Atorvastatin Failed to Slow Atherosclerosis in Pediatric Lupus

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APPLE May Help Target Subgroups

Although APPLE did not find atorvastatin to have any significant treatment benefit overall, it may identify subgroups who are more likely to benefit from statin therapy, Dr. Angelo Ravelli wrote in an accompanying editorial (Arthritis Rheum. 2012;64:33-6).

"Intriguingly, although statistical significance was not reached, the results suggest a trend in the direction of a positive effect of treatment," wrote Dr. Ravelli. "This observation, taken together with the average [low to moderate] level of disease activity in patients enrolled in the trial, indicates that statin therapy may not be necessary for every SLE patient, particularly those with less aggressive disease."

The key is to identify those patients who could reap the biggest benefit from treatment – a question that current post hoc analyses of APPLE may answer, he said.

Future studies "should assess the risk of early atherosclerosis and its progression by stratifying patients on the basis of the presence or absence of specific risk factors, such as family history of premature coronary heart disease, level of disease activity or severity, specific disease manifestations (namely, renal disease), burden of corticosteroid or immunosuppressive therapies, or sustained dyslipidemic state. These analyses may help select the patient subgroups that should be included in future clinical trials."

Dr. Angelo Ravelli

Until an appropriate subgroup may be identified, rheumatologists can still protect their young patients by helping them change those things that can be changed.

APPLE "underscores the importance of the routine identification and management of modifiable cardiovascular risk factors (dyslipidemia, hypertension, obesity, smoking, and low levels of physical exercise), an issue that is often neglected in pediatric rheumatology practice."

Dr. Ravelli is a pediatric rheumatologist at the University of Genoa (Italy). He did not disclose any financial conflicts of interest.



Atorvastatin did not confer any significantly lower progression of atherosclerosis in children and teens with systemic lupus erythematosus.

Although a 3-year course of the drug significantly improved lipid profiles, compared with placebo, it did not affect the mean progression of carotid intima media thickness, reported Dr. Laura E. Schanberg and colleagues in the January issue of Arthritis and Rheumatology (Arthritis Rheum 2012;64:285-96).

Dr. Laura E. Schanberg

"Collectively, these results suggest that the potential benefits of statin therapy for slowing carotid intima medial progression are not large enough to warrant routine use in children with systemic lupus erythematosus," wrote Dr. Schanberg, professor of pediatrics and co-chief of the division of pediatric rheumatology at Duke University, Durham, N.C.

The APPLE (Atherosclerosis Prevention in Pediatric Lupus) trial randomized 180 young patients with systemic lupus erythematosus (SLE) to 3 years of either atorvastatin or placebo. The primary outcome was a clinically meaningful reduction in mean-mean carotid intima medial thickness (CIMT). Secondary outcomes included changes in lipid profile, changes in mean-maximum CIMT, safety and tolerability, and the drug’s relationship to development of new white matter hyperintensities in the brain as seen on MRI.

The patients were a mean of 16 years old at the start of the study; their mean duration of disease was 31 months. The average Severity of Disease Index was 81.

In all, 113 patients were treated with atorvastatin at a dose of either 10 mg or 20 mg/day based on their weight. All patients received diet and exercise counseling.

At the end of 3 years, the mean-mean progression of CIMT was not significantly different between the active and placebo groups (0.0010 mm/year vs. 0.0024 mm/year). The relationship remained nonsignificant even after adjustment for multiple possibly confounding factors.

The placebo group did show significantly greater progression from baseline in every secondary CIMT end point. But only mean-maximum internal CIMT progression was significantly worse than the treated group. "This was the only CIMT outcome where the estimated treatment effect met or exceeded the prespecified definition of clinical significance (0.0045 mm/year)," the authors wrote.

Compared with the placebo group, the active treatment group also showed significant lessening of levels of total cholesterol, LDL cholesterol, and high-sensitivity C-reactive protein.

There were no concerning safety issues, the authors wrote. A subset of the entire group (24 treated and 20 placebo patients) underwent brain MRI. Three in the active group and two in the placebo group had developed new hyperintense lesions.

There were 17 pregnancies over the 3-year study period, with no significant between-group differences in outcome. Seven were live births, including one atorvastatin-exposed infant who died 2 hours after birth from birth defects consistent with methotrexate exposure.

The rest of the pregnancies ended in spontaneous abortion (5) and elective abortion (4). One pregnancy was lost to follow-up.

Although findings from APPLE do not point to a compelling reason to routinely prescribe atorvastatin to young SLE patients, they did suggest higher-than-expected CIMT progression rates in placebo-treated patients (from 0.0023 mm/year to 0.0144 mm/year). "These results underscore that subclinical atherosclerosis does indeed begin early in pediatric SLE, with CIMT progression rates comparable with those in children with familial hypercholesterolemia, a disease that is clearly associated with premature atherosclerosis and cardiovascular morbidity and mortality."

The study was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Schanberg reported receiving consulting fees from Pfizer, which also supplied the study drug. The coauthors reported multiple financial relationships, including relationships with Pfizer. Dr. Ravelli did not disclose any financial conflicts of interest.

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