Gout and hyperuricemia

Gout is an inflammatory crystal arthropathy caused by the precipitation and deposition of uric acid crystals in synovial fluid and tissues. Decreased renal excretion and/or increased production of uric acid leads to hyperuricemia, which is commonly asymptomatic but also predisposes to gout. Acute gout flares typically manifest with a severely painful big toe (podagra) and occur most often in men following triggers such as alcohol consumption. Diagnosis is based on clinical presentation and, ideally, by the demonstration of negatively birefringent monosodium urate (MSU) crystals on synovial fluid analysis. Acute attacks are treated with corticosteroids, NSAIDs (e.g., naproxen, indomethacin), or colchicine. The management of chronic gout includes lifestyle modifications and urate-lowering medications (e.g., allopurinol) to control hyperuricemia.

Acute calcium pyrophosphate crystal deposition (CPPD) disease, sometimes referred to as pseudogout, is another crystal arthropathy that resembles an acute gout flare and is managed similarly. It is covered in detail in a separate article.

• Sex: : ♂ > ♀ (3:1) [1]
• Age of onset: 2 peaks of incidence (at 30–39 years and at 60 years of age) [2]
• Prevalence: ∼ 8 million people in the US [1]

Epidemiological data refers to the US, unless otherwise specified.

Hyperuricemia

• Can be idiopathic (primary hyperuricemia) or secondary to insufficient excretion or increased production of purines
• Predisposes to gout and acute gout attacks
• Not obligatory for developing gout

Primary hyperuricemia

• Idiopathic extracellular supersaturation of uric acid
• No history of comorbidities or medications that affect uric acid formation or excretion [3]

Primary hyperuricemia can be aggravated by poor dietary habits.

Secondary hyperuricemia [4]

• Decreased uric acid excretion: most common cause
  • Medications (e.g., pyrazinamide, aspirin, loop diuretics, thiazides, niacin)
  • Chronic renal insufficiency, lead nephropathy [5]
  • Ketoacidosis (due to, e.g., starvation; , diabetes mellitus) and lactic acidosis
  • Postmenopause
• Increased uric acid production
  • High cell turnover, e.g.:
    • Tumor lysis syndrome
    • Hemolytic anemia [6]
    • Psoriasis
    • Myeloproliferative neoplasms
    • Chemotherapy, radiation
  • Enzyme defects, e.g.: [5]
    • Lesch-Nyhan syndrome
    • Phosphoribosyl pyrophosphate synthetase overactivity
    • von Gierke disease
  • Diet rich in protein and especially purine (e.g., red meat, seafood)
  • Obesity
  • Hypercholesterolemia, hypertriglyceridemia
  • Hypertension [7]
  • Sleep apnea [8][9]
• Combined decreased excretion and overproduction: high alcohol consumption
  • Organic acids from alcohol metabolism compete with uric acid to be excreted by the kidneys.
  • Many alcoholic beverages contain a high level of purines.

Imagine drugs associated with gout: AS a Guy painfully walking THe NIce PYRamid LOOP trail: aspirin, thiazides, niacin, pyrazinamide, loop diuretics.

• Gout
  • An inflammatory crystal arthropathy that is caused by the precipitation and deposition of uric acid crystals in synovial fluid and tissues.
  • It is typically associated with hyperuricemia, but can also occur if uric acid levels are normal.
• Uric acid
  • An end-product of purine metabolism that is excreted by the kidneys
  • Has somewhat poor water solubility
  • Predisposes to gout
• Triggers of urate crystal deposition
  • ↑ Uric acid levels (due to insufficient excretion or increased production of purines)
  • Acidosis
  • Low temperature (e.g., cool peripheral joints)
• Crystalline arthritis: supersaturation of uric acid in extracellular fluid → intraarticular uric crystal precipitation (coated by IgGs) → phagocytosis by polymorphonuclear cells → release of inflammatory mediators and enzymes → local joint inflammation
• Chronic effects: repeated attacks → aggregations of urate crystals and giant cells (tophi) → deformities and arthritis

Asymptomatic stage

• Hyperuricemia with no symptoms
• May last ≥ 10 years

Acute gouty arthritis

• Triggers
  • Sudden increase in uric acid, e.g.,: consuming a large amount of purine-rich foods or alcohol (see risk factors for gout)
  • Trauma, surgery
  • Diuresis
  • Dehydration
• Most common manifestation
  • Acute severe pain with overlying erythema, decreased range of motion, swelling, warmth
  • Possibly fever
  • Symptoms are more likely to occur at night, typically waking the patient.
  • Symptoms peak after 12–24 hours and regress over days to weeks. [10]
  • Desquamation of the skin overlying the joint may be seen during the recovery from an acute gout flare.
• Location
  • Usually monoarthritis during first attacks
    • In < 20% of cases, patients present with polyarthritis during first attacks.
    • Asymmetrical distribution is common if more than one joint is affected
  • Peripheral small joints in the lower extremities are especially affected.
  • Podagra: metatarsophalangeal joint (MTP joint) inflammation of the big toe (the most common site)
  • Gonagra: inflammation of the knee
  • Chiragra: inflammation of finger joints, especially metacarpophalangeal joint of the thumb
  • Others: ankle; , tarsus, other toe joints, wrist, elbow

Intercritical stage

• Asymptomatic
• May last up to several years

Chronic gouty arthritis

• Uncommon in these times
• Progressive joint destruction
• Tophi formation
  • Multiple painless hard nodules with possible joint deformities [11]
    • May appear yellow or white because of overlying attenuated skin
    • Ulceration and discharge (chalky white substance) may occur
  • Bone tophi: urate crystal deposition in bones (e.g., elbows, knees, extensor surfaces of forearms)
  • Soft tissue tophi: urate crystal deposition in the pinna of the external ear, subcutis, tendon sheaths (e.g., at the Achilles tendon), or synovial bursae (e.g., olecranon bursa)
• Renal manifestations with uric acid nephrolithiasis and uric acid nephropathy

Identification of monosodium urate (MSU) crystals on synovial fluid analysis of the affected joint is the gold standard to diagnose gout but requires an invasive technique (i.e., arthrocentesis), trained personnel, and specialized instruments to perform the test. In patients with typical clinical features, a clinical diagnosis may be considered with/without supportive diagnostic evidence on imaging and laboratory studies.

Approach [8][12][13]

• Acute gout (gout flare)
  • Assess the clinical probability of septic arthritis.
    • If relatively high, perform arthrocentesis for synovial fluid analysis
    • Consult orthopedics as needed (see “Diagnosis of septic arthritis” for details).
  • Assess the clinical probability of acute gout.
    • If relatively low :
      • Arthrocentesis with synovial fluid analysis is recommended.
      • Consider differential diagnoses of gout.
    • If relatively high : Diagnostic tests are not routinely required.
• Chronic gout: A combination of history (e.g., recurrent episodes), examination and imaging findings (e.g., tophi), and evidence of MSU crystals on aspirates of tophi or synovial fluid analysis confirms the diagnosis of chronic gout. [14][15]

Arthrocentesis and synovial fluid analysis [8][12]

Synovial fluid analysis is the gold standard for diagnosing gout but should only be performed if polarized light microscopy is available and providers are trained in the procedure and interpretation.

• Indications
  • Uncertain clinical diagnosis
  • Higher probability of septic arthritis
• Characteristic findings
  • Polarized light microscopy: needle-shaped monosodium urate crystals that are negatively birefringent ; [10]
    • Crystals appear yellow when their optical axis is oriented parallel to the polarizer.
    • Crystals appear blue when their axis is perpendicular to the polarizer.
  • Synovial fluid cell count: WBC > 2000/μL with > 50% neutrophils (see “Interpretation of synovial fluid analysis”)
  • Gram stain: negative; useful for ruling out septic arthritis

Clinical diagnosis of acute gout [8][12]

There is a lack of consensus regarding strict diagnostic criteria for gout in clinical settings. [8][14][15][16]

• A clinical diagnosis of acute gout can be considered in patients who fulfill all of the following parameters:
  • Typical clinical presentation
  • Low suspicion for septic arthritis
  • Monoarthritis
• The diagnostic rule for acute gout can improve diagnostic accuracy for patients with acute monoarthritis.

Laboratory studies

• Serum uric acid level ; [12][16]
  • Acute gout flare: often elevated (hyperuricemia) ; may also be normal or low
  • Intercritical stage or chronic gout
    • Baseline levels are useful to determine the need for urate-lowering therapy.
    • A normal or low level has a very low negative likelihood ratio for (but does not rule out) a diagnosis of gout.
• CBC and inflammatory markers: : WBC and ESR are typically elevated in an acute gout attack. [19]
• Urinary uric acid measurement (via 24-hour urine collection): not routinely recommended

Serum uric acid levels are not always elevated in acute gouty arthritis.

Imaging [8][12][16][20]

Imaging is indicated if synovial fluid analysis is unsuccessful or cannot be performed, and the diagnosis remains uncertain. It can be used to identify supportive findings of gout but cannot rule out septic arthritis.

• Ultrasound
  • Signs of acute joint inflammation
  • Bone erosions
  • Signs of urate crystal deposition
    • Double contour sign: a hyperechoic band of crystals covering the surface of the hypoechoic articular cartilage, which is over the hyperechoic bone contour
    • Tophi (pathognomonic for chronic gout)
• X-ray
  • Acute gout: typically normal; useful for ruling out a fracture in patients with posttraumatic joint inflammation
  • Chronic gout
    • Punched-out lytic bone lesions with spiky periosteal appositions (overhanging edges), known as “rat-bite erosions”
    • Radiopaque in surrounding soft tissue
    • Joint space is preserved until late stages.
• Conventional CT and MRI: can identify erosions and tophi; used less frequently
• Dual-energy CT : can detect crystals within deeper anatomical structures (e.g., the spine) and extra-articular sites

Ultrasound or DECT are preferred imaging modalities to detect MSU crystal deposition within affected joints.

Foreign body granuloma

• Caused by urate crystal deposition in cutis and subcutis
• Findings include:
  • Clusters of crystal deposits
  • Macrophages in the shape of epithelioid cells or polynuclear giant cells

• Septic arthritis
  • Can occur concomitantly with gout [21]
  • Joint damage from chronic gout may increase risk. [22]
• Inflammatory arthritis (other types): See “Differential diagnoses of inflammatory arthritis.”
  • Acute calcium pyrophosphate deposition disease (pseudogout)
  • Rheumatoid arthritis
  • Seronegative spondyloarthropathy (e.g. psoriatic arthritis, reactive arthritis)
  • Basic calcium phosphate crystal deposition diseases
• Erosive osteoarthritis

The differential diagnoses listed here are not exhaustive.

General measures [23]

• Lifestyle modifications may help reduce the risk of flares.
  • Limit alcohol consumption
  • Limit intake of purines (e.g., red meat and shellfish)
  • Limit high-fructose corn syrup (e.g., sugary foods, juices, and non-diet sodas)
  • Weight loss if patient is overweight
• Identify and treat sleep apnea. [24][25]
• Close management of comorbidities, such as diabetes and hypertension
• Adjust current antihypertensive regimen, if feasible: losartan preferred; avoid hydrochlorothiazide [23]

Approach [12][23][26][27][28]

• Nonpharmacological measures: Rest and ice the affected joint. [29]
• Pharmacotherapy: Initiate within 24 hours of onset.
  • First-line agents: glucocorticoids, NSAIDs, or colchicine (described in detail below) [23][27]
  • Second-line agents : IL-1 inhibitors or ACTH
  • Combination therapy options: indicated for attacks involving ≥ 4 joints, > 1 large joint, or severe pain
    • Glucocorticoids (any formulation) PLUS colchicine
    • NSAIDs PLUS colchicine
    • Intraarticular glucocorticoids PLUS NSAIDs
  • Consider initiating urate-lowering therapy in select patients (see “Indications” in “Urate-lowering therapy” for details).

If a patient is on long-term urate-lowering therapy, it should be continued during the treatment of an acute gout flare.

Avoid combining NSAIDs with systemic glucocorticoids. If prescribed together, add a proton pump inhibitor to reduce the risk of gastrointestinal ulcers.

Glucocorticoids [23][27]

• Systemic administration
  • Oral (e.g., prednisone or prednisolone; or equivalent )
    • Fixed-dose regimen: Treat for 5 days or until symptom resolution.
    • A tapered regimen may reduce the risk of a rebound flare. [30]
  • Parenteral or intramuscular (e.g., methylprednisolone ) if NPO
• Intraarticular administration: : Consider if there are 1–2 joints that are accessible and a trained provider is available.

Glucocorticoids are preferable if there are contraindications (e.g., CKD), intolerance, or inadequate response to colchicine or NSAIDs.

NSAIDs [23][27]

• Naproxen: or an alternative (e.g., indomethacin, ibuprofen; see “Pain management” for details)
  • Fixed-dose regimen: Treat for shortest duration necessary to resolve symptoms (often at least 3–5 days).
  • Tapered regimen for patients with:
    • Hepatic/renal impairment
    • Comorbidities
    • Severe symptoms
• Selective COX-2 inhibitors: Consider as an alternative to naproxen in patients without contraindications.

Low-dose aspirin can decrease uric acid excretion and trigger recurrent gout flares but it should not be stopped in patients taking it for specific indications (e.g., coronary artery disease, cerebrovascular disease), regardless of the severity of gout. [23][31]

Colchicine [23][27]

• Mechanism of action: binds and stabilizes tubulin subunits → inhibits microtubule polymerization → inhibits phagocytosis of urate crystals, neutrophil activation, migration, and degranulation [32]
• Administration
  • Administer within the first 12 hours of symptom onset to maximize efficacy.
  • Reduce dose and monitor closely when prescribed in patients with hepatic impairment or mild-moderate CKD.
• Adverse effects
  • Gastrointestinal symptoms, e.g., diarrhea, nausea, vomiting, and abdominal pain, are the most common.
  • Rhabdomyolysis , myopathy
  • Polyneuropathy [33]
  • Cardiac toxicity, arrhythmias
  • Nephrotoxicity
  • Myelosuppression
  • CNS symptoms (e.g., fatigue, headache)
• Contraindications
  • Severe CKD
  • Patients on prophylactic colchicine who received an acute gout dose of colchicine in the previous 14 days
• Drug interactions
  • Statins: Consider reducing dose of pravastatin, atorvastatin, or simvastatin when prescribed concomitantly.
  • Potent cytochrome P450 3A4 substrates or inhibitors
    • Reduce colchicine dose when prescribed concomitantly.
    • Avoid in patients with CKD or hepatic impairment.

Colchicine is unlikely to be effective when initiated > 24–36 hours after symptom onset. Colchicine is preferable in patients who cannot tolerate NSAIDs or systemic glucocorticoids (e.g., patients with gastrointestinal ulcers)

Monitor for myotoxicity when prescribing colchicine with statins. Reduce dose of pravastatin, atorvastatin, and simvastatin when prescribed concomitantly.

Approach [23]

• Urate-lowering therapy (ULT) is recommended for chronic gout.
  • First-line: xanthine-oxidase inhibitors (allopurinol)
  • Second-line: uricosurics (probenecid)
  • Third-line: recombinant uricase (pegloticase)
• Administer anti-inflammatory prophylaxis before initiating ULT as ULT may trigger, prolong, or worsen an acute gout flare.

Initial anti-inflammatory prophylaxis [23][26][28]

• Indication: pre-treatment in patients planned for ULT therapy
• Important consideration: should be initiated 1 week before starting ULT therapy
• Options: low dose of any one of the following agents [12][23][26]
  • Colchicine
  • NSAIDs (e.g., naproxen )
  • Glucocorticoids (e.g., prednisone )
• Treatment duration: Should be administered concomitantly with ULT for at least 3–6 months (or longer if flares continue).

Administering XOIs or uricosuric agents during an acute gout flare may worsen symptoms by mobilizing urate crystals. Anti-inflammatory prophylaxis with colchicine, NSAIDs, or glucocorticoids must be administered before initiating ULT.

Urate-lowering therapy (ULT) [23][26][27]

Indications

• Absolute indications
  • Damage due to chronic gout seen on imaging
  • Tophi development
  • Frequent gout attacks (≥ 2 per year)
• Relative indications
  • < 2 gout attacks per year
  • First episode of acute gout flare in patients with any of the following risk factors:
    • CKD ≥ stage 3
    • Serum uric acid > 9 mg/dL
    • History of urolithiasis

Contraindications

• Common to all ULT agents
  • Acute gout flare (in the absence of the above-mentioned risk factors)
  • Asymptomatic hyperuricemia
• Specific contraindications: see the table below for details

Important considerations

• Timing of initiating ULT: at least one week after initiating anti-inflammatory prophylaxis (see above)
• Titration target: serum urate < 6 mg/dL [23]
• Treatment duration: Continue indefinitely if tolerated and in remission
• Patient adherence: typically low ; monitoring and counseling recommended [34]

Agents

Test for the HLA-B*5801 allele before initiating allopurinol in black patients and patients of Southeast Asian descent.

The combination of allopurinol and azathioprine leads to increased bone marrow toxicity!

• Consider limb-threatening differential diagnoses (e.g., septic arthritis).
• Assess need for diagnostic arthrocentesis, laboratory studies, and/or imaging.
• Consult rheumatology if diagnosis remains uncertain.
• Provide adequate analgesia.
• Rest the joint and use local ice therapy.
• If the patient is on long-term urate-lowering therapy, it should not be discontinued.
• Initiate pharmacotherapy for acute gout as early as possible; select one of the following based on patient-specific factors:
• • Glucocorticoids
  • NSAIDs
  • Colchicine
• Consider indications for combination therapy.
• Ensure follow-up with the primary care provider or rheumatologist for complicated cases.

• Nephrolithiasis: uric acid stones
• Uric acid nephropathy
  • Acute uric acid nephropathy
    • Can occur in tumor lysis syndrome
    • Causes tubular obstruction → acute renal failure
  • Chronic uric acid nephropathy: a form of chronic tubulointerstitial nephropathy with monosodium urate crystal deposition in the stroma of the kidney, which causes inflammation
    • Clinical features
      • Hypertension
      • In rare cases, progressive renal failure

We list the most important complications. The selection is not exhaustive.

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