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New rheumatoid arthritis drug targets NIH-discovered protein

WHAT: The U.S. Food and Drug Administration recently approved a new oral medication for the treatment of rheumatoid arthritis that represents a new class of drugs for the disease. The drug, tofacitinib (Xeljanz), provides a new treatment option for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate, a standard therapy for the disease.

Affecting nearly 1.5 million adults, rheumatoid arthritis is an inflammatory disease that causes pain, swelling, stiffness, and loss of function in the joints. It occurs when the immune system, which normally defends the body from outside invaders such as bacteria and viruses, attacks the membrane that lines the joints.

Tofacitinib is from a new class of drugs developed to target Janus kinases. One member of this family, JAK3, was discovered in the early 1990s by a National Institutes of Health laboratory in the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Subsequent studies carried out at the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the NIAMS, showed that genetic defects in JAK3 can cause severe combined immunodeficiency. This discovery led to the idea that drugs blocking Janus kinases would suppress the immune system and might be protective against the damaging inflammation of rheumatoid arthritis and certain other autoimmune diseases.  

The approval of tofacitinib represents the first time in a decade that the FDA has approved an oral disease modifying antirheumatic drug, or DMARD, for the treatment of rheumatoid arthritis. This broad class of drugs slows or halts the progression of damage from the disease, rather than merely providing relief from symptoms. Unlike biologic treatments for rheumatoid arthritis— which are also DMARDs and target immune system proteins— tofacitinib is a pill, not an infusion or an injection. It is the first Janus kinase inhibitor to receive an FDA approval for rheumatoid arthritis.


John J. O'Shea, M.D., scientific director of the NIAMS, is the NIH researcher who discovered JAK3 and first cloned the human form of the protein. In 1993, shortly after O’Shea and his team discovered the JAK3 protein and established its role in inflammation, O’Shea learned that scientists at Pfizer were searching for drug targets to tackle autoimmunity and transplant rejection.  Subsequent discussions led to an innovative public-private collaboration between NIH and Pfizer, through a cooperative research and development agreement. This agreement allowed teams from both organizations to work together toward the common goal of finding a new immune-suppressing drug for this debilitating disease.

Warren J. Leonard, M.D., director of the Immunology Center in NHLBI, is a pioneer in immune research whose group first identified the genetic mutations that are responsible for X-linked severe combined immunodeficiency (XSCID), commonly known as the “Bubble Boy Disease.” Leonard, in collaboration with O’Shea, then demonstrated that the protein that is defective in XSCID associates with JAK3, and that humans with mutations in JAK3 have a form of immunodeficiency clinically similar to XSCID. That discovery led to their hypothesis that JAK3 inhibitors might be potent immunosuppressive agents, as is the case for tofacitinib.

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