W32 Gout (JD) Flashcards
What is gout?
2 most common crystals
Insoluble crystals are deposited in areas of the body leading to symptoms
– Monosodium urate = “gout”
– Calcium pyrophosphate =“pseudogout”
- In typical gout – crystals form in joint leading to arthritic pain
Gout – a “crystal deposition disease”
For info ([2nd-century Greek physician Aretaeus, describing the pain of gout]
No other pain is more severe than this, not iron screws, nor cords, not the wound of a dagger, nor burning fire.
Gout – a “crystal deposition disease”
- Features of gout
- Disease spectrum of hyperuricemia
– Uric acid ≥ 360 μl/L - High plasma urate = most important determinant for gout
– risk increases exponentially - may be asymptomatic
– (generally, do not treat) - Deposits of urate crystals in joints
- Deposits of urate crystals in connective tissues (tophi),
- Deposits of uric acid in kidney -nephrolithiasis (kidney stones)
Gout
What does Deposition of urate crystals in synovial fluid lead to? (3)
- Macrophages phagocytose Mono Sodium Urate (MSU) crystals → triggers cell lysis →discharge of proteolytic enzymes
- This results in an inflammatory reaction
with intense joint pain, erythema, warmth and swelling - If untreated, can result in extensive joint destruction and tophi formation (nodular accretion of MSU)
Epidemiology of gout:
* Serum urate concentration (and risk of gout) increases with…?
- Age
- Male gender (~ 10x more than women)
- High blood pressure
- Renal impairment
- Body weight
- High alcohol and soft drink intake, meat, seafood
- Metabolic X syndrome (insulin resistance – risk of type 2 diabetes/cardiovascular events – high BMI values)
- Certain medicines – (e.g., diuretics, low-dose aspirin)
- Familial tendency
Etiology of gout:
Overproduction of uric acid:
- Cytotoxic drugs, radiotherapy (increased
cell destruction) - Obesity, excessive consumption of
alcohol, or purines (meat) - Inherited enzyme defect
- High cell turnover (neoplastic diseases,
psoriasis
Etiology of gout
Under-excretion of uric acid
- Diuretics (especially thiazides), low dose
aspirin, ciclosporin - Renal impairment
- Heart failure
- Metabolic causes such as ketosis (DM), starvation
Pathophysiology of gout?
Purines, from which uric acid is produced,
originate from three sources:
- Dietary purines
- Conversion of tissue nucleic acid to purine
nucleotides
- De novo synthesis of purine base
- These purine precursors are metabolised by
the liver to uric acid – 2/3 cleared by the
kidneys and 1/3 by the GIT
What are 4 foods to avoid eating with gout?
- Alcohol
- Soft drinks
- Seafood
- Liver
Diagnosis of gout?
What steps are involved in diagnosis?
- History
-Dietary habit, comorbidities, family Hx, Drug Hx - Signs and symptoms
-Rapid onset (often overnight) of severe pain together with redness and swelling in one or both metatarsophalangeal (MTP) joints. - Serum urate level
- A serum urate level of ≥ 360 micromol/L (6mg/dL) confirm the diagnosis
- Crystals of urate in aspirate of synovial fluid (rarely performed)
- To identify crystals and hence type of gout
- Response to treatment
Differential diagnosis of gout:
- Bursitis, tenosynovitis, cellulitis
- Haemochromatosis
- Non-urate crystal-induced arthropathy, such as pseudogout
* Osteoarthritis - Psoriatic arthritis
- Reactive arthritis
- Rheumatoid arthritis
- Septic arthritis
- Trauma
What are the phases of gout? (2)
Acute
Chronic
Clinical presentation of acute gout?
- Men more than women, often 40-60 years old
-
Rapid onset of intense pain, swelling, redness and inflammation in affected joint
-Maximum severity reached within 12-24 hours - Acute attacks can be very severe - may mimic septic arthritis, with fever, malaise, leucocytosis and raised inflammatory markers
- Often begins at night, waking the sufferer from sleep (likely due to colder temperatures)
- Untreated attacks may last 3-14 days before spontaneous recovery
- Most typically affects one joint initially
-Most often occurs in the big toe (podagra)
-Other sites: ankle, heel, knee, wrist, finger, elbow
Chronic (tophaceous) gout
Clinical presentation?
- Eventually recurrent attacks may fail to
resolve completely → crippling destructive arthritis. -
Tophi – (firm, white nodules under translucent skin) after 10 -20 years.
-Common sites of tophaceous gout: elbows, hands, feet
-Less common sites: helix of the ear, Achilles tendon and knee joints
Treatment goals and desired outcomes in..
Acute gout:
* Terminate attack and provide symptom relief
Chronic gout:
* Prevent acute attacks
* Prevent joint destruction and disability
* Resolve tophi
* Prevent nephrolithiasis and renal disease
Asymptomatic hyperuricaemia:
* Treatment is not usually indicated
* Address lifestyle factors
Management of acute gout:
What medications are used first-line? (3)
- NSAIDs – 1st Line
- Colchicine – 1st Line
- Corticosteroids – 1st Line
NSAIDs- acute gout
- Treatment of choice when not contraindicated
- Does not modify plasma urate concentrations
- Probably all equally effective
-Naproxen is most commonly used
-short acting, easily titrated - Start with high dose until symptoms start to resolve (usually 3-5 days) then
reduce dose until signs of joint inflammation resolve (then cease) - Consider PPU with NSAIDs
Corticosteroids- acute gout
- Another option if NSAID is contraindicated
- A short course of oral corticosteroid — for example prednisolone 30-35 mg once a day for 3-5 days.
-Note: this is an off-label use of oral corticosteroids. - Corticosteroids can be given as an intra-articular injection – where 1 or 2 joints are affected
Colchicine- MoA
- Colchicine – an inhibitor of cellular microtubule function
- Inhibits neutrophil migration, chemotaxis, adhesion and phagocytosis in the inflamed area; reduces inflammatory reaction
- No effect on uric acid production or excretion
Colchicine – Toxicity
For info- (extract from an article)
● “near universally fatal consequence of a significant overdose”
● “cases series of 9 patients…. with a colchicine overdose”
● “significant number were accidental”
● “all cases, apart from one, resulted in death”
Acute gout – Colchicine
Dose?
Adult
* 500 micrograms orally 2–4 times a day until symptoms relieved
* Maximum 6 mg per course, do not repeat course within 3 days
Colchicine – other information
common se?
- Do not repeat the course within 3 days
- Takes 24 to 48 hours to relieve symptoms
- Signs of toxicity often occur within 24 hours of starting therapy, usually before pain subsides
- Common SE: nausea, vomiting, diarrhoea
- Severe SE: multi-organ failure, neuropathies, cardiovascular failure, low blood counts, convulsions, coma and death
- Drug interactions – Colchicine is a substrate of both cytochrome P450 3A4 and P glycoprotein
Management of chronic gout
Prophylactic treatment: Urate lowering therapy ( ULT)– two classes?
- Xanthine oxidase inhibitor – Decreases production of urate
- Such as allopurinol & febuxostat (1st line)
- Uricosuric agent – Increases renal excretion of uric acid
- Such as sulfinpyrazone or benzbromarone (specialist use – 2nd line)
Urate lowering therapy (ULT)
Indicated in? (4)
- Tophaceous gout
- Non-tophaceous gout if acute attacks are frequent
- CKD
- Chronic gouty arthritis
- ULT is a lifelong treatment – even if serum urate level is achieved .
- ULT to be started at least 2- 4 weeks after a flare
- Titrate the dose until target urate level achieved
Serum urate monitoring:
- Use monthly urate level to guide dose titration of ULT
- Once target achieved with ULT – consider annual monitoring of serum urate
Targets:
Chronic gout = < 360 μl/L
Tophaceous gout or those with frequent
flare despite serum urate level < 360 μ/L
= < 300 μ/L
Urate lowering therapy:
First line?
Give with what other medication?
- Allopurinol
- Febuxosta
Give with colchicine, NSAID or prednisolone on commencement to prevent exacerbation of gout (for ~ 6 months)
Allopurinol
What drug class?
When should it not be started?
- exception?
- Xanthine oxidase inhibitor that decreases production of urate
- Allopurinol should not be started during acute gout, due to the potential for worsening the arthritis when there are sudden changes to urate levels
- However, if the patient is taking allopurinol (already), it should always be continued during an acute attack.
Allopurinol
SE?
Monitoring?
- Common SE: Rash
- Severe SE: Severe cutaneous adverse reactions, hypersensitivity, hepatic disorder
- Monitor LFT
-Dose adjustment in hepatic impairment - Monitor RFT
-Renal impairment → increased risk of drug accumulation
→ increased risk of hypersensitivity
-Manufacture recommends dose adjustment
Febuxostat:
When to use?
- Novel, orally administered, non–purine analogue inhibitor of xanthine oxidase
- Biochemically unrelated to allopurinol therefore may be an alternative if intolerant to allopurinol
- More effective urate-lowering than allopurinol
300mg BUT no fewer gout attacks (CONFIRMS
trial)
Febuxostat- more info
Main SE?
- Mainly eliminated by glucuronidation in the liver
-Manufacturer advises max. 80 mg daily in mild impairment - No dose adjustments are recommended in patients with mild to moderate renal impairment →no data re severe impairment
- Main side effects – liver function abnormalities, diarrhoea, headache, nausea and rash.
- Sever SE – Serious hypersensitivity reactions, Increase risk of CV death in patient with Hx of major CVD (Clinical trial)
-MHRA/CHM Advice
Nonpharmacologic advice in chronic gout? (4)
- Diet – healthy, well-balanced diet
- Weight management – obesity can exacerbate flare
- Reduce alcohol intake – excess alcohol can exacerbate gout
- Advice to treat attack asap and that prophylactic treatment should not be discontinued
Nonpharmacologic advice - NHS
- Get to a healthy weight but avoid crash diets- try the NHS weight loss plan
- Eat a healthy, balanced diet- your gp may give you a list of foods to include or limit
- Have some alcohol free days each week
- Drink plenty of fluids to avoid getting dehydrated
- Exercise regularly- but avoid intense exercise or putting lots of pressure on joints
- Stop smoking
- Ask a GP about vitamin C supplements
Dont:
- have lots of sugary drinks and snacks
- eat a lot of fatty foods
- drink more than 14 units of alcohol a week, and spread your drinking over 3 or more days if you drink as much as 14 units
When is a referral needed for gout?
(to a rheumatology service) (4)
- The diagnosis of gout is uncertain
- Treatment is contraindicated, not tolerated or ineffective
- Patients with CKD stages 3b to 5 (K&L ISU)
- Those who have had an organ transplant
Which of the following drugs is the MOST appropriate option for patient with chronic gout and myocardial infarction?
A. NSAIDs
B. Febuxostat
C. Allopurinol
D. Sulfinpyrazone
= C
- clinical guidelines for gout recommend allopurinol as first-line treatment for patients with gout and major cardiovascular disease
