Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, 60 Fenwood Road, #6016U, Boston, MA, 02115, USA.
Harvard Medical School, Boston, MA, USA.
Arthritis Res Ther. 2019 Nov 21;21(1):246. doi: 10.1186/s13075-019-2035-3.
Anti-citrullinated protein antibodies (ACPA) are central to rheumatoid arthritis (RA) pathogenesis and may develop at inflamed mucosa. We investigated whether asthma, a disease of airway mucosal inflammation, was associated with elevated ACPA before RA diagnosis.
We performed a nested case-control study among women in two prospective cohorts, the Nurses' Health Study (NHS; 1976-2014) and NHSII (1989-2015). Blood was obtained on a subset (NHS: 1989-1990; NHSII: 1996-1999). Cases met 1987 ACR or 2010 ACR/EULAR RA criteria by medical record review and were classified as seropositive (ACPA+ or rheumatoid factor positivity) or seronegative by clinical laboratory testing at diagnosis. We identified RA cases with blood drawn before the date of RA diagnosis (index date), matching each to three controls by age, cohort, year, time from blood draw to index date, and menopause. Pre-RA ACPA elevation for cases was defined as >99th percentile of the control distribution on a research assay composed of autoantibodies targeting citrullinated protein epitopes or positivity on the second-generation commercial assay for cyclic citrullinated peptide. Asthma status and covariates were obtained through biennial questionnaires before blood draw. Conditional logistic regression estimated ORs and 95%CIs for RA by pre-RA ACPA and clinical serostatus, adjusted for matching factors, smoking pack-years, passive smoking, and body mass index (BMI).
We identified 284 incident RA cases and 849 matched controls; mean age at the index date was 61.2 years (SD 10.1). Blood was drawn 9.7 years (mean; SD 5.8) before the index date. We identified 96 (33.8%) RA cases with elevated pre-RA ACPA. At blood draw, 17.7% of pre-RA ACPA+ cases and 6.3% of matched controls (p = 0.0008) reported clinician-diagnosed asthma. After adjusting for matching factors, smoking pack-years, passive smoking, and BMI, asthma was significantly associated with pre-RA ACPA+ RA (OR 3.57, 95%CI 1.58,8.04). Asthma was not associated with overall RA (OR 1.45, 95%CI 0.91,2.31), but was significantly associated with seropositive RA (OR 1.79, 95%CI 1.01,3.18).
Asthma was strongly associated with ACPA elevation in blood drawn prior to RA diagnosis, independent of smoking. Chronic mucosal airway inflammation may contribute to ACPA development and RA pathogenesis.
抗瓜氨酸化蛋白抗体（ACPA）是类风湿关节炎（RA）发病机制的核心，可能在炎症黏膜中产生。我们研究了气道黏膜炎症性疾病哮喘是否与 RA 诊断前的 ACPA 升高有关。
我们在两项前瞻性队列研究中的女性中进行了巢式病例对照研究，护士健康研究（NHS；1976-2014 年）和 NHSII（1989-2015 年）。NHS 中（1989-1990 年）和 NHSII 中（1996-1999 年）有一部分人获得了血液。通过病历回顾，病例符合 1987 年 ACR 或 2010 年 ACR/EULAR RA 标准，并通过临床实验室检测在诊断时被分类为血清阳性（ACPA+或类风湿因子阳性）或血清阴性。我们确定了在 RA 诊断日期（索引日期）之前抽取血液的 RA 病例，并通过年龄、队列、年份、从采血到索引日期的时间以及绝经状态，为每位病例匹配了 3 名对照。病例的 RA 前 ACPA 升高定义为在由针对瓜氨酸化蛋白表位的自身抗体组成的研究检测中>对照分布的第 99 百分位数，或在第二代环瓜氨酸肽的商业检测中呈阳性。哮喘状况和协变量通过采血前的两年一次的问卷调查获得。条件逻辑回归估计了 RA 前 ACPA 和临床血清状态的 OR 和 95%CI，调整了匹配因素、吸烟包年数、被动吸烟和体重指数（BMI）。
我们确定了 284 例新发病例和 849 例匹配对照；索引日期的平均年龄为 61.2 岁（标准差 10.1）。索引日期前采血 9.7 年（平均；标准差 5.8）。我们确定了 96 例（33.8%）RA 病例的 RA 前 ACPA 升高。在采血时，17.7%的 RA 前 ACPA+病例和 6.3%的匹配对照（p=0.0008）报告有临床诊断的哮喘。调整匹配因素、吸烟包年数、被动吸烟和 BMI 后，哮喘与 RA 前 ACPA+RA 显著相关（OR 3.57，95%CI 1.58，8.04）。哮喘与总体 RA 无关联（OR 1.45，95%CI 0.91，2.31），但与血清阳性 RA 显著相关（OR 1.79，95%CI 1.01，3.18）。
哮喘与 RA 诊断前抽取的血液中 ACPA 升高密切相关，且与吸烟无关。慢性黏膜气道炎症可能导致 ACPA 的产生和 RA 的发病机制。
