Background: Cutaneous lupus has a large impact on the quality of life. The skin lesions are frequently disfiguring, easily visible, and resolve with scarring and hyperpigmentation. Treatment frequently begins with hydroxychloroquine, an antimalarial that modifies the activation of immune cells in the blood and skin. Only 50% of patients respond to hydroxychloroquine, and it takes at least 2 months to begin to see benefit. During that time the disease frequently continues to be active. Since half of patients don’t improve with this approach, the delay in treatment leads to a delay in identifying patients who need to move to other therapies. There is very little known about the differences in the cells and inflammatory pathways in the skin in patients who don’t respond to anti-malarials. Current new scientific approaches now allow for evaluation of potential markers of the heterogeneity of response, using a novel technique that allows simultaneous examination of 35 cellular and pathway markers in the affected skin from cutaneous lupus patients.

Focus Areas: The proposed studies will address a number of focus areas for the Fiscal Year 2019 Lupus Research Program (FY19 LRP). These include understanding lupus disease heterogeneity that will aid in subtyping patients and understanding clinical course and response to therapy.

Hypothesis or Objective: We hypothesize that antimalarial non-responders will have differentially expressed T cell subsets and unique pathway markers relative to antimalarial responders.

Specific Aims:

Aim 1. Immunologic analyses of the cellular infiltrate in lesional cutaneous lupus erythematosus (CLE) skin from well-characterized patients at baseline who subsequently were determined to be antimalarial responders or antimalarial non-responders.

Aim 2. Analysis of cells and corresponding signaling pathways together in lesional CLE skin from well-characterized patients at baseline who subsequently were determined to be antimalarial responders or antimalarial non-responders.

Research Strategy: Patients participating in a longitudinal database have been well-characterized using validated disease severity tools in terms of their baseline disease activity and therapeutic responses. Baseline skin from 20 antimalarial responsive and 20 antimalarial refractory biopsies will be utilized for the proposed studies and correlated with treatment responses.

Innovation: The proposed studies will provide a novel and systematic approach to better understand critical cells and pathways in refractory CLE. The ability to examine multiple cell types simultaneously, as well as their signaling pathways using CyTOF mass cytometry, provides a novel approach to a difficult and unexplored problem of refractory skin disease in lupus.

Impact: The proposed studies will address a number of focus areas for FY19 LRP. These include understanding lupus disease heterogeneity that will aid in subtyping patients and understanding clinical course and response to therapy. More specifically, this project will allow characterization of cells and pathways that distinguish refractory from antimalarial-responsive CLE, giving insight into development of future targeted therapy in refractory disease. These studies will allow a more individualized approach to treatment.