Departments of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-90185 Umeå, Sweden.
Arthritis Res Ther. 2011 Feb 3;13(1):R13. doi: 10.1186/ar3237.
We and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease. Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score.
A case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden. Patients with RA were identified from blood donors predating the onset of disease by years. Matched controls were selected randomly from the same registers. IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden).
Of 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses. The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years). The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM. The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls. IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3. Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP. IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals.
Anti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies.
我们和其他人之前已经表明，针对环瓜氨酸蛋白的抗体（抗-CCP）先于类风湿关节炎（RA）的发展，在最近的一项研究中，我们报告说，随后发展为 RA 的个体在关节疾病症状出现前数年就有几种细胞因子和趋化因子浓度升高。在这里，我们旨在评估随后发展为 RA 的个体中 IgG、IgM 和 IgA 同种型的抗-CCP 抗体的患病率和预测值，并将其与细胞因子、趋化因子、吸烟、遗传因素和放射评分相关联。
一项病例对照研究（1:4 比例）嵌套在瑞典北部的医学生物库和产科队列中。RA 患者是通过多年前的献血者预先从疾病发作中确定的。匹配的对照是从同一登记册中随机选择的。使用 ImmunoCAP 250（Phadia AB，Uppsala，瑞典）上的 EliA 抗-CCP 测定法测定 IgG、IgA 和 IgM 抗-CCP2 抗体。
在症状出现前作为献血者确定的 86 名 RA 患者中，有 71 名患者可用于分析。预测时间的中位数（Q1 至 Q3）为 2.5 年（1.1 至 5.9 年）。在患者前样本中，抗-CCP 抗体的灵敏度为 IgG 为 35.2%，IgA 为 23.9%，IgM 为 11.8%。与对照组相比，IgG 和 IgA 抗-CCP 抗体的存在具有高度显著性。在条件逻辑回归模型中，IgG 和 IgA 抗-CCP2 显著预测 RA 的比值比（OR）分别为 94.1（95%置信区间[CI] 12.7 至 695.4）和 11.1（95%CI 4.4 至 28.1），IgM 抗-CCP 则呈边缘显著性 OR = 2.5（95%CI 0.9 至 6.3）。随着样本采集时间越接近症状发作，所有抗-CCP 同种型的浓度都会升高，与 IgM 抗-CCP 相比，IgG 和 IgA 的升高更早且更高。IgA 和 IgG 抗-CCP 阳性个体的趋化因子上调模式不同，而且吸烟会使 RA 前个体的 IgA 抗-CCP 抗体出现。
抗-CCP2 抗体的 IgG 和 IgA 同种型均先于 RA 发作数年；此外，IgG 和 IgA 抗-CCP2 抗体均预测 RA 的发展，其中 IgG 抗-CCP2 抗体的预测价值最高。
