The Evolution of TNF-α Blockade for the Treatment of Rheumatoid Arthritis

Tumor necrosis factor (TNF)-α is a potent trimeric cytokine which plays a fundamental role in the host immuno-inflammatory response, as well as in homeostasis and development. Although critical for canonical immune function, TNF-α has great destructive potential and is implicated in the development of multiple immune-mediated disorders. Within the context of rheumatoid arthritis (RA), TNF-α acts as a primary pathogenic driver by precipitating a pro-inflammatory cytokine cascade and coordinating the attraction and activation of immune cells, all of which culminate in damage to the synovium. The discovery of the paramount role of TNF-α in the pathophysiology of RA motivated studies to understand the effects of TNF blockade in vitro and in vivo. Promising preclinical results provided the impetus for clinical trials, spearheaded in the 1980s and 90s by Marc Feldmann, which revealed significant improvements across RA symptom scores and finally led to FDA approval in 1998. As of 2021, five TNF-α blocking agents have been widely applied clinically, including infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GLM) and certolizumab pegol (CZP). All of them successfully ameliorated symptoms of RA and the associated tissue damage, especially in patients not responding to traditional treatment methods. Anti-TNFs are most often administered in combination with methotrexate (MTX) as part of Phase II treatment (i.e., second line). Although the general availability of anti-TNFs has dramatically improved patient outcomes, sustained remission is rare and the mechanism of RA remains incompletely understood. Thus, additional basic and translational research is warranted, towards the aim of developing novel RA treatments.