IC17 Gout

Question 1

What are the RF of gout? (10)

Answer 1

RF:

1. Alcohol
2. Sugary beverages
3. Red meat
4. Sedentary lifestyle
5. Obesity
6. Male
7. > 40y/o
8. Genetics/renal disease (if male<30y/o & premenopausal women)
9. HTN, diabetes, hyperlipidemia
10. Drugs e.g. thiazide/loops, low dose aspirin, ciclosporin

Question 2

What are the compartments of the immune system involved in gout?

Answer 2

Compartments of the immune system involved in gout:

• Innate immunity
  o Phagocytes e.g. neutrophils and macrophages
   Cytokine production
   Adhesion and trafficking
  o Cytokines & chemokines

Question 3

What is gout and its patho? (may want to explain the normal physio 1st)

Answer 3

Gout

• Imbalances in purine metabolism (hyperuricemia)
• Deposition of monosodium urate crystals in articular & periarticular tissues

Normal physio:
Glutamine de novo synthesis → nucleic acids breaks down into
→ guanine & adenine
→ this can come from diet (purine rich food)
→ guanine, adenine & hypoxanthine can be recycled to be used as nucleic acid “salvage pathway”
→ hypoxanthine (then xanthine oxidase convert it into)
→ xanthine (then xanthine oxidase convert it into)
→ uric acid
→ excreted in humans

Patho:

1. Overproduction of uric acid
   a. Drug/diet-induced e.g.
   i. alcohol,
   ii. purine diet,
   iii. fructose ingestion,
   iv. cytotoxic drugs
2. Under excretion of uric acid (majority)
   a. Drug/diet-induced e.g.
   i. alcohol,
   ii. diuretics,
   iii. low dose aspirin,
   iv. ethambutol,
   v. nicotinic acid
   - These leads to ↑[uric acid] → deposition of urate crystals in periarticular fibrous tissues of synovial tissues

• 1) Hyperuricemia → ppt of urate crystals in joints → complement activation → neutrophils chemotaxis → phagocytosis of crystals by neutrophils → lysis and activation of neutrophils → release lysosomal enzymes → tissue injury & inflammation
• 2) Hyperuricemia → ppt of urate crystals in joints → macrophages/monocytes phagocytose → release TNF, IL-1, IL-6 → release proteases → tissue injury & inflammation
• Positive feedback loop

Question 4

Why is it that the most common location for gout to occur is the MTP of the big toe?

Answer 4

Uric acid

• Weak organic acid (pKa 5.75 in blood)
• Soluble in normal arterial pH of 7.4
• Solubility limit at 6.8mg/dL → ppt when > this [ ]
• Less soluble at lower temp (peripheral joints e.g. big toe)

Question 5

What is the S&S of gout?

Answer 5

Recurrent acute gouty arthritis (urate crystals in synovial fluids)
Tophi (deposits of monosodium urate crystals in tissue & surrounding joints, white growth)

S&S:

1. Monoarticular (1 joint at a time), mainly big toe (others: foot, ankle, knee)
2. Pain
   a. Rapid onset of pain at night
   b. Excruciating Nocturnal pain, wake up from it
   c. last several hrs
3. Tender, hot, swollen and red
   a. Swelling and discomfort continues for days to weeks
4. Other problems: renal disease, kidney stones and Tophi

Question 6

How to diagnose gout?

Answer 6

Diagnosis:

1. Presence of monosodium urate crystals in synovial fluid (Joint aspiration) & tophi (biopsy)
   a. Yellow
   b. Cloudy
   c. ↓ viscosity
   d. ↑WBC
   e. No microbes
   f. Crystals
2. S&S

• Hyperuricemia alone is NOT gout
• Further investigations: FBC, CRP, ESR, antibodies, xray

Question 7

What are the goals of treatment for gout?

Answer 7

1. SAFE & effective pain relief of acute gouty attack
2. ↓future attacks (by ↓SU conc.)

Question 8

When do you treat gout?
Out of these 4:
Asymptomatic Hyperuricemia
Acute gout (1st attack)
Inter-critical phase
Chronic Gout

Answer 8

1. Acute gout (1st attack)

Features:

• Acute arthritis
• Typical 1st MTP big toe
• Excruciating pain

Medications:

• Colchicine
• NSAIDs
• Corticosteroids

2. Chronic Gout

Features:

• Hyperuricemia
• Develop Tophi
• Recurrent attack of acute gout

Medications:

• Allopurinol
• Febuxostat
• Probenecid

see pg 56 of notes

Question 9

How to treat acute flares? Give the dose.
If you are already on ULT, and an acute flare occurs can you continue it?

Answer 9

Acute flares:

• Treat asap (within 24 hrs)

1. (1st line) PO Colchicine loading dose 1mg, then 1hr later take 0.5mg (1 off treatment)
   OR PO Colchicine 0.5mg BD/TDS daily till acute flare is resolved
2. (2nd line) Loading dose PO celecoxib 400mg, then 200mg BD for 5-7 days
   OR PO prednisolone 30-40mg QD daily for 2-5days / till acute flare is resolved, then taper down for another 7 days by halving the dose then stop
3. Combination of colchicine + NSAIDs/coxib OR colchicine + prednisolone for 5-7days
4. (3rd line) Intra-articular corticosteroids

• If already on ULT, continue ULT during flare
• Ideally, start ULT 2-4wks after resolution of acute flare, but possible to start ULT during flares as well
  o Risk of not returning
  o Highly motivated to get prophylaxis

Question 10

When to start ULT (criteria)?

Answer 10

When to start ULT (criteria):

1. Frequent acute gout flares (2 or more per year)
2. Tophi
3. Gouty arthropathy
4. Urolithiasis (kidney stones)

Question 11

What is the treatment target when use ULT?

Answer 11

Treatment target:

1. Non-tophaceous gout: <6mg/dL (<360umol/L)
2. Tophaceous gout: <5mg/dL (<300umol/L)

Question 12

How to start ULT?

Answer 12

Prophylaxis:

• Start low, go slow

1. (1st line) PO Allopurinol 100mg/day, then increase to 300mg/day
2. If CKD > stage 3 (<60mL/min), PO Allopurinol 50mg/day, then increase to 300mg/day
3. (2nd line) PO febuxostat 40mg/day, if target <6mg/dL not met after 2-4wks, then 80mg/day
4. (3rd line) PO Probenecid 250mg BD for 1 wk, then 500mg BD (drink a lot of water to prevent kidney stone formation)
   + PO Colchicine 0.5mg QD for 3-6 months
   OR PO celecoxib 200mg QD / PO prednisolone 5-7.5mg QD

• Monitor Serum Urate, ADR, CI, DDI (ic13)

Question 13

What is the non-pharm for gout during acute and long term phase?

Answer 13

Non-pharmacological management

1. (During acute flare) Topical ice
   ↓flares
2. ↓alcohol
3. ↓purine-rich foods
   a. Red meat
   b. Seafood
   c. Ikan bilis
   d. Peanuts, liver, cauliflower, durian
4. ↓high-fructose corn syrup
5. Weight management

Question 14

What’s the MOA of NSAIDs/coxibs?
What’s the place in therapy for NSAIDs?

Answer 14

NSAIDs e.g. naproxen, indomethacin
Coxibs e.g. celecoxib, etoricoxib

• Anti-inflammatory & analgesia
• inhibit PGE2 & urate crystal phagocytosis

Naproxen: BD dosing
Indomethacin: broader spectrum of anti-inflammatory action & similar to steroids can ↓leukotrienes action

Place in therapy:

• 1st line when >24-36hrs (symptomatic relief of pain)

Question 15

Why does indomethacin have a broader spectrum of anti-inflammation?

Answer 15

Indomethacin: broader spectrum of anti-inflammatory action & similar to steroids can ↓leukotrienes action

Question 16

*What is the CI of NSAIDs?

Answer 16

1) Sev renal impairment:
CrCL <30mL/min
2) low dose aspirin, salicylate (anti-uricosuric agents, don’t allow uric acid to be excreted) → but don’t stop aspirin

Question 17

What’s the place in therapy for corticosteroids?

Answer 17

Corticosteroids e.g. prednisolone

Place in therapy:

• adjunct w colchicine since it takes time for colchicine to work if <36hrs after onset
• 1st line when >24-36hrs

Question 18

What’s the MOA of Colchicine?
What’s the place in therapy for Colchicine?

Answer 18

Colchicine
MOA:
1) binds to tubulin
2) prevent tubulin polymerization into microtubules (disrupts cytoskeleton of cell)
3) inhibits leukocyte migration to joints and phagocytosis → crucial in gout
4) inhibits leukotriene B3 and PG production → ↓inflammation & pain

• relieve pain & inflammation within 24-36hrs → beyond this, NOT effective as the neutrophil migration & phagocytosis would have already taken place

Place in therapy:

• 1st line when presented within 24-36hrs after onset
• CONTINUE when start allopurinol to prevent acute gout attack

Question 19

What is the ADR of colchicine?
What is the precaution for colchicine?

Answer 19

ADR:
1) diarrhea (due to MOA1&2, it inhibit rapid cell division of GIT walls, dose dependent)
2) Others: N&V, abdominal pain, muscle weakness, unusual bleeding, pale lips, change in urine amt, hair loss

Precaution:
1) Renal impairment → ↓dose

Question 20

What is the purpose of the medications for acute gouty arthritis?

Answer 20

Acute gouty arthritis (use anti-inflammatory meds)

• To ↓ongoing feedback loop of inflammation and pain

Question 21

Why shouldn’t ULT be started during an acute gout attack?

Answer 21

ULT → **Do NOT start during acute gouty episodes (CONTRAINDICATED in acute gout attack, but under IC17 technically can start but just go low and slow)

• Sudden ↓plasma [uric acid] would steepen gradient from joints to plasma, ↑mobilisation of crystals out the joints → cause immune cells to recognise them which leads to ongoing inflammation and pain → worsen acute episode (this can also happen during prevention period)

Question 22

What are the examples of ULT and their drug class?

Answer 22

Xanthine oxidase inhibitors
e.g. allopurinol, febuxostat

Uricosuric agents
e.g. Probenecid

Question 23

What’s the MOA of Xanthine oxidase inhibitors?
What’s the place in therapy for Xanthine oxidase inhibitors ?

Answer 23

Xanthine oxidase inhibitors
e.g. allopurinol, febuxostat

MOA:

• inhibit uric acid synthesis
• anti-hyperuricemia agents
• target: <6mg/dL

Place in therapy:

(1st line) Allopurinol
(2nd line) Febuxostat
Must be taken w colchicine (if already on it and tolerable )/ NSAIDs e.g. celecoxib or etoricoxib to prevent ppt of acute gout attack

Question 24

What are the ADR of xanthine oxidase inhibitors? (optional)

Answer 24

1) skin rash
2) N&V
3) Diarrhea
4) Fever
5) sore throat
6) stomach pain
7) dark urine
8) jaundice

Question 25

What are the precaution when taking allopurinol & febuxostat? What are the DDI?

Answer 25

Warning (allopurinol): 1) Hypersensitivity 2) **Serious Cutaneous Adverse Reaction (SCAR) esp. in 1st 3 months** → SJS/TEN/ DRESS RASHES - **renal impairment** - Agents e.g. **diuretics** - starting dose high - HLA-B 5801 (Han Chinese, thai, korean) - escalation quick - **aging** 3) **Renal impairment → ↓dose** (similar to colchicine) (febuxostat) 1) **use w caution HF & CHD → high risk of death** DDI: 1) **↑bone marrow suppression** [switch allopurinol] 2) **↑hypersensitivity (ACEi, diuretics, ampicillin, amoxicillin) [switch said drugs e.g. consider switching hydrochlorothiazide, use losartan/enalapril/captopril]** 3) **allopurinol ↑these drugs (CBZ, warfarin, theophylline)** 4) **↑ADR** of pegloticase

Question 26

What is the MOA of probenecid? What is its place in therapy?

Answer 26

Uricosuric agents e.g. Probenecid MOA: 1) inhibits proximal tubule anion transport (URAT1 & GLUT9 inhibitor) 2) inhibits uric acid reabsorption - ↑uric acid excretion Start 2-wks after an acute gout attack

Question 27

What are the ADRs of probenecid?

Answer 27

1) N&V 2) **painful urination** 3) lower back pain 4) allergic reactions, rash

Question 28

*What are the impt counselling points when taking probenecid? What are the CI for probenecid?

Answer 28

- **take a lot of water to minimize renal stone formation (urates may be pushed out of the kidneys)** - keep urine pH >6 by giving alkaline e.g. K citrate (since uric acid crystal form at pH<5.5) 1) **Urolithiasis (kidney stones)** 2) **Not effective in CKD, CrCL<50mL/min**