Low anti-TNF concentrations at week 14 linked to long-term loss of response in Crohn’s
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Key takeaways:
- Low anti-TNF drug concentrations at week 14 predicted loss of response at years 2 and 3.
- Optimal drug concentrations at week 14 were 6.1 mg/L to 10 mg/L for infliximab and 10.1 mg/L to 12 mg/L for adalimumab.
Approximately two-thirds of patients with Crohn’s disease who initially responded to anti-tumor necrosis factor therapy lost response by 3 years, with researchers suggesting that higher drug concentrations at induction may improve outcomes.
“Anti-TNF treatment failure is common, with a quarter of patients having primary nonresponse and a third of initial responders losing response by the end of the first year,” Neil Chanchlani, PhD, of the department of gastroenterology at Royal Devon University Healthcare NHS Foundation Trust, and colleagues wrote in The Lancet Gastroenterology & Hepatology. “In the first year of the Personalizing Anti-TNF therapy in Crohn’s disease (PANTS) study, we observed a complex multidirectional relationship between disease activity, anti-TNF drug concentrations and the development of anti-drug antibodies.”
They continued: “Data relating to the efficacy of anti-TNF therapies beyond 1 year of treatment are scarce. However, these data are increasingly important when weighing up the long-term risks and benefits of multiple new medical and surgical options.”
In an extension of the prospective, observational PANTS study, researchers investigated the effectiveness of infliximab and adalimumab over the first 3 years of treatment, as well as factors associated with treatment failure among patients aged 6 years and older with CD and active luminal disease.
According to results, 598 patients (median age, 32.5 years; 51% women; 93% white) were enrolled in the extension study between March 2014 and September 2017, of whom 389 received infliximab and 209 received adalimumab.
The estimated proportion of patients in remission was 40.2% (95% CI, 36.7-43.7) for infliximab and 35.9% (95% CI, 31.2-40.5) for adalimumab at the end of year 1, 34.4% (95% CI, 29.9-39) and 32.9% (95% CI, 26.8-39.2), respectively, at the end of year 2 and 34.7% (95% CI, 29.8-39.5) and 28.9% (95% CI, 21.9-36.3) at the end of year 3.
Optimal drug concentrations of 6.1 mg/L to 10 mg/L for infliximab and 10.1 mg/L to 12 mg/L for adalimumab at week 14 predicted remission at later timepoints, with low anti-TNF drug concentrations at week 14 predicting loss of response at years 2 and 3 for both infliximab (HR = 0.45; 95% CI, 0.3-0.67) and adalimumab (HR = 0.39; 95% CI, 0.22-0.7).
By the end of year 3, an estimated 44% (95% CI, 38.1-49.4) of patients treated with infliximab and 20.3% (95% CI, 13.8-26.2) of patients treated with adalimumab developed anti-drug antibodies associated with undetectable drug concentrations, which was significantly associated with treatment without concomitant immunomodulator use in both groups (HR = 0.4; 95% CI, 0.31-0.52 and HR = 0.42; 95% CI, 0.24-0.75, respectively) and with carriage of the HLA-DQA1*05 risk variant for infliximab (HR = 1.46; 95% CI, 1.13-1.88) but not adalimumab (HR = 1.6; 95% CI, 0.92-2.77).
Further, concomitant use of an immunomodulator prior to or on the day of infliximab initiation was associated with increased time without development of anti-drug antibodies vs. the use of infliximab alone (HR = 2.87; 95% CI, 2.2-3.74) or introduction of an immunomodulator following anti-TNF initiation (HR = 1.7; 95% CI, 1.11-2.59).
“We estimated that only around a third of patients with active luminal Crohn’s disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment,” Chanchlani and colleagues wrote. “Low drug concentrations at the end of induction predicted loss of response up to year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, could lead to improved long-term outcomes.”
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