Rodriguez-Merlos Pablo, Cabrera-Alarcón Jose Luis, Ruiz-Esquide Virginia, Chacur Chafik Alejandro, Sanmartí Raimon, De Miguel-Mendieta Eugenio, Álvaro-Gracia Jose María, Balsa Alejandro, Plasencia-Rodríguez Chamaida, Novella-Navarro Marta
Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
Arthritis Res Ther. 2025 Jul 19;27(1):153. doi: 10.1186/s13075-025-03621-9.
While risk factors for difficult-to-treat rheumatoid arthritis (D2TRA) have been studied in recent years, no studies have determined if there are differences between early and late developers of D2TRA. This study investigates whether patients can be classified by time to D2TRA development and examines risk factors for earlier onset.
Observational study involving D2TRA patients whose reason for switching b/tsDMARD therapy was inefficacy (D2TRA-Inneficacy). Demographic data, comorbidities and disease characteristics, acute phase reactants and Disease Activity Score-28 [DAS28-ESR]) at baseline and 6 months after initiation of the first b/tsDMARD, and duration of each treatment were recorded. Using LASSO (Least Absolute Shrinkage and Selection Operator) Cox-regression feature-selection strategy, we identified those factors influencing the time to D2TRA-Inneficacy. DBSCAN clustering was conducted to identify subgroups based on time to D2TRA. Finally, we used ROC and Precision-Recall curves in tandem with the Youden index to establish a cutoff point for differentiating early and late-D2TRA.
Of the 131 patients with D2TRA, 96 (72.7%) were classified as D2TRA-inefficacy. The variables presence of anxiety-depressive syndrome (ADS) at first b/tsDMARD, CRP at 6 months after starting the first b/tsDMARD and age at disease diagnosis were selected based on their contracted scores from the LASSO Cox-regression model, following the criterion of minimizing the cross-validated error. DBSCAN clustering based on selected variables identified three clusters. These clusters, differentiated by time to D2TRA, classified patients into early and late D2TRA groups. Finally, an optimal cut-off point of 44.5 months was determined using the Youden index to distinguish between the two groups.
In our cohort, the cut-off time for defining early developers of D2TRA-inefficacy was 44.5 months. The presence of ADS diagnosis, a higher CRP 6 months after the first b/tsDMARD, and being older at diagnosis were predictors of early development of D2TRA.
近年来，虽然对难治性类风湿关节炎（D2TRA）的危险因素进行了研究，但尚无研究确定D2TRA的早期发病者和晚期发病者之间是否存在差异。本研究调查了患者是否可以根据D2TRA发病时间进行分类，并探讨了发病较早的危险因素。
对因b/tsDMARD治疗无效而转换治疗方案的D2TRA患者进行观察性研究（D2TRA-无效组）。记录人口统计学数据、合并症和疾病特征、急性期反应物以及首次使用b/tsDMARD治疗基线时和治疗6个月后的疾病活动评分-28（DAS28-ESR），以及每种治疗的持续时间。使用LASSO（最小绝对收缩和选择算子）Cox回归特征选择策略，我们确定了那些影响D2TRA-无效发病时间的因素。进行DBSCAN聚类以根据D2TRA发病时间识别亚组。最后，我们结合使用ROC曲线和精确召回率曲线以及约登指数来确定区分早期和晚期D2TRA的临界点。
在131例D2TRA患者中，96例（72.7%）被归类为D2TRA-无效组。根据LASSO Cox回归模型的收缩分数，按照最小化交叉验证误差的标准，选择了首次使用b/tsDMARD时存在焦虑抑郁综合征（ADS）、开始首次使用b/tsDMARD治疗6个月时的CRP以及疾病诊断时的年龄等变量。基于选定变量的DBSCAN聚类识别出三个聚类。这些聚类根据D2TRA发病时间进行区分，将患者分为早期和晚期D2TRA组。最后，使用约登指数确定了区分两组的最佳临界点为44.5个月。
在我们的队列中，定义D2TRA-无效早期发病者的截止时间为44.5个月。ADS诊断的存在、首次使用b/tsDMARD治疗6个月后较高的CRP以及诊断时年龄较大是D2TRA早期发病的预测因素。
