To investigate the frequency of difficult-to-treat (D2T) rheumatoid arthritis (RA) in patients early escalated to biologic/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) after failure of treat-to-target with methotrexate (MTX). From a prospective cohort of early RA, all patients with their first access in the years 2005–2018, and eventually starting a b/tsDMARD before the end of 2022, were included and followed-up until April 2024. Study outcomes included drug survival on each consecutive b/tsDMARDs, development of D2T (according to the EULAR definition and subsequent modifications), and its predictors. Of a total cohort of 722 early RA patients treated with initial MTX and followed-up for at least 3 years from diagnosis, 155 (21.5%) had started a b/tsDMARD after a median of 19 months. In more than 70% of the cases, RA was uncontrolled despite optimal doses of MTX of ≥ 15 mg/day. The retention rates of the first and the second b/tsDMARD were approximatively 70% after 1 year but dropped to 40% after 5 years. After a median (IQR) follow up of 72.6 (34.5-134.2) months, 45 patients (29%) fulfilled the EULAR D2T criteria. At multivariable analysis, higher number of swollen joints and worse pain scores were confirmed as predictors of D2T. Furthermore, in this early RA cohort, shorter disease duration at the start of treatment with b/tsDMARDs, together with negativity for autoantibodies, were also independent predictors of D2T. Early implementation of treatment after failure of treat-to-target with MTX may not prevent the development of D2T in RA. Patients showing early refractoriness to conventional drugs and those lacking autoantibodies are at higher risk of multiple treatment failures.

中文翻译：

---

早期类风湿性关节炎患者甲氨蝶呤治疗失败后及时升级为二线治疗并不能降低难治性治疗的风险


研究甲氨蝶呤 （MTX） 治疗失败后早期升级为生物/靶向合成疾病缓解抗风湿药 （b/tsDMARDs） 的患者难治性 （D2T） 类风湿性关节炎 （RA） 的频率。从早期 RA 的前瞻性队列中，所有在 2005-2018 年期间首次通路并最终在 2022 年底前开始 b/tsDMARD 的患者都被纳入并随访至 2024 年 4 月。研究结果包括每个连续 b/tsDMARD 的药物生存率、D2T 的发展（根据 EULAR 定义和后续修改）及其预测因子。在接受初始 MTX 治疗并在诊断后随访至少 3 年的早期 RA 患者总数中，155 例 （21.5%） 在中位 19 个月后开始 b/tsDMARD。在超过 70% 的病例中，尽管 MTX 的最佳剂量为 ≥ 15 毫克/天，但 RA 仍不受控制。第 1 个和第 2 个 b/tsDMARD 的保留率在 1 年后约为 70%，但 5 年后下降到 40%。中位 （IQR） 随访 72.6 （34.5-134.2） 个月后，45 例患者 （29%） 符合 EULAR D2T 标准。在多变量分析中，更多的肿胀关节和更差的疼痛评分被证实是 D2T 的预测因子。此外，在这个早期 RA 队列中，b/tsDMARD 治疗开始时病程较短，以及自身抗体的阴性，也是 D2T 的独立预测因子。在 MTX 靶向治疗失败后早期实施治疗可能无法阻止 RA 中 D2T 的发展。对常规药物表现出早期难治性和缺乏自身抗体的患者多次治疗失败的风险更高。