ACR Session Shows Value of JAK Inhibitors in Autoimmune Diseases

Findings from recent studies suggest that the creation of targeted biologic drugs that inhibit Janus Kinase (JAK) could be just as revolutionary as the creation of tumor necrosis factor (TNF) inhibitors.

JAK inhibitors are currently in clinical trials for rheumatoid arthritis, psoriasis, inflammatory bowel disease, transplant rejection, and many other autoimmune diseases.

“Some clinicians know about the JAK inhibitors, but it’s new to many,” said John O’Shea, MD, Scientific Director and Senior Investigator of the Molecular Immunology and Inflammation Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “The first member of this class, tofacitinib, was approved in 2012, but it’s a very fast-moving field with multiple new agents being studied.”

The importance of these new drugs are being discussed at the American College of Rheumatology and Association of Rheumatology Health Professionals annual meeting. Baricitinib is an investigational JAK inhibitor developed by Eli Lilly, and is being evaluated in ongoing phase 3 trials.

Investigators have focused on targeting cytokines for the treatment of autoimmune diseases, but a majority of biologic drugs target them through the circulatory system, according to the session. A majority of biologics also must be injected, which can present a problem to a patient whose condition may prevent them from physically being able to do so, or if the patient is afraid of needles.

However, JAK inhibitors target cytokines through the cells themselves by disrupting signaling pathways. These drugs are also able to be administered orally, making it more convenient for patients.

While cytokines are a crucial part of a health, functioning immune system, they also play a key role in many autoimmune diseases. CD4+ cells produce these cytokines to orchestrate the immune response, but it can also lead to pathogenic cytokine production and diseases, according to the session.

Over 60 known cytokines bind to receptors associated with JAKs, a family of protein tyrosine kinases. Dr O’Shea and his research team have successfully cloned JAK3, which is a kinase that is involved with multiple interleukin signaling pathways.

Mutations in this kinase are associated with autosomal recessive severe combined immunodeficiency, which helped determine that JAK signaling could potentially be a valuable treatment target, Dr O’Shea said.

Due to how new JAK signaling is, a majority of physicians and clinicians who are practicing in the field have not been exposed to the importance of JAK signaling, which suggests that increased education in this area would benefit patients and physicians alike.

“This particular pathway is pretty simple, with just a few elements,” Dr. O’Shea said. “There is the receptor, the JAKs, and transcription factors called STATS. It’s a very simple pathway but so basic and so important that it is evolutionarily conserved from insects to mammals. This class of drugs has tremendous potential utility in a variety of clinical settings. There is even a canine JAK inhibitor that has been approved for allergic dermatitis in dogs. JAK inhibition is a huge area.”

JAK inhibitors do have their downfalls, and can increase the risk of infections in patients taking these medications. The rate of infections associated with JAK inhibitors is similar to the rate seen with other biologics, according to the session.

These new JAK inhibitors may even be superior to biologics in some cases, and can provide an effective treatment option for patients who did not respond to biologic treatments.

“Intracellular signaling and JAK inhibition may seem a little daunting at first encounter, but the number of agents in this class is poised to grow significantly,” Dr. O’Shea said. “This is an area that any clinician who works in autoimmune disease will want to know more about. This symposium will be an easy way to take that first leap toward understanding more about intracellular signaling as it relates to rheumatoid arthritis and other familiar autoimmune diseases.”