THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



JAK family breakthroughs show promise in rheumatology treatment

The arrival of a newer, more finely targeted class of biologics that inhibit the Janus kinase (JAK) family could be just as transformative for rheumatologists, their patients, and their outcomes as the advent of monoclonal antibody-based biologics that inhibit the activity of tumor necrosis factor (TNF).

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John O’Shea, MD

“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.”

Dr. O’Shea will explore the expanding clinical world of JAK inhibitors during the annual Immunology Update: That’s a Fact, Jak: Targeting Signaling Type I/II Cytokines in Rheumatic Diseases from 7:30 – 8:30 am Sunday in room 146A. In addition to tofacitinib, he will discuss the latest data on baricitinib, which finished its first phase 3 trial in rheumatoid arthritis last year. Other first- and second-generation JAK inhibitors are currently in clinical trials in psoriasis, inflammatory bowel disease, organ transplant rejection, and other immunological diseases.

Clinicians have been targeting cytokines to treat autoimmune disease for years, Dr. O’Shea said. But most biologics target cytokines through the circulatory system, and most biologics used to treat autoimmune disease must be injected. JAK inhibitors target cytokine activity within cells by disrupting intracellular signaling pathways. And JAK inhibitors are small molecule oral agents, and so are more convenient for patients.

Cytokines are critical elements in host defense, but they are also key mediators of immune-mediated diseases, Dr. O’Shea said. CD4+ helper cells produce a wide range of cytokines as part of their role of orchestrating immune response to pathogens but can also lead to pathogenic cytokine production and autoimmune disease.

A substantial portion of known cytokines, more than 60 at last count, bind to receptors that are associated with JAKs, a specific class of protein tyrosine kinases. O’Shea’s lab first cloned human JAK3, a kinase important in Interleukin-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signaling. Mutations to JAK3 underlie autosomal recessive severe combined immunodeficiency and helped identify JAK signaling as a viable therapeutic target.

Most current clinical training programs include kinases and intracellular signaling. But the field is so new that many clinicians who have been out of medical school and residency more than a few years have never been exposed to the details of JAK signaling or its potential clinical importance.

“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.”

For all their clinical utility, JAK inhibitors are not without problems. Like nearly every agent used to treat autoimmune disease, JAK inhibitors increase the risk of infection. The good news, Dr. O’Shea said, is that the rate of infection seen with JAK inhibitors is comparable to rates seen with more familiar biologics. The better news is that JAK inhibitors may be superior to biologics in some circumstances and can often be used in patients who have failed biologic therapy.

“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.”

BASIC SCIENCE TRACK
Immunology Update: That’s a Fact, Jak: Targeting Signaling Type I/II Cytokines in Rheumatic Diseases
7:30 – 8:30 am Sunday • Room 146A