Anti-TNF agents are effective in inducing remission in 14% to 35% of biologic-naïve patients with moderate-severe ulcerative colitis in clinical trials. Even patients who initially respond to anti-TNF therapy frequently lose response over time. With several new effective agents recently available or anticipated to become available, a synthesis of comparative efficacy of second line agents may inform clinical decision-making in this patient population. Hence, we conducted a systematic review with network meta-analysis of patients with moderate-severe UC with prior exposure to anti-TNF agents, to inform relative efficacy of second line agents for induction of clinical remission.Methods:
We conducted a systematic literature, through August 2016 of multiple electronic databases and conference proceedings, to identify randomized controlled trials (RCTs) in patients with moderate-severe UC treated with anti-TNF agents (infliximab, adalimumab, golimumab), anti-integrin agents (vedolizumab) or janus kinase inhibitors (tofacitinib) for induction of clinical remission. We included trials, which reported efficacy of intervention in a subset of patients with prior exposure to anti-TNF agents. To evaluate comparative efficacy, we performed direct and network meta-analysis of all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. Relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities (i.e., percentage of efficacy achieved by an agent compared to an imaginary agent i.e., always the best without uncertainty).Results:
We included 4 RCTs (967 patients) comparing adalimumab, vedolizumab and tofacitinib in patients with prior exposure to anti-TNF agents. Compared to placebo, high quality evidence supports the use of tofacitinib (failure to achieve remission: OR, 0.08; 95% CI, 0.02–0.43), whereas low quality evidence supports the use of vedolizumab (OR, 0.30; 95% CI, 0.06–1.48) and adalimumab (OR, 0.74; 95% CI, 0.26–2.06), for inducing remission in patients with prior exposure to anti-TNF agents. On comparison of active interventions, low quality evidence supports the use of tofacitinib over adalimumab (OR, 0.11; 95% CI, 0.02–0.79), and very low quality evidence supports the use of tofacitinib over vedolizumab (OR, 0.28; 95% CI, 0.03–2.71), and of vedolizumab over adalimumab (OR, 0.41; 95% CI, 0.06–2.73). Overall, tofacitinib is ranked highest (SUCRA, 0.96) followed by vedolizumab (SUCRA, 0.62) and adalimumab (SUCRA, 0.31) for inducing clinical remission in patients with prior exposure to anti-TNF agents. Tofacitinib was also superior to placebo (OR, 0.21; 95% CI, 0.10–0.45) and adalimumab (OR, 0.23; 95% CI, 0.09–0.63) for induction of mucosal healing. There is limited data to inform comparative safety of different agents.Conclusions:
Among patients with moderate-severe UC with prior exposure to anti-TNF agents, tofacitinib appears to be the most efficacious agent for inducing remission. Head-to-head trials and evaluation of relative safety are warranted to inform clinical decision-making with greater confidence.