Gout and Crystal Arthropathy

Gout is the most common inflammatory arthritis in adults, caused by deposition of monosodium urate (MSU) crystals in joints and soft tissues. It results from prolonged hyperuricemia leading to crystal formation when serum urate exceeds its saturation point of 6.8 mg/dL (404 micromol/L).

Epidemiology:

• Prevalence: 1-4% of adults in developed countries
• Male to female ratio: 4:1 (equalizes after menopause)
• Peak incidence: Males 40-50 years, females post-menopause
• Increasing prevalence due to obesity, metabolic syndrome, aging population

Risk Factors:

• Dietary: Purine-rich foods (red meat, seafood), alcohol (especially beer), fructose-sweetened beverages
• Medications: Thiazide diuretics, low-dose aspirin, cyclosporine
• Comorbidities: Chronic kidney disease, metabolic syndrome, hypertension, obesity
• Genetic: Variants in urate transporters (URAT1, GLUT9)

Understanding the pathophysiology of gout is essential for both diagnosis and management. The disease results from a complex interplay of uric acid metabolism, crystal formation, and inflammatory responses.

Uric Acid Metabolism

Production:

• Uric acid is the end product of purine metabolism in humans
• Purines derived from dietary intake (exogenous) and cellular turnover (endogenous)
• Key enzyme: Xanthine oxidase converts hypoxanthine to xanthine to uric acid
• Humans lack uricase enzyme (present in most mammals) - cannot break down uric acid further

Excretion:

• 70% renal excretion via complex tubular handling
• 30% gastrointestinal excretion
• Key transporters: URAT1 (reabsorption), ABCG2 (secretion), GLUT9

Crystal Formation

Saturation point:

• Monosodium urate (MSU) saturates at 6.8 mg/dL (404 micromol/L)
• Below this level, crystals gradually dissolve
• Above this level, crystals can precipitate in tissues

Factors promoting crystallization:

• Lower temperature (explains predilection for peripheral joints)
• Lower pH (trauma, exercise-induced acidosis)
• Presence of nucleating agents
• Connective tissue matrix components

Inflammatory Response

NLRP3 Inflammasome activation:

1. MSU crystals are phagocytosed by macrophages
2. Crystals destabilize lysosomal membranes
3. Cathepsin B released into cytoplasm
4. NLRP3 inflammasome assembly triggered
5. Caspase-1 activation
6. Pro-IL-1beta cleaved to active IL-1beta
7. Massive inflammatory cascade initiated

Resolution:

• Acute attacks are self-limiting (7-14 days)
• Aggregated neutrophil extracellular traps (NETs) help resolve inflammation
• Coating of crystals by proteins reduces immunogenicity
• Anti-inflammatory macrophage phenotype emerges

Acute Gouty Arthritis

Classic presentation:

• Rapid onset over 6-12 hours, often waking patient from sleep
• Exquisitely painful - unable to tolerate bedsheet contact
• Monoarticular in 85-90% of initial attacks
• Podagra (1st MTP) is the classic location - 50% of first attacks
• Signs of inflammation: Erythema, warmth, swelling mimicking cellulitis

Common joint involvement:

1. First metatarsophalangeal joint (podagra) - 50%
2. Ankle and midfoot - 25%
3. Knee - 15%
4. Wrist, fingers, elbow - 10%

Chronic Tophaceous Gout

Features:

• Tophi: Chalky deposits of MSU crystals in soft tissues
• Common locations: Fingers, olecranon bursa, Achilles tendon, ears
• Joint destruction: Erosive arthropathy with preserved joint space initially
• Tendon involvement: Can cause rupture (Achilles, patellar, extensor tendons)

Physical Examination

Inspection:

• Swelling and erythema over affected joint
• Tophi visible as subcutaneous nodules (white-yellow through skin)
• Skin ulceration over tophi in advanced cases

Palpation:

• Extreme tenderness - even light touch is painful
• Warmth over affected joint
• Tophi are firm, irregular nodules

Laboratory Studies

Synovial fluid analysis (Gold Standard):

• MSU crystal identification under polarized microscopy
• Needle-shaped, negatively birefringent crystals
• WBC count: 10,000-70,000/microL (predominantly neutrophils)

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Serum uric acid:

• May be normal during acute attack (paradoxical decrease)
• Elevated greater than 6.8 mg/dL (360 micromol/L) supports diagnosis
• Target for ULT: less than 6 mg/dL (360 micromol/L)

Additional labs:

• Renal function (CKD common comorbidity)
• Lipid profile and glucose (metabolic syndrome)
• CBC (elevated WBC during acute attack)

Imaging

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Plain Radiographs:

• Early: Soft tissue swelling, normal bone
• Established: Punched-out erosions with overhanging edges ("rat bite" or "mouse ear")
• Preserved joint space (unlike OA)
• Soft tissue tophi may calcify

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Ultrasound:

• Double contour sign: Hyperechoic line on hyaline cartilage surface
• Aggregates and tophi visible
• Useful for guided aspiration

Dual-Energy CT (DECT):

• Color-codes urate deposits (typically green)
• Pooled sensitivity approximately 0.87 and specificity 0.84 (Ogdie meta-analysis)
• Lower sensitivity in early/acute gout and small deposits (false negatives in disease under 6 weeks)
• Useful when aspiration not possible; can detect occult tophi
• Beware artefacts (nail-bed, skin, beam hardening) mimicking urate

Algorithm

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Acute Attack Management

First-line options:

1. NSAIDs: Indomethacin 50mg TDS, naproxen 500mg BD - continue until attack resolves
2. Colchicine: Most effective within 12 hours of onset. Loading dose 1mg, then 0.5mg 1 hour later. Low-dose regimen preferred.
3. Corticosteroids: Prednisolone 30-40mg daily for 5-7 days, or intra-articular injection

Refractory cases:

• IL-1 inhibitors (anakinra) for patients with contraindications to all above
• Joint aspiration alone provides significant relief

Urate-Lowering Therapy (ULT)

Indications for ULT:

• Recurrent acute attacks (2 or more per year)
• Presence of tophi
• Radiographic changes
• Chronic kidney disease stage 2 or greater
• Urolithiasis

Agents:

• Allopurinol: First-line xanthine oxidase inhibitor. Start low (50-100mg, lower in CKD), titrate to target. Consider HLA-B*58:01 testing before starting in high-risk ethnicities (Han Chinese, Thai, Korean with CKD) to reduce severe cutaneous adverse reactions (SCAR/SJS-TEN).
• Febuxostat: Alternative if allopurinol intolerant or target not reached. More potent urate lowering; cardiovascular safety debated (see Controversies).
• Probenecid / benzbromarone (uricosurics): Require adequate renal function and urine output; avoid with urolithiasis. Useful for under-excretors when xanthine oxidase inhibitors fail.
• Pegloticase (recombinant uricase): For severe refractory tophaceous gout; rapidly dissolves tophi but immunogenic.

Target:

• Serum urate less than 6 mg/dL (360 micromol/L)
• Less than 5 mg/dL if tophi present for faster dissolution

Indications for Surgery

1. Mechanical symptoms: Large tophi limiting joint motion or tendon function
2. Skin ulceration: Over tophi with risk of secondary infection
3. Secondary infection: Debridement of infected tophi
4. Nerve compression: Carpal tunnel, ulnar neuropathy from tophi
5. Joint destruction: Arthroplasty for end-stage arthropathy
6. Tendon rupture: Repair or reconstruction

Surgical Principles

Disease Complications

• Chronic erosive arthropathy: Joint destruction, subluxation
• Tendon rupture: Achilles, patellar, extensor tendons
• Carpal tunnel syndrome: From tophaceous deposits
• Renal complications: Uric acid stones, urate nephropathy
• Cardiovascular disease: Independent risk factor

Surgical Complications

• Wound healing problems: Skin necrosis, delayed healing over tophi
• Infection: Risk increased with ulcerated tophi
• Recurrence: If ULT not optimized
• Tendon injury: During tophus excision

The single most important mimic of acute gout is septic arthritis - the two can coexist, and a hot, swollen joint must be aspirated to exclude infection before attributing it to crystals.

• Febuxostat cardiovascular safety: CARES (29527974) showed higher all-cause and CV mortality with febuxostat versus allopurinol in patients with established CV disease, prompting an FDA boxed warning. The later EMA-mandated FAST trial (33181081) found febuxostat non-inferior with no excess mortality. The discrepancy (high CARES drop-out and on-treatment vs intention-to-treat handling) leaves the true CV risk unresolved; allopurinol remains the pragmatic first-line.
• Asymptomatic hyperuricaemia: routine urate-lowering for asymptomatic hyperuricaemia is not recommended by ACR or EULAR; whether high-risk subgroups (CKD, CV disease) benefit remains debated.
• Start ULT during a flare? ACR 2020 permits initiating allopurinol during an acute flare (with prophylaxis) on the basis it does not prolong the attack; traditional teaching and many other guidelines still defer ULT until the flare settles. Either way, never stop established ULT during a flare.
• Surgery for tophi: timing and technique are not standardised. Wide excision risks unclosable defects; many now favour debulking with optimised ULT to let residual deposits dissolve medically rather than aggressive resection.
• Diet vs drugs: dietary modification lowers urate only modestly (roughly 1 mg/dL); it supports but does not replace ULT, and over-emphasis can stigmatise patients and delay effective treatment.

Global Epidemiology

• Prevalence: ranges from under 1% to 6.8% of adults depending on population (Dehlin et al., Nat Rev Rheumatol 2020). Highest in Taiwanese aboriginal, Maori and Pacific Island populations (often greater than 6-10%), where reduced renal urate excretion and genetic urate-transporter variants combine with diet.
• Incidence: 0.58-2.89 per 1000 person-years; rising worldwide with obesity, ageing and metabolic syndrome.
• Sex/age: male predominance roughly 3-4:1, narrowing after menopause; peaks in men aged 40-60.
• Care gap: only one-third to one-half of patients ever receive urate-lowering therapy, and fewer than half adhere - the dominant problem in gout is implementation, not drug efficacy.

Side-by-side Guideline Comparison

Registry & Surgical Outcome Notes

• There is no dedicated international gout registry equivalent to arthroplasty joint registries, but national arthroplasty registries (NJR UK, AJRR US, AOANJRR Australia, SHAR Sweden) capture gout as a comorbidity. Crystal arthropathy is associated with modestly higher periprosthetic joint infection and wound-complication rates in some series, reinforcing the value of preoperative urate control.
• Hand-surgery series of tophaceous excision report good functional gain but real risks of delayed wound healing and recurrence if ULT is not optimised.

High- vs Limited-Resource Practice Variation

• Well-resourced settings: ready access to polarised microscopy, ultrasound and DECT; HLA-B*58:01 genotyping where indicated; biologic IL-1 inhibitors (anakinra, canakinumab) for refractory disease.
• Limited-resource settings: diagnosis often clinical or via serum urate; polarised microscopy and DECT may be unavailable. Allopurinol and colchicine are inexpensive and on the WHO model essential-medicines landscape, so treat-to-target ULT remains achievable even where advanced imaging is not. Counterfeit colchicine and lack of monitoring are practical hazards.
• Across all settings, cardiovascular and renal risk screening is integral given the strong, consistent association of gout with CKD and cardiovascular disease.