Higher Doses of Upadacitinib Increase Rate of Serious Infections

Kevin Winthrop, MD, MPH

Higher doses of upadacitinib increase the incidence rate of serious infection events and opportunistic infections in patients with rheumatoid arthritis.

The findings of the research were presented at the European E-Congress of Rheumatology 2020 (EULAR 2020) meeting, which is taking place due to the cancellation of the in-person meeting.

Kevin Winthrop, MD, MPH, from Oregon Health & Science University, and a team of international and US-based investigators, evaluated the incidence of serious infection events and opportunistic infections in patients with rheumatoid arthritis receiving upadacitinib and active comparators in the phase 3 SELECT clinical trial program. Upadacitinib is a reversible Janus kinase (JAK) inhibitor with an approved dose of 15 mg once daily to treat rheumatoid arthritis.

Winthrop and the investigators determined the exposure-adjusted event rate per 100 patient-years of serious infection events and opportunistic infections. Patients included were receiving upadacitinib in 5 randomized phase 3 trials—SELECT-EARLY, SELECT-MONOTHERAPY, SELECT-NEXT, SELECT-COMPARE, and SELECT-BEYOND. In 4 of the trials, investigators evaluated 15 mg and 30 mg once daily doses of upadacitinib and 1 trial (SELECT-COMPARE) only evaluated 15 mg of once daily upadacitinib.

The team also determined incidences of serious infection events and opportunistic infections in patients who received adalimumab plus methotrexate in SELECT-COMPARE and methotrexate monotherapy in SELECT-EARLY. The investigators analyzed the data descriptively with no statistical comparison between groups or doses. A univariate Cox regression model was used to determine risk factors for serious infection events.

In total, there were 2629 patients who received 15 mg of upadacitinib, 1204 patients who received 30 mg of upadacitinib, 579 patients who received adalimumab plus methotrexate, and 314 patients who received methotrexate monotherapy. The exposure-adjusted event rates of serious infection events were 3.2 (95% CI, 2.7-3.7) in the 15 mg group, 5.7 (95% CI, 4.8-6.8) in the 30 mg upadacitinib group, 3.9 (95% CI, 2.6-5.6) in patients who received adalimumab plus methotrexate combination therapy, and 3.1 (95% CI, 1.7-5.2) in those who had methotrexate monotherapy.

The most common side effect was pneumonia. The exposure-adjusted event rates were .7 (95% CI, .5-1), 1.3 (95% CI, .9-1.9), .7 (.2-1.5), and .7 (.1-1.9) in the upadacitinib 15 mg, upadacitinib 30 mg, adalimumab plus methotrexate, and methotrexate monotherapy groups, respectively.

For opportunistic infections, rates were .7 (95% CI, .5-1) in the 15 mg group, 1.3 (95% CI, .9-1.9) in the 30 mg upadacitinib group, .4 (.1-1.1) in patients who received adalimumab plus methotrexate combination therapy, and 0 (0-0) among patients who had methotrexate monotherapy. The most frequent opportunistic infection was oral candidiasis, with exposure-adjusted event rates of .4 (95% CI, .2-.6) in the 15 mg group,.6 (95% CI, .3-1) in the 30 mg group, .4 (95% CI, .1-1.1) in the adalimumab plus methotrexate group, and 0 (0-0) in the monotherapy group.

In both upadacitinib groups, patients >75 years old and smoking had hazard ratios >1.

Overall, the incidence rate of serious infection events and opportunistic infections was higher among the upadacitinib 30 mg group than the 15 mg group. The serious infection events seen with the 15 mg group were similar to those seen with adalimumab.

The study, “Characterization of Serious Infections With Upadacitinib in Patients With Rheumatoid Arthritis,” was published online on the EULAR 2020 website.