Assessment of gene signatures following the inhibition of IL-23: a study to evaluate the mechanistic effects behind the clinical efficacy of guselkumab in patients with psoriatic arthritis

Mirco Mastrangelo¹Piero Ruscitti^1*Manfredo Bruni¹Eleonora Lucantonio¹Andrea De Berardinis¹Antonio Barile¹Maria Concetta Fargnoli^1,2Paola Cipriani¹Maria Esposito¹Cristina Pellegrini¹

• ¹Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, L'Aquila, Italy
• ²Istituto Dermatologico San Gallicano, Rome, Italy

Objectives. To evaluate the transcriptome of peripheral blood mononuclear cells (PBMCs) derived from patients affected by psoriasis (PSO) and psoriatic arthritis (PSA) following treatment with guselkumab, an IL-23 inhibitor.Methods. mRNA was extracted by PBMCs, before and after 24 weeks of treatment with guselkumab and RNA sequencing was performed in paired-end mode by Illumina technology using the Novaseq6000 platform. The log2FoldChange>1 and padj<0.05 were the established cut-off to discriminate gene differentially expressed between Pre and Post-therapy. For annotation and predictive enrichment analysis of deregulated genes in biological pathways, RStudio was used, GO and KEGG databases were queried. Cytoscape_v3.10.3 was used for the development of the network between deregulated genes.Results: Six naïve active patients with PSO and PSA, diagnosed with a duration <2 years, were assessed before and after 24 weeks of treatment with guselkumab.Performing the quality check and filtering analyses, we found 506 transcripts deregulated between pre-and post-therapy, of which 129 were upregulated and 377 downregulated. The most upregulated mRNAs included: SYTL3, CPT1A, TMEM208, GINS4 and TNFRSF13C. The most downregulated mRNAs included: CCR2, TPT1, MYCBP, CMPK1 and TMEM65. Enrichment with GO database showed main deregulated processes: "protein targeting", "the establishment of protein localization to membrane" and "metabolism of fatty acids". The analysis of the main macro-process, showed the several pathways deregulated after therapy, including signalling related to ethanol metabolism, thermogenesis, oxidative phosphorylation and fatty acid metabolism (KEGG).Conclusions. Our findings may give further insights in manipulated mechanistic pathways by IL-23 inhibition in patients with PSO and PSA.