Gout: From Diagnosis to Treatment
Introduction
Gout is a chronic disease caused by disorders of purine metabolism and characterized by an increased concentration of uric acid. Due to elevated uric acid levels in the blood and other body fluids, sodium urate crystals form. They are deposited in the joints, surrounding tissues, and internal organs, causing clinical symptoms. The prevalence of gout is increasing in Europe and the United States and accounts for approximately 0.2% of the general population. The disease can manifest in various forms, including acute synovitis caused by the accumulation of sodium urate crystals (acute gout), chronic arthropathy (chronic gouty polyarthritis), gouty tophi, and gouty nephropathy.
In typical cases, an acute gout attack presents in middle-aged men with severe pain and redness of the first metatarsophalangeal joint, making gout relatively easy to suspect and diagnose. However, there are cases in which diagnosis is quite challenging. This article provides summarized information on the epidemiology, diagnosis, clinical features, and most effective treatment methods for gout and introduces one of the drugs used specifically to treat gout—febuxostat.
Gout Epidemiology
According to statistical data, approximately 0.2% of adults in Europe and the United States have gout. Elevated uric acid levels in the absence of typical gout symptoms are detected in 5% of adults [2]. It has been observed that men develop gout almost 10 times more frequently than women. The disease is rarely diagnosed in children and premenopausal women [1–3]. Gout is more commonly diagnosed in older individuals, those taking diuretics, and members of certain ethnic groups (e.g., Maori) [2, 3].
Other risk factors for hyperuricemia and gout include obesity, high consumption of protein-rich foods, alcohol abuse (especially beer), consumption of fructose-containing beverages, concomitant mixed hyperlipidemia, diabetes mellitus, ischemic heart disease, and hypertension (metabolic syndrome) [2, 3, 6]. Hyperuricemia is diagnosed when the serum uric acid concentration is 2 standard deviations above the mean and approaches the saturation concentration (420 micromol/l in men and 360 micromol/l in women) [2, 3]. Most patients diagnosed with hyperuricemia do not exhibit typical symptoms of gout, even when urate crystals are found in the synovial fluid [2, 6].
Pathophysiology
Uric acid is the final product of purine metabolism, and its concentration in the blood depends on synthesis, dietary intake, and elimination:
- Synthesis. The final stages of purine metabolism involve the conversion of hypoxanthine to xanthine and xanthine to uric acid. These processes are catalyzed by the enzyme xanthine oxidase. Another stage is the conversion of uric acid to the more soluble allantoin, catalyzed by the enzyme uricase, or urate oxidase;
- Excretion. Uric acid is filtered in the glomeruli, 98–100% is reabsorbed in the proximal tubules, and approximately 50% is subsequently secreted in the distal tubules. Low doses of aspirin block secretion, while high doses also block reabsorption. It has been established that insulin resistance and the resulting increase in circulating insulin levels in the blood (hyperinsulinemia) increase uric acid reabsorption [2, 6].
The main causes of hyperuricemia are presented in Table 1. An acute gout attack develops when sodium urate crystals formed as a result of a markedly elevated concentration of uric acid in the blood enter the body's tissues and organs. Immune system cells—polymorphonuclear phagocytes—accumulate at these sites. They phagocytose sodium urate crystals, release proinflammatory cytokines, and initiate and maintain the inflammatory process. Activated complement proteins also play an important role in inflammation [2].
Clinical Symptoms of Gout
Gout can manifest in several clinical forms:
- acute synovitis caused by the accumulation of sodium urate crystals (acute gout) [1–3];
- chronic arthropathy (chronic gouty polyarthritis);
- tophaceous urate crystal deposits (gouty nodules, tophi);
- gouty nephropathy (crystal deposition in the renal interstitium) [1].
In typical cases, an acute gout attack presents in a middle-aged man with severe pain, redness, and impaired movement of the first metatarsophalangeal joint. Characteristically, symptoms often appear at night and progress rapidly [1, 3]. An attack can begin at any time but occurs more frequently and is more severe after a large meal or alcohol consumption, substantial fluid loss, or treatment with diuretics [2, 3].
Possible prodromal symptoms include dyspepsia, fever, insomnia, and joint discomfort [1]. Without treatment, an exacerbation can last approximately 3–10 days [1, 3]. In many cases, the epidermis over the joint peels during recovery [2]. Approximately 25% of cases involve other joints, including the ankles, knees, elbows, and wrists [1–3]. If a gout exacerbation is very severe, cellulitis of the affected tissues may develop over the crystal deposits (pseudophlegmon) [1].
In many cases, gout symptoms completely regress between exacerbations [3]. Chronic gouty arthritis develops much less frequently [1, 3]. It is more commonly diagnosed in older and elderly patients after long-term treatment with diuretics, in the presence of renal failure, and when treatment with allopurinol is initiated promptly after an exacerbation [2]. Chronic gouty arthritis most commonly presents with joint deformities, bursitis (shoulder, olecranon, prepatellar joints), and bony outgrowths [1]. In some cases, chronic asymmetric synovitis develops after frequent episodes of acute gouty monoarthritis and oligoarthritis and can be quite difficult to distinguish from rheumatoid arthritis [3].
One of the clinical forms of gout is gouty tophi. These are deposits of urate crystals in the subcutaneous tissue, joints, cartilage, and/or tendons. When the tophi rupture, a whitish, chalk-like material usually oozes out [1]. Tophi without synovitis are extremely rare.
Table 1. Common Causes of Hyperuricemia [1, 2]
| Mechanism / Cause |
|---|
| Decreased uric acid excretion |
| Chronic kidney disease (clinical gout is rare) |
| Medications (thiazide diuretics, low-dose aspirin) |
| Hypertension |
| Lead intoxication |
| Primary hyperparathyroidism |
| Hypothyroidism |
| Increased lactic acid production due to alcohol consumption, fasting, or physical exertion |
| Glucose-6-phosphatase deficiency (excessive lactic acid production) |
| Increased uric acid production |
| Increased purine synthesis de novo |
| Hypoxanthine-guanine phosphoribosyltransferase deficiency (e.g., Lesch-Nyhan syndrome) |
| Phosphoribosyl pyrophosphate synthetase hyperactivity |
| Glucose-6-phosphatase deficiency with type I glycogen storage disease (hyperuricemia due to increased production and impaired excretion) |
| Increased purine turnover |
| Myeloproliferative diseases |
| Lymphoproliferative diseases |
| Other, e.g., carcinoma, psoriasis |
Diagnosis
Gout is diagnosed on the basis of clinical symptoms, laboratory findings, and radiological findings.
Laboratory parameters that help diagnose gout include:
- Serum uric acid concentration (>600 micromol/l). After a gout attack, it decreases rapidly (inflammatory cytokines are thought to have a uricosuric effect). It is recommended that uric acid testing be repeated several weeks after an exacerbation [2, 3];
- Complete blood count: elevated ESR, leukocytosis [1];
- Urea and creatinine levels, liver enzymes, and other diagnostic tests are required to assess concomitant diseases, possible primary causes of gout, and complications [2, 3];
- Synovial fluid examination. Microscopy is performed to assess turbidity, cell count, and crystals (polarized light microscopy) [1, 3]. If concomitant bacterial infection is suspected, synovial fluid culture is necessary [3];
- Aspiration and microscopic examination of subcutaneous deposits (tophi) [3].
Radiological Findings
- Joint radiographs may reveal soft tissue swelling (an early finding) and, in advanced disease, bone destruction and cystic degeneration [1, 3];
- Ultrasound examination of the joints, computed tomography, and magnetic resonance imaging may reveal early joint changes [3].
Differential Diagnosis
Several conditions can mimic acute gouty arthritis:
- Septic arthritis rarely accompanies gouty arthritis, but in some cases these conditions need to be differentiated [3, 4];
- Joint trauma. A mild gout exacerbation may be interpreted as joint trauma or a stress fracture [4];
- Pyrophosphate arthropathy (calcium pyrophosphate dihydrate deposition disease, pseudogout)—arthritis or periarthritis caused by calcium pyrophosphate deposition. Pyrophosphate crystals are not visible under polarized light microscopy because of their small size and optical properties [3, 4];
- Other conditions include reactive arthritis, palindromic rheumatism, rheumatic fever, rheumatoid arthritis, dactylitis, and osteomyelitis [4]. In many cases, synovial fluid aspiration and microscopic examination of the aspirate help establish the diagnosis [4].
Treatment
Treatment of an Acute Gout Attack
Once an acute gout attack has been diagnosed, treatment should be started as early as possible, as soon as the first symptoms of the disease appear. Treatment is recommended throughout the exacerbation and should be discontinued 2–3 days after complete resolution of symptoms (except when corticosteroids have been used). Depending on the severity of the exacerbation, treatment may last from several days (if started immediately) to several weeks (if started 4–5 days after symptom onset) [5].
Among the main medications used to relieve pain and inflammation are nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective and selective cyclooxygenase-2 inhibitors [1–3]. They help reduce gout symptoms in approximately 90% of patients [3]. However, it should be remembered that long-term use of NSAIDs may worsen already impaired renal function and provoke gastrointestinal bleeding, particularly when oral anticoagulants are administered concomitantly [1–3, 5]. The most commonly used anti-inflammatory drugs include indomethacin, dexketoprofen, naproxen, diclofenac, ibuprofen, and celecoxib (the recommended doses of these medications for relieving the symptoms of a gout attack are presented in Table 2).
Among the NSAIDs listed above, dexketoprofen warrants further mention. It is the R-enantiomer of water-soluble ketoprofen combined with trometamol and inhibits the cyclooxygenase enzyme 3,000 times more strongly than the S-enantiomer.
Table 2. Recommended NSAID Doses for Relieving the Symptoms of an Acute Gout Attack
| Medication | Recommended Dose |
|---|---|
| Indomethacin | 50 mg 4 times/day for 2–3 days, then reduce to 50 mg 3 times/day until the attack resolves [1, 3]. |
| Dexketoprofen | Usually 12.5 mg every 4–6 hours or 25 mg every 8 hours. The total daily dose should not exceed 75 mg. |
| Naproxen | Initial dose of 750 mg, followed by 500 mg every 8–12 hours [1, 3]. |
| Diclofenac | Initial dose of 75–100 mg, followed by 50 mg every 6–8 hours [1]. |
| Ibuprofen | Recommended dose of 400–600 mg twice daily [1, 3]. |
| Celecoxib | Initial dose of 800 mg, followed by 400 mg twice daily (a possible alternative to nonselective NSAIDs) [5]. |
Dexketoprofen trometamol is readily soluble in water and is well absorbed through the gastrointestinal mucosa. The usual dose is 25 mg of dexketoprofen trometamol 3 times daily (for mild pain, half this dose may be used). Food may delay the absorption of dexketoprofen; therefore, the medication is recommended to be taken 30 minutes before meals. Dexketoprofen blocks the transmission of nerve impulses to higher nerve centers both peripherally, i.e., at the site of injury (trauma, inflammation, etc.), and centrally (central nervous system) by inhibiting prostaglandin production in the CNS (11, 12). Thus, dexketoprofen acts both as an anti-inflammatory agent and as a potent analgesic with a rapid onset of action. For these reasons, it is one of the more effective medications for relieving an acute gout attack [8].
In some countries, colchicine is used to treat gout attacks. In Lithuania, this medication is not registered because of data regarding its myelosuppressive effects [1, 3, 5]. In some cases, corticosteroids may be used to relieve acute gout attacks (orally, intravenously, or by injection into the joint cavity). These medications are highly effective and may be administered when a patient cannot tolerate or use NSAIDs (e.g., a patient undergoing hemodialysis or with end-stage chronic kidney disease). However, because of their systemic adverse effects, corticosteroids may only be administered in short courses [3, 5].
One of the newer approaches to treating gout exacerbations is biological therapy. Interleukin-1 (IL-1) antagonists and monoclonal antibodies are currently used for treatment [5].
Long-Term Treatment of Gout and Prevention of Exacerbations
The main objectives of long-term gout treatment are to identify the cause of hyperuricemia, reduce inflammation, and normalize the concentration of uric acid in the blood [6]. Several approaches to long-term gout treatment can be distinguished: dietary and lifestyle modification and pharmacological treatment.
Dietary and Lifestyle Modification
Obesity is one of the most important risk factors for gout. It has been established that gout exacerbations become considerably less frequent when a patient loses weight [2, 3, 6]. Patients are advised to avoid foods high in purines, including animal organs, caviar, fish, beans, sorrel, and spinach [1, 3, 6]. However, in patients with normal dietary habits who have been diagnosed with hyperuricemia, reducing the amount of purine-containing foods in the diet decreases the blood urate concentration by only approximately 59 micromol/l [6].
If a patient reduces total daily caloric intake and increases the proportion of plant and dairy proteins in the diet at the expense of refined carbohydrates and saturated fats, the blood urate concentration may decrease by 100 micromol/l [6]. Alcohol, particularly beer, and soft drinks should also be avoided [2, 3, 6].
Pharmacological Treatment
Uricosuric medications increase urinary urate excretion. They should not be administered to patients with kidney stones. Patients taking these medications must also consume plenty of fluids [1]. This class includes benzbromarone at 50–100 mg/day [1, 6]. It is rarely used because cases of hepatotoxicity have been reported [6]; losartan at 50 mg/day, which has a moderate uricosuric effect [6]; and fenofibrate at 200 mg/day, which, in combination with allopurinol, effectively promotes urinary uric acid excretion.
Uricostatic medications are inhibitors of the enzyme xanthine oxidase and include allopurinol and febuxostat. The latter is a new-generation uricostatic medication. The usual dose of febuxostat is 80–120 mg/day [6]. Clinical studies have demonstrated that febuxostat at 80–120 mg/day achieves the target blood uric acid concentration more rapidly than allopurinol at 300 mg/day. Importantly, febuxostat dose adjustment is not required in patients with mild to moderate renal or hepatic impairment [7]. Adverse effects are similar to those caused by allopurinol, but their frequency is considerably lower [6]. Febuxostat may be the medication of choice when patients cannot tolerate allopurinol or when an effective reduction in blood uric acid concentration cannot be achieved even with the maximum doses of allopurinol [6].
Summary
Gout is becoming increasingly common. This is associated with population aging, high alcohol consumption, and the increasing number of people with obesity. In treating gout, it is important not only to relieve attacks rapidly but also to ensure long-term symptom control. Because the disease is chronic, treatment often continues for a very long time or even throughout life.
Allopurinol is currently the most commonly prescribed medication for long-term control of gout symptoms, but other options should not be overlooked. The newer uric acid-lowering medication febuxostat is an excellent option. It reduces elevated blood uric acid levels more effectively, is well tolerated, and does not require dose adjustment in patients with mild to moderate hepatic or renal impairment.
Prepared by Dr. Olesia Gaidej
Source: Rheumatology, supplement to the journal Internistas
