Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, United Kingdom.
J Autoimmun. 2019 Dec;105:102298. doi: 10.1016/j.jaut.2019.06.009. Epub 2019 Jul 4.
Many patients with rheumatoid arthritis (RA) achieve disease remission with modern treatment strategies. However, having achieved this state, there are no tests that predict when withdrawal of therapy will result in drug-free remission rather than flare. We aimed to identify predictors of drug-free remission in RA.
The Biomarkers of Remission in Rheumatoid Arthritis (BioRRA) Study was a unique, prospective, interventional cohort study of complete and abrupt cessation of conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Patients with RA of at least 12 months duration and in clinical and ultrasound remission discontinued DMARDs and were monitored for six months. The primary outcome was time-to-flare, defined as disease activity score in 28 joints with C-reactive protein (DAS28-CRP) ≥ 2.4. Baseline clinical and ultrasound measures, circulating inflammatory biomarkers, and peripheral CD4 T cell gene expression were assessed for their ability to predict time-to-flare and flare/remission status by Cox regression and receiver-operating characteristic (ROC) analysis respectively.
23/44 (52%) eligible patients experienced an arthritis flare after a median (IQR) of 48 (31.5-86.5) days following DMARD cessation. A composite score incorporating five baseline variables (three transcripts [FAM102B, ENSG00000228010, ENSG00000227070], one cytokine [interleukin-27], one clinical [Boolean remission]) differentiated future flare from drug-free remission with an area under the ROC curve of 0.96 (95% CI 0.91-1.00), sensitivity 0.91 (0.78-1.00) and specificity 0.95 (0.84-1.00).
We provide proof-of-concept evidence for predictors of drug-free remission in RA. If validated, these biomarkers could help to personalize immunosuppressant withdrawal: a therapy paradigm shift with ensuing patient and economic benefits.
许多类风湿关节炎（RA）患者通过现代治疗策略实现疾病缓解。然而，在达到这种状态后，目前还没有可以预测停止治疗后会出现无药物缓解还是疾病复发的检测手段。我们旨在确定 RA 患者无药物缓解的预测因素。
类风湿关节炎缓解的生物标志物（BioRRA）研究是一项独特的、前瞻性的、干预性队列研究，研究对象为完全和突然停止使用传统合成的疾病修饰抗风湿药物（DMARDs）的 RA 患者。至少有 12 个月病程且处于临床和超声缓解的 RA 患者停止使用 DMARDs，并在 6 个月内进行监测。主要结局是复发时间，定义为 C 反应蛋白（DAS28-CRP）≥2.4 的 28 个关节疾病活动评分（DAS28）。通过 Cox 回归和受试者工作特征（ROC）分析分别评估基线临床和超声指标、循环炎症生物标志物以及外周 CD4 T 细胞基因表达对复发时间和复发/缓解状态的预测能力。
在 DMARD 停药后中位（IQR）48（31.5-86.5）天，23/44（52%）符合条件的患者出现关节炎复发。一个包含五个基线变量（三个转录物[FAM102B、ENSG00000228010、ENSG00000227070]、一个细胞因子[白细胞介素-27]、一个临床[布尔缓解]）的综合评分可将未来的复发与无药物缓解区分开来，ROC 曲线下面积为 0.96（95%CI 0.91-1.00），灵敏度为 0.91（0.78-1.00），特异性为 0.95（0.84-1.00）。
我们为 RA 无药物缓解的预测因素提供了概念验证证据。如果得到验证，这些生物标志物可能有助于实现免疫抑制剂的个体化停药：这是一种具有潜在患者和经济效益的治疗范式转变。
