Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE)

• Organ system damage as measured by modified SELENA-SLEDAI and SLICC-ACR Damage Index [ Time Frame: 36 months ] [ Designated as safety issue: No ]
• Health-related quality of life as measured by PedsQL [ Time Frame: 36 months ] [ Designated as safety issue: No ]
• Inflammatory mediators such as hs-CRP [ Time Frame: 36 months ] [ Designated as safety issue: No ]
• Other IMT measures of progression rate [ Time Frame: 36 months ] [ Designated as safety issue: No ]
• Serum lipid levels [ Time Frame: 36 months ] [ Designated as safety issue: No ]

High cholesterol levels are common in people with Systemic Lupus Erythematosus (SLE). Atorvastatin is a drug that reduces cholesterol levels. This study will test whether atorvastatin can reduce cholesterol levels in children with SLE.

Children and adolescents with SLE represent 15% of all SLE patients. Children with SLE suffer high morbidity that affects many organ systems, reduces their quality of life, and shortens their lifespan. As more children with SLE survive into adulthood, atherosclerotic cardiovascular disease has emerged as a major concern. SLE is a significant risk factor for myocardial infarction and death in young premenopausal women with SLE, even after controlling for traditional cardiovascular risk factors. Acceleration of atherogenesis in SLE most likely reflects SLE-associated vascular immune and inflammatory changes.

Although limited, the data on cardiovascular and lipid abnormalities in children with SLE implicate atherosclerosis as an important cause of long-term morbidity and mortality. The 3-hydroxy-3-methlglutaryl-coenzyme A (HMG CoA) reductase inhibitors, or statins, reduce mortality and morbidity from atherosclerosis in adults and have intrinsic anti-inflammatory and immune modulatory properties. These anti-inflammatory and immune modulatory activities may have particular benefit in the prevention and treatment of atherosclerosis in SLE. This trial will evaluate atorvastatin in children with SLE in the largest cohort of pediatric SLE patients ever studied prospectively.

Children in this study will be randomized to receive either atorvastatin or a placebo. All children will be followed for 3 years, during which they will have 15 study visits. Study visits will generally last 2 hours and will include medical interview, medication review and pill count, physical examination, and blood and urine tests. Cardiovascular-specific outcome measures will include assessments of high sensitivity CRP; fasting lipid profile; homocysteine level; apolipoprotein A, B1, and Lp(a); carotid intima media thickness (IMT); and tensor diffusion/MRI.

• Drug: Atorvastatin
  Participants weighing more 50 kg will receive 10 mg of atorvastatin po qd as a starting dose, which will be increased to 20 mg po qd at the Day 30 visit and continue through month 36. Participants weighing less than 50 kg will receive a maximum of 10 mg po qd for 36 months.
  Other Names:

  • Lipitor
  • Atorvastatin Calcium
• Drug: Placebo atorvastatin
  Participants weighing more 50 kg will receive 10 mg of placebo po qd as a starting dose, which will be increased to 20 mg po qd at the Day 30 visit and continue through month 36. Participants weighing less than 50 kg will receive a maximum of 10 mg po qd for 36 months.

• Experimental: 1
  Patients will be treated with dietary intervention (AHA Therapeutic Lifestyle Changes [TLC] diet, [http://www.nhlbi.nih.gov/cgi-bin/chd/step2intro.cgi]), cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin, a multivitamin containing folate, plus atorvastatin at 10 mg or 20 mg depending on the patient's weight. Patients weighing more than 50 kg will receive 10 mg qd atorvastatin for the first month, which will be increased to 20 mg qd at the Day 30 visit and continue through month 36. Participants weighing less than 50kg will receive a maximum of 10 mg po qd for 36 months.
  Intervention: Drug: Atorvastatin
• Placebo Comparator: 2
  Patients will be treated with dietary intervention (AHA Therapeutic Lifestyle Changes [TLC] diet, [http://www.nhlbi.nih.gov/cgi-bin/chd/step2intro.cgi]), cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin, a multivitamin containing folate, plus placebo at 10 mg or 20 mg depending on the patient's weight. Patients weighing more than 50 kg will receive 10 mg qd placebo for the first month, which will be increased to 20 mg qd at the Day 30 visit and continue through month 36. Participants weighing less than 50kg will receive a maximum of 10 mg po qd for 36 months.
  Intervention: Drug: Placebo atorvastatin

• 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 M, 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, Thompson SD; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. 2012 Jan;64(1):285-96.
• Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, Mieszkalski KL, Ilowite NT, Eberhard A, Levy DM, 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 A; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum. 2009 May;60(5):1496-507.

Inclusion Criteria:

• Meets American College of Rheumatology (ACR) revised diagnostic guidelines for SLE
• Weight of 25 kg (55 lbs) or more
• Outpatient
• Ability to complete self-report questionnaires in either English or Spanish
• Willingness to comply with recommended diet
• Acceptable methods of contraception

Exclusion Criteria:

• Drug-induced lupus
• Liver disease (ALT or aspartate aminotransferase greater than 2 X normal value)
• Myositis (CK greater than 3 X normal value)
• Inability to obtain adequate-quality IMT images
• Current use of oral or parenteral tacrolimus or cyclosporine
• Dialysis or serum creatinine reater than 2.5 mg/dL
• Active nephrotic syndrome (urinary protein greater than 3 g/24 h and serum albumin less than 2.3 g/dl)
• Total cholesterol greater than 350 mg/dL
• Xanthoma
• Familial hypercholesterolemia
• Pregnant or breastfeeding
• Use of estrogen-containing contraceptives (e.g., Lo-Ovral)
• Unable to adhere to study regimen
• Life-threatening non-SLE illness that would interfere with ability to complete the study
• Current drug or alcohol abuse
• Anticipated poor compliance
• Participation in another drug intervention study within 30 days of study enrollment