Neither Cell-Surface Nor Soluble CD154 Levels Are Associated with Coronary Artery Disease in Systemic Lupus Erythematosus
To the Editor:
Kiani and colleagues recently presented data suggesting that soluble CD154 in the blood is not associated with atherosclerosis in systemic lupus erythematosus (SLE)1. Although they referenced our earlier work in abstract form2, we also previously reported similar findings of a lack of association between soluble CD154 levels and subclinical atherosclerosis in another large cohort of patients with SLE3. In our study, subclinical atherosclerosis was measured as coronary artery calcification by electron beam computed tomography (EBCT). In our cohort, as in Kiani's, soluble CD154 was not associated with cardiovascular risk factors, including cholesterol level, homocysteine level, and hypertension. Additionally, it was not associated with high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), a disease activity index (SLEDAI), or a damage index (Systemic Lupus International Collaborating Clinics-DI) (p > 0.40 for all comparisons). Therefore, both studies suggest that soluble CD154 levels do not confer an independent risk for atherosclerosis seen in SLE.
We also now report a lack of a difference of surface CD154 expression levels on activated CD4 T cells from SLE patients with or without coronary artery disease. Although soluble CD154 levels may not compound the risk for atherosclerosis in SLE, it is possible that increased surface CD154 present on activated SLE CD4 T cells4,5 may participate. We investigated surface CD154 levels on activated CD4 T cells from SLE patients with and without coronary atherosclerosis.
Twenty patients with SLE were studied. Ten patients with evidence of atherosclerotic cardiovascular disease (ASCVD) as determined by coronary artery calcification with EBCT (Group I) were compared to 10 patients without evidence of ASCVD (Group II, SLE controls; Table 1). Peripheral blood samples were drawn, and CD4 T cells were isolated by negative selection6, with comparable percentages of CD4 T cells in both groups following isolation (Table 2). CD4 T cells were analyzed by flow cytometry immediately ex vivo and 5 and 20 hours after polyclonal activation in vitro, for cell-surface CD154 expression, as well as for CD25 and CD69 activation controls, as described7. There were no differences in CD154 expression between the 2 SLE cohorts at any of the timepoints examined before or after CD4 T cell activation (Table 2). Moreover, CD25 and CD69 levels were comparable, and only minimal CD69 levels ex vivo were statistically significantly different (Student t test) between the groups (Table 2). Thus, surface CD154 levels on freshly isolated peripheral blood CD4 T cells or cells activated ex vivo were unlikely to contribute to the differences seen in ASCVD in the 2 SLE cohorts.
Several recent studies including ours have begun to explore the risk factors involved in increased atherosclerosis in patients with SLE3,8,9. It is also clear that surface and soluble CD154 levels are increased in patients with SLE6. Moreover, it is now apparent that CD154 levels contribute to atherosclerosis and coronary artery disease in the general population10. Nevertheless, our results suggest that neither soluble CD1543 nor CD4 T cell surface levels of CD154 (Table 2) account for the differences seen among SLE patients with or without ASCVD. CD154 may still serve as an attractive target of therapy11, but it is unlikely that CD154 levels will help in risk assessment for atherosclerosis in patients with SLE.
JOAN M. VON FELDT, MD, Associate Professor of Medicine; SHERIF LATIF, MD; ANNA GENIN, MD, PhD, Rheumatology Division, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, RANDY Q. CRON, MD, PhD, Associate Professor of Pediatrics, University of Alabama, Birmingham, Alabama, USA. E-mail: email@example.com
2. Scalzi LV, Cron RQ, Von Feldt JM. Correlation of increased soluble CD40 ligand levels and coronary artery calcification in SLE patients [abstract]. Arthritis Rheum 2002;Suppl 49:S55.
3. Von Feldt JM, Scalzi LV, Cucchiara AJ, et al. Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus. Arthritis Rheum 2006;54:2220-7. [MEDLINE]
4. Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996;97:2063-73. [MEDLINE]
9. de Leeuw K, Freire B, Smit AJ, Bootsma H, Kallenberg CG, Bijl M. Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. Lupus 2006;15:675-82. [MEDLINE]