Abstract
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-γ, 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-γ 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 immunogenicity. Our findings furthermore suggest that the contribution of TNF in inflammation might be higher in primary non-response, contradicting the non-TNF-driven concept.
Acknowledgments
The authors would like to thank Sophie Organe, Willem-Jan Wollants, Nooshin Ardeshir, Nikolai Hendriks, Sofie Tops and Griet Compernolle for an excellent job in maintaining the Biobank database and handling all the serum samples.
Disclosure statement
TB received speaker fees from Ferring Pharmaceuticals. FP and SS are employees of Prometheus Laboratories. MF received financial support for research from Janssen Biologics, lecture fees from MSD, Ferring Pharmaceuticals, Chiesi, MSD, Tillotts, Janssen Biologics, Abbott Laboratories and AbbVie, and consultancy fees from Abbott Laboratories, AbbVie, MSD and Janssen Biologics. GVA received financial support for research from Abbott and Ferring Pharmaceuticals, lecture fees from Janssen, MSD and Abbott, and consultancy fees from PDL BioPharma, UCB Pharma, Sanofi-Aventis, Abbott, AbbVie, Ferring, Novartis, Biogen Idec, Janssen Biologics, Novo Nordisk, Zealand Pharma A/S, Millennium/Takeda, Shire, Novartis and Bristol Mayer Squibb. AG received financial support for research from Pfizer, speaker fees for Pfizer, AbbVie, Janssen Biologicals and MSD, and consultant fees from UCB, and has licensed infliximab ELISA to apDia. SV received financial support for research from MSD, AbbVie and UCB Pharma, lecture fees from Abbott, AbbVie, MSD, Ferring Pharmaceuticals and UCB Pharma, and consultancy fees from Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, MSD and AstraZeneca Pharmaceuticals. IC, VB and KC disclose no conflicts of interest.