Background/Purpose:  Joint erosions and joint space narrowing may lead to impaired functional status and disability in rheumatoid arthritis (RA).  Autoantibodies to citrullinated proteins (ACPA) are present in RA sera, but the contribution of different specificities of ACPA to radiographic damage has not been studied. The objectives of this cross-sectional study were: to test the hypothesis that particular ACPA specificities are associated with radiographic damage in African-Americans with RA.

Methods:   Using a custom Bio-Plex™ bead-based autoantibody assay platform, we measured serum (N = 730 RA patients) concentration of antibodies targeting putative RA associated hyper-citrullinated autoantigens [vimentin, fibrinogen, histone 2A (H2A), histone 2B (H2B), and apolipoprotein A1 (Apo A1)] and their constitutively citrullinated forms.   Radiographic severity was defined as total Sharp/van der Heijde scores of hands/feet. Three negative binomial regression models of radiographic severity were fit: 1) conditional on sex, smoking, disease duration, BMI and ln(CCP), 2) Model 1 + each autoantibody, and 3) Model 2 without ln(CCP).  A highly conservative Bonferroni corrected alpha level of 0.005 for testing the autoantibodies was used.

Results:   Significant covariates from Model 1 included positive association of radiographic damage with disease duration and ln(CCP) (Table). In addition there was a weaker negative association of joint damage and body mass index (BMI).  Results for model 2 demonstrated significant associations of antibodies against native H2A, while antibodies against vimentin and histone 2B were nearly significant. There were no statistically significant associations between total radiographic score and antibodies to the hyper-citrullinated proteins. Results from Model 3 demonstrated that the associations between joint damage and the antibodies against native and hyper-citrullinated proteins were slightly stronger if anti-CCP antibodies were not taken into account.  The antibodies against native H2A, H2B, and vimentin remained statistically significantly associated with radiographic severity, but none of the antibodies against hyper-citrullinated proteins attained significance. 

Conclusion:  Autoantibodies against hyper- citrullinated proteins vimentin, fibrinogen, ApoA1, H2A and H2B were not associated with joint damage.   However, for African-Americans with established RA, antibodies to constitutively citrullinated proteins are most strongly associated with radiographic damage. 

Table.  Estimated parameters and negative binomial model fit statistics for the covariates and the natural logarithm of antibody concentrations given the covariates. 

Model 1
Variable	Estimate	p
Intercept	1.3	0.00073
Sex(Male)	0.19	0.39
Smoking(Never)	0.25	0.09
Disease duration	0.095	2.00E-16
BMI	-0.019	0.043
ln(CCP)	0.14	6.60E-07
Model 2
Constitutive	Estimate	p			Citrullinated			Estimate			p
Fibrinogen	0.29	0.082			Fibrinogen			-0.028			0.65
Vimentin	0.27	0.0067			Vimentin			0.014			0.77
Histone 2B	0.32	0.0073			Histone 2B			-0.079			0.17
Apolipoprotein A1	0.34	0.11			Apolipoprotein A1			0.022			0.71
Histone 2A	0.49	0.0018			Histone 2A			-0.085			0.11
Model 3
Constitutive	Estimate	p			Citrullinated			Estimate			p
Fibrinogen	0.37	0.029			Fibrinogen			0.07			0.2111
Vimentin	0.31	0.00256			Vimentin			0.087			0.033
Histone 2B	0.4	0.00057			Histone 2B			0.064			0.14
Apolipoprotein A1	0.44	0.042			Apolipoprotein A1			0.098			0.064
Histone 2A	0.58	0.00019			Histone 2A			0.051			0.2

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-relationship-between-anti-citrullinated-protein-antibodies-and-radiographic-damage-in-african-americans-with-rheumatoid-arthritis/