抗瓜氨酸化蛋白和天然蛋白自身抗体与类风湿关节炎相关间质性肺疾病的预测：一项巢式病例对照研究。
Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: A nested case-control study.
作者信息
Kronzer Vanessa L, Hayashi Keigo, Yoshida Kazuki, Davis John M, McDermott Gregory C, Huang Weixing, Dellaripa Paul F, Cui Jing, Feathers Vivi, Gill Ritu R, Hatabu Hiroto, Nishino Mizuki, Blaustein Rachel, Crowson Cynthia S, Robinson William H, Sokolove Jeremy, Liao Katherine P, Weinblatt Michael E, Shadick Nancy A, Doyle Tracy J, Sparks Jeffrey A
机构信息
Division of Rheumatology, Mayo Clinic; Rochester, Minnesota, USA.
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School; Boston, USA.
出版信息
Lancet Rheumatol. 2023 Feb;5(2):e77-e87. doi: 10.1016/s2665-9913(22)00380-0. Epub 2023 Jan 24.
BACKGROUND
To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD).
METHODS
This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and rheumatoid factor status. A multiplex assay measured ACPA and anti-native protein antibodies from stored serum prior to RA-ILD onset. Logistic regression models calculated odds ratios (OR) with 95% confidence intervals (CI) for RA-ILD, adjusting for prospectively-collected covariates. We estimated optimism-corrected area under the curves (AUC) using internal validation. Model coefficients generated a risk score for RA-ILD.
FINDINGS
We analyzed 84 incident RA-ILD cases (mean age 67 years, 77% female, 90% White) and 233 RA-noILD controls (mean age 66 years, 80% female, 94% White). We identified six fine specificity antibodies that were associated with RA-ILD. The antibody isotypes and targeted proteins were: IgA2 to citrullinated histone 4 (OR 0.08 per log-transformed unit, 95% CI 0.03-0.22), IgA2 to citrullinated histone 2A (OR 4.03, 95% CI 2.03-8.00), IgG to cyclic citrullinated filaggrin (OR 3.47, 95% CI 1.71-7.01), IgA2 to native cyclic histone 2A (OR 5.52, 95% CI 2.38-12.78), IgA2 to native histone 2A (OR 4.60, 95% CI 2.18-9.74), and IgG to native cyclic filaggrin (OR 2.53, 95% CI 1.47-4.34). These six antibodies predicted RA-ILD risk better than all clinical factors combined (optimism-corrected AUC=0·84 versus 0·73). We developed a risk score for RA-ILD combining these antibodies with the clinical factors (smoking, disease activity, glucocorticoid use, obesity). At 50% predicted RA-ILD probability, the risk scores both without (score=2·6) and with (score=5·9) biomarkers achieved specificity ≥93% for RA-ILD.
INTERPRETATION
Specific ACPA and anti-native protein antibodies improve RA-ILD prediction. These findings implicate synovial protein antibodies in the pathogenesis of RA-ILD and suggest clinical utility in predicting RA-ILD once validated in external studies.
FUNDING
National Institutes of Health.
背景
鉴定与类风湿关节炎相关间质性肺病（RA-ILD）发病相关的精细特异性抗瓜氨酸化蛋白抗体（ACPA）。
方法
在布莱根妇女医院类风湿关节炎序列研究中进行的这项巢式病例对照研究，将RA-ILD发病病例与无ILD的类风湿关节炎对照在采血时间、年龄、性别、类风湿关节炎病程和类风湿因子状态方面进行匹配。采用多重分析方法检测RA-ILD发病前储存血清中的ACPA和抗天然蛋白抗体。逻辑回归模型计算RA-ILD的比值比（OR）及95%置信区间（CI），并对前瞻性收集的协变量进行校正。我们使用内部验证估计曲线下经乐观校正的面积（AUC）。模型系数生成RA-ILD的风险评分。
结果
我们分析了84例RA-ILD发病病例（平均年龄67岁，77%为女性，90%为白人）和233例无ILD的类风湿关节炎对照（平均年龄66岁，80%为女性，94%为白人）。我们鉴定出六种与RA-ILD相关的精细特异性抗体。抗体亚型和靶向蛋白分别为：针对瓜氨酸化组蛋白4的IgA2（每对数转换单位的OR为0.08，95%CI为0.03 - 0.22）、针对瓜氨酸化组蛋白2A的IgA2（OR为4.03，95%CI为2.03 - 8.00）、针对环瓜氨酸化聚角蛋白微丝蛋白的IgG（OR为3.47，95%CI为1.71 - 7.01）、针对天然环组蛋白2A的IgA2（OR为5.52，95%CI为2.38 - 12.78）、针对天然组蛋白2A的IgA2（OR为4.60，95%CI为2.18 - 9.74）以及针对天然环聚角蛋白微丝蛋白的IgG（OR为2.53，95%CI为1.47 - 4.34）。这六种抗体预测RA-ILD风险的能力优于所有临床因素综合起来的预测能力（经乐观校正的AUC = 0.84对0.73）。我们开发了一个将这些抗体与临床因素（吸烟、疾病活动度、糖皮质激素使用、肥胖）相结合的RA-ILD风险评分。在预测RA-ILD概率为50%时，不使用生物标志物（评分 = 2.6）和使用生物标志物（评分 = 5.9）的风险评分对RA-ILD的特异性均≥93%。
解读
特异性ACPA和抗天然蛋白抗体可改善RA-ILD的预测。这些发现表明滑膜蛋白抗体在RA-ILD发病机制中起作用，并提示一旦在外部研究中得到验证，在预测RA-ILD方面具有临床应用价值。
资金来源
美国国立卫生研究院。
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