Advances in the use of Janus kinase inhibitors

Over the last two decades, oral small molecules that target intracellular protein kinases that mediate intracellular signaling have been found to be effective in multiple immune mediated inflammatory diseases (IMIDs). Tofacitinib was the first Janus kinase inhibitor (JAKi) approved for rheumatoid arthritis (RA) in 2012 and subsequently baricitinib, upadacitinib, and filgotinib have been approved by various regulatory agencies around the world. Substantial efficacy in RA as well as other rheumatic diseases (axial spondyloarthritis, psoriatic arthritis, giant cell arteritis) and other IMIDs (inflammatory bowel disease, atopic dermatitis) has been demonstrated. Various JAKi are in trials for lupus, inflammatory myopathies and Sjogrens with recent positive results noted in phase 2/3 clinical trials.

Although efficacy has been clearly demonstrated safety concerns have been raised based on the oral surveillance postmarketing clinical trial which demonstrated in RA patients ≥ 50 years old with cardiovascular risk factors treated with tofacitinib have an increase risk of venous thromboembolism and possibly major adverse cardiovascular events/malignancy compared to tumor necrosis factor inhibitor treated patients. Extensive investigations in clinical trials and real world observations over the last few years have addressed the safety issues with mixed results but have allowed for risk stratification and appropriate use of JAKi. Efforts to develop JAKi that are more selective for specific JAK isoforms are ongoing such as deucravacitinib - a TYK2 inhibitor with a different mechanism of action compared to other JAKi that might have an enhanced safety profile.

Increased use of JAKi in the management of IMIDs is ongoing and will accelerate if the positive results noted in trials for lupus, inflammatory myopathies, and psoriatic arthritis result in regulatory approval. The article highlighted in this review provide an update on the progress being made in newer rheumatic disease indications as well as efforts to better understand the adverse event profile for patients on treatment.

Delineation of the JAK-STAT pathway critical for type 1/II cytokine signaling in late 1990s resulted in the development of multiple JAKi for IMIDs. Tofacitinib was the original JAK inhibitor approved in 2012 followed by baricitinib in 2017 and upadacitinib in 2019 with filgotinib and pefecitinib approved ex-US all for rheumatoid arthritis. Since the original approval JAK inhibitors have been approved for multiple IMIDs. In this manuscript, data from clinical trials evaluating JAK inhibitors for new IMID indications will be reviewed as well as an update on safety data from real world experience.