Purpose

To investigate the role of Anti-Citrullinated Protein autoantibodies (ACPAs) in the pathology of dry eye disease (DED) and the therapeutic potential of pooled human immune globulin-eye drops in these patients.

Methods

We investigated the presence of citrullinated proteins and ACPAs in ocular surface wash (OSW) and conjunctival impressions from patients with DED and determined the pathological consequences of OSW with high ACPA using in vitro experiments and in vivo murine models. We performed a randomized, double-masked, pilot clinical trial to determine the safety, tolerability and preliminary efficacy of using pooled human immune globulin-eye drops to treat DED patients with ACPAs in OSW.

Results

We found that neutrophils are a source of citrullinated proteins on the ocular surface of DED patients. We detected significantly higher immunoglobulin amount and presence of several species of ACPAs in OSW from DED patients. We also found that OSW with high ACPA contributes to production of NETs, and that ACPAs cause ocular surface disease in murine eyes, both of which are reduced with addition of Immune globulins. As compared to Vehicle treatment, pooled human immune globulin-eye drops (IVIG 4 mg/mL) twice a day for 8 weeks caused significant reduction in signs and symptoms of DED with no difference in tolerability or adverse events.

Conclusions

This is the first report demonstrating ACPAs in OSW of DED patients and their contribution to ocular surface disease. The first-in-human clinical trial suggests that pooled immune globulin-eye drops are a potential new class of biologic therapies for Dry Eye patients.

中文翻译：

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抗瓜氨酸化蛋白抗体在眼泪液中的病理后果以及干眼病中合并的人类免疫球蛋白眼药水的治疗潜力。

目的

研究抗瓜氨酸化蛋白自身抗体（ACPA）在干眼病（DED）病理中的作用以及这些患者合并的人免疫球蛋白滴眼液的治疗潜力。

方法

我们调查了DED患者眼表清洗（OSW）和结膜印象中瓜氨酸化蛋白和ACPA的存在，并使用体外实验和体内鼠模型确定了高ACPA的OSW的病理学后果。我们进行了一项随机，双重掩盖的试验性临床试验，以确定使用合并的人免疫球蛋白滴眼液治疗OSW中ACPAs的DED患者的安全性，耐受性和初步疗效。

结果

我们发现中性粒细胞是DED患者眼表上瓜氨酸化蛋白的来源。我们在DED患者的OSW中检测到明显更高的免疫球蛋白量和几种ACPA的存在。我们还发现，具有较高ACPA的OSW有助于产生NET，并且ACPA会在鼠眼中引起眼表疾病，这两种情况均会因添加免疫球蛋白而降低。与媒介物治疗相比，每天两次连续8周，每天两次收集人免疫球蛋白滴眼液（IVIG 4 mg / mL），可导致DED的体征和症状明显减轻，但耐受性或不良事件无差异。

结论

这是第一份证明DED患者OSW中ACPA及其对眼表疾病的贡献的报告。一项人类首次临床试验表明，对于干眼症患者而言，合并的免疫球蛋白滴眼液是一种潜在的新型生物疗法。