Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease

Abstract

Background: Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD.

Methods: Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression.

Results: In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed.

Conclusions: Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients.

Keywords: adalimumab; infliximab; monogenic; very early onset inflammatory bowel disease; whole exome sequencing.

Figure 1.

Cumulative exposure to anti-TNF in very early onset inflammatory bowel disease. Censored subjects indicated by “+.” A, Cumulative exposure of the overall study population, with 95% confidence interval. B-D, Cumulative exposure stratified by IBD diagnosis, diagnosis before vs after January 1, 2012, and infantile onset disease vs onset at 2 to 6 years.

Figure 2.

Time from anti-TNF initiation to anti-TNF failure in very early onset inflammatory bowel disease. Multivariate cox regression with covariates IBD diagnosis, time to TNF start, age at diagnosis, stricturing, combination therapy, monogenic disease status, and sex. Inflammatory bowel disease diagnosis (P = .028), age at diagnosis (P = .01), stricturing behavior (P = .040) were significant in multivariate time to failure model. Time from diagnosis to TNF initiation (P = .11), monogenic disease status (P = .42), and sex (P = .19) were not significant predictors.

Figure 3.

Adverse events with infliximab use, stratified by age of initiation <6 years vs ≥6 years. The majority of patients (77.4%) experienced no adverse events.