In SLE patients a high frequency of atherogenic dyslipidemia related to cardiovascular risk disease have been described [6, 32, 33]. A longer disease evolution time, higher corticosteroids cumulative dose, and absence of antimalarial therapy have been described as predictor factors of cardiovascular disease in SLE .
However, in our study, SLE patients presented normal serum levels of lipid profile, with lower levels of TG, TC, and LDL-C compared with other studies performed in SLE patients [6, 33, 34]. Serum HDL-C levels in the present study were found within the normal range with higher values compared to other studies [6, 33].
The differences in the dyslipidemia frequency in our study in comparison to other studies could be explained in part by the low clinical activity disease and the high antimalarial pharmacological treatment observed. A high frequency of SLE patients evaluated in the present study, were in clinical activity remission (63%), in comparison to other studies in SLE patients from other countries, where the general prevalence of SLE patients with clinical activity has been described higher [6, 33, 35].
In several studies, SLE patients with dyslipidemia had a higher frequency of glucocorticoid administration, around of 70% [6, 35], while in the present study, it was only 31%. In contrast, the antimalarial pharmacotherapy was higher in our study, reaching almost 90% of SLE patients, considering CQ and HCQ administration, while in other studies the combined frequency has been described less than 64% [34, 35].
The CQ and HCQ use is effective in the treatment of SLE , it has been reported that SLE patients with this pharmacotherapy have a beneficial effect against the occurrence of diabetes, thrombotic events, and dyslipidemia, especially those treated with HCQ . Two prospective studies found significantly lower levels of LDL-C, VLDL, and triglycerides as well as higher HDL-C concentrations in SLE patients treated with HCQ [4, 37]. The antimalarial drugs promote the LDL-C receptors upregulation with an enhancement of the plasma removal of this lipoprotein; besides, an overall reduction in hepatic cholesterol synthesis by the accumulation of LDL-C in the lysosome and to block cholesterol transport out of this organelle have been described [4, 37–39].
The lipid-lowering effects of the antimalarial drugs were also observed in the present study, the CQ administration conferred significant lower TC serum levels. Nevertheless, this same pattern was no observed in SLE patients with HCQ treatment.
Notably, we found that CQ administration was associated with a pro-inflammatory diet status evaluated by the DII score. We hypothesized that this finding may be influenced by the secondary effect reported about of antimalarial treatment; in particular in the CQ administration . Approximately 20% of the patients treated with CQ had reported anorexia, abdominal pain, heartburn, nausea, vomiting, or diarrhea , which could influence the appetite and indirectly their food choices, for foods with a higher caloric density and simple sugar content.
Other gastrointestinal adverse effects that may occur with the CQ treatment are loss of taste functions of the tongue, such as ageusia . In a previous study conducted in patients with malaria, the CQ administration improved the symptoms of headache, fever, and chills, but it increases the frequency of nausea (46%), diarrhea (26%), abdominal pain (38%) and bitter taste in the mouth (60%) , which could be related to the high doses administered in patients with this pathology.
The relationship between a higher frequency of CQ administration with a more pro-inflammatory DII score observed in our study, could be influenced by the residual accumulation of antimalarials drugs in different organs and tissues [10, 41]. The antimalarials could modulate the taste functions because they may stimulate interactions between the innate immune response and the taste signal transmission in the taste bud cells . Taste bud cells have several signaling molecules associated with the innate immune response; express pathogen-associated molecular patterns (PAMPs) recognition receptors, such as Toll-like receptors (TLRs) and their adaptor proteins, as cytokines and chemokines [10, 44]. Whereby, these TLRs have an emerging role in the subsequent regulation of taste bud functions . Alterations in these signaling pathways could influence the food choices, decrease the appetite and contribute to have a lower consumption of their energy and nutrient requirements in patients with gastrointestinal adverse effects related with the CQ administration, and this would be reflected in higher pro-inflammatory DII scores.
The CQ gastrointestinal side effects may be controlled by reducing drug dose administered . Conversely, in the present study, SLE patients located in the most anti-inflammatory DII tertile (T1st ) had a higher CQ daily dose in comparison with SLE patients with the same antimalarial treatment located in the most pro-inflammatory DII scores (T3rd ), who had a higher frequency of CQ administration but in a lower dose, which could indicate that CQ may have a dose-dependent effect in the pro or anti-inflammatory diet status evaluated by the DII.
Patients with HCQ administration presented an anti-inflammatory diet status related to a negative DII score. One explanation to this finding could be the safety profile in the HCQ administration reported in other studies conducted in SLE patients [40, 41], because its administration has been related to lower frequency of adverse effects (< 10%), in comparison with CQ administration [40, 41], and only HCQ may cause a temporal and reversible ageusia , which could be reflected in greater availability of nutrients for the patients with this pharmacotherapy.
In several studies, a pro-inflammatory diet status has been related to high fats diets, simple carbohydrates, cholesterol, and saturated fats consumption [18, 45]. In contrast, an anti-inflammatory diet status has been characterized by an adequate content of nutrients such as omega 3 fatty acids, fiber, several, and minerals associated with decrease the levels of inflammation mediators . In our study was observed a pattern that while the DII was higher, the nutrient intake was lower, because the patients in the most pro-inflammatory DII tertile (T3rd ) had considerably lower consumption of 20/27 dietary parameters evaluated in the DII, compared with the SLE patients with lower DII scores.
When we evaluated the differences in the dietary intake of SLE patients with antimalarial pharmacotherapy, we observed that SLE patients with CQ treatment had lower consumption of nutrients evaluated in comparison to SLE patients with HCQ treatment. Highlighting those SLE patients with HCQ treatment had a better achievement of the 100% of daily DRI in the following nutrients: energy, cholesterol, vitamin A, fiber, riboflavin, saturated fat, thiamin, magnesium, β-carotene, folic acid, iron and vitamin D.
Regarding this, there are no studies in the literature evaluating the relationship of antimalarial pharmacotherapy with nutritional status and nutrient intake, which will be necessary in order to make an appropriate comparison with other SLE populations with a similar antimalarial treatment. Nevertheless, several studies have linked the presence of nutritional deficits with immune pro-inflammatory imbalances , SLE patients in the present study were deficient in the intake of the nutrients evaluated and few patients reached the daily DRI for these nutrients, which is indicative of a poor nutritional adequacy of the diet consumed by these patients.
Therefore, a correct nutritional adequacy is essential to ensure the adequate dietary intake of nutrients described with an anti-inflammatory effect in patients with autoimmune diseases, such as immune-modulatory vitamins like vitamins A, C, D and E, minerals such as magnesium, and zinc, as well as β-carotenes and polyunsaturated fats such as omega 3, because their intakes are characterized by contributing to the decrease of the levels of IL-1β, IL-6, TNF-ɑ and CRP, and increasing the levels of inmunomodulatory cytokines such as IL-4 and IL-10, which could influence to obtaining a general anti-inflammatory status .
Although we observed in SLE patients the relationship of CQ administration with a pro-inflammatory diet status, and HCQ administration with an anti-inflammatory diet status; these results should be interpreted with caution. The limitations of our study were that we were not able to assess the gastrointestinal symptoms related with CQ and HCQ administration in a dose-dependent manner, which could clarify part of the findings found, in order to make a complete comparison between SLE patients subgroups with antimalarial pharmacotherapy. Moreover, the consumption deficiencies found in SLE patients with CQ treatment may not be represented in their blood serum levels, because the dietary records are subject to memory errors, and may not represent fully the routine intake of the patients evaluated.
Statistically, our cross-sectional study design limits us by simply showing a relationship between antimalarial treatment and inflammatory diet status, but we do not suggest causality. Nonetheless, the present study provides evidence of the potential relationship of antimalarial pharmacotherapy with nutritional deficiencies related to a pro-inflammatory status of diet consumed by SLE patients.
Therefore, further prospective studies in a SLE Mexican population cohort will be necessary to perform, in order to evaluate causality in the relationship between antimalarial pharmacotherapy and dietary inflammatory status described in this cross-sectional study. This will help to support the nutritional interventions in subsequent studies conducted in autoimmune patients with antimalarial pharmacotherapy.