Interplay between iron metabolism, inflammation, and EPO-ERFE-Hepcidin axis in RDEB-associated chronic anemia

• Elevated hepcidin in anemic RDEB patients was mainly linked to high ferritin and a history of intravenous iron infusions/ blood transfusions

• 90% of anemic RDEB patients showed inadequate bone marrow response, irrespective of ERFE/EPO levels, pointing to individualized therapies

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis characterized by severe cutaneous and mucosal fragility, and frequently complicated by multifactorial chronic anemia that responds poorly to conventional therapies. This cross-sectional study investigates the factors contributing to anemia in RDEB by analyzing a representative cohort, that was stratified by disease severity, anemia and iron status, to examine their hematological parameters, cytokine profile and erythropoietin (EPO)-erythroferrone (ERFE)-hepcidin axis. Anemia was present in 50% of the cohort. Hemoglobin levels showed a strong negative correlation with the percentage of body surface area affected and C-reactive protein levels (CRP), identifying these as anemia risk factors in RDEB. Moderate-severe inflammation (CRP≥15mg/L) was observed in all anemics, but no specific cytokine profile was linked with anemia risk due to variability in IL6, IL1β, IL10, TNF, and IFN-γ levels. The regulation of the EPO-ERFE-hepcidin axis showed discrepancies with the patterns expected based on patients' anemia severity and iron status. According to reticulocyte production index, an inadequate bone marrow response was observed in 90% of anemics, irrespective of EPO levels. Patients with functional or true iron deficiency had higher ERFE levels, though ERFE showed no consistent correlation with EPO and was elevated in both anemic and non-anemic patients. Elevated hepcidin was primarily linked to the highest ferritin levels mostly in patients with a history of iron infusions and/or transfusions. These findings highlight the need for personalized, targeted approaches that address the complex interplay between inflammation and iron dysregulation, to improve anemia management in RDEB and other chronic inflammatory conditions.