Repurposing leflunomide and hydroxychloroquine to treat Sjögren's disease (RepurpSS-II): a randomised, double-blind, placebo-controlled, phase 2b trial.

We aimed to replicate the findings of the RepurpSS-I trial and determine the efficacy and safety of leflunomide and hydroxychloroquine combination therapy as a first conventional treatment for Sjögren's disease.

我们的目标是复制RepurpSS-I试验的结果，并确定来氟米特和羟氯喹联合疗法作为干燥综合征首选常规治疗的有效性和安全性。

Methods

This randomised, placebo-controlled, double-blind, phase 2b trial (RepurpSS-II) was done at University Medical Center Utrecht, The Netherlands.

这项随机、安慰剂对照、双盲的2b期临床试验（RepurpSS-II）在荷兰乌特勒支大学医学中心进行。

Eligible patients were adults aged 18-75 years with an European Alliance of Associations for Rheumatology Sjögren's Syndrome Disease Activity Index (ESSDAI) of at least 5.

符合条件的患者为年龄在18至75岁之间的成人，其欧洲风湿病学会联盟干燥综合征疾病活动指数（ESSDAI）至少为5。

Exclusion criteria included an active wish to conceive within 2 years or use of leflunomide or hydroxychloroquine in the past 6 months.

排除标准包括在未来2年内有生育意愿或在过去6个月内使用过来氟米特或羟氯喹。

Patients were randomly assigned (1:1) to receive placebo or leflunomide (20 mg) and hydroxychloroquine (400 mg) orally, once a day.

患者被随机分配（1:1）接受安慰剂或来氟米特（20毫克）和羟氯喹（400毫克）口服，每天一次。

Investigators, patients, and laboratory staff were masked to treatment until 24 weeks.

研究者、患者和实验室工作人员在24周之前对治疗方案保密。

The primary endpoint was the between-group difference in change in ESSDAI from baseline to 24 weeks.

主要终点是基线至24周两组间ESSDAI变化的差异。

Primary and secondary analyses were done in the intention-to-treatpopulation using mixed-effect analysis, accounting for repeated outcome assessment and controlling for baseline ESSDAI.

主要和次要分析是在意向治疗人群中进行的，使用混合效应分析，考虑了重复的结果评估并控制了基线ESSDAI。

This study was registered with the European Union Clinical Trials Register (EudraCT 2020-001933-11) and is completed.

该研究已在欧洲联盟临床试验注册处注册（EudraCT 2020-001933-11），并已完成。

Patients from the RepurpSS-I trial and Sjögren's disease patient representatives contributed to the study design.

RepurpSS-I试验的患者和干燥综合征患者代表参与了研究设计。

Results

Between Oct 12, 2021, and July 5, 2024, 243 patients were approached for inclusion. 158 were excluded before screening and 39 were excluded following screening. 46 patients were enrolled and randomly assigned to receive leflunomide-hydroxychloroquine (n=21) or placebo (n=25).

2021年10月12日至2024年7月5日期间，共有243名患者被接触以考虑纳入研究。在筛选前有158名患者被排除，筛选后又有39名患者被排除。最终有46名患者被纳入研究，并随机分配接受来氟米特-羟氯喹（n=21）或安慰剂（n=25）。

Median age was 55·00 years (IQR 51·00-60·50). 43 (93%) of 46 patients were female and three (7%) were male.

中位年龄为55.00岁（四分位数间距51.00-60.50）。46名患者中有43名（93%）为女性，3名（7%）为男性。

The mean difference in ESSDAI between the leflunomide-hydroxychloroquine group and placebo group at 24 weeks was -4·135 (95% CI -6·558 to -1·709, p=0·0012).

在24周时，来氟米特-羟氯喹组与安慰剂组之间ESSDAI的平均差异为-4.135（95%置信区间-6.558至-1.709，p=0.0012）。

One serious adverse eventoccurred in the treatment group; probably unrelated to study medication (hospital admission for myocardial infarction).

治疗组中发生了一例严重不良事件；可能与研究药物无关（因心肌梗死住院）。

Adverse events were similar between groups; gastrointestinal discomfort was most common (six [29%] of 21 patients in the leflunomide-hydroxychloroquine group and four [16%] of 25 in the placebo group).

两组之间的不良事件相似；胃肠道不适是最常见的（在来氟米特-羟氯喹组的21名患者中有六名[29%]，在安慰剂组的25名患者中有四名[16%]）。

There were no deaths during the study.

研究期间没有发生死亡事件。

interpretation

This study supports previous findings that leflunomide in combination with hydroxychloroquine is an effective treatment for systemically active Sjögren's disease and was generally well tolerated.

本研究支持了先前的发现，即来氟米特联合羟氯喹对系统性活动性干燥综合征是一种有效的治疗方法，并且通常耐受性良好。

This therapy might be an affordable and widely available option for patients with active systemic Sjögren's disease.

这种疗法可能是对于活动性系统性干燥综合征患者来说一种负担得起且广泛可用的治疗选择。

Future studies should investigate whether this combination is effective in other patient populations, such as those with low systemic disease activity but high patient-reported outcomes.

未来的研究应该调查这种联合疗法是否在其他患者群体中有效，例如那些系统性疾病活动度低但患者报告的结果高的患者。

funding

ZonMW and ReumaNederland.

荷兰卫生研究组织（ZonMW）和荷兰风湿病协会（ReumaNederland）