Serum Dysregulation of IL-36, IL-37, and IL-38 in Pyoderma Gangrenosum: Clinical Correlations and Implications for IL-36R-Targeted Therapy

Background: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by chronic, painful ulcerations. Despite increasing evidence suggesting immunological dysregulation, the role of IL-36 cytokines in PG remains poorly defined. Objectives: To evaluate serum levels of IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37, and IL-38 in PG patients compared to healthy controls, and to assess their correlation with selected clinical parameters and cytokine ratios. Methods: 44 PG patients and 40 healthy controls were included in this case–control study. Serum cytokine levels were measured using ELISA. Correlations between cytokine levels and clinical features were analyzed using nonparametric tests. Results: PG patients showed significantly lower serum levels of IL-36α and IL-36γ (p = 0.0003 and p = 0.02, respectively), with no difference in IL-36β. Conversely, levels of IL-36Ra, IL-37, and IL-38 were significantly higher in PG patients (p < 0.0001 for all). In the PG group, significant positive correlations were observed between IL-36α and IL-36β, and between IL-36β and IL-36γ, while IL-37 correlated negatively with IL-38. IL-36α was inversely associated with serum IgA levels and total ulcer surface area, and IL-36γ correlated negatively with white blood cell count. Conclusions: Our findings reveal a dysregulated IL-36 cytokine profile in pyoderma gangrenosum, marked by reduced serum levels of IL-36α and IL-36γ and elevated levels of IL-36Ra, IL-37, and IL-38. This may reflect a compensatory response to chronic inflammation. The inverse correlation between IL-36α and ulcer size suggests its potential involvement in wound healing. Despite lower serum levels of agonists, local biological activity of IL-36 cytokines may remain elevated due to tissue-level activation and consumption. These results highlight the therapeutic relevance of targeting the IL-36 pathway—particularly in treatment-resistant cases—and support further research into cytokine activity beyond serum concentration to guide novel therapeutic strategies.