IL-23 Blockade in Anti-TNF Refractory IBD: From Mechanisms to Clinical Reality

Abstract

Increasing insights into the immunopathogenesis of inflammatory bowel diseases [IBD] have led to the advent of targeted therapies that inhibit crucial mediators of the inflammatory process, thereby widening our available therapeutic armamentarium. Anti-tumour necrosis factor [anti-TNF] agents are still a mainstay of our therapeutic endeavours and the introduction of corresponding biosimilars has further widened their use. Nevertheless, only a subgroup of treated patients benefit from the initiated treatment and there is secondary non-response in the course of therapy. Initiation of subsequent therapy often poses a challenge to the treating physician, as non-response to primary anti-TNF treatment generally characterizes a patient group that is more treatment-resistant, which may be due to the immunological impregnation by prior anti-TNF exposure. At present, there is currently no guidance for the most appropriate second-line therapy after anti-TNF failure. Here, we review the efficacy of secondary biological therapy in anti-TNF-treated patients. We focus on and assess available clinical trial data of the emerging substance class of IL-23p19 inhibitors, which have demonstrated remarkable efficacy not only in anti-TNF-naïve but also refractory patients. We present molecular mechanisms that drive IL-23-mediated resistance to ongoing anti-TNF therapy and discuss the dynamic fluidity of the mucosal cytokine network in the course of therapy that perpetuates the mucosal inflammatory reaction. Translation of these findings into clinical practice might finally lead to initiation of the most appropriate therapy at the right time of the individual disease course, which would have important implications for the patient's probability of response to treatment.

Keywords: IL-23 inhibitors; IL-23p19; Inflammatory bowel diseases; anti-TNF; molecular resistance.

Figure 1.

Molecular mechanism of IL-23-driven resistance to anti-TNF therapy in Crohn’s disease. [A] Immune cell composition in a Crohn’s disease patient prior to the initiation of anti-TNF therapy. Perpetuation of mucosal inflammation due to an indication of apoptosis resistance in TNF receptor 2 [TNFR2]-expressing CD4⁺ T cells by transmembrane TNF [mTNF]-expressing CD14⁺ macrophages. [B] After commencement of efficacious anti-TNF therapy, there is induction of CD4⁺ T-cell apoptosis by binding of the anti-TNF antibody to mTNF-expressing CD14⁺ macrophages, thereby inhibiting the mTNF/TNFR2 co-stimulation pathway between CD14⁺ macrophages and CD4⁺ T cells in the mucosa. [C] In anti-TNF non-responders, there is heightened production of IL-23 by CD14⁺ macrophages, which leads to the expansion of apoptosis-resistant IL-23R⁺/TNFR2⁺ CD4⁺ T cells, which drive resistance to ongoing anti-TNF therapy. The expansion of IL-23R⁺ lymphocytes creates a novel immune phenotype that drives mucosal inflammation, non-responsive to anti-TNF therapy but potentially responsive to IL-23 inhibition.