Background
Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM.
Methods
Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations.
Results
After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β.
Conclusion
Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.
Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can be associated with systemic lupus erythematosus (SLE) symptoms. The pathogenesis of both CLE and SLE is multifactorial, involving genetic susceptibility, environmental factors, and innate and adaptive immune responses. Despite the efficacy of current medications, many patients remain refractory, highlighting the necessity for new treatment options. Unfortunately, owing to challenges related in part to trial design and disease heterogeneity, only one new biologic in the last 50 years has been approved by the US Food and Drug Administration for the treatment of SLE. Thus, although SLE and CLE have a similar pathogenesis, patients with CLE who do not meet criteria for SLE cannot benefit from this advancement. This article discusses the recent trials and emphasizes the need to include patients with single-organ lupus, such as CLE, in SLE trials.
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