Faculty Bibliography

OBJECTIVE: To test the feasibility of applying a mimetic (specific for a patient-derived prothrombotic anticardiolipin antibody [aCL]) to study the homologous, disease-associated aCL in patients with antiphospholipid syndrome (APS). METHODS: We used the CL15 monoclonal aCL to screen 17 phage-display peptide libraries. Peptides (corresponding to recurrent peptide sequences) and their derivatives were synthesized and analyzed for binding to CL15 and for their abilities to inhibit CL15 from binding to cardiolipin. A peptide was chosen and used to study CL15-like IgG aCL in plasma samples from patients with APS, patients with systemic lupus erythematosus (SLE) but without APS, and normal healthy donors. RESULTS: Library screening with CL15 yielded 4 recurrent peptide sequences. Analyses of peptides showed that peptide CL154C reacted with antibody CL15 and inhibited binding of CL15 to cardiolipin, indicating that peptide CL154C may be a peptide mimetic for the CL15 aCL. Initial studies with plasma samples revealed that CL154C-reactive IgG was present (positivity defined as the mean + 3 SD optical density of the 25 normal controls) in 15 of 21 APS patients and 1 of 12 SLE patients. CONCLUSION: These findings suggest that it is feasible to develop a specific enzyme-linked immunosorbent assay for each immunologically and functionally distinct disease-associated aCL. Additional testing of CL154C with a larger number of APS patients and SLE patients, as well as identification of peptide mimetics for each distinct aCL, will reveal the diagnostic potential of CL154C and other mimetics in identifying patients with aCL who are at risk of developing life-threatening thrombosis

OBJECTIVE: To evaluate the safety and efficacy of a humanized monoclonal antibody against CD154 (IDEC-131) in patients with active systemic lupus erythematosus (SLE). METHODS: In this phase II, double-blind, placebo-controlled, multiple-center, multiple-dose study, 85 patients with mild-to-moderately active SLE were randomized to receive 6 infusions of IDEC-131, ranging from 2.5 mg/kg to 10.0 mg/kg, or placebo over 16 weeks. Efficacy was assessed at week 20, primarily by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and secondarily, by multiple measures of disease activity. Safety was assessed through week 28 by clinical and laboratory evaluation. Immunogenicity studies were also performed. RESULTS: SLEDAI scores improved from the baseline levels of disease activity in all groups, including the placebo group. However, these scores were not statistically different among the IDEC-131 treatment and placebo groups at week 20. Evaluations of secondary variables did not indicate significant differences between the IDEC-131 treatment and placebo groups. The type and frequency of adverse events were similar between the IDEC-131 and placebo groups. CONCLUSION: IDEC-131 administered at doses ranging 2.5-10.0 mg/kg over 16 weeks was safe and well tolerated in patients with SLE. Efficacy of the drug compared with placebo was not demonstrated. There were statistically significant improvements from baseline in all groups, including the placebo group

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.