Serum sulfatide as a biomarker of carotid atherosclerosis in patients with rheumatoid arthritis

Purpose: Rheumatoid arthritis (RA) patients have accelerated atherosclerosis (AS) leading to excess cardiovascular morbidity and mortality, but traditional risk factors for cardiovascular disease (CVD) are invalid to explain the problem. Sulfatides, as major components of serum lipoproteins, are synthesized in the liver. These molecules are reported to play an important role in the development of AS, thrombogenesis, and inflammation. However, it is unclear whether sulfatides are responsible for such issue. To elucidate the possible association between serum sulfatide and the accelerated progress of AS, evaluated by carotid intima-media thickness (CIMT), and ascertain the related mechanism underlying the correlation in RA cases. Methods: We performed an observational study of 144 patients with RA and 120 sex and age-matched controls. Meanwhile, 107 patients (of the 144 RA patients enrolled at baseline) were invited to undergo a second measurement after 12 months. Serum sulfatide levels of all the enrolled subjects were quantified by mass spectrometry after they were converted into lysosulfatides (LS), and then calculated as the sum of the levels of seven LS molecular species. Serum oxidative stress marker, malondialdehyde (MDA) was detected by ELISA. We subsequently statistically analyzed the causalities between carotid AS and clinical parameters, and the association of serum sulfatide with other variables. Multivariable logistic regression analysis was finally employed by taking all factors to identify independent determinant for carotid atherosclerotic plaque and serum sulfatide level. Results: A gradual declined trend in serum sulfatide levels was observed in control subjects, non-plaque group, and the plaque group (8.56 +/- 1.37 nmol/mL, 5.63 +/- 1.57 nmol/mL, 3.18 +/- 1.32 nmol/mL, respectively, p < 0.01), along with an increased value of CIMT (0.63 +/- 0.07 mm, 0.92 +/- 0.14 mm, 1.43 +/- 0.22 mm, respectively, p < 0.01). Meanwhile, a negative linear correlation between CIMT and serum sulfatide was further confirmed by Spearman's analysis (r = -0.622, p < 0.01). Eventually, multivariate logistic regression analysis identified serum MDA as the only independent factor for the abnormal level of serum sulfatide, and serum sulfatide was detected as a significant protective factor for the occurrence of carotid plaques in RA cases (p < 0.01), which was confirmed repeatedly by our cross-sectional and longitudinal studies. Conclusion: Excessive abnormal levels of oxidative stress decreased serum sulfatide levels, followed by a high occurrence of AS in RA patients. Serum sulfatide level might be useful as a predictor (biomarker) for the progression of AS in RA cases.