Jan. 20, 2012

First Ever Study of Cholesterol-Lowering Drugs in Children With Lupus

Use of atorvastatin in systemic lupus erythematosus in children and adolescents.
Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, Mieszkalski KL, Ilowite NT, Eberhard A, Imundo LF, Kimura Y, von Scheven E, Silverman E, Bowyer SL, Punaro L, Singer NG, Sherry DD, McCurdy D, Klein-Gitelman M, Wallace C, Silver R, Wagner-Weiner L, Higgins GC, Brunner HI, Jung L, Soep JB, Reed AM, Provenzale J, and Thompson SD; for the APPLE investigators.  Arthritis & Rheumatism. 2011 October 26. doi: 10.1002/art.30645. [Epub ahead of print].

What is the topic?

Improvements in the diagnosis and management of lupus in children have enhanced short-term prognosis. Thus, much of clinical research has become focused on improving long-term outcomes in children with lupus. Children with lupus often have more severe organ involvement, as well as longer exposure to lupus treatments. Accelerated atherosclerosis (hardening of the arteries) is a risk factor for cardiovascular disease and has emerged as a considerable complication of lupus among children and adolescents. 

Increased cholesterol circulating in the blood is a significant risk factor for the development of atherosclerosis. Statins, or cholesterol-lowering drugs, are effective in the treatment of atherosclerosis for both adults and children in the general population. However, the safety and effectiveness of statins have never been studied in children with lupus. If statins could be used safely and effectively in children with lupus, it may offer an additional preventative strategy and may improve long-term outcomes for these children. 

What did the researchers hope to learn?

The researchers hoped to learn about the safety and efficacy of atorvastatin (Lipitor®) in reducing subclinical atherosclerosis in children with lupus. 

Who was studied?

182 children with lupus participated in the study through one of the 21 sites of the Childhood Arthritis and Rheumatology Alliance (CARRA) network in North America between August 2003 and December 2009. 

Inclusion criteria were as follows: a) aged 10-21 years old at enrollment; b) diagnosis of lupus; c) > 25 kg weight; d) ability to complete a questionnaire in English or Spanish; and e) willingness to comply with the American Heart Association Therapeutic Lifestyle Changes diet and approved birth control methods. 

Exclusion criteria included the following: a) active nephritis; b) myositis (inflammation of the skeletal muscles); c) liver disease; d) kidney failure; e) high cholesterol (total cholesterol > 350 mg/dL); or f) current treatment with cyclophosphamide or tacrolimus (an immune-suppressing drug). 

How was the study conducted?

Children with lupus were randomized to receive either atorvastatin (10 mg) or placebo daily, in addition to their standard care. After a month, the dose of atorvastatin was increased to 20 mg for children weighing > 50 kg, and doses were adjusted according to weight throughout the three-year trail. Participating children received cardiovascular disease risk and dietary counseling upon entry to the study and then annually thereafter. The children were seen for study visits at one and three months after study entry, and then every three months thereafter. 

In order to facilitate measurement of the thickness of the carotid artery wall (an early indicator of cardiovascular disease), the children received a total of seven ultrasound scans at different times throughout the study period. Due to concerns that atorvastatin could impair brain development, the children were also subject to brain magnetic resonance imaging scanning at three times throughout the study period in a subset of participants. 

Blood assessments conducted at multiple times throughout the study period included measurement of lipids, homocysteine, lipoprotein A and B, and high-sensitivity c-reactive protein (hsCRP). Lupus disease activity, as well as lupus-mediated organ damage and quality of life, were assessed every three months using standard instruments (SELENA-SLEDAI and SDI, respectively). Assessments of pubertal development were conducted every three months. Adverse events and drug adherence were recorded throughout the study. 

What did the researchers find?

Children who participated in the study were mostly Caucasian girls who were an average age of 15 years old, and had lupus for an average of about three years. Children were distributed relatively evenly between atorvastatin and placebo groups according to family history of atherosclerosis and high levels of fat in the blood, as well as personal history of high blood pressure, total cholesterol, nephritis, levels of anti-double-stranded DNA and complement proteins, disease activity and organ damage. The children in the two groups were also taking similar drug regimens (within the previous 30 days), which included hydroxychloroquine, steroids, aspirin, and multi-vitamins. The atorvastatin group, however, included children that had higher levels of LDL cholesterol, higher body mass index, and higher levels of hsCRP.

The occurrence of adverse events did not differ significantly between the atorvastatin and placebo groups. These included infections, myositis, muscle and connective tissue disorders, as well as toxicity of the muscles, liver, or brain. Dropout rates and drug adherence rates were also similar between groups. 

The primary outcome measure of the study, the average increased thickness of the carotid artery wall (an early indicator of cardiovascular disease), did not differ significantly between the atorvastatin and placebo groups. However, atorvastatin reduced levels of LDL cholesterol, fat, and hsCRP in the blood of children with lupus. 

What were the limitations of the study?

Recruitment of appropriate children with lupus to the study was slower than expected, which resulted in a change of primary outcome measure of the study. Also, exclusion of patients having high lupus disease activity and/or damage, severely high cholesterol, kidney failure, or active kidney disease may have omitted participants most likely to benefit from atorvastatin drug therapy. In addition, this study included children varying in age from 10 to 21 years old. It is possible that inclusion of a more focused age distribution (such as post-pubertal children or young adults) could have resulted in more significant effects of atorvastatin therapy. 

What do the results means for you?

The results indicate that children with lupus can take atorvastatin safely for three years. This drug regimen can reduce high levels of blood cholesterol in these children. However, the current results indicate that the potential benefits of atorvastatin in children with lupus do not warrant its routine use in this population. Future studies using the same datasets may reveal sub-groups of children with lupus that are most likely to benefit from atorvastatin therapy.


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