Crystal Arthropathies (Gout & CPPD)

1. Overview

Crystal arthropathies represent a group of inflammatory joint diseases caused by the deposition of crystals within synovial fluid and periarticular tissues. The two principal conditions in this category are gout (caused by monosodium urate crystals) and calcium pyrophosphate deposition disease (CPPD), also known as pseudogout. These conditions are clinically significant due to their high prevalence, substantial impact on quality of life, and association with important comorbidities including cardiovascular disease and chronic kidney disease. [1,2]

Gout is the most common inflammatory arthritis worldwide, with a global prevalence ranging from less than 1% to 6.8% depending on the population studied. [1] It results from chronic hyperuricaemia (serum urate > 0.4 mmol/L or > 6.8 mg/dL) leading to the formation and deposition of needle-shaped monosodium urate (MSU) crystals in joints, particularly cooler peripheral joints such as the first metatarsophalangeal joint (MTPJ). The classic presentation of acute gout—known as podagra when affecting the great toe—is characterized by sudden onset of exquisite pain, erythema, and swelling, often occurring at night.

CPPD disease (pseudogout) is caused by calcium pyrophosphate dihydrate crystals depositing in articular cartilage and synovial tissue. The prevalence increases dramatically with age, with chondrocalcinosis (radiographic evidence of CPPD crystal deposition) present in approximately 50% of individuals over 85 years. [3] CPPD can present acutely (mimicking gout or septic arthritis) or as a chronic arthropathy resembling osteoarthritis but affecting atypical joints.

The key clinical imperative in managing suspected crystal arthropathy is to exclude septic arthritis, as both gout and septic arthritis can present with a hot, red, swollen joint accompanied by fever and elevated inflammatory markers. Joint aspiration with synovial fluid analysis—including Gram stain, culture, and polarized light microscopy—is mandatory in the acute setting.

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2. Epidemiology

Gout Epidemiology

Gout prevalence has been rising globally over the past 50 years, likely driven by increasing rates of obesity, metabolic syndrome, hypertension, and aging populations. [1,2] Developed countries tend to have higher gout burden than developing nations. The male predominance is explained by the uricosuric effect of estrogen in pre-menopausal women, which increases renal excretion of urate. After menopause, when estrogen levels decline, the gender gap narrows considerably. [4]

Risk Factors for Gout

Non-modifiable:

• Male sex
• Age (risk increases with age)
• Genetic predisposition (family history, polymorphisms in urate transporter genes such as SLC2A9, ABCG2)
• Ethnicity (Pacific Islander, Māori, African-American populations at higher risk)

Modifiable:

• Dietary factors: High purine intake (red meat, organ meats, shellfish), alcohol consumption (particularly beer and spirits), high fructose corn syrup [5]
• Obesity: Increases urate production and reduces renal excretion [1,5]
• Medications: Thiazide and loop diuretics (reduce urate excretion), low-dose aspirin (less than 3g/day has net urate-retaining effect) [6]
• Comorbidities: Chronic kidney disease (CKD), hypertension, metabolic syndrome, diabetes mellitus [1,2]

Dietary Purine Content:

• High purine foods (150-1000 mg/100g): Organ meats (liver, kidney), game meats, anchovies, sardines, herring, scallops
• Moderate purine foods (50-150 mg/100g): Red meat, poultry, fish, seafood
• Low purine foods (less than 50 mg/100g): Dairy products, eggs, most vegetables, grains

CPPD/Pseudogout Epidemiology

Unlike gout, CPPD disease shows a strong age-related increase, with minimal prevalence below age 60 but exponential rise thereafter. [7] Most individuals with chondrocalcinosis remain asymptomatic; only a minority develop acute pseudogout attacks or chronic CPPD arthropathy.

Risk Factors for CPPD

Age-related (most common):

• Advanced age is the strongest risk factor
• Osteoarthritis (cartilage degeneration facilitates crystal deposition)

Metabolic Disorders (important in younger patients less than 50 years)—"The 5 Hs":

1. Hyperparathyroidism (elevated calcium promotes crystal formation) [8]
2. Haemochromatosis (iron deposition in cartilage) [8]
3. Hypomagnesaemia (magnesium inhibits crystal formation) [8]
4. Hypophosphatasia (low alkaline phosphatase, defective pyrophosphate metabolism) [8]
5. Hypothyroidism (associated with calcium metabolism abnormalities) [8]

Other associations:

• Familial CPPD (rare autosomal dominant forms)
• Gitelman syndrome (genetic hypomagnesaemia)
• Wilson's disease

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3. Aetiology & Pathophysiology

Gout: Urate Metabolism and Crystal Formation

Purine Metabolism and Urate Production

Uric acid is the end product of purine metabolism in humans. Purines are derived from:

1. Dietary sources (exogenous): meat, seafood, alcohol
2. Endogenous production: Cell turnover, de novo synthesis

Hypoxanthine and guanine are metabolized to xanthine, which is then oxidized to uric acid by the enzyme xanthine oxidase (XO). Humans lack the enzyme uricase (which breaks down uric acid to the more soluble allantoin), resulting in higher serum urate levels compared to other mammals. [9]

Urate Homeostasis

Two-thirds of urate is excreted renally, while one-third is eliminated via the gastrointestinal tract. Renal urate handling involves:

• Glomerular filtration: All urate is freely filtered
• Proximal tubule reabsorption: URAT1 (SLC22A12) and other transporters reabsorb ~90% of filtered urate
• Proximal tubule secretion: ABCG2, OAT1, OAT3 transporters secrete urate into tubular lumen
• Post-secretory reabsorption: URAT1, GLUT9 (SLC2A9) reabsorb additional urate

Net result: Only 5-10% of filtered urate is ultimately excreted. Genetic polymorphisms in these transporters influence individual predisposition to hyperuricaemia and gout. [9]

Hyperuricaemia: Causes

Overproduction (10% of cases):

• Increased cell turnover: myeloproliferative/lymphoproliferative disorders, hemolysis, psoriasis, tumour lysis syndrome
• Enzyme defects: HGPRT deficiency (Lesch-Nyhan syndrome), PRPP synthetase overactivity
• High purine diet, alcohol consumption (especially beer)

Underexcretion (90% of cases):

• Chronic kidney disease (most common cause overall)
• Diuretics (thiazides, loop diuretics inhibit urate secretion)
• Lead nephropathy ("saturnine gout")
• Volume depletion, lactic acidosis, ketoacidosis (compete for tubular secretion)
• Genetic: SLC2A9 variants, ABCG2 variants

Crystal Deposition and Inflammation

When serum urate exceeds the saturation point (~0.4 mmol/L or 6.8 mg/dL), MSU crystals can precipitate in:

• Synovial fluid (particularly in cooler peripheral joints where solubility is lower)
• Periarticular soft tissues (tophi)
• Kidneys (urate nephrolithiasis, chronic urate nephropathy)

Crystal deposition triggers acute inflammation through:

1. Phagocytosis by neutrophils and macrophages
2. NLRP3 inflammasome activation in macrophages [10]
3. IL-1β release (primary inflammatory mediator in gout) [10]
4. Neutrophil chemotaxis via IL-8 and other cytokines
5. Neutrophil activation → release of proteases, reactive oxygen species
6. Self-amplifying inflammatory cascade

This explains the exquisite pain and rapid onset of acute gout. Inflammation typically resolves spontaneously over 7-14 days, even without treatment, due to:

• Crystal coating by apolipoprotein E and B (reducing inflammatory potential)
• Release of anti-inflammatory mediators (TGF-β, IL-10)
• Neutrophil apoptosis and clearance

Exam Detail: Why the First MTPJ?

Podagra (gout affecting the 1st MTPJ) is the classic presentation, occurring in 70% of initial gout attacks. [11] Reasons include:

• Lower temperature in peripheral joints reduces MSU solubility
• Mechanical stress and microtrauma from weight-bearing promotes crystal deposition
• Relative avascular nature of articular cartilage
• High synovial fluid protein concentration in the foot

Acute Gout Triggers:

Even in patients with chronic hyperuricaemia, acute attacks are triggered by:

• Sudden fluctuation in urate levels (rapid rise or fall)
• Starting or stopping urate-lowering therapy (ULT)
• Dietary excess (purine binge, alcohol)
• Dehydration, fasting, surgery
• Acute illness, trauma, infection
• Medications (diuretics)

This is why starting allopurinol during an acute attack is contraindicated—it causes rapid urate reduction which paradoxically precipitates or prolongs the flare. However, if a patient is already on ULT, it should NOT be stopped during a flare. [12]

CPPD: Calcium Pyrophosphate Crystal Formation

Pathophysiology of CPPD

Calcium pyrophosphate dihydrate (CPPD) crystals form when inorganic pyrophosphate (PPi), generated by chondrocytes and synoviocytes, combines with calcium in the extracellular matrix. [13]

Normal PPi Metabolism:

• PPi is produced by nucleotide pyrophosphatase phosphodiesterase (ENPP1) on chondrocyte cell membranes
• Extracellular PPi is transported into the matrix via ANK protein (progressive ankylosis protein)
• Tissue-nonspecific alkaline phosphatase (TNAP) normally hydrolyzes PPi to inorganic phosphate, preventing crystal formation
• Balance between PPi production, transport, and degradation determines whether crystals form

Mechanisms Leading to CPPD Crystal Formation:

1. Increased PPi production: Familial forms due to ANKH gene mutations (increased ANK activity) [13]
2. Decreased PPi degradation: Hypophosphatasia (low TNAP activity) allows PPi accumulation [8]
3. Altered calcium/magnesium balance: Hyperparathyroidism (↑ Ca), hypomagnesaemia (Mg normally inhibits crystallization) [8]
4. Cartilage matrix changes: Aging, osteoarthritis create permissive environment for crystal nucleation [13]
5. Iron deposition: Haemochromatosis—iron directly promotes calcium crystal formation in cartilage [8]

CPPD Crystal Deposition and Clinical Phenotypes

CPPD crystals preferentially deposit in:

• Fibrocartilage: Knee menisci, triangular fibrocartilage of wrist, symphysis pubis
• Hyaline cartilage: Mid-zone cartilage layer (seen as linear calcification on X-ray—chondrocalcinosis)

Clinical manifestations vary:

Acute pseudogout attacks are triggered by:

• Crystal shedding into synovial fluid from cartilage
• Acute illness, surgery, trauma (similar to gout triggers)
• IL-1β–mediated inflammation (similar pathway to gout) [14]

Exam Detail: CPPD vs Gout: Pathophysiological Differences

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4. Clinical Presentation

Gout: Clinical Phases

Gout typically progresses through several distinct phases:

1. Asymptomatic Hyperuricaemia

• Elevated serum urate (> 0.4 mmol/L or > 6.8 mg/dL) without clinical manifestations
• May persist for years or decades before first gout attack
• Not all hyperuricaemic individuals develop gout (~20% lifetime risk)
• Not an indication for urate-lowering therapy unless other high-risk features present

2. Acute Gouty Arthritis (Acute Gout Flare)

Classic Presentation:

• Sudden onset (often overnight, peaks within 12-24 hours)
• Severe pain ("worst pain ever experienced," cannot tolerate bedsheet touching joint—"bedsheet sign")
• Monoarticular in 90% of first attacks [11]
• First MTPJ (podagra) in 50-70% of first attacks [11]
• Erythema and swelling (joint appears red, shiny, warm)
• Exquisite tenderness (pain disproportionate to examination findings)
• Systemic features: Low-grade fever (in 20%), malaise, elevated inflammatory markers

Joint Distribution:

Atypical Presentations:

• Elderly patients: Less dramatic inflammation, polyarticular, upper extremity involvement
• Women: More likely to affect finger joints (Heberden's/Bouchard's nodes with gout)
• Diuretic-induced gout: Older patients, often affects upper limbs
• Polyarticular gout: Can mimic septic polyarthritis or rheumatoid arthritis

Natural History of Untreated Acute Attack:

• Peaks at 24-48 hours
• Gradual resolution over 7-14 days (even without treatment)
• Complete resolution between attacks (intercritical period)

3. Intercritical Gout (Interval Between Attacks)

• Completely asymptomatic period between acute attacks
• Duration varies: months to years (average 1-2 years to second attack)
• MSU crystals still detectable in synovial fluid during asymptomatic periods
• Recurrence risk: 60% within 1 year, 90% within 3 years without treatment [15]
• Interval shortens with subsequent attacks (more frequent flares over time)

4. Chronic Tophaceous Gout

Develops after years of untreated or inadequately treated gout (typically 10-20 years, but accelerated with renal disease).

Tophi Formation:

• Definition: Nodular masses of MSU crystals surrounded by inflammatory reaction
• Composition: Chalky white material ("toothpaste-like" consistency when expressed)
• Common sites:
  • Olecranon bursa (most common)
  • Fingers and hands (PIP, DIP joints)
  • Achilles tendon
  • Helix and antihelix of ear (pathognomonic but uncommon)
  • Prepatellar bursa
  • Feet (first MTPJ, dorsum of foot)

Complications of Tophi:

• Skin ulceration: Overlying skin becomes thin, may ulcerate with discharge of white chalky material
• Secondary infection: Ulcerated tophi are infection-prone
• Joint destruction: Chronic tophaceous deposits erode bone, causing irreversible joint damage
• Functional impairment: Large tophi restrict joint movement
• Nerve compression: Tophi can compress nerves (e.g., carpal tunnel syndrome)

Chronic Gouty Arthropathy:

• Persistent joint pain and stiffness (usage-related pain, not acute inflammation)
• Symmetric polyarticular involvement in advanced disease
• Secondary osteoarthritis changes
• Joint deformity and loss of function

CPPD: Clinical Presentations

1. Asymptomatic Chondrocalcinosis

• Most common phenotype (60-70% of patients with radiographic chondrocalcinosis)
• Incidental finding on X-rays done for other reasons
• No treatment required

2. Acute CPP Crystal Arthritis (Pseudogout)

Presentation:

• Acute monoarticular arthritis (mimics gout or septic arthritis)
• Knee most common (50-70% of acute attacks), followed by wrist (10-20%), ankle, shoulder, elbow [16]
• Sudden onset pain, swelling, warmth, erythema
• Less severe than gout (generally), but still significantly painful
• Low-grade fever, elevated inflammatory markers (CRP, ESR, leukocytosis)
• Elderly patient (typically > 65 years)

Triggers:

• Acute medical illness (myocardial infarction, stroke, pneumonia)
• Surgery (especially parathyroidectomy for hyperparathyroidism—"post-parathyroidectomy pseudogout")
• Trauma to joint

Clinical Course:

• Self-limiting (resolves spontaneously in days to weeks)
• Recurrent attacks can occur but are less predictable than gout

3. Chronic CPP Crystal Inflammatory Arthritis

• Symmetric polyarthritis resembling rheumatoid arthritis
• Wrists, MCPs, knees commonly affected
• Morning stiffness (but usually less than 30 minutes, unlike RA)
• Low-grade inflammation with synovitis on examination
• Negative rheumatoid factor, anti-CCP antibodies (helps distinguish from RA)

4. Osteoarthritis with CPPD ("Pseudo-Osteoarthritis")

• Chronic progressive arthritis with features of OA but affecting atypical joints for primary OA:
  • Radiocarpal joint (unusual for OA)
  • Patellofemoral joint (isolated patellofemoral OA)
  • Glenohumeral joint (shoulder OA is uncommon in primary OA)
  • Ankles

"CPPD Arthropathy" Red Flags Suggesting Underlying Metabolic Disease:

If CPPD presents in a patient less than 50 years old, investigate for:

1. Hyperparathyroidism: Serum calcium, PTH
2. Haemochromatosis: Ferritin, transferrin saturation, genetic testing (HFE mutations)
3. Hypomagnesaemia: Serum magnesium
4. Hypophosphatasia: Alkaline phosphatase (low), urinary phosphoethanolamine
5. Hypothyroidism: TSH, free T4

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5. Differential Diagnosis

The single most important differential for both acute gout and acute pseudogout is septic arthritis, as all three can present with an acutely hot, red, swollen joint.

Key Differentials

Exam Detail: Clinical Clues to Distinguish Gout, Pseudogout, and Septic Arthritis:

Critical Teaching Point:

"A hot, red, swollen joint is septic arthritis until proven otherwise. You cannot reliably distinguish gout from sepsis clinically—both can have fever, leukocytosis, and elevated CRP. Joint aspiration is MANDATORY. If you see crystals on microscopy, it's gout/pseudogout. If you see bacteria on Gram stain or culture, it's septic arthritis. Importantly, gout and septic arthritis can coexist (the inflamed gouty joint is more susceptible to infection), so don't be falsely reassured by the presence of crystals—always send for culture." [17]

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6. Investigations

Synovial Fluid Analysis: The Gold Standard

Indications for Joint Aspiration:

• Every first presentation of acute monoarthritis (to exclude sepsis)
• Any acute monoarthritis with fever or systemic features
• Diagnostic uncertainty (even in known gout—can coexist with sepsis)
• Poor response to initial treatment

Technique:

• Aseptic technique (skin prep with chlorhexidine or iodine)
• Use largest gauge needle feasible (18-21G for knee)
• Aspirate as much fluid as possible
• Send for:
  1. Polarized light microscopy (crystals—fresh sample preferred)
  2. Gram stain and culture (septic arthritis—MUST be done even if crystals seen)
  3. Cell count and differential (inflammatory vs non-inflammatory)
  4. Glucose (if infection suspected—low in septic arthritis)

Crystal Identification: Polarized Light Microscopy

Principle:

Crystals exhibit birefringence (splitting of light into two rays). A red compensator is used to determine the type of birefringence.

Mnemonic:

• Gout = Negative = Yellow when Parallel
• CPPD = Positive = Blue when Parallel

Technical Pearls:

• MSU crystals are often intracellular (phagocytosed by neutrophils) during acute attacks
• CPPD crystals are more often extracellular (though can be intracellular)
• Crystal detection sensitivity: ~70-95% (operator-dependent)
• Crystals can persist in joints even during asymptomatic periods (finding crystals confirms diagnosis but doesn't prove acute attack is crystal-mediated)

Synovial Fluid Cell Count Interpretation

Important: Significant overlap exists. Synovial WCC > 50,000 suggests septic arthritis, but gout can occasionally reach this level. [17]

Serum Urate (Gout)

Interpretation Pitfalls:

• Serum urate may be NORMAL or even LOW during an acute gout attack (in up to 40% of cases) [18]
• Acute inflammation causes "urinary dumping" of urate → transient reduction in serum levels
• Do NOT rely on normal serum urate to exclude gout during an acute flare
• Measure urate 2-4 weeks after acute attack resolves for accurate baseline

Diagnostic Value:

• Hyperuricaemia (> 0.4 mmol/L or > 6.8 mg/dL) is necessary for MSU crystal formation
• However, hyperuricaemia alone does NOT diagnose gout (many hyperuricaemic individuals never develop gout)
• Serum urate is useful for:
  • Confirming hyperuricaemia (supports diagnosis in appropriate clinical context)
  • Monitoring urate-lowering therapy (target less than 0.36 mmol/L or less than 6 mg/dL, ideally less than 0.3 mmol/L or less than 5 mg/dL in severe gout) [12]

Inflammatory Markers (Non-specific)

These are non-specific and cannot distinguish gout/pseudogout from septic arthritis.

Renal Function and Metabolic Screen

For Gout:

• Urea, creatinine, eGFR: Assess for chronic kidney disease (common comorbidity)
• Urinalysis: Check for urate crystals (suggests urate nephropathy), proteinuria, hematuria
• 24-hour urinary urate excretion (optional, rarely done in routine practice):
  • less than 600 mg/24 hr (underexcretion) vs > 800 mg/24 hr (overproduction)
  • Helps guide choice of urate-lowering therapy (theoretical, but in practice allopurinol is first-line regardless)

For CPPD (especially if age less than 50 years):

Screen for metabolic causes—"The 5 Hs":

Radiographic Imaging

X-Ray Findings in Gout

Early Gout (first 5-10 years):

• Soft tissue swelling around affected joint
• Normal bone and joint space (no erosions initially)
• Possibly visible soft tissue tophi (radiopaque if calcified, but most are radiolucent)

Chronic Tophaceous Gout:

• "Punched-out" erosions with overhanging edges (Martel's sign)—pathognomonic for gout [19]
• Erosions are typically:
  • Juxta-articular (near but not in joint)
  • Well-defined, sclerotic margins
  • Asymmetric distribution
  • Spare the joint space until late disease (unlike RA which causes early joint space loss)
• Tophi: Soft tissue masses (radiopaque if calcified)
• Preserved joint space until late (cartilage destruction occurs late)

Radiographic Features: Gout vs Rheumatoid Arthritis

X-Ray Findings in CPPD

Chondrocalcinosis:

• Linear/punctate calcification within cartilage:
  • "Knee: Menisci (most common—lateral > medial), hyaline cartilage"
  • "Wrist: Triangular fibrocartilage complex (TFCC)"
  • "Symphysis pubis: Linear calcification"
  • "Hip: Acetabular labrum, hyaline cartilage"
  • "Shoulder: Glenoid labrum"

Degenerative Changes:

• Unusual distribution for OA:
  • Isolated patellofemoral compartment OA (knee)
  • Radiocarpal joint OA (wrist)
  • Scapholunate advanced collapse (SLAC) wrist
• Joint space narrowing, osteophytes, subchondral sclerosis (similar to OA)
• Subchondral cysts (can be prominent)

"Spider Fingers" Sign (Rare):

• Severe CPPD with tendon calcification in hands

Advanced Imaging (Selected Cases)

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7. Classification and Diagnostic Criteria

ACR/EULAR 2015 Gout Classification Criteria

Although synovial fluid MSU crystals remain the gold standard for diagnosis, the ACR/EULAR criteria are used for research and provide a framework for clinical diagnosis:

Sufficient Criterion:

• Presence of MSU crystals in symptomatic joint or bursa (synovial fluid or tophus) = Definitive gout

If crystals not available, score based on:

1. Clinical features: Pattern of joint involvement, characteristics of episodes
2. Laboratory: Serum urate level
3. Imaging: Double contour sign (ultrasound/DECT), erosions with overhanging edge

Score ≥8 = Classified as Gout (sensitivity 92%, specificity 89%)

EULAR 2011 CPPD Diagnostic Criteria

Definite CPPD:

• CPP crystals in synovial fluid (compensated polarized light microscopy showing rhomboid-shaped, weakly positive birefringent crystals)

Probable CPPD:

• Typical calcification on X-ray (chondrocalcinosis) in ≥1 joint
• Plus typical clinical presentation (acute pseudogout, chronic CPP crystal inflammatory arthritis, or OA with CPPD)

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8. Management

Acute Gout Management

Principles of Acute Attack Management

1. Start treatment as early as possible (within 24 hours of symptom onset for best efficacy)
2. Exclude septic arthritis (joint aspiration if any doubt)
3. Choose agent based on patient factors (comorbidities, contraindications, prior response)
4. Do NOT start urate-lowering therapy during acute attack (unless already on it, in which case continue)
5. Address triggers (dehydration, recent dietary indiscretion)

First-Line Acute Treatment Options

1. NSAIDs (First-Line in Most Patients)

Regimen:

• Naproxen 500 mg BD (or 750 mg initially, then 500 mg BD)
• Indomethacin 50 mg TDS (traditional choice, but no proven superiority over other NSAIDs)
• Etoricoxib 120 mg OD (COX-2 selective)
• Diclofenac 50 mg TDS

Duration: Until attack resolves (typically 5-7 days)

Co-prescribe: PPI for gastroprotection (omeprazole 20 mg OD, lansoprazole 30 mg OD)

Contraindications:

• Active peptic ulcer disease (absolute)
• CKD stage 4-5 (eGFR less than 30 ml/min)—relative contraindication, use lowest dose for shortest duration
• Heart failure (NSAIDs cause fluid retention)
• History of MI/stroke (increased cardiovascular risk)
• Concurrent anticoagulation (increased bleeding risk)

Advantages: Effective, rapid onset (12-24 hours), familiar to clinicians

Disadvantages: GI side effects, renal impairment (common in gout patients), cardiovascular risk

2. Colchicine

Mechanism: Inhibits microtubule polymerization → reduces neutrophil migration and activation

Regimen:

• Low-dose regimen (preferred): 500 mcg BD-TDS until attack resolves [20]
• Traditional high-dose regimen (obsolete): 1 mg initially, then 500 mcg every 2-3 hours until relief or diarrhea (NOT recommended due to toxicity)

Duration: Until attack resolves (typically 5-7 days, can extend to 10-14 days)

Efficacy: Most effective if started within 12-24 hours of symptom onset; less effective if delayed > 48 hours

Contraindications:

• Severe renal impairment (eGFR less than 10 ml/min)—absolute contraindication
• Severe hepatic impairment
• Concurrent use of strong CYP3A4 inhibitors (clarithromycin, erythromycin, ketoconazole, ritonavir) or P-glycoprotein inhibitors (ciclosporin, verapamil)—risk of colchicine toxicity

Side Effects:

• Diarrhea (dose-limiting, occurs in 30-50% with traditional high-dose regimen, less common with low-dose)
• Nausea, vomiting, abdominal pain
• Severe toxicity (rare): bone marrow suppression, rhabdomyolysis, multi-organ failure (with overdose or drug interactions)

Advantages: No renal impairment (unless severe), no cardiovascular risk, useful when NSAIDs contraindicated

Disadvantages: Narrow therapeutic window, frequent GI side effects, drug interactions

Dose Adjustment in Renal Impairment:

3. Corticosteroids

Indications:

• NSAIDs and colchicine both contraindicated (e.g., severe CKD, peptic ulcer, drug interactions)
• Polyarticular gout (oral steroids more practical than multiple intra-articular injections)
• Failure of NSAIDs/colchicine

Regimens:

Oral Prednisolone:

• 30-35 mg OD for 5 days (no taper needed for short course) [21]
• Alternative: 30 mg OD for 3-5 days, then taper over 7-10 days (0.5 mg/kg initially, taper by 5 mg every 1-2 days)

Intra-articular Corticosteroid:

• Triamcinolone acetonide 40 mg (large joint—knee, ankle, shoulder)
• Triamcinolone acetonide 20 mg (medium joint—wrist, elbow)
• Triamcinolone acetonide 10 mg (small joint—1st MTPJ, fingers)

Intramuscular Corticosteroid (if oral/intra-articular not feasible):

• Methylprednisolone acetate 120 mg IM (single dose, duration ~2 weeks)

Contraindications:

• Active infection (must exclude septic arthritis before giving intra-articular steroid)
• Poorly controlled diabetes (exacerbates hyperglycemia)
• Prosthetic joint (relative contraindication for intra-articular injection—infection risk)

Advantages: Very effective (equivalent to NSAIDs [21]), suitable in renal impairment, intra-articular route provides rapid local relief

Disadvantages: Hyperglycemia (problematic in diabetics), fluid retention, multiple systemic side effects with prolonged use

Adjunctive Measures

• Rest and elevation of affected joint
• Ice packs (may provide symptomatic relief, though evidence limited)
• Adequate hydration (reduces urate concentration)
• Analgesia: Paracetamol (inadequate as monotherapy), opioids (if pain severe and other agents contraindicated, but avoid if possible)

Refractory Acute Gout

If standard treatments fail or are contraindicated:

IL-1 Inhibitors (off-label, specialist use):

• Canakinumab (anti-IL-1β monoclonal antibody): 150 mg SC (single dose) [22]
• Anakinra (IL-1 receptor antagonist): 100 mg SC daily for 3 days
• Reserved for patients with refractory gout and multiple contraindications to conventional therapy

Urate-Lowering Therapy (ULT): Long-Term Management

Indications for ULT

Absolute Indications (EULAR 2016, ACR 2020): [12,23]

• Recurrent gout attacks (≥2 attacks per year)
• Tophaceous gout (any tophi, even if asymptomatic)
• Chronic gouty arthropathy (joint damage)
• Urate nephrolithiasis (kidney stones)
• CKD stage ≥3 (eGFR less than 60 ml/min) with gout

Relative Indications (Consider ULT):

• First gout attack if:
  • Age less than 40 years
  • Very high serum urate (> 0.54 mmol/L or > 9 mg/dL)
  • Comorbidities (CKD, hypertension, ischemic heart disease)
  • Diuretic therapy
• Asymptomatic hyperuricaemia: NOT routinely treated (ULT not indicated unless very high urate > 0.6 mmol/L or > 10 mg/dL with high cardiovascular/renal risk—controversial) [23]

Principles of ULT

1. Treat-to-Target: Aim for serum urate less than 0.36 mmol/L (less than 6 mg/dL); in severe gout (tophi, chronic arthropathy), target less than 0.3 mmol/L (less than 5 mg/dL) [12]
2. Start Low, Go Slow: Begin with low dose, titrate gradually every 2-4 weeks to avoid precipitating flares
3. Do NOT start during acute attack (wait 2-3 weeks after attack resolves)—exception: if already on ULT, do NOT stop it during a flare
4. Co-prescribe flare prophylaxis for first 6 months (colchicine 500 mcg OD or low-dose NSAID)
5. Lifelong therapy in most cases (ULT is curative if maintained, but stopping leads to relapse)
6. Monitor serum urate regularly (every 4-6 weeks during titration, then every 6-12 months once at target)

First-Line ULT: Allopurinol

Mechanism: Xanthine oxidase inhibitor (inhibits conversion of hypoxanthine → xanthine → uric acid)

Dosing:

• Starting dose: 100 mg OD (or 50 mg OD if eGFR less than 30 ml/min)
• Titration: Increase by 50-100 mg every 2-4 weeks based on serum urate
• Target dose: Dose required to achieve target urate (less than 0.36 mmol/L)—often 300-600 mg OD, may require up to 800-900 mg OD
• Maximum dose: 900 mg OD (no evidence for benefit > 900 mg/day)

Renal Dose Adjustment (Traditional vs Modern Approach):

Traditional (conservative, may lead to under-dosing):

Modern (EULAR 2016 approach—dose to target urate regardless of eGFR): [12]

• Start at reduced dose in CKD (50-100 mg), but titrate upwards as tolerated to achieve target urate, even if eGFR less than 30 ml/min
• Evidence shows higher doses are safe and necessary in CKD to control urate

Flare Prophylaxis:

• Colchicine 500 mcg OD for 6 months (first-line)
• Low-dose NSAID + PPI if colchicine contraindicated (naproxen 250 mg BD)
• Low-dose prednisolone 5 mg OD if both contraindicated

Side Effects:

• Rash (2-5%): Usually mild maculopapular rash (can continue if mild)
• Allopurinol Hypersensitivity Syndrome (AHS) (0.1-0.4%): SEVERE, potentially fatal
  • "Features: Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), acute renal failure, hepatitis, eosinophilia"
  • "Risk factors: HLA-B*5801 (strong association in Han Chinese, Thai, Korean populations [24]), CKD, starting dose > 100 mg, concurrent diuretics"
  • "Onset: Typically within first 3 months (median 3-4 weeks)"
  • "Management: STOP allopurinol immediately, supportive care (often requires ICU), never rechallenge"

HLA-B*5801 Screening:

• Recommended in Han Chinese, Thai, Korean populations before starting allopurinol [24]
• Not routinely recommended in Caucasian populations (lower prevalence of HLA-B*5801, lower risk of AHS)

Monitoring:

• Baseline: FBC, U&E, LFTs, urate
• During titration: Serum urate every 4-6 weeks, adjust dose to achieve target
• Once at target: Serum urate every 6-12 months, FBC/U&E/LFTs annually

Advantages: Low cost, extensive experience, effective in majority of patients

Disadvantages: Risk of AHS (although rare), requires dose adjustment in CKD, slow titration required

Second-Line ULT: Febuxostat

Mechanism: Non-purine xanthine oxidase inhibitor (more selective for XO than allopurinol)

Indications:

• Allopurinol intolerance (rash, AHS)
• Allopurinol failure (cannot achieve target urate despite adequate dose)
• Severe renal impairment (no dose adjustment needed for eGFR > 30 ml/min)

Dosing:

• Starting dose: 80 mg OD
• Usual dose: 80-120 mg OD
• No renal dose adjustment required if eGFR > 30 ml/min

Efficacy: Superior to allopurinol 300 mg in achieving target urate [25], but similar efficacy to higher-dose allopurinol

Cardiovascular Safety Concerns:

• CARES trial (2018): Increased cardiovascular mortality with febuxostat vs allopurinol in patients with established cardiovascular disease [26]
• Regulatory warnings: FDA/EMA issued warnings limiting febuxostat use to patients with contraindication or intolerance to allopurinol
• Current recommendation: Avoid febuxostat in patients with cardiovascular disease (ischemic heart disease, heart failure, stroke); allopurinol preferred [26]

Side Effects:

• Rash (less common than allopurinol)
• Hepatotoxicity (monitor LFTs)
• Cardiovascular events (see above)

Monitoring: As per allopurinol

Advantages: No dose adjustment in mild-moderate CKD, less cross-reactivity in allopurinol hypersensitivity (but caution—some cross-reactivity possible)

Disadvantages: Cardiovascular safety concerns, significantly more expensive than allopurinol

Third-Line ULT (Specialist Use)

Uricosuric Agents (increase renal urate excretion):

Probenecid:

• Dose: 500 mg BD, increase to 1-2 g/day in divided doses
• Mechanism: Inhibits URAT1 (blocks renal tubular reabsorption of urate)
• Contraindications: CKD (eGFR less than 50 ml/min), history of urate nephrolithiasis (increases urinary urate concentration → stone risk)
• Efficacy: Moderate (less effective than allopurinol/febuxostat as monotherapy)
• Rarely used in modern practice (replaced by XO inhibitors)

Lesinurad (URAT1 inhibitor):

• Approved as add-on to XO inhibitor (not monotherapy)
• Dose: 200 mg OD (with allopurinol or febuxostat)
• Limited availability, high cost

Benzbromarone:

• Potent uricosuric
• Withdrawn in many countries due to hepatotoxicity risk
• Still used in some European countries

Pegloticase (Recombinant Uricase Enzyme):

• Indication: Refractory severe tophaceous gout unresponsive to oral ULT
• Mechanism: Converts uric acid to allantoin (which is water-soluble and readily excreted)
• Dose: 8 mg IV infusion every 2 weeks
• Very effective (rapid reduction in urate, tophus resolution)
• Disadvantages: Expensive, requires IV infusion, risk of infusion reactions (30-50%), anaphylaxis (5%), development of anti-drug antibodies (loss of efficacy)
• Available in USA, not widely available in UK/Europe

Lifestyle and Dietary Modifications

While ULT is the cornerstone, lifestyle changes provide additional benefit:

Dietary Advice:

• Reduce purine-rich foods: Red meat, organ meats (liver, kidney), shellfish (prawns, mussels), oily fish (sardines, anchovies)
• Limit alcohol: Especially beer (contains guanosine, a purine precursor) and spirits; wine has less effect but still increases risk
• Limit fructose: High-fructose corn syrup (soft drinks, processed foods) increases urate production
• Increase low-fat dairy: Protective effect (milk, yogurt reduce gout risk) [5]
• Increase water intake: Aim for 2-3 L/day (reduces urate concentration)
• Vitamin C supplementation: 500-1000 mg/day may modestly reduce urate [5]

Weight Loss:

• Obesity is a strong risk factor; weight loss reduces urate levels and gout risk [5]
• Avoid crash diets or fasting (rapid weight loss causes ketosis → urate retention → flare risk)

Review Medications:

• Discontinue or reduce diuretics if possible (thiazides, loop diuretics)
• Consider losartan instead of other antihypertensives (losartan has mild uricosuric effect) [6]
• Consider atorvastatin or fenofibrate (both have modest urate-lowering effect)

CPPD Management

Acute Pseudogout Management

Principles: Similar to acute gout

First-Line:

1. NSAIDs (as per gout regimen)
2. Colchicine (500 mcg BD-TDS)—less evidence than for gout, but often effective
3. Intra-articular corticosteroid (highly effective for monoarticular pseudogout—triamcinolone 40 mg for knee)
4. Oral corticosteroids (prednisolone 30 mg OD for 5 days)

Choice depends on:

• Comorbidities (CKD, heart failure, peptic ulcer)
• Number of joints involved (monoarticular → intra-articular steroid ideal; polyarticular → oral therapy)

Long-Term CPPD Management

No Disease-Modifying Therapy:

• Unlike gout, there is NO treatment to dissolve CPPD crystals or prevent chondrocalcinosis progression
• No equivalent of urate-lowering therapy

Strategies:

1. Treat underlying metabolic disorders (if present):

   • Parathyroidectomy for primary hyperparathyroidism
   • Phlebotomy for haemochromatosis
   • Magnesium supplementation for hypomagnesaemia
   • Thyroid hormone replacement for hypothyroidism

2. Prophylaxis for recurrent acute attacks:

   • Colchicine 500 mcg OD (evidence limited, but may reduce attack frequency)
   • Low-dose NSAIDs (if tolerated)

3. Symptomatic management of chronic CPP arthropathy:

   • Analgesics (paracetamol, NSAIDs)
   • Intra-articular steroid injections (for symptom control)
   • Hydroxychloroquine or methotrexate (for chronic CPP inflammatory arthritis resembling RA—limited evidence)
   • Joint replacement surgery (for end-stage OA with CPPD—knee, hip arthroplasty)

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9. Complications

Gout Complications

Disease-Related

Cardiovascular and Metabolic Comorbidities

Gout is strongly associated with:

• Cardiovascular disease: 2-fold increased risk of MI, stroke [28]
• Hypertension: Present in 70-80% of gout patients [28]
• Chronic kidney disease: Bidirectional relationship (gout causes CKD, CKD causes gout) [2]
• Metabolic syndrome: Obesity, insulin resistance, dyslipidemia [28]
• Type 2 diabetes: 20-30% of gout patients [28]
• Atrial fibrillation: 1.5-fold increased risk [1]
• Obstructive sleep apnea, erectile dysfunction, venous thromboembolism (emerging associations) [1]

Implications:

• Aggressive cardiovascular risk management in gout patients (statin, ACE-I/ARB, aspirin if indicated)
• Screen for comorbidities (BP, lipids, HbA1c, renal function)
• Holistic approach (not just treat acute attacks—address underlying metabolic risk)

Drug-Related Complications

CPPD Complications

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10. Prognosis

Gout Prognosis

With Appropriate ULT:

• Excellent prognosis: Serum urate less than 0.36 mmol/L maintained → complete suppression of flares, tophus resolution (tophi can completely dissolve over months-years), prevention of joint damage [12]
• Flare frequency: Dramatically reduced (> 90% reduction in patients achieving target urate) [12]
• Tophus resolution: 50% reduction in tophus volume within 12 months, continued shrinkage thereafter [12]
• Joint damage: Prevented if ULT started before chronic arthropathy develops; partial reversal possible even in established disease
• Quality of life: Normalized with sustained urate control

Without ULT (Natural History):

• Increasing flare frequency: Intercritical periods shorten (years → months → weeks)
• Polyarticular involvement: Upper limb, axial skeleton involvement in late disease
• Chronic tophaceous gout: Develops after 10-20 years in 25-30% [15]
• Joint destruction: Chronic gouty arthropathy, disability
• Reduced life expectancy: Due to cardiovascular disease, CKD (excess mortality 1.5-2 fold vs general population) [28]

Prognostic Factors (Poor Prognosis):

• Age less than 40 at onset (longer disease duration)
• Very high baseline urate (> 0.54 mmol/L or > 9 mg/dL)
• CKD (harder to achieve urate target, accelerated disease)
• Polyarticular presentation
• Tophaceous disease at presentation
• Non-adherence to ULT (common—less than 50% of patients adhere long-term) [1]

CPPD Prognosis

Variable:

• Asymptomatic chondrocalcinosis: Benign (no intervention needed)
• Acute pseudogout: Self-limiting attacks, variable recurrence (less predictable than gout)
• Chronic CPP arthropathy: Progressive joint damage (no disease-modifying treatment), variable disability

No curative treatment available—management is symptomatic.

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11. Prevention & Screening

Gout Prevention

Primary Prevention (Prevent First Gout Attack):

• Maintain healthy weight (BMI less than 25)
• Limit alcohol consumption (especially beer)
• Avoid high-purine foods (organ meats, shellfish)
• Limit fructose intake (soft drinks, processed foods)
• Increase low-fat dairy consumption
• Stay well-hydrated (2-3 L water/day)
• Review medications: Avoid unnecessary thiazide diuretics (use alternative antihypertensives if possible)

Screening for Asymptomatic Hyperuricaemia:

• Not routinely recommended in general population
• Consider screening in:
  • Family history of gout (genetic predisposition)
  • Pacific Islander, Māori, African-American ethnicity (high-risk populations)
  • CKD patients (hyperuricaemia very common)
  • Patients on chronic diuretics

Treatment of Asymptomatic Hyperuricaemia:

• Controversial: No consensus on treating asymptomatic hyperuricaemia
• Not routinely recommended by EULAR/ACR guidelines [12,23]
• Consider ULT if:
  • Very high urate (> 0.6 mmol/L or > 10 mg/dL) AND high cardiovascular/renal risk
  • Chemotherapy planned (tumour lysis syndrome risk)
  • Recurrent urate nephrolithiasis (even without gout attacks)

CPPD Prevention

No primary prevention strategies (age-related, no modifiable risk factors in most cases)

Secondary Prevention (in patients with metabolic disorders):

• Treat hyperparathyroidism, haemochromatosis, hypomagnesaemia (may prevent progression, though evidence limited)

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12. Key Guidelines

Gout Guidelines

CPPD Guidelines

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Common Exam Questions

Clinical Scenarios (PACES, OSCE)

1. "This 58-year-old man presents with sudden onset pain and swelling of his right big toe. Examine his hands and give a differential diagnosis."

Model Answer:

"I would examine the hands for evidence of tophi, which appear as firm nodular swellings over the DIP/PIP joints, extensor tendons, or Heberden's/Bouchard's nodes. I would look for joint deformity, erythema, or asymmetric swelling. I would also inspect the elbows and ears for tophi. My differential diagnosis includes:

1. Gout (podagra)—most likely given acute monoarticular 1st MTPJ involvement in a middle-aged man
2. Septic arthritis—must exclude (joint aspiration mandatory)
3. Pseudogout—less likely (prefers knee/wrist), but possible
4. Trauma/fracture
5. Reactive arthritis (if history of urethritis/diarrhea)

I would confirm with joint aspiration (polarized microscopy for crystals, Gram stain/culture to exclude sepsis), serum urate (once acute phase resolves), and X-ray of the foot (look for erosions with overhanging edges in chronic gout)."

2. "What is your approach to managing this acute gout attack?"

Model Answer:

"My immediate priorities are to:

1. Confirm the diagnosis and exclude septic arthritis via joint aspiration (synovial fluid for polarized microscopy and culture)
2. Start acute treatment within 24 hours (early treatment is more effective)

For acute treatment, I would choose based on patient factors:

• First-line: NSAIDs (naproxen 500 mg BD with PPI) if no contraindications (no peptic ulcer, CKD, or heart failure)
• Colchicine 500 mcg BD-TDS if NSAIDs contraindicated (effective, but risk of diarrhea)
• Prednisolone 30 mg OD for 5 days or intra-articular triamcinolone if both NSAIDs and colchicine contraindicated

I would NOT start allopurinol during the acute attack (causes urate fluctuation, prolongs flare). If already on allopurinol, I would continue it.

Once the acute attack resolves (2-3 weeks), I would consider urate-lowering therapy (allopurinol) if this is a recurrent attack (≥2/year), if there are tophi, chronic arthropathy, CKD, or urate stones. I would start allopurinol 100 mg OD and titrate to target urate less than 0.36 mmol/L, with colchicine 500 mcg OD prophylaxis for 6 months."

3. "How do you distinguish gout from pseudogout on joint aspiration?"

Model Answer:

"The gold standard is polarized light microscopy of synovial fluid:

• Gout (MSU crystals): Needle-shaped, strongly negative birefringence (yellow when parallel to red compensator axis, blue when perpendicular)
• Pseudogout (CPPD crystals): Rhomboid/brick-shaped, weakly positive birefringence (blue when parallel, yellow when perpendicular)

I would also send synovial fluid for cell count (inflammatory pattern with WCC 2,000-100,000 in both), Gram stain and culture (exclude septic arthritis—critical as infection can coexist with crystals), and glucose if infection suspected.

Clinically, gout typically affects the 1st MTPJ in younger men (40-60) with hyperuricaemia and dietary/alcohol triggers, whereas pseudogout typically affects the knee/wrist in elderly patients (> 65) with X-ray chondrocalcinosis."

Viva Points

Viva Point: Opening Statement:

"Crystal arthropathies are inflammatory joint diseases caused by intra-articular crystal deposition. Gout results from monosodium urate crystals secondary to hyperuricaemia, most commonly presenting as acute podagra (1st MTPJ inflammation) in middle-aged men. Pseudogout (CPPD) is caused by calcium pyrophosphate dihydrate crystals, typically affecting the knee or wrist in elderly patients with chondrocalcinosis on X-ray. Both present with acute monoarthritis mimicking septic arthritis, making joint aspiration mandatory."

Key Facts to Mention:

• Gout epidemiology: Prevalence 1-6.8%, most common inflammatory arthritis, male:female 3-4:1 [1]
• Gout pathophysiology: Hyperuricaemia (> 0.4 mmol/L) → MSU crystal formation → NLRP3 inflammasome activation → IL-1β release → neutrophilic inflammation [10]
• Diagnostic gold standard: Synovial fluid polarized microscopy (MSU: needle-shaped, negative birefringence; CPPD: rhomboid, positive birefringence)
• Acute management: NSAIDs/colchicine/steroids; DO NOT start allopurinol during acute attack
• Chronic management (gout): Allopurinol (XO inhibitor), start low (100 mg), titrate to target urate less than 0.36 mmol/L (less than 0.3 mmol/L in severe gout), with colchicine prophylaxis for 6 months [12]
• Key complications: Tophi, chronic arthropathy, urate nephrolithiasis, cardiovascular disease (2-fold increased risk [28])
• Prognosis: Excellent with sustained ULT (complete flare suppression, tophus resolution); poor without treatment (chronic tophaceous gout, joint destruction)

Common Mistakes

❌ Mistakes that fail candidates:

1. Failing to exclude septic arthritis in acute monoarthritis (not aspirating joint)
2. Relying on normal serum urate to exclude gout during acute attack (can be normal/low in 40% [18])
3. Starting allopurinol during acute attack (precipitates/prolongs flare)
4. Stopping allopurinol during acute attack (if patient already on it—causes urate fluctuation, worsens flare)
5. Not prescribing flare prophylaxis when starting ULT (colchicine for 6 months essential)
6. Under-dosing allopurinol (many patients require 600-900 mg to reach target, not just 300 mg)
7. Not treating to target (random allopurinol dosing without monitoring urate—must titrate to achieve target less than 0.36 mmol/L)
8. Confusing crystal birefringence (MSU = negative/yellow when parallel; CPPD = positive/blue when parallel)
9. Missing metabolic screen in young CPPD patient (less than 50 years—check for 5 Hs: hyperparathyroidism, haemochromatosis, hypomagnesaemia, hypophosphatasia, hypothyroidism)
10. Prescribing febuxostat to patient with cardiovascular disease (increased CV mortality vs allopurinol [26])

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References

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2. Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol. 2015;11(11):649-662. doi:10.1038/nrrheum.2015.91

3. Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi:10.1056/NEJMra1511117

4. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10):3136-3141. doi:10.1002/art.30520

5. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004;350(11):1093-1103. doi:10.1056/NEJMoa035700

6. Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ. 2012;344:d8190. doi:10.1136/bmj.d8190

7. Zhang W, Doherty M, Bardin T, et al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011;70(4):563-570. doi:10.1136/ard.2010.139105

8. Abhishek A, Doherty M. Pathophysiology of articular chondrocalcinosis—role of ANKH. Nat Rev Rheumatol. 2011;7(2):96-104. doi:10.1038/nrrheum.2010.182

9. So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;120(6):1791-1799. doi:10.1172/JCI42344

10. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-241. doi:10.1038/nature04516

11. Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol. 2007;3(8):443-449. doi:10.1038/ncprheum0556

12. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42. doi:10.1136/annrheumdis-2016-209707

13. Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi:10.1056/NEJMra1511117

14. Martinon F. Mechanisms of uric acid crystal-mediated autoinflammation. Immunol Rev. 2010;233(1):218-232. doi:10.1111/j.0105-2896.2009.00860.x

15. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388(10055):2039-2052. doi:10.1016/S0140-6736(16)00346-9

16. Finckh A, Mc Carthy GM, Madigan A, et al. Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial. Arthritis Res Ther. 2014;16(5):458. doi:10.1186/s13075-014-0458-4

17. Swan A, Amer H, Dieppe P. The value of synovial fluid assays in the diagnosis of joint disease: a literature survey. Ann Rheum Dis. 2002;61(6):493-498. doi:10.1136/ard.61.6.493

18. Logan JA, Morrison E, McGill PE. Serum uric acid in acute gout. Ann Rheum Dis. 1997;56(11):696-697. doi:10.1136/ard.56.11.696

19. Dalbeth N, Clark B, Gregory K, et al. Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography. Ann Rheum Dis. 2009;68(8):1290-1295. doi:10.1136/ard.2008.094201

20. Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med. 1987;17(3):301-304. doi:10.1111/j.1445-5994.1987.tb01232.x

21. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008;371(9627):1854-1860. doi:10.1016/S0140-6736(08)60799-0

22. Schlesinger N, Alten RE, Bardin T, et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis. 2012;71(11):1839-1848. doi:10.1136/annrheumdis-2011-200908

23. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180

24. Halevy S, Ghislain PD, Mockenhaupt M, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008;58(25-32). doi:10.1016/j.jaad.2007.08.036

25. Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-2461. doi:10.1056/NEJMoa050373

26. White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018;378(13):1200-1210. doi:10.1056/NEJMoa1710895

27. Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994. Am J Kidney Dis. 2002;40(1):37-42. doi:10.1053/ajkd.2002.33911

28. Kuo CF, See LC, Luo SF, et al. Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology (Oxford). 2010;49(1):141-146. doi:10.1093/rheumatology/kep364

29. Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis. 2011;70(4):571-575. doi:10.1136/ard.2010.139360

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