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

Siddharth Singh, Mohammad Hassan Murad, Mathurin Fumery, Parambir S Dulai, William J Sandborn, Siddharth Singh, Mohammad Hassan Murad, Mathurin Fumery, Parambir S Dulai, William J Sandborn

Abstract

Background & aims: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Comparative Efficacy; GRADE; Inflammatory Bowel Disease; Pharmacotherapy; UC.

Conflict of interest statement

Conflicts of Interest:

Siddharth Singh has received research grants from AbbVie, and consulting fees from AbbVie, Takeda, Pfizer, AMAG Pharmaceuticals.

Mohammad Hassan Murad: No conflicts of interest

Mathurin Fumery has received consultant/lecture fees from Abbvie, Takeda, Ferring, MSD, Boehringer, Tillots, Gilead, Celgene, Janssen

Parambir Dulai has received research support from Takeda, Pfizer, Abbvie, Janssen, Polymedco, ALPCO, Buhlmann, and consulting fees from Takeda, Pfizer, Abbvie and Janssen.

William Sandborn has received research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, Abbvie, Janssen, Takeda, Lilly, Celgene/Receptos,Pfizer, Prometheus Laboratories (now Prometheus Biosciences); consulting fees from Abbvie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Spouse: Opthotech - consultant, stock options; Progenity - consultant, stock; Oppilan Pharma - employee, stock options; Escalier Biosciences - employee, stock options; Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories) - employee, stock options; Ventyx Biosciences – employee, stock options; Vimalan Biosciences – employee, stock options.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1A.
Figure 1A.
Network of included studies with the available direct comparisons for induction of clinical remission in biologic-naïve patients with moderate-severe ulcerative colitis. The size of the nodes and the thickness of the edges are weighted according to the number of studies evaluating each treatment and direct comparison, respectively.
Figure 1B.
Figure 1B.
Network of included studies with the available direct comparisons for induction of clinical remission in patients with prior TNFα antagonist exposure with moderate-severe ulcerative colitis. The size of the nodes and the thickness of the edges are weighted according to the number of studies evaluating each treatment and direct comparison, respectively.
Figure 2A.
Figure 2A.
Relative efficacy of different interventions for induction of clinical remission and endoscopic improvement in biologic-naïve patients with moderate to severely active ulcerative colitis
Figure 2B.
Figure 2B.
Relative efficacy of different interventions for induction of clinical remission and endoscopic improvement in patients with moderate to severely active ulcerative colitis with prior exposure to TNFα antagonists.

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Source: PubMed

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