Cytokine‐associated pathogenic profile as a guide for targeted therapy in pityriasis rubra pilaris

Pityriasis rubra pilaris (PRP) is a chronic, inflammatory dermatosis marked by follicular hyperkeratosis, widespread erythematous scaling plaques and palmoplantar keratoderma, all of which profoundly impair quality of life.1 Although PRP and psoriasis share clinical features, they differ in histopathology and immune signatures. The lack of large controlled trials has prevented standardized treatment guidelines, and conventional systemic regimens—acitretin or methotrexate with or without phototherapy—often yield suboptimal responses in refractory cases.2, 3 Biologics targeting TNF-α, IL-17A and small-molecule JAK inhibitors have shown promise, but treatment selection remains empirical.4-7 To address this therapeutic gap, we conducted a 52-week, immune profile-guided evaluation of IL-12/23 and IL-23 inhibitors in six adults with type I PRP unresponsive to at least one prior systemic agent. Six refractory PRP patients (3 female, 3 male; age 41–69) refractory to ≥1 systemic agent (methotrexate, cyclosporine A, acitretin, tofacitinib or anti–IL-17) were enrolled at Hong Kong University Shenzhen Hospital and the Eighth Affiliated Hospital of Sun Yat-sen University. All patients provided written, informed consent at enrolment for their participation. Baseline disease was moderate–severe: mean Psoriasis Area and Severity Index (PASI) 26.1 (range 6.3–54.0; Figure 2a), mean body surface area (BSA) involvement 42.0% (6.0%–100.0%; Figure 2c) and mean pruritus numeric rating scale (NRS) 7.8 (3.0–10.0; Figure 2d). Immunohistochemical staining of skin biopsies from six PRP patients, five plaque psoriasis controls and five healthy volunteers was quantified by ImageJ per tissue area and compared using Kruskal–Wallis with Bonferroni-adjusted post hoc tests (p < 0.05).8 PRP lesions revealed marked overexpression of Th1 (IFN-γ, IL-12, TNF-α) and Th17/22 (IL-23, IL-17, IL-22) cytokines, plus JAK1/2 (molecules of the JAK1/2-STAT3 pathway) activation profiles akin to psoriasis but with significantly higher IFN-γ in PRP (Figure 1a–h). Factoring in patient preference, cost and compliance, we selected ustekinumab (IL-12/23 inhibitor) for four patients and guselkumab (IL-23 inhibitor) for two, administering three to seven injections over 52 weeks. Clinical improvement was rapid and sustained (Figure 2a–d). By week 4, mean PASI fell to 16.2 and pruritus NRS to 5.2. At week 16, mean PASI was 6.8, with 83.3% (5/6) achieving PASI 75 and 66.7% (4/6) reaching PASI 90—including four patients with complete clearance (PASI 0). At the primary endpoint (week 28), all six had PASI 75 and 66.7% (4/6) attained PASI 100. Notably, the two most severe cases (baseline PASI 54.0/BSA 100% and PASI 48.6/BSA 100%) declined to PASI 11.6/BSA 35% and PASI 5.5/BSA 8%, respectively. Among the five patients who completed the 52-week follow-up, the mean PASI score was 0.96 ± 1.7, mean BSA involvement was 1.2 ± 2.4%, and mean pruritus NRS score was 0.4 ± 0.8 (n = 5). Treatment was well tolerated: no serious infections, malignancies or paradoxical reactions occurred. One patient experienced mild, transient injection-site erythema. Our data confirm that PRP lesions harbour a distinctive Th1/Th17 cytokine profile particularly heightened IFN-γ that supports a ‘dual-pathway’ model. Accordingly, targeting the IL-12/23 axis (dual-pathway: IL-23 → Th17 → IL-17/22–driven keratinocyte hyperproliferation; IL-12 → Th1 → IFN-γ/TNF-α–driven inflammation) emerges as a highly attractive strategy. IL-23 antagonism decreases IL17/IFNG mRNA and skin IL-17A/F, IFN-γ, TNF-α levels via combined Th1/Th17 cytokine blockade,9 delivering rapid, high-level skin clearance in refractory PRP. These outcomes compare favourably with historical benchmarks for retinoids, IL-17 inhibitors and JAK inhibitors and highlight the importance of tailoring therapy to lesional immune profiles.4-7 This small, two-centre study has several limitations: first, although immunohistochemistry is valuable for detecting specific cytokines, its limited multiplex precision and quantitative accuracy, coupled with the lack of serial biopsies, may constrain our ability to comprehensively profile dynamic immune changes and relate them to clinical responses; second, some patients experienced slow disease improvement, and without a control group, we cannot definitively distinguish true treatment efficacy from potential spontaneous remission. Therefore, future research should integrate quantitative molecular assays (e.g. RT-qPCR, multi-pathway heatmap analyses) in larger, randomized cohorts to refine biomarker-driven, personalized algorithms for PRP management.10 This study was supported by Futian District key specialty funds (QZDZK-202407/ZDXKJF-009) and Shenzhen Medical Research Fund (C2401032). None declared. Reviewed and approved by The University of Hong Kong–Shenzhen Hospital Ethics Committee; approval [2024] 151. The patients in this manuscript have given written informed consent to the publication of their case details. The data that support the findings of this study are available from the corresponding author upon reasonable request.