Outcomes of Second- and Third-LineTumor Necrosis Factor-α Antagonists in Inflammatory Bowel Disease

Introduction: Anti-Tumor Necrosis Factor-α (Anti-TNF) failure in inflammatory bowel diseases (IBD) due to intolerance or loss of response is common. We reviewed the safety and efficacy of second- and third-line Anti-TNF after failure of a first-line Anti-TNF to determine predictors and probabilities of treatment success. Methods: We conducted a retrospective chart review of outpatient records from January 2007 to November 2015 at McMaster University Medical Center (Hamilton, Ontario) to identify all patients exposed to at least two Anti-TNF. We recorded demographics, adverse events, and 12-week response and remission rates after second- and, if applicable, third-line Anti-TNF therapy. Multivariable logistic regression was used to identify predictors of second-line Anti-TNF failure. Kaplan- Meier survival curves were used to determine the probability of remaining on second-line Anti-TNF. Log rank tests were used to compare survival curves. Where available, we also reviewed therapeutic drug monitoring results. Results: 149 patients were included in the analysis (Table 1). Sixty-one patients (40.9%) discontinued the second Anti-TNF after a mean of 31.2 months and 9 of 61 (14.8%) switched to a third Anti-TNF. Six of 9 patients (66.6 %) on a third Anti-TNF discontinued therapy after a mean of 14 months. The primary reason of discontinuation for the second Anti-TNF was secondary loss of response (22/61 patients; 36%) and for the third Anti-TNF was adverse event (6/9 patients; 66.6%). 49.2% of patients receiving second Anti-TNF achieved clinical remission and 66.7% achieved clinical response at 12 weeks. Multivariable logistic regression identified concurrent steroid use at induction [OR 0.22 (0.09-0.50); p < 0.001] and early discontinuation of first Anti-TNF [OR 1.03 (1.01-1.05); p=0.006] as predictors of second-line Anti-TNF failure. The retention rate on second-line Anti-TNF was 44% at 60 months (Figure 1). Patients who achieved clinical remission at 12 weeks had a longer mean duration of second Anti-TNF therapy (Figure 2). Patients who remained on Adalimumab (ADA) as their second-line Anti-TNF had lower mean ADA levels (6.67) than patients who failed (10.3).Figure 1Figure 2Table 1: Characteristics of 149 Patients Exposed to at Least Two Anti-TNFConclusion: In our cohort, second-line Anti-TNF were effective and safe, and almost half patients remained on therapy at 5 years. Outcomes of third-line Anti-TNF were less favourable, likely due to selection of a refractory patient subgroup.

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