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ObjectiveParticipants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy.MethodsSubgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or ResultsSignificant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures.ConclusionsPubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy.ClinicalTrials.gov identifier:NCT00065806.

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 R2 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.

In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of0.05, were identified, and a number of noteworthy genes with FDR of0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Over the last 3 decades, lupus-related mortality has decreased in all categories except cardiovascular disease (1). The lack of improvement in cardiovascular morbidity and mortality in systemic lupus erythematosus (SLE) may reflect improved survival as patients with lupus now live long enough to develop cardiovascular disease; however, women under 40 years of age with SLE are at high risk of developing myocardial infarction (MI) with risks ranging up to 50 times higher than control populations (2). The unique convergence of immune and vascular pathology in SLE places young women at unusually high risk of cardiovascular disease (3)—a risk that is not well addressed by current treatment or prevention regimens. Atherosclerosis begins in childhood even in the absence of SLE. Autopsy studies of trauma victims commonly showed fatty streaks in the arteries of children (4). Children and adolescents with SLE are particularly at risk as they age given their life-long burden of exposure to multisystem inflammatory disease with high atherogenic potential. As a result, prevention of long-term cardiovascular complications in pediatric onset SLE presents a particularly attractive target for intervention with the possibility of significantly improving quality of life and increasing survival over many decades. Several investigators have demonstrated atherosclerotic heart disease in asymptomatic patients with SLE across the age range using noninvasive imaging techniques such as computerized tomography, carotid ultrasound and arterial flow-mediated dilatation (3, 5–8). These studies have identified a variety of factors contributing to the development of subclinical atherosclerosis, including traditional risk factors (obesity, smoking, glucose intolerance, family history), medications, hypertension, increased homocysteine levels, and renal disease (9, 10), but also indicate that important additional factors exist in this population. The identity of lupus-specific factors is not well defined but likely relates to the immune pathogenesis of SLE (6, 11), implicating SLE itself as a potent independent risk factor. Although few published studies specifically address cardiovascular risk factors in pediatric SLE, the pathogenesis of atherosclerosis in children and adolescents with SLE is likely multifactorial as in adults. Investigators have shown that nephrotic range proteinuria in children with SLE is associated with carotid intima media thickening (CIMT) (5). Since children and adolescents with SLE have fewer co-morbidities and traditional cardiovascular risk factors than adults with lupus, this population presents a unique opportunity to further understand the role of SLE in the pathogenesis of premature atherosclerosis. Currently there are no standard imaging procedures for assessment of preclinical atherosclerosis in young people; however, non-invasive techniques utilized in ongoing observational studies and clinical trials in a variety of disorders may result in clinically useful technology in the future. CIMT as measured by carotid ultrasound is a well studied surrogate marker of atherosclerosis which has been shown to predict cardiovascular events (strokes and myocardial infarction) (12). It has been used widely as an outcome measure in clinical trials including studies in children with increased risk of atherosclerosis due to familial hypercholesterolemia (13, 14). Although CIMT increases with age, the progression rate in healthy children and adolescents is negligible, 0.000 mm/year between 10–24 years of age in females and 10–19 years of age in males (15). In contrast, the progression rate as measured by CIMT in adult women with SLE is 0.004 mm/year (women 30 years of age) (Susan Manzi, personal communication) (16). Population studies show that increases in carotid wall thickening as small as 0.1 mm strongly correlate with increases in coronary and cerebral vascular events (17). The ongoing Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial is designed to prospectively assess the effect of atorvastatin on the progression of CIMT in children and young adults with SLE. While the final results of the APPLE Trial will not be available until 2010, the purpose of the current analysis is to investigate the association of traditional and non-traditional risk factors with a surrogate marker of early atherosclerosis (CIMT) in children and adolescents with SLE using APPLE baseline data.