Abstract
Objective
Polyunsaturated fatty acids (PUFAs) may modulate the inflammatory process in systemic autoimmune diseases, including systemic lupus erythematosus (SLE). The aim of this study was to assess the serum concentrations of essential 18-carbon PUFAs and their long-chain derivatives in patients with SLE and healthy controls, and to analyse their associations with laboratory and clinical features of the disease.
Method
n-6 and n-3 PUFA composition was assessed in the sera of 30 SLE patients and 20 healthy controls using gas chromatography–mass spectrometry. We investigated the associations between PUFAs and disease activity measured with Systemic Lupus Erythematosus Activity Index (SLEDAI) scores, erythrocyte sedimentation rate, C-reactive protein, complement C3 and C4 concentrations, anti-nuclear antibody (ANA) titre, anti-double-stranded DNA (anti-dsDNA) antibody concentration, and medications.
Results
Serum linoleic acid (LA) and α-linolenic acid concentrations were significantly higher in SLE patients compared with healthy controls. LA concentration correlated positively with the ANA titre and corticosteroid doses; eicosapentaenoic acid (EPA) and docosahexaenoic acid correlated inversely with anti-dsDNA antibody concentration. Patients treated with immunosuppressants had significantly lower concentrations of LA, arachidonic acid, and EPA.
Conclusion
Both n-6 and n-3 PUFA precursors can participate in the inflammatory process in SLE patients. The mechanism of the PUFA metabolism disturbance needs further exploration.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation and multiorgan involvement (Citation1). The pathogenesis of SLE involves the stimulation of the immune system by autoantigens exposed in apoptotic cells and the secretion of proinflammatory cytokines, such as interferon-γ, tumour necrosis factor-α, and interleukin-1 (IL-1), IL-6, and IL-12 (Citation2).
To date, few studies have analysed the role of nutrition in the pathogenesis of SLE and its impact on the suppression of inflammation (Citation3–5). Nutritional therapy, including modification of the diet and the use of nutritional supplements, can help to control the inflammatory features of the disease and the complications induced by the therapy (Citation6, Citation7). Published studies have investigated the anti-inflammatory effects of fatty acids, particularly polyunsaturated fatty acids (PUFAs) (Citation8). This direction of research is based primarily on the argument that a diet rich in linoleic acid (18:2n-6, LA) predominantly promotes the accumulation of tissue-originated arachidonic acid (20:4n-6, AA), enhances the production of proinflammatory eicosanoids derived from AA, and/or inhibits the conversion of α-linolenic acid (18:3n-3, ALA) to eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), along with their subsequent metabolism, mainly towards the anti-inflammatory compounds (Citation8, Citation9). Members of the n-3 PUFA family – EPA and DHA – cause a rise in anti-inflammatory and inflammation-resolving mediators, specifically, resolvins, neuroprotectins, and maresins (Citation10).
In vitro experiments and studies on SLE animal models have shown a beneficial effect of an n-3 PUFA-rich diet on kidney and brain involvement in lupus, as well as improved survival rates (Citation11–14). Bates et al revealed that DHA consumption suppresses the crystalline silica (cSiO2) triggering of autoimmunity in female lupus-prone mice, as manifested in the lung, blood, and kidney (Citation15). One potential mechanism of the beneficial effects of dietary DHA supplementation in lupus flaring and nephritis is the impeded interferon and chemokine-related gene expression (Citation16). Despite the promising results of animal studies, the outcomes of interventional studies in humans with SLE have not been as unequivocal. Some studies have shown a beneficial clinical effect of dietary n-3 PUFA supplementation in patients with SLE (Citation17–20). Other studies, however, have reported no impact of n-3 PUFA supplementation on disease activity, no reduction of inflammatory markers in SLE (Citation21–23), and no improvement in lupus nephritis (Citation24–26).
Considering the relationship between fatty acids and the immune system, it is important to highlight the different composition of fatty acids in patients with autoimmune diseases versus healthy individuals. Several studies have suggested specific fatty acid profiles associated with rheumatoid arthritis (Citation27), ankylosing spondylitis (Citation28), and Crohn’s disease (Citation29). As yet, little is known regarding the serum concentrations of essential PUFAs in patients with SLE (Citation30, Citation31).
The aim of this pilot study was to assess through analytical observational research the profiles of essential serum PUFAs in patients with SLE and in healthy subjects, and to determine the correlations between PUFA concentration and different clinical SLE-related features, such as disease activity, serological profile, and treatment.
Method
Patients
Patients with SLE were enrolled into a single-centre study (Rheumatology Department of Wroclaw Medical University), which lasted from January 2012 to December 2012. All subjects satisfied the classification criteria for SLE of the American College of Rheumatology (ACR) and the Systemic Lupus International Collaborating Clinics (SLICC) (Citation32, Citation33). The patients underwent clinical examination by a rheumatologist. The following data from their medical history and documentation were included: age at disease onset, duration of disease from the onset of symptoms, organ involvement, and treatment (drug and dosage). Participants were evaluated for disease activity using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (Citation34). The control group consisted of 20 healthy volunteers matched for age and gender.
The exclusion criteria for participants of both groups were an autoimmune disease other than SLE, gastrointestinal diseases (inflammatory bowel disease, gastritis, and duodenal ulcers), acute febrile illness, treatment based on biological therapy, and taking supplements containing n-6 and/or n-3 PUFAs, and antioxidants.
All subjects gave their informed consent to participate in the study. The study was carried out according to the protocol of the Declaration of Helsinki and approved by the Ethics Committee of Wroclaw Medical University (no. KB-117/2008).
Methods
Venous blood samples were collected from SLE patients and healthy controls once during the survey, on the day of the medical examination, after an overnight fast. Serum was separated and stored at −70ºC for fatty acid analysis. The method for the extraction and derivatization of fatty acids was adapted from Böcking et al (Citation35). The PUFA methyl esters were analysed using a gas chromatography–mass spectrometry (GC/MS) system: a Focus GC apparatus with an ITQ 700 ion trap (Thermo Scientific) and Trace GC with a TSQ Quantum XLS triple quadrupole (Thermo Fisher Scientific Inc, San Jose, CA, USA). For quantitative analysis, the tricosanoic acid methyl ester (C23:0) was added to the examined samples as the internal standard.
At the same time, laboratory tests were performed as part of the routine clinical assessment of SLE patients: complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement component (C3 and C4) level, titre of anti-nuclear antibodies by the indirect immunofluorescent test using Hep-2 cells (ANA titre), anti-phospholipid antibodies [anti-cardiolipin immunoglobulin G (IgG) and IgM antibodies, anti-beta2 glycoprotein I IgG and IgM antibodies, and the lupus anticoagulant assay], anti-double-stranded DNA (anti-dsDNA) concentration, creatinine concentration, glomerular filtration rate (GFR), and urinalysis.
Statistical analysis
The statistical analysis was performed using Statistica PL version 8 statistical software (StatSoft, Krakow, Poland). The normality of distribution in both groups was verified with the Shapiro-Wilk test. If a normal distribution and homogeneity of variances (checked with Levene’s test) were found, the groups were compared using the parametric Student’s t-test. If any of these assumptions were not met, the non-parametric Mann–Whitney U-test was used for the comparison. To assess the correlation between serum PUFA concentration and clinical variables, correlation coefficients were calculated. For normally distributed variables, the standard Pearson coefficient was used. Otherwise, the Spearman rank correlation was applied. A p-value of less than 0.05 was considered statistically significant.
Results
The SLE group included 30 patients (29 women and one man), the mean ± sd age was 47 ± 14 years, and SLE duration was 11 ± 7 years. The characteristics of the SLE patients are summarized in . Twenty age-matched (mean age 45 ± 13 years) and gender-matched (19 women and one man) healthy individuals were also included in the study as controls.
Table 1. Characteristics of patients with systemic lupus erythematosus
Serum fatty acids profiles showed significantly higher concentrations of LA and ALA in the SLE groups in comparison to the control group. No differences were found in the serum concentrations of AA, EPA, and DHA ().
Table 2. Serum polyunsaturated fatty acid concentrations (mg/L) in systemic lupus erythematosus (SLE) patients and healthy controls
The correlation analyses between serum PUFA concentrations and selected clinical and laboratory parameters associated with disease activity revealed that LA concentrations correlated positively with the ANA titre (r = 0.38, p = 0.035) and the dose of glucocorticoids (GCs) (r = 0.49, p = 0.008) (). A significant negative correlation was observed between AA, EPA, and DHA concentrations and the concentration of anti-dsDNA antibodies (r = −0.40, p = 0.029; r = −0.38, p = 0.036; and r = −0.37, p = 0.043, respectively). There were no correlations between the concentrations of the studied PUFAs and SLEDAI scores, or the levels of ESR, CRP, C3, and C4.
Table 3. Correlations between serum polyunsaturated fatty acid concentrations and systemic lupus erythematosus activity parameters
In SLE patients, treatment with an immunosuppressant other than GCs, such as azathioprine, methotrexate, or cyclophosphamide, resulted in a significant decrease in LA, AA, and EPA concentrations compared with patients who did not take immunosuppressive agents (p < 0.05) ().
Table 4. Polyunsaturated fatty acid serum concentrations in systemic lupus erythematosus patients with and without immunosuppressive treatment (mg/L)
Discussion
In this study, we investigated the serum PUFA profiles in SLE patients and in healthy individuals, and the associations with clinical and laboratory features of the disease.
The simplest members of the n-6 and n-3 families of PUFAs, LA and ALA, are the precursors to the formation of other fatty acids and lipid inflammatory mediators. Owing to their molecular similarity, LA and ALA compete for the same enzymes to synthesize derivatives (Citation8). EPA, by changing the phospholipid composition of the cell membrane, inhibits the production and interaction of the cytokine receptor, eventually affecting the level of inflammatory cytokines IL-1β and IL-6 (Citation6, Citation36). There is evidence suggesting that LA itself may have a proinflammatory potential, independent of its role as a tissue AA precursor (Citation37). This study demonstrated that serum concentrations of LA and ALA were higher in SLE patients than in healthy controls, whereas there were no differences in the serum concentrations of their derivatives, AA, EPA, and DHA.
To date, evidence concerning PUFA concentrations in blood in patients with SLE and healthy controls is quite limited. Aghdassi et al compared red blood cell (RBC) and plasma PUFA compositions between female SLE patients and healthy female controls (Citation30). In SLE patients, a lower EPA concentration and n-3 index (EPA + DHA) was revealed in RBCs but not in plasma. The same study showed that plasma total n-6 and LA concentrations were lower only in the SLE patients with a history of cardiovascular disease (CVD) in comparison to the SLE patients with no CVD history or the healthy controls. Wu et al carried out a metabolomic study using liquid chromatography (LC)/MS- and GC/MS-based platforms, and found that both n-3 and n-6 PUFA serum concentrations were significantly reduced in SLE patients (Citation31). In contrast, two eicosanoid metabolites in the n-6 PUFA pathway, leukotriene B4 and 5-hydroxyeicosatetraenoic acid, were also significantly elevated in SLE patients. It is unclear whether the differences in blood PUFA concentrations are the result of a disturbance in fatty acid metabolism due to the pathomechanism of the disease or due to an inappropriate diet (e.g. a high intake of n-6 or n-3 deficiency). In a 2020 study, a GC/MS-based fatty acid profiling analysis was performed in SLE model mice, which found significantly elevated concentrations of n-3 and n-6 PUFAs (Citation38). Moreover, the product/precursor fatty acid ratios representing the estimated activities of desaturase and elongase changed. From the perspective of our results, we hypothesize that the metabolic disturbance in the course of SLE could be related to elevated lipid peroxidation, desaturation and elongation defects, and decreased β-oxidation of lipids (Citation31, Citation39).
We think that the altered composition of n-6 and n-3 PUFAs in the blood is not a result of specific nutritional supply in the diet. Several previous studies aimed to examine the hypothesis that dietary n-3 PUFAs promote an anti-inflammatory response. Some authors claim that in SLE patients, the intake of n-6 and n-3 PUFAs may be lower than in controls (Citation40), and that EPA and DHA supplementation results in increased blood EPA and DHA concentrations (Citation17, Citation18, Citation25, Citation41, Citation42), delivering a beneficial but rather short-term decrease in SLE activity (Citation25, Citation43). However, the published intervention studies in SLE patients were designed without the assessment of total PUFA intake (supplements and diet); only one study (Citation41) evaluated the concentration of fatty acids in the plasma phospholipid fraction of SLE patients who were given EPA/DHA capsules orally and compared this with a control group of healthy individuals.
SLE is characterized by variable disease activity with interchanging periods of flares and remission. Disease flare is often preceded by an increase in anti-dsDNA antibodies and a decrease in the complement components. In the present study, we investigated the relationship between serum PUFA concentrations and SLE activity, measured by immunological and inflammatory markers. For the assessment of disease activity, we used SLEDAI (Citation34, Citation44), and we detected no association between serum n-3 PUFA and n-6 PUFA concentrations and SLEDAI scores. These results were in agreement with those of previous studies (Citation20, Citation22, Citation24). However, Elkan et al found that an increased level of EPA and DHA in fat cells of patients with SLE was negatively associated with SLEDAI (Citation40). Furthermore, other authors have reported on the beneficial effect of EPA and DHA supplementation in reducing disease activity, as measured by SLEDAI (Citation45) or the Systemic Lupus Activity Measure (SLAM) (Citation17, Citation18).
We were unable to detect any correlation between serum n-6 and n-3 PUFA concentrations and C3, C4, CRP, and ESR. These findings are in agreement with the intervention studies involving supplementation with n-3 fish oils in SLE patients (Citation17, Citation18, Citation26, Citation45). Decreased CRP levels in the n-3 fatty acids supplementation group have been observed by other researchers (Citation23, Citation46). However, Curado Borges et al observed no changes in the serum levels of IL-6, IL-10, leptin, and adiponectin (Citation23). To our knowledge, only Arriens et al have demonstrated a significant reduction of ESR in the fish oil group compared to a placebo-supplemented olive oil group (Citation20).
Our observation of an inverse association between serum EPA and DHA concentrations and anti-dsDNA is consistent with earlier animal studies, which showed a reduction of anti-dsDNA antibodies in mice fed an n-3 unsaturated fatty acid-rich diet (Citation13, Citation14, Citation47), as well as with human studies, where high-dosage EPA supplementation caused only a temporary reduction of anti-dsDNA antibodies (Citation17, Citation21). Other human intervention studies with n-3 PUFAs, providing as much as 1.8 g EPA and 1.2 g DHA daily, showed no effect on anti-dsDNA antibody levels (Citation18, Citation26, Citation45). Further studies are required to confirm whether an n-3 PUFA-rich diet can modify disease activity and, if so, at what doses and for how long.
Therapeutic intervention in SLE depends on disease activity; it also reflects the intensity of inflammation. GCs and anti-malarials have been the mainstay of lupus treatment owing to their effective anti-inflammatory and immunomodulatory effects. We found that serum LA concentration is positively associated with GC doses. Little is known about the relationship between PUFA profiles and treatment with GCs. In SLE patients, the use of prednisolone results in an alteration of PUFA composition (Citation30). On the other hand, Arriens et al showed that supplementation with fish oil did not lead to a change in the prednisolone dose (Citation20). One animal study showed that the total concentration of n-6 PUFAs returned to the control level following treatment of MRL/lpr mice with prednisolone; in particular, the concentration of AA estimated by the activity of Δ5-desaturase was reduced to the control concentration (Citation38). We found that serum LA, AA, and EPA concentrations decreased among SLE patients who received immunosuppressive treatment, such as azathioprine, methotrexate, or cyclophosphamide. It is noteworthy that several drugs used in SLE, especially GCs, elicit deleterious changes in the lipid profile (previously altered by the disease) (Citation6). The inhibition of AA biosynthesis may be one of the anti-inflammatory mechanisms of prednisone. The disease activity of SLE affected by immunosuppressive therapy is a factor that may cause a change in a patient’s lipid profile. The main therapeutic effect of azathioprine and cyclophosphamide relies on the inhibition of the proliferation and activity of T and B cells. For this reason, we hypothesize that our finding of the decrease in PUFAs may reflect the disease’s inflammatory activity. It cannot be excluded that serum PUFA composition can correlate with the oxidation of the unsaturated fatty acids owing to the increase in reactive oxygen species products associated with enhanced oxidative stress (Citation48). More studies in this field are required.
The strengths of our pilot study are its comprehensive analysis of serum n-3 and n-6 PUFA profiles in a well-defined group of SLE patients, and the recording of PUFA concentrations in a real clinical situation. Nevertheless, this study has certain limitations, including its design as a pilot investigation, i.e. a relatively small patient group, and the differences in disease activity and treatment strategies. Nevertheless, we found statistically significant changes in PUFA profiles. Although a causal relationship has been evoked, the mechanism or metabolic reasons still need clarification, and thus, a larger study should be conducted to confirm these findings. Another drawback is the assessment of PUFA profiles at a single time-point. A prospective analysis in this type of study would be more informative. Our findings suggest the need for a profound metabolomic analysis. Research has shown that a weekly intake of dietary LA and ALA correlates with plasma concentrations (Citation49, Citation50); unfortunately, important data on dietary fat intake have not been collected (Citation49).
Conclusion
We found significantly higher serum LA and ALA concentrations in patients with SLE compared to the control group, significantly positive correlations between serum LA concentration and the ANA titre and steroid dose, and inverse relationships between either EPA or DHA and serum anti-dsDNA concentrations in patients with SLE. The mechanism of the disturbance of fatty acid metabolism should be investigated to find an effective way to reduce systemic inflammation.
References
Acknowledgements
The authors are grateful to Professor P. Wiland for all the help with patient recruitment. The authors also thank the patients who consented to participate in this study.
This study was supported by the Wroclaw Medical University [grant no. ST-653] and by the Ministerstwo Nauki i Szkolnictwa Wyższego (Polish Ministry of Science and Higher Education) [Grant No. NN402 267 336].
The open access publication cost covered by the Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences is acknowledged.
Disclosure statement
No potential conflict of interest was reported by the authors.
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