Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials

Abstract

BACKGROUND AND AIMS: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). METHODS: This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of 18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], metaanalytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of 18 months (n ¼ 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n ¼ 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/ placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. CONCLUSIONS: There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROS-PERO registration: CRD42018041961.

Positioning biologics in the treatment of IBD: A practical guide – Which mechanism of action for whom?

“…Similarly, registration trials with adalimumab and certolizumab pegol, which stratified according to disease duration showed better responses in patients with shorter disease duration ( Colombel et al., 2007 ; Schreiber et al., 2010 ). A large meta-analysis of 6′168 CD patients, confirmed and extended this observation for other biological therapies, including golimumab and vedolizumab ( Ben-Horin et al., 2021 ). However, the same analyses, failed to show an association between disease duration and response in 3′227 UC patients.…”

Treat‐to‐target and sequencing therapies in Crohn's disease

“…Clinical trials have repeatedly demonstrated that early initiation of a biologic therapy either alone or in combination with an immune modulator is superior to immune modulator alone regardless of the biologic chosen. 26,27 However, a question regarding the sequencing F I G U R E 1 A practical approach to incorporating treat-totarget decision making into clinical practice. Modified from Christensen and Rubin.…”

“…Clinical trials have repeatedly demonstrated that early initiation of a biologic therapy either alone or in combination with an immune modulator is superior to immune modulator alone regardless of the biologic chosen. 26 , 27 However, a question regarding the sequencing of biologics in patients with moderate to severe CD remains. The SEAVUE study, a randomized, double blind, parallel group, active‐controlled phase 3b trial, found that ustekinumab and adalimumab are bot highly effective in treating moderately to‐severely active Crohn's disease in biologically naïve patients.…”

A scoping review on early inflammatory bowel disease: definitions, pathogenesis, and impact on clinical outcomes

“…A recent meta-analysis, including individual-patient data from 16 randomized controlled trials (RCT), used the cutoff of 18 months to define short-duration disease, regardless of other characteristics like phenotype or prior treatment. 26 Besides that, some studies have focused on the concept of ‘very early’ CD, again with variable definitions (up to 6 27 or 12 13 , 28 , 29 months since diagnosis). The current definitions of early CD have some main limitations: (i) they mostly rely on the time to a timely diagnosis, what is problematic considering the diagnostic delay that is frequently seen; (ii) inflammation may occur without symptoms; (iii) up to 20% of CD patients have stenosing and penetrating phenotypes without recalling prior symptomatology; and (iv) acute and chronic lesions may coexist, but as soon as irreversible bowel damage is detected, it appears legitimate to consider that the disease is no longer in an early stage.…”