IL ‐17/ IL ‐23 and JAK pathway protein expression in vulvar lichen sclerosus: Exploratory pilot study

Given emerging reports on cytokine blockade and JAK inhibition in vulvar lichen sclerosus (VLS),1-10 we hypothesized that the IL-17/IL-23 axis and JAK signalling are dysregulated in VLS and may relate to disease severity. Forty-six female VLS patients (>16 years) were recruited. Histopathologically confirmed VLS and complete clinical documentation (Table 1) were the key inclusion criteria. All patients underwent immunohistochemistry (IHC) using rabbit polyclonal antibodies (abcam, Cambridge, UK) targeting JAK1 (ab125051), JAK2 (ab39636), TYK2 (ab39550), IL-17 (ab91649) and IL-23 (ab45420). Slides were scanned at 20× using a NanoZoomer system (Hamamatsu, Germany) and evaluated with NDP.view2. H-scores (0–300) were obtained on Dako REAL™-stained sections and quantified using QuPath-0.2.3. Clinical data were collected by chart review. Statistical analyses included Mann–Whitney tests, Spearman correlations, ROC curves and logistic regression (MedCalc 23.3.7, Ostend, Belgium). Overall expression of the investigated markers was weak to modest (Table 1). Nevertheless, median IL-23 H-scores were higher in long-standing (≥5 years) compared to early-stage (<5 years) disease (3.5 [IQR 0.8–13.0] vs. 1.2 [0.4–2.0]; Hodges–Lehmann difference 2.1, 95% CI 0.2–5.3; p = 0.022), and IL-23 correlated positively with disease duration (r = 0.34, p = 0.020). IL-17 and IL-23 showed good diagnostic accuracy for atrophy (AUC 0.85 and 0.83, both p < 0.0001, Figure 1), while JAK2 and IL-17 were associated with erosive change (AUC 0.66, p = 0.043; and AUC 0.72, p = 0.0049). In regression analysis including IL-17 and IL-23, IL-17 remained independently associated with atrophy (OR 1.07 per H-score unit, 95% CI 1.004–1.15; p = 0.038), whereas IL-23 was borderline (p = 0.070). Model performance was strong (AUC 0.93; Hosmer–Lemeshow p = 0.88). For erosive disease, neither JAK2 nor IL-17 remained significant in the regression analysis. Of all markers, only IL-17 and JAK2 correlated significantly (r = 0.40; p = 0.0066). No additional comparisons were significant. This pilot-study suggests progressive IL-23 up-regulation with disease duration and highlights IL-17, and thereby the IL-17/IL-23 axis, as the strongest IHC indicator of atrophy. The IL-23 findings align with its emerging role in fibrotic autoimmune pathways.4 Our observations also complement recent studies demonstrating IL-17 overexpression in lesional VLS skin3 and elevated IL-17 levels in the blood of affected patients, which decreased under therapy.6 Although previous reports were limited by small samples, heterogeneous assays and lack of quantitative thresholds, they consistently pointed towards Th17-skewed inflammation in VLS. The present ROC-derived thresholds refine these earlier insights. The selective IL-17/JAK2 correlation observed, together with the epidermal distribution of JAK2, supports the biological plausibility of cytokine–JAK pathway coupling.5 Experimental data increasingly implicate keratinocyte-driven JAK activation in VLS pathogenesis.7 Therapeutically, evidence for JAK inhibitors in VLS remains preliminary, arising mostly from case reports, single-centre cohorts and small uncontrolled trials.8-10 While some studies observed high response rates with JAK1/2 inhibition, others documented relapse with JAK-sparing or monotherapy strategies. Evidence for IL-17/IL-23 blockade is even more limited. Overall, the existing literature is constrained by small cohorts, inconsistent treatment endpoints and short follow-up periods. Our study also has limitations: modest sample size, absence of controls, multiple comparisons and missing spatial transcriptomics or functional validation. Associations between markers were mild to moderate and should be interpreted cautiously. In summary, our findings support dysregulation of the IL-17/IL-23 axis and JAK signalling in VLS, with IL-23 linked to disease chronicity and IL-17 emerging as the strongest predictor of atrophy. These data offer quantitative thresholds relevant for prospective trials evaluating IL-17 and IL-23 antagonists or JAK2-selective blockade. Longitudinal studies are now needed to clarify causality, treatment responsiveness and whether cytokine–JAK signatures normalize with effective therapy. This work is part of the doctoral thesis of Hadil Devrim. This research received external funding by Almirall Hermal GmbH, Reinbek, Germany. T.G. has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, UCB, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. L.S. has received speakers and/or advisory board honoraria from UCB, Almirall, BMS, Sun-Pharma, MSD, and Novartis. The study was approved by the ethics review board of the University Witten/Herdecke (UWH: ID #17/2024). This study was conducted according to the Declaration of Helsinki. Not applicable. The data that support the findings of this study are available from the corresponding author upon reasonable request.