NIH Research Leads to New Rheumatoid Arthritis Drug
Posted on by Dr. Francis Collins
About 1.5 million  people in the US suffer from rheumatoid arthritis (RA). It is a chronic illness in which the immune system, which protects us from viral and bacterial invaders, turns on our own body and viciously attacks the membranes that line our joints. The consequences can be excruciating: pain, swelling, stiffness, and decreased mobility. Over time, the joints can become permanently contorted, as in this X-ray image.
There are several RA medications on the market, but I want to tell you about a new one called tofacitinib, a pill which the FDA approved late last year . The drug works by targeting a protein called Janus kinase 3, which was discovered by John O’Shea and colleagues here at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 20 years ago . As I mentioned in a previous post it takes a really long time to go from a basic discovery to a drug—in most cases nearly 15 years. This drug has been even longer in the making! Shortly after discovering Janus kinase 3 in 1993, NIAMS researchers also revealed its role in inflammation, leading to a public-private collaboration with Pfizer that has now culminated in the approval of tofacitinib.
These Janus kinases (we call them JAKs) are critical messengers in the cell. They receive signals from immune proteins and growth hormones, among others, and convey that message to another group of proteins called STATs (signal transducers and activators), which then alter the activity of particular genes. This JAK-STAT messenger system is absolutely essential for regulating cell growth and development, metabolism, blood cell formation, immune system function, and many other activities critical for normal health and development.
Mutations in a particular JAK or STAT can make these proteins too active, or not active enough, disrupting the messenger system and causing diseases ranging from cancer to dwarfism to autoimmune conditions, including rheumatoid arthritis. Other mutations in the JAKs and STATs make some people more vulnerable to viruses and bacteria, or block the development of their white blood cells.
Tofacitinib is particularly noteworthy because it is the first FDA approved drug for treatment of an autoimmune disease that works by inhibiting a JAK protein.
There’s a terrific review article on the role of JAKs and STATs in the January 10th issue of the New England Journal of Medicine  that describes the four JAK proteins, and the seven STAT proteins, and their roles in health and disease. For example, a mutation in JAK3 that makes the protein less active causes an immune deficiency condition similar to that suffered by the Bubble Boy, David Vetter, 30 years ago. On the other side of the coin, mutations in other JAKs that make these proteins hyperactive can trigger T-cell and B-cell acute leukemia or types of lymphomas. Hindering the activity of STAT1 leaves a person vulnerable to bacteria and viruses. You get the idea. Each of these proteins has a specific job, so if you are developing a drug you want to target only the misbehaving protein—you don’t want to disrupt the functions of all members of that protein family as well.
Tofacitinib inhibits three of the four JAKs, ratcheting down the overactive immune response that drives RA. It changes the way the immune system works, potentially raising the risk of some cancers. However, the most common side effects have been upper respiratory infections, headaches, and diarrhea.
Ultimately researchers will likely discover drugs that specifically target each one of these JAK and STAT proteins, so that we can minimize drug side effects and treat the broad array of diseases that occur when the JAK-STAT pathway is disrupted. But for now, having the first magic bullet to target this pathway in autoimmune disease and help the legions of people with RA is a great step forward.
 Rheumatoid Arthritis. (CDC Factsheet)
 FDA approves Xeljanz for rheumatoid arthritis. (FDA News Release, Nov. 6, 2012)
 Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O’Shea JJ. Nature. 1994 Jul 14;370(6485):151-3.
 JAKs and STATs in immunity, immunodeficiency, and cancer. O’Shea JJ, Holland SM, Staudt LM. N Engl J Med. 2013 Jan 10;368(2):161-70.