A nonpsychoactive cannabinoid receptor-2 agonist to treat itch and inflammation in dermatomyositis

摘要 皮肌炎（DM）是一种多器官自身免疫性疾病，导致显着的皮肤活动 和严重瘙痒，这两种情况都使患者的生活质量（QoL）恶化。尽管其临床 然而，重要的是，DM中皮肤活动和瘙痒的发病机制仍然不清楚 明白因此，在过去的70年里，没有新的糖尿病治疗方法被批准。 目前可用的标签外治疗通常无效或具有重大风险。我们 最近完成了一项成功的NIH资助的lenabasum的第二阶段随机对照试验， 一种新的非精神活性CB2反向激动剂，用于治疗皮肤型糖尿病。lenabasum 在皮肤病活动性、瘙痒和关键QoL指标方面产生了显著改善。 我们实验室使用有限数量的病变皮肤活检进行的机制研究 试验表明，lenabasum减少了真皮CD4 + T细胞的数量， 干扰素（IFN）β、IFN γ和白细胞介素（IL）的真皮染色区域31。这四个人 安慰剂组的参数发生变化。其中前三个变化显著 与皮肤病活动的改善相关。皮肤IFN γ染色减少 和IL 31各自与瘙痒的改善显著相关。我们最近的研究表明 在糖尿病患者皮肤中的突出的髓样树突状细胞（mDC）， 许多狼疮患者皮肤中浆细胞样DC（pDC）和IFN α特征占优势 患者鉴于先前在DM中报告的皮肤中显著的IFN γ信号和 IFN-γ和皮肤病活动的反应lenabasum，我们现在建议评估的作用， 在DM中产生IFN γ中的mDC。我们有机会扩大科学研究 我们在即将到来的lenabasum第三阶段国际试验的第二阶段试验中取得的进展 对于DM。我们假设，通过mDC上的CB 2受体起作用的lenabasum， 通过对IRF-3、IRF-5和IRF-7的影响，表达IFN γ。我们还假设， lenabasum，通过下调mDC的IFN γ或直接作用于T细胞， 细胞，减少皮肤中IFN γ和IL 31的产生。在接受lenabasum治疗的DM患者中， 在3期试验中，我们将确定与皮肤相关的通路中的细胞和分子变化， 疾病活动性和瘙痒预测临床改善或与临床改善相关。我们还将 对DM中促进活动和瘙痒的途径进行机制研究， 关于Lenabasum我们提议的研究将利用即将到来的3期试验的样本， 提高我们对lenabasum如何工作的理解，从而阐明关键疾病 机制，并可能为其他新的治疗方法提供基础。

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.