Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis.

There are limited data to inform positioning of agents for treating moderate-severe ulcerative colitis (UC). To assess comparative efficacy and safety of different therapies as first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor(TNF)-α) agents for moderate-severe UC, through a systematic review and network meta-analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach. We identified randomised controlled trials (RCTs) in adults with moderate-severe UC treated with anti-TNF agents, anti-integrin agents and janus kinase (JAK) inhibitors, as first-line or second-line agents, and compared with placebo or another active agent. Efficacy outcomes were induction/maintenance of remission and mucosal healing; and safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. In biologic-naïve patients (12 trials, no head-to-head comparisons), infliximab and vedolizumab were ranked highest for induction of clinical remission (infliximab: odds ratio [OR], 4.10 [95% confidence intervals [CI], 2.58-6.52]; SUCRA,0.85; vedolizumab:SUCRA,0.82) and mucosal healing (infliximab:SUCRA,0.91; vedolizumab:SUCRA,0.81) (moderate QoE). In patients with prior anti-TNF exposure (4 trials, no head-to-head comparisons), tofacitinib was ranked highest for induction of clinical remission (OR, 11.88 [2.32-60.89]; SUCRA, 0.96) and mucosal healing (moderate QoE). Differences in trial design limited comparability of trials of maintenance therapy for efficacy. Vedolizumab was ranked safest in terms of serious adverse events (SUCRA, 0.91), and infection (SUCRA, 0.75) in maintenance trials. Infliximab and vedolizumab are ranked highest as first-line agents, and tofacitinib is ranked highest as second-line agent, for induction of remission and mucosal healing in patients with moderate-severe UC, based on indirect comparisons. Head-to-head trials are warranted to inform clinical decision-making with greater confidence.

Singh S ，Fumery M ，Sandborn WJ ，Murad MH ... -  《-》

Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease.

There are limited data to inform positioning of agents for treating moderate-severe Crohn's disease (CD). We assessed comparative efficacy and safety of first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor [TNF]-α) agents) biologic therapy for moderate-severe CD, through a systematic review and network meta-analysis, and appraised quality of evidence (QoE) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We identified randomised controlled trials (RCTs) in adults with moderate-severe CD treated with approved anti-TNF agents, anti-integrin agents and anti-IL12/23 agents, first-line or second-line, and compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of clinical remission; safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. No head-to-head trials were identified. In biologic-naïve patients, infliximab (SUCRA,0.93) and adalimumab (SUCRA,0.75) were ranked highest for induction of clinical remission (moderate QoE). In patients with prior anti-TNF exposure, adalimumab (SUCRA, 0.91; low QoE, in patients with prior response or intolerance to anti-TNF agents) and ustekinumab (SUCRA, 0.71) were ranked highest for induction of clinical remission. In patients with response to induction therapy, adalimumab (SUCRA, 0.97) and infliximab (SUCRA, 0.68) were ranked highest for maintenance of remission. Ustekinumab had lowest risk of serious adverse events (SUCRA, 0.72) and infection (SUCRA, 0.71; along with infliximab, SUCRA, 0.83) in maintenance trials. Indirect comparisons suggest that infliximab or adalimumab may be preferred first-line agents, and ustekinumab a preferred second-line agent, for induction of remission in patients with moderate-severe CD. Head-to-head trials are warranted.

Singh S ，Fumery M ，Sandborn WJ ，Murad MH ... -  《-》

First- and Second-Line Pharmacotherapies for Patients With Moderate to Severely Active Ulcerative Colitis: An Updated Network Meta-Analysis.

We compared the efficacy and safety of different first-line (biologic-naïve) and second-line (prior exposure to tumor necrosis factor [TNF] antagonists) agents for treatment of moderate to severely active ulcerative colitis in a systematic review and network meta-analysis. We searched publication databases through September 30, 2019, for randomized trials of adults with moderate to severe ulcerative colitis treated with TNF antagonists, vedolizumab, tofacitinib, or ustekinumab, as first-line or second-line agents, compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of remission and endoscopic improvement; safety outcomes were serious adverse events and infections. We performed a fixed-effects network meta-analysis using the frequentist approach, and calculated odds ratios (ORs) and 95% CI values. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Overall quality of evidence was rated using GRADE (Grading of Recommendations, Assessment, Development and Evaluation). In biologic-naïve patients, infliximab was ranked highest for induction of clinical remission (OR vs placebo, 4.07; 95% CI, 2.67-6.21; SUCRA, 0.95) and endoscopic improvement (SUCRA, 0.95) (moderate confidence in estimates [CE]). In patients with prior exposure to TNF antagonists, ustekinumab (SUCRA, 0.87) and tofacitinib (SUCRA, 0.87) were ranked highest for induction of clinical remission and were superior to vedolizumab (ustekinumab vs vedolizumab: OR, 5.99; 95% CI, 1.13-31.76 and tofacitinib vs vedolizumab: OR, 6.18; 95% CI, 1.003-8.00; moderate CE) and adalimumab (ustekinumab vs adalimumab: OR, 10.71; 95% CI, 2.01-57.20 and tofacitinib vs adalimumab: OR, 11.05; 95% CI, 1.79-68.41; moderate CE). Vedolizumab had the lowest risk of infections (SUCRA, 0.81), followed by ustekinumab (SUCRA, 0.63) in maintenance trials. In a systematic review and network meta-analysis, we found infliximab to be ranked highest in biologic-naïve patients, and ustekinumab and tofacitinib were ranked highest in patients with prior exposure to TNF antagonists, for induction of remission and endoscopic improvement in patients with moderate to severe ulcerative colitis. More trials of direct comparisons are needed to inform clinical decision making with greater confidence.

Singh S ，Murad MH ，Fumery M ，Dulai PS ，Sandborn WJ ... -  《-》

Efficacy and safety of biologics and small molecule drugs for patients with moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis.

There is a growing armamentarium for the treatment of moderate-to-severe ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics and small molecule drugs for the treatment of patients with moderate-to-severe ulcerative colitis. In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials without language restrictions for articles published between Jan 1, 1990, and July 1, 2021. Major congresses' databases from Jan 1, 2018, to July 3, 2021, were reviewed manually. Phase 3, placebo-controlled or head-to-head randomised controlled trials (RCTs) assessing the efficacy and safety of biologics or small molecule drugs as induction or maintenance therapies for patients with moderate-to-severe ulcerative colitis were included. Phase 2 RCTs were excluded because of their small sample sizes and inclusion of doses not further explored in phase 3 RCTs. Summary data from intention-to-treat analyses were extracted from included reports by JSL and PAO. The primary outcome was the induction of clinical remission. A network meta-analysis was done under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. The surface under the cumulative ranking (SUCRA) was used to rank the included agents for each outcome. Higher SUCRA scores correlate with better efficacy, whereas lower SUCRA scores correlate with better safety. Maintenance data on efficacy for treat-straight-through and randomised responder trials are also presented. This study is registered with PROSPERO, CRD42021225329. Our search yielded 5904 results, from which 29 studies (four being head-to-head RCTs) fulfilled our inclusion criteria and were included. Of these, 23 studies assessed induction therapy with either a biologic or small molecule drug, comprising 10 061 patients with ulcerative colitis. A risk of bias assessment showed a low risk of bias for most of the included studies. Upadacitinib was significantly superior to all other interventions for the induction of clinical remission (infliximab [OR 2·70, 95% CI 1·18-6·20], adalimumab [4·64, 2·47-8·71], golimumab [3·00, 1·32-6·82], vedolizumab [3·56, 1·84-6·91], ustekinumab [2·92, 1·31-6·51], etrolizumab [4·91, 2·59-9·31], tofacitinib [2·84, 1·28-6·31], filgotinib 100 mg [6·15, 2·98-12·72], filgotinib 200 mg [4·49, 2·18-9·24], and ozanimod (2·70, 1·18-6·20), and ranked highest for the induction of clinical remission (SUCRA 0·996). No differences between active interventions were observed when assessing adverse events and serious adverse events. Vedolizumab ranked lowest for both adverse events (SUCRA 0·184) and serious adverse events (0·139), whereas upadacitinib ranked highest for adverse events (0·843) and ozanimod ranked highest for serious adverse events (0·831). Upadacitinib was the best performing agent for the induction of clinical remission (the primary outcome) but the worst performing agent in terms of adverse events in patients with moderate-to-severe ulcerative colitis. Vedolizumab was the best performing agent for safety outcomes. With the paucity of direct comparisons in the published literature, our results might help clinicians to position drugs in treatment algorithms. None.

Lasa JS ，Olivera PA ，Danese S ，Peyrin-Biroulet L ... -  《The Lancet Gastroenterology & Hepatology》

Systematic review with network meta-analysis: comparative assessment of tofacitinib and biological therapies for moderate-to-severe ulcerative colitis.

Biological therapies have improved the care of patients with ulcerative colitis (UC). Tofacitinib, an oral small-molecule Janus kinase inhibitor, is potentially a new treatment option. To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists. We performed a comprehensive search of PubMed, Embase, Scopus, clinical trial registries, regulatory authorities' websites and major conference proceedings, through August 2017, to identify randomised, placebo-controlled or head-to-head trials assessing tofacitinib or biologics as induction and/or maintenance therapy in moderate-to-severe UC. Two reviewers independently extracted study data and outcomes, and investigated each trial's risk-of-bias. We used conventional meta-analysis to synthesise direct evidence, and network meta-analysis for adjusted indirect treatment comparisons. Fifteen randomised, double-blind, placebo-controlled trials (n = 3130) contributed data for induction: All treatments are superior to placebo. Indirect treatment comparisons showed that infliximab is better than adalimumab (OR: 2.01, 95% CI: 1.36-2.98) and golimumab (1.67, 1.08-2.59) in clinical response, better than adalimumab (2.10, 1.21-3.64) in clinical remission, and better than adalimumab (1.87, 1.26-2.79) and golimumab (1.75, 1.13-2.73) in mucosal healing. No indirect comparisons between tofacitinib and biologics reached statistical significance. Nine studies (n = 1776) contributed maintenance data showing that all treatments have higher clinical efficacy than placebo. Safety analyses indicated no increased rates of adverse events for the treatments under evaluation (except for infliximab), while vedolizumab may have an advantage regarding the occurrence of serious adverse events. Tofacitinib and biologics are efficacious and safe for UC. Further high-quality research is warranted to establish the best therapeutic option.

Bonovas S ，Lytras T ，Nikolopoulos G ，Peyrin-Biroulet L ，Danese S ... -  《-》