ARTRITA REUMATOIDA

ARTRITA REUMATOIDA

afectiune inflamatorie sistemica, cu etiologie necunoscuta si patogenie autoimuna, caracterizata prin artrita cronica, progresiva, deformanta, distructiva si manifestari sistemice multiple.

ARTRITA REUMATOIDA

aproximatv 10% din totalul bolilor reumaticeAR este raspandita pe tot globul, afecteaza toate grupurile etnice,

Incidenta este mai mare la femei cu varsta de 30-50aniramane constanta pana la aprox 75 ani la barbati este rara sub 45 ani

Prevalenta bolii este 1,37% pentru femei si 0,7% pentru barbati, creste cu varsta.este de 2-2,5 ori mai mare la femei. Mortalitatea este crescuta la femeile cu un debut tardiv al AR.

ETIOPATOGENIE

ETIOLOGIEeste multifactoriala

incomplet cunoscuta prezenta unor factori favorizanti: sexul, statusul hormonal, agentii infectiosi actioneaza pe o gazda cu predispozitie genetica

factorul imun statusul imun si autoimunitate: rol central in aparitia si in intretinere bolii

factorul genetic - HLA clasa II DR1 si DR4

PATOGENIE incomplet elucidata PR este determinata de un raspuns imun aberant favorizat de un factor din mediu, aparut la un individ cu o predispozitie genetica inflamatie sinoviala cronica, progresiva si in final la distructia articulatiei.in patogenia PR este greu de identificat o succesiune riguroasa a evenimentelor, deoarece celulele si sistemele biologice implicate actioneaza complex, simultan si se desfasoara atat in structura sinovialei cat si in cavitatea articulara

Procesele patologice fundamentaleInflamatieNeoangiogeneza Distructia osteo-cartilaginoasaAR precocePMN HiperplaziesinovialaHipertrofiesinoviociteLy T Ly B Plasmocite AR evolutiva PanusPMN

Localizarea proceselor patologice Periferic Ser

Sinovita Sistemic

ELEMENTELE CELULARE

celulele sinoviale tip A (macrofag-like) si tip B (fibroblastic-like)

macrofage si celule dendritice sinoviale - celule prezentatoare de antigen, cu rol in initierea si intretinerea procesului imun reumatoid

limfocite T (ThCD4+, cu memorie, 45RO+; CD8+, Ts), limfocite B si plasmocite - rol in sinteza anticorpilor antinucleari, anticitrulina, anti-perinucleari, anti-filagrina, factor reumatoid;

polimorfonucleare neutrofile, prezente mai ales la nivelul cavitatii articulare, cu rol in eliberarea enzimelor lizozomale si a radicalilor liberi de oxigen implicati in patogenia distrugerii cartilajului articular si leziunilor osului subcondral;

celulele endoteliale, cu rol in major in extravazarea celulelor inflamatorii in tesutul sinovial;

fibroblasti, osteoblasti, osteoclasti, condrocite, avind rol in initierea si progresia leziunilor erozive caracteristice PR.

Rolul Ly TCK, MMPs, prostaglandine, oxid nitricdistructie osteo-cartilaginoasa

Activarea ly TSEMNAL IantigenSEMNAL IICo-stimulare CD28Activare Ly T

Rolul Ly Bproductiecitokineprezentareantigenproductie anticorpiactivare complementINFLAMATIEdistructie cartilajeroziuni osoaseactivare complement

SISTEMELE BIOLOGICE UMORALEcitokineimunoglobulinesistemul complementuluisistemele coagularii si fibrinolizeiprodusii acidului arahidonic, prostaglandine, leucotriene si tromboxaniprodusii din metabolismul kininelormatrixmetaloproteinazefactorii de stimulare a proliferarii si cresterii celulare.

CitokineRaspuns Th1: IL-2, IFN gama,TNF alfa

ALTE CITOKINE: IL-1, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, etc

Caracteristic: dezechilibrul intre CK pro- si anti-inflamatorii si factorii de neutralizare, receptor antagonist si receptor solubil

BALANTA CK PRO-/ ANTI-INFLAMATORII CK pro-inflamatoriiCK anti-inflamatorii

IL-1 si TNF-a: CK PIVOTIL1NeutrphilsOsteoclastsOSCartilajOsteobBoneSpatiu articularIL-6PGE2IL-8Venule endoteliale inalteMembrana sinovialaCapsulaPanusosteoblastosteoclastPGE2 = prostaglandin-E2Dinarello C, Moldawer L. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis: A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca, USA: Amgen Inc.; 2001.neutrofilecondrociteTNF

IL-1 rol central Activare monocite/ macrofage Activare condrocite

Induce proliferare fibroblast

Activare osteoclasteINFLAMATIEFORMAREPANUS SINOVIALDISTRUCTIECARTILAJRESORBTIEOSOASAIL-1

MfTNF alfaEfect pe vase

up-reglare R adeziune: ICAM1, VCAM1, E-selectina via activare NF-kB

Stimulare angiogeneza

Creste activ procoagulanta a endoteliuluiEfect pe celule

Activare Ly , PMN

Proliferare fibroblastiEfect pe mediatori

Sinteza CK proinflam

Sinteza chemokine proinflam

Pg (PgE2), LT, PAF, NO, rad O

Sinteza MMP

Altele: durere, febra, casexie

Central Role of TNFa in RAKirwan JR. J Rheumatol. 1999;26:720-725.

din stadiile initiale pana in stadiile tardive de boala , AR este rezultatul comunicarilor intercelulare mediate de contactul intercelular cu mediul citokinic local.

etapa initiala : sinovita exudativa, caracterizata prin leziuni microvasculare, edem , proliferari discrete ale celulelor sinoviale si vasodilatatie locala;

etapa intermediara produsa prin activarea celulei T( CD4 +) , interventia citokinelor proinflamatoare ( IL1, TNF ) , productia de FR etc.. corespunde sinovitei infiltrativ proliferative, caracterizata prin acumulare celulara masiva la nivelul intimei si subintimei, angiogeneza .

etapa finala de distructii osteo-cartilaginoase este mediata de sinoviocitele fibroblast like si macrofage, cu formarea panusului si activarea locala a osteoclastelor

dizabilitate handicap moarte prematurahallmark-ul in AR = structural damagedistructia articulara ireversibila

DIAGNOSTIC CLINIC

ISTORIC

istoric familial de ARistoricul afectiunii articulare: debut: insidios (60-65%), acut/subacut (15-20%), mono-/oligo-articular, reumatism palindromictipul/numarul articulatiilor interesate-simetrie, aditivitateevolutia: cronica (> 6 sapt)

EXAMEN FIZIC-ARTICULARSIMPTOME ARTICULARE

durere artic. tip inflamatortumefiere articulararedoare matinala>30minimpotenta functionala

SIMPTOME NESPECIFICE

asteniesubfebrilitate/febrainapetenta

MODIFICARI OBIECTIVE

mana reumatoida

picior reumatoid

genunchi reumatoid

coxita reumatoida

subluxatia atlanto-axoidiana

MANA REUMATOIDATUMEFIERE RC,MCF, IFPDEVIERE CUBITALA DEGETEPOLICE IN ZDEGETE FUZIFORMEtumefiere artic RC, MCF, IFP

degete fuziforme

atrofie interososi dorsali

tenosinovita

MANA REUMATOIDATUMEFIERE RC,MCF, IFPDEVIERE CUBITALA DEGETEPOLICE IN Zdeformare:

deviere radiala carp

deviere cubitala degete

police in Z

police in baionetaATROFIE INTEROSOSIDEVIERE CUBITALA DEGETE

MANA REUMATOIDADEGETE IN BUTONIERANODULI REUMATOIZIARTRITA MUTILANTADEGETE IN GAT DE LEBADADEGETE IN GAT DE LEBADAdegete in gat de lebada

degete in butoniera

degete in ciocan

artrita mutilanta

PICIOR REUMATOIDDEGETE IN CIOCANPICIOR COMPLEX DEFORMATSUBLUXATIE MTFPICIOR TRIUNGHIULAR

GENUNCHI REUMATOIDTUMEFIERE GENUNCHICHIST BAKERtumefiere articulara

chist Baker

deformare:

genu flexumgenu valgumgenu varum

ALTE MODIFICARI ARTICULAREBURSITA SUBACROMIALABURSITA OLECRANIANANODULI REUMATOIZI

EXAMEN FIZIC-GENERAL(I)TEGUMENTE:

Noduli reumatoizi

20-35% cazuriin formele de boala erozive, agresive, seropozitivenoduli subcutanati, de consistenta variabila, mobili/ficsilocalizare: olecran, ulna proximal, burse, tendoane, laringe, sclere, cord, pulmon, rinichiNODULI REUMATOIZI

EXAMEN FIZIC-GENERAL(II)TEGUMENTE

Vasculita

frecventa la barbatiin forme de boala erozive, severeclinic: ulceratii cutanatepurpura palpabilaarterita distala cu eroziuni/ulceratii/gangrenaarterita viscerala

EXAMEN FIZIC-GENERAL(III)APARAT RESPIRATOR

pleureziefibroza pulmonara difuzanoduli pulmonari-periferie/lobi superioripneumotoraxbronsiolitaarterita vase pulmonare: HTAPsdr Caplan (pneumoconioza+AR)FIBROZA PULMONARANODULI PULMONARI

EXAMEN FIZIC-GENERAL(IV)APARAT CARDIO-VASCULAR

pericarditamiocardita: tulb de ritm/conducereendocardita: stenoza/insuficienta valvulara (aorta)vasculita coronariana: angina pectorala/infarct miocardic

EXAMEN FIZIC-GENERAL(V)SISTEM NEUROLOGIC

polinevrita senzitivo-motoriemononevrita multiplexsdr de canal carpiancompresie medulara

SDR CANAL CARPIAN

EXAMEN FIZIC-GENERAL(VI)OCULAR

keratoconjunctivita sicca (30%)irita/iridociclitaepisclerita/scleritascleromalacie perforansvasculita retinianaEPISCLERITASCLERITASCLEROMALACIE PERFORANS

EXAMEN FIZIC-GENERAL(VII)APARAT RENAL

vasculitanoduli reumatoizi parenchim renalamiloidoza

APARAT DIGESTIV

vasculita mezentericasplenomegalie (+neutropenie +/- hepatomegalie,adenopatie, anemie, trombocitopenie = sdr Felty)

EXAMEN FIZIC-GENERAL(VIII)SISTEM OSOS

osteoporoza juxtaarticularaosteoporoza sistemica osteonecroza aseptica

SISTEM MUSCULAR

miopatie de inactivitatemiopatie corticoid-indusamiozita

OSTEOPOROZA JUXTA-ARTICULARA

DIAGNOSTIC PARACLINIC

DIAGNOSTIC PARACLINICreactanti de faza acutabilant hematologicteste functionale hepatice si renalesindrom imunologicexamen lichid sinovialbilant metabolism glucidic si lipidicbilant fosfo-calcicmarkeri formare/resorbtie osoasabilant imagistic: Rgf maini/antepicior/col cervicala; Rgf toracica; Eco articulara; IRM articular

REACTANTII DE FAZA ACUTAVSH, CRP, si globuline, fibrinogen,amiloidul A seric, haptoglobina, feritina, etc stabilirea activitatii bolii (DAS) monitorizarea evolutiei bolii aprecierea raspunsului terapeutic (ACR20, 50, 70) evaluarea prognosticului

VSH si CRP- RFA nespecifici, sensibili, accesibili- permit diferentierea de o afectiune non-inflamatorie- permit monitorizarea activitatii bolii- valoare prognostica - valorile crescute sunt asociate cu progresie Rg la 6 si 12 luniCRPmet. de determinare: nefelometrie, ELISAse coreleaza mai bine cu activitatea boliivaloare prognostica (% scazuta este asociata cu o probabilitate scazutade aparitie a eroziunilor osoase)reflecta activit. bolii pe termen scurt

VSHmet. de determinare: Wintrobe / Westergren (mm/1h) crescut (>30 mm/h) in 90% din cazuri N in 10% din cazuri, nu exclude dg reflecta activitatea bolii in ultimele saptamani

BILANT HEMATOLOGIChemoleucograma completa (inclusiv formula leucocitara) sideremie, capacitate totala de legare a fierului (CTLF), reticulocite, frotiu de sange periferic, punctie medulara, etc. Anemie- anemie cronica simplaLeucocite: normale crescute: infectie, postcorticoterapie scazute: tox. medic/complicatii-sdr Felty (tipic: neutropenie)Trombocite: normale crescute: in cadrul activitatii bolii scazute: toxic medic/ sdr Felty/ sdr antifosfolipidic secundar

ANEMIA DIN ARmanifestare hematologica frecventa (20-30% din cazuri)se coreleaza cu activitatea boliide obicei este usoara sau mediemecanisme multiple

tipuri :

anemie cronica inflamatorie (normocroma, normocitara, sideremia N/scazuta CTLF, indice saturare transferina crescut)anemie feripriva (hipocroma, microcitara, CTLF , indice saturare transferina scazut) anemie aplastica tratament cu DMARDs (MTX, LEF, SSZ, AZA)anemie hemolitica autoimuna rar anemia din sindromul Felty

SINDROMUL IMUNOLOGICfactor reumatoid, anticorpi anti peptid ciclic citrulinat, anticorpi antinucleari totali, imunelectroforeza, complement total;

Ac antiRo, Ac antiLa, Ac antiADNdc, Ac anti fosfolipidici, cANCA, pANCA, serologie Borelia Burgdorferi, parvovirus B19, HIV, Ag HBs, Ac anti HVCdiagnostic pozitiv: FR, Ac antiCCPdiagnostic diferential in AR precoce: serologie Borelia burgdorferi, Parvovirus B19, HIV, Ag HBs, Ac anti HVCdiagnostic manifestari extraarticulare: Ac antiRo, Ac antiLa, Ac AFL, cANCA, pANCAaprecierea severitatii bolii: Ac antiCCP, ANA totalidiagnostic co-morbiditati: Ag HBs, Ac anti HVCevaluare efecte secundare medicamentoase: Ac antiADNdc (terapia antiTNFalfa)

FACTORUL REUMATOIDnespecifictitru crescut la debut in 30% din cazurititru crescut in 65-80% din cazuri (dupa 6-12 luni de la debut)marker de diagnosticse coreleaza cu activitatea si severitatea boliiasociat cu manifestari extraarticulareare valoare prognosticaprezenta in ser a mai mult de un izotip al FR creste specificitate pt. AR

FACTORUL REUMATOIDmetode de determinare:aglutinare (Latex, Waaler Rose)nefelometrieRIA (radiommunossay)ELISA: identificare FR total si/sau izotipuri FR (M, G, A, E)

identifica FR tip Ig M izotipuri FR si corelatii clinico-evolutive:

tip Ig A: AR forma eroziva si manifestari extraarticulare (sdr sicca, vasculita) tip Ig G: manifestari extraarticulare (vasculita) tip Ig E: manifestari extraarticulare tip Ig M: factor de prognostic

ANTICORPII ANTI PEPTID CICLIC CITRULINAT (CCP)au specificitate (95%) si sensibilitate (80%) inaltapreced debutul clinic al bolii cu aprox 10 ani diagnostic precoce au valoare prognostica: asociat cu forme erozive, rapid progresivemarker de diagnostic si prognosticnu se asociaza cu debutul manif extraarticularepermit monitorizarea bolii si a raspunsului terapeutic

ANTICORPII ANTINUCLEARIasociati cu formele active, severe de boala20% din cazuriANA tip Ig Mcorelat cu titrul crescut al FR

TESTE FUNCTIONALE HEPATICETGO, TGP, albumina, GGT, fosfataza alcalinadiagnostic co-morbiditatievaluare efecte secundare medicamentoase (AINS, MTX, LEF, SSZ, AZA)

TESTE FUNCTIONALE RENALEuree, creatinina, acid uric, electroliti (Na, K), sumar urinaspeciale: urocultura, proteinurie/24h, proba Addisevaluare efecte secundare medicamentoase: AINS, CSP,diagnostic complicatii: infectioase, amiloidoza diagnostic co-morbiditati (ex. nefropatie hipertensiva, nefropatie diabetica)

BILANT METABOLISM GLUCIDIC SI LIPIDICglicemie, lipide totale, HDL-colesterol, LDL-colesterol, trigliceride,TTGO, glicozurie diagnostic co-morbiditati diagnostic complicatii: ATS evaluare efecte secundare medicamentoase: CS

EXAMEN LICHID SINOVIALlichid serocitrinexsudat- proteine crescute, glucoza scazutacelularitate crescuta (10-50 000/mm3-PMN 75%), ragociteFR titru crescutcomplement scazuttestul cheagului de mucina negativ diagnostic precoce in caz de debut atipic (monoarticular) diagnostic diferential: artrita infectioasa/microcristalinaexamen macroscopic, citologic, biochimic, imunologic

Osteoporoza juxtarticulara

Eroziuni si scleroza in std avansate

Eroziuni marginale

Eroziuni precoce (IRM)

Serial X-rays of a knee in RA

Subluxatie atlanto-axiala

Fibroza pulmonara

Sdr Caplan

Noduli reumatoizi pulmonar

DIAGNOSTIC POZITIV

DIAGNOSTIC POZITIVCRT DE CLASIFICARE AR, 1987

1. Redoare matinal 60 minute, de cel putin 6 saptamani

2. Artrit simultana la minim trei arii articulare (din cele 14 arii articulare posibile: IFP, MCF, pumni, umeri, genunchi, glezne i MTF), de cel putin 6 saptamani

3. Artrita articulatiilor mainilor, de cel putin 6 saptamani

4. Artrita simetric, de cel putin 6 saptamani

5. Prezenta nodulilor reumatoizi, observai de medic

6. Prezenta FR seric, in conditiile unei reactii pozitive la

AR PRECOCE (EARLY)in primele 3-6 luni crt de clasificare nu pot fi aplicate

CRITERII AR PRECOCE:

cel putin 3 articulatii tumefiateafectarea MCF si/sau MTF cu test squeeze +redoare matinala 30 min

TEST SQUEEZE

DIAGNOSTIC DIFERENTIAL

DIAGNOSTIC DIFERENTIAL (I)in caz de monoartrita cronica:

artrita infectioasa: Brucella, Mycobacterie, Borreliaartrita microcristalina-guta/condrocalcinozaartrita reactivasarcoidozaspondilartrita-debut perifericartroza reactivatahidartroza recurentaosteonecroza asepticadistrofia simpatica reflexaartropatia neuropata Charcotsinovita vilonodulara

DIAGNOSTIC DIFERENTIAL (II)in caz de poliartrita cronica simetrica aditiva:

LESsdr Sjogrenpolimiozitaboala mixta de tesut conjunctivartrita psoriazica-forma poliarticularacondrocalcinoza-forma pseudoreumatoidaartroza maini (poliartroza)guta poliarticularaartrita virala: parvovirus B19, HIV, hepatita B/CARTROPATIE JACOUDARTRITA PSORIAZICA-FORMA POLIARTICULARA

DIAGNOSTIC DIFERENTIAL (III)in caz de oligo-/poliartrita cronica asimetrica:

artrita psoriazica-forma oligoarticularaartroza maini (poliartroza)artropatia sarcoida cronicaartrita reactivaartrita enteropaticaguta-forma poliarticularapseudoguta

POLIARTROZAARTRITA PSORIAZICA-FORMA OLIGOARTICULARA

DIAGNOSTIC DIFERENTIAL (IV)in caz de poliartrita cronica cu manifestari sistemice:

LESartrita reactivaartrita viralaboala Still a adultului

FORME CLINICE

FORME CLINICE (I)clasificare in functie de:

crt evolutiv,crt imunologic,crt activitatii bolii,crt raspunsului la tratament,crt clinico-radiologic,crt clinico-functional.

FORME CLINICE (II)crt evolutiv:

AR precoce (early) vs avansata (established)

crt imunologic:

AR seropozitiva vs seronegativaAR antiCCP pozitiva vs antiCCP negativa

FORME CLINICE (III)

crt. activitatii bolii (DAS28):

forma usor/moderat/sever activa

crt. raspunsului la tratament (crt EULAR, ACR)remisiuneraspuns partialfara raspuns (non-responder primar vs non-responder secundar).

FORME CLINICE (IV)Std I, precoce:

aspect Rx normal +/- osteoporozaStd II, moderat:

osteoporoza Rx +/- distructii osoaseatrofie muscularalimitarea miscarilor articulareabsenta deformarilor articulare+/- leziuni de parti moi, noduli reumatoizi, tenosinoviteStd III, sever:

osteoporoza, distructiile osului si cartilajuluideformare articulara cu subluxatii, deviere ulnara sau hiperextensieatrofie musculara marcata si extinsaprezenta de noduli reumatoizi si tenosinovite.

Std IV, terminal:

crt std IIIfibroza articulara si anchiloza

crt clinico-radiologic:

FORME CLINICE (V)crt. clinico-functional Steinbroker

clasa I: activitate fizica normalaclasa II: activitatile zilnice pot fi efectuate dar cu durere si cu reducerea mobilitatii articulareclasa III: capacitate functionala limitata la autoingrijireclasa IV: imobilizarea la pat sau in scaun cu rotile, incapacitate de autoingrijire.

EVOLUTIE

SEVERITATE0DURATA BOLII (ANI)51015202530EVOLUTIA PROGRESIVA A ARPRECOCE INTERMEDIARTARDIVGraph: Adapted from Kirwan JR. J Rheumatol. 2001;28:881-886. Photo: Copyright American College of Rheumatology.InflamatieDisabilitateRadiologic ACR

FACTORI DE PROGNOSTIC NEGATIVsexul feminin; vrsta avansat la debut; terenul genetic (HLA DRB1*04); interesarea > 12 articulaii (mici i mari); deficit functional important (HAQ > 1 la un an de la debut); manifestari extra-articulare (noduli subcutanai, ulceraii cutanate, rash vasculitic, neuropatie, sclerit, etc); eroziuni precoce, decelabile radiologic (< 2 ani de la debut); titru crescut factor reumatoid (ELISA), anticorpi anti-CCP; cresterea reactanilor de faz acut; nivelul educaional si statusul socio-economic sczut

TRATAMENT

TRATAMENT MEDICAMENTOSbaza abordarii terapeutice in ARObiective:prevenire si stoparea procesului distructiv articular si a deformarilormentinerea functiei articulare si a calitatii vietiiprevenirea handicapului fizic si a riscului de deces prematur

REMISIUNEA - UN EL REALIZABIL

DIAGNOSTICPRECOCEcrt ACR

REMISIUNE COMPLETA clinica si RxsauSCADEREA ACTIV BOLII

TRATAMENTDMARDs terapie biologicaeducational/kinetoterapicocupational/ortopedic

MONITORIZAREAACTIVITATII BOLII DAS28, DAS44, ACR70, SDAIHAQ, evaluare pacient/medic

REMISIUNEA posibila daca:TRATAMENT: precoce, agresiv, intensiv,sustinut, adaptat:stadiului PR: * precoce early * avansat/definit established * final endactivitatii si severitatii boliiprezentei factorilor de prognostic negativraspunsului la terapiile anterioareprezentei co-morbiditatilor

MONITORIZAREA ACTIVITATII BOLII: DAS28,DAS44, SDAI, ACR70, HAQ, evaluare pacient /medic, durereVAS

TRATAMENT PRECOCEavansatfereastra oportuna primele 6 lunistadiu finalDeficit functional sever

Distructie articulara

Dizabilitate

Deces prematurEmery P., Burmester G.R., Breedveld F. etc, Is Remission the Mission in RA? New Information from the 2005 EULAR Conference; www.medscape.com, 2005

debut

SMARD- symptom modifying antirheumatic drugs: AINS si CS

DMARD - disease modifying antirheumatic drugs: saruri de aur, antimalarice de sinteza, sulfasalazina, D-penicilamina, metotrexat, leflunomid, azatioprina, ciclofosfamida

TERAPIA BIOLOGICA: antiTNF alfa, antiIL1, antiCD20, etc

SMARDAINS-tratament simptomatic

Controleaza durerea si tumefactia articularaAmelioreaza usor sdr biologic inflamator nespecificNu influenteaza eroziunile articulare si progresia boliiNu influenteaza manif extraarticulareRisc crescut de rct adverseAsociate intotdeauna unui DMARD

AINS neselectiveAINS selectiveAINS specifice

SMARDCORTICOTERAPIA

SistemicaIn doze mici (PDN 7,5-10mg/zi) si pe termen scurt la inceputul initierii terapiei remisive, pana la instalarea efectului acesteia=bridge therapyIn doza foarte scazuta (PDN 5010mg/zi) pe termen lung in forme active care nu raspund suficient la terapia remisiva.In doza mare (PDN 0,5-1mg/kgc/zi) pe termen scurt in caz de toxicitate medicamentoasa (leucopenie dupa MTX), vasculita,

Locala-in formele mono-/oligoarticulare

DMARDMETOTREXATcel mai utilizat agent remisiv-standard de auranalog structural de acid folicinhiba dihidrofolat reductaza-----inhiba sinteza sinteza metabolitilor purinici si a acizilor nucleiciinhiba expansiunea clonala a Ly T si Bcreste conc adenozinei..efect antiinflamatorscade sinteza de CK inhiba angiogeneza si proliferarea cel endoteliale.

7,5-25mg/sapt, po sau imefect terapeutic la 4-6 sapt

DMARDMETOTREXAT-efecte secundareHepaticePulmonareHematologiceMucoase: aftoza, stomatitaDigestiveCutanate

MONITORIZARE lunara a HLG, creatininei, transaminaze, proteine serice

DMARDLEFLUNOMIDInhiba dihidro-orotat dehidrogenaza.blocarea proliferarii limfocitelorInhiba actiunea CK

20mg/zi, po

Efect terapeutic in 4 sapt

Reactii adverse:HepaticeDigestiveHematologiceCutanateCardiovasculare: HTA usoara

MONITORIZARE lunara a HLG, transaminaze, creatinina serica

DMARDSALAZOPIRINAAntiinflamator (prin ac 5 amino salicilic)Antibacterian (prin sulfapiridina)Imunomodulator

2-3g/zi

Efecte secundare: hepatice, hematologice, digestive, cutanate

MONITORIZARE lunara a HLG, transaminaze, creatinina

DMARDs*Physicians Desk Reference, 1998. Recommended doses are not necessarily those utilized in clinical practice.AgentAzatioprinaCiclosporinaSaruri aur oralSaruri aur parenteral HidroxicloroquineLeflunomidMetotrexatD-PenicilaminSulfasalazinaDoza recomandata*1.0-2.5 mg/kg/zi2.5-4.0 mg/kg/zi6-9 mg/zi25-50 mg la 2-4 sapt 200-400 mg/zi20 mg/zi7.5-20 mg/sapt125-750 mg/zi0.5-3.0 g/zi

Selection of an Initial DMARDToxicities to monitorMyelosuppression, hepatotoxicity, lymphoproliferative Renal, hyperuricemiaMyelosuppression, rash, proteinuria, gastrointestinalMyelosuppression, rash proteinuriaMacular damageHepatotoxicity, gastrointestinalHepatotoxicity, pulmonary, myelosuppressionMyelosuppression, proteinuriaMyelosuppression, gastrointestinal

Potential toxicityModerate

HighLow

Moderate

LowLow

Moderate

High

Low

Time to benefit2-3 months

4-8 weeks4-6 months

3-6 months

2-4 months4-8 weeks

1-3 months

3-6 months

1-3 months

AgentAzathioprine

CyclosporinGold, oral

Gold, parenteral

HydroxychloroquineLeflunomide

Methotrexate

D-Penicillamine

Sulfasalazine

DMARDMONOTERAPIE

TERAPIE COMBINATAMTX+SSZMTX+LEF+HCQMTX+HCQSSZ+HCQ+LEF

TERAPIA BIOLOGICA ANTI TNF

Anticorpi monoclonali

INFLIXIMAB (REMICADE)ADALIMUMAB (HUMIRA)

Receptori solubili

ETANERCEPT (ENBREL)

ANTI TNF-MECANISM DE ACTIUNEDown-regleaza alti mediatori inflamatori:CK: IL-1, IL-6, GM-CSFchemokine: IL-8, RANTESalti mediatori: MMPs, PG E2, PDGF

Influenteaza functia vasculara, traficul si activarea leucocitelor:expresia si functia moleculelor de adeziuneangiogeneza

Influenteaza functia sistemului imun:expresia TLR2/4

Moduleaza functia celulelor imunocompetente (macrofage, Ly T)creste nr si functia Ly T reglatoriiinfluenteaza fenotipul Ly Th1/ Th2 si secretia de CK

Choy EHS, Panayi GS. N Engl J Med. 2001;344:907-16. Feldmann M, et al. Cell. 1996;85:307-10.

INFLIXIMAB (REMICADE)

Ac monoclonal chimeric de tip Ig G1

origine murinica (25%)-contine situsul de legare pentru TNForigine umana-responsabila de functiile efectoare

leaga TNF solubil si membranar

are inalta afinitate si specificitate

INFLIXIMAB (REMICADE)se adm. in combinatie cu MTX- efect sinergicprelungeste durata remisiuniiinhiba formarea Ac impotriva portiunii murinicedoza: 3 mg/kgc,piv, So, S2, S6 si ulterior la 8 saptamani intervalraspuns insuficient: se creste doza pana la maxim 10 mg/kgc sau se poate micsora intervalul dintre administrari la 4-6 sapt

ADALIMUMAB (HUMIRA)Ac monoclonal tip Ig G1 complet uman

mare afinitate si specificitate pentru TNF

ADALIMUMAB (HUMIRA)doza: 40 mg, sc, la 2 sapt interval

adm. in monoterapie sau terapie combinata (+MTX) in AR moderata/severa cu raspuns inadecvat la DMARDs

fara rct alergice si aparitia Ac ( rar anticorp umani-anti-umani

ETANERCEPT (ENBREL)proteina de fuziune obtinuta prin inginerie genetica formata prin combinarea a 2 lanturi identice ale R TNF p75 (tip II) cu fragmente Fc al Ig G1 umaneleaga TNF solubilpoate lega si TNF

ETANERCEPT (ENBREL)doza: 25mg x 2/sapt sau 50mg/sapt, sc

in monoterapie sau in terapie combinata (+MTX)

rct adverse: asemanatoare INF

TERAPIA BIOLOGICA ANTI TNF IN ARinaintea initierii tratamentului este obligatoriu:

screening TBC: test PPD si Rg toracicascreening infectie virala: Ag HBs, Ac anti HVC, HIVexcluderea neoplaziei, boli demielinizanteexcluderea fen autoimune asociate Ac anti ADN dc

TERAPIA ANTI TNF-INDICATIIFDA: AR moderata sau severa fara raspuns la MTX si/sau alt DMARDsRomania: AR activa fara raspuns la cel putin 2 DMARDs in doza maxima:AR activa 5 articulatii active+ 2 din 3:Redoare matinala > 60 minuteVSH > 28mm/hCRP > 20 mg/llipsa de raspuns la cel putin 2 DMARDs, din care unul a fost MTX, dupa minim 12 saptamani de adm in doza maxima

TERAPIA ANTI TNF-CONTRAINDICATII

LESScleroza multiplaNevrita opticaInfectii active/ cronice/ recurenteAntecedente de tuberculoza sau test PPD pozitivInsuficienta cardiaca cronica severa

REACTII ADVERSEreactii adverse acute ale piv: febra, frisoane, cefalee, prurit, urticarie, hipotensiune, dispnee infliximab

infectii reactivarea tuberculozei toate anti TNF

hipersensibilitate de tip intarziat: mialgii, artralgii, eritem, edeme

fen autoimune: anticorpi antimolecula chimerica (HACA), ANA, Ac anti ADNdc (fen lupus-like)-infliximab

fen CV: agravarea insuf cardiace, aritmii

fen digestive: greata , diaree

fen neurologice: sdr demielinizante

fen hematologice: leucopenie, anemie, trombocitopenie

neoplazii: limfoame

RITUXIMABAc monoclonal chimeric anti CD20 de pe suprafata Ly BIndicat la cei cu forme medii sau severe de AR care au indicatie de terapie biologica si au avut un raspuns inadecvat la 1 sau mai multi ag biologici

1000mg, piv cu repetarea adm la 2 sapt + MTXInaintea piv se adm 100mg metilprednisolon iv

Interleukin-1 (IL-1) and tumour necrosis factor- (TNF-) have been identified as pivotal proinflammatory cytokines in the pathogenesis of the rheumatoid joint.1,2In this slide, IL-1 and TNF- are shown in the joint space; however, concentrations of these cytokines are likely to be higher in the tissues.1Increased concentrations of IL-1 and TNF- are found in the synovial fluid and tissue of patients with rheumatoid arthritis (RA). These cytokines act to stimulate the production of each other, that is, IL-1 stimulates production of TNF- and vice versa.1Early in the RA disease process, IL-1 and TNF- act synergistically to increase production of matrix metalloproteases, such as collagenase, by chondrocytes. These enzymes degrade components of the cartilage matrix.1IL-1 also activates osteoclasts in bone.2IL-1 and TNF- also increase expression of adhesion molecules on the endothelium, contributing to the migration of neutrophils and lymphocytes from the circulation.1In addition, IL-1 and TNF- stimulate synovial fibroblasts to produce additional proinflammatory mediators, such as IL-8, prostaglandin-E2, and IL-6. These mediators are responsible for the acute and chronic inflammation characteristic of RA.1

1.Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87:2095-2147.2.Gravallese EM, Goldring SR. Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum. 2000;43:2143-2151.3. Dinarello CA, Moldawer LL. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis. A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca: Amgen Inc.; 2001.

Interleukin-1 (IL-1) is a key mediator of synovial inflammation and pannus formation. Furthermore, it is involved in eliciting the effects of bone and cartilage destruction, and impairment of tissue repair in patients with rheumatoid arthritis. IL-1 activates monocytes and macrophages. In turn, these cells produce more proinflammatory cytokines and other proinflammatory mediators, contributing to a cascade of acute and chronic inflammatory changes in the joint.1 IL-1 induces fibroblast proliferation, which culminates in the overgrowth of synovial tissue, known as pannus.2 IL-1 activates chondrocytes in the cartilage, which release destructive proteolytic enzymes, culminating in the eventual breakdown of cartilage. IL-1 also impairs mechanisms of cartilage repair.13 IL-1 activates osteoclaststhe cells responsible for bone resorption.2

1.Dinarello CA. The role of interleukin-1 receptor antagonist in blocking inflammation mediated by interleukin-1. N Engl J Med. 2000;343:732-734.2.Arend WP, Dayer J-M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990;33:305-315.3.van den Berg WB. Arguments for interleukin-1 as a target in chronic arthritis. Ann Rheum Dis. 2000;59(suppl 1): i81-i84.RA Progression The relationship between the development of radiographic joint destruction in RA and its long-term consequences for the patient is not well understood, but one view of the disease process is that inflammatory joint symptoms are the main determinant of disability early in the disease, while joint destruction dominates in late disease. Presentations and discussions at OMERACT IV (the 4th International Consensus Conference on Outcome Measures in Rheumatoid Arthritis Clinical Trials) are consistent with this view, suggesting a high correlation between inflammation and disability in early RA, but that the strength of this relationship declines over time.Discussions at OMERACT IV also indicated that fluctuations in disability become less pronounced in later-stage RA and more closely correlated with radiographic evidence of joint damage.Kirwan JR. Links between radiological change, disability, and pathology in rheumatoid arthritis. J Rheumatol. 2001;28:881-886.

TNF Antagonists: Relative ContraindicationsThere are a number of relative contraindications for the use of TNF antagonists. These include systemic lupus erythematosus (SLE), multiple sclerosis, optic neuritis, current active serious infections, chronic recurrent infections, a history of TB or positive purified protein derivative (PPD) skin tests, or congestive heart failure.