Gout Flashcards
What is the pathophysiology behind gout?
When there is high uric acid in the body, uric acid crystals form in the joints
Inflammatory response to MSU occurs in a wide range of immune cells e.g. macrophages, dendritic cells
Signal 1 – normal production of inflammasome components, can be stimulated by a wide range of stimuli
Signal 2 – MSU crystals recognised by (unknown) receptor, which results in inflammasome activation
Inflammasome activation activates Caspase 1, which catalyses activation of IL-1β and Gasdermin-D
- Gasdermin-D cleavage results in the formation of pyroptotic pores
- IL-1β exits cell via pyroptotic pores, and other foreign materials can also enter the cell
- IL-1β binds to IL-1 receptors to result in inflammatory responses – eg translocation of p65 and p50 into the nucleus for DNA transcription of cytokine and chemokine genes
- Foreign materials may stimulate inflammatory responses in the cells that they enter as well
Inflammasome formation also results in potassium efflux via potassium channels
How does gout present?
- Usually monoarticular – e.g. 1st joint of big toe
- Pain wakes one up from sleep
- Severe pain for several hours, with the swelling & discomfort continuing for days to weeks thereafter
How is gout diagnosed?
Presence of MSU crystals in
- Synovial fluid – via joint aspirate
- Tissue sections of tophaceous deposits
Presence of Tophi – though they may only start appearing later on
Joint Aspirate Findings (not always helpful)
What are the goals of treatment for gout?
- Provide rapid, safe and effective pain relief
- Reduce future attacks
- Address associated comorbidities
- Prevent joint destruction and tophi formation
- Increase QoL
What are the stages of gout?
Asymptomatic hyperuricemia
Acute gout (1st attack)
Inter-critical phase (b/w flares)
Chronic gout
What therapy options can be used during acute gout attacks?
PO Colchicine, PO NSAIDs, PO/Intra-articular Corticosteroids
What is the MOA of colchicine?
- Binds to tubulin
- Prevents tubulin polymerization into microtubules
- Inhibits leukocyte migration and phagocytosis
- Inhibits leukotriene B4 (LTB4) and prostaglandin production
How should colchicine be dosed?
Load 1mg, then take another 0.5mg 1h later OR
0.5mg BD-TDS until the acute flare resolves
Note: greater likelihood of GI AE if dose >1.5mg/day
What are the side effects of colchicine?
N/V/D, abd pain, muscle weakness, unusual bleeding, pale lips, change in urine amt
When should urate-lowering therapy be started for patients with an acute flare?
Already on ULT – continue during the flare
Not on ULT yet – best to wait for flare to resolve for 2-4 weeks
* Rationale: ULT reduces plasma urate, which may cause uric acid from joints to leave and worsen the attack and/or cause periarticular involvement
* Can consider to not wait for flare to resolve – give them colchicine on standby
When should urate-lowering therapy be started for patients without an active acute flare?
Offer ULT to people with gout who have
→ Multiple or troublesome flares
→ CKD stages 3-5 (GFR categories G3-G5)
→ Diuretic therapy
→ Tophi
→ Chronic gouty arthritis
Discuss the option of ULT with patients who are not within these groups
What are the possible ULT options for gout?
Xanthine oxidase inhibitors - allopurinol, febuxostat
Uricosuric agents - probenecid
What is the MOA of the xanthine oxidase inhibitors?
Decrease uric acid production
What are the side effects of the xanthine oxidase inhibitors?
Rash, N/V/D, fever, sore throat, stomach ache, dark urine, jaundice
What is a precaution that needs to be taken before using xanthine oxidase inhibitors?
SCAR – test for HLA-B*5801 genotype (esp Chinese) + patient education
- Test if renally impaired, or older age (higher SCAR risk)
- Sx: Flu-like Sx, Mouth ulcers, sore throat, red/sore eyes, rash
- Rare, but can happen – esp 1st 3 months
What is the dosing for allopurinol?
Initiate at ≤100mg/day, titrate by ↑50-100mg Q2-8/52 based on Sx (monitor serum urate, toxicity)
Dose range: 100-800mg/day, usual maintenance >300mg/day
Start even lower if renally impaired
What is the dosing for febuxostat?
Initiate at 40mg OD
Increase to 80mg if not at target after 2-4/52
What are the contraindications for the xanthine oxidase inhibitors?
Pts w SCAR/hypersensitivity to allopurinol/febuxostat in the past
What is the MOA of probenecid?
Inhibit proximal tubule anion transport to inhibit uric acid reabsorption - ↑uric acid excr
What are the side effects of probenecid?
N/V, painful urination, lower back pain, allergic rxn, rash
What precautions need to be taken with probenecid?
Take plenty of fluid to minimize kidney stone formation (>2L)
Admin potassium citrate to keep urine pH >6.0
What is the dosing for probenecid?
Initiate 150mg BD 1/52, then 500mg BD
Continue increasing dose by 500mg Q4/52 as tolerated if Sx not controlled
Dose range is 500-3000mg/day, but usually ≤2g/day
Avoid in CrCl <50, contraindicated if CrCl <30
What are the contraindications for probenecid
G6PD deficiency
Avoid in CrCl <50, contraindicated if CrCl <30
What are the lab targets for gout?
Uric acid
→ Non-tophaceous gout <360 μmol/L
→ Tophaceous gout < 300 μmol/L
What prophylaxis regimens can be initiated for acute gout flares while starting ULT?
Initiate ULT with anti-inflammatory prophylaxis for 3-6 months – either
→ Colchicine 0.5mg OD
→ Low dose PO NSAID/coxib (e.g. celecoxib 200mg OD)
→ Low dose PO corticosteroid (e.g. prednisolone 5-7.5mg OD)
How long does chronic gout treatment last for?
- Remission = no flares for ≥ 1 year and no tophi
- If Tx is well-tolerated and not burdensome, can SDM to continue or stop Tx
What are the non-pharm strategies for gout?
Limit alcohol intake
Limit purine-rich foods
→ Asparagus
→ Cauliflower
→ Mushroom
→ Oatmeal
→ Red meat
→ Meat extracts (e.g. broth)
→ Seafood (incl ikan bilis)
→ Strawberry
→ Durian
→ Peanuts
→ Bean cake
→ Organ meat e.g. liver
Limit high fructose corn syrup
Weight management
What are some medication optimization considerations for gout patients?
Switch HCTZ to alternate antihypertensive – decreases urate excretion
Use losartan preferentially as antihypertensive – uricosuric effect
→ Enalapril & captopril also have uricosuric effect
DO NOT stop low dose aspirin if indicated – though it increases urate reabsorption
DO NOT add fenofibrate or switch cholesterol lowering agents to fenofibrate (despite uricosuric effect)
