Gout and Crystal Arthropathy

Gout is the most common inflammatory arthritis in adults. It is caused by deposition of monosodium urate (MSU) crystals in joints and soft tissues, and it results from prolonged hyperuricaemia, crystals forming once serum urate exceeds its saturation point.

Who gets it. Prevalence is 1-4% of adults in developed countries, and it is rising with obesity, the metabolic syndrome and an ageing population. Men outnumber women 4:1, a ratio that equalises after the menopause; incidence peaks in men at 40-50 years and in women after the menopause.

Risk factors.

• Dietary: purine-rich foods (red meat, seafood), alcohol (especially beer), fructose-sweetened beverages
• Medications: thiazide diuretics, low-dose aspirin, ciclosporin
• Comorbidities: chronic kidney disease, metabolic syndrome, hypertension, obesity
• Genetic: variants in the urate transporters (URAT1, GLUT9)

Production. Uric acid is the end product of purine metabolism in humans. Purines come from the diet (exogenous) and from cellular turnover (endogenous), and xanthine oxidase converts hypoxanthine to xanthine and xanthine to uric acid. Humans lack uricase, the enzyme most mammals use to break uric acid down further, so the pathway stops there.

Excretion. About 70% of uric acid leaves through the kidney, by way of complex tubular handling, and 30% through the gut. The tubular transporters that matter are URAT1 (reabsorption), ABCG2 (secretion) and GLUT9.

Crystal formation. Monosodium urate saturates at 6.8 mg/dL (404 micromol/L). Below that level crystals gradually dissolve; above it they can precipitate in tissue. Several local factors favour crystallisation:

• Lower temperature, which explains the predilection for peripheral joints
• Lower pH (trauma, exercise-induced acidosis)
• Nucleating agents
• Connective tissue matrix components

The inflammatory response. The acute attack is an innate immune reaction to the crystal, run through the NLRP3 inflammasome:

1. MSU crystals are phagocytosed by macrophages
2. The crystals destabilise lysosomal membranes
3. Cathepsin B is released into the cytoplasm
4. NLRP3 inflammasome assembly is triggered
5. Caspase-1 is activated
6. Pro-IL-1beta is cleaved to active IL-1beta
7. A massive inflammatory cascade follows

Resolution. Attacks are self-limiting, settling in 7-14 days. Aggregated neutrophil extracellular traps (NETs) help resolve the inflammation, protein coating of the crystals reduces their immunogenicity, and an anti-inflammatory macrophage phenotype emerges.

The tophus is the pathological hallmark of chronic gout and the structure the surgeon excises. What it actually is explains both its radiographic appearance and the principle that optimised urate-lowering therapy can dissolve it medically: a tophus is not a simple lump of crystal but an organised, chronic foreign-body granulomatous response to deposited monosodium urate.

Microscopic zones. A mature tophus has three concentric zones:

Why tophi are reversible. The crystals are in equilibrium with the serum urate, so sustained urate-lowering therapy below the saturation point lets a tophus slowly dissolve (the target is set lower still when tophi are present; see Management). This is why many surgeons now favour debulking plus optimised medical therapy over aggressive wide excision, which risks an unclosable defect.

The acute attack. Onset is rapid, over 6-12 hours, and often wakes the patient from sleep. The joint is exquisitely painful, to the point that the patient cannot tolerate the bedsheet touching it, and it is erythematous, warm and swollen enough to mimic cellulitis. The first attack is monoarticular in 85-90% of patients.

Where. The first metatarsophalangeal joint, podagra, is the classic site:

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

Chronic tophaceous gout. Tophi are chalky deposits of MSU crystals in soft tissue, found most often on the fingers, in the olecranon bursa, in the Achilles tendon and on the ears. The joints develop an erosive arthropathy in which the joint space is preserved initially; the tendon ruptures and nerve compressions of this phase are listed under Complications.

Examination. The acute joint is swollen, erythematous and warm, and so tender that even light touch is painful. Tophi are firm, irregular subcutaneous nodules, white-yellow through the skin, and in advanced cases the skin over them ulcerates.

Synovial fluid analysis is the gold standard. Aspirate the joint (or a tophus) and look for MSU crystals under polarised microscopy: needle-shaped and negatively birefringent, yellow when parallel to the compensator slow axis and blue when perpendicular. The white cell count runs at 10,000-70,000/microL, predominantly neutrophils.

View larger

Serum urate. A level above the saturation point supports the diagnosis, but the serum urate may be normal during an acute attack (a paradoxical decrease). Send renal function as well, because chronic kidney disease is a common comorbidity, a lipid profile and glucose for the metabolic syndrome, and a full blood count, in which the white cell count is elevated during an attack.

Plain radiographs. Early in the disease they show soft-tissue swelling and normal bone. Established disease produces punched-out erosions with overhanging edges (the "rat bite" or "mouse ear"), a joint space that is preserved, unlike osteoarthritis, and soft-tissue tophi that may calcify.

View larger

Ultrasound. The double contour sign is a hyperechoic line on the surface of the hyaline cartilage. Aggregates and tophi are also visible, and ultrasound is useful for guided aspiration.

Dual-energy CT. DECT colour-codes urate deposits, typically green, with a pooled sensitivity of about 0.87 and specificity of 0.84 (Ogdie meta-analysis). It is useful when aspiration is not possible and can detect occult tophi, but sensitivity is lower in early or acute gout and with small deposits (false negatives in disease under 6 weeks), and artefacts from the nail bed, skin and beam hardening can mimic urate.

View larger

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.

Pseudogout. Calcium pyrophosphate deposition is the crystal mimic to know. Its risk factors are age, osteoarthritis and metabolic disease, and unlike gout it has no specific therapy. Its imaging signature is chondrocalcinosis, shown below in the knee, wrist and shoulder.

View larger

View larger

View larger

View larger

Algorithm

View larger

The acute attack. Three first-line options, and one thing not to do.

The first-line options:

1. NSAIDs: indomethacin 50mg TDS or naproxen 500mg BD, continued until the attack resolves
2. Colchicine: most effective within 12 hours of onset. Loading dose 1mg, then 0.5mg one hour later; the low-dose regimen is preferred
3. Corticosteroids: prednisolone 30-40mg daily for 5-7 days when the attack is polyarticular or the other agents are contraindicated, or an intra-articular injection for a monoarticular attack when NSAIDs are contraindicated

Refractory cases. IL-1 inhibitors (anakinra) are for patients with contraindications to all of the above. Joint aspiration alone provides significant relief.

Urate-lowering therapy. ULT is indicated for:

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

The agents.

• Allopurinol: first-line xanthine oxidase inhibitor. Start low (50-100mg, lower in CKD) and 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 is not tolerated or the target is 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

The target. Serum urate below 6 mg/dL (360 micromol/L), and below 5 mg/dL if tophi are present, for faster dissolution.

Colchicine appears throughout gout management, in acute flares, as prophylaxis when starting urate-lowering therapy and as perioperative cover, yet how it works and why it is dangerous in overdose are commonly examined.

Mechanism. Colchicine is an anti-mitotic alkaloid that binds tubulin and prevents microtubule polymerisation. In gout this disrupts neutrophil function (chemotaxis, adhesion and motility) and impairs assembly and activation of the NLRP3 inflammasome, reducing IL-1beta-driven inflammation. It is anti-inflammatory only: it is not an analgesic and not urate-lowering, so it treats the crystal-induced inflammatory response and does nothing to the serum urate.

Toxicity.

Drug interactions. Colchicine is metabolised by CYP3A4 and is a substrate of the P-glycoprotein efflux transporter. Co-administration with strong inhibitors of either, clarithromycin and other macrolides, azole antifungals, ciclosporin, verapamil and diltiazem, raises colchicine levels and can precipitate life-threatening toxicity.

Indications. Six situations bring the patient to the surgeon:

1. Mechanical symptoms: large tophi limiting joint motion or tendon function
2. Skin ulceration over tophi, with the risk of secondary infection
3. Secondary infection: debridement of infected tophi
4. Nerve compression: carpal tunnel syndrome or ulnar neuropathy from tophi
5. Joint destruction: arthroplasty for end-stage arthropathy
6. Tendon rupture: repair or reconstruction

Of the disease. The complications extend beyond the joint:

• 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: an independent risk factor

Of surgery. The skin over a tophus is the recurring problem:

• Wound healing problems: skin necrosis, delayed healing over tophi
• Infection: risk increased with ulcerated tophi
• Recurrence: if ULT is not optimised
• Tendon injury: during tophus excision

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.

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 versus 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 that 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; the case for debulking with optimised ULT rather than wide excision is made under Tophus Pathology.

Diet versus 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.