Personalised Medicine with IL-23 Blockers: Myth or Reality?

Abstract

Background and aims: The medical management of inflammatory bowel disease [IBD] has become increasingly targeted, through the identification of specific immune mediators involved in its pathogenesis. IL-23 is an inflammatory cytokine involved in both innate and adaptive immunity, which has been identified as a therapeutic target in Crohn's disease [CD] and ulcerative colitis [UC] through its upstream inhibition of the T helper 17 [Th17] pathway. We sought to review available data on the efficacy of IL-23 inhibitors in the treatment of IBD and the potential for clinical and molecular predictors of response to facilitate a personalised medicine approach with these agents.

Methods: We reviewed and summarised available clinical trial data on the use of the IL-23 inhibitors risankizumab, brazikumab, mirikizumab, and guselkumab in the treatment of IBD, as well as the evidence from studies of these agents in IBD and other immune-mediated conditions which might inform prediction of response to IL-23 inhibition.

Results: Early clinical trials have demonstrated promising results following both induction and maintenance therapy with IL-23 inhibitors in CD and UC. Pre- and post-treatment levels of IL-22 and post-treatment levels of IL-17 have been identified as potential molecular predictors of response to therapy, in several studies. No significant clinical predictors of response have been identified thus far.

Conclusions: IL-23 antagonism is a promising therapeutic approach in IBD. Further exploration of molecular and clinical predictors of response may identify patients most likely to benefit from these medications.

Keywords: IBD; IL-23; p19.

Figure 1.

Schematic of the IL-23 pathway. Following activation by innate immune cells, IL-23, in combination with TGFβ, IL-6, IL-21, and IL-1β, influences differentiation of naïve T cells into Th17 cells. These, in turn, produce several inflammatory cytokines, including IL17A and IL17F [which themselves produce TNFα, IFNγ, GM-CSF, and inflammatory chemokines], IL-22, and IL-21.