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Editorial: restoring therapeutic infliximab drug levels in patients with loss of response—pharmacokinetics and anti‐drug antibodies as useful guidance tools

While the anti-TNF infliximab is efficacious for the treatment of Crohn’s disease (CD), a non-negligible proportion of patients present with loss of response (LOR) to the drug at some time point during therapy. The conventional rescue strategy, first described in the ACCENT I trial, has been to increase the dosing of the drug. In this issue, Dreesen and colleagues describe a retrospective study on the outcomes of dose intensification, either by dose doubling or interval shortening, in a cohort of CD patients with LOR to infliximab. Overall, 37% of the 103 patients did not respond to dose intensification, underscoring once more the need to identify patients who will respond to dose optimisation, while sparing this costly and potentially detrimental intervention from patients with low likelihood to respond. Several interesting findings were observed when authors looked at the drug levels at the time of LOR (T0) and after the interventions (T+1). Firstly, patients with quantifiable antibodies-to-infliximab (ATI) above 282 ng/mL equivalent at T0 were significantly less likely to achieve T+1 therapeutic drug levels of >3 mcg/mL, whereas drug levels at LOR were less correlated with the outcome of the intervention. Previous studies have shown that patients with low drug/low anti-drug antibodies—even if anti-drug antibodies were quantifiable—were more likely to respond to anti-TNF dose intensification compared with patients with low drug/high anti-drug antibodies. The findings by Dreesen et al, nicely show how this is also true not only for re-gaining clinical response but also for the pharmacokinetic restoration of post-intervention trough drug level, which is an important objectively measurable outcome. They also find that dose doubling was more effective in restoring a drug level of>3 mcg/mL compared with interval shortening. The interval of dose shortening was not reported, so some patients may have had an every 6-week shortening rather than interval halving which is more comparable to dose doubling. Nonetheless, these data are in line with prior observations on overall non-inferiority of dosedoubling vs interval halving, and together they support double dosing over interval-shortening as a viable option which may save patients the need for another infusion visit and contribute to improved quality of life. In the present study, the focus was on dose-intensification outcomes, and clinical course after other interventions was not explored. Other studies have shown different drug-level/ATI results at the time of LOR can guide optimal interventions aside from dose doubling, for instance, switching within class or outside the biologic class in certain situations, and one such algorithm has been shown to offer significant cost-saving as compared with universal dose-doubling strategy. Notwithstanding, the present observations contribute to our understanding on how best to individually tailor the optimal intervention for a patient with LOR to infliximab. As mentioned by the authors, the best strategy in this respect may ultimately be the prevention of LOR by a proactive approach utilising—among other factors— drug and ATI measurements. Until then, data such as presented by Dreesen and colleagues are important for advancing our knowledge on how to implement pragmatic yet rational-based approach to patients with LOR to anti-TNFs.