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Omega-3 fatty acids, inflammatory status and biochemical markers of patients with systemic lupus erythematosus: a pilot study Study conducted at Unidade de Reumatologia, Hospital das Clínicas; Faculdade de Medicina, Departamentos de Sistema Locomotor, Cirurgia e Medicina Interna, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Abstract

Background:

Studies have shown that omega-3 fatty acids reduce the concentrations of eicosanoids, cytokines, chemokines, C-reactive protein (CRP) and other inflammatory mediators.

Objective:

To investigate the effects of omega-3 fatty acids on circulating levels of inflammatory mediators and biochemical markers in women with systemic lupus erythematosus (SLE).

Methods:

Experimental clinical study (clinical trial: NCT02524795); 49 women with SLE (ACR1982/1997) were randomized: 22 to the omega-3 group (daily intake of 1080 mg EPA + 200 mg DHA, for 12 weeks) and 27 to the control group. The inflammatory mediators and biochemical markers at T0 and T1 in omega-3 group were compared using Wilcoxon test. U-Mann-Whitney test was used to compare variations of measured variables [ΔV = pre-treatment (T0) − post-treatment (T1) concentrations] between groups. p < 0.05 was considered significant.

Results:

The median (interquartile range - IQR) of age was 37 (29-48) years old, of disease duration was 7 (4-13) years, and of SLEDAI-2K was 1 (0-2). The median (IQR) of variation in CRP levels between the two groups showed a decrease in omega-3 group while there was an increase in control group (p = 0.008). The serum concentrations of IL-6 and IL-10, leptin and adiponectin did not change after a 12 week treatment.

Conclusions:

Supplementation with omega-3 had no impact on serum concentrations of IL-6, IL-10, leptin and adiponectin in women with SLE and low disease activity. There was a significant decrease of CRP levels as well as evidence that omega-3 may impact total and LDL-cholesterol.

Keywords:
Omega 3; Cytokines; Adipokines; C reactive protein; Systemic lupus erythematosus

Resumo

Introdução:

Estudos têm mostrado que os ácidos graxos ômega-3 reduzem as concentrações de eicosanoides, citocinas, quimiocinas, proteína C-reativa (PCR) e outros mediadores inflamatórios.

Objetivo:

Investigar os efeitos dos ácidos graxos ômega-3 sobre os níveis circulantes de mediadores inflamatórios e marcadores bioquímicos em mulheres com lúpus eritematoso sistêmico (LES).

Métodos:

Ensaio clínico randomizado (ensaio clínico: NCT02524795); randomizaram-se 49 mulheres com LES (ACR1982/1997): 22 para o grupo ômega-3 (dose diária de 1.080 mg de EPA + 200 mg de DHA durante 12 semanas) e 27 para o grupo controle. Os mediadores inflamatórios e marcadores bioquímicos em T0 e T1 no grupo ômega-3 foram comparados pelo teste de Wilcoxon. O teste U de Mann-Whitney foi usado para comparar variações das variáveis mensuradas [ΔV = concentrações pré-tratamento (T0) menos concentrações pós-tratamento (T1)] entre os grupos. Um p < 0,05 foi considerado significativo.

Resultados:

A mediana (intervalo interquartil-IIQ) da idade foi de 37 anos (29-48), a duração da doença foi de sete anos (4-13) anos e o Systemic Lupus Disease Activity Index (Sledai-2 K) foi de 1 (0-2). A mediana (IIQ) da variação nos níveis de PCR entre os dois grupos mostrou um decréscimo no grupo ômega-3, enquanto houve um aumento no grupo controle (p = 0,008). As concentrações séricas de IL-6 e IL-10, leptina e adiponectina não se alteraram após um tratamento de 12 semanas.

Conclusões:

A suplementação de ômega-3 não teve impacto sobre as concentrações séricas de IL-6, IL-10, leptina e adiponectina em mulheres com LES e baixa atividade da doença. Houve uma diminuição significativa nos níveis de PCR, bem como evidências de que o ômega-3 pode impactar sobre o colesterol total e LDL.

Palavras-chave:
Ômega-3; Citocinas; Adipocinas; Proteína C-reativa; Lúpus eritematoso sistêmico

Introduction

Omega-3 fatty acids have been considered antiinflammatory lipids based on epidemiological studies of Greenland Eskimos, whose diet is rich in polyunsaturated fatty acids from fish. The prevalence of diseases with an inflammatory component such as acute myocardial infarction, diabetes mellitus, multiple sclerosis, asthma and thyrotoxicosis, was lower in the Eskimos compared to Western countries populations.11 Kronmann N, Green A. Epidemiological studies in the Upernavik district, Greenland: incidence of some chronic diseases 1950-1974. Acta Med Scand. 1980;208:401-6.

Fatty acids of the omega-3 family [mainly the α-linolenic acid, eicosapentaenoic (EPA) and docosahexaenoic (DHA)], as well as those of the omega-6 family [represented mainly by linoleic acid and arachidonic acid (AA)] are essential for the synthesis of eicosanoids, prostaglandins, leukotrienes, thromboxanes and other oxidative factors, major mediators and regulators of inflammation.22 Bhangle S, Kolasinski SL. Fish oil in rheumatic diseases. Rheum Dis Clin North Am. 2011;37:77-84.,33 Li K, Huang T, Zheng J, Wu K, Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor alfa: a meta-analysis. PLOS ONE. 2014;9:e88103. Studies have shown that omega-3 fatty acids control inflammation by reducing C-reactive protein (CRP), eicosanoid proinflammatory cytokines, chemokines and other inflammatory mediators.44 Schwab JM, Serhan CN. Lipoxins and new lipid mediators in the resolution of inflammation. Curr Opin Pharmacol. 2006;6:414-20.

5 Thies F, Miles EA, Nebe-von-Caron G, Powell JR, Hurst TL, Newsholme EA, et al. Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults. Lipids. 2001;36:1183-93.

6 Trebble T, Arden NK, Stroud MA, Wootton SA, Burdge GC, Miles EA, et al. Inhibition of tumor necrosis factor-α and interleukin-6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Br J Nutr. 2003;90:405-12.
-77 Wallace FA, Miles EA, Calder PC. Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Br J Nutr. 2003;89:679-89. Furthermore, they present beneficial effects in the prevention and control of cardiovascular diseases, dyslipidemia and diabetes mellitus.88 Cawood AL, Ding R, Napper FL, Young RH, Williams JA, Ward MJ, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;20:252-9.

9 Skulas-Ray AC, Kris-Etherton PM, Harris WS, Vanden Heuvel JP, Wagner PR, West SG. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr. 2011;93:243.

10 Udupa AS, Nahar PS, Shah SH, Kshirsagar MJ, Ghongane BB. Study of comparative effects of antioxidants on insulin sensitivity in type 2 diabetes mellitus. J Clin Diagn Res. 2012;6:1469-73.

11 Browning LM, Krebs JD, Moore CS, Mishra GD, O'Connell MA, Jebb SA. The impact of long chain n-3 polyunsaturated fatty acid supplementation on inflammation, insulin sensitivity and CVD risk in a group of overweight woman with an inflammatory phenotype. Diabetes Obes Metab. 2007;9:70-80.

12 Hartweg J, Farmer AJ, Holman RR, Neil A. Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes. Curr Opin Lipidol. 2009;20:30-8.
-1313 He K, Liu K, Daviglus ML, Jenny NS, Mayer-Davis E, Jiang R, et al. Associations of dietary long-chain n-3 polyunsaturated fatty acids and fish with biomarkers of inflammation and endothelial activation (from the Multi-Ethnic Study of Atherosclerosis [MESA]). Am J Cardiol. 2009;103:1238-43.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by loss of cellular immune regulation balance and increased levels of circulating inflammatory mediators.1414 Hahn BH, Ebling F, Singh RR, Singh RP, Karpouzas G, La Cava A. Cellular and molecular mechanisms of regulation of autoantibody production in lupus. Ann N Y Acad Sci. 2005;1051:433. Thus, omega-3 supplementation could represent additional therapy for individuals with SLE. However, little is known on the role of these fatty acids in patients with SLE, including the effects on inflammatory cytokine concentrations and on disease activity.

The aim of this study was to investigate the effects of omega-3 fatty acids on circulating levels of inflammatory mediators and biochemical markers in women with SLE.

Patients and methods

This is a clinical trial of the use of omega-3-polyunsaturated fatty acids in SLE patients followed at the Rheumatology Unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, UFMG (clinical trial: NCT02524795). The Research Ethics Committee of UFMG approved the study. All patients provided a written informed consent.

Study participants

Female patients who met the revised American College of Rheumatology (ACR) classification criteria for SLE (1982/1997),1515 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:25. aged over 18 years old and below 60 years old, taking stable doses of medications for SLE treatment in the last three months were included. Exclusion criteria were the following: pregnancy, disease duration of less than one year, allergy to fish, fish oil or any omega-3 product, omega-3 use within the previous six months and diagnosis of diabetes mellitus, liver disease, active nephritis, chronic renal failure, any type of infection at enrollment and/or throughout the study.

A total of 153 patients were screened for the trial and 66 patients were included, with 33 randomized to each arm. Twenty-two women in the study group and 27 in the control group completed the whole protocol and had both their first and 12-week visit assessments (Fig. 1).

Fig. 1
Study design.

Study design

A 12 week clinical trial of omega-3 fatty acids supplementation was conducted. Participants were seen at baseline (T0) and at week 12 (T1) for clinical, laboratory and nutritional assessment. Participants were also contacted by telephone at week 6 to check on compliance and any adverse events. The patients were randomized into one of two groups in a 1:1 ratio. Patients in the study group received, throughout 12 weeks, two tablets taken orally once daily of omega-3 fatty acids (540 mg of EPA and 100 mg of DHA; Hiomega-3 supplement of Naturalis® company - registered in the National Health Department number 4.1480.0006.001-4). Patients in the control group did not receive the nutrient nor any kind of placebo. All participants were instructed not to take omega-3 rich foods during the study period. The researcher (FMMS) who did clinical assessment and the inflammatory and biochemical data assessment was blind to randomization and intervention. Any adverse events observed during the study were recorded and managed according to local clinical practice.

Variables measured at each visit included: disease activity index, using the Systemic Lupus Disease Activity Index (SLEDAI-2k)1616 Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2001;29:288-91.; damage index (Systemic Lupus International Collaboration Clinics/American College of Rheumatology damage index - SLICC/ACR)1717 Gladman D, Goldsmith C, Urowitz MB. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1997;40:809-13.; fasting lipid and glucose profile; standard laboratory tests to assess SLE (red and white blood count, platelet count, creatinine, urinalysis, urine protein/creatinine ratio, anti-dsDNA, anticardiolipin, C3 and C4 levels); cytokines (IL-6, IL-10), adipokines (leptin, adiponectin) C-reactive protein (CRP), nutritional assessment, and medications being used.

Nutritional status was assessed by body mass index (BMI) and patients were classified as malnourished (BMI ≤ 18.5 kg/m2), normal weight (BMI = 18.6-24.9 kg/m2), overweight (BMI = 25-29.9 kg/m2) and obese (BMI ≥ 30 kg/m2).1818 WHO (World Health Organization). Obesity: preventing and managing the global epidemic. Report of WHO consultation. Geneva: WHO; 1997, 276 p. Body composition assessment was performed by using bioimpedance (RJL Quantum X®) and patients were classified in accordance to Gallagher et al. 1919 Gallagher D, Heymsfield SB, Heo M, Jebb SA, Murgatroyd PR, Sakamoto Y. Healthy percentage body fat ranges: an approach for developing guidelines based on body mass index. Am J Clin Nutr. 2000;72:694-701. as normal or above the recommended percentage body fat according to sex and age.

The IL-6 and IL-10 levels were assessed by ultrasensitive flow cytometry (Cytometric Bead Array), leptin and adiponectin levels by ELISA.

Outcome variables

The primary outcomes were median (interquartile range - IQR) variations [ΔV = pre-treatment (T0) − post-treatment (T1) concentrations], between groups, of serum cytokines, adipokines, C-reactive protein and biochemical markers (glucose and lipids) after a 12 week treatment.

Statistical analysis

The Statistical Package of Social Sciences Software (SPSS) version 19.0 (SPSS Inc., Chicago, IL, USA) was used. Comparison of groups at baseline (with versus without omega-3, with versus without excess weight and with adequate versus above recommended percentage body fat) were performed by non-parametric U-Mann-Whitney test for continuous variables, and Pearson's chi-square or Fisher's exact test for categorical variables. The median (IQR) of inflammatory and biochemical markers at T0 and T1 in omega-3 and in control group were compared using nonparametric Wilcoxon test.

To investigate the effect of omega-3 on inflammatory mediators and biochemical markers the variations of laboratory variables [ΔV = pre-treatment (T0) − post-treatment (T1) concentrations] between omega-3 and control groups were analyzed using U-Mann-Whitney test. All analyses were considered significant at a level of 2-sided 5% (p < 0.05).

Results

Seventeen randomized patients, out of 66, did not complete the trial (Fig. 1). Two patients interrupted supplementation due to adverse events (one patient with diarrhea and the other reporting fish aftertaste). Both patients where discontinued from the trial. The final sample of this pilot study consisted of 49 patients. Cumulative revised ACR classification indicated mucocutaneous manifestations in 86.3% of the patients, hematological disorders in 80.0%, immunological disorders in 77.6%, arthritis in 66.7%, nephritis in 56.9%, serositis in 16.0% and neuropsychiatric disorders in 11.8%.

Baseline analysis

The median (IQR) of age was 37 (29-48) years old, of disease duration was 7 (4-13) years, of disease activity index was 1 (0-2) and of damage index was 0 (0-1).

Baseline (T0) clinical, laboratory and disease treatment characteristics, disease activity index and nutritional status of participants per treatment groups were not statistically different (Table 1).

Table 1
Baseline (T0) characteristics of each group.

Nutritional status of 49 patients, according to BMI, showed that 13 patients (26.5%) had normal weight, 19 (38.8%) were overweight and 17 (34.7%) were obese. This distribution was similar in both groups (p = 0.875). Bioelectrical impedance analysis indicated that 29 (59.2%) patients had percentage body fat above recommended: 12 patients (54.5%) in the omega-3 group and 17 (63.0%) in the control group (p = 0.574).

Serum concentrations of cytokines were similar in normal weight and excess weight participants (BMI ≥ 25 kg/m2) [IL-6:1.38 (0.48-3.13) pg/mL versus 0.92 (0.40-1.95) pg/mL; p = 0.429; IL-10: 19.30 (7.85-53.35) pg/mL versus 21.42 (9.40-51.16) pg/mL; p = 0.956]. IL-10 levels were similar in both study groups considering patients with adequate and above recommended percentage body fat [16.26 (5.51-22.25) pg/mL versus 22.53 (9.78-55.79) pg/mL; p = 0.192]. However, serum concentrations of IL-6 were higher in above recommended percentage body fat patients, showing a trend toward significance [0.48 (0.19-1.04) pg/mL versus 1.22 (0.47-2.38) pg/mL; p = 0.053].

Serum leptin concentrations were higher in excess weight patients comparing to normal weight ones [84.0 (52.9-12.3) ng/mL versus 47.6 (33.5-73.5) ng/mL; p = 0.033], and in individuals with above recommended percentage body fat compared to those with normal percentage body fat [93.8 (56.5-143.6) ng/mL versus 45.8 (33.5-63.6) ng/mL; p = 0.002]. In contrast, adiponectin levels did not differ between groups [normal weight: 46.4 (34.6-61.0) µg/mL versus excess weight: 42.5 (24.7-58.0) µg/mL; p = 0.571; and normal percentage body fat: 46.4 (35.1-59.4) µg/mL versus above recommended percentage body fat: 42.9 (24.3-59.6) µg/mL; p = 0.365].

Serum levels of IL-6, IL-10 and adipokines, serum fasting glucose, lipid profile and C-reactive protein at baseline were similar in omega-3 and control groups (Table 2).

Table 2
Serum concentrations of cytokines, adipokines and biochemical markers of SLE patients at baseline (T0) by treatment groups.

The serum levels of IL-6 and IL-10, leptin and adiponectin did not change after a 12 week treatment. The concentrations of fasting blood glucose, total cholesterol and LDL-cholesterol increased in the omega-3 group, and of LDL-cholesterol increased in control group, although they remained within normal limits (Table 3).

Table 3
Serum concentrations of cytokines, adipokines and biochemical markers at T0 and T1 in both groups.

Comparison of variations (ΔV) between the two groups

The median (IQR) variations (ΔV = T1-T0) of cytokines, adipokines, fasting glucose and lipids concentrations were similar for the two groups (Table 4). The median (IQR) in CRP levels variation between the two groups is represented in Fig. 2, showing a decrease in the omega-3 group while there was an increase in the control group (p = 0.008).

Table 4
Variation (ΔV) of serum cytokines and biochemical markers considering the end (T1) and the beginning (T0) of the study by treatment groups.

Fig. 2
Box-plot of median (range) of C-reactive protein levels variations (ΔV) between T0 and T1 in treatment and control groups.

Discussion

Supplementation with omega-3 (2 g: 1080 mg of EPA and 200 mg of DHA) for 12 weeks had no impact on serum concentrations of IL-6 and IL-10 cytokines as well as on adipokines (leptin and adiponectin) in 49 women with SLE and low disease activity. Bello et al.2020 Bello KJ, Fang H, Fazeli P, Bolad W, Corretti M, Magder LS, et al. Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus. Rheumatol Int. 2013;33:2789-96. reported similar results studying 85 SLE patients who presented no reduction in inflammatory mediators levels (sICAM-1, sVCAM-1 and IL-6) after the use of higher doses of this fatty acid (3 g of omega-3: 1800 mg of EPA and 1200 mg of DHA) for 12 weeks. In contrast, in healthy subjects, cell culture studies demonstrated that EPA and DHA can inhibit the production of IL-6, TNF-α, IL-1 and IL-1β.77 Wallace FA, Miles EA, Calder PC. Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Br J Nutr. 2003;89:679-89.,88 Cawood AL, Ding R, Napper FL, Young RH, Williams JA, Ward MJ, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;20:252-9.,2121 Schubert R, Kitz R, Beermann C, Rose MA, Baer PC, Zielen S, et al. Influence of low-dose polyunsaturated fatty acids supplementation on the inflammatory response of healthy adults. Nutrition. 2007;23:724-30.,2222 Fujioka S, Hamazaki K, Itomura M, Huan M, Nishizawa H, Sawazaki S, et al. The effects of eicosapentaenoic acid-fortified food on inflammatory markers in healthy subjects - a randomized, placebo-controlled, double-blind study. J Nutr Sci Vitaminol. 2006;52:261-5. In a review study, we found conflicting results of the effects of omega-3 on disease activity, on cytokines and on biochemical markers levels, due to the many different methods used.2323 Borges MC, Santos FMM, Telles RW, Correia MITD, Lanna CCD. Polyunsaturated omega-3 fatty acids and systemic lupus erythematosus: what do we know?. Br J Rheumatol. 2014;54:459-66.

This paper indicates an effect of omega-3 on CRP levels as there was a significant variation of serum levels between groups: there was a decrease in the omega-3 group while there was an increase in the control group. Studies in healthy subjects and in patients with chronic inflammatory diseases including diabetes, coronary heart disease, ulcerative colitis, dyslipidemia and rheumatoid arthritis,2424 Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab. 2006;91:439-46.

25 Tsitouras PD, Gucciardo F, Salbe AD, Heward C, Harman SM. High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults. Horm Metab Res. 2008;40:199-205.

26 Micallef MA, Munro IA, Garg ML. An inverse relationship between plasma n-3 fatty acids and C-reactive protein in healthy individuals. Eur J Clin Nutr. 2009;63:1154-6.

27 Farzaneh-Far R, Harris WS, Garg S, Na B, Whooley MA. Inverse association of erythrocyte n-3 fatty acid levels with inflammatory mediators in patients with stable coronary artery disease: the Heart and Soul Study. Atherosclerosis. 2009;205:538-43.

28 Kelley DS, Siegel D, Fedor DM, Adkins Y, Mackey BE. DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men. J Nutr. 2009;139:495-501.

29 Li K, Huang T, Zheng J, Wu K, Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor α: a meta-analysis. PLoS ONE. 2014;9:e88103.
-3030 Julia C, Touvier M, Meunier N, Papet I, Galan P, Hercberg S, et al. Intakes of PUFAs were inversely associated with plasma C-reactive protein 12 years later in a middle-aged population with vitamin E intake as an effect modifier. J Nutr. 2013;143:1760-6. have shown that consumption of omega-3 fatty acids is inversely associated with serum CRP. No information could be found in the literature about the effects of omega-3 on CRP levels in SLE patients.

The higher serum concentrations of leptin described in this study in overweight individuals and in those with above recommended percentage body fat were also observed by other researchers.3131 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:772-83.

32 Al-Suhaimi EA, Shehzad A. Leptin, resistin, and visfatin: the missing link between endocrine metabolic disorders and immunity. Eur J Med Res. 2013;18:12.

33 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-56.
-3434 Van Harmelen V, Reynisdottir S, Eriksson P, Thorne A, Hoffstedt J, Lonnqvist F, et al. Leptin secretion from subcutaneous and visceral adipose tissue in women. Diabetes. 1998;47:913-7. Studies evaluating leptin levels in SLE patients are consistent and indicate higher levels of leptin compared to control subjects, even after statistical adjustment for body mass index (BMI), hypertension, hyperlipidemia and diabetes.3535 Chung CP, Long AG, Solus JF, Rho YH, Oeser A, Raggi P, et al. Adipocytokines in systemic lupus erythematosus: relationship to inflammation, insulin resistance and coronary atherosclerosis. Lupus. 2009;18:799-806.

36 Garcia-Gonzalez A, Gonzalez-Lopez L, Valera-Gonzalez IC, Cardona-Muñoz EG, Salazar-Paramo M, González-Ortiz M, et al. Serum leptin levels in women with systemic lupus erythematosus. Rheumatol Int. 2002;22:138-41.

37 Vadacca M, Margiotta D, Rigon A, Cacciapaglia F, Coppolino G, Amoroso A, et al. Adipokines and systemic lupus erythematosus: relationship with metabolic syndrome and cardiovascular disease risk factors. J Rheumatol. 2009;36:295-7.
-3838 Kim HA, Choi GS, Jeon JY, Yoon JM, Sung JM, Suh CH. Leptin and ghrelin in Korean systemic lupus erythematosus. Lupus. 2010;19:170-4. This finding suggests that adipose tissue could have a significant role in SLE inflammatory response. In contrast to obesity and metabolic diseases, elevated systemic and local levels of adiponectin are present in patients with inflammatory and immune-mediated conditions, like SLE.3131 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:772-83. Since adiponectin has been found to present both pro and anti-inflammatory activities, controversial findings have been observed on the role of total adiponectin in systemic autoimmune and inflammatory diseases.3232 Al-Suhaimi EA, Shehzad A. Leptin, resistin, and visfatin: the missing link between endocrine metabolic disorders and immunity. Eur J Med Res. 2013;18:12.

To our knowledge, the analysis of serum leptin and adiponectin levels after omega-3 fatty acid supplementation in SLE patients is original data of our study. In healthy subjects the results are conflicting. Ramel et al.3939 Ramel A, Parra D, Martinéz JA, Kiely M, Thorsdottir I. Effects of seafood consumption and weight loss on fasting leptin and ghrelin concentrations in overweight and obese European young adults. Eur J Nutr. 2009;48:107-14. found that daily consumption of 1.3 g EPA + DHA caused a significant reduction in serum levels of leptin, noting that there was concomitant weight loss of about 1 kg in these individuals, which could bias these results. Itoh et al.4040 Itoh M, Suganami T, Satoh N, Tanimoto-Koyama K, Yuan X, Tanaka M, et al. Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects. Arterioscler Thromb Vasc Biol. 2007;27:1918-25. reported that after treatment with daily doses of 1.8 g of EPA there was a significant increase in adiponectin production in obese rodents and humans. Studies evaluating omega-3 and omega-6 concentrations in red cell membranes demonstrated positive association between omega-3 with increased adiponectin and decreased leptin serum levels, indicating a potential effect of this fatty acid in controlling inflammation.4141 An WS, Son YK, Kim SE, Kim KH, Bae HR, Lee S, et al. Association of adiponectin and leptin with serum lipids and erythrocyte omega-3 and omega-6 fatty acids in dialysis patients. Clin Nephrol. 2011;75:195-203.,4242 Min Y, Lowy C, Islam S, Khan FS, Swaminathan R. Relationship between red cell membrane fatty acids and adipokines in individuals with varying insulin sensitivity. Eur J Clin Nutr. 2011;65:690-5. However, other authors showed no relationship between the consumption of this nutrient and serum concentrations of those adipokines.4343 Olza J, Mesa MD, Aguilera CM, Moreno-Torres R, Jiménez A, Pérez de la Cruz A, et al. Influence of an eicosapentaenoic and docosahexaenoic acid-enriched enteral nutrition formula on plasma fatty acid composition and mediators of insulin resistance in the elderly. Clin Nutr. 2010;29:31-7.,4444 Wright SA, O'Prey FM, McHenry MT, Leahey WJ, Devine AB, Duffy EM, et al. A randomised interventional trial of w-3 polyunsaturated acids on endothelial function and disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2008;67:841-8.

An increase of total serum cholesterol (p = 0.012) and LDL-c (p = 0.003) in patients receiving omega-3 fatty acid was seen in our study, as well as an increase in serum LDL-c (p = 0.019) in control group individuals. Nonetheless, the median serum concentrations between T1 and T0 remained within the laboratory normal levels. In accordance with our findings, Bello et al.2020 Bello KJ, Fang H, Fazeli P, Bolad W, Corretti M, Magder LS, et al. Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus. Rheumatol Int. 2013;33:2789-96. and Wright et al.4444 Wright SA, O'Prey FM, McHenry MT, Leahey WJ, Devine AB, Duffy EM, et al. A randomised interventional trial of w-3 polyunsaturated acids on endothelial function and disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2008;67:841-8. also described an increase in total cholesterol and in LDL-c in SLE patients who received omega-3. Studies in non SLE subjects with hypertriglyceridemia demonstrated increased serum levels of LDL-c after supplementation with this fatty acid.4545 Pownall JH, Brauchi D, Kilinc C, Osmundsen K, Pao Q, Payton-Ross C, et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Arteriosclerosis. 1999;143:285-97.,4646 Harris WS, Ginsberg HN, Arunakul N, Shachter NS, Windsor SL, Adams M, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4:385-91. This is a clinically important finding, since SLE patients are at increased risk of atherosclerotic cardiovascular disease, which is one of the leading causes of mortality in these individuals.4747 Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med. 1976;60:221-5.

48 Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jansen-McWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997;145:408-15.

49 Telles RW, Lanna CC, Sousa AJ, Navarro TP, Souza FL, Rodrigues A, et al. Progression of carotid atherosclerosis in patients with systemic lupus erythematosus. Clin Rheumatol. 2013;32:1293-300.
-5050 Telles RW, Lanna CC, Souza FL, Rodrigues LA, Reis RC, Ribeiro AL. Causes and predictors of death in Brazilian lupus patients. Rheumatol Int. 2013;33:467-73. Interestingly, in two meta-analysis of population with high risk of cardiovascular and cerebrovascular diseases there was no reduction in the frequency of cardiovascular events, coronary and cerebrovascular as well as overall mortality with this supplementation.5151 Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula S, Chowdhury S, et al. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ. 2012;345:e6698.,5252 Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2012;5:808-18.

In the present study, the low levels of inflammation of the SLE patients may have contributed to the absence of changes in serum cytokine levels after omega-3 supplementation. Therefore, it is not possible to rule out a potential reduction in serum concentrations in patients with moderate to high inflammatory activity indexes. Longer periods of supplementation would yield different results? Larger doses could be beneficial with no risks to the patients? These questions can only be answered by long term randomized studies in which compliance must be controlled by omega-3 cell uptake, which we did not perform.

In conclusion, in this 12 weeks study in low disease activity lupus patients, the supplementation with omega-3 fatty acids was not associated with changes in serum levels of IL-6, IL-10, leptin and adiponectin, although a significant decrease of CRP concentrations was observed.

  • Study conducted at Unidade de Reumatologia, Hospital das Clínicas; Faculdade de Medicina, Departamentos de Sistema Locomotor, Cirurgia e Medicina Interna, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Acknowledgements

The authors thank Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) for the research grant (CDS - APQ-02095-08).

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Publication Dates

  • Publication in this collection
    Nov-Dec 2017

History

  • Received
    1 Apr 2016
  • Accepted
    30 Aug 2016
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