revista romana de reumatologie - 2009 - nr.1

Revista Romn de

REUMATOLOGIEVolumul XVIII Nr. 1 An 2009 ISSN 1843-0791 Cod CNCSIS 378 Redactor ef:Horaiu D. BOLOIU

Redactori onorifici:tefan UEANU Eugen POPESCU

Secretar General de Redacie: Laura DAMIAN COLEGIUL DE REDACIEGeza Balint (Budapesta) Mioara Banciu (Timioara) Rodica Chiriac (Iai) Paulina Ciurea (Craiova) Ctlin Codreanu (Bucureti) Constantin Dumitrache (Bucureti) Lia Georgescu (Trgu Mure) Philippe Goupille (Tours) Walter Grassi (Ancona) Laszlo Hodinka (Budapesta) Ruxandra Ionescu (Bucureti) Nicolae Iagru (Bucureti) Marco Matucci (Florena) Nicolae Miu (Cluj-Napoca) Sarah Nica (Bucureti) Gyula Poor (Budapesta) Simona Rednic (Cluj-Napoca) Zoltan Szekanecz (Debrecen) Maria ua (Constana) Coman Tnsescu (Bucureti) Francesco Trotta (Ferarra) Jean-Pierre Valat (Tours) Sjef van den Linden (Maastricht)

CONSILIUL TIINIFIC:Codrina Ancua (Iai) Andra Blnescu (Bucureti) Mihai Bojinc (Bucureti) Violeta Bojinc (Bucureti) Tatiana Bratu (Timioara) Dorica Crstei (Brila) Anca Cozo (Trgu Mure) Lucia Cucu (Oradea) Daniela Fodor (Cluj-Napoca) Constantin Gaube (Piatra Neam) Daniel Grigorie (Bucureti) Bogdan Jante (Bucureti) Victoria Jugravu (Bucureti) Radu Miclu (Deva) Mihaela Micu (Cluj-Napoca) Claudia Mihailov (Constana) Mariana Mihailov (Bile Felix) Gavril Mirea (Braov) Eugenia Mociran (Baia Mare) Corina Mogoan (Timioara) Laura Muntean (Cluj-Napoca) Dan Neme (Timioara) Ioan Parasca (Cluj-Napoca) Horaiu Popoviciu (Trgu Mure) Denisa Predeeanu (Bucureti) Alina Rdulescu (Bucureti) Florin Rdulescu (Bucureti) Elena Rezu (Iai) Sio-pin Simon (Cluj-Napoca) tefni Tnseanu (Bucureti) Maria Vaida-Voevod (Arad) Editura Medical AMALTEAEditori: Dr. M.C. Popescu Dr. Cristian Crstoiu Director executiv: George Stanca Redactori: Oana Cristina Plcint, Alina-Nicoleta Ilie Prepress: AMALTEA TehnoPlus Tehnoredactor: Gabriela Cpitnescu DTP: Petronella Andrei, Gabriela Cpitnescu Producie: Mihaela Conea Distribuie: Mihaela Stanca ________________ CONTACT: [email protected] ABONAMENTE: [email protected] TIPAR: EMPIRE Print RomExpo, Pavilion T, Bucureti tel.: 021 / 316 96 40, 031 / 405 99 99 email: [email protected]

Cuprins

EDITORIAL H.D. Boloiu O schimbare de paradigm n boala artrozic ________________________________________ 5 ARTICOLE DE ORIENTARE H.D. Boloiu Dactilita: o manifestare insolit de interes reumatologic ________________________________ 7 Mariana Mihailov, Daiana Popa Cultural and social influences on pain and disability __________________________________ 13 LUCRRI ORIGINALE B. Gallaraga, M. Ho, H.M. Youssef, A. Hill, H. McMahon, H. Hall, S. Ogston, G. Nuki, J.J.F. Belch Cod liver oil (n-3 fatty acids) as non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis _______________________________________________ 18 K.L. Hyrich, M. Lunt, W.G. Dixon, D.K. Waston, D.P.M. Symmons Effects of switching between anti-TNF therapies on HAQ response in patients who do not respond to their first anti-TNF drug _______________________________________ 25 Carolina Negrei, D. Bllu, Andra Blnescu, A. Bl, Mihaela Ilie, Denisa Margin, Daniela Baconi, Andreea-Letiia Arsene, Cristina Drgoi, Denisa Predeeanu, Violeta Bojinc, F. Berghea, Daniela Opri, Ruxandra Ionescu Evaluarea comparativ clinic, paraclinic i toxicologic a tratamentului cu leflunomid i metotrexat la pacieni cu poliartrit reumatoid ________________________ 33 A. Caraba, Viorica Crian, I. Romoan Rolul examenului histopatologic n evaluarea nefropatiei lupice ________________________ 38 CAZUISTIC INSTRUCTIV Domnia-Georgiana Ptracu, Mihaela Agache, Cristina Iosif, Denisa Predeeanu Artrita psoriazic sever, cu coxit invalidant sever, tratat cu etanercept _____________ 46 LA GRANIELE REUMATOLOGIEI H.D. Boloiu Bolile lui John Fitzgerald Kennedy _________________________________________________ 5 2 GHIDURI DE PRACTIC Ghidul Societii Britanice de Reumatologie i al Asociaiei Profesionitilor din Reumatologie din Marea Britanie pentru monitorizarea tratamentului cu medicamente remisive __________________________________________________________ 5 8

Contents

EDITORIAL H.D. Bolosiu A change of view on degenerative joint disease ________________________________________ 5 LEADING ARTICLES H.D. Bolosiu Dactylitis: an unusual manifestation in rheumatology __________________________________ 7 Mariana Mihailov, Daiana Popa Cultural and social influences on pain and disability __________________________________ 13 ORIGINAL PAPERS B. Gallarnga, M. Ho, H.M. Youssef, A. Hill, H. McMahon, H. Hall, S. Ogston, G. Nuki, J.J.F. Belch Cod liver oil (n-3 fatty acids) as non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis _______________________________________________ 18 K.L. Hyrich, M. Lunt, W.G. Dixon, D.K. Waston, D.P.M. Symmons Effects of switching between anti-TNF therapies on HAQ response in patients who do not respond to their first anti-TNF drug _______________________________________ 25 Carolina Negrei, D. Balalau, Andra Balanescu, A. Bala, Mihaela Ilie, Denisa Margina, Daniela Baconi, Andreea-Letitia Arsene, Cristina Dragoi, Denisa Predeteanu, Violeta Bojinca, F. Berghea, Daniela Opris, Ruxandra Ionescu Clinical, paraclinical and toxicological comparative evaluation of leflunomide and metotrexat treatment in patients with rheumatoid poliarthritis _______________________ 33 A. Caraba, Viorica Crisan, I. Romosan Histopathology in lupus nephritis ___________________________________________________ 38 CASE REPORT Domnita-Georgiana Patrascu, Mihaela Agache, Cristina Iosif, Denisa Predeteanu Severe psoriatic arthritis with invalidant bilateral coxitis treated with etanercept __________ 46 CONFINING RHEUMATOLOGY H.D. Bolosiu John Fitzgerald Kennedys diseases ________________________________________________ 5 2 PRACTICAL GUIDELINES Guidelines of British Society for Rheumatology (BSR) and Association of Rheumatology Health Professionals of Great Britain for supervising remissive drugs treatment _________________________________________________________ 5 8

EDITORIAL

O SCHIMBARE DE PARADIGM N BOALA ARTROZICA change of view on degenerative joint disease

Autorii clasici distingeau dou mari categorii de boli, n conformitate cu ideile fiziopatologice ale momentului; net inflamatoare i degenerative sau metabolice, atand organului lezat sufixul itis, respectiv osis (sau eclecticul pathia) (ex.: nefrit/ nefroz, arterit/arteriopatie, periostit/periostoz etc.). Aceast dihotomie nu se mai poate susine astzi, cnd inflamaia ca proces reactiv i de aprare, manifestat altfel dect n maniera rspunsului acut la invazia cu ageni infecioi de exemplu, este gsit ca verig patogenetic, uneori esenial, n boli considerate tradiional ca fiind pur degenerative (ex.: ateroscleroza). n reumatologie, exemplul cel mai eclatant n acest sens este perechea artrit/ artroz. Deosebirea dintre cele dou forme principale ale afectrii articulaiilor periferice este faptul c artritele sunt boli n care procesul patologic ncepe cu o inflamaie clasic a membranei sinoviale, n vreme ce artrozele i au originea n cartilajul articular, un esut avascular, care nu este de ateptat s rspund n modul obinuit la stimulii nocivi. Se tia c integritatea cartilajului hialin depinde de echilibrul ntre procesele anabolice i catabolice ale condrocitului. Recent ns, a fost elaborat o concepie nou, conform creia artroza ar fi n realitate o boal inflamatoare sistemic. n acest caz, termenul de osteoartrit, utilizat n literatura anglosaxon, ar putea fi considerat ca vizionar. Trei direcii de cercetare i de gndire au acreditat aceast nou paradigm a bolii artrozice: descoperirea mecanoreceptorilor condrocitului, definirea esutului adipos ca un organ endocrin i reactivarea tardiv a unor gene. Condrocitele sunt celulele care posed mecanoreceptori de suprafa (intergrin, CD44) i ciliari,

care intervin n exprimarea citokinelor proinflamatoare, ca rspuns la stresul mecanic. n plus, acetia pot activa cile de semnalizare pentru proteinkinaze i factorul nuclear kB. Modificrile structurale observate n stadiile iniiale ale artrozei ar putea fi explicate prin sporirea sintezei factorilor de cretere, capabili s stimuleze sinteza componentelor matricii, dar i s genereze enzime proteolitice care s o degradeze. S-ar adeveri astfel o concepie mai veche, n coformitate cu care boala ar avea o faz iniial hiperanabolic. Obezitatea promoveaz artroza nu numai prin efectul de ncrcare, ci i prin adipokine, care acioneaz ca mesageri n cadrul unui sistem neuroendocrino-imun, care leag obezitatea de diferite alte boli n care inflamaia joac un rol mai recent recunoscut: ateroscleroza, diabetul zaharat i osteoporoza. Adipocitele au numeroase similitudini cu alte celule provenite din celula stem mezenchimal condrocite, osteoblaste, mioblaste etc. i secret numeroase adipokine (leptin, visfatin, adiponectin, rezistin etc.), care pot fi gsite n lichidul sinovial al bolnavilor cu artroz sau artrit. Leptina, un produs al genei ob, nu intervine numai pentru a regla apetitul, saietatea sau greutatea corporal, ci posed, printre altele, un rol n homeostazia cartilajului i formarea osoas. Substana, care circul la niveluri nalte n sngele obezilor, este capabil s intervin n distrugerea cartilajului prin inducerea apoptozei condrocitare i activarea metaloproteinazelor. Alt adipokin visfatina sau factorul de stimulare a coloniilor de celule pre-B este secretat att de adipocite, ct i de condrocite, n cazul celor din urm sub aciunea interleukinei1beta, pentru a induce mediatori proinflamatori i prodegradativi.

Adres de coresponden: Prof. Dr. Horaiu D. Boloiu, Clinica Reumatologic, Str. Clinicilor, Nr. 4, cod 400006, Cluj-Napoca email: [email protected]

REVISTA ROMN DE REUMATOLOGIE VOL. XVIII, NR. 1, AN 2009

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Diferenierea embrionar a condrocitelor se face sub controlul unor gene care, din motive nc necunoscute, pot s sufere o reactivare anormal la vrste avansate. Dereglarea funcional tardiv a acestor celule este o alt direcie de cercetare n patogenia artrozelor.

n concluzie, artroza nu este o simpl mbtrnire sau uzur a cartilajului articular, ci se situeaz n mijlocul interferenelor ntre procese aparent att de diferite ca stresul mecanic, reglarea metabolic subtil i inflamaie. Prof. Dr. Horaiu D. Boloiu

n actualitate FRAX contribuie la indicaia terapeutic pentru osteoporoz FRAX este un sistem nou introdus, destinat evalurii riscului de fracturi osteoporotice pentru urmtorii 10 ani, bazat pe analiza unor statistici globale care a inclus datele a aproape 250.000 de pacieni/an. Aplicarea metodei aduce un criteriu suplimentar pentru indicaia terapeutic prin introducerea criteriului FRAX dup cum urmeaz: Femeile dup menopauz cu vrsta de peste 50 de ani trebuie tratate pentru osteoporoz dac probabilitatea de a suferi o fractur de old n urmtorii 10 ani este = 3% sau alt fractur major osteoporotic = 20%. Acest criteriu se adaug indicaiilor curente ale NOF (National Osteoporosis Foundation) care se bazau pn acum numai pe criteriul clinic i/ sau densitometric (DXA) (HDB).

Sursa: Informaiile din acest numr, pe care le gsii n rubrica n actualitate, provin din publicaia Rheumatology News, SUA

Vizitai site-ul

SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro

ARTICOLE DE ORIENTARE

DACTILITA: O MANIFESTARE INSOLIT DE INTERES REUMATOLOGICDactylitis: an unusual manifestation in rheumatologyProf. Dr. H.D. Boloiu Centrul de Cercetare n Boli Reumatologice, Clinica Reumatologic, UMF Cluj-Napoca

REZUMATAceast trecere n revist a literaturii este dedicat unui aspect clinic ntlnit n cadrul bolilor reumatologice, care uneori trece neobservat sau nu este interpretat corect inflamaia unui deget n ntregime, care poart denumirea de dactilit. Dactilita zis reumatologic se ntlnete cel mai frecvent asociat bolilor din grupul spondiloartropatiilor, unde servete diagnosticului, urmririi evoluiei i prognosticului, n vreme ce alte dactilite apar n boli cu care reumatologul ar putea veni n contact n cadrul diagnosticului diferenial. Sunt discutate aspectele moderne ale fiziopatologiei acestei determinri. Cuvinte cheie: dactilit, spondiloartropatii, entezit, tuberculoz, sifilis, siclemie, sarcoidoz.

SUMMARYThis is a review of the literature dedicated to a clinical manifestation of some rheumatic disorders frequently overlooked or wrongly appreciated in current practice inflammation of a whole digit or dactylitis. The socalled rheumatologic dactylitis is strongly associated to spondyloarthropathies where it may represent a criterion for diagnosis, evolution or prognosis. In addition, other forms of dactylitis are of interest for the rheumatologist in differentiating the true dactylitis from similar manifestations that occur in other diseases, such as tuberculosis, syphilis, sarcoidosis or sickle cell anemia. Pathophysiology of the dactylitis is also discussed. Key words: dactylitis, spondyloarthropathy, enthesitis, tuberculosis, syphilis, sickle cell disease sarcoidosis.

INTRODUCEREn sens etimologic, termenul de dactilit (gr. dactylos = deget, itis = inflamaie) definete inflamaia localizat la nivelul degetelor de la mini sau picioare. Dei numeroase boli pot evolua cu o astfel de manifestare, n literatur, noiunea este circumscris numai ctorva mprejurri (tabelul 1). Unele forme de dactilit au ca substrat numai osul (lues, siclemie), altele osul i esuturile moi (tuberculoz, sarcoidoz) i altele numai esuturile moi (spondiloartropatii, dactilita distal buloas). Interesul reumatologiei pentru acest fel de manifestri clinice rezid n relaia care exist ntre

dactilita non-infecioas i non-proliferativ ntlnit n spondiloartropatii, cu semnificaie diagnostic, prognostic i doctrinar, precum i n faptul c unele dintre celelalte forme ar putea intra n discuie n cadrul diagnosticului diferenial al unor boli reumatologice. Orict ar prea de ciudat, dactilita nu este dect trziu intrat n literatura de specialitate. Prima meniune este cea fcut de Verna Wright n capitolul dedicat artritei psoriazice din ediia anului 1978 a volumului Copemas Textbook of the Rheumatic Diseases, unde autoarea descrie interesarea articulaiilor interfalangiene proximale i

Adres de coresponden: Prof. Dr. Horaiu D. Boloiu, Clinica Reumatologic, Str. Cliicilor, Nr. 4, cod 400006, Cluj-Napoca email: [email protected]


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Tabelul 1. Principalele boli care evolueaz cu dactilit

nedifereniate i chiar ca una izolat asociat fonotipului HLA-B27 (2). Dactilita din artrita psoriazic este frecvent (22%) i poate cel mai bine studiat. Pentru aceast boal, manifestarea este deopotriv specific (82,4%) i sensibil (84,9%) (3), motiv pentru care a fost introdus ca i item n criteriile CASPAR (Classification Criteria for Psoriatic Arthritis) pentru diagnosticul bolii.

Figura 1. Dactilita degetului II de la piciorul drept la un bolnav cu sindrom Reiter

distale, mpreun cu tecile tendinoase, care confer degetului aspectul de crnat. Ediia din anul urmtor a celebrei Arthritis and Allied Conditions nu face referire la acest semn i abia n cea din anul 1985 se scrie c n unele cazuri, afectarea articulaiilor metacarpofalangiene i interfalangiene proximale este asociat cu tenosinovita flexorilor, ceea ce duce la realizarea aspectului de deget n form de crnat. Nu se cunoate cine este cel/ cea care a introdus pentru aceast manifestare denumirea sub care este cunoscut astzi.

Figura 2. Dactilit psoriazic

DACTILITA DIN SPONDILOARTROPATIIDactilita de interes primar reumatologic este o manifestare caracteristic spondiloartropatiilor, pentru care are specificitate de 96,4%, dar sensibilitate de numai 17,9%. Toate bolile acestui grup pot evolua cu dactilit, dar cele mai frecvente sunt asocierile cu artrita psoriazic i cu sindromul Reiter, cum arat statistica pe 10 ani a unui centru de reumatologie din Ohio, SUA, unde nu s-a menionat nici o asociere cu poliartrita reumatoid (1). Manifestrea apare i n spondiloartropatiile

Studiul extins al lui Brockbank i col. (4), care a inclus 537 de bolnavi, a nregistrat 260 de cazuri cu cel puin un episod de dactilit acut (48%). Manifestarea, cu uoar predominan maculin (57%), a survenit n medie la 8 ani de la debutul bolii, fiind prezent la unul sau mai multe degete (43%, respectiv 57%), mai frecvent la cele de la picioare (78%) n comparaie cu minile (34%), n cazul celor din urm cu localizare mai ales la mna dominant (33%, fa de 25%) (tabelul 2). Determinarea a fost asimetric n 58% dintre cazuri i recurent pe acelai deget n 44%. n 185 de cazuri, dactilita a evoluat cu manifestri radiologice (tabelul 3), care n jumtate dintre acestea erau de tip eroziv, confirmat i ultrasonografic. Eroziunile osoase, caracterul progresiv al semnelor radiologice i accentuarea acestora cu ocazia episoadelor recurente, i-au fcut pe autori s considere c dactilita este un criteriu de gravitate, cel puin n cadrul acestei boli. Prezena dactilitei, asociat


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sau nu cu entezita periferic izolat n proporie de 3,5% dintr-un grup de 400 de bolnavi cu artrit psoriazic neselecionat, i-a fcut pe Salvarani i col. (5) s vorbeasc despre un subset al bolii, cu particulariti clinice insolite, independent de artrita porpiu-zis.Tabelul 2. Distribuia dactilitei n rndul a 259 de degete la bolnavi cu artrit psoriazic (N/%) (dup Bochbank i col., 2005)

Tabelul 3. Dactilita radiografic la 185 de bolnavi cu artrit psoriazic (dup Brockbank i col., 2005)

Articulaii: MCF= metacarpofalangiene, PIF = proximale interfalangiene, DIF= distale interfalangiene, MTF= metacarpofalangiene

Incidena dactilitei n rndul altor spondiloartropatii este diferit apreciat n literatur. Pe seria de bolnavi publicat de Rotschild i col. (1), 12% aveau dactilit, iar dintre acetia, 28% sufereau de sindrom Reiter i 7% de spondilit anchilozant. n cadrul grupului heterogen, clasificat ca spondiloatropatii nedifereniate, dactilita se asociaz cu alte manifestri din categoria celor ntlnite la subiecii HLA-B27-pozitivi: artrit i entezit periferic, rahialgie inflamatoare cu sciatic basculant, uveit anterioar acut sau insuficien aortic. Care este substratul lezional al dactilitei reumatologice? Rspunsul la acest ntrebare a ntziat pn n epoca extinderii ultrasonografiei musculoscheletale i a introducerii rezonanei magnetice. Ideea iniial, deloc eronat, c boala ar fi o combinaie ntre sinovita celor trei articulaii ale degetului afectat, tenosinovita tendoanelor flexorilor i polientezita local (6), la care s-ar aduga

leziunea, mai degrab obscur, caracterizat ca pseudosinovit, a avut, pe rnd, susintori i critici, practic pentru fiecare dintre cele trei modificri menionate. Autorii care au semnalat pentru prima dat dactilita credeau c aceasta s-ar datora sinovitei concomitente a articulaiilor metacarpofalangiene i interfalangiene proximale i distale. n afar de faptul c o astfel de asociere ar fi greu de explicat pentru un singur sau mai multe degete izolate (nu toate!), ideea nu pare s fie suficient pentru a explica aspectul local, care nu este al unui deget moniliform, ci al unuia n ntregime tumefiat. Mai mult, n poliartrita reumatoid, unde dou dintre cele trei artrite menionate sunt caracteristice, dactilita, n sensul strict al termenului, lipsete aproape cu desvrire. Tenosinovita flexorilor a fost considerat ca substratul primar al dactilitei, n lumina examinrilor prin ultrasunete i rezonan magnetic. Studiind amnunit 24 de degete afectate, Olivieri i col. (7) au gsit ntotdeauna exsudaie lichidian n tecile tendoanelor flexorilor i numai 3 articulaii cu distensie capsular, din cele 72 supuse acestor examinri. Ali autori au confirmat ubicuitatea tenosinovitei n cadrul dactilitei, dar au semnalat n peste 50% dintre cazuri i prezena artritei (8). Contribuia tenosinovitei flexorilor la realizarea aspectului de dactilit este n concordan cu observaia clinic, dup care atunci cnd afectarea intereseaz degetele minii ale cror teci tendinoase comunic cu bursele radial sau ulnar, acestea din urm sunt i ele afectate. Semnul menionat prin ultrasonografie ca pseudosinovit este o tumefiere difuz a prilor moi ale degetelor afectate. Este rezonabil s presupunem c aceast anomalie este secundar difuzrii inflamaiei de-a lungul i n afara tecilor tendinoase (9). Ipoteza c entezita ar fi leziunea iniial a complexului dactilitic era la ndemn, ct vreme dactilita prezint o relaie evident i demult cunoscut cu grupul bolilor n care inflamaia la nivelul entezelor este o trstur caracteristic. Primele constatri fcute prin ecografie i rezonan magnetic au fost mai puin clare dect cele care au urmat i n care au fost utilizate dezvoltrile tehnologice ale acestor metode. Acestea din urm au confirmat ubicuitatea entezitei, genernd ideea c aceasta este leziunea din care deriv toate celelalte i care este sursa citokinelor care pot difuza n toate

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structurile anatomice digitale. Unele dintre entezele de la nivelul degetelor sunt de un tip structural special, n sensul c sunt funcionale, adic asociate cu fibrocartilajele, sau intraarticulare (ex.: cele ale tendoanelor extensorilor la nivelul articulaiilor interfalangiene). Acestea condiii anatomice ar putea explica propensiunea mediatorilor inflamaiei de a induce i modificri regionale. Rmne totui o ntrebare nelinititoare: De ce degetul dactilitic dezvolt o inflamaie att de rspndit n rndul structurilor care l compun i de ce un astfel de fenomen nu apare asociat cu artrosinovita local att de exprimat din poliartrita reumatoid? n concluzie, dactilita asociat spondiloartropatiilor este iniial o entezit local, care induce n mod secundar artrit, tenosinovit i infiltrarea difuz a prilor moi ale degetetului afectat. Geniul morbid al bolii de baz este cel care alege localizarea la nivelul unora sau altora dintre degete. Evaluarea clinic a dactilitei ar putea fi i este un criteriu de cunoaterea a bolilor cu care se asociaz, sub aspectele diagnosticului, evoluiei i prognosticului. n acest sens, exist cteva metode care pot fi aplicate n practic: scale de gradare semicantitativ cu 3 trepte, cuantificare pe baza comparrii cu imagini-standard (ex.: Comparator Dactylitis Tool) sau sistemul de criterii cunoscut ca Leeds Dactyits Index (10). Tratamentul dactilitei asociate spondiloartropatiilor se suprapune celui adresat bolii de baz. De obicei, aceste msuri (antiinflamatoare i medicamente remisive) sunt suficiente, dar uneori trebuie s se recurg la la infliltrarea cu glucocorticoizi a tecilor tendinoase i a articulaiilor. Singurele metode generale care intervin direct n influenarea fenomenelor locale sunt cele care utilizeaz ageni anti-TNF alfa, o dovad indirect a implicrii citokinelor proinflamatorii n producerea acestei manifestri.

afectate mai frecvent degetele minilor dect cele ale picioarelor, falangele mai des dect metacarpienele, iar dintre cele dinti ndeosebi falanga proximal a degetelor II i III (11). Leziunea este caracteristic una izolat, dar au fost descrise i forme multifocale (12). Manifestarea clinic iniial, prezent n toate cazurile, este o tumefiere indurativ dureroas i sensibil, prezent n jurul diafizei osului afectat, uneori cu debutul precedat de un traumatism local. Examenul radiologic arat aspectul tipic cunoscut ca o leziune central litic i expansiv, parc suflat (de unde i denumirea), nsoit de reacie periostal i, n cazurile vechi, de scleroz (13). Distrugerea corticalei permite formarea de traiecte, vizibile n rezonan magnetic, care conduc spre leziuni granulomatoase uneori evideniabile la suprafaa pielii. Evoluia este cronic.

Figura 3. Spina ventosa

DACTILITA DIN ALTE BOLIDactilita tuberculoas Tuberculoza osteoarticular reprezint 10-15% din totalul formelor extrapulmonare ale bolii, care, n ordine, afecteaz coloana vertebral (morbul lui Pott), articulaiile mari ale membrelor (ex.: tumora alb a genunchiului) i oasele scurte tubulare ale degetelor (dactilita tuberculoas). Cazul celei din urm este o osteomielit bacilar i survine cu frecvena de 4%, ndeosebi la copii. Sunt

Diagnosticul de dactilit tuberculoas este stabilit pe baza examenului radiografic, iar confirmarea vine de la examenul histologic al materialului bioptic recoltat cu ac fin, care arat leziuni granulomatroase i prezena bacililor lui Koch (13). Chimioterapia antituberculoas, nsoit la nevoie de excizie chirurgical, este atitudinea de urmat. Dactilita luetic Acest manifestare face parte dintre semnele precoce ale sifilisului congenital (2% dintre determinrile sale scheletale), care apar n primii


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doi ani de via i sunt produse prin transmiterea tranplacentar a Treponema pallidum (14). Clinic, se caracterizeaz prin tumefiere la nivelul degetelor minilor, rareori ale picioarelor, adesea bilateral i simetric. Aspectul radiologic este identic cu cel din dactilita tuberculoas, dar cu tumefierea prilor moi mai puin exprimat i cu periostit mai exuberant. Tratamentul de elecie este cu penicilin. Dactilita sarcoidozic Cunoscut ca dactilita cu deget n mciuc, aceasta este o manifestare foarte rar n cadrul sarcoidozei. Aspectul este de tumefiere distal bulboas, moale, chiar pseudoveziculoas i violacee a unui singur deget, nsoit de modificri unghiale. Tratamentul este cu cortizonice pe cale general i local (15). Alte manifestri digitale ale sarcoidozei, care sunt diferite de precedenta, dei i-ar putea revendica denumirea de dactilit dac ar afecta numai degetele, sunt ceva mai frecvente (0,2%), asociind tumefierea prilor moi cu leziunile litice osoase. Aspectul clinic este cel al unei tumefieri fusiforme a degetelor, bilateral i asociat lupusului pernio. Dactilita din siclemie Aceast form de dactilit, inaugurat n cadrul drepanocitozei, este la nceput confundat cu osteomielita sau cu artrita juvenil cronic. Apare la copiii homozigoi care motenesc hemoglobina S, cu o frecven de 20% dintre cazuri, care poate ajunge la subiecii africani chiar la 80%. Manifestarea este mai frecvent observat n primii 4 ani de via i nu apare niciodat dup mplinirea vrstei de 7 ani. Debutul este acut, cu febr, durere i tumefiere la nivelul degetelor de la mini i picioare (sindromul mn-picior), nsoite de impoten funcional (ex.: a mersului), iar pe plan biologic de leucocitoz, accelerarea VSH i anemie. Sunt afectate mai frecvent degetele I i II, adesea asimetric. Uneori, manifestarea local se rezum la apariia edemului dur pe suprafeele dorsale ale extremitilor. n primele cteva zile, examenul radiografic este neconcludent, rezumndu-se la a descrie numai tumefierea prilor moi. Mai trziu ns, se concretizeaz dou aspecte: a) neoformare osoas subperiostal la nivelul falangelor i/sau a articulaiilor

degetelor afectate i b) subierea corticalei, cu neregulariti ale canalului medular. Boala este autolimitant n interval de aproximativ 30 de zile, iar semnele radiologice dispar n aproximativ 6 sptmni. Recidivele sunt posibile (16). Substratul dactilitei siclemice nu este nc identificat cu certitudine. Dou mecanisme au fost incriminate: hiperplazia medular reactiv i tromboza cu celule falciforme, urmat de hipoxie i moartea celulelor din osul metafizar (17). Tratamentul este simptomatic. Dactilita distal buloas Aceast form a fost descris n anul 1972 de ctre Hays i Mullard i este o infecie acral cu streptococ beta-hemolitic A (primele cazuri descrise) sau cu stafilococ aureu, ntlnit mai ales la copii, dar i la aduli, fie acetia imunocompeteni sau imunodeprimai (ex.: infecie cu HIV). Microorganismele ptrund n piele prin mici leziuni, care adesea scap neobservate (ex.: neptur de insect, leziuni de grataj etc.) (18).

Figura 4. Dactilit distal buloas

Leziunea caracteristic este o bul dur, uneori cu coninut hemoragic, care apare pe suprafaa volar a falangei distale. Aceasta se poate extinde dorsal, pentru a invada patul unghial. Bulele multiple pledeaz pentru etiologia stafilococic. Dup spargere, acestea las eroziuni superficiale, care cu timpul se epitelizeaz. Fenomenele generale lipsesc (19). Diagnosticul etiologic se bazeaz pe frotiuri i culturi, iar tratamentul const din incizie i antibiotice, n aplicaie local sau, pentru a preveni diseminrile posibile, pe cale general.

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BIBLIOGRAFIE1. 2. 3. 4. Rotschild BM, Pingitore C, Eaton M Dactylitis: implication for clinical practice, Sem Arthr Rheum 2003, 32: 341-342 Padula A, Giasi V, Olivieri I Early onset isolated B27-associated dactylitis, Ann Rheum Dis 2002, 61: 259-260 Treitl M, Panteleon A, Korner M et al Soft tisuue manifestation of early rheumatic diseases, Radiol 2006, 46: 667-680; 682-688 Brockbank JE, Stein M, Schentag CT, Gladman DD Dactylitis in psoriatic arthritis: a marker of disease severity, Ann Rheum Dis 2005, 64: 188-190 Salvarani C, Cantini F, Olivieri I et al Isolated peripheral entesitis and/or dactylitis: a subset of psoriatic arthritis, J Rheumatol 1997, 24: 1106-1110 Healy PJ, Helliwell PS Dactylitis: pathogenesis and clinical considerations, Curr Rheumatol Rep 2006, 8: 338-341 Olivieri I, Barrozzi L, Favaro L et al Dactylitis in patients with seronegative spondyloarthropathy: assessment by ultrasonography and magnetic resonance imaging, Arthr Rheum 1996, 39: 15241528 Kane D, Gearney T, Bresniham B et al Ultrasonography in the diagnosis and management of psoriatic dactylitis, J Rheumatol 1999, 25: 1746-1751 Oliveri I, D Angelo S, Scarano E, Padula A What is primary lesion in SpA dactylitis?, Rheumatol 2008, 47: 561-562 10. Helliwell PS, Firth J, Ibrahim GH et al Development of an assessment tool for dactylitis in patients with psoriatic arthritis, J Rheumatol 2005, 32: 1745-1750 11. Andronikou S, Smith B, tuberculous dactylitis, Arch Dis Child 2002, 86: 206-208 12. Chowdhari V, Aggrawall A, Misra M Multifocal tubercular dactylitis in an adult, J Clin Rheumatol 2002, 87, 35-37 13. Cremlin BJ, Jamieson DH Childhood Tuberculosis, Springer Verlag, London, 1995: 99-113 14. Rasool MN, Govender S The skeletal manifestations of congenital syphilis, J Bone Jt Surg 1989, 71: 752-755 15. Weaver J, Morris E, Ramer SS, Colome-Grimmer MI Drumstick dactylitis: an unusual manifestation of sarcoid, Internet J Dermatol 2004, 5 16. Olivieri I, Scarano E, Padula A et al Dactylitis, aterm for different digit disease, Scand J Rheumatol 2006, 35: 333-340 17. Worral VT, Butera V Sickle-cell dactylitis, J Bone Jt Surg 1976, 58A: 1161-1163 18. Scheinfeld A A review and report o blistering distal dactylitis, J Rheumatol 2007, 31: 1903-1905 19. Mc Cray MK, Esterly NB Blistering distal dactylitis, J Amer Acad Dermatol 1981, 5: 592-594

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n actualitate Acidul zolendronic reduce disabilitatea legat de lombalgie Fracturile osteoporotice produc lombalgie, disabilitate i reducerea calitii vieii persoanelor care le-au suferit. Studiul pivotal cu acid zolendronic (HORIZON), care a inclus peste 7000 de femei tratate cu doza anual de 5 mg n perfuzie, a evideniat reducerea semnificativ a tuturor tipurilor de fractur, n comparaie cu placebo. Datele colectate la cte 3 luni timp de 3 ani consecutivi au artat c numrul zilelor de repaus la pat i al zilelor de inactivitate generat de fracturi a fost semnificativ mai redus la grupul tratat (1,6 respectiv 2,2 i 5,9 respectiv 9,9). Acest beneficiu a fost similar i dup aplicarea criteriului interveniei fracturilor incidente (HDB).

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ARTICOLE DE ORIENTARE

CULTURAL AND SOCIAL INFLUENCES ON PAIN AND DISABILITYDr. Mariana Mihailov, Dr. Daiana Popa University of Oradea, Faculty of Medicine and Pharmacy Medical Rehabilitation Hospital Felix Spa, Romania

SUMMARYThe nature of pain has puzzled humanity for centuries. As a personal experience, pain has an immediacy and impact. For centuries, there has been a sustained attempt to develop a philosophical and scientific understanding of pain. The response to pain in terms of pain associated incapacity (or functional disability) has been demonstrated and it is clear that adjustment to pain is also a subject to a wide variety of influences. Without references to the social framework of the patient and how they see their symptoms we can not really understand their behavior. Evaluation of pain and disability and consideration for pain management need to recognize the influence of age and gender differences. There may be a complex and significant role for the patients family and social network in understanding of pain and perpetuation of disability. Potential influences on professional judgment need to be recognized. In conclusion, the experience of pain and response to it can only be understood within the individuals social and cultural framework. Key words: pain, disability, cultural framework

REZUMATInfluene culturale asupra durerii i disabilitii Durerea i aspectele ei clinice au fost o enigm pentru umanitate timp de secole. Ca o experien personal, durerea a fost o urgen i un impact sever asupra fiinei umane. Rspunsul la durere n termeni de incapacitate funcional asociat durerii a fost demonstrat i este evident c adaptarea la durere este un subiect supus unor numeroase influene. Este important s trecem n revist cteva dintre mecanismele fundamentale sociale i culturale care ne pot contura percepia asupra durerii. Evaluarea durerii i disabilitilor pe care aceasta le creeaz, precum i managementul acesteia, sunt influenate de sexul (gen) i de vrsta pacientului. De asemenea, familia, profesia i relaiile de la locul de munc joac un rol complex n nelegerea disabilitilor, ca rezultat al durerii cronice. n concluzie, experiena personal la durere i comportamentul dureros, pot fi nelese doar ntr-un cadru social i cultural bine definit. Cuvinte cheie: durere, disabilitate, context cultural

The nature of pain has puzzled humanity for centuries, and as a personal experience, pain has an immediacy and impact. The experience of pain seems difficult to capture in words, yet such is the power of its impact that it could be considered that pain can be described adequately only in picture or metaphor. For centuries, there has been a sustained attempt to develop a philosophical and scientific understanding of pain, although any

contemporary model of pain will include both physiological and psychological factors, early theories of pain were very different. Early civilizations offered a variety of explanations for pain and attributed it to such factors as religious influences of Gods, the intrusion of magical fluids, the frustration of desires and deficiency or excess in the circulation of Qi. In the 17th century, the Cartesian theory represented a

Adres de coresponden: Dr. Mariana Mihailov, Str. Pescruului, Nr. 7, tel. 0259 411125, Oradea email: [email protected]


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significant advance of its predecessors in postulating a mechanism of pain transmission from the periphery of the body to higher centers in the brain, but every theory has its limitation. Two major physiological theories of pain became the object of research in the 19th century (Intensity summation theory and Pain original sensation plus psychic reaction theory). With the addition of the later sensory interaction theory (postulating a fast and a slow system of pain transmission) the foundation of the gate control theory (1) was laid. The response to pain in terms of pain associated incapacity (or functional disability) is obvious and it is clear that adjustment to pain is also subject to a wide variety of influences. How we interpret pain and how we respond, and when or indeed weather we seek treatment is subject to social learning. We learn which symptoms to take seriously and which requires treatment. Without reference to the social framework to the patient and how they see their symptoms we cannot really understand their behavior. Cultural and subcultural factors are not in themselves obstacles to rehabilitation, except in so far as they translate into difficulties in comprehension mistaken believes about the nature of pain and disability, resistance to seek treatment, unwillingness to comply with treatment procedures or failure to accept a degree of personal responsibility for the outcome of rehabilitation. Culture can be defined in terms of individuals sense of ethnicity, religion, historical roots and general value systems. Cross cultural differences are evident in many aspects or human behavior and certainly in prevalence of illness and in healthcare usage. The global population is in a pattern of migration, never seen before in history. The healthcare practitioner, especially in urban areas, regularly comes into contact with people from other countries and cultures which may not speak the language of the host nation. In Europe there is a stereotypical view of stoical northern Europeans and more emotionally expressive southern Europeans, in reaction to pain, but it is not clear whether differences in pain expression are a product of different believes about pain and injury or differing acceptability of types of expression regardless of the pain believes. Ethnic differences in the reporting of low back pain have been observed; in Australian aborigines one third of men and half of the women experienced

back pain. However, they did not perceive it as a health issue and consequently did not report symptoms openly, display behavior or seek medical treatment. A study in rural Nepal reported that back symptoms were very common, although virtually no one sought help for symptoms when medical services were made available. It appeared that the symptoms of back trouble were perceived as part of normal ageing process. This demonstrated that the importance of a symptom like back pain and what a person does as a consequence is subject to social norms. Some countries have tried to change the perceptions about back pain in the population to reduce consulting and give people a more benign impression of back pain through an intensive media campaign. Interestingly, there may be psychological differences as well as social differences related to ethnicity. Greater psychological disability, increased report of post traumatic distress syndrome and more sleep impairment has been demonstrated in Africans and Americans and Hispanic groups with chronic pain compared with non Hispanic whites (2). Recently there has been concern that people who are ethnically different from a host nation are at a disadvantage with respect to treatment for painful condition (3). One obvious explanation for the undertreatment of people from ethnic minority groups is the problem of communication. Newly arrived emigrants and those who live in communities may not be fluent in the language of their adopted country, and health care providers may not have easy access to interpretation services. The Medical Outcomes Study (4) demonstrated that ethnic minority people were less likely to become involved in medical decision about their own treatment than non minority groups. This is ameliorated somewhat if the treating physician is from the same ethnic group as the patient. Further more, the manner of health care delivery often does not take account of cultural differences. Some cultures cannot accept mix treatment groups delivered by both male and female health care professionals. In some cultures, women may not be able to venture out of the house for long periods unaccompanied. These issues need to be addressed to ensure that those who need treatment are receiving it. Most good health care providers have advisors from different ethnic groups who can be a fund of


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information when developing services, and it is necessary to integrate the insights into the development and evaluation of culturally competent pain management for people from ethnic minority. Cultural factors can be best understood perhaps in terms of socialization mechanisms, and how this may affect both the perceptions of pain and response to pain (including both treatment seeking and response to treatment). Although we are biologically programmed to respond immediately to sudden unexpected pain in terms of escape, our response to pain frequently also has to be understood in a social context. We arrive in the world with a set of instinctive responses which are then shaped by social processes. The constructivist perspective on pain has deep roots in evolution and pain is viewed not as an accident of human development, but as a protective factor for adaptation and survival in a primitive world. Pain has to be understood as emerging from a biological substrate anchored in social processes. According to Hadjistavropoulos and Craig (5) observational measures of pain such as nonverbal components, reflect involuntary features of pain under the control of lower levels of brain activity to a greater extent, associated with language and they describe nonlinguistic vocalizations and facial expressions as prime survival mechanisms in neonates. During the last decade, there have been still further levels of sophistication in computerized analysis of expression. Later, as we mature from neonates into infants and then young children, we learn about the meaning and significance of sensation, including pain. We observe how others react to situations and in turn develop behavior repertoires of our own by observation and by imitation. Gradually, through social learning processes, we have become more skilled and effective in our interactions with others, so that our needs are met (these learning processes have been specifically investigated in children with pain). Young children learn to attribute significance to various sensations and thus develop a set of responses which become established behavior patterns. As children mature into adults, they develop a wide range of communication skills. Pain is a common fact of life, yet not everyone consults a professional about it. Whether individuals seek treatment seems to be determined not

only by the severity of the pain but by a further set of considerations such as the significance given to the pain, the treatment options available and access to health care. Treatment seeking can also be understood from a social perspective, and indeed the term illness behavior was originally a social construct. These ideas have had a powerful influence and more recent terms such as chronic illness behavior invalidism, or more specific pain behavior and chronic pain syndrome. Potential differences between the pain management, needs of the infant and those of the elderly patient, are clearly evident but there are also important sex/gender differences in health care seeking and response to treatment; the one size fits all is clearly inappropriate. While it might be argued that ensuring equality of health care provision across communities is a mater for the politician rather than the clinician, in delivery of a person centered approach to treatment, it is necessary to examine the influences of age and gender on perception of pain and response to treatment. Chronic and recurrent pain in children has a point prevalence of at least 15% (6) and a noteworthy number of children and their families are severely affected by pain. Fortunately, multidisciplinary programs tailored for the needs of adolescents are now being developed and new assessment tools are becoming available (7). The vast majority of treatments for chronic pain have been developed in younger people and there have been few investigations of age differences over the life span. As a consequence, clinicians have had to extrapolate from guidelines develop for young people. Yet, ageing is a prime candidate as a pain modulating factor (8) and although complications such as co morbidity can accentuate differences and complicate management it is important to appreciate the influence of age. Most clinical studies suggest that the peak incidence of back pain and sciatica is at about 40 years of age, and epidemiological studies suggest that life time prevalence increases from the late teens up to the 45-55 age groups. Waddell (9) suggests that the peak prevalence of back pain is somewhere between 40 and 60 years and all forms of disability increase with age and particularly affect the elderly, and the proportion of individuals reporting restricted activity rises linearly until retirement age.

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According to Gibson (8) there is some evidence of a modest age related increase in experimental pain threshold, but is it not clear how or indeed if this translates directly into clinical pain experience since the picture is complicated by increased levels of co morbidity with age in the context of multiple influences of pain reporting. For example, increasing levels of depression associated with lack of social support may adversely influence pain tolerance or enhance treatment seeking. As far as pain management is concerned, it is important therefore to consider age not necessarily as a barrier to treatment, but as a factor which may influence the understanding of the individuals adjustment to pain associated incapacity. Although our understanding of the effects of age on pain has become a sophisticated, the interplay of pain and co morbidity generally and of pain and dementia specifically are critical issues that remain unresolved. The prevalence of most pain condition appears to be higher in women than men, although it is not possible to observe the extent to which these differences are attributable to different rates of exposure to other risk factors for pain in men and women. Although women are more likely to report multiple pain problems, this is not the case for every pain condition at every stage in the life. Thus while for back pain differences in prevalence are small, there are more marked differences in joint pain, chronic widespread pain, fibromyalgia, headache. The fact that most condition show at least somewhat higher prevalence in women than men, suggests that a generic gender factor (or factors) are present. Women are more likely to have had experience of recurrent pain as a result of menstruation;

pregnancy and childbirth are further biological events which are sex specific, and the proportion of women suffer chronic pain as a consequence of gynecological problems or the physical demands of childbirth. Men and women appear to differ in the significance they attribute to painful events. The reason for this is not entirely clear but may be related to difference in the interpretation of pain as well as socially determined differences in how they respond to pain. There are gender differences in consulting behavior. A possible explanation for that reason is as a consequence of their role as primary careers within the family. Men may be more likely to consult if pain is perceived as a threat to work. Differences in consulting also may be a consequence of gender differences in the emotional response to pain an in type of coping strategies. While women may be more worried and irritated about pain, men may be more embarrassed about it. Both genders differ in their use of coping strategies (10). Stress and depression may be more closely associated with pain in women than men. Finally, there may be differences in the willingness to consult. Difference in the manner of presentation on symptoms and in particular the emotional component may have a significant effect on the patient doctor communication process and the treatment actually received. Beliefs about the nature of pain have a powerful influence on adjustment to pain and the development of incapacity. In addressing the impact of chronic pain within the context of pain management it is important to consider not only the content of communication process but also the process of communication.

REFERENCES1. Melzack R Pain and stress: A new perspective, in: Gatchel RJ, Turk CD, Psychosocial Perspectives in Pain, Guilford Press, New York, 1999: 89 106 McCracken LM, Matthews AK, Tang TS, et al A comparison of black and whites seeking treatment for chronic pain, Clin J Pain 2001, 17: 49 55 Green C, Anderson KO, Baker TA et al The unequal burden of pain: confronting rasial and ethnic disparities in pain, Pain Med 2003, 4: 277 294 Hays RD, Kravitz RL, Mazel RM et al The impact of patient adherence on health outcomes for patients with chronic disease in 5. the medical outcomes study, J Behav Med 1994, 17: 347 360 Hadjistavropoulos T, Craig K A theoretical framework for understanding self report and observational measures of pain: a communication model, Behav Res Therapy 2002, 40: 551 570. Eccleston C, Crombez G, Scotford A et al Adolescent chronic pain: patterns and predictors of emotional distress in adolescent with chronic pain and their parents, Br Med J, 2004, 108: 221 229 Eccleston C, Jordan A, Mc Cracken LM et al The Bath Adolescent Pain Questionnaire (BAPQ): Development and preliminary psychometric evaluation of an instrument to assess the impact of chronic pain on adolescents, Pain 2005, 118: 263 270

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REVISTA ROMN DE REUMATOLOGIE VOL. XVIII, NR. 1, AN 20098. Helme RD, Gibson SJ Pain management in the elderly: the epidemiology of pain in elderly people, in: Ferrell BA, Clinics in Geriatric Medicine, Vol 17, WB Saunders, Philadelphia, 2001: 417 431 9. Waddell G The back pain revolution, Churchill Livingstone Edinburgh, 1998. 10. Unruh A Review article: Gender variations in clinical pain experience, Pain 1996, 65: 123 167

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n actualitate Metotrexatul aduce beneficii bolnavilor cu artrit psoriazic n viaa real Dei metotrexatul (MTX) este prescris frecvent pentru tratarea artritei psoriazice (AP), datele despre eficacitatea sa n practic sunt relativ srace. Un studiu norvegian de 6 luni (NORDMARD), n care au colaborat 5 centre din aceast ar, aduce date n legatur cu acest aspect. Studiul a inclus 430 de subieci cu AP i 1.218 cu poliartrit reumatoid (PR) MTX-naivi, crora li s-a administrat doza medie sptmnal de 13,7 mg, respectiv 13,9 mg. Ambele grupuri au rspuns similar la medicaie, cu un grad de avantaj nesemnificativ n cazul PR, boal n care MTX a fost mai avantajos sub aspectul combaterii durerii i a oboselii (HDB).

n actualitate Aspirina profilactic dup artroplastia genunchiului Aspirina (ASA) se dovedete eficient n combaterea manifestrilor tromboembolice, la fel ca alte medicamente anticoagulante. A fost efectuat un studiu retrospectiv pe 93.840 de pacieni care au suferit artroplastie de genunchi pentru gonartroz sau pentru alte motive. Acetia au primit ASA (5%), warfarin (55%) sau heparinoizi injectabili (40%). Nu au existat diferene n producerea tromboflebitei profunde i a emboliilor pulmonare ntre grupurile astfel tratate (HDB).

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LUCRRI ORIGINALE

COD LIVER OIL (N-3 FATTY ACIDS) AS NON-STEROIDAL ANTI-INFLAMMATORY DRUG SPARING AGENT IN RHEUMATOID ARTHRITISB. Galarraga1, MD, M. Ho1, MD, H.M. Youssef2, MD, A. Hill1, MD, H. McMahon1, MD, C. Hall2, MD, S. Ogston3, MD, G. Nuki2, MD, J.J.F. Belch1, MD 1Vascular and Inflammatory Diseases Research Unit, University Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee 2Rheumatic Diseases Unit, Western General Hospital, Edinburgh 3Public Health Section, Community Health Science Division, University of Dundee, Dundee, UK.

SUMMARYObjectives. Dose-dependant gastrointestinal and cardiovascular side-effects limit the use of NSAIDs in the management of RA. The n-3 essential fatty acids (EFAs) have previously demonstrated some anti-inflammatory and NSAID-sparing properties. The objective of this study was to determine whether cod liver oil supplementation helps reduce daily NSAID requirement of patients with RA. Methods. Dual-centre, double-blind placebo-controlled randomized study of 9 months duration. Ninety-seven patients with RA were randomized to take either 10 g of cod liver oil containing 2.2 g of n-3 EFAs or air-filled identical placebo capsules. Documentation of NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake. Relative reduction of daily NSAID requirement by >30% after 9 months was the primary outcome measure. Results. Fifty-eight patients (60%) completed the study. Out of 49 patients 19 (39%) in the cod liver oil group and out of 48 patients 5 (10%) in the placebo group were able to reduce their daily NSAID requirement No differences between the groups were observed in the clinical parameters of RA disease activity or in the sideeffects observed. Conclusion. This study suggests that cod liver oil supplements containing n-3 fatty acids can be used as NSAID-sparing agents in RA patients. Key words: RA, fish oil, n-3 fatty acids, NSAIDs.

REZUMATUleiul din ficatul de cod ca medicament de nlocuire a antiinflamatoarelor nesteroidiene n poliartrita reumatoid Obiective: Efetele adverse digestive i cardiovasculare limiteaz aplicarea antiinflamatoarelor nesteroidiene (AINS) pentru tratamentul poliartritei reumatoide (PR). Acizii grai eseniali (AGE) n-3 sunt dotai cu proprieti antinflamatoare. Obiectivul acestui studiu a fost s stabileasc dac acetia ar putea nlocui AINS convenionale n tratamentul PR. Metode: Studiul dublu-orb, placebo-controlat cu durata de 9 luni a fost efectuat n dou centre i a inclus 97 de bolnavi, care au primit AINS i 2,2g AGE sau placebo. Nevoia actual de AINS, evaluarea clinic i de laborator i analiza efectelor adverse au fost fcute la 0, 4, 12, 24 i 36 de sptmni. Dup 12 sptmni, pacienii au fost instruii s reduc sau chiar s suspende, n msura posibilitii, utilizarea AINS. Reducerea cu >30% a dozei de AINS a fost obiectivul primar al evalurii. Rezultate: Cincizeci i opt de pacieni (60%) au terminat studiul. Din 49 de subieci care au luat AGE, 19 (39%) au putut s-i reduc doza de AINS, fa de 5 din 48 (10%) din grupul care a luat placebo. Nu s-a gsit nici o diferen ntre grupuri n privina parametrilor bolii sau a efectelor secundare. Concluzie: Datele prezentate sugereaz c suplimentarea cu AGE din uleiul de cod poate nlocui AINS pentru bolnavii cu PR. Cuvinte cheie: poliartrit reumatoid, ulei de pete, acizi grai n-3, antiinflamatoare nesteroidiene.

Correspondence to: B. Galarraga, The Institute of Cardiovascular Research, Vascular and Inflammatory Diseases Research Unit, University Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. E-mail: [email protected]

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INTRODUCTIONRA is a chronic autoimmune inflammatory joint disease in which inflammation plays a key role. Pharmacotherapy with NSAIDs, DMARDs and biologic agents is the cornerstone of treatment, with NSAIDs being frequently used for symptomatic control of pain. Although NSAID are widely prescribed in RA, concerns about their side-effects have limited their use. Furthermore, with the recent finding that selective cyclo-oxygenase-2 (COX-2) inhibitors are associated with an increased frequency of cardiovascular (CV) events, concerns about the CV safety of the non-selective NSAID have been raised, prompting the search for alternative medications. The potential anti-inflammatory effects of essential fatty acids (EFAs) were suggested by epidemiological studies in Greenland Eskimos, where n-3 fatty acid intake from seafood is high and there is lower prevalence of autoimmune and inflammatory conditions (1). This concept has now been supported by several studies (2). Dietary EFAs are precursors of prostaglandins (PGs) and leucotrienes (LTs) both of which are inflammatory mediators. There are different series of PGs and LTs with various pro- or anti-inflammatory properties. As EFA competition for the metabolic enzymes occurs in their production, altering the EFA content in the diet, or by administration of supplements, can modify the type of PGs and LTs formed (3). Western diets are rich in n-6 but low in n-3 EFA. The most potent inflammatory PGs (those of the two series) originate from n-6 EFA arachidonic acid. The n-3 EFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the other hand, originate from fish oils. EPA competitively inhibits the production of PGs and LTs derived from arachidonic acid and is a precursor of the less inflammatory series-3 PGs and series-5 LTs (2). Increasing the ingestion of n-3 EFAs may result in a reduction of inflammation via these and other mechanisms (4). Several groups including ourselves have looked at the effect of DHA and EPA in RA. These studies have shown significant improvement in at least two clinical variables of disease activity in patients taking n-3 EFA (5). Additionally, we and others have reported a significant decrease in NSAID requirement in patients taking fish oils (68).

Although these studies were double blind and placebo controlled, most have been short, with small numbers of patients, based in one centre only, and did not include a reduction of NSAID requirement as their primary end point. The objective of this study was to determine whether Seven Seas Marine Oil 1 (SSMO1), an n3 long-chain EFA-rich clinical grade high-strength cod liver oil, helps to reduce the daily NSAID requirement of patients with RA by at least 30% without any worsening of their disease activity.

PATIENTS AND METHODSStudy design This was a randomized, prospective, investigator-initiated dualcentre, double-blind placebocontrolled study carried out between August 1997 and December 2002. Patients were recruited from the rheumatology departments in Ninewells Hospital and Medical school, Dundee and the Western General Hospital in Edinburgh, UK. Randomization was done separately in each of the two study centres. The randomization code was generated manually in blocks of 10. Patients consent was obtained according to the Declaration of Helsinki. This study was approved by the Tayside Committee on Medical Ethics and the Lothian Research Ethics Committee. Patient selection Ninety-seven patients aged 18 yrs or over and with RA as defined by the ARA (9) were enrolled, and gave written informed consent. The inclusion criteria were, stable RA disease activity and RA medication for at least 3 months prior to entering the study, regular NSAID therapy and Steinbrocker functional class I, II or III (10). The exclusion criteria included ongoing RA disease activity requiring change of therapy, prednisolone at a daily dose >7.5 mg/day, severe intercurrent illness or patients routinely taking supplements containing EPA or other EFA. Patients were randomly allocated to receive either 10 g of SSMO1 a day (10 capsules) or identical air-filled placebo capsules for 9 months. SSMO1 is a blend of cod liver oil and fish oil and each 1000mg capsule contains 150mg of EPA (C20: 5 n-3), 70 mg of DHA (C22: 6 n-3), 80 g of vitamin A, 0.5 g of vitamin D and 2.0 IU of vitamin E.

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Clinical assessment Patients were assessed at baseline, 4, 12, 24 and 36 weeks. The week 4 visit was mainly a safety and compliance assessment. During the other visits, a clinical evaluation was performed that consisted of 28 tender joint count, 28 swollen joint count, grip strength, duration of early morning stiffness (EMS), visual analogue scale (VAS) of pain (100 mm), Stanford HAQ (11) and subjective response (patients were asked whether they were better, the same or worse at each visit). Bloods were taken for full blood count, biochemistry, CRP and IgM RF. Patients NSAID dose at baseline was assigned as 100%. NSAID dose reductions were calculated from the baseline. Those patients taking daily preparations once had their NSAID changed to a shorter-acting equivalent of the total dose, e.g. diclofenac slowrelease 75 mg twice a day was changed to six 25 mg tablets of diclofenac a day. Patients were asked to document their daily NSAID intake and the average daily requirement from the previous visit was compared with the baseline dose. Any reduction or increase in NSAID dose was documented in percentages. All patients were encouraged to reduce the dosage of their NSAID from the 12-week visit, with the aim of stopping them if possible. Outcome measures The primary outcome measure was relative reduction of daily NSAID requirement by >30% after 9 months. Secondary outcome measures were stability or improvements in disease activity score28 three variables (DAS-28 3v)-CRP, HAQ, VAS pain, grip strength, EMS and subjective response. Assessment of compliance and safety parameters Compliance was assessed by counting the total number of returned capsules and by measuring EPA levels in plasma at baseline and after 3 and 9 months. Safety was assessed by routine laboratory tests and patients were asked to report any adverse events encountered. Power calculation Power calculation suggested that with a sample size of 47 patients per treatment group, it would be possible to detect a mean difference in the daily NSAID requirement of >30% with a probability

of 90% at a predetermined level of P30% after 9 months) a non-completer imputation, in which noncompleters were assumed to have had no reduction in NSAID consumption, was done. For the secondary outcomes, the last datum was used in place of any missing follow-up values (last data carried forward).Table 1. Baseline characteristics of study patients

Values are mean S.E.M.

SPSS and Minitab statistical packages were used for all statistical analyses. Two-tailed independent Students t-test was used to compare the distribution of quantitative variables between the treatment groups and chi-squared tests for categorical variables. To estimate differences between treatments, 95% CIs were used.

RESULTSNinety-seven patients (52 patients in Dundee and 45 in Edinburgh) aged 3778 yrs were enrolled in the trial. Of these, 69 were females and 28 males. Both groups were similar in their baseline characteristics (Table 1). All patients were on NSAIDs and 36 (75%) of placebo patients and 39 (79.6%) of the SSMO1 patients were on DMARDs. Only two patients in each group were on more than one DMARD. The two most frequently used DMARDs in both groups were


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methotrexate and sulphasalazine (taken by 32 and 31% of patients, respectively). Seven (16%) patients in the placebo group and 9 (18%) of those in the SSMO1 group were on oral prednisolone at doses of 7.5 mg/day (mean dose 4.9 mg (37.5 mg)). Thirty-two out of 49 (65%) patients in the SSMO1 group and 26 out of 48 (54%) patients in the placebo group completed the study (Fig. 1). Four patients in the SSMO1 group and three in the placebo group had their DMARD or prednisolone dose increased. As these changes in their anti-rheumatic drugs can influence the primary outcome of the study, a secondary analysis was also carried out excluding these patients. Compliance Mean (S.D.) plasma EPA levels (expressed as percentage of total fatty acids) at 3 and 9 months were significantly higher in the SSMO1 (8.675% and 8.135%, respectively) than in the placebo group (2.962% and 3.042%, respectively) (P30% at 9 months (P=0.002, chisquared test; 95% CI for difference, 12.2, 44.5) (Fig. 2). Mean (_S.E.M.) daily NSAID requirement reduction was also significantly higher in the SSMOI group (266%) than the placebo group (93%) (P=0.010, independent sample t-test; CI for difference, 4.15, 30).Figure 1. Participant flow diagram

Figure 2. Achievement of 30% reduction in average daily dose of NSAID by treatment

When only those patients who completed the study were analysed; 19 out of 32 (59%) patients in the active group and 5 out of 26 (19%) patients in the placebo group were able to reduce their daily NSAID requirement by >30% at 9 months (P=0.003, chi-squared test; 95% CI for difference, 17.4, 62.9). The mean (S.E.M.) daily NSAID requirement of those patients who completed the study decreased by 407.6% in the SSMO1 group and by 165.5% in the placebo group (P=0.021, independent sample t-test; CI for difference, 3.69, 43.07). When those patients who had their DMARD or corticosteroid dose increased during the study

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period were excluded from the analysis, the results remained highly significant with 17 out of 28 (61%) patients in the SSMO1 group and 5 out of 24 (21%) patients in the placebo group being able to reduce their NSAID daily dose by more than a third (P=0.005, chi-squared test, 95% CI for difference, 15.6, 64.2). Clinical parameters The main objective of the study was to assess whether RA patients were able to reduce their NSAID intake without any worsening of their disease activity. This was achieved in all of the clinical parameters studied. There were no statistically significant differences between groups in the HAQ, EMS, DAS-28-CRP, CRP, right and left grip strength (Table 2). Indeed there was a modest but statistically significant improvement in the mean (S.E.M.) VAS for pain from baseline to the 9-month visit in the SSMO1 group (6.73.05 mm) when compared with the placebo group (1.92.40 mm) (P=0.029, independent sample t-test; CI for difference, 16.38, 0.92). Adverse events and withdrawals There were no statistically significant differences in the number or type of side-effects reported by patients in the active and placebo groups (P=0.709). Most of the side-effects were mild and consisted of nausea (10 patients in the SSMO1 group and 6 in the placebo group), vomiting (four and two), diarrhoea (nine and five), flatulence or inability to swallow the capsules (seven and six). Six of the patients in the SSMO1 group experienced adverse events considered to be moderate or severe but these were not felt to be related to the study medication (two had cellulitis, one a transient ischaemic attack and three sustained fractures after falling). In the placebo group, 10 patients had moderate-to-severe adverse events but none of these were believed to be related to the study medication (eight mild infections, one myocardial infarction and one deep vein thrombosis). Seventeen patients (35%) in the SSMO1 group and 22 (46%) in the placebo group withdrew before the end of the study. The main reasons for withdrawal were: (i) adverse events judged to be unrelated to study medication (three in the SSMO1

group and two in the placebo group); (ii) adverse events judged to be related to study medication (three and seven); (iii) voluntary withdrawal (9 and 11); and (iv) lack of efficacy of study medication (two and two). There were no statistically significant differences in the number of withdrawals from the active and placebo groups, or in the type of adverse events that were the cause of withdrawal (P=0.304, chi-squared test; 95% CI for difference, 30.54, 8.26). Three of the withdrawals from the SSMO1 group were judged to be unrelated to the study medication. One patient developed diverticulitis, one had chest pain believed to be cardiac in origin and the third developed fibrosing alveolitis. In the two patients from the placebo group that withdrew with an adverse event unrelated to the study medication, one had cellulitis and the other developed probable NSAID-induced hypertension. The study medication related adverse events that led to withdrawals were all due to gastrointestinal complaints such as diarrhoea, nausea, vomiting and abdominal bloating. Voluntary withdrawal unrelated to adverse events was more frequent, with 9 patients in the SSMO1 group and 11 in the placebo group doing so. Among concerns raised by this group of patients were the large size and number of capsules to be taken daily, awareness that the capsules were empty and dislike of the fishy taste of the capsules. The rest of the withdrawals were due to failure to attend study visits or patients perceived lack of efficacy of the study drugs.

DISCUSSIONTo our knowledge this is the largest and the only dual-centre study to have investigated the effect of n-3 EFAs in RA. In this trial, we have shown that a daily intake of 10 g of cod liver oil significantly reduces the daily NSAID requirement by more than a third in 39% of patients with RA that started it and almost two-thirds of patients who continue to take it. This reduction of antiinflammatory intake was achieved without worsening of disease activity. Indeed, there was a significant improvement in the pain VAS of those patients taking daily SSMO1. These findings are important at a time when there are increasing concerns about adverse events associated with NSAID use. NSAIDs are among


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Table 2. Clinical and laboratory parameters of study patients

Values are mean S.E.M. SSMOI (n=49) and Placebo (n=48). VAS pain diff.: reduction of VAS pain from baseline; Subjective response (B/S/W): number of patients that felt better (B), the same (S) or worse (W) at each visit; R grip: right grip strength; L grip: left grip strength.

the most frequently prescribed medications worldwide with over 111 million prescriptions being written between September 1999 and August 2000 in the United States (13). NSAIDs are frequently used in RA with one study reporting regular NSAID use in over 70% of the RA patients studied (14). NSAID have been linked with important adverse events such as gastrointestinal toxicity, increases in blood pressure, aggravation of heart failure in elderly patients (15) and excess risk of cardiovascular events (16, 17). This may be particularly important in RA that is known to be associated with increased CV mortality (15). The potential for side-effects associated with these drugs are prompting patients with RA to seek alternative therapies to manage their disease. Recently, 60-90% of patients with arthritis have been reported to use complementary and alternative medicine options (18). Few placebo-controlled randomized trials assessing the effect of fish oils on RA disease activity have been published. Of those that have, the majority have shown an improvement in at least two clinical variables or a reduction in the NSAID requirement. These have been summarized by other authors (4, 5, 19). As most of the studies included only small numbers of patients and were of short duration (6 months) we were encouraged to undertake a larger two-centre study. Previous studies, including one from our group, used the reduction of the daily requirement of NSAID as an outcome measure (68, 20); but only in our own previous study (7) and the present trial has NSAID requirement been the main outcome measure, with a specified protocol for the reduction of the NSAID dose. The current study differed from our earlier trial in which patients on DMARD

were excluded because of the possibility that these drugs might attenuate the effects of fish oils by interfering with the metabolism of PGs and LTs (21). As DMARDS are now so widely used in the treatment of patients with RA, exclusion of patients with RA receiving DMARD from the current study would have severely restricted the applicability and clinical relevance of any trial conclusions. This is the first study in which the proportion of patients achieving a clinically significant NSAID reduction of 30% has been used as the primary outcome measure, rather than simply seeking a statistically significant mean reduction in consumption of NSAID. The results are encouraging with almost two-thirds of patients who continued to take the SSMO1 supplements achieving this goal. A total of 30% was considered an appropriate cut-off point as the risk of upper gastrointestinal bleeding and perforation with NSAID is dose dependent; with those on low/medium daily doses having a 2- to 3-fold increase in relative risk while those patients on high doses may have a >5-fold increase in risk (22). A limitation of this study was the relatively large number of withdrawals. Most of these were attributable to patients wishes (particularly patients unwillingness to take 10 large capsules a day in addition to their regular medication) or gastrointestinal intolerance. Despite the large number of withdrawals observed in this study, 39% of all patients starting SSMO1 were still able to reduce their NSAID daily intake by a third. We may have compromised the double blinding of the study by using air-filled capsules as placebo. Although it was recognized that some patients would discover their capsules to be empty and others may realize about the capsules lack of fishy smell and taste, air-filled capsules were

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selected as being the most appropriate placebo available after critical appraisal of alternatives. The possibility of using capsules filled with other fatty acids was rejected as none are believed to be truly inert, and saturated fats may be associated with a health risk. In summary, we have demonstrated that oral supplements of 2.2 g a day of EPA and DHA reduces the daily intake of NSAIDs by more than a third in almost 40% of patients with RA, without any worsening of their disease activity. Fish oil supplementation should be considered in RA patients to help them reduce their NSAID intake in order to attenuate the risks of gastrointestinal and cardiovascular adverse events associated with these drugs.

Rheumatology key message Cost liver oil supplements containing n-3 fatty acides can be used as NSAID sparing agents in RA patients.

ACKNOWLEDGEMENTSFunding: We are grateful to Willem Vas Dias and Seven Seas Ltd, for funding the study and for provision of SSMO1 and placebo capsules. Funding to pay the Open Access publication charges for this article was provided by Seven Seas Ltd. Disclosure statement: The authors have declared no conflicts of interest.

REFERENCESKromann N, Green A Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med Scand 1980;208:4016. 2. Simopoulos AP Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002;21:495505. 3. Belch JJ, Hill A Evening primrose oil and borage oil in rheumatologic conditions. Am J Clin Nutr 2000;71(1 Suppl):352S 6S. 4. Ariza-Ariza R, Mestanza-Peralta M, Cardiel MH Omega-3 fatty acids in rheumatoid arthritis: an overview. Semin Arthritis Rheum 1998;27:36670. 5. James MJ, Cleland LG Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum 1997;27:8597. 6. Geusens P, Wouters C, Nijs J, Jiang Y, Dequeker J Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis. A 12-month, double-blind, controlled study. Arthritis Rheum 1994;37:8249. 7. Lau CS, Morley KD, Belch JJ Effects of fish oil supplementation on nonsteroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritisa double-blind placebo controlled study. Br J Rheumatol 1993;32:9829. 8. Skoldstam L, Borjesson O, Kjallman A, Seiving B, Akesson B Effect of six months of fish oil supplementation in stable rheumatoid arthritis. A double-blind, controlled study. Scand J Rheumatol 1992;21:17885. 9. Arnett FC, Edworthy SM, Bloch DA et al The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:31524. 10. Steinbrocker O, Traeger CH, Batterman RC Therapeutic criteria for rheumatoid arthritis. J Am Med Assoc 1949;140:65966. 11. Hagglund KJ, Roth DL, Haley WE, Alarcon GS Discriminant and convergent validity of self-report measures of affective distress in patients with rheumatoid arthritis. J Rheumatol 1989;16:142832. 1. 12. Bland M An introduction to medical statistics, 3rd edn. Oxford: Oxford University Press, 2000. 13. Laine L Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120:594606. 14. Aletaha D, Smolen JS Advances in anti-inflammatory therapy. Acta Med Austriaca 2002;29:16. 15. DeMaria AN Relative risk of cardiovascular events in patients with rheumatoid arthritis. Am J Cardiol 2002;89(6 Suppl 1):338. 16. Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee of the US food and drug administration; February 1618, 2005. 2006. 17. Hippisley-Cox J, Coupland C Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional nonsteroidal antiinflammatory drugs: population based nested casecontrol analysis. Br Med J 2005;330:1366. 18. Soeken KL, Miller SA, Ernst E Herbal medicines for the treatment of rheumatoid arthritis: a systematic review. Rheumatology 2003;42:6529. 19. Stamp LK, James MJ, Cleland LG Diet and rheumatoid arthritis: a review of the literature. Semin Arthritis Rheum 2005;35:7794. 20. Belch JJ, Ansell D, Madhok R, ODowd A, Sturrock RD Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study. Ann Rheum Dis 1988;47:96104. 21. Davidson EM, Rae SA, Smith MJ Leukotriene B4, a mediator of inflammation present in synovial fluid in rheumatoid arthritis. Ann Rheum Dis 1983;42:6779. 22. Hernandez-Diaz S, Garcia-Rodriguez LA Epidemiologic assessment of the safety of conventional nonsteroidal antiinflammatory drugs. Am J Med 2001; 110(9 Suppl. 3A):s207.

LUCRRI ORIGINALE

EFFECTS OF SWITCHING BETWEEN ANTI-TNF THERAPIES ON HAQ RESPONSE IN PATIENTS WHO DO NOT RESPOND TO THEIR FIRST ANTI-TNF DRUGK.L. Hyrich, MD, M. Lunt, MD, W.G. Dixon, MD, K.D. Watson MD and D.P .M. Symmons DM on behalf of the BSR Biologics Register Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK

SUMMARYObjectives. Small studies have shown an improvement in disease activity in patients with RA who have switched between anti-TNF therapies for reasons of inefficacy. However, it is not clear whether switching improves longer term outcomes, such as disability. This analysis compares changes in HAQ scores 1 yr following lack of response to a first anti-TNF based on subsequent treatment during that year. Methods. Analysis was limited to RA patients with inefficacy to a first anti-TNF based on (i) clinician opinion and/ or (ii) disease activity score in 28 joints and had an HAQ measured at time of non-response and 12 months later. Patients were classified into three groups based on treatment during the next 12 months: (i) continued anti-TNF despite non-response; (ii) stopped anti-TNF with no further biologics; and (iii) switched to a second anti-TNF. Mean improvement in HAQ was compared among the groups using multivariable linear regression models. Results. As of July 2006, 868 patients met the inclusion for this analysis. Four hundred and seventy-nine patients stopped anti-TNF of whom 331 switched to a second anti-TNF. Three hundred and eighty-nine continued treatment. Patients who continued and those who switched had improvements in HAQ over the 12 months, unlike patients who discontinued all biologic therapy. The best improvement was seen in those who switched [adjusted mean improvement in HAQ 0.15 (95% CI 0.26, 0.05)]. Conclusion. There is a significant improvement in HAQ in patients who switch to a second anti-TNF, providing an effective next choice of therapy for some patients who fail to respond to their first anti-TNF. Key words: rheumatoid arthritis, anti-tumour necrosis factor therapy, disease-modifying anti-rheumatic drugs, disability, treatment response.

REZUMATEfectul terecerii la un alt agent TNFalfa asupra scorului HAQ la pacienii cu poliartrit reumatoid care nu au rspuns la primul medicament biologic Obiective: Studii anterioare au artat o ameliorare a activitii bolii la pacieni cu poliartrit reumatoid (PR) care au fost trecui de la un tratament anti-TNF la altul pentru lips de efect iniial. Totui, nu este clar dac aceast schimbare are vreun impact asupra beneficiului pe termen lung, cum ar fi cel asupra disabilitii. Aceast analiz compar modificrile scorului HAQ la un an de la tratamentul cu un agent anti-TNFalfa i la un an dup ce a fost introdus un al doilea. Metode: Analiza a fost limitat la pacienii cu lips de eficacitate la primul agent anti-TNFalfa stabilit prin aprecierea medicului (i) sau prin DAS28 (ii) i care aveau o evaluare HAQ la momentul lipsei de rspuns i 12 luni dup aceea. Subiecii au fost clasificai n trei grupuri pe baza tratamentului avut n ultimele 12 luni: (i) aflai sub tratament, n ciuda lipsei de rspuns, (ii) au oprit tratamentul i nu au continuat cu alt biologic i (iii) au fost trecui pe un alt agent antiTNFalfa. Ameliorarea scorului HAQ a fost comparat ntre grupuri prin modelul regresiei liniare multivariate. Rezultate: Pn n luna iulie 2006, 868 de pacieni au fost inclui n aceast analiz. Dintre acetia, 479 au oprit tratamentul, dintre care 331 au trecut la alt agent anti-TNF alfa i 389 l-au continuat. Cei care au continuat sau au fost trecui pe alt medicament au nregistrat ameliorri ale scorului HAQ, n vreme ce toi ceilali nu. Cele mai bune rezultate le-au avut cei care au fost trecui pe alt bioloigic (ameliorare medie de 0.15, IC95% 0,26-0,05). Concluzie: A existat o ameliorare semnificativ a scorului HAQ la bolnavii cu PR care au trecut la alt agent anti-TNFalfa pentru c nu au rspuns la primul. Cuvinte cheie: poliartrit reumatoid, tratament anti-TNFalfa, medicamente remisive, disabilitate, rspuns terapeutic.

Correspondence to: K. L. Hyrich, Arthritis Research Campaign Epidemiology Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail: [email protected]


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INTRODUCTIONAnti-TNF therapies represent a significant advance in the management of severe RA. Randomized controlled trials estimated upwards of 5070% of patients achieve at least an ACR20 response (14). More recently, observational data of large patient registries have shown similar results with ~70% of patients achieving at least a European League Against Rheumatism (EULAR) moderate response [5]. However, what is inevitable in these data is that approximately one-third of the patients do not achieve these minimum responses. Recent observational data has also shown that ~30% of patients will discontinue their first course of antiTNF therapy within the first year (69). After failing anti-TNF therapy, the further management options for these patients remain limited. Many will have already failed multiple traditional DMARDs prior to starting their first anti-TNF therapy. Options include yet another trial of traditional DMARDs, or even corticosteroids, continuing on their initial anti-TNF therapy despite an inadequate response or switching to a different biologic agent. Until recently, the choice of switching to a second biologic agent has been limited to switching between anti-TNF therapies and the availability of newer biologic agents remains limited in many countries. The evidence for switching between anti-TNF therapies in patients who have had lack of response to their first anti-TNF therapy is growing. Many small case series and open-label studies have demonstrated good responses in patients switching for both primary and secondary inefficacy, as well as adverse events (10). However, the majority of these studies were very small and often combined patients who have switched for inefficacy or adverse events. The response to a second anti-TNF will differ based on the reason for the switch (11, 12). In addition, most studies to date have not included a comparison with other treatment options and have only focused on disease activity and not longer term outcomes, such as disability. Therefore, the aim of this analysis was to assess disability in a group of RA patients 12 months after failing to respond to a first anti-TNF therapy, depending on subsequent management over those 12 months.

Register (BSRBR). The details of this study have been described elsewhere (13). Briefly, as part of the UK national guidelines, patients with RA starting anti-TNF therapy are registered with the BSRBR, the purpose being to systematically follow these patients for short- and long-term outcomes including drug safety and efficacy. The register is still actively recruiting and following new patients starting anti-TNF therapy. The UK national guidelines recommend that anti-TNF therapies are administered to patients with active RA, defined as a disease activity score in 28 joints (DAS28) >5.1 despite previous therapy with at least two DMARDs, one of which should be MTX. During the period of recruitment, etanercept was administered as a subcutaneous injection either once (50 mg) or twice (25 mg) weekly and adalimumab was administered as a subcutaneous injection 40 mg fortnightly. The suggested starting dose of infliximab was 3 mg/ kg administered in conjunction with MTX. Baseline assessment Baseline data, including demographics, diagnosis, disease duration, DAS28 (14), past and current anti-rheumatic therapies and comorbidities are collected by the patients rheumatologist and/ or rheumatology nurse. In addition, each patient completes a separate questionnaire as well as the HAQ adapted for British use (15). Follow-up Rheumatologists are sent a follow-up questionnaire every 6 months. Of relevance to this analysis, the rheumatologist records whether their patients registered anti-TNF drug has been continued, switched to another biologic drug or stopped. The reasons for stopping or switching treatment are based on the physicians opinion, as recorded in the medical charts, and classified into lack of efficacy, adverse events or other reasons. Changes in nonbiologic DMARDs are also captured. In addition, the most recent DAS28 is recorded at each 6-month follow-up. This measurement may or may not correlate with changes in therapy. Patients are contacted separately by post and asked to complete a HAQ score on a 6-monthly basis. Statistical analysis This analysis was limited to patients with a physicians diagnosis of RA who were classified

PATIENTS AND METHODSPatient selection Patients for this study were selected from the large British Society for Rheumatology Biologics


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as non-responders to their first anti- TNF agent within the first 12 months of therapy. Patients who discontinued their first anti-TNF therapy for an adverse event were excluded. Patients could be classified as non-responders in two separate ways: (i) Drug discontinuation: Patients who discontinued their first anti-TNF therapy in the first 12 months of use with the reason listed as inefficacy were classified as non-responders, regardless of changes in their DAS28 score. The date of discontinuation, defined as the first missed dose, was taken as the date of first non-response. (ii) EULAR response: Using the DAS28 measured at baseline, 6 and 12 months, patients could also be classified as nonresponders based on the EULAR improvement criteria (16). Response was first assessed in all patients after 6 months. To account for possible secondary inefficacy, patients who were responders at 6 months but nonresponders at 12 months were also included. The date of non-response was taken as the date of the first DAS28 score (i.e. 6- or 12month follow-up date) which classified the patient as a non-responder. The primary outcome measure in the study was change in HAQ score in the subsequent 12 months following classification as a non-responder. Patients were only included in the analysis if they had a HAQ score recorded within 90 days of the date on which they were first classified as a nonresponder and a subsequent HAQ recorded two follow-ups (or 12 months) later. Non-responders were divided into three separate groups based on subsequent management over the following 12 months (Fig. 1): (i) Group 1 Stoppers: discontinued anti-TNF therapy within the first 12 months and did not start a subsequent anti-TNF agent or other biologic drug during the next 12 months. (ii) Group 2 Stayers: continued on their original anti-TNF agent despite being classified as a non-responder and remained on therapy until at least within 90 days of the final HAQ measurement (i.e. for a minimum of further 9 months). (iii) Group 3 Switchers: stopped their first anti-TNF therapy within the first 12 months of therapy for non-response but started a second anti-TNF therapy during the subsequent 12 months. To capture the full experience of patients who switched between

anti-TNF therapies, Group 3 included all patients who

revista romana de reumatologie - 2009 - nr.1

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