Adipose tissue inflammation is associated with insulin resistance and lower production of adiponectin. Wasko et al. found that HCQ improves both beta-cell function and insulin sensitivity in healthy subjects . HCQ significantly increased adiponectin levels, indicating a possible anti-inflammatory effect in adipose tissue. Adiponectin has been shown to influence insulin sensitivity [24–26], and the mechanism by which HCQ affects insulin sensitivity is thought to be via the modulation of adipose tissue inflammation and adiponectin production [27–29].
In patients with SLE, increased serum adiponectin, leptin and resistin levels have been reported compared with healthy subjects [30–34], but several reports showed no difference. Therefore, there is no consensus on whether adipokines are elevated in SLE [35–39]. However, it has been reported that serum adiponectin and serum resistin as well as urinary adiponectin levels are elevated in patients with SLE with renal involvement compared to those without renal involvement [30, 31, 33, 40, 41]. These findings indicate that adiponectin and resistin are useful markers associated with LN. In this study, there was no significant difference in adipokine levels between patients with and without preexisting renal involvement. Since only patients with LN who were in remission were included in this study, no significant difference in serum adipokine levels was observed between patients with LN and those without LN.
The relationship between adipokines and disease activity in patients with SLE other than in those with LN has also been reported in several studies. In addition, serum adiponectin levels have been positively correlated with disease activity and negatively correlated with serum C3 levels [33, 35]. Additionally, serum leptin levels were negatively correlated with disease activity and anti-dsDNA antibodies and positively correlated with hypocomplementemia . In this study, we also showed an association between adiponectin or leptin and complement factors as in previous reports. On the other hand, there are reports that there is no association between SLE disease activity and adipokines [30, 33].
Resistin is an inflammatory regulator that acts downstream of inflammation [42, 43]. Upon stimulation with resistin, macrophage cells, peripheral blood mononuclear cells and hepatic stellate cells increase the release of TNF-α, IL-6, IL-1β, IL-12, IL-8 and MCP-1 via NF-κB [44–48], which promotes an inflammatory response. However, several endogenous substances, such as proinflammatory cytokines, also upregulate resistin expression [42, 45, 46, 48]. Thus, resistin and proinflammatory cytokines are related, and circulating resistin levels are positively correlated with proinflammatory cytokines such as CRP, TNF-α and IL-6 in type 2 diabetes, rheumatoid arthritis, chronic kidney disease, sepsis and coronary atherosclerosis [49, 50]. In SLE, a correlation between serum resistin level and serum TNF-α and IL-6 levels has been demonstrated [39, 51], but reports are scarce and the relationship between cytokines and resistin in SLE needs to be thoroughly investigated.
HCQ blocks the processing and assembly of self-peptides into complexes with major histocompatibility complex class II proteins by increasing the pH within intracellular vacuoles . As a result, HCQ interferes with lysosomes and autophagy and inhibits the production of proinflammatory cytokines, including type I interferon, by inhibiting the Toll-like receptor (TLR)7 and TLR9 signaling pathways and the activity of cyclic GMP-AMP synthase [53, 54].
In this study, we found a positive correlation between the HCQ-induced decrease in resistin and a decrease in TNF-α, IL6, IL-8, and IL-1RA. This suggests that the suppression of proinflammatory cytokines by HCQ may decrease serum resistin. However, since no association was found between HCQ-induced changes in adipokine levels and changes in SLE disease activity in this study, we could not determine that SLE disease activity is related to changes in adipokine levels. It is also possible that improvement in insulin resistance decreases resistin, as reported for adiponectin in healthy subjects [13, 14]. Ahmed et al. reported that HCQ improves glucose homeostasis in high-fat diet-induced insulin resistance, which is accompanied by a correction in the adipokine imbalance and an alleviation of insulin resistance-induced endothelial dysfunction . Qatanani et al. reported that in transgenic mice expressing human resistin, inflammation of adipose tissue is promoted, lipolysis is enhanced and free fatty acids are accumulated, resulting in increased insulin resistance . This could indicate that a decrease in resistin improved insulin resistance, but the mechanism of how HCQ impacts adipokine levels is not fully understood, and further research is needed.
Persistent disease activity, LN, the presence of antiphospholipid antibodies and glucocorticoid use may be risk factors for CVD in SLE [3, 4], but none were associated with HCQ-induced increases in adiponectin levels in the current study. This indicates that supplemental HCQ improved adipokine levels independent of cardiovascular risk factors and steroid-reducing effects. This effect on adipokines may contribute to the beneficial effects of HCQ on atherosclerosis [7–11] and life expectancy [16–18].
This study has some limitations. First, we excluded patients whose disease activity was improved by HCQ by excluding patients from the analysis who had reduced their glucocorticoid dose within 3 months of HCQ administration, which may have resulted in selection bias. Second, we did not monitor adherence by measuring blood HCQ levels. Third, the sample size was small. Finally, we did not include a healthy control group in this study. Nevertheless, our study has the advantage that, to the best of our knowledge, it is the first to show an effect of HCQ on adiponectin and resistin levels in patients with SLE.