A phase I clinical trial of Anakinra for Steroid-Resistant AIED

自身免疫性内耳疾病是进行性感音神经性听力的一种鲜为人知的病因 在大约60%的病例中，可接受皮质类固醇治疗的丢失。这种反应会随着时间的推移而消失 由于未知的机制。对于那些对皮质类固醇耐药的AED患者来说，几乎没有其他治疗选择 对恢复或维持听力是有效的。大多数关于AIE患者的研究都集中在 皮质类固醇反应受试者，因为他们更容易被识别为队列，并被认为是 更有可能是炎症性病因导致他们的感觉神经性听力损失。到目前为止，没有生效 对耐糖皮质激素的AIED患者进行治疗干预。 IL-1b是介导先天免疫反应的典型细胞因子。IL-1b的表达决定了 许多后来的适应性T细胞反应在其他自身免疫和炎症性疾病中。我们有 初步证据表明，几个IL-1�家族成员在糖皮质激素非激素类药物中存在异常调节 AED的应答者，并可能导致类固醇耐药。到目前为止，关于这方面的研究有限 与激素抵抗相关的机制在这种疾病中。我们的发现为IL-1提供了理论基础 AEDI期开放标签的糖皮质激素耐药(无反应)患者使用阿纳金纳阻断 临床试验，以确定使用阿纳金拉是否可以改善这些患者的听力阈值。R21将 允许在小规模上检验这一假设。如果Anakinra听力恢复的有效性证据可以 在这些患者中显示(主要里程碑)，我们建议在更大的队列中验证Anakinra的使用 糖皮质激素耐药的AIED患者(R33期)。

Autoimmune Inner Ear Disease (AIED) is a poorly understood etiology of progressive sensorineural hearing loss that is amenable to corticosteroid therapy in approximately 60% of cases. This response is lost over time due to unknown mechanisms. For those corticosteroid resistant AIED patients, few therapeutic alternatives are effective to restore or maintain hearing. The majority of studies on AIED patients have focused on corticosteroid responsive subjects as they have been easier to identify as a cohort, and are believed to be more likely to have an inflammatory etiology mediating their sensorineural hearing loss. To date, no effective therapeutic intervention exists for corticosteroid-resistant patients with AIED. IL-1b is the quintessential cytokine that mediates the innate immune response. Expression of IL-1b dictates many of the later adaptive T-cell responses in other autoimmune and inflammatory disorders. We have preliminary evidence that several IL-1� family members are aberrantly regulated in corticosteroid non- responders with AIED, and may contribute to steroid resistance. To date, there have been limited studies on the mechanisms related to steroid resistance in this disorder. Our findings provide the rationale for IL-1 blockade with Anakinra in corticosteroid resistant (non-responders) patients with AIED as a phase I open label clinical trial to determine if use of Anakinra can improve audiometric thresholds in these patients. The R21 will permit testing the hypothesis on a small scale. If evidence of efficacy for hearing restoration with anakinra can be shown in these patients (primary milestone), we propose to validate the use of anakinra in a larger cohort of corticosteroid resistant AIED patients (R33 phase).