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

摘要 皮肌炎(DM)是一种引起显著皮肤活动的多器官自身免疫性疾病。 和严重瘙痒，这两者都恶化了患者的生活质量(QOL)。尽管它在临床上 然而，重要的是，糖尿病患者皮肤活动和瘙痒的发病机制仍不清楚。 明白了。因此，在过去的70年里，没有任何治疗糖尿病的新疗法被批准。 目前可用的非标签疗法往往无效或有重大风险。我们 最近成功完成了一项由美国国立卫生研究院资助的利纳巴松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 在皮肤病活跃度、瘙痒和关键的QOL指标方面有显著改善。 在我们实验室使用有限数量的皮损皮肤活检进行的机制研究 从试验中证明，来纳香降低皮肤CD4T细胞的数量和 干扰素、干扰素γ和白介素31的真皮染色区域。这四个都不是 安慰剂组的参数发生了变化。这些变化中的前三个显著 与皮肤病活动性的改善有关。干扰素γ皮肤染色的减少 IL31和IL31均与瘙痒改善显著相关。我们最近的工作证明 糖尿病患者皮肤中显著的髓系树突状细胞(MDCs)，与 许多狼疮患者皮肤中浆细胞样树突状细胞和干扰素α的优势 病人。考虑到之前报道的糖尿病患者皮肤中显著的干扰素信号，以及 干扰素和皮肤病活性对来纳假单胞菌的反应，我们现在建议评估其作用 在DM的干扰素的生产中的MDCS。我们有机会扩大科学研究领域 我们在即将到来的Lenabasum国际试验的第二阶段试验中取得的进展 对于DM。我们假设，莱纳巴松通过MDCS上的CB2受体发挥作用，减少 干扰素通过对IRF-3、-5和-7的影响表达MDC。我们还假设 Lenabasum，通过下调MDCS的干扰素或直接作用于T细胞 细胞，减少干扰素γ和白介素31在皮肤中的产生。利纳巴松对糖尿病患者的治疗作用 在3期试验中，我们将确定与皮肤相关的细胞和分子通路的变化 疾病活动性和瘙痒可预测或与临床改善相关。我们还将 糖尿病患者活动和瘙痒促进途径及其改善的机制研究 加了羊肚菌。我们利用即将到来的第三阶段试验的样本进行的拟议研究将 加深我们对莱纳巴斯菌工作原理的了解，从而揭示关键疾病 这可能会为更多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.