Background Although PsA is heterogeneous and shows signs of rheumatoid arthritis (RA) and psoriasis (PsO), genetic studies indicate that PsA is a distinct disease with a strong heritable component. PsA is categorized into 5 overlapping clinical patterns: polyarthritis (POLY), arthritis of distal interphalangeal joints (DIP), spondylitis (SPON), and asymmetric peripheral arthritis (ASYM).
Objectives This study examines if whole blood (WB) gene expression profiles can be utilized to: identify a baseline disease profile (DP) for pts with PsA, differentiate among the clinical subtypes, and compare/contrast the disease mechanisms of PsA, RA and PsO.
Methods mRNA from 270 WB samples collected at wk0 in a Ph3 study of ustekinumab (PSUMMIT I) from pts with active PsA were isolated and profiled using the Affymetrix HT HG-U133+ PM Array (Santa Clara, CA). 36 healthy control WB samples were obtained from Bioreclamation (Hicksville, NY). Baseline gene expression profiling data comparing disease to healthy control (mRNA isolated from WB and run on Affymetrix HT HG-U133+ PM Array) from 487 RA patients in a Ph3 study of golimumab (GO-FURTHER) and 186 PsO patients in a Ph4 study of ustekinumab (TRANSIT) were used to compare the PsA disease profile to RA and PsO. All data were analyzed by iReport® and Ingenuity Pathway Analysis® (Ingenuity Systems).
Results We identified a disease profile for PsA (PsA vs Healthy); the majority of the differentially expressed genes are upregulated and fall into diverse categories, such as cellular proliferation, inflammation and immune response. There were no differentially expressed genes that separated PsA subtypes. PsA showed a distinct gene expression profile from RA and PsO with moderate overlap at the gene level. The genes common to all 3 diseases are largely upregulated and the biology represented by these shared genes comprise immune/inflammatory processes and connective tissue disorders. Although PsA shows greater similarity to RA than PsO at the functional pathway level, the PsA disease profile is significantly different in that a majority of the genes are upregulated in PsA. Pathways related to cell proliferation, inflammation, B and T cell signaling are increased in PsA (these pathways are largely downregulated or not significant in RA and PsO). The differentially expressed genes unique to PsA were enriched for the Protein Kinase A and Ephrin signaling pathways. There is emerging evidence that the Ephrin signaling pathway is implicated in bone remodeling and homeostasis and these data may suggest evidence for differential pathways related to structural damage in PsA than RA.
Conclusions PsA has a distinct gene expression profile, although the PsA clinical subtypes could not be differentiated at a molecular level. Disease profile is best represented by activated pathways related to immune function and immune response; data showed a novel association of PsA with the Ephrin signaling pathway. Majority of the differentially expressed genes are unique to PsA and provide molecular support for PsA as a distinct disease entity. WB gene expression profile of PsA pts may help in the diagnosis of PsA, provide insight into disease pathogenesis, and identification of novel disease markers and therapeutic targets.
Disclosure of Interest B. Dasgupta Employee of: Janssen Research & Development, LLC, Y. Cherkas Employee of: Janssen Research & Development, LLC, S. Lamberth Employee of: Janssen Research & Development, LLC, C. Brodmerkel Employee of: Janssen Research & Development, LLC.