Treating to a target of clinical remission or low disease activity is an important principle for managing
rheumatoid arthritis (RA). Despite the availability of biologic
disease-modifying antirheumatic drugs (bDMARDs), a substantial proportion of patients with RA do not achieve these treatment targets.
Upadacitinib is a once-daily, oral
Janus kinase (
JAK) inhibitor with increased selectivity for JAK1 over JAK2, JAK3, and
tyrosine kinase 2. The SELECT phase III
upadacitinib clinical program comprised five pivotal trials of approximately 4400 patients with RA, including inadequate responders (IR) to conventional synthetic (cs)DMARDs or bDMARDs. This review aims to provide insights into the benefit-risk profile of
upadacitinib in patients with RA.
Upadacitinib 15 mg once daily, in combination with csDMARDs or as monotherapy, achieved all primary and ranked secondary endpoints in the five pivotal trials across csDMARD-naïve, csDMARD-IR, and bDMARD-IR populations.
Upadacitinib 15 mg also demonstrated significantly higher rates of remission and low disease activity in all five pivotal trials, compared with placebo,
methotrexate, or
adalimumab. Labeled warnings of
JAK inhibitors include serious
infections,
herpes zoster,
malignancies, major cardiovascular events, and venous thromboembolic events. Short- and long-term integrated analyses showed that
upadacitinib 15 mg was associated with increased risk of
herpes zoster and
creatine phosphokinase elevations compared with
methotrexate and
adalimumab but otherwise had comparable safety with these active comparators. This review suggests that
upadacitinib 15 mg had a favorable benefit-risk profile. The safety of
upadacitinib will continue to be monitored in long-term extensions and post-marketing studies.