Guselkumab Modulates Differentially Expressed Genes in Blood of Patients With Psoriatic Arthritis: Results from Two Phase 3, Randomized, Placebo-Controlled Trials

• Published in: ACR open rheumatology Vol. 5; no. 9; pp. 490 - 498
• Main Authors: Siebert, Stefan, Sweet, Kristen M, Ritchlin, Christopher T, Hsia, Elizabeth C, Kollmeier, Alexa P, Xu, Xie L, Seridi, Loqmane, Song, Qingxuan, Gao, Sheng, Chen, Warner, Miron, Michelle
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2023; Wiley Periodicals, Inc; Wiley
• Subjects: Biomarkers; Clinical medicine; Gene expression; Generalized linear models; Original; Psoriasis; Psoriatic arthritis; Steroids
• ISSN: 2578-5745; 2578-5745
• DOI: 10.1002/acr2.11589

To evaluate gene expression in blood of patients with psoriatic arthritis (PsA) versus healthy controls and identify changes associated with guselkumab treatment. Whole blood transcriptome profiling via paired-end RNA sequencing was conducted using samples from DISCOVER-1 and DISCOVER-2 at baseline (n = 673) and at weeks 4 and 24 from a representative subgroup that received placebo or guselkumab (n = 227 [longitudinal PsA cohort]). Baseline samples were compared with demographically matched healthy controls (n = 21). Guselkumab-mediated changes in gene expression were assessed in participants from the longitudinal PsA cohort who did versus did not achieve at least 20% improvement in American College of Rheumatology response criteria (ACR20) or at least 75% improvement in Psoriasis Area and Severity Index (PASI75). Differential gene expression was analyzed using edgeR. At baseline, 355 upregulated and 314 downregulated genes (PsA-associated genes) were identified in patients with PsA versus healthy controls. Upregulated genes were related to neutrophil, mononuclear cell, and CD11b+ gene sets. No cell type-specific gene sets were identified among downregulated genes. Most PsA-associated genes were modulated by guselkumab treatment. At week 24, genes downregulated by guselkumab were enriched with neutrophil, monocyte, eosinophil, and macrophage gene sets; genes upregulated by guselkumab were enriched with B cell, T cell, and natural killer cell gene sets. Reductions in expression of upregulated PsA-associated gene sets were more pronounced in ACR20 and PASI75 responders than in nonresponders. These findings suggest a dysregulation of immune cell profiles in blood from patients in the baseline PsA cohort that approached levels in healthy controls after guselkumab treatment.