Examining the Safety Profile of Janus Kinase (JAK) Inhibitors in the Management of Immune-Mediated Diseases: A Comprehensive Review

Abstract

Janus kinase (JAK) inhibitors have heralded a paradigm shift in the management of immune-mediated diseases. While their efficacy is well-established, the safety concerns associated with these agents, particularly regarding thromboembolic events (TE), remain a focus of extensive research and clinical scrutiny. This comprehensive literature review embarks on an exploration of the multifaceted landscape of JAK inhibitors, providing insights into their safety profiles across diverse immune-mediated diseases. The introduction highlights the transformative influence of JAK inhibitors in the treatment of immune-mediated diseases. Historically, the therapeutic arsenal for these conditions included corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologics. The advent of JAK inhibitors has revolutionized this landscape, although concerns about their safety persist. This review strives to comprehensively evaluate their safety, amalgamating knowledge from multiple studies and trials. The subsequent sections delve into the safety of specific JAK inhibitors in the context of rheumatoid arthritis, inflammatory bowel diseases, and dermatologic conditions and their associations with venous thromboembolism. The evolving understanding of TE risk, particularly the intricate relationship between these agents and immune-mediated diseases, is meticulously unravelled. The concluding remarks underscore the dynamic nature of TE risk assessment with regard to immune-mediated diseases involving JAK inhibitors. It underscores that risk assessment is multifactorial, influenced not only by the choice of JAK inhibitor but also by the nuances of the underlying immune-mediated disease and the unique patient characteristics. This review offers a holistic perspective on TE risks associated with JAK inhibitors and contributes to the ongoing dialogue regarding their safety in the realm of immune-mediated diseases.

Keywords: JAK inhibitors; adverse events; immune-mediated diseases; safety profile.

Figure 1

Overview of Janus kinase (JAK) signalling pathways in autoimmune diseases and cancers. The binding of different type I and II cytokines to specific receptor subunits associated with JAKs leads to the activation of specific downstream intracellular signals. STATs represent a prominent class of molecules that can transmit signals from cytokine receptors to the nucleus to activate the transcription of several specific target genes. Different JAK/STAT signalling pathways contribute to the pathogenesis of various immune-mediated diseases [4]. MPN—myeloproliferative neoplasms, PMF—primary myelofibrosis, AML—acute myeloid leukaemia, CLL—chronic lymphocytic leukaemia, ALL—adult acute lymphoblastic leukaemia, SLE—systemic Lupus erythematosus, PsO—psoriasis, PsA—psoriatic arthritis, IBD—inflammatory bowel diseases, and RA—rheumatoid arthritis.

Figure 2

Cytokine signalling through JAK/Stat combination [2].

Figure 3

Timeline of approved indications for Janus kinase inhibitors for rheumatic diseases [19].

Figure 4

Possible mechanism behind the prothrombotic effects associated with the administration of Jakinibs. JAKs in various combinations bind to cytokine receptors that transmit prothrombotic and proinflammatory signals from a wide range of cytokines. With the exception of IL-10, IFNβ, and IFNλ that have anti-thrombotic potential, signalling downstream of these cytokines creates a permissive background for thrombus formation. Non-specific Jakinibs that target both of the IL-10R-associated JAKs (JAK1 and TYK2) or IFNβ- and IFNλ-associated JAKs (JAK1 and TYK2) may result in an imbalance in the pro- and anti-thrombotic signalling resulting in thrombus priming [47].

Figure 5

Exposure-adjusted event rates for TEAEs of special interest [56]. † excluding TB, oral candidiasis, and herpes zoster. ‡ defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. § including deep vein thrombosis and pulmonary embolism. RA: UPA 15 mg QD (n = 3209), ADA 40 mg EOW (n = 579), MTX (n = 314); PsA: UPA 15 mg QD (n = 907), ADA 40 mg EOW (n = 429); AS: UPA 15 mg QD (n = 182); AD: UPA 15 mg QD (n = 1340), UPA 30 mg QD (n = 1353). AD, atopic dermatitis; ADA, adalimumab; AS, ankylosing spondylitis; CPK, creatine phosphokinase; E, event; EOW, every other week; GI, gastrointestinal; MACE, major adverse cardiovascular event; MTX, methotrexate; NMSC, non-melanoma skin cancer; PsA, psoriatic arthritis; PY, patient years; QD, once a day; RA, rheumatoid arthritis; TB, tuberculosis; TEAE, treatment-emergent adverse event; UPA, upadacitinib; VTE, venous thromboembolic event.