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 attacks 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. Calcium pyrophosphate deposition (CPPD) disease, sometimes referred to as pseudogout, is another crystal arthropathy that may be idiopathic or triggered (e.g., by minor trauma). Acute management of CPPD disease is similar to that of gout.
- Sex: : ♂ > ♀ (3:1) 
- Age of onset: 2 peaks of incidence (at 30–39 years and at 60 years of age) 
- Prevalence: ∼ 8 million people in the US 
Epidemiological data refers to the US, unless otherwise specified.
- Idiopathic extracellular supersaturation of uric acid
- No history of comorbidities or medications that affect uric acid formation or excretion 
Primary hyperuricemia can be aggravated by poor dietary habits.
Secondary hyperuricemia 
- Decreased uric acid excretion: most common cause
Increased uric acid production
- High cell turnover, e.g.:
- Enzyme defects, e.g.: 
- Diet rich in protein and especially purine (e.g., red meat, seafood)
- Hypercholesterolemia, hypertriglyceridemia
- Hypertension 
- Sleep apnea 
- Combined decreased excretion and overproduction: high alcohol consumption
- Uric acid is an end-product of purine metabolism that is excreted by the kidneys.
- Uric acid has poor water solubility, even under physiological conditions.
- Factors that trigger urate crystal deposition include:
- 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
- Hyperuricemia with no symptoms
- May last ≥ 10 years 
Acute gouty arthritis
- Definition: an inflammatory arthropathy caused by urate crystal deposition within a joint
Triggers: Anything that leads to a sudden increase in uric acid, e.g., consuming a large amount of purine-rich foods or alcohol (see risk factors for gout)
- Trauma, surgery
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 regression may take days to weeks. 
- Desquamation of the skin overlying the joint may be seen during the recovery from an acute gout flare.
Usually monoarthritis during first attacks
- In < 20% of cases, patients present with polyarthritis during first attacks.
- Asymmetrical distribution 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, esp. metacarpophalangeal joint of the thumb
- Others: ankle; , tarsus, other toe joints, wrist, elbow
- Usually monoarthritis during first attacks
- May last up to several years
Chronic gouty arthritis
- Progressive joint destruction
Multiple painless hard nodules with possible joint deformities 
- 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)
- Multiple painless hard nodules with possible joint deformities 
- Renal manifestations with uric acid nephrolithiasis and
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., ), 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.
Acute gout (gout flare)
- Assess the clinical probability of : If relatively high, perform arthrocentesis for synovial fluid analysis; consult orthopedics as needed (see “” for details).
- Assess the clinical probability of acute gout.
- 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. 
Arthrocentesis and synovial fluid analysis 
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.
Polarized light microscopy: needle-shaped monosodium urate crystals that are negatively birefringent 
- 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 “”)
- Gram stain: negative; useful for ruling out septic arthritis
- Polarized light microscopy: needle-shaped monosodium urate crystals that are negatively birefringent 
Clinical diagnosis of acute gout 
There is a lack of consensus regarding strict diagnostic criteria for gout in clinical settings. 
- A clinical diagnosis of acute gout can be considered in patients who fulfill all of the following parameters:
- Typical clinical presentation
- Low suspicion for
- The accuracy for patients with acute monoarthritis. can improve diagnostic
|Diagnostic rule for acute gout |
|Criterion||Number of points|
History of previous arthritis attack
|Features of current attack||Onset within 24 hours||0.5|
|Affects 1st metatarsophalangeal joint||2.5|
|Serum uric acid level > 5.88 mg/dL (0.35 mmol/L)||3.5|
- Serum uric acid level 
- CBC and inflammatory markers: : WBC and ESR are typically elevated in an acute gout attack. 
- Urinary uric acid measurement (via ): not routinely recommended
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.
- Dual-energy CT : can detect crystals within deeper anatomical structures (e.g., the spine) and extra-articular sites
- Acute gout: typically normal; useful for ruling out a fracture in patients with posttraumatic joint inflammation
- Chronic gout
- Conventional CT and MRI: can identify erosions and tophi; used less frequently
Foreign body granuloma
- Caused by urate crystal deposition in cutis and subcutis
- Findings include:
- Inflammatory arthritis: (other types): See “.”
- Others: erosive osteoarthritis
The differential diagnoses listed here are not exhaustive.
General measures 
- 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. 
- Close management of comorbidities, such as diabetes and hypertension
- Adjust current antihypertensive regimen, if feasible: losartan preferred; avoid hydrochlorothiazide 
- Nonpharmacological measures: Rest and ice the affected joint. 
Pharmacotherapy: Initiate within 24 hours of onset.
- First-line agents: glucocorticoids, NSAIDs, or colchicine (described in detail below) 
- Second-line agents : IL-1 inhibitors or ACTH
- Combination therapy options: indicated for attacks involving ≥ 4 joints, > 1 large joint, or severe pain
- Consider initiating urate-lowering therapy in select patients (see “Indications” in “Urate-lowering therapy” for details).
- Systemic administration
- Intraarticular administration: : Consider if there are 1–2 joints that are accessible and a trained provider is available.
Naproxen: or an alternative (e.g., indomethacin, ibuprofen; see “” 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
- 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. 
- Mechanism of action: binds and stabilizes tubulin subunits → inhibits microtubule polymerization → inhibits phagocytosis of urate crystals, neutrophil activation, migration, and degranulation 
- 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
- Drug interactions
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)
- Urate-lowering therapy (ULT) is recommended for chronic gout.
- Administer anti-inflammatory prophylaxis before initiating ULT as ULT may trigger, prolong, or worsen an acute gout flare.
Initial anti-inflammatory prophylaxis 
- 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 
- 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) 
- Absolute indications
- Relative indications
- Common to all ULT agents
- Specific contraindications: see the table below for details
|Urate-lowering therapy |
Xanthine oxidase inhibitors (XOIs)
|Indications || || || |
|Mechanism of action|| |
|Side effects|| |
|Important drug interactions|
Acute management checklist for acute gout flare
- 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:
- Consider indications for combination therapy.
- Ensure follow-up with the primary care provider or rheumatologist for complicated cases.
Uric acid nephropathy 
- Acute uric acid nephropathy
- Chronic uric acid nephropathy: a form of chronic tubulointerstitial nephropathy with monosodium urate crystal deposition in the stroma of the kidney, which causes inflammation
We list the most important complications. The selection is not exhaustive.
- Paroxysmal joint inflammation due to calcium pyrophosphate dihydrate (CPP) crystal deposition
- Commonly referred to as simply CPPD or pseudogout
- Mostly idiopathic (primary form)
- Secondary form: joint trauma; , familial chondrocalcinosis, hyperparathyroidism, hemochromatosis, gout, hypophosphatemia 
Clinical presentation 
- Often asymptomatic
- Acute pseudogout attack
- Chronic CPPD disease
- Most accurate diagnostic method
- Expected findings
- X-ray: often shows calcification of cartilage in the affected joints (chondrocalcinosis); cartilage involved includes:
- Ultrasound: can help differentiate CPPD from gout
- Serum uric acid: typically normal
- Investigate for the underlying cause (e.g., serum levels of calcium, PTH, iron, ferritin)
- Screen for associated conditions (especially in patients < 60 years old).
- Treat the underlying condition (e.g., treatment of hyperparathyroidism)
- Asymptomatic patients: no further treatment required
- Treatment of acute pseudogout: symptomatic therapeutic options in order of preference include the following
- Prophylaxis: Consider low-dose colchine to decrease the frequency of acute attacks.
To remember the main features of PSeudogout (positive birefringence, CAlcium pyrophosphate depositions, RhOMboid-shaped crystals, CHOndrocalcinosis, most often affects the knee), think of: “My PSychic is positive that I CAn find ROMance if I smear CHOcolate on my knee.”