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(Circulation. 2004;109:2744-2748.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

CD4+CD28– T Lymphocytes Contribute to Early Atherosclerotic Damage in Rheumatoid Arthritis Patients

Roberto Gerli, MD; Giuseppe Schillaci, MD; Andrea Giordano, MD; Elena Bartoloni Bocci, MD; Onelia Bistoni, BiolSc; Gaetano Vaudo, MD; Simona Marchesi, MD; Matteo Pirro, MD; Federica Ragni, MD; Yehuda Shoenfeld, MD, FRCP; Elmo Mannarino, MD

From the Section of Internal Medicine and Oncological Sciences, Center for the Study of Rheumatic Diseases (R.G., A.G., E.B.B., O.B., F.R.), Section of Internal Medicine, Angiology, and Atherosclerosis Diseases (G.S., G.V., S.M., M.P., E.M.), Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy, and Department of Medicine B and Center for Autoimmune Diseases, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Israel (Y.S.).

Correspondence to R. Gerli, MD, Center for the Study of Rheumatic Diseases, Section of Internal Medicine and Oncological Sciences, Department of Clinical and Experimental Medicine, University of Perugia, Policlinico di Monteluce, I-06122 Perugia, Italy. E-mail gerlir{at}unipg.it

Received September 9, 2003; de novo received December 1, 2003; revision received March 4, 2004; accepted March 9, 2004.

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- 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- 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.

Key Words: arthritis, rheumatoid • cells • endothelium • vasodilation

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