摘要

BACKGROUND:The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). METHODS AND FINDINGS:This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. CONCLUSIONS:In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. TRIAL REGISTRATION:The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.

译文

背景: 对 2 型糖尿病 (T2D) 的炎症作用已经提出了新的治疗靶点,使用为类风湿性关节炎 (RA) 设计的生物药物。在此基础上,我们旨在研究重组人 interleukin-1 受体拮抗剂 anakinra 是否 IL-1 (IL-1) 抑制, 与肿瘤坏死因子抑制剂 (TNFis) 相比,可以改善 RA 和 T2D 参与者的血糖和炎症参数。方法和结果: 本研究是一项多中心、开放标签、随机对照试验,招募参与者,随访 6 个月, 2013年至 2016 间,在 12 个意大利风湿病单位进行 RA 和 T2D 治疗。参与者被随机分配到 anakinra 或 TNFi (即阿达木单抗、 certolizumab pegol 、依那西普、英夫利昔单抗或 golimumab), 主要终点是糖化血红蛋白百分比的变化 (HbA1c %) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481)。总共 41 名 RA 和 T2D 参与者被随机分组,39 名合格参与者接受治疗 (年龄 62.72 ± 9.97 岁,74.4% 女性)。大多数参与者有血清反应阳性的 RA 疾病 (类风湿因子和/或抗环瓜氨酸肽抗体 [ACPA] 70.2%) 和活动性疾病 (疾病活动评分-28 [DAS28]: 5.54 ± 1.03; C 反应蛋白 11.84 ± 9.67 mg/L,分别)。所有参与者都有 T2D (HbA1c %: 7.77 ± 0.70,空腹血糖: 139.13 ± 42.17 mg)。当所有登记的参与者达到 6 个月的随访时,主要终点的重要的粗略差异,由一项计划外的 ad 中期分析证实,该分析显示了 anakinra 的显著影响, 在另一组中没有观察到这一点,导致研究因早期益处而停止。在未调整的线性混合模型中,anakinra 组的参与者在 3 个月后 HbA1c % 显著降低 (β:-0.85,p <0.001, 95% CI-1.28 至-0.42) 和 6 个月 (β:-1.05,p <0.001,95% CI-1.50 至-0.59)。观察到类似的结果,调整相关 RA 和 T2D 临床混杂因素的模型 (男性性别、年龄、 ACPA 阳性、皮质类固醇的使用、 RA 持续时间、 T2D 持续时间、口服抗糖尿病药物的使用, 体重指数 [BMI]) 3 个月后 (β:-1.04,p <0.001,95% CI-1.52 至-0.55) 和 6 个月 (β:-1.24,p <0.001,95% CI-1.75 至-0.72)。TNFi 组参与者 HbA1c % 无显著轻微下降。假设成功阈值为 HbA1c % ≤ 7,我们认为绝对风险降低 (ARR) = 0.42 (实验事件率 = 0.54,控制事件率 = 0.12); 因此, 我们估计,四舍五入,需要治疗的数字 (NNT) = 3。关于 RA,观察到两组的疾病活动度逐渐降低。未观察到严重不良事件、低血糖发作或死亡。注射部位的荨麻疹病变导致 4 例 (18%) anakinra 治疗的参与者停药。此外,我们在两组中观察到非严重感染,包括流感、鼻咽炎、上呼吸道感染、尿路感染和腹泻。我们的研究有一些局限性,包括开放标签设计和先前计划外的 ad 中期分析、体积小、缺乏一些实验室评估以及其他药物的持续使用。结论: 在这项研究中,我们观察到 IL-1 抑制对 RA 和 T2D 参与者有明显的益处,达到了两种疾病的治疗目标。我们的结果表明,IL-1 抑制可能被认为是 RA 和 T2D 的靶向治疗。试验注册: 该试验在欧盟临床试验注册处注册,欧盟试验注册号: 2012-005370-62,在 ClinicalTrial.gov 注册,编号 nct02236481。

Interleukin (IL)

免疫 白细胞介素 临床研究术语
概述  :  

白细胞介素(IL)是由多种细胞产生并作用于多种细胞的一类细胞因子。主要由多种免疫细胞合成与分泌,包括单核细胞、T细胞与淋巴细胞等,其作用能刺激T、B淋巴细胞及其他参与免疫反应的细胞增殖、分化并提高其功能,还参与机体的多种生理及病理反应。   分类 自发现IL-1的40多年来,共有38种IL先后被找到,分别命名为IL-1~IL-38。分为白细胞介素-1家族、白细胞介素-2家族(γc家族)、趋化因子家族、趋化因子家族C-X-C/α亚族、

Interleukin    英 [ɪn'tə'lʊkɪn] 美 [ɪn'tə'lʊkɪn]

释    义    n. [生化]白介素

例    句    First, they read an emotional story to 17 volunteers. Then the participants were given a nasal spray of either the molecule interleukin-6 or a placebo.首先,他们给17位志愿者读了一则动人的故事,然后给受试者喷鼻白细胞介素-6分子或安慰剂。

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