Systematic Review With Network Meta-analysis

Comparative Assessment of Tofacitinib and Biological Therapies for Moderate-to-Severe Ulcerative Colitis

S. Bonovas; T. Lytras; G. Nikolopoulos; L. Peyrin-Biroulet; S. Danese

Disclosures

Aliment Pharmacol Ther. 2018;47(4):454-465. 

In This Article

Abstract and Introduction

Abstract

Background 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.

Aim To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists.

Methods 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.

Results 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.

Conclusions Tofacitinib and biologics are efficacious and safe for UC. Further high-quality research is warranted to establish the best therapeutic option.

Introduction

Ulcerative colitis (UC) is a chronic, idiopathic, remitting and relapsing inflammatory bowel disease, usually afflicting adults of 30–40 years of age, and resulting in disability.[1] It involves the rectum, and may extend proximally in a contiguous pattern to affect part of the colon, or the entire colon. Patients experience abdominal cramps, urgency or tenesmus, fever, malaise, weight loss and fatigue, mucosal ulcers, rectal bleeding and diarrhoea, depending on the extent and severity of disease.[2] The incidence and prevalence of UC are rising over time, and in different regions around the world, indicating its emergence as a global health issue.[3]

The short-term treatment goal of an active disease flare is to provide relief to the patient by reducing the severity of, or achieving resolution of, the signs and symptoms of active disease (induction phase). After this has been achieved, the long-term treatment goal is to prevent the occurrence of subsequent disease flares (maintenance phase). In both treatment phases, a related goal is to affect the disease process itself by reducing the mucosal inflammation of the colon.[4] Currently, aminosalicylates are first-line therapy for induction and maintenance of remission in active, mild-to-moderate disease; corticosteroids are prescribed when symptoms of active colitis do not respond to aminosalicylates, while immunosuppressants and biologics are used in moderate-to-severe UC.[5,6]

Over the last decade, biological therapies have significantly improved the care of patients with UC. Infliximab was the first biologic approved for moderate-to-severe disease; then, 2 more tumour necrosis factor (TNF) antagonists, adalimumab and golimumab, and 1 anti-α4β7 antibody, vedolizumab, received regulatory approval. They have shown good efficacy and safety profiles.[[7–9]] Recently, tofacitinib, an oral small-molecule Janus kinase inhibitor, was shown to be more effective than placebo for induction and maintenance of remission in adults with moderate-to-severe UC. Tofacitinib is potentially a new treatment option for these patients, pending review by the US Food and Drug Administration, the European Medicines Agency and other international regulators.[10]

Acquiring comparative evidence on tofacitinib and approved biologics for UC would be very useful. To this aim, we conducted a systematic review of randomised controlled trials (RCTs) assessing tofacitinib and biologics as induction and/or maintenance therapy for moderate-to-severe UC in adults. In addition to conventional meta-analytic techniques, network meta-analysis was performed, allowing for adjusted indirect treatment comparisons relative to a common comparator (placebo) and yielding estimates of comparative efficacy and harm,[[11–13]] based on high-quality randomised trial evidence. We aimed to provide a summary of the evidence to inform patient management decisions.

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