Efficacy and Safety of Advanced Oral Small Molecules for Inflammatory Bowel Disease: Systematic Review and Meta-Analysis

Oral small-molecule drugs (SMDs) are expanding the therapeutic landscape for inflammatory bowel disease (IBD). This systematic review and meta-analysis summarises the efficacy and safety of JAK inhibitor (JAKi) and sphingosine-1-phosphate (S1P) receptor modulator treatments for ulcerative colitis (UC) and Crohn's disease (CD).MEDLINE, Embase, and CENTRAL were searched from inception to May 30, 2022. Randomised controlled trials (RCTs) of JAKi and S1P receptor modulators in adults with UC or CD were eligible. Clinical, endoscopic, histologic, and safety data were pooled and analysed using a random-effects model.Thirty-five RCTs (26 UC, 9 CD) were included. In UC, JAKi therapy was associated with induction of clinical (risk ratio [RR] 3.16, 95% confidence interval [CI] 2.03-4.92; I2=65%) and endoscopic (RR 3.99, 95% CI 2.36-6.75; I2=36%) remission compared to placebo. Upadacitinib was associated with histologic response (RR 2.63, 95% CI 1.97-3.53). S1P modulator therapy was associated with induction of clinical (RR 2.52, 95% CI 1.88-3.39; I2=1%) and endoscopic (RR 2.39, 95% CI 1.07-5.33; I2=0%) remission relative to placebo. Ozanimod was superior to placebo for inducing histologic remission in UC (RR 2.20, 95% CI 1.43-3.37; I2=0%), while etrasimod was not (RR 2.36, 95% CI 0.71-7.88; I2=0%). In CD, JAKi therapy was superior to placebo for induction of clinical remission (RR 1.53, 95% CI 1.19-1.98; I2=31%), and endoscopic remission (RR 4.78, 95% CI 1.63-14.06; I2=43%) compared to placebo. The risk of serious infections was similar for oral SMDs and placebo.JAKi and S1P receptor modulator therapies are effective in IBD for inducing clinical and endoscopic remission and, in some circumstances, histologic response.