Then came the serendipitous discovery that anti-TNF antibodies markedly improved the synovitis and systemic features in patients with rheumatoid arthritis (RA), ushering in our current era of using biological therapeutics in clinical medicine.
Another successful offshoot of the cancer wars was the recognition that the anti-B cell therapy, rituximab—originally developed as a treatment for lymphoma—was highly useful in combating a variety of autoimmune diseases, including RA, vasculitis and a host of rarer conditions—some B cell mediated and others not.
Not all of rheumatology’s novel therapies were derived from the cancer research lab. For example, the realization that interleukin-6 (IL-6) was a critical mediator of systemic inflammation was understood in the 1980s, although it took another decade of research, primarily in Japan, to develop the first monoclonal antibody targeting the IL-6 receptor.
Beating these diseases requires a prolonged conflict, perhaps another Hundred Years’ War.
Sometimes, the flow of discovery shifts into reverse and the rheumatology lab becomes the source of a novel cancer therapy. One recent example was the elegant elucidation of how extracellular cues are sensed by living cells and translated into the control of gene expression. This work, carefully ushered from the bench to the bedside, was based on the pivotal research of John O’Shea, MD, senior investigator in the Molecular Immunology and Inflammation Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in Bethesda, Md., and colleagues. Their work helped identify the critical role of tyrosine kinases in cell signaling via the Janus kinase-signal transducer and activator of transcription pathway, better known by its acronym, Jak-STAT.7 The pharmacologic inhibition of this pathway has led to the creation of several drugs that have shown efficacy in treating RA and an array of cancers, as well.
The Intersection of Cancer & Autoimmunity
Historically, the drugs in the rheumatologist’s armamentarium have evolved from a number of broad-based therapies that have a wide array of effects (think prednisone), some good and some not. The story is no different for oncologists. Perhaps the greatest thrust of the Cancer Moonshot and similar efforts has been to supplant some of the highly toxic alkylating cancer drugs with an ever-widening selection of more targeted therapies.
Lately, the buzz has been all about drugs that can deactivate the switches that, when tampered with, unleash the power of the immune system. Move over Bacillus Calmette-Guerin! These switches, better known as the checkpoints, include the solemnly named programmed death-1 (PD-1), a term that conjures up images of a heavy metal band, and the equally dour, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Checkpoints normally prevent the immune system from attacking its unsuspecting host, a deleterious activity that can trigger the development of autoimmune diseases.
