Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Drugs. 2020 Jun;80(9):849-857. doi: 10.1007/s40265-020-01309-9.
Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6-21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.
难治性类风湿关节炎（RA）在疾病控制良好的背景下，已成为一个未满足需求的领域。虽然大多数患者在接受甲氨蝶呤和其他一线疾病修饰抗风湿药物（DMARDs）治疗时病情得到了充分控制，但仍有一部分患者需要使用生物制剂（b）和靶向合成 DMARDs（tsDMARDs）治疗，还有一部分患者使用多种药物治疗后仍无效。最近的观察性研究采用了基于失败的 DMARDs 数量的难治性 RA 工作定义，根据阈值和研究人群的不同，患病率估计为 6-21%。危险因素包括治疗延迟、基线疾病活动度和功能、女性、吸烟、肥胖和较低的社会经济地位。由于用于评估反应的疾病活动评分存在局限性，以及同时存在非炎症性病理的误诊风险，以及未能捕捉到其他结果，如具有可变治疗反应的疲劳，因此在定义难治性 RA 时会出现实际和概念上的挑战。时间是定义难治性疾病的一个重要因素；登记研究表明，治疗选择的增加导致了 b/tsDMARD 的快速循环和更早的难治性状态，难治性 RA 本身就是一个动态的概念，随着每一种新的治疗类别而不断发展。虽然难治性 RA 的生物学基础在很大程度上仍然未知，但对生物标志物研究和新旧临床试验的概述提供了对反应和治疗失败预测的深入了解。尽管未来充满希望，但目前的数据还不足以实现 b/tsDMARDs 的个性化或有意义的排序。因此，通过遵循已证明的管理模式（例如早期诊断和靶向治疗）、解决可改变的危险因素，并考虑参与新的试验，最好避免难治性疾病的发生。
