692 Interrogating mechanisms of granuloma annulare pathogenesis through RNA sequencing

Granuloma annulare (GA) is a cutaneous granulomatous disease with a wide array of clinical presentations but occurs most often as localized, non-scaly, erythematous, annular plaques on the distal extremities. While lesions are typically self-limited, they may recur and become chronic, negatively impacting patient quality of life and leading many to seek therapy due to cosmetic concerns. Although GA is quite common, with a prevalence of 0.1-0.4%, the etiology and pathogenesis of the disease remain unknown. Thus, therapies offered to patients, especially those with recurrent or chronic disease, are unstandardized and rarely evidence based. In one study of 67 GA patients, duration of lesions did not differ significantly between treated and untreated patients, suggesting current treatments are not efficacious. To investigate the transcriptomic differences between GA lesional skin vs. healthy skin, we isolated and sequenced RNA from FFPE blocks of 32 patients with clinically defined GA and 6 healthy controls. Using two-fold changes in expression and false discovery rate of 10% as criteria, we identified 3,512 differentially expressed genes (DEGs) in GA, with 1,583 upregulated. Gene ontology analysis of these upregulated genes revealed significant immune dysregulation, including reactome pathways for innate immunity, adaptive immunity, cytokine signaling, toll like receptor (TLR) cascades, and T cell receptor signaling. The top activated canonical pathways include Th1, Th2, TREM1 signaling, and granulocyte/agranulocyte trafficking. Upstream analyses reveal downstream expression patterns responsive to activation of innate transcriptional regulators, including TLRs, MYD88, NFkB, TNF, IL-1B, and many more. These transcriptional analyses support findings from prior studies which implicate dysregulation in innate and adaptive pathways as central to GA pathogenesis, provide a closer look at the downstream networks, and suggest intriguing new therapeutic avenues.