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

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. 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. 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. 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. 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.