Background

Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden.

Methods

We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599.

Findings

Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0·81, 95% CI 0·45 to 1·48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: –0·09, 95% CI –0·16 to –0·03; p=0·0042). Similarly, pain (on scale 0–100, mean between-group difference: –8, 95% CI –12 to –4; p<0·0001), morning stiffness of joints (–12, –16 to –8; p<0·0001), presenteeism (–8%, –13 to –3; p=0·0007), and MRI-detected joint inflammation (–1·4 points, –2·0 to –0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate.

Interpretation

Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo.

Funding

Dutch Research Council (NWO; Dutch Arthritis Society).

中文翻译：

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对有类风湿性关节炎风险的关节痛患者进行甲氨蝶呤干预，以减少持续性关节炎的发展及其疾病负担（TREAT EARLIER）：一项随机、双盲、安慰剂对照、概念验证试验

背景

类风湿性关节炎是全球最常见的自身免疫性疾病，需要长期治疗以抑制炎症。目前，当关节炎临床表现明显时开始治疗。我们旨在评估早期干预，在关节痛和亚临床关节炎症的前一阶段，是否可以预防临床关节炎的发展或减轻疾病负担。

方法

我们在荷兰莱顿的莱顿大学医学中心进行了一项随机、双盲、安慰剂对照、概念验证试验。年龄在 18 岁或以上且临床怀疑进展为类风湿性关节炎和 MRI 检测到亚临床关节炎症的成人有资格在荷兰西南部地区的 13 家风湿病门诊就诊，并随机分配 (1:1) 到单次肌肉注射糖皮质激素注射液（120 毫克）和为期 1 年的口服甲氨蝶呤（最多 25 毫克/周）或安慰剂（单次注射和片剂 1 年）。参与者和调查人员被掩盖到小组分配。1年治疗期结束后继续随访1年。主要终点是持续至少 2 周的临床关节炎（满足 2010 年类风湿性关节炎分类标准或涉及两个或更多关节）的发展。患者报告的身体机能、症状和工作效率是次要终点，每 4 个月测量一次。此外，还研究了 MRI 检测到的炎症过程。所有参与者都进入了意向治疗分析。该试验已在 EudraCT，2014-004472-35 和荷兰试验注册，NTR4853-trial-NL4599 注册。所有参与者都进入了意向治疗分析。该试验已在 EudraCT，2014-004472-35 和荷兰试验注册，NTR4853-trial-NL4599 注册。所有参与者都进入了意向治疗分析。该试验已在 EudraCT，2014-004472-35 和荷兰试验注册，NTR4853-trial-NL4599 注册。

发现

在 2015 年 4 月 16 日至 2019 年 9 月 11 日期间，对 901 名患者进行了资格评估，其中 236 名患者入组并随机分配至积极治疗组（n=119）或安慰剂组（n=117）。2 年时，各组之间主要终点的频率相似（治疗组 119 名参与者中的 23 名 [19%] vs安慰剂组 117 人中有 21 人 [18%]；风险比 0·81, 95% CI 0·45 至 1·48)。治疗组在前 4 个月的身体功能改善更多，并且仍然优于安慰剂组（2 年内健康评估问卷残疾指数的平均组间差异：–0·09，95% CI –0·16 至–0·03；p=0·0042)。同样，疼痛（量表 0-100，平均组间差异：–8，95% CI –12 至 –4；p<0·0001），关节晨僵（–12，–16 至 –8；p <0·0001），出勤率（–8%，–13 到 –3；p=0·0007）和 MRI 检测到的关节炎症（–1·4 分，–2·0 到 –0·9；p< 0·0001) 显示治疗组与安慰剂组相比持续改善。两组严重不良事件的数量相等；不良事件与已知的甲氨蝶呤安全性特征一致。

解释

甲氨蝶呤是类风湿性关节炎的基石治疗药物，在症状和亚临床炎症的关节炎前阶段开始，并没有阻止临床关节炎的发展，但改变了病程，如 MRI 检测到的炎症、相关症状的持续改善所示，和与安慰剂相比的损伤。

资金

荷兰研究委员会（NWO；荷兰关节炎协会）。