The present study showed that dyslipidemia affected more than three-quarters of JIA patients, with predominance of borderline-low HDL-c based on classical lipid profile. Similar results were found in a retrospective study published by our research group[23]. We observed a higher frequency of increased LDL-c, NHDL-c and Apo B in the systemic subtype compared to the polyarticular subtype. Systemic-onset JIA and elevated ESR were associated with lower concentrations of Apo A-I, suggesting the involvement of the inflammatory process.
Studies evaluating non-classical biochemical markers related to lipid metabolism in children and adolescents with autoimmune rheumatic diseases are scarce [12, 22, 24–26].
The mechanisms involved in the pathogenesis of dyslipidemia and cardiovascular risk in patients with JIA have not yet been fully elucidated. Inflammation with endothelial dysfunction and increased levels of proinflammatory cytokines have been described [27]. In addition, inadequate food intake, physical inactivity, overweight and the use of certain medications, such as glucocorticoids, also aggravate dyslipidemia [28]. The use of glucocorticoids seems to play an important role in dyslipidemia, considering that, in our study, we observed an association between a higher cumulative dose and alterations in TC, LDL-c and NHDL-c.
In patients with rheumatoid arthritis, the prevalence of dyslipidemia varies between 55 and 65%[29]. In our sample, the prevalence was 82.3% when we considered changes in Apo A-I and Apo B. Although these apolipoproteins are considered good biomarkers for cardiovascular risk, several studies did not consider them in the evaluation of dyslipidemia [24, 30, 31].
Anthropometric markers of adiposity, such as BMI, waist circumference and intake of fats and carbohydrates, were normal for most patients. This fact could be explained by the role of the multi-professional team in our service and suggests important participation of the disease and its treatment in the pathogenesis of dyslipidemia.
Although glucocorticoids were used in only about 10% of our patients, we observed an association between the cumulative dose and dyslipidemia. Marangoni et al. reported a trend of association between glucocorticoid use and increased levels of LDL-c[30]. They also pointed out that the decrease in HDL-c level was not associated with the use of glucocorticoid medication. The progressively increasing use of synthetic DMARDs and biological agents minimizes the harmful effects of glucocorticoids on lipid metabolism [32].
We know that systemic-onset JIA is associated with greater laboratory and inflammatory alterations, such as anemia, increased platelet count and acute phase proteins and frequent use of corticosteroids. This explains the major changes in LDL-c, Apo B and NHDL-c found in our patients with this JIA subtype. In a longitudinal study, Yeh et al. evaluated the lipid profile and atherogenic index of JIA patients after treatment with etanercept and found higher concentrations of HDL-c and lower TG and TC/HDL in the group they called responders (with inactive disease) compared to non responders [33]. The non responder group, which basically consisted of patients with the systemic subtype, did not show improvement in the lipid profile. Other studies addressing dyslipidemia in JIA patients did not individualize the different subtypes and did not evaluate biomarkers such as Apo A-I and Apo B [24, 31].
Although an adequate HDL-c level was not associated with demographic and clinical characteristics, nutritional status or food intake, patients with an adequate HDL-c had a higher value and higher frequency of normal levels of Apo A-I. In the literature, it is well-established that adequate levels of HDL-c, due to its antioxidant (mainly by the presence of Apo A-I), anti-inflammatory, antiatherogenic, antithrombotic functions and cholesterol transportation, are related to a reduction in cardiovascular risk [34, 35]. However, it is worth mentioning that, in the presence of systemic inflammation, there may be a conversion of protective HDL-c to proinflammatory HDL-c, and the reduction in the production of Apo A-I is one of the proposed mechanisms of this transformation[34, 35].
Studies have shown an association between disease activity and dyslipidemia[33, 36]. Although we have a larger sample compared to other studies[33, 36], we found only a tendency towards an association between JIA activity and altered levels of Apo A-I, that is, patients with active disease had a higher frequency of reduction in Apo A-I than patients with inactive disease (in remission or not).
The decrease in Apo A-I level was more frequent in patients who did not use biological agents (83% versus 16%). This can be explained by the action of these agents inhibiting the production of cytokines and, consequently, inflammation, thus improving the lipid profile.
Rodriguez-Jimenez showed that tumor necrosis factor-α (TNF-α) is associated with increased cardiovascular risk, increased hepatic CRP synthesis and decreased HDL-c levels[37]. Under normal conditions, the major protein fraction of HDL is Apo A-I. However, the literature has shown that, in the presence of inflammation, mainly in increased interleukin-1 and TNF-α conditions, there is an increase in the production of serum amyloid A (SAA) by hepatocytes[38, 39]. This protein, on the other hand, has atherogenic action, and when released into the bloodstream rapidly, it associates with the third fraction of HDL (HDL3), decreasing serum concentrations of Apo A-I. A study in patients with JIA has shown that anti-TNF-α therapy alters the proatherogenic lipid profile of these patients [40].
Interestingly, a negative correlation between the ESR and Apo A-I concentration was observed. We did not find any studies in the literature in adults or children with chronic arthritis that correlated inflammatory markers with lipid biomarkers. Although other inflammatory markers, such as proinflammatory cytokines, have been described as being present in active JIA[41], studies show that a high ESR is a good parameter of disease activity [42], and when it is normal, it is one of the variables included in Wallace's inactivity criteria [15]. Based on this, our findings suggest that, in the presence of high disease activity and/or a high ESR, the investigation of lipid metabolism biomarkers should be expanded.
This study has some limitations, such as the absence of a control group and the lack of evaluation of the practice of physical activity by the patients. In addition, the sample size may have been insufficient to show significant differences between the various variables. However, this study is relevant and original because it is the first study on dyslipidemia showing differences between the JIA subtypes.