JAK-Inhibitors – A Story of Success and Adverse Events

Abstract

Rheumatoid arthritis (RA) is a systemic, chronic, immune-mediated inflammatory condition. Treatments options encompass conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors (TNFis) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) including Janus Kinase inhibitors (JAKinibs). Orally administered JAKinibs have demonstrated comparable or, in specific cases, superior efficacy compared to bDMARDs in inflammatory conditions. However, the escalating clinical utilization has been accompanied by the emergence of serious adverse effects, including major adverse cardiac events (MACE), malignancies and venous thrombotic episodes (VTE), leading to regulatory restrictions imposed by health authorities in both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Keywords:

• rheumatoid arthritis
• treatment
• safety restrictions
• major adverse cardiac events
• malignancies
• venous thrombotic episodes

Abbreviations

RA, rheumatoid arthritis; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; bDMARDs - biologic disease-modifying antirheumatic drugs; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs; TNF, Tumor Necrosis Factor; TNFi, Tumor Necrosis Factor inhibitor; JAK, Janus Kinase; JAKinibs, Janus Kinase inhibitors; MACE, major adverse cardiac events; VTE, venous thromboembolism; FDA, Food and Drug Administration; EMA, European Medicines Agency; TYK2, Tyrosine Kinase 2; JAK1, Janus Kinase 1; JAK2, Janus Kinase 2; JAK3, Janus Kinase 3; ATP, Adenosine Triphosphate; HZ, Herpes Zoster; bd, twice daily; DSMB, data safety monitoring board; PE, pulmonary embolism; MAA - Marketing Authorization Application; CHMP - Committee for Medicinal Products for Human Use; PRAC - Pharmacovigilance Risk Assessment Committee; EULAR - European League against Rheumatism; IR, incidence rates; NNH, number needed to harm; RCT, randomized controlled trial; CI, confidence interval; DVT, deep venous thrombosis; LTE, long-term extension study.

Authors´contribution

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work

Disclosure

The authors report no financial or non-financial competing interests.

Additional information

Funding

MM is funded by the Austrian Science Fund (FWF) Special Research Program (SFB) F6101.