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3154 MSK > gout > Flashcards

gout Flashcards

1
Q

gout definition

A

Imbalance in purine metabolism (production > excretion)
Deposits of monosodium urate (MSU) crystals in articular & periarticular tissues
* Leads to inflamm: pain & swelling

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2
Q

gout syndrome

A
  • Recurrent acute gouty arthritis
    ○ Assoc w/ urate crystals in synovial fluid
  • Tophi
    ○ Deposits of MSU crystals in tissue & surrounding joint
  • Interstitial renal disease
    ○ Gouty nephropathy
  • Uric acid nephrolithiasis
    ○ Uric acid kidney stones
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3
Q

risk factors

A
  • dietary and lifestyle factors
  • obese pts

Asx hyperuricemia (uric acid) assoc w/ HTN, CKD, insulin resistant, CVD

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4
Q

purine metabolism

A
  • Glutamine + PRPP –> nucleic acids in body tissues (RNA, DNA)
  • Break down —> Guanine & Adenine
    ○ Recycled to form nucleic acids (HGPRT + PRPP)
  • Break down —> hypoxanthine
    ○ Recycled to form nucleic acids
  • XANTHINE (XO)
  • URIC ACID (XO)
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5
Q

uric acid properties

A

○ Weak organic acid (Pka 5.75 in blood)
○ Soluble in normal arterial pH of 7.4
○ Solubility limit at 6.8mg/dL
○ Less soluble at lower temp = Peripheral joints

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6
Q

uric acid animal vs human

A
  • Excreted in humans
    ○ 65% in urine (reabsorbed by urate transporter 1, URAT1 & GLUT9)
    ○ 35% in GI (degrade by intestinal flora)
  • animals (uric acid –> allantoin) by uricase
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7
Q

gout patho

A
  • High uric acids –> crystallised and hidden in joints
  • TRAUMA Releases crystals into blood plasma
  • Immune cells activated, recognise and attack crystals
    ○ Proliferation of immune cells (neutrophils, macrophage)
    ○ Cytokine production
    ○ Adhesion and trafficking
  • Inflammation as leukocytes attack urate crystals
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8
Q

+ve feedback that incr inflammation

A
  • Incr inflammation as neutrophils try unsuccessfully to phagocytize urate crystals
    ○ Crystals lyse neutrophils (released out)
    ○ Release lysosomal enzymes too
    ○ More damage to joint & tissues

+ve feedback loop

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9
Q

2 main pathways

A

1) Over production of uric acids (excrete > 600mg)

2) Underexcretion of uric acid (<600mg/24h)

Incr uric acid > solubility = deposition of urate crystals
- Periarticular fibrous tissue of synovial joints
- Renal tubules

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10
Q

overprod

A

> 600mg excrete
* PRIMARY: inborn error in metabolism
* Secondary: conditions that incr cell turnover & purine generation
* Diet (purine rich foods)
* Incr Guanine & Adenine

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11
Q

underexcretion

A

<600mg excrete
* Incr uric acid conc (reabsorbed by urate transporter 1, URAT1 & GLUT9)
* 90% of gout cases

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12
Q

measure uric acid excretion

A

not commonly done as diet is difficult

  • Serum uric acid & 24h urine
  • purine free diet

> 600mg excrete: OVER-production
<600mg excrete: UNDER-excretion

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13
Q

gout presentation

A
  • Usually monoarticular (MTP of great toe)
    • Most common at periphery (lower temp = incr ppt)
    • Occur one joint at a time
  • Sleep disrupted by pain
  • Severe pain x hrs
    • Pain resolves but swelling and discomfort continues days~wks
  • Joint red, hot, swollen, tender
  • Chronic gout
    • Tophaceous/ tophi formation
      ○ Pus (urate crystals + inflamm cells, no microog)
    • Joint damage
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14
Q

dx of gout

A

Monosodium urate crystals Microscopy (birefringent 2 sharp points)
* Synovial fluid (joint aspirate)
* May look diff: turbid, pus (infection), blood
* Yellow, cloudy, low viscosity
* High WBC, neut
* -ve microbial (not septic)
* Tophaceous deposits (tissue secretions)

Asx hyperURICemia =/= gout

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15
Q

hyperuricemia levels

A
  • W: > 6mg/dL (450umol/L)
    • M: > 7 mg/dL (360umol/L)
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16
Q

stages of gout

A
  • Asx hyperuricemia = no tx
  • Acute attack = colchicine, NSAID, CS
    • Acute arthritis
    • 1st MTP
    • Excruciating pain
  • Intercritical phase = no tx (10% not have another acute attack)
  • Chronic gout = ULT
    • Clinical or imaging findings of gouty arthropathy damage
    • Hx of urolithiasis (kidney stone)
    • Tophi formation
    • freq acute gout attack (≥2/yr)
      Consider: diuretic therapy, CKD stage 3-5
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17
Q

goals of gout tx

A
  1. Provide rapid, safe, effective pain relief
  2. Reduce future attacks
    • Reduce SU conc (taken at baseline + monitored)
    • Treat to target conc
  3. Address assoc comorbidities (kidney, medication use)
  4. Prevent complications
    • joint destruction and tophi formation
      • Incr QOL
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18
Q

tx acute inflamm

A
  • Colchicine
    ○ Reduce leukocyte migration into joints
  • Non-selective NSAIDs (naproxen, indomethacin)
    ○ Anti-inflamm and analgesic
    Indomethacin: older NSAID (wider MOA = inhibit phospholipase A2 + COX)
  • COX2 selective NSAIDs (celecoxib)
  • Glucocorticoids (prednisolone PO or intra-articular inj)
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19
Q

consideration of acute gout tx

A
  • Combi therapy (reduce inflamm asap)
    • Colchicine + NSAID/ COXIBS
    • Colchicine + prednisolone
    • X NSAID + CS
  • Non-pharm: topical ice
  • Start ULT (if indicated)
    • 2-4wks later after acute, sx resolved
    • Start even when on flare if
      * Pt non-adherence, not return
      *Pt highly motivated for tx
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20
Q

chronic gout prevention tx

A
  • Xanthine oxidase inhibitors [allopurinol, febuxostat]
    ○ Decr production of uric acid
    ○ Incr migration of crystals from joint to plasma
  • Uricosuric agents [Probenecid]
    ○ Incr excretion of urate through kidneys
    ○ Push uric acids from blood to kidney
  • incr uric acid metabolism [pegioticase]
    ○ recombinant PEGylated uricase, incr uric acid metabolism
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21
Q

monitor

A
  • SU level (tx to target: base, mnthly – until reach target)
  • Annual if continue tx
    ○ Non-tophaceous: <360umol/L (6mg/dL)
    ○ Tophaceous: <300umol/L (5mg/dL)
  • Assess lifestyle and comorbidities
    ○ Obesity, HTN, CKD
  • Review meds (int?)
  • Non-pharm
    ○ Diet, weight, alcohol
  • Need for ULT? (freq attack)
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22
Q

ULT duration

A
  • Clinical remission = no flares ≥ 1 yr + no tophi
    ○ Low SU < 7mg/dL
  • If discontinue + higher SU ==> more freq flares (worsening/ return of gout sx, tophi, joint damage)
  • Therapy well-tolerated, not burdensome: pt can continue/ stop
23
Q

celecoxib dose acute & prophylaxis

A

acute: 400mg LD -> 200mg
200mg BD (5-7d, until sx resolve)

Prophylaxis: 200mg OD

24
Q

CS prednisolone dose acute & prophylaxis

A

acute: 30-40mg OD (or divide to 2 dose), 2-5d until sx resolve
* Taper by half dose over 7d (discontinue)
* (weight) 0.5mg/kg OD 2-5 d –> taper

Prophylaxis: 5-7.5mg OD

25
Q

colchicine used within

A

○ Reduce leukocyte migration into joints
○ Only use at start of gouty attack (24-36hr)
○ Phagocytosis, feedback loop would have started (cytokines released alr)

○ ceiling effect (high dose leads to SE)

26
Q

colchicine MOA

A
  1. Binds to tubulin
  2. Prevent tubulin polymerisation into microtubules
  3. Inhibit leukocyte migration and phagocytosis
  4. Inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production (pain sensitisation)

Relieve pain and inflammation in acute gouty attack within 24-36hrs

27
Q

colchicine SE

A
  • Inhibit microtubule polymerisation, at high conc inhibits cell proliferation. - Affects rapidly multiplying cells (GI epithelial cells, hair, growth factors)
    • Hair loss
    • GIT: NVD, abdominal pain
    • Muscle weakness
    • Unusual bleeding, pale lips, change in urine amt.
28
Q

coclchicine dose (acute flares)

A

max 1.5mg/day
* 1mg LD –> 0.5 mg 1hr later
* OR 0.5mg BD-TDS

29
Q

colchicine prophylaxis dose

A

adjunct with ULT:
0.5mg OD/ BD (max 1.2mg/day)

If flare up occurs: incr dose to acute flare dose

30
Q

DDI colchicine

A

CYP3A4i: Macrolide, azoles, statins, verapamil, diltiazem
Grapefruit juice

CYP3A4inducers: PT, CBT, st john’s wort, rifampicin

31
Q

colchicine CI/ caution

A

Renal (< 30ml/min)
Hepatic impairment (severe)
- Incr risk of toxicity (myopathy, neuropathy, pancytopenia)

32
Q

XOi used when

A

Not in acute attacks:
○ Lowers plasma uric acid conc
○ Incr migration of crystals from joint to plasma
○ Attacked by immune cells. Exacerbates inflammation

33
Q

allopurinol/ febuxostat MOA

A
  • Anti-hyperuricemic agents
    • Allopurinol: analogue of xanthine
    • Febuxostat: competitive inhibitor of xanthine oxidase
      (hypoxanthine –> xanthine –> uric acid)
  • Decr uric acid production
    • <6.0mg/dL
34
Q

indication of XOi

A
  • Debilitating gout attacks
  • Chronic erosive arthritis
  • Urate nephrolithiasis (kidney stones)
35
Q

XOi ADR

A

Skin rash, NVD, fever, sore throat, stomach pain, dark urine, jaundice

36
Q

allopurinol vs febuxostat

A

allopurinol
* (1st line, cheap $0.10/tab)
* renal metabolism
* higher risk of SCAR

febuxostat
* (if cannot tolerate, $3.90/tab)
* liver metabolism
* caution: HF, CHD
* lower risk of SCAR

37
Q

allopurinol dose

A
  • Initiate: ≤100mg/day
    • CKD stage ≥3, <50ml/min: ≤50mg/day
  • Titrate: 50-100mg incr every 2-8wks
    • Monitor SU, clinical resp (dose adj to target), drug toxicity SCAR
  • maintain: > 300mg/day

Max 800-900mg/day (normal RF)
100-800mg/day

38
Q

febuxostat dose

A

40-80mg OD

Initiate: ≤40mg/day
Titrate: 80mg/day
If target not met after 2-4 wks

39
Q

febuxostat CI

A

Liver metabolism
Risk of SCAR (< allopurinol)
Caution: HF, CHD

40
Q

caution of XOi (allopurinol mainly)

A
  • Allopurinol hypersensitive syndrome (AHS)
  • Severe cutaneous adr (SCAR)

incr SCAR RISK:
○ Renal impaired (CrCL < 60ml/min)
○ Thiazide therapy
○ HLA-B*58:01 genotype (chinese, thai, korean)

41
Q

SCAR presentation

A

SCAR within first 3mnths (but monitor throughout)

SJS, TEN: Fever + mucocutaneous lesions –> necrosis, slough of epidermis

DRESS: Rash + fever + multiorgan failure (Liver, kid, heart, lungs)

42
Q

PGx of allopurinol

A
  • HLAA-B*5801 allele
    • More common in Asians (Han Chinese, Thai), Black, Native
    • Testing more useful in pts alr at higher risk of allopurinol-induced SCAR
      • Renal impairment
      • Older age
  • just counsel for ULT (allopurinol & febuxostat)
  • monitor initial 3 mnths (after that too)
43
Q

why testing not routine

A
  • Rarity of allopurinol-induced SCAR (3 in 1,000) pts may develop SCAR
  • Low PPV (2 in 1000) pts that test +ve actually develop SCAR
  • Lack of alternative cost-effective ULT options
  • Reaction can happen w/o the allele due to non-genetic factors
44
Q

DDI with allopurinol
incr bone marrow sup

A

6-mercaptopurine
azathioprine
cyclophosphamide

45
Q

DDI with allopurinol
monitor tx as incr conc of ___

A

CBP
warfarin
theophylline
pegloticase

46
Q

DDI with allopurinol
incr hypersensitivity rxn

A

ACEi
loop diuretics
thiazide
ampicillin/ amoxicillin

47
Q

probenecid used when

A
  • Not in acute attacks
    • Push uric acids from blood to kidney
    • Risk kidney stones formation when uric acid conc too high
  • When allopurinol CI in tophaceous gout (sustained high lvl of uric acids)
  • Incrly freq gout attack

2-3wk after acute attack

48
Q

probenecid MOA

A

URAT1 & GLUT9 inhibitor
decr uric acid reabsorption, increase excretion

49
Q

probenecid dose

A
  • Initiate: 250mg BD 1wk –> 500mg BD
  • Titrate: 500mg every 4wks
    • As tolerates, to reach target
  • Maintain: ≤2g/day

500-3000mg/ day

50
Q

probenecid caution

A
  • Plenty of fluids to minimise renal stone formation (>2L/day)
  • Keep urine pH > 6
    • Admin alkaline (K citrate)
    • Less renal stones formed
51
Q

probenecid adr

A

NV, painful urination, lower back pain, allergic rxn, rash

52
Q

probenecid CI/ caution

A

Not recom: crcl <50ml/min
G6PD def (Risk of haemolytic anemia)

CI: urolithiasis , CKD

53
Q

non-pharm

A
  • healthy lifestyle
    * weight (obesity)
    * exercise
    * avoid smoke, alcohol intake
    * diet (high purine: seafood, red meat, peanuts, high fructose)
54
Q

med review

A
  • ALT antihypertensives (maybe ACEi, ARB - uricosuric effect)
    * Hydrochlorothiazide decr urate excretion
    * ACEi DDI w/ allopurinol
  • Do not stop low-dose aspirin (CVS prophylaxis)
    * Despite incr urate reabsorption
  • Do not ADD/ SWITCH antihyperlipidemic meds
    * Esp fenofibrate despite uricosuric effects

3154 MSK (9 decks)

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