Long-term durability of a time-limited methotrexate intervention in patients with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative arthralgia at increased risk for rheumatoid arthritis (TREAT EARLIER): 5-year data from a double-blind, randomised, placebo-controlled trial.

Long-term follow-up is needed to assess the durability of the effects.

需要长期随访来评估效果的持久性。

In addition, heterogeneity in pathophysiological subtype (with or without anti-citrullinated protein antibodies [ACPA]) and disease risk was not considered in the 2-year analysis.

此外，在2年的分析中，没有考虑病理生理亚型（有无抗环瓜氨酸肽抗体[ACPA]）和疾病风险的异质性。

Therefore, we investigated the long-term effect of methotrexate in reducing disease burden and progression to rheumatoid arthritis in ACPA-positive and ACPA-negative individuals at increased risk of rheumatoid arthritis.

因此，我们研究了甲氨蝶呤在减少疾病负担和防止抗环瓜氨酸肽抗体阳性（ACPA+）和阴性（ACPA-）个体发展为类风湿性关节炎的长期效果，这些个体有发展类风湿性关节炎的高风险。

Methods

The TREAT EARLIER trial was a randomised, placebo-controlledtrial of participants aged 18 years or older, with clinically suspect arthralgia and subclinical joint inflammation.

TREAT EARLIER试验是一项随机、安慰剂对照试验，招募了18岁或以上的参与者，这些参与者有临床可疑的关节痛和亚临床关节炎症。

Participants were recruited from 13 rheumatology outpatient clinics in the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (methylprednisolone 120 mg) followed by a 1-year course of methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year).

参与者是从荷兰的13个风湿病门诊诊所招募的，并被随机分配（1:1）接受一次肌肉内糖皮质激素注射（甲基强的松龙120毫克），随后接受为期一年的甲氨蝶呤治疗（每周最多25毫克），或者接受安慰剂（单次注射和一年的药片）。

Participants and investigators were masked to group assignment for at least 2 years.

参与者和研究人员在至少2年内对组别分配进行了盲法处理。

Follow-up continued for 5 years.

随访持续了5年。

The two primary endpoints in this 5-year follow-up analysis were disease burden (physical disability) and development of rheumatoid arthritis, assessed on an intention-to-treatbasis.

在这项为期5年的随访分析中，两个主要终点是疾病负担（身体残疾）和类风湿性关节炎的发展，基于意向治疗原则进行评估。

Patients were stratified for ACPA; only those at increased predicted risk (>10%) were included in the 5-year analysis.

患者根据ACPA进行分层；只有那些预测风险增加（>10%）的患者才被纳入5年分析。

People with lived experience of clinically suspect arthralgia or rheumatoid arthritis were involved in the study design.

本研究设计中涉及了具有临床疑似关节痛或类风湿性关节炎经验的人群。

This trial is registered with EudraCT (2014-004472-35) and the Netherlands Trial Register (NTR4853-trial-NL4599), and is complete.

该试验已在EudraCT (2014-004472-35)和荷兰试验注册处(NTR4853-trial-NL4599)注册，并已完成。

Results

Between April 16, 2015, and Sept 11, 2019, we enrolled 236 participants; 119 were assigned to active treatment and 117 to placebo. 215 (91%) participants completed the 5-year follow-up. 120 participants at increased predicted risk of rheumatoid arthritis were analysed at 5 years, of whom 66 (55%) were ACPA-negative and 54 (45%) were ACPA-positive.

2015年4月16日至2019年9月11日期间，我们招募了236名参与者；其中119人被分配到活性治疗组，117人被分配到安慰剂组。215名（91%）参与者完成了5年的随访。分析了120名有增加类风湿性关节炎预测风险的参与者，其中66人（55%）为ACPA阴性，54人（45%）为ACPA阳性。

Mean age was 48 (SD 12) years, 72 (60%) of 120 participants were female, and 48 (40%) were male.

平均年龄为48（标准差12）岁，120名参与者中有72人（60%）为女性，48人（40%）为男性。

Over 5 years, ACPA-negative participants in the active treatment group (n=35) had sustained improvement in physical disability compared with ACPA-negative participants in the placebo group (n=31; mean difference in Health Assessment Questionnaire disability index [HAQ] -0·16 [95% CI -0·29 to -0·04], p=0·0082) whereas, in ACPA-positive participants, the previously reported benefit in physical disability at 2 years in the treatment group versus placebo group was not sustained (-0·12 [-0·26 to 0·03], p=0·12).

在5年的观察期内，接受主动治疗的ACPA阴性参与者（n=35）与接受安慰剂的ACPA阴性参与者（n=31）相比，在身体残疾方面持续改善（健康评估问卷残疾指数[HAQ]平均差异为-0.16 [95% 置信区间 -0.29至-0.04]，p=0.0082），而在ACPA阳性参与者中，之前报告的在治疗组与安慰剂组之间2年时身体残疾的益处并未持续（-0.12 [-0.26至0.03]，p=0.12）。

Three (9%) of 35 ACPA-negative participants in the treatment group developed rheumatoid arthritis compared with ten (32%) of 31 in the placebo group over 5 years (hazard ratio[HR] 0·24 [95% CI 0·07 to 0·87], p=0·018), corresponding to a number needed to treat of four.

在5年的观察期内，治疗组中有3名（9%）ACPA阴性参与者发展为类风湿性关节炎，而在安慰剂组中有10名（32%）（风险比[HR] 0.24 [95% 置信区间 0.07至0.87]，p=0.018），相当于需要治疗的患者数为4人。

In ACPA-positive participants, 18 (58%) of 31 in the treatment group developed rheumatoid arthritis versus 15 (65%) of 23 in the placebo group (HR 0·75 [0·38-1·49], p=0·41).

在ACPA阳性参与者中，治疗组的31人中有18人（58%）发展成类风湿性关节炎，而安慰剂组的23人中有15人（65%）发展成类风湿性关节炎（风险比0.75 [0.38-1.49]，p=0.41）。

In the full trial cohort of 236 participants, physical disability in the treatment group improved durably over 5 years compared with the placebo group (mean difference in HAQ -0·06 [95% CI -0·14 to -0·05], p=0·048), though development of rheumatoid arthritis was not prevented, with 26 (22%) of 119 participants developing rheumatoid arthritis in the treatment group and 31 (27%) of 117 in the placebo group (HR 0·79 [95% CI 0·47 to 1·34], p=0·38).

在236名参与者的完整试验队列中，治疗组的物理残疾在5年内持续改善，与安慰剂组相比（HAQ平均差异-0.06 [95% 置信区间-0.14至-0.05]，p=0.048），尽管未能预防类风湿性关节炎的发生，治疗组有119名参与者中的26人（22%）发展成类风湿性关节炎，而安慰剂组117名参与者中有31人（27%）发展成类风湿性关节炎（风险比0.79 [95% 置信区间0.47至1.34]，p=0.38）。

interpretation

Secondary prevention with a single intramuscular glucocorticoid injection and 1 year of methotrexate has different long-term effects on developing rheumatoid arthritis in ACPA-positive participants and in ACPA-negative participants.

在ACPA阳性参与者和ACPA阴性参与者中，通过单次肌肉注射糖皮质激素和1年的甲氨蝶呤进行二级预防，对发展类风湿性关节炎的长期效果存在差异。

ACPA-negative participants had a long-term reduction in inflammatory disease burden and development of rheumatoid arthritis whereas there was no sustained improvement with ACPA-positive participants.

ACPA阴性参与者在长期炎症性疾病负担和类风湿性关节炎的发展上有所减轻，而ACPA阳性参与者则没有持续的改善。

These results imply that different treatment strategies are needed for ACPA-positive and ACPA-negative individuals with arthralgia who are at risk of rheumatoid arthritis.

这些结果暗示，对于有患类风湿性关节炎风险的关节痛患者，需要根据ACPA（抗环瓜氨酸肽抗体）阳性或阴性采取不同的治疗策略。

funding

Dutch Research Council (NWO), Dutch Arthritis Society.

荷兰研究委员会（NWO），荷兰关节炎协会。