Immunologic properties of cutaneous lupus erythematosus (CLE) patients refractory to antimalarials compared to patients that respond to antimalarials

Summary: Abstract Background: Two major therapies for cutaneous lupus erythematosus (CLE) are the antimalarials, hydroxychloroquine (HCQ) and quinacrine (QC). HCQ is often the first-line therapy for CLE, but only half of patients show a response to it. While some of the patients that do not initially respond to HCQ benefit from the addition of QC, there is a subset of patients that are refractory to both antimalarials. Refractoriness poses a huge challenge because these patients will often continue to have active disease when they are initially started on antimalarials. To better characterize these refractory patients, we investigated the immunologic characteristics of patients that respond to antimalarials versus those that do not. Methods: CLE patients were classified as HCQ-responders, HCQ/QC-responders, or HCQ/QC-nonresponders. Immunohistochemistry was used to characterize the inflammatory cell composition and cytokine expression in lesional skin biopsies from patients. Total RNA was extracted from these biopsies to analyze specific gene signatures. The patient’s CLASI score – a measure of disease activity – at the time of the biopsy was also determined. Results: Immunohistochemistry showed that myeloid dendritic cells (mDCs) were significantly higher in HCQ/QC-responders compared to HCQ-responders and HCQ/QC-nonresponders, while plasmacytoid dendritic cells, neutrophils, macrophages, and autoreactive T cells did not differ significantly among the three groups. The HCQ/QC-nonresponder group was distinct from the other groups in that their CLASI scores did correlate positively with the number of macrophages (p<0.05, figure 1). Staining also showed that IL-22 expression was significantly higher in HCQ/QC nonresponders versus the HCQ or HCQ/QC- responders while IL-17 expression was not significantly different between the responders and nonresponders. Analyzing the mRNA expression demonstrated a high type I IFN signature (LY6E, OAS1, ISG15, MX1) in HCQ-responders but a low type I IFN signature and higher TNF-alpha expression in both HCQ/QC-nonresponders and HCQ/QC-responders. Conclusions: An increased number of mDCs may contribute to HCQ-refractoriness and predict a better response to treatment with both HCQ and QC but do not contribute to HCQ/QC-refractoriness. The significant correlation between macrophages and CLASI scores in the HCQ/QC-nonresponders, a finding not seen in either HCQ or HCQ/QC-responders, may also indicate that macrophages are more involved in antimalarial-refractory skin disease. The difference between the responders and nonresponders is further confirmed by the cytokine staining and mRNA expression. Our data is an initial step in determining the activation pathways that account for the lack of response to antimalarials.