Introduction
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation, affecting approximately 0.5% to 1% of the global population, with increased prevalence among individuals aged over 60 years [
1]. The primary cause of RA is inflammation of the synovial membrane, leading to cartilage and bone degradation, joint damage, and impaired joint function [
2–
4]. RA typically presents with debilitating joint pain, morning stiffness, and swelling [
5]. Additionally, extra-articular manifestations may involve other organ systems, including renal, cardiovascular, ocular, and respiratory systems [
6]. Besides the burden of the disease itself, RA patients frequently develop metabolic abnormalities such as type 2 diabetes, hypertension, arteriosclerosis, and osteoporosis, significantly increasing cardiovascular risk [
7], mortality, and disability rates [
8]. Although RA’s exact etiology remains unclear, genetic predisposition, autoimmune responses, environmental influences, and gut microbiota are believed to play critical roles in disease development [
9,
10].
Previous studies have reported disturbances in metabolic factors, including fasting blood glucose (FBG) and lipid profiles, among RA patients [
11–
13]. Dyslipidemia observed in RA differs from the general population, typically involving reduced total cholesterol (Chol) and low high-density lipoprotein (HDL) [
14,
15]. An imbalance in HDL and Chol leads to increased atherogenicity (elevated Chol/HDL ratio), an important cardiovascular prognostic marker. Previously, Chol, HDL, and low-density lipoprotein (LDL) levels were thought to decrease during active, untreated RA [
16–
18]. Recent studies have supported these findings, reporting decreased HDL and LDL [
17–
21] and increased Chol/HDL ratios [
17,
19] in RA patients.
Changes in blood lipids have also been linked with inflammatory markers in RA [
22,
23]. Recent investigations have further proposed that glucose metabolism disruption in RA might influence inflammatory properties of rheumatoid synovial fibroblasts. This metabolic alteration could significantly contribute to autoimmune disease pathogenesis by affecting immune responses and altering autoantigen expression [
24].
Existing studies have frequently attributed elevated FBG levels to RA itself. However, studies addressing the predictive roles of blood glucose and lipid profiles regarding RA risk remain scarce. Examining lipid and glucose metabolism and their metabolic pathways may enhance our understanding of their roles in RA onset and persistence, as well as other autoimmune disorders. Thus, this study was designed to explore relationships between metabolic factors (blood lipids and glucose), inflammatory markers (including tumor necrosis factor-alpha [TNF-α] and high-sensitivity C-reactive protein [hs-CRP]), disease activity, and RA risk.
Materials and Methods
Study Design and Setting
In this cross-sectional study, participants were recruited consecutively from patients referred to the rheumatology clinic of Imam Khomeini Hospital in Urmia City, from January 2019 to February 2020.
Participants
One hundred newly diagnosed RA patients aged 20 to 50 years, comprising both males and females, were enrolled in the study. A control group consisting of 100 healthy participants was also included. These individuals were selected from people visiting the clinic for routine health check-ups. The sample size determination was based on previously published studies [
25]. Convenience sampling was employed for participant selection. Participants in both groups were balanced for age, sex, and body mass index (BMI). Exclusion criteria included pregnant and lactating women, individuals with other chronic diseases such as diabetes, and those following special diets.
Variables
The primary outcomes of the study were the risk and severity of RA. Exposure variables were metabolic factors (including blood lipids and glucose) and inflammatory markers (including TNF-α and hs-CRP). Potential confounders included age, sex, BMI, and energy intake.
Data Sources/Measurement
RA diagnosis was confirmed by a rheumatologist according to the American College of Rheumatology/European League Against Rheumatism criteria [
26]. The severity of RA was evaluated using the disease activity score of 28 joints (DAS-28) [
27]. DAS-28 incorporates tender and swollen joint counts (TJC and SJC) of 28 joints, erythrocyte sedimentation rate (mm/h) or C-reactive protein (CRP, mg/L) levels, and general health assessed via visual analogue scale (VAS). DAS-28 (CRP) scores were calculated as follows:
DAS−28(CRP)=0.56×√TJC28+0.28×SJC28+0.70× Ln(CRP)+0.014×VAS
DAS-28 scores were categorized into disease activity levels as follows: remission (≤2.6), low activity (>2.6 to ≤3.2), moderate activity (>3.2 to ≤5.1), and high activity (>5.1).
Participants’ body weight was measured using a SECA scale (Germany, model 769) to the nearest 0.1 kg, with participants wearing minimal clothing and no footwear. Height was measured to the nearest 0.5 cm. BMI was calculated as weight (kg) divided by height squared (m²).
After 12 hours of overnight fasting, 5 mL blood samples were collected. Serum was separated by centrifugation at 3,500 rpm for 10 minutes at 4 °C and stored at −70 °C for subsequent analysis. Levels of total Chol, HDL, and triglycerides (TG) were quantified using a biochemical auto-analyzer and enzymatic kits (Pars Azmoon). LDL levels were calculated using the Friedewald equation [
28]. FBG concentrations were measured using the glucose oxidase technique with a commercial kit (Pars Azmoon).
Serum levels of TNF-α were measured using an enzyme-linked immunosorbent assay kit from Glory Science Co., Ltd. Additionally, hs-CRP levels were quantified using an immunoturbidimetric assay (Pars Azmoon).
Bias
To minimize potential bias, participants in both groups were matched according to age, sex, and BMI.
Statistical Methods
Data analysis was conducted using IBM SPSS ver. 21 software (IBM Corp.). The normality of data was evaluated using skewness and kurtosis tests. Qualitative results were presented as frequency (%), and quantitative results as mean±standard deviation. For comparisons between the 2 groups, the independent-samples t-test (for continuous variables) or the chi-square test (for categorical variables) was employed. Binary logistic regression analysis was conducted to estimate odds ratios (ORs) for RA disease risk, in both univariate and multivariate models. Linear regression analysis was used to evaluate associations between serum metabolic factors and disease activity, as well as inflammatory markers. Age, sex, BMI, and energy intake were considered as covariates. Receiver operating characteristic (ROC) curves were used to assess and compare the predictive ability of serum metabolic factors for RA disease. A p-value <0.05 was considered statistically significant in all analyses.
Ethics Statement
The study protocol was approved by the Institutional Review Board (IRB) of Tabriz University of Medical Sciences (No. IR.TBZMED.REC.1403.045, IRB No: 73560). The requirement for informed consent was waived by the IRB.
Results
Participants
The study included 100 subjects in the RA group and 99 healthy individuals in the control group. One healthy participant was excluded from the study due to abnormal serum results.
Descriptive Data
As presented in
Table 1, no significant differences were observed between the RA patients and healthy individuals regarding age, sex, smoking status, BMI, and total energy intake (
p>0.05). According to
Table 2, serum levels of FBG (
p<0.001), TG (
p=0.013), Chol/HDL (
p=0.003), and TG/HDL (
p<0.001) were significantly higher in RA patients compared to healthy participants, whereas HDL levels were significantly lower (
p<0.001). Levels of total Chol and LDL did not differ significantly between the 2 groups (
p>0.05). Serum TNF-α and hs-CRP levels were significantly elevated in RA patients.
Main Results
As presented in
Table 3, increased serum FBG and Chol/HDL significantly elevated the odds of RA disease in the multivariate model. Specifically, each unit increase in serum FBG was associated with a 64% increase in the odds of RA (OR, 1.639; 95% confidence interval [CI], 1.381−1.946;
p<0.001). Each 1-unit increase in Chol/HDL corresponded to a 52% increase in the odds of RA (OR, 1.519; 95% CI, 1.119−2.061;
p=0.007), and each 1-unit increase in TG/HDL corresponded to a 54% increase (OR, 1.539; 95% CI, 1.203−1.968;
p=0.001). Conversely, increased HDL was protective, with each 1-unit increase in serum HDL associated with approximately a 7% reduction in RA odds (OR, 0.926; 95% CI, 0.886−0.968;
p=0.001), both in univariate and multivariate analyses. No significant associations were found between RA odds and SBP, DBP, total Chol, TG, or LDL serum levels (
p>0.05).
As shown in
Table 4, none of the metabolic factors studied were significantly correlated with disease activity (
p>0.05). Among all participants, serum levels of FBG (β=0.399,
p<0.001), TG (β=0.164,
p=0.024), and TG/HDL (β=0.256,
p<0.001) were positively associated with hs-CRP. Additionally, serum levels of FBG (β=0.253,
p=0.001), TG (β=0.314,
p<0.001), and TG/HDL (β=0.295,
p<0.001) were positively associated with TNF-α. Serum HDL levels showed an inverse association with hs-CRP (β=−0.199,
p=0.008).
In RA patients specifically, TNF-α correlated positively with TG (β=0.312, p=0.001) and TG/HDL (β=0.248, p=0.011), but not with other metabolic factors (p>0.05). In this group, hs-CRP correlated only with TG/HDL (β=0.203, p=0.047). In healthy individuals, neither TNF-α nor hs-CRP significantly correlated with metabolic factors (p>0.05) (data not shown).
ROC curve analysis showed a considerable predictive role for serum FBG regarding RA disease (
Figure 1). FBG exhibited the highest area under the curve (AUC=0.981,
p<0.001), indicating strong predictive capacity, whereas HDL had the lowest predictive capacity (AUC=0.337). The AUC values for TG, total Chol, LDL, Chol/HDL, and TG/HDL were 0.577, 0.548, 0.498, 0.641, and 0.635, respectively (
Table 5).
Discussion
The present study found that patients with RA had higher serum levels of FBG, TG, Chol/HDL, and TG/HDL, and lower HDL levels compared with healthy individuals. Elevated serum levels of FBG, Chol/HDL, and TG/HDL were associated with increased odds of having RA, whereas higher HDL levels reduced the odds. Among all participants, FBG, TG, and TG/HDL showed positive associations with hs-CRP and TNF-α, while HDL was inversely correlated with hs-CRP. Within the RA group, TNF-α correlated positively with TG and TG/HDL, whereas hs-CRP correlated only with TG/HDL. Among metabolic factors studied, FBG showed the strongest predictive power for RA.
The current study highlights the potential role of elevated FBG levels in RA development. Extensive evidence suggests that RA is associated with increased diabetes mellitus risk. Ruscitti et al. [
29], in a study involving 500 RA patients and 500 matched controls, observed a higher prevalence of type 2 diabetes and abnormal fasting glucose levels among RA patients. Similarly, Ali et al. [
30], in research with 70 females with early RA and 35 healthy controls, reported significantly elevated insulin resistance and FBG concentrations in the RA group. Another single-center study with 90 RA patients and 37 matched controls also identified significantly greater insulin resistance in RA individuals [
31]. Furthermore, a high prevalence of diabetes has been reported in patients with RA [
32]. Current studies have often compared serum FBG between RA patients and healthy controls [
29,
30,
33], attributing elevated FBG levels to RA and suggesting inflammation-induced insulin resistance as a causal factor for increased blood glucose [
34]. However, research examining whether elevated blood glucose itself independently increases RA risk remains limited.
Elevated FBG levels may increase RA risk through several mechanisms. High glucose concentrations could promote immune dysregulation, contributing to autoantibody production and synovial inflammation [
35]. Hyperglycemia also leads to chronic inflammation, a central aspect of RA pathogenesis. Specifically, high glucose stimulates the release of inflammatory mediators such as TNF-α and IL-6, involved in joint inflammation and damage [
36,
37]. The positive relationship between FBG and inflammatory markers observed in this study further corroborates these mechanisms. Additionally, hyperglycemia-induced oxidative stress may worsen inflammatory responses, potentially triggering autoimmune reactions against joint tissues [
38]. Collectively, these findings underscore the potential importance of controlling blood glucose levels to mitigate RA risk.
In our study, lower HDL levels were associated with increased RA risk. Dyslipidemia has frequently been observed in RA patients. Erum et al. [
39], investigating 200 RA patients, found dyslipidemia in 53.5% and low HDL in 41.5%. Similarly, Lakatos and Harsagyi [
40], in a study including 129 RA patients and 1,374 controls, reported significantly lower HDL levels in the RA group. Likewise, Dursunoglu et al. [
41], studying 87 women with RA and 50 healthy women, observed lower HDL levels among the RA participants. Associations between RA severity and HDL functionality indicators have also been noted [
42]. HDL possesses anti-inflammatory and antioxidant properties, potentially mitigating the chronic inflammation characteristic of RA [
43]. HDL particles inhibit adhesion molecule expression on endothelial cells, reducing inflammatory cell recruitment into joint tissues [
44]. Furthermore, HDL neutralizes oxidized lipids and decreases inflammatory cytokine release, such as TNF-α and IL-6 [
45]. RA patients often exhibit reduced HDL levels, impairing HDL's anti-inflammatory functions [
46]. The inflammatory score in RA patients depends not only on plasma HDL levels but also on HDL particle structure, composition, and functionality [
47]. The inverse correlation between HDL and inflammatory markers noted in this study aligns with these earlier reports. Certain biological therapies, such as tofacitinib, may also improve disease activity and functional status in RA patients experiencing lipid alterations [
48]. These mechanisms collectively suggest a protective role of HDL in RA prevention and management, highlighting the importance of maintaining healthy HDL levels.
In this study, higher Chol/HDL ratios correlated with an increased RA risk. Elevated Chol/HDL ratios, indicative of higher cardiovascular risk, are frequently observed in RA patients [
19,
41]. This scenario, termed the “lipid paradox,” involves lower total Chol and LDL-Chol levels in RA patients alongside paradoxically elevated cardiovascular disease risk [
49]. Chronic inflammation in RA, reflected by increased CRP and TNF-α levels, disrupts lipid metabolism, reducing total Chol, LDL, and HDL levels; however, this reduction does not equate to decreased cardiovascular risk [
50,
51]. Despite lower Chol concentrations, the atherogenic index (Chol/HDL ratio) may remain elevated, indicating greater atherosclerosis risk [
15]. Thus, the higher Chol/HDL ratio observed in RA patients highlights the importance of careful cardiovascular risk management in this group.
The present study identified higher TG levels as associated with increased RA risk. Elevated TG concentrations have been implicated in RA pathogenesis [
19,
52]. Hypertriglyceridemia can aggravate systemic inflammation characteristic of RA [
53]. Increased TG levels facilitate the production of pro-inflammatory cytokines [
53,
54], exacerbating joint inflammation and damage. The direct correlation between TG and inflammatory markers observed in this research further supports these previous findings. Thus, monitoring lipid profiles, particularly TG levels, is essential as part of comprehensive RA management.
The integration of antioxidants, complementary therapies, and dietary modifications plays a crucial role in managing RA, particularly through modulating lipid profiles, glycemic factors, and inflammatory processes. Pycnogenol, as an antioxidant, has demonstrated effectiveness in reducing oxidative stress and stabilizing inflammatory biomarkers [
55], potentially aiding lipid metabolism regulation. In addition, propolis exhibits significant anti-inflammatory properties, offering therapeutic benefits for individuals with RA [
56]. Royal jelly has also been reported to enhance glycemic control among individuals with compromised health [
57]. Moreover, conjugated linoleic acids have shown the ability to reduce inflammation and oxidative stress while simultaneously improving physical performance and metabolic parameters [
58]. Taurine, flaxseed oil, and
Gundelia tournefortii supplementation might further improve glycemic control and lipid metabolism [
59–
61]. Collectively, these findings emphasize the multifaceted benefits of integrating antioxidants, complementary therapies, and dietary interventions as adjunctive approaches to conventional RA treatment strategies.
Regarding clinical and therapeutic implications, the findings from this study suggest that routine monitoring and management of FBG, TG, and HDL levels should become integral components of care for individuals at risk of or diagnosed with RA. Clinicians should consider strategies such as dietary modifications, increased physical activity, and pharmacological interventions to control blood glucose and lipid levels, thereby reducing systemic inflammation. Addressing these metabolic factors could reduce both the incidence and severity of RA, ultimately enhancing patient outcomes and quality of life. This highlights the importance of adopting a comprehensive, multidisciplinary approach in RA management.
A major limitation of the current study is the inherent potential for selection bias associated with case-control studies. The selected cases and controls may not precisely represent the broader population, limiting the ability to establish causal relationships. Further investigations are necessary to clarify exact mechanisms and determine optimal therapeutic strategies. Large-scale prospective cohort studies would be beneficial in confirming cause-and-effect relationships between metabolic factors and RA.
