Combined – whole blood and skin fibroblasts- transcriptomic analysis in Psoriatic Arthritis reveals molecular signatures of activity, resistance and early response to treatment

Abstract

BackgroundAn interplay between immune cells and resident skin and joint stromal cells is implicated in psoriatic arthritis (PsA), yet the mechanisms remain elusive with a paucity of molecular biomarkers for activity and response. Combined transcriptomic and immunophenotypic analysis of whole blood and skin fibroblasts could provide further insights.MethodsWhole blood RNA-seq was performed longitudinally in 30 subjects with PsA at the beginning, one and six months after treatment, with response defined at six months. As control groups, 10 healthy individuals and 10 subjects with rheumatoid arthritis (RA) were recruited combined with public datasets from patients with psoriasis (PsO) and systemic lupus erythematous (SLE). Differential expression analysis and weighted gene co-expression network analysis were performed to identify gene expression signatures, while deconvolution and flow cytometry to characterize the peripheral blood immune cell profile. In a subset of affected and healthy individuals, RNA-seq of skin fibroblasts was performed and subjected to CellChat analysis to identify the blood-skin fibroblast interaction network.ResultsPsA demonstrated a distinct “activity” gene signature in the peripheral blood dominated by TNF- and IFN-driven inflammation, deregulated cholesterol and fatty acid metabolism and expansion of pro-inflammatory non-classical monocytes. Comparison with the blood transcriptome of RA, PsO, and SLE revealed a “PsA-specific signature” enriched in extracellular matrix remodeling. This was further supported by the skin fibroblast gene expression profile, displaying an activated, proliferating phenotype, and by skin-blood interactome analysis revealing interactions with circulating immune cells through WNT, PDGF and immune-related semaphorins. Of note, resistance to treatment was associated with upregulation of genes involved in TGFβ signaling and angiogenesis and persistent increase of non-classical monocytes. Differentially expressed genes related to platelet activation and hippo signaling discriminated responders and non-responders as early as one month after treatment initiation.ConclusionTranscriptome analysis of peripheral blood and skin fibroblasts in PsA reveals a distinct disease activity signature and supports the involvement of skin fibroblasts through their activation and interaction with circulating immune cells. Aberrant TGFβ signaling and persistently increased non-classical monocytes characterize treatment-resistant PsA, with pro-inflammatory pathways related to platelet activation and Hippo signaling predicting early response to treatment.

Type-I interferon pathway and DNA damage accumulation in peripheral blood of patients with psoriatic arthritis

“…study of PBMCs derived from PsA patients vs healthy controls showed a positive enrichment in PsA of several terms related to inflammation such as 'inflammatory response', 'TNFa signaling via NFkB', 'complement', 'IL2 signaling', and 'IFNa and IFNg response' (49) consistent with our results. Interestingly, longitudinal assessment of PBMC transcriptome revealed that transcriptomic alterations as soon as 1 month after treatment initiation could predict response at 6 months, with responders showing early downregulation of the proinflammatory gene signatures (49).…”

Computational approaches in rheumatic diseases – Deciphering complex spatio-temporal cell interactions

“…Surprisingly, the expression of PD-1 and its ligands PD-L1 and PD-L2 showed a stepwise increase early in disease progression to RA, however, histological examination of synovial tissue biopsies showed very low levels of PD-L1 possibly due to epitope masking mediated by the increased levels of soluble PD-1 in the serum of patients with RA [50] . In addition to the identification of signalling pathway enrichment in RA synovial inflammation during different stages of disease, the potential identification of PsA specific transcriptomic signature in the blood could facilitate diagnostic biomarker discovery [51] .…”

Pharmacodynamic effects of filgotinib treatment driving clinical improvement in patients with active psoriatic arthritis enrolled in the EQUATOR trial

“…In a recently published observational study including 30 PsA patients, similar pathways including inflammatory response, complement, IFNα and IFNγ response, oxidative phosphorylation, adipogenesis, fatty acid metabolism, EMT, angiogenesis and signalling cascades related to WNTβ catenin and TGFβ where identified. 14 Another observational study of 60 patients also identified inflammation, immune response, apoptosis, cell cycle regulation and proliferation, cell migration and invasion, extracellular matrix remodelling, bone remodelling, angiogenesis, signal transduction as important pathways reflected in the peripheral blood cells of PsA patients. 15 Thus, our results provide insights to biomarkers and pathways driving disease activity in PsA and highlights the importance of IL6-JAK-STAT3 signalling.…”