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Bruno Amato » 11.Artrite Reumatoide. Terapia con Farmaci Biologici


Corso integrato di medicina clinica e chirurgia generale 1

Artrite Reumatoide. Terapia con Farmaci Biologici

Prof. Gianni Marone

Definizione

L’ artrite reumatoide (RA) è una malattia autoimmune sistemica con andamento cronico e con carattere di aggressività.

Sebbene la RA sia caratterizzata da infiammazione cronica con interessamento sistemico, la malattia presenta una elettiva localizzazione poliarticolare ed è frequentemente responsabile di grave disabilità.

Epidemiology of RA


Symmetric Synovitis in Early RA


Ulnar Deviation in Chronic RA


Homunculus for Recording Joint Disease in RA


Systemic Rheumatoid Arthritis

  • A, Extra-articular disease manifestations affect about 42% of patients with rheumatoid arthritis and can include multiple organ systems. Turesson C, O’Fallon WM, Crowson: Occurrence of extra-articular disease manifestations is associated with excess mortality in a population-based cohort of patients with rheumatoid arthritis. Arthritis Rheum 2000 43(9S) S385
  • B, Constitutional symptoms and signs. Constitutional symptoms and signs can vary with disease activity. Most patients with active arthritis experience more than 1 hour of morning stiffness.

Criteri ARA

  1. Rigidità mattutina: Rigidità mattutina articolare o periarticolare per almeno 1 h prima del miglioramento massimo
  2. Artrite di 3 o più articolazioni: Almeno 3 articolazioni con rigonfiamento dei tessuti molli o versamento articolare (non solo esuberante crescita ossea) osservati da un medico; le 14 possibili articolazioni interessate sono: interfalangee prossimali, metacarpo-falangee, polso, gomito, ginocchio, caviglia, metatarso-falangee
  3. Artrite delle mani: Artrite delle articolazioni del polso, metacarpo-falangee, interfalangee prossimali
  4. Artrite simmetrica: Simultaneo interessamento di aree articolari da ambo i lati del corpo ( per le interfalangee prossimali, le metacarpo-falangee e le metatarso-falangee la simmetria può non essere assoluta)
  5. Noduli reumatoidi: Noduli sottocutanei in prossimità delle prominenze osse, sulle superfici estensorie,o in regioni iuxtaarticolari osservati da un medico
  6. Fattore reumatoide sierico: Dimostrazione di livelli patologici di fattore reumatoide nel siero utilizzando qualsiasi metodica i cui risultati siano positivi in meno del 5% dei soggetti normali di controllo
  7. Alterazioni radiografiche: Alterazioni radiologiche tipiche per artrite reumatoide (erosioni o decalcificazioni iuxtaarticolari) alle mani e ai polsi, in proiezione anter-posteriore; le alterazioni osteoartrosiche non soddisfano questo criterio

Ai fini diagnostici occorre la presenza di almeno 4 criteri su 7.

I criteri 1 e 4 devono essere presenti per almeno 6 settimane.

Clinical Course of Joint Disease in Rheumatoid Arthritis


Course of Rheumatoid Arthritis: Schematic Representation

“The relationship between radiological change and the consequences of RA for the patient has not yet been fully established. In particular, the link with long-term disability is assumed rather than proven. One view of this relationship is shown in this slide. The effect of joint destruction comes to dominate disability late in the disease course, while inflammatory joint symptoms are the main determinant of disability early in the disease. Furthermore, the potential consequences for disability of various changes to the rate of radiographic progression may not be immediate. For example, if radiographic progression is halted for four years, it will take perhaps 10 years for the benefit to be clearly appreciated against the background of variation within individual patients. The need for a long-term view makes it difficult to investigate the detailed consequences for disability of a reduction in radiographic change by using randomized, controlled trials of interventions that slow or stop radiographic progression.” Kirwan JR. Conceptual issues in scoring radiographic progression in rheumatoid arthritis. J Rheumatol. 1999;26:720-725


Parametri Laboratoristici

  • Anemia
  • Piastrinosi
  • Riduzione della sideremia
  • Aumento della VES
  • Aumento della PCR
  • Aumento del Fibrinogeno
  • Aumento della frazione gamma al QPE
  • Incremento della fosfatasi alcalina, AST, ALT, gGT
  • Riduzione dell’albumina sierica

I suddetti paramentri di laboratorio sono non specifici e riflettono sia lo stato di flogosi acuta che cronica, e in talune condizioni possono non essere correlate con la malattia.

Rheumatoid Factors (RFs) in Rheumatoid Arthritis (RA)

  • RFs are IgM antibodies directed to the Fc fragment of IgG and are found in the majority of RA patients
  • However, patients with other chronic inflammatory diseases, infectious diseases, as well as many healthy individuals, also produce RFs
  • Therefore, RFs are not very specific for RA

Antibodies against Unusual Aminoacid Citrulline in RA

  • Guy Serre and Walther van Venrooij demonstrated the presence of autoantibodies against proteins containing the unusual amino acid citrulline
  • Citrullination is the posttranslational modification of protein-bound arginine into the unusual amino acid citrulline and results in a small change in molecular mass and the loss of a positive charge in the modified protein
Enzymatic conversion of arginine to citrulline 
is catalyzed by peptidylarginase deiminases (PADs)

Enzymatic conversion of arginine to citrulline is catalyzed by peptidylarginase deiminases (PADs)


Anti-citrullinated Protein/Peptide Antibodies (ACPAs)

  • ACPAs are found in 50 – 70% of patients with RA. ≈ 20% of RA patients do not harbor these antibodies
  • ACPAs of the IgG isotype have been detected up to 9 years before symptoms of RA occurred
  • Patients with undifferentiated arthritis with ACPAs have a chance of 90% to progress to RA within 3 years
  • There is a strong association between ACPAs and the presence of RA susceptibility HLA – DRB1 genes

Anti-citrullinated Protein Antibodies (ACPAs/CCP) in Rheumatic Diseases

Closed  squares  RF-;  open  squares  RF+

Closed squares RF-; open squares RF+


Immunohistochemical Staining of Citrullinated Proteins in Synovial Tissue


Patogenesi

Stadi patogenetici

  • Fase iniziale
    • Etiologia sconosciuta
    • Produzione di anticorpi anti-proteine citrullinate
    • Rilascio di citochine e chemiochine a livello sinoviale
    • Attivazione di cellule dendritiche, macrofagi e mastociti
  • Progressione
    • Attivazione di cellule T
    • Stimolazione di cellule B e plasmacellule
    • Produzione di fattori reumatoidi ed ulteriore rilascio di citochine
  • Infiammazione cronica
    • Disregolazione policellulare
    • Proliferazione di fibroblasti
    • Rimodellamento tessutale

Events in Rheumatoid Arthritis

Cytokines involved are: GM-CSF, IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-15, IL-2, IL-17, TGF-β, TNF-α. Early cartilage and bone erosion in rheumatoid arthritis is associated with the accumulation of several cell populations in the synovial membrane and the formation of a proliferating pannus. The synovial sublining layer contains several cell populations including macrophages, T and B lymphocytes, dendritic cells, and polymorphonuclear leukocytes. The lining layer contains large numbers of macrophages and fibroblast like synoviocytes. The interface between pannus and cartilage is occupied pre dominantly by activated macrophage populations and synoviocytes capable of secreting cytokines and destructive proteases in abundance. (Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 1999;26:717-719). The greater production of IL-1 by rheumatoid synovium, in comparison with that from patients with osteoarthritis, may be due primarily to the greater numbers of macrophages and higher degree of vascularity of rheumatoid tissue. (Farahat MN, Yanni G, Poston R, Panayi GS. Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis. 1993;52:870-875). These results all suggest that IL-1 production is abundant in synovial macrophages, and may be associated with a more active destructive stage of rheumatoid synovitis.


Cytokine Network in Rheumatoid Arthritis

Cytokines present in the joint fluid from patients with rheumatoid arthritis exhibit proinflammatory and anti-inflammatory activities:

  • Proinflammatory cytokines, shown above the dotted line, include interleukin-8, tumor necrosis factor-alpha (TNF-α), interleukin-17, interleukin-18, and interleukin-1.
  • Anti-inflammatory cytokines, shown below the dotted line, include interleukin-4, interleukin-13, interleukin-10, and interleukin-11
  • Interleukin-6, interferon gamma (IFN-Υ), interleukin-16 and transforming growth factor-beta (TNF-β) are shown straddling the dotted line because they possess both proinflammatory and anti-inflammatory properties

Cytokine Network in Synovitis


Two Pivotal Cytokines in the Pathogenesis of RA

“Once in the synovium, activated neutrophils release mediators that stimulate mononuclear leukocytes, synoviocytes, and chondrocytes. These cells release IL-1 (more specifically, IL-1β) and other pro- and anti-inflammatory cytokines. Then, once IL-1 and TNF-α are present, other interleukins (IL-6, IL-8, and IL-10) stimulate local fibroblast proliferation and recruit leukocytes. Although inflamed synovial cells express TNF-α, it is secreted to a far lesser extent than IL-1. Early in the RA disease process, IL-1 causes cartilage degradation by inducing rapid loss of proteoglycans and stimulating the production of neutral proteinases in chondrocytes. Since IL-1 also stimulates osteoclasts, bone resorption occurs”. Van den Berg WB. Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol. 1998;20:149-164


Proinflammatory Effects of IL-1 and TNF-α

Overlapping Proinflammatory Effects of IL-1 and TNF-α

Although more than a dozen cytokines are believed to be involved in rheumatoid arthritis, IL-1 and TNF-α are thought to play central roles in the pathogenesis of the disease. A listing of the inflammatory effects of IL-1 and TNF-α demonstrates the degree to which their effects are shared. In addition, IL-1 is able to induce the expression of TNF-α, and vice versa, providing further evidence of their functional interrelationship in the pathogenesis of rheumatoid arthritis.

Although overlapping, their effects are not identical. IL-1 has been particularly associated with osteoclast activation and upregulation of angiogenic factors, which may contribute to the bone and cartilage destruction and neovascularization seen in rheumatoid arthritis. TNF-α has been particularly associated with induction of apoptosis, or programmed cell death.


Terapia Farmacologica dell’Artrite Reumatoide

  • FANS tradizionali e anti-COX-2 selettivi
  • Corticosteroidi
  • DMARDs (Farmaci in grado di modificare il decorso della malattia) “sintetici”: Methotrexate; Sali d’oro; Idrossiclorochina; Sulfasalazina; Leflunomide; Altri
  • DMARDs “biologici”
  • Terapie di combinazione

The current treatment options for RA are multifocal. First, nonsteroidal anti-inflammatory drugs are commonly used. In addition, we often use corticosteroids, such as low-dose prednisone, which are often used as bridge therapy or to allow treatment for acute flares. In addition, there are a variety of other more potent, so-called disease-modifying drugs including methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and others. In the past 5 to 6 years, there have been biologic modifiers, or biologic disease-modifying drugs, approved. Moreover, in the past few years, clinicians have learned that the combination of biologic disease-modifying drugs with some of the synthetic disease-modifying drugs has added benefit and may provide more complete response than either synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs when used as monotherapy.

Obiettivi della Terapia

  • Ridurre dolore ed infiammazione
  • Migliorare la funzionalità articolare
  • Ritardare/bloccare la progressione del danno articolare
  • Indurre la remissione
  • Aumentare la sopravvivenza

Gli obiettivi principali della terapia dell’AR sono: la riduzione dei sintomi dipendenti dalla infiammazione, quali il dolore, la tumefazione articolare e la rigidità; il miglioramento/ripristino della capacità a svolgere ogni funzione; il ritardare o bloccare l’evoluzione del danno anatomico alle articolazioni. Ciò significa puntare ad un obiettivo ambizioso: la remissione (che significa guarigione di una malattia di cui non si conosce la causa che non può quindi essere eliminata). L’abolizione dell’infiammazione può ripristinare una sopravvivenza paragonabile a quella della popolazione sana.

Methotrexate


Methotrexate

Potente inibitore competitivo della diidrofolato reduttasi con inibizione dei processi di sintesi del DNA

Impiego terapeutico

  • trapianto d’organo (alti dosaggi)
  • malattie autoimmuni sistemiche (AR, LES)
    • 7,5-15 mg i.m. o per os/settimana

Effetti Collaterali del Methotrexate

  • Ematologici: neutropenia, anemia, piastrinopenia (effetto dose dipendente)
  • Gastrointestinali: stomatite, enterite, megacolon
  • Epatici: ipertensione portale, fibrosi epatica, cirrosi
  • Polmonari: interstiziopatia e fibrosi polmonare
  • Dermatologici: eritema cutaneo, eruzione cutanee, fotosensibilizzazione
  • Renali: insufficienza renale deposito di cristalli di methotrexate (effetto dose dipendente)

Biological Therapy for Rheumatoid Arthritis


New Therapies for Rheumatoid Arthritis


Infliximab


Infliximab: Meccanismo d’ Azione


Studi Clinici su Infliximab nell’AR

  • Infliximab è efficace nel controllo di segni e sintomi della AR, migliorando la funzionalità e la qualità della vita
  • Nella maggior parte dei pazienti trattati con Infliximab si verifica un arresto del danno strutturale progressivo
  • Infliximab è ben tollerato in associazione con MTX
  • La terapia con Infliximab + MTX sembra esercitare un’azione prolungata sull’AR non riscontrata con le precedenti terapie

Etanercept


Etanercept

Il trattamento con Etanercept è ben tollerato

  • Le biopsie sinoviali mostrano una diminuzione significativa del numero di linfociti T, plasmacellule, molecole di adesione e di IL-1
  • La combinazione dell’Etanercept con il Methotrexato è significativemente più efficace della monoterapia con Methotrexato

Adalimumab

  • Anticorpo monoclonale completamente umanizzato
  • Antagonista selettivo del TNF-α
  • Somministrazione in monoterapia od in combinazione con MTX
  • Struttura indistinguibile da una IgG1 umana con una emivita di circa 14 giorni
  • Iniettabile sottocute con siringa pre-riempita

Adalimumab

  • Approvato in 58 paesi, inclusi USA e paesi europei per artrite reumatoide
    • HUMIRA, in combinazione con MTX, è indicato per:
      • il trattamento di pazienti adulti affetti da artrite reumatoide attiva di grado da moderato a severo quando la risposta ai DMARDs compreso il metotressato, risulta inadeguata
      • il trattamento dell’artrite reumatoide grave, attiva e progressiva in adulti non precedentemente trattati con metotressato
  • >125.000 pazienti trattati con adalimumab nel mondo dall’approvazione nell’AR

Inibitori del TNF-α: Sicurezza

Reazioni sistemiche all’infusione (infliximab); Reazioni nei siti di iniezione (adalimumab, etanercept); Infezioni (vie aeree superiori, tubercolosi, infezioni opportunistiche); Altre potenziali complicazioni (sindrome Lupus-like, malattie demielinizzanti, tumori); Sviluppo di anticorpi bloccanti

In general, the TNF inhibitors have been shown to be fairly safe in clinical trials. However, some issues have developed at the postmarketing stage that clinicians need to be aware of as they see patients and advise them about these drugs. Infliximab is an agent that is given IV, and infusion reactions have been reported. Although they have been rare, serious, life-threatening anaphylactic reactions may occur. Injection-site reactions, again, are not a serious problem, but they are commonly reported with adalimumab and etanercept; they usually do not result in the need to discontinue the use of the drug. Common infectious complications, such as upper respiratory tract infections, sinus congestion, or infections, have been reported and are easily managed in those patients; however, there have been data published with postmarketing information that opportunistic infections and tuberculosis can be an issue with the TNF inhibitors. It is thus important to carefully screen patients by performing a purified protein derivative (PPD) skin test and chest X-ray prior to starting these drugs to make sure there is no active infection. Less common are drug-induced lupus-like syndrome, demyelinating disorders, and malignancies. These issues continue to be an area of research and need to be resolved with appropriate databases to determine if they are problems that may be part of the RA clinical spectrum or if the TNF inhibitors actually increase the risk of these side effects. Finally, some of these agents may be associated with the appearance of human antichimeric antibodies (HACAs), antibodies that develop against the TNF protein that has been administered. To date, there is very little data published about the clinical significance of these antibodies.

Anakinra

Antagonista ricombinante del recettore dell’IL-1

  • Espresso in E. coli
  • La sequenza aminoacidica è identica a quella della proteina nativa IL-1Ra eccetto che per l’aggiunta di un residuo di metionina al N-terminale aminico
  • Iniettabile sottocute con siringa pre-riempita

Anakinra: Sicurezza

  • Reazioni nei siti di iniezione
  • Infezioni (vie aeree superiori)
  • Neutropenia
  • Sviluppo di anticorpi bloccanti

Anakinra Therapy: Safety

The safety profile with anakinra has been generally positive. Some patients develop injection site reactions. Infectious complications, although not severe, have been reported, including upper respiratory tract infections. More recently, a study published in Arthritis and Rheumatism by Genovese and colleagues has shown that anakinra, when used in combination with etanercept, increases the risk for serious adverse events, and the combination of anakinra with a TNF inhibitor is no longer indicated based on the safety profile as well as data demonstrating that the combination was not more effective in suppressing the disease activity. Although not a major issue, neutropenia has been reported in the clinical trials, especially in combination with the TNF inhibitors. This has been reversible when the TNF inhibitor and the IL-1 blockers were stopped. As with the TNF inhibitors, there is also the potential of developing antibodies to anakinra, but again, these are felt not to be of major clinical significance. Of course, much more work needs to be done in order to understand the true significance and clinical consequences of antibodies to all of the biologic response modifiers.

Rituximab

Rituximab  agisce selettivamente sul CD20 
presente sulle B cellule causandone una rapida deplezione

Rituximab agisce selettivamente sul CD20 presente sulle B cellule causandone una rapida deplezione


CD20 – Antigene dei B Linfociti

  • È una fosfoproteina di 297 amino acidi (35 kDa)
  • Non è espressa sulle cellule staminali, linfociti T, cellule dendritiche e plasmacellule
  • Non sono noti ligandi naturali per il CD20
Proteina transmembrana CD20

Proteina transmembrana CD20


Rituximab (MabThera®)

Anticorpo monoclonale disegnato per depletare selettivamente i B linfociti CD20+


Rituximab – Meccanismo d’ Azione

  • La regione di derivazione murina si lega all’antigene CD20 presente sulla superficie delle B cellule
  • La regione di derivazione umana attiva i meccanismi cellulari che avviano la deplezione delle B cellule

Rituximab – Meccanismo d’ Azione

La deplezione dei linfociti B avviene mediante tre possibili meccanismi:

  • citotossicità cellulo-mediata
  • citotossicità complemento-mediata
  • apoptosi
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