Background/Purpose: Despite advancements in rheumatoid arthritis (RA) treatment, standardized mortality rates remain up to 3 times higher than in the general population. Cardiovascular disease (CVD) is the leading cause of excess deaths in RA. Our group has recently found lower left ventricular (LV) mass in RA patients which was associated with anti-CCP antibody levels. Although anti-CCP Abs have been associated with increased CVD and mortality in RA, little is known about the underlying pathophysiology and whether specific anti-citrullinated peptide antibodies (ACPAs) play a role in altering cardiac function or structure. Our objective was to test the association of autoreactivity of a selected panel of ACPAs with myocardial function and structure parameters in RA patients.

Methods:  This study was nested in an RA cohort without known CVD. A cross-sectional analysis was performed using clinical data and collected serum from a subset of participants who underwent cardiac magnetic resonance (CMR) imaging at baseline. With a custom multiplex bead based antigen array using the BioPlex platform and ran on the Luminex 200 instrument, the autoreactivity against a panel of 17 ACPAs was tested. The association of each ACPA with CMR-derived cardiac measures was tested by linear regression analyses, adjusting for potential confounders.

Results: A total of 76 RA patients underwent CMR [mean age 59±9 years, 49% male, mean disease duration 12 ± 11 years, mean DAS28=3.5 ± 1.1].  At an established level of significance of <0.05, categories of anti-citrullinated vimentin (epitopes 58-77), anti-citrullinated histone2b (epitopes 62-81) and anti-citrullinated enolase antibodies were associated with a decrease in LV end diastolic mass. A decrease in LV mass index was associated with categories of anti-citrullinated histone2b, anti-citrullinated histone2b (epitopes 62-81), anti-citrullinated fibrinogen (epitopes 211-230, 556-575), anti-citrullinated histone2a (epitopes 1-20) and anti-citrullinated enolase antibodies. These and additional associations with other tested cardiac parameters are shown in table 1.

Table 1. Summary of Linear Regression Analysis of the Associations between Specific ACPAs and statistically significant directional changes in each individual left ventricular measure.

ACPA categories-per quartile	EDM	MI	EDVI	HR	ESV	EF	SV	CO	ESVI
Anti-cit-vimentin			↓
Anti-cit-fibrinogen
Anti-cit-histone2b *		↓
Anti-citfibrinogen (616-635)				↑
Anti-cit-vimentin (58-77)	↓			↑
Anti-cit-fibrinogen (41-60)									↓
Anti-cit-fillagrin (48-65)
Anti-cit-biglycan (247-266)				↑	↓				↓
Anti-cit-clusterin (231-250)				↑					↓
Anti-cit-histone2b (62-81)	↓	↓	↓	↑	↓		↓
Anti-cit-fibrinogen (211-230)		↓	↓	↑	↓				↓
Anti-cit-fibrinogen (556-575)		↓	↓	↑	↓
Anti-cit-histone2a (1-20)		↓	↓	↑
Anti-cit-apo E (277-296)
Anti-cit-apo A				↑				↑
Anti-cit-apo E				↑				↑
Anti-cit-enolase	↓	↓	↓	↑	↓				↓

EDM=LV end diastolic mass, MI= LV mass index, EDVI= LV end diastolic volume index, HR= heart rate, ESV= end systolic volume, EF=ejection fraction, SV=stroke volume, CO=cardiac output, ESVI= end systolic volume index. ↑=increase, ↓=decrease. *Adjusted for Framingham score. Statistical significance: p-value <0.05.

Conclusion: Our results suggest that categories of specific ACPAs are associated with alterations in cardiac parameters in RA patients. Identifying the specific peptide(s) against which the anti-CCP reactivity is directed represents an indirect, but important, advance in understanding the pathophysiology of accelerated CVD in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fine-specificity-of-anti-citrullinated-peptide-auto-antibodies-associations-with-cardiac-structure-and-function-in-rheumatoid-arthritis/