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In the last 20 years, the survival of children and adolescents with systemic lupus erythematosus (SLE) has increased substantially. Explanations for the improved prognosis include earlier diagnosis, enhanced recognition of milder forms, judicious use of treatments such as corticosteroids and immunosuppressive agents, and improved management of comorbidities associated with the disease. However, as a result of the prolonged life expectancy, patients with pediatric-onset SLE are now exposed to an increased risk of morbidity related to the sequelae of disease activity, side effects of medications, and comorbid conditions, such as recurrent infections, osteoporosis, hypertension, and accelerated atherosclerosis (1).

The risk of early atherosclerosis is a matter of growing concern to rheumatologists who care for adults or children with SLE (2). Patients with SLE are 5–8 times more likely to develop premature coronary heart disease compared with the general population. Furthermore, over the past 3 decades mortality in patients with SLE has decreased for all causes except cardiovascular disease. Atherosclerosis is known to begin in childhood, even in healthy populations. Hence, patients who are diagnosed as having SLE during childhood or adolescence are particularly susceptible to a long-term threat to their cardiovascular health, owing to their life-long burden of exposure to a multisystem inflammatory disease with a high atherogenic potential. Noticeably, increased rates of subclinical atherosclerosis, measured by noninvasive imaging techniques, such as carotid intima-media thickening (CIMT), flow-mediated brachial artery dilation, and myocardial perfusion, have been reported in patients with pediatric-onset SLE (3–5). In addition, dyslipidemia is found in 60–85% of these patients, a rate much higher than that in the general pediatric population.

These issues make the prevention of premature atherosclerosis and resulting long-term cardiovascular complications in children and adolescents with SLE a particularly attractive target for intervention. This objective can be pursued by addressing and treating any potentially modifiable risk factors beginning in the early stages of the illness. The potential benefit that may ensue to patient health is important, as it may result in a prolonged lifespan and improved quality of life over many decades.

Although cardiovascular risk factors have seldom been investigated specifically in pediatric-onset SLE, the pathogenesis of atherosclerosis in children and adolescents with SLE is probably multifactorial, as in adults. Proposed causes include traditional risk factors, such as obesity, smoking, glucose intolerance, and family history, treatment-related factors, such as steroid-induced hyperlipidemia, and other known risk factors, such as hypertension and nephrotic syndrome associated with lupus nephritis. In addition, other important pathophysiologic mechanisms exist in the SLE population. These disease-specific factors are not well defined and are likely to be intrinsic in the basic immunopathogenesis of SLE (e.g., arterial vasculitis, immune complex–mediated endothelial cell damage, antiphospholipid antibodies, and others), which makes SLE itself a potent, independent, cardiovascular risk factor.

Statins, which are widely used in adults who are at risk of atherosclerosis, have emerged as the most effective treatment for dyslipidemia and for prevention of coronary artery disease and stroke. Data from multiple large clinical trials suggest that lipid-lowering interventions with statins in the general population and in high-risk individuals, such as those who have suffered a myocardial infarction or have type 1 or type 2 diabetes mellitus or chronic renal failure, may be helpful not only for preventing the emergence of the atherosclerotic lesions, but also for actually reversing the process (6).

It appears that the marked cardiovascular improvements associated with statin use are not accounted for by their lipid-lowering effect alone (7). Indeed, these medications reduce the progression of atherosclerosis not only by reducing low-density lipoprotein (LDL) cholesterol, but also through pleiotropic antiinflammatory effects, including decreasing adhesion molecules, reducing tissue factor expression, reducing inflammatory cytokines, increasing fibrinolytic activity, and inhibiting expression of class II major histocompatibility complex antigens and costimulatory molecules by antigen-presenting cells. In addition, they may prevent endothelial cell activation induced by antiphospholipid antibodies. Because premature atherosclerosis in patients with SLE is associated with perturbation of many of the pathways that are affected by statins, these medications seem to be an ideal choice for preventative interventions.

Unexpectedly, however, a recent large study in patients with adult-onset SLE, the Lupus Atherosclerosis Prevention Study (LAPS), failed to show that statin therapy reduces subclinical measures of atherosclerosis (8). This 2-year, double-blind, placebo-controlled trial enrolled 200 patients without clinical cardiovascular disease who were randomized to receive atorvastatin 40 mg daily or placebo. Results showed no difference in either the primary outcome (coronary artery calcium) or secondary outcomes (CIMT and carotid plaque) between treatment groups. In addition, there was no reduction in high-sensitivity C-reactive protein (hsCRP) levels or any of the markers of endothelial activation. Notably, patients who took the active compound had more liver toxicities compared with those who received placebo.

Because children and adolescents with SLE have fewer comorbidities and traditional cardiovascular risk factors than adults with this disease, lipid abnormalities may be important targets of therapy to reduce the risk of premature atherosclerosis. However, until recently there were no data specifically related to the use of lipid-lowering medications in pediatric-onset SLE. Clinical trials of statins in the pediatric age group were limited to populations with homozygous and heterozygous familial hypercholesterolemia, in which statins were proven safe and effective. The gap was filled by Schanberg et al (9), whose article in this issue of Arthritis & Rheumatism presents the results of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, which was designed to assess whether 36 months of atorvastatin therapy in children and adolescents with SLE is effective and safe in reducing atherosclerotic progression, as measured by CIMT.

The APPLE trial is a multicenter, randomized double-blind, placebo-controlled clinical trial conducted at 21 pediatric rheumatology sites in North America, in which 221 children and adolescents with SLE (ages 10–21 years) were randomized to receive either atorvastatin (n = 113) or placebo (n = 108) at 10 or 20 mg/day, depending on weight, over a 3-year period. Patients who had active nephrotic syndrome, myositis, liver disease, renal insufficiency, or hypercholesterolemia or were receiving cyclosporine or tacrolimus were excluded. The primary end point was progression of mean-mean common CIMT, measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures as well as measures of SLE disease activity, organ system damage, and health-related quality of life, and laboratory parameters, including hsCRP and serum lipid levels. A clinically significant change in the primary end point was defined as a 0.0045 mm/year difference in the mean CIMT progression rates between the atorvastatin and placebo groups. This threshold was based on epidemiologic studies in adults, which showed a 41–47% increase in the risk of cardiovascular events for every 0.16–0.20 mm increase in CIMT. It was estimated that for a 15-year-old patient with SLE to achieve a 40% reduction in risk by age 50, a decrease in the CIMT progression rate of at least 0.0045 mm/year over 35 years (0.0045 mm/year × 35 years = 0.16 mm) would be required.

At 3 years, there was no difference in the progression of CIMT between the atorvastatin- and placebo-treated groups for either the primary outcome of mean-mean common IMT or the important secondary outcome of mean-max CIMT. In addition, the 95% confidence interval for the primary end point did not include the prespecified clinically relevant reduction of 0.0045 mm/year. In exploratory analyses adjusting for baseline confounders or covariates known to impact CIMT, the adjusted difference in mean-mean common CIMT progression rate remained nonsignificant, whereas the adjusted difference in mean-max CIMT progression rate was significant at P = 0.006. Although the results of other CIMT secondary end points demonstrated lower IMT progression rates in the atorvastatin group compared with the placebo group, none of the observed differences were statistically significant, except for that for mean-max internal CIMT. This was the only CIMT outcome where the estimated treatment effect exceeded the clinically relevant threshold of 0.0045 mm/year. These results led the authors to conclude that the observed effect of statin therapy on slowing CIMT progression was not large enough to warrant routine administration of statins to children and adolescents with SLE.

Several reasons may explain why the APPLE trial failed to achieve its primary efficacy end point. The lack of statistically significant results (in spite of a trend in the direction of a positive effect of treatment) could be due to the large proportion of subjects with poor adherence to study drug (which is common in this age group) coupled with a high dropout rate. Another possibility is that the medication dosage was insufficient. In the above-mentioned LAPS trial, adult patients with SLE were given atorvastatin at 40 mg daily, whereas in the APPLE trial patients weighing more than 50 kg (many of whom likely were the size of an adult) were given 20 mg daily. However, the most likely explanation could lie in the exclusion (due to safety concerns) of some subgroups of patients at highest risk of atherosclerotic disease, such as those with renal insufficiency or active nephrotic syndrome, or in the underrepresentation of African American patients, who tend to have greater disease severity. A previous study, which showed that the CIMT was increased in patients with pediatric-onset SLE compared with healthy controls, found that this difference was entirely dependent on the presence of nephrotic-range proteinuria, because the CIMT of patients without nephrotic-range proteinuria was comparable to that of healthy controls (3). In another study, in patients who were assessed at the time of diagnosis, prior to corticosteroid therapy, the presence of proteinuria was found to be the most important individual disease factor associated with an abnormal lipid profile (10).

The baseline patient features shown in Table 1 in the article by Schanberg et al (9) indicate that patients enrolled in the APPLE trial had, on average, mild-to-moderate disease. This is suggested by the mean SLE Disease Activity Index score of <5, the high mean value of serum complement fractions, the frequency of proteinuria of <30%, and the lack of damage in >70% of the patients. If patients with more active disease and higher damage indices had been included in the trial, a benefit from statin therapy might have been more likely to be observed. As pointed out by the authors, a study focused on an older population of postpubertal adolescents and young adults, who are at an age when normal age-related increases in CIMT begin to occur, may also have been more likely to demonstrate a significant response to statin therapy.

Nevertheless, although the primary efficacy end point was not reached, the APPLE trial provided some clinically important information. CIMT progression rates in all but one carotid segment were found to be higher in the placebo group than the rates previously reported for the general pediatric population as well as for children with familial hypercholesterolemia. Because the latter condition is known to be associated with premature atherosclerosis and cardiovascular morbidity and mortality, this finding corroborates the notion that subclinical atherosclerosis does begin early in pediatric-onset SLE. The atorvastatin group achieved significant reductions from baseline in total cholesterol, LDL, and hsCRP levels, and these reductions were maintained over time. These findings suggest that the medication achieved the expected lipid-lowering effects that are known to impact atherosclerosis risk and CIMT progression in other susceptible populations. Importantly, the APPLE trial showed that 3 years of statin therapy is safe in pediatric patients with SLE, with the rate of adverse events, namely, muscle, liver, and central nervous system toxicities, being comparable between treatment groups.

Although the APPLE trial did not find a positive effect of atorvastatin in pediatric SLE patients, it represents an important piece of work and offers valuable insights and information on a critical clinical issue. Intriguingly, although statistical significance was not reached, the results suggest a trend in the direction of a positive effect of treatment. 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. Thus, an important issue is to identify which patients with pediatric SLE would be most likely to benefit from receiving preventive treatment with statins. Useful answers may come from post hoc subgroup analyses of the APPLE trial, which are under way. Nevertheless, 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 of lipid-lowering agents.

On clinical grounds, the observation of a significant progression of all CIMT outcomes in the placebo group strengthens the view that subclinical atherosclerosis in SLE does begin in the pediatric age and 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. Unfortunately, as pointed out by Schanberg et al, a feasible and reliable measure of subclinical atherosclerosis is currently not available, and routine CIMT measurement cannot be recommended in standard clinical care.

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Dr. Ravelli drafted the article, revised it critically for important intellectual content, and approved the final version to be published.

REFERENCES

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