Lee, E. Y.; Patterson, S.; Cutts, Z.; Lanata, C. M.; Dall'Era, M.; Yazdany, J.; Criswell, L. A.; Haemel, A.; Katz, P.; Ye, C. J.; Langelier, C.; Sirota, M.

Systemic lupus erythematosus (SLE) presents with diverse and heterogenous cutaneous manifestations. However, the molecular and immunologic pathways driving specific cutaneous manifestations of SLE are poorly understood. Here, we leverage transcriptomics from a large well-phenotyped longitudinal cohort of SLE patients to map molecular pathways linked to ten distinct SLE-related rashes. Through whole blood and immune cell-sorted bulk RNA sequencing, we identified immune signatures specific to cutaneous subtypes of SLE. Subacute cutaneous lupus (SCLE) exhibited broad upregulation of type I interferon, TNF-, and IL6-JAK-STAT3, pathways suggesting potential unique therapeutic responses to JAK and type I interferon inhibition. While interferon signaling is prominent in SCLE, discoid lupus, and acute lupus, it is unexpectedly absent in patients with skin and mucosal ulcers. Pathway and cell-type enrichment analysis revealed unexpected roles for CD14+ monocytes in photosensitivity of SLE and NK cells in alopecia, mucosal ulceration, and livedo reticularis. These findings illuminate the immune heterogeneity of rashes in SLE, highlighting subtype-specific mechanistic targets, and presenting opportunities to identify precision therapies for SLE-associated skin phenotypes.