Thomas Billiet1, Isabelle Cleynen1, Vera Ballet2, Karolien Claes1, Fred Princen3, Sharat Singh3, Marc Ferrante1,2, Gert Van Assche1,2, Ann Gils4, Severine Vermeire1,2. 1. a Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID) , KU Leuven , Leuven , Belgium. 2. b Department of Gastroenterology and Hepatology , University Hospitals Leuven, KU Leuven , Leuven , Belgium. 3. c Department of Research and Development , Prometheus Laboratories , San Diego , CA , USA. 4. d Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies , KU Leuven , Leuven , Belgium.
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.
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 diseasepatients 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 diseasepatients, 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.
Authors: Lorenzo Bertani; Gian Paolo Caviglia; Luca Antonioli; Rinaldo Pellicano; Sharmila Fagoonee; Marco Astegiano; Giorgio Maria Saracco; Elisabetta Bugianesi; Corrado Blandizzi; Francesco Costa; Davide Giuseppe Ribaldone Journal: J Clin Med Date: 2020-05-02 Impact factor: 4.241
Authors: Ariela K Holmer; Robert Battat; Parambir S Dulai; Niels Vande Casteele; Nghia Nguyen; Anjali Jain; Ara Miralles; Jennifer Neill; Helen Le; Siddharth Singh; Jesus Rivera-Nieves; William J Sandborn; Brigid S Boland Journal: Therap Adv Gastroenterol Date: 2020-11-12 Impact factor: 4.409