Introduction

Gout is a common metabolic disease, and its prevalence is increasing annually. Most gout is over 1% in most developed countries, particularly in North America and Europe1, whereas in China, it ranges between 1 and 3%2. Although gout attacks result from hyperuricemia, the levels can be falsely low during acute attacks. Currently, some studies suggest that C-reactive protein (CRP) levels may increase during the acute phase of gout3; however, CRP is not highly specific, and its elevation can be observed in various other diseases. Despite CRP increasing with acute attacks, more particular biomarkers are still desirable.

Glycoantigen 724 (CA72-4) is a widely used clinical tumor marker that shows increased expression in various types of tumors, such as gastrointestinal and ovarian tumors4,5. Nevertheless, several studies have reported that CA72-4 levels are also significantly elevated in non-cancerous diseases, such as pancreatic, biliary, liver, and type 2 diabetes6,7. This study suggested that CA72-4 was not exclusively produced by cancer cells or tumors. Previous studies have reported an association between gout and CA72-48,9. Gout is recognized as an inflammatory disease, and some studies have proposed that CA72-4 may play a significant role in the inflammatory response. CA72-4 is a high molecular weight mucin with a pan-cancerous tissue distribution that can provoke an immune response, leading to inflammation9. However, it was not explicitly stated whether CA72-4 is associated with gout at all stages, and further analysis is required to determine if other markers are also associated with gout.

In this cross-sectional study, we comprehensively analyzed the relationship between acute and remissive phases of gout, pure hyperuricemia, and CA72-4 levels while also analyzing the impact of gout medications on CA72-4 levels. Additionally, we investigated the correlation between gout and other tumor markers.

Methods

Participants information

A total of 850 participants were enrolled in this study as inpatients or outpatients at the Second Hospital of Fujian Medical University from 2020 to 2023. Of these registered individuals, 535 were diagnosed with gout based on the 2015 ACR/EULAR gout classification criteria. Senior gout experts and rheumatologists confirmed the diagnoses. They were divided into the gout flare group and the gout no flare group. Gout flare is divided into two subgroups: a group receiving colchicine and a group receiving without colchicine. Of these enrolled individuals, 315 volunteers were enrolled as healthy controls. The exclusion criteria were various carcinomas, non-gouty arthritis (rheumatoid arthritis, spondyloarthritis, osteoarthritis, septic arthritis), age < 20 years or > 70 years, long-term alcohol abuse, pregnancy, kidney or liver insufficiency, perioperative, severe infection, and blood disease. In this study, the enrolled patients continued to use their previous urate-lowering regimen. All participants were informed about the study and signed consent forms. The Ethics Committee of the Second Affiliated Hospital of Fujian Medical University has approved this study.

Indicator measurement

The same one-piece scale measured standing height and weight while fasting without shoes. The BMI value was calculated by dividing the participant’s weight (in kilograms) by the square of their size (in meters). The participant’s blood pressure was measured on their right arm using a mercury sphygmomanometer after 30 min of sitting and resting. Venous blood was collected from each participant in the morning after a 10–12 h fast. An electrochemiluminescence immunoassay was used to measure CA72-4, Glycoantigen 125 (CA12-5), Glycoantigen 199 (CA19-9), and Carcinoembryonic antigen (CEA) using the Modular E601 automated analyzer (Roche, Basel, Switzerland), according to the manufacturer’s instructions. HbA1c was measured using high-performance liquid chromatography (D10; Bio–Rad, Berkeley, CA). We used automatic biochemical analyzers (Cobas 8000; Roche, Germany) to measure sUA, CRP, kidney function (serum creatinine), liver function (aspartate transaminase (AST), alanine transaminase (ALT)), and blood lipids (low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and total cholesterol (TC)) uniformly. The glomerular filtration rates were calculated using the formula “Ccr= {[140-age (years) × weight (kg)]/[0.818 × serum creatinine (Scr, µmol/L)]} for men and Ccr × 0.85 for women”.

Statistical analysis

Statistical analysis was performed on most of the data using SPSS version 19.0 and GraphPad Prism version 8.0. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD), while non-normally distributed variables were presented as median (interquartile range, IQR). Categorical variables were described as frequencies (percentages)10. One-way analysis of variance (ANOVA) and Kruskal-Wallis were used for two-way comparisons between the three groups. Data were compared between the two subgroups using a t-test. The chi-square test was used to compare count data of characteristics. Logistic regression was performed by adding CA72-4, CRP, etc., to control for possible confounding factors. A receiver operating characteristic (ROC) curve was used to determine a cutoff value for CA72-4 and CRP in people with gout. A p-value of less than 0.05 was considered statistically significant.

Results

A total of 850 participants were included in the study. Among them, 315 were healthy controls, 286 had gout no flare, and 249 had gout flare (Table 1). CA72-4 and CRP levels were significantly higher in participants with gout flare than those with no flare and healthy controls (Table 1). There were no significant differences between the three groups regarding CA12-5, CA19-9, CEA, age, duration, BMI, blood pressure (DBP and SBP), hypertension history, diabetes history, cardiac disease history, smoking history, drinking history, tophi, LDL, HDL, TC, AST, ALT, and UACR (Fig. 1A,B). The participants with gout were predominantly male (Table 1). After adjustment, CA72-4, CRP, tophi, and BMI remained independently associated with acute phase of gout (odds ratio 1.438 [1.240 ~ 1.668], P < 0.01; odds ratio 1.533 [1.282～1.834], P < 0.01; odds ratio 3.368 [1.229～9.230], P = 0.018; odds ratio 1.451 [1.020～2.064], P = 0.038) (Table 2). However, in participants with gouty flares, CA72-4 levels were significantly higher in participants receiving colchicine than in those not. There was no significant difference in CRP, NSAID use, and other tumor marker indicators (Table 3).

Table 1 Comparison of clinical features between different groups.
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Table 2 Multifactorial logistic regression predicts the likelihood of gout attacks.
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Table 3 Comparison of clinical features between two subgroups.
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Fig. 1
figure 1

(A) Comparison of serum CA72-4 levels in four groups. (B) Serum CA72-4, CA12-5, CA19-9 and CEA levels in gout patients.

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The cutoff value for CA72-4 measured using the ROC curve was 9.1 U/mL, with an area under the curve of 0.966, a sensitivity of 94.49%, and a specificity of 90.38% (95% CI: 0.944–0.981, P < 0.001). The optimal cutoff point for CRP was 7.01 mg/L, with the highest AUC of 0.900, a sensitivity of 83.46%, and a specificity of 85.58% (P < 0.001) (Fig. 2).

Fig. 2
figure 2

ROC curve of CA72-4 and CRP.

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Discussion

Based on a gout study in China, our study revealed that CA72-4 levels were significantly higher during gouty flares. Interestingly, these levels increased even further after treatment with colchicine. In contrast, other tumor markers and medications commonly used for gout treatment did not show significant changes. Moreover, we found that similar to CRP, CA72-4 can be a useful diagnostic biomarker for gouty flares. However, CA72-4 demonstrated better diagnostic accuracy than CRP in this regard. About CA72-4 being better, the gouty flare patients were being treated, so CRP was less than it should be. This study suggests that CA72-4 may have better clinical significance as a more reliable and sensitive marker for diagnosing gouty flares than CRP rather than just showing statistical significance.

Gout is a type of joint disease due to the accumulation of sodium urate crystals in the bloodstream caused by prolonged hyperuricemia11. Nevertheless, epidemiological studies have indicated that up to 90% of individuals with hyperuricemia do not develop gout12,13,−14. Furthermore, high uric acid levels are not necessarily present in individuals with gout3, consistent with our findings that the blood uric acid level was lower during the gouty flares. CRP is a commonly used biomarker for determining the onset of gouty flares, but its specificity is low.

In the past, CA72-4 was considered a high-molecular-weight mucin 5 with a broad distribution in cancer tissues6. However, increasing evidence suggests that elevated levels of CA72-4 are not only expressed in cancerous diseases but also non-cancerous conditions, including diabetes, liver disease, etc7,8. Recently, some studies9,15, primarily retrospective, have suggested a link between gout and CA72-4. Our study conducted further prospective research and found that CA72-4 only significantly increased during gouty flares, while it remained unchanged during the remission phase of gout. Our study also found that only CA72-4 among the tumor serum markers increased during gouty flares, while other tumor markers, such as CEA, CA19-9, and CA12-5, remained unchanged. In addition, our study found that during gouty flares, patients who received colchicine treatment showed a further increase in CA72-4, while there was no change in CA72-4 levels in patients receiving other drug treatments.

Here, we will attempt to analyze the potential mechanisms that may lead to the increase in CA72-4 during acute gout attacks and after colchicine treatment, even though we did not conduct such an analysis in our study. CA72-4 acts as an adhesion molecule during the inflammatory process16. Gout is an inflammatory disease; therefore, CA72-4 may play an unknown but crucial role in the inflammatory response9. Another study on autoimmune inflammatory diseases also reported similar results, where patients showed an increase in CA72-4 levels, while the other three glycoproteins did not increase17. There is still limited research on the specific mechanisms of CA72-4 during acute gout attacks. The exact mechanism of colchicine’s effect on CA72-4 is still unclear. It may be related to the stimulation of the gastrointestinal tract by oral colchicine, resulting in a series of inflammatory reactions and an increase in CA72-4. It is also possible that colchicine or its metabolites interfere with the conditions of CA72-4 detection, leading to a rise in its level.

As far as we know, CRP is a standard marker of inflammation during gouty flares and is often used to indicate whether the patient is in the acute phase17. Moreover, we used ROC curve analysis to evaluate the diagnostic value of CA72-4 in acute gout attacks, and our study found that the area under the ROC curve was 0.966 (greater than 0.9), indicating that CA72-4 has a high diagnostic value for acute gout attacks. Furthermore, compared to CRP, CA72-4 has higher diagnostic value, specificity, and sensitivity.

Conclusions

In conclusion, serum CA72-4 was closely associated with the gouty flares and it may be considered as a potential serum marker for diagnosing the acute phase of gout, in conjunction with CRP. In addition, clinicians can provide explanations to patients with elevated serum CA72-4 levels who are without cancer but in the acute phase of gout and/or undergoing colchicine treatment. However, our study has some limitations. This study was conducted at a single center with a relatively small sample size, consisting only of Chinese participants. This study was the relatively high proportion of participants with diabetes, hypertension, or a history of smoking. Since these conditions—along with their associated medications and the biochemical effects of smoking—may influence the measured outcomes. Additionally, since the majority of gout patients are male, the inclusion of very few female patients may have an impact on the study results. Therefore, further comprehensive research with larger sample sizes and more diverse ethnic groups is needed.