New strategies for rheumatoid arthritis

New strategies for rheumatoid arthritis - Drug therapy for rheumatoid arthritis (RA), a chronic infl ammatory and destructive joint disease, rests on two bases: symptomatic treatment with NSAIDs, not interfering with the underlying immuno-infl ammatory and disease-modifying ntirheumatic drugs (DMARDs), “ modifying” the disease process. DMARDs are divided into small-molecule drugs and biological therapies. The initial approach to understanding the pathogenesis of RA and defi ning a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro . In a series of experiments using tissue taken from joints, Marc Feldmann and Ravinder Maini (Kennedy Institute, London) investigated the role of cytokines ( Figure 1.8 ), protein messenger molecules that drive infl ammation, and found that a number of pro-infl ammatory cytokines were indeed present in the infl amed joints.

Picture of the join with rheumatoid arthritis

Rheumatoid arthritis

These investigations suggested that neutralization of tumor necrosis factor-alpha (TNF- ) with antibodies significantly inhibited the generation of other pro-infl ammatory cytokines. Their fi rst clinical trial was performed in 1992 at Charing Cross Hospital and revealed rapid and dramatic improvement of rheumatoid disease activity with anti-TNF therapy. The blockade of a single cytokine, TNF- , had farreaching effects on multiple cytokines and thereby exerted signifi cant anti-infl ammatory and protective effects on cartilage and bone of joints. A chimeric anti-TNF- highaffi nity antibody was initially tested, with substantial and universal benefi t. Then, a randomized placebo-controlled double-blind trial supported the proposition that TNF- was implicated in the pathogenesis of RA and was thus a key therapeutic target. 46 Three TNF inhibitors have been approved since 1998 for the treatment of RA.

First was infliximab (Remicade®), a chimeric (human-murine) IgG1 anti-TNF- antibody, administered intravenously. It binds with high affi nity to soluble and membrane-bound TNF-thus inhibiting it. The two others are Etanercept (Enbrel®) and Adalimumab (Humira®) a recombinant humanized monoclonal anti-TNF- antibody administered subcutaneously. 47 Feldmann and Maini received the Albert Lasker award for their discovery in 2003.