Gout is a crystalline arthropathy caused by the deposition of monosodium urate crystals in joints and soft tissues due to hyperuricemia, resulting in acute inflammatory episodes of severe joint pain and swelling.

Gout

Epidemiology

Risk Factors

Factor	Explanation
Male sex	Oestrogen promotes renal urate excretion; testosterone does not → men have higher baseline urate from puberty
Age	Cumulative urate burden increases with time; renal function declines with age → reduced urate excretion
Genetics	Polymorphisms in urate transporters (SLC2A9, ABCG2, SLC22A12/URAT1) account for the majority of genetic variance in serum urate. Family history of gout is a strong risk factor
Ethnicity	Polynesian/Pacific Islander, Han Chinese, certain African populations

Factor	Mechanism
Purine-rich diet	Seafood, red meat, organ meats (viscera, brain, sardines, shellfish) → substrate for urate production ^[2]^[3]
Alcohol	Beer (high guanosine/purine content) > spirits > wine. Alcohol ↑ urate production (ATP → AMP → urate) AND ↓ renal excretion (lactic acid competes with urate for tubular secretion) ^[3]
Fructose/sugar-sweetened beverages	Fructose metabolism rapidly depletes ATP → ↑ AMP degradation → ↑ urate production
Obesity/metabolic syndrome	Insulin resistance ↓ renal urate excretion; visceral adiposity ↑ purine turnover
Hypertension	One of the most common comorbidities of gout ^[5]. Renal microvascular disease → ↓ urate excretion; diuretic use worsens hyperuricaemia
Chronic kidney disease (CKD)	↓ GFR → ↓ filtered urate load → ↓ excretion ^[2]
Dehydration	Concentrated urine, reduced renal urate clearance
Drugs (see below)	Multiple medications alter urate handling

Drug Class	Mechanism
Thiazide / Loop diuretics	↓ renal urate excretion via volume contraction (↑ proximal tubular reabsorption) and direct competition at tubular transporters ^[2]^[3]
Pyrazinamide	Pyrazinoic acid (active metabolite) inhibits URAT1-mediated urate secretion. All patients taking pyrazinamide will have hyperuricaemia, but not all develop gout → no point measuring blood urate routinely during TB treatment ^[6]
Ethambutol	↓ renal urate excretion
Cyclosporine / Tacrolimus (calcineurin inhibitors)	↓ GFR + direct tubular effects → ↓ urate excretion ^[2]
Low-dose aspirin (≤1–2 g/day)	Inhibits tubular urate secretion (high-dose aspirin is paradoxically uricosuric) ^[2]^[3]
Levodopa	↓ renal urate excretion
ACEI (some sources)	Mild ↓ urate excretion ^[2]

Protective Factors

Dairy products (especially low-fat): contain orotic acid and casein which are uricosuric
Coffee: xanthine content inhibits xanthine oxidase; also has antioxidant effects
Vitamin C: mildly uricosuric at high doses
Losartan and calcium channel blockers: have mild uricosuric properties (useful antihypertensives in gout patients)

Anatomy and Function: Uric Acid Metabolism

To understand gout, you need to understand purine metabolism and renal urate handling from first principles.

Purines (adenine, guanine) come from three sources:

Dietary intake (~one-third): purine-rich foods
De novo purine synthesis in the liver
Cellular turnover/catabolism: breakdown of nucleic acids from dying cells

The degradation pathway:

Purines (adenine, guanine)
    ↓ (hypoxanthine → xanthine → uric acid)
    ↓ Catalysed by XANTHINE OXIDASE
    → Uric acid (end product in humans)

Why is uric acid a problem in humans but not most other mammals? Most mammals possess the enzyme uricase (urate oxidase) which further converts uric acid to the highly soluble allantoin. Humans (and great apes) lost the functional uricase gene during evolution (~15 million years ago), probably because uric acid is a potent antioxidant that conferred a survival advantage. The trade-off is susceptibility to hyperuricaemia and gout.

Enzyme	Function	Clinical Relevance
Xanthine oxidase (XO)	Converts hypoxanthine → xanthine → uric acid	Target of allopurinol (competitive inhibitor, purine analogue) and febuxostat (non-purine, selective inhibitor)
HGPRT (hypoxanthine-guanine phosphoribosyltransferase)	Salvage pathway: recycles hypoxanthine and guanine back into purines, reducing de novo synthesis and urate production	HGPRT deficiency → Lesch-Nyhan syndrome: X-linked recessive, severe hyperuricaemia + gout in childhood + self-mutilation + intellectual disability ^[2]
PRPP synthetase	Catalyses the first step of de novo purine synthesis	PRPP synthetase overactivity → excessive de novo purine synthesis → hyperuricaemia ^[2]

Etiology and Pathophysiology

Causes of Hyperuricaemia — A Systematic Framework

The fundamental equation is simple:

Serum urate = Urate production − Urate excretion

Hyperuricaemia therefore arises from increased production, decreased excretion, or both.

Category	Examples
Primary (genetic)	Idiopathic ↑ renal tubular reabsorption (majority — genetic variants in SLC2A9, ABCG2, URAT1) ^[3]
Renal impairment	CKD, dehydration, lead nephropathy ("saturnine gout")
Metabolic	Metabolic acidosis (lactic acid, ketoacids compete with urate for tubular secretion), hypothyroidism
Drugs	Thiazides, loop diuretics, pyrazinamide, ethambutol, cyclosporine/tacrolimus, low-dose aspirin, levodopa ^[2]^[6]
Alcohol	Lactic acid from ethanol metabolism competes with urate for renal tubular secretion ^[3]

Category	Examples
Primary (genetic)	HGPRT deficiency (Lesch-Nyhan) ^[2], PRPP synthetase overactivity ^[2], G6P / F1PA deficiency ^[3]
Secondary — increased cell turnover	Myeloproliferative neoplasms (polycythaemia vera, primary myelofibrosis), lymphoproliferative disease, tumour lysis syndrome, haemolytic diseases, psoriasis ^[2]^[3]
Dietary	High purine intake (viscera, seafood, sardines) ^[3]
Alcohol	Beer especially (high in guanosine → purine). Ethanol metabolism: ATP → AMP → IMP → hypoxanthine → xanthine → uric acid ^[3]

Pathophysiology of Crystal Formation and Inflammation

Understanding the pathophysiology of gout requires understanding two sequential processes:

This is a beautifully understood innate immune pathway:

Crystal shedding: MSU crystals shed from cartilage surface into synovial space (triggered by trauma, surgery, dietary indiscretion, dehydration, rapid change in urate levels)
Phagocytosis by resident macrophages: Synovial macrophages and monocytes phagocytose MSU crystals
NLRP3 inflammasome activation: The ingested crystals are recognized as danger signals (DAMPs) and activate the NLRP3 (NOD-like receptor protein 3) inflammasome — a cytoplasmic multiprotein complex
Caspase-1 activation: NLRP3 activates caspase-1
IL-1β and IL-18 release: Caspase-1 cleaves pro-IL-1β into active IL-1β — the central cytokine driving gouty inflammation. IL-1β causes:
- Vasodilation → redness, warmth
- Increased vascular permeability → swelling, oedema
- Neutrophil chemotaxis → massive neutrophil influx into the joint
- Pain sensitisation
Neutrophil influx: The hallmark of acute gouty arthritis. Neutrophils amplify inflammation by releasing:
- Reactive oxygen species (ROS)
- Lysosomal enzymes
- More pro-inflammatory cytokines (TNFα, IL-6, IL-8)
- Neutrophil extracellular traps (NETs)
Self-resolution: Uniquely, acute gout flares are self-limiting (typically resolve within 7–14 days even without treatment). This is because:
- Neutrophils undergo apoptosis and are cleared by macrophages (efferocytosis)
- Anti-inflammatory mediators are released: TGF-β, IL-10, annexin A1
- MSU crystals become coated with apolipoprotein B and other proteins that reduce their inflammatory potential

Why Does Starting/Stopping Urate-Lowering Therapy Trigger Flares?

Any rapid change in serum urate — either up OR down — can precipitate a flare. When urate drops quickly (e.g., starting allopurinol), existing MSU crystal deposits partially dissolve, shedding crystal fragments into the synovial space, which triggers the inflammatory cascade above. This is why flare prophylaxis (with colchicine or NSAID) is essential when initiating urate-lowering therapy (ULT) ^[2].

Classification

Gout progresses through a well-defined clinical spectrum:

Stage	Description
1. Asymptomatic hyperuricaemia	Elevated serum urate without any clinical manifestation. Most patients never progress beyond this stage. No treatment indicated for asymptomatic hyperuricaemia alone (controversial)
2. Acute gouty arthritis	Explosive onset of joint inflammation (classically monoarticular). Self-limiting over 7–14 days. Between attacks, the patient is completely symptom-free
3. Intercritical gout	The "silent" period between acute flares. MSU crystal deposits persist in joints even when asymptomatic. Without treatment, intervals between attacks shorten over time
4. Chronic tophaceous gout	Sustained polyarticular arthritis with formation of tophi (aggregates of MSU crystals surrounded by granulomatous inflammation). Leads to joint destruction and disability

Feature	Gout	Pseudogout (CPPD)
Crystal	Monosodium urate (MSU)	Calcium pyrophosphate dihydrate (CPPD)
Shape	Needle-shaped	Rhomboid-shaped
Birefringence	Negatively birefringent (yellow when parallel to compensator axis)	Positively birefringent (blue when parallel)
MC joint	1st MTPJ	Knee, shoulders
XR	Punched-out erosions, preserved joint space	Chondrocalcinosis (linear calcification in cartilage)
Associations	Metabolic syndrome, CKD, diet	OA, haemochromatosis, hyperPTH, hypoMg

Mnemonic: "Needle-shaped, Negatively birefringent = gout (two N's)" vs. "Pseudogout = Positively birefringent, Pyrophosphate" ^[1]^[2]

Clinical Features

A. Symptoms (with Pathophysiological Basis)

B. Signs (with Pathophysiological Basis)

Sign	Description	Pathophysiological Basis
Severe swelling	Dramatic periarticular oedema, often extending beyond the joint	IL-1β → ↑ vascular permeability → plasma leakage into tissues
Erythema	Intense redness overlying the joint, may extend proximally	IL-1β → vasodilation of superficial vessels
Warmth	Joint feels hot to touch	↑ blood flow from vasodilation
Exquisite tenderness	Even light touch (bedsheet) causes severe pain	Sensitisation of nociceptors by prostaglandins, bradykinin, and IL-1β; capsular distension by effusion
Reduced range of motion	Patient holds joint still, refuses to move it	Pain-mediated guarding + mechanical effect of effusion distending capsule
Overlying skin desquamation	As the attack resolves (days 5–10), skin over the joint peels	Intense dermal oedema stretches the epidermis; as oedema resolves, the stretched skin desquamates — this can mimic cellulitis
Low-grade fever	Mild pyrexia (37.5–38.5°C)	Systemic IL-1β and IL-6 → hypothalamic PGE2 → fever. Important: high fever (>39°C) should raise concern for septic arthritis

Sign	Description	Pathophysiological Basis
Tophi	Firm, non-tender (or mildly tender), yellowish-white subcutaneous nodules	Organised granulomatous tissue (macrophages, giant cells) surrounding MSU crystal aggregates
Joint deformity	Bony swelling, deviation, subluxation of digits	Progressive bone and cartilage erosion by tophi
Ulcerating tophi	White chalky material visible through skin or actively discharging	MSU crystite eroding through skin surface
Ear helix tophi	Characteristic location (cooler, peripheral)	Low temperature at ear helix → low urate solubility → crystal deposition
Olecranon bursa tophi	Bursal swelling at elbow	Common site due to mechanical pressure + relatively superficial/cool location

This is a commonly examined point — any factor causing rapid change in serum urate or crystal shedding:

Category	Examples	Mechanism
Surgery	Usually post-op day 3–5 ^[2]	Tissue catabolism, dehydration, starvation, stress
Trauma	Direct joint injury	Physical disruption of crystal deposits → shedding into synovial fluid
Dietary	Starvation, dehydration ^[2]; meat and seafood binge ^[2]	Starvation → ketoacidosis → ↓ urate excretion; purine load → ↑ production
Alcohol	Especially beer	↑ production + ↓ excretion (dual mechanism)
Drugs ↑ urate	Thiazide or loop diuretics ^[2]	↓ renal excretion
Drugs ↓ urate	Allopurinol, probenecid (when initiated) ^[2]	Rapid ↓ urate → crystal dissolution → shedding of crystal fragments
Infection / acute illness	Sepsis, pneumonia	Dehydration, catabolism, acidosis

Exam Pitfall — Drugs That Both Treat and Trigger Gout

Students often forget that initiating ULT (e.g., allopurinol) can itself precipitate an acute flare. This is why we always co-prescribe flare prophylaxis (colchicine 0.5 mg daily or NSAID) for the first 3–6 months of ULT. Never start ULT during an acute flare — wait at least 2 weeks after resolution ^[2].

Exception to the above (2023+ guideline shift): Some guidelines (ACR 2020, updated EULAR) now suggest it is acceptable to initiate ULT during an acute flare if appropriate anti-inflammatory cover is given, as delaying may lead to loss to follow-up. However, the traditional teaching (and the approach likely expected in HKUMed exams) is to wait ^[1]^[2].

Gout is not merely a joint disease — it is a marker of systemic metabolic derangement and is strongly associated with cardiovascular disease. In the HK population, the following comorbidities are particularly relevant:

Comorbidity	Relationship
Hypertension	Most common comorbidity of gout ^[5]. Bidirectional: HT → renal impairment → ↓ urate excretion; hyperuricaemia → endothelial dysfunction → HT
Metabolic syndrome	Obesity, dyslipidaemia, insulin resistance — insulin ↓ renal urate excretion
Type 2 diabetes mellitus	Shared risk factors; paradoxically, very high glucose may be mildly uricosuric (glycosuric state)
CKD	↓ GFR → ↓ urate excretion. Conversely, urate crystal deposition → urate nephropathy
Cardiovascular disease	Hyperuricaemia is an independent CV risk factor (controversial whether causal or merely a marker)
Nephrolithiasis	10–25% of gout patients; uric acid stones (radiolucent) or mixed calcium-urate stones ^[7]
Transplant recipients	Calcineurin inhibitors (cyclosporine/tacrolimus) cause hyperuricaemia → high prevalence of gout post-transplant

From GC 075 (Pain red joint) and Block A - Painful red joint:

Gout is the most common crystal-induced arthropathy

MSU crystals are needle-shaped and negatively birefringent under polarised light microscopy

The gold standard for diagnosis is joint aspirate showing MSU crystals

1st MTPJ is the MC joint affected (podagra)

Must always exclude septic arthritis when a joint is red, hot, swollen and tender — joint aspiration with Gram stain and culture is essential

From GC 074 (Multiple joint pain):

Crystal arthropathy should be considered in the differential diagnosis of acute monoarthritis AND polyarthritis

Chronic tophaceous gout can present as polyarticular disease mimicking RA

From GC 079 (Prescribing in older people) and STOPP/START criteria:

STOPP: Long-term colchicine for chronic gout if CrCl < 10 mL/min (risk of colchicine toxicity)

STOPP: Long-term NSAID use (≥ 3 months) in gout if alternative exists — GI bleeding, renal, CV risk

Consider renal dose adjustment of allopurinol in elderly with CKD

In older patients, polypharmacy increases the risk of drug-induced hyperuricaemia (diuretics, low-dose aspirin)

From GC 048 (Fever):

Crystal arthritis (gout/pseudogout) is a differential for monoarticular arthritis with fever — must differentiate from septic arthritis

Septic arthritis and crystal arthritis can coexist

From Upper Limb Painful Conditions (Inflammatory conditions):

Gout can affect upper limb joints including wrist, MCP, elbow (olecranon bursitis)

Upper limb gout is more common in chronic/tophaceous disease and in women

From CFB (OT01) Introduction to Orthopaedic Surgery:

Crystal arthropathy is listed as a cause of inflammatory joint disease requiring differentiation from degenerative (OA) and infective arthritis

From GC 234 (Common Foot and Ankle Conditions):

Gout affecting the 1st MTPJ is one of the common foot conditions

Must differentiate from hallux rigidus (OA of 1st MTPJ), bunion (hallux valgus), and septic arthritis

From Block A - Drugs and the Kidney / Nephrology:

Urate stones are radiolucent on plain XR

CKD both causes and is caused by gout (bidirectional relationship)

High Yield Summary

Definition: Crystal arthropathy from MSU crystal deposition in joints/tissues due to chronic hyperuricaemia (> 6.8 mg/dL).

Epidemiology: M>>F (5–9:1), prevalence ~1–4%, rising. Males from 4th–5th decade; females post-menopausal. HK: HLA-B*5801 prevalence ~8% (must screen before allopurinol).

Risk Factors: Male, age, genetics (SLC2A9, ABCG2), purine-rich diet, alcohol (esp. beer), fructose, obesity, HT, CKD, drugs (thiazides, pyrazinamide, cyclosporine, low-dose aspirin). Protective: dairy, coffee, vitamin C, losartan.

Pathophysiology: Hyperuricaemia (90% underexcretion, 10% overproduction) → MSU crystal formation in cooler/peripheral joints → crystal shedding → macrophage phagocytosis → NLRP3 inflammasome → caspase-1 → IL-1β → massive neutrophilic inflammation. Self-limiting due to anti-inflammatory resolution.

Classification: Asymptomatic hyperuricaemia → acute gouty arthritis → intercritical gout → chronic tophaceous gout. Compare with pseudogout: CPPD, rhomboid, positively birefringent.

Clinical Features: Explosive monoarthritis (1st MTPJ most common = podagra), nocturnal onset, exquisite tenderness, erythema, swelling, warmth, desquamation on resolution. Tophi in chronic disease (ears, fingers, olecranon, Achilles). Extra-articular: urate nephrolithiasis, urate nephropathy.

Key Precipitants: Surgery (post-op D3–5), dietary indiscretion, alcohol, dehydration, drugs altering urate, trauma, starting ULT.

Comorbidities: HT (most common), metabolic syndrome, CKD, CVD, DM, dyslipidaemia.

Active Recall - Gout (Definition, Epidemiology, Risk Factors, Etiology, Pathophysiology, Classification, Clinical Features)

Differential Diagnosis of Gout

Detailed Differential Diagnosis

Feature	Septic Arthritis	Gout
Onset	Acute (hours to days)	Acute (reaches peak within 6–12 hours)
Fever	High fever (>38.5°C) is common	Low-grade fever possible; high fever should raise alarm
Joint count	Monoarthritis (~80–90%) ^[8]	Monoarthritis (~80%) ^[1]^[2]
Preferred sites	Knee > hip > ankle > wrist ^[8]^[10]	1st MTPJ > ankle > midfoot > knee ^[1]
Risk factors	Extremes of age, IV drug use, prosthetic joint, RA, DM, immunosuppression, skin infection, recent joint procedure ^[8]	Male, metabolic syndrome, diet, CKD, drugs
Synovial fluid WBC	>50,000/mm³ (often >100,000), ≥75% PMNs ^[11]	10,000–100,000/mm³, >90% PMNs ^[3]^[11]
Gram stain/culture	Positive (Gram stain ~50–75%; culture ~80–90%)	Negative
Crystals	Absent (but can coexist with crystals) ^[9]	MSU: needle-shaped, negatively birefringent ^[1]^[2]
Blood cultures	Often positive	Negative
Imaging	Joint effusion; periarticular osteopenia on XR ^[10]	Punched-out erosions, overhanging margin (chronic)

Why must you aspirate the joint? Because the clinical features alone cannot reliably distinguish gout from septic arthritis. Both can present with an explosive, exquisitely tender, red, hot, swollen joint with fever and raised inflammatory markers. The only way to definitively differentiate is joint aspiration for Gram stain, culture, AND crystal analysis. Crucially, gout and septic arthritis can coexist — finding crystals does NOT exclude infection ^[1]^[8]^[9].

Microbiology of septic arthritis ^[8]^[10]:

S. aureus is the most common organism in adults and children >2 years
N. gonorrhoeae in sexually active young adults (disseminated gonococcal infection — often polyarticular, associated with tenosynovitis, dermatitis)
Group B Streptococcus and Gram-negative bacilli in neonates
H. influenzae type B in unvaccinated children <2 years
Salmonella in sickle cell disease

Feature	Gout	Pseudogout
Crystal	MSU: needle-shaped, negatively birefringent	CPPD: rhomboid-shaped, positively birefringent
MC joint	1st MTPJ	Knee, shoulders, wrist
Demographics	M>>F, 40–60 years	M≈F, rare <55 years, increases with age
Associations	Metabolic syndrome, CKD, diet	OA, haemochromatosis, hyperPTH, hypoMg, hypophosphatasia, Wilson's disease ^[3]
XR	Punched-out erosions, preserved joint space	Chondrocalcinosis (linear calcification in hyaline/fibrocartilage)
Acute management	Same (NSAIDs, colchicine, steroids)	Same principles

Why does pseudogout affect different joints? CPPD crystals deposit preferentially in fibrocartilage (menisci, triangular fibrocartilage of the wrist, labrum) and hyaline cartilage of larger joints. Unlike MSU, CPPD crystal formation is less temperature-dependent and more related to local cartilage matrix factors (proteoglycan degradation in OA, ATP release from damaged chondrocytes) ^[3].

Pseudogout Secondary Causes — Screen for Metabolic Disease

When pseudogout presents in a patient younger than 55 years, always screen for secondary metabolic causes: haemochromatosis (iron studies + transferrin saturation), hyperparathyroidism (calcium, PTH), hypomagnesaemia, hypophosphatasia (low ALP), Wilson's disease (ceruloplasmin) ^[3].

Feature	RA	Gout
Pattern	Symmetrical, polyarticular	Asymmetrical, typically monoarticular (polyarticular in chronic disease)
Joints	MCP, PIP, wrist (spares DIP)	1st MTPJ, ankle, midfoot, knee
Morning stiffness	>1 hour	Brief (<30 min) or absent
Nodules	Rheumatoid nodules (extensor surfaces)	Tophi — can be confused with rheumatoid nodules ^[3]
Serology	RF+, anti-CCP+	Negative
Synovial fluid	Inflammatory, no crystals	MSU crystals
XR	Periarticular osteopenia, marginal erosions, joint space narrowing	Punched-out erosions with overhanging margins, preserved joint space

From Ryan Ho Rheumatology: "tophi can be confused with rheumatoid nodules, but gout typically associated with asymmetrical and asynchronous involvement + urate crystal in joint fluid" ^[3]. In chronic tophaceous gout, polyarticular involvement can genuinely mimic RA clinically and radiologically. The key differentiator is crystal analysis on aspiration.

Feature	Psoriatic Arthritis	Gout
Pattern	Asymmetric oligoarthritis; dactylitis ("sausage digit"); enthesitis	Monoarticular (acute), may become polyarticular
Skin	Psoriatic plaques, nail pitting/onycholysis	Tophi, skin desquamation over joint
DIP involvement	Characteristic	Can occur with tophi
Dactylitis	Classic for spondyloarthritis	Can occur in gout (tophaceous inflammation along tendon)
Imaging	"Pencil-in-cup" erosions, periostitis, enthesophytes	Punched-out erosions, overhanging margins

Ryan Ho: "Dactylitis in spondyloarthritis" is a key differential for chronic gout affecting digits ^[3]. Psoriasis itself is also a risk factor for hyperuricaemia (increased skin cell turnover → increased purine catabolism), so gout and psoriatic arthritis can coexist.

Feature	OA	Gout
Onset	Gradual; acute flares are milder	Explosive acute onset
Pattern	Weight-bearing joints, DIP (Heberden nodes), 1st CMC	1st MTPJ, ankle, knee
Inflammation	Mild or absent ("cool" joint)	Marked inflammation ("hot" joint)
Morning stiffness	<30 minutes ("gelling")	Variable
XR	Joint space narrowing, osteophytes, subchondral sclerosis/cysts	Punched-out erosions, preserved joint space (early)

Why can OA predispose to crystal deposition? Damaged cartilage in OA releases matrix fragments and alters local pH/ionic milieu, promoting both MSU and CPPD crystal nucleation. OA-affected joints are a common site for pseudogout flares ^[3].

Feature	Haemarthrosis	Gout
Typical patient	Haemophilia, anticoagulant use, trauma, pigmented villonodular synovitis	Hyperuricaemia, metabolic syndrome
Joint	Large joints (knee most common)	1st MTPJ, ankle, knee
Synovial fluid	Bloody/xanthochromic, high RBC ^[11]	Turbid, yellow, high WBC, MSU crystals
Onset	Acute (within hours of bleeding trigger)	Acute (hours)

Haemarthrosis is characterised by bloody joint aspirate. In the context of a patient on warfarin or with known haemophilia who develops an acutely swollen joint, haemarthrosis is the primary concern. However, always send fluid for Gram stain and crystal analysis because infection and crystals should still be excluded.

Feature	Reactive Arthritis	Gout
Pattern	Asymmetric oligoarthritis, lower limb predominant	Monoarticular
Preceding illness	1–4 weeks after urethritis or gastroenteritis	Dietary/surgical/drug trigger
Extra-articular	Conjunctivitis, urethritis, enthesitis, keratoderma blennorrhagicum	Tophi, nephrolithiasis
Association	HLA-B27 positive	HLA-B*5801 relevant for treatment (allopurinol safety)

Condition	Key Distinguishing Features
Cellulitis / Periarticular soft tissue infection	Spreading erythema without true intra-articular effusion; no pain on passive ROM (unless overlying a joint). Gout desquamation can mimic cellulitis
Osteomyelitis	Can mimic gout with extensive inflammation and destruction ^[3]; usually contiguous with open wound or haematogenous; MRI is best for diagnosis ^[10]
Sarcoid arthropathy	Acute polyarthritis (Löfgren syndrome) with bilateral hilar lymphadenopathy, erythema nodosum
Palindromic rheumatism	Recurrent self-limiting monoarthritis lasting 1–3 days; may be precursor to RA; no crystals on aspiration
Tumour (pigmented villonodular synovitis, synovial chondromatosis)	Chronic monoarthritis; MRI diagnostic; PVNS gives bloody aspirate
Paget's disease	Can cause secondary arthritis at joints adjacent to pagetic bone; XR shows characteristic thickened, sclerotic bone ^[12]

Clinical Approach to DDx: How to Differentiate

The approach to differentiating gout from its mimics hinges on three pillars: history, examination, and — most importantly — joint aspiration.

Red Flag	Suggests
High fever (>39°C), rigors	Septic arthritis
Prosthetic joint, recent joint injection, skin breach	Septic arthritis
IV drug use, immunosuppression	Septic arthritis
Preceding urethritis/diarrhoea	Reactive arthritis
Morning stiffness >1 hour, symmetrical small joints	RA
Psoriatic plaques, nail changes	Psoriatic arthritis
Trauma with immediate swelling	Haemarthrosis / fracture
Bleeding diathesis, anticoagulant use	Haemarthrosis
Young female (<30), migratory polyarthralgia, skin pustules	Disseminated gonococcal infection

Joint aspiration is the single most important investigation for differentiating the causes of acute monoarthritis ^[1]^[2]^[8]. Every aspirated fluid should be sent for:

Gross appearance (colour, turbidity, viscosity)
Cell count with differential (WBC, % PMNs)
Compensated polarised light microscopy (crystal identification)
Gram stain and culture (to exclude infection)
Additional: AFB smear/culture if TB suspected

Synovial fluid analysis reference table ^[11]:

Parameter	Normal	Non-Inflammatory	Inflammatory	Septic	Haemorrhagic
Volume (knee, mL)	<3.5	>3.5	>3.5	>3.5	>3.5
Clarity	Transparent	Transparent	Translucent–Opaque	Opaque	Bloody
Colour	Clear	Yellow	Yellow	Yellow	Red
Viscosity	High	High	Low	Variable	Variable
WBC/mm³	<200	0–2,000	>2,000	>20,000 (often >50,000)	Variable
PMNs (%)	<25%	<25%	≥50%	≥75%	50–75%
Culture	−ve	−ve	−ve	+ve	−ve
Crystals	Absent	Absent	Present (if crystal arthritis)	Usually absent	Absent

Key exam point: Gout produces an inflammatory synovial fluid (WBC typically 10,000–100,000/mm³, >90% PMNs) ^[3]^[11]. This overlaps significantly with the septic range. The WBC count alone cannot distinguish gout from septic arthritis — you need Gram stain, culture, AND crystal analysis. And remember: finding crystals does NOT rule out concurrent infection ^[1]^[8].

GC 075 — Serum Uric Acid Level: Useful But NOT Diagnostic

From GC 075: "Serum UA level useful but not diagnostic" ^[1].

During an acute flare, serum urate can be normal in up to 50% of cases ^[2] because:

Acute-phase reactant proteins have uricosuric properties
Urate is being consumed into crystal formation
IL-6 increases renal urate excretion transiently

Therefore, a normal serum urate does NOT exclude gout, and an elevated serum urate alone does NOT confirm gout (hyperuricaemia is extremely common in the general population). Best time to measure serum urate is ≥2 weeks post-flare ^[2]^[3].

Feature	Gout	Pseudogout	Septic Arthritis	RA	Reactive Arthritis
Age/Sex	M, 40–60	Either, >55	Any	F, 30–50	M, 20–40
Pattern	Mono (80%)	Mono/oligo	Mono (80–90%)	Symmetric poly	Asymmetric oligo
MC joint	1st MTPJ	Knee	Knee	MCP, PIP, wrist	Knee, ankle
Crystal	MSU, needle, neg birefringent	CPPD, rhomboid, pos birefringent	None	None	None
XR	Punched-out erosions	Chondrocalcinosis	Effusion, osteopenia	Marginal erosions, JSN	Normal or periostitis
Synovial WBC	10–100k	10–100k	>50k	5–50k	5–50k
Culture	−ve	−ve	+ve	−ve	−ve
Key clue	Podagra, tophi, nocturnal	Elderly, OA, metabolic screen	Fever, bacteraemia source	Symmetry, RF/CCP+	Preceding GU/GI infection

Chronic tophaceous gout mimicking RA: Polyarticular involvement of small hand joints with subcutaneous nodules (tophi vs rheumatoid nodules). Differentiate by crystal analysis and serology (RF/anti-CCP negative in gout) ^[3].
Gout mimicking cellulitis: The intense periarticular erythema and skin desquamation of acute gout can extend beyond the joint, closely resembling cellulitis. Key difference: cellulitis has no true intra-articular effusion and no pain on passive ROM through the arc of the joint itself; gout has a clear effusion and pain through all planes of motion.
Gout mimicking osteomyelitis: Gout with extensive inflammation and destruction can mimic osteomyelitis ^[3]. Imaging (MRI) and aspiration/biopsy differentiate.
Gout + septic arthritis coexistence: A known gout patient who presents with an unusually severe or prolonged attack, high fever, or systemic sepsis should have the joint aspirated even if the clinical picture "looks like gout." Crystal-proven gout does not exclude concurrent infection ^[1]^[8].

Clinical Pearl — The 'Too Sick for Gout' Rule

If a patient looks systemically unwell (high fever, rigors, tachycardia, haemodynamic instability) with a hot swollen joint, treat as septic arthritis until proven otherwise — even if they have a history of gout. Always aspirate, always send for Gram stain and culture. Empiric antibiotics should not be delayed for crystal analysis if septic arthritis is strongly suspected.

High Yield Summary — DDx of Gout

Always exclude septic arthritis first — it is a rheumatological emergency that can destroy cartilage in days. A hot swollen joint = septic arthritis until proven otherwise.
Joint aspiration is the cornerstone investigation — send for crystals (polarised microscopy), Gram stain, culture, cell count. Finding crystals does NOT exclude infection.
Key DDx: Septic arthritis, pseudogout (CPPD), RA flare, psoriatic arthritis, reactive arthritis, haemarthrosis, OA flare, cellulitis, osteomyelitis.
Gout crystals: MSU, needle-shaped, negatively birefringent. Pseudogout crystals: CPPD, rhomboid, positively birefringent.
Serum urate is useful but not diagnostic — normal in ~50% of acute flares; elevated in many people without gout. Best measured ≥2 weeks post-flare.
Chronic tophaceous gout can mimic RA (polyarticular, nodular) or osteomyelitis (destructive). Crystal analysis and serology differentiate.
Gout + septic arthritis can coexist — never assume a known gout patient with an acute flare is "just gout" if clinically unwell.

Active Recall - Differential Diagnosis of Gout

References

^[1] Lecture slides: GC 075. Pain red joint.pdf (p.27 and related sections) ^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.327–329) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Crystal-Induced Arthritis, p.35–41) ^[8] Senior notes: Adrian Lui Pediatrics Notes.pdf (Septic Arthritis, p.453) ^[9] Lecture slides: GC 048. Fever.pdf (crystal arthritis and septic arthritis can coexist) ^[10] Senior notes: Maksim Surgery Notes.pdf (Septic arthritis, Osteomyelitis, p.274–275) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Synovial fluid analysis table, p.1695–1697) ^[12] Senior notes: Ryan Ho Endocrine.pdf (Paget's disease, p.53)

Diagnostic Criteria, Algorithm, and Investigations for Gout

2015 ACR/EULAR Gout Classification Criteria

These are the current gold-standard classification criteria (note: classification criteria are designed for research cohort entry; they are not diagnostic criteria per se, but are widely used clinically as a structured checklist).

If joint aspiration has not been performed or crystals were not identified, a point-based scoring system is used across 8 domains. A score of ≥8 out of 23 classifies the patient as having gout.

Domain	Category	Score
1. Pattern of joint involvement	Ankle or midfoot (as monoarthritis or oligoarthritis)	1
	1st MTP joint involvement	2
2. Characteristics of episode
	One characteristic: great difficulty walking / inability to use affected joint / inability to be touched or bear weight	1
	Two characteristics	2
	Three characteristics: erythema, inability to bear touch, great difficulty walking	3
3. Time course of episode	One typical episode: time to maximal pain <24h, resolution ≤14d, complete resolution between episodes	1
	Recurrent typical episodes	2
4. Clinical evidence of tophus	Draining or chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity, at typical locations	4
5. Serum urate	<4 mg/dL (0.24 mmol/L)	−4
	4– <6 mg/dL (0.24– <0.36 mmol/L)	0
	6– <8 mg/dL (0.36– <0.48 mmol/L)	2
	8– <10 mg/dL (0.48– <0.60 mmol/L)	3
	≥10 mg/dL (≥0.60 mmol/L)	4
6. Synovial fluid analysis	Not done	0
	MSU crystals negative	−2
7. Imaging: urate deposition	USG double contour sign OR DECT demonstrating urate deposition	4
8. Imaging: gout-related damage	XR hands/feet showing ≥1 characteristic erosion	4

Total threshold: ≥ 8 points = classified as gout ^[3]

Key Points About the 2015 ACR/EULAR Criteria

A negative synovial fluid crystal analysis scores −2 — this appropriately penalises the diagnosis if you looked and didn't find crystals
A very low serum urate (<4 mg/dL) scores −4 — strongly argues against gout (though not impossible during an acute flare)
Clinical evidence of tophi scores the highest single domain (4 points) — because tophi are pathognomonic for chronic gout
Imaging (USG double contour or DECT) also scores 4 points — these are newer modalities increasingly used when aspiration is not feasible
The criteria have sensitivity ~92% and specificity ~89% for gout

Investigation Modalities: Detailed Interpretation

1. Joint Aspiration and Synovial Fluid Analysis (MOST IMPORTANT TEST)

From Ryan Ho Fundamentals: "Joint fluid analysis: MOST IMPORTANT TEST" ^[13]

Test	What You're Looking For	Why
Gross appearance	Colour (yellow = inflammatory, red = haemorrhagic), turbidity (turbid = high cell count), viscosity (low in inflammatory)	Quick bedside triage
Compensated polarised light microscopy	MSU crystals: needle-shaped, strongly negatively birefringent ^[1]^[2]^[13]	Definitive diagnosis of gout
Cell count with differential	WBC count, % PMNs	Distinguish inflammatory (>2,000) vs non-inflammatory (<2,000) vs septic (>50,000)
Gram stain (urgent if septic arthritis suspected)	Bacteria	Rapid bedside diagnosis of septic arthritis (~50–75% sensitivity)
Bacterial culture	Organisms and sensitivities	Definitive microbiological diagnosis (~80–90% sensitivity)
AFB smear + culture	Mycobacteria	If TB arthritis suspected (chronic monoarthritis, immunosuppressed)

Parameter	Normal	Non-Inflammatory	Inflammatory (Gout)	Septic	Haemorrhagic
Volume (knee)	<3.5 mL	>3.5 mL	>3.5 mL	>3.5 mL	>3.5 mL
Clarity	Transparent	Transparent	Translucent–Opaque	Opaque	Bloody
Colour	Clear	Yellow	Yellow	Yellow	Red
Viscosity	High	High	Low	Variable	Variable
WBC/mm³	<200	0–2,000	2,000–100,000	>20,000 (often >50,000)	Variable
PMNs (%)	<25%	<25%	≥50% (typically >90%)	≥75%	50–75%
Culture	−ve	−ve	−ve	+ve	−ve
Crystals	Absent	Absent	MSU: needle, neg birefringent	Usually absent	Absent

Why is viscosity LOW in inflammatory fluid? Normal synovial fluid has high viscosity due to hyaluronic acid (hyaluronan). In inflammatory conditions, neutrophil-derived enzymes (hyaluronidase, proteases) degrade hyaluronic acid, reducing viscosity. This can be tested clinically with the "string test" — normal synovial fluid strings out >4 cm when allowed to drip from a syringe; inflammatory fluid drips like water.

Feature	Gout (MSU)	Pseudogout (CPPD)
Shape	Needle-shaped (elongated, slender)	Rhomboid or pleomorphic
Birefringence	Strongly negatively birefringent	Weakly positively birefringent
Colour when parallel to compensator	Yellow	Blue
Colour when perpendicular to compensator	Blue	Yellow
Location	Intracellular (within PMNs) ± extracellular	Intracellular ± extracellular

How does polarised light microscopy work?

A polarising microscope has two polarising filters at 90° to each other (crossed polarisers) — normally no light passes through

Birefringent crystals split light into two rays that travel at different speeds → some light passes through → crystals appear bright against a dark background

A first-order red compensator (λ plate) is added to determine the sign of birefringence:

If the crystal appears yellow when parallel to the compensator axis → negative birefringence (MSU / gout)

If the crystal appears blue when parallel → positive birefringence (CPPD / pseudogout)

Mnemonic: "Yellow Parallel = Negative = gout" — think "YPN" or remember "Needle, Negative, gout" (all N's) ^[1]^[2]

Exam Pitfall — Intracellular vs Extracellular Crystals

Intracellular crystals (within PMNs) are the hallmark of active crystal-induced inflammation — the neutrophil has phagocytosed the crystal, which is what drives the NLRP3 inflammasome pathway. Extracellular crystals can be seen in intercritical gout or in the absence of active inflammation. During an acute flare, you expect to see both intracellular and extracellular crystals, but the presence of intracellular MSU crystals is the key diagnostic finding ^[11]^[13].

GC 075 — Serum UA: Useful But NOT Diagnostic

From GC 075: "Serum UA level useful but not diagnostic" ^[1].

This is one of the most commonly tested concepts in exams.

Aspect	Detail
During acute flare	Can be high, normal, or even low ^[11]. Normal in ~12–43% (some sources say up to 50%) ^[2]^[3]. Acute-phase response has uricosuric effects; urate is consumed into crystal formation
Best time to measure	≥2 weeks after resolution of acute flare ^[2]^[3]^[13]
Interpretation	Elevated serum urate supports the diagnosis but is neither diagnostic nor required ^[11]. Many people have asymptomatic hyperuricaemia and never develop gout
Target for monitoring	Used to monitor response to urate-lowering therapy (ULT). Target: < 6 mg/dL (0.36 mmol/L), or < 5 mg/dL in tophaceous gout (to promote tophus dissolution)
Saturation point	~6.8 mg/dL (0.41 mmol/L) at 37°C — above this, MSU crystals can theoretically precipitate

Why can serum urate be normal or low during a flare?

Acute-phase proteins (released during inflammation) have uricosuric properties — they promote renal urate excretion

IL-6 (elevated in acute gout) directly increases renal urate clearance

Urate is being consumed — shifting from solution into crystalline form within the joint

Volume expansion from IV fluids (if hospitalised) dilutes serum urate

Test	Expected Findings in Gout	Rationale
CBC with differential	Leukocytosis with neutrophil predominance ^[11]	IL-1β and IL-6 stimulate granulopoiesis and neutrophil demargination. Not specific — also seen in septic arthritis
ESR, CRP	Both elevated ^[3]^[11]	Acute-phase response to IL-6. CRP can be markedly elevated (>100 mg/L in severe flares), mimicking sepsis
RFT (+ eGFR)	May show renal impairment	CKD is both a cause and consequence of hyperuricaemia ^[2]
Fasting glucose	May show impaired fasting glucose / diabetes	Screen for metabolic syndrome ^[2]
Fasting lipid profile	May show dyslipidaemia	Screen for metabolic syndrome ^[2]
*HLA-B5801**	Must check before prescribing allopurinol	~8% carrier rate in Hong Kong Han Chinese; dramatically ↑ risk of SJS/TEN with allopurinol ^[4]

Comorbidity Screening — Essential in Every Gout Patient

From Maksim Medicine Notes: "Screen comorbidities: RFT (+ eGFR), fasting glucose, lipids, BP, BMI" ^[2].

Gout is a systemic metabolic disease. Every gout patient must be screened for:

Renal function (eGFR) — affects drug choices and is both cause and effect
Fasting glucose — diabetes / pre-diabetes
Lipid profile — dyslipidaemia
Blood pressure — hypertension is the most common comorbidity ^[5]
BMI — obesity

This is not just "nice to have" — it directly changes management.

Plain XR is often the first imaging performed but is insensitive in early/acute gout (may be completely normal). Its value is in chronic disease and excluding other pathology.

Finding	Description	Pathophysiology	Stage
Normal	No bony changes	Early gout — crystals are in soft tissue/synovium, not yet eroding bone	Acute/early
Soft tissue swelling	Periarticular density	Effusion and oedema	Acute
"Punched-out" erosions	Well-demarcated, round/oval lytic lesions at joint margins	Tophus eroding into cortical bone from outside → the tophus sits on the bone surface and "punches" inward	Chronic
"Overhanging sclerotic margin" (overhanging edge/lip)	Bone extends over the erosion like a lip or shelf	Reactive new bone formation at the edge of the erosion around the tophus — pathognomonic sign	Chronic
Preserved joint space (initially)	Unlike RA, joint space is maintained early	Tophaceous erosion is periarticular (outside-in), not pannus-driven cartilage destruction (inside-out) as in RA	Chronic (early)
Joint space narrowing	Loss of cartilage	Late chronic tophaceous gout with extensive cartilage destruction	Chronic (late)
Soft tissue tophi	Asymmetric soft tissue nodules, may show calcification	MSU crystal aggregates in periarticular tissues	Chronic

Key XR distinction from RA: In RA, erosions are marginal (at the "bare area" of bone not covered by cartilage), with early joint space narrowing and periarticular osteopenia. In gout, erosions are punched-out with overhanging margins and joint space is preserved until late disease ^[2]^[3].

From Ryan Ho Fundamentals: "Arthritic changes, eg. joint space narrowing, periarticular erosion, chondrocalcinosis (pseudogout), tophaceous erosion" ^[13] — these are the key XR findings to look for in the approach to any arthritis.

Musculoskeletal ultrasound is increasingly used as a bedside, non-invasive tool for gout diagnosis.

Finding	Description	Significance
Double contour sign	Hyperechoic irregular line over the surface of articular cartilage (in addition to the normal subchondral bone echo)	MSU crystal deposition on the cartilage surface creates a second "contour" — highly specific for gout (≥90%) ^[3]
Tophus	Heterogeneous hyperechoic/hypoechoic aggregates within joints, tendons, or soft tissues, often surrounded by a hypoechoic halo	Organised MSU crystal deposits
Snowstorm appearance	Bright hyperechoic foci within synovial fluid	Floating MSU crystals
Bone erosion	Cortical break at joint margin	Chronic tophaceous damage

The double contour sign is included in the 2015 ACR/EULAR criteria (scores 4 points) ^[3]. It is caused by MSU crystals depositing as a thin layer on the surface of hyaline cartilage, creating a second echogenic line parallel to the subchondral bone echo — hence "double contour."

DECT is an advanced imaging modality that can specifically identify and colour-code urate deposits in tissues.

Aspect	Detail
Principle	Uses two X-ray beams at different energy levels; different materials (urate, calcium) attenuate these beams differently, allowing computational separation and colour-coding
Appearance	MSU deposits are colour-coded (typically green) against the bone (purple/blue)
Sensitivity/Specificity	Sensitivity ~78–100%, specificity ~89–100% for established gout; lower sensitivity for first-attack/early gout
2015 ACR/EULAR criteria	DECT demonstrating urate deposition scores 4 points ^[3]
Advantages	Non-invasive; can identify urate deposits in areas difficult to aspirate (spine, SI joints); quantifies urate burden for monitoring
Limitations	Expensive; not widely available; lower sensitivity in early disease; false positives (nail beds, cartilage artifacts); radiation exposure

Modality	Role in Gout
MRI	Not first-line; can show tophi (low T1, variable T2 signal, enhancing rim), synovitis, erosions. Useful when DDx includes osteomyelitis or soft tissue tumour
CT (conventional)	Can show tophi as hyperdense deposits, bone erosions. Useful for urate renal stones (visible on CT despite being radiolucent on plain XR)

Aspect	Detail
Indication	Diagnostic uncertainty — subcutaneous nodule of unclear aetiology (DDx: rheumatoid nodule, xanthoma, ganglion, soft tissue tumour)
Findings	Urate crystals (needle-shaped, negatively birefringent) surrounded by granulomatous inflammation (macrophages, multinucleated giant cells, fibrous tissue) ^[3]
Clinical utility	Confirms diagnosis of tophaceous gout definitively; sufficient criterion in 2015 ACR/EULAR classification

Common Exam Mistakes in Gout Investigations

Never use serum urate alone to diagnose or exclude gout — it can be normal during an acute flare and elevated in asymptomatic people.
Never assume that finding MSU crystals rules out concurrent septic arthritis — they can coexist. Always send for Gram stain and culture.
Never start allopurinol without checking HLA-B*5801 in Hong Kong — the carrier rate is ~8% in Han Chinese, and SJS/TEN can be fatal ^[4].
XR is often normal in acute gout — a normal XR does not exclude gout. The classic radiographic changes (punched-out erosions, overhanging margins) are features of chronic tophaceous disease.
All patients with pyrazinamide will have hyperuricaemia — no point measuring blood urate in this context ^[6]. But if they develop clinical gout, that is still a clinical diagnosis.

High Yield Summary — Diagnosis of Gout

Gold Standard: Joint aspirate with compensated polarised light microscopy showing MSU crystals: needle-shaped, strongly negatively birefringent, intracellular (within PMNs). Simultaneously send for Gram stain + culture to exclude septic arthritis.

2015 ACR/EULAR Criteria: Sufficient criterion = MSU crystal demonstration. Otherwise, scoring system ≥ 8/23 = classified as gout. Highest-scoring domains: tophi (4), imaging evidence of urate deposition (4), imaging evidence of erosion (4), serum urate ≥ 10 mg/dL (4).

Serum Urate: Useful but NOT diagnostic. Can be normal during acute flare. Best measured ≥ 2 weeks post-flare. Used for monitoring ULT.

XR: Normal acutely. Chronic: punched-out erosions with overhanging sclerotic margins, preserved joint space (early), soft tissue tophi.

USG: Double contour sign (highly specific). DECT: Colour-coded urate deposits (expensive, not first-line).

Bloods: CBC (neutrophilic leukocytosis), ESR/CRP (elevated), RFT, fasting glucose, lipids (comorbidity screen), HLA-B*5801 before allopurinol.

Key Principle: Gout is primarily a clinical diagnosis, confirmed by crystal analysis when aspiration is performed.

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for Gout

References

^[1] Lecture slides: GC 075. Pain red joint.pdf (p.27) ^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.327–329) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Crystal-Induced Arthritis, p.35–41) ^[4] Senior notes: Learning_Points_All_Lectures.txt (HLA-B*5801 screening) ^[5] Senior notes: Block A - High blood pressure_ hypertension.pdf (p.21) ^[6] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p.41 — pyrazinamide and hyperuricaemia) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Synovial fluid analysis table, p.1695–1697) ^[13] Senior notes: Ryan Ho Fundamentals.pdf (Physical Examination and Investigations, p.407–410)

Management of Gout

Part 1: Acute Gout Management

The goal is rapid suppression of the acute inflammatory response. Three first-line options exist, and the choice depends on the patient's comorbidities, timing of presentation, and contraindications.

GC 075 / Block A — Acute Management Triad

From Block A - Painful red joint: "Acute crystal deposition arthritis is treated symptomatically with NSAIDs, corticosteroids or colchicine" ^[1]^[14].

These are the three pillars of acute gout treatment. The choice between them is dictated by the patient's comorbidity profile.

Pharmacological Options: Head-to-Head Comparison

Feature	NSAID / COX-2 inhibitor (+PPI)	Colchicine	Corticosteroid (PO/IM/IA)
Administration	High dose, tapering over 5 days	Low-dose regimen preferred	Oral / IM / Intra-articular
Example regimen	Indomethacin 50 mg TDS × 2 days → 25 mg TDS × 3 days OR Naproxen 500 mg BD × 5 days ^[2]	0.5 mg TDS × 1 day, then 0.5 mg BD, tapering (or simpler: 1.2 mg stat then 0.6 mg 1 hour later, then 0.5 mg BD–TDS)	Prednisolone 20–30 mg/day × 3–5 days then taper OR IA triamcinolone 10–40 mg ^[3]
Onset	12–24 hours	12–24 hours (best if started within 12h of onset)	12–24 hours (IA: often resolves within 24h) ^[3]
Best for	Young, otherwise healthy patients	When NSAIDs contraindicated; best within first 12–36h	Renal impairment, elderly, multiple comorbidities, monoarticular (IA)
Key CI	CKD, active PUD, GI bleeding, CVD, heart failure, anticoagulants	Severe CKD (CrCl < 10 mL/min), severe hepatic impairment, concurrent CYP3A4/P-gp inhibitors (clarithromycin, cyclosporine)	Active infection (must exclude septic arthritis first), uncontrolled DM (worsens glucose control)

Mechanism: Corticosteroids (Greek: cortex = bark/outer layer [of adrenal gland], stereos = solid) work by:

Binding to intracellular glucocorticoid receptors → translocating to nucleus → suppressing NF-κB and AP-1 transcription factors → ↓ production of IL-1β, IL-6, TNFα, prostaglandins, leukotrienes
↓ Neutrophil chemotaxis and adhesion
↓ Vascular permeability

Routes and indications:

Route	Indication	Regimen
Intra-articular (IA)	Monoarticular flare when septic arthritis has been excluded	Triamcinolone acetonide 10–40 mg after arthrocentesis ^[3]. Often highly effective with resolution ≤24h
Oral	Polyarticular flare, or when IA not feasible	Prednisolone 20–30 mg/day × 3–5 days then taper over 7–10 days
IM	Patient cannot take oral medications, renal impairment	Single IM injection of methylprednisolone or triamcinolone

Slow Taper If Chronic Gout

From Ryan Ho Rheumatology: "Slow taper if chronic gout (shorter intercritical period, ↑chance of rebound flare)" ^[3].

In patients with chronic gout (frequent flares, short intercritical periods), abruptly stopping steroids can trigger a rebound flare. Always taper over 7–14 days rather than stopping abruptly.

Agent	Mechanism	Indication
Anakinra	IL-1 receptor antagonist	Refractory acute gout when NSAIDs, colchicine, AND steroids are all contraindicated or ineffective
Canakinumab	Anti-IL-1β monoclonal antibody	Same as above; very expensive

These target the central cytokine of gouty inflammation (IL-1β) directly. They are not first-line but are increasingly used in complex patients (e.g., CKD + heart failure + anticoagulation where all three first-line agents are problematic).

Part 2: Long-Term Management

From Maksim Medicine Notes: "Lifestyle modification: avoid triggers" ^[2]:

Intervention	Details	Mechanism
Low purine diet	Limit red meat, organ meats (viscera), shellfish, sardines	↓ substrate for urate production
Limit alcohol	Avoid beer (high purine content); spirits in moderation; wine may be less harmful	Beer: ↑ production (purines) + ↓ excretion (lactic acid). All alcohol ↑ ATP breakdown
Limit fructose	Limit high-fructose corn syrup (e.g., soft drinks) ^[2]	Fructose metabolism depletes ATP → ↑ AMP → ↑ urate
Adequate hydration	≥2L fluid daily	Dilute urine, promote urate excretion, prevent urate stones
Weight reduction	Gradual weight loss (avoid crash diets — starvation triggers flares)	↓ insulin resistance → ↑ renal urate excretion
Review medications	Switch thiazide → losartan (losartan has mild uricosuric properties); switch statins to atorvastatin/fenofibrate (mild uricosuric); avoid low-dose aspirin if possible ^[2]	Remove drug-induced hyperuricaemia

Protective foods: Low-fat dairy, cherries, coffee, vitamin C — promote urate excretion or have anti-inflammatory effects. These are not strong enough to replace pharmacotherapy but are helpful adjuncts.

B. Urate-Lowering Therapy (ULT)

From Block A - Painful red joint: "Remember to implement long term prevention treatment in patients with recurrent attacks of gouty arthritis" ^[14].

Indication	Rationale
Recurrent attacks ≥ 2 per year	Indicates significant crystal burden requiring dissolution ^[2]
Chronic tophaceous gout	Tophi cause joint destruction and disability; ULT dissolves tophi over months–years
Urate kidney stones	Reduce urate excretion and stone recurrence
CKD / gout nephropathy	Prevent further renal urate damage
Very high serum urate (>12 mg/dL or 0.72 mmol/L)	Very high crystal burden even without frequent attacks
Young patient with first attack and significant comorbidities	Some guidelines now advocate earlier ULT

Check	Why
*HLA-B5801**	Mandatory before allopurinol — carrier frequency ~8–14% in Hong Kong Han Chinese; dramatically ↑ risk of SJS/TEN ^[4]^[17]
RFT (+ eGFR)	Dose adjustment needed for renal impairment; allopurinol and colchicine both need renal dosing ^[2]^[17]
Baseline serum urate	To establish starting point and track response
Comorbidity screen	Fasting glucose, lipids, BP, BMI — guides holistic management
Medication review	Check for drug interactions (especially azathioprine with XOI)

ULT Options: Detailed Comparison

These are the backbone of ULT. They work by blocking xanthine oxidase, the enzyme that catalyses the final two steps of purine catabolism (hypoxanthine → xanthine → uric acid).

Feature	Allopurinol	Febuxostat
Chemistry	Purine analogue, non-selective XOI	Non-purine, selective XOI
Mechanism	Structural analogue of hypoxanthine → competitive inhibition of XO. Its active metabolite oxypurinol also inhibits XO (long half-life = once daily dosing)	Binds to the molybdenum pteridine active site of XO → potent, selective inhibition
First-line?	Yes — first-line ULT worldwide	*Second-line: alternative for allopurinol cutaneous ADR, HLA-B5801 positive, or severe renal impairment** ^[2]^[17]
Starting dose	100 mg daily (even lower — 50 mg — in CKD) ^[2]^[17]	40 mg daily
Titration	Increase by 100 mg weekly to target urate < 0.36 mmol/L ^[2]	Increase to 80 mg daily if needed
Max dose	800 mg daily (FDA approved) ^[17]	80–120 mg daily
Renal impairment	Further reduce dose (< 100 mg daily), step up slowly ^[17]	Further reduce dose (< 40 mg daily), step up slowly ^[17]
Must check before starting	*HLA-B5801** ^[2]^[4]^[17]	Not required (no HLA association)

Side Effects of Allopurinol ^[2]^[17]:

Side Effect	Details	Management
Skin rash (~5%)	Maculopapular rash, usually appears around 3 weeks	Stop stat; inform patients to stop if skin reaction and seek medical attention early ^[17]
Allopurinol Hypersensitivity Syndrome (AHS) (~0.1%)	Severe: rash (SJS/TEN), eosinophilia, fever, hepatitis, progressive renal failure. Mortality ~27%	Stop permanently; supportive care; this is a medical emergency
AHS risk factors	*Han Chinese (HLA-B5801), elderly, poor RFT; NOT dose-dependent** ^[2]	Prevented by HLA screening
Interstitial nephritis	Drug-induced AIN	Stop allopurinol
Diarrhoea (3–5%)	GI intolerance	Dose adjustment

Drug Interaction: Allopurinol/Febuxostat + Azathioprine — CRITICAL

From Handbook of Internal Medicine: "Xanthine oxidase inhibitors — Do NOT use with azathioprine!" ^[17]

From Maksim Medicine Notes: "DDI: azathioprine (XO metabolises azathioprine to inactive metabolite) → reduce azathioprine dose by 50% to prevent severe myelosuppression" ^[2]

From Block A - IBD / Pharmacogenomics: Azathioprine is a prodrug metabolised via three pathways. XO converts active 6-MP into inactive 6-TU. If XO is inhibited by allopurinol/febuxostat, the active metabolite 6-TGTP accumulates to toxic levels → life-threatening pancytopenia/neutropenic fever ^[18]^[19].

Rule: If a patient absolutely requires both drugs, reduce azathioprine dose by ≥50% and monitor CBC closely. Ideally, avoid the combination or use an alternative immunosuppressant.

Side Effects of Febuxostat ^[2]:

Side Effect	Details
Liver impairment	Stop if LFT > 3× ULN ^[2]
Cardiovascular risk	Avoid in patients with history of IHD or CHF — the CARES trial showed higher CV mortality with febuxostat vs allopurinol, though later trials showed equipoise. The clinical teaching remains to be cautious in high CV risk patients ^[2]^[17]
GI upset	Nausea, diarrhoea
Drug interaction	Same as allopurinol regarding azathioprine

These drugs work by increasing renal urate excretion. They block URAT1 (urate transporter 1) in the proximal tubule → ↓ renal urate reabsorption → ↑ urate excretion.

Feature	Probenecid	Benzbromarone
Mechanism	Inhibits URAT1 → ↓ tubular urate reabsorption → ↑ urinary urate excretion	Same mechanism, more potent
Dose	250 mg BD, titrate to 1000 mg TDS ^[3]^[17]	50–200 mg daily
Contraindications	Moderate renal impairment (eGFR < 50), urate renal stone, high 24h urine uric acid excretion ^[3]^[17] — because ↑ urinary urate → ↑ stone risk	Severe hepatic impairment
Side effects	Rash, precipitation of gout flare, GI intolerance, urate stone formation ^[3]	Hepatotoxicity (rare but serious)
Drug interactions	↓ excretion of organic anions → ↑ half-life of penicillin, ampicillin ^[3]; uricosuric effect interfered by high-dose salicylates	—
Availability in HK	Available	Licensed in HK but not under HA formulary ^[17]

Mnemonic for Probenecid side effects (PROB): Precipitation of gout, Rash, Obstruction (urate stones), Bowels (GI upset) ^[3]

Why are uricosuric agents contraindicated in renal stones? By definition, they increase the amount of urate in the urine. If a patient already has urate stones or high urinary urate excretion, flooding the urine with even more urate will promote further stone formation. These patients need XOI instead (which decreases total body urate production, reducing both serum AND urinary urate).

Feature	Pegloticase	Rasburicase
Mechanism	Recombinant urate oxidase — catalyses conversion of urate into allantoin (≥5× more soluble, readily excreted by kidney) ^[3]^[20]	Same enzyme mechanism
Indication	Severe refractory gout where other agents are ineffective ^[3]	Pre-chemotherapy prevention of tumour lysis syndrome (TLS) — NOT for chronic gout ^[17]^[20]
Administration	8 mg IV infusion over ≥2h, every 2 weeks, with paracetamol/antihistamine pre-med ^[3]	0.2 mg/kg IV over 30 min, daily up to 7 days ^[20]
Key contraindication	G6PD deficiency — hydrogen peroxide is generated as a byproduct of urate oxidation; in G6PD-deficient patients, this cannot be neutralised → haemolysis ^[17]^[20]	Same
Limitation	Patients develop antibodies against pegloticase → ↓ therapeutic response → limiting factor for long-term treatment ^[3]	Short-term use only

Why does rasburicase require stopping allopurinol? From Ryan Ho Haematology: "Stop allopurinol if rasburicase has been started: allopurinol blocks conversion of xanthine to urate and affects rasburicase efficacy" ^[20]. Rasburicase converts urate to allantoin. If allopurinol blocks urate production, there is less substrate for rasburicase to act on, and xanthine/hypoxanthine may accumulate (potentially causing xanthine nephropathy).

Agent	Class	Mechanism	First-Line?	Key Contraindication
Allopurinol	XOI	Purine analogue, competitive XO inhibition	Yes	*HLA-B5801 positive**
Febuxostat	XOI	Non-purine, selective XO inhibition	Second-line	IHD / CHF
Probenecid	Uricosuric	URAT1 inhibition → ↑ renal urate excretion	Second-line	CKD, urate stones
Pegloticase	Uricase	Urate → allantoin	Reserve	G6PD deficiency

From Ryan Ho Rheumatology: "Surgical treatment: primarily limited to complications of tophaceous disease, e.g., infection, local compression (nerve, spinal cord), joint deformity, intractable pain" ^[3].

Indication	Procedure
Tophus excision	Large, symptomatic tophi causing nerve/tendon compression, joint destruction, or cosmetic concerns
Joint replacement	End-stage tophaceous joint destruction (rare)
Drainage of infected tophus	Superinfected tophus requiring surgical debridement

Key principle: Systemic ULT should take precedence over surgery — dissolving tophi with ULT is preferred. Surgery is reserved for complications that ULT cannot address ^[3].

Parameter	Frequency	Target
Serum urate	Every 2–4 weeks during titration, then every 3–6 months	< 0.36 mmol/L (< 0.30 if tophaceous)
RFT	Regularly, especially with XOI or if CKD	Stable eGFR
LFT	If on febuxostat	< 3× ULN
CBC	If on colchicine long-term or azathioprine interaction	Normal counts
Flare frequency	Each visit	Decreasing over time
Tophus size	Each visit	Shrinking / resolving
Comorbidities	Annually	BP, glucose, lipids, BMI controlled

From Ryan Ho Rheumatology: "Dramatic improvement in outcome following introduction of urate-lowering treatment, but prognosis depends on predisposing factors, e.g., diet, alcohol, diuretic use, renal impairment" ^[3].

Without ULT: 2nd flare within 1 year in 62%, within 2 years in 78%, within 10 years in 93% ^[3]
With ULT: Flare frequency decreases dramatically; tophi dissolve over 6–24 months; joint damage stabilised
Key determinant of outcome: Patient adherence to ULT and lifestyle modifications

High Yield Summary — Management of Gout

Acute Management: Three pillars — NSAID (+PPI), colchicine, corticosteroid. Choice depends on comorbidities (renal → steroid; GI risk → colchicine/steroid; CVD/HF → avoid NSAID). Do NOT start ULT during flare; continue if already on it.

Long-Term Management:

Lifestyle: Low purine diet, limit alcohol (esp. beer) and fructose, adequate hydration, weight loss, medication review (switch thiazide → losartan).
ULT indications: ≥2 attacks/year, tophi, urate stones, CKD/nephropathy.
First-line ULT: Allopurinol — start 100 mg daily, titrate weekly, target urate < 0.36 mmol/L. Must check HLA-B*5801 first. Cover with colchicine 0.5 mg daily for 3–6 months.
Alternatives: Febuxostat (if HLA-B*5801+, allopurinol ADR, severe CKD — avoid in IHD/CHF). Probenecid (if XOI contraindicated — avoid in CKD, urate stones).
Drug interaction: XOI + azathioprine → reduce azathioprine by ≥50% or avoid.
Rasburicase: For TLS only, not chronic gout. CI in G6PD deficiency.

Surgery: Reserved for complications of tophaceous disease. ULT takes precedence.

Active Recall - Management of Gout

References

^[1] Lecture slides: GC 075. Pain red joint.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.327–330) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Crystal-Induced Arthritis, p.35–41) ^[4] Senior notes: Learning_Points_All_Lectures.txt (HLA-B5801 screening) ^[14] Senior notes: Block A - Painful red joint_ monoarthropathy, gouty arthritis, septic arthritis, haemarthrosis.pdf (p.23) ^[15] Senior notes: Block A - Upper abdominal pain_ peptic ulcer; pancreatitis and gallstone.pdf (p.25 — NSAID + PPI co-prescription) ^[16] Lecture slides: GC 079. Prescribing in older people.pdf; GC 079 (supp-2) STOPP-START-V3.pdf ^[17] Senior notes: Handbook of Internal Medicine 2024.pdf (p.428 — Allopurinol, Febuxostat, Probenecid, Rasburicase) ^[18] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (p.45 — azathioprine and XOI interaction) ^[19] Senior notes: Introduction to Clinical pharmacology (I) (Pharmaco-Genomics, Precision Medicine).pdf (p.5 — HLA-B5801, azathioprine) ^[20] Senior notes: Ryan Ho Haemtology.pdf (Tumour lysis syndrome, p.72 — rasburicase)

Complications of Gout

Gout is far more than "just a sore joint." It is a systemic metabolic disease with complications spanning the musculoskeletal, renal, cardiovascular, and metabolic systems. These complications arise from two fundamental processes: (1) the direct consequences of MSU crystal deposition in tissues, and (2) the metabolic milieu (hyperuricaemia and its comorbid cluster) that drives gout in the first place.

Category	Complications
Musculoskeletal	Chronic tophaceous gout → joint destruction, deformity; tophus infection; tophus-related nerve/tendon compression
Renal	Urate nephrolithiasis; chronic urate nephropathy (CKD); acute urate nephropathy (AKI)
Cardiovascular	Accelerated atherosclerosis; increased CV events (MI, stroke)
Metabolic	Association with metabolic syndrome (HT, DM, dyslipidaemia, obesity)
Treatment-related	Allopurinol hypersensitivity syndrome (SJS/TEN); NSAID-related GI/renal/CV complications; colchicine toxicity

1. Musculoskeletal Complications

This is the end-stage of untreated or inadequately treated gout, typically developing after ≥10 years of recurrent attacks.

Pathophysiology from first principles:

Persistent hyperuricaemia → ongoing MSU crystal deposition in cartilage, synovium, periarticular bone, and soft tissues
These deposits organise into tophi — collections of solid MSU crystals surrounded by granulomatous inflammation (macrophages, multinucleated giant cells, fibroblasts)
Tophi behave like slow-growing erosive masses:
- They erode bone from outside-in (periarticular erosion) → producing the characteristic "punched-out" erosions with overhanging sclerotic margins on XR ^[2]
- They destroy cartilage → eventual joint space narrowing and loss of function
- They destroy tendons and ligaments → instability, subluxation, deformity

Clinical manifestations of tophaceous complications ^[3]:

Complication	Mechanism	Clinical Features
Progressive joint destruction	Tophaceous erosion of bone and cartilage	Chronic pain, stiffness, reduced ROM, joint deformity. Hands and feet most commonly affected
Ulceration of tophi	Tophus erodes through overlying skin	Discharging whitish, chalky, gritty material (MSU crystite) through skin defects. Looks alarming but is sterile ^[3]
Secondary infection of tophi	Open ulceration provides a portal of entry for bacteria	Cellulitis, abscess formation, osteomyelitis. Can be difficult to distinguish from simple tophaceous inflammation
Tophaceous inflammation mimicking dactylitis	When inflammation extends along the entire digit	May mimic dactylitis of spondyloarthritis — swollen "sausage digit" ^[3]
Nerve/tendon compression	Tophi in periarticular soft tissues compress adjacent structures	Carpal tunnel syndrome (median nerve compression by wrist tophi), Achilles tendon rupture, triggering of fingers
Spinal cord compression	Rare: tophi in vertebral canal	Myelopathy — a surgical emergency

From Ryan Ho Rheumatology: "Surgical treatment: primarily limited to complications of tophaceous disease, e.g., infection, local compression (nerve, spinal cord), joint deformity, intractable pain" ^[3]. Surgery is reserved for these structural complications that medical ULT alone cannot address — but systemic ULT should always take precedence and can dissolve tophi over 6–24 months if the target urate (< 0.30 mmol/L for tophaceous gout) is achieved.

2. Renal Complications

The kidney is the second most important target organ in gout, because it handles the majority of urate excretion and is therefore exposed to high urate concentrations.

Gout and hyperuricaemia are strongly associated with cardiovascular disease. Whether this is a causal relationship or merely association through shared risk factors (metabolic syndrome) remains debated, but the clinical consequence is the same: gout patients have significantly higher CV morbidity and mortality.

Proposed mechanisms of urate-mediated CV harm:

Endothelial dysfunction: Uric acid inhibits nitric oxide (NO) production → ↓ vasodilation → ↑ blood pressure → accelerated atherosclerosis
Oxidative stress: Although uric acid is an extracellular antioxidant, intracellular urate generates reactive oxygen species via NADPH oxidase → vascular smooth muscle proliferation → atherogenesis
Inflammation: Chronic low-grade inflammation from persistent crystal deposits → systemic release of IL-1β, IL-6, TNFα → promotes atherogenesis
Insulin resistance: Hyperuricaemia and insulin resistance are bidirectionally linked → both promote endothelial dysfunction

Clinical CV associations:

CV Complication	Relationship to Gout
Hypertension	Most common comorbidity of gout ^[5]. Bidirectional causation
Coronary artery disease / MI	Increased risk (OR ~1.2–1.6 in epidemiological studies)
Heart failure	Independent association; hyperuricaemia is a poor prognostic marker in HF
Stroke	Modestly increased risk
Peripheral arterial disease	Increased risk
Atrial fibrillation	Emerging association

Clinical implication: Every gout patient should receive a comprehensive cardiovascular risk assessment — BP, lipids, fasting glucose, smoking status, BMI. Managing gout in isolation without addressing CV risk is incomplete care.

Gout is considered a "red flag" for metabolic syndrome. The clustering is not coincidental — insulin resistance is the common thread:

Component	Link to Hyperuricaemia
Obesity	Adipose tissue increases purine turnover; insulin resistance ↓ renal urate excretion
Hypertension	Renal microvascular changes ↓ urate excretion; hyperuricaemia causes endothelial dysfunction
Dyslipidaemia	Shared dietary/lifestyle risk factors; fenofibrate and atorvastatin are mildly uricosuric
Impaired glucose tolerance / T2DM	Insulin resistance directly ↓ renal tubular urate secretion via SLC2A9/GLUT9

A gout diagnosis should prompt screening for all components of metabolic syndrome. From Maksim Medicine Notes: "Screen comorbidities: RFT (+ eGFR), fasting glucose, lipids, BP, BMI" ^[2].

These are complications arising from the drugs used to treat gout rather than from gout itself, but they are frequently examined.

From pharmacogenomics lecture: "Allopurinol and carbamazepine — always [check HLA before prescribing]" ^[19]. From Learning Points: "HLA-B*5801 screening before allopurinol initiation, particularly important in Han Chinese populations with 8% carrier frequency. This genetic variant dramatically increases severe cutaneous adverse reaction risk including Stevens-Johnson syndrome" ^[4].

Feature	Details
Incidence	*~0.1% overall, but much higher in HLA-B5801 carriers**
Risk factors	*HLA-B5801 positive (8–14% carrier rate in HK Han Chinese), elderly, CKD, NOT dose-dependent** ^[2]
Onset	Usually within 3 weeks of starting allopurinol ^[2]
Clinical syndrome	Severe cutaneous adverse reaction (SCAR): SJS/TEN + fever + eosinophilia + hepatitis + progressive renal failure
Mortality	~27% ^[2] — this is why screening is so critical
Prevention	*Mandatory HLA-B5801 screening before allopurinol prescription. If positive → do NOT prescribe allopurinol; use febuxostat or alternative** ^[4]^[17]^[19]
Management	Immediate drug discontinuation, supportive care (often ICU), dermatology/burns unit for SJS/TEN

Exam Must-Know: HLA-B*5801 and Allopurinol

From the Hong Kong HA Expert Panel Meeting (November 2022): Universal screening for HLA-B*5801 allele is recommended before starting allopurinol for all HA patients ^[17].

This is one of the clearest examples of pharmacogenomics in clinical practice. The cost of HLA screening (~HKD 500–800) is trivial compared to the cost (financial and human) of managing SJS/TEN. This is a favourite exam question at HKUMed.

Complication	Mechanism	Prevention
GI bleeding / peptic ulcer	COX-1 inhibition → ↓ gastric mucosal prostaglandins → ↓ mucus and bicarbonate secretion → mucosal injury	Co-prescribe PPI; use COX-2 selective if high GI risk ^[15]
AKI	Renal prostaglandin (PGE2, PGI2) inhibition → afferent arteriolar vasoconstriction → ↓ GFR	Avoid in CKD; ensure adequate hydration; monitor RFT
Cardiovascular events	COX-2 inhibition → ↓ PGI2 (vasodilator, anti-thrombotic) with preserved TXA2 → prothrombotic state	Avoid in high CV risk; use shortest course at lowest dose
Fluid retention / worsening HF	↓ Renal prostaglandins → sodium and water retention + ↑ afterload	Avoid in heart failure

Complication	Mechanism	Prevention
GI toxicity (diarrhoea, nausea, vomiting)	Inhibition of microtubule function in GI epithelial cells → disrupted enterocyte turnover	Use low-dose regimen
Bone marrow suppression (pancytopenia)	Antimitotic effect on rapidly dividing haematopoietic precursors	Avoid prolonged high-dose use; avoid in severe CKD
Fatal multi-organ failure	Severe toxicity when combined with strong CYP3A4 inhibitors (clarithromycin, ketoconazole) or P-gp inhibitors (cyclosporine) → colchicine accumulation	Check drug interactions; reduce dose or avoid combination ^[16]
Myopathy/neuropathy	Chronic colchicine use → disruption of microtubule-dependent axonal transport and muscle function	Monitor for weakness/paraesthesia; avoid in severe CKD/hepatic impairment

STOPP criteria: Long-term colchicine for chronic gout if CrCl < 10 mL/min — risk of fatal accumulation ^[16].

Often overlooked but clinically important:

Complication	Explanation
Impaired quality of life	Recurrent excruciating flares, chronic pain, disability from joint destruction
Work productivity loss	Acute attacks cause days of immobility; chronic disease impairs function
Depression and anxiety	Chronic pain, dietary restrictions, disability
Social stigma	Historical association of gout with overindulgence ("disease of kings") → patients feel blamed for their condition

System	Complication	Key Feature	Reversible?
MSK	Chronic tophaceous gout	Joint destruction, deformity, tophi	Partly (tophi dissolve with ULT; joint damage permanent)
MSK	Tophus infection	Ulcerated tophus + portal of entry	Yes (antibiotics ± surgery)
MSK	Nerve/tendon compression	Carpal tunnel, trigger finger, Achilles rupture	May need surgery
Renal	Urate nephrolithiasis	Renal colic; radiolucent stones	Yes (dissolution, prevention)
Renal	Chronic urate nephropathy	Progressive CKD, interstitial fibrosis	Partially (ULT may slow progression)
Renal	Acute urate nephropathy	AKI from tubular crystal obstruction (TLS)	Yes (rasburicase, dialysis)
CV	Accelerated atherosclerosis	↑ MI, stroke, PAD, HF risk	Risk modification
Metabolic	Metabolic syndrome	HT, DM, dyslipidaemia, obesity	Modifiable
Treatment	AHS / SJS / TEN	Allopurinol + HLA-B*5801	Prevented by screening
Treatment	NSAID complications	GI bleed, AKI, CV events, HF	Prevented by careful prescribing
Treatment	Colchicine toxicity	Pancytopenia, multi-organ failure	Prevented by dose/interaction awareness

High Yield Summary — Complications of Gout

Musculoskeletal: Chronic tophaceous gout → joint destruction (punched-out erosions, overhanging margins), deformity, disability. Tophi can ulcerate (discharge chalky material), become infected, compress nerves/tendons, or mimic dactylitis. Without ULT, intercritical periods shorten and disease becomes polyarticular and continuous.

Renal: (1) Urate nephrolithiasis (~10–25%; radiolucent stones; prevented by hydration, urine alkalinisation, ULT). (2) Chronic urate nephropathy (medullary interstitial crystal deposition → fibrosis → CKD). (3) Acute urate nephropathy (massive crystal precipitation in tubules → AKI; classically in TLS; treat with rasburicase).

Cardiovascular: HT is the most common comorbidity. Hyperuricaemia is an independent CV risk factor → increased MI, stroke, HF. Screen and manage all CV risk factors.

Treatment-related: AHS/SJS/TEN from allopurinol (mortality ~27%; prevented by mandatory HLA-B*5801 screening in HK). NSAID GI/renal/CV toxicity. Colchicine toxicity (especially with CYP3A4 inhibitors or in CKD). Febuxostat hepatotoxicity and CV risk.

Key principle: Gout is a systemic disease. Managing the joint alone is insufficient — you must screen and treat comorbidities and prevent both disease-related and treatment-related complications.

Active Recall - Complications of Gout

References

^[2] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.327–330) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Crystal-Induced Arthritis, p.35–41) ^[4] Senior notes: Learning_Points_All_Lectures.txt (HLA-B*5801 screening) ^[5] Senior notes: Block A - High blood pressure_ hypertension.pdf (p.21) ^[6] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p.41 — pyrazinamide and hyperuricaemia) ^[7] Senior notes: Maksim Surgery Notes.pdf (Urinary stones, p.312–313) ^[15] Senior notes: Block A - Upper abdominal pain_ peptic ulcer; pancreatitis and gallstone.pdf (p.25) ^[16] Lecture slides: GC 079. Prescribing in older people.pdf; GC 079 (supp-2) STOPP-START-V3.pdf ^[17] Senior notes: Handbook of Internal Medicine 2024.pdf (p.428) ^[19] Senior notes: Introduction to Clinical pharmacology (I) (Pharmaco-Genomics, Precision Medicine).pdf (p.5) ^[20] Senior notes: Ryan Ho Haemtology.pdf (Tumour lysis syndrome, p.72)

High Yield Summary

Definition: Crystal arthropathy from MSU crystal deposition in joints/tissues due to chronic hyperuricaemia (> 6.8 mg/dL).

Epidemiology: M>>F (5–9:1), prevalence ~1–4%, rising. Males from 4th–5th decade; females post-menopausal. HK: HLA-B*5801 prevalence ~8% (must screen before allopurinol).

Classification: Asymptomatic hyperuricaemia → acute gouty arthritis → intercritical gout → chronic tophaceous gout. Compare with pseudogout: CPPD, rhomboid, positively birefringent.

Key Precipitants: Surgery (post-op D3–5), dietary indiscretion, alcohol, dehydration, drugs altering urate, trauma, starting ULT.

Comorbidities: HT (most common), metabolic syndrome, CKD, CVD, DM, dyslipidaemia.

High Yield Summary — DDx of Gout

Always exclude septic arthritis first — it is a rheumatological emergency that can destroy cartilage in days. A hot swollen joint = septic arthritis until proven otherwise.
Joint aspiration is the cornerstone investigation — send for crystals (polarised microscopy), Gram stain, culture, cell count. Finding crystals does NOT exclude infection.
Key DDx: Septic arthritis, pseudogout (CPPD), RA flare, psoriatic arthritis, reactive arthritis, haemarthrosis, OA flare, cellulitis, osteomyelitis.
Gout crystals: MSU, needle-shaped, negatively birefringent. Pseudogout crystals: CPPD, rhomboid, positively birefringent.
Serum urate is useful but not diagnostic — normal in ~50% of acute flares; elevated in many people without gout. Best measured ≥2 weeks post-flare.
Chronic tophaceous gout can mimic RA (polyarticular, nodular) or osteomyelitis (destructive). Crystal analysis and serology differentiate.
Gout + septic arthritis can coexist — never assume a known gout patient with an acute flare is "just gout" if clinically unwell.

High Yield Summary — Diagnosis of Gout

Serum Urate: Useful but NOT diagnostic. Can be normal during acute flare. Best measured ≥ 2 weeks post-flare. Used for monitoring ULT.

XR: Normal acutely. Chronic: punched-out erosions with overhanging sclerotic margins, preserved joint space (early), soft tissue tophi.

USG: Double contour sign (highly specific). DECT: Colour-coded urate deposits (expensive, not first-line).

Bloods: CBC (neutrophilic leukocytosis), ESR/CRP (elevated), RFT, fasting glucose, lipids (comorbidity screen), HLA-B*5801 before allopurinol.

Key Principle: Gout is primarily a clinical diagnosis, confirmed by crystal analysis when aspiration is performed.

High Yield Summary — Management of Gout

Long-Term Management:

Lifestyle: Low purine diet, limit alcohol (esp. beer) and fructose, adequate hydration, weight loss, medication review (switch thiazide → losartan).
ULT indications: ≥2 attacks/year, tophi, urate stones, CKD/nephropathy.
First-line ULT: Allopurinol — start 100 mg daily, titrate weekly, target urate < 0.36 mmol/L. Must check HLA-B*5801 first. Cover with colchicine 0.5 mg daily for 3–6 months.
Alternatives: Febuxostat (if HLA-B*5801+, allopurinol ADR, severe CKD — avoid in IHD/CHF). Probenecid (if XOI contraindicated — avoid in CKD, urate stones).
Drug interaction: XOI + azathioprine → reduce azathioprine by ≥50% or avoid.
Rasburicase: For TLS only, not chronic gout. CI in G6PD deficiency.

Surgery: Reserved for complications of tophaceous disease. ULT takes precedence.

High Yield Summary — Complications of Gout

Cardiovascular: HT is the most common comorbidity. Hyperuricaemia is an independent CV risk factor → increased MI, stroke, HF. Screen and manage all CV risk factors.

Gout

Definition

Epidemiology

Global & Hong Kong Context

Temporal Trends

Risk Factors

Non-Modifiable

Modifiable

Drug-Induced Hyperuricaemia (High Yield)

Anatomy and Function: Uric Acid Metabolism

Purine Metabolism (Source of Uric Acid)

Renal Urate Handling

Key Enzymes

Etiology and Pathophysiology

Causes of Hyperuricaemia — A Systematic Framework

1. Decreased Excretion (~90% of cases) [2][3]

2. Increased Production (~10% of cases) [2][3]

Pathophysiology of Crystal Formation and Inflammation

Step 1: Crystal Formation (Why do crystals form?)

Step 2: Inflammatory Response (Why does crystal deposition cause inflammation?)

Classification

Classification by Clinical Stage

Classification by Crystal Type (Important for DDx)

Clinical Features

A. Symptoms (with Pathophysiological Basis)

1. Acute Gouty Arthritis

2. Intercritical Period

3. Chronic Tophaceous Gout

4. Extra-Articular Manifestations

B. Signs (with Pathophysiological Basis)

During Acute Attack

Signs of Chronic Tophaceous Gout

Signs to Look For on Examination (Systematic Approach)

Precipitating Factors for Acute Gout Attacks (Summary)

Associations and Comorbidities (Hong Kong Focus)

Key Points from Lecture Slides

Active Recall - Gout (Definition, Epidemiology, Risk Factors, Etiology, Pathophysiology, Classification, Clinical Features)

References

The Clinical Problem: Why is DDx Important?

Framework for DDx: The "Painful Red Joint"

Detailed Differential Diagnosis

1. Septic Arthritis (THE Must-Not-Miss Diagnosis)

2. Pseudogout (CPPD Crystal Arthritis)

3. Rheumatoid Arthritis (RA)

4. Psoriatic Arthritis / Spondyloarthritis

5. Osteoarthritis (OA) Flare / Erosive OA

6. Haemarthrosis

7. Reactive Arthritis (Reiter Syndrome)

8. Other Important Differentials

Clinical Approach to DDx: How to Differentiate

History Clues Favouring Gout

History Clues Against Gout (Red Flags for Other Diagnoses)

Synovial Fluid Analysis — The Diagnostic Cornerstone

Summary Comparison Table: Key Differentials at a Glance

When Gout Mimics Other Conditions (Important Exam Scenarios)

Active Recall - Differential Diagnosis of Gout

Diagnostic Approach: First Principles

Definitive Diagnosis: Joint / Tophus Aspirate

2015 ACR/EULAR Gout Classification Criteria

Entry Criterion (Mandatory)

Sufficient Criterion (Overrides Everything)

Scoring Criteria (When Crystal Demonstration Not Available)

Diagnostic Algorithm

Investigation Modalities: Detailed Interpretation

1. Joint Aspiration and Synovial Fluid Analysis (MOST IMPORTANT TEST)

Indications for Joint Aspiration [13]

What to Send For [11][13]

Synovial Fluid Interpretation Table [11]

Crystal Microscopy: The Details

2. Serum Uric Acid Level

3. Blood Tests (Supportive, Not Diagnostic)

4. Plain Radiograph (XR)

5. Ultrasound (USG)

6. Dual-Energy CT (DECT)

7. Other Imaging

8. Tophus Biopsy / Aspiration

Summary of Investigation Approach

Key Investigation Pitfalls

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for Gout

Management Principles: A Conceptual Framework