gout

Question 1

general gout

Answer 1

inflammation caused by

• imbalance in purine metabolism
• deposition of monosodium urate (MSU) crystal in articular and periarticular tissues

Question 2

heterogenous clinical spectrum for gout

Answer 2

1) recurrent gouty arthritis

• urate crystals in synovium joint

2) tophi

• deposition of monosodium urate crystals in tissues and surrounding joint

3) interstitial renal diseases

• gouty nephritis

4) uric acid nephrolithiasis

• uric acid kidney stones

Question 3

risk factors for gout

Answer 3

1) obese > non obese
2) male > female but gender gap narrow after menopause
3) occurrence in male < 30 yo and premenopausal women indicate inherited enzyme deficit or presence of renal disease
4) alcohol, red meat, sugar beverages, sedentary lifestyle

Question 4

physiology for normal times pre gout

Answer 4

• nucleic acid -> guanine and adenine -> hypoxanthine
  ** salvage pathway: hypoxanthine and guanine recycled to form nucleic acid
• hypoxanthine oxidised to xanthine by xanthine oxidase
• xanthine oxidised to uric acid by xanthine oxidase
• uric acid excreted in humans

Question 5

pathophysiology of gout

Answer 5

• increase in uric acid -> precipitate as monosodium urate crystals -> trigger deposition of urate crystals -> inflammation

Question 6

pathophysiology of gout - why increase in uric acid concentration

Answer 6

1) overproduction of uric acid (urate concentration > 2 -7 mg/dL)

• primary cause: inborn errors of metabolism
• secondary cause
  ** condition that increase cell turnover and purine generation
  ** drug/diet induced purine/urate overproduction

2) under excretion of uric acid via kidneys

• drug/diet induced decreased uric acid clearance

Question 7

pathophysiology of gout - how inflammation occur

Answer 7

1) Activation of inflammasome through 2 signals

• signal 1 occur naturally
• signal 2 triggered by monosodium urate crystals -> activate inflammasome

2) inflammasome activate caspase 1 which:

• catalyse maturation of pro-IL-1b to IL-1b -> stimulate innate immune response -> act on IL-1 receptive cells -> stimulate transcription factor P650P50 through phosphorylation cascade -> transcription of cytokines and chemokines -> promote inflammation
• catalyse cleavage of gasdermin D -> cell death -> formation of pyrototic pores in membrane -> allow IL-1b and other intracellular shit to escape -> damage

3) efflux of K+ out of cell through K+ channel -> mitochondria produce RoS -> Activate inflammasome

4) precipitation of urate crystals in joint -> activate neutrophils to mobilise and phagocytose crystals

• if unsuccessful -> crystals lyse w neutrophils -> re-release of crystals and release of lysosomal enzymes -> damage at joints -> further inflammation and release of leukotrienes and prostaglandins -> further inflammation (+ve feedback loop)

Question 8

clinical presentation of gout

Answer 8

1) monoarticular at 1st MTP of big toe
2) inflammation at big toe -> red, swell, warm, pain
3) sudden onset over night

• can wake up w excruciating pain
• can occur when drop in temperature

4) swelling, discomfort for days to wks after
5) can be self-limiting

Question 9

stages of gout

Answer 9

1) asymptomatic hyperuricemia
2) acute gout (1st attack)
3) inter-critical phase (between flares)
4) chronic gout

• hyperuricemia
• development of tophi (uric acid crystals in soft tissue and joints change underlying structure of soft tissue and joints -> bumps)
• recurrent attack of acute gout

Question 10

diagnosis of gout

Answer 10

based on presence of monosodium urate crystals in

• synovial fluid
• tissue sections of tophaceous deposits

Question 11

non pharmaco for gout

Answer 11

1) ICE to alleviate flares
2) reduce risk of flares

• limit alcohol intake
• limit purine-rich food
  ** asparagus, cauliflower, mushroom, red meat, anchovies, durian, peanut, organ meat
• limit fructose corn syrup
• weight management

3) meds management

• switch hydrochlorothiazide to losartan/ACEi for uricosuric effect
• X stop low dose aspirin treatment
• X add/switch cholesterol lowering agents to fenofibrate

Question 12

tldr treatment of acute gout

Answer 12

treated ASAP within 24 hrs

1) colchicine
2) PO NSAID
3) PO corticosteroids
4) intra-articular corticosteroids (X take PO meds)

Question 13

why give colchicine ASAP

Answer 13

not as effective after 36h cuz +ve feedback loop and inflammation went on

Question 14

colchicine dosing

Answer 14

• 1 off treatment 1mg loading dose then 0,5mg one hour later OR
• 0.5mg 2-3 times per day until acute flare resolve

Question 15

MOA of colchicine

Answer 15

• bind to bilirubin
• prevent tubulin polymerisation into microtubules
• inhibit leukocyte migration and phagocytosis -> block +ve feedback
• inhibit leukotrienes B4 and prostaglandin production

Question 16

colchicine SE

Answer 16

1) muscle weakness, unusual bleeding, pale lips, change in urine output
2) GI: N/V, D, abdominal pain, bleeding

• increase freq w higher dose and longer duration of use
• why bleed?
  ** cells in GI tract rapidly dividing cells
  ** when cells divide they need microtubule skeleton to divide effectively
  ** colchicine impair cell division (esp actively dividing)
  ** need dose titration to control output

Question 17

colchicine DDI

Answer 17

macrolide Abx, azoles, statins

Question 18

colchicine caution

Answer 18

renal and hepatic impairment need dose adjust

Question 19

PO NSAID types to use

Answer 19

1) non-selective: naproxen, indomethacin
2) selective: celecoxib

Question 20

what to do for acute flare if alr on ULT?

Answer 20

continue ULT during flare

Question 21

indication for ULT

Answer 21

1) frequent acute gout flare (2/> per yr)
2) tophaceous formation
3) imaging shows damage to joint/gouty arthropathy
4) history of urolithiasis

Question 22

treatment target on ULT

Answer 22

1) non-tophaceous gout: < 6mg/dL
2) tophaceous gout: < 5mg/dL

Question 23

initiation of ULT

Answer 23

1) start low go slow
2) initiate 2 - 4 wks after acute gout flares

• why not initiated during acute gout flares?
  ** ULT dramatically lower plasma urate concentration -> increase gradient from joint to plasma -> increase mobilisation of crystals out of joint -> recognised by immune cell -> inflammation and pain -> make acute attack worse
• what situations can initiate wo waiting for resolution?
  ** when got chance patient don’t come back to take ULT drugs
  ** when pt highly motivated to start regardless of chance of acute flare
  ** increase in flare frequency

3) initiated w colchicine 0.5mg BD for 3-6 months to prevent acute gout flare due to ULT initiation

Question 24

types of ULT

Answer 24

1) uric acid synthesis inhibitors (xanthine oxidase inhibitors)

• allopurinol (1st line)
• feboxustat

2) uricosuric agents

• probenecid

Question 25

allopurinol dose

Answer 25

- initiation 100mg OD ** ≤ 50mg OD if CKD stage ≥ 3 - titration in 50-100mg increments every 2-8 wks ** monitor SU, clinical response, drug toxicity - usual maintenance > 300mg/day ** ok for renal impairment too - max dose 800-900 mg/day if normal renal function

Question 26

MOA of allopurinol

Answer 26

decrease uric acid production

Question 27

SE of allopurinol

Answer 27

1) allopurinol hypersensitivity syndrome (AHS) 2) SCAR - hypersensitivity on skin that occur within wks to months of initiation - bad skin reaction, increased temperature until skin peel -> stop meds and A&E - also flu-like symptoms, body ache, mild ulcer, sore throat, rashes w/wo peeling 3) N/V/D, fever, stomach pain, dark urine, jaundice

Question 28

allopurinol cautino

Answer 28

1) renal adjustment 2) genetic testing for HLA-B*5801 - patient w risk factors for SCAR ** renal impairment (CrCl < 60) ** concomitant meds (diuretics) ** high starting dose or rapid titration ** old age ** Han Chinese/Thai/Korean - but not routinely tested for new pt cuz low +ve predictive value + lack of cost-effective alternatives - why HLA-B*5801? ** allopurinol bind to self-peptide then bind to HLA-B*5801 -> complex activate T cell -> cytotoxicity -> SCAR

Question 29

allopurinol DDI

Answer 29

1) increase bone marrow suppression w azathioprine, cyclophosphamide 2) increase hypersensitivity reaction/toxicity of allopurinol w ACEi/diuretic/ampicillin,/amoxicillin 3) monitor treatment of carbamazepine, warfarin, theophylline 4) increase AE/toxic effect of pegloticase

Question 30

feboxostat dose

Answer 30

- initiation ≤ 40mg/day - titration by 80mg/day if treatment target not met after 2-4 wks

Question 31

feboxostat caution

Answer 31

avoid if HF or CHD cuz associated w MACES

Question 32

probenecid indication

Answer 32

1) allopurinol CI in tophaceous gout 2) increasingly freq gouty attack

Question 33

probenecid dose

Answer 33

1) start 2-3 wks after acute attack 2) initiation 250mg BD for 1 wk then 500mg BD 3) titration in 500mg every 4 wks as tolerated if symptoms not controlled 4) usual maintenance ≤ 2g/day

Question 34

probenecid MOA

Answer 34

- inhibit proximal tubule anion transport - inhibit uric acid reabsorption - increase uric acid excretion

Question 35

probenecid SE

Answer 35

N/V, painful urination, lower back pain, allergic reaction, rash

Question 36

probenecid precaution

Answer 36

1) hydration > 2L to prevent kidney stone formation 2) keep urine pH > 6 by administration of alkaline (potassium citrate) 3) ineffective in CKD 4) risk of haemolytic anaemia if G6PD deficiency

Question 37

probenecid CI

Answer 37

urolithiasis

Question 38

ULT treatment duration

Answer 38

- stop once remission (X gout flare and tophi formation for >/= 1 yr) - but if therapy well tolerated and not burdensome then can choose to continue treatment