Study: JAK Inhibitors May Have Different Side Effects

The FDA has required boxed warnings on three JAK inhibitors to warn about the risk of heart-related events such as heart attack or stroke, cancer, blood clots. But those adverse events may differ among the three products, according to new research published in the September 2022 issue of the Journal of Managed Care + Specialty Pharmacy.

In this study, investigators found that 91.5% of adverse event reports included were from Pfizer’s Xeljanz/Xeljanz XR (tofacitinib). Investigators, however, also found there were differences in patient characteristics and types of adverse for the three products analyzed: Xeljanz/Xeljanz XR, Eli Lilly’s Olumiant (baricitinib), and AbbVie’s Rinvoq (upadacitinib).

The FDA in September began requiring an updated boxed warning on the three top-selling therapies used to treat rheumatoid arthritis and other inflammatory conditions.

Related: FDA Requires New Boxed Warning on Xeljanz, other JAK Inhibitors

Jingjing Qian, Ph.D.

Investigators, led by Jingjing Qian, Ph.D., department of Health Outcomes Research and Policy at Harrison College of Pharmacy, Auburn University, Alabama, analyzed the FDA’s Adverse Event Reporting System data to examine reported adverse events of the three drugs. They analyzed data between Jan. 1, 2019, and Sept. 30, 2021, for the frequency of reports by patient demographics, seriousness, and reactions related to death, cardiovascular, cancer, and blood clots.

They found more adverse events among patients using Xeljanz and Xeljanz XR (56,833) than for Olumiant (2,318) or Rinvoq (5,359). Higher proportions of patients reporting adverse events for Xeljanz were older and female than the other two drugs. But higher proportions of Rinvoq adverse events were more serious. Olumiant had highest proportions of death (7.2%) and cancer-related (4.1%) events, whereas Xeljanz AEs had the highest proportions of cardiovascular-related (14.1%) and blood clot–related (14.8%) events.

Investigators pointed out that the FDA warnings were based on a completed review of a large, randomized safety clinical trial comparing Xeljanz with TNF blockers in patients with rheumatoid arthritis. But at that time, Olumiant and Rinvoq had not been studied in similar large safety clinical trials.

“We found the highest proportion of cardiovascular-related and blood clot-related events for tofacitinib/XR AE reports, which also supports the FDA Boxed Warning on such AEs,” investigators wrote. “However, the heterogeneity in AE profiles for these three JAK inhibitors found in our study highlight the necessity in monitoring routine clinical practice for each individual drugs. Future research using longitudinal, real-world databases is warranted to test the hypotheses of individual JAK inhibitor exposures and these AE outcomes.”

A limitation of the study, investigators said, is that the FAERS adverse event database used in this analysis may underreport adverse events. Additionally, the adverse event reporting for Xeljanz and Olumiant might have been impacted by COVID-19 cases because these three drugs were tested in clinical trials for treating severe acute respiratory syndrome coronavirus 2 pneumonia during the study period.