Cytokine Signalling Forum

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Thromboembolism with Janus Kinase (JAK) Inhibitor for Rheumatoid Arthritis: How Real is the Risk?

Scott IC, Hider SL, Scott DL. - Drug Safety 2018 Jul;41(7):645–53

Current data suggests that JAK inhibitors may increase the risk of thromboembolism and pulmonary thrombosis (PT) in RA.

Two JAK inhibitors – baricitinib (BARI) and tofacitinib (TOF) – are considered effective treatments for RA, however, there are concerns about the thromboembolic risks associated with them. In August 2017, the summary of product characteristics for BARI was revised to include a warning of developing DVT and pulmonary embolism (PE), with recommendations that BARI should be used with caution in high-risk patients. Risks have also been identified in TOF, with post-marketing surveillance data suggesting an association with PT.

This paper reviews the evidence for thromboembolic events associated with BARI; assessing thromboembolic risk with RA, other drugs to treat RA, and other JAK inhibitors. The authors also considered the challenges of unexpected adverse events (AEs) with new RA treatments.

Network meta-analysis of Phase 2 and 3 trials found that significantly more patients achieved ACR20 with BARI 4 mg + MTX, or other DMARDs versus control. Rates of treatment-emergent AEs were similar between BARI and control patients¹. In six BARI trials, three thromboembolic events were reported: one control patient developed a fatal PE; one patient taking BARI 4 mg developed a PE and another developed thrombophlebitis; neither was fatal2–7. During analysis, no new safety concerns emerged during the observation period.

Data from FAERs identified increased risks of PT associated with TOF, TOF extended release, and ruxolitinib, although these findings should be viewed with caution due to limitations with post-marketing surveillance9.

Due to limitations with the data, large observational studies are needed to accurately calculate the risks attributable to new and existing drugs used to treat RA, and to differentiate them from the underlying disease. Until more information is available, clinicians prescribing JAK inhibitors for RA should use them cautiously in patients with pre-existing potential thromboembolic risks.

1. Lee YH, et al. Z Rheumatol 2017. doi: 10.1007/s00393-016-0254-4.
2. Fleischmann R, et al. Arthritis Rheumatol 2017;69:506–17.
3. Taylor PC, et al. N Engl J Med 2017;376:652–62.
4. Dougados M, et al. Ann Rheum Dis 2017;76:88–95.
5. Tanaka Y, et al. J Rheumatol 2016;43:504–11.
6. Keystone EC, et al. Ann Rheum Dis 2015;74:333–40.
7. Genovese MC, et al. N Engl J Med 2016;374:1243–52.
8. Verden A, et al. Drug Saf 2017. doi: 10.1007/s40264-017-0622-2.