Circulating Cytokines and Cytokine Receptors in Infliximab Treatment Failure Due to TNF-α Independent Crohn Disease

Abstract

The inflammatory response at infliximab (IFX) treatment failure due to tumor necrosis factor (TNF)-α-independent Crohn disease activity is unknown.This is an exploratory, hypothesis-generating study based on samples collected in a clinical trial among patients failing conventional IFX dosages and treated with an intensified IFX regimen for 12 weeks. Patients with clinical response at week 12, as defined by a reduction of Crohn disease activity index by ≥70, were considered to suffer from nonimmune pharmacokinetic (PK) treatment failure (n = 18), and nonresponders had a presumed pharmacodynamic (PD) failure due to non-TNF-driven disease (n = 8). Patients failing IFX due to functional anti-IFX antibodies (n = 2) were excluded. The study population also comprised a group of 12 patients in long-term remission on IFX. A functional cell-based reporter gene assay was applied to measure IFX and anti-IFX antibodies. Circulating cytokines and cytokine receptors were assessed by enzyme-linked immunosorbent assay: granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1α, IL-1β, IL-1Ra, IL-6, IL-10, IL-12p70, soluble TNF receptor (sTNF-R) 1, sTNF-R2, IL-17A, and monocyte chemotactic protein 1.The IFX levels were similar between patients with IFX failure caused by nonimmune PK or PD at treatment failure (median 1.4 vs 2.4 μg/mL; P = 0.52), during treatment intensification (8.1 vs 5.6; P = 0.85), and after 12 weeks (8.8 vs 7.7; P = 0.93), congruent with nonresponders failing IFX due to predominantly TNF-α-independent signaling pathways in their disease. Cytokine and cytokine receptor levels were comparable between patients with nonimmune PK failure and PD failure at time of manifestation of IFX failure, but with higher IL-6 and sTNF-R2 levels among IFX treatment failures as compared with patients in remission (IL-6 median 3.6 vs <3.1 pg/mL; P = 0.03; sTNF-R2 3207 vs 2547 pg/mL; P = 0.01). IL-6 and sTNF-R2 were lower after 12 weeks in nonimmune PK failures than in PD failures (<3.1 vs 4.0; P = 0.02; 3209 vs 4740; P = 0.04, respectively), and were measured at levels comparable with patients in remission. Further, trends of decreased IL-6 and sTNF-R2 levels among nonimmune PK failures during IFX intensification (P < 0.05 and P = 0.12) were observed.These observations indicate that IL-6 and sTNF-R2 are of potential relevance in driving the inflammatory response in IFX refractory Crohn disease caused by TNF-α-independent disease activity.

Putative biomarkers of vedolizumab resistance and underlying inflammatory pathways involved in IBD

“…This finding might further be supported by a recent study in IBD as well as experimental colitis showing that inflammation involving the cytokine oncostatin M and IL-6 is capable of driving a TNF-independent intestinal inflammation. 33 34 …”

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—personalised medicine in its infancy

“…Reduction in tenascin C (an extracellular matrix glycoprotein) predicted downregulation of CCL2 (a proinflammatory chemokine), which was associated with response at week 14 . Nonresponders to anti‐TNF dose intensification had high IL‐6 and sTNFR2 compared to responders . In UC, anti‐TNF nonresponse was associated with high baseline TNF, IL‐1β, IL‐10 and IFN‐γ, and decreased TNF, IL‐1β, IL‐6 and IL‐10 production upon peripheral blood mononuclear cell stimulation in vitro .…”

ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases

“…Thus, alternative pathways are involved in IFX therapy failure . For example, high levels of IL‐6 and TNF‐R2 were reported to be associated with refractoriness to IFX in CD through a TNF‐α‐independent pathway . IL‐33 or IL‐12B has been shown to be related with modulation and activity of the disease .…”

“…34 For example, high levels of IL-6 and TNF-R2 were reported to be associated with refractoriness to IFX in CD through a TNF-α-independent pathway. 35 IL-33 or IL-12B has been shown to be related with modulation and activity of the disease. 36,37 These cytokines might be associated with IFX resistance in IBD patients through an alternative pathway, without TNF-α.…”