Revista Romana de REUMATOLOGIE - 2008 - Nr.3

Revista Romn de

REUMATOLOGIEVolumul XVII Nr. 3 An 2008 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 (Budapest) 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 (Budapest) Ruxandra Ionescu (Bucureti) Nicolae Iagru (Bucureti) Marco Matucci (Firenze) Nicolae Miu (Cluj-Napoca) Sarah Nica (Bucureti) Gyula Poor (Budapest) Simona Rednic (Cluj-Napoca) Zoltan Szekanecz (Debrecen) Maria ua (Constana) Coman Tnsescu (Bucureti) Francesco Trotta (Ferarra) Jean-Pierre Valat (Tours) Sjef van den Linden (Maastricht)

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

EDITORIAL

Cuprins

EDITORIAL N. Iagru Reumatologia pediatric n Romnia _______________________________________________ 133 ARTICOLE DE ORIENTARE N. Iagru Orientarea fenotipic a tratamentului n artrita idiopatic juvenil _____________________ 135 Mariana tefan, Andreea Ceau, Anca Sandu Sindroamele autoinflamatorii _____________________________________________________ 141

LUCRRI ORIGINALE N. Adib, K. Hynich, J. Thornton, M. Lunt, J. Davidson, J. Gardner-Medwin, H. Foster, E. Balidam, L. Waddesburn, W. Thomson Association between duration of symptoms and severity of disease at first presentation to pediatric rheumatologist: results from the Childhood Arthritis Prospective Study _______ 148 J. Thornton, M. Lunt, D. M. Aschcroft, E. Balidam, H. Foster, J. Davidson, J. Gardner-Medwin, D. Symmons, W. Thomson, P. A. Elliott Costing juvenile idiopathic arthritis: examining patient-based costs during the first year after diagnosis ______________________________________________________ 155

CAZUISTIC INSTRUCTIV P. Riley, L. J. Mc Cann, S.M. Maillard, P. Woo, K.J. Murray, C.A. Pilkington Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcionosis __________________________________________________ 163 N. Iagru, Carmen Ciofu, Gabriela Oproiu, C. Nu Artrit idiopatic juvenil asociat cu manifestri pulmonare de sclerodermie ___________ 168 Mariana tefan, Andreea Ceau Febra periodic la copil: dificulti de diagnostic ____________________________________ 173 N. Iagru, Mirela Iuan, F. Colcer, Livia Sorohan Artrit idiopatic juvenil cu debut sistemic, rezistent la tratament ____________________ 175

QUIZ

EDITORIAL

REUMATOLOGIA PEDIATRIC N ROMNIA

Reumatologia pediatric este o specialitate emergent de o stringent actualitate n Romnia atta timp ct sute i mii de copii suferinzi de boli reumatice sunt diagnosticai i tratai de pediatri tradiionali (generaliti) sau chiar de medici de familie. Aa cum rezult din datele oferite de Centrul de Calcul i Statistica Sanitar (2004), alturi de diagnosticul de artrit reumatoid juvenil, o parte dintre bolnavi sunt codificai cu poliartrit reumatoid, sugernd preluarea lor de reumatologii de aduli. Exist ns diferene att de importante ntre cele dou entitai nct puini dintre acetia se ncumet s trateze copii, mai ales atunci cnd realizeaz c acetia nu sunt nite aduli n miniatur, ci fiine cu particulariti anatomice, fiziologice, imunologice i funcionale distincte pentru o plaj larg de vrste, de la aceea de sugar pn la cea de 16 ani. Spre deosebire de artrita reumatoid, artrita idiopatic juvenil nu reprezint o singur entitate, ci reunete sapte categorii, iar dup ultima revizie de la Edmonton, chiar opt (forme, subtipuri) care difer ntre ele; doar una dintre acestea (forma poliarticular factor reumatoid pozitiv), putnd fi considerat ca artrit reumatoid la vrsta de copil. Un mai vechi adagiu conform cruia medicina copilului urmeaz medicina adultului ar fi trebuit s impulsioneze de mult timp apariia i dezvoltarea reumatologiei pediatrice n ara noastr. Explicabil sau nu, ntrzierea desprinderii acesteia din trunchiul comun al pediatriei ca specialitate distinct trebuie recunoscut i corectat. Inculparea conservatorismului unora dintre personalitile pediatriei tradiionale sau a atitudinii cvasiobstructive a unor lideri ai specialitilor medicale de aduli, sceptici n privina abilitii pediatrilor de a se converti sau forma profesional n domeniile respective (conflict de interese?), poate fi considerat n egal msur tentativa de a gsi circumstane atenuante pentru un anumit imobilism sau inerie a lumii pediatrice. Aceast stare de lucruri trebuie privit totui cu calm i optimism devreme ce chiar n Statele Unite, la ACR/ARHP Annual Scientific Meeting San Antonio,REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008

Texas, 2004 s-a deplns existena a doar 200 de reumatologi pediatri i absena total a acestora n unele state ale uniunii. Evocnd teoria jocului a lui Wright pentru a explica viziunea sa asupra direciei de dezvoltare a lumii n care trim ctre o lume a sumei-zero (suma nul) i a sumei non-zero, C. H. Spencer realizeaz o interesant extrapolare la domeniul reumatologiei pediatrice. n termeni de competiie ctigtor/nvins (rzboaie, concursuri profesionale, competiii sportive, politic etc), suma zero pare a fi nscris n genele noastre, fiind necesar pentru supravieuire. Wright sugereaz c societatea uman i viaa pe pmnt au progresat printr-un gen de for dinamic non-zero care face ca interaciunile s fie calificate non-zero atunci cnd ambele pri nregistreaz beneficii. Astfel, de la apariia vieii, organismele cu ADN identic interacioneaz altruist, sugernd ca biologia ar putea fi vzut ca transfer de informaie i feedback ntr-un mod similar cu interaciunea dintre savani i inventatori pe calea scrisorilor, manuscriselor i Internetului. Pediatrii reumatologi ar putea i ei contribui (presa scris, Internet, globalizare) la ameliorarea diagnosticului i tratamentului bolnavilor, precum i la dezvoltarea specialitii pe plan local, regional, naional i internaional prin colaborare, cooperare i perspectiv global. Suma nonzero ar putea prevala astfel asupra sumei-zero. n acest scop, pediatrii reumatologi trebuie s participe la organismele de conducere (consilii, comitete executive) ale diverselor organizaii naionale i internaionale. n acest proces, unii medici se vor identifica mai mult ca reumatologi dect ca pediatri, adernd la organizaiile de profil pur reumatologic (Societatea Romn de Reumatologie, Liga European contra Reumatismului, American College of Rheumatologists etc), n timp ce alii se vor simi mai degrab pediatri reumatologi cu relaii orientate prioritar ctre organizaii pediatrice (Societatea Romn de Pediatrie, AAP, Pediatric Rheumatology European Society etc). Reumatologia pediatric are nevoie de toate aceste organizaii133

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REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008

pentru creterea performanelor sale, urmnd ca ambele laturi, pediatric i reumatologic, s beneficieze reciproc. Dei se afirm c reumatologii de aduli i au propria lor agend, n care reumatologia pediatric este frecvent o preocupare periferic, sau c reumatologii de copii i pacienii lor sunt tratai de sus, n experiena personal am constatat o disponibilitate total a ntregii ierarhii, ncepnd cu Societatea Romn de Reumatologie i Clinicile de Reumatologie din toate centrele universitare. Conflictul de interes generat de preluarea unor bolnavi, n special n a doua decad de via, de reumatologii de aduli va disprea n momentul n care va exista un numr suficient de mare de reumatologi pediatri. La noi n ar, conducerea Societii Romne de Reumatologie (Prof H. D. Bolosiu) a oferit cu civa ani n urm o ni pentru reumatologia pediatric. Medicii pediatri cu preocupri de reumatologie au fost invitai s participe la congresele acestei organizaii n cadrul dezbaterii unor teme de actualitate n patologia copilului. n anul 2005 a fost nfiinat Grupul de Lucru pentru Reumatologie Pediatric cu dubla afiliere (Societatea Romn de Reumatologie i Societatea Romn de Pediatrie) care i propune sistematizarea eforturilor pediatrilor cu preocupri de

reumatologie din ara noastr (reumpedrom@yahoo. com). n viitor, pentru a nu rmne o form fr fond, reumatologia pediatric trebuie s realizeze urmtoarele obiective: asigurarea unor strategii de pregtire a pediatrilor cu preocupri de reumatologie n centrele universitare din ar i invitarea acestora la manifestrile tinifice ale reumatologilor non-pediatri, transferul de know how pentru organizarea serviciilor de reumatologie pediatric (cu ajutorul clinicilor de reumatologie pentru aduli), realizarea unor ghiduri de practic pentru principalele boli reumatice infantile, aderarea la organizaii internaionale cu profil de reumatologie pediatric din cadrul EULAR, ACR etc, Civa pediatri romani, printre care i autorul acestor rnduri, sunt deja membri ai PRINTO - Pediatric Rheumatology International Trials Organization. Recunoaterea specialitii de reumatologie pediatric i rezervarea de locuri n cadrul concursurilor de rezideniat organizate de Ministerul Sntii i Familiei (obiectiv neagreat n prezent), alctuirea unui Registru Naional al Bolilor Reumatice Pediatrice i formarea grupurilor de claborare, fundaii, centre filantropice n beneficiul copiilor cu boli reumatice cronice ar fi activiti binevenite.

Conf N. Iagru

ARTICOLE DE ORIENTARE

ORIENTAREA FENOTIPIC A TRATAMENTULUI N ARTRITA IDIOPATIC JUVENILN. Iagru Clinica II Pediatrie, IOMC, UMF Carol Davila,Bucureti

INTRODUCEREObiectivul fundamental al medicilor curani este de a crete la maximum capacitatea copiilor cu artrita idiopatic juvenil (AIJ) de a tri ca indivizi normali n societate. Aceasta presupune un diagnostic precoce i un tratament prompt pentru prevenirea complicaiilor i ameliorarea calitii vieii. n acest scop, este necesar suprimarea sinovitei inflamatoare i prevenirea pe termen lung a leziunilor osteocartilaginoase. n plus, o evoluie optim necesit i reducerea impactului psihosocial al bolii asupra copilului i familiei sale. Medicul trebuie s evalueze n permanen severitatea procesului inflamator, eficacitatea medicaiei antiinflamatoare, impactul bolii i al tratamentului asupra familiei, precum i posibilele efecte toxice ale acestuia. Prima treapt n acest demers este contientizarea faptului c AIJ nu reprezint o singur boal bine definit, cu etiopatogenie clar i evoluie uniform. AIJ include o varietate de subtipuri distincte cu un istoric natural i un rspuns foarte diferit la tratament, impactul asupra bolnavului i familiei fiind i el diferit. De exemplu, o feti cu un singur genunchi tumefiat (AIJ oligoarticular tipic), difer n mod esenial de un biat adolescent cu un genunchi tumefiat dar care acuz i talalgii (artrit asociat cu entezit tipic, alt subtip al AIJ). n acelai sens, un copil cu febr i rash de AIJ cu debut sistemic difer enorm de unul cu AIJ poliarticular cu FR pozitiv. nainte de introducerea tratamentului biologic, medicii pediatri se limitau la tratamentul antiinflamator nespecific. Cnd alegerea se reducea la utilizarea dozelor terapeutice de aspirin, injeciile de sruri de aur sau corticosteroizi, relativa siguran, eficacitatea i toxicitatea fiecrui medicament n parte erau bine cunoscut. SchemaREVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008

terapeutic adecvat pentru fiecare bolnav n parte lua n consideraie severitatea evoluiei procesului patologic, dar i posibilele efecte toxice ale medicamentelor alese. n ciuda eforturilor, pe lng succese notabile, o proporie semnificativ dintre bolnavi rmneau cu infirmiti permanente. Introducerea metotrexatului n arsenalul terapeutic a ameliorat posibilitile de reducere a inflamaiei conducnd la o cretere dramatic a ratei succeselor, dar reprezint de fapt tot un antiinflamator nespecific (1). n prezent dispunem de mult mai multe mijloace terapeutice care au ca int suprimarea inflamaiei. Agenii biologici care blocheaz n mod specific TNF- i interleukina-1 (IL-1) sunt deja disponibili, alturi de alii aflai n studii avansate asupra copiilor cu AIJ: anti-IL-6 (tocilizumab); blocani ai costimularii (abatacept, deja aprobat pentru uz pediatric de ctre FDA), ageni anti-limfocite B (rituximab), etc. Aceste medicamente, cu eficien crescut, au condus la ameliorri dramatice ale copiilor cu AIJ. Posibilitile crescute ale pediatrilor de a suprima componente specifice ale rspunsului inflamator trebuie nsoite de o mai mare acuratee n recunoaterea eficacitii cu care fiecare agent terapeutic suprim acest rspuns, precum i subtipurile AIJ n care anumii mediatori specifici joac cel mai important rol. Prin urmare, nainte de a se discuta despre terapia cea mai potrivit, este necesar o descriere clar a fenotipului (formei, subtipului, categoriei) de AIJ care trebuie tratat. n ciuda eficacitii diferiilor ageni terapeutici n tratamentul sinovitei cronice, care urmeaz dup faza acut a anumitor subtipuri ale AIJ, este puin probabil ca toi agenii biologici s aib aceeai eficacitate pe durata fazei acute iniiale, indiferent de fenotipul bolii. ntr-adevr, unul dintre cele mai importante elemente ale unei ngrijiri optime a copiilor cu AIJ

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este suprimarea sinovitei din faza acut iniial a bolii, deoarece dup apariia leziunilor articulare exist puine mijloace de a preveni extinderea acestora, exceptnd procedurile de reabilitare fizic, terapia ocupaional i sperana (folcloric!) ca organismul copilului i revine singur, pe msur ce crete. Dei calitatea vieii bolnavilor cu leziuni distructive severe a fost mult mbuntit dup introducerea protezrii articulare totale, este indiscutabil preferabil prevenirea distrugerilor articulare. Totui, studiile efectuate n artrit precoce la aduli care au demonstrat ameliorarea evoluiei utiliznd combinaii agresive de medicamente imediat dup prezentare, dei demne de luat n consideraie, nu pot fi extrapolate la copiii cu AIJ. Pe de o parte, tocmai pentru c artritele juvenile includ o larg varietate de boli, multe dintre ele autolimitate (de aceea este nevoie pentru diagnosticul AIJ de persistenta artritei timp de minimum 3 luni ntr-o articulaie sau de cel puin 6 sptmni n 2 sau mai multe articulaii!), iar pe de alta, riscul toxicitii acestor medicamente i reinerea prinilor n acordarea consimmntului pentru tratament. n plus, pentru definirea subtipului de AIJ sunt necesare 6 luni de la debutul clinic al artritei, interval care ntrzie oricum un eventual tratament agresiv precoce. Utilizarea agresiv a agenilor terapeutici intii pentru suprimarea precoce a inflamaiei n AIJ ntlnete dou obstacole majore. Primul este reprezentat de reinerea clinicienilor fa de introducerea terapiilor avansate eficiente fr studii adecvate, motiv invocat de exemplu pentru infliximab, adalimumab i, mai nou, pentru rituximab. Unii practicieni cred c agenii biologici nu pot fi introdui naintea unui tratament timp de 3 luni cu un antiinflamator nesteroidian, urmat de unul chiar mai lung cu metotrexat, aseriune care amintete de vetusta paradigm a piramidei terapeutice. Ca s nu mai menionm c unii medici se mpotrivesc tratamentului cu metotrexat la copii, refuznd s-l prescrie sau s-l monitorizeze (2). Dei medicamentele biologice au fost iniial studiate ntr-adevr la bolnavii rezisteni la metotrexat, prezentrile actuale pentru etanercept, adalimumab i abatacept au nscris aprobarea pentru tratamentul AIJ fr condiia eecului la tratamentul cu metotrexat (1). Nencrederea n terapiile agresive iniiale, n stadiile timpurii ale inflamaiei, deriv i din includerea eronat a unor afeciuni uoare i autolimitate sub denumirea de AIJ. Dar, n timp ce unii bolnavi cu

forme uoare de oligoartrit sau de artrit asociat cu entezita pot rspunde favorabil la administrarea exclusiv de antiinflamatoare nesteroidiene, la cei cu forme mai severe de boal acest tratament va eua i fr o terapie agresiv vor aprea dizabiliti cronice. Cum ntotdeauna vor fi prini sau cadre medicale ngrijorate de posibile efecte pe termen lung ale noilor medicamente, medicii curani pediatri, ei nii preocupai de aceast eventualitate, sunt obligai, n contrapartid, s aduc la cunotina prinilor alternativa disabilitilor induse de boal pe termen lung. Aceste disabiliti aprute n copilrie au un efect mult mai profund asupra respectului de sine al copilului, asupra dezvoltrii psihosociale i realizrii sale pe termen lung dect aceleai dizabiliti aprute la adult.

ETAPE SPRE ORIENTAREA FENOTIPICTrebuie reamintit practicienilor pediatri c artrita este definit, fie de prezena durerii i tumefactie articulare, fie de durere i limitarea micrii. Astfel, dac un copil are durere i redoare el poate avea artrit chiar i n absena tumefaciei articulare. Optimizarea tratamentului AIJ ncepe odat cu recunoaterea heterogenitii acesteia. Prima treapt este depistarea copiilor cu risc crescut de distrucie osteoarticular cronic: bolnavii cu AIJ cu debut sistemic, cei cu AIJ poliarticular (cu sau fr FR pozitiv) i copiii cu oligoartrit care prezint, fie afectarea articulaiilor mici, fie afectarea membrelor superioare (3). O alt categorie cu risc crescut este reprezentat de copiii cu oligoartrit cu afectarea articulaiilor mari i VSH semnificativ crescut sau cu anemie remarcabil i istoric familial pozitiv pentru psoriazis. Artrita sistemic Acest fenotip al AIJ reprezint oaia neagr" n practic pediatric prin manifestrile sale extraarticulare cu alura amenintoare de via din faza acut i prin dificultile de tratament, frecvent enorme. Contrar reinerilor actuale n rndul reumatologilor, corticoterapia este deseori necesar pentru controlul tabloului clinic. Discutabil nu este faptul c se indic, ci dozele i durata tratamentului care implic preocuparea de a se reduce riscurile toxicitii cortizonice. Metotrexatul (MTX) este considerat mai eficace n artrita sistemic dect agenii anti-TNF-alfa. Oricum, etanerceptul este mai puin


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eficace n acest subtip dect n formele poliarticulare ale AIJ (4). Anakinra i tocilizumabul par s controleze semnificativ manifestrile sistemice n lumina rolului pe care l au IL-1 i, respectiv, IL-6 n patogenia fenotipului sistemic (5). Abataceptul, aprobat recent de FDA pentru utilizarea n AIJ, este indicat numai dup faza acut a bolii, copiii cu artrit

sistemic acut fiind exclui din studiile comunicate (6). Rilonacept (molecul capcana IL-1), recent introdus n tratamentul unor criopirinopatii, probeaz eficacitate n artrita sistemic (1). Talidomida este de asemenea creditat cu bune rezultate n cazurile refractare la alte terapii, n timp ce ciclosporina pare s aib rezultate remarcabile la bolnavii cu

puls-terapie prednison prednisolon

Etanercept eventual, imunoglobuline IV

Figura 1. Algoritm de tratament n artrita idiopatic juvenil sistemic

sindrom de activare macrofagic n asociere cu medicaia cortizonic. Oligoartrita Cei mai muli copii cu AIJ cu debut realmente oligoarticular rspund favorabil la antiinflamatoarele nesteroidiene (AINS) sau la injeciile intraarticulare cu preparate cortizonice (triamcinolon hexacetonid). Acestea din urm sunt indicate la

copii cu o singur mare articulaie tumefiat, n cazul n care AINS au fost ineficiente, avnd reputaia remisiunii prompte a durerii i reducerea riscului apariiei inegalitii membrelor inferioare. La debut se consider potrivit o cur de minimum 3 luni cu antiinflamatoare nesteroidiene, deoarece exist cazuri de artrit tranzitorie care mimeaz iniial AIJ, dar care se remit spontan dup cteva sptmni. Se atrage ns atenia ca AINS nu au aceeai

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eficien la toi pacienii cu oligoartrit (n timp ce unii rspund foarte bine la ibuprofen sau la naproxen, alii rspund mai bine la diclofenac sau la altele). La copiii cu factori de risc semnificativi este ns necesar recunoaterea mai rapid a ineficacitii AINS. n general, dac la aceti bolnavi rspunsul nu a fost favorabil dup 4-6 sptmni, nu mai este necesara prelungirea tratamentului cu AINS pn la 3 luni i, n consecin, se va lua n discuie decizia de introducere a unei terapii cu un agent remisiv de tip anti-TNF-(1). Oricum, chiar dac aceast conduit agresiv pare hazardat, se

atrage atenia c bolnavii cu tumefacie articular persistent dup un tratament adecvat mai lung de 6 luni prezint un risc semnificativ de dizabilitate cronic, n ciuda debutului oligoarticular i de aceea vor fi ncadrai n categoria de risc crescut. n astfel de situaii se apeleaz de obicei la metotrexat, dei ntr-adevr inhibitorii TNF- (etanercept) au o eficacitate mai mare i un efect terapeutic mai rapid (7). Combinaia ntre anti-TNF- i MTX este de notorietate sinergic (4). Amnarea terapiei remisive poate agrava riscul leziunilor articulare progresive. Monitorizarea oftalmologic (examenul polului

Figura 2. Algoritm de tratament pentru artrit idiopatic juvenil, forma oligoarticular


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anterior) rmne bineneles obligatorie, uveita anterioar fiind complicaia cea mai temut a oligoartritelor. Poliartrita FR-pozitiva i/sau negativ Majoritatea copiilor cu AIJ nregistreaz un rspuns rapid la agenii anti-TNF- (etanercept, adalimumab i infliximab (1), mai ales atunci cnd se asociaz cu MTX). AIJ cu FR i anti-CCP pozitivi

refractar la tratamentul cu anti-TNF- i MTX pot fi tratai cu abatacept sau cu rituximab (Autorul acestui articol, extrapolnd datele de eficacitate la adulii cu poliartrit reumatoid, a administrat rituximab fr incidene, cu bune rezultate n dou cazuri de artrit sistemic disperant refractare la antiTNF- i MTX, la bolnavi cu vrsta de 16 i respectiv 18 ani). Oricum, pentru abatacept exist studii controlate-placebo precum i aprobarea FDA pentru AIJ, n timp ce pentru rituximab nu exist (1,6).

Figura 3. Algoritm de tratament n artrita idiopatic juvenil, forma poliarticular, cu factor reumatoid pozitiv sau negativ

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Artrita asociat cu entezit este un subtip distinct de AIJ, cu un istoric natural i prognostic diferit de celelalte. Poate debuta fie oligo-, fie poliarticular n adolescena timpurie, bolnavii prezentnd entezita remarcabil i artrit de anvergur variat. Incidena este mai mare la biei. Atunci cnd debutul are loc la copilul mic, boala poate fi catalogat ca oligoartrit, subtip de care este practic imposibil de difereniat la aceast grup de vrst. Copiii cu artrit asociat entezitei acuz frecvent dureri periarticulare fr articulaii tumefiate, cu reactani de faz acut n limite normale i anticorpi antinucleari i FR negativi. Adesea, evident eronat, aceste dureri sunt considerate dureri de cretere, fr a se indica un tratament specific, dei ar putea rspunde satisfctor la AINS. Prezena entezitei (n special n jurul genunchilor, gleznelor, la baza clcielor, a tendonului lui Ahile i la nivelul inseriei fasciei plantare), afectarea coloanei lombosacrate (redoare i limitarea flexiei anterioare) i sacroiliita, alturi de uveita anterioar acut i de prezena HLA-B27 i a anamnezei familiale pozitive pentru spondiloartrit, reprezint trsturile distincte ale acestui fenotip. Tratamentul iniial const n administrarea AINS, eficiente n cazurile uoare, dar nu i n cele cu sacroiliit. Dintre remisivele conventionale, cea mai mare eficienta o are sulfasalazina. La cei cu semne severe de boal, refractri la AINS i la remisivele tradiionale, se recomand medicaia anti-TNF-?, etanerceptul demonstrnd o bun eficacitate (4).

CONSIDERAII FINALEFenotipurile AIJ posed etiopatogenii diferite. n timp ce unele medicamente sunt eficiente pentru c suprim n mod nespecific inflamaia, altele i datoreaz eficiena anihilrii citokinelor implicate n majoritatea proceselor inflamatoare. MediciiBIBLIOGRAFIE1. 2. 3. Lehman TJA Optimizing the management of juvenile idiopathic arthritis, http://www.medscape.com/viewprogram/15784_index, 2008 McNamara D JIA, Clinical Presentation Is Key to Diagnosis. Pediatric Rheumatology. www.rheumatologynews.com, 27 Wallace CA, Huang B, Bandeira M etc Patterns of clinical remission in select categories of juvenile idiopathic arthritis, Abstr Arthr Rheum 2005, 52: 3554-3562 Iagru N, Grigorescu-Sido P, Miu N etc Combination therapy with etanercept and MTX in children with JIA THU0413, Abstr Ann Rheum Dis 2008: 266 Yokota S, Imagava T, Mori M etc Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis:

practicieni ncep s neleag rolul pe care l joac anumite tipuri de citokine n diferitele subtipuri ale AIJ. Cel mai ilustrativ exemplu este al artritei sistemice (IL-1 si IL-6) i se sper ca n viitor s fie edificate i altele deoarece cu ct este mai bine documentat o boal, cu att mai bun va fi i terapia sa (1). Numai cunoscnd diferitele subtipuri ale AIJ din clasificarea ILAR, clinicienii pediatri vor fi api s recunoasc probabilitatea ca un copil s evolueze bine sau dac este mai indicat s introduc un tratament agresiv. Din momentul recunoaterii riscului de boal distructiv evolutiv tratamentul trebuie s previn progresiunea inflamaiei i rezultanta sa, leziunile articulare i invaliditatea. n acest scop, trebuie iniiat fr ntrziere un tratament remisiv agresiv. Dac n trecut aceasta nsemn introducerea MTX, n prezent trebuie avute n vedere medicamentele remisive biologice, cu aciune mai rapid instalat i risc mai redus sau inexistent de toxicitate (supresie medular i hepatotoxicitate) (1, 7, 8). Pentru optimizarea acestei conduite este necesar ameliorarea compliantei prinilor i obinerea unui beneficiu terapeutic maxim. Prinilor li se va explica natura bolii i se va risipi mitul dispariiei de la sine a bolii odat cu creterea copilului. Se va accentua asupra riscurilor previzibile ale bolii i beneficiile terapiei agresive n comparaie cu leziunile cauzate de inflamaia netratat. Toate ambalajele i fisele de prezentare ale MTX i agenilor biologici abund n atenionri despre reacii adverse care terifiaz familia i antreneaz refuzul acceptrii tratamentului. De aceea prinii trebuie pregtii nc de la prima vizit asupra probabilitii ca n viitor copilul s aib nevoie de un tratament agresiv deoarece n acest fel acordm familiei ansa s se documenteze i s evalueze situaia bolnavului nainte ca decizia s fie luat (1). n plus, apare i oportunitatea de a dicuta la urmtoarea vizit despre progresele nregistrate de copil sau despre lipsa acestora, prinii fiind mai degrab pregtii dect surprini, cu anse mai mari de a accepta un tratament agresiv.a randomised, doble-blind, placebo-controlled, withdrawal phase III trial. Abstr Lancet 2008, 371: 998-1006 Ruperto N, Lovell DJ, Quartier P etc for PRINTO and PRSCG, Abatacept in children with juvenile idiopathic arthritis: a randomised,double-blind, placebo-controlled withdrawal trial, Lancet.2008 Early Online Publication, 5 July 2008 Haines KA Juvenile idiopathic arthritis: therapies in 21st century. Abstr Bull NYU Hosp Jt Dis 2007, 65: 205-211 Bankhead C Biologic and combination top arthritis recommendations, http://www.medpagetoday.com/Rheumatology/ Arthritis/tb/10252

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ARTICOLE DE ORIENTARE

SINDROAMELE AUTOINFLAMATORIIMariana tefan, Andreea Ciau, Anca Sandu Spitalul Clinic de Urgen pentru Copii M. S. Curie, BucuretiRezumatSindroamele autoinflamatorii sunt reprezentate de un numr de boli ce apar secundar mutaiilor la nivelul unei gene care codific proteine cu rol esenial n reglarea rspunsului inflamator. Sunt caracterizate prin episoade inflamatorii aparent nedeclanate de o cauz cunoscut i fr a fi nsoite de un titru crescut de autoanticorpi sau limfocite T autoreactive. Aspectul clinic al sindroamelor autoinflamatorii este extrem de variabil fiind reprezentat de: episoade febrile recurente de durat variabil (febra periodic/recurent), manifestri cutanate (criopirinopatii), formaiuni granulomatoase non-cazeoase (afeciunile granulomatoase) i, rar, abcese piogene sterile (afeciunile piogenice). Lucrarea de fa i propune o scurt trecere n revist a acestor afeciuni. Cuvinte-cheie: Sindroame autoinflamatorii, inflamaie, criopirinopatie, granulom, abces steril.

Summary Autoinflammatory syndromesMonogenic autoinflammatory syndromes comprise disorders caused by mutations of different genes encoding for proteins that play a major role in the inflammatory response. They are characterized by seemingly unprovoked inflammatory episodes lacking high concentrations of autoantibodies or autoreactive T cells. The clinical spectrum of these syndromes are extremely variable and is represented by: recurrent fever episodes of variable duration (periodic/recurrent fever), skin lesions (cryopyrinopathies), noncaseating granulomas (granulomatous disorders) and, rarely, by sterile pyogen abscesses (pyogenic disorders). This paper represents a briefly presentation of these disorders. Key words: Autoinflammatory syndrome, inflammation, cryopyrinopathy, granuloma, sterile absecess.

INTRODUCERESindroamele autoinflamatorii sunt afeciuni ereditare caracterizate prin episoade inflamatorii aparent nedeclanate de o cauz cunoscut i fr a fi nsoite de un titru crescut de autoanticorpi sau de limfocite T autoreactive (1). Evaluarea pacienilor la care se suspecteaz un sindrom autoinflamator este dificil. Studiile recente sugereaz c testele genetice trebuie rezervate pacienilor al cror tablou clinic orienteaz diagnosticul ctre un sindrom specific autoinflamator. Un studiu european multicentric a nrolat 87 de pacieni diagnosticai clinic i anamnestic cu boal autoinflamatorie. Diagnosticul a fost confirmat genetic la 84 dintre acetia (2). Cercetarea cauzelor genetice a acestor sindroame este un domeniu care a progresat rapid n ultimii 10 ani, identificndu-se noi mutaii att n sindroamele autoinflamatorii tipice, ct i n cele atipice. n prezent nu exist ghiduri general acceptate pentru testarea genetic, iar indicaiile pentru efectuarea acestor teste se vor modifica pe msura descoperirii de noi informaii legate de aceste afeciuni.REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008

DEFINIIE I CLASIFICAREConceptul de boal autoinflamatorie a fost introdus iniial la sfritul anilor 80 i era folosit pentru a caracteriza sindroamele de febr periodic familial. n prezent acest termen reunete 9 entiti separate, ncadrate n patru grupe (3): Febra periodic/recurent care cuprinde: febra mediteranean familial (FMF), sindromul de hiperimunoglobulinemie (HIDS, hyperimmunoglobulinemia D syndrome) i sindromul periodic asociat cu receptorul factorului de necroz tumoral (TRAPS, TNF receptor associated periodic fever syndrome). Criopirinopatiile care cuprind: sindromul autoinflamator familial la rece (FCAS, familial cold autoinflamatory syndrome), sindromul MuckleWells (SMW) i sindromul infantil cronic neurologic, cutanat i articular (CINCA, chronic infantile neurological cutaneous and articular syndrome), care mai este cunoscut i sub denumirea de boala inflamatorie multisistemic cu debut neonaltal (NOMID, neonatal-onset multisystem inflammatory disease).141

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Afeciunile granulomatoase, n care este inclus sindromul Blau. Afeciunile piogenice care cuprind: sindromul periodic asociat cu artrita purulenta sterila, pyoderma gangrenosum i acnee (PAPA, pyogenic sterile arthritis, pyoderma gangrenosum and acnee) i sindromul Majeed.

FORME CLINICEFebra periodic/recurent reprezint un grup de sindroame a cror manifestare clinic dominant este febra recurent nsoit de alte semne i simptome de inflamaie sistemic. Simptomatologia apare sub form de atacuri, separate ntre ele de perioade asimptomatice, de durat variabil. De cele mai multe ori atacurile se remit spontan i nu exist o durat constant de timp pn la reapariia acestora, de aceea termenul de recurent pare a fi mai adecvat dect cel de periodic (4). Febra mediteraneean familial FMF este o afeciune ereditar cu transmitere autozomal-recesiv. Gena responsabil de apariia este situat pe cromozomul 16 i a fost denumit MEFV. MEFV codific o protein numit pirin sau marenotrin i este o gen care se gsete aproape exclusiv n celulele mieloide (5). Boala apare n special la cei care triesc n bazinul mediteranean, dar au fost descrise cazuri sporadice pretutindeni n lume. La dou treimi din pacieni manifestrile clinice se instaleaz sub vrsta de 5 ani. Febra este constant i este nsoit de serozite: peritonit (95%), sinovit (50%, mai ales la nivelul articulaiei genunchiului, oldului i gleznelor), pleurit (45%), inflamaia tunicii vaginale a scrotului (3%) i pericardit (1%) (6).

Manifestrile cutanate apar relativ frecvent i au un aspect erizipeloid. Vasculitele apar frecvent n FMF, aproximativ 3 - 11% din pacieni prezentnd purpur Henoch-Schonlein (6). De asemenea, mai ales la pacienii la care FMF are un debut precoce, a fost diagnosticat mai frecvent poliarterita nodoas. Au fost descrise diferite tipuri de glomerulonefrite, dar nu se cunoate nc dac acestea apar cu o frecven mai mare la pacienii cu FMF dect n populaia general. O manifestare clinic frecvent este reprezentat de hematuria microscopic tranzitorie. Mialgiile apar la aproximativ 10% din copiii cu FMF (2). Durerile sunt prezente mai ales la nivelul musculaturii membrelor inferioare, apar n special dup efort i cedeaz la medicaia antiinflamatoare nesteroidian (AINS). Artrita apare mai frecvent la articulaiile mari, este monoarticular, afecteaz n ordinea frecvenei articulaia gleznei, genunchilor sau oldului i n majoritatea cazurilor rspunde la AINS i se vindec fr sechele. Rareori, mai ales la articulaia oldului sau genunchiului artrita poate fi sever, determinnd leziuni destructive, ulterior fiind nevoie de artroplastie. n majoritatea cazurilor, n timpul unui atac este afectat un singur organ. Durata unui atac variaz de la cteva ore la 3-4 zile. Atacurile se remit spontan i se repet la intervale neregulate. Frecvena acestor atacuri este diferit pentru fiecare pacient i variaz cu vrsta. Manifestrile clinice pot s apar spontan sau pot s fie declanate de anumii triggers (infecii virale, stres emoional, medicamente, ca de exemplu cisplatina). Uneori, naintea unui atac pacienii pot prezenta sindrom prodromal: iritabilitate, vertij, creterea poftei de mncare. Criteriile de diagnostic pentru FMF, numite criteriile Israeli, sunt descrise n tabelul 1(6).

Tabelul 1. Criterii de diagnostic pentru febra mediteranean familial


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Pentru diagnosticul pozitiv de FMF sunt necesare: 1 criteriu major sau 2 criterii minore sau 1 criteriu minor plus 5 criterii de susinere sau 1 criteriu minor plus 4 din primele 5 criterii de susinere. Atacurile complete sunt definite ca recurente ( 3 de acelai fel), nsoite de febr (>38C), de durat scurt (ntre 12 ore i 3 zile). Din punct de vedere paraclinic, investigaiile de laborator, evideniaz leucocitoz i creterea reactanilor de faz acut (VSH, CRP, fibrinogen, i amiloidul seric A). Nivelurile de haptoglobin, C3, C4, pot fi de asemenea crescute. n formele netratate de FMF, n timp pot s apar proteinurie i alte semne de insuficien renal, secundar amiloidozei. La pacienii diagnosticai cu FMF examenul de urin trebuie efectuat anual pentru detectarea microalbuminuriei. Tratamentul FMF const n administrarea zilnic a colchicinei i are ca scop prevenirea recurenei atacurilor i prevenirea amiloidozei. Doza de colchicin este de 1 mg/zi. Uneori aceast doz poate fi crescut pn la 2,5 mg/zi. La copii doza este de 0,07mg/kg/zi sau 1,9mg/m2/zi. Majoritatea pacienilor care nu rspund la tratament sunt noncompliani. La cei la care ntr-adevr acest tratament

nu este eficace se poate ncerca tratamentul cu antagoniti ai receptorilor de IL-1 sau inhibitori de TNF. Sindromul de hiperimunoglobulinemie (HIDS) HIDS este o boal autozomal recesiv. Gena responsabil de apariia este situat pe cromozomul 12 i codific mevalonat kinaza (MVK), enzim implicat n metabolismul colesterolului. n HIDS clasic activitatea MVK este redus la 5-15% fa de normal, iar nivelul seric de colesterol este redus uor. Mai puin de 1% din pacieni prezint un deficit total al MVK, situaie calificat ca acidurie mevalonic. Aciduria mevalonic se caracterizeaz prin dismorfism, retard staturo-ponderal, retard mental, ataxie, deces n prima copilrie. Au fost descrii 5 pacieni aduli care asociau deficien de MVK i semne i simptome neurologice, sugernd existena unor sindroame suprapuse (6). Prin urmare, devine clar c aciduria mevalonic i HIDS reprezint cele dou extreme ale unui sindrom mai vast (5). HIDS are un debut precoce, n majoritatea cazurilor n prima decad de via, frecvent chiar n perioada de sugar. Exist trei variante ale HIDS sistematizate n tabelul 2.Tabelul 2. Clasificarea HIDS

Din punct de vedere clinic, HIDS se caracterizeaz prin episoade recurente de febra care se instaleaz brusc, sunt nsoite de frison, dureaz 37 zile si frecvent au o periodicitate de 4-8 sptmni. Aceste episoade sunt nsoite de urmtoarele tipuri de manifestri: digestive (dureri abdominale nsoite de vrsturi si diaree), cutanate reprezentate de rash care poate mbrca aspect nodular, urticarian, morbiliform sau chiar peteial (figura 1), adenopatii (predominant cervicale sau abdominale), artrit/ artralgie, dar fr modificri articulare n afara episodului acut, hepato/splenomegalie (rar). Intercritic, pacienii sunt asimptomatici.

Figura 1. Erupie peteial la nivelul gambei drepte n cazul unui pacient cu HIDS

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Biologic, n timpul atacurilor febrile, HIDS se caracterizeaz prin: reactani de faza acut intens pozitivi, leucocitoz, Ig D crescut, Ig A crescut, creterea concentraiei urinare a acidului mevalonic. TNF poate fi crescut la unii pacieni n timpul atacului febril, dei acesta nu reprezint cauza principal a bolii (7). Episoadele febrile din HIDS rspund extrem de bine la administrarea de prednison (1mg/zi, doz unic), dar datorit frecvenei crescute a episoadelor de febr din prima decad de via, unii pacieni ar necesita tratament aproape continuu. Exist studii care au evideniat o posibil eficacitate a inhibitorilor de HMG-CoA reductaz (statine). La unii pacieni tratamentul cu inhibitori de TNF sau antagoniti ai receptorilor de IL-1 s-a dovedit a avea succes n ceea ce privete reducerea frecvenei i intensitii atacurilor febrile. Totui acestea sunt raportri sporadice i va fi nevoie de confirmare prin studii multicentrice. Din punct de vedere al evoluiei la majoritatea pacienilor atacurile febrile devin din ce n ce mai rare odat cu naintarea n vrst. Dei pn n prezent s-a considerat c prognosticul pe termen lung este bun, pacienii nedezvoltnd amiloidoz, n anul 2004 Obici i colab au raportat primul caz de amiloidoz la un pacient cu HIDS (8). Sindromul periodic asociat cu receptorul TNF (TRAPS) TRAPS este o boal ereditar cu transmitere autozomal dominant. Acest sindrom a fost descris prima dat n anul 1982 i era cunoscut sub numele de febra hibernian familial. Gena responsabil de apariia este situat pe cromozomul 12 i codific proteina TNFRSF1A (TNF receptor superfamily 1A) (3). Vrsta medie de debut este de 3 ani, ns cel mai frecvent manifestrile clinice apar la vrsta colar. Atacurile dureaz ntre 5 zile i 3 sptmni. Mialgiile sunt prezente aproape ntotdeauna, afectnd o singur arie a corpului. Zonele n care exist afectare muscular sunt calde i sensibile la palpare. Dac musculatura afectat se afl periarticular, la nivelul articulaiei respective poate s apar sinovit. Frecvent atacurile febrile sunt anunate de contracturi musculare localizate, la majoritatea pacienilor aceste simptome fiind migratorii. Manifestrile cutanate prezente la 3/4 din pacieni includ o serie de rash-uri sensibile la atingere i presiune, care apar frecvent la nivelul

membrelor dar pot s apar i la nivelul toracelui. Cea mai caracteristic leziune o constituie plcile eritematoase dure, de dimensiuni diferite i cu margini neregulate care apar n ariile n care sunt afectai muchii. Alte manifestri frecvente includ durerile abdominale care uneori pot mima un abdomen acut chirurgical. De asemenea mai pot s apar conjunctivita, edemele periorbitale, durerile toracice de origine musculara, osoasa sau pleural (9). Paraclinic, n cursul unui atac de TRAPS reactanii de faz acut sunt crescui. Enzimele musculare sunt normale. Biopsia muscular evideniaz c durerile musculare sunt rezultatul unei fasciite cu infiltrat limfo-monocitar i nu a unei miozite. Biopsia cutanat (la nivelul plcilor eritematoase) arat prezena unui infiltrat limfomonocitar, fr a evidenia existena unui granulom sau a unei vasculite (6). Ca tratament, au fost ncercate AINS. Cu toate c acestea au efecte evidente asupra febrei, nu pot rezolva manifestrile musculare i/sau abdominale. Prednisonul n doz de 1 mg/kg/zi scade severitatea simptomelor, dar nu modific frecvena atacurilor. Etanerceptul i ali inhibitori de TNF s-au dovedit a avea succes la unii pacieni, scznd durata, severitatea i frecvena atacurilor. Exist ns unii pacieni cu TRAPS care nu rspund la acest tip de medicamente. De asemenea la unii pacieni a fost observat un rspuns favorabil dup tratamentul cu antagoniti ai receptorilor de IL-1. Evoluia i prognosticul bolii depind n mare parte de prezena amiloidozei, care apare la aproximativ 10-25% din pacienii afectai (5). Criopirinopatii sau indroame autoinflamatorii asociate CIAS-1 Sindroamele autoinflamatorii asociate CIAS-1 sunt trei afeciuni distincte cu transmitere autozomal dominant, determinate de mutaii la nivelul genei CIAS-1. n ordinea severitii sunt reprezentate de: boala inflamatorie multisistemic cu debut neonatal (NOMID/CINCA), sindromul Muckel-Wells i sindromul autoinflamator familial declanat la frig (FCAS). Gena CIAS-1, localizat pe cromozomul 1, codific o protein pirin-like, numit criopirin. Aceast protein este predominant prezent n monocite, neutrofile, dar i n condrocite. Criopirina interacioneaz cu o protein adaptor asociat apoptozei, iar acest complex determin creterea produciei de IL-1?. S-au descris 20 de mutaii la


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nivelul acestei gene, explicnd astfel spectrul larg de afeciuni produse de acestea. Primele semne clinice apar n copilrie, uneori chiar de la natere prin rash neonatal i cuprind: urticarie, febr recurent, artrit, mialgii, meningit cronic, conjunctivit, defecte vizuale progresive, surditate senzorial i uneori amiloidoz. Severitatea afeciunii este influenat numai parial de mutaiile CIAS-1; trebuie luai n considerare i ali factori genetici precum i factorii de mediu (7). Sindromul CINCA/NOMID este caracterizat de triada rash, meningit cronic aseptic i artropatie. Este o afeciune inflamatorie cronic cu debut nc de la natere i care dureaz toat viaa. Simptomele dominante sunt febra i rashul. Manifestrile cutanate sunt prezente n 75% dintre cazuri nc de la natere (urticarie migratorie nonpruriginoas) i sunt persistente (6). Pacienii prezint un aspect tipic cu macrocefalie, bose frontale, baza nasului largit, nchiderea tardiv a fontanelei anterioare. Afectarea sistemului nervos central include cefalee, convulsii, episoade tranzitorii de hemiplegie, spasticitate la nivelul membrelor inferioare secundare meningitei cronice aseptice, hipertensiune intracranian, atrofie cerebral, surditate neurosenzorial, edem papilar cronic asociat cu atrofie de nerv optic. La 50% dintre pacieni este prezent uveita anterioar cronic (3). S-au raportat cazuri de retard mental. Frecvent n timpul atacurilor apar adenopatia i hepatosplenomegalia. Disfonia este frecvent. Anomaliile musculoscheletice sunt reprezentate de deformarea exremitilor, a genunchilor, a metafizelor i epifizelor oaselor lungi. Radiologic, epifizele sunt lrgite, existnd zone de osificare neregulat cu aspect de miez de pine (6). Cartilajul de cretere este de asemenea afectat. S-au descris cazuri de amiloidoz secundar, consecin a inflamaiei cronice. Biologic, pacienii prezint anemie hipocrom, leucocitoz cu predominana granulocitelor, trombocitoz i reactani de faz acut pozitivi. Evoluia este nefavorabil, iar prognosticul pe termen lung este prost cu surditate progresiv, afectare ocular i agravarea manifestrilor neurologice la majoritatea pacienilor. AINS amelioreaz durerea. Glucocorticoizii reduc febra i durerea dar nu acioneaz asupra leziunilor cutanate, manifestrilor articulare i ale sistemului nervos central. Tentativele de utilizare a citotoxicelor au avut rezultate slabe. Recent s-au

obinut rezultate favorabile prin utilizarea anakinrei - antagonist al receptorului IL-1. Sindromul Muckle-Wells (urticarie, surditate, amiloidoz) Primele manifestri ale sindromului apar n copilrie i sunt reprezentate de: urticarie nonpruriginoas, subfebrilitate, artrit i conjunctivit. Pe parcursul adolescenei se instaleaz hipoacuzia neurosenzorial care evolueaz lent spre surditate. Alte manifestri sunt reprezentate de afte bucale i genitale, cistinurie, ihtioz, poliartralgii, hematurie microscopic, dureri abdominale recurente. Severitatea afeciunii const n dezvoltarea amiloidozei. Reactanii de faz acut sunt prezeni n episoadele febrile dar pot persista i n perioadele asimptomatice. Recent, la aceti pacieni s-a utilizat cu succes antagoniti ai receptorilor de IL-1 (anakinra). Nu se cunoate nc dac terapia cu anakinra este eficient n prevenirea apariiei amiloidozei. Sindromul autoinflamator familial la rece (FCAS) este caracterizat prin febr, rash i artralgii/ artrit declanate de expunerea la frig. Intervalul de la expunere pn la apariia simptomelor poate varia ntre 30 minute i 6 ore. Biologic, n timpul atacului apare leucocitoz. Evoluia este nefavorabil cu dezvoltarea amiloidozei sistemice (o cauz frecvent de deces o reprezint nefropatia amiloid). Pacienii trebuie s evite expunerea la frig i s cunoasc metode de nclzire. Terapia cu antiinflamatoare nesteroidiene, corticosteroizi n doze mari, colchicina a avut efecte variabile. Antihistaminicele nu sunt eficiente. Studii recente arat un rspuns favorabil la administrarea de steroizi anabolizani i antagoniti ai receptorilor de IL-1. Afeciunile granulomatoase Sindromul Blau (granulomatoza familial sistemic juvenil) Sindromul Blau este o afeciune inflamatorie cu transmitere autosomal dominant caracterizat prin granuloame inflamatorii non--cazeoase ce afecteaz articulaiile, pielea i tractul uveal (triada artrit, dermatit, uveit). Gena responsabil, NOD2/CARD15, este localizat la nivelul cromozomului 16 i codific o protein ce conine un domeniu NACHT. Gena

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aparine superfamiliei NOD (nucleotide oligomerization domain) like receptors - receptori intracelulari pentru peptidoglicanii bacterieni. Dup stimulare, gena induce activarea factorului nuclearkB i eliberarea formei active de IL-1. Mutaiile la nivelul NOD2/CARD15 duc la o intensificare a funciilor proteinei, susinndu-se astfel un status proinflamator. Debutul este de obicei n primii ani de via. Manifestarea clinic tipic este poliartrita simetric. Afectarea oftalmologic cuprinde uveit/panuveit, cataract, glaucom secundar. Dermatita este prezent la 90% dintre pacieni care prezint un rash tipic, ihtiosiform (3). Tratamentul const n corticoterapie oral, medicaie imunosupresoare (metotrexat, cyclosporina A), posibil inhibitori ai TNF i ali anticorpi monoclonali, ns cu rezultate variabile. Studii recente sugereaz efecte benefice n urma terapiei cu anti-TNF i anti IL-1. Afeciunile piogenice Sindromul PAPA este o afeciune caracterizat prin atacuri recurente de febr, artrit, mialgii i leziuni cutanate variate. Intervalul dintre atacuri este de 3-6 sptmni. Sindromul este rezultatul mutaiilor la nivelul genei ce codific CD2 binding protein 1/PSTPIP1 localizat pe cromozomului 15q24. La nivelul PSTPIP1 se leag pirina. Se pare c mutaiile PAPA duc la o intensificare a legrii pirinei la acest nivel cu alterarea susceptibilitii inflamatorii (5). Manifestrile clinice cele mai frecvente sunt gangrena piogenic, acneea chistic i artrita piogenic steril. Artrita are debut la varst mic, este pauciarticular, afecteaz concomitent 1-3 articulaii i se caracterizeaz prin episoade inflamatorii recurente similare artritei septice cu acumulare de material bogat n neutrofile, ducnd la distrugerea important a cartilajului i sinovialei. Manifestrile cutanate sunt episodice, recurente, cu debut n a doua decad a vieii i constau n leziuni ulcerate, agresive, mutilante, localizate de obicei la nivelul extremitilor inferioare, ce nu pot fi difereniate de gangrena piogenic. Se pot observa abcese sterile la locul injeciilor. Culturile din articulaii i de la nivelul pielii sunt sterile. Sindromul PAPA rspunde de obicei la terapia cu glucocorticoizi orali. Studii recente au artat c terapia cu anti-TNF i anti-IL-1 a indus obinerea

unei remisiuni susinute n cazul pacienilor corticorezisteni precum i ameliorarea semnificativ a leziunilor cutanate. Sindromul Majeed este o afeciune ereditar cu transmitere autozomal recesiv. Gena responsabil pentru apariia acestui sindrom este situat pe braul scurt al cromozomului 18. Prima dat sindromul a fost descris la 2 frai de sex masculin i la o verioar a acestora ntr-o familie de origine arab n care exista consangvinitate. Acest sindrom asociaz osteomielit cronic recurent multifocal (CRMO, chronic recurrent multifocal osteomyelitis) anemie diseritropoietic congenital i dermatoz inflamatorie. Manifestrile osoase debuteaz la vrst mic, apar n episoade mai frecvente dect n CRMO izolat i au o durat mai mic i o frecven mai redus a remisiunilor (3). Datorit anemiei diseritropoietice aceti pacieni necesit frecvent transfuzii de snge. Dermatoza inflamatorie poate avea diferite grade i variaz de la sindrom Sweet (dermatoz neutrofilic) pn la pustuloz cronic. De asemenea pacienii prezint episoade recurente de febr, hepatoslenomegalie, retard de cretere. Din punct de vedere bacteriologic, culturile sunt sterile. AINS pot s amelioreze simptomatologia pacienilor, dar steroizii previn rapid recderile. Manifestrile hematologice pot s fie controlate prin splenectomie. La cel de-al patrulea congres internaional privind bolile autoinflamatorii din noiembrie 2005 au fost sugerate i alte afeciuni care ar putea fi ncadrate ca sindroame autoinflamatorii. Printre acestea se numr boala Behet i sindromul de febr periodic asociat adenopatiilor, faringitei i stomatitei aftoase (PFAPA, periodic fever adenopathy pharingitis and aphtous stomatitis) (1) Boala Behcet este o boal rar, multisistemic, de cauz necunoscut. Debutul este n a doua decad de via i afecteaz predominant sexul masculin. Pentru diagnosticul acestei boli este necesar prezena episoadelor recurente (>3/an) de ulceraii la nivelul mucoasei bucale i cel puin dou din urmtoarele: ulceraii recurente genitale, manifestri oculare (uveit anterioar, posterioar, vasculit retinian), manifestri cutanate (tip eritem nodos, foliculit, acnee) i testul de patergie pozitiv (apariia de pustule sterile la locul unui traumatism


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minor). Boala Behet prezint similitudini cu sindroamele autoinflamatorii descrise mai sus, ca de exemplu natura recurent i implicarea granulocitelor n patogenez. Diferenele constau n faptul c nu este o boal monogenic, se asociaz cu sistemul HLA i deseori necesit tratament imunosupresor.

PFAPAAcest sindrom include copiii care prezint episoade recurente de febr similare cu cele din sindroamele febrile monogenice, dar care nu sunt asociate cu mutaii cunoscute ale genelor. Sindromul PFAPA nu prezint o asociere familial i de cele mai multe ori dispare la adolescen. A fost descris pentru prima dat de ctre Marshall et al n anul 1987. De obicei debuteaz sub vrsta de 5 ani i este caracterizat de episoade de febr i frison cu debut brusc i durat de pn la o sptmn. Deseori aceste episoade se repet la un interval de 2-6 sptmni, dar cauza acestei periodiciti nu este cunoscut De obicei, n timpul unei acutizri starea general nu este afectat, ceea ce deosebete sindromul PFAPA de sindroamele autoinflamatorii monogenice. n majoritatea cazurilor, n timpul fazei acute, pacienii prezint adenopatii predominant cervicale, care dispar intercritic. De asemenea episoadele febrile se

nsoesc de faringit/faringoamigdalit i afte la nivelul mucoasei bucale. Pacienii mai pot prezenta manifestri digestive (dureri abdominale, grea, diaree) artrit/artralgii, cefalee, manifestri cutanate (rash). Investigaiile de laborator pun n eviden leucocitoza i creterea reactanilor d faz acut. Episoadele febrile scad n frecven i n intensitate sub tratament cu steroizi per os. Ca metod de tratament a fost propus amigdalectomia, dar ulterior s-a constat c la un sfert din cei care au suferit aceast intervenie atacurile febrile au continuat. Din aceast cauz, la cei diagnosticai cu sindrom PFAPA aceast intervenie nu mai este recomandat.

CONCLUZIISindromul autoinflamator reprezint o entitate relativ nou, luat mai puin n considerare n diagnosticul diferenial al febrei recurente i trebuie avut n vedere la copilul la care s-a exclus o boal malign sau infecioas. Pacienii diagnosticai cu sindrom autoinflamator ereditar trebuie s beneficieze de consult i consiliere genetic. Progresele majore n ceea ce privete clarificarea etiopatogenezei acestor afeciuni i au condus la intervenia terapeutic intit la nivelul cascadei imune (administrarea anti-TNF, anatagoniti ai receptorilor IL-1) (4).

BIBLIOGRAFIE1. 2. Ozen S, Hoffman HM, Kastner J etc Familial mediteranean fever (FMF) and beyond: a new horizon, Ann Rheum Dis 2006, 65: 961-964 Ryan JG, Goldbach-Mansky S The spectrum of autoinflammatory diseases: recent bench to bedside observations, Curr Opinn Rheumatol 2008, 20: 66-75 Gattorno M, Stankovic K, Pelagatti MA etc Eular on-line course on rheumatic diseases - module n26 2007-2008 Tsz-leung L Clinical evaluation of a patient with familial periodic fever syndrome, The Hong-Kong medical diary 2007, 12: 26-27 Grateau G Clinical and genetic aspects of the hereditary periodic fever syndromes, Rheumatology 2004, 43: 410-415 6. 7. Padeh S Periodic fever syndromes, Pediatr Clin N Am 2005, 52: 577-609 Simon A, van der Meer JWM Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes, Am J Physiol Regulatory Integrative Comp Physiol 2007, 292: 86-98 Obici L, Manno C, Muda AO etc First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome, Arthritis Rheum 2004, 50: 2966 - 2969 Drenth JPH, van der Meer JWM Hereditary periodic fever, N Engl J Med 2001, 345:1748-1757

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ASSOCIATION BETWEEN DURATION OF SYMPTOMS AND SEVERITY OF DISEASE AT FIRST PRESENTATION TO PAEDIATRIC RHEUMATOLOGY: RESULTS FROM THE CHILDHOOD ARTHRITIS PROSPECTIVE STUDYN. Adib1,*, K. Hyrich1,*, J. Thornton1, M. Lunt1, J. Davidson2, J. Gardner-Medwin2, H. Foster3, E. Baildam4, L. Wedderburn5 and W. Thomson1 1Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, 2Department of Child Health, Royal Hospital for Sick Children, Glasgow, 3Department of Rheumatology, Medical School, Newcastle upon Tyne, 4Department of Rheumatology, Royal Liverpool Childrens Hospital, Alder Hey, Liverpool and 5Rheumatology Unit, Institute of Child Health, London, UK. Submitted 13 September 2007; revised version accepted 4 February 2008. *N Adib and K Hyrich equally contributed to this work.

AbstractObjectives. To study the association between disease severity at first presentation to paediatric rheumatology (PRh) and length of time since symptom onset in children recruited to the Childhood Arthritis Prospective Study. Methods. Children 16 yrs with inflammatory arthritis persisting 2 weeks were recruited from five UK hospitals. Data including demographics, disease features, Childhood Health Assessment Questionnaire (CHAQ), physician and parent global assessment and blood tests were collected at the first appointment with PRh (baseline). The association between symptom duration (defined as time from first reported symptom onset to presentation at PRh) and baseline disease characteristics was evaluated using nonparametric descriptive statistics and multivariable logistic regression analyses. Results. Five hundred and seven children (65% female) were included: median age at onset was 6.8 yrs. Two hundred and thirtythree had oligoarthritis, 68 had RF-negative polyarthritis, 27 had systemic onset arthritis and 29 had arthritis that was not JIA. The median symptom duration was 4.6 months. Median symptom duration was shortest for children presenting with systemic arthritis (1.6 months) and longest for those with PsA (8.6 months). Children with a longer duration of symptoms were older and had higher median active joint counts but lower median ESR. Symptom duration did not correlate with CHAQ score at presentation. Conclusions. Children who have systemic arthritis had the shortest delay to PRh presumably because they are profoundly unwell. Children with joint pain/stiffness but normal ESR had longer delays suggesting that if blood tests do not indicate inflammation, the diagnosis of JIA may be overlooked. KEY WORDS: Inflammatory arthritis, Juvenile idiopathic arthritis, Presenting symptoms, Symptom duration, Outcome, Paediatric rheumatology.

INTRODUCTIONEach year ~10/100 000 children develop inflammatory arthritis [1] with many subsequently being diagnosed as juvenile idiopathic arthritis (JIA). Many children continue to have some disability and limitation of their activities of daily living and ~5070% are estimated to have active disease into adulthood [2]. In adults with RA, guidelines from both ACR [3] and the British Society for Rheumatology [4] emphasize the need for early diagnosis and treatment to reduce subsequent functional disability. Early disease-modifying drug148

intervention slows the progression of structural joint damage and improves long-term outcomes as well as overall quality of life [5]. The inherent problem is the long lag time between onset of disease and referral to rheumatologist for treatment with the length of time required to make the diagnosis being the major contributor to this delay. Arthritis in children is a different condition from adult inflammatory arthritis and one cannot directly extrapolate data from adult disease to that of JIA. However, it is recognized that arthritis in children should also be treated early and aggressively to prevent significant structural damage and that clinicians should not assume that JIA is a selfREVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008


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limiting condition that will remit as the child grows [2]. Prompt diagnosis and referral to experienced care, ideally a paediatric rheumatology (PRh) multidisciplinary team, are essential and the UK Arthritis and Musculoskeletal Alliance (ARMA) recommend in their Standards of Care for People with Inflammatory Arthritis (http://www.arma.uk. net/pdfs/ia. pdf) that children with inflammatory arthritis should be assessed by a specialist in rheumatology within 4 weeks of GP referral. However, there remain few data on the factors associated with delay to PRh care and the effects of this delay on both short- and long-term outcomes. The aim of this initial study was to assess whether there was an association between demographic and disease characteristics at first presentation to a paediatric rheumatologist and the length of time since first symptom onset.

The initial invitation was made by the paediatric rheumatologist and followed-up by the research nurse after the parent had had time to read the study information sheet. CAPS was approved by the UK multicentre research ethics committee. Written informed consent was obtained from the parent(s)/ guardian for all participant children according to the Declaration of Helsinki [6], and children, if considered able, were asked to provide assent. Baseline data collection Data for this study is collected from the PRh and the parent/child. All children undergo a rheumatological exam at their first appointment with the PRh (baseline). All children have an active and limited joint count recorded as well as a physician global assessment. At the first visit, the PRh is asked to assign a best guess ILAR classification, if the child is felt to have JIA [79] or to indicate Other inflammatory arthritis where appropriate. For this analysis, the ILAR classification is assigned at baseline (and for many children within the first weeks of disease) so can only be regarded as a predicted subtype. In addition, the childrens clinical case notes are reviewed by a study research nurse using standard data collection forms. Here, other disease features relating to inclusion and exclusion criteria for ILAR classification, as recorded in the clinical case notes, are collected and include systemic rash, fever, lymphadenopathy, serositis, psoriasis, nail pitting, dactylitis, enthesitis, sacroiliitis and uveitis. Finally, the results from any laboratory investigations, if performed, are recorded from the clinical case notes and include, where undertaken, a full blood count, ESR and CRP, RF, ANA and HLA-B27. The parent or, where appropriate, the child completes a Childhood Health Assessment Questionnaire (CHAQ) [10] including a parent general evaluation and pain visual analogue scale (VAS). Within 3 months of this PRh appointment, children and their parents are interviewed by the specialist rheumatology research nurse using a standard proforma and questionnaires either in the clinic or at home. Data collected includes demographic details, birth and health history as well as family history. The parent/child is asked to recall the date of first symptom onset related to the childs arthritis. If an exact date is not known, the month and year of symptom onset is recorded and the date et to the first of the month.

PATIENTS AND METHODSPatient selection Children in this study were participants in the Childhood Arthritis Prospective Study (CAPS), an ongoing prospective longitudinal inception cohort study which aims to follow children presenting with new onset inflammatory arthritis for a minimum of 5 yrs. The overall aim of this study is to identify genetic and environmental predictors of short- and long-term outcomes of inflammatory arthritis (including response to treatment) in children and to identify the relative contributions of sociodemographic, clinical, psychological, laboratory and genetic factors and treatment in explaining outcome. The study was launched in September 2001 and aims to recruit 1100 children from five tertiary referral centres in England and Scotland: Royal Liverpool Childrens Hospital, Liverpool; Booth Hall Childrens Hospital, Manchester; Royal Victoria Infirmary, Newcastle; Royal Hospital for Sick Children, Glasgow; and Great Ormond Street Hospital, London. All children aged 16 yrs either presenting to the PRh outpatient clinic or admitted as inpatients, with newly diagnosed inflammatory arthritis in one or more joints, which had persisted, according to parent/child history for at least 2 weeks, are invited to participate. Exclusion criteria are septic arthritis, haemarthrosis, arthritis caused by malignancy or trauma, connective tissue disorders such as SLE, MCTD or dermatomyositis.

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Analysis This preliminary cross-sectional analysis focuses on the disease characteristics at presentation to PRh and their association with time since first symptom onset. The total symptom duration was calculated using the date of first reported onset of musculoskeletal symptoms and the date of the first paediatric rheumatologist visit. To further study the length of symptom duration in more detail, the time was divided into two components: symptom onset up to referral to PRh and the time between referral and PRh appointment date. This was subsequently analysed according to the source of the referral. Presenting characteristics and median symptom duration are given for the group as a whole and for each ILAR subtype, where assigned. The total symptom duration was subsequently categorized as a dichotomous variable (short and long symptom duration) approximated to the cohort median and differences between the two groups were compared using Wilcoxan rank sum statistics for continuous variables and Pearsons chi-squared test for proportional variables. A multivariable logistic regression model was developed to assess the independent association of presenting characteristics with long symptom duration. The resulting odds ratio (OR) is a measure of the probability of having a symptom duration greater than the cohort median. All analyses were undertaken using STATA version 9.2 (StataCorp, 4905 Lakeway Drive, College Station, TX 77845, USA).

including 17 children with reactive arthritis and 2 children with Downs syndrome-associated arthritis. In 51 children (10%), no specific diagnosis had been assigned and further investigations were awaited. For all children, the median number of joints with active inflammation or limited range of movement were 1 [Interquartile range (IQR) 1, 4] and 1 (IQR 0, 3), respectively (Table 2). The median CHAQ score was 0.63 (IQR 0.13, 1.38). When the analysis was limited to those children who had been assigned a JIA subtype, CHAQ scores were higher in those with polyarthritis (RF-positive and negative) and systemic arthritis compared with the other subtypes. Children presenting with systemic JIA had the highest median ESR (93 mm/h; IQR 60, 109) and CRP (98 mg/l; IQR 36, 246). Symptom duration The median symptom duration at the first presentation to PRh was 4.6 months (IQR 2.3, 9.5) (Table 1). However, 108 (21%) children had had symptoms longer than 1 yr. The shortest symptom duration was seen in those children presenting with systemic JIA (median 1.6 months; IQR 0.9, 5.6) and the longest in those presenting with PsA (median 8.6 months; IQR 3.2, 29.3) (Table 2). The total symptom duration differed depending on the source of the referral to PRh (Table 3), although the number of physicians seen by the children prior to this referral was not known. Most children (155; 37%), were referred from a general paediatrician with a lesser proportion being referred via their GP, orthopaedic, Accident and Emergency or another medical specialist. The promptest referrals came via the Accident and Emergency Department. The total symptom duration was longest (median 7.8 months; IQR 4.6, 16.8) when children were referred from other medical specialists, for example, plastic surgery, neurology, ophthalmology, otolaryngology or adult rheumatologists. Once referred, 295 (62%) children were seen by a paediatric rheumatologist within 4 weeks. For 17 children, the source of the referral was missing. However, the median duration of symptoms in this group (3.8 months; IQR 2.6, 7.5) was similar to that seen among those children where the source was known.

RESULTSCharacteristics at presentation to PRh Up to 20 December 2006, a total of 507 children with inflammatory arthritis were recruited to CAPS and included in this analysis. The median age at symptom onset was 6.8 yrs and the median age at first presentation was 7.8 yrs, 65% were female and 92% were Caucasian (Table 1). At presentation, 427 (84%) were assigned a JIA ILAR subtype: 233 (46%) children were classified as having oligoarthritis (children were not yet assigned to either persistent or extended oligoarthritis classifications), 68 (13%) had RF-negative polyarthritis and 27 (5.3%) had systemic onset arthritis (Table 1). Twenty-nine children (5.7%) were classified as having inflammatory arthritis other than JIA,


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TABLE 1. Demographics and disease characteristics of children with inflammatory arthritis at first appointment with paediatric rheumatologist

TABLE 2. Source of referral to first PRh appointment and total symptom duration in months prior to first assessment by PRh: median (IQR)

TABLE 3. Association between baseline disease characteristicsa and symptom duration at first PRh assessment

Total duration of symptoms and presenting disease characteristics As the median symptom duration was 4.6 months, the characteristics associated with symptoms of 4 and >4 months were examined (Table 3). Additional analysis of those children with >6 and >12 months was also performed. For the cohort as a whole, a total of 279 children (55%)

had symptoms >4 months. Those with longer symptoms had higher active and limited joint counts but lower ESR and CRP compared with children with symptoms 4 months. Overall, 35% of the cohort had a normal ESR (defined as 10 mm/h) at first presentation to a paediatric rheumatologist. However, only 22% of children with shorter symptom duration (4 months) had a normal ESR

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REVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008TABLE 4. Association between baseline disease characteristicsa and symptoms duration at first PRh assessment (oligoarthritis only)

at presentation compared with 46% of children with longer symptoms at first presentation (P < 0.001). There was no difference in the predominance for either upper limb or lower limb joint involvement between those with shorter or longer total symptom duration (data not shown). There was a trend towards those children with a longer symptom duration being older at symptom onset (7.3 vs 6.5 yrs) although this did not reach statistical significance. There were no significant differences in CHAQ, physicians global assessment, parents general evaluation and pain scores between the two groups. Very few children had a diagnosis of uveitis at first presentation (7 with acute uveitis and 10 with chronic uveitis), which did not differ between those with longer and shorter symptom duration. It was not known as to how many children had been referred to an ophthalmologist prior to the first PRh consultation, but only three children had been referred directly from an ophthalmologist to PRh. Using a multivariable logistic regression model, only ESR remained an independent factor associated with total symptom duration. In those children with a normal ESR at presentation, the odds of a total symptom duration >4 months between symptom onset and first appointment with PRh was 3.32 (95% CI 1.93, 5.69). As some of these findings could be explained by the very short symptom duration in those children presenting with systemic JIA, a further analysis limited to those children assigned to the JIA subtype oligoarthritis, the largest ILAR subtype, was undertaken (Table 4). Again, longer total symptom duration was associated with a lower ESR at presentation (10 vs 25 mm/h; P < 0.001). Those children with longer symptoms were also older at

symptom onset (6.1 vs 4.3 yrs; P = 0.03) but had a lower median CHAQ score at presentation (0.50 vs 0.75; P = 0.04). There was also a trend towards lower pain scores in patients with longer symptom duration at first presentation, although this did not reach statistical significance. Using a multivariable logistic regression model, the strong association between a normal ESR and longer symptom duration at presentation remained (OR 2.71; 95% CI 1.24, 5.92). In addition, the odds of longer symptom duration increased by 9% for each increasing year of age at symptom onset (OR 1.09; 95% CI 1.00, 1.19). CHAQ score was not independently associated with a longer total symptom duration (OR 0.77; 95% CI 0.45, 1.31).

DISCUSSIONThe results of this study demonstrate that many children have had a long duration of symptoms prior to first assessment by a paediatric rheumatologist, with a median total duration of 4.6 months. For >20% of children, this duration was >1 yr. An interesting association between normal ESR at presentation and longer duration of symptoms at first presentation might suggest that a diagnosis of inflammatory arthritis may not be considered in the setting of normal inflammatory markers, thus delaying a referral to specialist PRh care. The symptom duration was shortest in those presenting with systemic JIA, presumably because these children are typically very unwell with high inflammatory markers. The longest symptom duration was seen among children with PsA. Although it is difficult to draw any firm conclusions from this observation, the possibility exists that if


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children are undergoing treatment for psoriasis, joint complaints may be initially overlooked. An audit of the delay in diagnosis of inflammatory arthritis in 42 children who presented over a 12-month period in Western Australia found similar patterns to our study. The mean delay was 39.9 weeks (range 1208 weeks) [11]. As in CAPS, Manners [11] noted that the delay to diagnosis was significantly decreased if ESR at presentation was high and the child had signs of active inflammation. They found that the factors that did not affect delay included subtype of inflammatory arthritis, the discipline of referring practitioner, age at disease onset, presence of ANA, HLA-B27, RF, visible swelling of joints, involvement of any particular joint, number of joints and place of residence (rural vs urban). One limitation of this study was the accuracy with which the date of symptom onset was recorded. It has been shown that the ability of adults to recall the date of symptom onset becomes less reliable with time since symptom onset [12], and therefore, is likely to be most accurate for those with a very short duration. In addition, for younger children, the date of symptom onset was provided by the parent, who may have had difficulty in assigning an accurate date. This may have affected our estimated median symptom duration, although most likely this would have affected the extremes of the estimates, for which the median would be least affected. Our study is also limited by the lack of details regarding the features present in the child when the disease first manifested, and therefore, those presenting symptoms recorded in the CAPS database may not necessarily be an accurate reflection of how ill the child was in the early days/ weeks of the disease. It is therefore possible that certain characteristics, such as ESR, may have been affected by interventions or therapies received before rheumatology care, particularly if these children with a longer symptom duration had received care by other medical specialists first. However, this is unlikely to be the case for such a large proportion of the cohort. For many of these children, they may have been symptomatic for a significant length of time even before the parent sought primary care. Delay in presenting to medical care after onset of symptoms may arise because onset can be insidious and signs and symptoms can be non-specific and parents may be unaware of the severity of the problem. Other factors, such as socio-

economic status, may also influence this delay and could be analysed in further studies. Delays in referral to PRh may also occur after the child enters medical care. Three published case reports describe children in which diagnosis of inflammatory arthritis was delayed because of nonrecognition of early symptoms by parents and physicians [11]. UK trainees in paediatrics and primary care have reported low self-confidence in their ability to assess a childs musculoskeletal system and poor documentation of musculoskeletal assessment possibly as a result of inadequate training in rheumatology [13]. Based on the adult Gait, Arms, Legs, Spine screen, a musculoskeletal screening examination for children (pGALS) has now been developed, which could be used to improve paediatric clinical rheumatology skills [14]. Therefore, the delay will consist in both the parent and child recognizing the illness, and subsequently, the appropriate referral being made. A Brazilian study found that a mean of 3.6 physicians (range 120) were consulted between onset of symptoms and first consultation with paediatric rheumatologist, with a time interval ranging from a few days to 10 yrs (mean 1.4) [15]. More recently, a UK study also found that children with JIA had been referred to a median of 3 (05) medical specialists prior to consultation with PRh. Despite this, most children had untreated active disease at presentation and no childhad been referred for an ophthamological assessment [16]. In our study, the longest delay occurred in those children who were referred from routes other than general or musculoskeletal care. Once referral was made, however, most children were seen within 4 weeks, according to ARMA standards. Overall, we found that those children with the most severe disease presented earlier and as a result, we could not demonstrate a significant detrimental effect of prolonged symptom duration prior to the first PRh visit. It is possible that those children with the longest symptom duration had received at least some appropriate treatment elsewhere. However, all children still had some evidence of active disease at the time of this first consultation, suggesting that any prior treatment had not been definitive. What this study has not yet shown is whether or not this delay in reaching a paediatric rheumatologist will have longterm detrimental effects. When 683 Italian children with JIA were followed for 10 yrs, the probability of

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attaining remission decreased in proportion to delay in entering tertiary care [17]. Children referred within 1 yr from disease onset had a statistically significant higher remission rate than children referred 15 yrs or >5 yrs of onset (35.7, 32.4, 22.8, respectively, P = 0.0124). Further follow-up of our cohort will address this issue in the future. In conclusion, this analysis has demonstrated that many children subsequently diagnosed with inflammatory arthritis have a significantly long period of symptoms prior to referral to specialist care. Children with distinct signs and symptoms were referred more quickly, particularly in the setting of raised inflammatory markers. This is of concern as institution of appropriate medical therapies and referral for ophthamological assessment may therefore be delayed, possibly resulting in poorer long-term outcomes such as irreversible joint deformity and subsequent functional loss. Increased public awareness of this condition as well as improvements to musculoskeletal training for physicians may reduce the time taken to initial contact by patients with the medical system as well as expedite appropriate referrals. The strength of CAPS lies in its design. As a prospective inception cohort of children presenting with inflammatory arthritis toPRh, the influence of this delay to presentation as well as other diseaseand treatmentREFERENCES1. Symmons DP, Jones M, Osborne J, Sills J, Southwood TR, Woo P. Pediatric rheumatology in the United Kingdom: data from the British Pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 1996;23:197580. Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. J Am Med Assoc 2005;294:167184. Kwoh CK, Anderson LG, Greene JM et al. Guidelines for the management of rheumatoid arthritis: 2002 update American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum 2002;46:32846. Luqmani R, Hennell S, Estrach C et al. British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the Management of Rheumatoid Arthritis (The first 2 years). Rheumatology 2006;45:11679. Combe B, Landewe R, Lukas C et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:3445. Vollmann J, Winau R. Informed consent in human experimentation before the Nuremberg code. Br Med J 1996;313:14459. Fink CW. Proposal for the development of classification criteria for idiopathic arthritides of childhood. J Rheumatol 1995;22:15669. Petty RE, Southwood TR, Baum J et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 1998;25:19914. Petty RE, Southwood TR, Manners P et al. International League of Associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:3902.

Rheumatology key messages

Many children with inflammatory arthritis have a significantly long period of symptoms prior to referral to rheumatology. Normal blood tests, including ESR, do not preclude the diagnosis of inflammatory arthritis.

related factors on outcome can be fully assessed. Recruitment and follow-up of children to CAPS continues.

ACKNOWLEDGEMENTSThe authors would like to thank the CAPS specialist rheumatology nurses (Carol Lydon, Sharon Bradshaw, Joanne Buckley, Julie Jones, Alexandra Meijer, Vicki Price and Mick Eltringham) who collected the data, Peter Ward for coordinating the study, Mark Lay for running the database and Prof. Alan Silman, Medical Director of the ARC for his help in establishing the study. Funding: CAPS is funded by the Arthritis Research Campaign (ARC): ARC grant reference no: 17552. Disclosure statement: The authors have declared no conflicts of interest.

2. 3.

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7. 8.

9.

10. Nugent J, Ruperto N, Grainger J et al. The British version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ). Clin Exp Rheumatol 2001;19:S1637. 11. Manners PJ. Delay in diagnosing juvenile arthritis. Med J Aust 1999;171:3679. 12. Mjadi-Begvand S, Khanna D, Park GS, Bulpitt KJ, Wong WK, Paulus HE. Dating the window of therapeutic opportunity in early rheumatoid arthritis: accuracy of patient recall of arthritis symptom onset. J Rheumatol 2004;31:168692. 13. Myers A, McDonagh JE, Gupta K et al. More cries from the joints: assessment of the musculoskeletal system is poorly documented in routine paediatric clerking. Rheumatology 2004;43:10459. 14. Foster HE, Kay LJ, Friswell M, Coady D, Myers A. Musculoskeletal screening examination (pGALS) for school-age children based on the adult GALS screen. Arthritis Rheum 2006;55:70916. 15. Len CA, Terreri MT, Puccini RF et al. Development of a tool for early referral of children and adolescents with signs and symptoms suggestive of chronic arthropathy to pediatric rheumatology centers. Arthritis Rheum 2006;55:3737. 16. Foster HE, Eltringham MS, Kay LJ, Friswell M, Abinun M, Myers A. Delay in access to appropriate care for children presenting with musculoskeletal symptoms and ultimately diagnosed with juvenile idiopathic arthritis. Arthritis Rheum 2007; 57:9217. 17. Fantini F, Gerloni V, Gattinara M, Cimaz R, Arnoldi C, Lupi E. Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup. J Rheumatol 2003;30:57984. (Articol publicat n parteneriat cu Rheumatology 2008;47:991995)

LUCRRI ORIGINALE

COSTING JUVENILE IDIOPATHIC ARTHRITIS: EXAMINING PATIENT-BASED COSTS DURING THE FIRST YEAR AFTER DIAGNOSISJ. Thornton1, M. Lunt1, D. M. Ashcroft2, E. Baildam3, H. Foster4, J. Davidson5, J. Gardner-Medwin6, M. W. Beresford7, D. Symmons1, W. Thomson1 and R. A. Elliott8 1Arthritis Research Campaign Epidemiology Unit, Division of Epidemiology and Health Sciences, 2School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, 3Royal Liverpool Childrens Hospital, Department of Rheumatology, Liverpool, 4Department of Rheumatology, Medical School, Newcastle upon Tyne, 5Department of Rheumatology, Royal Hospital for Sick Children, 6Department of Child Health, Royal Hospital for Sick Children, Glasgow, 7University of Liverpool and Royal Liverpool Childrens Hospital, Department of Rheumatology, Liverpool and 8Division of Social Research in Medicines and Health, School of Pharmacy, University of Nottingham, Nottingham, UK.AbstractObjectives. There are few data on the treatment patterns and associated cost of treating children with inflammatory arthritis including juvenile idiopathic arthritis (JIA), in the short or long term. The aim of this study was to obtain patient-based costs for treating children with JIA in the UK, in the first year from diagnosis and from the secondary health care payer perspective. Methods. The Childhood Arthritis Prospective Study (CAPS) is an ongoing longitudinal study recruiting children with inflammatory arthritis from four UK hospital centres. Included children are newly diagnosed, 16 years old with inflammatory arthritis of one or more joints, which has persisted for at least 2 weeks. Health service resource use data were collected as part of routine clinical care at study entry, 6 months and 1 year. Reference unit costs were applied to these data and the cost of treatment per child calculated for the first year from diagnosis. Results. A total of 297 children attended a 12-month follow-up visit. The mean annual total cost per child was 1649 (S.D. 1093, range 4016967). The highest cost component was for appointments with paediatric rheumatologists. Mean total costs were highest for children with enthesitis-related, systemic JIA or extended oligoarthritis. Conclusions. In the first 12 months after diagnosis, children with all JIA disease subtypes consume large, but highly variable quantities of health service resources. Individual patient costs are required to reflect the wide variation in cost between patients and allow appropriate recouping of costs for contracted services and for assessing the economic impact of interventions. KEY WORDS: Inflammatory arthritis, Juvenile idiopathic arthritis, Economics, Costing study.

INTRODUCTIONJuvenile idiopathic arthritis (JIA) is a debilitating chronic disease in children. Early, intensive, multidisciplinary management is needed to reduce joint and other damage from the disease and achieve the best outcomes for these children [1]. Chronic treatment into adulthood is often necessary, placing a long-term economic burden on health care providers. However, many bodies with purchasing responsibility have limited knowledge of the costs of treating such patients. Recent pharmaceutical advances, such as anti-TNF therapy, may be useful for improving the health of these children but are associated with increased costs [2]. Individual patient cost data are required to assess the economic impact of these interventions. There are few data on the cost of treating children with JIA. SevenREVISTA ROMN DE REUMATOLOGIE VOL. XVII NR. 3 - 2008

studies have reported costs of management and suggest a substantial economic impact but do not provide sufficient data to describe the long-term resource use requirements of children with the different subtypes of JIA [28]. Therefore, the aim of this study was to obtain accurate patientbased costs for the cost of treating children with JIA in the UK, in the first year after diagnosis.

PATIENTS AND METHODSThe patients The Childhood Arthritis Prospective Study (CAPS) is an ongoing UK longitudinal study conducted by the Arthritis Research Campaign (ARC) Epidemiology Unit, the University of Manchester. The aim of CAPS is to identify predictors of outcome, both short- and long-term,155

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following presentation with childhood-onset inflammatory arthritis and to identify the relative contributions of socio-demographic, clinical, psychological, laboratory and genetic factors in explaining outcome. In total, children are recruited from five paediatric rheumatology centres; this analysis used data from four centres (Booth Hall Childrens Hospital in Manchester, Royal Liverpool Childrens Hospital, Royal Victoria Infirmary in Newcastle and Royal Hospital for Sick Children in Glasgow). The inclusion criteria are children 16 years old with newly-diagnosed inflammatory arthritis of one or more joints, which has persisted for at least 2

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Revista Romana de REUMATOLOGIE - 2008 - Nr.3