lenabasum and Dermatomyositis

In the past decade, there have been six industry-sponsored phase 3 trials in adult patients with dermatomyositis (DM), primarily focusing on improving muscle weakness. However, skin disease is a cardinal manifestation of DM. This study evaluated the sensitivity of Cutaneous Dermatomyositis Disease Area and Severity Index Activity score, Cutaneous Dermatomyositis Activity Investigator Global Assessment, Total Improvement Score, and other outcome measures used in DM clinical trials to detect improvement in DM skin disease activity. Data analyzed from the lenabasum phase 3 trial in DM showed that improvement in Cutaneous Dermatomyositis Disease Area and Severity Index Activity score increased proportionately with the degree of patient- or physician-reported improvement in skin disease, consistently measuring improvement when clinically meaningful improvement was reported at weeks 16-52. In contrast, Cutaneous Dermatomyositis Activity Investigator Global Assessment measured little change from baseline with reported no improvement in skin disease but also a similar change from baseline with slight improvement. No Skindex-29+3 subscale performed well at reflecting increasing degrees of improvement in skin disease. Extramuscular Global Assessment and Total Improvement Score generally showed increasing levels of improvement as the degree of patient- and physician-reported improvement in skin disease increased, but these are composite measures and are not specific to improvement in DM skin disease. To measure clinically meaningful improvement in skin disease in a DM trial, Cutaneous Dermatomyositis Disease Area and Severity Index Activity score is the more sensitive outcome measure across time points.

Topics: Adult; Dermatomyositis; Humans; Outcome Assessment, Health Care; Severity of Illness Index; Skin

Treatment options are limited for skin disease in dermatomyositis. Lenabasum is a cannabinoid receptor type 2 agonist that triggers the resolution of inflammation.. The objective of this study was to evaluate the safety and efficacy of lenabasum in patients with refractory cutaneous dermatomyositis.. This study was a single-center, double-blind, randomized, placebo-controlled phase 2 study conducted from July 2015 to August 2017.. The population included subjects aged ≥18 years with at least moderately active dermatomyositis skin activity by Cutaneous Dermatomyositis Disease Area and Severity Index activity ≥ 14 and failure or intolerance to hydroxychloroquine.. Participants received 20 mg lenabasum daily for 28 days and then 20 mg twice per day for 56 days or placebo.. The primary outcome was a change in Cutaneous Dermatomyositis Disease Area and Severity Index activity. Safety and other secondary efficacy assessments were performed till day 113.. A total of 22 subjects were randomized to lenabasum (n = 11) or placebo (n = 11). No serious or severe adverse events were related to lenabasum, and no participants discontinued the study. The adjusted least-squares mean for Cutaneous Dermatomyositis Disease Area and Severity Index activity decreased more for lenabasum, and the difference was significant on day 113 (least-squares mean [standard error] difference = ‒6.5 [3.1], P = 0.038). Numerically greater improvements were seen in multiple secondary efficacy outcomes and biomarkers with lenabasum.. Lenabasum treatment was well tolerated and was associated with greater improvement in Cutaneous Dermatomyositis Disease Area and Severity Index activity and multiple efficacy outcomes.. This study was registered at ClinicalTrials.gov, NCT02466243.

Topics: Adolescent; Adult; Biomarkers; Cannabinoid Receptor Agonists; Dermatomyositis; Double-Blind Method; Dronabinol; Humans; Hydroxychloroquine; Receptors, Cannabinoid; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Dermatomyositis; Dronabinol; Humans; Leukocytes, Mononuclear; Receptors, Cannabinoid

Topics: Cannabinoids; Cohort Studies; Cytokines; Dermatomyositis; Dronabinol; Humans; In Vitro Techniques; Interferon Type I; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; Tumor Necrosis Factor-alpha