Frequency of fractures in women with systemic lupus erythematosus: comparison with United States population data.

OBJECTIVE: To describe the frequency of self-reported fractures in a large population-based cohort of women with lupus, to compare the frequency of self-reported fractures between lupus patients and women of similar age in the general population by use of data from the 1994 National Health Interview Survey (NHIS), and to describe the associated risk factors for fracture in women with lupus. This study is a secondary analysis of data collected to assess cardiovascular risk in women with lupus. METHODS: Fractures and associated risk factors were ascertained by self report in this retrospective cohort study of 702 living women with lupus who were followed up for 5,951 person-years. Self-reported fractures were verified in a subset of patients. A Weibull regression model was used to assess risk factors associated with time from lupus diagnosis to fracture in the univariate and multivariate analyses. Age-specific standard morbidity ratios (SMRs) were calculated to determine whether fracture occurrence was greater than expected in women with lupus. RESULTS: Eighty-six (12.3%) of 702 women reported at least 1 fracture following the diagnosis of lupus. The sites of the first fracture were the leg (n = 32), foot (n = 16), arm (n = 15), spine (n = 9), rib (n = 7), hip (n = 2), pelvis (n = 2), hand (n = 1), shoulder (n = 1), and finger (n = 1). Fracture risk was increased in the lupus cohort compared with women of similar age from the United States population, using weighted data from the 1994 NHIS (SMR 4.7; 95% confidence interval 3.8, 5.8). Variables in the univariate analysis that were significantly associated (P < 0.05) with time from lupus diagnosis to fracture were older age at lupus diagnosis, longer disease duration, longer duration of corticosteroid use, less use of oral contraceptives, and menopause status. In the multivariate analysis, independent determinants of time from lupus diagnosis to fracture were older age at lupus diagnosis and longer duration of corticosteroid use. CONCLUSION: Fractures occurred in 12.3% of lupus patients who were followed up for 5,951 person-years. There was nearly a 5-fold increase in fracture occurrence in the women with lupus compared with women from the US population. Older age at lupus diagnosis and longer use of corticosteroids were associated with time from lupus diagnosis to fracture. With increased life expectancy of lupus patients, fracture occurrence is a major threat to the health of these women. Prevention strategies must be directed toward minimizing the occurrence of fractures in these patients.

Recombinant human Dnase I (rhDNase) in patients with lupus nephritis.

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 microg/kg rhDNase (n = 8); (2) 125 microg/kg rhDNase (n=6); or (3) placebo (n = 3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre- and post-treatment were studied for immune complex deposition by immunofluorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 microg/kg, but not after SC administration at either dose. A t 1/2 of 3-4h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre- and post-treatment] for the 25 microg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 microg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.

Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of carotid atherosclerosis and associated risk factors in women with systemic lupus erythematosus (SLE). METHODS: Carotid plaque and intima-media wall thickness (IMT) were measured by B-mode ultrasound in women with SLE. Risk factors associated with carotid plaque and IMT were determined at the time of the ultrasound scan and included traditional cardiovascular risk factors, SLE-specific variables, and inflammation markers. RESULTS: The 175 women with SLE were predominantly white (87%), with a mean age of 44.9 years (SD 11.5). Twenty-six women (15%) had a previous arterial event (10 coronary [myocardial infarction or angina], 11 cerebrovascular [stroke or transient ischemic attack], and 5 both). The mean +/- SD IMT was 0.71 +/- 0.14 mm, and 70 women (40%) had focal plaque. Variables significantly associated with focal plaque (P < 0.05) included age, duration of lupus, systolic, diastolic, and pulse pressure, body mass index, menopausal status, levels of total and low-density lipoprotein (LDL) cholesterol, fibrinogen and C-reactive protein levels, SLE-related disease damage according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index (modified to exclude cardiovascular parameters), and disease activity as determined by the Systemic Lupus Activity Measure. Women with longer duration of prednisone use and a higher cumulative dose of prednisone as well as those with prior coronary events were more likely to have plaque. In logistic regression models, independent determinants of plaque (P < 0.05) were older age, higher systolic blood pressure, higher levels of LDL cholesterol, prolonged treatment with prednisone, and a previous coronary event. Older age, a previous coronary event, and elevated systolic blood pressure were independently associated with increased severity of plaque (P < 0.01). Older age, elevated pulse pressure, a previous coronary event, and a higher SLICC disease damage score were independently related to increased IMT (P < 0.05). CONCLUSION: B-mode ultrasound provides a useful noninvasive technique to assess atherosclerosis in women with SLE who are at high risk for cardiovascular disease. Potentially modifiable risk factors were found to be associated with the vascular disease detected using this method.

Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.

The authors ascertained cardiovascular events (myocardial infarction and angina pectoris) in 498 women with systemic lupus erythematosus seen at the University of Pittsburgh Medical Center from 1980 to 1993 (3,522 person-years). Subjects were stratified by age, and cardiovascular event incidence rates were determined. The authors compared these rates with cardiovascular event rates were determined. The authors compared these rates with cardiovascular event rates occurring over the same time period in 2,208 women of similar age participating in the Framingham Offspring Study (17,519 person-years). Age-specific rate ratios were computed to determine whether the cardiovascular events in the lupus cohort were greater than expected. The risk factors associated with cardiovascular events in women with lupus were determined. There were 33 first events (11 myocardial infarction, 10 angina pectoris, and 12 both angina pectoris and myocardial infarction) after the diagnosis of lupus: two thirds were under the age of 55 years at the time of event. Women with lupus in the 35- to 44-year age group were over 50 times more likely to have a myocardial infarction than were women of similar age in the Framingham Offspring Study (rate ratio = 52.43, 95% confidence interval 21.6-98.5). Older age at lupus diagnosis, longer lupus disease duration, longer duration of corticosteroid use, hypercholesterolemia, and postmenopausal status were more common in the women with lupus who had a cardiovascular event than in those who did not have an event. Premature cardiovascular disease is much more common in young premenopausal women with lupus than in a population sample. With the increased life expectancy of lupus patients due to improved therapy, cardiovascular disease has emerged as a significant threat to the health of these women. The impact of this problem has been underrecognized, with little focus placed on aggressive management of hypercholesterolemia and other possible risk factors.

Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity.

OBJECTIVE: To determine if measurement of serum complement split products (C4d, Bb, C5b-9) is better than conventional C3 and C4 measurements in distinguishing patients with varying degrees of lupus disease activity, and to determine if the presence of C3d in urine is helpful in distinguishing lupus patients with from those without early lupus nephritis. METHODS: Lupus disease activity was prospectively determined at 3 consecutive visits an average of 4 months apart, using the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and physician global assessment (PGA). Blood samples were evaluated for the presence of C4d, Bb, and C5b-9 by quantitative microassay plate enzyme immunoassay at each patient visit. We characterized urinary excretion of C3 fragments (with attention to C3d) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western blotting. RESULTS: Thirty-one SLE patients were enrolled in the study. The mean SLAM score and the mean SLEDAI score each correlated well with the PGA at all 3 visits. A SLAM score of 6 and a SLEDAI score of 4 had the best overall sensitivity and specificity for predicting moderate-to-severe disease activity by PGA (100% and 73%, respectively, for the SLAM and 86% and 94%, respectively, for the SLEDAI). Serum C4d and Bb were more sensitive indicators of current moderate-to-severe lupus disease activity at all 3 visits than were serum C5b-9, C3, and C4. C3 and C4 were more specific indicators of moderate-to-severe disease activity. Serum C4d and Bb were more sensitive at predicting moderate-to-severe disease activity at subsequent visits than were C5b-9, C3, and C4. Urine C3d was better than C3, plasma C4d, Bb, C5b-9 and anti-double-stranded DNA antibody in distinguishing patients with from those without acute lupus nephritis (P = 0.02). CONCLUSION: C4d and Bb are sensitive indicators of moderate-to-severe lupus disease activity and may be most helpful in situations where conventional measurements are not, such as in lupus patients whose C3 and C4 levels remain normal despite evidence of clinical disease activity. It appears from this study that detection of urine C3d may be a simple way of measuring complement activation in the setting of lupus renal disease. The availability of instruments for clinical disease activity measurement such as the SLAM and the SLEDAI may enable more consistent definition of lupus disease activity and may thus provide a means for better examining the role of complement activation products in predicting lupus disease activity in larger patient populations.