Gout

Overview

• Definition: gout is a crystal arthropathy in which monosodium urate (MSU) crystals deposit in joints and soft tissues because of chronic hyperuricemia, producing recurrent flares of acute inflammatory arthritis.
• Cardinal presentation: sudden, severe monoarticular arthritis, classically the first metatarsophalangeal joint (podagra), peaking within 12 to 24 hours.
• Root cause: a serum urate sustained above the saturation point of 6.8 mg/dL, most often from renal underexcretion of urate.
• Why it matters: untreated gout progresses to frequent polyarticular flares, bone-eroding tophi, and chronic destructive arthritis, and it clusters with chronic kidney and cardiovascular disease.
• Two treatment arms: anti-inflammatory therapy aborts the flare, while lifelong urate-lowering therapy to a target below 6.0 mg/dL dissolves crystals and prevents recurrence.

Epidemiology

• Prevalence: affects roughly 4 percent of US adults and is rising with obesity, diet, and an aging population.
• Sex and age: predominantly men after puberty; premenopausal women are protected by the uricosuric effect of estrogen, so first flares occur in men in the third to fifth decade and in women after menopause.
• Comorbidity burden: nearly all patients carry hypertension, coronary disease, hyperlipidemia, diabetes, or chronic kidney disease, which both drive hyperuricemia and constrain therapy.
• Risk scales with urate: a serum urate above 10 mg/dL carries about a 30 percent chance of a first flare within 5 years.

Risk factors

• Hyperuricemia from renal underexcretion: the dominant risk factor; hereditary underexcretion is the most common mechanism.
• Chronic kidney disease: reduces urate excretion and raises serum urate.
• Urate-raising drugs: thiazide and loop diuretics, cyclosporine, tacrolimus, low-dose aspirin, ethambutol, pyrazinamide, and niacin.
• Diet and alcohol: red meat, shellfish, high-fructose corn syrup beverages, and alcohol.
• High cell turnover: myeloproliferative and lymphoproliferative disease, psoriasis, hemolytic anemia, and tumor lysis, which increase purine load.
• Metabolic factors: male sex, obesity, and metabolic syndrome.

Pathophysiology

• Urate accumulation: uric acid is the end product of purine metabolism, and because humans lack uricase, urate is not broken down to soluble allantoin and accumulates.
• Crystal precipitation: above the saturation point of 6.8 mg/dL, and preferentially in the cooler, more acidic distal joints, urate precipitates as MSU crystals.
• Underexcretion predominates: about 90 percent of filtered urate is reabsorbed in the proximal tubule, and most patients with gout underexcrete urate; overproduction accounts for a minority.
• Flare mechanism: synovial macrophages ingest MSU crystals and activate the NLRP3 inflammasome, generating interleukin-1 beta, which drives vasodilation, cytokine release, and neutrophil recruitment.
• Chronic deposition: persistent crystal accumulation forms tophi, chalky MSU masses that erode bone and damage soft tissue.

Clinical features

• Acute monoarticular flare: abrupt severe pain, swelling, erythema, and warmth that peaks within 12 to 24 hours and often begins at night.
• Podagra: the first metatarsophalangeal joint is involved in at least half of first flares; the midfoot, ankle, and knee are also common.
• Self-limited course: untreated flares resolve over days to a few weeks.
• Recognizable triggers: infection, surgery, myocardial infarction, trauma, dietary or alcohol excess, and starting a diuretic.
• Chronic tophaceous gout: polyarticular persistent arthritis with tophi over the extensor elbows, Achilles tendon, finger joints, and ear helices.
• Intercritical periods: patients are asymptomatic between flares, but crystals persist and the flare-free interval shortens as disease progresses.
• Postmenopausal pattern: first flares often involve the knees or osteoarthritic finger joints.

Differential diagnosis

• Septic arthritis: may be clinically identical and can coexist with gout, so synovial fluid Gram stain and culture are mandatory when infection is possible (septic arthritis).
• Pseudogout (calcium pyrophosphate deposition): less likely in the great toe; distinguished by rhomboid, positively birefringent crystals (Pseudogout).
• Cellulitis: overlying erythema without a joint effusion or crystals, though gouty cellulitis can mimic it.
• Rheumatoid arthritis: symmetric small-joint polyarthritis with rheumatoid factor or anti-CCP and a chronic course (rheumatoid arthritis).
• Reactive arthritis: oligoarticular arthritis following a gastrointestinal or genitourinary infection.
• Psoriatic arthritis: psoriasis with distal interphalangeal involvement and dactylitis.
• Basic calcium phosphate deposition: periarticular disease with crystals too small to see on routine light microscopy.
• Trauma or fracture: localized pain and swelling by history, which can also trigger a flare.
• Acute rheumatic fever: migratory polyarthritis after streptococcal infection.

Diagnosis

• Confirm with synovial fluid crystal analysis (gold standard): aspiration showing negatively birefringent, needle-shaped MSU crystals within neutrophils under polarized light establishes the diagnosis; the fluid is inflammatory with leukocytes above 2,000/microL (often far higher) and neutrophil predominance. Validated ACR/EULAR classification criteria (about 92 percent sensitive, 89 percent specific) combine clinical features, serum urate, and imaging when aspiration is not feasible.
• First step, arthrocentesis: aspirate the affected joint for polarized-light microscopy, and when infection is at all possible send Gram stain and culture, because septic arthritis can mimic or coexist with a flare.
• Serum urate, timed correctly: an elevated level supports the diagnosis but does not confirm it, and a normal level during a flare does not exclude it because urate falls with acute inflammation; measure a baseline 2 weeks after the flare resolves, and treat to below 6.0 mg/dL.
• Inflammatory markers: CRP and ESR are elevated during a flare but are nonspecific.
• Imaging when aspiration is not feasible: ultrasound shows the double-contour sign or tophi, dual-energy CT demonstrates urate deposition, and radiographs of chronic disease show punched-out erosions with sclerotic borders and overhanging edges.
• Supportive clinical features when a tap is impossible: rapid onset of severe pain, involvement of the first MTP or midfoot and ankle, erythema, and prior similar episodes.

Clinical pearl. A normal serum urate during an acute attack never rules gout out, because levels drop with inflammation. Aspirate the joint whenever feasible, and if infection is at all plausible send Gram stain and culture, since septic arthritis can masquerade as, or coexist with, a gout flare.

Management

• Treat the flare first, as early as possible (most effective within 24 hours of onset), choosing the agent by comorbidity:
  • Colchicine 1.2 mg PO at the first sign of a flare, then 0.6 mg PO 1 hour later, then 0.6 mg PO once or twice daily until the flare resolves.
  • Naproxen 750 mg PO once, then 250 mg PO every 8 hours until the flare resolves (or indomethacin 50 mg PO three times daily); avoid in chronic kidney disease, peptic ulcer disease, and heart failure.
  • Prednisone 0.5 mg/kg PO daily for 5 to 7 days then stop or taper, or an intra-articular or intramuscular glucocorticoid (methylprednisolone 40 to 80 mg) for a monoarticular flare or when oral therapy is contraindicated.
• If the flare is severe or refractory or all of the above are contraindicated, use an interleukin-1 inhibitor (anakinra or canakinumab).
• Do not react to the flare by changing chronic therapy: continue urate-lowering therapy through a flare if the patient is already on it, and start urate-lowering therapy during a flare only when effective anti-inflammatory cover is running.
• Then start urate-lowering therapy (treat-to-target) for indicated patients (two or more flares per year, tophi, radiographic damage, or, conditionally, a first flare with CKD stage 3 or worse, urate above 9 mg/dL, or urolithiasis):
  • Allopurinol, first-line: start 100 mg PO daily (50 mg if CKD stage 4 to 5) and titrate by 100 mg every 2 to 4 weeks to a serum urate below 6.0 mg/dL, up to 800 mg/day; test HLA-B*58:01 in patients of Han Chinese, Thai, Korean, or African descent, and stop for rash.
  • Febuxostat 40 mg PO daily, increased to 80 mg if not at target (no adjustment in mild-to-moderate CKD).
  • Probenecid 250 mg PO twice daily, then 500 mg twice daily, titrated to target (uricosuric; avoid in CKD or urolithiasis).
  • Pegloticase 8 mg IV every 2 weeks for refractory or tophaceous disease.
• Give flare prophylaxis when starting urate-lowering therapy: colchicine 0.6 mg PO once or twice daily for at least 3 to 6 months, because falling urate mobilizes crystals and provokes flares.
• Address diet and comorbidity: limit alcohol, red meat, shellfish, and high-fructose beverages, pursue weight loss, and for hypertension prefer losartan over diuretics because it is uricosuric.

Complications

• Tophi: deforming monosodium urate masses that erode bone, ulcerate through skin, and become difficult to treat if infected because they are avascular.
• Chronic gouty arthritis: persistent, polyarticular, destructive joint disease when flares are left untreated.
• Urate nephrolithiasis and urate nephropathy: uric acid stones and renal deposition (Nephrolithiasis).
• Joint damage and disability: progressive erosive change and functional loss.
• Associated organ disease: strong links to chronic kidney disease and cardiovascular disease (chronic kidney disease).

Prognosis

• Excellent with treat-to-target therapy: sustaining a serum urate below 6.0 mg/dL dissolves crystals, stops flares, and resorbs tophi over months to years.
• Poor with undertreatment: flares become more frequent, polyarticular, and tophaceous, and joints are progressively destroyed.
• Adherence is decisive: urate-lowering therapy is lifelong, and long-term outcome tracks with whether patients stay on it.

Prevention

• Maintain serum urate below 6.0 mg/dL (below 5.0 mg/dL with tophi) on lifelong urate-lowering therapy, the central preventive target.
• Cover the initiation period: colchicine 0.6 mg once or twice daily for 3 to 6 months when starting urate-lowering therapy prevents mobilization flares.
• Remove urate-raising drugs: replace thiazide and loop diuretics where possible and use losartan for hypertension.
• Modify diet: limit alcohol, red meat, shellfish, and high-fructose corn syrup beverages, pursue weight loss, and increase low-fat dairy.
• Screen before allopurinol: test HLA-B*58:01 in patients of Han Chinese, Thai, Korean, or African descent to prevent severe hypersensitivity.

Key points

• Gout is monosodium urate crystal disease driven by chronic hyperuricemia, with podagra of the first MTP joint the classic flare.
• The gold standard is negatively birefringent needle-shaped crystals in synovial fluid; serum urate may be normal during a flare.
• Always exclude septic arthritis with Gram stain and culture when infection is possible, since the two can coexist.
• Treat the flare with colchicine, an NSAID, or a glucocorticoid, chosen by comorbidity and started early.
• Urate-lowering therapy (allopurinol first-line) is treat-to-target below 6.0 mg/dL, lifelong, with 3 to 6 months of colchicine prophylaxis at initiation.
• Reserve urate-lowering therapy for recurrent flares, tophi, erosions, or a high-risk first flare, and check HLA-B*58:01 in at-risk ancestries.