Background/Purpose:

Rheumatoid arthritis (RA) is characterized by systemic inflammation and immune dysregulation, including the presence of autoantibodies and elevated inflammatory biomarkers in subjects with classifiable RA as well as prior to the development of clinically-apparent RA.  In addition, the risk for cardiovascular disease (CVD) is greatly increased in patients with RA, with autoantibodies and systemic inflammation believed to be major contributors to the pathogenesis of CVD. Furthermore, the increased risk for CVD may precede the development of classifiable RA, leading to the hypothesis that autoantibodies and systemic inflammation are influencing the development of CVD in subjects even prior to the onset of joint symptoms in RA.  The Studies of the Etiology of RA (SERA) demonstrated previously an association between autoantibody positivity and increased levels of circulating cytokines in subjects without RA but at elevated risk for future RA, as they are first-degree relatives (FDRs) of probands with RA.  We utilized SERA FDRs to test the hypothesis that CVD may be apparent in subjects at-risk for future RA, and related to the presence of RA-related autoantibodies.

Methods:

Eighty-six autoantibody positive and negative FDRs from the larger SERA cohort were evaluated after a 10-hour fast for the following measures related to CVD: carotid intima media thickness (cIMT), carotid stiffness, flow-mediated dilation (FMD) of the brachial artery, abdominal adipose tissue using computed tomography (CT), blood pressure, lipids, lipoproteins and adipokines.  Levels of these pre-clinical CVD phenotypes were log-transformed and compared by current autoantibody positivity status using mixed linear models to account for varying group sizes, adjusting for age, sex and ever smoked status.  

Results:

Nineteen FDRs were positive for anti-cyclic citrullinated peptide (either CCP2 or CCP3.1), 22 FDRs were positive for rheumatoid factor (RF) (either RF by nephelometry, or RF isotype-IgM, IgA, IgG), and 45 were negative for CCP and RF.  The ApoB/ApoA ratio differed across autoantibody groups, with the Ab negative FDRs having the highest ratio, indicating increased CVD risk.  Otherwise, there were no significant differences in CVD-related measures and current autoantibody status in FDRs (see Table). 

 

Table:  CVD-related measures between CCP positive, RF positive and Ab Negative FDRs.  Adjusted for age, gender, race, and smoking status; values are back-transformed.
	CCP Positive  n=19† Mean (SE)	RF Positive n=22 Mean (SE)	Ab Negative n=45 Mean (SE)	P
Age (years)*	51.42 (3.37)	49.86 (3.72)	53.44 (2.00)	0.67
Sex (% Female)	84.2	77.3	60.0	0.11
Ethnicity (% non-Hispanic white)	84.2	95.5	88.9	0.52
Ever Smoker (% Yes)	21.1	27.3	42.2	0.20
Blood Pressure
Systolic (mm/Hg)	118.6  (4.1)	115.9 (4.9)	118.1 (2.8)	0.85
Diastolic (mm/Hg)	72.0 (2.5)	69.9 (2.9)	73.6 (1.8)	0.38
Lipids, lipoproteins and adipokines
LDL (mg/dL)	93.2 (9.0)	82.2 (8.0)	91.2 (7.0)	0.33
HDL (mg/dL)	51.4 (3.8)	50.9 (4.6)	47.0 (2.6)	0.34
Cholesterol (mg/dL)	167.0 (11.3)	161.5 (8.5)	161.5 (8.5)	0.63
Triglycerides (mg/dL)	113.1 (15.5)	105.4 (18.5)	107.2 (11.3)	0.87
ApoB (mg/dL)	78.7 (5.5)	71.6 (4.8)	79.4 (4.3)	0.17
ApoA (mg/dL)	151.0 (6.5)	150.8 (7.1)	141.5 (4.5)	0.17
ApoB/ApoA	0.53 (0.04)	0.48 (0.04)	0.58 (0.03)	0.02
Adiponectin (ug/mL)	8.9 (1.6)	9.1 (1.9)	8.9 (1.2)	0.99
Leptin (ug/mL)	15.8 (4.4)	13.6 (4.7)	16.9 (3.5)	0.72
ICAM (ug/mL)	91.8 (11.9)	80.5 (10.6)	106.2 (11.3)	0.06
VCAM (ug/mL)	605.6 (64.3)	599.4 (71.6)	591.8 (59.0)	0.98
E-Selectin (ug/mL)	30.2 (4.3)	36.9 (6.1)	35.7 (3.3)	0.35
Adiposity
BMI (kg/m2)	28.8 (1.8)	28.4 (2.3)	29.9 (1.4)	0.68
Subcutaneous Fat Area (cm2) at L4/5*	362.3 (110.0)	324.5 (74.3)	379.2 (55.0)	0.70
Visceral Fat (cm2) at L4/5*	155.2 (90.0)	98.9 (36.7)	136.9 (27.0)	0.50
Carotid Intima Medial Thickness (averaged over left and right cIMT)
cIMT, carotid bulb (max mm)	0.9 (0.07)	1.0 (0.09)	1.1 (0.07)	0.08
cIMT, carotid bulb (avg mm)	0.7 (0.05)	0.8 (0.06)	0.8 (0.05)	0.15
cIMT, common carotid artery (max mm)	0.7 (0.04)	0.7 (0.04)	0.7 (0.03)	0.85
cIMT, common carotid artery (avg mm)	0.6 (0.04)	0.6 (0.03)	0.6 (0.02)	0.69
cIMT, internal carotid artery (max mm)	0.6  (0.06)	0.6 (0.05)	0.7 (0.05)	0.16
cIMT, internal carotid artery (avg mm)	0.5 (0.04)	0.5 (0.03)	0.5 (0.03)	0.19
Measures of Carotid Stiffness
Peterson’s Elastic Model (mmHg)	413.4 (48.9)	379.3 (53.5)	423.4 (44.9)	0.66
Circumferential Arterial Strain (no units)	0.1 (0.01)	0.1 (0.02)	0.1 (0.01)	0.84
Beta Stiffness Index (no units)	4.3 (0.5)	4.1 (0.5)	4.4 (0.4)	0.75
Elastic Modulus, Incremental (mmHg)	1873.8 (286.3)	1688.2 (292.1)	1909.5 (270.5)	0.69
Young’s Elastic Pressure Modulus (mmHg/mm)	355.2 (49.3)	327.0 (51.9)	361.4 (48.2)	0.75
Arterial Compliance (mm2/mmHg)	0.1 (0.01)	0.1 (0.01)	0.1 (0.01)	0.34
Flow Mediated Dilatation (FMD) (Δ%)**	6.6 (1.7)	6.7 (1.4)	5.7 (0.9)	0.58
*Sample size reduced as not everyone participated in CT scan (CCP n=5, RF n=16, Ab- n=28). **Sample size reduced as not everyone was measured for FMD (CCP n=11, RF n=13, Ab- n=20). † 11 CCP positive cases were also positive for RF.

Conclusion: This analysis suggests that CCP and RF positive FDRs did not have worse biochemical, structural or functional indicators of vascular health compared to autoantibody negative FDRs, which is contrary to our a priori hypothesis.  These results tentatively indicate that the increased risk for CVD that is seen in RA is not detectable in the early preclinical autoantibody phase of the disease, using the biochemical, structural or functional vascular changes measured herein. It is possible that the increased CVD risk seen in RA is manifested outside of these pathways and other mechanisms/measures should be explored.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lack-of-association-between-preclinical-markers-for-cardiovascular-disease-and-rheumatoid-arthritis-related-autoimmunity-in-first-degree-relatives-without-rheumatoid-arthritis/