Gout 2 Flashcards
what is chronic gout
destructive polyarticular involvement with low grade joint inflammation, joint deformity and tophi
when does tophaceous gout develop
develops within 5 years of onset of gout in 30% of untreated patients
describe the effect of tophi
- tophi are painless and rarely become infected
- but function and health related quality of life can be severely affected with chronic gout - large tophi can reduce joint movement and may be surgically removed
what are tophi
- a sign of chronic gout
- build up of uric acid crystals under skin
- anti gout treatment can gradually shrink tophi
outline the treatment of chronic gout in all patients
- patient education
- optimise weight
- modify diet
- reduce alcohol intake
- discontinue diuretic
- treat underlying CV risk factors
- Discuss ULT with patient
outline the treatment of chronic gout in initiating ULT
- first line ULT- allopurinol
- start at low dose 50-100mg daily
- dose reduce all patients with renal insufficiency or use alternative - titrate allopurinol dose every 4 weeks dependant on sUA
- target sUA <300umol/l
- maximum dose 600mg daily
- consider prophylaxis
- don’t stop allopurinol during acute attacks
describe allopurinol toxicity
- careful use in patients with renal failure
- metabolites are renally cleared
- hypersensitivity reactions more common - purine associated hypersensitivity syndrome is different from allergic rash
- systemic and sometimes life threatening illness
- fever, hepatitis, nephritis - the role of HLA B5801 and allopurinol hypersensitivity is unquestionned
- all patients from populations with a high allele frequency for HLA B5801 and high hazard ratio for developing hypersensitivity should be screened
- allopurinol is a purine derivative
describe the second line therapy for gout treatment
- if inability to tolerate allopurinol or renal function prevents sufficient dose escalation,
- consider switch to febuxostat
- increase dose after 4 weeks if target sUA not reached
what is febuxostat
a non purine selective inhibitor of xanthine oxidase
what are the uses of febuxostat
- first treatment in 40 years for chronic gout
- theoretically safe to use in patients with allopurinol sensitivity reactions
- has been studied in patients with mild renal insufficiency
- dosed at 40-80mg/od
describe the benefits of febuxostat
- more potent than 300mg/day allopurinol
- not a purine- appropriate for patients with allopurinol hypersensitivity
- can be used safely in patients with mild renal insufficiency
describe the action of uricosuric agents
- URAT1 is a member of the OAT (organic anion transporter) family and an anion exchange uptake transporter
- blocking URAT1 reduces uric acid reabsorption
describe the role of sulfinpyrazone
- inhibits URAT 1
- can cause GI upset
- needs to be taken with large quantities of water to prevent kidney stones
- there are better alternatives
what is the role of probenecid
- uricosuric agent that blocks tubular reabsorption of uric acid
- useful in patients who under excrete uric acid
when should probenecid not be used
don’t use in
- tophi
- renal impairment
- clear overproduction syndrome
describe the role of benzbromarone
- unlicensed in UK- needs to be imported
- non competitive inhibitor of XO
- can be used in renal impairment
- withdrawn from several markets because of hepatotoxicity
- must have regular lFTs
describe the role of lesinurad
- used in combination with a XO inhibitor where this alone doesn’t achieve target
- inhibits URAT 1 and so reduces reabsorption of uric acid in kidneys
- 200mg od with XO
- NICE rejected in 2018
outline the renal complications that could occur
- nephrolithiasis- kidney stones
- chronic urate nephropathy
what are the risk factors of nephrolithiasis
- increased uric acid excretion
- reduced urine volume
- low urine pH
what is chronic urate nephropathy
urate crystals can deposit in renal medullary interstitium, producing inflammatory changes and fibrosis
- biopsy confirms diagnosis
describe the role of uricase
- enzyme that converts insoluble uric acid to more soluble metabolite allantoin
- humans have lost gene function to produce uricase
- rasburicase- drug delivered from aspergillus, used to treat tumour lysis syndrome
- extremely immunogenic, which limits its half life and use in chronic diseases
what is the role of pegloticase
- mammalian uricase
- peglyated- increases half life and reduces immunogenicity
- administered by IV infusion every 2 weeks
what are the adverse effects of pegloticase
- infusion reactions
- many patients develop antibodies to drug that increase its clearance
- anaphylaxis
- 80% of patients had gout flares despite prophylaxis
- contraindicated in G6PD deficient patients
what are the adverse effects of pegloticase
- infusion reactions
- many patients develop antibodies to drug that increase its clearance
- anaphylaxis
- 80% of patients had gout flares despite prophylaxis
- contraindicated in G6PD deficient patients
- may exacerbate heart failure
describe how IL1 and urate driven inflammation occurs
- inflammatory cells can innately recognise common microbial features as danger signals
- flagella, viral RNA
- excess uric acid and associated crystals recognised in same way - leads to rapid inflammation
- microbial patterns bind to toll like receptors and lead to increase in pro IL1
what are the biologic targets in gout therapy
- gout pathogenesis:
- super saturated serum levels of uric acid lead to crystal formation and deposits in joints
- crystals are engulfed by macrophages
- macrophages release inflammatory cytokines
- recruit more inflammatory cells and perpetuate joint inflammation
describe the production of IL1
- pro IL1 is inactive but capable of being rapidly metabolised to active IL1
- machinery that cleaves pro IL1 to active IL1 is called the inflammasone
give examples of IL1 blockers
- IL1 receptor antagonist- anakinra
- anti IL1 antibody- canakinumab
- IL1 decoy receptor fusion protein- rilanocept
