Comparative Genomic Profiling of Synovium Versus Skin Lesions in Psoriatic Arthritis

Abstract

ObjectiveTo our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA.MethodsWe conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence.ResultsGlobally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL-17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-γ gene signatures in both tissues. These results were confirmed with real-time PCR.ConclusionThis is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA.

Responsiveness of Serum C‐Reactive Protein, Interleukin‐17A, and Interleukin‐17F Levels to Ustekinumab in Psoriatic Arthritis: Lessons From Two Phase III, Multicenter, Double‐Blind, Placebo‐Controlled Trials

“…A stronger correlation of IL‐23/IL‐17 levels with the severity of skin disease is consistent with the emerging evidence base suggesting tissue‐specific variations in the pathologic drivers within PsA. Recent pathogenesis and therapeutic studies indicate a dominant role for IL‐17–related pathways in the skin in psoriatic disease . In contrast, the musculoskeletal component of PsA appears more heterogeneous and less clearly defined.…”

Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies

“…83). This therapeutic effectiveness in blocking IL-17 in psoriatic arthritis is despite differences in skin IL-17 and joint IFN-γ expression signatures 84 .…”

Psoriasis and Psoriatic Arthritis: Flip Sides of the Coin?

“…In this study, the PsA gene expression profile is more closely related to that of PsO than to other types of arthritis. But there were still substantial differences, as skin showed a stronger IL-17 gene signature than PsA synovium, while TNF-α and interferon gamma gene signatures were more equivalent in both tissues (43).…”