Dysfunctional proinflammatory high‐density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus

Objective

Women with systemic lupus erythematosus (SLE) have an increased risk of atherosclerosis. Identification of at‐risk patients and the etiology underlying atherosclerosis in SLE remain elusive. The antioxidant capacity of normal high‐density lipoproteins (HDLs) is lost during inflammation, and these dysfunctional HDLs might predispose individuals to atherosclerosis. The aim of this study was to determine whether dysfunctional proinflammatory HDL (piHDL) is associated with subclinical atherosclerosis in SLE.

Methods

Carotid artery ultrasound was performed in 276 women with SLE to identify carotid plaques and measure intima‐media thickness (IMT). The antioxidant function of HDL was measured as the change in oxidation of low‐density lipoprotein after the addition of HDL cholesterol. Two antiinflammatory HDL components, paraoxonase 1 and apolipoprotein A‐I, were also measured.

Results

Among the SLE patients, 48.2% were determined to have piHDL on carotid ultrasound, while 86.7% of patients with plaque had piHDL compared with 40.7% of those without plaque (P < 0.001). Patients with piHDL also had a higher IMT (P < 0.001). After multivariate analysis, the only factors found to be significantly associated with plaque were the presence of piHDL (odds ratio [OR] 16.1, P < 0.001), older age (OR 1.2, P < 0.001), hypertension (OR 3.0, P = 0.04), dyslipidemia (OR 3.4, P = 0.04), and mixed racial background (OR 8.3, P = 0.04). Factors associated with IMT measurements in the highest quartile were the presence of piHDL (OR 2.5, P = 0.02), older age (OR 1.1, P < 0.001), a higher body mass index (OR 1.07, P = 0.04), a cumulative lifetime prednisone dose ≥20 gm (OR 2.9, P = 0.04), and African American race (OR 8.3, P = 0.001).

Conclusion

Dysfunctional piHDL greatly increases the risk of developing subclinical atherosclerosis in SLE. The presence of piHDL was associated with an increased prevalence of carotid plaque and with a higher IMT. Therefore, determination of piHDL may help identify patients at risk for atherosclerosis.

     

Antibodies to high‐density lipoprotein and β2‐glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome

Objective

To determine the prevalence of anti–high‐density lipoprotein (anti‐HDL) antibodies and to establish a possible relationship between anti‐HDL, anticardiolipin antibodies (aCL), anti–β₂‐glycoprotein I (anti‐β₂GPI), and paraoxonase (PON) activity in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS).

Methods

Thirty‐two patients with SLE and 36 with primary APS were enrolled in a cross‐sectional study. Twenty age‐ and sex‐matched healthy subjects were used as controls. Serum levels of IgG and IgM aCL, anti‐β₂GPI, and antiprothrombin antibodies and IgG anti‐HDL were measured by enzyme‐linked immunosorbent assay. Total cholesterol, HDL cholesterol, HDL₂, and HDL₃ were determined by standard enzymatic techniques. PON activity was assessed by quantification of nitrophenol formation, and total antioxidant capacity (TAC) by chemiluminescence.

Results

Levels of total HDL, HDL₂, and HDL₃ were reduced in patients with SLE compared with controls (mean ± SD 0.51 ± 0.3, 0.37 ± 0.3, and 0.14 ± 0.1 mmoles/liter, respectively, versus 1.42 ± 0.9, 1.01 ± 0.7, and 0.40 ± 0.2). Patients with SLE and primary APS had higher titers of anti‐HDL antibodies and lower PON activity than controls. In the SLE population, PON activity was inversely correlated with IgG anti‐HDL titers (r = −0.48, P = 0.005) whereas in the primary APS population, IgG anti‐β₂GPI was the only independent predictor of PON activity (r = −0.483, P = 0.003). In the SLE group, anti‐HDL was inversely correlated with TAC (r = −0.40, P < 0.02), and PON activity was positively correlated with TAC (r = 0.43, P < 0.02).

Conclusion

IgG anti‐HDL and IgG anti‐β₂GPI antibodies are associated with reduced PON activity in patients with SLE and primary APS. Since the physiologic role of PON is to prevent low‐density lipoprotein oxidation with its attendant atherogenic effects, the reported interactions may be relevant to the development of atherosclerosis in SLE and primary APS.

     

Elevated triglycerides and low levels of high‐density lipoprotein as markers of disease activity in association with up‐regulation of the tumor necrosis factor α/tumor necrosis factor receptor system in systemic lupus erythematosus

Objective

To investigate how blood lipid levels are related to disease activity, clinical characteristics, and serum levels of tumor necrosis factor α (TNFα) and its soluble type 1 and 2 receptors, sTNFR1 and sTNFR2, in systemic lupus erythematosus (SLE).

Methods

Fasting blood samples were obtained from an unselected cohort of SLE patients at Karolinska Hospital (n = 208, mean ± SD age 45.7 ± 14.2 years). Disease activity was estimated using the SLE Disease Activity Measure (SLAM). Levels of circulating TNFα, sTNFR1, and sTNFR2 were determined by enzyme‐linked immunosorbent assay. Blood lipid levels obtained after overnight fasting were analyzed by routine chemistry.

Results

Triglyceride (TG) levels were associated with the SLAM score (r = 0.48, P < 0.0001) and with the activities of TNFα (r = 0.29, P = 0.0001), sTNFR1 (r = 0.38, P < 0.0001), and sTNFR2 (r = 0.40, P < 0.0001). High‐density lipoprotein (HDL) levels were negatively associated with the SLAM score (r = −0.27, P = 0.0003) and with the activities of TNFα (r = −0.15, P = 0.04) and sTNFR2 (r = −0.19, P = 0.01). High levels of TGs, total cholesterol, TNFα, sTNFR1, and sTNFR2 all showed close correlations with the presence of nephritis and arterial disease (P < 0.05). In multiple logistic regression models, the TNFα activity and TG levels were independent determinants (P = 0.003 for both) of active disease (SLAM score ≥7).

Conclusion

Dyslipoproteinemia with high TG/low HDL levels correlates with disease activity in SLE, and enhanced activity in the TNFα/sTNFR system seems to be an important underlying factor. Both dyslipoproteinemia and enhanced activity of the TNFα system are closely related to cardiovascular and renal manifestations in SLE, and thus both may serve as markers of more severe disease.

     

Proinflammatory high‐density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis

Objective

Women with systemic lupus erythematosus (SLE) have a 7–50‐fold increased risk of coronary artery disease (CAD). In the general population, oxidized low‐density lipoprotein (ox‐LDL) increases the risk for CAD. Normal high‐density lipoproteins (HDLs) protect LDL from oxidation; proinflammatory HDLs do not. This study was undertaken to determine whether patients with SLE, who have chronic inflammation that causes oxidative damage, have more proinflammatory HDL and higher levels of ox‐LDL, thus predisposing them to atherosclerosis.

Methods

One hundred fifty‐four women with SLE, 48 women with rheumatoid arthritis (RA), and 72 healthy controls were studied. The ability of the patients' HDL to prevent oxidation of normal LDL was measured. Values >1.0 (the value assigned for LDL oxidation in the absence of HDL) after the addition of HDL indicated proinflammatory HDL. Plasma ox‐LDL levels were measured as the amount of oxidation produced by the patient's LDL after the removal of HDL.

Results

SLE patients had more proinflammatory HDL (mean ± SD score 1.02 ± 0.57, versus 0.68 ± 0.28 in controls [P < 0.0001] and 0.81 ± 0.22 in RA patients [P = 0.001 versus SLE patients]). A higher proportion of SLE patients had proinflammatory HDL: 44.7% of SLE patients versus 4.1% of controls and 20.1% of RA patients had scores >1.0 (P < 0.006 between all groups). Levels of ox‐LDL correlated with levels of proinflammatory HDL (r = 0.37, P < 0.001). SLE patients with CAD had significantly higher proinflammatory HDL scores than patients without CAD (P < 0.001).

Conclusion

HDLs are proinflammatory in a significant proportion of SLE patients and are associated with elevated levels of ox‐LDL. Abnormal HDLs impair the ability to prevent LDL oxidation and may predispose to atherosclerosis.

     

Lymphopenia is a risk factor in the progression of carotid intima‐media thickness in juvenile‐onset systemic lupus erythematosus

Objective

To characterize the atherosclerotic risk factors in the progression of subclinical atherosclerosis in patients with juvenile‐onset systemic lupus erythematosus (SLE).

Methods

This was a longitudinal study of 76 patients with juvenile‐onset SLE. Carotid arteries were evaluated using ultrasonography at baseline and at followup visits at 6‐month intervals over the 6‐year study period. Clinical and laboratory parameters, disease activity, treatment, and traditional risk factors for atherosclerosis were evaluated. Data were analyzed using generalized estimating equations.

Results

The mean ± SD age of the patients at baseline was 15.01 ± 3.48 years and the mean ± SD disease duration was 2.65 ± 2.5 years. The mean ± SD duration of followup was 3.74 ± 1.24 years. The mean ± SD intima‐media thickness (IMT) of the common carotid arteries differed significantly between the patient and control (n = 38) groups (0.63 ± 0.08 mm versus 0.54 ± 0.06 mm; P < 0.001). The presence of lymphopenia at diagnosis and at baseline and higher levels of serum creatinine and C‐reactive protein at baseline were positively associated with progression of carotid IMT (P = 0.006, P = 0.043, P = 0.037, and P = 0.049, respectively). In multivariate analysis, only lymphopenia at baseline and at diagnosis were consistently associated with progression of IMT (P = 0.012 and P = 0.045, respectively).

Conclusion

In patients with juvenile‐onset SLE, some nontraditional risk factors for the progression of subclinical atherosclerosis were identified. Lymphopenia was the only independent risk factor for the progression of IMT. The pathogenic mechanisms warrant further investigation.

     

Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric‐onset systemic lupus erythematosus

Objective

To characterize atherosclerotic risk factors and endothelial function in pediatric‐onset systemic lupus erythematosus (SLE).

Methods

Lipoproteins, oxidized state, and autoantibodies to oxidized low‐density lipoprotein (Ox‐LDL) were assessed. Endothelial function was evaluated using brachial artery reactivity.

Results

Thirty‐three SLE patients and 30 controls were studied. SLE subjects had significantly decreased mean high‐density lipoprotein (HDL) cholesterol (41 mg/dl versus 51 mg/dl; P = 0.002) and apolipoprotein A‐I (97 mg/dl versus 199 mg/dl; P = 0.0004). There was no difference between groups in markers of oxidized state (including nitric oxide metabolites, isoprostanes, and Ox‐LDL) or in endothelial function. However, SLE subjects had increased median anti‐Ox‐LDL IgG (2,480 relative light units [RLU] versus 1,567 RLU; P = 0.0007) and IgG immune complexes with LDL (4,222 RLU versus 2,868 RLU; P = 0.002).

Conclusion

Pediatric SLE patients had significantly decreased levels of HDL cholesterol and apolipoprotein A‐I and elevated titers of autoantibodies to Ox‐LDL. Despite these atherosclerotic risk factors, SLE patients had normal measures of oxidized state and endothelial function.

     

Rheumatologists' quality of care for lupus: Comparison study between a university and county hospital

Objective

Quality of care received from physicians may impact health outcomes in systemic lupus erythematosus (SLE). We compared physician quality of care (P‐QOC), health‐related quality of life (HRQOL), and disease activity and damage between SLE patients receiving outpatient care at a university and a county rheumatology clinic.

Methods

Forty‐two university and 41 county clinic SLE patients provided data on 5 P‐QOC parameters and HRQOL health outcomes (Short Form 36 [SF‐36] health survey and EuroQol 5‐domain instrument [EQ‐5D]). Disease activity and damage were measured. Chi‐square analysis and Student's t‐tests were used for comparisons.

Results

Overall satisfaction with medical care was similar; however, university patients had higher P‐QOC scores than county patients in “perception of doctor's understanding of impact of SLE on patient's life” (P = 0.02) and “providing education/educational information to understand their disease” (P = 0.05). HRQOL, disease activity, and damage were similar in the 2 groups. Overall satisfaction with medical care was directly related SF‐36 general health (r = 0.34, P = 0.03) and EQ‐5D visual analog scale on state of health (r = 0.39, P = 0.01), and inversely related EQ‐5D pain (r = ?0.37, P = 0.02).

Conclusion

Patient perceptions of P‐QOC differed across the 2 centers despite similar demographics, clinical and HRQOL outcomes, and significant overlap in the physicians serving each clinic. Patients' overall satisfaction with medical care is associated with better HRQOL.

     

Atherosclerosis in patients with biopsy‐proven giant cell arteritis

Objective

To examine the presence of atherosclerosis in a series of giant cell arteritis (GCA) patients attended to in a community hospital and to determine whether clinical features or steroid therapy might be associated with the development of atherosclerotic disease.

Methods

Forty consecutive patients diagnosed with biopsy‐proven GCA, periodically followed at the rheumatology outpatient clinic of Hospital Xeral‐Calde, Lugo (Spain), who had ended steroid therapy and had at least 3 years of followup were assessed for the presence of atherosclerosis by determination of the carotid intima‐media thickness (IMT) and carotid plaques using high‐resolution B‐mode ultrasound. Forty matched controls were also studied.

Results

GCA patients exhibited less carotid artery IMT than did matched controls (mean ± SD 1.01 ± 0.16 mm versus 1.13 ± 0.20 mm; P = 0.005; difference in means 0.12, 95% confidence interval 0.04–0.20). Patients who required steroid therapy for >2 years had greater mean ± SD carotid IMT (1.04 ± 0.17 mm versus 0.95 ± 0.15 mm) but the difference was not statistically significant (P = 0.10). A positive correlation between age at the time of the study and the carotid artery IMT in GCA patients was observed (r = 0.673, P < 0.001). However, adjusting for age, sex, and classic atherosclerosis risk factors, no significant correlation between carotid IMT and the routine laboratory markers of inflammation assessed at the time of disease diagnosis, disease duration, or cumulative prednisone dose was found.

Conclusion

The present study demonstrates that atherosclerotic macrovascular disease is not increased in patients with GCA.     

Anti–topoisomerase I (Anti–Scl‐70) antibodies in patients with systemic lupus erythematosus

Objective

To investigate the presence and clinical significance of anti–Scl‐70 antibodies in patients with systemic lupus erythematosus (SLE).

Methods

Levels of antibodies against Scl‐70 were determined by a commercial clinical enzyme‐linked immunosorbent assay (ELISA) during routine evaluation. Results were verified by an additional ELISA with a characterized bovine Scl‐70, by ELISA with a recombinant human topoisomerase I, by Western blot, and by double diffusion in agar gel. Disease activity was estimated retrospectively by the Systemic Lupus Activity Measure (SLAM).

Results

Of 128 consecutive SLE patients, 25% were positive for anti–Scl‐70 antibody; this antibody activity was cognate in nature. No SLE patient could be classified as also having systemic sclerosis. The levels of anti–Scl‐70 were significantly correlated with the SLAM score for the entire cohort (r = 0.563, P < 0.001) and for 7 individual patients with multiple longitudinal measurements (r = 0.755–0.951, P < 0.001; n = 6) (r = 0.378, P < 0.05; n = 1). A significant correlation was also found between the levels of anti–Scl‐70 and anti–double‐stranded DNA antibodies (r = 0.558, P < 0.001). Patients with anti–Scl‐70 had significantly higher risk of pulmonary hypertension (P < 0.01) and renal involvement (P < 0.001) than patients without this antibody.

Conclusion

Anti–Scl‐70 antibody is present in a significant subset of patients with SLE. For this subset, it offers a good correlate of disease activity and suggests increased risk for pulmonary hypertension and nephritis.

     

Using exercise training to counterbalance chronotropic incompetence and delayed heart rate recovery in systemic lupus erythematosus: A randomized trial

Objective

To evaluate the efficacy of a 3‐month exercise training program in counteracting the chronotropic incompetence and delayed heart rate recovery in patients with systemic lupus erythematosus (SLE).

Methods

A 12‐week randomized trial was conducted. Twenty‐four inactive SLE patients were randomly assigned into 2 groups: trained (T; n = 15, 3‐month exercise program) and nontrained (NT; n = 13). A sex‐, body mass index–, and age‐matched healthy control (C) group (n = 8) also underwent the exercise program. Subjects were assessed at baseline and at 12 weeks after training. Main measurements included the chronotropic reserve (CR) and the heart rate (HR) recovery (ΔHRR) as defined by the difference between HR at peak exercise and at both the first (ΔHRR1) and second (ΔHRR2) minutes after the exercise test.

Results

Neither the NT SLE patients nor the C group presented any change in the CR or in ΔHRR1 and ΔHRR2 (P > 0.05). The exercise training program was effective in promoting significant increases in CR (P = 0.007, effect size [ES] 1.15) and in ΔHRR1 and ΔHRR2 (P = 0.009, ES 1.12 and P = 0.002, ES 1.11, respectively) in the SLE T group when compared with the NT group. Moreover, the HR response in SLE patients after training achieved parameters comparable to the C group, as evidenced by the analysis of variance and by the Z score analysis (P > 0.05, T versus C). Systemic Lupus Erythematosus Disease Activity Index scores remained stable throughout the study.

Conclusion

A 3‐month exercise training program was safe and capable of reducing the chronotropic incompetence and the delayed ΔHRR observed in physically inactive SLE patients.     

Platelet‐activating factor–acetylhydrolase and other novel risk and protective factors for cardiovascular disease in systemic lupus erythematosus

Objective

There is an important inflammatory component to atherosclerosis and cardiovascular disease (CVD). It is therefore interesting that the risk of CVD is high in inflammatory diseases such as systemic lupus erythematosus (SLE). In this study, we investigated nontraditional risk factors for the development of CVD in patients with SLE.

Methods

Twenty‐six women (mean age 52 years) with SLE and a history of CVD were compared with 26 age‐matched women with SLE and no clinical manifestations of CVD (SLE controls) and 26 age‐matched healthy women (population controls). Serum levels of several novel nontraditional risk and protective factors were determined: heat‐shock protein (HSP)–related factors (Hsp60, Hsp70, anti–human Hsp60, anti–human Hsp70, and anti–mycobacterial Hsp65), platelet‐activating factor–acetylhydrolase (PAF‐AH) activity, secretory phospholipase A₂ GIIA (sPLA₂), and anti–endothelial cell antibody (AECA). The intima‐media thickness and the presence of plaques in the common carotid arteries were determined by B‐mode ultrasound as a surrogate measure of atherosclerosis.

Results

Levels of PAF‐AH, but not HSP‐related factors, AECA, or sPLA₂, were significantly increased in SLE cases. Only PAF‐AH discriminated between SLE cases and SLE controls (P = 0.005). PAF‐AH was significantly associated with low‐density lipoprotein (LDL) cholesterol and total cholesterol in the SLE cases (r = 0.50, P = 0.0093 and r = 0.54, P = 0.0045), but not in either control group.

Conclusion

The increased levels of PAF‐AH in SLE cases and the association between PAF‐AH and LDL cholesterol adds support to the notion that PAF‐AH may promote atherothrombosis in SLE. The role of HSPs in CVD is complex, since anti‐Hsp65 appears to be associated with the presence of CVD, whereas Hsp70 might protect against it. In this cross‐sectional study, levels of HSP‐related factors, AECA, and sPLA₂ were not associated with CVD in SLE.

     

Increased Insulin Resistance and Glucagon Levels in Mild/Inactive Systemic Lupus Erythematosus Patients Despite Normal Glucose Tolerance

Objective

To assess insulin sensitivity in patients with systemic lupus erythematosus (SLE) in response to a meal tolerance test (MTT).

Methods

In this cross‐sectional study, 33 adult females with mild/inactive SLE (SLE group) and 16 age‐ and body mass index–matched female healthy controls (CTRL group) underwent an MTT and were assessed for insulin sensitivity and beta cell function. Skeletal muscle protein expressions of total and membrane insulin‐dependent glucose transporter 4 (GLUT‐4) were also evaluated (SLE group: n = 10, CTRL group: n = 5); muscle biopsies were performed after MTT. Further measurements included inflammatory cytokines, adipocytokines, physical activity level, body composition, and food intake.

Results

SLE and CTRL groups showed similar fasting glucose, glucose response, and skeletal muscle GLUT‐4 translocation after MTT. However, the SLE group demonstrated higher fasting insulin levels (P = 0.01; effect size [ES] 1.2), homeostatic model assessment insulin resistance (IR) (P = 0.03; ES 1.1), insulin‐to‐glucose ratio response to MTT (P = 0.02; ES 1.2), fasting glucagon levels (P = 0.002; ES 2.7), glucagon response to MTT (P = 0.0001; ES 2.6), and a tendency toward lower Matsuda index of whole‐body insulin sensitivity (P = 0.06; ES ?0.5) when compared with the CTRL group. Fasting proinsulin‐to‐insulin ratio and proinsulin‐to‐insulin ratio response to MTT were similar between groups (P > 0.05), while the SLE group showed a higher insulinogenic index when compared with the CTRL group (P = 0.02; ES = 0.9).

Conclusion

We have identified that SLE patients had a bi‐hormone metabolic abnormality characterized by increased IR and hyperglucagonemia despite normal glucose tolerance and preserved beta cell function and skeletal muscle GLUT‐4 translocation. Strategies capable of ameliorating insulin sensitivity to reduce the risk of type 2 diabetes mellitus and cardiovascular disease in SLE may require more than targeting IR alone.

     

Significance of Chronic Tachycardia in Systemic Lupus Erythematosus

Objective

A significant subset of systemic lupus erythematosus (SLE) patients exhibit chronic tachycardia (CT) of unknown significance. We postulated that CT is a marker of lupus activity and severity.

Methods

A cross‐sectional database at the University of Chicago recorded disease activity, damage, disease manifestations, pain, anxiety, and physical function (PF). CT was defined as a heart rate of ≥95 beats per minute in at least 3 out of 4 sequential visits. Demographic, disease‐specific, and self‐reported symptoms were compared between groups with and without tachycardia.

Results

Of the 243 subjects analyzed, 14.8% had CT. On univariate analysis, CT was associated with younger age at the time of enrollment (P = 0.004), number of hospitalizations adjusted for years of SLE (P = 0.001), current prednisone dose (P < 0.0001), history of serositis (P = 0.03), anxiety score (P = 0.004), and poor PF (P = 0.0017). All domains of the Short Form 36 (SF‐36) health survey correlated strongly with CT, but on multivariate regression this correlation appeared to be driven by poor PF. On multivariate regression, the Systemic Lupus Erythematosus Disease Activity Index score (P = 0.03), younger age (P = 0.04), and poor PF by the SF‐36 domain (P = 0.006) were independently correlated with CT, and anxiety trait and hemoglobin both trended closely to significant association (P = 0.08 for both).

Conclusion

CT is prevalent in SLE and is a clinically relevant physical finding. It implies greater lupus activity and physical frailty. Univariate association with serositis raises the possibility of subclinical serositis or pancarditis. Further study to elucidate the cardiopulmonary status of SLE patients with unexplained CT is planned.     

Development and validation of a short form of the valued life activities disability questionnaire for rheumatoid arthritis

Objective

To develop and validate a shortened version of the Valued Life Activities disability and accommodations scale (VLA) for individuals with rheumatoid arthritis (RA).

Methods

To shorten the existing VLA measure, item response theory analyses were conducted using data from 449 patients with RA. Next, the resulting 14‐item shortened version of the VLA scale (S‐VLA) was evaluated by structured interviews among 20 RA patients. Lastly, the S‐VLA was administered to 150 RA patients along with other measures, including the Health Assessment Questionnaire (HAQ) and Short Form 36 (SF‐36). A random sample of 50 patients completed the S‐VLA 2 weeks later to assess reliability. Item statistics were calculated to evaluate correlations between individual items and the S‐VLA total score. Correlations between the S‐VLA and other measures were used to evaluate validity.

Results

Test–retest reliability was 0.91, while Cronbach's alpha for the S‐VLA was 0.95. None of the 14 items was associated with improved alpha coefficients when omitted. All of the items were strongly correlated with the S‐VLA total score. S‐VLA scores were highly positively correlated with the HAQ (r = 0.81, P ≤ 0.001), patient‐reported disease activity (r = 0.71, P ≤ 0.001), satisfaction with abilities (r = 0.82, P ≤ 0.001), and number of days with activity limitations (r = 0.65, P ≤ 0.001). In addition, as hypothesized, the S‐VLA was inversely correlated with the SF‐36 physical component summary score (r = ?0.78, P ≤ 0.001) and the physical functioning (r = ?0.80, P ≤ 0.001), role physical (r = ?0.67, P ≤ 0.001), and social functioning (r = ?0.72, P ≤ 0.001) subscales.

Conclusion

The S‐VLA is a short, valid, and reliable instrument that may prove useful for monitoring disability among individuals with RA.

     

Abnormal function of high‐density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis

Objective

To characterize the antiinflammatory function of high‐density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL‐associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL.

Methods

We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell‐free assay, and proinflammatory HDL was defined by an HDL inflammatory index ≥1. Plasma and HDL‐associated protein levels of apolipoprotein A‐I (Apo A‐I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme‐linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay.

Results

Age, disease activity, the presence of erosive disease, non‐Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A‐I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001).

Conclusion

Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality.

     

A phase II,randomized, double‐blind,placebo‐controlled,dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

Objective

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods

Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52‐week study. Coprimary end points were the percent change in the SELENA–SLEDAI score at week 24 and the time to first SLE flare.

Results

Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA–SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer ≥1:80 and/or anti–double‐stranded DNA [anti‐dsDNA] ≥30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA–SLEDAI score (?28.8% versus ?14.2%; P = 0.0435), physician's global assessment (?32.7% versus ?10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63–71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti‐dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion

Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

     

Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus

Objective

To examine the lifetime prevalence of mood and anxiety disorders in patients with systemic lupus erythematosus (SLE). Demographic and disease‐related variables were examined for association with lifetime major depressive disorder (MDD) and the presence of any mood or anxiety disorder.

Methods

Three hundred twenty‐six white women with SLE completed the Composite International Diagnostic Interview and the Systemic Lupus Activity Questionnaire, a self‐report measure of SLE disease activity. The binomial test was used to compare the prevalence of psychiatric diagnoses in patients with SLE with a population sample of white women.

Results

Sixty‐five percent of the participants received a lifetime mood or anxiety diagnosis. MDD (47%), specific phobia (24%), panic disorder (16%), obsessive‐compulsive disorder (9%), and bipolar I disorder (6%) were more common among patients with SLE than among other white women (P = 0.00009 for specific phobia; for all other values P = 0.00001). Although most patients with histories of mood disorders reported their psychiatric symptoms to a medical provider, a substantial number of patients with anxiety disorders did not. Self‐reported disease activity was associated with a lifetime history of MDD (P = 0.001) and presence of a mood or anxiety disorder (P = 0.001), after controlling for demographic and clinical characteristics.

Conclusion

Several mood and anxiety disorders were more common in women with SLE compared with the general population, and disease activity may contribute to this higher risk. Brief self‐report questionnaires may help providers identify patients with these conditions, particularly when patients are reluctant to disclose their symptoms.     

Exercise training in juvenile dermatomyositis

Objective

To investigate the effects of a supervised exercise training program on health parameters, physical capacity, and health‐related quality of life in patients with mild and chronic juvenile dermatomyositis (DM).

Methods

This was a prospective longitudinal study following 10 children with mild and chronic juvenile DM (disease duration >1 year). The exercise program consisted of twice‐a‐week aerobic and resistance training. At baseline and after the 12‐week intervention, we assessed muscle strength and function, aerobic conditioning, body composition, juvenile DM scores, and health‐related quality of life.

Results

Child self‐report and parent proxy‐report Pediatric Quality of Life Inventory scores were improved after the intervention (?40.3%; P = 0.001 and ?48.2%; P = 0.049, respectively). Importantly, after exercise, the Disease Activity Score was reduced (?26.9%; P = 0.026) and the Childhood Muscle Assessment Scale was improved (+2.5%; P = 0.009), whereas the Manual Muscle Test presented a trend toward statistical significance (+2.2%; P = 0.081). The peak oxygen consumption and time‐to‐exhaustion were increased by 13.3% (P = 0.001) and 18.2% (P = 0.003), respectively, whereas resting heart rate was decreased by 14.7% (P = 0.006), indicating important cardiovascular adaptations to the exercise program. Upper and lower extremity muscle strength and muscle function were also significantly improved after the exercise training (P < 0.05). Both the whole‐body and the lumbar spine bone mineral apparent density were significantly increased after training (1.44%; P = 0.044 and 2.85%; P = 0.008, respectively).

Conclusion

We showed for the first time that a 12‐week supervised exercise program is safe and can improve muscle strength and function, aerobic conditioning, bone mass, disease activity, and health‐related quality of life in patients with active and nonactive mild and chronic juvenile DM with near normal physical function and quality of life.

     

Anti‐C1q antibodies are associated with systemic lupus erythematosus global activity but not specifically with nephritis: A controlled study of 126 consecutive patients

Objective

Several studies have shown that anti‐C1q antibodies correlate with the occurrence and activity of nephritis in systemic lupus erythematosus (SLE). However, the significance of anti‐C1q antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti‐C1q antibodies and clinical and serologic parameters of SLE.

Methods

An enzyme‐linked immunosorbent assay kit was used to measure anti‐C1q antibodies in the sera of 126 consecutive patients with active SLE who were admitted to our university hospital from 2007 through 2009. Sera obtained from patients with high titers of anti‐C1q antibodies at the initial evaluation (n = 20) were reevaluated following treatment. Control sera were obtained from patients with other autoimmune diseases and from normal healthy control subjects (n = 20 in each group). Associations between anti‐C1q antibodies and clinical and serologic parameters of SLE were statistically analyzed.

Results

Anti‐C1q antibodies were detected in the sera of 79 of 126 patients with SLE. The prevalence and titers of anti‐C1q antibodies were significantly (P < 0.0001) higher in SLE patients than in patients with rheumatoid arthritis, patients with systemic sclerosis, and normal healthy control subjects. The prevalence and titers of anti‐C1q antibodies were not significantly associated with active lupus nephritis (P = 0.462 and P = 0.366, respectively). Anti‐C1q antibody titers were significantly correlated with SLE Disease Activity Index 2000 scores and the levels of anti–double‐stranded DNA antibodies, C3, C4, CH50, and C1q (P < 0.0001 for all comparisons). Moreover, anti‐C1q antibody titers significantly decreased as clinical disease was ameliorated following treatment (P = 0.00097).

Conclusion

These findings indicate that anti‐C1q antibodies are associated with SLE global activity but not specifically with active lupus nephritis.