FormalPara Key Summary Points

Why carry out this study?

Surgery increases the risk of gout flare; however, the endovascular interventional procedures associated with this risk are not well understood.

We hypothesized that endovascular interventional procedures and uric acid-related factors influence postoperative gout flares.

What was learned from the study?

Endovascular interventional procedure and presurgical uric acid level of ≥ 7 mg/dl are risk factors for postoperative gout flares. Prophylactic treatment with colchicine is a protective factor.

Introduction

Gout is one of the most common inflammatory joint diseases, caused by the deposition of urate crystals in the joints or soft tissue[1]. In China, Gout affects 1.1% of Chinese adults [2]. In addition to hyperuricemia, which is the most important risk factor for gout, surgery is another important independent risk factor causing an acute gout flare. Postoperative gout flares may lead to unnecessary antibiotic therapy, and increasing days of hospitalization by delaying early ambulation [3, 4].

Interventional radiology (IR) involves percutaneous puncture under the guidance of medical imaging equipment (angiography, fluoroscopy, computed tomography, magnetic resonance imaging, B-scan ultrasound, etc.) to perform minimally invasive diagnosis and treatment of diseases. Endovascular interventional radiology is among the most crucial procedures widely employed for treating vascular diseases due to its advantages over traditional open surgeries, including minimal invasiveness, shorter hospital stays, and reduced complications [5, 6]. Previous studies on postoperative gout flares have focused only on surgical procedures and did not include endovascular interventional procedures, and the results of these studies were different.

In this study, endovascular procedures were incorporated to assess the clinical characteristics and risk factors associated with gout flare during the postoperative period. The aim was to assist clinicians in better predicting, identifying, and managing gout flares both before and after surgery.

Methods

Patients

Subjects were selected from patients aged 18 years or older who had undergone surgery at the Second Affiliated Hospital, Zhejiang University School of Medicine from January 2020 to December 2021. Exclusion criteria included those having gout or gout-related complications as the primary admission diagnosis for surgery or having incomplete laboratory data or diagnosed as reactive arthritis or infectious arthritis. Gout flare was diagnosed by the consultant rheumatologist or attending doctors or the episode satisfied the 2015 ACR/EULAR gout classification criteria. The study was approved by the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine (approval No. 2021-0783). The requirement for written informed consent was waived by the Ethics Committee owing to the retrospective nature of the study. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Main Outcome Variable

The following were collected: (1) demographic data including age, gender, weight, height, and body mass index (BMI); (2) comorbidities, such as hypertension, diabetes, hypohepatia, renal insufficiency, fatty liver, and kidney stones; (3) laboratory results before surgery such as serum uric acid; (4) surgical factors such as medicines in the operation, body sites involved in surgery and operation duration; (5) medications before surgery, including urate-lowering agents, glucocorticoid, colchicine, diuretic, hypotensor, antidiabetic agent and aspirin; (6) postoperative nutrition and analgesic medication, which including desocine, non-steroidal anti-inflammatory drugs (used in the absence of gout flares), tramadol hydrochloride, buprenorphine, parecoxib, ketorolac tromethamine, oxycodone, methocarbamol, ibuprofen and codeine phosphate tablets, morphine.

Statistical Analysis

All statistical analyses were conducted using STATA statistical software (STATA13.1, StataCorp, College Station, TX, USA), and P < 0.05 was considered statistically significant. We used Kolmogorov–Smirnov tests to check the normality of continuous variables, after which we used t test in instances where the numerical variable had normal distribution, and we used the rank sum test if there was no normal distribution. Categorical variables were analyzed using Chi-square test. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). The figures were done by software (GraphPad Prism 9, GraphPad Software, La Jolla, CA, USA).

Results

From January 2020 to December 2021, there were 1761 individuals who underwent surgery at the Second Affiliated Hospital of Zhejiang College School of Medicine with a history of gout. Among them, 277 patients were diagnosed with postoperative gout flares. Sixteen patients with gout-related complications requiring surgery and 39 patients with incomplete information were excluded, leaving 222 eligible patients for analysis. Among the patients without gout flares, 222 individuals were selected according to the random number method, 26 cases were excluded according to the exclusion criteria, (ten surgery of gout-related complications, one reactive arthritis, 15 incomplete information), and 196 patients without gout flare were finally enrolled as controls.

Clinical Features of Postsurgical Gout Flares

The clinical characteristics of the flare group and no-flare group are shown in the Table 1. Patients in the flare group were older than in no-flare group. Patients in the flare group who had combined hypertension, diabetes, and renal insufficiency were significantly more than those in the no-flare group. Colchicine (0.5–1.0 mg/day), postoperative pain medication and glucocorticoid were more frequently taken in the no-flare group than in the flare group, respectively. Diuretic, hypotensor, antidiabetic agents, and aspirin were more frequently taken in the flare group than in the no-flare group. However, the rate of postoperative nutritional support (both oral and intravenous) was higher in the flare group. Preoperative uric acid levels were significantly higher in the flare group than in the no-flare group, while the hemoglobin and eGFR (estimated glomerular filtration rate) were lower. For patients with comorbidities, we supplemented the specific data on relevant medications, as shown in Supplementary Materials Table 1.

Table 1 Comparison of clinical characteristics between patients with gout flare and without gout flare
Full size table

The type of surgery was classified according to the surgical site, and the results of the analysis are detailed in the Table 1. The patients in the flare group more frequently underwent endovascular interventional procedures than the no-flare group. However, orthopedic surgery was more frequent in the no-flare group. The duration of surgery and anesthesia were significantly longer in the flare group than in the no-flare group, respectively, and the intraoperative use of sodium hyaluronate and compound betamethasone were less.

The uric acid-related factors in orthopedic surgery and endovascular surgery were analyzed in Supplementary Materials Table 2, which suggested that there were no statistically significant differences in uric acid levels, the proportion of uric acid higher than 7 mg/dl, colchicine, and uric acid-lowering agents.

Risk Factors for Postsurgical Gout

The analysis of whether different types of surgery were risk factors for postoperative gout flares is shown in detail in Fig. 1. Among them, endovascular interventional procedure was a risk factor (P < 0.001), while orthopedic surgery was a protective factor (P < 0.001).

Fig. 1
figure 1

Logistic regression analysis of the operation site and postoperative gout flares. OR odds ratio

Full size image

To determine the impact of endovascular interventional procedure on postsurgical gout flare, a Cox regression analysis adjusted for potential confounding factors (Fig. 2) was performed. The Cox model showed that endovascular interventional procedures (HR 1.752; 95% CI 1.126–2.724, P = 0.013) and presurgical uric acid levels of ≥ 7 mg/dl (HR 1.489; 95% CI 1.081–2.051, P = 0.015) were significantly associated with increased risks of postsurgical gout flare, and taking colchicine before surgery were significantly associated with decreased risk of postsurgical gout flare (HR 0.264; 95% CI 0.090–0.774, P = 0.015).

Fig. 2
figure 2

Cox regression analysis of the development of postoperative recurrent gout flares. Hb hemoglobin, UA uric acid, eGFR estimated glomerular filtration rate, CI confidence interval, HR hazard ratio

Full size image

A cumulative hazard plot is shown in Fig. 3. Patients undergoing endovascular interventional procedure were at greater risk of postsurgical gout flare.

Fig. 3
figure 3

Cumulative hazard plot

Full size image

Type of Endovascular Interventional Procedure and Postsurgical Gout

We divided the endovascular interventional procedures into three types, including radiofrequency catheter ablation, pacemaker implantation and treatment of intravascular lesions under the guidance of X-rays (percutaneous transluminal angioplasty, percutaneous endovascular stent implantation, etc.). Then we analyzed the types of endovascular interventional procedure, which is showed in Fig. 4. There was no significant difference in the types of endovascular interventional procedures between the flare group and the no-flare group by the χ2 test (P = 0.443).

Fig. 4
figure 4

Comparison of the types of endovascular interventional procedure between patients with gout flare and without gout flare. TILUGX treatment of intravascular lesions under the guidance of X-rays, RCA radiofrequency catheter ablation, PI pacemaker implantation

Full size image

Discussion

Recurrent gout flares are a major clinical burden of gout, and despite available uric acid-lowering therapies, the risk of recurrent gout remains high. Sixty-seven percent of patients who have already had a previous gout flare would have at least one flare within a year [7]. Surgery is an important trigger for gout flares, with studies finding that 17.2% of patients with gout will experience a gout flare after surgery, and observers in China have found this flare rate to be as high as 40.3% [8, 9].

No previous studies have included endovascular interventional procedures to analyze, and our study found that endovascular interventional procedures were an important risk factor for postoperative gout flares. There may be several reasons for this: (1) Inflammation from mechanical endothelial injury caused by endovascular interventional procedures may lead to gout flares. It has been found that percutaneous coronary intervention (PCI) causes mechanical endothelial injury and endothelial denudation, resulting in elevated inflammatory markers such as hyper-sensitivity CRP (hs-CRP), and this significantly raised inflammatory markers after the procedure suggests a close association with poor prognosis [10, 11]. Similar results have been found in radiofrequency ablation, and studies have shown that the concentration of vascular hemophilia factor (vWF), an important plasma component that is elevated when endothelial cells are injured or receive stimulation, is elevated 24 h after radiofrequency ablation, thus suggesting that radiofrequency ablation can also cause endothelial injury [12, 13]. Initial endothelial activation was related to leukocyte recruitment, which would release intracellular serine proteases [e.g., neutrophil elastase, histone G, and proteinase 3 (PR3)] in response to cell recruitment, causing MSU crystal-mediated cell injury and death, and secrete IL-1β to increase inflammation [14, 15]. Therefore, we speculate that endothelial damage induced by interventional procedures may recruit leukocytes and accelerate the inflammatory response caused by urate crystals, thus causing gout flares [16]. (2) Coronary microembolization (CME) is a common complication of percutaneous coronary intervention (PCI) [17]. It has been found that inflammatory responses in the myocardium after CME involved TLR4/MyD88/NF-κB signaling and the NLRP3 inflammasome, with increased expression levels of pro-inflammatory factors TNF-α, IL-1β [18]. Also, the TLR4/NF-κB pathway plays an important role in the pathogenesis of gout as well. The priming signal effectively promotes the transcriptional activation of NLRP3 inflammasome-containing genes such as NLRP3, pro-IL-1β, and pro-IL-18 in a TLR4/NF-κB pathway-dependent manner [19, 20].

The traditional anti-inflammatory and analgesic drugs for gout treatment include colchicine, NSAIDs, and glucocorticoids [21]. Our study showed that only taking colchicine before surgery was a protective factor for postoperative gout flares, which is consistent with previous findings [9, 22, 23]. The mechanism of colchicine is mainly to bind to β-microtubulin and inhibit cytoskeletal microtubule polymerization, thereby inhibiting the formation of NLPR3 inflammasomes and suppressing the inflammatory response to gout [21, 24]. This may be the reason why colchicine reduces gout flares after endovascular interventional procedures. Besides, colchicine has an endothelial protective effect [25], which can increase plaque stability and decrease plaque progression [26]. Adding low-dose (0.5 mg/day) colchicine to the optimal medical treatment significantly reduced the risk of acute coronary events, cardiovascular death, and resuscitated cardiac arrest [27, 28]. Therefore, prophylactic treatment with colchicine (0.5–1.0 mg/day) can prevent not only postoperative gout flares but also cardiovascular events, which we used if appropriate as a first-line option.

Previous studies have found that the rate of achieving target uric acid in patients with gout in China is low, with only 39.2% of patients reaching the target uric acid (6 mg/dl), even among those who have received long-term uric acid lowering therapy [29]. Therefore, we chose 7 mg/dl (the diagnosis of hyperuricemia) rather than 6 mg/dl as the cutoff. Our results suggested that presurgical uric acid level of ≥ 7 mg/dl before operation was a risk factor for postoperative gout flares, but taking uric acid-lowering agents was not associated with gout flares, which is consistent with previous findings [30]. Therefore, even though target uric acid (6 mg/dl) is difficult to achieve in the short term, controlling preoperative uric acid levels below 7 mg/dl remains an important method of preventing postoperative gout flares.

The limitations of this study are as follows. First, the study was a cross-sectional design with a single race and a small sample size. Second, in the collection of study data, although the exact risk factors were studied extensively, surgery-related factors (e.g., preoperative preparation, surgical technique, postoperative management) was not included. Third, ophthalmologic surgery was not included due to limitations in data collection. Therefore, the results of this study may not be fully applicable to all surgical options. A future well-designed study is needed to investigate the pathogenesis of postoperative gout flares.

Conclusions

Our study findings revealed that the endovascular interventional procedure was a significant risk factor for postoperative gout flares, but there was no significant difference in the types of endovascular interventional procedures for postoperative gout flares. Controlling preoperative uric acid levels below 7 mg/dl is crucial for preventing postoperative gout flares. Additionally, prophylactic treatment with colchicine may be effective in averting gout flares.