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PY365 Autoimmune Cluster > Gout 2 > Flashcards

Gout 2 Flashcards

1
Q

what is chronic gout

A

destructive polyarticular involvement with low grade joint inflammation, joint deformity and tophi

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2
Q

when does tophaceous gout develop

A

develops within 5 years of onset of gout in 30% of untreated patients

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3
Q

describe the effect of tophi

A
  1. tophi are painless and rarely become infected
    - but function and health related quality of life can be severely affected with chronic gout
  2. large tophi can reduce joint movement and may be surgically removed
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4
Q

what are tophi

A
  1. a sign of chronic gout
  2. build up of uric acid crystals under skin
  3. anti gout treatment can gradually shrink tophi
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5
Q

outline the treatment of chronic gout in all patients

A
  1. patient education
  2. optimise weight
  3. modify diet
  4. reduce alcohol intake
  5. discontinue diuretic
  6. treat underlying CV risk factors
  7. Discuss ULT with patient
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6
Q

outline the treatment of chronic gout in initiating ULT

A
  1. first line ULT- allopurinol
  2. start at low dose 50-100mg daily
    - dose reduce all patients with renal insufficiency or use alternative
  3. titrate allopurinol dose every 4 weeks dependant on sUA
  4. target sUA <300umol/l
  5. maximum dose 600mg daily
  6. consider prophylaxis
  7. don’t stop allopurinol during acute attacks
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7
Q

describe allopurinol toxicity

A
  1. careful use in patients with renal failure
    - metabolites are renally cleared
    - hypersensitivity reactions more common
  2. purine associated hypersensitivity syndrome is different from allergic rash
    - systemic and sometimes life threatening illness
    - fever, hepatitis, nephritis
  3. the role of HLA B5801 and allopurinol hypersensitivity is unquestionned
  4. 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
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8
Q

describe the second line therapy for gout treatment

A
  1. if inability to tolerate allopurinol or renal function prevents sufficient dose escalation,
  2. consider switch to febuxostat
    - increase dose after 4 weeks if target sUA not reached
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9
Q

what is febuxostat

A

a non purine selective inhibitor of xanthine oxidase

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10
Q

what are the uses of febuxostat

A
  1. first treatment in 40 years for chronic gout
  2. theoretically safe to use in patients with allopurinol sensitivity reactions
  3. has been studied in patients with mild renal insufficiency
  4. dosed at 40-80mg/od
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11
Q

describe the benefits of febuxostat

A
  1. more potent than 300mg/day allopurinol
  2. not a purine- appropriate for patients with allopurinol hypersensitivity
  3. can be used safely in patients with mild renal insufficiency
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12
Q

describe the action of uricosuric agents

A
  1. URAT1 is a member of the OAT (organic anion transporter) family and an anion exchange uptake transporter
  2. blocking URAT1 reduces uric acid reabsorption
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13
Q

describe the role of sulfinpyrazone

A
  1. inhibits URAT 1
  2. can cause GI upset
  3. needs to be taken with large quantities of water to prevent kidney stones
    - there are better alternatives
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14
Q

what is the role of probenecid

A
  1. uricosuric agent that blocks tubular reabsorption of uric acid
  2. useful in patients who under excrete uric acid
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15
Q

when should probenecid not be used

A

don’t use in
- tophi
- renal impairment
- clear overproduction syndrome

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16
Q

describe the role of benzbromarone

A
  1. unlicensed in UK- needs to be imported
  2. non competitive inhibitor of XO
  3. can be used in renal impairment
  4. withdrawn from several markets because of hepatotoxicity
  5. must have regular lFTs
17
Q

describe the role of lesinurad

A
  1. used in combination with a XO inhibitor where this alone doesn’t achieve target
  2. inhibits URAT 1 and so reduces reabsorption of uric acid in kidneys
  3. 200mg od with XO
  4. NICE rejected in 2018
18
Q

outline the renal complications that could occur

A
  1. nephrolithiasis- kidney stones
  2. chronic urate nephropathy
19
Q

what are the risk factors of nephrolithiasis

A
  • increased uric acid excretion
  • reduced urine volume
  • low urine pH
20
Q

what is chronic urate nephropathy

A

urate crystals can deposit in renal medullary interstitium, producing inflammatory changes and fibrosis
- biopsy confirms diagnosis

21
Q

describe the role of uricase

A
  1. enzyme that converts insoluble uric acid to more soluble metabolite allantoin
  2. humans have lost gene function to produce uricase
  3. rasburicase- drug delivered from aspergillus, used to treat tumour lysis syndrome
    - extremely immunogenic, which limits its half life and use in chronic diseases
22
Q

what is the role of pegloticase

A
  1. mammalian uricase
  2. peglyated- increases half life and reduces immunogenicity
  3. administered by IV infusion every 2 weeks
23
Q

what are the adverse effects of pegloticase

A
  1. infusion reactions
  2. many patients develop antibodies to drug that increase its clearance
  3. anaphylaxis
  4. 80% of patients had gout flares despite prophylaxis
  5. contraindicated in G6PD deficient patients
24
Q

what are the adverse effects of pegloticase

A
  1. infusion reactions
  2. many patients develop antibodies to drug that increase its clearance
  3. anaphylaxis
  4. 80% of patients had gout flares despite prophylaxis
  5. contraindicated in G6PD deficient patients
  6. may exacerbate heart failure
25
Q

describe how IL1 and urate driven inflammation occurs

A
  1. inflammatory cells can innately recognise common microbial features as danger signals
    - flagella, viral RNA
    - excess uric acid and associated crystals recognised in same way
  2. leads to rapid inflammation
  3. microbial patterns bind to toll like receptors and lead to increase in pro IL1
26
Q

what are the biologic targets in gout therapy

A
  1. 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
27
Q

describe the production of IL1

A
  1. pro IL1 is inactive but capable of being rapidly metabolised to active IL1
  2. machinery that cleaves pro IL1 to active IL1 is called the inflammasone
28
Q

give examples of IL1 blockers

A
  1. IL1 receptor antagonist- anakinra
  2. anti IL1 antibody- canakinumab
  3. IL1 decoy receptor fusion protein- rilanocept

PY365 Autoimmune Cluster (19 decks)

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