Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein

Abstract

Objective Participants 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. Methods Subgroups 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 <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. Results Significant 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. Conclusions Pubertal 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.

The vascular phenotype of children with systemic lupus erythematosus

“…In contrast, our patients showed a greater prevalence of active LN. Secondary analysis of the data reported by Schanberg et al [22,24] showed that atorvastatin may slow the progression of cIMT thickening only in a subgroup of pubertal patients with higher high-sensitivity C-reactive protein [23]. In contrast to our findings, Boros et al [27] found an increase in PWV, but no increase in cIMT or flow-mediated dilatation, among a cohort of children with SLE.…”

“…Likewise, Ghosh et al observed increased fibromuscular dysplasia (FMD) and cIMT in 60 Indian patients with SLE who showed impaired FMD and abnormal IMT [48]. Our group has a greater proportion of African American patients than other paediatric studies [22][23][24][25][26][27], and this may have affected the results.…”

“…Despite the wealth of data available on CVD risk in adults with SLE, there is a dearth of information about CVD risk in children with juvenile-onset SLE (JSLE), and most of our knowledge is extrapolated from adult studies. Although childhood lupus is often a more aggressive disease than its adult form, the greater plasticity of children's vessels may protect them from vascular disease, making extrapolations from adult studies difficult; published studies [22][23][24][25][26][27] to date have reported conflicting results. The cross-sectional study reported here was designed to establish the baseline CV risk of a cohort of children with JSLE prior to subsequent longitudinal follow-up studies.…”

An update on childhood-onset systemic lupus erythematosus

“…Secondary analyses showed a trend in favor of atorvastatin for other CIMT endpoints. Post-hoc exploratory subgroup analyses showed a trend toward reduced CIMT progression in patients with high-sensitivity C-reactive protein (!1.5 mg/l) and in those who were postpubertal [18]. Results of these secondary and post-hoc analyses need to be taken cautiously as performing multiple comparisons increases the risk of type I error.…”

Limitations of Standard Immunosuppressive Treatment in ANCA-Associated Vasculitis and Lupus Nephritis

“…The data supporting the use of statins specifically in SLE are also scarce and controversial. On one hand, statin use had no effect on the progression of subclinical atherosclerosis (assessed as progression of carotid intima-media thickness) in an unselected group of pubertal SLE patients [73], but, on the other hand, atorvastatin was effective in a subgroup of patients with elevated CRP [74]. Interestingly, statin use was associated with a decrease of SLE activity, but statins had no effect on measured proinflammatory/prothrombotic biomarkers [75].…”