Loss of Response to Anti-TNFα Agents Depends on Treatment Duration in Patients With Inflammatory Bowel Disease

Johannes P. D. Schultheiss; Remi Mahmoud; Jonas M. Louwers; Michiel T. van der Kaaij; Boris P. van Hellemondt; Petra G. van Boeckel; Nofel Mahmmod; Bindia Jharap; Herma H. Fidder; Bas Oldenburg


Aliment Pharmacol Ther. 2021;54(10):1298-1308. 

In This Article

Abstract and Introduction


Background: Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α therapy (anti-TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%-21% per patient-year).

Aims: To assess whether the incidence of loss of response decreases with longer treatment duration

Methods: This was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti-TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation.

Results: We included 844 anti-TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti-drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three-fold higher than after four years of treatment (17.2% vs 4.8% per patient-year, P < 0.001). The incidence of anti-TNFα discontinuation (28.6% vs 14.0% per patient-year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient-year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10–2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15–2.46) and male sex (aHR 0.55, 95% CI 0.38–0.78). Immunomodulators were protective against loss of response with anti-drug antibodies (aHR 0.42, 95% CI 0.24–0.74).

Conclusions: Patients with sustained benefit to anti-TNFα after 2 years are at low risk of subsequent loss of response.


Anti-tumour necrosis factor α (anti-TNFα) agents are widely used as maintenance treatment for patients with inflammatory bowel disease (IBD). After successful induction of remission, the risk of a subsequent loss of response to anti-TNFα has been estimated to be as high as 13%-21% per patient-year, mostly based on studies with less than two years of follow-up.[1–4] In clinical practice, however, anti-TNFα treatment is frequently continued much longer with, anecdotally, favourable long-term outcomes. Quantitative characterisation of long-term efficacy might help to balance the benefits of prolonged treatment against the risks of infections and malignancies, as well as treatment costs.[5–7] We hypothesised that although the yearly risk of treatment failure is relatively high immediately after anti-TNFα initiation, it is likely to decrease with a longer treatment duration.

We conducted a large, multicentre, retrospective cohort study evaluating nine years of anti-TNFα treatment in patients with IBD. Our primary aim was to assess whether the incidence of loss of response—defined as drug discontinuation because of disease activity—declines with a longer treatment duration. Secondary aims were to identify predictors of loss of response (with and without anti-drug antibodies), and to define the time-dependent risk of overall drug discontinuation and anti-TNFα dose intensifications.