Elsevier

Digestive and Liver Disease

Volume 51, Issue 9, September 2019, Pages 1232-1240
Digestive and Liver Disease

Alimentary Tract
Effectiveness and safety of Ustekinumab for Crohn's disease; systematic review and pooled analysis of real-world evidence

https://doi.org/10.1016/j.dld.2019.05.002Get rights and content

Abstract

Background

Ustekinumab [UST] is effective in Crohn’s disease (CD) in the UNITI studies. Several real-world experience (RWE) studies with UST have been published to date. Our aim was to summarize the available RWE data for UST effectiveness and safety.

Methods

A systematic review of the available RWE studies of UST for CD and pooled analysis of the available effectiveness and safety data was performed.

Results

Eight relevant studies of 6 RWE were included for analysis. Data from 578 patients were pooled for analysis. Most patients (97.7%) were anti-TNF experienced. Pooled clinical response rate was 60%, 62%, 49% at 12, 24 and 52 weeks respectively (95% CI (0.42–0.77), (0.48–0.75), (0.37–0.62)). Pooled remission rate was 39% (95% CI (0.18–0.65)) at 24 weeks and pooled endoscopic response rate was 63% (95% CI (0.53–0.72)) after approximately one year of UST; 134 adverse events (AE) were reported in total, pooled proportion 21% (95% CI (0.12–0.35)). Serious AE were reported in 19 patients, pooled proportion 5% (95% CI (0.03–0.08)). Infections were reported in 38, pooled proportion 6% (95% CI (0.04–0.11)).

Conclusion

Pooled analysis of the RWE data suggests that the real-world effectiveness and safety are comparable to that reported in the randomized control trials.

Introduction

Although medical treatment options in inflammatory bowel disease (IBD) have improved dramatically over the last few decades with the introduction of anti-TNF antibodies and selective anti-integrin therapy, patients with refractory disease, as well as primary and secondary non-responders, still pose a major clinical challenge. A substantial number of primary responders to anti-TNF agents (as high as 46%) relapse despite continued treatment or dose escalation, with quite a substantial rate of early discontinuation of anti-TNF therapy [[1], [2], [3]].

There is a growing demand for novel therapeutic agents targeting alternative disease mechanisms. Although effective and relatively safe for the treatment of Crohn’s disease (CD), the efficacy of vedolizumab for treatment of anti-TNF-resistant CD appears to be quite modest. In real-world cohorts of patients with CD whose disease has failed to respond to previous anti-TNF therapy, approximately one-third of patients achieved steroid-free clinical remission after 14 weeks of treatment with vedolizumab. Discontinuation rate at 52 weeks was also significant (up to 42%) [[4], [5], [6], [7], [8], [9], [10], [11]].

Interleukin (IL)-12 and IL-23, 2 heterodimeric cytokines sharing the common p40 subunit, are over-produced in IBD and play a major role in promoting the pro-inflammatory cytokine response. These observations together with the demonstration that IL-12 and IL-23 drive pathogenic responses in animal models have paved the way for the development of IL-12p40 blockers [12,13].

Ustekinumab (UST) is a monoclonal antibody that targets the standard p40 subunit of the cytokines IL-12 and IL-23 (IL-12/23p40), which are involved in the pathogenesis of CD [[14], [15], [16]]. UST was shown to be effective in inducing and maintaining clinical remission in CD patients with moderate to severe CD [14]. UST has a favorable safety profile and a substantial body of safety data is available from psoriasis studies [15,17]. Several studies describing real-world experience (RWE) with UST have been published demonstrating effectiveness and safety comparable to those reported in the RCT's. RWE allows bridging of some data gaps and describing real-world patient experiences that are lacking in RCTs that tend to exclude certain groups of patients (such as patients with isolated small bowel disease inaccessible to ileocolonoscopy, patients with multiple comorbidities and other special population) [18]. Real world experience series add substantial data on safety, efficacy, optimal treatment interval and dosing [[19], [20], [21], [22], [23], [24], [25], [26], [27]].

Our aim was to summarize the currently available knowledge and to perform a pooled analysis of the effectiveness and safety of UST in CD patients, as reported by the real-world studies.

Section snippets

Methods

A structured search of the Pubmed and Embase database was performed, on March 1, 2018, to identify all studies that describe a real-world experience with UST. Search terms that were used: Ustekinumab, Crohn’s disease. For the purposes of the pooled analysis of effectiveness and safety, only reports published in complete form in peer-reviewed literature were included. We extracted the baseline characteristics, efficacy, and safety data from the manuscripts. When further clarifications were

Definitions

Clinical response and remission were defined as a reduction in Harvey Bradshaw Index (HBI), physician global assessment (PGA) or both for all cohorts as per the definition used in the original publication. Two cohorts used PGA [21,26], two used both PGA and HBI [19,20,27] and the rest used only HBI for definition of clinical response and remission [[22], [23], [24], [25]].

An endoscopic response was defined as a significant reduction in the number of visible ulceration and mucosal healing was

Statistical methods

For each outcome measure, the pooled proportion of patients (with 95% confidence intervals) for the outcome in question was calculated. We examined the pooled proportions of patients who had responded to UST at various time points following initiation of treatment, and the pooled proportions of patients who had experienced adverse events. The fixed effects (Mantel–Haenszel) and random effects (DerSimonian–Laird) models were used for pooling, depending on heterogeneity. Statistical heterogeneity

Results

The literature search identified 173 publications. After excluding duplicates and ineligible studies by title/abstract screening, 20 studies underwent full-text review. Excluding case reports, cohorts not based on real-world patients, reviews and editorials, one pediatric paper, and one study missing crucial data (time point for response and remission) [25]. Eight studies were included in a quantitative meta-analysis (Fig. 1).

Two of the 8 relevant studies included in the pooled analysis

Discussion

Data from randomized controlled trials have demonstrated that UST is an effective agent for the treatment of moderate-to-severe CD with a good safety profile and favorite response rates for anti-TNF experienced patients. Herein, the current pooled analysis of the RWE data suggests that the real-world effectiveness and safety are comparable and even somewhat better to what reported in the CERTIFI and UNITI studies [14,17,42,43].

The vast majority of patients in the included studies had a long

Conflict of interest

Uri Kopylov — Speaker/advisory fees — Avbbvie, Jannsen, Takeda, MSD, Medtronic. Research support — Jannsen, Takeda, Medtronic

Tal Engel — No conflict of interest

Diana E. Yung-No conflict of interest

Christopher Ma — supported by a Clinician Fellowship from the Canadian Association of Gastroenterology and the Canadian Institutes of Health Research

Pariente B — Consulting fees from, Abbvie, Janssen, Ferring, Hospira, Takeda, Biogaran, Lilly, Pfizer, Lecture fees from Abbvie, Takeda, Janssen, Ferring.

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