Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis

Abstract

Background: Hypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives. Methods: We evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications. Results: Average age was 51 and 69% were women. Mean SBP was 119 ± 18 and DBP was 74 ± 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for ≥1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 ± 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 ± 0.3 mm Hg (p = 0.04) higher. Anti-cit-fibrinogen A (211–230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit-clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7–8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first-degree relatives had 16.4± (p = 0.03) higher SBP and 12.1± mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives. Conclusion: In first-degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset.

Admixture mapping identifies genetic regions associated with blood pressure phenotypes in African Americans

“…Previously, this gene had been reported to be associated with asthma [34], ichthyosis [32] and abnormal inflammatory response [35,36]. In a study of rheumatoid arthritis patients, first-degree relatives who were negative for rheumatoid arthritis but were positive for antibodies to citrullinated filaggrin had higher SBP and DBP than those who were antibody-negative [37], suggesting that there may be a correlation, although not necessarily a causation, between blood pressure and FLG.…”

Periodontal status correlates with anti‐citrullinated protein antibodies in first‐degree relatives of individuals with rheumatoid arthritis

“…The association between RA and periodontitis could be due to the RA condition and RA medications, or it could be that RA patients even before developing the disease are through their genetic make‐up already susceptible to both RA and periodontitis. A similar analysis has been made with respect to the association between hypertension and RA (Hughes‐Austin et al., ). A two‐hit model has already been suggested, in which periodontitis serves as a first hit and a second (unknown) hit induces RA in susceptible individuals.…”

Serum reactivity to citrullinated protein/peptide antigens and left ventricular structure and function in the Multi-Ethnic Study of Atherosclerosis (MESA)

“…Among individuals with rheumatoid arthritis (RA), risk for heart failure is 70% higher compared to the general population [1]. Given that traditional cardiovascular disease (CVD) risk factors do not explain the higher CVD risk or the higher rates of heart failure in patients with RA [1][2][3][4][5][6], it is thought that RA-related autoantibodies may predispose individuals to early subclinical cardiovascular changes ultimately resulting in these adverse cardiac outcomes [7,8]. It has been proposed that RA begins with a genetic predisposition to develop autoantibodies in response to an environmental trigger [9].…”