Measuring Antibodies to Infliximab To Guide Treatment Intensification in Crohn Disease

A significant proportion of patients with Crohn disease (CD) who initially respond to infliximab therapy experience secondary loss of response with symptom flares. Treatment intensification (using increases in dose, dose frequency, or a combination of both to implement intensification) is a suggested strategy for regaining response. However, the development of antibodies to infliximab (ATI) negatively impacts the effectiveness of treatment intensification. Now, a new study, by Erwin Dreeson, PhD, and colleagues, published in the December 11, 2017, issue of Alimentary Pharmacology & Therapeutics, reports that therapeutic drug monitoring (TDM) of ATI concentrations can guide clinical decision-making on treatment intensification in patients with CD who have lost clinical response to infliximab.

Their retrospective cohort study was conducted in 103 Belgian patients with CD between January 2000 and October 2015. Patients who lost clinical response during infliximab maintenance therapy received an infliximab treatment intensification: 45 (44%) received a double dose; 45 (44%) underwent interval shortening, and 13 (13%) underwent combined interval shortening and dose doubling in an attempt to restore clinical response. No significant differences in baseline characteristics were found between the 3 intervention groups. Infliximab and ATI concentrations were measured via enzyme-linked immunosorbent assay (ELISA) in 2 consecutive trough samples, just before (at T0) and after (at T+1) treatment intensification.

Clinical response to infliximab treatment intensification was defined as a marked decrease in or a disappearance of symptoms (based on the physicians’ global assessment). Biological response was evaluated in the subgroup of patients with elevated C-reactive protein (CRP) before treatment intensification, and was defined as a decrease from baseline CRP of at least 50% or a normalization of CRP. Biological remission was defined as a normalization of CRP. Clinical and biological outcomes were evaluated at T+1; follow-up continued for 1 year to assess treatment discontinuation and safety issues.

The researchers report that:

• Clinical response rates were similar among the different treatment intensification strategies. Overall, 63% of patients experienced clinical response after treatment intensification (at T+1). Interval shortening was clinically successful in 73%, dose doubling in 53%, and combined interval shortening and dose doubling in 62% of patients.
• Biological response and remission rates did not differ between the intervention groups. Treatment intensification resulted in short-term biological response in 42% and in short-term biological remission in 24% of patients.
• There was a poor correlation between clinical response and biological response/remission, and clinical response and infliximab trough concentration at T+1, which might be explained by a temporal relation between changes in CRP, mucosal healing, and clinical symptoms; anatomical location of disease; an overlap with irritable bowel syndrome; a switch to disease mechanism that does not respond to tumor necrosis factor inhibitors; or a placebo response.

The authors conclude that their data support a role for measuring ATI concentrations in the context of “reactive” TDM—that is, to regain response. However, because it is not possible to act upon the measurement at the time samples are taken, the authors suggest performing TDM in a proactive manner to preventing loss of response. “When loss of response occurs, we recommend performing dose doubling over interval shortening,” they state. In the foreseeable future, the development of point-of-care assays will allow on-site availability of the analytical result, improving flexibility of both proactive and reactive TDM. Finally, the authors say that larger cohorts must be studied to explore the cost effectiveness of TDM based on infliximab and/or ATI concentrations.