Leiden University Medical Center, Leiden, The Netherlands.
Stanford University School of Medicine, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
Arthritis Rheumatol. 2016 Sep;68(9):2090-8. doi: 10.1002/art.39664.
OBJECTIVE: Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies, including seropositivity for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). In addition, antibodies to carbamylated proteins (anti-CarP) are present in patients with RA and are associated with joint damage. This study was undertaken to assess the presence of anti-CarP antibodies in indigenous North Americans (First Nations [FN] populations) with RA compared to their at-risk first-degree relatives (FDRs) and healthy controls. METHODS: Anti-CarP IgG and ACPAs (specifically, anti-cyclic citrullinated peptide [anti-CCP] antibodies) were measured by enzyme-linked immunosorbent assay in the sera of FN patients with RA (n = 95), their unaffected FDRs (n = 109), and healthy FN controls (n = 85). Antibodies to additional citrullinated peptides were measured using a multiplex ACPA array, and the number of peptides recognized was reported as an ACPA score. Groups were compared using the chi-square test and Mann-Whitney U test. Associations between RA and seropositivity for RF, ACPAs, and anti-CarP antibodies were determined by logistic regression. RESULTS: Anti-CarP antibodies were more frequent in FN patients with RA (44.3%) compared to FDRs (18.3%) and FN controls (4.7%) (both P < 0.0001 versus RA). Moreover, anti-CarP antibodies were more frequent in FDRs than in FN controls (P = 0.008). The ACPA score was higher in anti-CCP-positive FN patients with RA than in anti-CCP-positive FN FDRs (median score 7 [interquartile range (IQR) 7] versus median score 1 [IQR 4]; P = 0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and anti-CarP) were present in the patients' serum (odds ratio 194, 95% confidence interval 23-1,609, P < 0.0001). CONCLUSION: Anti-CarP antibodies are prevalent in FN patients with RA and also more common in their at-risk FDRs compared to healthy controls. The results indicate an association of RF, ACPAs, and anti-CarP with RA that is strongest when all 3 autoantibodies are present. These findings may provide new insights into the evolution of autoimmunity in preclinical RA.
目的：类风湿关节炎（RA）的特征是存在自身抗体，包括类风湿因子（RF）和抗瓜氨酸化蛋白抗体（ACPAs）的血清阳性。此外，在 RA 患者中还存在针对氨甲酰化蛋白的抗体（抗-CarP），并与关节损伤有关。本研究旨在评估与高危一级亲属（FDR）和健康对照相比，患有 RA 的土着北美人（第一民族[FN]人群）中抗-CarP 抗体的存在情况。
方法：通过酶联免疫吸附试验（ELISA）测量 FN 患者 RA 血清中的抗-CarP IgG 和 ACPAs（具体为抗环瓜氨酸肽[抗-CCP]抗体）（n=95），未受影响的 FDR（n=109）和健康 FN 对照组（n=85）。使用多重 ACPA 阵列测量针对其他瓜氨酸化肽的抗体，并且报告识别的肽的数量作为 ACPA 评分。使用卡方检验和曼-惠特尼 U 检验比较各组。通过逻辑回归确定 RA 与 RF、ACPAs 和抗-CarP 抗体血清阳性之间的关联。
结果：与 FDR（18.3％）和 FN 对照组（4.7％）相比，FN 患者 RA 中抗-CarP 抗体更为常见（均 P<0.0001）。此外，与 FN 对照组相比，FDR 中抗-CarP 抗体更为常见（P=0.008）。与抗-CCP 阳性的 FN 患者 RA 相比，抗-CCP 阳性的 FN FDR 中 ACPA 评分更高（中位数评分 7 [四分位距（IQR）7]与中位数评分 1 [IQR 4]；P=0.04）。当患者血清中存在所有 3 种自身抗体（RF、抗-CCP 和抗-CarP）时，与 RA 的关联最强（优势比 194，95％置信区间 23-1,609，P<0.0001）。
结论：FN 患者 RA 中存在抗-CarP 抗体，并且与健康对照组相比，其高危 FDR 中也更为常见。结果表明，RF、ACPAs 和抗-CarP 与 RA 相关，当所有 3 种自身抗体均存在时，相关性最强。这些发现可能为临床前 RA 中自身免疫的演变提供新的见解。
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