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

Abstract Background and Aims Oral small-molecule drugs [SMDs] are expanding the therapeutic landscape for inflammatory bowel disease [IBD]. This systematic review and meta-analysis summarizes 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]. Methods MEDLINE, Embase, and CENTRAL were searched from inception to May 30, 2022. Randomized controlled trials [RCTs] of JAKi and S1P receptor modulators in adults with UC or CD were eligible. Clinical, endoscopic, histological, and safety data were pooled and analysed using a random-effects model. Results Thirty-five RCTs [26 UC, nine 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 histological 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 histological 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. Conclusion JAKi and S1P receptor modulator therapies are effective in IBD for inducing clinical and endoscopic remission and, in some circumstances, histological response.