Updates on JAK Inhibitor Safety, COVID-19 Vaccination in Immunosuppressed Patients & More

Dr. Jeffrey Curtis

ACR CONVERGENCE 2021—The ACR Convergence 2021 meeting reflected the continued advancement of science and practical research in the field of rheumatoid arthritis (RA). Among the most important topics this year in RA was the evolution of the risk-benefit profile of Janus kinase (JAK) inhibitors, for which new safety data emerged in a series of related abstracts.

JAK RESEARCH

Results from the recently completed, worldwide, randomized, head-to-head comparison of a JAK inhibitor therapy (tofacitinib) vs. tumor necrosis factor (TNF) inhibitor therapy, adalimumab or etanercept, were reported in a series of four important presentations.

Abstract 0831: Safety and efficacy of tofacitinib vs TNF inhibitors in RA patients aged 50 years or older with one or more cardiovascular risks: Results from a phase 3b/4 randomized safety trial

Research by Ytterberg SR, et al.¹

The comparative safety of JAK inhibitor therapy on the pre-specified outcomes of major adverse cardiac events (MACE) and malignancy from the Oral Surveillance trial were unveiled for the first time. This trial fulfilled a regulatory requirement and was designed to demonstrate the non-inferiority of tofacitinib compared with adalimumab (in North America) or etanercept (in the rest of the world) in 4,362 patients randomized to tofacitinib 10 mg twice daily, 5 mg twice daily, or TNF inhibitor therapy.

For both MACE and malignancy outcomes, tofacitinib failed to meet the pre-specified non-inferiority outcomes. The risk (hazard ratio) of MACE events was 1.33 (95% confidence interval [CI] 0.91, 1.94) in tofacitinib-treated patients, a non-significant result that failed to meet the non-inferiority margin of 1.8. For malignancies, the risk was 1.48 (95% CI 1.04, 2.00), consistent with a significantly increased risk. The number of patients needed to be treated with tofacitinib for one year to result in one extra MACE event or malignancy (i.e., the number needed to harm; NNH) was 567 for MACE and 276 for malignancy.

These unexpected results had important implications from both a regulatory and practical perspective, and led to a label change the first week of December 2021 in the prescribing indications for tofacitinib and upadacitinib. These and existing JAK inhibitor therapies (e.g., baricitinib) for RA are now indicated only for patients who have failed at least one TNF inhibitor. New and updated Boxed Warnings in the revised label relate to further information outlined in the related abstracts below.

Abstract 0958: Risk factors for major adverse cardiovascular events in patients aged ≥50 years with RA and ≥1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors²