Body Weight-Related Differences in Adipokines and Inflammatory Markers Among Women with Systemic Lupus Erythematosus

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease that affects millions of individuals worldwide,¹ with a predominance in female gender.² The pathophysiology of SLE involves a complex interplay of environmental, hormonal, and genetic/epigenetic factors^3,4 that lead to the production of autoantibodies against cellular antigens, promoting excessive immune activation and resulting in progressive inflammation and tissue damage.⁵ The immune dysregulation in SLE is largely driven by the inflammatory response of autoreactive CD4+ T lymphocytes. These cells initiate a cascade of events that lead to the overproduction of pro-inflammatory cytokines, including interleukin (IL)-6, IL-2, IL-17, IL-22, and tumor necrosis factor (TNF)-α.^6,7 Clinical manifestations are notably complex and diverse, reflecting the multifaceted nature of this autoimmune disease.⁸ Common manifestations include skin lesions (the most frequent one), joint involvement, nephritis, neuropsychiatric symptoms, and hematological abnormalities.^5,9

The treatment of SLE focuses on symptom control, complication prevention, and reducing organ damage. This therapeutic approach typically includes medications such as glucocorticoids, immunosuppressants, and antimalarial drugs, complemented by lifestyle modifications like physical exercise and dietary adjustments.¹⁰ Antimalarial drugs, particularly hydroxychloroquine (HCQ), play a crucial role in SLE management by controlling inflammation, reducing disease activity, and preventing organ damage.^10–12 Beyond these immunomodulatory effects, HCQ has demonstrated significant metabolic benefits. Studies indicate that HCQ use is associated with a 71% reduction in the prevalence of metabolic syndrome among patients, highlighting its potential to mitigate metabolic risks commonly seen in SLE.^13–17 Additionally, HCQ appears to exert a protective effect against the adverse metabolic consequences of corticosteroid therapy, improving lipid profiles and enhancing insulin sensitivity in patients with SLE.¹⁸

The presence of metabolic disorders in SLE adds complexity to disease management, potentially impacting symptom severity, disease progression, and treatment efficacy.^19–21 Obesity potentially accelerates the progression of SLE,^22,23 likely due to adipose tissue (AT) accumulation, which plays significant immunometabolic effects.^24–26 Several studies have shown a link between chronic low-grade inflammation due to excess AT and poor outcomes in SLE,^27–30 such as an increase exacerbation of disease activity,²³ impairment of renal function,³¹ and worsening of cognitive and functional capacity,³² as well as overall quality of life.³³ Additionally, excess AT is known to contribute to endothelial dysfunction, thereby increasing the risk of cardiovascular disease in patients with SLE.^34,35 Morphological changes in AT associated with obesity are driven by the activation of immune cells and the secretion of key adipokines such as leptin, adiponectin, and inflammatory cytokines.³⁶ Moreover, hypertrophy and hyperplasia of the AT lead to tissue expansion, resulting in hypoxia and increased lipolysis rates. This, in turn, promotes elevated fatty acid circulation, insulin resistance, and increased oxidative stress.^20,37

As for AT, body mass index (BMI) also positively associates with serum leptin^38,39 and negatively with serum adiponectin.⁴⁰ However, there are conflicting results regarding adipokine levels in SLE.^41–43 Some studies have reported elevated serum levels of leptin^44,45 and adiponectin^43,46 in patients with SLE compared to controls, but the precise mechanisms remain unclear. A recent meta-analysis that included 34 studies (1,844 SLE patients and 1,511 healthy controls) revealed elevated plasma leptin levels in SLE.⁴⁷ In contrast, other recent studies have demonstrated either unchanged or decreased levels in SLE patients.^48,49 Given the role of body fatness in these parameters, it is possible to speculate that nutritional status could partially explain this discrepancy.

This study aimed to investigate the influence of body weight on serum adipokine profiles and adipose tissue gene expression in women with SLE. Specifically, it evaluated leptin, adiponectin, the adiponectin-to-leptin ratio, IL-6, and TNF-α according to nutritional status, and explored their associations with metabolic, anthropometric, and immunological parameters. In addition, the study examined the relationship between HCQ dosage and metabolic–inflammatory markers to elucidate potential protective metabolic effects of HCQ in SLE.

Patients and Methods

Study Design and Patients Selection

We performed a cross-sectional study nested within a randomized controlled trial (clinicaltrials.org: NCT05097365).⁵⁰ Consecutive recruitment was conducted at the Lupus Outpatient Clinic of the Rheumatology Division, HCFMUSP, and all patients fulfilled the 2019 European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria for SLE.⁵¹ Inclusion criteria were as follows: 1. female gender; 2. pre-menopausal status, 3. aged between 18 and 45 years; 4. inactive disease (SLEDAI-2K score ≤ 4);⁵² 5. prednisone uses ≤ 10 mg/day, 6. hydroxychloroquine use at a stable dose at least 3 months, 7. BMI greater than 18.5 kg/m². Additionally, exclusion criteria included 1. current chronic disease (diabetes mellitus, arterial hypertension, or cancer), 2. current smokers, 3. use of anticoagulants, 4. current methotrexate use, 5. current infection, 6. pregnancy, 7. current use of any supplementation with methyl donor micronutrients (eg vitamin B12, folic acid), 8. cognitive dysfunctions that impede adequate comprehension of the intervention recommendations.

Patients with SLE were categorized into two groups based on nutritional status according to BMI: Normal Weight (NW) group (BMI between 18.5 and 24.9 kg/m²) and Excess Body Weight (EBW) group (BMI ≥ 25 kg/m²).

Ethical Considerations

Ethical approval was obtained by the Ethics Committee of the Clinical Hospital of the Faculty of Medicine of the University of São Paulo (CAAE.: 47,317,521.8.0000.0068). All participants signed the Informed Consent Form. All procedures were carried out following ethical standards and recommendations of the Declaration of Helsinki.

Patients Protocol

Patients with SLE attended our laboratory and completed phenotypic assessments (clinical, anthropometric, and biochemical). Personal characteristics (ie age, self-declared race, previous smoking history) and disease parameters [ie disease duration and disease activity (according SLEDAI-2K)],⁵³ and current drug therapy were obtained during personal interview and medical records. Patients were evaluated during periods of clinical remission, defined by low disease activity (SLEDAI-2K), to minimize the influence of active clinical manifestations on metabolic and inflammatory outcomes.

Blood samples were collected for biochemical analysis. In addition, patients had adipose tissue collected via percutaneous biopsies for gene expression analysis. Immediately after the biopsy procedure, the adipose tissue sample was placed in a cryogenic tube and immersed in liquid nitrogen solution for instant freezing.

Anthropometric Analysis

For weight and height measurements, a Filizola scale (Campo Grande, MS, Brazil), 1–200 kg, with an error margin of 50 g and a stadiometer coupled to the same Filizola scale were used, respectively. The formula BMI = weight (kg)/height (m²) was applied to BMI calculation. For abdominal circumference measurements, a plastic tape measure was placed midway between the lowest rib and the iliac crest. Abdominal obesity was considered if the abdominal circumference was ≥80 cm.⁵⁴

Serum Biochemical Analysis

Laboratory measures included serum levels of serum antibodies against double-stranded DNA (anti-dsDNA) detected by enzyme-linked immunosorbent assay (ELISA) (INOVA Diagnostics Inc., San Diego, CA) and confirmed by indirect immunofluorescence within Crithidia luciliae; serum complement levels (C3 and C4) [measured by immunoturbidimetric assay], fasting blood glucose, triglycerides, total cholesterol and its fractions [measured by the enzymatic colorimetric technique], and C-reactive protein (CRP) [measured by the immunoturbidimetric technique].

The analysis of serum leptin and adiponectin was performed using the commercial kit MILLIPLEX MAP Human Adipocyte Magnetic Bead Panel – Endocrine Multiplex Assay and TNF-α and IL-6 were assessed by MILLIPLEX® Human Cytokine/Chemokine/Growth Factor Panel A – Immunology Multiplex Assay (Millipore, Missouri, USA) on a Luminex® analyzer (Luminex®, MiraiBio, USA) according to the manufacturer’s instructions. Finally, the data obtained were normalized and expressed using Milliplex Analyst 5.1 software (EMD Millipore). The adiponectin:leptin (adipo/lep) ratio was determined using the equation: (adiponectin (μg/mL)/leptin (ng/mL).⁵⁵ Adipo/lep ratio of <0.5 indicates a severe increase in cardiometabolic risk.⁵⁶

TNF-α, IL6, LEP, and ADIPOQ Gene Expression Analysis

RNA was extracted using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s instructions and cDNA synthesis was carried out with the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems), following the manufacturer’s guidelines on a thermocycler (MJ Research PTC-100®). Expression of TNF-α, IL6, LEP, and ADIPOQ genes were analyzed in duplicate using quantitative real-time polymerase chain reaction (PCR) on a Step One Plus Real-Time PCR System (Applied Biosystems). The reaction included 10 ng of cDNA, TaqMan MGB 6-FAM fluorogenic probes (Applied Biosystems), and TaqMan™ Gene Expression Master Mix (Applied Biosystems). The thermal cycling conditions were 50°C for 2 minutes, 95°C for 10 minutes, followed by 40 cycles of denaturation at 95°C for 15 seconds, and annealing/extension at 60°C for 60 seconds. Relative expression levels were calculated using the 2-ΔΔCt method⁵⁷ with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin (ACTB) as endogenous controls.^58,59 Relative gene expression was calculated using the comparative Ct (2−ΔΔCt) method, with the normal-weight group used as the calibrator (expression = 1).

Statistical Analysis

All analyses were conducted using the Statistical Package for the Social Sciences (SPSS version 22.0 [IBM Corp., Chicago, IL]). Variables were reported as mean and standard deviation. The normality of data distribution was assessed using the Shapiro–Wilk test. Independent samples t-tests and Mann–Whitney tests were employed to compare numeric variables between groups. Multiple linear regression was used to determine the contribution of HCQ use (per kg) to lipid profile, leptin, adiponectin serum levels and adipo/lep ratio, as well as, the contribution of leptin, adiponectin serum levels to metabolic parameters. Separate linear regression models were constructed for each outcome variable. Statistical significance was set at 5% (p < 0.05).

Results

Participant Characteristics

Fifty patients with SLE were enrolled in this study; classified according to BMI as normal weight (NW; n= 23) and excess body weight (EBW; n = 27). As expected, BMI, abdominal circumference, and body fat percentage were significantly higher in the EBW group compared with normal-weight women (p < 0.001). Additionally, the EBW group had elevated serum levels of total cholesterol, LDL-c, and CRP compared to the NW group (p < 0.05) (Table 1). The groups were comparable in age, disease duration, SLEDAI scores, anti-dsDNA, and complement C3 and C4 levels (all p > 0.05), confirming that disease activity was similarly low across participants. HCQ use by body weight (mg/kg/day) was higher in NW group (p < 0.05) (Table 1). Glucocorticoid use was similar between groups, with 5 patients in the NW group and 5 in the EBW group receiving treatment (p > 0.05).

Table 1 General Characteristics of Patients with Systemic Lupus Erythematosus by Body Weight Category

Adipokine and Inflammatory Profiles

Serum leptin levels were higher, while adiponectin levels were lower in the EBW group compared to those of NW group. The leptin/adiponectin ratio was markedly elevated in the EBW group (p < 0.001), indicating an adipose tissue dysfunction pattern. In contrast, TNF-α and IL-6 levels were similar in both groups (p > 0.05) (Table 1).

Associations Between Adipokines and Metabolic–Inflammatory Parameters

Serum leptin levels correlated positively with BMI (r = 0.66; p < 0.001), abdominal circumference (r = 0.61; p < 0.001), and CRP (r = 0.36; p = 0.01). In contrast, serum adiponectin levels showed inverse correlations with BMI (r = - 0.58; p < 0.001), abdominal circumference (r = - 0.66; p < 0.001), total cholesterol (r = - 0.30; p = 0.034) and LDL-c (r = - 0.32; p = 0.026). The leptin/adiponectin ratio correlated negatively with BMI (r = - 0.69; p < 0.001), abdominal circumference (r = - 0.72; p < 0.001), total cholesterol (r = - 0.30; p = 0.040) and LDL-c (r = - 0.31; p = 0.030). No significant correlations were observed between adipokines levels and C3, C4, or anti-dsDNA levels, however, the adipo/lep ratio showed inverse correlations with C4 complement levels (r = - 0.31; p = 0.030).

Gene Expression in Adipose Tissue

Expression of TNF-α, IL6, LEP, and ADIPOQ genes were significantly upregulated in EBW groups compared with normal-weight women (p < 0.05) (Figure 1). No significant correlations were observed between adipose tissue gene expression levels serum levels (all p > 0.05).

Figure 1 Relative TNF-α ((A), n = 36), IL-6 ((B), n = 39), LEP ((C), n = 44) and ADIPOQ ((D), n = 45) expressions in patients with systemic lupus erythematosus according to nutritional status. Expression of TNF-α, IL-6, LEP and ADIPOQ were higher in patients with systemic lupus erythematosus and excess body weight than normal weight. NW values were used as the calibrator (expression = 1) in the 2−ΔΔCt analysis. The indicated sample size (n) corresponds to samples with valid amplification included in each gene expression analysis. *: p <0.05. Abbreviations: NW, Normal Weight; EBW, excess body weight.

Stratification by Adipo/Lep Ratio

To further explore the relationship between adipose dysfunction and immunological parameters, patients were divided into two groups according to the adipo/lep ratio: ≤ 5 (adipose dysfunction) and > 5 (normal adipose function). Both groups were comparable in age, disease duration, SLEDAI scores and anti-dsDNA levels (all p > 0.05), indicating similar levels of clinical disease activity. Notably, serum C4 levels were significantly higher in patients with an elevated adipo/lep ratio (p = 0.004), whereas C3 levels showed a similar upward trend that did not reach statistical significance (p = 0.055) (Table 2).

Table 2 Clinical and Complement Profile in Patients Stratified by Adiponectin/Leptin Ratio

Impact of Hydroxychloroquine

Multiple linear regression analyses were performed to examine the associations between HCQ use and anthropometric or metabolic parameters (Table 3). HCQ daily dose normalized by body weight (mg/kg/day) showed negative associations with abdominal circumference (β = −0.43; 95% CI: −5.91 to −1.34; p = 0.003) and fat mass percentage (β = −0.38; 95% CI: −1.83 to −0.27; p = 0.009). Conversely, HCQ use was positively associated with adiponectin levels (β = 0.45; 95% CI: 6.85 to 28.8; p = 0.002) and the adipo/lep ratio (β = 0.39; 95% CI: 2.98 to 19.5; p = 0.009), suggesting a protective metabolic profile. There was also a trend for higher HCQ doses to be associated with increased HDL-c (p = 0.059) and reduced leptin levels (p = 0.058).

Table 3 Multiple Linear Regression Models Showing the Relationship Between Hydroxychloroquine Use (mg/kg/Day) and Metabolic and Body Composition Parameters in SLE

Discussion

In this study involving women with SLE and low disease activity, excess body weight was associated with a pro-inflammatory and adverse metabolic profile, characterized by elevated TNF-α, IL-6, LEP expression in adipose tissue, higher serum leptin and lower adiponectin levels, and a decreased adiponectin/leptin ratio. Despite similar SLEDAI scores and immunological markers across BMI groups, patients with adipose tissue dysfunction, defined by a low adipo/lep ratio, showed higher C4 complement levels.⁶⁰ Additionally, HCQ dosage adjusted by body weight correlated with more favorable metabolic parameters, including lower adiposity and higher adiponectin levels.

The great advantage of the present study was to include patients with definitive SLE diagnosis according to 2019 European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria.⁵¹ The main strength of this study was the robust control of confounders provided by a homogenous sample. First, only female patients were consecutively included due to avoid any specific sex-differences in metabolic patterns. Moreover, only patients with SLE and inactive disease were selected to avoid the influence of the exacerbated inflammation in the variables of interest.⁶¹ Also, only patients with SLE and current, stable use of HCQ, the cornerstone treatment of the disease⁶¹ to prevent heterogeneities in response to this drug.^62,63 In this regard, all included patients should be at stable daily dose for at least 3 months since this period is required to promote significant metabolic changes.⁶⁴ Importantly, any supplementation with vitamin B12 or folic acid was excluded, as it is part of the exclusion criteria of the clinical trial related to this study.⁵⁰

Patients with SLE and excess weight demonstrated increased body fat and abdominal obesity which were indicative of significant adipose tissue accumulation, particularly in the abdominal region.⁶⁵ This adipose tissue accumulation may exacerbate inflammatory status associated with SLE.⁶⁶ The role of TNF-α and IL-6 in inflammatory processes, as well as their pleiotropic effects in autoimmune diseases^67,68 and metabolic disorders,⁶⁹ is well-established. Elevated IL-6 and TNF-α expression were observed in previous findings linking these cytokines to SLE serological activity⁷⁰ and to metabolic–immune interactions.⁷¹ Therefore, it would be expected that both TNF-α and IL-6 levels would be increased in SLE^68,72–74 and obesity.^75–78 Despite these findings, the present study did not identify increased levels of TNF-α and IL-6 in patients with EBW. Importantly, transcriptional changes observed in adipose tissue should be interpreted cautiously, as mRNA levels do not necessarily correspond to protein expression or functional activity.

Corroborating our expectations, patients with excess body weight exhibited elevated gene expression levels and serum levels of leptin, along with a high incidence of hyperleptinemia. Elevated levels have been documented in patients with SLE,^79,80 with prevalence rates reaching approximately 74%.⁸¹ Additionally, obesity has been extensively associated with increase serum leptin levels in different populations.^82–84 The exact role of leptin in SLE disease is still unknown.⁸⁵ Leptin, a pro-inflammatory adipokine produced by adipose tissue, contributes to SLE-related inflammation by promoting the proliferation of naïve T and B cells and enhancing the production of autoantibodies and pro-inflammatory cytokines.^85,86 This increase in inflammatory biomarkers due to leptin could exacerbate symptoms, potentially accelerating the risk of metabolic syndrome and cardiovascular disease in patients with SLE, a hypothetical physio pathological mechanism illustrated in Figure 2.^87,88

Figure 2 Possibles metabolic consequences of excess body weight in patients with systemic lupus erythematous. (A) Process of excess weight gain. (B) Possible risk factors that contribute to excessive weight gain or obesity: Stress, nutritional imbalance, microbiome, sedentary lifestyle. (C) Chronic inflammatory process mediated by adipose tissue, in which hypertrophy and hyperplasia of the cellular matrix and consequently increased hypoxia and inflammatory cytokines, leptin secretion. (D) Imbalance in the adiponectin/leptin ratio, higher serum inflammatory cytokines and lipoproteins levels and insulin resistance.

Regarding adiponectin, a meta-analysis involving eight studies found that patients with SLE had higher serum adiponectin levels compared to controls.⁸⁹ Moreover, our study aligns with previous research demonstrating lower serum adiponectin levels in individuals with excess body weight.^90,91 Adiponectin is also secreted by adipose tissue and plays an anti-inflammatory role by modulating M2 macrophage functions, such as proliferation, plasticity, and polarization,⁹² and by inhibiting the production of pro-inflammatory cytokines.⁹³ Low levels of adiponectin may exacerbate the inflammatory processes associated with obesity⁹³ and contribute to insulin resistance in affected individuals.⁹⁴ The relationship between obesity, adiponectin, and SLE activity suggests a complex interaction between nutritional status and immunological factors of the individual, highlighting how systemic inflammation and body composition can influence the progression of this autoimmune disease.^41,46

Studies have been pointed out that adipo/lep ratio may serve as a marker of cardiometabolic protection and adipose tissue functionality.^55,56 In fact, the relationship between the adipo/lep ratio and cardiometabolic markers has been demonstrated across various populations.^95–98 A recent clinical trial involving 28 adults with obesity found that a lower adipo/lep ratio was correlated with higher BMI values.⁹⁷ Additionally, some studies observed a negative correlation between the adipo/lep ratio and CRP levels.⁵⁵ Elevated serum leptin levels, combined with a reduced response to leptin’s appetite-suppressing effects, suggest the presence of leptin resistance. Furthermore, individuals with low adiponectin levels may lose the hormone’s cardioprotective and anti-inflammatory benefits. Consequently, a low adipo/lep ratio indicates dysfunctional adipose tissue, which may be associated with metabolic disturbances linked to excess body weight.⁵⁶ This finding, particularly among patients with SLE, is novel and suggests that the adipo/lep ratio could serve as a predictive marker for the development of cardiovascular complications in these patients. Moreover, in the present study, patients with a higher adipo/lep ratio (>5) exhibited higher complement C4 levels, suggesting that preserved adipose tissue function may be associated with reduced complement consumption and lower subclinical immune activation, even in clinically inactive disease.⁶⁵ A higher adipo/lep ratio likely reflects a metabolically protective state characterized by anti-inflammatory adipokine balance. Collectively, these findings support the potential of the adipo/lep ratio as a sensitive marker of metabolic–immune interactions in SLE, warranting further investigation.

Clinical factors influencing lipid metabolism, such as disease activity, age, menopause, presence of serum autoantibodies and inflammatory cytokines, are similar between NW and EBW groups. Thus, we hypothesize that despite high body weight, HCQ use may have a significant impact on the metabolic profile of these patients, indicating potential predictors of lipid profile changes from drug therapy. According to EULAR recommendations, the target dose of HCQ should stay at 5 mg/kg/day; however, it should be individualized based on the risk of flare-ups and retinal toxicity, without exceeding 400 mg/day.⁶¹ In our sample, despite daily dose be, in most cases, 400 mg, the average daily use/kg was higher in patients with SLE, and normal weight compared to those patients with excess body weight. Interestingly, higher HCQ dose adjusted per weight was associated with lower abdominal circumference, fat mass, and with higher adiponectin level and adipo/lep ratio. Additionally, higher HCQ daily dose was associated with higher HDL-c serum levels. These findings suggest that individualized HCQ therapy may positively impact the lipid profile and metabolic homeostasis in patients with SLE.^70,71,99 Furthermore, the increase in adiponectin, which has anti-inflammatory properties and enhances insulin sensitivity, indicates that HCQ may not only help control disease activity but also promote a healthier metabolic environment.

Several studies previously demonstrated the hypolipidemic property of antimalarials drugs in SLE.^100–103 The potential influence of HCQ specifically in HDL function is not completely defined, however, recent studies evidenced that HCQ use may increase HDL levels in lupus patients, reducing atherosclerosis risk.⁶³ Considering that patients with SLE have less efficient incorporating unesterified cholesterol (UC) for subsequent esterification, some in vitro results demonstrated higher transfer of UC in those patients under HCQ treatment.⁶³ Curiously, an experimental study showed that HCQ improved body weight gain, hyperglycemia, and lipid profile, while also preserving heart and liver function in rats fed with a high-fat diet, ameliorating obesity negative effects.¹⁰⁴

Previous studies have documented improvements in adiponectin levels in animal models of obesity treated with hydroxychloroquine. It has been proposed that HCQ might help to normalize leptin levels, alleviate leptin resistance, and restore the leptin-to-adiponectin balance in rats fed a high-fat diet and treated with hydroxychloroquine, suggesting an adiponectin-mediated mechanism for hydroxychloroquine’s effects on obesity.¹⁰⁴ In a clinical study involving 41 patients with SLE (mean age 41.3 ± 13.2 years) treated with supplemental hydroxychloroquine, serum adiponectin levels significantly increased after three months. The authors proposed that this increase in adipokine levels might contribute to hydroxychloroquine’s beneficial effects on dyslipidemia in SLE patients.¹⁰⁵

Considering that high abdominal obesity, fat mass and low adiponectin levels and adipo/lep ratio contribute to the development of metabolic disturbances, we suggest that patients with SLE associated with overweight or obesity would have an increased risk of metabolic syndrome and consequently, cardiovascular diseases.¹⁰⁶ These findings underscore the importance of an integrated approach that addresses both metabolic and inflammatory aspects in managing patients with SLE, to better understand and treat the disease’s complications, including cardiovascular diseases. Additionally, early identification of individuals at high risk for metabolic complications, through the assessment of adipose tissue dysfunction and the staging of obesity and its early forms, can enhance therapeutic decision-making. An integrated approach to investigating gene expression and serum levels is crucial for understanding the underlying mechanisms of SLE heterogeneity and its correlation with other medical conditions and treatment responses. Precision medicine and nutrition emerge as promising paradigms, aiming to individualize therapeutic measures for more accurate prognoses,¹⁰⁷ thereby improving functional and prognostic evaluations for patients with SLE.¹⁰⁸

It is important to acknowledge that, while the present results presented are novel and bring promising perspectives, this study has several limitations. First, the relatively small sample size reflects the complexity of recruiting patients with SLE willing to undergo adipose tissue biopsy, which may limit statistical power and generalizability. Second, the cross-sectional design precludes causal inference. Third, gene expression analysis does not necessarily reflect protein abundance or biological activity in adipose tissue. Although protein-level measurements would strengthen the findings, the available adipose tissue samples were limited and prioritized for RNA extraction. Finally, the absence of a healthy control group should be considered when interpreting the results. The primary aim of this study was to investigate body weight–related differences within SLE patients, minimizing heterogeneity related to disease status, immune activation, and medication exposure. Future studies including healthy controls and longitudinal designs are warranted.

Conclusions

In conclusion, women with SLE and excess body weight exhibit a distinct inflammatory–metabolic profile characterized by higher leptin levels, lower adiponectin, and increased expression of pro-inflammatory and adipokine-related genes in adipose tissue. These findings support the concept that adipose tissue dysfunction may contribute to systemic inflammation and cardiometabolic risk in SLE. Additionally, hydroxychloroquine dosage adjusted by body weight was associated with lower adiposity and a more favorable adipokine profile, suggesting a potential metabolic benefit of weight-adjusted dosing. The association between the adiponectin-to-leptin ratio and complement C4 levels further highlights the interaction between metabolic regulation and immune activity in SLE. Together, these results reinforce the importance of considering metabolic status in the clinical management of SLE.