Upadacitinib Effective in RA Patients with Inadequate Methotrexate Response

Rheumatoid arthritis (RA) patients who do not respond to methotrexate may have improved clinical and functional outcomes with upadacitinib monotherapy as opposed to continuing methotrexate, according to the results of a recent study.

“Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs,” wrote the researchers, whose findings appeared in The Lancet. “We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate.”

SELECT-MONOTHERAPY was a randomized, placebo-controlled, double-blind phase 3 study that spanned 138 sites in 24 countries. Patients aged ≥ 18 years were eligible for inclusion if they met the 2010 American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) classification RA criteria. Patients who took methotrexate and still had active RA were randomized 2:2:1:1 to change to a once-daily dose of upadacitinib alone, or continue methotrexate, and at week 14, the continuing methotrexate group was assigned to either 15 mg or 30 mg once-daily doses of upadacitinib. The primary endpoints were the proportions of patients who achieved 20% improvement in ACR criteria (ACR20) and low disease activity (28-joint Disease Activity Score using C-reactive protein [DAS28{CRP}] of 3.2 or lower).

When Methotrexate Fails, Upadacitinib More Effective

Of the 648 patients randomized to treatment, 598 (92%) completed week 14: 216 continuing methotrexate patients, 217 upadacitinib 15 mg patients, and 215 upadacitinib 30 mg patients. After 14 weeks, ACR20 was achieved by 41% of the methotrexate group, 68% of the upadacitinib 15 mg group, and 71% of the upadacitinib 30 mg group (P < 0.0001 for both doses vs. continued methotrexate). DAS28(CRP) of 3.2 or lower was attained in 19% of the methotrexate group, 45% of the upadacitinib 15 mg group, and 53% of the upadacitinib 30 mg group (P < 0.0001 for both doses vs. continued methotrexate). Adverse events rates were similar among all three groups: continued methotrexate, 47%; upadacitinib 15 mg, 47%; and upadacitinib 30 mg, 49%. Herpes zoster presented in <1% (n = 1) of the continued methotrexate group, 1% (n = 3) of the upadacitinib 15 mg group, and 3% (n = 6) of the upadacitinib 30 mg group. There were three malignancies—one (<1%) in the continued methotrexate group, and two (1%) in the upadacitinib 15 mg group. Three adjudicated major cardiovascular adverse events occurred—one (<1%) in the upadacitinib 15 mg group, and two (<1%) in the upadacitinib 30 mg group. One upadacitinib 15 mg patient experienced adjudicated pulmonary embolism. One patient died from hemorrhagic stroke due to a ruptured aneurysm, in the upadacitinib 15 mg group.

In summary, the study authors wrote, “Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies.”