Define gout.
Disease caused by imbalances in purine metabolism that lead to deposition of monosodium urate (MSU) crystals in articular & periarticular tissues that induces inflammatory response
Briefly describe gout syndrome.
Heterogenous spectrum of clinical diseases that include
- Acute gouty arthritis (urate crystals in synovial fluid)
- Tophi (crystal deposits in tissue and surrounding joint)
- Extra-articular presentations (gouty nephropathy i.e intersitial renal disease, nephrolithiasis)
Briefly name some of the risk factors for gout. (4)
- Genetics (inherited enzyme defects, impaired metabolism of uric acid)
- Other medical conditions (e.g. renal disease)
- Diet (alcohol, sweetened beverages, red meats) (more impt)
- Lifestyle (sedentary) (more impt)
Describe the pathophysiology of gout.
(~10%) Uric acid overproduction
- (primary) inborn errors of metabolism
- (secondary) conditions causing increased cell turnover and purine generation
E.g a lot of nucleic acid synthesis, decrease in salvage pathway, increased dietary intake of purines (guanine and adenine) which are subsequently metabolised to hypoxanthine –> xanthine –> uric acid
(~90%) Under-excretion of uric acid
• Largely excreted in urine (~65%); some reabsorbed via URAT1 and GLUT9 transporters
o Excretion affected by renal function
• Degradation also occurs in GIT by intestinal flora (35%)
Uric acid forms crystals and deposits into periarticular fibrous tissue of synovial joints, where eventually they get exposed to immune cells, provoking an immune response leading to inflammation
Describe the clinical presentation of gout. (4+-1)
- Usually monoarticular (MTP of great toe)
- Red, hot, swollen and tender; rapid onset of pain
- Pain is esp severe at night/early morning, is waking, and lasts for several hours (feels like joint is on fire)
- Swelling and discomfort continues days-weeks after
- +/- Tophi (masses of white growths visible as nodules under skin)
List the 4 different stages of gout, their features, and how they are managed.
1) Asymptomatic hyperuricemia
- (F) >6mg/dL; (M) >7mg/dL
- No treatment needed; Lifetstyle modifications
2) Acute gout attack (first episode)
- Monoarticular (usually MTP of great toe), Acute arthritis with excruciating pain
- Management: NSAIDs, colchicine or corticosteroids
3) Inter-critical phase (between gout attacks)
- Asymptomatic hyperuricemia
- No treatment needed unless pt prone to recurrent attacks (see chronic gout); lifestyle modifications
4) Chronic gout
- 2 or more attacks in 1 year (recurrent attacks)
- Hyperuricemia + development of tophi
- Management: Urate lowering therapy (e.g Allopurinol, febuxostat, probenecid)
List drugs/ diet induced decreased uric acid clearance. (10)
- Cyclosporin/tacrolimus
- Ethambutol
- Levodopa
- Laxative (overuse)
- Pyrazinamide
- Salt retention
- Diuretics
- Ethanol
- Nicotinic acid (Niacin; not in SG)
- Low-dose salicylates (e.g Aspirin)
What are the typical diagnostic requirements for gout? (2; 1 may or may not be there)
- Hyperuricemia (>6mg/dL in females, >7mg/dL in males)
- Presence of MSU crystals in joint aspirate (synovial fluid) [confirmatory diagnosis]
- Tissue biopsy of tophi (if any)
What are the goals of gout treatment? (5)
- Provide rapid, safe, effective pain relief
- Prevent gout attacks through lowering of uric acid concentration
- Address associated comorbidities
- Prevent joint destruction and tophi formation
- Improve QoL
Which drugs are typically used to manage acute gout attacks? (3 + 1 absolute last-line)
1) Colchicine
2) NSAIDs
3) Corticosteroids (PO, IA, IM)
4) IL-1 inhibitor (absolute last line)
Describe the use of colchicine in managing acute gout attacks.
(Hint: when to start, onset of effect, dose, max dose and why there is max dose)
Best started within 24 hrs of sx onset. (max 36 hours of sx onset) Beyond 36 hours, use NSAID or Steroid to bring down inflammation
Onset of effect: usually relieves pain and inflammation within 24-36 hours
1mg STAT f/b 0.5mg 1h later
OR
0.5mg BD/TDS until sx resolved (Max daily dose = 1.5mg; above which, more ADR w/o added benefit)
Can be combined with PO NSAIDs/corticosteroids
Describe the use of corticosteroids in managing acute gout attacks.
State what other drugs used in gout steroids should not be combined with.
PO Prednisolone 30-40mg/d in 1 or 2 divided doses for 2-5d, then taper off by halving dose over 7-10 days, slower for those with multiple recent attacks (e.g over 2-3wk)
IA/IM injections can be considered if NSAIDs/colchicine are ineffective/CI (cannot take PO medications)
Avoid combination with NSAIDs
What is the typical treatment duration for ULT?
State what is to be done once remission is achieved.
Until remission: No flares for at least 1 year AND no tophi
Shared Decision Making needed to evaluate the need to continue ULT
Describe the dosing regimen for allopurinol in ULT.
Take into consideration adjustments for special populations.
- (Initial) 100mg/d or less; 50mg/d or less for CKD stg 3 and above
- Inc in 50-100mg intervals q2-8w
- (Maintenance) > 300mg/d (ok for renal impairment)
- (Max) 800-900mg/d
List the risk factors for SCAR development during use of allopurinol. (6) (RASHES)
- High starting dose
- Escalation of dose too rapid
- Agent (Concomitant diuretic, fenofibrate use)
- Renal impairment
- HLA-B*5801 positive
- Seniority (Old age)
How should patients be counselled regarding SCAR development during allopurinol use?
(What symptoms should patients look out for in relation to, when to esp look out for it)
- Flu-like sx (fever, body ache or malaise)
- Mouth ulcers, sore throat
- Red/sore eyes
- Rash
Take more note esp during first 3 months of taking allopurinol.
If any SCAR symptoms develop or unsure of symptoms, seek medical attention, photograph rash if possible.
In which group of patients should febuxostat use be cautioned?
HF and CHD (generally any major CVD)
Describe the dosing regimen of febuxostat as part of ULT
- (Initial) 40mg/d
- Can increase up to 80mg/d, if no/inadequate response by 2-4w
Describe the dosing regimen of probenecid as part of ULT
- (Initial) 250mg BD x 1wk
- Then increase to 500mg BD 1w later
- Can increase in 500mg intervals q4w
- (Max) 2g/d
In which groups of patients is probenecid not recommended/contraindicated?
- History of urolithiasis
- CrCl <50mL/min
What are the criteria for initiating ULT? (6)
Any of the following:
- 2 or more gout attacks in a year
- Presence of tophi
- History of urolithiasis (kidney stones)
- Clinical/imaging findings of gouty arthropathy (joint damage)
- Have CKD stage 3-5 (NICE)
- On diuretic tx (NICE)
What are the usual plasma [uric acid] targets for ULT?
- Usual: <6mg/dL
- Tophaceous gout: <5mg/dL
List the DDIs with allopurinol (4 broad categories).
- (Inc bone marrow suppression) 6-mercaptopurine, azathioprine, cyclophosphamide
- (inc hypersensitivity/SCAR) ACEi, loop diuretics, thiazides, ampicillin/amoxicillin
- (inc conc of) CBZ, warfarin, theophylline
- (inc toxicity of) pegloticase
State when ULT should ideally be started, and considerations for starting earlier than stipulated
Ideally 2-4w after resolution of flare (lowering plasma [uric acid] can result in more precipitation and inflammation)
However, ULT can be started without waiting for flare resolution in patients whom are more non-compliant/unlikely to come back for consult.
