甲氨蝶呤-他克莫司联合疗法与甲氨蝶呤单药疗法在停用肿瘤坏死因子抑制剂后减少类风湿关节炎发作方面的长期有效性和安全性：一项回顾性队列研究

Long-term effectiveness and safety of methotrexate-tacrolimus combination therapy versus methotrexate monotherapy in reducing rheumatoid arthritis flares after TNF inhibitor discontinuation: a retrospective cohort study.

作者信息

Naniwa Taio, Kajiura Mikiko

机构信息

Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital, and Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan.

Takeuchi Orthopedics & Internal Medicine, Chita, Aichi, Japan.

出版信息

BMC Rheumatol. 2025 Apr 7;9(1):39. doi: 10.1186/s41927-025-00489-9.

BACKGROUND

This study evaluates the long-term effectiveness and safety of methotrexate-tacrolimus combination therapy compared to methotrexate monotherapy in maintaining successful tumor necrosis factor (TNF) inhibitor discontinuation in rheumatoid arthritis (RA) patients.

METHODS

We retrospectively analyzed consecutive RA patients who discontinued TNF inhibitors after achieving disease control by October 2022 and received either methotrexate monotherapy or methotrexate-tacrolimus combination therapy for up to 10 years. Per-observation time-to-event analyses assessed treatment failure, treatment intensification, first disease flare, and irreversible functional deterioration. Mixed-effects Cox models, time-dependent Cox models without random effects, and Kaplan-Meier estimates with inverse probability weighting were applied. Safety assessment included treatment-limiting adverse events and renal function trends.

RESULTS

A total of 147 treatment lines (96 methotrexate monotherapy and 51 combination therapy) in 116 patients were analyzed. The combination therapy significantly reduced treatment failure (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.24-0.72), treatment intensification with the index drugs (HR, 0.38; 95% CI, 0.22-0.67) and with biologics or Janus kinase inhibitors (HR, 0.39; 95% CI, 0.22-0.71), and first flare (HR, 0.55; 95%CI 0.36-0.84), with consistent findings across models. The benefit was most pronounced in patients with prior flares during methotrexate monotherapy after TNF inhibitor discontinuation, with HRs as low as 0.04-0.12 across outcomes. No significant differences in treatment-limiting adverse events were observed. The annual increase in serum creatinine for tacrolimus users was 0.0032 mg/dL, suggesting minimal long-term renal impact.

CONCLUSIONS

Methotrexate-tacrolimus combination therapy significantly reduces relapse risk following TNF inhibitor discontinuation without compromising safety, offering a potentially sustainable treatment alternative after achieving remission with TNF inhibitor therapy.

背景

本研究评估了甲氨蝶呤 - 他克莫司联合疗法与甲氨蝶呤单药疗法相比，在类风湿关节炎（RA）患者中维持成功停用肿瘤坏死因子（TNF）抑制剂的长期有效性和安全性。

方法

我们回顾性分析了截至2022年10月在疾病得到控制后停用TNF抑制剂，并接受甲氨蝶呤单药疗法或甲氨蝶呤 - 他克莫司联合疗法长达10年的连续性RA患者。按观察时间进行的事件分析评估了治疗失败、治疗强化、首次疾病复发和不可逆功能恶化情况。应用了混合效应Cox模型、无随机效应的时间依赖性Cox模型以及逆概率加权的Kaplan - Meier估计。安全性评估包括限制治疗的不良事件和肾功能趋势。

结果

共分析了116例患者的147条治疗线路（96条甲氨蝶呤单药疗法线路和51条联合疗法线路）。联合疗法显著降低了治疗失败（风险比[HR]，0.42；95%置信区间[CI]，0.24 - 0.72）、使用索引药物的治疗强化（HR，0.38；95%CI，0.22 - 0.67）以及使用生物制剂或Janus激酶抑制剂的治疗强化（HR，0.39；95%CI，0.22 - 0.71），以及首次复发（HR，0.55；95%CI 0.36 - 0.84），各模型结果一致。在TNF抑制剂停用后甲氨蝶呤单药治疗期间有过复发的患者中，这种益处最为明显，各结局的HR低至0.04 - 0.12。未观察到限制治疗的不良事件有显著差异。使用他克莫司的患者血清肌酐年增加量为0.0032mg/dL，表明长期肾脏影响极小。