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Gout Flashcards

1
Q

Define Gout.

A

Gout is a type of arthritis and is a clinical manifestation of hyperuricaemia resulting in the deposition of mono sodium urate monohydrate crystals in and around the joints causing acute inflammation and tissue damage.

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2
Q

What is hyperuricaemia caused by?

A

Either caused by an increase in production of uric acid and / or reduced excretion.

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3
Q

What is the prevalence and incidence of Gout in the UK?

A

The prevalence of gout in the UK is 2.49%.
The incidence in the UK is 1.77 per 1000 people a year

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4
Q

What is the US prevalence of Gout?

A

3.9%

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5
Q

What age is Gout more prevalent?

A

Men between 30-60 years
Women after menopause

Very rare under the age of 20

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6
Q

Will Gout always occur when a patient has hyperuricaemia?

A

No, Gout is a clinical manifestation of hyperuricaemia and does not develop in every patient.
Alternatively there are incidents where a patient has normal uric acid levels but suffers from gout attacks.
Therefore, the risk of developing is higher then uric acid levels are higher.

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7
Q

What is the ratio of prevalence of men and women who develop Gout?

A

4.3 : 1

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8
Q

What are some of the risk factors for Gout?

A

Obesity, High blood pressure and/or Diabetes

Having a close relative with gout (family history)

Kidney problems

Eating foods that cause a build-up of uric acid, such as red meat, offal and seafood

Drinking too much beer or spirits

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9
Q

Briefly describe the pathophysiology of Gout?

A

Gout occurs when there is an increase in uric acid levels. Uric acid is produced as an end product of purine metabolism.
Hypoxanthine is converted Xanthine and then to Uric acid by a single enzyme Xanthine Oxidase. The kidneys are responsible for the majority of excretion of uric acid - 2/3 in the urine, whilst the other 1/3 is excreted in the faeces facilitated by bile. When the kidneys are working normally they work very specifically to ensure the uric acid range in the blood is very controlled, however when there is either an overproduction of uric acid (over-producers) or the kidneys are not working properly (under-excreters) the levels of uric acid build up in the blood, potentially leading to the development of Gout.

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10
Q

Describe the overall reabsorption and excretion amounts of uric acid.

A

When Uric Acid is first filtered in the glomerular, 90-100% of the uric acid is reabsorbed in the proximal tubule.
50% is then actively secreted in the distal tubule.
40-45% is post secretory reabsorbed. 5-10% of the original glomerular load is excreted.

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11
Q

Of those who develop Gout, what percentage is due to being over-producers and what percentage is due to being under secretors.

A

10% of patients with Gout are due to the increased rate of synthesis of purine precursors of uric acid.

90% is due to the reduced elimination of uric acid y the kidney.

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12
Q

State the differences in aetiology of primary and secondary Gout.

A

Primary Gout has no singular identifiable cause other than possibly genetic predisposition.

Secondary Gout is the type of Gout caused by another condition or factor that affects the levels of uric acid in the body.

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13
Q

State some foods that have a high purine content and hence result in over production.

A

Red meat
Offal
Sea food

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14
Q

What are some of the conditions that can cause over production of purine precursors?

A

Neoplasia
Psoriasis
Haemolytic anaemias
Cell lysis due to chemotherapy
Enzyme defects leading to increased synthesis (Xanthine Oxidases)

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15
Q

What are some of the contributing factors that can result in uric acid under excretion?

A

Hyperuricaemia
Alcohol
Drugs affecting kidney reabsorption

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16
Q

What are some other independent factors that lead to Gout development?

A

Triggers- physical stress
Joint trauma- tight shoes, hill walking, hiking, history of joint trauma
Hypertension
Obesity
Hypertriglyceridemia

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17
Q

What are some drugs that can affect renal function and hence excretion of UA?

A

Diuretics - especially thiazide (due to volume depletion and reduced tubular excretion.

Other drugs include:
Aspirin
Ciclosporin
Omeprazole
Ethambutol
Pyrazinamide
Niacin
Didanosine
Levodopa
Cytotoxics

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18
Q

How does hyperuricaemia then contribute to a reduction in UA excretion?

A

High circulating levels of UA results in a high urate loading passing through the kidney. This then results in an increase of urate reabsorption to avoid the dumping of insoluble urate into the urinary tract.
Consequently this results in a reduction of tubular secretion and an overall reduction in excretion.

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19
Q

What UA level is monosodium urate crystallisation most likely to occur?

A

When UA levels are persistently over 380 micromol/mL which is known as the solubility limit.

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20
Q

What is the pka of UA?

A

Uric acid is a weak acid with a pka of 5.8, meaning that at physiological pH it is ionised and able to form a salt (hence formation of monosodium urate.

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21
Q

When does crystallisation of monosodium urate crystals occur?

A

Once supersaturation has occurred, the solubility limit has been reached.

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22
Q

What is solubility influenced by?

A

Temperature
pH
Cation concentration
Articular dehydration and presence of nucleating agents

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23
Q

What are some examples of nucleating agents which influences solubility?

A

Non-aggregated proteoglycans
Insoluble collagens
Chondroitin

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24
Q

Do symptoms of Gout begin and soon as crystal formation occurs?

A

No, deposition and formation of monosodium urate crystals can occur for years before symptoms appear.
Usually symptoms only occur once the crystals have been shed into the bursa (which are small sacs of synovial fluid surrounding the joint), this then triggers an inflammatory reaction.

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25
Q

What are some of the precipitating factors that can cause shedding of these crystals?

A

Trauma
Dehydration
Rapid weight loss
Illness
Surgery

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26
Q

What is the effect of urate crystals presence on the immune response?

A

Initiates amplifies and sustains inflammatory responses by:
Humoral and cellular inflammatory mediators
Complement system

By triggering these inflammatory pathways this then results in:

Pro-inflammatory cascade of cytokines, chemotactic factors, TNF

Inflammatory cell accumulation (monocytes and mast cells in the early early stage, neutrophils in the late stage).

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27
Q

What is a crucial pro-inflammatory mediator involved in Gout?

A

IL-1B

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28
Q

State the 5 progressive stages of Gout.

A

Asymptomatic hyperuricaemia
Acute gouty arthritis
Interval gout/ Intercritical Gout
Chronic tophaceous Gout
Gouty nephropathy

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29
Q

Which joints are normally first affected by Gout?

A

90% of Gout first precipitates in one joint
80% of cases begin in the first metatarsophalangeal joint (big toe)

Other joints that can be affected:
Small joints of feet/ankles
Hands
Elbow
Knees

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30
Q

What are some of the first symptoms of Gout?

A

Severe pain with hot, red, swollen joints
Abrupt start, maximum intensity at 8-12 hours
Weight bearing is impossible
Erthyema
Synovitis
Increase in WBC (Leucocytosis)
Confusion in the elderly

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31
Q

When is a Gout attack most likely to happen?

A

Normally after a trigger such as alcohol or food

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32
Q

What happens if Gout is left untreated?

A

After 7 days it resolves itself
But there will be desquamation of the overlying skin (skin shedding)

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33
Q

Describe what occurs in the Intercritical Gout stage.

A

This is simply the time between Gout attacks.
This can be months to years without the patient experiencing any symptoms

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34
Q

Describe what occurs in the Chronic tophaceous Gout stage.

A

In this stage, which is normally 10 years plus after Gout diagnosis / of hyperuricaemia, there is the development of tophi.

Tophi are white deposits of monosodium urate crystals which appear as nodules on the joint.

These usually occur subcutaneously or in the periarticular areas.

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35
Q

What are some of the complications that can occur in Gouty nephropathy?

A

Due to crystal deposition around the renal tubules.

Complications include:
Interstitial nephritis
Proteinuria
Renal impairment
Renal stone formation

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36
Q

What are some of the complications of Gout in general?

A

Cardiovascular disease and cardiovascular mortality.
Chronic arthritis.
Chronic kidney disease.
Joint damage.
Reduced quality of life.
Renal stones.
Tophi.

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37
Q

When should Gout be suspected?

A

Rapid onset of severe pain together with redness and swelling in one or both metatarsophalangeal joints.
Tophi.

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38
Q

What may the assessment for Gout include?

A

Assessment of gout should include taking a medical history, examining the person, and measuring the serum urate level.

May also involve:
Joint fluid microscopy - presence of crystals and absence of infection (rule out septic arthritis)

Joint X-ray - rule out other causes
Standard bloods - RF, lipids, glucose

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39
Q

What serum urate level will confirm the diagnosis of Gout?

A

A serum level of 360 micromol/L (6 mg/dL) or more confirms the diagnosis

40
Q

Why might a joint fluid microscopy not always be done?

A

Due to the increased risk of infection

41
Q

What are the aims of treatment for Gout?

A

Relieve pain and inflammation of acute attacks
Terminate attack
Prevent further attacks
Prevent long-term complications of joint and organ damage
Avoid precipitating factors

42
Q

What should the treatment of an acute attack involve?

A

Offering a nonsteroidal anti-inflammatory drug, colchicine, or a short course of oral corticosteroid.

Giving appropriate self-care advice

43
Q

Which NSAID should be avoided in treatment of an acute attack and why?

A

Aspirin as it competes with uric acid for excretion and worsens the attack

44
Q

What counselling would you give to patient with Gout regarding NSAID therapy?

A

NSAIDs are used to treat the pain and reduce inflammation associated with Gout.
They can abort attacks if given early enough therefore the patient should carry a supply with them at all times.
Treating a patient early with NSAIDs is more important than the NSAID of choice

45
Q

What may need to be co-administered with an NSAID?

A

PPI for gastro-protection

46
Q

What NSAID dose should a patient be given?

A

Full therapeutic high dose for 24-48 hours, lower doses then for 7-10 days until completely resolved.

47
Q

When may colchicine be used?

A

Used as alternative to NSAID when patients are contra-indicated to NSAID use.

For example,
CVD, hypertension, diuretic use
Renal disease
GI toxicity

48
Q

What are some of the disadvantages of Colchicine?

A

Slower onset
Higher levels of toxicity
Must be given ASAP as again it is less effective over time

49
Q

How does Colchicine work?

A

Inhibits neutrophil migration into the joint

50
Q

What is the dose for Colchicine?

A

Take 0.5mg 2-4 times a day until relief of joint pain or until GI side effects develop

Or total 6mg, this should not be repeated within 3 days

51
Q

When would a patient experience the effects of Colchicine?

A

Normally after 6 hours
Pain relief at 12 hours
Resolution after 48-72 hours

52
Q

What are some of the key interactions of Colchicine?

A

Interacts with glycoproteins and CYP3A4 inhibitors such as Clarithromycin causing an increase in Colchicine levels

53
Q

What are some of the side effects of Colchicine?

A

Nausea and vomiting
Abdominal pains
Diarrhoea
Rashes
Peripheral neuropathy
Blood dyscrasis

54
Q

What side effect of Colchicine if it occurs you must stop immediately?

A

Diarrhoea as it is a sign of mucosal damage

55
Q

What corticosteroid dosing should be used in the treatment of flares?

A

Prednisolone 35mg for 5 days as effective as Naproxen 500mg twice a day for 5 days

So normally Prednisolone 30-35mg for 5 days

56
Q

What is the benefit of using articular Thamcinolone?

A

Has a good safety profile
Used in the treatment when there is monoarthritic of an easily accessible joint

57
Q

What is the example of combination therapy used in the treatment of flares?

A

NSAID with Colchicine or a corticosteroid

58
Q

When should urate lowering therapy be offered?

A

Multiple or troublesome flares (more than two attacks a year)

CKD stages 3 to 5 (glomerular filtration rate [GFR] categories G3 to G5)

Diuretic therapy

Tophi

Chronic gouty arthritis

Also possibly if they are a young patient, have urolithiasis, joint damage.

59
Q

When should ULT be initiated?

A

At least 2 to 4 weeks after a flare has settled

60
Q

Why are not all people who suffer from Gout attacks started on ULT?

A

Initially Gout attacks are infrequent and self limiting, it is only as the Gout progresses they must be offered.
That being said if somebody with Gout does not fall into one of the categories for initiating ULT, there can be a discussion with a specialist to discuss it as an option.

61
Q

Why is ULT not started during an acute attack?

A

Patient has had hyperuricaemia for several years and therefore it is not crucial to start it straight away.

Agents used for prophylaxis lower the levels of uric acid and it has been shown that changes in uric acid levels causes mobilisation of uric acid stores which prolongs the attack or causes another.

62
Q

If Allopurinol is started during an attack will it prolong or precipitate another attack?

A

No unlike most ULT which is contra-indicated during an attack or shortly afterwards, allopurinol has been shown not to have this effect.

63
Q

What are the four aims of ULT?

A

Reduce the frequency of flares
Dissolve the crystals and avoid recurrence
Reduce the size and number of tophi
Facilitate tophi disappearance

64
Q

What monitoring is required for ULT and how often?

A

Monthly serum urate levels which helps to guide the up-titration of ULT to reach negotiated patient targets.

65
Q

What is the serum urate level target for patients on ULT?

A

Aim for a target serum urate level below 360 micromol/L (6 mg/dL)

66
Q

When may a lower serum urate target of 300 micromol/L (5 mg/dL)?

A

Have tophi or chronic gouty arthritis.

Continue to have ongoing frequent flares despite having a serum urate level below 360 micromol/L (6 mg/dL)

67
Q

Why is low dose Colchicine used when initiating a patient on ULT?

A

To reduce the risk of flares (ULT causes mobilisation of uric acid stores which can precipitate another attack).

68
Q

What dose of Colchicine is used for flare prophylaxis?

A

0.5-1mg daily (may have a reduced dose due to renal impairment).

69
Q

If colchicine is contra-indicated which drug is used?

A

NSAID and PPI

70
Q

How does Allopurinol work?

A

It is a Xanthine oxidase inhibitor and therefore prevents the formation of Uric acid.

71
Q

Allopurinol is the pro-drug, what is the name of the active metabolite it is converted to?

A

Oxy-purinol

72
Q

What is the dosing regime for Allopurinol?

A

Starting dose is 100mg
Increase dose every 3-4 weeks according to serum urate levels
Maintenance dose is 300-600mg

73
Q

What should the dose of Allopurinol be for somebody with Renal impairment?

A

50-100mg daily

74
Q

What are the main side effects of Allopurinol?

A

Rashes
Hypersensitivity
GI
Accumulation in renal impairment

75
Q

When should Allopurinol be initiated?

A

1-2 weeks after the acute attack subsides

If patient is already on the drug during an acute attack, continue the drug and treat the acute attack appropriately

76
Q

What type of hyperuricaemia can Allopurinol be used to treat?

A

Can be used for the prevention of drug induced particularly diuretic induced hyperuricaemia when there is no option to switch the anti-hypertensive for example, in heart failure.

77
Q

What is Febuxostat and when is it used?

A

Febuxostat is a non-purine selective inhibitor of Xanthine Oxidase

It is used as an alternative to Allopurinol when it is contra-indicated or the patient is intolerant.

78
Q

What is the dosing regime for Febuxostat?

A

80mg once a day

This can be increased to 120mg if uric acid levels are still above 375 micromol/L after 2-4 weeks

79
Q

What is the appropriate management if an acute attack occurs when a patient is on Febuxostat?

A

Continue treatment and treat flare appropriately

80
Q

What are the main side effects of Febuxostat?

A

GI
Headache
Increase in LFTs
Oedema
Rash
Serious hypersensitivity reactions

81
Q

What is the second line treatment for Gout?

A

The uricosuric agents

Examples include:
Sulfinpyrazone
Probencid (unlicensed)
Benzbromarorle (unlicensed)

82
Q

What is the mechanism of action of the Uricosuric agents?

A

They increase uric acid secretion by a direct action on the renal tubule.

83
Q

By considering the mechanism of action of the Uricosuric agents, when may the drugs be contra-indicated?

A

Must be avoided in urate nephropathy
Ineffective with poor renal function (Creatinine clearance below 20-30 mL/min)

Patients must also maintain a high fluid concentration to reduce the risk of kidney stone formation.

84
Q

Can Uricosuric agents be used in combination with Allopurinol or Febuxostat?

A

Yes if target serum urate levels are not achieved by monotherapy.

85
Q

What type of drug is Canakinumab and how is it administered?

A

It is a recombinant monoclonal antibody and it is administered by s/c injection.

86
Q

At what progressive stage of Gout is Canakinumab used?

A

Used in severe refractory tophaceous Gout.

87
Q

How does Canakinumab work?

A

Targets IL-1B, a pro-inflammatory cytokine which is stimulated by the formation of urate crystals.

88
Q

When is Canakinumab contra-indicated?

A

When there is a current infection present, increases the risk of a more severe infection occurring
e.g. Sepsis

89
Q

Can Canakinumab be used in an acute flare?

A

Does have evidence but not approved by NICE

90
Q

What are some drugs that have not been approved by NICE but have some evidence of activity?

A

Pegloticase
Anakinra
Rilonacept

91
Q

How does Pegloticase work?

A

It is a pegylated uricase which catalyses the oxidation of Uric Acid into Allantoin (which is the soluble end product).

92
Q

When would Pegloticase be indicated?

A

For those with severe dehabilitating tophaceous Gout and a poor quality of life - and the serum urate level target has not been achieved.

93
Q

What type of drug is Anakinra?

A

IL-1 anatagonist

94
Q

When is Anakinra licensed?

A

Rheumatoid arthritis
Not yet licensed for Gout

95
Q

What is the target of Rilonacept?

A

It is a IL-1a/b and IL-1r antagonist

96
Q

Explain the key drug interaction with Allopurinol?

A

There is a severe drug interaction between Allopurinol and Azathioprine.

Azathioprine is converted to its active metabolite Mercaptopurine in vivo.

Mercaptopurine is then metabolised by the drug Xanthine oxidase, which Allopurinol inhibits meaning concurrent use causes accumulation in the body resulting in fatal bone marrow suppression.

97
Q
A

Inflammation (11 decks)

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