Evolution of Cytokines and Inflammatory Biomarkers During Infliximab Induction Therapy and the Impact of Inflammatory Burden on Primary Response in Patients with Crohn's Disease

Objective: Primary non-response to infliximab in Crohn's disease is still incompletely understood. Our aim was to further characterize the role of inflammatory burden during infliximab induction therapy. Materials and Methods: We studied a well-characterized cohort of 201 anti-TNF naive Crohn's disease patients treated with infliximab 5mg/kg at week 0, 2, 6 and 14 who had serum samples drawn just before every infusion. All serum samples were analyzed for CRP, albumin, TNF, IFN-gamma, IL-6, IL-8, IL-10, infliximab trough concentrations (in-house-developed ELISA) and antibodies to infliximab (HMSA, Prometheus Laboratories Inc., San Diego, CA). Primary non-response was defined as the absence of clinical improvement at week 14. Results: The incidence of primary non-response to infliximab was 8% (n = 16). IL-8 concentrations at baseline were higher (p = .01) and albumin at week 6 was lower in primary non-responders (p = .01) compared to responders. During induction, IFN-c and IL-6 concentrations decreased significantly at week 2 and week 6 in responders compared to primary non-responders (p < .05). Serum TNF increased significantly after each infliximab infusion and this increase from week 0 to week 14 was more pronounced in responders (p = .03). Multiple logistic regression identified TNF/CRP ratio at baseline as predictive for primary non-response to infliximab at week 14 (OR 2.8 (95% CI 1.4-5.5; p = .003)). Conclusions: In this intensively sampled cohort of Crohn's disease patients, we demonstrate that inflammatory burden is more determining for primary non-response than drug exposure or immuno-genicity. Our findings furthermore suggest that the contribution of TNF in inflammation might be higher in primary non-response, contradicting the non-TNF-driven concept.