Disclosure(s): No financial relationships with ineligible companies to disclose
Background/Purpose: Psoriatic arthritis (PsA) is a chronic inflammatory disease for which TNFα inhibitors are the standard first-line biologic therapy. Nonetheless, a significant proportion of patients exhibit an inadequate response, requiring a switch to alternative agents. There are several second-line treatment options, such as IL-17 inhibitors, IL-23 inhibitors, or JAK inhibitors. Among these options, IL-23 inhibitors are increasingly used, yet there is no clear guidance to inform their selection in clinical practice. Exploring how TNFα inhibition influences the IL-23 levels may offer valuable insights into whether anti-IL-23 therapies represent a rational and effective choice after anti-TNF failure. This study aims to investigate the effect of anti-TNFa therapy on IL-23 serum levels in PsA patients and explore the mechanistic regulation of IL-23 and other inflammatory markers by TNFa in vitro. Methods: Serum IL-23 levels were measured by ELISA in a cohort of 40 PsA patients before and after six months of anti-TNFa therapy. In parallel, primary human dermal fibroblasts were cultured and stimulated with recombinant TNFα in the presence or absence of anti-TNFα agents using varying concentrations and exposure times (6h, 24h and 48h). IL-23 expression and other key inflammatory markers were assessed by RT-qPCR to evaluate the impact of TNFα blockade. Results: Serum IL-23 levels were significantly reduced after six months of anti-TNFα therapy. In vitro, TNFα stimulation induced a robust upregulation of IL-23 expression in dermal fibroblasts which was effectively reversed by anti-TNFα agents. Additionally, anti-TNFα exposure led to a significant decrease in the expression of inflammatory mediators such as IL-6, while genes like IL-17 remained largely unchanged. These findings suggest that TNFα directly promotes IL-23 production in resident skin cells, and that its inhibition downregulates this axis both systemically and at the tissue level. Conclusion: Our findings demonstrate that anti-TNFα therapy significantly modulates key inflammatory pathways in PsA. Anti-TNFα treatment leads to a notable reduction in IL-23 levels both in vivo and in vitro, highlighting IL-23 as a downstream target of TNF signaling in PsA. Therefore, quantification of IL-23 could serve as a promising biomarker for personalizing biologic sequencing and guiding second-line therapy selection in PsA patients with suboptimal responses to anti-TNFα agents.
Acknowledgements. Project " PMP21/00119", funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union.
