Anti-tnf therapy: 20 years from our first therapeutic adventure

Abstract

Anti-tumor necrosis factor (TNF) therapy was the first successful anti- cytokine therapy, and its discovery was based on detailed examination of human disease tissue in rheumatoid arthritis and on exploring the dysregulation of cytokine expression within that tissue. From those first successful clinical trials we conducted in 1992 with infliximab, which were widely publicized more than a year before publication, a competition emerged between a set of companies that had made anti-TNF monoclonals and receptor fusion proteins to treat sepsis to get their products on the market for rheumatoid arthritis (RA). Subsequent clinical trials based on RA success took place in other diseases: Crohn's disease, ankylosing spondylitis, psoriasis, psoriatic arthritis, and ulcerative colitis. By 1999 etanercept, a tumor necrosis factor-receptor (TNF-R) p75: IgG Fc fusion protein, was approved for RA and infliximab, a chimeric anti- TNF monoclonal antibody, was approved for RA and Crohn's disease. The foregoing diseases subsequently all became approved indications for anti-TNF therapy that has emerged as the first successful anti-cytokine therapy. By 2013 anti-TNF had become a huge commercial success with global sales of US$27 billion, replacing statins as the most valuable drug class. But there are many challenges remaining. There are many other diseases that could benefit from anti-TNF therapy, and we discuss many but not all of them in this review. And then, it is clear that anti-TNF therapy is not a cure. We need to get closer to a cure and find complementary therapeutics that when added to anti-TNF would take us closer to a cure. Doing so safely and reproducibly is a challenge, but great understanding of the pathogenesis of RA and how anti-TNF works will be helpful.