Study on the expression characteristics of CA125 in patients with SLE and its correlation with clinical indicators.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the involvement of multiple organs and systems. [ 1 ] Its primary pathogenic mechanism involves chronic immune activation and complex immunophenotypic abnormalities. [ 2 ] The disease can affect various organs and tissues, including the skin, joints, kidneys, nervous system, and serous membranes. Carbohydrate antigen 125 (CA125) is a glycoprotein commonly expressed in tissues derived from embryonic coelomic epithelium, such as the endometrium, peritoneum, pleura, and pericardium. In the presence of inflammation or mechanical stimulation in these tissues, CA125 may be released into the bloodstream, resulting in elevated serum levels. [ 3 ] In addition to its association with gynecological conditions such as uterine fibroids and endometriosis, CA125 levels may also be elevated in a range of non-gynecological diseases, including heart failure, cirrhosis, and pulmonary lesions. [ 4 , 5 ] Recent studies have shown that CA125 levels may also be increased in patients with SLE. Szekanecz et al reported that CA125 is correlated with disease activity in SLE. [ 6 ] However, other studies have reached different conclusions. [ 7 ] This study aims to clarify the clinical significance of CA125 in SLE by investigating its expression and its correlation with disease activity and multisystem involvement in a larger cohort.

Data curation: Shasha Xu, Xiaoheng Guo. Funding acquisition: Changgeng Zhang. Investigation: Xiaoheng Guo, Ting Lu. Writing – original draft: Shasha Xu. Writing – review & editing: Shasha Xu, Changgeng Zhang.

A total of 220 patients with SLE hospitalized in the Department of Rheumatology and Immunology between January 2021 and January 2025 were included in this study. Patients were divided into 2 groups according to serum CA125 levels: The CA125-positive group (>35.00 U/mL) comprised 63 cases, including 56 females and 7 males, aged 13 to 78 years, with a mean age of 45 ± 13 years, and 157 CA125-negative cases (≤35.00 U/mL), including 140 females and 17 males, aged 14 to 82 years, with a mean age of 46 ± 15 years. No statistically significant differences were observed in the age and sex distribution between the 2 groups ( P  > .05). All patients were initially admitted. CA125 positivity was defined as serum levels exceeding the upper limit of the respective reference range (>35 U/mL). CA125 is detected using the Chemiluminescence method. The detection instrument is the Beckman Coulter UniCel DxI800 Access. The detection reagent is the Beckman Coulter Access OV Monitor. All procedures were strictly performed in accordance with the manufacturer’s instructions. The quality control was within acceptable limits. The upper limit of the reference range for healthy individuals as specified in the kit manual is 35 U/mL. All patients diagnosed with SLE met the criteria revised by the American College of Rheumatology in 1997. [ 8 ] The study protocol adhered to the ethical principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of Hengshui People’s Hospital. All participants provided written informed consent before their participation in the study. Exclusion criteria: Patients with SLE who satisfied any of the following conditions were excluded: individuals diagnosed with a malignant tumor confirmed through CT, B-ultrasound, endoscopy, or other diagnostic methods; additional conditions that may influence CA125 levels, including but not limited to pregnancy, cirrhosis, gynecological inflammation, heart failure, and infectious diseases such as tuberculosis; and concurrent presence of other autoimmune disorders such as rheumatoid arthritis, systemic sclerosis, Sjögren’s syndrome, etc. The patient’s case data is incomplete and laboratory test results are missing. The following data was collected from the electronic medical record system: Basic patient information: including gender, age, disease duration, place of residence, average length of hospital stay, and frequency of hospitalization; clinical manifestations: fever, oral ulcers, joint swelling and pain, facial rash, alopecia, photosensitivity, Raynaud’s phenomenon, interstitial pneumonia, renal involvement, hematological involvement, hypoproteinemia, and serous cavity effusion; laboratory test indicators: In addition to serum CA125, blood routine: white blood cells (WBC), hemoglobin (HB), platelets (PLT); inflammatory markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR); liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin (ALB); renal function: urea, creatinine (crea); immune-related indicators (complement C3, C4, immunoglobulins IgA, IgG, IgM, 25-(OH)D3, CD3/CD4/CD8 lymphocyte subsets, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-γ (IFN-γ), and autoantibody spectrum) and SLE Disease Activity Index (SLEDAI). [ 9 ] The SLEDAI score was independently determined by the clinician without knowledge of the patient’s CA125 test result. Statistical analysis was performed using SPSS version 23.0 (IBM Corp). Measurement data conforming to a normal distribution are expressed as ( x ¯ ± S ), and the t test was used to compare differences between groups. Non-normally distributed measurement data were expressed as M(P25, P75), and the Mann–Whitney U test was used to compare differences between groups. Count data are presented as percentages, and the chi-square test was used for comparisons between groups. Univariate and binary logistic regression analyses were used, and statistical significance was set at P  < .05.

Based on the inclusion and exclusion criteria, 220 patients were ultimately included in this study, including 63 cases (28.64%) in the CA125-positive observation group and 157 cases (71.36%) in the CA125-negative control group. The screening process is illustrated in Figure 1 . Flow diagram of sample collection for the study. CA125 = carbohydrate antigen 125, SLE = systemic lupus erythematosus. Univariate analysis of the fundamental data from both the observation and control groups revealed that the difference in the average hospital stay duration between the 2 groups was statistically significant ( P  < .05; Table 1 ). Comparison of basic data between the control group and the observation group. P  < .01. Univariate analysis of clinical symptoms in patients with SLE within the observation and control groups revealed that Raynaud’s phenomenon, interstitial pneumonia, hypoproteinemia, and serous cavity effusion were significantly different between the 2 groups ( P  < .05; Table 2 ). Univariate analysis of clinical symptoms in patients with SLE. Serous cavity effusions included pleural effusion, ascites, and pericardial effusion. SLE = systemic lupus erythematosus. P  < .05. P  < .01. Univariate analysis of laboratory results comparing the SLE patient observation group with the control group showed statistically significant differences in white blood cell count (WBC), hemoglobin (HB), erythrocyte sedimentation rate (ESR), complement C3, serum albumin (ALB), immunoglobulin IgA, immunoglobulin IgG, 25-(OH)D3, SLEDAI, IL-6, IL-10, and anti-dsDNA levels ( P  < .05; Table 3 ). Univariate analysis of laboratory results in the patients of SLE. ALB = albumin, ALT = alanine aminotransferase, ANA = antinuclear antibody, AST = aspartate aminotransferase, C3 = complement C3, C4 = complement C4, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, HB = hemoglobin, IgA = immunoglobulin A, IFN-γ = interferon-γ, IgG = immunoglobulin G, IgM = immunoglobulin M, IL = interleukin, PLT = platelets, SLE = systemic lupus erythematosus, SLEDAI = Systemic Lupus Erythematosus Disease Activity Index, SSA = Sjögren’s syndrome A antigen, SSB = Sjögren’s syndrome B antigen, WBC = white blood cell count. P  < .05. P  < .01. Variables in the univariate analysis ( P  < .05) were incorporated into the multivariate logistic regression analysis, which identified hypoproteinemia, serous cavity effusion, ALB, C3, 25(OH)D3, SLEDAI, and IL-6 as significant factors influencing elevated CA125 levels (Table 4 ). Multivariate analysis of the influencing factors of CA125 positive. ALB = albumin, C3 = complement C3, CA125 = carbohydrate antigen 125, ESR = erythrocyte sedimentation rate, HB = hemoglobin, IgA = immunoglobulin A, IgG = immunoglobulin G, IL-6 = interleukin-6, IL-10 = interleukin-10, OR = odds ratio, PLT = platelets, SE = standard error, SLEDAI = Systemic Lupus Erythematosus Disease Activity Index, WBC = white blood cell count. P  < .05. P  < .01. Linear regression analysis shows that CA125 levels were positively correlated with SLEDAI ( P  < .001, R 2  = 0.3390; Fig. 2 ); CA125 was negatively correlated with 25(OH)D3 ( P  = .001, R 2  = 0.3187; Fig. 3 ); negatively correlated with ALB ( P  < .001, R 2  = 0.4190; Fig. 4 ), and positively correlated with IL-6 ( P  < .001, R 2  = 0.5085; Fig. 5 ). SLEDAI was negatively correlated with 25(OH)D3 levels ( P  < .001, R 2  = 0.1959; Fig. 6 ). Positive correlation between serum CA125 levels and SLEDAI score in SLE patients. CA125 = carbohydrate antigen 125, SLE = systemic lupus erythematosus, SLEDAI = Systemic Lupus Erythematosus Disease Activity Index. Negative correlation between serum CA125 levels and 25(OH)D3 in SLE patients. CA125 = carbohydrate antigen 125, SLE = systemic lupus erythematosus. Negative correlation between serum CA125 levels and ALB in SLE patients. ALB = albumin, CA125 = carbohydrate antigen 125, SLE = systemic lupus erythematosus. Positive correlation between serum CA125 levels and IL-6 in SLE patients. CA125 = carbohydrate antigen 125, IL-6 = interleukin-6, SLE = systemic lupus erythematosus. Negative correlation between serum 25(OH)D3 levels and SLEDAI score in SLE patients. SLE = systemic lupus erythematosus, SLEDAI = Systemic Lupus Erythematosus Disease Activity Index.

CA125 is a glycoprotein that was initially recognized by Bast et al [ 10 ] using the monoclonal antibody OC125, prepared after immunizing mice with human ovarian cancer cells. CA125 has long been regarded as an important biomarker for ovarian cancer. However, subsequent studies have found that elevated CA125 levels are not only seen in ovarian cancer, but also in a variety of benign diseases, other malignant tumors, and even certain physiological states. [ 11 ] Recently, researchers have gradually attracted attention to the clinical significance of non-neoplastic elevation of CA125 levels in patients with systemic lupus erythematosus (SLE). This study aimed to explore the relationship between elevated CA125 levels in patients with SLE and their clinical characteristics and laboratory indicators to further clarify the clinical significance of elevated CA125 levels in SLE. These findings indicate that elevated CA125 levels are associated with hypoproteinemia and serous cavity effusion in SLE patients. Effusion within the serous cavity encompasses the pleural, peritoneal, and pericardial cavities. CA125 is encoded by the human MUC16 gene and is synthesized by mesothelial cells. [ 12 ] And mesothelial cells are monolayer flat epithelial cells covering the surface of body cavities (such as the pleura, peritoneum, and pericardium). Mechanical stress, oxidative stress, and inflammation activate the epithelium of the pleura, peritoneum, and pericardium, resulting in an elevation of CA125 secretion, which is consistent with the findings of Huang. [ 13 ] Serum albumin, a major protein in plasma, plays a crucial role in maintaining colloid osmotic pressure, substance transport, and nutrition in the blood. Patients with systemic lupus erythematosus (SLE) often have renal involvement, which manifests as proteinuria and leads to hypoproteinemia. [ 14 ] Hypoproteinemia may result in a reduction in plasma colloid osmotic pressure, thereby facilitating the development of serous cavity effusion and indirectly contributing to elevated CA125 levels. Additionally, this study found a negative correlation between ALB and CA125 levels, contrasting with the findings of Gupta et al, who did not identify a significant correlation between these 2 levels. [ 15 ] This difference may be related to the different subjects and sources of CA125 secretions. During the active phase of SLE, the body is in an inflammatory state, with increased permeability of capillaries and increased exudation of serum albumin, leading to a decrease in albumin levels. [ 16 ] Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease. Patients need long-term drug treatment and often have chronic fatigue, depressive states, and multiple complications. [ 17 ] All these factors can cause changes in appetite, thereby increasing the risk of malnutrition. In an inflammatory state or in cases of malnutrition, serum albumin levels often decline, resulting in hypoproteinemia. This indicates that inflammation can lead to a decrease in albumin in SLE patients, which is consistent with previous literature reports. [ 18 ] Vitamin D is a fat-soluble steroid hormone that exerts immunomodulatory effects along with its role in modulating calcium and phosphorus metabolism. 25(OH)D3, as the main form of vitamin D, plays a role in the immune response through diverse mechanisms, including modulation of antigen presentation and direct regulation of T and B lymphocyte activity, thereby serving as a therapeutic option for autoimmune diseases. [ 19 ] Studies have shown that insufficient levels of vitamin D are associated with increased disease activity in SLE, and patients with low levels of vitamin D often have significantly higher SLEDAI scores. [ 20 ] This study identified a negative correlation between 25(OH)D3 levels and CA125, while SLEDAI scores exhibited a positive correlation with CA125. Additionally, 25(OH)D3 was negatively correlated with SLEDAI, consistent with the findings of several prior studies. [ 21 , 22 ] Unlike Kim’s study, it is speculated that the variation in findings may be associated with race, ethnicity, geographic location, and daylight duration. [ 23 , 24 ] Research indicates that the majority of patients with SLE exhibit decreased complement C3 levels, and the degree of reduction correlates with heightened disease activity. [ 25 ] Patients with SLE possess a significant quantity of autoantibodies that generate immune complexes (ICs) with their respective autoantigen components. The complement system is activated via the classical and bypass pathways, contributing to the clearance of immune complexes. This process involves substantial consumption of complement C3, leading to a reduction in serum C3 levels. [ 26 ] Previous research has demonstrated that complement C3 plays a role in the disease activity phase in patients with SLE. [ 27 ] The findings of this study indicated that complement C3 levels in CA125-positive SLE patients were lower than in CA125-negative patients, with the difference reaching statistical significance, implying that CA125-positive patients may be in an active phase of the disease. Further correlation analysis demonstrated a negative relationship between CA125 and complement C3, indicating an association between CA125 levels and SLE disease activity from an alternative perspective. Cytokine-mediated immune responses are pivotal in the pathophysiology of SLE. [ 28 ] In individuals with SLE, IL-10 promotes B-cell proliferation and immunoglobulin class switching, thereby increasing antibody and immunoglobulin production and correlating with disease activity. [ 29 ] A univariate analysis of laboratory indicators in this study revealed that both IL-10 and IgG levels were increased in the CA125-positive group, corresponding with findings from prior research. [ 30 ] Tackey proved that IL-6 plays a role in the tissue injury process and the pathogenesis of SLE. [ 31 ] Joonhong showed that elevated levels of IFN-γ in patients with SLE are correlated with disease activity. [ 32 ] In this investigation, however, no statistically significant difference in IFN-γ levels was observed between the CA125-positive and CA125-negative groups, potentially due to subject selection. Joonhong’s investigation included patients exhibiting renal involvement; however, the population in this study was different. Furthermore, IL-6 was an influencing factor for CA125 positives in this study, similar to the findings of Torres, [ 33 ] who suggested that IL-6 could serve as a predictor or biomarker of SLE disease activity and promote the proliferation of serum CA125-secreting cells, thereby increasing serum CA125 levels. This study indicates that IL-6 is an independent predictor of elevated CA125, suggesting that it may play a direct role in the regulation of CA125 expression. CA125 (encoded by the MUC16 gene) is mainly expressed by mesothelial cells in the serosa. Previous studies [ 34 ] have shown that an increase in IL-6 levels can activate the NF-κB signaling pathway, and the activated NF-κB binds to the MUC16 promoter, upregulating the expression of this gene; the extracellular domain of MUC16 is cleaved to release CA125, thereby increasing the level of CA125. Additionally, IL-6 can also induce the expression and secretion of MUC16 mucin in human peritoneal mesothelial cells through an Akt-dependent signaling pathway, further increasing the concentration of CA125. [ 35 ] In summary, CA125 and IL-6 can serve as important indicators reflecting systemic inflammation involving the serosa. Therefore, an increase in CA125 levels is not necessarily a tumor signal. It may be an important indicator of the presence of hypoproteinemia, serous cavity effusion, and the active state of systemic immune inflammation in the body. This level can be used to assist in the evaluation of SLE disease activity. This study is a single-center retrospective study, which has the risks of selection bias and information bias. Moreover, the data from a single center is limited by the population characteristics and clinical practices of the hospital. The general applicability of the conclusion needs to be further verified. Although the total sample size is acceptable, the sample size of the key subgroups (CA125 positive group, n = 63) is relatively small, which limits the variable correction ability of the multivariate regression. When conducting further stratified analysis, the statistical power is lower, increasing the risk of false negatives. For example, indicators such as IFN-γ did not show differences between groups, which may be related to the insufficient sample size. Nevertheless, this study provides preliminary evidence for the non-oncological elevations of CA125 in patients of SLE. In the future, a multicenter prospective study should be conducted to expand the CA125 positive cohort and verify the conclusion and further explore its association with related indicators.