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Revista Romn de

REUMATOLOGIE
Volumul 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 REDACIE


Geza 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 AMALTEA
Editori: 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: AMR@medica.ro ABONAMENTE: redactia@amaltea.ro TIPAR: EMPIRE Print RomExpo, Pavilion T, Bucureti tel.: 021 / 316 96 40, 031 / 405 99 99 email: office@empireprint.ro

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 ARTROZIC


A 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: hbolosiu@yahoo.com

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

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

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 REUMATOLOGIC


Dactylitis: an unusual manifestation in rheumatology
Prof. Dr. H.D. Boloiu Centrul de Cercetare n Boli Reumatologice, Clinica Reumatologic, UMF Cluj-Napoca

REZUMAT
Aceast 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.

SUMMARY
This 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.

INTRODUCERE
n 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: hbolosiu@yahoo.com

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

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

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 SPONDILOARTROPATII


Dactilita 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

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

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 BOLI


Dactilita 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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BIBLIOGRAFIE
1. 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 DISABILITY


Dr. Mariana Mihailov, Dr. Daiana Popa University of Oradea, Faculty of Medicine and Pharmacy Medical Rehabilitation Hospital Felix Spa, Romania

SUMMARY
The 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

REZUMAT
Influene 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: mariana_mihailov@yahoo.com

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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.

REFERENCES
1. 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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8. 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 ARTHRITIS
B. 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.

SUMMARY
Objectives. 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.

REZUMAT
Uleiul 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: b.galarraga@dundee.ac.uk

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INTRODUCTION
RA 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 METHODS


Study 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 P<0.05 (two sided), assuming an S.D. of 45% (12). Statistical analysis Analysis was performed by intention to treat. The missing data were completed as follows: for the primary outcome (relative reduction of daily NSAID requirement by >30% 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.

RESULTS
Ninety-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) (P<0.0001, independent sample t-test; CI for difference at 3 and 9 months, 3.94, 7.49 and 3.44, 6.74, respectively) confirming compliance. There were no differences in the number of capsules returned by patients in each group 246 (9.1% of the total number of tablets) returned in the SSMO1 group and 297 (11%) in the placebo group, (P=0.722, independent sample t-test; CI for difference, 91.2, 63.5). NSAID requirements All patients were on NSAID at baseline. The most common NSAIDs were diclofenac, naproxen and ibuprofen taken by 41, 31 and 4% of patients in the SSMO1 group and by 46, 17 and 10% of patients in the placebo group, respectively. There was a significant difference in the primary outcome variable between the two groups. Nineteen out of 49 (39%) patients in the SSMO1 group and 5 out of 48 (10%) patients in the placebo group were able to reduce their daily NSAID requirement by >30% 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.

DISCUSSION
To 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.

ACKNOWLEDGEMENTS
Funding: 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.

REFERENCES
Kromann 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 DRUG
K.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

SUMMARY
Objectives. 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.

REZUMAT
Efectul 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: kimme.hyrich@manchester.ac.uk

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INTRODUCTION
Anti-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 METHODS


Patient 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 started a second anti-TNF at any time during the next 12 months. As this group was quite varied, we also identified a group of patients within Group 3 who switched early (within 90 days of being classified as a non-responder) and remained on the second anti-TNF therapy at least until within 90 days of the second HAQ measurement (Group 4 Early Switchers) to ensure at least 6 months treatment with the second anti-TNF therapy. Baseline characteristics (at the start of the first anti-TNF therapy) were compared among the groups using Pearson chisquared and Kruskal Wallis tests. The primary outcome was the mean change in HAQ score in the 12 months following classification as a non-responder. This outcome was compared between those patients who discontinued all biologic therapy (Stoppers) and each of the other three treatment groups, using multivariable linear regression models. The models were adjusted for age, gender, disease duration, DAS28 score at the start of first therapy, DAS28 score at first non-response and HAQ score at first nonresponse, as it was felt that these factors may have influenced which treatment group patients were allocated to and may also have influenced any further change in HAQ during the follow-up period. All analysis was performed in STATA Version 9.2 [College Station (TX), Stata Corporation] (17). Ethical approval The BSRBR received ethical approval from the United Kingdom North West Multi-centre Research Ethics Committee (MREC 00-8-53). Written informed consent was obtained from the participants according to the Declaration of Helsinki (18).

RESULTS
As of July 2006, a total of 10 993 patients with RA were registered with the BSRBR. Of these, 4458 (41%) started etanercept, 3956 (36%) infliximab and 2579 (23%) adalimumab as their first anti-TNF drug. As of July 2006, 9026 (82%) had reached at least 6 months of follow-up, 7640 (69%) at least 1 yr, 5885 (53%) at least 18 months and 5002 (46%) at least 2 yrs of follow-up. During the first 12 months, 424 had stopped their first

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anti-TNF drug for an adverse event and were not included in this analysis. During this same period, 978 patients had stopped for inefficacy (726 with an HAQ recorded within 90 days of stop date) and 1925 were classified as EULAR nonresponders based on change in DAS28 (1384 with a HAQ recorded within 90 days of DAS28 date). As many patients who stopped for inefficacy were also classified as non-responders using the EULAR response, a total of 1725 patients were classified as non-responders and had a HAQ score recorded within 90 days of being classified as a nonresponder (Fig. 1). The majority of these nonresponders (88%) were classified as nonresponders at 6 months and 12% were classified at 12 months.

Of the 1725 non-responders, 1222 (71%) had completed a further 12 months of follow-up. Of these, 1033 (85%) patients had a HAQ score recorded at this later follow-up. Of these 1033 nonresponders, 148 (14%) received no further antiTNF therapy during the subsequent 12 months (Stoppers), 331 (32%) switched to a second antiTNF therapy (Switchers) and 389 (38%) continued on their first anti-TNF therapy for at least a further 9 months (Stayers), giving a total of 868 patients for this analysis (Table 1). The remaining patients continued on their first anti-TNF therapy beyond the date of non-response but discontinued within the next 9 months and were not included in this analysis, as disability measures did not correlate with drug discontinuation.

Figure 1. Patient flow. FUP, follow-up

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Compared with patients who were either Stayers or Switchers, Stoppers were slightly older (61 vs 58 yrs, P=0.01) when starting their first anti-TNF therapy (Table 2). Stayers tended towards a lower HAQ and DAS28 at the start of their first antiTNF therapy (Tables 2 and 3). Overall, the mean change in HAQ score with the first anti-TNF agent in this group of non-responders (measured at the point of first designation as non-responder) was 0.08U (S.D. 0.32), demonstrating a small improvement. However, when comparing the improvements between the three groups, Stayers had a greater mean improvement in HAQ score with the first anti-TNF therapy compared with both Stoppers and Switchers (Table 3). During the subsequent 12 months, Stoppers experienced no change in their mean HAQ score. The greatest mean improvement in HAQ score in the 12 months after classification as nonresponders was observed among Switchers, with Stayers falling in between. This trend remained after adjusting for differences in age, gender, disease duration, HAQ score and DAS score (at start of first antiTNF therapy and at time of failure). As these scores represent mean improvements among the groups, the proportion of patients who achieved a minimum clinically important difference (MCID) (defined as improvement in HAQ score of at least 0.22 U) (19) were also identified. Among Stoppers, only 22% reached this MCID compared with 31% of Stayers and 36% of Switchers (P<0.01 compared with Stoppers). The best response (46%) was seen among patients who switched anti-TNF therapy early (n=147) following inefficacy and remained on therapy for at least 6 months (Early Switchers), which was significantly greater than Stayers (31%) (P<0.01). To explore the possible effects of background DMARD therapy, the proportion of patients receiving DMARDs with their first anti-TNF drug and the proportion that had a change to therapy during the subsequent 12 months were analysed. Overall, 61% of patients were receiving a DMARD with their first anti-TNF therapy, which did not differ significantly among the groups (Table 2). The majority of these patients were receiving MTX (49% of all patients, 80% of all DMARD prescriptions). Only 13% of Stayers reported a change in DMARD therapy over the subsequent 12 months (change in dose or new DMARD) compared with 32% of Stoppers and 32% of Switchers (P<0.05).

DISCUSSION
Data from small open-label studies and clinical trials have shown that patients who are not responding to a first anti-TNF drug can gain significant improvements in disease activity when switched to a second anti-TNF agent (10) and a recent clinical trial has suggested that this improvement will exceed any further improvement in disease activity which may be expected from staying on the less effective drug (20). Our data suggest that patients who do not respond to a first anti-TNF drug may also subsequently gain improvements in HAQ score, if switched to a second agent. Why patients should respond to one anti-TNF and not another, despite similar mechanisms of action, remains unexplained, but possible hypotheses include differential bioavailability of these drugs, differences in stability of the drugTNF complex and the development of anti-drug antibodies (21). Differences in patient adherence among these three agents may also play a role. Unfortunately, the relatively small number of patients who switched therapy in this analysis precluded any specific betweendrug comparisons. Inherent to this analysis is the limitation of using observational data to measure treatment response. Thus, while the analysis did capture outcomes among patients as they occurred in the real world, there is no doubt that there was still some selection of patients as to whether they started any anti-TNF therapy in the first instance, whether they stopped therapy if they were not responding adequately, and later whether they switched to a second agent. Decisions on treatment and thresholds for stopping will have changed over the course of this study, due to availability of different anti-TNF agents and physicians experience over time, which may act to limit the external validity of these results. We attempted to adjust for factors which may have influenced a physicians decision to start and stop therapy, including age, disease duration, DAS28 and HAQ scores, and found that this actually made little difference to the results. Further adjustment used to model physicians decisions using inverse probability of treatment weighting (22), which included DAS28 scores 6 months after a patient was classified as a non-responder, were also employed, but did not alter the results (data not shown). Unfortunately, as discussed

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subsequently, missing DAS28 scores excluded many patients from this model. There is also a strong possibility that other unmeasured confounders, particularly related to the patient, may have influenced these results. Although all of these patients were classified as non-responders, only half stopped therapy and only two-thirds of these switched to a second agent. Factors such as past experience of DMARD therapy, the occurrence of minor adverse events alongside the lack of response and other psychological factors may have influenced a patients decision to switch to a second anti-TNF agent. These same factors may also have influenced the patients HAQ scores. In addition, as during the main BSRBR study, HAQ scores were not obtained at the time of treatment decisions but rather at regular 6-month intervals, we had to exclude a proportion of patients in order to only use those scores that did correlate with changes to treatment or measures of disease activity. It is possible that the outcomes of these excluded patients may have differed.
Table 1. Details of anti-TNF therapy

Table 2. Characteristics of patients at start of first antiTNF therapy

*Difference observed between Stoppers, Stayers and Switchers, P<0.01. +Difference observed between Stoppers, Stayers and Switchers, P=0.07. All results are given in median (IQR) unless state Table 3. Mean changes in HAQ scores

In this large cohort of anti-TNF-treated RA patients, over 50% of patients remained on therapy despite a sub-optimal response. Interestingly, this group of patients continued to gain further improvements in HAQ score, despite fewer changes to background DMARD therapy. Why so many patients should remain on a therapy without a significant improvement in DAS28 remains unclear. In the UK, practice guidelines suggest that patients should discontinue therapy if an improvement in DAS28 of at least 1.2U is not achieved after 3 months (or after 6 months if other improvements in disease had been observed at 3 months) (23). The treatment options in the UK at the time of this analysis (as of July 2006) for patients who had failed anti-TNF therapy were limited to stopping anti-TNF therapy and reverting to traditional DMARDs and/or corticosteroids, continuing anti-TNF therapy despite a lack of response or switching to a second anti-TNF agent. Both rituximab and abatacept received a European licence in 2007, a year following this analysis. Initial UK guidelines (23) for the use of anti-TNF agents in RA did not recommend switching between therapies, and therefore many hospitals may have been unable to obtain funding for a second course of anti-TNF therapy. As most of these patients had already failed on average four DMARDs, there likely remained no other alternative other than continue a less effective therapy. However, we also observed that the best improvement in HAQ scores with the first antiTNF therapy were observed among patients who subsequently remained on therapy, and therefore, it is possible that despite a lack of significant improvement in DAS28, patients may have felt better and therefore, their rheumatologist elected to maintain this therapy despite a suboptimal response. It is also likely that, due to reasons discussed earlier, patients may also have been kept on their second anti-TNF drug despite a lack of

aUsing

HAQ scores measured at start of first anti-TNF therapy and at time of first designation as non-responder. bAdjusted for age, gender, disease duration, HAQ at first failure, DAS28 at start of first anti-TNF, DAS28 at first failure. cDifference in proportion between Stayers/Stoppers and Switchers/Stoppers (P 0.01). Difference between All Switchers and Stayers (P 0.19). Difference between Early Switchers and Stayers (P=0.03).

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response, and therefore our measurement of response among Switchers may also be an underestimate of the treatment effect. The primary outcome measure chosen in this analysis was mean change in HAQ score in the 12 months following non-response to a first antiTNF therapy. The HAQ was selected as it is a good measure of longer-term outcomes in arthritis. However, in patients with long-standing RA, HAQ scores may correlate more with damage rather than with disease activity, and it has been shown that HAQ scores are less responsive to treatment at this later stage (24). The median disease duration in this cohort was 12 yrs. However, despite this possible limitation, HAQ scores can still improve significantly in patients with long-standing disease following effective disease control. During clinical trials of anti-TNF therapies in biologically naive patients, the mean improvement in HAQ score in the active treatment arms was in the range of 0.5 U over 612 months (13). However, it may not be realistic to expect such an improvement among a group of patients who have already failed one anti-TNF agent. Patients are also more likely to stop a second anti-TNF agent for inefficacy if they had also stopped their first agent for inefficacy (25). Thus, while the degree of response among individual patients who do respond to a second anti-TNF drug may be equivalent to that seen with a first agent, the proportion of patients who do respond will be lower and thus, the mean improvement among a group of patients will also be lower. DAS28 was not selected as the primary outcome measure for two main reasons. First, it was felt that, in this uncontrolled study, where other non-biologic therapies are allowed, changes in DAS28 over 12 months may not necessarily reflect only changes to anti-TNF therapies. Shortterm interventions, such as corticosteroid injections, are as likely to reduce swollen and tender joint counts and ESR. Whilst we have shown that DMARD use did not vary significantly between the groups in the subsequent 12 months of follow-up, unfortunately, we did not record details of joint injections or details of intramuscular injections, which may also have had an influence upon DAS28 scores. In addition, we found that over time, patients were less likely to have a DAS28 recorded, particularly if anti-TNF therapy was discontinued or if there had been no changes to therapy for a prolonged period of time.

In conclusion, patients with long-standing disease who do not respond to their first anti-TNF therapy discontinue this first drug and receive no biologic therapy in the subsequent 12 months do not experience any further mean improvements in HAQ score over this 12-month period. Patients who continue on their first anti-TNF drug despite a suboptimal improvement in DAS28 gain some further improvement in HAQ score, suggesting that biologics may continue to provide additional benefit to patients beyond the first few months of treatment. However, the best response was seen among patients who switched to a second anti-TNF therapy. Rheumatology key messages Many patients who fail to respond to one antiTNF agent switch to a second anti-TNF drug. A significant proportion of these patients will demonstrate improvements in HAQ score on their second drug.

ACKNOWLEDGEMENTS
The authors acknowledge the enthusiastic collaboration of all consultant rheumatologists and their specialist nurses in the UK in providing the data used in this report. We also acknowledge the significant contribution of Prof. Alan Silman in the conception and establishment of the BSRBR. The substantial contribution of Andy Tracey and Katie McGrother in database design and manipulation is recognized. We also acknowledge the support from Dr Ian Griffiths, Chairman of the BSRBR Management Committee, Prof. Gabriel Panayi, Prof. David G. I. Scott and Prof. David Isenberg, Presidents of the BSR during the period of data collection, for their active role in enabling the Register to undertake its tasks and to Mervyn Hogg and Samantha Peters, CEO of the BSR, and the BSR staff for considerable administrative support. Funding: The BSRBR was established primarily to investigate the safety of biologic agents in routine practice. The financial support to the BSRBR comes indirectly from the following UK companies marketing biologic agents in the UK: Schering-Plough, Wyeth Laboratories, Abbott Laboratories and Amgen. The resources used to fund the BSRBR are received under contract by the BSR, which then provides a research grant

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under a separate contract to the University of Manchester, allowing the investigators normal academic freedom in relation to the data, their analysis and use. Under the terms of the contract between the BSR and the pharmaceutical companies, all publications are sent in advance to the companies prior to submission, for the purposes of information. The companies can, if they wish, point out factual errors. Any comments are vetted by three members of the BSRBR Scientific Steering Committee, who decide whether they should be

passed on to the authors. All publications are also reviewed by the BSR, but the material presented and the views expressed in all publications from the BSRBR are those of the authors and do not necessarily represent the views of the BSR. Funding to pay the Open Access publication charges for this article was provided by a grant from the British Society for Rheumatology. Disclosure statement: The authors have declared no conflicts of interest.

REFERENCES
1. Lipsky PE, Van der Heijde DMFM, St Clair EW et al Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594602. 2. Weinblatt ME, Keystone EC, Furst DE et al Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:3545. 3. Weinblatt ME, Kremer JM, Bankhurst AD et al A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:2539. 4. Bathon JM, Martin RW, Fleischmann RM et al A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:158693. 5. Hyrich KL, Symmons DP, Watson KD, Silman AJ Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another diseasemodifying antirheumatic drug in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006;54:178694. 6. Zink A, Listing J, Kary S et al Treatment continuation in patients receiving biological agents or conventional DMARD therapy. Ann Rheum Dis 2005;64:12749. 7. Carmona L, Gomez-Reino JJ Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER. Arthritis Res Ther 2006;8:R72. 8. Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007;56:1320. 9. Duclos M, Gossec L, Ruyssen-Witrand A et al Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients. J Rheumatol 2006;33:24338. 10. van Vollenhoven RF Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue. Ann Rheum Dis 2007;66:84951. 11. Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007;56:1320. 12. Gomez-Reino JJ, Carmona L Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period. Arthritis Res Ther 2006;8:R29. 13. Silman A, Symmons D, Scott DG, Griffiths I British Society for Rheumatology Biologics Register. Ann Rheum Dis 2003;62(Suppl 2):ii289. 14. Prevoo ML, vant Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:448. 15. Kirwan JR, Reeback JS Stanford Health Assessment Questionnaire modified to assess disability in British patients with rheumatoid arthritis. Br J Rheumatol 1986;25:2069. 16. van Gestel AM, Prevoo ML, vant Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/ International League Against Rheumatism Criteria. Arthritis Rheum 1996;39:3440. 17. Stata Statistical Software: release 9.2. College Station, TX: Stata Corporation, 2007. 18. Vollmann J, Winau R Informed consent in human experimentation before the Nuremberg code. Br Med J 1996;313:14459. 19. Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier DA Minimum important difference between patients with rheumatoid arthritis: the patients perspective. J Rheumatol 1993;20:55760. 20. Furst DE, Gaylis N, Bray V et al Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Ann Rheum Dis 2007;66:8939. 21. Haraoui B Is there a rationale for switching from one anti-tumor necrosis factor agent to another? J Rheumatol 2004;31:10212. 22. Robins JM, Hernan MA, Brumback B Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:55060. 23. National Institute for Clinical Excellence. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis, 2002. http://www. nice.org.uk (August 15 2007, date last accessed). 24. Aletaha D, Ward MM Duration of rheumatoid arthritis influences the degree of functional improvement in clinical trials. Ann Rheum Dis 2006;65:22733. 25. Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007;56:1320.

LUCRRI ORIGINALE

EVALUAREA COMPARATIV CLINIC, PARACLINIC I TOXICOLOGIC A TRATAMENTULUI CU LEFLUNOMID I METOTREXAT LA PACIENI CU POLIARTRIT REUMATOID
Clinical, paraclinical and toxicological comparative evaluation of leflunomide and metotrexat treatment in patients with rheumatoid arthritis
Dr. Carolina Negrei1, Prof. Dr. D. Bllu1, Conf. Dr. Andra Blnescu2, Dr. A. Bla Mihaela Ilie1, Dr. Denisa Margin3, Conf. Dr. Daniela Baconi1, Dr. Andreea-Letiia Arsene3, Dr. Cristina Drgoi3, Conf. Dr. Denisa Predeeanu2, Dr. Violeta Bojinc2, Dr. F. Berghea2, Dr. Daniela Opri2, Prof. Dr. Ruxandra Ionescu2 1Universitatea de Medicin i Farmacie Carol Davila, Facultatea de Farmacie, Disciplina de Toxicologie 2Universitatea de Medicin i Farmacie Carol Davila, Centrul de Cercetare n Patogenia i Tratamentul Bolilor Reumatice, Spitalul Clinic Sfnta Maria 3Universitatea de Medicin i Farmacie Carol Davila, Facultatea de Farmacie, Disciplina de Biochimie

REZUMAT
Obiective: Evaluarea efectelor tratamentului cu leflunomid (LF) i metotrexat (MTX) asupra unor parametri biochimici, hematologici i markeri ai inflamaiei. A fost urmrit, de asemenea, influena tratamentului cu LF i MTX asupra fluiditii membranare a celulelor mononucleare periferice (PBMC) izolate din sngele periferic al pacienilor cu poliartrit reumatoid (PR), prin studii toxicologice in vitro. S-a utilizat pentru comparaie un grup de control format din voluntari sntoi. Materiale i metode. Au fost selectai 28 pacieni cu poliartrit reumatoid (71% femei i 29% brbai), diagnosticai conform criteriilor revizuite din 1987 ale Colegiului American de Reumatologie. Toi pacienii cu PR erau pe terapie imunosupresoare (LF sau MTX), nici unul nu a primit terapie cu corticosteroizi sau antagoniti de TNF-. Parametrii biochimici, hematologici i marker ai inflamaiei, precum i fluiditatea membranar a PBMC au fost evaluate pe probe de snge recoltate jeun de la subiecii luai n studiu. Fluiditatea membranar a PBMC a fost evaluat spectrofluorimetric, n lumin polarizat, folosind sonda fluorescent 1-(4-trimetil amoniu fenil)-6-fenil-1,3,5hexatrien p-toluen-sulfonat (TMA-DPH), urmrindu-se evoluia acestui parametru ca nivel de baz i dup stimularea in vitro a celulelor cu MTX i dexametazon (D). Rezultate: Rezultatele au indicat valori mai sczute ale activitii transaminazelor serice la pacienii tratai cu LF comparative cu MTX. Nivelele creatininei, acidului uric, i CRP serice au fost de asemenea mai sczute la pacienii tratai cu LF, n timp ce VSH-ul i fibrinogenul au nregistrat valori mai crescute. Stimularea chimic in vitro a PBMC cu MTX i D a determinat, la grupul de control, creterea semnificativ a fluditii membranare, dar nu a avut nici o influen la grupurile tratate cu LF sau MTX. Discuii: Rezultatele prezentate sunt pariale, urmnd ca n continuare, n funcie de datele finale ale studiului s se fac corelaii ntre toxicitatea terapiei folosite i condiiile patologice coexistente. Concluzii: Rezultatele asupra parametrilor biochimici, hematologici i ai markerilor inflamatori sugereaz o toxicitate mai mic a LF; de asemenea, activitatea antiinflamatorie este comparativ pentru ambele medicamente. Studiile in vitro privind fluiditatea membranar PBMC indic faptul c MTX i D au efecte asupra membranei (concretizate prin creterea fluiditii membranare) numai n cazul grupului de control; nu s-au evideniat modificri ale fluiditii membranare a PBMC izolate de pacieni tratai cu LF i MTX, n condiii de suprastimulare in vitro. Cuvinte cheie: poliartrit reumatoid, leflunomid, metotrexat

Adres de coresponden: Carolina Negrei, Str. Traian Vuia, Nr. 6, tel./fax 0213111152, Bucureti email: carol_n2002@hotmail.com

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SUMMARY
Aims: The evaluation of the leflunomide (LF) and methotrexate (MTX) treatment on certain biochemical, hematological and inflammation markers. Another aim was to evaluate the influence of LF and MTX on the membrane fluidity of peripheric blood mononuclear cells (PBMC) isolated from rheumatoid poliartritis (RA) patients via in vitro toxicological studies. As a comparison, a lot of healthy volunteers were used. Materials and methods. The study included 28 (71% female and 29% male) RA patients diagnosed according to the 1987 revised criteria of the American College of Rheumatology. All patients received immunosupressive therapy (LF or MTX), neither received corticosteroids or TNF- antagonists. The biochemical, hematological, inflammation markers as well as the PBMC membrane fluidity was evaluated on blood samples collected jeun from the participants to the study. The PBMC membrane fluidity was spectrofluorimetrically evaluated in polarized light using 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH) as a fluorescent probe; the basic membrane fluidity and following in vitro stimulation of the cells with MTX and dexamethasone (D) was evaluated. Discussion. The presented results are preliminary and the final ones will be correlated with the pathology associated. Results. The obtained results indicate a lower activity of seric transaminases in patients treated with LF compared to those trated with MTX. The creatinine, uric acid and C reactive protein (CRP) levels were lower as well in LF-treated patients as compared to MTX-treated patients, whereas erythrocythes sedimentation rate (ESR) and fibrinogen level were higher. The in vitro stimulation with MTX and D of the PBMCs resulted in an increased membrane fluidity in controls, but had no influence in the groups treated with LF or MTX. Conclusions. The obtained results for the biochemical, hematological and inflammation markers suggest a lower toxicity of LF treatment, provided that the antinflammatory activity of the drugs is almost the same. The in vitro studies regarding the membrane fluidity of PBMC suggests that MTX and D stimulation result in an increased fluidity in controls, but has no influence on the fluidity of the cells prelevated from RA patients treated with LF or MTX, in the conditions of in vitro overstimulation. Key words: rheumatoid arthritis, leflunomide, methotrexate

Abrevieri: PR=poliartrita reumatoid, PBMC=celule mononucleare separate din snge periferic uman, MTX=metotrexat, LF=leflunomid, D=dexametazon, TMA-DPH=1-(4-trimetil amoniu fenil)-6-fenil-1,3,5-hexatrien p-toluen-sulfonat.

INTRODUCERE
Imunoreglarea este mediat de o complex reea de interaciuni celulare care implic att contacte celul-celul, ct i factori solubili. Poliartrita reumatoid (PR) se caracterizeaz prin modificri complexe la nivelul sistemului imun, puse n eviden prin dereglri ale rspunsului imun. n toate aceste evenimente, un rol cheie este jucat de membrana celular, att cea plasmatic, ct i cea intracelular, atta vreme ct sunt implicate n fenomenul de recunoatere celular i n transducie (1,2). Dei etiologia PR este nc necunoscut, a devenit evident c limfocitele au un rol important n patogenia PR. Cteva studii au artat limfocite cu morfologie i funcii anormale n sngele periferic al pacienilor cu PR i o cretere a limfocitelor activate. Dat fiind faptul c membrana celular este implicat n rspunsul imun, n procesele inflamator i citotoxic, n cadrul mecanismelor de instalare a PR trebuie luat n considerare posibilitatea

alterrii structurale i funcionale membranei limfocitare (3). Fluiditatea membranar este o caracteristic fizico-chimic, n care mobilitatea, ordonarea i proprietile componentelor membranare sunt strns interconectate. Fluiditatea memebranar are un rol important n reglarea conformaional a receptorilor membranari i a altor proteine membranare cu rol metabolic, n legarea enzimelor, n difuzia sau gradul de expunere a receptorilor (4). Modificrile n compoziia i n organizarea molecular sunt factori determinani ai alterrii fluiditii membranare observate n cazul diferitelor boli. Astfel, alterrile n comportamentul limfocitelor de la pacienii cu PR pot fi puse n legtur cu anormaliti n fluiditatea membranar (5). Lucrarea i propune s investigheze fluiditatea membranar a celulelor mononucleare provenite din snge periferic recoltat de la pacieni cu PR, aflai sub tratament cu leflunomid (LF) i metotrexat (MTX), att n stare de baz, ct i n urma suprastimulrii in vitro cu MTX sau dexametazon (D).

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MATERIALE I METODE
Pacieni: Am realizat un studiu clinic care a inclus 28 de pacieni cu PR, diagnosticai conform criteriilor revizuite din 1987 ale Colegiului American de Reumatologie i tratai cu medicamente de tipul DMARD (disease modifying antirheumatic drugs), 12 dintre acetia cu LF i 16 cu MTX. Nici unul nu a primit corticosteroizi sau antagoniti de TNF-. Conform evalurii clinice bazate pe scorul DAS28, toi pacienii aveau boal activ (DAS28>5.1). Grupul de control a fost format din 19 voluntari sntoi. Au fost exclui din studiu pacienii care fuseser diagnosticai cu boli renale, hepatice, hematologice, cardiovasculare severe sau cu afeciuni maligne. A fost obinut acordul subiecilor inclui n studiu, iar protocolul de lucru a fost supus aprobrii Comitetului de Etic. Probe biologice: Au fost recoltai jeun 4-5 ml de snge uman periferic de la subiecii luai n studiu. Celulele mononucleare sanguine (PBMC) au fost separate prin tehnica gradientului de densitate, folosind Histopaque 1077 (Sigma), splate de dou ori cu mediu de cultur RPMI 1640 (Sigma), apoi normalizate la 10 5 celule/mL n mediu de cultur RPMI 1640. Aparate: Analizor semi-automat pentru biochimie/turbidimetrie/coagulare AE-600, spectrofluorimetru Perkin-Elmer model LS 50 B, echipat cu sistem de lucru n fluorescen polarizat, cuv termostatat extern i cu posibilitatea de agitare magnetic continu a probei n cuva de msur. Determinrile de fluiditate membranar: n cuva de msur se introduc 2 ml de suspensie PBMC normalizat se determin iniial autofluorescena (n modul TimeDrive al spectrofluorimetrului la excitare 355 nm, emisie 430 nm, cu fante de excitare i emisie de 10 nm, timp de 4 secunde, n pai de 0,02s) n 4 poziii ale polarizorilor n fascicolul de excitare i de emisie (vertical-vertical, vertical-orizontal, orizontal-orizontal, orizontal vertical). n cuva de msur se adaug sonda fluorescent 1-(4-trimetil amoniu fenil)-6-fenil-1,3,5-hexatrien p-toluen-sulfonat (TMA-DPH Molecular Probes) astfel nct aceasta s aib concentraia final 2,5 M n cuva de msur, se las la incubat 2 minute sub agitare continu, apoi se reiau determinarile de polarizare a fluorescenei.

Se calculeaz media intensitii de emisie fluorescent determinate la fiecare poziie a polarizorilor, apoi se calculeaz valorile intensitii corectate de fond (autofluorescen). Anizotropia fluorescenei (r) se calculeaz cu formula (1): (1) unde Ivv, Ivo, Iov and Ioo reprezint valorile mediate i corectate de fondul autofluorescent pentru orientarea relativ a polarizorilor vertical-vertical, vertical-orizontal, orizontal-orizontal i verticalvertical, respectiv, iar G = Iov/ I00 este un factor de corecie. Fluiditatea n zona capetelor polare a bistratului lipidic (f) a fost calculat ca funcie de valorile r0 i r8 ale sondei i de cele determinate experimental pentru anizotropia fluorescenei folosind formula (2): (2) unde r8 = 1.270r 0.076 pentru 0<r<0.28 i r8 = 1.100r 0.032 pentru 0.28<r<0.34, r0=0.362 (1, 2, 3, 4). Pentru suprastimularea in vitro a PBMC cu MTX i D, la 2 mL de suspensie celular normalizat au fost adugai stimulii, astfel nct s se obin n cuv concentraii de 1M i 10M; probele au fost incubate timp de 20 de minute la temperatura camerei, la ntuneric, apoi au fost reluate determinrile de fluiditate membranar descrise anterior. Rezultatele au fost prezentate ca medii deviaii standard, semnificaia statistic a parametrilor determinai a fost evaluat cu ajutorul testului t Student.

REZULTATE
Au fost investigai urmtorii parametri biochimici i markeri ai PR: activitatea transaminazelor, nivelul creatininei, acidului uric, proteinei C reactive (CRP), precum i valorile VSH i concentraia de fibrinogen. Rezultatele sunt centralizate n tabelul 1. Rezultatele au indicat valori sczute ale activitii transaminazelor la pacienii tratai cu LF comparativ cu MTX. Nivelul creatininei, acidului uric, i CRP au fost de asemenea sczute la pacienii

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Tabelul 1. Parametrii biochimici i markeri ai RP pentru subiecii luai n studiu

tratai cu LF, n timp ce VSH-ul i fibrinogenul au nregistrat valori crescute. Un nivel crescut al transaminazelor i creatininei la lotul de pacieni tratai cu MTX indic o tulburare a funciei hepatice respectiv renale, mai important dect n cazul terapiei cu LF. Valorile CRP-ului mai sczute n cazul terapiei cu LF indic o eficacitate terapeutic mai crescut n cazul acestuia. Conform literaturii de specialitate, se observ des creterea nivelului enzimelor hepatice, de obicei temporar i asimptomatic n cazul MTX (6,7,8). n cazul administrrii LF, au mai fost observate creteri ale valorilor transaminazelor i testelor renale (9,10). Nivelul de baz ale fluiditii PBMC n cazul celor trei grupuri nu difer semnificativ (1.14770.0776, 1.16050.093 i 1.1577 0.1175 pentru lotul de control, lotul tratat cu MTX, respectiv cel tratat cu LF figura 1). Ca urmare a suprastimulrii in vitro cu MTX sau D, n cazul lotului de control se produce, n general, o cretere a fluiditii membranei celulare,

lucru care nu se observ la celulele provenite de la pacieni cu PR (figura 2). Acest lucru, corelat cu faptul c pentru unii pacieni cu PR sonda fluorescent nu a ptruns n interiorul bistratului lipidic membranar, sugereaz faptul c membrana PBMC este profund afectat n cazul pacienilor cu PR.

DISCUII
Rezultatele prezentate n acest articol sunt preliminarii, urmnd ca n continuare, n funcie de datele finale ale studiului, s se fac unele corelaii ntre toxicitatea terapiei folosite i condiiile patologice coexistente.

CONCLUZII
Rezultatele asupra parametrilor biochimici, hematologici i ai markerilor inflamatori sugereaz o toxicitate mai mic a LF; de asemenea, activitatea antiinflamatorie este comparativ pentru ambele medicamente.

Figura 1. Valorile fluiditii membranare de baz la cele trei grupuri luate n studiu

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Figura 2. Efectul suprastimulrii in vitro a PBMC cu MTX sau D

Studiile in vitro privind fluiditatea membranar PBMC indic faptul c MTX i D au efecte asupra membranei (concretizate prin creterea fluiditii membranare) numai n cazul grupului de control; nu s-au evideniat modificri ale fluiditii membranare a PBMC izolate de pacieni tratai cu LF i MTX, n condiii de suprastimulare in vitro.

MULUMIRI
Experimentele au fost realizate n cadrul grantului CNCSIS TD 126/01.10.2007.

BIBLIOGRAFIE
1. Lakowicz JR Principles of Fluorescence Spectroscopy, Second edition, Springer Science and Business Media Inc., 2004, pp 298299 Katona E, Katona G, Caplanusi A et al Drug Induced Membrane Effects in Metabolically Impaired and Nonimpaired Human T (Jurkat) Lymphoblastoid Cells, Romanian J. Biophys, 2004, 14(1-4): 2936 Blnescu A Poliartrita reumatoid de la patogenie la clinic, Editura Medical Amaltea, Bucureti, 2007 Van Blitterswijk WJ, Van Hoeven RP, Van Der Meer BW et al Lipid structural order parameters (reciprocal of fluidity) in biomembranes derived from steady-state fluorescence polarization measurements, Biochim. Biophys. Acta, 1981, 644: 323332 Pottel H, Van Der Meer W, Herreman W et al Correlation between the order parameter and the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene and an evaluation of membrane fluidity, Biochim. Biophys. Acta, 1983, 730: 181-186 6. Lee D, Weinblatt M Methotrexate In: St. Clair E., Pisetsky D., Haynes B., eds. Rheumatoid Arthritis, 1 ed. Philadelphia: Lippincott Williams&Wilkins, 2004:303-14 7. Battistone M, Williams H Disease-modifying antirheumatic drugs: methotrexate. In Hochberg M., Silman A., Smolen J., Weinblatt M., Weisman M., eds. Rheumatology, London: ElsevierSaunders, 2003:417-30 8. Schnabel A, Gross W Low dose methotrexate in rheumatic diseases efficacy, side effects and risk factors for side effects, Semin Arthritis Rheum 1994; 23:310-27 9. Dougados M, Emery P, Lemmel E Efficacy and safety of leflunomide and predisposing factors for treatment response in patients with active rheumatoid arthritis: RELIEF 6-month data, J Rheumatol 2003; 30:2572-9 10. Emery P, Breedveld F, Lemmel E A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis, Rheumatology 2000;39:655-65

2.

3. 4.

5.

LUCRRI ORIGINALE

ROLUL EXAMENULUI HISTOPATOLOGIC N EVALUAREA NEFROPATIEI LUPICE


Histopathology in lupus nephritis
Dr. A. Caraba1, Dr. Viorica Crian2, Prof. Dr. I. Romoan1 1Clinica Medical IV, U.M.F. Victor Babe, Timioara 2Spitalul Clinic Municipal, Departamentul de Reumatologie, Timioara

REZUMAT
Nefropatia lupic (NL) este una dintre cele mai severe manifestri ale lupusului eritematos sistemic (LES), fiind o cauz major de morbiditate i mortalitate. Incidena sa este variabil, n funcie de metodele utilizate n diagnosticarea sa. Bazat pe tabloul clinico-biologic, incidena sa este de 40-70%, pe cnd cea bazat pe tabloul histologic este de 95100%. n NL sunt afectate toate structurile renale: glomerulii (cea mai important determinare), tubii, interstiiul, vasele. Tabloul clinico-biologic este foarte variat: sindrom nefritic, sindrom nefrotic, sindrom de insuficien renal, sindrom hipertensiv, manifestri urinare izolate, sindrom de insuficien tubular, sindrom interstiial izolat, pseudopielonefritic. n cadrul lupusului eritematos sistemic cu nefropatie nu exist o corelaie strict ntre tabloul clinico-biologic i cel histologic. De aceea, diagnosticul histologic, realizat prin puncie biopsie renal i examinarea fragmentului de esut renal n microscopie optic, electronic i imunofluorescen este necesar. Examinarea histologic va rspunde la mai multe ntrebri: Are pacientul NL sau o alt patologie renal asociat ori neasociat bolii lupice? Care este structura renal predominant afectat? Care este gradul activitii sau cronicitii leziunilor renale identificate? Clasificarea ISN/RPS, 2003 identific 6 clase ale NL: mezangial minim (clasa I), mezangial proliferativ (clasa II), focal (clasa III), difuz (clasa IV), membranoas (clasa V), cu scleroz avansat (clasa VI). Asociat sunt prezentate leziunile tubulo-interstiiale (infiltrat inflamator, fibroz interstiial, atrofie tubular) i cele vasculare (vasculopatie, vasculit, microangiopatie trombotic, scleroz). Leziunile renale pot fi active sau cronice. naintea efecturii biopsiei renale vor fi puse n balan riscurile (mici) ale acestei manevre versus riscurile care decurg dintr-un diagnostic incomplet sau greit, favoriznd fie progresiunea unei boli renale potenial tratabile, fie utilizarea nefondat a unor medicamente cu efecte adverse importante Examenul histologic confer certitudine diagnosticului pozitiv de boal renal lupic, apreciaz clasa i gradul de activitate, furniznd astfel informaii prognostice i ghidnd terapia. Cuvinte cheie: lupus eritematos sistemic, nefropatie lupic, examen histopatologic renal

SUMMARY
Lupus nephropathy (LN) is one of the most severe organ involvement in systemic lupus erythematosus and the main cause of morbidity and mortality. Its incidence is variable, depending on the methods used for the diagnosis. Based on clinical-biological picture, LN incidence is between 40-70%, whereas based on histology, the incidence is between 95-100%. In LN are affected all renal structures: glomeruli (the most important involvement), tubules, interstitium and vessels. The clinical-biological picture is very different: nephritic, nephrotic or renal insufficiency syndromes, hypertension, isolated urinary manifestations, tubular insufficiency, isolated interstitial syndrome, and pseudopyelonephritis. There is no strict correlation between clinical-biological and histological pictures. Histological diagnosis, performed with renal biopsy and examination of renal tissue fragment in light microscopy, immunofluorescence and electron microscopy is useful. Histological exams will answer many questions: Has the patient lupus nephropathy or another renal pathology associated or independent from the disease? What are the affected renal structures? What is the grade of renal lesions activity or chronicity? ISN/RPS classification of LN (2003) identified six classes of LN: minimal mesangial LN (class I), mesangial proliferative NL (class II), focal LN (Class III), diffuse LN (class IV), and membranous LN (class V), and advanced sclerosis LN (class VI). Tubulo-interstitial (inflammatory infiltrate, interstitial fibrosis, tubular atrophy) and vascular (vasculopathy, vasculitis, thrombotic microangiopathy, sclerosis) lesions are presented. Renal lesions may be active or chronic. Before renal biopsy, it will be assessed the risks of this method versus the risks which result from the incomplete or missed diagnosis, favoring the progression of a potential treatable renal disease or using drugs with important sides effects. Histological exam gives certainty of positive diagnosis of lupus renal disease, assesses the class and grade of activity, giving information about the prognosis and guiding treatment. Key words: systemic lupus erythematosus, lupus nephropathy, histopathologic examination

Adres de coresponden: Dr. Alexandru Caraba, Clinica Medical IV, Splaiul Tudor Vladimirescu, Nr. 13-15, tel. 0744769860, Timioara email: alexcaraba@yahoo.com

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Lupusul eritematos sistemic (LES) este o afeciune cu etiologie necunoscut, patogenez autoimun, caracterizat printr-un proces inflamator cronic asociat cu producia de anticorpi (Ac) dirijai mpotriva antigenelor (Ag) nucleare, citoplasmatice, membranare. LES reprezint prototipul bolii autoimune (1). Tabloul clinic are o mare diversitate, reflectnd tocmai inflamaia cronic a diferitelor organe i sisteme. Pentru diagnosticul bolii lupice, sunt utilizate criteriile de clasificare ale LES (tabelul 1); prezena a cel puin 4 criterii stabilete diagnosticul pozitiv (2). Existena a mai puin de 4 criterii definete lupusul latent sau incomplet (1).

Nefropatia lupic (NL) este una dintre cele mai severe manifestri ale LES, reprezentnd o cauz major de morbiditate i mortalitate. Afectarea renal joac un rol determinant n evoluia bolii, insuficiena renal rmnnd una dintre principalele cauze de deces n LES (3, 4). Incidena NL este variabil, n funcie de metodele de diagnostic utilizate. Dac diagnosticul este stabilit doar pe baza criteriilor clinico-biologice (proteinurie, hematurie, cilindrurie, retenie azotat, hipertensiune arterial, sindrom edematos), incidena NL este cuprins ntre 40 i 70%. n schimb, diagnosticul stabilit pe baza explorrii histologice a fragmentului de esut renal obinut
Tabelul 1. Clasificarea LES

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prin puncie biopsie renal (PBR) arat c NL are o inciden cuprins ntre 95-100% (5, 6). Afectarea rinichiului n LES este consecina particularitilor morfo-funcionale renale: debit sanguin ridicat, suprafa de filtrare ntins, fore hidrostatice crescute, existena receptorilor C3b i Fc la nivel endotelial i mezangial, sarcina electric a pereilor capilarelor glomerulare. Tipul i gravitatea leziunilor renale depind de particularitile, cantitatea i locul de depozitare a complexelor imune (7, 8). n cadrul NL, pot fi afectate toate structurile renale: glomerulii (cea mai important determinare), tubii, interstiiul, precum i vasele. Dei afectarea glomerular are o importan prognostic deosebit, la unii pacieni au fost descrise leziuni tubulo-interstiiale sau vasculare severe, n ciuda unor modificri glomerulare uoare (9). De asemenea, exist suferine asociate bolii lupice, cu impact i asupra rinichiului. Sindromul antifosfolipidic asociat determin la nivel renal microangiopatie trombotic, iar utilizarea antiinflamatoarelor nesteroidiene duce la apariia nefropatiilor toxic-medicamentoase (10, 11, 12). Manifestrile clinico-biologice ale NL sunt foarte variate. Afectarea renal poate fi prezent n momentul diagnosticrii LES la 25% dintre pacieni; peste 60% dintre bolnavi vor dezvolta boal renal clinic manifest pe parcursul evoluiei lupusului. n 5% dintre cazuri, anomaliile urinare pot precede chiar cu civa ani apariia criteriilor de diagnostic al LES. O atenie deosebit necesit pacientele cu LES incomplet, la care apariia proteinuriei stabilete diagnosticul pozitiv al bolii. De

aceea, acest grup de paciente necesit o investigare atent, repetat a funciei renale (4, 13). Din punct de vedere clinico-biologic, NL poate mbrca mai multe forme de manifestare (tabelul 2) (12). Proteinuria este prezent la aproape fiecare bolnav, avnd intensitate variabil, pn n domeniul nefrotic. Traseul electroforetic evideniaz proteinurie de tip glomerular neselectiv sau de tip mixt, rareori doar de tip tubular, n funcie de structurile histologice predominant afectate. Un alt semn urinar este reprezentat de hematuria microscopic, foarte rar aceasta fiind macroscopic. Hipertensiunea arterial (HTA) este asociat nefropatiei lupice severe, iar edemele reflect prezena sindromului nefrotic. Nicturia caracterizeaz afectarea tubulo-interstiial. Azotemia semnific existena insuficienei renale. n unele cazuri, NL poate debuta sub forma insuficienei renale acute, asociat frecvent altor manifestri severe (miocardit, suferin a sistemului nervos central) (2, 4, 14). Acest spectru de manifestri clinico-biologice este regsit i n alte suferine renale, ce pot aprea la aceti pacieni, suferine care beneficiaz de terapii specifice. Sindromul antifosfolipidic asociat LES (15% dintre pacientele cu LES dezvolt Ac antifosfolipidici) determin la nivel renal microangiopatie trombotic, a crei semne clinico-biologice sunt: proteinuria, hematuria, azotemia. Terapia microangiopatiei trombotice este specific; de aceea, existena acestei leziuni histologice trebuie confirmat sau infirmat, n special n cazul pacienilor cu Ac antifosfolipidici prezeni (11). Utilizarea

Tabelul 2. Tabloul clinico-biologic al nefropatiei lupice

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antiinflamatoarelor nesteroidiene pentru manifestrile extrarenale ale LES poate genera nefropatii tubulo-interstiiale acute sau cronice (proteinurie, leucociturie, hematurie, cilindrurie, azotemie) ori nefropatie glomerular cu leziuni minime (sindrom nefrotic) (12). Nu n ultimul rnd, trebuie excluse nefropatiile glomerulare primitive coexistente cu boala lupic. Aceast variabilitate clinico-biologic este expresia diversitii tabloului histologic, ceea ce impune necesitatea diagnosticului histologic n NL (15). Explorarea histologic trebuie s rspund mai multor ntrebri: Are pacientul NL sau o alt patologie renal independent sau asociat bolii lupice? Care este structura renal predominant afectat? Care este gradul activitii sau cronicitii leziunilor renale descrise? Rspunsurile la aceste ntrebri vor conduce la stabilirea unei scheme terapeutice eficiente, care pe de o parte va prezerva/ameliora funcia renal, iar pe de alta nu va expune pacientul efectelor secundare inerente terapiei citotoxice. Examenul histologic ofer informaii despre structura renal predominant afectat n NL (glomeruli, tubi, interstiiu, vase). Pentru ca rezultatele s fie interpretabile, fragmentul de esut renal obinut prin PBR trebuie s conin minim 10 glomeruli (16). Prelucrarea n imunofluorescen (IF) necesit utilizarea serurilor anti IgG, IgA, IgM, lanuri uoare k i , componente ale complementului (C3, C1q) (17). Explorarea n microscopie electronic (ME) este rezervat cazurilor n care microscopia optic (MO) i IF nu reuesc stabilirea diagnosticului histopatologic (18). Leziunile histologice renale, alturi de funcia renal la momentul diagnosticrii NL reprezint factorii prognostici, n funcie de care se stabilete strategia terapeutic (4). Nu exist o corelaie strict ntre manifestrile clinico-biologice i tipul histologic n NL. Multe studii au demonstrat lipsa de certitudine n diagnosticul stabilit doar pe datele clinico-biologice. Chiar i pacienii fr boal renal clinic manifest au deseori depozite imune mezangiale, astfel nct tabloul clinico-biologic nu este predictiv pentru severitatea leziunilor histologice (19, 20, 21). De obicei, proteinuria mai mic de 1g/24 ore apare n nefropatia lupic mezangial i nefropatiile tubulointerstiiale; valori ale proteinuriei cuprinse ntre

1 i 3 g/24 ore sunt ntlnite n: glomerulonefritele proliferative focale sau difuze, precum i n cele membranoase; peste 3,5 g/24 ore n glomerulonefritele proliferative difuze sau membranoase. Au fost descrise proteinurii nefrotice i n cazurile n care examenul histologic a evideniat fuziunea proceselor podocitare, asociat sau nu modificrilor endocapilare. Hematuria poate fi ntlnit n: glomerulonefritele lupice mezangiale, proliferative focale, difuze i n nefropatiile tubulointerstiiale. Cilindruria nsoete proteinuriile importante i hematuria, iar HTA este prezent n unele forme de glomerulonefrite proliferative focale, n glomerulonefritele proliferative difuze i, tardiv, n glomerulonefrita membranoas i n nefropatiile tubulo-interstiiale. Studiind un grup de paciente cu NL care au avut proteinurie mai mic de 1 g/24 ore i funcie renal normal, Christopher-Stine L i colab. au identificat tipurile II, III, IV i chiar V de nefropatii glomerulare lupice. Mai mult, la un caz de glomerulonefrit lupic focal, proteinuria a avut valori inferioare celei de 500 mg/24 ore, iar hematuria a fost absent (15, 17, 22, 23, 24, 25). Romoan i colab. au evideniat slaba corelaie ntre manifestrile clinico-biologice i tipul histologic n NL (26, 27). Au fost propuse asocieri ntre diferitele tipuri histologice ale NL, activitatea bolii i prezena unor markeri serici (Ac anti ADN nativ, anti Sm, anti C1q). Dei anticorpii anti ADN nativ se coreleaz cu clasa histologic i cu activitatea bolii, aceast corelaie nu este suficient de puternic pentru a intensifica schema terapeutic atunci cnd se constat creteri ale acestor anticorpi. Se pare c anticorpii anti C1q ar putea fi utilizai pentru estimarea riscului recderilor n NL (2, 28). Prima clasificare OMS a nefropatiei lupice a fost formulat de Pirani i Pollak n 1974 (tabelul 3) (17). Aceasta se refer doar la compartimentul glomerular, cel tubulo-interstiial i vascular nefiind incluse. Ulterior, au fost propuse noi sisteme pentru clasificarea NL, care s cuprind toate structurile renale. n 2003, Societatea Internaional de Nefrologie/Societatea de Patologie Renal (ISN/RPS) abordeaz o nou clasificare a NL (tabelul 4) (17, 29, 30). Spre deosebire de clasificarea iniial (din 1974), absena oricror anomalii glomerulare n MO, IF, ME nu mai este compatibil cu clasa I. Prezena oricrui depozit subendotelial sau

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Tabelul 3. Clasificarea OMS a nefropatiei lupice (1974)

Tabelul 4. Clasificarea ISN/RPS a nefropatiei lupice (2003)

cicatrice glomerular este incompatibil cu clasa II, ncadrnd leziunea respectiv n clasele III sau IV, n funcie de extensia i distribuia depozitelor, respectiv a cicatricilor glomerulare. n clasa III (NL focal), glomerulii afectai prezint de obicei leziuni proliferative endocapilare segmentale sau cicatrici glomerulare cu/fr necroze

ale pereilor capilari i semilune epiteliale. Depozitele sunt localizate subendotelial, avnd de obicei distribuie segmental. Exist glomeruli cu leziuni active, ct i sclerotice, inactive. Modificrile mezangiale (proliferare mezangial sau depozite imune la acest nivel) pot acompania leziunile focale. Leziunile tubulo-interstiiale sau

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vasculare se pot asocia celor glomerulare. Combinaia claselor III cu V necesit prezena leziunilor membranoase la cel puin 50% din populaia glomerular (evideniabile n MO, IF, ME) (17, 29). Clasa IV (NL difuz) este subdivizat n: IV-S (NL difuz segmental), cnd peste 50% dintre glomerulii afectai au leziuni segmentale i IV-G (NL difuz global), cnd peste 50% dintre glomerulii afectai prezint leziuni globale. n clasa IV-S, apare de obicei proliferarea endocapilar segmental, cu/fr necroze. n clasa IV-G, exist proliferare difuz i global, endocapilar, extracapilar sau mezangiocapilar ori leziuni wireloop extinse. Orice tip de leziune activ poate fi ntlnit. Rareori sunt ntlnite depozite glomerulare subendoteliale difuze i globale, fr/cu proliferare celular minim. Leziunile tubulo-interstiiale i vasculare sunt mult mai severe. Combinaia claselor IV cu V necesit prezena leziunilor membranoase la cel puin 50% dintre glomeruli (evideniabile n MO, IF, ME) (17, 31). Nefropatia lupic membranoas (clasa V) poate asocia un grad de proliferare mezangial (32). NL cu scleroz avansat este consecina evoluiei n timp a claselor III, IV sau V. n acest stadiu exist posibilitatea de a nu mai fi prezente elemente care s trdeze activitatea bolii. Fr biopsii renale anterioare, este imposibil de precizat care a fost clasa NL ce a evoluat spre scleroz glomerular avansat (17, 33). Depozitele imune glomerulare caracteristice NL, detectate n IF, conin IgG policlonal i C3 (ntotdeauna), C 1q (n cele mai multe cazuri) i IgA, IgM (variabil). Depozitele glomerulare formate exclusiv din IgA i/sau IgM exclud diagnosticul de nefropatie lupic (17, 29, 30). La nivelul compartimentului tubulo-interstiial se evideniaz: infiltrat inflamator (limfocite T

CD45RO, limfocite B CD45RA, macrofage CD68), atrofie tubular, fibroz interstiial. Explorarea n IF identific depozite de IgG, C3, C1q de-a lungul membranei bazale tubulare i n interstiiu, iar cea n ME, depozite electron-dense, cu aceeai topografie. Modificrile interstiiale acute i depozitele imune tubulo-interstiiale sunt frecvent identificate n glomerulonefritele lupice clasele III i IV. Fibroza interstiial i atrofia tubular constituie leziuni cronice, existnd o corelaie invers ntre gradul afectrii tubulo-interstiiale cronice i prognosticul renal (4, 25). Afectarea vascular renal n NL reprezint un marker de prognostic nefavorabil. Leziunile vasculare n NL au fost descrise pentru prima dat de ctre Klemperer n 1941 (34). Se descriu 4 tipuri de leziuni vasculare n LES: vasculopatie lupic, microangiopatie trombotic (asociat sindromului antifosfolipidic), vasculita lupic, arterio-/arterioloscleroza vaselor renale. Vasculopatia lupic afecteaz predominant arteriolele preglomerulare, precum i arterele interlobare care sunt sever ngustate, peretele acestora prezentnd necroz fibrinoid, fr infiltrat inflamator leucocitar, iar lumenul, depozite masive eozinofile. n IF se evideniaz depozite de imunoglobuline i complement. Vasculita lupic, rar identificat, se caracterizeaz prin necroz fibrinoid asociat unui infiltrat inflamator celular al peretelui arterial. ngroarea fibroas a intimei vasculare, fr necroze, proliferare sau formare de trombi definete arterio-, respectiv arterioloscleroza (4, 35). Pe lng stabilirea diagnosticului histologic i clasificarea NL, biopsia renal ofer informaii referitoare la activitatea/cronicizarea leziunilor renale identificate (tabelul 5), avnd rol important n stabilirea prognosticului (36). Leziunile active sunt potenial reversibile, necesitnd intensificarea terapiei, pe cnd cele cronice sunt ireversibile, dar
Tabelul 5. Clasificarea leziunilor din nefropatia lupic

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importante pentru prognosticul renal. Se apreciaz c un IA de peste 12 i n special un IC de peste 4 implic un prognostic renal nefavorabil (4). Pe parcursul evoluiei bolii, tipul histologic nu este fix, putndu-se trece dintr-o clas n alta. Transformarea histologic este ntlnit la 20-30% dintre cazuri, fiind consecina evoluiei naturale a bolii sau a terapiei administrate. Evoluia din clasele II sau III spre IV este frecvent ntlnit (37). ntre glomerulonefrita membranoas i cea proliferativ difuz exist posibilitatea evoluiei n ambele sensuri (12). n faa deciziei de a efectua PBR, vor fi puse n balan riscurile acestei manevre versus riscurile care decurg dintr-un diagnostic incomplet sau greit, favoriznd fie progresiunea unei boli renale potenial tratabil, fie utilizarea nefondat a unor medicamente cu efecte adverse notabile. Unii autori sugereaz c PBR ar trebui efectuat la toi pacienii cu LES naintea iniierii tratamentului, iar cu ajutorul rezultatelor explorrilor histologice s fie apreciat prognosticul i ghidat terapia. Indicaiile PBR n LES sunt reprezentate de: insuficiena renal acut, proteinuria peste 500 mg/24 ore, hematuria n prezena oricrei valori a proteinuriei, sedimentul urinar activ. Contraindicaiile

relative ale manevrei sunt: diateza hemoragic, boala avansat, cu rinichi de dimensiuni reduse (38, 39). Complicaiile severe ale PBR sunt rar ntlnite; sngerrile postpuncie, care s necesite transfuzii, au fost raportate la maxim 6,4% dintre cazuri. Factorii predictori pentru apariia sngerrilor sunt: insuficiena renal avansat, disfunciile plachetare, valorile reduse ale hematocritului (13). O problem ce poate aprea la pacienii cu LES care necesit PBR este terapia anticoagulant cronic pe care o urmeaz unii dintre acetia. Se va ntrerupe anticoagularea oral, iar bolnavului i se va administra heparin, ce va fi neutralizat naintea punciei. Aspirina i alte antiinflamatoare nesteroidiene vor fi ntrerupte naintea procedurii. Momentul relurii terapiei anticoagulante/antiagregante depinde de riscul de tromboz, respectiv de sngerare (poate persista pn la 6 sptmni postpuncie) (38). Aadar, PBR este necesar n evaluarea oricrui pacient cu NL, deoarece examenul histologic confer certitudine diagnosticului pozitiv de boal renal lupic, apreciaz clasa i gradul de activitate, furniznd astfel informaii prognostice i ghidnd terapia.

BIBLIOGRAFIE
Wallace DJ, Hahn BH Dubois Lupus Erythematosus, 6th Ed, Lippincot Williams&Wilkins, Philadelphia, 2002 2. Edworthy SM Clinical manifestation of systemic lupus erythematosus, n: Harris ED, Budd RC, Firenstein GS etc, Kelleys Textbook of Rheumatology vol II, 7th Ed, Elsevier Saunders, Philadelphia, 2005: 1201-1224 3. Contreras G, Pardo V, Cely C et al Factors associated with poor outcomes in patients with lupus nephritis, Lupus 2005, 14: 890895 4. Appel GB, Radhakrishnan J DAgati V, Secondary glomerular disease, n: Brenner BM, Brenner & Rectors The Kidney, 8th Ed, Elsevier Saunders, Philadelphia, 2007: 1067-1079 5. Font J, Torras A, Cervera R et al Silent renal disease in systemic lupus erythematosus, Clin Nephrol 1987, 27: 283-285 6. Zabaleta-Lanz M, Vargas-Arena RE, Tapanes F et al Silent nephritis in systemic lupus erythematosus, Lupus 2003, 12: 26-30 7. Lewis EJ, Schwartz MM Pathology of lupus nephritis, Lupus 2005, 14: 31-38 8. Voiculescu M Sindromul nefrotic n lupusul eritematos sistemic, n: Romoan I, Voiculescu M, Golea O, Sindromul Nefrotic, Editura Academiei Romne, Bucureti, 1992: 195-214 9. Chan TM Histological reclassification of lupus nephritis, Curr Opin Nephrol Hypertens 2005, 14: 561-566 10. Moroni G, Ventura D, Riva P et al Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis, Am J Kidney Dis 2004, 43: 28-36 1. 11. Daugas E, Nochy D, Huong DLT et al Antiphospholipid syndrome nephropathy in systemic lupus erythematosus, J Am Soc Nephrol 2002, 13: 42-52 12. Romoan I, Caraba A, Timar R Bolile Rinichiului, Editura Solness, Timioara, 2002 13. Hill GS, Delahousse M, Nochy D et al Outcome of relapse in lupus nephritis: role of reversal of renal fibrosis and response of inflammation to therapy, Kidney Int 2002, 61: 2176-2186 14. Lea J Lupus nephritis in African Americans, Am J Med Sci 2002, 323: 85-89 15. Cagnoli L Italian Society of Nephrology, Instructions and implementations for percutaneous renal biopsy. Guidelines for the therapy of glomerular nephropaties, G Ital Nefrol 2003, 20 (Suppl): 3-47 16. Corwin HL, Schwartz MM, Lewis EJ The importance of sample size in the interpretation of the renal biopsy, Am J Nephrol 1988, 8: 85-89 17. Weening JJ, DAgati VD, Schwartz MM et al The classification of glomerulonephritis in systemic lupus erythematosus revisited, J Am Soc Nephrol 2004, 15: 241-250 18. Herrera GA The value of electron microscopy in the diagnosis and clinical management of lupus nephritis, Ultrastruct Pathol 1999, 23: 63-77 19. Gladman DD, Urowitz MB, Cole E et al Kidney biopsy in SLE. I A clinical-morphological evaluation, Q J Med 1989, 73: 1125-1133 20. Nezhad ST, Sepaskhah R Correlation of clinical and pathological findings in patients with lupus nephritis: a five-year experience in Iran, Saudi J Kidney Dis Transpl 2008, 19: 32-40

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21. McLaughlin J, Bombardier C, Farewell VT et al Kidney biopsy in systemic lupus erythematosus. III Survival analysis controlling for clinical and laboratory variables, Arthritis Rheum 1994, 37: 559-566 22. Christopher-Stine L, Siedner M, Lin J et al Renal biopsy in lupus patients with low levels of proteinuria, J Rheumatol 2007, 34: 332-5 23. Kraft SW, Schwartz MM, Korbet SM et al Glomerular podocytopathy in patients with systemic lupus erythematosus, J Am Soc Nephrol 2005, 16: 175-179 24. Han TS, Schwartz MM, Lewis EJ Association of glomerular podocytopathy and nephrotic proteinuria in mesangial lupus nephritis, Lupus 2006, 15: 71-75 25. Mori Y, Kishimoto N, Yamahara H et al Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis, Clin Exp Nephrol 2005, 9: 79-84 26. Romoan I Modern aspects of renal biopsy and its value for diagnosis and therapy of lupus nephropathy, Timioara Medical 1993, 38: 1-2 27. Romoan I, Dorobanu M, Barbu N, Georgescu L Nefropatia lupic: analiz n microscopie optic i imunofluorescne privind 31 cazuri, Medicina Intern 1983, 35: 503-509 28. Marto N, Bertolaccini ML, Calabuig E et al Anti-C 1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus, Ann Rheum Dis 2005, 64: 444-448 29. Nasr SH, Markowitz GS The ISN/RPS 2003 revised classification of lupus nephritis. What have we learned?, Adv Anat Pathol 2006, 13: 142-143

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30. Furness PN, Taub N Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis. A UK wide study, Am J Surg Pathol 2006, 30: 1030-1035 31. Hill GS, Delahousse M, Nochy D et al Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis, Kidney Int 2005, 68: 2288-2297 32. Austin HA, Illei GG Membranous lupus nephritis, Lupus 2005, 14: 65-71 33. Glassock RJ Reclassification of lupus glomerulonephritis: Back to the future, J Am Soc Nephrol 2004, 15: 501-503 34. Klemperer P, Pollack AD, Baehr G Pathology of disseminated lupus erythematosus, Arch Pathol 1941, 32: 569-631 35. Sung JM, Hsu SC, Chen FF, Huang JJ Systemic lupus erythematosus presented as non-inflammatory necrotizing vasculopathy-induced ischemic glomerulopathy and small vesselsrelated ischemic cardiomiopathy, Lupus 2002, 11: 458-462 36. Mittal B, Rennke H, Singh AK The role of kidney biopsy in the management of lupus nephritis, Curr Opin Nephrol Hypertens 2005, 14: 1-8 37. Tam LS, Li EK, Lai FM et al Mesangial lupus nephritis in Chinese is associated with a high rate of transformation to higher grade nephritis, Lupus 2003, 12: 665-671 38. Bihl GR, Petri M, Fine DM Kidney biopsy in lupus nephritis: look before you leap, Nephrology Dialysis Transplantation 2006, 21: 1749-1752 39. Oates J Renal biopsy at the onset of clinical lupus nephritis: can it yield useful information? J Rheumatol 2007, 34: 256-258

n actualitate Tanezumab pentru gonartroz Tanezumabul, un anticorp monoclonal umanizat ndreptat mpotriva factorului de cretere a nervului, a fost gsit capabil s reduc intensitatea gonalgiei la bolnavi cu artroza genunchiului ntr-un studiu dublu-orb, controlat de faza II. n interval de 3 zile dup administrarea primei doze s-a obinut o reducere de peste 50% a timpului de ambulaie la 440 de pacieni tratai. La doze mari, ameliorarea de 70-80% a durerii s-a resimit peste 8 sptmni. Alte indicaii posibile ale tanezumabului ar fi durerea neoplazic, sindroamele acute lombo-radiculare i fibromialgia (HDB).

Vizitai site-ul

SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro

CAZUISTIC INSTRUCTIV

ARTRITA PSORIAZIC SEVER CU COXIT BILATERAL INVALIDANT, TRATAT CU ETANERCEPT


Severe psoriatic arthritis with invalidant bilateral coxitis treated with etanercept
Dr. Domnia-Georgiana Ptracu, Dr. Mihaela Agache, Dr. Cristina Iosif, Conf. Dr. Denisa Predeeanu Clinica de Medicin Intern i Reumatologie Sf. Maria, Centrul de Cercetare n Patologia i Tratamentul Bolilor Sistemice Reumatismale U.M.F. Carol Davila, Bucureti

REZUMAT
Artrita psoriazic (APs) este o boal reumatic inflamatoare asociat cu psoriazisul, care face parte din grupul spondilartropatiilor seronegative. Prezentm cazul unui pacient tnr cu o form eroziv i non-responsiv la tratamentul cu medicamente remisive i coxit bilateral invalidant, care a avut un rspuns bun la tratamentul cu etanercept. Pacientul a prezentat aproape toi factorii de prognostic negativ cunoscui (vrsta tnr, HLAB27, afectarea poliarticular etc.) Hiperexpresia tumor factorului de necroz tumoral (TNF) n biopsia sinovial recoltat n cursul tratamentului chirurgical este un indicator de ncredere pentru un rspuns bun la terapia biologic anti-TNF. Monitorizarea strict a efectelor adverse ale tratamentului cu etanercept este obligatorie n practica curent. Cuvinte cheie: artrit psoriazic, coxit bilateral, etanercept

SUMMARY
Psoriatic arthritis (PsA) is an inflammatory joint disorder associated with psoriasis, which belongs to the group of seronegative spondylarthropaties. We present a case of a young patient with erosive arthritis and invalidant bilateral coxitis nonresponsive to disease modifying antirheumaic drugs (DMARDs) successfully treated etanercept. The patient presented almost all negative prognostic known factors (young age, HLA-B27, polyarticular involvement etc.). Over expression of tumor necrosis factor (TNF) in synovial biopsy removed in the course of the surgical treatment is a reliable indicator for a good response to biological treatment antiTNF. The strict monitoring of the side effects during etanercept treatment is mandatory in daily clinical practice. Key words: psoriatic arthritis, bilateral coxitis, etanercept

INTRODUCERE
Artrita psoriazic (APs) este o boal reumatic inflamatoare asociat psoriazisului (1). Prevalena sa n populaia general variaz ntre 0,1% i 0,67%, dar la pacienii cu psoriazis prevalena este mai mare, fiind cuprins ntre 6% i 42% (2) .

Exist numeroase subseturi clinice de APs, care reflect caracteristici clinice variabile: oligoartrit asimetric, arthritis mutilans, artrit interfalangian distal, poliartrit asemntoare poliartritei reumatoide i spondilit. Aceste criterii de clasificare au sensibilitate de 97% i specificitate de 99% pentru APs (3). Recent, grupul pentru

Adres de coresponden: Conf. Dr. Denisa Predeeanu, Clinica de Medicin Intern i Reumatologie Sf. Maria, Centrul de Cercetare n Patologia i Tratamentul Bolilor Sistemice Reumatismale U.M.F. Carol Davila, Bd. Ion Mihalache, Nr. 37-39, cod 011172, Tel./Fax +40 21 222 40 64, Bucureti email: dpreded@rdslink.ro

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Classification of Psoriatic Arthritis (CASPAR) a propus un nou set de criterii de clasificare a APs care include: dovada psoriazisului (prezena bolii, anamnez personal sau familial de psoriazis), unghii psoriazice, test negativ pentru factorul reumatoid, dactilit i dovada radiologic de formare de os nou juxtaarticular. Aceste criterii de clasificare au sensibilitate de 91,4% i specificitate de 98,7% (4). De menionat c 40-60% dintre pacienii cu APs spitalizai prezint precoce, dup aproximativ un an de evoluie, afectare periferic i axial eroziv i deformant responsabil de disabilitate, pierderea locului de munc i scderea speranei de via (5). APs este iniiat de interaciunea dintre factorii genetici i de mediu, implicnd rspunsuri imune nnscute i dobndite care se produc iniial n piele i care ulterior vor implica i articulaiile la indivizii susceptibili. Limfocitul T are un rol major att n psoriasis, ct i n APs. Studii recente au stabilit rolul central al citokinelor att n leziunea cutanat, ct i n inflamaia articular. n acest context, tumor necrosis factor (TNF ) este un mediator cheie n imunopatogeneza APs, el fiind prezent att n leziunea psoriazic, ct i n lichidul sinovial i membrana sinovial la pacienii cu aceast suferin. Terapia cu antiinflamatoare nonsteroidiene (AINS), utilizat ca monoterapie sau n combinaie cu alte terapii, amelioreaz semnele i simptomele bolii. Terapia remisiv cu metotrexat (MTX), leflunomid (LF), sulfasalazin (SSZ), ciclosporin A (CiS A) poate opri procesul patologic al bolii. Terapia antiTNF, scznd rata distruciilor osteoarticulare, mbuntind funcionalitatea articular i ameliornd calitatea vieii pacienilor, a deschis noi perspective terapeutice n APs (6).

n anul 2002 pacientul s-a prezentat n Clinica de Medicin Intern i Reumatologie a Spitalului Clinic Sfnta Maria, acuznd dureri i tumefacii la nivelul pumnilor i gleznelor bilateral, dureri i tumefacii la nivelul articulaiilor interfalagiene proximale (IFP) ale degetelor III de la mini bilateral i unghii psorizice. Examenul obiectiv la internare a evideniat un subiect uor supraponderal, cu stare general relativ bun, afebril, cu tegumente i mucoase uor palide, modificri distrofice la nivel unghial (onicoliz, pitting, modificri de culoare, hiperkeratoz), fr leziuni cutanate de psoriazis. Examenul clinic articular a aratat limitarea mobilitii articulaiilor radiocarpiene (RCC) bilateral, coate n semiflexie, articulaile IFP de la ambele mini fixate n flexie, halux valgus bilateral si degete n ciocan la nivelul antepicioarelor, coloana cervical blocat n semiflexie i limitarea marcat a mobilitii coloanei dorso-lombare. Mersul era posibil doar cu sprijin n baston. n rest examenul clinic pe aparate i sisteme a fost normal. Tensiunea arterial era 120/ 60mmHg iar frecvena cardiac 72 bti/minut, ritmic (figurile 1 i 2).

PREZENTAREA CAZULUI
Pacientul M.C., n vrst de 28 ani, diagnosticat cu psoriazis vulgar n anul 1997, asociaz un an mai trziu APs cu afectare periferic i axial, prezentnd la debut dureri i tumefacii la nivelul halucelui i genunchilor bilateral, n asociere cu lombalgie de tip inflamator. La acel moment s-a iniiat terapia cu MTX n doz de 10mg per os/ sptmnal, pe care pacientul a ntrerupt-o dup 3 luni din cauza ineficienei clinice. Ulterior, bolnavul a urmat doar tratament cu AINS n doze maxime, fr ameliorare clinic evident i cu persistena sindromului biologic inflamator.

Figura 1. Carpit bilateral, artrit a degetelor III de la ambele mini

Figura 2. Artrita gleznelor, halux valgus i unghii psoriazice

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Investigaiile biologice au evideniat un intens sindrom inflamator nespecific (VSH = 60mm/h, fibrinogenemie = 601mg/dl, CRP = 76mg/l), uoar leucocitoz i trombocitoz reactiv (leucocite = 10 200/mmc, trombocite = 528.000/mmc), moderat anemie hipocrom, microcitar (Hb = 9g/dl). De menionat c celelalte investigaii biochimice (transaminaze, glicemie, creatinin) au fost n limite normale iar factorul reumatoid a fost negativ. HLA-B27 a fost pozitiv. Diagnosticul pozitiv al pacientului a fost de artrit psoriazic form periferic i axial intens activ cu afectare de tip asemntor poliartritei reumatoide i cu evoluie pe teren HLA-B27. Forma intens activ a bolii, cu afectare poliarticular i nonresponsiv la monoterapia cu MTX a impus o terapie remisiv combinat (MTX 15 mg/sptmn + SSZ 3g/zi) n asociere cu AINS. Evoluia clinico-biologic a fost parial favorabil, cu pusee repetitive de activare i remisiune clinic. n anul 2003, pacientul prezenta dureri cu caracter inflamator la nivel coxofemural bilateral, cu limitarea marcat a mobilitii la acest nivel. Examenul radiologic al bazinului a evideniat sacroiliit bilateral asimetric (gr. II n dreapta i gr. III n stnga) i pensare important a articulaiilor coxofemurale bilateral (figura 3), iar examenul RMN al articulaiilor coxofemurale a evideniat edem local i eroziuni (figura 3), ambele investigaii stabilind diagnosticul de coxit bilateral.

Figura 4. Edem i eroziuni la nivelul articulaiilor coxofemurale n RMN

+ ciclosporin A 200 mg/zi) n asociere cu AINS la doza maxim (diclofenac 150 mg/zi), terapie ntrerupt dup 6 luni, din cauza apariiei reaciilor adverse renale (creatinin = 1,8 mg/dl), pacientul rmnnd sub tratament cu MTX 15mg/sptmn i SSZ 3g/zi, n asociere cu corticoterapie la doze medii. Din cauza agravrii simptomatologiei la nivelul articulaiei coxofemurale i avnd n vedere caracterul invalidant al coxitei bilaterale (ortostatism i mers imposibile fr sprijin), n iulie 2005, respectiv iunie 2006 s-a practicat protezarea oldului bilateral (artroplastie total cu protez necimentat), urmat de o mbuntire funcional evident prin reluarea treptat a mersului fr sprijin (figura 5).

Figura 3. Sacroiliit asimetric (stg>dr), pensarea spaiilor articulare coxofemurale

Figura 5. Protez total de old bilateral

innd seama de agresivitatea bolii prin afectarea articulaiilor coxofemurale i meninerea bolii n activitate n ciuda tratamentului aplicat, se iniiaz terapia combinat cu MTX 20 mg/sptmn

Studiul imunohistochimic cu anticorpi monoclonali anti-TNF al membranei sinoviale obinute n cursul protezrii oldurilor a evideniat o hiperexpresie a TNF localizat la nivelul zonei subintimale i perivascular (figura 6).

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Evoluia sindromului inflamator a fost favorabil cu ameliorarea important a tuturor parametrilor lui. Rspunsul la tratament a fost evaluat i cu ajutorul scorurilor i indicilor de activitate ai bolii: DAS28 (3V), evaluarea global a pacientului (VAS), BASDAI i BASFI (Bath Ankylosing Spondylitis Index) (tabelul 1).

DISCUIA CAZULUI
Pacientul prezentat este un caz sever de APs forma periferic i axial care se integreaz n cele 20% dintre cazuri cu evoluie rapid progresiv, eroziv exprimat prin handicapul motor. Pacientul prezint toi factorii de prognostic negativ din APs (vrsta tnar, afectare poliarticular de tip periferic, apartenena la genotipul HLA B 27, lipsa de rspuns la tratamentul remisiv tradiional), exceptnd afectarea cutanat prezent numai la debutul bolii. Aceasta ntrete ideea cunoscut c APs evolueaz ulterior debutului pe cont propriu, chiar n absena leziunilor cutanate. n APS, tratamentul este n principal remisiv, pentru a preveni distruciile i deformrile articulare. Dintre medicamentele remisive care modific evoluia bolii, de prim intenie este MTX folosit n doz de 7,5-25mg/sptmn, cu eficien dovedit att n APs, ct i n psoriazisul cutanat. De menionat ca i LE are studii care dovedesc eficacitatea n leziunea cutanat i articular. Antiinflamatoarele non steroidiene i corticosteroizii reprezint medicaia simptomatic, ameliornd durerile i tumefaciile articulare, fr a influena ns evoluia cu potenial distructiv la nivel articular. n decizia terapeutic este util algoritmul de tratament ilustrat n figura 7. innd seama de faptul c la pacientul prezentat boala a fost sever i rapid progresiv, nonresponsiv la tratament remisiv convenional (MTX,
Tabelul 1. Evoluia sub tratament a sindromului inflamator nespecific i a scorurilor de activitate sau funcionale

Figura 6. Hiperexpresia TNF n membrana sinovial (regiunea perivascular)

Pentru evaluarea activitii bolii am utilizat scorurile compozite de activitate a bolii: DAS28 (Disease Activity Score) pentru afectarea periferic i BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) pentru afectarea axial, care, dei nevalidate pentru Aps, sunt utilizate n practic pentru simplitatea i fezabilitatea lor. Valorile crescute ale DAS28 (5,3) i BASDAI (6,9) ne-au confirmat faptul c la momentul evalurii, boala se afla n puseu de activitate. Statusul funcional i calitatea vieii pacientului le-am apreciat prin indexul HAQ (Health Assessment Questionnaire), validat n artrita psoriazic, valoarea acestuia iniial n cazul nostru fiind 4,7. n faa unei forme severe de APs, cu afectare periferic i axial la care am obinut un rspuns parial la terapia remisiv clasic fie ca monoterapie fie n combinaie, n septembrie 2006 a fost iniiat terapia biologic cu etanercept (Enbrel) 25mg x 2/sptmn n asociere cu MTX 15mg/ sptmn. Sub terapia biologic simptomatologia s-a ameliorat considerabil cu dispariia durerilor i tumefaciilor articulare i numai cu persistena sechelelor de artrit de la nivelul degetelor de la mini i picioare.

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Figura 7. Algoritm de tratament n artrita psoriazic

MTX+SSZ, MTX+cliclosporina A) s-a decis iniierea terapiei biologice anti TNF cu etanercept n asociere cu MTX. Etanerceptul reprezint o protein de fuziune ntre domeniul extracelular p75 al receptorului TNF- uman i poriunea Fc a Ig G1 umane. Eficacitatea etanerceptului n psoriazis i APs se bazeaz pe rezultatele mai multor studii clinice (7,8), cel mai important fiind un studiu de faza 3 de tip dublu orb, controlat placebo efectuat la 205 pacieni cu artrita psoriazic (8). Acesta a artat la 12 sptmni c 59% dintre pacienii cu etanercept au realizat un scor ACR 20 comparativ cu 15% la pacienii pe placebo (p<0.001). n acelai moment de evaluare, 72% dintre pacienii pe etanercept au realizat scorul PsARC comparativ cu 31% dintre pacienii din grupul placebo.
Tabel 2. Indicaiile terapiei biologice n artrita psoriazic Diagnostic cert de APs Pacieni cu APs sever, activ, nonresponsiv la tratamentul remisiv clasic

Pacientul este considerat ca nonresponsiv la terapia remisiv clasic n cazul persistenei semnelor i simptomelor de APs activ, n ciuda a cel puin 2 cure terapeutice cu cte un preparat remisiv, administrat la dozele maxime recomandate, respectiv: MTX (20 mg/sptmn), leflunomid (20 mg/zi), SSZ (3000 mg/zi), ciclosporin A (3-5 mg/kgc/zi); minim 12 sptmni fiecare. Forma activ de APs se definete ca prezena a cel puin una sau mai multe articulaii dureroase (din 78) i tumefiate (din 76) (prezena dactilitei sau a entezitei se cuantific ca o articulaie), n cel puin dou ocazii diferite, separate ntre ele printr-un interval de cel puin o lun, cu cel puin 2 criterii din urmtoarele 4: VSH > 28 mm/h, proteina C reactiv > 20 mg/l, evaluarea global a pacientului privind evoluia bolii cu un scor ntre 6 i 10 i evaluarea global a medicului privind evoluia bolii cu un scor ntre 6 i 10.

Pacientul prezentat a ndeplinit criteriile de terapie biologic (tabelul 2), motiv pentru care din 2006 urmeaz tratament cu etanercept 50 mg/ sptmn n asociere cu MTX 15 mg/sptmn, cu evoluie favorabil clinic i biologic.
(Acest caz a fost prezentat la Simpozionul TNFalfa in imunopatogenia bolilor inflamatorii reumatice: certitudini i controverse, Cancun, Mexic 2009)

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


1. 2. Moll JMH, Wright V Psoriatic arthritis, Semin Arthr Rheum 1973, 3: 55-78 Gladman D Epidemiology. Psoriatic arthritis, in: Gordon G.B., Ruderman E., Psoriasis and Psoriatic Arthritis: An Integrated Approach, Springer-Verlag, Heidelberg, 2005: 57-65 Taylor WJ, Marchesoni A, Arreghini M et al A comparison of the performance characteristics of classification criteria for the diagnosis of psoriatic arthritis, Semin Arthr Rheum 2004, 34: 575584 Taylor W, Gladman D, Heliwell P et al CASPAR Study Group. Classification criteria for psoriatic arthritis: development of new criteria from a large international study, Arthr Rheum 2006, 54: 2665-2673 5. 6.

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3.

7.

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4.

Soriano ER Therapies for peripheral joint disease in psoriatic arthritis, J Rheumatol 2006, 33: 1422-1430 Mease PJ Psoriatic arthritis. Treatment and Assessement, in: Klippel JH, Stone JH, Crofford Lj, White PH Primer on the Rheumatic Diseases, Arthritis Foundation, 2008: 185-192 Yazici Y, Erkan D A preliminary study of etanetcept in the treatment of severe, resistant psoriatic arthritis, Clin Exp Rheumatol 2000, 18: 732-734 Mease PJ, Kivitz A, Burch J et al Improvement in disease activity in patients with psoriatic arthritis receiving etanercept. Results of a phase 3 multicenter trial. Arthr Rheum 2001, 44 (Suppl): S90

n actualitate Golimumab ca al doilea agent anti-TNF-alfa Puinele cazuri de eec la tratamentele curente cu ageni antiTNF-alfa pentru poliartrit reumatoid beneficiaz de pe urma schimbrii tratamentului cu alt medicament similar. Golimumabul, o nou substan din aceast categorie, pare s fie deosebit de eficient sub acest aspect, cum a artat primul studiu controlat GO-AFTER. Dozele de 50 i 100 mg, administrate la 4 sptmni timp de 14 sptmni, au indus un rspuns ACR 20 la 35%, respectiv 38% dintre pacienii tratai cu golimumab fa de 18% n grupul placebo. Reaciile adverse au fost mai rare la grupul tratat cu substan activ, exceptnd fenomenele locale la locul administrrii. Anticorpii antigolimumab au aprut la aproximativ 3% dintre cazuri (HDB).

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LA GRANIELE REUMATOLOGIEI

BOLILE LUI JOHN FITZGERALD KENNEDY


John Fitzgerald Kennedys diseases
Prof. Dr. H.D. Boloiu Clinica Reumatologic, UMF I. Haieganu, Cluj-Napoca

Aproape toat viaa a trebuit s lupte cu nenorocirile sntii sale (Rose Kennedy, mama) Jumtate din zilele pe care le-a petrecut pe pmnt au fost zile de durere intens. (Robert Kennedy) caracterizat, n lumina datelor disponibile astzi, cel puin ca precar, dac nu dezastruoas. John Kennedy, Jack cum l alinta familia, a fost un copil foarte, foarte fragil. A suferit de aproape toate bolile infecioase ale copilriei scarlatin, varicel, tuse convulsiv, difterie, numeroase rceli iar prima dintre acestea era aproape s-i pun capt vieii la vrsta de 2 ani. Familia spunea c dac un nar l-ar nepa pe Jack, acesta (narul) ar muri imediat. Mai trziu, era caracterizat ca un adolescent bolnvicios, iar printre bolile pe care i le-a druit natura, medicii au descris alergii, limfatism (tonsilectomie, adenoidectomie!), dispepsie, colon iritabil, leinuri frecvente etc. La vrsta de 13 ani, a intervenit un episod cu vedere ceoas, discromatopsie unilateral (?), scderea acuitii vizuale i a auzului, care a fost interpretat ca o complicaie a difteriei, mai ales c a fost silit s poarte ochelari pentru citit pentru o perioad de timp (presbiopie). Convalescena dup o pneumonie i un icter recidivat, pentru care a trebuit s stea n spital 2 luni (probabil cele care n tabelul cronologic apar n anul 1935 ca fiind pentru motive neprecizate) (tabelul 1) l trimite pentru refacere n Florida i Arizona, unde va trebui s-i urmeze studiile pentru un timp.

Figura 1. Preedintele John F. Kennedy aa cum l cunoteau cei mai muli dintre americani

John F. Kennedy, cel de al 35-lea preedinte al Statelor Unite ale Americii i fr ndoial cel mai carismatic dintre cei care l-au precedat sau urmat, a avut o via neobinuit i, din pcate, o moarte pe msur. Dincolo de biografia oficial, care arta un tnr nzestrat cu toate calitile, provenit dintr-o familie bogat i cu tradiie n Massachusetts, au existat mprejurri mai puin fericite, care l-au urmrit de-a lungul ntregii sale existene. Acestea au fost ndeosebi cele legate de sntatea sa, care ar putea fi

Adres de coresponden: Prof. Dr. Horaiu D. Boloiu, Clinica Reumatologic, Str. Cliicilor, Nr. 4, cod 400006, Cluj-Napoca email: hbolosiu@yahoo.com

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Tabelul 1. Cronologia internrilor lui John F.Kennedy*

* Lista ar putea s nu fie complet

Problemele mai nsemnate de sntate, sau cel puin care l vor marca pentru toat viaa, par s nceap n anul 1937, cnd i s-ar fi diagnosticat o colit spastic, pentru care s-a instituit corticoterapia (?). n realitate, s-ar fi putut ca boala misterioas despre care ncepea s se vorbeasc s fi fost o boal celiac, dac inem seama de severitatea sanciunii terapeutice i de cele dou internri din anul 1938, pentru infecie intestinal. Doi ani mai trziu, sufer de uretrit i prostatit cu Chlamidia, dup un contact sexual n colegiu, care, sub form cronic recidivant, l vor urmri toat viaa, nct la un moment dat i-a pus ntrebarea: Oare o s pot avea copii? Pentru aceasta a utilizat timp ndelungat sulfamide. Tot de atunci dateaz primul episod cunoscut de suferin lombar, care a debutat n timpul unui joc de tenis, cu dureri att de mari, nct s-a diagnosticat ruptura discului intervertebral.

Lucrurile se precipit n anul 1947, cnd tnrul congresman de 30 de ani sufer un episod grav cu astenie, grea, vrsturi i hipotensiune arterial, nct Biserica Catolic i-a acordat absoluiunea in articulo mortis. Medicul curant a diagnosticat boal Addison (criz addisonian, i-am fi zis noi astzi) i i-a dat maximum un an de trit. Din relatrile ulterioare a reieit c John Kennedy mai avusese o astfel de manifestare, cu un an nainte, cu ocazia unei parade din Cherlestown la care participa pe cnd candida pentru Camera Reprezentanilor. n anul 1953 par s se agraveze problemele cu spatele. Durerile devin cu timpul att de mari i de invalidante, nct este nevoit s se supun la dou intervenii chirurgicale, ambele fiind de fapt nite eecuri (figura 2). Cu ocazia primei (1954), s-a vorbit despre o fuziune vertebral lombar i sacroiliac (?) iar la cea de-a doua plac metalic

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utilizat a trebuit s fie ndeprtat pentru c ar fi generat o infecie supurativ local. Speculaiile despre natura acestei suferine au fost alimentate de numeroasele declaraii ale familiei, mai nti c ar fi fost vorba despre o boal din natere, apoi c era o sechel a episodului din timpul rzboiului cnd tnrul locotenent Kennedy a notat cteva ore n Oceanul Pacific innd cu dinii centura de salvare a unui matelot din subordine, dup ce vedeta-torpilor pe care serveau s-a ciocnit cu un distrugtor japonez. Cert este faptul c aceast suferina l-a marcat att de mult, nct din nou a trebuit s primeasc absoluiunea, iar mai trziu, ca preedinte, nu au fost rare situaiile n care trebuia s fie purtat pe brae. Dar aceste lucruri nu erau cunoscute atunci poporului american... S-a speculat c faptul de a fi fost nevoit s poarte n permanen un corset rigid, l-ar fi costat chiar viaa dup atentatul de la Dallas. Dac dup primul glon tras de Oswald (?), preedintele ar fi fost capabil s se aplece nainte, cel de-al doilea nu i-ar fi ptruns n craniu.

Figura 2. J.F. Kennedy la prsirea spitalului dup una dintre interveniile asupra coloanei vertebrale

Acestea sunt n mare faptele. Cum s-ar putea ns lega acestea ntre ele? Interpretrile las loc mai multor presupuneri i nu pot rspunde la toate ntrebrile. Ne gsim ns pe teren sigur atunci cnd trebuie s admitem c preedintele Kennedy suferea de insuficien corticosuprarenal i de o boal invalidant a coloanei vertebrale lombare. John Kennedy a suferit n mod cert de insuficien corticosuprarenal. Punctele relativ neclare

n acest cadru morbid sunt cele legate de perioada debutului i cauzele acestei boli. n legtur cu primul aspect, exist convingerea istoricilor c boala a debutat cu mult timp nainte de a fi fost formal diagnosticat, explicnd o parte dintre antecedentele morbide ale cazului (ex.: starea de ru pentru care a fost supus observaiei n anul 1934 sau boala misterioas despre care el nsui a vorbit adesea). Ct despre forma fiziopatologic, cea mai plauzibil este cea primar (boala Addison), mai degrab dect una secundar. Boala lui Addison, insuficiena corticosuprarenal primar sau periferic, este n 70% dintre cazuri produs printr-un mecanism autoimun, iar n afara acestui cadru, cauza principal este tuberculoza. Nu exist date documentate care s ne fac s credem c John Kennedy ar fi suferit de tuberculoz, dar putem s ne gndim la aceasta pe baza adenopatiei din adolescen, a suferinei intestinale trenante i a suferinei vertebrale care a necesitat fuziune spinal (morbul lui Pott?). n parantez fie spus, n cadrul suferinei spinale s-a fcut referire i la afectarea articulaiilor sacroiliace, care, la un bolnav cu repetate infecii urogenitale cu Chlamydia, ar putea sugera posibilitatea unui sindrom Reiter. Dac ndeprtm ideea originii tuberculoase, atunci ar rmne ipoteza autoimun. n afara argumentului statistic, aceasta ar putea fi sugerat i de faptul c sora sa, Eunice Shriver, suferea de boal Addison i de mprejurarea c John Kennedy a fost bnuit de i tratat pentru boal celiac, una n care mecanismele imunologice joac un rol bine cunoscut. Argumentul clinic principal pentru insuficiena corticosuprarenal periferic este faptul c bolnavul prezenta pigmentare cutanat verosimil addisonian, dei acesta a ncercat s o nege sau s-i ascund originea. Contemporanii au remarcat c Preedintele Kennedy era ntotdeauna bronzat i n form, punnd aceast stare de invidiat pe seama grijii pe care o purta pentru sntatea sa. Nici una dintre aceste presupuneri nu era n realitate adevrat. Acesta avea de obicei pielea brunglbuie cu nuan cenuie i unii au speculat c icterul din anul 1935 ar fi fost n realitate o hiperpigmentaie melanic. Cineva care l-a vzut n campania din anul 1960 remarca faptul c avea faa ca suprafaa unui steak bine prjit iar consilierul su, Th. Sorensen, a relatat c un reporter bnuitor i-a adresat o ntrebare direct n acest sens. Reacia a fost c viitorul preedinte i-a artat

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acestuia o suprafa de piele neexpus la soare, care era de culoare normal. Aceast demonstraie nu ar fi fost acceptat de un medic, deoarece se tie c pigmentarea addisonian nu este uniform i apare mai ales n ariile expuse la radiaia natural i acolo unde pielea este n mod normal mai pigmentat. Altui ziarist i-a spus, probabil glumind: Doctorul mi-a spus c am o leucemie lent, la care ns nu m gndesc dect atunci cnd trebuie s iau injeciile. S mai adugm c subiectul lua atebrin pentru o malarie contactat n timpul rzboiului. Posibilitatea ca insuficiena corticosuprarenal a lui John Kennedy s fi fost secundar corticoterapiei de durat nu poate fi totui nlturat, pentru c acesta era sub tratament cu cortizonice cu muli ani nainte de diagnosticul de boal Addison sau s fi avut simptomele acesteia. Dar pentru care motiv ar fi fost astfel tratat? Unii afirm c acesta ar fi fost boala celiac, care este frecvent n SUA (1 caz la 5000 de locuitori). A suferit Kennedy de boal celiac? n anul 2008, au fost desecretizate cteva documente medicale care sugereaz aceast posibilitate. Din adolescen, acesta avea tulburri gastrointestinale i ntrziere n cretere iar mai trziu a suferit de dureri abdominale, diaree cronic i a pierdut n greutate. Este totui greu de crezut c medicii timpului ar fi ratat acest diagnostic, mai ales ntr-un caz ca cel al unui fiu provenit dintr-o familie cu resurse materiale practic nelimitate i ntr-un stat ca Massachusetts. Iar dac au fcut-o, atunci de ce au recurs la corticoterapie? Se tie c n aceast boal soluia simpl este eliminarea glutenului din alimentaie i c administrarea glucocorticoizilor este soluia de salvare n caz de eec (sau de diagnostic eronat!). Suferina vertebral este aproape la fel de dificil de descifrat. n ciuda constituiei fragile i bolnvicioase, Jack a fost deosebit de activ pe linie sportiv i a suferit numeroase traumatisme cu ocazia sporturilor individuale sau de contact, unul chiar soldat cu ceea ce pare s fi fost o hernie discal, motiv pentru care a fost internat. n timpul serviciului militar, pentru care s-a nscris fornd ncorporarea prin ascunderea strii reale a sntii sale, a fost de asemenea supus unor suprasolicitri fizice. Interesant este faptul c staff-ul de campanie a negat cu ostentaie c boala vertebral a candidatului lor ar avea o legtur cu fotbalul sau cu rzboiul, datorndu-se unui defect din natere (spina bifida?).

mprejurrile care l-au adus n situaiile chirurgicale din care nu i-a revenit niciodat cu adevrat ar putea fi interpretate n cadrul unei patologii mecanice sau inflamatorii, ambele cu legtur verosimil cu corticoterapia de durat. Morbul lui Pott, dac John Kennedy ar fi suferit de aceast form de tuberculoz, ar fi putut fi precicipitat de glucocorticoizii administrai de ani de zile, dar la fel de plauzibil ar fi osteoporoza cu fracturi vertebrale. Acest diagnostic apare ntr-adevr pe un rezultat radiologic, menionat de istorici dar care nu a putut fi gsit, dar rmne o umbr de ndoial legat de faptul c fracturile osteoporozei cortizonice sunt mai rare la brbai i se localizeaz mai degrab la niveluri superioare ale coloanei. Indiferent care ar fi fost cazul, acest om s-a calificat ca cel mai tnr preedinte al Statelor Unite, dar i cel mai bolnav (dup F.D. Roosevelt?). Apropiaii si au relatat c uneori nu se putea ncla singur sau c trebuia s coboare scrile pind lateral, iar odat a trebuit s fie urcat n avion cu ajutorul ascensorului pentru cattering (figura 3). Evident, toate acestea au fost ecranate de mass-media, att ct s-a putut. Este de remarcat faptul c s-a ratat ocazia de a afla adevrul despre suferina sa vertebral, inclusiv cu ocazia autopsiei, n raportul creia se menioneaz nici o anomalie notabil a scheletului, evident n afara leziunilor craniene. S fie vorba numai de o scpare...?

Figura 3. Preedintele Kennedy urcat n Air Force One cu ajutorul ascensorului pentru alimente

ntr-unul dintre numerele din noiembrie 1955 al JAMA, R. Reeves publica un eseu, care printre altele spunea: Un brbat suferea de boala lui Addison de mai muli ani. El era tratat cu succes prin implanturi

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cu acetat de hidrocortizon de cte 150 mg la fiecare 3 luni i cu 25 mg cortizon oral zilnic. n urma unui traumatism al spatelui, prezenta dureri att de violente, nct avea probleme mari n viaa de zi cu zi. Consultul ortopedic a sugerat c acesta ar putea fi ajutat printr-o intervenie chirurgical de fuziune lombo-sacrat i sacro-iliac. Din cauza traumei severe pe care ar reprezenta-o o astfel de operaie i a insuficienei corticosuprarenale de care suferea, pacientului i s-a sugerat c riscul vital ar fi enorm n cazul n care s-ar supune acestei proceduri. Totui, pentru c acest tnr ar fi rmas invalid fr intervenia chirurgical, s-a decis ca aceasta s fie efectuat n doi timpi. Cu toate riscurile asumate... pacientul a evoluat post-operator favorabil i nu s-a declanat nici un fel de criz addisonian. Evident, identitatea pacientului a rmas necunoscut atunci. n timpul numeroaselor campanii politice pe care le-a purtat, John Kennedy a negat cu ostentaie c ar fi bolnav, din motive strategice, desigur. Biograful su, A.M. Schlessinger, l cita astfel: Nici un om care are ntr-adevr boala lui Addison nu ar trebui s candideze pentru preedinie, dar eu nu o am. Dar o avea i tia acest lucru. ncercrile de a ascunde relitatea n faa presei au fost att de stngace (sau manipulatoare?) nct este de mirare c nimeni nu a aflat adevrul, dei acesta era evident din nsei declaraiile fcute n mai multe ocazii, n care se vorbea despre o uoar atrofie a glandelor suprarenale, mai degrab dect de o distrugere primar (ceea ce ar confirma ipoteza formei secundare, mai puin gravitatea bolii) sau despre o insuficien a glandelor suprarenale cauzat de tuberculoz (sic) (ceea ce ar nsemna recunoaterea formei primare). Totui, ntrebat direct despre boala Addison, candidatul la preedinie John Kennedy, a negat-o categoric i nici nu a recunoscut ca ar lua cortizon. Desigur, ne putem ntreba ct de corect a fost aceast atitudine. Dar nu era singura mprejurare n care acesta nu a spus adevrul... John Kennedy a evitat s rspund n totalitate la ntrebrile privind viaa sa intim sau a dat rspunsuri evazive. Dei nu are dect tangenial legtur cu subiectul dezbtut aici (ex.: msura n care ipotetica tuberculoz sau corticoterapia ar explica situaia), este evident c un anume comportament sexual, s-i spunem mai impetuos, i-a marcat i acesta viaa. O coleg de colegiu spunea

despre el c nu sttea prea mult pe gnduri i aa se explic numeroasele ocazii n care a trebuit s apeleze la medic pentru infecii repetate ale cilor urinare inferioare, la care mai trziu a contribuit ca factor favorizant corticoterapia. Un coleg de Senat, G. Smathers, nota c avea cel mai activ libido dintre toi oamenii pe care i-am cunoscut, iar el nsui se confesa n anul 1963 Primului Ministru al Marii Britanii, H. McMillan c l doare capul dac nu merge un timp cu o femeie. Toate acestea erau cunoscute familiei, inclusiv soiei sale, dar nu au fost scoase la iveal dect dup moartea sa. Se pune ntrebarea dac toate aceste aspecte medicale i mai ales numeroasele medicamente pe care trebuia s le utilizeze, nu i-au afectat preedintelui Kennedy capacitatea de a reaciona corect n numeroasele mprejurri n care l-a plasat calitatea de ef al celei mai puternice ri din lume, ntr-o perioad istoric de o remarcabil complexitate politic. John Kennedy era n mod evident un subiect corticodependent i nc de la nceputul corticoterapiei, niciodat cunoscut cu exactitate, purta asupra sa medicamentul necesar i, mai mult dect att, avea depuse n safe-uri din mai multe orae ale Americii rezerve din acesta, pentru a le avea la ndemn cu ocazia cltoriilor sale. I se administrau injecii cu cortizonice nainte de conferinele de pres sau de apariiile televizate i probabil acesta a fost cazul i n marile momente de decizie ale carierei sale, cum au fost invazia din Cuba sau criza rachetelor din acest ar. Suferea de boal Cushing iatrogen iar acest lucru se observa i l deranja. nainte de a depunde jurmntul, privindu-se n oglind a spus: Doamne, uit-te la faa mea; dac nu slbesc 3 kilograme sptmna aceasta, va trebui s-mi amn instalarea (figura 4).

Figura 4. La instalarea ca preedinte

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Un cunoscut spunea odat: Poart n cltoriile sale mai multe medicamente dect se gsesc ntr-un mic dispensar. S-a relatat c preedintele ia mai multe medicamente dect tie publicul, iar mai trziu s-a vorbit despre 10-12 substane pe zi, dintre care 4-5 injectabile, inclusiv infiltraii. Lista acestora, ntocmit de J. Travell, medicul su curant la un moment dat, includea, n afar de cortizonice: anticolinergice (n combinaie cu opium pentru diaree), barbiturice (inclusiv sub form de combinaii), amfetamin, testosteron, miorelaxante, meprobamat, codein, metadon, anestezice locale, hormoni tiroidieni, anxiolitice, gamaglobuline intravenos i poate altele. ngrijortor este faptul c pe aceast list se gsesc substane care influeneaz sistemul nervos central i nsui Kennedy recunoatea: Sunt ntotdeauna n pragul iritabilitii, n vreme ce alii l-au vzut adesea deprimat (figura 5). J. Dallek, autorul a mai multe cri despre preedinte, scria c nu exist dovezi c problemele de sntate ar fi jucat vreun rol n succesul sau insuccesul activitii sale fizice. O formulare mai degrab abil, care las loc la ntrebarea dar psihice? i la comentariul c lipsa dovezilor nu este o dovad. S-a afirmat c atunci cnd a rostit celebrul discurs Ich bin

ein Berliner, care a fost deopotriv admirat dar i criticat ca cel puin inoportun sau chiar provocator, preedintele era sub influena amfetaminelor. Referindu-se la amfetamin, autorul unui articol din New York Times scria n anul 1972: Nici un preedinte care st cu degetul pe butonul nuclear nu poate lua astfel de medicamente.

Figura 5. Unul dintre momentele de depresie (sau ngrijorare) ale Preedintelui Kennedy

O via chinuit, o carier strlucit, un destin tragic, un ntreg capitol de patologie!

BIBLIOGRAFIE
1. 2. 3. 4. 5. 6. Altman LK, Purdin TS JFK file, hidden illness, pain and pills, NY Times, 17 nov 2002 Bumgarnedr JR The Health of the Presidents, McFarlane Col, Jefferson, 1994 Crenshaw CH, Hansen J, Gray SJ JFK: Conspiracy of Silence, Signet, New York, 1992 Dallek R The medical ordeals of JFK, Atl Month 2002, 290: 49-61 Dallek R An Unifinished Life: John F. Kennedy 1917-1963, Little Brown, Boston, 2003 JFK: Causal diagram of medical problems, www.doctorzebra.com 7. Lattimer JK An experimental study of backward movement of the President Kennedys head, Surg Gynecol Obstet 1976, 142: 246-254 8. McMahon EB, Curry L Medical Cover-Ups in the White House, Farragut, Washington, 1987 9. Leary C, Walsh CH, Wieneke P et al Celic disease and the autoimmune Addison s disease, Quart Med J 2002, 95: 79-82 10. Shepard J Modern medicins perspective on John F. Kennedy: Did he have celiac disease?, wwww.nearlynormalcooking.com 11. Travell J Office Hours: Day and Night, New American Library, Cleveland, 1968

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SOCIETII ROMNE DE REUMATOLOGIE www.srreumatologie.ro

GHIDURI DE PRACTIC

GHIDUL SOCIETII BRITANICE DE REUMATOLOGIE I AL ASOCIAIEI PROFESIONITILOR DE SNTATE DIN REUMATOLOGIE DIN MAREA BRITANIE PENTRU MONITORIZAREA TRATAMENTULUI CU MEDICAMENTE REMISIVE
Guidelines of British Society for Rheumatology (BSR) and Association of Rheumatology Health Professionals of Great Britain for supervising remissive drugs treatment
Recent, Societatea Britanic de Reumatologie (BSR) a emis un ghid pentru utilizarea medicamentelor remisive (DMARDs) care sunt utilizate larg n tratarea diferitelor forme de reumatisme inflamatoare. Scopul declarat al acestui demers a fost dublu: actualizarea recomandrilor precedente i punerea de acord a acestora cu recentele recomandri ale Ageniei Naionale de Siguran. Aceste recomandri au fost limitate la 10 substane terapeutice majore, cu excluderea biologicelor, nu sunt destinate utilizrii n pediatrie i se refer esenialmente la monoterapie. Cele 10 medicamente remisive luate n discuie au fost: auranofirmul, azatioprina, ciclosporina, dpenicilamina, hidroxiclorochina, leflunomidul, metotrexatul, micofenolatul mofetil, aurotiomalatul de sodiu i sulfasalazina. Ciclofosfamida va face obiectul unei reglementri n cadrul unui ghid pentru vasculite, care este n preparare. Recomandrile cheie pentru monitorizarea tratamentului sunt cele care urmeaz: 1. Este important de avut n vedere c, n complearea aprecierii bazate pe valorile absolute ale oricror indicatori reumatologici sau biochimici, s se ia n consideraie imediat i s se manifeste o vigilen crescut fa de orice cretere sau scdere sau tendin n aceste sensuri a valorilor examinrilor biologice. 2. E nevoie de o pruden deosebit nainte de a recomanda sau aviza subiectul pentru imunizare, deoarece se tie c vaccinurile vii nu sunt recomandate persoanelor aflate sub tratament cu unele imunomodulatoare. 3. Interaciunile medicamentoase sunt importante i trebuie ntotdeauna atent cntrite n raport cu nevoile clinice.
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4. Sarcina i alptarea trebuie luate n consideraie la bolnavele supuse tratamentului. Este nevoie de a cunoate exact efectul acestor medicamente asupra ftului i a lactaiei. 5. Toate cazurile de toxicitate trebuie inute n evidene scrise i pacientul informat asupra lor. 6. ntruct reaciile adverse nu sunt totdeauna menionate n prospectul fiecrui medicament (sic) cei care le utilizeaz trebuie s consulte documentele ageniilor specializate (ex.: British National Formulary). 7. Toi pacienii vor avea un carnet pentru evidena evenimentelor privind eficacitatea i tolerana medicamentului pe care l utilizeaz. 8. Pacienii vor fi ncurajai s participe la programe de autoevaluare i monitorizare a propriului tratament, ntruct studiile au artat clar beneficiul acestora de a se implica personal, nu numai de a fi informat. 9. Ar fi ideal ca toi pacienii s participe la un program educaional regulat nainte de a li se prescrie un medicament remisiv. 10. Este de dorit s se aplice un sistem de cuantificare a beneficiului terapeutic n care medicul i pacientul s coopereze pentru a cunoate mai bine rolul medicamentului n controlarea bolii. 11. Dei toate ghidurile sunt bazate pe dovezile existente, acestea prezint i slbiciunea de a nu exista dovezi exacte n legtur cu momentul la care se manifest unele reacii adverse dup iniierea tratamentului.
Sursa: Chakavarty K, McDonald H, Pullar T et al, BSR/ BPHR guideline for disease- modifying anti-rheumatic drugs therapy in consultatin with British Association of Dermatologists, Rheumatology 2008, 47: 924-925

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

Instruciuni pentru autori


Structura revistei

Revista Romn de Reumatologie public urmtoarele tipuri de materiale: editoriale, articole de orientare, lucrri originale, cazuri clinice, subiecte pentru rezideniat, vignete terapeutice sau imagistice, chestionare de autoevaluare, quiz-uri, actualiti i articole de sociomedicin i educaie medical, coresponden (ntrebri, comentarii, puncte de vedere etc.), recenzii. Principalele seciuni cu format impus sunt: Articole de orientare Coninut: informaie general de actualitate axat pe probleme teoretice i/sau practice (revista literaturii). Dimensiuni: maximum 12 pagini (la nevoie, articolul poate fi mprit pentru a fi publicat n numere consecutive). Format: text compact (nu schematizat), fr sau cu puine subcapitole. Bibliografie: recent (75% titluri din ultimii 5 ani), cu prioritate pentru articole publicate in extenso, citnd puine rezumate, capitole de manual sau cri n ntregime, introdus n text. Lucrri originale Coninut: cercetri fundamentale sau clinice (diagnostic sau tratament). Dimensiuni: 6-8 pagini, cu 4-5 materiale ilustrative (texte, grafice sau figuri). Format: introducere (starea actual a problemei, premisele i scopul cercetrii), material i metode, rezultate, discuii, concluzii (numerotate, redactate sintetic i strict referitoare la constatrile personale). Bibliografia introdus n text (vezi mai jos). Cazuri clinice Coninut: observaii clinice de excepie sau care pun/clarific o problem, din categoria celor care se ncheie cu o confirmare (morfologic, terapeutic, evolutiv etc.). Dimensiuni: 3-5 pagini, cu 1-2 ilustraii originale (clinice, imagistice, morfologice etc.). Format: prezentarea cazului, comentarii. Bibliografie n text (la comentarii). Instruciuni pentru redactare Autorii sunt rugai s respecte cu strictee toate recomandrile care urmeaz, pentru a facilita munca de (tehno)redactare. Materialele trimise pentru publicare vor fi culese n programul Word cu caractere Arial de 12, la un rnd i jumtate, n trei exemplare, tiprite pe o singur parte a filei i salvate pe dischet (pstrai i dvs. un exemplar!). Pentru a evita ntrzierile i corespondena inutil, v rugm s avei n vedere urmtoarele: Titlul cu font 14 bold. Numele autorilor precedat de iniiala prenumelui pentru brbai i de prenumele n ntregime pentru femei. Denumirea complet a instituiei/instituiilor crora le aparin autorii indicnd prin cifre apartenena (dac este cazul) i localitatea, culese cu corp italic (cursive). Adresa complet a primului autor sau a celui din colectivul de autori, care este abilitat s poarte corespunden n numele acestuia (cu redacia, pentru cerere de extrase etc.), cu numerele de telefon/ fax i, dac exist, adresa de e-mail. Rezumat n limbile romn i englez, redactat sintetic, de preferin structurat pe scop, material i metode, rezultate, discuii i concluzii (pentru lucrrile originale). Rezumatul trebuie ntocmit i pentru articolele de orientare. Nu utilizai prescurtri. Folosii acronime, sub form de caractere capitale, numai dac un termen revine de mai multe ori n text i avei grij s le explicai la prima utilizare. Evitai termenii mprumutai din alte limbi, prefernd traducerea romnesc acceptat n literatur. Dac acest lucru nu este posibil, culegei-i cu italice.

Bibliografia va fi alctuit n sistemul Oxford (adaptat ca mai jos). Indicai n text numrul titlului bibliografic de pe lista citrilor, acolo unde ideea a fost preluat, ntre paranteze. Lista bibliografic va fi ntocmit n ordinea citrilor n text, nu dup alfabet. Componentele surselor, care trebuie redactate strict ca n exemplele de mai jos, pot fi: Cri n ntregime: Autori/editori, cu numele i iniiala prenumelui Titlul ntre ghilimele i cu majuscule iniiale Ediia (dac este cazul) Editura Locul publicrii Anul apariiei Exemplu: Iagru N., Reumatologie Pediatric, Editura Medical Amaltea, Bucureti, 2003 Capitole din cri sau tratate, semnate de autori distinci: Autorul capitolului, cu numele i iniiala prenumelui Titlul capitolului Autorii sau editorii volumului, cu nume i iniiala prenumelui, urmai de Titlul volumului, ntre ghilimele i cu majuscule iniiale, introdui prin particula n: Ediia (dac este cazul) Editura Locul publicrii Anul apariiei urmat de dou puncte Paginile ntre care este cuprins capitolul Exemplu: Boloiu H.D., Man L., Rednic S., The effect of methylprednisolone pulse therapy in polymyositis/dermatomyositis, in: Mallia C., Uitto J. Current Issues in Rheumatology and Dermatology, Kulver Academic and Plenum Press, New York, 1999: 349-358 Articole: Autori, cu numele i iniiala prenumelui (numai primii trei, urmai de etc., n cazul n care sunt mai muli de patru) Titlul articolului Titlul revistei n prescurtare internaional, n italice Anul, urmat de virgul Volumul, urmat de dou puncte Paginile ntre care este cuprins articolul Not: Dac articolul citat este publicat n rezumat (ex.: revist, volum cu rezumatele unor manifestri tiinifice), sursa va fi indicat precedat de Rez. n: sau Abstr. in: Exemplu: Lems W.F., Ader H.J., Lodder M.C. etc, Reproductibility of bone mineral density measurements in daily practice, Ann Rheum Dis 2004, 63: 285-289 Exemplu: Blnescu A., Nat R., Predeeanu D. etc., Influena tratamentului imunosupresor asupra imunofenotipului celulelor dentritice din sinoviala reumatoid, Rez. n: Rev Reumatol 2003, 11 (Supliment): 56 Coresponden Orice coresponden adresat revistei va fi expediat la urmtoarea adres: Dr. Laura Damian, Secretar de redacie, Revista Romn de Reumatologie, Clinica Reumatologic, Str. Clinicilor nr. 4, 400006 Cluj-Napoca, tel 0264 598443 sau 0264 591942 int 464, fax 0264 431040, e-mail: meddoi@cluj.astral.ro Abonamente Membrii Societii Romne de Reumatologie sunt abonai de drept la Revista Romn de Reumatologie, prin efectul plii cotizaiei. Persoanele din afar se pot abona adresndu-se secretariatului redaciei, la adresa de mai sus. Reclame Angajarea activitilor de reclam i plata pentru aceste servicii se face prin negociere cu editorul (Editura Medical AMALTEA, Bucureti, Str. Sptarului nr. 31, tel. 021/210.45.55; Persoan de contact: Dr. M.C. Popescu). Societatea Romn de Reumatologie i rezerv dreptul de a aviza includerea oricrui material promoional n revista sa i percepe o cot parte din beneficii, n condiiile contractului cu acesta.