Effects of BAFF Neutralization on Atherosclerosis Associated With Systemic Lupus Erythematosus

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Abstract
Objective: Cardiovascular disease (CVD) is the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus, and anti‐BAFF therapy has been approved for use in SLE. Since mature B cells also promote atherosclerosis, we undertook this study to evaluate, in a mouse model and in SLE patients, whether BAFF neutralization has an atheroprotective effect in SLE.Methods: The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis/lupus‐prone apolipoprotein E–knockout D227K mouse model and in a cohort of SLE patients. Mice were treated with a blocking anti‐BAFF monoclonal antibody (mAb), while fed a standard chow diet. Carotid plaque and carotid intima‐media thickness were assessed by ultrasound at baseline and during follow‐up in SLE patients who were asymptomatic for CVD.Results: Anti‐BAFF mAb in ApoE−/− D227K mice induced B cell depletion, efficiently treated lupus, and improved atherosclerosis lesions (21% decrease; P = 0.007) in mice with low plasma cholesterol levels but worsened the lesions (17% increase; P = 0.06) in mice with high cholesterol levels. The atheroprotective effect of the BAFF–BAFF receptor signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF–TACI signaling inhibition on macrophages. In SLE patients, blood BAFF levels were associated with subclinical atherosclerosis (r = 0.26, P = 0.03). Anti‐BAFF mAb treatment had a differential effect on the intima‐media thickness progression in SLE patients depending on body mass index.Conclusion: Depending on the balance between lipid‐induced and B cell–induced proatherogenic conditions, anti‐BAFF could be detrimental or beneficial, respectively, to atherosclerosis development in SLE.

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