Farmaci per il trattamento della Artrite Reumatoide

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Edmondo Calabrese
7 anni fa
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1 Farmaci per il trattamento della Artrite Reumatoide

2 Artrite reumatoide Farmaci per il controllo del dolore e dell infiammazione delle articolazione (FANS) Farmaci che riducono il danno e la distruzione delle articolazioni (disease modifying antirheumatic drugs, DMARDs)

3 Smolen & Steiner, 2003

4 Schematic representation of events occurring in rheumatoid arthritis. The T cells invading the synovial membrane are primarily CD4+ memory cells, which produce interleukin-2 (IL-2) and interferon- (IFN- ) to a similar extent as antigen-triggered T cells21, and which are either already pre-activated or become (further) activated by antigen-presenting cells (APCs) in conjunction with arthritogenic (auto)antigen(s) and appropriate major histocompatibility complex (MHC) class II molecules, co-stimulation (mainly through CD80/81 and CD28) and certain cytokines (IL-1, IL-15, IL-18). Through cell cell contact (for example, through CD11- and CD69- mediation28, 29) and through different cytokines, such as IFN-, tumour-necrosis factor (TNF)- and IL-17, these T cells activate monocytes, macrophages and synovial fibroblasts The latter then overproduce pro-inflammatory cytokines, mainly TNF-, IL-1 and IL-6, which seem to constitute the pivotal event leading to chronic inflammation21, Through complex signal transduction cascades (Fig. 4), these cytokines activate a variety of genes characteristic of inflammatory responses, including genes coding for various cytokines and matrix metalloproteinases (MMPs) involved in tissue degradation. TNF- and IL-1 also induce RANK expression on macrophages which, when interfering with RANKL on stromal cells or T cells, differentiate into osteoclasts that resorb and destroy bone. In addition, chondrocytes also become activated, leading to the release of MMPs. Initial events might also involve activation of APCs through Toll-like receptors (TLRs) before T-cell engagement. RANK, receptor activator of nuclear factor- B; RANKL, RANK ligand; RF, rheumatoid factor; TCR, T-cell receptor. Smolen & Steiner, Nature Review-Drug Discovery, 2, , 2003

5 Smolen & Steiner, 2003

6 Simplified overview of pathways involved in TNF- and IL-1 signalling. Two major pathways, the NF- B (left) and the MAPK pathway (right) are activated by the proinflammatory cytokines TNF- and IL-1. a On the left of the figure, in the cytoplasm, NF- B PROTEINS are usually associated with inhibitors of NF- B (I Bs). Various stimuli, including ligation of receptors of pro-inflammatory cytokines, activate the I B kinase (IKK) complex, which consists of IKK1 ( ), IKK2 ( ), and the regulatory subunit NEMO (also known as IKK ). IKK phosphorylates I Bs, leading to their degradation, thereby allowing NF- B to enter the nucleus and activate genes coding for various molecules, such as cytokines, chemokines, cyclooxygenase-2, anti-apoptotic and stress proteins. NF- B can be activated by a variety of engaged receptors and various other signalling pathways than the one depicted here, which all involve activation of IKKs. b On the right of the figure, MAPKs are regulated by several (two or more) upstream phosphorylation cascades initialized after receptor ligation and recruitment of adaptor proteins. The kinases immediately upstream of the MAPKs belong to the MAPK or ERK kinase (MKK or MEK) family. The three major MAPK families are the extracellular-signal-regulated kinases (ERKs), the c-jun N-terminal kinases (JNKs) and the p38 enzymes. The ERK subgroup of MAPKs is mainly activated by growth factors, whereas pro-inflammatory cytokines mostly induce the JNK and p38 MAPK cascades. After phosphorylation of its components (primarily members of the Fos and Jun families), the TRANSCRIPTION FACTOR AP-1 induces activation of genes coding for various cytokines (including TNF- and IL-1 themselves), other inflammatory molecules, such as prostaglandins (PGs), and proteases, such as the matrix metalloproteinases (MMPs). In addition, AP-1 regulates cell proliferation, survival and apoptosis. As also shown, capture of TNF- by TNFblocking agents, or interaction of IL-1ra with the IL-1 receptor, prevents TNF- and IL-1, respectively, from ligation to their receptors, induction of signal transduction cascades and activation of transcription factors AP-1 and NF- B. Likewise, the different kinases, as well as the transcription factor activity itself, constitute therapeutic targets. AP-1, activator protein-1; IL, interleukin; IRAK, IL-1 receptor-associated kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation protein 88; NEMO, NF- B essential modulator; NF- B, nuclear factor- B; TNF, tumour-necrosis factor; TRADD, TNF receptor-associated death domain protein;traf, TNF receptor-associated factor. Smolen & Steiner, Nature Review-Drug Discovery, 2, , 2003

7 Hogan et al., Gene and Development, 17, , 2003

8 Hogan et al., Gene and Development, 17, , 2003

10 A. FANS: COX-1/COX-2 inibitori Farmaci per la terapia dell' ARTRITE REUMATOIDE Derivati dell'acido propionico Ibuprofen Flurbiprofen Fenoprofen Ketoprofen Inibitori selettivi COX-2 Celecoxib Rofecoxib B. Steroidi Antiifiammatori C. Agenti citotossici Ciclosporina Azotioprina Metotrexato D. Penicillamina, Sali d oro E. Idroclorochina Farmaci antinfiammatori FANS e steroidi Controllo del dolore e della flogosi intraarticolare Farmaci modificanti la malattia (DMARDs) F. Anticorpi anti-tnf recettori solubili anti TNF

11 Farmaci modificanti la malattia (DMARDs)

12 Farmaci modificanti la malattia (DMARDs)

14 SUMMARY OF THE STATUS OF TREATMENT FOR RA IN 2003 (1) L AR è una malattia ancora invalidante e causa di mortalità (2) Nessun farmaco in monoterapia si è rivelato migliore del metotrexate (3) La tendenza generale è di anticipare il trattamento con DMARD (4) L intervento precoce con DMARD produce migliori risullatati clinici (5) I corticosteroidi continuano ad essere utilizzati comne terapia intermedia (6) La terpaia di associazione è efficace e dovrebbe essere considerata come terapia iniziale (7) Il trattamento Anti-TNF sembra essere un concreto avanzamento (8) La malattia resta comunque attiva nonostante gli sforzi terapeutici (

15 DMARDS E NEOPLASIE MALIGNE EMATOLOGICHE CONTESTO C'è un dibattito crescente circa gli effetti della terapia dell'artrite reumatoide sul rischio di neoplasie maligne ematologiche. RISULTATI Durante lo studio, le neoplasie maligne ematologhe si sono sviluppate in 619 pazienti, comprendenti linfomi in 346 pazienti, leucemia in 178, e mielosi multiple in 95 pazienti. I RR non aggiustati per neoplasmi maligni ematologi dopo l'esposizione al farmaco, sono stati i seguenti: metotrexato, 1,18 (intervallo di confidenza al 95% 0,99-1,40); azatioprina 1,44 (1,01-2,03); ciclofosfamide 2,21 (1,52-3,20). Poiché gli agenti biologici erano apparsi per la prima volta sul formulario Régie d'assurance Maladie du Quebec nel 2002, ci sono state poche esposizioni a questi farmaci. Le stime aggiustate suggeriscono che il rischio di cancro ematologico è stato maggiormente elevato dopo l'esposizione a ciclofosfamide (RR 1,84; 1,24-2,73). Solo per i linfomi, il RR aggiustato, dopo esposizione a ciclofosfamide, era di 2,12 (1,33-3,54). CONCLUSIONI In questa ampia coorte di pazienti con artrite reumatoide, il rischio relativo maggiore di neoplasie maligne ematologiche è stato osservato dopo l'uso di ciclofosfamide. Le stime di rischio correlato alle terapie più nuove ed emergenti dovrebbero considerare attentamente le esposizioni alla terapia precedente e concomitante.

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