van Baarsen Lisa G M, Bos Wouter H, Rustenburg François, van der Pouw Kraan Tineke C T M, Wolbink Gerrit Jan J, Dijkmans Ben A C, van Schaardenburg Dirkjan, Verweij Cornelis L
VU University Medical Center, Amsterdam, The Netherlands.
Arthritis Rheum. 2010 Mar;62(3):694-704. doi: 10.1002/art.27294.
OBJECTIVE: To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers. METHODS: The study group comprised 109 anti-citrullinated protein antibody (ACPA)- and/or rheumatoid factor-positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction. RESULTS: In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at-risk patients, based on differential expression of immune-related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN)-mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8-156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN-mediated immunity and/or cytokine/chemokine-activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21-0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease. CONCLUSION: The results of this study indicate that IFN-mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine.
目的：识别与类风湿关节炎（RA）发病相关的分子特征，了解RA临床前期发展的病理生理学，并确定预测性生物标志物。 方法：研究组包括109例抗瓜氨酸化蛋白抗体（ACPA）和/或类风湿因子阳性、有关节痛但无关节炎但有RA风险的患者，以及25例RA患者。通过DNA微阵列分析和定量聚合酶链反应确定从这些患者获得的血液样本的基因表达谱。 结果：在109例有RA风险的关节痛患者中，20例在中位时间7个月后发生了关节炎。血细胞的基因表达谱显示，基于免疫相关基因的差异表达，有风险的患者之间存在异质性。本报告首次描述了与关节炎发展相关的基因特征。与关节炎发展显著相关的特征涉及干扰素（IFN）介导的免疫、造血以及趋化因子/细胞因子活性。逻辑回归分析显示，对于以IFN介导的免疫和/或细胞因子/趋化因子活性相关基因表达增加为特征的亚组，在12个月内发生关节炎的优势比（OR）为21.0（95%置信区间[95%CI]2.8 - 156.1[P = 0.003]）。参与B细胞免疫学的基因与预防进展为关节炎相关（OR 0.38，95%CI 0.21 - 0.70[P = 0.002]）。这些过程让人联想到RA患者的情况，这意味着疾病的临床前期阶段与已确诊疾病的特征相关。 结论：本研究结果表明，IFN介导的免疫、造血和细胞运输确定了与关节炎进展相关的过程，与ACPA阳性无关。这些发现强烈表明，某些基因特征对于预测进展为关节炎具有价值，这将为预防医学铺平道路。
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