Dr. Roy Fleischmann discusses JAK inhibitors from a rheumatologist’s perspective, addressing their structure and function as well as the pathways utilizing JAKs, and the safety and utility of these drugs across a variety of disease states.
This is Part 1 in a 3-part series.
Roy Fleischmann, MD, MACR, is Clinical Professor of Medicine at the University of Texas Southwestern Medical Center and Co-Medical Director of the Metroplex Clinical Research Center, Dallas, Texas.
“The Metroplex Clinical Research Center has been involved with studies of [Janus kinase] JAK inhibitors over the past 15 years. I will first address what inhibition of the JAK pathway means clinically.”
JAK1, JAK2, JAK3, and tyrosine kinase (TYK2) compose the JAK family.
“And they form different combinations, usually dimers but occasionally trimers. There is only one homodimer and that is JAK2.”
The combination of JAK1 and 3 affect the gamma chain cytokines interleukin- (IL-) 2, 4, 7, 9, 15, and 21. The combination of JAK2 and TYK2 is particularly interesting to dermatologists, as this dimer signals through IL-12 and IL-23. There other combinations of JAKs affecting different cytokines with resulting different biological functions, depending on the combination, said Dr. Fleischmann.
“The functions of JAK1/3 dimer, for example, are growth and maturation of lymph cells, differentiation and homeostasis of T-cells and NK cells, B-cell class switching, and inflammation. The biological function of JAK2/TYK2 are innate immunity, differentiation and proliferation of Th17 cells, and inflammation.”
JAK inhibitors are oral, synthetic small molecules. They are chemicals and not proteins that have specific targets, according to Dr. Fleischmann.
“The approved Janus kinase (JAK) inhibitors, tofacitinib (pan JAK inhibitor), baricitinib (JAK1/2 inhibitor), and upadacitinib (preferentially JAK1 inhibitor), are targeted competitive inhibitors of the adenosine triphosphate [ATP] binding site (also referred to as the ‘catalytic binding site’) on JAKs, while deucravacitinib, a TYK2 inhibitor, binds to the ‘pseudokinase domain’ of TYK2 and ‘allosterically’ (via conformational changes in TYK2) alters the catalytic ATP binding site preventing ATP binding.”
Cytokine signaling occurs through multiple intracellular pathways, including the JAK pathway, said Dr. Fleischmann.
“Cytokine receptor activation and JAK pathway signaling occur in the following sequence. First, a cytokine binds to type I and type II cell surface receptors followed by JAK activation and phosphorylation by ATP. Signal transducers and activators of transcriptions (STATs) then bind at the receptor and are phosphorylated by activated JAKs, which is followed by the STAT translocating to the nucleus to alter gene transcription and cytokine production.”
The cytokines produced usually are a combination of both pro-inflammatory and anti-inflammatory molecules, said Dr. Fleischmann.
“JAK inhibitors target this intracellular cytokine signaling cascade by competitive inhibition of JAK1/2/3 or by binding to the pseudokinase domain of TYK2, as noted previously. As a result of the inhibition of the binding of ATP by either mechanism, the JAKs cannot phosphorylate the cytokine receptors, STATs cannot dock and are not phosphorylated or thus not activated.”
The end result, according to Dr. Fleischmann, is decreased gene transcription and cytokine production.
“By inhibiting JAK pathways, JAK inhibitors modulate signaling of multiple cytokines involved in the pathogenesis of rheumatoid arthritis and psoriatic arthritis, as well as other diseases.”
JAKs in Rheumatology
Three JAK inhibitors are approved in the U.S.—tofacitinib (Xeljanz, Pfizer), baricitinib (Olumiant, Lilly), and upadacitinib (Rinvoq, AbbVie). All are approved for rheumatoid arthritis. Upadacitinib and tofacitinib also are approved for psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis, said Dr. Fleischmann.
“We find these drugs very useful as they are not only very effective but are also oral and patients prefer oral medications.”
JAK inhibitors work by inhibiting multiple cytokines, but they don’t inhibit the cytokine fully, according to Dr. Fleischmann.
“An anti-tumor necrosis factor (TNF) may inhibit 90% or 92% of TNF but the JAKs inhibit 40% or 50% of each of multiple cytokines. Published head-to-head studies have demonstrated that JAKs are at least as effective as TNFs in rheumatoid arthritis.2,3.4 JAK inhibition has been found effective in psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. The fact that they inhibit the production of multiple cytokines, although not fully, is probably the reason why they are effective and relatively safe.”
With respect to relative efficacy of the JAK inhibitors, “There are no head-to-head studies of JAKs, but it appears that they have similar efficacy at least in rheumatoid arthritis. In psoriatic arthritis (PsA) there may be a difference—there may be an advantage to upadacitinib over tofacitinib, but tofacitinib is effective. I can’t comment on baricitinib because I haven’t seen those studies. In ankylosing spondylitis and ulcerative colitis, both tofacitinib and upadacitinib are effective,” said Dr. Fleischmann.
As for their safety profiles, although tofacitinib is a pan JAK inhibitor and upadacitinib affects primarily JAK1, their safety is actually very similar when you look at the integrated safety databases, according to Dr. Fleischmann.
“So, the differences are in the test tube but not what we see clinically.”
“Prior to the FDA change5 to the product label earlier this year, tofacitinib and upadacitinib were popular drugs that we used as first-line therapy after methotrexate. The reason for that is they are oral with a great deal of patient acceptance. And there are many patients who can take these drugs as monotherapy, many more so than with biologics which are generally more effective in combination with methotrexate,” said Dr. Fleischmann.
In Part 2 of this series, Dr. Fleischmann goes in-depth into JAK inhibitor safety, the ORAL surveillance study, and the impact of the FDA’s recent label change.
References
- Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927.
- van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis [published correction appears in N Engl J Med. 2013 Jul 18;369(3):293]. N Engl J Med. 2012;367(6):508-519. doi:10.1056/NEJMoa1112072.
- Fleischmann RM, Genovese MC, Enejosa JV, et al. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann Rheum Dis. 2019;78(11):1454-1462. doi:10.1136/annrheumdis-2019-215764.
- Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. doi:10.1136/annrheumdis-2021-221276.
- FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. FDA.gov. December 2021 Update. Accessed March 23, 2022. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions | FDA
Disclosures: Dr. Fleischmann is a consultant with AbbVie, Amgen, and Pfizer.
