Background— Peripheral blood expansion of an unusual CD4+ T-cell subset lacking surface CD28 has been suggested to predispose rheumatoid arthritis (RA) patients to develop more aggressive disease. However, the potential association between CD4+CD28 null T cells and early atherosclerotic changes in RA has never been investigated. Methods and Results— The number of circulating CD4+CD28 null cells was evaluated in 87 RA and 33 control subjects who also underwent evaluation of carotid artery intima-media thickness (IMT) and endothelial function via flow-mediated vasodilation (FMV). Patients had higher IMT and lower FMV compared with control subjects. The frequency of CD4+CD28 null cells was significantly higher in patients than in control subjects. Twenty patients with persistent expansion of circulating CD4+CD28 null cells had more marked increase of carotid artery IMT and stronger decrease of brachial artery FMV. Blockade of tumor necrosis factor-α led to a partial reappearance of the CD28 molecule on the CD4+ cell surface. Conclusions— Circulating CD4+CD28 null lymphocytes are increased in RA. Patients with persistent CD4+CD28 null cell expansion show preclinical atherosclerotic changes, including arterial endothelial dysfunction and carotid artery wall thickening, more significantly than patients without expansion. These findings suggest a contribution of this cell subset in atheroma development in RA. Moreover, the demonstration that tumor necrosis factor-α blockade is able to reverse, at least in part, the CD28 deficiency on the CD4+ cell surface may be of interest for possible innovative therapeutic strategies in cardiovascular diseases.

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Objective. Systemic lupus erythematosus and rheumatoid arthritis represent independent risk factors for atherosclerosis (ATS), although this may be confounded by continuous pharmacologic treatment. Primary Sjögren's syndrome (SS) shares several features of these diseases and may therefore represent an interesting model for verifying the presence of accelerated ATS in the absence of pharmacologic interference. The present study therefore used this model to describe the presence of accelerated ATS in a group of young women.Methods. Thirty-seven untreated white women with primary SS were evaluated clinically and serologically. Carotid and femoral artery intima-media thickness (IMT) was evaluated in the patients and in 35 age-matched healthy women who served as controls.Results. The patients had a higher IMT than did the controls at both the carotid (mean ؎ SD 0.82 ؎ 0.24 mm versus 0.63 ؎ 0.20 mm; P < 0.001) and the femoral (0.81 ؎ 0.26 mm versus 0.67 ؎ 0.23 mm; P < 0.019) levels, and had a higher prevalence of carotid intimamedia thickening (49% versus 11% of controls; P < 0.001). The patient subset with high carotid IMT showed an increased prevalence of leukopenia and circulating anti-SSA antibodies; interestingly, the number of leukocytes was inversely correlated with the level of arterial IMT in patients with SS. Multivariate analysis demonstrated that anti-SSA antibodies were independent predictors of carotid artery thickening, while leukopenia was a predictor of both carotid and femoral artery thickening.Conclusion. Subclinical ATS was evident in about one-half of the patients with SS.