Sequencing JAK-inhibitors in ulcerative colitis: effectiveness and safety of switching within treatment class

Background and aims: Evidence from rheumatology supports a within-class treatment switch for JAK-inhibitors (JAKi), but data in ulcerative colitis (UC) remain limited. We aimed to assess the effectiveness and safety of initiating a second JAKi in patients with UC previously treated with another JAKi. Methods: We conducted a multicenter retrospective study, including patients with UC starting a second JAKi after prior JAKi exposure. The primary endpoint was Week 12 steroid-free clinical remission (SFCR-rectal bleeding subscore = 0, stool frequency subscore <= 1, and no steroids). Results: We included 243 patients (median follow-up: 38 [21-57] weeks). At Weeks 12, 26, and 52, SFCR was achieved in 116/243 (48%), 120/243 (49%), and 69/243 (28%), respectively. Secondary loss of response to the first JAKi was associated with higher SFCR at Week 12 compared to primary failure (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.11-3.30, P = 0.02). Higher baseline disease activity (OR = 0.68, 95% CI = 0.68-0.55, P < 0.01) and steroid use (OR = 0.23, 95% CI = 0.13-0.42, P < 0.01) had lower odds of Week 12 SFCR. Endoscopic remission occurred in 22/243 (9%) (< Week 26) and 27/243 (11%) (26-78 weeks), and endoscopic improvement in 53/243 (22%) and 45/243 (19%), respectively. Sixty-seven (28%) patients discontinued the second JAKi, mostly due to primary (36/67) or secondary failure (22/67). Sixty-six adverse events (mostly acne and infections) occurred in 56 (23%) patients, without major thromboembolic or cardiovascular events. Conclusion: Treatment with a second JAKi is effective and safe in patients with UC already exposed to JAKi. Primary failure to a first JAKi and steroid use at initiation of the second JAKi might reduce the likelihood of success with the second JAKi.