Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial
Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial
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DOI：
10.1016/s2665-9913(19)30018-9
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发表时间：
2019-09-01
影响因子：
25.4
通讯作者：
Riemekasten, Gabriela
中科院分区：
文献类型：
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作者：
Humrich, Jens Y.;Von Spee-Mayer, Caroline;Riemekasten, Gabriela
背景获得性白细胞介素2（IL-2）缺乏及相关调节性T细胞稳态缺陷被认为在系统性红斑狼疮的发病机制中起关键作用。我们假设用低剂量IL-2重建调节性T细胞稳态对系统性红斑狼疮患者有益。方法在柏林Charite-University Medicine的流变学和临床免疫学系进行的这项非对照的1期和2a期试验中，（柏林，德国），我们评估了低剂量重组人IL-2（阿地白介素）的安全性和耐受性及其对调节性T细胞的作用。我们招募了18-75岁的患者，确诊为系统性红斑狼疮，尽管既往接受过至少两种常规治疗，但仍有中度至重度疾病活动。患者每天给予4个周期的低剂量阿地白介素，持续5天，然后休息9-16天。主要终点是安全性和在第62天（即，在四个治疗周期后），在循环CD 3 + CD 4 + F0 XP 3 + CD 127 lo调节性T细胞中实现CD 25 hi表达细胞比例至少100%增加的患者数量。次要终点包括通过狼疮雌激素安全性国家评估-系统性红斑狼疮疾病活动指数（SELENA-SLEDAI）和不列颠群岛狼疮评估组（BILAG）评分测量的疾病活动性、通过SLEDAI发作指数测量的疾病发作、第62天的自身抗体和补体浓度。探索性终点包括各种细胞和免疫学参数。该试验在WHO/ICTRP注册，编号DRKS 00004858。结果2014年3月31日至2016年5月27日期间，筛选了13名患者，其中10名符合资格标准并入选试验。2013年4月1日至2014年3月11日期间，在同情使用环境中对另外2例患者进行了治疗。12例患者中有11例（92%）达到了主要终点。记录了159起不良事件，其中75起（47%）与治疗相关。大多数治疗相关不良事件为一过性和轻度至中度（1-2级）。最常见的不良事件是注射部位反应（20%）。治疗期间未发生严重不良事件。12例患者中有10例（83%）在第62天的SELENA-SLEDAI评分低于基线，治疗期间未观察到重度疾病发作。疾病活动度的降低与活化调节性T细胞比例的增加幅度相关。IL-2处理导致保留抑制能力的调节性T细胞的优先增殖。我们观察到参与生殖中心反应调节的细胞减少。解释低剂量IL-2治疗安全且耐受性良好，并选择性地促进中重度系统性红斑狼疮患者功能性调节T细胞的扩增。低剂量IL-2治疗也可能有利于减少疾病活动，尽管需要更大规模的试验来解决疗效。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background An acquired deficiency of interleukin-2 (IL-2) and related defects in regulatory T cell homeostasis are thought to play a crucial role in the pathogenesis of systemic lupus erythematosus. We hypothesised that reconstitution of regulatory T-cell homoeostasis with low doses of IL-2 would be beneficial to patients with systemic lupus erythematosus.Methods In this uncontrolled, phase 1 and 2a trial done in the Department of Rheumatology and Clinical Immunology at Charite-University Medicine Berlin (Berlin, Germany), we assessed the safety and tolerability of low-dose recombinant human IL-2 (aldesleukin) and its effects on regulatory T cells. We recruited patients aged 18-75 years with a confirmed diagnosis of systemic lupus erythematosus and moderate-to-severe disease activity despite previous treatment with at least two conventional therapies. Patients were given four cycles of low-dose aldesleukin daily for 5 days followed by a 9-16 day rest. The primary endpoints were safety and the number of patients who achieved at least a 100% increase in the proportion of CD25hi-expressing cells among circulating C D3 + C D4 + FOXP3 +CD127lo regulatory T cells at day 62 (ie, after four treatment cycles). Secondary endpoints included disease activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and the British Isles Lupus Assessment Group (BILAG) score, disease flares as measured by the SLEDAI flare index, auto-antibody and complement concentrations at day 62. Exploratory endpoints included various cellular and immunological parameters. The trial is registered with WHO/ICTRP, number DRKS00004858.Findings Between March 31, 2014, and May 27, 2016, 13 patients were screened, of whom ten met eligibility criteria and were enrolled in the trial. Two additional patients were treated between April 1, 2013, and March 11, 2014, in a compassionate use setting. Eleven (92%) of the 12 patients achieved the primary endpoint. 159 adverse events were recorded, 75 (47%) of which were treatment related. Most treatment-related adverse events were transient and mild to moderate (grade 1-2). The most common adverse event was injection-site reaction (20%). No serious adverse events occurred during the treatment period. In ten (83%) of 12 patients, SELENA-SLEDAI scores were lower at day 62 than at baseline, and no severe disease flares were observed during the treatment period. Decreased disease activity correlated with the magnitude of increase in the proportion of activated regulatory T cells. IL-2 treatment resulted in a preferential proliferation of regulatory T cells that retained suppressive capacity. We observed decreases in cells that are involved in the regulation of germinal-centre reactions.Interpretation Low-dose IL-2 therapy is safe and well tolerated and selectively promotes the expansion of functional regulatory T cells in patients with moderate-to-severe systemic lupus erythematosus. Low-dose IL-2 treatment might also be beneficial in reducing disease activity, although larger trials are needed to address efficacy. Copyright (C) 2019 Elsevier Ltd. All rights reserved.