Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands.
Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands; Department of Rheumatology, St Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea.
Lancet. 2022 Jul 23;400(10348):283-294. doi: 10.1016/S0140-6736(22)01193-X.
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.
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.
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.
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.
Dutch Research Council (NWO; Dutch Arthritis Society).
类风湿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,在关节炎出现临床症状时开始治疗。我们旨在评估在关节痛和亚临床关节炎症的前期阶段进行早期干预是否可以预防临床关节炎的发生或减轻疾病负担。
我们在荷兰莱顿大学医学中心进行了一项随机、双盲、安慰剂对照的概念验证试验。在荷兰西南部的 13 家风湿病门诊中,招募了临床疑似进展为类风湿关节炎且 MRI 检测到亚临床关节炎症的 18 岁及以上成年人。他们符合入组条件,并随机(1:1)分配到单次肌肉注射糖皮质激素(120mg)和 1 年口服甲氨蝶呤(最高 25mg/周)治疗组,或安慰剂(单次注射和 1 年片剂)治疗组。参与者和研究者对分组情况均不知情。随访持续 1 年,从 1 年治疗期结束后开始。主要终点是出现持续至少 2 周的临床关节炎(符合 2010 年类风湿关节炎分类标准或涉及两个或多个关节)。患者报告的身体功能、症状和工作生产力是次要终点,每 4 个月测量一次。此外,还研究了 MRI 检测到的炎症过程。所有参与者均纳入意向治疗分析。该试验在 EudraCT(2014-004472-35)和荷兰试验注册中心(NTR4853-trial-NL4599)注册。
在 2015 年 4 月 16 日至 2019 年 9 月 11 日期间,对 901 名患者进行了入选评估,其中 236 名患者符合入组条件并被随机分配至治疗组(n=119)或安慰剂组(n=117)。在 2 年时,两组的主要终点发生率相似(治疗组 23[19%]例,安慰剂组 21[18%]例;风险比 0.81,95%CI 0.45 至 1.48)。在治疗的前 4 个月内,治疗组的身体功能改善更明显,且一直优于安慰剂组(2 年时健康评估问卷残疾指数的组间平均差异:-0.09,95%CI -0.16 至 -0.03;p=0.0042)。同样,疼痛(0-100 分,组间平均差异:-8,95%CI -12 至 -4;p<0.0001)、关节晨僵(-12,-16 至 -8;p<0.0001)、现患率(-8%,-13 至 -3;p=0.0007)和 MRI 检测到的关节炎症(-1.4 分,-2.0 至 -0.9;p<0.0001)也显示出治疗组相对于安慰剂组的持续改善。两组的严重不良事件数量相当;不良事件与甲氨蝶呤已知的安全性特征一致。
甲氨蝶呤是类风湿关节炎的基础治疗药物,在症状和亚临床炎症的关节炎前期阶段开始使用,并未预防临床关节炎的发生,但与安慰剂相比,它改变了疾病进程,表现为 MRI 检测到的炎症、相关症状和功能障碍的持续改善。
荷兰研究理事会(NWO;荷兰关节炎协会)。