Juvenile myositis is frequently associated with insulin resistance and hyperlipidemia(2
). Similar to previous reports, we showed that these metabolic abnormalities, although characteristic of LD, are present in patients with JDM even in the absence of LD (2
). This study also highlights the increased prevalence of the metabolic syndrome in JDM. However, this finding needs to be placed in perspective. The usefulness of metabolic syndrome definitions in childhood for the prediction of future cardiovascular disease remains controversial (22
). In addition, our relatively small sample size and the fact that this is a referral population may contribute to an overestimate of the prevalence of the metabolic syndrome in this disorder. The patients included in this study, for example, had a chronic or polycyclic course of illness and these findings may not be relevant to patients with milder disease, such as those who achieve remission and are able to discontinue medications.
Half of the patients studied had hyperlipidemia, which is consistent with reports of dyslipoproteinemias in JDM, as well as in adult and pediatric SLE (1
). Longitudinal studies in SLE show two lipid patterns. The first pattern, associated with active disease, is characterized by low HDL and Apo A-1 and high VLDL and triglyceride levels, similar to that seen in the metabolic syndrome (23
). The second, thought to be corticosteroid induced, is associated with high total cholesterol, VLDL and triglycerides (24
). HDL levels are thought to represent a balance between active disease (which depresses HDL) and corticosteroid use (which elevates HDL). Thus, our findings of a significant correlation of HDL with CMAS and a significant inverse correlation with AST are consistent with an inverse relationship of HDL with active myositis. Our results are similar to those of Huemer et al. who also found inverse correlations of HDL with transaminases and von Willebrand factor VIII related antigen and a direct correlation of triglycerides with ALT (2
). It is possible that the trend in our cohort toward low HDL, high total cholesterol and triglycerides and LDL is the result of a complex interplay of disease activity, insulin resistance and chronic prednisone usage. Consideration should also be given to the potential contribution of hydroxychloroquine use, as it may decrease total cholesterol, LDL, and triglycerides in patients receiving corticosteroids. Longitudinal evaluation of a larger cohort would enable greater clarification of these factors.
Multiple separate validated measures (HOMA, G:I ratio, ISI0,120,
/HOMA-IR) demonstrated that this cohort had impaired glucose regulation. These measures have well-established limitations, including their inability to account for hepatic glucose production (25
). Although our study lacked a control group, our results are consistent with the increased prevalence of insulin resistance seen in JDM (2
), rheumatoid arthritis, and adult (26
) and pediatric SLE (1
). Also, a hereditary component appears to contribute to alterations in glucose metabolism as evidenced by the greater fasting insulin and HOMA values in patients with a family history of diabetes.
In addition to glucocorticoids, which can induce insulin resistance (27
), the chronic inflammation present in rheumatic diseases may have resulted in findings of heightened insulin resistance (29
). This concept of inflammation causing insulin resistance is also supported in our study by the strong correlations of glucose with the pro-inflammatory cytokines IL-2 and IL-12, and inverse correlations with the anti-inflammatory cytokines IL-10 and IL-1RA (35
). Our finding of a positive correlation of IL-2 with markers of insulin resistance is mirrored by similar findings in patients with rheumatoid arthritis (30
). We did not find significant correlations between these indicators and IL-6 or TNF-α; however, these cytokines have been reported to be elevated in diabetic and insulin resistant states and in patients with JDM with a chronic illness course (29
). The inverse correlation of glucose metabolism indices with cytokines with anti-inflammatory effects such as IL-1 RA and IL-10 is consistent with current literature on cytokines in insulin resistance (32
). It should be noted that cytokine levels were not analyzed in all patients and although our results are consistent with previous findings, the small sample size limits their interpretability.
We also found correlations of glucose/insulin variables with MRI muscle atrophy and fatty infiltration. Since insulin mediated glucose disposal occurs principally in skeletal muscle and fatty acid in muscle modulates insulin action (33
), it is feasible that skeletal muscle inflammation and/or fibrosis may contribute further to glucose and insulin dysregulation. A potential mechanism may include an insulin receptor metabolic defect in affected muscle, as seen in myotonic dystrophy, which is also associated with insulin resistance (34
Medications are potential confounders of our results. We likely did not find significant correlations of glucose abnormalities with prednisone dose or duration due to the overall low dose (range 0.08–1.10 mg/kg/day). These doses in children have the potential to contribute to the underlying insulin resistance. Despite previous work suggesting that hydroxychloroquine may be protective against abnormal glucose metabolism and hyperlipidemia in SLE, type II diabetes and RA (35
), we did not find differences in these measures based on administration of hydroxychloroquine. However, our study was underpowered to detect such differences.
Our study and others (2
) indicate that metabolic abnormalities are frequent in patients with juvenile myositis, with a high frequency of the metabolic syndrome that could predispose to early cardiovascular disease. Our study, however, is limited primarily to a population of patients with severe, chronically active disease. The chronic inflammatory state of juvenile myositis, muscle damage, as well as long term high dose corticosteroid therapy, appear to contribute to an increased cardiovascular risk. Importantly, although atherosclerotic complications generally do not emerge until adulthood, the atherosclerotic process begins in childhood. Thus, interventions directed at reducing or preventing atherosclerosis should also begin in childhood. There are only four reports characterizing asymptomatic atherosclerosis in pediatric patients with rheumatic disease. Pachman reported premature carotid artery disease in young adults with JDM (37
). Reports in pediatric SLE revealed significantly increased carotid artery intima-media thickness (38
) and significant myocardial perfusion abnormalities on thallium scanning (39
), while a third report failed to show abnormalities in endothelial function (40
Limitations of this study include potential confounding of prednisone dosage and duration, use of a single blood pressure measurement rather than the average of two readings, and the study population, which is a small referral population that may be biased towards more severe underlying disease. We did not use the euglycemic insulin clamp study to determine insulin resistance. We did not include measurements of the waist: hip ratio for several reasons, including the confounding effects of corticosteroid therapy which can increase central obesity and the controversial utility of waist: hip ratio in childhood (22
Close attention should be paid to monitoring blood pressure according to age and sex norms. The systolic blood pressure was >90th percentile in half of the cohort. It is important to note that a cursory review of the blood pressure readings appear normal (the mean systolic blood pressure was 117 mm Hg, while mean diastolic blood pressure was 66 mm Hg), whereas quite a few were abnormal based on age-, height- and sex defined normal limits. Blood pressure elevation in juvenile myositis may be related to small vessel vasculopathy, corticosteroid use with consequent weight gain, as well as sodium and water retention.
Metabolic abnormalities and cardiovascular risk factors were common in this juvenile myositis cohort. These appear to be related to underlying myositis disease activity, muscle damage and cytokine release. Our findings point to a need for risk factor evaluation and modification in this population.