Associations of osteoprotegerin with coronary artery calcification among women with systemic lupus erythematosus and healthy controls.

Objective We tested the hypothesis that higher circulating levels of osteoprotegerin (OPG) are related to higher levels of coronary artery calcification (CAC) among women with systemic lupus erythematosus (SLE) compared with healthy controls (HCs). Methods Among 611 women in two age- and race-matched SLE case-control studies, OPG was assayed in stored blood samples (HEARTS: plasma, n cases/controls = 122/124, and SOLVABLE: serum, n cases/controls = 185/180) and CAC was measured by electron beam computed tomography. Results In both studies, SLE patients had higher OPG and CAC levels than HCs. Higher OPG was associated with high CAC (>100 vs.100) among SLE, and with any CAC (>0 vs. 0) among HCs. Multivariable-adjusted OR (95% CI) for OPG tertile 3 vs. 1 was 3.58 (1.19, 10.76), p trend = 0.01 for SLE, and 2.28 (1.06, 4.89), p trend = 0.04 for HCs. Associations were attenuated when age-adjusted, but remained significant for HC women aged ≥ 40 and SLE women aged ≥ 50. ROC analyses identified 4.60 pmol/l as the optimal OPG cutpoint for predicting high CAC (>100) among SLE patients with sensitivity = 0.74 and specificity = 0.61, overall, but 0.92 and 0.52, respectively, for SLE patients aged ≥ 50. Conclusion Our cross-sectional results suggest that higher OPG levels are related to higher CAC levels among women with SLE vs. healthy controls.

Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study.

Complement activation plays a key role in the pathogenesis of lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE). We prospectively evaluated 15 LN subjects and two control groups: 13 non-SLE renal subjects (control A) and 239 SLE subjects without LN (control B). All had C4d levels on circulating erythrocytes (E-C4d), reticulocytes (R-C4d) and platelets (P-C4d) measured by flow cytometry, while C4d deposition in renal tissue was semiquantitatively assessed in LN subjects and control A using immunoperoxidase staining. Compared with control A, LN biopsies had higher glomerular-C4d scores (p = 0.003), which were associated with more frequent granular glomerular immunofluorescence staining and electron dense deposits (p < 0.001). Compared with control A and B groups, LN subjects had higher E-C4d (p = 0.002 and p = 0.005) and R-C4d levels (p = 0.002 and p = 0.008), respectively. LN subjects were more likely to have P-C4d compared with control A (p = 0.016). In LN, only E-C4d correlated with National Institutes of Health (NIH) activity index (r = 0.55, p = 0.04). In conclusion, LN biopsies showed frequent glomerular-C4d staining associated with immune complex deposits. LN subjects had higher E-C4d and R-C4d levels compared with both control groups. E-C4d levels also correlated with NIH activity index. These findings suggest a potential role of C4d on circulating cells as a biomarker for lupus nephritis.

The BBZ/Wor rat: clinical characteristics of the diabetic syndrome.

The BBZ/Wor rat is a model of obesity and autoimmune diabetes mellitus developed by crossing the BB/Wor and Zucker rats. We studied circulating glucose and insulin levels, islet morphology and lymphocyte subsets in lean and obese BBZ/Wor rats before and after the onset of diabetes, and studied the clinical course of diabetes in animals after interruption of exogenous insulin therapy. Lean BBZ/Wor rats developed insulin-dependent diabetes and died in ketoacidosis within 1 week after cessation of insulin injections. Diabetes also developed in obese rats, but these animals were not insulin-dependent and survived for months without insulin therapy. The islets of the lean diabetic rats revealed complete destruction of pancreatic beta cells and plasma insulin levels were virtually undetectable. In contrast, the islets of the obese rats revealed insulitis and substantial beta-cell loss, however autoimmune beta-cell destruction was incomplete, and residual beta cells were presumably responsible for the presence of measurable levels of plasma insulin and the long-term survival of obese diabetics without insulin therapy. Obese rats were hyperinsulinaemic, developed diabetes significantly earlier, and with a greater incidence than lean rats, suggesting a possible relationship between enhanced beta-cell metabolic activity and immune destruction. Obese males became diabetic more frequently and at an earlier age than obese females and lean rats of both sexes, suggesting a role for gender in the pathogenesis of diabetes. We conclude that the BBZ/Wor rat is a unique animal model for investigating the interaction of obesity, beta-cell metabolism, autoimmune insulitis and genetic predisposition to diabetes.