Young Kendra A, Deane Kevin D, Derber Lezlie A, Hughes-Austin Jan M, Wagner Catriona A, Sokolove Jeremy, Weisman Michael H, Buckner Jane H, Mikuls Ted R, O'Dell James R, Keating Richard M, Gregersen Peter K, Robinson William H, Holers V Michael, Norris Jill M
Colorado School of Public Health, Aurora, CO, USA.
Arthritis Rheum. 2013 Aug;65(8):1995-2004. doi: 10.1002/art.38022.
OBJECTIVE: To examine reactivity to anti-citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)-related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. METHODS: Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 [anti-CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for ≥9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for ≥9 ACPAs) and RA-related characteristics were examined. RESULTS: Fifty-seven percent of anti-CCP-2-positive first-degree relatives and 8% of anti-CCP-2- negative first-degree relatives were positive for ≥9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of ≥1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04-1.34), with the greatest risk of having ≥1 tender joint seen in first-degree relatives positive for ≥9 ACPAs (OR 5.00, 95% CI 1.37-18.18). CONCLUSION: RA-free first-degree relatives (even those negative for RF and anti-CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted.
目的：检测抗瓜氨酸化蛋白/肽抗体（ACPAs）的反应性，并确定ACPAs与其他类风湿关节炎（RA）相关自身抗体以及RA患者未受影响的一级亲属中临床评估的肿胀或压痛关节之间的关联。 方法：根据1987年美国风湿病学会（ACR）和2010年ACR/欧洲抗风湿病联盟分类标准，从无RA的一级亲属中获取血清样本。采用基于微珠的检测方法，对111名至少有1次检测显示5种RA相关自身抗体（类风湿因子[RF]、抗环瓜氨酸肽2[抗CCP-2]及RF亚型）中任何一种呈阳性的抗体阳性一级亲属的血清以及99名从未出现自身抗体阳性的抗体阴性一级亲属的血清中的16种不同ACPAs进行检测。使用从200例RA患者和98名献血者对照的数据得出的受试者工作特征曲线，确定每种ACPA的阳性临界值，其中≥9种ACPA呈阳性对RA具有92%的特异性和62%的敏感性。在一级亲属中，评估ACPA反应性，并检测ACPA（阳性数量以及≥9种ACPA呈阳性）与RA相关特征之间的关联。 结果：57%的抗CCP-2阳性一级亲属和8%的抗CCP-2阴性一级亲属≥9种ACPA呈阳性。在调整年龄、性别、种族和吸烟包年数后，ACPA数量增加与检查时≥1个压痛关节的存在直接相关（优势比[OR]1.18，95%置信区间[9%CI]1.04 - 1.34），在≥9种ACPA呈阳性的一级亲属中出现≥1个压痛关节的风险最高（OR 5.00，95%CI 1.37 - 18.18）。 结论：无RA的一级亲属（即使RF和抗CCP-2阴性者）表现出对多种ACPA的反应性，且ACPA数量增加可能与关节炎症体征相关。有必要对这些发现与可分类RA进展之间的关系进行前瞻性评估。
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