Historically, gout was seen in individuals with access to an abundance of protein-rich food and alcohol, leading scholars to coin the phrase “arthritis of the rich” to describe gout. Monarchs, who often indulged in feasts served with wine and beer, would be the highest risk group for developing gout, which led to other colloquialisms for the disease such as “the disease of kings.”1 Urate crystals were first described in the 17th century and their chemical composition was later elucidated as monosodium urate (MSU).2
Gout is the most common type of inflammatory arthritis in the world. Dietary, environmental, and genetic factors appear to play a role in disease pathogenesis which is reflected in the varying distributions of prevalence by region and demographic factors. Globally, the prevalence rate is between less than 1% to 6.8%.3
Oceanic countries are the most burdened population with prevalence rates of 1.5% to 6.8%; the highest rates are seen among Taiwanese Aboriginals and Maori ethnic groups,4 where prevalence exceeds 10%.3 A study based on the US National Health and Nutrition Examination Survey indicated that the prevalence of gout in the United States has increased from 2.7% from 1988 through 1994 to 3.9% from 2007 through 2008.4
Prevalence in the United States and Europe (1%-4%) is relatively high compared with Scandinavian (0.02%-1.8%) and Asian countries (China, 1.3%; South Korea, 0.76%). Data are scarce concerning the prevalence of gout in Africa, and prevalence in Central and South America has previously been reported as low.3
Ethnicity-related differences in diet and genetics also influence prevalence rates. Prevalence in non-Hispanic Black Americans (4.8%) and non-Hispanic White Americans (4.0%) are at least 2 times higher than in Hispanic Americans (2%).3
The prevalence rate of gout among premenopausal women is very low but increases with age, possibly due to the uricosuric properties of estrogen. Age is a major factor affecting prevalence, with rates increasing over the entire lifespan in men and after menopause in women. After 85 years of age, 4.64% of women and 11.05% of men will experience gout, with increasing global prevalence likely related to increased life expectancy.3,5
Gout Etiology & Risk Factors
Gout is a chronic, inflammatory crystalopathy characterized by precipitation of uric acid crystals in synovial joint spaces, usually in the setting of increased serum uric acid concentration. The progression of gout can be defined by 4 stages, although these stages may overlap and progression to the next stage may not occur.1
Stage 1. Hyperuricemia without evidence of MSU crystal deposition or gout
At hyperuricemic concentrations, defined as serum urate levels greater than 6.8 mg/dL, uric acid crystals precipitate at physiologic pH and temperature. An increased serum urate level is the result of overproduction and/or underexcretion of urate. Two-thirds of urate is eliminated via the kidneys and the remaining one-third is eliminated via the gut. Several transports are implicated in the renal elimination of urate (Table 1).3,5
Stage 2. Crystal deposition without symptomatic gout
In small peripheral joints, crystallization can occur at serum urate levels lower than 6.8 mg/dL due to lower tissue pH and decreased local temperature in the distal limbs.5 There is uncertainty regarding why crystal deposition occurs in some patients without triggering acute flares.
Stage 3. Crystal deposition with acute gout attacks
The presence of uric acid crystals in synovial fluid leads to acute gout attacks when macrophages phagocytose the crystals. The MSU crystal-containing phagosome recruits caspase-1, which is activated via proximity-induced autocatalytic activation upon recruitment to an inflammasome. Pro-interleukin (pro-IL)-1β is then converted to IL-1β, a proinflammatory cytokine that induces the expression of genes that mediate fever, pain threshold, vasodilatation, and hypotension, and leads to an endothelial cell results in an acute gout flare.6
The resolution of an acute gout attack is thought to be mediated primarily by the formation of neutrophil extracellular traps (NETs). Inflammation resolves spontaneously within a few days after recruited neutrophils undergo oxidative burst and form neutrophil extracellular traps that degrade cytokines and chemokines via serine proteases. It is still possible to isolate uric acid crystal from synovial fluid even after resolution of the acute flare.7
Stage 4. Advanced gout with tophi, chronic gouty arthritis, and radiologic joint erosion
Chronic accumulation of uric acid crystals and inflammation leads to tophaceous gout, which is often destructive and leads to changes in the surrounding connective tissue. Tophi are nontender, irregularly shaped nodules that are often visible and/or palpable.
They can present on the ears or in soft tissues including articular structures, tendons, or bursae.5 They may attenuate the skin, revealing a yellow or white color, and may fistulize with the overlying skin, draining a thick, white, paste-like material.1
There are genetic and nongenetic risk factors associated with increased risk of developing gout (Table 2).1,4,5,8-13 Any condition that causes alterations in extracellular urate concentration has the potential to trigger a flare-up, including stress, strenuous exercise, starvation, and dehydration.8
Patients with heart disease, diabetes, hypertension, obesity, renal disease, and hyperlipidemia are also at a higher risk of developing gout. Select ethnicities are at increased risk for gout and over 183 loci have been isolated to improve gout risk prediction.4
Persistent hyperuricemia is associated with recurrence of gout attacks which can be polyarticular and affect both upper and lower limbs. Advanced gout will occur if initiatives to reduce hyperuricemia are not taken. Advanced gout is characterized by formation of tophi (tophaceous gout), chronic joint pain, activity limitation, chronic gouty synovitis, structural joint damage, and frequent flares.5
Gout Diagnosis & Presentation
The inflammatory response associated with an acute gout attack is intense and produces severe pain and tenderness, erythema, warmth, and swelling that peaks within 24 hours from onset. Onset typically occurs at night and acute joint pain may wake patients from sleep. The pain is usually described as throbbing or burning in nature and rates above a 7 on a numeric pain rating scale from 0 to 10.
The most frequently involved joint is the first metatarsophalangeal joint although polyarticular involvement is possible. Less common sites of gout flares include the spine, hips, or shoulders.5 When taking the patient history, it is important to ask about potential triggers for gout attacks (surgery, trauma, dehydration, alcohol use, diuretic use, dietary changes) and history of similar joint pain. Some patients will endorse a history of less intense episodes that did not merit medical attention.5
Physical Examination Findings
On physical exam, inflammatory synovitis, tenderness, and erythema are present in the affected joint. Bursitis may or may not be present. Desquamation of the overlying skin may be seen in acutely inflamed joints. Patient may also present with signs of systemic inflammation such as fever, fatigue, and/or malaise.
The presence of subcutaneous nodules over the affected joint or joints corresponds to tophus formation and suggests long-standing disease; nodules typically vary in size. Tophi may drain a white, “chalk-like” liquid or paste. Tophi are not painful unless acutely inflamed.5
The gold standard for diagnosis is synovial fluid analysis. Once obtained, the specimen is sent for gram staining, cultures, white blood cell (WBC) count, total cell count, and polarized light microscopy. Findings compatible with gout on synovial fluid analysis are5:
- Appearance is cloudy, yellow, and nonviscous.
- WBC count greater than 5,000/mm3 with neutrophilic predominance. Cell count above 50,000/mm3 is suggestive of an infectious cause but is possible with gout.
- MSU crystals appear as negatively birefringent needle-shaped crystals measuring 1 to 20 μm in length.
When synovial fluid analysis cannot be conducted, clinical, radiological, and laboratory criteria are helpful.
Laboratory Testing for Gout
The following laboratory tests may be ordered for patients who may have gout14:
- Serum urate concentration: Increased levels are highly suggestive of gout; however, levels can be falsely normal during acute flares.
- C-reactive protein and erythrocyte sedimentation rate: These nonspecific markers of inflammation are usually elevated in gout.
- Complete blood count: Can be used to exclude myeloproliferative disorders. Raised white cell count may indicate septic arthritis.
- Renal function: Hyperuricemia can occur in renal failure. If diagnosed, chronic kidney disease may be the underlying cause of gout.
- Lipid panel, HbA1c, and fasting glucose: Hyperlipidemia, diabetes, and hypo/hyperthyroidism may be associated with gout.1
Note: Patients who present with gout present with an acute inflammatory arthritis. The differential diagnosis is broad and includes crystal-induced, rheumatologic, and infectious causes.
Gout Imaging Studies
X-rays of the affected joint may be used to assess the degree of joint involvement or assist in differentiating gout from bone and joint infections.5,17 Findings include periarticular osteopenia and, in advanced disease, periarticular erosions.17
The presence of chondrocalcinosis on plain radiograph is suggestive of pseudogout due to calcium pyrophosphate deposition.5 Entheseal calcifications can be seen in seronegative spondyloarthritis.16
Trauma. A history of traumatic injury will be present.16
Cellulitis. Subcutaneous infection presents with poorly demarcated erythema, warmth, and tenderness of the involved skin.5
Calcium pyrophosphate deposition disease (pseudogout). Frequently affects large, weight-bearing joints such as the waist, knees, and shoulders. Microscopic confirmation is the most reliable form of differentiation. Synovial fluid analysis reveals rhomboid-shaped calcium pyrophosphate crystals under polarized light; these crystals present positive birefringence.5,16
Septic arthritis. Synovial fluid analysis with greater than 50,000 cells/mm3 with 90% predominance of neutrophils is strongly suggestive, but may present without fever or elevated WBC. Arthrocentesis is required to differentiate from acute gout. No crystals are present in septic arthritis.5,16
Osteoarthritis. Insidious onset and polyarticular involvement is common. Frequently involved joints are the knees, hips, lumbar spine, first metatarsophalangeal joints in the feet, proximal and distal interphalangeal joints in the hands, and first carpometacarpal joint in the wrist. Synovial fluid analysis reveals noninflammatory findings.5
Rheumatoid arthritis. With insidious onset and polyarticular involvement, rheumatoid arthritis frequently involves the proximal interphalangeal and metacarpophalangeal joints and the wrist. It is associated with morning stiffness that improves with use after a few hours.5
Indications to Initiate Pharmacologic Urate-Lowering Therapy18
- Recommended for patients experiencing any of the following: at least 1 subcutaneous tophi, evidence of radiographic damage attributable to gout, or frequent gout flares (≥2 annually).
- Recommended for patients who previously experienced more than 1 flare but have infrequent flares (<2) and no tophi.
- Recommended for patients with comorbid moderate-to-severe chronic kidney disease (CKD; stage ≥3), serum urate concentration greater than 9 mg/dL, or urolithiasis.
- Recommended against for patients with asymptomatic hyperuricemia or experiencing their first gout flare.
Recommendations for Urate-Lowering Therapy Selection18
- Allopurinol is recommended for all patients, including those with moderate-to-severe CKD.
- For patients with moderate-to-severe CKD, allopurinol or febuxostat is recommended over probenecid.
- Treatment initiation with low-dose allopurinol (≤100 mg/day or lower in patients with CKD stage ≥3), febuxostat (≤40mg/day), or probenecid (500 mg once to twice daily) with subsequent dose titration is preferred over initiation at a higher dose.
- Pegloticase is not recommended as a first-line therapy option.
- Concomitant anti-inflammatory prophylaxis therapy with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or prednisone/prednisolone is recommended.
- Continuation of anti-inflammatory prophylaxis for 3 to 6 months is recommended over less than 3 months, with ongoing evaluation and continued prophylaxis as needed if the patient continues to experience gout flares.
Timing of Urate-Lowering Therapy Initiation18
- When urate-lowering therapy (ULT) is indicated, initiation while patient is experiencing a gout flare is recommended over initiation after the gout flare has resolved.
- Achieving and maintaining a serum urate target less than 6 mg/dL is recommended over no target serum urate.
Duration of Urate-Lowering Therapy18
- Continuing ULT indefinitely is recommended over discontinuing ULT.
Recommendations for Patients Receiving Urate-Lowering Therapy18
- Testing for HLA-B*5801 allele prior to initiation is recommended for patients of Southeast Asian descent and African American patients, but not recommended for other ethnic or racial backgrounds.
- Desensitization is recommended for patients with prior allergic response to allopurinol who cannot be treated with other oral ULT agents.
- If patient has a history of cardiovascular disease or experiences a new cardiovascular disease-related event, switching to an alternative ULT agent is recommended over continuation with febuxostat.
- Not recommended to check urinary uric acid.
- Not recommended to alkalinize the urine.
Considerations for Changing Urate-Lowering Therapy Strategy18
- Switching to a second xanthine oxidase inhibitor (XOI) is recommended over adding a uricosuric agent for patients who have:
- Persistently high serum urate concentrate (>6 mg/dL) despite maximum-tolerated XOI dose and who have continued frequent gout flares (≥2 flares annually); or
- Nonresolving subcutaneous tophi.
- Switching to pegloticase is recommended over continuing current ULT for patients
- With gout for whom XOI, uricosurics, and other therapies have failed to achieve serum urate target and who continue to have frequent gout flares (≥2 flares/year); or
- Who have nonresolving subcutaneous tophi.
Gout Flare Management18
- For patients experiencing a gout flare, use of colchicine, NSAIDS, or glucocorticoids (intramuscular, intravenous, or intraarticular) as first-line therapy is recommended over use of interleukin (IL)-1 inhibitors or adrenocorticotropic hormone (ACTH).
- Low-dose colchicine is recommended over high-dose colchicine.
- Use of topical ice as an adjuvant treatment is recommended over no adjuvant treatment.
- In patients who are unable to use anti-inflammatory therapies, use of an IL-1 inhibitor is recommended over no therapy.
- Treatment with glucocorticoids (intramuscular, intravenous, or intraarticular) is recommended over treatment with IL-1 inhibitors for patients unable to take oral medications.
Nonpharmacologic interventions aim to lower serum urate and improve comorbid conditions when present.
Limiting alcohol. Limiting alcohol intake is recommended. While beer and liquor are typically associated with increased risk of gout, a prospective internet-based case crossover study found that episodic alcohol consumption, regardless of alcohol type, was associated with an increased risk of recurrent gout attack.19
Limiting purine-rich foods. Seafood, shellfish (anchovies, sardines, herring, mussels, codfish, scallops, trout, and haddock), alcohol (particularly purine-rich beer), red meats, and organ meats such as liver and kidneys are rich in purine.5,20
Avoiding high-fructose corn syrup. High-fructose corn syrup is found in sweetened soft drinks, fruit juices, and fructose-rich vegetables and fruits. Fructose intake is directly correlated with higher serum levels of uric acid. Ongoing studies are reviewing a potential link between fructose-derived uric acid in the pathogenesis of cardiometabolic disorders.21
Weight loss. A 5% increase in BMI is associated with a 60% higher odds of recurrent gout flare, while a 5% decrease in BMI is associated with a 40% lower odds of recurrent gout flare.18 Weight loss and maintaining weight loss can reduce serum uric acid levels and reduce gout attacks.22
Management of an Acute Gout Attack
Reducing the acute inflammation is achieved with NSAIDs, colchicine, or glucocorticoids.18 All are considered equivalent and the choice of agent depends on the presence of contraindications, as well as patient and physician preference.
NSAIDs. Indomethacin is the most-studied agent in this drug class. Other options include naproxen sodium or ibuprofen (off-label use).5,23 Avoid NSAIDs in patients with severe or decompensated heart failure, hyperkalemia, duodenal or gastric ulcer, platelet dysfunction, poorly controlled hypertension, concurrent use of aspirin or anticoagulants, and cirrhotic liver disease.24
Colchicine. Colchicine binds to tubulin dimers and prevents the polymerization of microtubules.25 In a multicenter, randomized, double-blind, placebo-controlled study, 74 patients received low-dose colchicine, 52 patients received high-dose colchicine, and 58 patients received placebo.
Low-dose colchicine yielded comparable efficacy compared with high-dose colchicine. High-dose colchicine was associated with significantly more adverse effects compared with low-dose colchicine and placebo.26 Use with caution in patients with hepatic or renal impairment and in patients receiving strong CYP3A4 or P-glycoprotein inhibitors.25
Glucocorticoids. Glucocorticoids are very effective for the relief of gout flares. They can be administered via the oral (preferred: prednisone, prednisolone), intramuscular (preferred: triamcinolone), intravenous, or intraarticular routes. Oral route is preferred, with intravenous route favored over alternative agents if oral dosing is not possible.27,28
Pegloticase. Pegloticase is not recommended for use during an acute gout flare.18
Canakinumab. Canakinumab is an anti-interluekin-1β monoclonal antibody. It is not FDA approved for the treatment of an acute gout flare. A randomized, multicenter, active-controlled, double-blind study found that use of canakinumab reduced the risk of flares by 62% compared with triamcinolone.
Results also show that use of canakinumab provided significant pain and inflammation relief and reduced the risk of new flares in patients who are unable to use first-line therapies. There is a higher risk of adverse events, including infections, low neutrophil count, and low platelet count.29
Tip: Regimens that involve less-frequent dosing intervals (eg, naproxen twice daily vs ibuprofen 3 times daily) may improve patient adherence to medication.
Prevention of Chronic Gout and Initiation of Urate-Lowering Therapy
The decision to initiate ULT depends on serum urate levels, the presence of CKD or tophi (which may be clinically or radiological evident), and the frequency of gout flares. In patients experiencing their first gout flare, lifestyle recommendations are appropriate.
If patients experience at least 2 flares annually, they are considered to have chronic gout and ULT should be initiated. The presence of at least 1 subcutaneous tophi and any evidence of radiographic damage also merits initiation of ULT. Goal of treatment is to achieve and maintain a serum urate level less than 6 mg/dL.18
Allopurinol. Allopurinol, an XOI, is the preferred first-line agent for all patients, including patients with CKD stages 3 to 5.18 Patients may experience an increase of gout attacks upon initiation. Allopurinol reduces the production of uric acid by inhibiting biochemical reactions immediately preceding its formation.30
Febuxostat. Febuxostat, an XOI, is an alternative first-line agent for patients who cannot tolerate allopurinol.31 Febuxostat is contraindicated in patients receiving azathioprine and mercaptopurine. Patients with a history of cardiovascular disease or a cardiovascular disease-related event should be switched to an alternative oral ULT agent, if available and able to be tolerated.18,32
Probenecid. Probenecid is a uricosuric and a second-line agent for patients unable to tolerate allopurinol or febuxostat. In patients with moderate-to-severe CKD, XOIs are recommended over probenecid.18,33
Pegloticase. Pegloticase would be appropriate for patients who have failed to achieve their serum urate target and continue to have frequent gout flares, or who have nonresolving subcutaneous tophi despite XOI treatment, uricosurics, and other interventions.18,34 Patients must be premedicated with antihistamines and corticosteroids.35
Colchicine. Colchicine prevents gout flares at a dose of 0.6 to 1.2 mg/day.5
Monitoring Gout Side Effects
Initiation of ULT therapy may increase the risk of a gout flare. Concomitant anti-inflammatory prophylaxis with colchicine, NSAIDs, or glucocorticoids (prednisone, prednisolone) is recommended upon ULT initiation and can be discontinued after 3 to 6 months.18
For patients receiving allopurinol, testing for the HLA-B*5801 allele in patients of Southeast Asian descent and African American patients is warranted prior to initiation.18,33 Presence of HLA-B*5801 is associated with allopurinol-induced toxic epidermal necrolysis and Steven-Johnson syndrome.35
Short-term corticosteroid use is associated with mild side effects, including hypertension, hyperglycemia, cutaneous effects, electrolyte abnormalities, and hematologic, immunologic, and neuropsychological effects.36
NSAIDs should be used with caution in patients who are older, who are receiving anticoagulation therapy, and with renal insufficiency, heart failure, peptic ulcer disease, or liver disease. Adverse effects include gastric bleeding and kidney injury.
Colchicine is contraindicated in patients receiving clarithromycin. Use with caution in patients receiving strong CYP3A4 or P-glycoprotein inhibitors (cyclosporine, ketoconazole, ritonavir, azithromycin, verapamil extended-release, diltiazem extended release). Dose adjustments are needed when colchicine is used concomitantly with these drugs except for azithromycin.37
Febuxostat is contraindicated in patients receiving azathioprine and mercaptopurine. Common adverse reactions include liver function abnormalities, nausea, arthralgia, and rash. Discontinue immediately if liver injury is detected.28
Probenecid is associated with a high risk of nephrolithiasis. Patients should be encouraged to stay hydrated. Probenecid may elevate plasma concentrations of penicillin and other β-lactams.39
Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. Common adverse reactions include gout flares, infusion reactions, nausea, ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis, and vomiting. Serum urate levels should be monitored prior to infusion.
Consider discontinuation of therapy if serum urate levels increase to above 6 mg/dL, particularly if they remain above 6 mg/dL after 2 consecutive draws.35
Patients with gout often have comorbidities that should be managed accordingly.3 It is important to recall that frequently used medications for the treatment of hypertension can cause increased uric acid levels in patients with gout.
Untreated hyperuricemia is associated with recurrent flares and tophi formation. Additionally, hyperuricemia is associated with arthritis, soft tissue masses, urate nephropathy, and nephrolithiasis.40 Patients with poorly managed gout, especially in the setting of uncontrolled comorbidities, are likely to suffer from poor health-related quality of life.5
Gout Patient Education
Which medications increase uric acid and may lead to the development of gout?
Diuretics, cyclosporin, tacrolimus, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (except losartan), beta-blockers, pyrazinamide, and ritonavir increase uric acid levels.
What are the risk factors for developing gout?
Risk factors include increased age, male sex, obesity, chronic kidney disease, hypertension, family history, medications, and diet.
How is gout diagnosed?
The gold standard for diagnosis is synovial fluid analysis. The pathognomonic feature is the presence of MSU crystals that appear as negatively birefringent needle-shaped crystals.
What lifestyle modifications are recommended to avoid future flares?
Recommended lifestyle modifications include limiting consumption of red meat, organ meats, seafood, purine-rich foods (sardines, shellfish), alcohol, and sugar-sweetened beverages. Weight loss and exercise also may be recommended.
How is an acute gout attack treated?
Reducing the acute inflammation is achieved with NSAIDs, colchicine, or glucocorticoids. All are considered equivalent, and the choice of agent depends on the presence of contraindications as well as patient and physician preference.
When should prophylactic urate-lowering therapy (ULT) be initiated?
Initiate ULT for patients with gout who experience at least 2 flares annually, have 1 or more subcutaneous tophi, or have evidence of radiographic damage attributable to gout. ULT may be initiated following the first gout flare for patients with chronic kidney disease (CKD) stages 3 to 5, serum urate greater than 9 mg/dL, or urolithiasis. Do not initiate ULT in patients with asymptomatic hyperuricemia.
What is the preferred agent in ULT?
Allopurinol is the first-line agent for ULT. Second- and third-line agents include febuxostat and probenecid.
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