Cross-sectional characteristics of pediatric-onset discoid lupus erythematosus: Results of a multicenter, retrospective cohort study.

BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.

Bone turnover markers in relation to vitamin D status and disease activity in adults with systemic lupus erythematosus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have altered bone metabolism and are at risk of osteoporosis. The aim of this study was to examine bone turnover markers in relation to vitamin D, disease activity, and clinical risk factors in patients with established SLE. METHODS: Clinical registry and biorepository data of 42 SLE patients were assessed. Serum samples were analyzed for osteocalcin as a marker of bone formation, C-terminal telopeptide of type 1 collagen (CTX) as a marker for bone resorption, and 25-hydroxy vitamin D. RESULTS: Patients with a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI) score of 3 or greater had a lower median osteocalcin level ( P = 0.02) and lower 25-hydroxy vitamin D levels ( P = 0.03) than those with a score of less than 3. No significant differences in bone turnover markers were observed between patients dichotomized into subgroups using a 25-hydroxy vitamin D cut-off of 30 ng/mL or by a daily prednisone dose greater than or 5 mg or less. Osteocalcin levels were negatively correlated with SLEDAI scores ( P = 0.034), and were positively correlated with the CTX index (a ratio of measured CTX value to the upper limit of the normal value for age and gender) ( P < 0.01). No association between the CTX index and SLEDAI scores was found. CONCLUSION: SLE disease activity may have direct effects on bone formation, but no effects on bone resorption in this cohort of established SLE patients, probably related to the inflammation-suppressing effects of glucocorticoids, thereby inhibiting cytokine-induced osteoclast activity. A fine balance exists between disease control and the use of glucocorticoids with regard to bone health.

Screening for cognitive impairment in SLE using the Self-Administered Gerocognitive Exam.

Objective Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can affect the central nervous system in multiple ways, including causing cognitive dysfunction. Cognitive dysfunction is a common complaint of SLE patients yet diagnosis is challenging, time consuming, and costly. This study evaluated the Self-Administered Gerocognitive Exam (SAGE) as a screening test for cognitive impairment in a cohort of SLE patients. Methods A total of 118 SLE patients completed the SAGE. Providers completed the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI). SAGE scores were grouped into normal (>16) and abnormal (≤16) categories. Univariate and multivariate analyses were performed. Results Of the 118 participants, 21(18%) scored ≤16 on the SAGE instrument. In univariate analysis, race, ethnicity, household income, and SLICC-DI scores were associated with the SAGE ( p < 0.05). In multivariable analysis, abnormal SAGE score was independently associated with higher SLICC-DI score (odds ratio (OR) = 1.44, 95% confidence intervals 1.04-1.99, p = 0.03)), Hispanic ethnicity (OR = 43.4, 95% CI 3.1-601, p = 0.005), and lower household income (OR = 11.9 for ≤$15,000 vs >$50,000, 95% CI 2.45-57, p = 0.002). Conclusions In SLE patients, this study demonstrates an independent relationship between neurocognitive impairment (as measured by the SAGE) and higher lupus-related damage, as measured by the SLICC-DI, and lower household income. Abnormal SAGE scores were also associated with Hispanic ethnicity. A language barrier could explain this because the SAGE instrument was conducted in English only. The SAGE was feasible to measure in the clinic setting.

Prospective validation of a novel renal activity index of lupus nephritis.

Objectives The renal activity index for lupus (RAIL) score was developed in children with lupus nephritis as a weighted sum of six urine biomarkers (UBMs) (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1) measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with lupus nephritis. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL UBMs. Using receiver operating characteristic curve analysis, we evaluated the accuracy of the RAIL to discriminate high lupus nephritis activity status (National Institutes of Health activity index (NIH-AI) score >10), from low/moderate lupus nephritis activity status (NIH-AI score ≤10). Results In this mixed racial cohort, high lupus nephritis activity was present in 15 patients (19%), and 71% had proliferative lupus nephritis. Use of the identical RAIL algorithm developed in children resulted in only fair prediction of lupus nephritis activity status of adults (area under the receiver operating characteristic curve (AUC) 0.62). Alternative weightings of the six RAIL UBMs as suggested by logistic regression yielded excellent accuracy to predict lupus nephritis activity status (AUC 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL UBMs provide excellent prediction of lupus nephritis activity in adults. Age adaption of the RAIL is warranted to optimize its discriminative validity to predict high lupus nephritis activity status non-invasively.

Factors associated with thrombosis in pediatric patients with systemic lupus erythematosus.

OBJECTIVE: The risk of thrombosis is increased in patients with systemic lupus erythematosus (SLE). Few studies have assessed factors associated with thrombosis within the pediatric SLE (pSLE) population. We sought to better characterize these associated factors in pSLE patients using the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry. METHODS: Within the CARRA registry, patients with a history of thrombosis were compared to those without. Univariate logistic regression was used to calculate odds ratios. A multivariable logistic regression model was conducted that included variables from the univariate analysis that had a p value < 0.10 and other variables identified as clinically significant from published literature. RESULTS: Among the 979 pSLE patients in the CARRA registry, 24 (2.5%) patients had a history of arterial thrombosis and 35 (3.6%) of venous thrombosis. In the univariate analysis, the odds ratio of having a thrombotic event were found to be significantly higher in patients with a history of vasculitis, avascular necrosis (AVN), or antiphospholipid antibody (aPL). Similar results were found for vasculitis, AVN, and aPL in the multivariable analysis. CONCLUSION: Our study of pSLE patients suggests that vasculitis, positive APL, and AVN are associated with thrombotic events in this population.

Juvenile idiopathic arthritis and future risk for cardiovascular disease: a multicenter study.

OBJECTIVES: To evaluate the frequency of cardiovascular disease (CVD) and CVD risk factor development in adult patients previously diagnosed with juvenile idiopathic arthritis (JIA). METHOD: A cohort study was conducted utilizing patients at two academic institutions (cohorts 1 and 2). Each institution evaluated the common endpoint of CVD outcomes and CVD risk factor development in adults aged ≥ 30 years and at the 29-year follow-up from disease onset in cohorts 1 and 2, respectively, with comparison to control groups of similar age and sex. RESULTS: Cohort 1 included 41 patients with JIA and follow-up ≥ 30 years of age with comparison to 41 controls. Three patients (7%) had CVD, compared to one control (2%; p = 0.31). Cohort 2 included 170 patients with JIA and a median of 29 years of follow-up from disease onset with comparison to 91 controls. Two patients (2%) had CVD, compared to none of the controls (p = 0.29). The presence of CVD risk factors was found to be increased in the JIA group compared to the controls in three categories: family history of CVD (cohort 1), hypertension (cohort 2), and ever smokers (cohorts 2). CONCLUSIONS: There is no increase in CVD events in patients with JIA 29 years following disease onset when compared to the general population. As these cohorts age, it will be informative to evaluate whether this baseline risk remains present or a trend towards increasing CVD emerges. Continued longitudinal follow-up of these cohorts and larger population-based studies are needed to establish a definitive relationship between JIA and CVD.

Use of atorvastatin in systemic lupus erythematosus in children and adolescents.

OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Testing the ability of children with attention deficit hyperactivity disorder to accurately report the effects of medication on their behavior.

Children with attention deficit hyperactivity disorder (ADHD) are often treated with central nervous system stimulants, making the evaluation of medication effects an important topic for applied behavior analysts. Because assessment protocols emphasize informant reports and direct observations of child behavior, little is known about the extent to which children themselves can accurately report medication effects. Double-blind placebo-controlled procedures were used to examine whether 6 children with ADHD could recognize the effects of their medication. The children were given math worksheets to complete for 15 min during each of 14 sessions while on medication and placebo. Children completed a self-evaluation form at the end of each session, and ratings were compared to observed behavior and academic performance. Results indicated that 3 children were able to accurately report their medication status at levels greater than chance, whereas the accuracy of reports by all children was related to dosage level, differences in behavior, and the presence of adverse effects. The implications of these results for placebo-controlled research, self-monitoring of dosage levels, and accuracy training are discussed.

The role of microparticles in inflammation and thrombosis.

Microparticles (MP) are small membrane-bound vesicles that circulate in the peripheral blood and play active roles in thrombosis, inflammation and vascular reactivity. While MP can be released from nearly every cell type, most investigation has focused on MP of platelet, leucocyte and endothelial cell origin. Cells can release MP during activation or death. Flow cytometry is the usual method to quantify MP; the small size of these structures and lack of standardization in methodology complicate measurement. As MP contain surface and cytoplasmic contents of the parent cells and bear phosphatidylserine, antibodies to specific cell surface markers and annexin V can be used for identification. Through various mechanisms, MP participate in haemostasis and have procoagulant potential in disease. MP contribute to inflammation via their influence on cell-cell interactions and cytokine release, and MP also function in mediating vascular tone. In several disease states characterized by inflammation and vascular dysfunction, MP subpopulations are elevated, correlate with clinical events, and may have important roles in pathogenesis. In the rheumatic conditions such as rheumatoid arthritis and systemic lupus erythematosus, MP are potentially important markers of disease activity and have an increasingly recognized role in immunopathogenesis. It is clear that MP play an important role in atherosclerosis, and study of these structures may provide insight into the link between chronic inflammatory conditions and accelerated atherosclerosis. As biomarkers, MP allow access to usually inaccessible tissues such as the endothelium. Further research will hopefully lead to interventions targeting MP release and function.

Management of dyslipidemia in children and adolescents with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an independent risk factor for atherosclerosis, placing children and adolescents with SLE at great risk for developing cardiovascular sequelae, including myocardial infarction, in adulthood. Dyslipidemia and other traditional cardiac risk factors occur frequently in pediatric SLE and are often under-recognized and under-treated. Two dyslipidemia patterns are evident in pediatric SLE. Active disease is characterized by elevated triglycerides (TG) and low high density lipoprotein (HDL). With SLE treatment HDL and TG often normalize, while total cholesterol and low density lipoprotein (LDL) rise. The complex pathophysiology of dyslipidemia in SLE involves cytokines, autoantibodies, disease activity, medications, diet, and physical activity level, as well as other factors. Routine screening for dyslipidemia with fasting lipid profiles is indicated for children and adolescents with SLE. If lipoprotein levels are abnormal, first line therapy involves diet and exercise interventions for a minimum of six months. For persistent dyslipidemia, several pharmacologic therapies are available. Hydroxychloroquine, a common treatment for SLE, can improve lipid profiles and should be considered for all patients with SLE. Statins and bile acid sequestrants are typically added first for dyslipidemia, while niacin and fibrates are reserved for refractory disease and optimally prescribed in a multidisciplinary lipid clinic. Future research is needed to further illuminate the mechanisms of dyslipidemia in pediatric SLE with well designed clinical trials to determine the safest and most effective interventions to correct lipid profiles and prevent atherosclerosis.