Crystal diseases including gout

Crystal arthropathies are a group of inflammatory joint diseases caused by the deposition of crystals within joints and periarticular tissues. Gout — caused by monosodium urate (MSU) crystal deposition — is the most common inflammatory arthritis in adults and the most important crystal arthropathy in clinical practice. Other crystal diseases include calcium pyrophosphate deposition (CPPD) disease and basic calcium phosphate (BCP) deposition. This guideline focuses primarily on gout, with key points on CPPD and BCP.

Gout results from persistent hyperuricaemia leading to MSU crystal deposition. Uric acid is the final product of purine metabolism in humans (lacking uricase). Hyperuricaemia (serum urate >0.42 mmol/L) occurs from overproduction, underexcretion, or both. Crystal deposition in joints, bursae, tendons, and soft tissue triggers neutrophil-mediated inflammation via NLRP3 inflammasome activation, IL-1β release, and intense acute inflammatory arthritis.

Causes of Hyperuricaemia

Stages of Gout

• Asymptomatic hyperuricaemia: Elevated serum urate without symptoms — not all patients progress to gout
• Acute gout flare: Sudden-onset, intensely painful inflammatory arthritis, typically monoarticular, peaking within 12–24 hours
• Intercritical gout: Symptom-free period between flares — MSU crystals persist in joints
• Chronic tophaceous gout: Persistent hyperuricaemia leads to visible tophi (urate deposits), chronic joint destruction, and deformity

CPPD disease results from inorganic pyrophosphate accumulation in synovial fluid, causing CPP crystal precipitation in cartilage (chondrocalcinosis) and joint fluid. Triggers include ageing, hypomagnesaemia, hyperparathyroidism, haemochromatosis, and hypothyroidism.

Gout classically presents as an acute monoarthritis with rapid onset, severe pain, swelling, warmth, and erythema. The first metatarsophalangeal (MTP) joint is the classic site (podagra), but any joint may be affected.

Gout Flare — Classic Features

• Sudden onset, often nocturnal — may wake patient from sleep
• Exquisite tenderness — even bed sheets intolerable
• Monoarthritis or oligoarthritis
• Classic sites: 1st MTP (podagra) — 50% of first attacks; also ankle, midfoot, knee, wrist, small joints of hands
• Erythema, warmth, and oedema — may mimic cellulitis
• Systemic features: fever, elevated inflammatory markers (CRP, ESR)
• Spontaneous resolution without treatment within 7–14 days

Chronic Tophaceous Gout

• Tophi: firm subcutaneous nodules — ear helix, olecranon bursa, Achilles tendon, digits, extensor tendons
• Chronic joint destruction with persistent pain, stiffness, and deformity
• Polyarticular attacks become more common
• Renal involvement: urate nephropathy, nephrolithiasis (uric acid stones — 10–25% of gout patients)

CPPD Disease — Clinical Patterns

Diagnosis of gout is clinical in classic presentations but joint aspiration with crystal analysis remains the gold standard. Investigations are used to confirm diagnosis, exclude differentials, assess for complications, and guide treatment.

• Essential
  Serum urate

  Elevated in most patients (>0.42 mmol/L). Note: serum urate may be normal or low during an acute flare — do not use to exclude gout in acute setting. Check 2–4 weeks after flare resolves for baseline.
• Essential
  Joint aspiration and synovial fluid analysis

  Gold standard. MSU crystals: needle-shaped, negatively birefringent (yellow parallel to axis). CPP crystals: rhomboid, positively birefringent. Cell count: >50,000 WBC/mm³ raises concern for septic arthritis. Always send for MC&S if septic arthritis cannot be excluded.
• Essential
  FBC, CRP, ESR

  Elevated WBC and CRP during acute flare. Useful to assess severity of inflammation and monitor treatment.
• Essential
  Renal function (UEC)

  Renal impairment is both a cause (underexcretion) and complication of gout. Required before initiating ULT (allopurinol dosing is renal-adjusted).
• Recommended
  X-ray of affected joint

  Acute gout: normal or soft tissue swelling. Chronic gout: punched-out erosions with overhanging edges (rat bite lesions), preserved joint space until late, tophi. CPPD: chondrocalcinosis (calcification of cartilage) — knee, wrist, symphysis pubis.
• Recommended
  Urinalysis and urine urate:creatinine ratio

  Assess for uric acid stones, renal involvement. 24-hour urine uric acid if overproduction suspected.
• Recommended
  Fasting glucose, lipids, LFT

  Metabolic syndrome is strongly associated with gout. Required before allopurinol initiation (LFT baseline). Cardiovascular risk assessment.
• Available
  MSU crystal DECT (Dual Energy CT)

  Non-invasive detection of MSU deposits in joints and tendons — useful when joint aspiration not possible or in atypical presentations. Not widely available in all Australian centres.
• Available
  Ultrasound of joint

  Double contour sign (urate coating cartilage surface) and tophus detection — useful adjunct when diagnosis uncertain. Operator-dependent.
• Available
  Secondary causes screen

  If CPPD suspected: serum calcium, PTH, ferritin/transferrin saturation (haemochromatosis), magnesium, TSH, phosphate. Consider in younger patients or florid disease.

Key Differential Diagnoses

Risk stratification in gout determines the urgency and intensity of urate-lowering therapy (ULT). Patients with recurrent flares, tophi, renal disease, or radiographic damage represent high-risk groups requiring prompt ULT initiation.

Indications for Urate-Lowering Therapy (ULT)

• ≥2 acute gout flares per year
• Any tophus (subcutaneous or radiological)
• Gout with renal impairment (eGFR <60)
• Uric acid nephrolithiasis
• Radiographic joint damage
• Gout in a transplant recipient (cyclosporin-associated)
• Consider after first flare in: young patient (<40), serum urate >0.54 mmol/L, or significant comorbidities

Serum Urate Targets

• Non-tophaceous gout: Target serum urate <0.36 mmol/L (<6 mg/dL)
• Tophaceous gout: Target serum urate <0.30 mmol/L (<5 mg/dL) — to dissolve existing tophi
• Check serum urate every 4–6 weeks when titrating ULT; every 6 months once target achieved

Treatment of crystal diseases has two distinct phases: (1) acute flare management — rapid anti-inflammatory therapy; and (2) long-term urate-lowering therapy (ULT) — reducing serum urate to prevent recurrence and dissolve tophi. Both phases require careful medication selection based on comorbidities.

Acute Flare Management

Urate-Lowering Therapy (ULT)

Lifestyle and Dietary Modification

• Weight reduction: Obesity is a major risk factor — weight loss reduces serum urate
• Alcohol: Reduce or eliminate — beer and spirits particularly elevate urate; wine less so
• Purine-rich foods: Limit red meat, organ meats, shellfish, anchovies; low-fat dairy is beneficial
• Fructose: Limit fructose-containing beverages (soft drinks, fruit juice)
• Hydration: High fluid intake promotes urate excretion
• Vitamin C: 500 mg/day has modest uricosuric effect
• Diuretics: Review medications — thiazide and loop diuretics elevate urate; switch if possible (losartan has uricosuric effect and is preferred antihypertensive in gout)

Crystal diseases require tailored management for specific patient scenarios including renal impairment, transplant recipients, and CPPD disease.

Gout in Chronic Kidney Disease

• Allopurinol is safe and effective in CKD — start low, titrate slowly (not limited to creatinine-based dosing as historically used — titrate to serum urate target with gradual dose escalation)
• Avoid NSAIDs in eGFR <30 — use colchicine (dose-reduced) or short-course corticosteroids for acute flares
• Febuxostat may be safer than allopurinol in severe CKD — less renal excretion
• Urate-lowering therapy may slow progression of CKD — emerging evidence

Gout in Transplant Recipients

• Cyclosporin markedly elevates serum urate (reduced renal excretion + decreased tubular secretion)
• Azathioprine + allopurinol interaction: allopurinol inhibits xanthine oxidase → accumulation of 6-mercaptopurine → severe myelosuppression. AVOID concurrent allopurinol + azathioprine unless azathioprine dose reduced to 25% under haematology guidance.
• Febuxostat or rasburicase (in acute tumour lysis) are alternatives in this setting
• Colchicine interacts with cyclosporin — risk of myopathy and neuropathy; use with caution

Refractory Gout

• Defined as failure to reach serum urate target on maximum tolerated ULT
• Options: Pegloticase (recombinant uricase — not PBS-listed in Australia; used in specialised centres); combination therapy; review diet and medication adherence
• Rheumatology referral for tophaceous or refractory gout

CPPD Disease Management

• Acute pseudogout: Colchicine, NSAIDs, or intra-articular corticosteroids — same principles as acute gout flare
• Prophylaxis: Low-dose colchicine 0.5 mg BD if frequent attacks
• Chronic CPPD arthritis: NSAIDs, low-dose corticosteroids, or hydroxychloroquine in refractory cases
• No specific crystal-dissolving therapy available for CPPD — treat underlying secondary causes (hyperparathyroidism, haemochromatosis, hypomagnesaemia)
• CPPD in elderly with knee involvement may overlap with osteoarthritis — physiotherapy and analgesia important

Intercritical Gout (Between Flares)

• Maintain ULT throughout — do not stop during acute flares
• Monitor serum urate every 6 months once target achieved
• Review adherence, diet, alcohol, and concomitant urate-elevating medications at each visit
• Reassess need for prophylactic colchicine at 6–12 months

Non-pharmacological management is an essential component of gout treatment. Lifestyle modification can reduce serum urate by 0.06–0.12 mmol/L — meaningful but often insufficient as sole treatment. Patient education about the chronic nature of gout and the necessity of long-term ULT adherence is critical.

Patient Education — Key Messages

• Gout is caused by persistently elevated uric acid — it is a chronic metabolic disease, not just an "attack"
• Urate-lowering therapy must be taken long-term, even when feeling well — stopping causes recurrence
• Serum urate is the target, not symptoms alone — monitoring blood tests are necessary
• Lifestyle changes complement but rarely replace medications in patients with established gout
• Flares during early ULT treatment are expected (mobilisation flares) — do not stop ULT; take the prophylactic colchicine
• Tophi are reversible with adequate urate lowering over time

Dietary Advice

• Limit purine-rich foods: organ meats (liver, kidney), red meat, seafood (especially anchovies, sardines, mussels)
• Reduce or eliminate alcohol — especially beer and spirits (high purine content + fructose)
• Avoid fructose-sweetened beverages and foods
• Increase low-fat dairy consumption (has uricosuric properties)
• Maintain adequate hydration (aim ≥2 L/day)
• Mediterranean-style diet is broadly beneficial

Medication Review

• Review all medications contributing to hyperuricaemia: thiazide diuretics, loop diuretics, low-dose aspirin, cyclosporin, pyrazinamide
• Where clinically safe, switch thiazide diuretics to losartan (has uricosuric effect) or amlodipine
• Review low-dose aspirin indication — if for genuine cardioprotection, continue (benefit outweighs urate elevation)

Acute Flare Advice

• Rest the affected joint; elevate and ice-pack the joint (20 minutes every 2–3 hours)
• Start anti-inflammatory treatment early (within 24 hours) — carry colchicine prescription for patient-initiated treatment
• Maintain fluid intake — dehydration worsens hyperuricaemia
• Avoid aspirin for analgesia (raises urate)

Monitoring in gout targets serum urate levels, medication toxicity, and comorbidity management. Regular monitoring is essential during ULT titration and 6-monthly once stable.

Monitoring Allopurinol Safety

• Allopurinol hypersensitivity syndrome (AHS): Rare but potentially fatal — fever, rash (SJS/TEN/DRESS), eosinophilia, hepatitis, renal failure. Risk factors: renal impairment, HLA-B*58:01 (Han Chinese, Korean, Thai), high starting dose, diuretic use.
• Advise patients to stop allopurinol and present urgently if any rash develops
• Febuxostat: Monitor LFTs — hepatotoxicity; watch for cardiovascular events in high-risk patients
• Colchicine toxicity: GI toxicity (diarrhoea), myopathy, neuropathy with chronic use; myelosuppression in overdose — particularly dangerous with CYP3A4 inhibitors

Monitoring Serum Urate

• Do not check serum urate during an acute flare (spuriously low during acute inflammation)
• Check 4–6 weeks after each dose change
• Once target achieved and stable: check every 6–12 months
• Target: <0.36 mmol/L (non-tophaceous); <0.30 mmol/L (tophaceous)

Gout requires modified management in several key populations.

👶 Gout in Young Adults (<40 Years)

• Early-onset gout suggests strong genetic predisposition (HGPRT deficiency, PRPP overactivity) or significant metabolic syndrome
• Investigate for secondary causes including renal disease, enzyme deficiencies, early metabolic syndrome
• More aggressive ULT recommended — higher risk of tophi and joint destruction over lifetime
• Genetic counselling may be indicated for rare enzymatic causes

👵 Gout in Older Adults

• Often polyarticular, upper limb joints (wrists, MCPs, interphalangeal joints) more commonly involved
• Tophi may develop rapidly in older women on diuretics after menopause
• Nodal osteoarthritis tophi may be mistaken for Heberden/Bouchard nodes — aspiration differentiates
• NSAIDs generally avoided (renal, cardiovascular risk) — colchicine or corticosteroids preferred for acute flares
• Start allopurinol at lowest dose (50 mg/day) and titrate slowly in elderly (renal function decline)

🤰 Gout in Pregnancy

• Gout is uncommon in pre-menopausal women but can occur in pregnancy — particularly with pre-eclampsia (elevated urate)
• Allopurinol: category C in Australia — avoid in first trimester; discuss risk-benefit
• NSAIDs: contraindicated after 20 weeks (premature closure of ductus arteriosus)
• Colchicine: category B3 — generally avoided, but may be used under specialist guidance
• Prednisolone: preferred treatment for acute flares in pregnancy
• Refer to rheumatology for gout management in pregnancy

💊 Gout with Cardiovascular Disease

• Hyperuricaemia is an independent cardiovascular risk factor — ULT may reduce CV events (emerging evidence)
• Avoid NSAIDs in heart failure, post-MI, anticoagulation — use colchicine or corticosteroids for acute flares
• Losartan preferred antihypertensive — uricosuric effect (reduces serum urate ~15%)
• Febuxostat: caution in established cardiovascular disease (CARES trial signal) — allopurinol preferred
• Colchicine has proven anti-inflammatory cardiovascular benefit (COLCOT, LoDoCo2 trials) — may be particularly beneficial in gout with established CVD

🧬 Gout with Renal Transplant

• Cyclosporin-associated gout is common and often severe
• Allopurinol + azathioprine combination is CONTRAINDICATED — risk of fatal myelosuppression
• Uric acid-lowering requires specialist coordination with transplant team
• Tacrolimus is less uricogenic than cyclosporin — switching may help

Stewardship in gout management addresses two major problems: undertreatment of hyperuricaemia (failure to initiate or maintain ULT) and inappropriate medication use (NSAIDs in high-risk patients, aspirin for analgesia).

GP Role in Stewardship

• Initiate ULT when indicated — do not wait for specialist referral for uncomplicated gout
• Titrate allopurinol to serum urate target — check urate 4–6 weeks after each dose change
• Co-prescribe prophylactic colchicine when starting ULT — explain to patient why flares may increase initially
• Conduct annual metabolic review — gout is a marker of metabolic syndrome; address obesity, hypertension, dyslipidaemia, glucose
• Review urate-elevating medications and substitute where clinically appropriate

Gout is a preventable chronic disease. With adequate urate lowering, flares stop, tophi dissolve, and joint damage is halted. Long-term follow-up focuses on maintaining urate target, monitoring for medication toxicity, and managing cardiovascular and renal comorbidities.

Prevention

• Primary prevention of gout: treat hyperuricaemia, address metabolic syndrome, avoid uricosuric-blocking medications
• Secondary prevention (recurrence): long-term ULT adherence is the cornerstone — most recurrences are due to ULT non-adherence or inadequate dosing
• Renal protection: maintaining urate <0.36 mmol/L may slow CKD progression
• Annual influenza vaccination recommended (associated with reduced gout flare risk)

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