Gout: Symptoms, Stages, Tests, Treatment, and Prognosis

Gout is a chronic crystal-induced arthropathy caused by the deposition of monosodium urate crystals in joints and soft tissues against a background of persistent hyperuricemia. The classic manifestation is acute, very painful monoarthritis (most often the first metatarsophalangeal joint, or "gout"), while long-term progression leads to the formation of tophi, erosive changes, and chronic inflammation. In recent years, the effectiveness of a "treat to target uric acid" strategy with systematic titration of urate-lowering therapy and exacerbation prevention has been confirmed. [1]

A key feature of gout is its close association with metabolic syndrome, chronic kidney disease, and cardiovascular risk. Therefore, current guidelines emphasize not only relieving attacks but also long-term control of serum uric acid, risk factor correction, and concomitant therapy. [2]

The introduction of imaging has significantly impacted diagnostics: dual-contour ultrasound and dual-energy CT (DECT) improve accuracy in incomplete clinical cases and help assess crystal burden early. However, the "gold standard" remains the detection of monosodium urate crystals in synovial fluid or tophi. [3]

Epidemiology

Gout is the most common inflammatory joint disease in adults. According to GBD global estimates, approximately 55.8 million people lived with gout in 2020 (standardized prevalence ≈ 659 per 100,000)—an increase of more than 20% over 30 years. Incidence and prevalence are consistently higher in men and increase with age. [4]

Systematic reviews confirm wide variability: depending on the region, prevalence ranges from < 1% to ~6-7%; in high-income countries, it is 3-6% in men and 1-3% in women. However, an increasing burden has been observed in older and even younger adults (15-39 years), which is associated with obesity, sugar, and dietary changes. [5]

Gout increases years lived with disability (YLD), hospitalizations, and healthcare system costs. This underscores the importance of early initiation of urate-lowering therapy and adherence to treat-to-target therapy. [6]

Reasons

The underlying cause is long-term hyperuricemia (serum uric acid > 6.8 mg/dL), leading to synovial fluid oversaturation and the precipitation of monosodium urate crystals. Hyperuricemia occurs due to an imbalance between the formation and excretion of urate: in most patients, decreased renal excretion predominates, while hyperproduction is less common. [7]

Hyperuricemia is influenced by genetic variants of transporters (URAT1, GLUT9), renal dysfunction, diets high in purines and fructose, alcohol (especially beer and spirits), and medications (thiazides, loop diuretics, cyclosporine, low-dose aspirin). The 2020 ACR guidelines emphasize modifying these factors and, if possible, substituting hyperuricemic medications (e.g., preferring losartan over other antihypertensive agents). [8]

Risk factors

Key factors include male gender, age, obesity and metabolic syndrome, chronic kidney disease, hyperuricemic medications (diuretics), high consumption of alcohol and beverages containing high-fructose corn syrup, and purine-rich foods (red meat, organ meats, and some seafood). The contribution of diet is moderate, but clinically significant when combined with other factors. [9]

Family history, urate nephrolithiasis, rapid weight loss, and highly catabolic conditions (cytolysis, hemoblastosis) also increase the risk. In postmenopausal women, the risk increases due to changes in urate metabolism. [10]

Pathogenesis

An acute attack is triggered by monosodium urate crystals, which activate the NLRP3 inflammasome in macrophages, leading to the maturation of interleukin-1β and a neutrophilic inflammatory cascade. This IL-1β-dependent response explains the severe pain, swelling, and hyperemia, as well as the effectiveness of IL-1 blockers in resistant attacks. [11]

Chronic crystal burden promotes granulomatous inflammation and synovial and bone remodeling (erosions, tophi). Associated metabolic disturbances (insulin resistance, CKD) exacerbate hyperuricemia, creating a "vicious cycle." Breaking this cycle requires simultaneous control of inflammation at onset and sustained reduction of urate levels over the long term. [12]

Table 1. Factors that increase uric acid

Category	Examples	Clinical notes
Medicines	Thiazides, loop diuretics, cyclosporine, low-dose aspirin	Replace if possible; among antihypertensive agents, losartan is preferred. [13]
Food and drinks	Beer, strong alcohol, sweetened drinks with fructose, organ meats, some seafood	Restriction reduces urate moderately; more important when combined with weight loss. [14]
Diseases	CKD, metabolic syndrome, psoriasis, hemato-oncology	Increase production or decrease excretion of urate. [15]

Symptoms

An acute attack develops quickly (within hours), with pain peaking within the first 24 hours. Typical symptoms include monoarthritis, severe hyperemia and swelling, nocturnal pain, and difficulty supporting weight. The first metatarsophalangeal joint is most often affected, but the ankle, knee, and arch of the foot can also be affected. Without treatment, attacks subside within 7-14 days, but they can recur. [16]

As the disease progresses, polyarthritis, tophi (auricle, Achilles tendon, joints of the hands and feet), urate nephrolithiasis, and erosive changes with deformities develop. Factors that contribute to frequent attacks include recently initiated urate-lowering therapy without prophylaxis and high urate fluctuations. [17]

Forms and stages

Classically, the following are distinguished: 1) asymptomatic hyperuricemia, 2) acute gout attack, 3) inter-attack period, 4) chronic tophaceous gout. The transition to the chronic form is accelerated by high urate levels, frequent attacks without basic therapy, CKD, and poor adherence to treatment. [18]

According to the severity, chronic gout is stratified by the frequency of exacerbations, the presence of tophi and X-ray lesions, as well as by the level of urate and concomitant CKD - this determines the choice of a urate-lowering regimen and target urate (< 6 mg/dl; in severe tophus form - aim for < 5 mg/dl). [19]

Complications and consequences

Without urate control, gout leads to progressive joint destruction, chronic pain, disability, urate nephrolithiasis, and urate nephropathy. Tophi can ulcerate and become infected, causing difficult-to-treat conditions. [20]

Epidemiologically, gout is associated with increased cardiovascular risk; part of the risk is explained by comorbid pathology, but the inflammatory process itself and hyperuricemia also contribute. This requires cardiometabolic prevention in parallel with urate reduction. [21]

Diagnostics

The "gold standard" is the detection of needle-shaped, negatively birefringent monosodium urate crystals in synovial fluid or tophi. If puncture is impossible, the ACR/EULAR 2015 criteria are used, where the presence of crystals is a sufficient criterion, and in their absence, the sum of clinical, laboratory, and imaging scores is taken into account. [22]

Laboratory assessments include urate (outside the acute peak), inflammatory markers, renal function, lipids, and glycemia. Instrumental methods include ultrasound (the "double contour" sign), DECT for visualizing deposits and quantifying crystal load, and plain radiographs of the hands and feet for erosions. EULAR 2023 specifically emphasizes the role of ultrasound/DECT in clinical practice. [23]

Table 2. Diagnostic minimum

Block	What to do	For what
Joint/tophus puncture	Polarization microscopy	Confirmation of MUN crystals is the final diagnosis. [24]
Laboratory	Urate, creatinine/SCF, CRP/ESR, lipid profile, glucose	Assessment of activity, comorbidities, therapy planning. [25]
Visualization	Double-contour ultrasound, DECT, hand/foot X-ray	Verification of crystals and structural damage. [26]

Differential diagnosis

Gout must be distinguished from septic arthritis (especially with fever and severe synovitis), calcific pyruvic arthropathy (CPPD, "pseudogout"), reactive arthritis, periarthritis, and trauma. Joint puncture with crystalloscopy and culture is key to excluding infection and mimic crystallopathies. [27]

Ultrasound and DECT are helpful when puncture is difficult and the clinical picture is atypical (women, multiple joints, long-term pre-treatment with NSAIDs/corticosteroids). The presence of a "double contour" and stained urate foci on DECT ("green-purple" maps) increases diagnostic confidence. [28]

Treatment

Goals: 1) rapid and safe relief of attacks; 2) long-term control of urate with achievement of a target level of < 6 mg/dL (in severe tophaceous form, aim for < 5 mg/dL); 3) prevention of exacerbations and complications (“treat-to-target”). [29]

Attack relief. A low-dose colchicine regimen (1.2 mg then 0.6 mg every 1 hour), NSAIDs in anti-inflammatory doses, or GCS (orally, intramuscularly, or intra-articularly) are recommended—the choice depends on contraindications and localization. In case of refractoriness or contraindications to standard agents, IL-1 blockade is possible: anakinra (off-label in some countries) and canakinumab (in the EU—for frequent attacks in adults with intolerance/ineffectiveness of standard agents; in the USA, the indication was expanded in 2023). [30]

Initiation of urate-lowering therapy (UST). ACR 2020: UST is indicated for all patients with tophi, radiographic lesions due to gout, or frequent attacks; allopurinol is the first-line drug (including CKD ≥ stage III). Initiate with a low dose (≤ 100 mg/day, 50 mg/day in CKD) and titrate every 2-5 weeks to target urate; relapse prophylaxis for 3-6 months (colchicine 0.5-0.6 mg/day, low-dose NSAIDs, or low-dose GCS) is mandatory. Febuxostat is an alternative in cases of allopurinol intolerance/ineffectiveness. [31]

Febuxostat Safety. The FAST study (Lancet 2020) demonstrated non-inferiority of febuxostat in terms of long-term cardiovascular safety compared with allopurinol in patients with gout, allaying concerns raised by earlier studies. The decision to choose a drug should be individualized, taking into account comorbidities. [32]

Uricosurics. Probenecid is effective in patients with normal renal function and low urate excretion; it can be combined with allopurinol. Benzbromarone was historically a potent uricosuric but was withdrawn in most European countries (2003) due to rare but severe hepatotoxicity; it remains in circulation in some Asian and LA countries, and limited use in carefully selected patients is under discussion. [33]

Uricase. Pegloticase is an option for "uncontrolled" gout, when oral regimens are ineffective or intolerable. The main concern is immunogenicity with loss of response and infusion reactions; the addition of methotrexate (and some other immunosuppressants) significantly improves the durability of response and safety (MIRROR and subsequent studies), which is already reflected in practices and regulatory decision markers. [34]

Lifestyle. Weight loss in overweight individuals and moderate limitation of alcohol (especially beer and spirits), fructose-sweetened beverages, and high-purine foods are recommended; however, the contribution of diet is moderate, and vitamin C has not been shown to have a clinically significant effect. Consistent adherence to UST and urate control are more important. [35]

Table 3. Urate-lowering agents: how to choose

Class	Medicines	Who is it indicated for?	Key Notes
Xanthine oxidase inhibitors	Allopurinol (1st line), febuxostat	Most, including CKD ≥ III	Low start, step titration to target urate; FAST supported the cardiovascular safety of febuxostat. [36]
Urikosuriki	Probenecid, (± benzbromarone*)	Low urate excretion, SCF is preserved	Probenecid can be combined; *benzbromarone is limited due to hepatotoxicity. [37]
Uricases	Pegloticase	Refractory gout	Consider co-therapy with methotrexate to reduce immunogenicity. [38]

Prevention

Primary. Maintaining a normal body weight, limiting alcohol and sugar-sweetened beverages, adequate hydration, moderating purine-rich foods, monitoring blood pressure and glucose, and, if possible, avoiding (or replacing) hyperuricemic medications reduce the risk of hyperuricemia and a first attack. The effect is moderate, but significantly significant when combined with correction of comorbidities. [39]

Secondary. In patients with established gout - systematic UST with titration to the target, prevention of exacerbations in the first 3-6 months of UST (colchicine/NSAIDs/low-dose GCS), patient education and regular monitoring of urate (every 2-5 weeks during titration, then 3-6 months). [40]

Forecast

With adherence to the treat-to-target strategy and achieving target urate levels, the prognosis is excellent: the frequency of attacks decreases to zero, tophi resolve, and the risk of nephrolithiasis and joint destruction is reduced. The key is regular dose titration and prevention of exacerbations at the start of UST. [41]

Poor prognosis is associated with inadequate urate control, frequent breakthrough attacks, severe CKD, severe tophaceous disease, and poor adherence. In these cases, early consideration of combination regimens (xanthine oxidase inhibitor ± uricosuric) or uricase with immunomodulation is warranted. [42]

FAQ

• Is it necessary to start urate-lowering therapy already at the first attack?

Routinely - no. ACR 2020 recommends UST for tophi, radiographic lesions, or frequent attacks; in other cases, the decision is individualized (taking into account the patient's SCF, comorbidities, and preferences). [43]

• What is the target urate level? Is it the same for everyone?

The goal is <6 mg/dL; in severe tophaceous gout, it is advisable to aim for <5 mg/dL to accelerate the resolution of tophi. The dose is titrated according to urate ("treat-to-target") rather than fixed in advance. [44]

• Is Febuxostat dangerous for the heart?

Current FAST data (Lancet 2020) demonstrate non-inferiority in cardiovascular safety compared with allopurinol; drug choice is individualized based on history and tolerability. [45]

• What to do with refractory gout when pills don't help?

Consider pegloticase; to reduce the risk of loss of response and infusion reactions, it is advisable to combine with methotrexate (MIRROR and other study data show a marked increase in the rate of sustained response). [46]

• Can IL-1 blockade be used during an attack?

Yes, if NSAIDs, colchicine, and GCS are contraindicated or ineffective, anakinra (off-label) or canakinumab (in the EU - for frequent attacks in adults; in the US, the indication was expanded in 2023) are possible. The decision will be made after assessing the risk of infections and costs. [47]