Karlson Elizabeth W, Chibnik Lori B, Tworoger Shelley S, Lee I-Min, Buring Julie E, Shadick Nancy A, Manson Joann E, Costenbader Karen H
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Arthritis Rheum. 2009 Mar;60(3):641-52. doi: 10.1002/art.24350.
To examine the association of biomarkers of inflammation with preclinical rheumatoid arthritis (RA).
A nested case-control study was performed using samples from 2 large, prospectively studied cohorts of women (the Women's Health Study [WHS] and the Nurses' Health Study [NHS]). Blood samples obtained prior to symptom onset in women who later developed RA were selected as incident RA cases, and 3 controls per case were randomly chosen, matched for age, menopausal status, postmenopausal hormone use, and day, time, and fasting status at the time of collection. Plasma was tested for levels of interleukin-6 (IL-6), soluble tumor necrosis factor receptor II (sTNFRII) (as a proxy for TNFalpha), and high-sensitivity C-reactive protein. Relationships between biomarkers and RA were assessed using conditional logistic regression models, adjusting for age, body mass index, smoking habits, ethnicity, and reproductive factors.
In 93 incident cases in the NHS and 77 incident cases in the WHS, the mean time between blood collection and the onset of RA symptoms was 5.2 years (range 0.3-12 years). Median IL-6 and sTNFRII levels were significantly higher in preclinical RA cases compared with matched controls in the NHS (P = 0.03 and P = 0.003, respectively) though not in the WHS. Pooled analysis of the NHS and WHS cohorts demonstrated significant association of sTNFRII with RA (relative risk 2.0 [95% confidence interval 1.1-3.6], P for trend = 0.004), and a modest association of IL-6 with RA (relative risk 1.4 [95% confidence interval 0.8-2.5], P for trend = 0.06).
Levels of sTNFRII, a biomarker typically associated with active RA, were elevated up to 12 years prior to the development of RA symptoms and were positively associated with incident RA in these nested case-control studies. Studies with repeated assessments of biomarkers prior to RA development may provide further insight into the timing of biomarker elevation in preclinical RA.
研究炎症生物标志物与临床前期类风湿关节炎（RA）之间的关联。
采用来自两项针对女性的大型前瞻性队列研究（女性健康研究[WHS]和护士健康研究[NHS]）的样本进行巢式病例对照研究。将后来患RA的女性在症状出现前采集的血样选为RA发病病例，并为每个病例随机选择3名对照，对照在年龄、绝经状态、绝经后激素使用情况以及采集时的日期、时间和空腹状态方面进行匹配。检测血浆中白细胞介素-6（IL-6）、可溶性肿瘤坏死因子受体II（sTNFRII）（作为TNFα的替代指标）和高敏C反应蛋白的水平。使用条件逻辑回归模型评估生物标志物与RA之间的关系，并对年龄、体重指数、吸烟习惯、种族和生殖因素进行校正。
在NHS的93例发病病例和WHS的77例发病病例中，采血与RA症状出现之间的平均时间为5.2年（范围0.3 - 12年）。在NHS中，临床前期RA病例的IL-6和sTNFRII水平中位数显著高于匹配的对照（分别为P = 0.03和P = 0.003），而在WHS中则不然。对NHS和WHS队列的汇总分析显示，sTNFRII与RA存在显著关联（相对风险2.0[95%置信区间1.1 - 3.6]，趋势P值 = 0.004），IL-6与RA存在适度关联（相对风险1.4[95%置信区间0.8 - 2.5]，趋势P值 = 0.06）。
sTNFRII是一种通常与活动性RA相关的生物标志物，在RA症状出现前长达12年其水平就已升高，并且在这些巢式病例对照研究中与RA发病呈正相关。在RA发病前对生物标志物进行重复评估的研究可能会进一步深入了解临床前期RA中生物标志物升高的时间。
