020100

Pre-OLZ 5 5 10 40 40 35 35 60

Post-OLZ 10 15 22 45 50 54 53 64

Social Support

COPE test

AvoidanceStrategies

Positiveattitude

Turning toReligion

ProblemSolving

454035302520151050

Pre-OLZ 17 25 19 14 32

Post-OLZ 42 30 40 40 38

Figure1.Tests scores before and after OLZ treatment.SF-36, Short Form Health Survey; COPE, Coping Orientation to the Problems Experienced; OLZ, Olanzapine; FIQ, Fibromyalgia Impact Questionnaire.


313

c a r ta a o e d i t o r

n e u r o p at i a p e r i f é r i c a e l e f l u n o m i d a

Santiago T*, Rovisco J*, Silva J**, Malcata A***

*Interno do Internato Complementar de Reumatologia, Serviço

de Reumatologia, Hospitais da Universidade de Coimbra

**Assistente Hospitalar Graduado de Reumatologia, Serviço de

Reumatologia, Hospitais da Universidade de Coimbra

***Chefe de Serviço, Serviço de Reumatologia, Hospitais da

Universidade de Coimbra

O estudo electromiográfico confirmou uma po-lineuropatia axonal sensitiva. Após 10 meses dasuspensão de LEF, o doente apresenta melhoria sin-tomática, comprovada clinicamente.

No caso clínico descrito decorreu uma larga re-lação temporal entre o início dos sintomas e o usode LEF. No entanto, verificou-se melhoria signifi-cativa da neuropatia após suspensão da LEF, en-quanto todos os outros medicamentos, incluindoa dose de corticóides foi mantida. Apesar da poli-neuropatia sensitiva ser reconhecida como mani-festação extra-articular da artrite reumatóide, naverdade, o doente não tinha nódulos reumatóides,e para além disso, o início da neuropatia ocorreudurante uma fase de doença pouco activa, pare-cendo pouco provável a associação com a doençade base.

A neuropatia periférica reversível é um efeito ad-verso para o qual o clínico deve estar alerta, ocor-rendo nalguns doentes tratados com LEF4.

A acumulação dos metabolitos tóxicos da LEFprovocam morte axonal podendo ocasionar irre-versibilidade da neuropatia5. A suspensão do fár-maco e a administração de colestiramina para au-mentar a depuração, têm bons resultados6. Umarevisão de 80 casos reportados à Food and Drug Ad-ministration, mostrou que sintomas de disfunçãodo sistema nervoso periférico, tipicamente com po-lineuropatia axonal, iniciavam-se 6 meses após oinício do fármaco, embora possa variar entre 3 a1126 dias5. A maioria dos casos apresentam-se comquadro de parestesias periféricas, disestesias, dor,sensação de frio nas extremidades distais, oufraqueza extrema.

Num outro estudo, 5 de 50 doentes com artritereumatóide sob LEF, desenvolveram sintomas deneuropatia periférica, melhorando após a suspen-são do fármaco7.

Dadas as limitações inerentes a relatos de casosisolados, seriam úteis estudos adicionais para me -lhor estabelecer a natureza da associação entre ouso de LEF e neuropatia periférica.

Ao considerar o diagnóstico de neuropatia peri-férica devem ser excluídas outras causas, nomea-

Ao Exmo. EditorA leflunomida (LEF) é um fármaco com pro-

priedades anti-inflamatórias que resultam da con-versão do seu metabolito activo, o A77 1726, ini-bindo a síntese dos nucleótidos de pirimidina. Estaacção é mediada fundamentalmente pela enzimadihidroorotato desidrogenase. Trata-se de um fár-maco modificador da doença aprovado para o tra-tamento da artrite reumatóide, quer em monote-rapia quer em terapêutica de combinação (com ometotrexato), estruturalmente diferente de outrosimunomoduladores e com um mecanismo de acção único no tratamento da artrite reumatóide1.

Os efeitos colaterais mais comummente obser-vados em doentes sob LEF são diarreia, elevação deenzimas hepáticas, alopécia, rash e hipertensão ar-terial2,3.

Os autores descrevem um caso de neuropatia pe-riférica associada à LEF. Descreve-se o caso clínicode um doente do sexo masculino, 62 anos, com ar-trite reumatóide erosiva seronegativa, com 20 anosde evolução, previamente tratado com metotrexa-to, sulfassalazina e hidroxicloroquina, que iniciouLEF numa dose de manutenção de 20mg/dia. Dosantecedentes pessoais salienta-se enfarte agudo domiocárdio e hipertensão arterial. Após 3 anos de te-rapêutica com LEF iniciou quadro de disestesias naperna esquerda com distribuição em meia, asso-ciada a hiporeflexia e diminuição da força muscu-lar. A LEF foi suspensa. A restante medicação con-sistia em metilprednisolona, omeprazol, sinvasta-tina, ramipril, que o doente já tomava há algunsanos e sem efeitos adversos. A glicémia, vitaminaB12, ácido fólico, função tiróideia, proteínas séricas,proteinograma electroforético, crioglobulinas,ANA�s e ANCA�s, VDRL, hepatite B e C, pesquisa desubstância amilóide na gordura abdominal, esta-vam normais ou negativas.


314

damente metabólicas e medicamentosas, e poste-riormente confirmar com estudos electromiográ-ficos. Deste modo, os reumatologistas deverão terem consideração esta causa possível de neuropa-tia periférica em doentes com artrite reumatóide.

Correspondência paraTânia SantiagoHospitais da Universidade de CoimbraServiço de ReumatologiaPraceta Mota Pinto3000 CoimbraE-mail: [email protected]

Referências1. Strand V, Cohen S, Schiff M, et al. Treatment of active

rheumatoid arthritis with leflunomide comparedwith placebo and methotrexate. LeflunomideRheumatoid Arthritis Investigators Group. Arch In-tern Med 1999; 21:2542.

2. Kremer JM, Cannon GW. Benefits / risk of lefluno-mide in rheumatoid arthritis. Clin Exp Rheumatol2004; 22: S95-100.

3. O'Dell JR. Therapeutic Strategies for RheumatoidArthritis. New England Journal of Medicine 2004; 17:2591-2602.

4. Metzler C, Arlt AC, Gross WL, Brandt J. Peripheralneuropathy in patients with systemic rheumatic dis-eases treated with leflunomide. Ann Rheum Dis2005; 12: 1798-1800.

5. Bonnel RA, Graham DJ. Peripheral neuropathy in pa-tients treated with leflunomide. Clin Pharmacol Ther2004; 6:580-585.

6. Hill CL. Leflunomide-induced peripheral neuropa-thy: rapid resolution with cholestyramine wa -shout.Rheumatology 2004; 43:809.

7. Bharadwaj A, Haroon N. Peripheral neuropathy inpatients on leflunomide. Rheumatology (Oxford)2004; 43:934.

neuropatia periférica e leflunomida

órgão of ic ial da soc iedade portuguesa de reumatologia - acta reumatol port. 2011;36:316

316

a g e n d a

g Jornadas de Outono SPR 2011

Local e Data: Viseu, Portugal, 30 de Setembro a 2 de Outubro 2011

g I Curso Básico de Ecografia Músculo-Esquelética

Local e Data: Castelo Branco, Portugal, 14 a 16 Outubro 2011

g EuroSpine 2011

Local e Data: Milão, Itália, 19 a 21 Outubro 2011

g 75th Annual Meeting of the American College of Rheumatology

Local e Data: Chicago, EUA, 5 a 9 Novembro 2011

g XIX Jornadas Internacionais do Instituto Português de Reumatologia

Local e Data: Lisboa, Portugal, 24 a 25 Novembro 2011

g 24e Congrès Français de Rhumatologie

Local e Data: Paris, França, 11 a 14 Dezembro 2011

g World Congress on Debates and Consensus on Bone, Muscle & Joint Diseases

Local e Data: Barcelona, Espanha, 19 a 22 Janeiro 2012

g 2nd Systemic Sclerosis World Congress

Local e Data: Madrid, Espanha, 2 a 4 Fevereiro 2012

g PANLAR

Local e Data: Punta Cana, República Dominicana, 18 a 21 Abril 2012

g XVI Congresso Português de Reumatologia

Local e Data: Algarve, Portugal, 1 a 5 Maio 2012

g XXXVIII Congreso Nacional de la SER

Local e Data: Saragoça, Espanha, 16 a 18 Maio 2012

g 39th European Symposium on Calcified Tissues

Local e Data: Estocolmo, Suécia, 19 a 23 Maio 2012

g 13th Annual European Congress of Rheumatology

Local e Data: Berlim, Alemanha, 6 a 9 Junho 2012

órgão of ic ial da soc iedade portuguesa de reumatologia - acta reum port. 2011;36:317-320

317

n o r m a s d e p u b l i c a ç ã o

Os ma nus cri tos de vem ser acom pa nha dos de de cla ra -ção de ori gi na li da de e de ce dên cia dos di rei tos de pro prie -da de do ar ti go, as si na da por to dos os au to res, con for memi nu ta pu bli ca da em ane xo.

O tex to deve ser en vi a do em for ma to di gi tal (e-mail),a dois es pa ços, com le tra ta ma nho12 e com mar gens nãoin fe rio res a 2,5 cm, em Word para Win dows. To das as pá -gi nas de vem ser nu me ra das.

As ima gens de vem ser for ne ci das in de pen den te men -te do tex to em for ma to JPEG ou TIFF.

Os tex tos de vem ser or ga ni za dos da se guin te for ma:Pá gi na 1a) Tí tu lo em por tu guês e in glês b) Nome dos au to res e res pec ti va afi li a ção c) Ser vi ço(s) ou or ga nis mo(s) onde o tra ba lho foi exe -

cu ta do d) Sub sí dio(s) ou bol sa(s) que con tri bu í ram para a rea -

li za ção do tra ba lho e) Mo ra da e e-mail do au tor res pon sá vel pela cor res -

pon dên cia re la ti va ao ma nus cri to f) Tí tu lo bre ve para ro da pé

Pá gi na 2a) Tí tu lo (sem au to res)b) Re su mo em por tu guês e in glês, que para os ar ti gos

ori gi nais deve ser es tru tu ra do da se guin te for ma: Ob jec -ti vos, Ma te ri al e Mé to dos, Re sul ta dos, Con clu sões. O re -su mo dos ar ti gos ori gi nais não deve ex ce der as 350 pa la -vras e o dos ca sos clí ni cos as 180 pa la vras.

c) Pa la vras-cha ve em por tu guês e em in glês (Key -words)

Um má xi mo de 5 pa la vras-cha ve, uti li zan do a ter mi -no lo gia que cons ta na lis ta do In dex Me di cus: «Me di calSub ject He a dings» (MeSH), deve se guir-se ao re su mo.

Pá gi na 3 e se guin tesAr ti gos ori gi nais: O tex to deve ser apre sen ta do com os

se guin tes sub tí tu los: In tro du ção (in clu in do Ob jec ti vos),Ma te ri al e Mé to dos, Re sul ta dos, Dis cus são, Conclusões,Agra de ci men tos (se apli cá vel), Re fe rên cias.

Os ar ti gos ori gi nais não de ve rão ex ce der as 4.000 pa -la vras, com um to tal de 6 fi gu ras/ta be las e 60 re fe rên cias.

Caso clí ni co: os sub tí tu los se rão, In tro du ção, Caso clí -ni co, Dis cus são, Re fe rên cias.

O caso clí ni co não deve ex ce der as 2.000 pa la vras e 25re fe rên cias. Deve ser acom pa nha do de fi gu ras ilus tra ti -vas. O nú me ro de ta be las/fi gu ras não deve ser su pe riora 6.

A par tir da se gun da pá gi na, in clu si ve, to das as pá gi nasde vem ter em ro da pé o tí tu lo bre ve in di ca do na pá gi na 1.

Re fe rên cias: As re fe rên cias bi bli o grá fi cas de vem serclas si fi ca das e nu me ra das por or dem de en tra da no tex -to, em su pers cript e não en tre pa rên te sis. As abre vi a tu rasusa das na no me a ção das re vis tas de vem ser as uti li za daspelo In dex Me di cus.

Nas re fe rên cias com 6 ou me nos au to res to dos de vemser no mea dos. Nas re fe rên cias com 7 ou mais au to res de -vem ser no mea dos os 3 pri mei ros se gui dos de et al.

No tas: Os nú me ros da pá gi na ini ci al e fi nal de vem serto tal men te apre sen ta dos (565-569 e não 565-9)

A Acta Reu ma to ló gi ca Por tu gue sa pu bli ca ar ti gos ori -gi nais so bre to dos os te mas da Reu ma to lo gia ou com elare la ci o na dos. São tam bém pu bli ca dos ar ti gos de re vi são,ca sos clí ni cos, ima gens, car tas ao edi tor e ou tros que sein cluam na es tru tu ra edi to ri al da re vis ta (re co men da ções,ar ti gos so bre prá ti ca clí ni ca reu ma to ló gi ca, no tí cias dere u ni ões de so ci e da des ci en tí fi cas, por ex.).

A Acta Reu ma to ló gi ca Por tu gue sa sub scre ve os re qui -si tos para apre sen ta ção de ar ti gos a re vis tas bi o mé di casela bo ra das pela Co mis são In ter na cio nal de Edi to res deRe vis tas Mé di cas (In ter na ti o nal Com mi tee of Me di calJour nal Edi tors), pu bli ca da na ín te gra ini ci al men te em NEngl J Med 1991; 324: 424-28 e ac tu a li za da em Ou tu bro de2008 e dis po ní vel em www.ICMJE.org. A po tí ti ca edi to rialda Acta Reu ma to ló gi ca Por tu gue sa se gue as Re co men da -ções de Po lí ti ca Edi to ri al (Edi to ri al Po licy Sta te ments) emi -ti das pelo Con se lho de Edi to res Ci en tí fi cos (Coun cil ofSci en ce Edi tors), dis po ní veis em www.coun cil sci en ce e di -tors.org/ser vi ces/draft_ap pro ved.cfm.

A Re vis ta está in de xa da no Pub Med/Med li ne e os ar ti -gos es tão dis po ní veis on li ne na ín te gra, com aces so aber -to e gra tui to.

Os ar ti gos de vem pre fe ren ci al men te ser re di gi dos emin glês. Os ar ti gos em lín gua por tu gue sa tam bém po demser sub me ti dos para apre cia ção.

O ri gor e a exac ti dão dos con te ú dos, as sim como asopi ni ões ex pres sas são da ex clu si va res pon sa bi li da de dosau to res.

Os au to res de vem de cla rar po ten ci ais con fli tos de in -te res se.

Os ar ti gos não po dem ter sido an te rior men te pu bli ca -dos nou tra re vis ta. Quan do o ar ti go é acei te para pu bli ca -ção é man da tó rio o en vio via e-mail de do cu men to di gi -ta li za do, as si na do por to dos os au to res, com a trans fe rên -cia dos di rei tos de au tor para a Acta Reu ma to ló gi ca Por -tu gue sa.

Os ar ti gos pu bli ca dos fi ca rão pro pri e da de da re vis ta,não po den do ser re pro du zi dos, no todo ou em par te, semau to ri za ção dos edi to res.

A acei ta ção dos ori gi nais en vi a dos para pu bli ca ção ésem pre con di cio na da a ava lia ção pe los con sul to res edi -to ri ais. Nes ta ava lia ção os ar ti gos po de rão ser:

a) acei tes sem al te ra ções;b) acei tes após mo di fi ca ções pro pos tas pe los re vi so res;c) re cu sa dos.Em to dos os ca sos os pa re ce res dos con sul to res se rão

in te gral men te co mu ni ca dos aos au to res.Quan do são pro pos tas al te ra ções, o au tor de ve rá en -

vi ar via e-mail no pra zo de 1 mês, uma car ta ao edi tor e acada um dos re vi so res res pon den do a to das as ques tõesco lo ca das e uma ver são re vis ta do ar ti go com as al te ra çõesin se ri das des ta ca das com cor di fe ren te.

Ins tru ções aos Au to resTo dos os ma nus cri tos que não es te jam em con for mi -

da de com as ins tru ções que se se guem po dem ser en vi a -dos para mo di fi ca ções an tes de se rem re vis tos pe los con -sul to res.

To dos os tra ba lhos de vem ser en vi a dos por e-mail para:[email protected].


318

Não in di car o nú me ro da re vis ta nem o mês da pu bli -ca ção.

Seguem-se alguns exemplos de como devem constaros vários tipos de referências:– Re vis ta

Ape li do e ini ci ais do(s) au tor(es). Tí tu lo do ar ti go.Nome da re vis ta Ano; Vo lu me: Pá gi nas.

Ex.: Hill J, Bird HA, Hopkins R, Lawton C, Wright V. Sur -vey of sa tis fac ti on with care in a rheu ma to logy out pa -tient cli nic. Ann Rheum Dis 1992; 51:195-197.– Ar ti go pu bli ca do on li ne (in se rir DOI )

Ex.: Pe ter A Merkel, Da vid Curthbertson, Ber nhardHellmich et al. Com pa ri son of di se a se ac ti vity me a su resfor ANCA-as so cia ted vas cu li tis. Ann Rheum Dis Pu blis hedOn li ne First: 29 July 2008. doi:10.1136/ard.2008. 097758 – Ca pí tu lo de li vro

Nome(s) e ini ci ais do(s) au tor(es) do ca pí tu lo. Tí tu lodo ca pí tu lo. In: Nome(s) e ini ci ais do(s) edi tor(es) mé di -co(s). Tí tu lo do li vro. Ci da de: Nome da casa edi to ra, anode pu bli ca ção: pri mei ra a úl ti ma pá gi na do ca pí tu lo.

Ex.: Stewart AF. Hyper cal ce mia re sul ting from me di ca -ti ons. In: Fa vus MJ, ed. Pri mer on the Me ta bo lic Bone Di -se a ses and Di sor der of Mi ne ral Me ta bo lism. New York:Ra ven Press, 1993: 177-178.– Li vro

Nome(s) e ini ci ais do(s) au tor(es). Tí tu lo do li vro. Ci -da de: Nome da casa edi to ra, ano de pu bli ca ção: pá gi na(s).

Ex.: Lo rig K. Pa ti ent Edu ca ti on. A prac ti cal ap pro ach.St. Lou is: Mosby-Year Book;1992: 51.– Do cu men to elec tró ni co

Ex: Pro gra ma Na ci o nal de Luta Con tra a Tu ber cu lo se.Sis te ma de Vi gi lân cia (SVIG-TB). Di rec ção-Ge ral da Saú -de - Di vi são de Doen ças Trans mis sí veis, Mar ço de 2005http://www.dgsau de.pt/uplo ad/mem bro.id/ fi chei ros/i006875.pdf. Ace di do em 25 Ja nei ro de 2008

As re fe rên cias a tra ba lhos ain da não pu bli ca dos, co -mu ni ca ções em re u ni ões, não pu bli ca das em li vros dere su mos, ou co mu ni ca ções pes so ais de vem ser ci ta das notex to e não como re fe rên cias for mais.

A exac ti dão e o ri gor das re fe rên cias são da res pon sa -bi li da de do au tor.

Ta be las: As ta be las a in se rir de vem ser as si na la das notex to em nu me ra ção ro ma na e cum prir o li mi te des cri toaci ma. Cada ta be la de ve rá ser apre sen ta da em fo lha se -pa ra da, dac ti lo gra fa da a 2 es pa ços. Na par te su pe rior de -vem apre sen tar um tí tu lo su cin to mas in for ma ti vo, demodo a po der ser com pre en di do sem re cur so ao tex to. Napar te in fe rior da ta be la deve cons tar a ex pli ca ção dasabre vi a tu ras uti li za das. Nas ta be las de vem ser evi ta dos ostra ços ver ti cais e os tra ços ho ri zon tais, es tes de vem ser -vir ape nas como se pa ra do res de tí tu los e sub tí tu los.

Fi gu ras: As fi gu ras a in se rir de vem ser as si na la das notex to em nu me ra ção ára be e cum prir o li mi te de fi ni doaci ma. As le gen das das fi gu ras de vem ser dac ti lo gra fa dasa dois es pa ços numa fo lha se pa ra da, de pois da bi bli o gra -fia. As fi gu ras de vem ser en vi a das em su por te in for má ti -co com fi chei ros se pa ra dos para cada fi gu ra, em for ma -to JPEG ou TIFF.

Edi to ri ais: Os edi to ri ais se rão so li ci ta dos por con vi tedo Edi tor. Os edi to ri ais se rão co men tá rios so bre tó pi cos actuais ou so bre ar ti gos pu bli ca dos na re vis ta. O tex to dos

edi to ri ais não deve ex ce der as 1.200 pa la vras, um má ximode 15 re fe rên cias e não deve con ter qua dros ou fi gu ras.

Ar ti gos de re vi são:Es tes ar ti gos se rão pre fe ren ci al men -te so li ci ta dos pelo Edi tor. No en tan to, os au to res in te res -sa dos em apre sen tar um ar ti go de re vi são po dem con tac -tar o Edi tor para dis cus são dos tó pi cos a apre sen tar.

O ar ti go de re vi são não deve ex ce der as 4.000 pa la -vras, 6 ta be las/fi gu ras e 100 re fe rên cias.

Car tas ao Edi tor: As car tas ao edi tor de vem cons ti tuirum co men tá rio crí ti co a um ar ti go da re vis ta ou uma pe -que na nota so bre um tema ou caso clí ni co. Não de vemex ce der as 600 pa la vras, uma fi gu ra ou um qua dro, e ummá xi mo de 10 re fe rên cias bi bli o grá fi cas.

Ima gens em reu ma to lo gia: Po dem ser sub me ti dasima gens de par ti cu lar in te res se. As fi gu ras, no má xi mo de4, de vem ser en vi a das em for ma to JPEG ou TIFF de boare so lu ção. O tex to acom pa nhan te não deve ul tra pas sar as500 pa la vras.

Mo di fi ca ções e re vi sões: No caso da acei ta ção do ar -ti go ser con di cio na da a mo di fi ca ções, es tas de ve rão serfei tas pe los au to res no pra zo de 1 mês.

Quan do são pro pos tas al te ra ções, o au tor de ve rá en -de re çar uma car ta ao edi tor e a cada um dos re vi so resres pon den do a to dos as ques tões co lo ca das. De ve rá ain -da sub me ter uma ver são re vis ta do ar ti go com as al te -ra ções in se ri das des ta ca das com cor di fe ren te.

As pro vas ti po grá fi cas se rão, sem pre que pos sí vel, en -vi a das aos au to res con ten do a in di ca ção do pra zo parare vi são con so an te as ne ces si da des edi to ri ais da re vis ta.

Mi nu ta da car ta de sub mis são a en vi ar ao Edi tor, di gi -ta li za da, por e-mail:

Enviar este documento com o manuscrito para:[email protected]

Edi torActa Reu ma to ló gi ca Por tu gue saO(s) au tor(es) cer ti fi ca(m) que o ma nus cri to in ti tu la -do: ____________________________________________(ref. ARP_________) é ori gi nal, que to das as afir ma çõesapre sen ta das como fac tos são ba sea dos na in ves ti ga -ção do(s) au tor(es), que o ma nus cri to, quer em par tequer no todo, não in frin ge ne nhum copyright e nãovio la ne nhum di rei to da pri va ci da de, que não foi pu -bli ca do em par te ou no todo e que não foi sub me ti dopara pu bli ca ção, no todo ou em par te, nou tra re vis ta,e que os au to res têm o di rei to ao copyright.To dos os au to res de cla ram ain da que par ti ci pa ram notra ba lho, se res pon sa bi li zam por ele e que não exis te,da par te de qual quer dos au to res con fli to de in te res -ses nas afir ma ções pro fe ri das no tra ba lho.Os au to res, ao sub me te rem o tra ba lho para pu bli ca -ção, trans fe rem para a Acta Reu ma to ló gi ca Por tu guesato dos os di rei tos a in te res ses do copyright do ar ti go.

Todos os autores devem assinarData: __________________________________________Nome (maiúsculas): ____________________________Assinatura: ____________________________________


319

i n s t r u c t i o n s f o r a u t h o r s

Manuscripts should be organized as explained below:

Page 1a) Tit le in Por tu gue se and in En glish; b) Au thors' na mes and af fi li a ti ons;c) Ins ti tu ti on(s) to which the work should be at tri -

buted; d) Sour ce(s) of grants sup port;e) Name, ad dress and e-mail of the cor res pon ding au -

thor f) Short run ning tit le.

Page 2a) Title (without authors)b) AbstractAbstract in English structured as follows for the origi-

nal articles: Objectives; Patients and Methods; Results;Conclusions. The abstract should not exceed 350 words fororiginal articles and 180 words for case reports.

c) KeywordsA maximum of 5 keywords – must be MeSH terms –

should be presented after the abstract.

Page 3 and following pagesOriginal papers: The text of original papers should be

presented with the following subtitles: Introduction, Ob-jectives, Patients and Methods, Results, Discussion, Con-clusions, Acknowledgements, References.

Original papers should not exceed 4,000 words, 6 Ta-bles/Figures and 60 references.

Case report: Subtitles for case reports should be: In-troduction, Case report, Discussion, References.

A case report should not exceed 2,000 words and 25references. It should present illustrative figures. Thenumber of Tables/Figures should not exceed 6.

From the second page on, all pages should have a shorttitle on footnote.

References: References should be cited by the numeri -cal system, superscript and listed, in the order cited in thetext. Journal titles are abbreviated in accordance with thestyle of Index Medicus.

List all authors when 6 or less; when 7 or more list onlyfirst 3 and add “et al”.

Do not abbreviate the page number (i.e. correct: 565--569 and not: 565-9).

The Journal number and the month of publicationshould not be presented.

References of unpublished work, presentations or per-sonal observations should be inserted in the text (inparenthesis) and not as a “classical” or true reference.

Authors are responsible for the accuracy of the refe rences.

Examples:

– Journal articleName(s) and ini ti als of au thor(s). Ar ti cle tit le. Jour nal

name Year; Vo lu me or num ber: Page(s).Ex: Hill J, Bird HA, Hopkins R, Lawton C, Wright V. Sur -

vey of sa tis fac ti on with care in a rheu ma to logy out pa ti entcli nic: Ann Rheum Dis 1992; 51: 195-197.

Acta Reumatologica Portuguesa publishes original ar-ticles, reviews, case reports, images and letters to the ed-itor on all subjects related to Rheumatology.

Acta Reumatologica Portuguesa subscribes the re-quirements for the acceptance of manuscripts in biomed-ical journals proposed by the International Committee ofMedical Journal Editors, published initially in N Engl JMed 1991; 324: 424-28, updated in October 2008 and avail-able in www.ICMJE.org. The editorial policy of ActaReumatológica Portuguesa follows the Editorial PolicyStatements published by the Council of Science Editors,available in www.councilscienceeditors.org/services/draft_approved.cfm.

The Journal is indexed on PubMed/Medline. The arti-cles are available online with open and free access.

The articles should be written in English. Portuguesewritten manuscripts can also be submitted.

The accuracy of the manuscript contents as well aswritten opinions are of the exclusive responsibility of theauthor(s).

Published articles will remain property of the journaland cannot be reproduced, as a whole or as a part, with-out the authorization of the editor.

For accepted articles a statement signed by all authorstransferring the copyright to Acta Reumatologica ismandatory and should be send by e-mail.

Authors have to disclose potential conflicts of interest.The acceptance of articles is subjected to the evalua-

tion of the editorial board. Articles may be:a) accepted without changes;b) accepted after modifications suggested by the board;c) refused.All the comments made by the reviewers will be sent

to the author.When changes are proposed, the author should

send reply letters to the editor and to each of the revie -wers answering to all the raised questions. The authorshould also send a reviewed version of the manuscriptwith the changes highlighted in a different colour within1 month.

Instructions to authorsManuscripts not in accordance with the instructions

may be sent for modification before review by the edito-rial board.

All manuscripts must be sent by e-mail to:[email protected]

Manuscripts must be accompanied by a cover letter,signed by all authors, stating the name of the article, thatit is an original work, that the authors held the copyrightof the manuscript, that it does not represent any conflictof interest, and that they transfer the copyright to the jour-nal (se form below).

Text should be sent in digital support by e-mail, ty-ped double-spaced, type 12, with 1-inch margins, in Word for Windows. All pages must be sequentially num-bered.

Images should be sent independently from the text inJPEG or TIFF file.

– Ar ti cle pu blis hed On li ne (in sert DOI )Ex.: Pe ter A Merkel, Da vid Curthbertson, Ber nhard

Hellmich et al. Com pa ri son of di se a se ac ti vity me a su resfor ANCA-as so cia ted vas cu li tis. Ann Rheum Dis Pu bli -shed On li ne First: 29 July 2008. doi:10.1136/ard.2008.097758

– Chapter in BookName(s) and ini ti als of au thor(s) of chap ter. Chap ter

tit le. In: Name(s) and ini ti als of edi tor(s). Book tit le. City:Name of pu blis her, year of pu bli ca ti on: pa ges.

Ex: Stewart AF. Hyper cal ce mia re sul ting from me di ca -ti ons. In: Fa vus MD, ed Pri mer on the Me ta bo lic Bone Di -se a ses and Di sor ders of Mi ne ral Me ta bo lism. New York:Ra ven Press, 1991: 177-178.

– BookName(s) and ini ti als of au thor(s). Book tit le. City:

Name of pu blis her, year of pu bli ca ti on: page(s).Ex: Lo rig K. Pa ti ent Edu ca ti on. A prac ti cal ap pro ach.

St Lou is: Mosby-Year Book, 1992: 51.

– On li ne do cu mentEx:Pro gra ma Na ci o nal de Luta Con tra a Tu ber cu lo se.

Sis te ma de Vi gi lân cia (SVIG-TB). Di rec ção-Ge ral da Saú -de - Di vi são de Doen ças Trans mis sí veis, Mar ço de 2005http://www.dgsau de.pt/uplo ad/mem bro.id/ fi chei ros/i006875.pdf. Ac ces sed em 25 Ja nei ro de 2008

Tables: Ta bles should be ci ted in the text with Ro mannu me rals. Each ta ble should be dou ble typed on a se pa -ra te she et, have a tit le and con tain no ver ti cal ru lers. Ho -ri zon tal li nes should be used only as se pa ra tors betwe entit les and sub tit les. Ex plain all ab bre vi a ti ons at the bot -tom.

The num ber of ta bles should be li mi ted as des cri bedabo ve.

Figures: Cite each fi gu re in the text in con se cu ti ve or -der using Ara bic nu me rals. Le gends should be lis ted at theend of the ma nus cript, af ter the re fe ren ces, dou ble typed.Send the fi gu res in se pa ra te fi les to each fi gu re in the for -mat JPEG or TIFF.

The num ber of fi gu res should be li mi ted as des cri bedabo ve.

Editorials: Editorials will be requested by the editorand will be comments on important issues or on articles

published in the journal. Editorials should not exceed1200 words, with a maximum of 15 references and no ta-bles or figures.

Re vi ew ar ti cles: Re vi ew ar ti cles will be com mis si o nedby the edi tor. Howe ver, au thors in te res ted in pre sen tinga re vi ew ar ti cle are wel co med to con tact the edi tor.

Re vi ew ar ti cles should not ex ce ed 4000 words, 6 ta -bles/fi gu res and 100 re fe ren ces.

Let ters: Let ters to the edi tor must be a com ment on ajour nal ar ti cle or a short cli ni cal study or case re port. Theycan not ex ce ed 600 words, a ma xi mum of 10 re fe ren cesand one ta ble or one fi gu re.

Ima ges in Rheu ma to logy: Ima ges of par ti cu larly in -te rest can be sub mit ted. They should con tain a ma xi mumof 4 fi gu res, in JPEG or TIFF for mat. The ac com panyingtext must have a ma xi mum of 500 words.

Mo di fi ca ti ons and pro o fre a ding: Ar ti cles ac cep tedsub ject to mo di fi ca ti ons, will be sent to the au thors thatwill have 1 month to mo dify them ac cor ding to sug ges ti -ons. A let ter should be writ ten for each re vi ewer and thechan ges should be highlighted in the main ma nus criptwith a dif fe rent font co lor. Con tri bu tors will re cei ve pagepro ofs of the ac cep ted pa pers for ap pro val.

Co ver Let ter draft:Send with ma nus cript to The Edi tor: edtecnicarp@

gmail.com

The au thors cer tify that the ma nus cript en tit led_________________________________________ (refARP______) is ori gi nal, all data are ba sed on their ownre se arch and that the ma nus cript does not vi o la tecopyright or pri vacy re gu la ti ons. They fur ther sta tethat the ma nus cript hasn’t been partly or to tally pu blis -hed or sub mit ted to pu bli ca ti on el sewhe re.The au thors de cla re that they hold to tal copyright forthis pa per and that they as su me col lec ti ve res pon si bi -lity for its con tents and also that any con flict of in te -rest is acknowled ged.And sub mit ting this pa per, the au thors trans fer copy-rights in te rests to Acta Reu ma to ló gi ca Por tu gue sa.

All authors must sign.Name (capitals): ________________________________Date:___________________________________________Signature: ______________________________________

320


Documents

Acta Reumatológica Portuguesa Rahman (UK) Bernard Mazières (França) Carmo Afonso (Portugal) Clovis Silva (Brasil) Dafna Gladman (Canada) ... A Tabela I resume as prevalências en