2-HOBA Phase 2 Clinical Trial in Rheumatoid Arthritis

类风湿关节炎(RA)是一种全身性炎症性自身免疫性疾病，影响1%的 人口。积极治疗是改善疾病相关疾病的基本治疗策略 结果和心血管疾病，这是导致类风湿关节炎死亡率过高的原因。因此，治疗学 针对治疗类风湿性关节炎和降低心血管风险的新途径是必要的。一个潜在的目标是 阻断异胡萝卜素的促炎、免疫和致动脉粥样硬化作用 (等长)。 IsoLGs是氧化应激的高度活性的二羰基产物，与蛋白质共价结合 导致构象变化，使其具有免疫原性和促炎作用。二十年来 范德比尔特的工作使2-羟基苯甲胺(2-HOBA)被鉴定为一种高效的 反应性二羰基的清除剂，如异丙基葡萄糖。清除反应性二羰基比使用 抗氧化剂，因为活性氧是细胞正常功能所必需的。在动物模型中 自身免疫、高血压和动脉粥样硬化2-HOBA可减少炎症、自身抗体、 健康志愿者的血压、动脉粥样硬化和人类1期临床研究2-HOBA 被很好地容忍了。 我们建议进行二期研究，以确定2-HOBA的耐受性、安全性和对Isolg-Lg的影响。 类风湿关节炎患者的加合物、炎症和血压。28名受试者将被随机分配到 750 mg 2-HOBA或与之匹配的安慰剂，每天三次，持续12周(每组14人)。第16周的来访将会 评估4周洗涤后的持久效果。目标1将比较耐受性和不良事件 在积极的和安慰剂的怀抱中。目标2将比较细胞和血浆等LG加合物、标记物的变化 活动组和安慰剂组的炎症、DAS28评分和24小时血压。这项初步研究将 告知未来研究的可行性和设计，以检验2-HOBA在RA患者中的疗效。

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting 1% of the population. Aggressive treatment is a fundamental therapeutic strategy to improve disease-related outcomes and cardiovascular disease, which contributes to excess mortality in RA. Thus, therapeutics targeting novel pathways that treat RA and reduce cardiovascular risk are needed. A potential target is blocking the proinflammatory, immunogenic, and proatherogenic consequences of isolevuglandins (isoLGs). IsoLGs are highly reactive dicarbonyl products of oxidative stress that bind covalently to proteins causing conformational changes rendering them immunogenic and proinflammatory. Two decades of work at Vanderbilt led to the identification of 2-hydroxybenzylamine (2-HOBA) as a highly effective scavenger of reactive dicarbonyls such as isoLGs. Scavenging reactive dicarbonyls is preferable to using antioxidants because reactive oxygen species are necessary for normal cellular function. In animal models of autoimmunity, hypertension, and atherosclerosis 2-HOBA reduced inflammation, autoantibodies, blood pressure, and atherosclerosis, and in human phase 1 clinical studies in healthy volunteers 2-HOBA was well tolerated. We propose a phase 2 study to determine 2-HOBA’s tolerability, safety, and effect on isoLG- adducts, inflammation and blood pressure in RA patients. Twenty-eight subjects will be randomized to 750mg 2-HOBA or matching placebo three times a day for 12 weeks (14 per group). A visit at week 16 will assess for persisting effects after a 4-week washout. Aim 1 will compare tolerability and adverse events in active and placebo arms. Aim 2 will compare changes in cellular and plasma isoLG-adducts, markers of inflammation, DAS28 score, and 24-hour blood pressure in active and placebo arms. This pilot study will inform the feasibility and design of future studies to examine the efficacy of 2-HOBA in RA patients.