Faculty Bibliography

Blood vessel homeostasis involves a complex interplay between inflammatory signals, hormones, and other mediators. Recent research suggests that although atherosclerosis is primarily a problem of impaired lipid regulation, the very processes of cholesterol and triglyceride metabolism are intrinsically tied to inflammatory and hormonal regulatory signals. Similarities between inflammatory and endocrine disturbances in systemic lupus and the predicted consequences for vascular regulation help explain the high incidence of premature atherosclerosis in lupus. Atherosclerosis in systemic lupus, then, may be a consequence of imbalances in what are intrinsic homeostatic mechanisms, rather than a result of externally superimposed pathologic changes

OBJECTIVE: To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to < or = 7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid-dependent women with systemic lupus erythematosus (SLE). METHODS: In a double-blind, randomized trial, 191 female SLE patients receiving prednisone (10-30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7-9-months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (< or = 7.5 mg/day) was achieved for at least the last 2 months of the 7-9-month treatment period were classified as responders. RESULTS: Response rates were 41% in the placebo group, 44% in the 100-mg prasterone group, and 55% in the 200-mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100-mg group, and 45 in the 200-mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone. CONCLUSION: Among women with lupus disease activity, reducing the dosage of prednisone to < or = 7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo

Despite an active international effort to improve diagnosis and treatment of the antiphospholipid syndrome (Hughes syndrome), there remain problems of lack of standardization and lack of prospective and multivariate epidemiologic analysis which restrict the diagnostic and predictive ability of commercially available tests. Nevertheless, current published series provide some data from which strategic approaches can be used to maximize the efficiency and usefulness of available tests. For further updates on new research and developments of interest to physicians and patients with this syndrome, the following web sites may prove helpful: www.slrapls.org, www.hematology.org, www.acforum.org, www.americanheart.org, www.rarediseases.org, www.aarda.org, and www.lupus.org.

The antiphospholipid syndrome (APS) is characterized by unpredictable, sporadic, thrombotic events. The cause of the thrombosis is probably multifactorial and may involve disparate effects of the autoantibodies associated with the syndrome, which are known to interfere with various protein regulators of hemostasis. An integrated theory of pathogenesis that accounts for the diversity of autoantibodies and their effects suggests that cellular inflammation or apoptosis within the vasculature may lead to oxidation or turnover in phospholipid membranes. Thus, normally cryptic, functionally important epitopes of phospholipid-binding proteins are subjected to increased exposure to immune surveillance.

OBJECTIVE: To determine the frequencies at which either a valine or leucine occurs at position 247 in the beta2-glycoprotein I (beta2GPI) gene of normal individuals of the Caucasian, African American, and Asian ethnic groups and to compare these data with those in patients with the antiphospholipid syndrome (APS), with and without anti-beta2GPI antibodies. METHODS: The DNA segment containing the position-247 polymorphism was amplified by seminested polymerase chain reaction, and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 370 healthy controls of different racial backgrounds were analyzed, and the results were compared with those from 149 APS patients (66 primary; 83 secondary). Allele and genotype frequencies were compared using Fisher's exact test. When significant differences were detected, pairwise comparisons were made using Fisher's exact test with a Bonferroni adjustment. RESULTS: Allele and genotype expression was significantly different (P < 0.0001 for both) among the 3 races, with the V allele and the VV genotype occurring most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian APS patients than among controls (P = 0.0028 and P = 0.0023, respectively). No significant differences in allele or genotype frequencies were seen in comparisons of the Caucasian or the African American patients with appropriate controls. The differences in allele and genotype frequencies seen in the Asian APS patients were restricted to the anti-beta2GPI-positive patients (P = 0.0018 and P = 0.0005, respectively). CONCLUSION: In Asian patients with APS, expression of a V at position 247, especially in the homozygous state, is significantly associated with the presence of anti-beta2GPI antibodies and, therefore, can be viewed as a major risk factor in this ethnic group (odds ratio 9.19 and 16.33, respectively)