Faculty Bibliography

The predictive value (PV) and association of 4 antiphospholipid antibodies with clinical manifestations of the antiphospholipid syndrome (APS) were evaluated in 90 patients with systemic lupus erythematosus (SLE) and 100 with APS. Patients with APS were classified into arterial thrombosis, venous thrombosis, and pregnancy morbidity subgroups. IgG, IgM, and IgA anticardiolipin (aCL), antiphosphatidylserine (aPS), anti-beta 2-glycoprotein I (anti-B2GPI), and antiprothrombin (aPT) antibodies were determined by enzyme-linked immunosorbent assay. Individually, anti-B2GPI and aPS antibodies had the strongest PV for APS (86.4%-94.1%; P < .001) in patients with SLE. The PV for APS reached 100% when 2 or more antibodies were present. Similarly, anti-B2GPI and aPS antibodies had a stronger PV and association for arterial thrombosis (87%-95%; P < .001) compared with venous thrombosis (80%-92%; P = .01). Weak PV and association with pregnancy morbidity were seen with all antibodies. These results suggest an important pathogenic role of anti-B2GPI antibodies in arterial thrombosis. In addition, anti-B2GPI and aPS antibodies seem to provide the best diagnostic value for the laboratory assessment of APS

Regulation of blood vessels is intrinsically tied to inflammatory signaling. Recent research suggests that chronic inflammation is associated with atherosclerosis risk. The antiphospholipid syndrome is a prototypic autoimmune disease. Disturbance of blood vessel homeostasis in this disorder may increase risk for atherosclerosis by mechanisms that are direct (through antibody targeting of blood vessel-regulating proteins) or indirect (via inflammatory mechanisms that have recently been implicated in autoantibody-mediated thrombosis)

Antibodies directed against protein S (anti-ProtS) may be involved in the development of thrombosis in patients with the antiphospholipid syndrome. We assessed the prevalence and clinical significance of anti-ProtS and evaluated their immunological characteristics in 184 patients with SLE and 99 healthy donors. All patients were tested for IgG anti-ProtS by an in-house ELISA. Plasma levels and functional activity of protein S were also tested. Anti-ProtS were found in 57 patients (31%) and 4 healthy controls (4%). Patients with thrombosis had anti-ProtS more frequently than controls (29% vs 4%, OR 9.5 [95% CI 3.07-29.3], p<0.0001). Anti-ProtS were more frequent in patients with venous thrombosis and in those with arterial thrombosis, than in controls (41% vs. 4%, OR 16.5 [95% CI 5-54], p<0.0001 and 23% vs. 4%, OR 7 [95%CI 2.1-23.5], p=0.0008, respectively). Patients with prematurity, preeclampsia and intrauterine growth restriction had anti-ProtS more frequently than the control group (36%, 47% and 44% vs. 4%; OR 13.6 [95% CI 2.8-66], p=0.003, OR 21 [95% CI 5-86], p<0.0001 and OR 19 [95% CI 4-99], p=0.0014, respectively). Plasma levels of free protein S were not statistically different between patients with and without anti-ProtS and controls (77.9% [20.7-100] vs. 83.7% [52.7-100] vs. 89% [62-101], respectively). Free protein S functional activity was no different between subgroups (105% [48-230] in anti-ProtS positive vs. 123% [95-283] in anti-ProtS negative vs. 136% [60-174] in controls). Anti-ProtS are frequent in SLE patients with thrombosis and pregnancy morbidity. These antibodies do not interfere with free protein S in plasma since its level and/or functional activity are not impaired

We recently reported [J. Lipid Res. 42 (2001), 697; 43 (2002), 1486; 44 (2003), 716] that [beta2-glycoprotein I (beta2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of beta2GPI/oxLDL complexes and IgG autoantibodies against beta2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The beta2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-beta2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with beta2GPI in SLE and APS patients. In contrast, anti-beta2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against beta2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS

Deficiency of the weak androgen dehydroepiandrosterone (DHEA) and its sulfoconjugated metabolite DHEA-S has been associated with a number of serious illnesses, including lupus, diabetes, Alzheimer's disease and some cancers. Accordingly, supplementation with DHEA has been proposed for a variety of illnesses. Observational clinical studies and in vitro experiments have suggested that DHEA treatment might have a significant impact on immunological function, bone density, cognition, atherosclerotic disease, some malignancies, insulin resistance and obesity. Endogenous circulating DHEA levels, however, may vary widely by gender, age and ethnicity and can be affected by acute changes in corticosteroid production, alcohol intake, smoking, body mass index, medications and thyroid function [1-3]. Clearly, these variables complicate the interpretation of clinical data. DHEA also gives rise to a number of as yet poorly characterised metabolites, further confusing the assessment of its net effects when considered as treatment in heterogenous populations. Given the complexity of potential effects of DHEA and its metabolites, coupled to the diversity of clinical conditions that they might, at least in theory, affect, it is not surprising that clinical confirmation of efficacy in several clinical contexts has been inconsistent and controversial, hampering drug development in what might potentially be an important and widespread market. The current review will consider recent work suggesting efficacy of DHEA (GL-701, prasterone, Prestara( trade mark ) [US], Anastar( trade mark ) [Europe]; Genelabs) in systemic lupus erythematosus