The Safety of Estrogens in Lupus Erythematosus, National Assessment (SELENA) consists of two randomized double blind placebo-controlled equivalence trials. The first examines the effect of hormonal replacement therapy (HRT) on disease activity in postmenopausal women with SLE, the primary outcome being severe flare. Current enrollment is 314 patients and should reach the target of 350 by April 2001. The second trial, initiated in April 1997, examines the effect of oral contraceptive pills (OCP) on disease activity. To date, 159 subjects have been enrolled at an average rate of month. This application seeks an additional 5 years of enrollment for the OCP trial to achieve adequate power for assessing equivalence in severe flare rates across treatment arms; determining potential salutary effects of estrogens on two clinical concerns in SLE, osteoporosis and atherosclerosis; and studying two research themes often linked to estrogen use, autoimmunity and thrombosis. Three new investigations have been added to the proposal, each of which optimally utilizes the unique resources of this prospective clinical trial. These complementary projects have a dual purpose: to evaluate hormonal effects in vitro with respect to fundamental pathophysiologic questions, and to determine whether laboratory markers can be established to select subsets of patients who may either benefit from OCP or be at increased risk for exacerbation of 1upus or cardiovascular sequelae. Accordingly, 4 specific aims are proposed in this application.
Specific Aim 1 : To evaluate the safety of OCP by assessing whether the rates of severe flare in the OCP and placebo groups are clinically equivalent.
Specific Aim 2 : To assess protection from and risk of osteoporosis and atherosclerosis by pre- and post-study evaluation of DEXA scans, fasting lipids, fibrinogen, CRP, plasminogen activator inhibitor, homocysteine, lipoprotein(a), and carotid duplex.
Specific Aim 3 : To understand whether there is a change in B cell subsets in the peripheral blood of SLE patients receiving OCP; whether there are changes in expression of candidate autoimmunity genes in peripheral blood B cells (including SHP-1, VCAM-1, Bcl-2, and CD22); and whether there are changes in the number or phenotype of B cells spontaneously secreting anti-DNA antibody.
Specific Aim 4 : To address the hemostatic effects of estrogen (with focus on the protein S system) which may increase the risk for thrombosis even in patients screened out by virtue of high levels of anticardiolipin antibodies or a lupus anticoagulant. The SELENA-OCP trial offers the best (and perhaps only) opportunity to firmly answer the concerns of clinical safety and potential cardiovascular and skeletal efficacy of exogenous hormones in women with SLE. Moreover, this translational research trial, at least with regard to the estrogen and progesterone load imposed by OCP, will facilitate answers to the ever-pressing basic biologic issues of the effect of female hormones on autoimmunity and thrombosis.
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