OC4 Understanding anti-TNF treatment failure in Crohn’s disease: mechanisms and management of loss of response to anti-TNF therapy, three-year data from the PANTS study

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Background We sought to report the effectiveness of infliximab and adalimumab over the first three years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent and/or mitigate loss of response (LOR). Methods Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in Crohn’s disease in patients aged 6 years and over.1 At the end of the first-year, sites were invited to enrol participants still receiving drug in to the two year PANTS-extension study between March 19th 2014 and September 21st 2017. We estimate rates of remission across the whole cohort at the end of years one, two and three using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with LOR in patients who had initially responded to anti-TNF therapy. Results 387/955 infliximab-treated patients and 207/655 adalimumab-treated patients, 44% (96/219) paediatric patients aged 10 - 17 years, were recruited to the PANTS study entered the PANTS-extension The estimated proportion of patients in remission at the end of years one, two, and three were, for infliximab: 40.1% (95%CI 36.7 – 43.7), 34.4% (95%CI 29.9 – 39.0), and 34.7% (95%CI 29.8 – 39.5) and for adalimumab: 36.0% (95%CI 31.4 – 50.6), 32.9% (95%CI 26.8 – 39.2), and 28.9% (95%CI 21.9 – 36.3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6.1 - 10 mg/L for infliximab and 10 - 12 mg/L for adalimumab. LOR events for infliximab and adalimumab-treated patients were predicted by low anti-TNF concentrations at week 14 (infliximab: hazard ratio [HR] 0.43 [95%CI 0.29 – 0.63] for each 10-fold increase in drug concentration, adalimumab: HR 0.33 [95%CI 0.19 – 0.56]). For infliximab-treated patients, LOR was also associated with female sex (HR 1.47 [95%CI 1.12 - 1.92] and obesity (HR 1.88 [95%CI 1.25 – 2.82]). Anti-drug antibodies associated with undetectable drug concentrations were detected in 44.0% (95%CI 38.1 – 49.4) and 20.3% (95%CI 13.8 – 26.2) of infliximab and adalimumab-treated patients by the end of year three, respectively. Treatment with an immunomodulator prior to, or at the time of, starting infliximab, but not adalimumab, was associated with increased survival without immunogenicity. The optimal thiopurine dose when used with infliximab was at least 2.2 mg/kg azathioprine and 1.1 mg/kg mercaptopurine. Amongst infliximab-treated patients whose dose was intensified at the point of LOR, those who experienced immune-mediated pharmacokinetic failure had the lowest rates of drug persistence. Conclusion Only about one-third of patients with active luminal Crohn’s disease treated with an anti-TNF drug are in remission at the end of three years of treatment. LOR was predicted by low drug level. The emergence of anti-drug antibodies associated with undetectable drug concentrations can be mitigated by an immunomodulator started prior to, or on the day of, the first infliximab infusion. Reference Kennedy NA, Heap GA, Green HD, et al. UK Inflammatory Bowel Disease Pharmacogenetics Study Group. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019 May;4(5):341–353.

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