Abstract Dermatomyositis (DM) is a multiorgan autoimmune disease that causes significant skin activity and severe pruritus, both of which worsen the patients’ quality of life (QoL). Despite its clinical importance, however, the pathogenesis of skin activity and itch in DM remains poorly understood. Accordingly, no new therapies for DM have been approved in the last 70 years. Currently available off-label therapies are frequently ineffective or have significant risks. We recently completed a successful NIH-funded phase 2 randomized controlled trial of lenabasum, a novel nonpsychoactive CB2 inverse agonist, to treat skin-predominant DM. Lenabasum produced significant improvements in skin disease activity, itch, and key QoL measures. Mechanistic studies performed in our lab using the limited number of biopsies of lesional skin from the trial demonstrated that lenabasum decreased the numbers of dermal CD4+ T-cells and dermal staining areas for interferon (IFN)ß, IFNγ, and interleukin (IL)31. None of these four parameters changed in the placebo group. The first three of these changes significantly correlated with improvement in skin disease activity. The decreases in dermal staining for IFNγ and IL31 each significantly correlated with improvement in itch. Our recent work demonstrates prominent myeloid dendritic cells (mDCs) in the skin of patients with DM, in contrast to the predominance of plasmacytoid DCs (pDCs) and the IFNα signature in the skin of many lupus patients. Given the prominent IFNß signal in skin previously reported in DM and the decrease in IFNß and skin disease activity in response to lenabasum, we now propose to evaluate the role of mDCs in the production of IFNß in DM. We have an opportunity to expand the scientific advances we made in the phase 2 trial in an upcoming phase 3 international trial of lenabasum for DM. We hypothesize that lenabasum, acting through the CB2 receptor on mDCs, decreases mDC expression of IFNß through effects on IRF-3, -5, and -7. We also hypothesize that lenabasum, either through the downregulation of IFNß from mDCs or by direct effects on T cells, decreases production of IFNγ and IL31 in skin. In DM patients treated with lenabasum in the phase 3 trial, we will identify cellular and molecular changes in pathways relevant to skin disease activity and itch that predict or correlate with clinical improvements. We will also perform mechanistic studies of pathways promoting activity and itch in DM and the improvement with lenabasum. Our proposed studies utilizing samples from the upcoming phase 3 trial will enhance our understanding of how lenabasum works, thereby shedding light on key disease mechanisms and possibly providing a basis for additional novel therapeutic approaches.