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Assessing Disease-Modifying Effects of IL-23 Inhibition by Guselkumab on T-Cell Profile Shifts

ABSTRACT: Anti-IL-23 antibody therapies result in improvements to the underlying immunopathology of psoriasis. However, the dynamics of the immune profile after the administration of anti-IL-23 biologics, along with their association with treatment response, remain unclear investigation. We focused on guselkumab, an anti-IL-23p19 antibody, and performed a comprehensive analysis of immune cells, serum inflammatory molecules, and transcriptomics of CD4+ T cells, aiming to identify disease-modifying drug effects in psoriasis. A total of 24 biologic-naive patients were enrolled. Peripheral and skin lesional blood samples were collected at baseline and after treatment with guselkumab. We conducted FACS analysis of regulatory T cells (Tregs), resident memory T cells (TRMs), and dendritic cells, measured serum cytokine and chemokine levels, and examined gene expression changes using RNA-seq data for peripheral CD4+ T cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290870 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Importance: There is no FDA-approved treatment for pityriasis rubra pilaris and it is common for patients to fail several systemic options. Involvement of IL-23 pathway suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for subjects with PRP. Design: Single-arm, investigator-initiated trial from October, 2019 to August, 2022. Primary outcome was observed at 24 weeks, and additional patient follow-up occurred at 36 weeks. Participants: 14 adult subjects with moderate-to-severe pityriasis rubra pilaris were enrolled; 12 completed the trial. Age- and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. Intervention: Guselkumab is a humanized IgG1 lambda antibody that selectively binds and inhibits the p19 subunit of interleukin-23. Subcutaneous injections were performed at the FDA-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was mean change in psoriasis area and severity index (PASI) at week 24. Secondary outcomes included improvement in body surface area, quality of life, time to improvement, sustained remission at 36 weeks, and correlation to germline mutations and cytokine expression. Results: An intention-to-treat analysis was performed for our cohort of ten males and six females, with a median age of 59.5 years. The mean improvement in psoriasis area and severity index, body surface area, and dermatology life quality index (DLQI) were 18.9 ± 12.5 (p<0.001), 40.5 ± 36.5 (p=0.003), and 12.2 ± 7.8 (p<0.001), respectively. 11 subjects showed sustained remission off therapy, evidenced by decreased PASI scores between week-24 and week-36. No subjects had CARD14 gene variations. There was one serious adverse event, unrelated to study drug. Proteomics and gene expression profiles improved with clinical improvement. Conclusion and Relevance: Guselkumab appears to be efficacious in the treatment of refractory PRP.

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Assessing Disease-Modifying Effects of IL-23 Inhibition by Guselkumab on T-Cell Profile Shifts

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