Gout and CPPD Flashcards
1
Q
Epidemiology of gout
A
- 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
2
Q
Aetiology and pathophysiology of gout
A
- 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
3
Q
Causes of urate over-production
A
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
4
Q
Causes of underexcretion of urate in gout
A
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.
5
Q
Presentation of gout
A
- 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
6
Q
Diagnosis, differential diagnosis, investigations for gout
A
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
7
Q
Treatment options for gout flare
A
- 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
8
Q
Options for urate-lowering therapy in gout
A
- Xanthine oxidase inhibitors
- Allopurinol
- Febuxostat
- Uricosuric agents - promote urinary excretion of uric acid
- Probenecid
- Benzbromarone
9
Q
Notes on allopurinol in gout
A
- 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
- Increased by 100mg every 2-4 weeks until target serum urate reached
Adverse effects
- Allopurinol hypersensitivity syndrome
- Rare, usually <2 months treatment
- Desquamating rash, fever, eosinophilia, end-organ damage
- Prevention → adjust initial dose for renal function, HLA B*5801 genotyping in high risk populations (Han Chinese, Thai), rash → discontinue
- Increase in gout flares on initiation or titration of ULT
- Thiazide diuretics can decrease renal excretion → increased allopurinol hypersensitivity risk
10
Q
Notes on febuxostat
A
- 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
11
Q
Notes on uricosuric therapy - probenecid and benzbromarone
A
- 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
12
Q
Notes on gout flare prophylaxis
A
- 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
13
Q
Epidemiology and pathogenesis of calcium pyrophosphate deposition disease
A
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
14
Q
Clinical presentation CPPD
A
- 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)
15
Q
Diagnosis of CPPD
A
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
