key: cord-0028558-zoiefmy9
authors: Goessler, Karla F.; Gualano, Bruno; Nonino, Carla B.; Bonfá, Eloisa; Nicoletti, Carolina Ferreira
title: Lifestyle Interventions and Weight Management in Systemic Lupus Erythematosus Patients: A Systematic Literature Review and Metanalysis
date: 2022-01-31
journal: J Lifestyle Med
DOI: 10.15280/jlm.2022.12.1.37
sha: 987cbdbc8833350c0224f6a5b3997480e623254c
doc_id: 28558
cord_uid: zoiefmy9

BACKGROUND: We aimed to identify and describe different types of lifestyle interventions primarily or secondarily focused on weight loss in SLE patients. METHODS: A systematic search of controlled trials published until June 2021 that assigned adults patients after dietary or exercise intervention resulted in 248 studies initially screened. RESULTS: Six studies with seven interventions (3 dietary and 4 exercise training programs) fulfilled the eligibility criteria and were included in the meta-analysis with a median of age 35.8 (31.3 to 49.0 years); median of BMI 26.6 (25.2 to 33.6 kg/m(2)). After six to twelve weeks of diet or exercise program, no differences were observed in body weight [-1.539 (-4.482 to 1.405) kg (CI 95%), p = 0.306]. Also, a subgroup analysis also revelated no body weight difference following dietary intervention [-3.561 (-9.604 to 2.481) kg (CI 95%), p = 0.248] or exercise intervention [-0.910 (-4.279 to 2.460) kg (CI 95%), p = 0.597]. CONCLUSION: The results showed that different protocols of exercise intervention or diets were not effective to reduce body weight in patients with SLE. However, only one of the selected trials had a specific study design and protocol focusing on weight loss management.

Obesity is a public-health condition associated with various comorbidities and disabilities, with an increasing prevalence across the world. In systemic lupus erythematosus (SLE) patients, the frequency of obesity is similar to or higher than in general populations [1] , with prevalence ranging from 28% to 50% [2, 3] .

Considering that obesity may induce a systemic low-grade inflammatory environment, by increasing the production of cytokines [e.g. tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)] [4] , this condition has been associated with the pathogenesis of SLE [2] . Obesity-driven events (such as oxidative stress) can initiate inflammation through the transition of adipose tissue macrophages from M2 to M1, leading T cells recruitment [5] . This condition is also associated with lower B-regulatory and invariant natural killer (NK) cells within the adipose tissue [6] . Furthermore, chronic overnutrition-driven adipocyte hypertrophy leads to tissue growth with consequent hypoxia and chronically elevated basal lipolysis, which increased the fat free acids release [7] . Lastly, these mechanisms promote pro-inflammatory cytokine release, adipocyte dysfunction and may lead to insulin resistance [8] , which if not appropriately resolved, can underlies or exacerbates autoimmunity [9] .

Other mechanisms have been appointed to connect obesity with SLE, such as prolonged use of corticosteroid therapy [10] , vitamin D deficiency (which are frequently observed in SLE patients and in obese subjects), hypoactivity [11] , and dysbiosis of gut microbiota ( Fig. 1 ) [1] . A high-fat diet is responsible for excess of weight and also for gut microbiota dysbiosis, which per se may lead to a deregulation of intestinal immune responses [6, 12] . On the other hand, vitamin D deficiency levels have been related to changes on immune cell differentiation [6, 13] . Moreover, regular exercise strengthens the immune system [14] by promoting a release of antinflammatory cytokines [14] , reduction in neutrophil chemotaxis [15] , increasing the concentration of circulating leukocytes [16] , decreasing of lymphocyte levels [17] and inhibition of monocyte and/or macrophage infiltration into adipose tissue [18] . Thus, sedentary behavior and low physical activity levels is related to an unfavorable level of adiposity-associated inflammation [19] .

In this context, several studies have shown that obesity is an independent risk factor associated with worse SLE disease activity [2] , dyslipidemia [20] , cumulative organ damage [e.g. nephritis] [21] , depression [22] , fatigue [22, 23] and decreased quality of life [20, 23] . A meta-analysis published by Sun et al., 2017 [24] showed that patients with SLE were more susceptible to develop metabolic syndrome compared with healthy individuals.

In view of this, weight loss interventions have been thought to ameliorate symptoms and minimize the need for medications among rheumatic diseases [25] . However, there is large uncertainty regarding the impact of different types of interventions (e.g., diet, exercise, behavior changes) on body weight in SLE patients. Therefore, the objective of this systematic review and meta-analysis was to (1) identify and describe different types of lifestyle interventions primarily or secondarily focused on weight loss in SLE patients and

(2) verify if these interventions promote weight loss. Based on the findings, we also pointed out the main gaps in the field.

This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO CRD42021276607) and the protocol was designed and conducted in accordance with the recommendations of Preferred

Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [26] .

A systematic search of the literature was independently con- These were combined with a sensitive search strategy in order to identify 'randomized controlled trials' or 'randomized study design' performed in 'humans'. Observational studies and non-randomized and non-controlled trials (quasi-experimental designs) were excluded (Supplementary File 1).

Studies were included if they had a randomized controlled design and included adults (≥ 18 years) with SLE disease.

Trials should evaluate a lifestyle intervention (diet, exercise or both) and report the effect on body weight or body mass index (BMI) (pre-and/or post-intervention data). Only data from full-text, peer-reviewed publications were considered for inclusion. Filters for language were not applied.

All identified studies were imported into Rayyan, a specific electronic application for systematic review and meta-analysis (https://rayyan.qcri.org/welcome). Duplicates were identified and removed. According to eligibility criteria, two reviewers independently screened the titles and abstracts of all studies. Disagreements between both reviewers were discussed and resolved by consensus.

The following data were extracted: (1) first author's surname, (2) publication year, (3) country, (4) study design, (5) sample size, (6) participant characteristics (mean age, sex and baseline BMI), (7) disease duration, (8) disease activity, (9) intervention characteristics (type, duration, frequency), and (10) body weight data (pre and post intervention). For those studies that met the inclusion criteria but did not report absolute body weight data at pre-and/or post-intervention period, the corresponding author was contacted twice by e-mail over a 15-day period to provide the missing information. were first converted to standard deviation (SD) by the formula: SD = SEM ×    . We used only pre-to-post data for SLE patients, without including data from healthy individuals when used as control comparator. Individual studies were pooled using random-effect model using p ＜ 0.05

(two-tailed) as significance level. Additionally, standardized mean difference (SMD) (mean difference between pre-and post-intervention divided by the pooled SD) was also computed. Descriptive data for each study is reported as mean ± SD and mean weighted difference (95% confidence interval (CI)). I 2 statistics were calculated to provide an estimation of the degree of heterogeneity in effect among studies (25-50% small amounts of inconsistency; 50-75% medium amounts of inconsistency and ＞ 75% large amounts of inconsistency) [27] . Publication bias was examined by visual inspection of the different funnel plots' asymmetry.

The effect of publication bias on the results was verified by Duval and Tweedie's Trim and Fill procedure [28] .

Finally, sensitivity analysis excluding selected trials with discrepant results from the overall trials were performed to explore results' robustness. analysis (Fig. 2) . The full-text was retrieved from 19 articles, and 17 met the inclusion criteria. Four studies reported complete weight data (pre-and post-intervention) and 13 articles reported only baseline data. Two authors provided more detailed information, whereas two others reported the lack of body weight data following the intervention. The other authors (from nine studies) did not reply to the contact.

Therefore, six studies were included in the analysis. A total of seven distinct interventions were included in the metaanalyses. One study performed an exercise protocol with only aerobic exercise at a public park [32] . Two studies assessed dietary interventions (duration ranged from 6 to 12 weeks) [33, 34] .

One of them [33] tested two different types of diet (low caloric diet vs. low glycemic index diet). Another study [34] assessed a low cholesterol diet (30% or less calories from fat, in which 7% were from saturated fat, 13% from monounsaturated fat, 10% from polyunsaturated fat, and ＜ 200 mg of cholesterol per day).

All studies had sufficient data to warrant inclusion in the meta-analysis. Fig. 4 (Fig. 4C ).

Funnel plots were generated and analyzed by visual inspection, indicating that there was not publication bias (Fig. 5) . Epidemiological studies have consistently demonstrated a predominance of women with lupus compared to men [35, 36] , highlighting some distinct clinical features between them, such as severest disease form among male patients [37] . Sex-related differences regarding body weight loss also must be taken into consideration when analyzing interventions related to SLE. Of note, men appear to be more likely to lose weight than women [35] , which might explain in part the null effect of the interventions on body weight.

It is therefore relevant that all studies included in this meta-analysis involved only women, minimizing this possible confounding variable.

The accelerated development of cardiovascular disease and other comorbidities in SLE is determined by traditional risk factors, including obesity, and disease-specific factors [immunogenetics, immune dysfunction, chronic inflammation, and medication toxicity] [38] . In the studies assessed herein, four of them had patients with overweight [29] [30] [31] [32] , and two with obesity [33] . In fact, SLE patients present with a high frequency of overweight and obesity [2, 39] , and the prevalence of excess body weight (BMI ＞ 25 kg/m 2 ) in Brazilian SLE patients varied from 62.4% to 64.1% [3, 39] .

The use of corticosteroids was reported in most study [29, 30, [32] [33] [34] . Corticosteroids are often used in SLE treatment [40] and its prolonged use was reported to be related to weight gain (ranged from less than 10 to almost 30 pounds) [41] . Study with a different population (adolescents) reported that some patients became overweight or obese after corticosteroids treatment and weight gain was associated with cumulative medications dose [42] . Indeed, the excess of body weight observed in SLE patients on chronic use of corticosteroids determines higher risk of cardiovascular disease, generating a vicious cycle in which weight gain can maintain disease activity, requiring the maintenance of these medication [43] . Thus, it is plausible to assume that the chronic use of corticosteroids may have accounted for the inefficacy of the lifestyle interventions on weight loss management on this meta-analysis. However, the objective analysis of this confounding variable was not tested, as the studies did not provide consistent medication data.

Excess body weight is a multifactorial condition in SLE and may have several deleterious effects. In fact, obesity condition and excess of adipose tissue could increase the levels of pro-inflammatory cytokines which can intensify the inflammatory process and increase the risk of higher mortality in SLE patients [2, 6] . Also, excess weight was associated with an increase in the clinical activity [44] . [45] , especially because exercise may reduce possible side effects of glucocorticoid treatment, including muscle weakness and overweight [46] , and also, may have positive effects on cardiovascular function [47] .

In addition, a cross-sectional study evidenced that lower physical fitness (e.g. muscular strength, and flexibility) is associated with higher body weight and central adiposity in women with SLE [48] , showing the importance of exercise training for these patients. Recent overview of reviews focusing on the effects of exercise training programs on weight loss in adults with overweight or obesity had shown that exercise training promotes body weight reduction in these patients, but in a relatively small magnitude [49] . More importantly, despite outcomes of weight, exercise training programs promoted fat, and visceral fat loss, which is crucial to enhance cardiometabolic health [49] . However, in this meta-analysis, the different protocols of exercise programs

were not able to change body weight. The present review has some limitations to be point out. Our findings demonstrate that specifics protocol of exercise training and low-calorie, low-lipid and low-glycemic diets are not effective to reduce weight of SLE patients with overweight or obesity. However, most of these protocols were not specifically designed for weight management.

Given that obesity is highly prevalent amongst patients with SLE, we highlight the importance of establishment of efficient strategies and guidelines for weight loss and reduction of excessive adipose tissue.

This study was supported by Sao Paulo Research Foundation -FAPESP (grants #2019/18039-7, #2020/01893-2 and #2020/15126-3).

None to declare. 

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