The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis

Erythromelalgia, a rare cutaneous pain syndrome, is characterized by acral burning pain and flushing, often alleviated by cold and rest. Primary erythromelalgia is caused by gain-of-function mutations of genes encoding for sodium channels, resulting in hyperexcitability of pain signaling neurons. Autoimmunity and hematologic dyscrasias such as thrombocythemia have been implicated in secondary erythromelalgia. The pathology of this rare disease remains poorly defined. The Weill Cornell dermatopathology database was analyzed for acral biopsies procured from patients here there was a clinical concern for erythromelalgia. We identified 9 patients with clinical diagnoses of erythromelalgia who had a skin biopsy from an affected area. The female-to-male ratio was 2:1. Three of 9 individuals had concurrent diagnoses of autoimmune disease including vitiligo, lupus erythematosus, and psoriatic arthritis. Biopsies showed superficial vascular ectasia in association with microvascular C5b-9 and variable upregulation of type I interferon expression in endothelial cells. CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy. This study suggests that erythromelalgia is a dysautonomia syndrome with reproducible findings on biopsy, hallmarked by vascular ectasia and denervation of the eccrine coil and arteries. In addition, there is a potential link to immune and nonimmune-based microvascular compromise.