The clinical significance of serum complement fibroblast growth factor 21 in patients with rheumatoid arthritis

Abstract

Objective

This study aimed to assess serum fibroblast growth factor 21 (FGF-21) levels and explore their clinical significance in patients with rheumatoid arthritis (RA).

Methods

A total of 187 patients with RA, who were treated at Xuzhou Central Hospital between January 2023 and December 2024, were enrolled in this study. Based on carotid intima-media thickness (cIMT) measurements, they were categorized into a plaque group (n = 118) and a plaque-free group (n = 69). Additionally, 139 healthy individuals undergoing routine physical examinations were recruited as healthy controls (HC). Clinical data were collected from all participants, including lipid profiles, HOMA-IR, ESR, CRP, RF, anti-CCP antibody levels, and serum FGF-21 concentrations. We analyzed the associations between serum FGF-21 levels and both disease activity and atherosclerotic status in RA patients. Statistical analyses, including the chi-square test, Student’s t-test, Pearson correlation analysis, and logistic regression, were performed to evaluate these relationships.

Results

Serum levels of FGF-21 were significantly elevated in patients with RA compared with healthy controls (805.7 ± 188.68 vs. 203.8 ± 50.7 pg/mL, p < 0.001). Among RA patients, those with carotid plaques exhibited higher FGF-21 levels than those without plaques (840.7 ± 203.6 vs. 745.6 ± 142.2 pg/mL, p < 0.001). Correlation analyses revealed that serum FGF-21 levels were positively associated with LDL-C (r = 0.544), HOMA-IR (r = 0.625), anti-CCP antibodies (r = 0.617), rheumatoid factor (r = 0.366), DAS28 (r = 0.309), and cIMT (r = 0.604) (all p < 0.001). Conversely, FGF-21 levels were negatively correlated with the use of disease-modifying antirheumatic drugs (DMARDs) (r = − 0.569, p < 0.001) and flow-mediated dilation (FMD) (r = − 0.294, p < 0.001). Multivariate logistic regression analysis identified the serum FGF-21 level as an independent factor associated with increased cIMT (odds ratio [OR] = 1.003, 95% confidence interval [CI]: 1.001–1.006, p = 0.006).

Conclusions

Our findings suggest a potential correlation between elevated FGF-21 levels and RA disease activity as well as certain metabolic parameters. Further replication studies are needed to clarify whether FGF-21 might serve as a research biomarker in the context of cardiovascular comorbidity in RA.

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by persistent synovial inflammation, progressive joint destruction, and a myriad of systemic complications. The pathogenesis of RA is multifactorial, involving a complex interplay of genetic predisposition, dysregulated immune responses, and pro-inflammatory cytokine networks [1–3]. Despite advances in targeted therapies, a significant number of patients exhibit inadequate responses or experience side effects, underscoring the need for a deeper understanding of the disease mechanisms and the discovery of novel biomarkers for diagnosis, prognosis, and therapeutic targeting. Fibroblast growth factor 21 (FGF-21) is a metabolic hormone predominantly secreted by the liver, it acts as a key regulator of glucose and lipid metabolism during metabolic stress [4, 5]. Beyond its metabolic roles, FGF21 has gained significant attention for its endocrine functions, including modulation of inflammatory pathways, it exerts its effects by binding to FGF receptors in the presence of the co-receptor β-Klotho [6]. Several studies have reported elevated serum FGF-21 levels in patients with RA compared to healthy control subjects [7]. This increase is widely interpreted as a compensatory mechanism, in response to the inherent chronic systemic inflammation and related metabolic stress in RA, the body may up regulate FGF-21 to counteract excessive immune activation and mitigate tissue damage [8, 9]. Given the central role of these cytokines in the pathogenesis of RA, investigating the function of FGF-21 in RA has become a compelling area of research. Currently, there are no reported studies on FGF-21 levels and their clinical relevance in RA patients. This study aims to measure serum FGF-21 levels in RA patients and examine their relationship with disease markers, disease activity, and traditional risk factors for atherosclerosis.

Materials and methods

Data source and study population

A total of 187 patients with RA were consecutively recruited from our hospital between January 2023 and December 2024. The cohort comprised 33 males and 154 females, aged 28–72 years (mean age: 48 ± 17). All patients met the 2010 ACR/EULAR classification criteria for RA. The exclusion criteria were as follows: presence of comorbid systemic or organ diseases such as diabetes, hypertension, malignancies, or dyslipidemia; a history of lipid-lowering medication use; and impaired organ function. Additionally, patients with coronary heart disease (CHD) were excluded based on either no prior CHD diagnosis or coronary computed tomography angiography (CTA) or coronary angiography within the past six months showing < 50% vascular stenosis. A total of 139 healthy adults without autoimmune diseases were enrolled as the healthy control (HC) group, including 26 males (18.7%) and 113 females (81.3%). This study was approved by the Ethics Committee of Xuzhou Central Hospital (Approval No: XZXY-LJ-2021-10-019). Informed consent was obtained from all individual participants involved in the study.

Study period and data collection

Patient demographic and clinical data were systematically collected. This included the recording of body weight, blood pressure, and the calculation of body mass index (BMI). Relevant medical information for RA patients was obtained, encompassing smoking and family history, disease onset characteristics, and treatment regimens, specifically the use of glucocorticoids, conventional synthetic or targeted disease-modifying antirheumatic drugs (DMARDs), and the duration of biologic agent therapy. Physical examinations were conducted, with all baseline parameters documented in detail. Additionally, articular and extra-articular manifestations, such as pain severity and location, were meticulously recorded. Disease activity was primarily assessed using the Disease The 28-joint Disease Activity Score (DAS28) was calculated using the DAS28-ESR version, which is based on the count of swollen and tender joints and the erythrocyte sedimentation rate (ESR).

Measurement of general parameters and serum FGF-21 levels

All participants were instructed to maintain a vegetarian diet for two days prior to the examination and to fast for 12 h overnight. On the morning of the examination, 8 mL of venous blood was drawn from the antecubital vein under resting, fasting conditions and immediately sent for analysis. Serum samples were obtained to measure various indicators, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose (GLU), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies). Based on the assay results, additional parameters, such as the homeostasis model assessment of insulin resistance (HOMA-IR), were calculated.

Serum FGF-21 levels in all subjects were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Wuhan Moshake Biotechnology Co., Ltd.), strictly following the manufacturer’s instructions. Briefly, the microplate was configured with designated wells for standards, blanks, and samples. A 50 µL aliquot of each processed (diluted) sample was added to the respective sample wells. The plate was then incubated at 37 °C for 30 min. After incubation, the liquid was aspirated, and the plate was dried. A wash buffer was added, incubated for 30 s, and then removed; this wash cycle was repeated five times. Subsequently, with the exception of the blank wells, a 50 µL aliquot of the enzyme-conjugated antibody (diluted at a predetermined ratio) was added to all wells, followed by another 30-minute incubation at 37 °C and a subsequent wash. Next, 100 µL of chromogen substrate was added to each well, and the plate was incubated at 37 °C for 30 min. The reaction was stopped by adding the stop solution. Absorbance was immediately measured at 450 nm, and all samples were tested in duplicate. The assay has a detection range of 8 to 2,000 pg/mL, an analytical sensitivity of 8 pg/mL, and an intra-assay and inter-assay coefficient of variation (CV) of < 10% and < 12%, respectively. All procedures were conducted according to the manufacturer’s protocol.

Ultrasonic assessment of carotid intima-media (cITM) thickness and brachial artery flow-mediated dilation (FMD)

All ultrasound examinations were performed using an HDI 5000 SonoCT color Doppler ultrasound system (Philips Healthcare, Bothell, WA, USA) equipped with a linear array transducer operating at 7–12 MHz. A single certified physician with more than 5 years of experience in vascular ultrasound, who was blinded to the participants’ clinical and laboratory data, conducted all assessments. Ultrasonic evaluations were completed on the same day as the participants’ data collection. Participants rested in a supine position with the head slightly extended and rotated away from the scanned side. The examination started at the root of the common carotid artery (CCA), continued through its extracranial segment, and extended cranially to the skull base. Both longitudinal and transverse views were obtained. The carotid intima-media thickness (cIMT) was measured on the far wall of the CCA, 1–2 cm proximal to the carotid bifurcation. Three consecutive measurements were taken on each side (left and right), and the average value of these six measurements was used for analysis. The maximum IMT (M-IMT) was also recorded. According to the predefined criteria: M-IMT ≤ 0.9 mm was considered normal; M-IMT > 0.9 mm indicated abnormal thickening of the carotid intima-media; and M-IMT > 1.3 mm indicated the presence of carotid plaque. To ensure reproducibility, inter-observer reliability was assessed by having a second independent physician re-measure 20 randomly selected participants. The intraclass correlation coefficient (ICC) for cIMT measurements was > 0.90, indicating excellent agreement. For flow-mediated dilation (FMD) of the brachial artery, the distance between the anterior and posterior intima at end-diastole was measured at baseline and after cuff-induced reactive hyperemia. Three consecutive measurements were taken, and the average value was used for analysis. FMD was calculated as the percentage change in diameter from baseline to post-hyperemia.

Outcome measures

Comparison of Baseline Characteristics: A comparative analysis was performed regarding clinical data, DAS28 scores, conventional atherosclerosis risk factors, FGF-21 levels, and cIMT measurements among the following groups: RA patients versus healthy controls; RA patients with plaques versus those without plaques. Correlation Analysis: Within the RA patient group, correlation analyses were conducted to assess the relationships between serum FGF-21 levels and conventional atherosclerosis risk factors, DAS28 score, and cIMT values. Regression Analysis: A stepwise multiple linear regression analysis was employed to identify determinants of cIMT in RA patients. The independent variables included FGF-21 levels, DAS28 score, and conventional atherosclerosis risk factors.

Statistical analysis

R Studio (embedded R 3.6.3) was used for data analysis. Variables with normal distribution are presented as mean ± standard deviation (SD), and intergroup comparisons were performed using the independent samples t-test (Student’s t-test). Non-normally distributed variables are expressed as median with inter-quartile range (Q1, Q3), and comparisons between groups were performed using the Mann-Whitney U test (Wilcoxon rank-sum test). Categorical variables are presented as frequencies (percentages) and compared using the Pearson chi-square test. The Spearman’s correlation coefficient was used to evaluate relationships between non-normally distributed variables (e.g., FGF-21 with other variables). Multivariable binary logistic regression analysis was performed to identify independent predictors of cIMT, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. A two-sided P value < 0.05 was considered statistically significant.

Results

Comparison of baseline characteristics and FGF-21 levels between RA patients and healthy controls

Compared to the control group, the RA group exhibited significantly higher levels of TG, LDL-C, HOMA-IR, ESR, CRP, RF, anti-CCP antibody, and cIMT, along with significantly lower levels of HDL-C and FMD (all p < 0.05). Among the 187 RA patients, 118 were categorized into the plaque group and 69 into the plaque-free group based on carotid ultrasound findings; all patients received traditional synthetic DMARDs (csDMARDs), and 99 of them additionally received biologics (with or without csDMARDs). Compared to the plaque-free group, the plaque group had a longer disease duration and higher levels of TG, LDL-C, HOMA-IR, RF, anti-CCP antibody and cIMT, but lower levels of HDL-C, FMD (all p < 0.05). Compared to patients receiving conventional synthetic DMARDs (csDMARDs) alone, those treated with csDMARDs plus biologics showed significantly lower levels of HOMA-IR, RF, anti-CCP antibody, DAS28, and FGF-21, as well as higher FMD (all p < 0.05). In contrast, no significant differences were observed between the two groups in age, sex, disease duration, BMI, lipid profiles (TC, TG, HDL-C, LDL-C, ApoA-I, ApoB), ESR, or CRP. Furthermore, among RA patients, those additionally treated with biologics had significantly lower plasma FGF-21 levels than those receiving csDMARDs alone (p < 0.05). Notably, within the RA cohort, FGF-21 levels were also significantly higher in the plaque group than in the plaque-free group (p < 0.05, Tables 1, 2 and 3).

Table 1.

Clinical characteristics of study subjects of patients with rheumatoid arthritis (RA) and healthy controls (HC)

Group	HC (n = 139)	RA (n = 187)	t/χ2/z	P
Age (years mean ± SD)	52.3 ± 4.6	51.0 ± 6.7	-1.045	0.296
Male/Female	26/113	33/154	0.060	0.806
Disease Duration, (months mean ± SD)	-	48.6 ± 12.6	-	-
Glucocorticoid Use (months mean ± SD)	-	23.4 ± 6.4	-	-
Conventional DMARD use (months mean ± SD)	-	45.0 ± 13.4	-	-
Biologic(s) Use (months mean ± SD)	-	27.6 ± 6.7	-	-
Current smoker, n (%)	21 (15.1)	26 (13.9)	0.094	0.760
Alcohol drinker, n (%)	19 (13.7)	30 (16.0)	0.352	0.553
Blood pressure (mmHg)
Systolic	131.8 ± 9.8	132.6 ± 10.6	1.184	0.237
Diastolic	72.2 ± 4.3	73.1 ± 6.2	0.610	0.542
BMI (kg/m2 mean ± SD)	25.8 ± 2.7	25.4 ± 2.7	-0.950	0.342
TC (mmol/L mean ± SD)	5.32 ± 1.08	5.46 ± 1.26	0.519	0.604
TG [mmol/L M (Q1, Q3) ]	1.56 (1.24, 1.88)	1.64 (1.35, 1.97)	-2.167	0.030
HDL-C (mmol/L mean ± SD)	1.19 ± 0.26	1.15 ± 0.28	-1.160	0.246
LDL-C (mmol/L mean ± SD)	2.81 ± 0.53	3.04 ± 0.59	3.621	< 0.001
ApoA-I (g/L mean ± SD)	1.32 ± 0.22	1.31 ± 0.17	-0.943	0.345
ApoB (g/L mean ± SD)	0.93 ± 0.18	0.94 ± 0.15	0.846	0.389
HOMA-IR [M (Q1, Q3) ]	1.3 (0.7, 1.7)	2.1 (1.7, 2.6)	-9.668	< 0.001
ESR [mm/1h M (Q1, Q3) ]	11.0 (8.0, 13.0)	24.0 (21.0, 30.0)	-15.214	< 0.001
CRP [mg/L M (Q1, Q3) ]	5.5 (3.9, 7.1)	15.6 (12.6, 26.7)	-15.342	< 0.001
RF [U/ml M (Q1, Q3) ]	10.3 (8.6, 12.4)	108.2 (95.8, 121.2)	-15.443	< 0.001
anti-CCP [U/L M (Q1, Q3) ]	5.8 (4.7, 6.8)	203.5 (172.0, 242.5)	-15.443	< 0.001
DAS28 (mean ± SD)	-	4.4 ± 2.2	-	-
cIMT (mm mean ± SD)	-	0.97 ± 0.21	-	-
FMD (% mean ± SD)	-	6.5 ± 1.3	-	-
FGF-21 [pg/mL M (Q1, Q3) ]	200.5 (171.4, 233.8)	805.7 (660.8, 931.6)	-13.576	< 0.001

Table 2.

Clinical characteristics of study subjects in RA patients of plaque-free and plaque group

Group	Plaque-free group (n = 69)	Plaque group (n = 118)	t/χ2/z	P
Age (years mean ± SD)	50.9 ± 6.4	51.0 ± 7.0	0.198	0.843
Male/Female	13/56	20/98	0.107	0.743
Disease Duration, (months mean ± SD)	44.9 ± 13.0	50.8 ± 11.8	3.263	< 0.001
Glucocorticoid Use (months mean ± SD)	23.6 ± 6.7	23.9 ± 6.3	0.167	0.867
Conventional DMARD use (months mean ± SD)	45.3 ± 13.8	44.8 ± 13.1	-0.371	0.710
Biologic(s) Use (months mean ± SD)	27.2 ± 6.6	27.6 ± 6.9	0.721	0.471
Current smoker, n (%)	8 (11.6)	18 (15.3)	0.487	0.485
Alcohol drinker, n (%)	11 (15.9)	19 (19.2)	0.001	0.977
Blood pressure (mmHg)
Systolic	131.7 ± 11.3	133.0 ± 12.1	0.920	0.357
Diastolic	72.8 ± 4.8	72.1 ± 5.7	0.276	0.782
BMI (kg/m2 mean ± SD)	25.6 ± 2.6	25.4 ± 2.8	-0.218	0.827
TC (mmol/L mean ± SD)	5.28 ± 1.16	5.54 ± 1.32	1.163	0.245
TG [mmol/L M (Q1, Q3) ]	1.52 (1.27, 1.90)	1.71 (1.45, 1.99)	-2.092	0.036
HDL-C (mmol/L mean ± SD)	1.21 ± 0.27	1.12 ± 0.28	-2.124	0.034
LDL-C (mmol/L mean ± SD)	2.83 ± 0.55	3.17 ± 0.57	4.074	< 0.001
ApoA-I (g/L mean ± SD)	1.33 ± 0.15	1.29 ± 0.17	-1.044	0.296
ApoB (g/L mean ± SD)	0.94 ± 0.14	0.94 ± 0.15	0.109	0.913
HOMA-IR [M (Q1, Q3) ]	1.9 (1.6, 2.3)	2.3 (1.9, 2.6)	-4.093	< 0.001
ESR [mm/1h M (Q1, Q3) ]	24.0 (21.0, 27.5)	25 (21.0, 31.0)	-1.155	0.248
CRP [mg/L M (Q1, Q3) ]	14.6 (12.7, 24.4)	16.8 (12.6, 26.9)	-0.907	0.364
RF [U/ml M (Q1, Q3) ]	105.3 (92.7, 113.4)	110.1 (97.0, 126.0)	-2.954	0.009
anti-CCP [U/L M (Q1, Q3) ]	192.0 (162.8, 230.9)	214.5 (175.1, 247.3)	-2.134	0.033
DAS28 (mean ± SD)	4.2 ± 1.9	4.6 ± 2.3	1.130	0.258
cIMT (mm mean ± SD)	0.89 ± 0.18	1.01 ± 0.22	4.056	< 0.001
FMD (% mean ± SD)	7.1 ± 1.4	6.1 ± 1.1	-4.882	< 0.001
FGF-21 [pg/mL M (Q1, Q3) ]	706.0 (639.0, 864.2)	800.6 (697.4, 979.4)	-3.361	< 0.001

Table 3.

Clinical characteristics of study subjects in RA patients with or without biologic treatment

Group	csDMARDs alone (n = 88)	csDMARDs+biologics (n = 99)	t/χ2/z	P
Age (years mean ± SD)	51.4 ± 6.9	50.5 ± 6.9	-0.457	0.648
Male/Female	74/14	80/19	0.345	0.557
Disease Duration, (months mean ± SD)	47.0 ± 12.6	50.1 ± 12.4	1.943	0.052
Current Smoker, n (%)	10 (11.4)	16 (16.1)	0.896	0.344
Alcohol Drinker, n (%)	13 (14.8)	17 (17.2)	0.199	0.655
Blood pressure (mmHg)
Systolic	131.5 ± 10.6	133.5 ± 11.0	0.846	0.397
Diastolic	71.9 ± 5.0	72.1 ± 5.8	0.079	0.937
BMI (kg/m2 mean ± SD)	25.8 ± 2.2	25.2 ± 3.0	-1.851	0.064
TC (mmol/L mean ± SD)	5.41 ± 1.20	5.50 ± 1.31	0.244	0.808
TG [mmol/L M (Q1, Q3) ]	1.68 (1.38, 1.97)	1.63 (1.31, 1.96)	-0.952	0.341
HDL-C (mmol/L mean ± SD)	1.16 ± 0.28	1.14 ± 0.27	-0.544	0.586
LDL-C (mmol/L mean ± SD)	3.01 ± 0.59	3.08 ± 0.59	0.692	0.489
ApoA-I (g/L mean ± SD)	1.30 ± 0.16	1.31 ± 0.17	0.160	0.873
ApoB (g/L mean ± SD)	0.92 ± 0.16	0.96 ± 0.14	1.146	0.252
HOMA-IR [M (Q1, Q3) ]	2.4 (1.9, 2.7)	2.0 (1.6, 2.4)	-4.422	< 0.001
ESR [mm/1h M (Q1, Q3) ]	24.0 (21.0, 28.0)	26.0 (21.0, 31.0)	-1.477	0.140
CRP [mg/L M (Q1, Q3) ]	14.9 (12.6, 22.5)	16.6 (12.7, 26.9)	-1.048	0.295
RF [U/ml M (Q1, Q3) ]	113.2 (103.3, 127.1)	103.1 (92.8, 112.7)	-3.813	< 0.001
anti-CCP [U/L M (Q1, Q3) ]	220.9 (176.5, 250.0)	192.7 (161.8, 231.8)	-2.557	0.011
DAS28 (mean ± SD)	4.8 ± 2.3	4.0 ± 2.0	-2.349	0.019
cIMT (mm mean ± SD)	1.05 ± 0.20	0.89 ± 0.19	-5.406	< 0.001
FMD (% mean ± SD)	6.3 ± 1.4	6.6 ± 1.1	2.355	0.019
FGF-21 [pg/mL M (Q1, Q3) ]	818.6 (687.2, 1017.1)	724.0 (646.4, 881.6)	-2.841	0.005

Analysis of the correlation between FGF-21 levels in RA patients and traditional atherosclerotic risk factors, disease activity, and ultrasound indicators

Serum FGF-21 levels in RA patients showed a positive correlation with LDL-C (r = 0.544, p < 0.001), HOMA-IR (r = 0.625, p < 0.001), anti-CCP (r = 0.617, p < 0.001), RF (r = 0.366, p < 0.001), DAS28 (r = 0.309, p < 0.001), and cIMT (r = 0.604, p < 0.001), while exhibiting a negative correlation with the duration of DMARDs use (r = -0.569, p < 0.001) and FMD (r = -0.294, p < 0.001) (Table 4; Fig. 1).

Table 4.

Correlations between serum FGF-21 levels and traditional atherosclerotic risk factors, disease activity, and ultrasonographic parameters in patients with RA

Variable	r	p
Age	0.007	0.923
Male/Female	-0.178	0.032
Disease Duration	0.001	0.988
Glucocorticoid Use	0.078	0.287
Biologic(s) Use	0.002	0.973
Current Smoking	0.006	0.568
Alcohol Drinking	0.012	0.745
Systolic	0.142	0.256
Diastolic	0.084	0.331
BMI	0.048	0.514
TC	0.005	0.947
TG	-0.134	0.068
HDL-C	-0.050	0.459
LDL-C	0.544	< 0.001
ApoA-I	0.130	0.076
ApoB	0.116	0.115
HOMA-IR	0.625	< 0.001
ESR	0.041	0.575
CRP	0.058	0.432
RF	0.366	< 0.001
anti-CCP	0.617	< 0.001
DAS28	0.309	< 0.001
cIMT	0.604	< 0.001
Conventional DMARD use	-0.569	< 0.001
FDM	-0.294	< 0.001

Fig. 1.

Analysis of the associations between serum FGF-21 levels and conventional atherosclerotic risk factors, disease activity, and ultrasonographic parameters in patients with rheumatoid arthritis

Logistic regression analysis of factors influencing cIMT in RA patients

A logistic regression analysis was performed to identify independent predictors of cIMT. First, univariable analyses were conducted, and variables with a significance level of P < 0.05 were subsequently entered into a multivariable model. The final multivariable analysis identified disease duration, LDL-C level, and FGF-21 level as independent predictors of cIMT, with the following odds ratios: disease duration (OR = 1.043, 95% CI: 1.011–1.070, p = 0.008), LDL-C (OR = 1.033, 95% CI: 1.017–1.056, p = 0.018), and FGF-21 (OR = 1.003, 95% CI: 1.001–1.006, p = 0.006) (Table 5).

Table 5.

Multivariable binary logistic regression analysis of factors independently associated with carotid plaque in RA patients

Variable	OR (95% CI)	P value
Age (years)	1.052 (0.985–1.126)	0.152
Male sex	1.325 (0.624–2.819)	0.471
Disease Duration	1.043 (1.011–1.070)	0.008
BMI (kg/m²)	0.985 (0.884–1.093)	0.712
LDL-C	1.033 (1.017–1.056)	0.018
DAS28-ESR	1.126 (0.928–1.367)	0.252
FGF−21	1.003 (1.001–1.006)	0.006

Model adjusted for age, sex, disease duration, BMI, LDL-C, DAS28-ESR, and FGF-21. cIMT > 1.3 mm defined as plaque

Discussion

The primary pathological manifestation of RA is chronic persistent synovitis, which ultimately leads to structural damage to bones and joints, including localized bone erosion and systemic bone loss, resulting in joint destruction, deformities, and loss of function. Although arthritis itself does not directly cause mortality, it may elevate the risk of vascular complications, thereby increasing patient fatality rates [10, 11]. Statistics indicate that RA patients face a significantly higher risk of cardiovascular and cerebrovascular events such as myocardial infarction, heart failure, stroke, and sudden death, with over 40% of RA-related deaths attributable to cardiovascular incidents. Additionally, the incidence of carotid atherosclerosis is notably elevated among RA patients [12–14]. The pathogenesis of RA results from a complex interplay of genetic predisposition, environmental factors such as smoking and infection, and immune system dysregulation [15]. At its core, the aberrant activation of autoreactive T and B cells, the overproduction of pro-inflammatory cytokines such as TNF-α, IL-6, IL-17, and the emergence of antibodies together form the essential pathophysiological network of the disease [16]. In recent years, growing attention has been paid to the roles of metabolic disturbances, adipokines, and fibroblast growth factors in both the onset and systemic manifestations of RA. A previous study reported that RA patients exhibit lower vitamin D levels and reduced CD34 + progenitor cell counts, which correlate positively with each other and negatively with arterial stiffness markers and cIMT, suggesting that vitamin D may influence endothelial homeostasis via progenitor cell mobilization [17].

This study found that serum levels of FGF-21 were significantly elevated in RA patients. Elevated FGF-21 levels showed positive correlations with indicators of disease activity such as DAS28, anti-CCP, RF, metabolic disturbances such as LDL-C, HOMA-IR, and subclinical atherosclerosis cIMT, but negative correlations with disease management factors such as DMARDs treatment and a favorable body composition indicator FMD%. More importantly, multivariate logistic regression analysis indicated that FGF-21 is an independent factor influencing cIMT in RA patients, along with disease duration and LDL-C, independent variables for predicting cardiovascular risk. However, caution is warranted when interpreting the correlation between DAS28 and FGF-21. When the two cases with extremely high FGF-21 levels were excluded from the analysis, this correlation virtually disappeared (as shown in Figure E). This observation suggests that the overall positive association may be heavily driven by these outliers rather than reflecting a consistent relationship across the entire RA population. Therefore, this finding should be interpreted with considerable caution, and further replication studies with larger sample sizes are needed to determine whether FGF-21 truly correlates with disease activity in RA. These findings provide new clues for understanding the complex role of FGF-21 in the pathogenesis and progression of RA.

FGF-21 is recognized as a metabolic regulatory hormone primarily secreted by the liver, playing a central role in modulating glucose homeostasis, lipid metabolism, and energy balance [18]. In this study, the positive correlations of FGF-21 with HOMA-IR and LDL-C suggest that elevated FGF-21 levels in RA patients may be closely associated with a state of metabolic inflammation characterized by insulin resistance and abnormal lipid metabolism. The chronic systemic inflammation inherent to RA can induce insulin resistance and adipose tissue dysfunction, which may represent a key trigger for the compensatory increase in FGF-21 secretion. However, persistently elevated levels of FGF-21 may not effectively correct metabolic disturbances, instead potentially reflecting an adaptive failure of the organism to inflammatory stress or the development of an FGF-21 resistant state. Furthermore, the positive correlations between FGF-21 and anti-CCP, RF, and DAS28 suggest that its expression is also driven by autoimmune inflammatory activity. Inflammatory cytokines such as IL-1β and TNF-α have been shown to induce FGF-21 expression [19]. Therefore, elevated FGF-21 in RA can be regarded as a key biomarker at the interface of immune-metabolic crosstalk, reflecting both inflammatory and metabolic challenges. This finding suggests a potential correlation between elevated FGF-21 levels and the presence of carotid plaque in RA patients, but further studies are needed to confirm this association and to explore whether FGF-21 might reflect a stress-response process. Experimental evidence directly supports an anti-atherosclerotic role of FGF-21. In an apoE-/- mouse model, FGF-21 administration significantly reduced atherosclerotic plaque formation by inhibiting Fas-mediated endothelial cell apoptosis [20]. The mechanisms underlying these associations may involve several aspects. First, the positive correlation between FGF-21 and LDL-C, coupled with its independent association with cIMT, suggests that elevated FGF-21 reflects underlying lipid abnormalities, particularly a pro-atherogenic lipoprotein profile [21, 22]. Second, given that receptors for FGF-21 are expressed on vascular endothelial cells, smooth muscle cells, and macrophages, elevated FGF-21 levels may indicate ongoing vascular inflammation, oxidative stress, or plaque instability, rather than directly causing these processes [23, 24]. Third, as a signaling molecule of systemic inflammation and metabolic stress, the sustained elevation of FGF-21 could serve as an integrative indicator reflecting continuous vascular exposure to a detrimental milieu [25, 26]. Therefore, serum FGF-21 levels hold promise as a novel and comprehensive biomarker for assessing cardiovascular risk in RA patients.

Conclusions and future perspectives

Collectively, our study demonstrates that FGF-21 is significantly elevated in RA patients, and its levels are closely associated with disease activity, autoimmune responses, metabolic disturbances, and early atherosclerosis. Furthermore, FGF-21 serves as an independent correlate of carotid intima-media thickening in RA. These preliminary findings indicate a potential correlation between FGF-21 dysregulation and immune-metabolic abnormalities in patients with RA, as well as a marginal association between FGF-21 levels and carotid plaque. Further large-scale, prospective studies are required to verify the clinical applicability of FGF-21 as a candidate biomarker for RA-related cardiovascular comorbidities. Future investigations should aim to elucidate: (1) the precise cellular and molecular mechanisms by which FGF-21 mediates both local joint inflammation and systemic vascular pathology in RA. (2) whether the FGF-21 signaling pathway could offer novel therapeutic avenues for improving metabolic comorbidities and reducing cardiovascular risk. (3) whether dynamic monitoring of FGF-21 levels could facilitate earlier identification of high-risk patients and guide personalized management strategies. Several limitations should be acknowledged. First, the cross-sectional design of this study precludes any causal inference, and the sample size is relatively modest; therefore, the observed associations between serum FGF-21 levels, disease activity, and cIMT should be interpreted as statistical correlations rather than causal relationships. Second, although our exclusion of patients with diabetes, hypertension, and dyslipidemia was necessary to reduce confounding and isolate RA-specific effects, it limits the generalizability of our findings. Consequently, our results are primarily applicable to RA patients without these common cardiometabolic comorbidities, whereas a large proportion of RA patients in clinical practice do have one or more of these conditions. Caution is therefore warranted when extrapolating our conclusions to the broader RA population. Future longitudinal studies or mechanistic investigations are needed to establish causality, and these findings warrant validation in larger prospective cohorts that include RA patients with these comorbidities, in order to confirm whether the observed associations remain consistent across the full spectrum of RA patients.

Abbreviations

RA

Rheumatoid arthritis

FGF-21

Fibroblast growth factor-21

CHD

coronary heart disease

CTA

computed tomography angiography

HC

healthy control

BMI

body mass index

DMARDs

disease-modifying antirheumatic drugs

DAS28

Disease Activity Score 28

ESR

erythrocyte sedimentation rate

CRP

C-reactive protein

TC

total cholesterol

TG

triglycerides

HDL-C

high-density lipoprotein cholesterol

LDL-C

low-density lipoprotein cholesterol

GLU

glucose

RF

rheumatoid factor

anti-CCP antibodies

anti-cyclic citrullinated peptide antibodies

HOMA-IR

homeostasis model assessment of insulin resistance

ELISA

enzyme-linked immunosorbent assay

cIMT

carotid intima-media thickness

CCA

common carotid artery

ICA

internal carotid artery

cIMT

carotid intima-media thickness

FMD

flow-mediated dilation

IQR

inter-quartile range

Authors’ contributions

MLC and YF contributed equally to this study. MLC, YF and BBZ contributed to the conception and design of the work, data analysis, interpretation of the data, and manuscript writing. XLL, TTZ, LLL and JG collected and analyzed data. YF, HYL and BBZ searched and interpreted the data and critically revised the manuscript. All authors approved the final version of the manuscript for publication and they agreed to be accountable for all aspects of the work. MLC, YF and BBZ were the guarantors of this study, and as such, had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China [grant number 82202001]. The authors declare that there are no conflicts of interest.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Committee of Xuzhou Central Hospital [XZXY-LJ-2021-10-019] and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all individual participants involved in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.