ABSTRACT
Introduction
Systematic lupus erythematosus is a complex fundamental autoimmune disease with relapsing‐remitting course and spectrum of disease ranging from mild to life‐threatening illness. Approximately half of women diagnosed with systemic lupus erythematosus (SLE) are affected by obesity, with rates reaching up to 50%. Adropin, a peptide hormone, plays a crucial role in regulating lipid and glucose metabolism while exhibiting protective effects against oxidative stress and inflammation. It further modulates the immune response. Given these functions, our study aimed to explore variations in the serum levels of adropin among patients diagnosed with SLE. Additionally, we sought to investigate its association with coronary risk factors and the clinical manifestations of the disease.
Method and Material
In this cross‐sectional study, we included 59 SLE patients and 30 age‐matched healthy individuals. Utilizing high sensitivity human ELISA kits, we measured serum adropin levels.
Result
The SLE group exhibited significantly lower serum adropin levels compared to the control group (0.41 vs. 0.69 ng/mL, p = 0.001). In SLE patients with hyperlipidemia, hypertension (HTN), nephritis, serositis, hypocomplementemia, and positive anti‐phospholipid antibodies (APLAs), serum adropin levels were significantly lower. However, female SLE patients showed higher serum adropin level. A significant and negative correlation was observed between serum adropin levels and disease duration. Multiple linear regression analysis indicated that serum adropin levels retained association with HTN and positive APLAs.
Conclusion
Our study revealed a significant decrease in serum adropin levels among patients with SLE compared to healthy controls. The independent association between serum adropin levels and HTN suggests that adropin may serve as a potential predictor of coronary artery disease in individuals with rheumatic diseases. Results deepen our understanding of adropin in SLE, emphasizing its clinical relevance for assessing cardiovascular risk in this population.
Keywords: adropin, biomarker, coronary risk factor, endothelial dysfunction, systemic lupus erythematosus
1. Introduction
Systematic lupus erythematosus (SLE) is a complex fundamental autoimmune disease with a relapsing‐remitting course and spectrum of disease ranging from mild to life‐threatening illness. The clinical resumption of SLE drives from genetic predisposition and environment and immunological disfunction. A variety of pathogenic mechanisms can converge into a clinical symptom known as SLE. Although many organs and tissues are affected by SLE, clinical symptoms and patterns of autoimmune events vary from patient to patient and may change over time in an individual patient. interaction between genetic susceptibility and environmental, immunological and hormonal factors with a strong predisposition in women of childbearing age [1, 2, 3]. The symptoms of systemic lupus erythematosus (SLE) are linked to the existence of numerous autoantibodies (Ab) that lead to the creation and accumulation of immune complexes (ICs), along with various other immune mechanisms [4].
Constitutional, muco‐cutaneous, and musculoskeletal manifestations are frequently observed as the initial and prevailing symptoms among the majority of patients diagnosed with SLE. Nevertheless, it is important to note that SLE can affect any organ system, such as the skin, hematologic, renal, neuropsychiatric (NP), cardiovascular, and/or respiratory systems [5].
Approximately half of women diagnosed with SLE are affected by obesity, with rates reaching up to 50%. Despite limited knowledge regarding the specific impact of obesity on SLE patients, it has been observed that obesity is linked to both reduced functional capacity and increased levels of inflammation markers [6, 7]. These findings suggest that obesity may independently contribute to the deterioration of physical abilities and the presence of inflammatory processes in individuals with SLE. Obesity is a pathological state characterized by the involvement of mediators like leptin, and it is connected to changes in immune function and the presence of a persistent low‐grade inflammatory condition [8]. Additionally, there is a significant correlation between elevated levels of leptin and SLE, suggesting a potential association between obesity and SLE. The occurrence of obesity is starting to level off, indicating a potential stabilization in its prevalence [9]. Nevertheless, the proportion of overweight children is still on the rise, implying that there will be a greater burden of obesity‐related diseases in the coming years. Interestingly, individuals with SLE exhibit an even higher prevalence of obesity [10]. Truncal obesity, a prevalent chronic condition, presents notable health hazards including diabetes, cardiovascular ailments, hypertension, and certain autoimmune diseases. In the context of SLE, truncal obesity serves as a risk factor for coronary heart disease (CHD), often accompanied by the formation of atheroma and the onset of metabolic syndrome [11].
The occurrence of subclinical atherosclerosis in individuals with SLE is believed to range from 30% to 40% according to estimates [12]. This condition is characterized by the lipid peroxidation of protective high‐density lipoprotein (HDL), which transforms them into pro‐inflammatory HDL. Additionally, the presence of highly oxidized low‐density lipoprotein (LDL) further elevates the risk of coronary artery events and the development of carotid artery plaque in SLE patients [13]. It is worth noting that the abnormal lipid profile observed in these individuals, such as elevated cholesterol and triglyceride levels, may be attributed to the prolonged use of corticosteroid therapy in the management of SLE [14].
Adropin, a peptide hormone consisting of 76 amino acids, is synthesized by the ENHO gene, which is expressed in both the liver and brain. This suggests that adropin may play a role in various physiological processes such as combating obesity and insulin resistance, enhancing endothelial function, and regulating functions within the Central Nervous System (CNS) [15, 16].
Adropin has been observed to decline as body mass index (BMI) rises, while an elevation in adropin concentrations is linked to the progression of insulin resistance, endothelial dysfunction, and deterioration of lipid metabolism. A segment of the initial 33 amino acids of adropin, a peptide composed of a total of 76 amino acids, has demonstrated its role as a signal peptide and is expressed within the body, predominantly in the liver and brain [17]. Investigations exploring the correlation between adropin and obesity have revealed that reduced adropin levels are linked to obesity in studies involving adult individuals [18, 19, 20].
Numerous research studies conducted on genetically modified animals have provided compelling evidence of a noteworthy association between adropin overexpression and enhanced glucose tolerance, diminished insulin resistance (as measured by the homeostatic model assessment of insulin resistance–HOMAIR), as well as the facilitation of carbohydrate utilization in oxidative reactions. In addition to its well‐studied roles in maintaining glucose homeostasis and regulating lipid metabolism, recent research has shed light on the potential significance of adropin as a key regulatory component of the vascular endothelium. Several studies have indicated that adropin may play a role in various pathologies, including diabetes mellitus (DM) [21], coronary artery disease, arterial hypertension, inflammatory bowel disease (IBD) [22], and osteoarthritis (OA) [23]. Interestingly, patients with these aforementioned diseases have been found to have low levels of adropin in their serum. Furthermore, investigations into systemic sclerosis (SSc) and Sjögren's syndrome (SS) have also explored the relationship between adropin and these autoimmune diseases, suggesting a possible interconnection [23, 24]. we hypothesized that adropin may be implicated in the pathophysiology of SLE. Hence, the aim of this study was to evaluate the relationship between serum adropin levels and SLE disease activity.
2. Materials and Methods
2.1. Study Design
This cross‐sectional study was conducted at the Department of Internal Medicine, Division of Clinical Rheumatology, University Hospital of Imam Reza, between May and December 2022.
2.2. Ethical Considerations
This study was conducted in accordance with the ethical standards of the Declaration of Helsinki and was approved by the local ethics committee.
2.3. Subjects
Patients with SLE who met the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 criteria [4] and were aged ≥ 18 years were included. Healthy participants matched for age, gender, and body mass index (BMI) were enrolled as a control group. Exclusion criteria included the presence of other autoimmune disorders, liver or renal impairment, malignancies, and pregnancy. Detailed demographic and clinical data from all participants were collected through interviews and medical record reviews. Weight and height were measured for all participants, and BMI was calculated. Clinical manifestations, laboratory test results, and current medications were recorded. Disease activity in the patient group was assessed by a rheumatologist using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI‐2K) [25].
2.4. Blood Sampling and Laboratory Assessment
A 5 mL venous blood sample was collected from each participant after a 12‐h overnight fast. After collection, the whole blood was left undisturbed at room temperature for 15–30 min to clot. The clot was then removed by centrifuging at 2000 rpm for 10 min in a refrigerated centrifuge. The resulting serum was aliquoted and stored at −70°C until biochemical analysis.
Serum adropin concentration was determined using a commercial enzyme‐linked immunosorbent assay (Human Adropin ELISA kit, Cat. No. E3231Hu, Lot: 202106016; Intra‐Assay: CV < 8%, Inter‐Assay: CV < 10%, Sensitivity: 0.00249 ng/mL). Briefly, ELISA solutions, samples, and standards were added to wells pre‐coated with a capture antibody. After incubation, a biotinylated detection antibody was added, followed by streptavidin‐HRP. The serum adropin concentration was finally measured using a plate reader (STATFAX2100, Multi‐detection Microplate Reader, USA).
2.5. Statistical Analysis
Statistical analysis was performed using SPSS software version 16.0 (SPSS Inc., USA). The normality of data distribution was assessed using the Kolmogorov‐Smirnov test. Categorical and continuous variables were compared between the patient and control groups using the chi‐square test, independent samples t‐test, and Mann‐Whitney U test, as appropriate. Pearson correlation analysis was used to assess the relationships between continuous variables and serum adropin levels in SLE patients. To identify independent predictors of serum adropin levels, parameters with a p < 0.1 in univariate analysis were included in a multiple linear regression model. Variable selection was performed using a backward stepwise method based on P‐value. A p < 0.05 was considered statistically significant.
3. Result
In this study, 59 patients with SLE and 30 healthy participants were included. Case ant control groups were age, gender and BMI matched (Table 1). Cytopenia, nephritis and skin lesion were the most common clinical manifestations of SLE patients. Serum adropin levels in SLE and control groups were compared (Figure 1). The median (interquartile range) of serum adropin levels in the SLE and control groups was 0.46 ± 0.28 ng/mL and 0.66 ± 0.29 ng/mL, respectively (p ≤ 0.001). Then, we assessed the association between serum adropin levels with gender, classic atherosclerosis risk factors including diabetes, hyperlipidemia, and hypertension (HTN), clinical manifestations of SLE and laboratory findings (Table 2). In patients with hyperlipidemia, HTN, nephritis, serositis, hypocomplementemia and positive anti‐phospholipid antibodies (APLAs) serum adropin level was significantly lower (Table 2). In female patients' serum adropin level was significantly higher (Table 2). In addition, we assessed the correlation between serum adropin levels with continuous variables including age (Figure 2a), disease duration (Figure 2b), erythrocyte sedimentation rate (ESR) (Figure 2c) and SLEDAI (Figure 2d). There was a significant and negative correlation between serum adropin levels with disease duration (Figure 2). Then, we used a linear regression model for predicting effect of variables with p < 0.001 on the serum adropin levels (Table 3). Multiple linear regression analysis showed that serum adropin levels retained a significant association with HTN and positive APLAsafter model adjustment for sex, disease duration, nephritis, serositis, hyperlipidemia, HTN, hypocomplementemia, APLAs and C‐reactive protein (Table 3).
Table 1.
Demographics and clinical characteristics of the participants.
| Parameters | SLE group (n = 59) | Control group (N = 30) | p value |
|---|---|---|---|
| Female (%) | 55 (93.2) | 28 (93.3) | 0.677 |
| Age, mean ± SD, years | 35.2 ± 11.1 | 35.8 ± 13.6 | 0.326 |
| BMI, median (IQR) kg/m2 | 29.8 (26, 28) | 24.2 (22, 27) | 0.058 |
| Duration of disease, median (IQR) years | 4.5 (1.1, 7.0) | ||
| Clinical manifestations | |||
| Cytopenia (%) | 35 (59.3) | ||
| Renal involvement (%) | 30 (50.8) | ||
| Skin lesions (%) | 23 (40.0) | ||
| Musculoskeletal involvement (%) | 19 (32.2) | ||
| Nervous system involvement (%) | 10 (16.7) | ||
| Vasculitis (%) | 10 (16.7) | ||
| Serositis (%) | 9 (15.3) | ||
| Myocarditis (%) | 2 (3.4) | ||
| Laboratory findings | |||
| Positive ANA (%) | 59 (100) | ||
| Positive anti‐dsDNA (%) | 53 (89.8) | ||
| Hypocomplementia (%) | 33 (55.9) | ||
| Positive APLAs (%) | 16 (27.1) | ||
| Positive anti SSA/SSB (%) | 16 (27.1) | ||
| ESR, median (IQR) mm/hr | 33 (20.58) | ||
| High CRP (%) | 41 (69.5) | ||
| SLEDAI, median (IQR) | 6 (4.10) | ||
| Medications | |||
| Prednisolone (%) | 51 (86.4) | ||
| Hydroxychloroquine (%) | 50 (84.7) | ||
| Mycophenolate mofetil (%) | 25 (42.4) | ||
| Cyclosporine (%) | 17 (28.9) | ||
| Cyclophosphamide (%) | 15 (25.4) | ||
| Azathioprine (%) | 10 (16.9) | ||
| Methotrexate (%) | 4 (6.8) | ||
| Rituximab (%) | 2 (3.4) | ||
Abbreviations: ANA, anti‐nuclear antibodies; anti‐dsDNA, anti‐double stranded DNA; APLAs, anti‐phospholipid antibodies; BMI, body mass index; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IQR, interquartile range; SD, standard deviation; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.
Figure 1.
Serum adropin levels in the systemic lupus erythematosus (SLE) and control groups.
Table 2.
Serum adropin levels in SLE patients with various demographic, clinical and laboratory characteristics.
| Parameters | Adropin [median (IQR)] | p value | |
|---|---|---|---|
| Yes | No | ||
| Female | 0.41 (0.26, 0.52) | 0.22 (0.2, 0.35) | 0.046 |
| Diabetes | 0.46 (0.22, 0.69) | 0.41(0.26, 0.5) | 0.683 |
| Hyperlipidemia | 0.23 (0.21, 0.41) | 0.42(0.27, 0.51) | 0.046 |
| Hypertension | 0.31 (0.21, 0.41) | 0.43 (0.35, 0.63) | 0.004 |
| Skin lesions | 0.43 (0.26, 0.55) | 0.39 (0.24, 0.46) | 0.144 |
| Serositis | 0.29 (0.21, 0.42) | 0.42 (0.29, 0.55) | 0.036 |
| Musculoskeletal system involvement | 0.42 (0.25, 0.46) | 0.38 (0.23, 0.58) | 0.953 |
| Hematologic system involvement | 0.42 (0.22, 0.5) | 0.39 (0.28, 0.54) | 0.744 |
| Nephritis | 0.26 (0.21, 0.48) | 0.43 (0.39, 0.52) | 0.003 |
| Nervous system involvement | 0.43 (0.24, 0.5) | 0.41 (0.25, 0.47) | 0.808 |
| Vasculitis | 0.38 (0.23, 0.72) | 0.41 (0.25, 0.51) | 0.956 |
| High CRP | 0.36 (0.22, 0.49) | 0.45 (0.41, 0.58) | 0.057 |
| Anti‐ds DNA positive | 0.41(0.25, 0.49) | 0.38 (0.32, 0.6) | 0.971 |
| Hypocomplementemia | 0.35 (0.22, 0.49) | 0.44 (0.38, 0.56) | 0.043 |
| APLAs positive | 0.25 (0.22, 0.43) | 0.42 (0.33, 0.58) | 0.033 |
| Anti‐SSA/SSB positive | 0.41 (0.23, 0.51) | 0.41 (0.25, 0.47) | 0.986 |
Abbreviations: anti‐dsDNA, anti‐double stranded DNA; APLAs, antiphospholipid antibodies; CRP, C‐reactive protein; IQR, interquartile range; SLE, systemic lupus erythematosus.
Figure 2.
The correlation between serum adropin levels with age (A), disease duration (B), erythrocyte sedimentation rate (ESR) (C) and systemic lupus erythematosus disease activity index (SLEDAI) (D).
Table 3.
Multiple linear regression model* of independent predictors for serum adropin levels.
| Dependent variables | Predictor | β | SE | t value | p value |
|---|---|---|---|---|---|
| Serum adropin | Disease duration | −0.162 | 0.789 | −1.191 | 0.239 |
| Female | 0.061 | 170.64 | 0.401 | 0.691 | |
| Nephritis | −0.154 | 73.44 | −1.214 | 0.230 | |
| Serositis | −0.039 | 102.26 | −0.256 | 0.779 | |
| Hyperlipidemia | 0.079 | 115.78 | 0.531 | 0.598 | |
| Hypertension | −0.294 | 80.01 | −2.195 | 0.033 | |
| Hypocomplementemia | −0.046 | 78.93 | −0.344 | 0.732 | |
| APLAs | −0.250 | 80.18 | −2.033 | 0.047 | |
| High CRP | −0.119 | 78.53 | −0.968 | 0.338 |
Abbreviations: APLAs, antiphospholipid antibodies; CRP, C‐reactive protein; SE, standard error.
Backward stepwise method was used.
4. Discussion
Our study showed that in patients with SLE, serum adropin levels were significantly lower than healthy controls. We found no independent association between SLE disease characteristics including disease duration, disease activity, clinical manifestations and laboratory findings with serum adropin level, except for APLAs positivity. Interestingly, HTN was an independent predictor of serum adropin levels.
Although several studies have reported dysregulation of adropin in patients with autoimmune diseases, there is considerable disagreement on the role of adropin in the pathogenesis of these diseases. In a study on 27 patients with systemic sclerosis (SSc), 39 patients with Behcet's disease (BD) and 20 healthy subjects, serum adropin was significantly higher in patients with SSc and BD than in healthy subjects (Yolbas et al., 2016). There was no significant difference between serum adropin levels and disease activity, severity and subtype (limited vs diffuse) of SSc [25]. Despite the higher serum adropin levels in SSc patients, there was no significant difference in ENHO gene expression between SSc and the control group, which can be concluded that adropin production does not increase in SSc, but its degradation decrease [25]. In another study on 36 patients with rheumatoid arthritis (RA), 22 patients with SLE and 20 healthy subjects, there was no significant difference between ENHO gene expression and serum adropin level between studied groups [26]. In addition, no correlation was observed between ENHO gene expression and serum adropin levels with disease activity, organ involvement, autoantibodies and medications in RA and SLE groups [26]. In a recent study, although the serum adropin level in the RA group was significantly lower than the control group (2.85 vs. 4.02 ng/mL), in multivariate regression analysis after adjusting the model for age, BMI, Disease Activity Score‐28, Health Assessment Questionnaire, disease duration and fasting blood glucose (FBS), adropin levels only maintained a significant correlation with FBS levels [27]. In another study, the level of adropin in patients with primary Sjogren's syndrome was significantly higher than the control group [24]. In multivariate linear regression analysis, adropin levels were independently associated only with high density lipoprotein and Sjogren's syndrome disease damage index (SSDDI) [24]. Brnić et al. reported lower serum adropin levels in patients with inflammatory bowel disease (IBD)compared with the control group (2.89 vs. 3.37 ng/mL) [22]. In multivariate regression analysis after adjusting the model for age, BMI, gender and waist circumference, serum adropin level was an independent predictor for positive IBD status [22]. Serum adropin levels had negative correlation with fecal calprotectin and positive correlation with IBD severity scores [22].
The absence of an independent association between the serum adropin levels and the characteristics of SLE in our study and other rheumatic diseases in most of the previous studies may mean that the change in the level of adropin is a secondary phenomenon and does not play a role in the pathogenesis of the disease. Alteration of ENHO expression by nuclear factor‐κB may be an explanation for alteration of adropin level in rheumatic diseases [28, 29]. The independent association between serum adropin levels and coronary artery disease risk factors such as HTN may mean that adropin may have the potential to be used as a predictor of coronary artery disease (CAD) in individuals with rheumatic diseases. Recent studies have shown that adropin, in addition to affecting sugar and fat metabolism and modulating the immune system, also has an effect on endothelium function and angiogenesis [15, 30]. Adropin stimulates neovascularization by inducing endothelial cell proliferation and migration, inhibiting endothelial cell apoptosis, as well as affecting vascular endothelial growth factor receptor‐2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and intracellular signaling pathways with PI3K‐Akt and ERK1/2 [15, 30]. It has been reported that adropin is a risk factor for HTN [31]. In a study on patients with essential hypertension, there was an inverse relationship between plasma adropin and endothelin 1 levels [31].
Our study is the first study that investigated the association between the serum level of adropin and the demographic and clinical characteristics of SLE in a relatively large sample size. However, several important limitations exist. This was a single‐center, cross‐sectional study, and it was not possible to completely eliminate all confounding factors that might affect serum adropin levels. To determine the efficacy of adropin in predicting the risk of atherosclerosis, a prospective study is needed in which the severity of atherosclerosis is assessed by methods such as measuring the thickness of the intima‐medial carotid with ultrasound.
5. Conclusions
In patients with SLE, serum adropin levels were significantly lower than healthy controls. The independent association between serum adropin levels and HTN may mean that adropin may have the potential to be used as a predictor of coronary artery disease in individuals with rheumatic diseases.
Author Contributions
Mehrzad Hajialilo: patients selection and investigation. Amir Ghorbanihaghjo: methodology. Kamran Javidi‐Aghdam: writing orginal draft and editing. Seyed Amir Hossein Seyeddorraji: formal analysis. Alireza Khabbazi: conceptualization and data curation. Mehdi Jafarpour: project administration, validation.
Ethics Statement
This study protocol was approved by the ethical committee of Tabriz University of Medical Sciences. Informed consent forms were obtained from all study participants. The study protocol was approved by the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1400.067) and performed according to the Helsinki humanity research declaration.
Conflicts of Interest
The authors declare no conflicts of interest.
Transparency Statement
The lead author Alireza Khabbazi, Mehdi Jafarpour affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Acknowledgments
The authors gratefully acknowledge the Connective Tissue Diseases Research Center for supporting study.
Contributor Information
Alireza Khabbazi, Email: dr_khabbazi@yahoo.com.
Mehdi Jafarpour, Email: jafarpourmehdi1360@gmail.com.
Data Availability Statement
Data are available by request from corresponding author. All authors have read and approved the final version of the manuscript, Dr. Mehdi Jafarpour had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available by request from corresponding author. All authors have read and approved the final version of the manuscript, Dr. Mehdi Jafarpour had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.