03/06/2022
Safety concerns with JAK inhibition (Xeljanz, Olumiant, Rinvoq)
Nature, rheumatology, Jan 2022:
As potent immunosuppressive agents, the incidence rates of infections, including opportunistic infections, are comparable with those for bDMARDs (eg Humira), with the exception of the rate of herpes zoster infections, which is slightly higher for JAK inhibitors.
Studies on the long-term safety of tofacitinib with follow-up of up to 9.5 years identified no changes over time in incidence rates of infection, opportunistic infection, serious infection, malignancy, thrombosis or cardiovascular disorders.
In an integrated safety analysis of five phase III trials, upadacitinib (Rinvoq) had comparable short-term and long-term safety with methotrexate and adalimumab (Humira), except for a higher risk of herpes zoster.
JAK inhibitors are also associated with potentially serious effects, including malignancy, major adverse cardiovascular events (MACEs) and venous thromboembolic events.
The ORAL-Surveillance study (NCT02092467) compared the safety of tofacitinib (Xeljanz) and TNF inhibitors. The results of the study have not yet been published, but the preliminary data are available on the sponsor’s website and in the trial register (NCT02092467).
The initial preliminary result in 2019 demonstrated an association with the risk of venous thromboembolism and death in patients taking tofacitinib 10 mg twice-daily dosage, but not 5 mg twice-daily dosage, prompting an FDA warning in relation to high-dose tofacitnib. However, later results show a higher incidence of MACEs and malignancies excluding non-melanoma skin cancer in patients with RA treated with either 5 mg or 10 mg twice-daily dosage of tofacitinib than in patients treated with a TNF inhibitor. In response to this study, the FDA released an updated boxed warning in September 2021 regarding the increased risk of death, MACEs, malignancies and thrombosis with JAK inhibitors compared with TNF inhibitors.
It also limits all approved uses to certain patients who have not responded to or cannot tolerate one or more TNF blockers. Although this study only compared tofacitinib with adalimumab, the FDA was concerned about a JAK-inhibitor class effect, and the warning was extended to two other JAK inhibitors approved in the USA for treatment of inflammatory diseases, baricitinib and upadacitinib.
Additionally, in clinical scenarios where TNF inhibitors have failed or not been appropriate, the choice between other biologics and JAK inhibitors is unclear.
Some of the adverse events associated with JAK inhibitors are predicted by mechanisms related to the blockade of cytokines that use JAK–STAT for signalling, which could explain the risk of serious and/or opportunistic infections such as herpes zoster. However, the occurrence of thromboembolism, although relatively rare, is an unexpected and unexplained event.
Thus, although the use of JAK inhibitors is convenient because of their oral administration, it should be carefully considered. Adequate screening should be performed for factors such as infection, cardiovascular disorders, thrombosis and malignancy. Contraindications to the use of JAK inhibitors are related to pharmacokinetic and pharmacodynamic profiles and adverse events, and include: severe active infection (acute or chronic), including latent tuberculosis and opportunistic infections with the apparent exception of COVID-19; active malignancy; severe organ damage (including severe hepatic or renal disease); pregnancy and lactation; and history of venous thromboembolism.
Ruxolitinib (an inhibitor of JAK1 and JAK2) is approved for treatment of both acute and chronic graft-versus-host disease in patients >12 years old.
Finally, appropriately and regularly planned monitoring during treatment should be performed for known risks including infection, cardiovascular disorders, thrombosis and malignancy. Long-term safety studies regarding the development of infection and malignancy (such as lymphoma) need to be conducted.
Janus kinase inhibition modulates a range of immune and inflammatory processes. In this Review, the authors discuss progress in the therapeutic use of Janus kinase inhibitors in autoimmune rheumatic diseases, with a focus on their disease-specific mechanisms of action.
