Vitamin D and estrogen may provide the basis for a new generation of nonimmunosuppressive therapies for systemic lupus erythematosus, Dr. Betty Diamond predicted at a symposium sponsored by the American College of Rheumatology.
Presenting vitamin D to cultured SLE dendritic cells inhibits expression of interferon-inducible genes, decreasing the pro-immunogenic inflammatory cascade. Vitamin D also promotes expression of regulatory T cells, suppresses interleukin-12, and balances Th1 and Th2 T-cell responses.
Vitamin D deficiency is highly prevalent in patients with SLE, and serum vitamin D levels correlate inversely with SLE Disease Activity Index scores.
Dr. Diamond, head of the Center for Autoimmune Diseases at the Feinstein Institute for Medical Research, Manhassett, N.Y., and her coinvestigators are launching a clinical trial of vitamin D supplementation in patients with mild lupus. “I don't think vitamin D is going to change fulminant disease. It's not going to change fixed damage. It's not going to treat rip-roaring lupus nephritis or vasculitis or clots. But I think it may be able to prevent progression to lupus,” she said.
Turning to estrogen as a potential therapeutic target in SLE, Dr. Diamond said her interest was initially piqued by the epidemiology of the disease.
“The greatest risk factor for lupus is being female,” she said. And, “Before puberty the ratio of girls to boys who get lupus is about 3:1, after puberty it's 9:1, and after menopause it goes down to 2:1.”
In mouse models of lupus, physiologic titers of estradiol alter the B-cell repertoire by promoting rescue of pathogenic high-affinity DNA-reactive B cells while impairing maturation of low-affinity DNA-reactive B cells. This is accomplished through increased expression of B-cell activating factor. The high-affinity DNA-reactive B cells generate antibodies which form proinflammatory immune complexes, suggesting antiestrogenic therapies might reduce the risk of lupus in women in their reproductive years to a level comparable to that of prepubertal girls or postmenopausal women.
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