Esophagus to Small Intestine
Lancet Gastroenterol Hepatol. 2024;9(6):521–38
Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn’s disease: 3-year data from the prospective, multicentre PANTS cohort study
Background: The authors sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-tumour necrosis factor (anti-TNF) treatment failure and the strategies that prevent or mitigate loss of response.
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 anti-TNF-naive patients with active luminal Crohn’s disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. The authors estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure.
Findings: Between March 19, 2014, and September 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age, 32.5 years [interquartile range, 22.1–46.8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40.2% (95% confidence interval [CI]: 36.7–43.7), 34.4% (29.9–39.0), and 34.7% (29.8–39.5), and for adalimumab 35.9% (95% CI: 31.2–40.5), 32.9% (26.8–39.2), and 28.9% (21.9–36.3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6.1–10.0 mg/l for infliximab and 10.1–12.0 mg/l for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34.4% (95% CI: 30.4–38.2), 54.5% (49.4–59.0), and 60.0% (54.1–65.2), and for adalimumab 32.1% (26.7–37.1), 47.2% (40.2–53.4), and 68.4% (50.9–79.7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each 10-fold increase in drug concentration = 0.45 [95% CI: 0.30–0.67], adalimumab: 0.39 [0.22–0.70]). For patients treated with infliximab, loss of response was also associated with female sex (vs. male sex; HR = 1.47 [95% CI: 1.11–1.95]), obesity (vs. not obese 1.62 [1.08–2.42]), baseline white cell count (1.06 [1.02–1.11) per 1 x 109 increase in cells per l), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR = 1.95 [95% CI: 1.17–3.25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44.0% (95% CI: 38.1–49.4) among patients treated with infliximab and 20.3% (13.8–26.2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0.40 [95% CI: 0.31–0.52], adalimumab 0.42 [95% CI: 0.24–0.75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1.46 [1.13–1.88]) but not for adalimumab (HR = 1·60 [0.92–2.77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR = 2.87 [95% CI: 2.20–3.74]) or introduction of an immunomodulator after anti-TNF initiation (1.70 [1.11–2.59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and 2 (1%) of those treated with adalimumab had serious infections in years 2 and 3.
Interpretation: Only around a third of patients with active luminal Crohn’s disease treated with an anti-tumour necrosis factor drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs.