Gout and CPPD

Question 1

Epidemiology of gout

Answer 1

• Most common inflammatory arthritis
  
  • Western developed countries → 3.6% male, 1-2% female
• Prevalence increases with age and serum urate
  
  • SU rises in puberty in males, after menopause in females
• Peak age onset 40-50 men, > 60 in females
• Higher incidence in Maori and Pacific Islanders
• Common co-morbidities: obesity, hypertension, CKD, diabetes

Question 2

Aetiology and pathophysiology of gout

Answer 2

• Hyperuricaemia → precipitation of monosodium urate crystals → inflammatory response to MSU crystal deposition
• Central risk factor → hyperuricaemia
  
  • Serum urate concentration > solubility threshold for MSU under physiologic conditions: 0.45 → gout increases exponentially beyond this though most at this threshold won’t develop gout
• Other factors affecting crystallisation → temperature, pH, other ionic concentrations, connective tissue factors

Urate

• Metabolic end-product of purine catabolism
  
  • Purine enzymatic catabolism → xathine → converted to urate by xanthine oxidase
  • Humans and primates lack uricase to convert urate to allantoic acid
• Urate concentration depends on
  
  • Intrinsic purine production
  • Purine intake through diet
  • Excretion - renal and gastrointestinal

Precipitation of MSU crystals in joint

• Recognised by TLR 2 → proinflammatory cytokines
• MSU coated with IgG → activates complement → phagocytosis
• Cytokine production → IL1

Question 3

Causes of urate over-production

Answer 3

10% cases of hyperuricaemia

Primary urate over-production due to inborn errors of metabolism

• Accelerated purine synthesis (PRPP synthase enzyme hyperactivity)
• Impaired purine salvage (HGPRT1 deficiency)
  
  • Complete → Lesch-Nyhan syndrome: X linked recessive, severe hyperuricaemia, gout, nephrolithiasis, mental retardation, movement and behavioural disorders
  • Partial → Kelley-Seegmiller syndrome: gout, no neuro symptoms
• Hereditary defects of energy metabolism (accelerated ATP consumption): glucose-6-phosphatase deficiency, fructose-1-phosphate aldolase deficiency

Increased cell turnover

• Autoimmune and haemolytic anaemia
• Sickle cell disease
• Polycythaemia vera
• Ineffective erythropoiesis (megaloblastic anaemia, thalassemia)
• Myeloproliferative and lymphoproliferative disorders
• Tumour lysis syndrome

Dietary

• Foods high in purine → seafood (shellfish), red meat (particularly organ meat). Fructose (sucrose in soft drinks metabolised to fructose + glucose - alters hepatic metabolism to increase purines)
• Alcohol → increased ATP degradation & purine turnover, increased lactate reduces renal urate excretion, beer → high in purines
• (Foods associated with lower serum urate) → low fat dairy products or milk proteins, cherries (uricosuric effect), heavy caffeine consumption

Question 4

Causes of underexcretion of urate in gout

Answer 4

Most hyperuricaemia due to underexcretion gout

Gastrointestinal

• Responsible for 20-30% urate excretion
• Exocrine secretion, urate transporter ABCG2

Renal

• All urate → ultrafiltration at glomerulus
• Proximal tubule reabsorption (90-98%) - URAT1, OAT4, 10, Glut9a
• Proximal tubule secretion → 10% excretion of filtered load - OAT1, ABCG2 transporter, MRP4, NPT1, NPT4

Primary underexcertion

• ABCG2 loss of function → decreased renal and gastrointestinal excretion
• URAT1 gain of function → increased reabsorption

Secondary underexcretion

• CKD
• Medications → diuretics (thiazide, loop), low dose aspirin (promote urate reabsorption by URAT1, OAT 10), pyrazinamide, ciclosporin
• Toxins → lead.

Question 5

Presentation of gout

Answer 5

• Asymptomatic hyperuricaemia - less than ⅔ will develop gout
• Gout flares - acute inflammatory arthritis
  
  • First flare - usually monoarticular, MTP1
  • Any joint, tendon and bursa, acute onset maximum in 4-24 hours, resolution within 1-2 weeks
  • Recurrent episodes separated by asymptomatic periods → intercritical gout
• Subcutaneous tophi → macroscopic collections of MSU cystals & associated host tissue response
  
  • Most common sites → fingers - IP joints, wrists, olecranon bursae, ulnar aspect forearm, helix of ear
• Chronic gouty arthritis - persistent synovitis secondary to MSU crystal mediated inflammation. Can be polyarticular and mimic RA

Question 6

Diagnosis, differential diagnosis, investigations for gout

Answer 6

Differential diagnosis

• CPPD, septic arthritis, trauma, spondyloarthritis, sarcoidosis

Investigations

• Bloods → urate (may be reduced during flares), inflammatory markers raised
• Joint aspiration with polarised light microscopy → intra-cellular needle shaped negatively birefringement crystals
• Imaging
  
  • Plain films → gouty bone erosions, evidence of cortical break in bone, overhanging edge with sclerotic margin
  • Ultrasound → MSU crystal deposition (double contour sign, hyperechoic aggregates, tophi), synovitis, erosions
  • Dual energy CT → erosions, MSU crystal deposition

Question 7

Treatment options for gout flare

Answer 7

• NSAID, COX-2 inhibitor
• Prednisone - may require high doses
• Colchicine
  
  • 1mg followed by 500 micrograms one hour later, adjusted for renal insufficiency
• Intra-articular corticosteroid injection

Question 8

Options for urate-lowering therapy in gout

Answer 8

• Xanthine oxidase inhibitors
  
  • Allopurinol
  • Febuxostat
• Uricosuric agents - promote urinary excretion of uric acid
  
  • Probenecid
  • Benzbromarone

Question 9

Notes on allopurinol in gout

Answer 9

• First line ULT → inhibits xanthine oxidase, disrupts purine catabolism
• Half life short - 1-2 hours
  
  • Metabolised to oxypurinol: long half life (15 hours); increased by kidney failure
• Start at 100mg (50mg if eGFR < 60)
  
  • Increased by 100mg every 2-4 weeks until target serum urate reached
    
    • <0.36 in all patients, <0.3 in severe gout - frequent flares, subcut tophi, gouty bone erosions
    • UK study comparing nurse-led treat to target ULT vs GP led care (usual) → nurse led group significant reductions in → gout flare frequency, tophus size, improved quality of life
  • Max dose 800-900mg

Adverse effects

1. Allopurinol hypersensitivity syndrome
   
   1. Rare, usually <2 months treatment
   2. Desquamating rash, fever, eosinophilia, end-organ damage
   3. Prevention → adjust initial dose for renal function, HLA B*5801 genotyping in high risk populations (Han Chinese, Thai), rash → discontinue
2. Increase in gout flares on initiation or titration of ULT
3. Thiazide diuretics can decrease renal excretion → increased allopurinol hypersensitivity risk

Question 10

Notes on febuxostat

Answer 10

• Non-purine, selective inhibitor of xanthine oxidase → inhibits production of uric acid by preventing normal oxidation of purines to uric acid
• Causes inhibition of both reduced and oxidised forms of xanthine oxidase → more potent than allopurinol
• All cause and CVS mortality higher with febuxostat → reserved for patients who are allergic to allopurinol or do not benefit from it. Allopurinol remains first line

Question 11

Notes on uricosuric therapy - probenecid and benzbromarone

Answer 11

• Inhibit URAT1 and GLUT9 in proximal tubule
  
  • Reduce reabsorption and promote elimination of urate
  • Contraindicated if history of nephrolithiasis
  • Less effective in CKD
• Probenecid
  
  • Short half life - BD dosing
  • Can be used as mono- or combination ULT
• Benzbromarone
  
  • OD dosing
  • Hepatotoxic, not available through PBS

Question 12

Notes on gout flare prophylaxis

Answer 12

• Initiation of ULT associated with increased risk gout flares → may be reduced by slow upward titration of ULT
• Limited evidence
  
  • Benefit of low dose colchicine in gout flare prophylaxis
  • 6 months duration from initiation of ULT
  • Colchicine 500 micrograms daily or BD - avoid in CKD, or statin therapy
  • Low dose NSAIDs if not contraindicated
  • Rarely - low dose prednisone

Question 13

Epidemiology and pathogenesis of calcium pyrophosphate deposition disease

Answer 13

Epidemiology

• Prevalence unclear
• Strong associations with age (rare <55 years), osteoarthritis
• A/W metabolic disease, hypomagnesaemia (renal or GIT loss), hyperparathyroidism, haemochromatosis, hypophsphatasia, joint injury

Aetiology/pathogenesis

• Calcium pyrophosphate dihydrate deposition in articular cartilage
• Requires high levels of inorganic pyrophosphate: produced by chondrocytes and moved extracellularly by transmembrane protein ANKH
• CPP crystals → inflammation, including activation of NLRP3 inflammasome
• Nucleation CPP crystals enhanced by → increased calcium (hyperparathyroidism) and iron (haemochromatosis), decreased magnesium (Mg inhibits nucleation), cartilage damage due to osteoarthritis

Question 14

Clinical presentation CPPD

Answer 14

• Acute
  
  • Monoarthritis, knee most common, wrist, shoulder, ankle, elbow. Acute inflammatory arthritis, self limited 1-3 weeks duration
• Chronic CPP inflammatory arthritis
  
  • Can mimic seronegative RA, PMR
• Osteoarthritis with CPPD
  
  • Causes OA in joints not typically involved (MCP joints, wrists, elbows)

Question 15

Diagnosis of CPPD

Answer 15

Note radiographic chondrocalcinosis common in elderly and often asymptomatic

Diagnostic approach

• Synovial fluid aspirate
  
  • Leucocytosis >90% neutrophils
  • Rhomboid/rod-shaped crystals
  • Compensated polarised light microscopy: minority (20%) show weak positive birefringence
  • Harder to identify than MSU crystals
• Plain films or MSK ultrasound ?crystal deposition
  
  • Involvement at sites uncommon for primary OA - MCP, wrists, elbows shoulders
  • Xrays knees, pelvis, wrists → may show chondrocalcinosis
  • Prominent osteophyte formation, hook osteophytes of the MCP joints
  • Ultrasound → higher sensitivity than xray for chondrocalcinosis, fouble contour sign, crystal deposition often within hyaline articular cartilage
• CT spine for axial involvement
  
  • Cervical stenosis - from CPPD in the ligamentum flavum +/- transverse ligament of the atlas
  • Crowned dens syndrome (neck, shoulder girdle pain): CPPD surrounding odontoid process
  • Intervertebral disc calcifications and sacro-iliac joint involvement
• In patients < 55 years → evaluate for primary metabolic disorder
  
  • Serum calcium, phosphate, ALP, PTH
  • Magnesium
  • Iron studies

Question 16

Management and monitoring of CPPD

Answer 16

• Acute inflammatory arthritis
  
  • NSAID and COX-2 inhibitor therapy
  • Prednisone
  • Intra-articular steroid injection
• Prophylaxis to reduce frequency of flares
  
  • Low dose colchicine
  • Limited evidence for hydroxychloroquine and methotrexate