Background/Purpose: PsA is a chronic heterogeneous inflammatory condition affecting up to 30% of patients with skin and/or nail psoriasis and the IL-23/IL-17 axis is believed to be key in psoriasis and PsA pathogenesis. Several drugs targeting the IL-23/IL-17 axis have been successfully tested in the context of psoriasis and PsA but, while 50-60% of patients achieve almost complete psoriasis clearance upon treatment, the joint disease improvement is modest. To date, the mechanism for the divergent skin-joint response remains largely unexplained. This study aims to determine the relationship between synovial versus skin transcriptional/histological profiles in patients with active PsA and to explore mechanistic links between diseased tissue pathology and clinical outcomes.

Methods: Twenty-seven patients fulfilling the ClASsification for Psoriatic ARthritis (CASPAR) criteria with active peripheral joint disease ( >3 tender and >3  swollen joints) despite an adequate trial of at least two conventional synthetic DMARDs and either biologic-naïve or failing one or more TNF-α-inhibitor (anti-TNF) were enrolled in an observational/open-label study. Patients underwent biopsies of synovium and paired lesional/non-lesional skin before starting anti-TNF (if biologic-naïve; n=18) or ustekinumab (anti-IL-12/IL-23p40; if anti-TNF inadequate responders; n=9). Molecular analysis of 80-inflammation-related genes and protein levels for IL-23p40/IL-23p19/IL-23R were assessed by real-time-PCR and immunohistochemistry, respectively.

Results: At baseline, all patients had persistent active disease as per inclusion criteria. At 16-weeks-post-treatment, skin responses favoured ustekinumab, while joint responses favoured anti-TNF therapies. Principal-component-analysis revealed distinct clustering of synovial tissue gene expression away from the matched-skin. While IL12B–IL23A-IL23R were homogeneously expressed in lesional skin, their expression was extremely heterogeneous in paired synovial tissues. Here, IL-23 transcriptomic/protein expression was strongly linked to patients with high-grade synovitis who, however, were not distinguishable by conventional clinimetric measures.

Conclusion: PsA synovial tissue shows a heterogeneous IL-23 axis profile when compared to matched skin. Synovial molecular-pathology may help to identify among clinically indistinguishable patients those with a greater probability of responding to IL-23 inhibitors.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-23-skin-and-joint-profiling-in-psoriatic-arthritis-novel-perspectives-in-understanding-clinical-responses-to-il-23-inhibitors/