Systematic review and meta-analysis: evaluating response to empiric anti-TNF dose intensification for secondary loss of response in Crohn’s disease

Abstract

Introduction: Anti-tumor necrosis factor (TNF) dose intensification represents an effective method of overcoming secondary loss of response (LOR); however, a subset of patients may not respond (tertiary non-response), or fail to demonstrate durable response (tertiary LOR) to intensified dosing. This systematic review and meta-analysis aimed to evaluate these outcomes to determine the clinical effectiveness of empiric dose intensification in Crohn’s disease. Methods: Multiple databases including MEDLINE and EMBASE were interrogated to identify studies that reported outcomes following anti-TNF dose intensification to address secondary LOR in Crohn’s disease. Studies that used anti-TNF levels as the primary basis for dose intensification were excluded. Studies that reported (1) tertiary response and tertiary non-response within 6 months or (2) tertiary response and tertiary LOR beyond 6 months, were pooled using a random effects model with risk ratio (RR) derived, quantifying the effect of each comparison. Results: Twenty-six studies reported outcomes following anti-TNF dose intensification to address secondary LOR. Short-term response within 12 weeks of any dose-intensification strategy was 33–90%, while sustained response (⩾48 weeks) was achieved in 25–85%. Tertiary non-response occurred in up to 45% of intensified patients within 6 months of anti-TNF dose intensification, while tertiary LOR beyond 6 months occurred in up to 64% of patients. Tertiary response was more likely than tertiary non-response within 6 months (RR 2.58, 95% CI (1.76, 3.79), I2 = 82%, 12 studies), while sustained response beyond 6 months compared to tertiary LOR (RR 1.10 (0.75, 1.61) I2 = 85%, 7 studies) was less convincing. Conclusion: Although anti-TNF dose intensification is clinically effective in patients with Crohn’s disease, particularly within the first 6 months, a proportion of patients will fail to demonstrate short-term and/or sustained clinical response. Hence, clinical reassessment following anti-TNF dose intensification, particularly beyond 6 months, remains important to differentiate between effective and ineffective dose-intensification strategies.

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“…4 Furthermore, the utility of measuring infliximab trough levels in the absence of clinical remission to optimise infliximab dosing to mitigate SLOR has also been well described. 5 This highlights the need to document whether or not this occurred across the infliximab cohort in the present study, especially in light of the lower than expected rates of clinical remission. Unfortunately, data pertaining to immunomodulator co-therapy, therapeutic drug monitoring, and infliximab dose intensification were unavailable.…”

Design, Synthesis and Biological Evaluation of Potent and Selective S1PR1 Agonists for the Treatment of Ulcerative Colitis

“…However, many IBD patients do not respond to current biologics. [ 2 ] And adverse drug reactions can increase the risk of serious infections. [ 3 ] In recent years, significant progress has also been made in the treatment of UC with small molecule drugs.…”

Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses

“…[2][3][4][5] Moreover, a subset of patients do not respond or fail to demonstrate durable response to intensified dosing in a phenomenon termed tertiary nonresponse or LOR, respectively. 6 This highlights the potential utility of identifying early predictors capable of differentiating between future response and nonresponse to intensified dosing.…”

“…Anti‐TNF dose intensification is an effective method of overcoming secondary LOR; however, the optimal strategy and duration of intensification remain to be clarified 2–5 . Moreover, a subset of patients do not respond or fail to demonstrate durable response to intensified dosing in a phenomenon termed tertiary nonresponse or LOR, respectively 6 . This highlights the potential utility of identifying early predictors capable of differentiating between future response and nonresponse to intensified dosing.…”