ic17 gout

Question 1

what is “gout” and what are the types of gout

Answer 1

gout is a disease caused by
i) imbalances in purine metabolism
ii) deposition of monosodium urate (MSU) crystals in articular and periarticular tissues

types of gout:
i) recurrent acute gouty arthritis (assoc w urate crystals in synovial fluid)
ii) tophi; chronic (assoc w MSU crystals in tissue and in surrounding joints)
iii) interstitial renal disease (gouty nephropathy); chronic w extraarticular presentation
iv) uric acid nephrolithiasis (uric acid kidney stones); chronic w extraarticular presentation

Question 2

what are the risk factors for gout

Answer 2

i) dietary and lifestyle factors (alcohol consumption, sugary beverages, red meat, sedentary lifestyle)
ii) obese > non obese
iii) male > female (but gender gap narrows after menopause)
iv) occurrence in male <30yo and premenopausal women suggests inherited enzyme defect or presence of renal disease

Question 3

outline the purine metabolism pathway (and salvage pathway)

Answer 3

PURINE METABOLISM
glutamine + phosphoribosyl. pyrophosphate (PRPP) undergoes de novo synthesis to form nucleic acids in body tissues which breaks down into guanine and adenine -> hypoxanthine -> converted into xanthine by xanthine oxidase -> converted into uric acid by xanthine oxidase and is excreted in humans (65% in urine (reabsorbed by urate transprorter 1 and GLUT 9) 35% in GI (degraded by intestinal flora))

a source of adenine and guanine is diet (purine rich food)

in animals, there is presence of uricase which converts uric acid to allantoin (but not a pathway in humans)

SALVAGE PATHWAY
hypoxanthine-guanine phosphoribosyltransferase (HGPRT) + phosphoribosyl pyrophosphate (PRPP) converts guanine and hypoxanthine to form back nucleic acids

Question 4

what are the physicochemical properties of uric acid

Answer 4

i) weak organic acid w pKa 5.75 in blood
ii) soluble in normal arterial pH of 7.4
iii) solubility limit at 6.8mg/dL (will precipitate if conc > than this limit)
iv) less soluble at lower temp (at peripheral joints, thus most common site of MSU crystal deposition is at big toe)

Question 5

what are the possible causes of gout (and how to determine the exact cause)

Answer 5

1. overproduction of uric acid
   i) primary: inborn errors of metab
   ii) secondary: conditions that incr cell turnover and purine generation
2. under excretion of uric acid (90% of gout)
   i) underexcreters excrete <600mg/24h

TO FIND OUT EXACT CAUSE
measure serum uric acid and 24h urine on a purine free diet (but not freq done)

Question 6

what are the factors that contribute to the overproduction or under excretion of uric acid (drug and diet induced)

Answer 6

DRUG AND DIET INDUCED OVER PRODUCTION
i) excessive ethanol ingestion
ii) excessive dietary purine ingestion
iii) excessive fructose ingestion
iv) cytotoxic drugs

DRUG AND DIET INDUCED UNDER EXCRETION
i) diuretics (thiazide and loop)
ii) cyclosporin, tacrolimus
iii) low dose salicylates (eg. aspirin)
iv) ethambutol
v) pyrazinamide
vi) ethanol
vii) levodopa
viii) laxative abuse (alkalosis)
ix) salt restriction
x) nicotinic acid

Question 7

what is the presentation during a gout attack

Answer 7

i) monoarticular (usually first MTP of big toe)
ii) asymmetrical
iii) wakes up from sleep due to pain
iv) severe and excruciating pain for severeal hours
v) rapid onset (usually overnight)
vi) swelling and discomfort continues days to weeks after (worst pain will slowly ease off after a few hrs but there would still be continued swelling and discomfort over the next few days or weeks)
vii) joint is red, hot, swollen, tender and presence of tophi

Question 8

how is gout diagnosed

Answer 8

presence of MSU either in
i) synovial fluid (detected in joint aspirate)
*joint aspirate = needle inserted to withdraw joint fluid and look at it under microscope then if see bifringent crystals would be confirmatory presence of uric acid crystals

or
ii) biopsy on tissue sections of tophaceous deposits

Question 9

what can joint aspirate distinguish (elaborate on colour, clarity, viscosity, WBC count, neutrophil count, gram stain, crystals)

Answer 9

1. normal (colourless, translucent, more viscous, <200cells/mm3, <25%, neg gram stain, no crystals)
2. acute gouty attack (yellow, cloudy, less viscous, 2000-50,000cells/mm3, >50%, neg gram stain, got crystals)
3. infection (yellow or green, cloudy or opaque, less viscous, >50,000cells/mm3, >75%, pos gram stain, no crystals)
4. bleeding inside the joint (red, bloody, variable viscosity, 200-2000cells/mm3, 50-75%, neg gram stain, no crystals)

*neutrophil is a wbc impt when fighting infections

Question 10

what are the goals of tx for management of gout (incl target levels)

Answer 10

GOALS OF TX
i) rapid, safe and effective pain relief
ii) reduce future attacks
iii) address assoc comorbs
iv) prevent joint destruction and tophi formation
v) incr QoL

TARGET LEVELS
normal SU levels are 210-420µmol/L (4.0-8.5mg/dL) for males, 150-350µmol/L (2.7-7.3mg/dL) for females

target SU levels <6mg/dL aka 360µmol/L (or <5 (300) for tophaceous gout)

Question 11

what are the stages of gout along with its assoc features and its appropriate management

Answer 11

STAGE 1: asymptomatic hyperuricemia
i) considered hyperuricemia if >6mg/dL (360µmol/L) for women, >7mg/dL for males (450µmol/L)
ii) no pharmacotx

STAGE 2: acute gout (first attack)
i) presents with acute arthritis (typically first MTP)
ii) excruciating pain
iii) pharmacotx: colchicine, NSAIDs, corticosterouds
iv) non pharmacotx: topical ice, reduce risk for flares

STAGE 3: inter-critical phase (between flares)
i) asymptomatic hyperuricemia (10% may never have another acute attack)
ii) no pharmacotx
iii) non pharmacotx: reduce risks for flares

STAGE 4: chronic gout
i) presents with hyperuricemia, development of tophi, recurrent attack of acute gout
ii) pharmacotx: initiate ULT (allopurinol, febuxostat, probenecid) after acute gouty attack if any
iii) non pharmacotx: topical ice, reduce risk for flares

Question 12

what should be considered to be added on whenever NSAIDs are considered to be used

Answer 12

add on PPI

Question 13

how are acute gouty flares managed

Answer 13

EACH ATTACK
i) treated asap within 24h

ii) first line is colchicine (either one of tx with 1mg LD f/b one dose of 0.5mg 1hr later or 0.5mg BD/TDS until acute flare resolves)

iii) PO NSAIDs/ coxibs (for PO celecoxib, 400mg LD f/b 200mg 12h later on d1 f/b 200mg BD for 5-7d (for sx to resolve completely)

iv) PO corticosteroids or IA corticosteroids (for PO prednisolone, 30-40mg QD for 2-5d until sx resolve f/b taper by halving it for another 7d f/b discontinuing; if dosed by weight is 0.5mg/kg/d with same schedule as ^)

iv) combination tx if ok but avoid NSAID with steroid

v) after sx resolves, measure SU level, assess lifestyle and comorbs, review meds and consider ULT

PT ALR ON ULT DURING FLARE
i) continue ULT during flare

PT NOT YET ON ULT BUT IS INDICATED TO START
i) initiate ULT after resolution of sx typically 2-4w after gout flare settled (or w/o waiting for flare to resolve if pt unlikely to return for tx)
ii) bc considered freq attacks
iii) with anti-inflamm prophylaxis for 3-6m using either colchicine 0.5mg QD or low dose PO NSAID/coxib (celecoxib 200mg QD) or low dose PO corticosteroid (prednisolone 5-7.5mg QD)

Question 14

what are the s/e, ddi, caution for colchicine

Answer 14

s/e: N/V/D (incr freq w higher doses or longer duration of use)

ddi: macrolide abx, azole antifungals, statins, verapamil, diltiazem

caution: renal impairment (either decr dose or incr dosing interval)

Question 15

what are the indications for initiating ULT

Answer 15

i) freq acute gout flares (two or more per year)
ii) presence of any tophus
iii) clinical or imaging findings of gouty arthropathy (disease of joint)
iv) hx of urolithiasis (kidney stones)

Question 16

what are the agents that can be used for ULT (drug, drug type, moa, dose range, other considerations, s/e, ddi)

Answer 16

ALLOPURINOL
drug type: antihyperuricemic agents

moa: xanthine oxidase inhibitor to decr uric acid synthesis

dose: initiate at 100mg/d or lower, titrate 50-100mg q2-8w while monitoring SU, clinical response and drug toxicity (SCAR), MD >300mg/d (max 800mg/d if normal renal func)

other considerations: cheaper, renal metabolism thus lower dose in renal impairment (initiate at 50mg/d or lower if CKD stage 3 and above)

s/e: may precipitate acute flares during initial period, risk of SCAR

ddi:
i) 6-mercaptopurine, azathioprine, cyclophosphamide (can incr bone marrow suppression due to incr conc of these drugs)
ii) CBZ, warfarin, theophylline (allopurinol can incr the conc of these drugs)
iii) ACEi, loop and thiazide diuretics, ampi/amoxicillin (can incr hypersensitivity rxn or toxicity of allopurinol)

FEBUXOSTAT
drug type: anti hyperuricemic agent

moa: inhibit xanthine oxidase to decr uric acid synthesis

dose: initiate at 40mg/d or lower, titrate until 80mg/d if target not met after 2-4w

other considerations: more expensive, liver metabolism, caution in HF and CHD

s/e: may precipitate acute flares during initial period, risk of SCAR (but lower risk than allopurinol)

PROBENECID
drug type: uricosuric agent

moa: URAT1 and GLUT1 transporter inhibitor to decr reabsorption and thus incr uric acid secretion

dose: initiate 250mg BD for 1w f/b 500mg BD, titrate 500mg q4w as tolerated if sx not controlled or at target, MD 2g/d and lower

other considerations: not rec for CrCl <50, c/i in urolithiasis and CKD, ensure hydrated (fluid 2L/d or more) to prevent kidney stones from forming

s/e: may precipitate acute flares during initial period

LESINURAD *not in SG
moa: selective URAT1 inhibitor which incr uric acid secretion

PEGLOTICASE *not in SG
moa: recombinant PEGylated uricase to incr uric acid metabolism into allantoin

Question 17

which drugs have s/e of SCAR and what is the onset, risk factors, and presentation of different types of SCAR, and how to counsel pt about SCAR

Answer 17

allopurinol and febuxostat (but lower risk than allopurinol)

onset: most occur within first few weeks to months after initiation

types: SJS/TEN, DRESS

risk factors: (RASHES)
R enal impairment
A gent (eg. concom use of diuretics)
S tarting dose (high)
H LAB*5801 (not routinely done bc low positive predictive value of 2% and lack of alternative cost effective ULT options, testing more useful if pt alr at higher risk of SCAR)
E scalation (rapid)
S eniority (older age)

presentation:
1. SJS/TEN - fever with mucotaneous lesions leading to necrosis and sloughing of epidermis
2. DRESS - rash w fever w multiorgan failure (liver, kidney, heart and/or lungs are most often affected)

pt counselling:
i) SCAR are serious and generally affects skin, eyes or mouth but are uncommon
ii) look out for early sx of SCAR - flu like sx (fever, body aches, feeling unwell), mouth ulcers or sore throat, red or sore eyes, rash
iii) sx may not happen tgt and not the only ones
iv) monitor for these sx esp in first 3m after starting (although can also happen after 3m)
v) if sx occur, stop medication and seek medical attention immediately, photograph the rash if possible

Question 18

when would you consider discontinuing ULT

Answer 18

if clinical remission (no flares) for 1yr or longer and no tophi

but pt can also decide to continue on tx if they want to

Question 19

what are the non pharmacotx for managing gout flares

Answer 19

1. to reduce pain in acute flares
   i) topical ice therapy
2. to reduce risk for flares
   i) limit alcohol intake
   ii) limit purine rich food (asparagus, cauliflower, mushroom, oatmeal, red meat, meat extracts (broth), salmon, anchovies (ikan bilis), prawn, sardines, cockles, mussels, fish roe, durian, peanuts, organ meat, scallops, strawberry, bean cake)
   iii) limit high fructose corn syrup
   iv) weight management (maintain a healthy weight, exercise regularly but rest affected joints during a gout attack)
   v) diet (drink plenty of fluids of >2L/d unless fluid restriction, eat low fat diary products, eat vegetables)

Question 20

what are some notable medications changes that can be considered for gout pts

Answer 20

1. switch hydrochlorothiazide to alt antihypertensive (bc HCTZ decr urate excretion)
2. losartan preferred as antihypertensive (bc ACEi like enalapril and ARBs like losartan have uricosuric effects)
3. do NOT stop low dose aspirin tx if indicated (despite effect in incr urate reabsorption but bc may have more risks if stop or switched out)
4. do NOT add or switch cholesterol lowering agents to fenofibrate (despite uricosuric effect)

*whenever see ddi, just determine whether medication is a MUST HAVE then see how from there

Question 21

what are the risk factors (comorbs) of gout

Answer 21

renal impairment, T2DM, obesity, HTN, hyperlipidemia