Introduction

Gout is the most common inflammatory arthritis, affecting approximately 55 million people worldwide [1]. It is caused by dysregulation of purine metabolism, which contributes to elevated uric acid concentrations, crystal formation, and subsequent phagocytosis by leukocytes, resulting in recurrent inflammation of the joints and periarticular tissues [2]. Gout has been shown to be associated with a substantially increased disease burden and mortality compared with the general population [3]. These findings indicate that gout is not merely a joint disease but a chronic inflammatory metabolic disorder with significant socioeconomic impact.

The concept of multimorbidity, defined as the coexistence of two or more chronic conditions within an individual, has emerged as an important concept in chronic disease management [4]. Patients with gout frequently present with multiple comorbid conditions, including chronic kidney disease (CKD), diabetes mellitus and cardiovascular disease [5]. The high prevalence of comorbid conditions in patients with gout adds complexity to disease management and may adversely affect clinical outcomes. These comorbidities share common metabolic and inflammatory pathways with hyperuricemia and may mutually exacerbate disease progression [6]. Understanding the patterns and clinical implications of multimorbidity in gout may help improve risk stratification and guide more comprehensive management strategies.

Epidemiology of gout

The global prevalence of gout ranges from 0.68% to 3.90% and has been steadily increasing [1]. Data from the Global Burden of Disease study indicate that gout prevalence has risen by approximately 22.5% over the past 30 years [7]. Data from the National Health and Nutrition Examination Survey (NHANES) 2007–2016 indicate that approximately 20% of US adults have hyperuricemia, and the prevalence of gout has risen to 5.1%, compared with 3.9% in earlier reports [8]. In Korea, three epidemiologic studies using Health Insurance Review and Assessment Service data reported a gout prevalence ranging from 0.4% to 2.0% [9]. The number of patients with gout has exceeded 500,000, and cumulative healthcare expenditures over 5 years have surpassed US $3.5 billion [10]. Notably, the number of younger patients with gout has increased markedly, likely due to the higher prevalence of hyperuricemia in younger populations [11].

Risk factors for gout

1. Hyperuricemia

Hyperuricemia is the primary risk factor for gout, and the risk of gout increases in a dose-dependent manner with rising serum urate levels. Compared with individuals with baseline serum urate levels below 6 mg/dL, a pooled analysis of four cohort studies has shown that the risk of incident gout increased by approximately 15–30-fold in those with serum urate levels of 8.0–9.9 mg/dL, and by nearly 40-fold in those with levels exceeding 10 mg/dL [12]. Nevertheless, more than half of individuals with hyperuricemia never develop clinical gout, suggesting that additional factors beyond hyperuricemia, such as genetic predisposition, smoking, and physical activities, contribute to gout pathogenesis [13].

Hyperuricemia results from an imbalance between uric acid production and excretion, with reduced renal urate excretion being the most common mechanism. This condition is closely associated with the use of medications such as diuretics, aspirin, and cyclosporine, as well as comorbid conditions including CKD, obesity, and metabolic syndrome [14-16]. In contrast, increased uric acid production is associated with purine-rich dietary intake (e.g., red meat and alcohol) and conditions characterized by increased cell turnover, such as hematologic malignancies [17].

2. Genetic predispositions

Genetic variation represents one of the most important risk factors for the development of hyperuricemia and gout [17]. A meta-analysis demonstrated that dietary factors account for only approximately 1% of the variance in serum urate levels, whereas genetic factors explain up to 23.9% of the variation [17]. Genetic variants in urate transporter genes are strongly associated with interindividual differences in serum urate concentrations [18]. In addition to well-established urate transporter genes such as SLC2A9 and ABCG2, a recent genome-wide association study including approximately 120,000 patients with gout identified 377 genetic loci, including NLRP3 and IL1R1, which are implicated in the inflammatory pathogenesis of gout [19].

3. Gut microbiota

The gut microorganisms also play essential roles in the regulation of the immune system. Dysbiosis of the gut microbiota has been associated with various diseases and inflammation [20]. More recently, the gut microbiota has emerged as a novel contributing factor in gout pathogenesis. Several studies have reported that patients with gout exhibit reduced gut microbial diversity and a microbial composition distinct from that of healthy controls. These alterations, along with microbial metabolites, may influence purine metabolism and uric acid homeostasis, leading to the onset of gout [21,22].

Inflammatory pathways in the pathogenesis of gout

Approximately one-third of the body urate pool is derived from dietary sources, whereas two-thirds originate from endogenous production, primarily through nucleic acid degradation (Fig. 1) [23]. After ingestion of purine-containing foods, purines are metabolized in the liver, leading to increased serum urate levels. Approximately 90% of filtered urate is reabsorbed, with only 10% excreted; of total urate elimination, about two-thirds occurs via the kidneys and the remaining one-third through the intestine. Increased urate production or impaired urate excretion results in hyperuricemia, which can ultimately lead to the development of gout.

Acute gout flares result from monosodium urate (MSU) crystal-induced activation of innate immune responses [24]. MSU crystals interact with synovial macrophage receptors, such as Toll-like receptors, or are phagocytosed by monocytes and macrophages. These processes activate the NLRP3 inflammasome, leading to the maturation of interleukin-1β (IL-1β), which subsequently promotes the production and release of proinflammatory cytokines, including tumor necrosis factor and interleukin-6 (IL-6). This inflammatory cascade is further amplified through the activation of neutrophils and mast cells, resulting in an acute gout flare [25,26].

With disease progression, tophi formation and structural joint damage may occur [27]. Tophi are commonly found in joints, bones, cartilage, tendons, and subcutaneous tissues. Although primarily composed of MSU crystals, tophi exhibit a structure resembling chronic granulomas, surrounded by inflammatory cells and connective tissue [24]. Tophi are closely associated with structural joint damage [28], as MSU crystals and activated macrophages promote inflammation and osteoclast activation, leading to increased bone resorption and subsequent bone erosion [29,30].

Comorbidities and pharmacologic implications

Approximately half of patients with gout meet the World Health Organization criteria for metabolic syndrome [31]. An increased risk of type 2 diabetes mellitus has been observed among patients with gout. A US-based study indicated that 26% of patients with gout had diabetes, with the prevalence rising to 33% among those with higher serum urate levels [32]. In addition, 75% of patients with gout have hypertension [1], along with an elevated risk of cardiovascular diseases, including coronary artery disease, heart failure and peripheral vascular disease, is approximately twofold higher compared with the general population [33,34]. CKD is also closely associated with gout. A recent meta-analysis demonstrated that when serum urate levels were stratified into quartiles, individuals in the third and fourth quartiles had a 1.5–2-fold increased risk of incident CKD compared with individuals in the lowest quartile [35]. However, large randomized controlled trials, including the Febuxostat versus Allopurinol Streamlined Trial (FEATHER), Controlled Trial of Slowing of Kidney Disease Progression From the Inhibition of Xanthine Oxidase (CKD-FIX), Preventing Early Renal Loss in Diabetes (PERL) studies, showed that although urate-lowering therapy effectively reduced serum urate levels, evidence for improvement in renal function or reduction in mortality remains insufficient [36-38].

The development of these comorbidities has been linked to gout-related inflammation. Uric acid can directly stimulate the renin–angiotensin–aldosterone system [39], and impair endothelial function through oxidative stress and nitric oxide dysregulation [40]. In addition, urate crystal-induced inflammation has been associated with an increased risk of cardiovascular disease and diabetes [41,42]. Notably, studies using dual-energy computed tomography (DECT) have shown that a greater volume of MSU crystal deposition is associated with conditions such as chronic heart failure, type 2 diabetes, and hypertension [43].

In patients with gout and concomitant hypertension, the use of urate-lowering antihypertensive agents, particularly angiotensin receptor blockers, is preferred over diuretics. In those with coexisting dyslipidemia, treatment with statins may provide additional benefit [44].

In patients with a history of myocardial infarction, low-dose colchicine (0.5 mg daily) was associated with a reduced risk of ischemic cardiovascular events compared with placebo, leading to approval by the US Food and Drug Administration (FDA) for primary and secondary prevention of cardiovascular disease [45,46]. Although IL-1 inhibitors, such as canakinumab, have demonstrated efficacy in reducing cardiovascular events, their use for cardiovascular risk management remains limited [47]. The effects of allopurinol and febuxostat on the progression of cardiovascular disease, diabetes, and CKD remain controversial [48,49].

In a cohort study of patients with concomitant gout and type 2 diabetes, treatment with sodium–glucose cotransporter 2 inhibitors (SGLT2i) was associated with a 19% reduction in gout flares and a 29% lower mortality rate compared with nonusers [50]. These findings indicate that SGLT2i may represent a promising therapeutic option for patients with gout and diabetes by mitigating comorbidity risk while simultaneously reducing the overall burden of gout [51].

Diagnosis criteria and modalities for gout

In general, gout is diagnosed when clinical symptoms become apparent [52]. The 2015 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) gout classification criteria specify a history of at least one episode of swelling, pain, or tenderness involving a peripheral joint or bursa as an entry requirement for gout classification [53]. The gold standard for definitive diagnosis is identification of needle-shaped MSU crystals under polarized light microscopy following arthrocentesis of the affected joint [54]. However, in routine clinical practice, the use of joint aspiration is limited by the availability of trained personnel and appropriate equipment. Data from several European countries indicate that only 18%–32% of cases are definitively diagnosed as gout in rheumatology clinics, and the proportion is likely even lower in primary care settings [55,56].

Imaging modalities can aid in the diagnosis of gout. Plain radiographs are often normal at the time of initial diagnosis but may reveal soft tissue tophi and, in advanced disease, characteristic gouty bone erosions [57]. An enhanced understanding of crystal-induced arthritis has led to greater recognition of the diagnostic utility of musculoskeletal ultrasonography and DECT. On ultrasonography, MSU crystal deposition on the cartilage surface may produce the double contour sign, and hyperechoic aggregates within the joint space may appear as a snowstorm pattern [58]. DECT allows visualization of urate deposition, typically displayed as green-colored tophaceous deposits [59]. Both the double contour sign on ultrasonography and DECT have demonstrated high sensitivity and specificity (74%–90%), whereas the diagnostic accuracy of tophi detection alone is somewhat lower [60]. A key limitation is that urate crystal deposition may not be detectable in early disease, resulting in variability in diagnostic sensitivity depending on disease duration [61]. Therefore, continued efforts are needed to improve the early detection of crystal deposition in gout.

Treatment framework and emerging therapies

Treatment of gout can be broadly divided into acute flare management and urate-lowering therapy (ULT). Antiinflammatory agents used for the treatment of acute gout flares include colchicine, nonsteroidal antiinflammatory drugs, and glucocorticoids. In patients with monoarticular involvement, such as the knee, who are unable to tolerate oral medications, intraarticular corticosteroid injection may be considered, provided that septic arthritis has been excluded. Clinicians should be familiar with the adverse effects and precautions associated with each therapeutic agent (Table 1) [62]. Canakinumab, an IL-1 antagonist, has been approved by the FDA for the treatment of gout flares; however, its clinical use remains limited due to its high cost [63,64].

During an acute gout flare, patients are advised to minimize joint movement and rest, and local ice application may help alleviate symptoms. Pharmacologic treatment should be started as early as possible, preferably within 24 hours of symptom onset, as early intervention is associated with more rapid symptom improvement. Both the 2020 ACR guidelines and the 2024 Korean College of Rheumatology guidelines support the initiation of urate-lowering therapy during an acute flare, noting that patients may be more motivated to adhere to ULT when symptoms are present [62,65].

ULT reduces serum urate levels, decreases recurrent gout flares, promotes resolution of tophi, and prevents progression to more severe forms of gout [66]. Pharmacologic options include xanthine oxidase inhibitors, such as allopurinol and febuxostat, which inhibit uric acid production, and uricosuric agents including probenecid and benzbromarone, which reduce serum urate by enhancing renal uric acid excretion [67]. Benzbromarone is currently not available in Korea. Allopurinol and febuxostat are considered first-line treatment options. Allopurinol is primarily excreted by the kidneys and accordingly requires dose modification in patients with CKD; and carries the highest risk of severe cutaneous adverse reactions (SCARs) among available agents [68]. In Korea, the prevalence of the HLA-B*58:01 allele, which is strongly associated with allopurinol-induced SCARs, is relatively high. Consequently, HLA-B*58:01 genotyping, which is reimbursed by the national health insurance system, should be performed prior to initiating allopurinol therapy [69]. In contrast, febuxostat is less affected by renal function and has potent urate-lowering efficacy, leading to its widespread use in Korea. Although a black box warning regarding increased cardiovascular risk was issued following the Cardiovascular Safety of Febuxostat and Allopurinol in Participants with Gout and Cardiovascular Comorbidities (CARES) trial [70], subsequent evidence from the Febuxostat Versus Allopurinol Streamlined Trial (FAST) study did not demonstrate an increased cardiovascular risk with febuxostat use [71]. ULT should be initiated at a low dose, with titration every 2–4 weeks until the target serum urate level is achieved, and a uricosuric agent may be added if adequate control is not achieved with monotherapy [44]. Allopurinol is typically initiated at 100 mg daily, or 50 mg daily in patients with CKD, whereas febuxostat is commonly started at 40 mg daily. To prevent acute gout flares during ULT initiation, low-dose antiinflammatory prophylaxis may be co-administered for approximately 6 months [72]. Alternatively, gradual up-titration of febuxostat starting at 10 mg has been shown to provide flare prevention efficacy comparable to that of colchicine prophylaxis [73].

According to the ACR guidelines, ULT is indicated in patients with frequent gout flares (≥2 per year), the presence of tophi, or radiographic evidence of erosive disease [44]. In addition, ULT may be beneficial even after a first gout flare in patients with a serum urate level ≥9 mg/dL, a history of urolithiasis, or CKD stage 3 or higher. Both the ACR and EULAR recommend a treat-to-target strategy, with a target serum urate target of <6 mg/dL in patients without tophi and <5 mg/dL in those with frequent flares or tophaceous gout [44,74].

Among emerging therapies, agents targeting the NLRP3 inflammasome, which plays a central role in the pathogenesis of gout, are currently under clinical investigation. Dapansutrile, an oral NLRP3 inhibitor, has demonstrated effective analgesic and antiinflammatory effects with no significant safety concerns reported to date [75]. Dotinurad is a selective urate reabsorption inhibitor that reduces serum urate levels through selective inhibition of URAT1 in the renal proximal tubules. In two randomized controlled trials, dotinurad has demonstrated noninferiority to febuxostat and benzbromarone in reducing serum urate levels [76,77]. Dotinurad was approved in Japan in 2020, and approval in other countries may follow. Beyond gout, its potential use has been suggested in conditions such as metabolic syndrome, CKD, and cardiovascular disease [78,79].

Pegloticase, a recombinant uricase, is indicated for refractory chronic gout, particularly in patients with tophaceous disease who are unresponsive to or have contraindications to xanthine oxidase inhibitors. It is currently approved by the FDA for this indication [52]. Due to the potential for infusion reactions and anaphylaxis, premedication and close monitoring of serum urate levels prior to each infusion are required. To minimize the risk of infusion-related reactions, the FDA has recently approved the concomitant use of methotrexate with pegloticase [80,81].

Long-term prognosis and therapeutic optimization in gout

When mortality rates among patients with gout were compared between an early cohort (1988–1994) and a later cohort (2007–2016) using data from NHANES, mortality remained similar in both periods (hazard ratios, 1.20 [1.03–1.40] and 1.19 [1.04–1.37], respectively) [3]. While survival outcomes in diseases such as rheumatoid arthritis and systemic lupus erythematosus have improved over recent decades [82,83], mortality associated with gout has not shown comparable improvement. The persistently high mortality in gout is likely related to suboptimal implementation of current therapies and insufficient long-term disease management. Between 2007 and 2016, only 35.5% of patients with gout in the US were treated with ULT, indicating that fewer than one-third of eligible patients were treated [84]. Moreover, a meta-analysis demonstrated that adherence to ULT was poor, with an estimated adherence rate of approximately 46% [85]. Because ULT is intended for long-term use over many years rather than short-term treatment, multiple factors contribute to difficulties in maintaining therapy. One important factor is the perception that gout is a condition that requires medication only during painful episodes, leading patients to discontinue treatment during asymptomatic periods [86]. In addition, some patients intentionally stop therapy to assess whether they can manage without treatment or as an expression of resistance to chronic medication use [87]. Poor adherence contributes substantially to increased healthcare costs and unfavorable clinical outcomes. Patients should be educated that gout is a chronic metabolic disease and that sustained ULT can dissolve urate crystals and improve long-term clinical outcomes [88]. Regular monitoring of serum urate levels and imaging findings is also essential to encourage continued adherence to therapy [89]. Indeed, several studies have reported that intensive care delivered by specially trained nurse educators significantly improved gout flare frequency, tophus burden, and treatment adherence [90]. Continuous efforts to optimize gout management and further research in this field are therefore needed.

Conclusions

Gout is an increasingly prevalent inflammatory metabolic disease driven by hyperuricemia. Beyond joint involvement, it is strongly associated with major comorbidities, contributing to increased morbidity and mortality. Although effective diagnostic tools and urate-lowering therapies are available, suboptimal treatment implementation and poor adherence remain significant challenges. Early diagnosis, a treat-to-target strategy, and sustained patient education are essential to reduce the long-term burden of gout.

Article information

Conflicts of interest

Jihun Kang is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Acknowledgments

Hyeong Taek Woo (Keimyung University, Daegu, Korea) provided statistical support.

Funding

None.

Author contributions

Conceptualization: PJK, JK, GTK, YK. Investigation: PJK, JK, GTK, YK. Supervision: JY, GTK, YK. Validation: PJK, JY. Visualization: YK. Writing-original draft: PJK, JK. Writing-review & editing: GTK, YK. All authors have read and approved the final manuscript.

Fig. 1.

Pathogenesis of gout. Purine-rich diets and other hyperuricemia-promoting factors increase serum urate levels. Approximately 70% of urate is excreted by the kidneys and 30% by the intestine, and impaired excretion leads to hyperuricemia. Monosodium urate crystals deposit in joints and activate the NLRP3 inflammasome, leading to caspase-1–mediated interleukin-1β (IL-1β) production and the release of proinflammatory cytokines (e.g., tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6]). These processes result in the acute joint inflammation and pain characteristic of gout. CD14, cluster of differentiation 14; TLR2/4, Toll-like receptor 2/4; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; NLRP3, NOD-like receptor protein 3. Schematic illustration of monosodium urate crystal-induced NLRP3 inflammasome activation, created with reference to previous studies (Busso & So, 2010; Liu-Bryan, 2010).

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