selenium and systemic lupus erythematosus (SLE): A double- blind randomised controlled trial

doi:10.21203/rs.3.rs-3956860/v1

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selenium and systemic lupus erythematosus (SLE): A double- blind randomised controlled trial

https://doi.org/10.21203/rs.3.rs-3956860/v1

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Objective: This randomized trial aimed to investigate the effects of selenium on patients diagnosed with systemic lupus erythematosus (SLE).

Design: 50 SLE patients were randomly assigned to receive daily either 200 μg of selenium supplement or a placebo for eight weeks. Both groups received general healthy lifestyle recommendations. Blood samples to measure the stress markers were assessed before and after the intervention. The systemic lupus erythematosus disease activity index (SLEDA) was used to assess the clinical signs of the patients before and after the intervention.

Results: Selenium supplementation compared with the control group significantly reduced serum high-sensitive reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), Malondialdehyde (MDA), and increased Glutathione peroxidase (GPX), and total antioxidant capacity (TAC). Except for ESR (p= 0.019), the p value of all of the said parameters was ˂0.001. Clinical manifestations of the disease such as arthritis (p= 0.012) and alopecia (p= 0.011) were also improved following the intervention.

Conclusion: A daily intake of 200 μg of selenium supplements for 8 weeks could significantly improve several metabolic markers and clinical manifestations in lupus patients.

Biological sciences/Immunology

Health sciences/Diseases

Health sciences/Rheumatology

Selenium

Systemic Lupus Erythematosus

Glutathione Peroxidase

Malondialdehyde

Lupus is an autoimmune disease in which one’s body's immune system attacks its own tissues and organs which in severe cases, leads to an extremely defective immune system. Systemic lupus erythematosus (SLE), is the most common type of lupus (1), causing widespread inflammation throughout the body and incurring considerable damage to various organs (2). The areas that are most likely to be affected are the joints, skin, brain, lungs, and kidneys (3, 4). It has been reported that patients with SLE are complicated with chronic inflammation and an increased prevalence of insulin resistance, endothelial dysfunction, metabolic syndrome, and coronary atherosclerosis (5, 6). Hence making it a priority to continuously investigate the potential treatment for the disease.

While the etiology of SLE is not fully understood, it has been proposed that it might be multifactorial, in which both genetic and environmental factors might play a role (7, 8). Among environmental factors, multiple mechanisms associated with disease onset and progression have been introduced, and one key mechanism implicated in SLE is oxidative stress, which may be modifiable through diet and/or antioxidant supplements (9).

There is almost no doubt that antioxidant interventions can effectively counteract oxidative stress (10). Selenium supplementation has been reported to improve antioxidant parameters in patients with autoimmune diseases (11). In the human body, selenium tends to attach itself to other molecules, especially proteins and forming selenoproteins (12). Some selenoproteins act as antioxidants thus protecting the body against free radicals and mitigating general inflammation (13). Interestingly, Studies showed that people suffering from lupus had significantly lower serum levels of Selenium than the controls (14). Animal studies have also stated that supplementation with selenium could significantly increase the lifespan of mice involved with an autoimmune disease (15).

As selenium, due to its general anti-inflammatory effects, have been shown to improve metabolic profiles and attenuate oxidative stress (16), we hypnotize that its supplementation might benefit SLE patients. Moreover, to the best of our knowledge, no other study has ever been conducted to investigate the effect of selenium supplementation on metabolic markers and clinical manifestations in patients suffering from lupus. Thus, we conducted this clinical trial study to investigate the matter.

This randomized double-blinded, placebo-controlled trial was approved by the Ethics Committee of Ahvaz University of Medical Sciences under the registration number IR.AJUMS.REC.1401.357, all procedures were conducted in accordance with the institute's regulations and a signed written informed consent was obtained from each participant. The trial was registered at Iranian registry of clinical trials (www.IRCT.IR) on 2022/12/09 under the registration number IRCT20210717051914N2. Participants were recruited from a Rheumatology subspecialty clinic in Ahvaz between November 2022 to March 2023. People who were diagnosed with lupus by a rheumatologist, whose body mass index (BMI) was below 35, and who didn’t have any other autoimmune disease were recruited for the current study. individuals who were pregnant and lactating, or suffered from severe kidney or liver disorders, had severe active inflammation, were diagnosed with a mental illness or took drugs or supplementation affecting mental status were excluded.

Trial procedures

After screening for inclusion and exclusion criteria, A total of 50 patients were selected, randomly assigned to receive either selenium tablet (L-selenomethionine) supplement at a dose of 200 µg once daily for eight weeks (selenium group) or tablets of corn starch (control group). Both groups received lifestyle recommendation and were encouraged to eat healthy and engage in regular exercise. The participants’ compliance was checked every once in three days through phone calls (Fig. 1).

Anthropometric measurements

The Height was measured to the nearest 0.5 cm with a tape measure while the subjects were in a standing position, with their shoulders in a normal alignment and shoes removed. The weight was measured by a digital scale (SECA, Hamburg, Germany. With an accuracy of 0.1 kg) while the subjects were barefoot and wearing a minimum of clothes. Body fat percentage was also measured by BF306 OMRON. For the waist circumference (WC), the narrowest abdominal circumference between the iliac crest and the rib cage was measured. Body mass index was calculated by dividing the weight (kg) by height squared (m2 ). Physical activity was evaluated using an international physical activity questionnaire (IPAQ) and the results were reported as metabolic equivalent hours per week (METs hr/wk) (17).

Table 1

Baseline characteristics and nutrient intakes of the study participants at the baseline (n = 50).
Variables	Selenium group (n = 25)	Placebo group (n = 25)	P-value
Age (year) ¹	38.08 ± 7.66	41.48 ± 10.72	0.203
Physical activity (MET-h/week) ¹	901.11 ± 360.71	871.84 ± 337.84	0.768
BMI (kg/m²) ¹	28.47 ± 3.62	27.17 ± 4.05	0.238
Fat percent (%) ¹	39.20 ± 4.39	37.34 ± 6.72	0.254
WHR ¹	0.82 ± 0.06	0.79 ± 0.07	0.150
Energy intake (kcal/day) ¹	2212.31 ± 225.76	2170.70 ± 213.87	0.507
Carbohydrate intake (g/day) ¹	285.19 ± 60.17	288.29 ± 63.04	0.860
Protein intake (g/day) ²	80.01 (65.39–93.19)	85.64 (70.15–103.20)	0.607
Fat intake (g/day) ¹	81.67 ± 22.66	82.02 ± 26.37	0.959
Fiber intake (g/day) ¹	27.19 ± 13.32	19.02 ± 15.13	0.651
Selenium intake (mg/day) ¹	0.10 ± 0.02	0.12 ± 0.05	0.249
Magnesium intake (mg/day) ¹	340.98 ± 130.51	365.53 ± 131.26	0.510
Zinc intake (mg/day) ¹	9.97 ± 3.95	9.87 ± 2.97	0.920
Vitamin C intake (mg/day) ²	145.69 (25.37–192.90)	100.63 (29.71-189.75)
Gender, % ³ Male Female	1 (4.0) 24 (96.0)	1 (4.0) 24 (96.0)	1.000
Medication, % ³ First group Second group Third group Fourth group Fifth group Sixth group Seventh group	0 (0.0) 9 (36.0) 4 (16.0) 4 (16.0) 3 (12.0) 4 (16.0) 1 (4.0)	1 (4.0) 10 (40.0) 3 (12.0) 3 (12.0) 4 (16.0) 3 (12.0) 1 (4.0)	0.951

- BMI: body mass index, kg/m: kilogram / meter, WHR: waist-to-hip ratio, g: gram, mg: milligram.

- Using independent samples T-test or Mann-Whitney for continuous and chi-square test for categorical variables.

¹ Values are mean ± SD.

² Values are median (25th -75th ).

³ Values are number (percent).

Laboratory investigation

At the start and the end of the trial, 10 cc of blood samples were collected from the participants. The samples were stored at -20 degrees Celsius and after a few days were stored at -70 and were kept there till the end of the examination. After serum separation, the samples were used for the following measurement; Erythrocyte Sedimentation Rate (ESR), C reactive protein (CRP), Anti-ds DNA, total antioxidant capacity (TAC) glutathione peroxidase (GPX), and malondialdehyde (MDA). GPX, TAC, and MDA were measured by the Spectrophotometric method using Germany zellbio ELISA kits. Anti-ds DNA was measure using germany AESKU kits. One-hour ESR measurement was done by tubes containing sodium citrate anticoagulant and THERMA device. Measurement of CRP serum level was done using iranian ENISON kits.

Evaluation of clinical manifestations

Systemic lupus erythematosus disease activity index (SLEDA) is commonly used to investigate and measure the disease activity and response to treatment which assess the disease in separate organs. In this method, each complication of lupus is given a specific score. Psychosis, seizure, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, CVA, and vasculitis are given a score of 8. arthritis, myositis, urinary casts, hematuria, pyuria, proteinuria, are given a score of four. Rash, mucosal ulcers, alopecia, pleurisy, pericarditis, low complement, increased DNA binding are given a score of two. Fever, thrombocytopenia, and leukopenia are given a score of one. The final score spans from zero to 105. A score of six or more indicates the activeness of the disease. A score of five calls for the start of the treatment (18).

Statistical analysis

Data were analyzed using SPSS 23 software. Qualitative variables were compared between the groups by chi-square test. The quantitative variables are all expressed as mean ± standard variation (SD). Kolmogrov–Smirnov test was used to determine the normality of data distribution. For quantitative variables, the means of the two groups were compared by independent t-test and Mann-Whitney test for the parametric and nonparametric data, respectively. Paired t-test and Wilcoxon signed-rank were used to compare the pre and post-intervention variables within groups. ANCOVA test was used to determine any differences in the treatment group at the end of the trial with adjusting for baseline values. Differences were considered significant at p ≤ 0.05.

Fifty-six people were initially recruited for the present study, among which 6 people refrained from participating due to various reasons, remaining 50 people to be matched and then categorized into treatment (n = 25) and control (n = 25) groups.

The baseline characteristics of the subjects are shown in Table 1. Between group analysis showed that there were no significant differences between the two groups when age, weight, BMI, energy intake, body fat percentage, and physical activity are considered. Moreover, based on 3-day dietary records obtained at baseline, no significant difference was found in mean dietary macro- and micro-nutrient intakes among the two groups.

As it is presented in Table 2, between groups analysis showed that there were significant differences between the two groups in regards to the levels of CRP (p = 0.023), GPX (p = 0.017), MDA (p = 0.001), and TAC (p= ˂0.001). Within group analysis showed that after eight weeks of supplementation with 200 micrograms of selenium, participants in the intervention group had significantly lower ESR, CRP, and MDA levels and higher GPX and TAC levels compared with the placebo group. The p value for all of which were ˂0.001 except for ESR which was 0.019. the effect of selenium on dsDNA was not significant (p = 0.45).

Table 2

The effect of the selenium and placebo on stress oxidative and inflammation markers in the study population (n = 50).
Variables	Selenium group (n = 25)	Placebo group (n = 25)	P-value¹
CRP (mg/dl) ³ Before After P-value ²	14.35 ± 4.30 10.94 ± 3.73 ˂0.001	11.70 ± 3.65 11.80 ± 3.73 0.903	0.023 0.422
ESR (mm/h) ⁴ Before After P-value ²	21.0 (13.0-36.5) 18.0 (10.0–30.0) 0.019	22.0 (11.5–37.0) 22.0 (12.0–39.0) 0.770	0.938 0.286
Anti dsDNA (IU/ml) ⁴ Before After P-value ²	0.81 (0.67–0.91) 0.83 (0.65–0.93) 0.627	0.80 (0.68–0.94) 0.81 (0.73–1.14) 0.459	0.969 0.684
GPx (U/Ml) ³ Before After P-value ²	47.59 ± 14.84 75.67 ± 14.34 ˂0.001	58.23 ± 15.63 56.67 ± 16.26 0.197	0.017 ˂0.001
MDA (uM) ³ Before After P-value ²	16.22 ± 2.75 8.16 ± 2.68 ˂0.001	12.19 ± 4.77 12.10 ± 2.82 0.434	0.001 0.001
TAC (mM) ³ Before After P-value ²	0.36 ± 0.15 0.68 ± 0.14 ˂0.001	0.55 ± 0.13 0.55 ± 0.13 0.942	˂0.001 0.002

- CRP: c-reactive protein, ESR: erythrocyte sedimentation rate, GPx: glutathione peroxidase, MDA: malondialdehyde, TAC: total antioxidant capacity.

¹ Using independent samples T-test or Mann-Whitney U-test.

² Using paired-sample T-test or Wilcoxon U-test.

³ Values are mean ± SD.

⁴ Values are median (25th -75th ).

Table 3

The effect of the selenium and placebo on disease activity and disease features in the study population (n = 50).
Variables	Selenium group (n = 25)	Placebo group (n = 25)	P-value¹
SLEDAI score ³ Before After P-value ²	12.0 (6.0-16.5) 9.0 (4.5–15.5) 0.005	10.0 (6.5–15.0) 8.0 (6.0-14.5) 0.038	0.741 0.733
Arthritis score ³ Before After P-value ²	6.0 (3.5-8.0) 4.0 (0.5-6.0) 0.012	5.0 (3.5-6.0) 5.0 (3.5-6.0) 0.083	0.316 0.723
Alopecia score ³ Before After P-value ²	4.0 (0.0-6.5) 2.0 (0.0–4.0) 0.011	0.0 (0.0-6.5) 0.0 (0.0–6.0) 0.084	0.452 0.911
Rash score ³ Before After P-value ²	0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.276	0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.317	0.805 0.584

¹ Using Mann-Whitney U-test.

² Using Wilcoxon U-test.

³ Values are median (25th -75th ).

Table 3 shows that there were no significant differences between the two groups regarding any of the parameters. However, it is clearly shown that supplementation with selenium could notably improve scores of arthritis (p = 0.012) and alopecia (p = 0.011) and total score of clinical manifestation (p = 0.005). while its effect on rash score was not significant (p = 0.276).

The present study showed that supplementation with selenium significantly lowered the amounts of CRP, MDA, while elevating GPX, TAC levels. Moreover, the intervention proved beneficial in regards to the clinical manifestations of the disease.

In line with our findings, a small case control study conducted on 62 teenagers, showed that individuals suffering from lupus had significantly lower selenium and GPX levels than healthy controls (19). However, the study did not fully disregard the fact that this finding may solely be due to the low consumption of selenium food sources in the patients. A systematic review revealed a positive correlation between selenium deficiency and higher levels of specific antibodies in SLE patients but it denied a therapeutical role for selenium (20). On the other hand, another observational study recruiting 111 patients and 118 controls whose selenium consumption did not differ, found that higher selenium intake was inversely associated to the presence of atherosclerotic plaques in the SLE group, but not in healthy subjects (21). A study in healthy volunteers assessed lipid profile and inflammatory markers after a single intake of 20g of Brazil nut, showing its significant effect on lowering levels of IL-1, IL-6, tumor necrosis factor—alpha (TNF-α) and interferon gamma (IFN-γ) (22).

The exact mechanism through which selenium implements its effects is not clear, but there are some conjectures. Several biological effects of selenium occur through its incorporation into selenoproteins, many of which are through the regulation of immune cells (23). In vitro studies have shown that increased selenium availability leads to impaired differentiation and maturation of macrophages and inhibited optimal B cell activation (24). Selenuproteins have been found to significantly reduce the number of B cells in the body. Since overactive B cells produce the autoantibodies that cause tissue damage in lupus patients, reducing their overall number is a sure way to decrease the complications (20). Another study demonstrated that supplementation with selenized-yeast in healthy men results in reduction of activated T and natural killer (NK) cells and related cellular pathways (25). Furthermore, it has been shown that supplementation with selenium-enriched broccoli enhanced immune response in healthy individuals (26). GPX, an intracellular antioxidant enzyme whose primary job is to reduce hydrogen peroxide to water to protect body against free radicals, is known to be dependent on selenium (27). A study confirmed that elevated consumption of selenium-rich foods resulted in a significant elevation of GPX (28). Moreover, selenium deficiency was associated with increased the expressions of TNF-α and IL-1β and increased activity of COX and NOS (29). The proposed mechanism can be confirmed by the present study in which supplementation with selenium increased the levels of GPX and decreased stress markers.

The beneficial effects of selenium on autoimmune markers have been seen in other studies. In a six-month intervention program in which 200 µg of selenium supplements were given to patients suffering from cervical intraepithelial cancer, MDA levels have been significantly reduced while TAC levels were risen. Aside from improved metabolic profile, the intervention also led to the regression of the tumor (30). In a study conducted on women suffering from polycystic ovary syndrome, supplementation with selenium resulted in decreased levels of CRP and MDA (31). Finally, a meta-analysis comprised of 13 clinical trial studies have shown that selenium supplementation could significantly reduce oxidative stress by increasing TAC and GPX levels (32).

The present study showed that supplementation with selenium could notably improve the clinical manifestations of the disease, namely alopecia and arthritis. These results could also be ascribed to the general anti-inflammatory effects of selenium. Other literature has also confirmed that oxidative stress could be strongly associated with androgenic alopecia (33). It was shown that higher levels of stress markers, such as MDA and CRP, are associated with higher incidence of alopecia (34, 35). (36). High levels of serum stress markers such as CRP and the subsequent inflammation are widely recognized in the onset, progression, and exacerbation of arthritis (37). Li et al, reported that supplementation with selenium reduced the degree of articular cartilage irregularity and knee joint stenosis in mice (38).

There were also some studies whose results were not entirely in agreement with ours. For instance, Bahmani et al, reported that supplementation with selenium on nephropathic diabetic patients did not have a significant effect on serum CRP and MDA levels (39). Valenta et al. reported that high-dose supplementation with selenium for a period of 14 days on septic patients did not significantly alter CRP levels and could not reduce mortality (40). In another study conducted on adults suffering from obesity who had started participating in vigorous exercise, it was reported that supplementation with 200 µg of selenium for 3 weeks did not have a significant effect on TAC levels (41). The conflicting results may be due to different sample size or characteristics, study durations, and/or methodological factors. Nonetheless, evidence abounds pointing out the many beneficial effects of selenium, entailing improved metabolic health, increased longevity, and enhanced quality of life (42, 43).

To the best of our knowledge, the present study was the first to examine the effects of selenium supplementation on a wide range of anthropometric and metabolic markers in lupus patients. However, some limitations should be noted. First is the relatively low number of recruited subjects and the short period of intervention, which might weaken the study results. Second was the few number of male participants which might have weaken its generalization ability. Lastly, by categorizing the participants into several groups, each receiving a different dose of MCP could have given us a chance to see if the said effects were dose-dependent.

We found that supplementation with selenium could notably improve the stress markers of the patients suffering from SLE. These results call for a need for further clinical trials with a larger sample size and longer period of intervention to further our understanding of the effects of selenium on lupus.

Author Contribution

author 1 wrote the main manuscript text and. All authors reviewed the manuscript.

Data Availability

All data generated or analysed during this study are included in this published article.

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No competing interests reported.

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selenium and systemic lupus erythematosus (SLE): A double- blind randomised controlled trial

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Anthropometric measurements

Laboratory investigation

Evaluation of clinical manifestations

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