Management of Gout

Dr Jennifer HamiltonConsultant RheumatologistQueen Elizabeth Hospital

Gateshead

Overview

• Background• Pathophysiology of gout• Gateshead Gout Guideline

– Patient information– Costings

Why do we need a gout guideline?

• Gout prevalence is increasing-Diet-Obesity-Ethanol use-Increased use of low dose

aspirin• Prevalence 4.1% by age of 75

Treatment options

• Cheap• Tried and tested• Opportunity to reduce utilisation of

health resources• Reduce costs as can be largely

managed in primary care

MetabolismSynthesis

Dietary purine

Purine synthesisBody purinenucleotides

Tissue nucleic acids

Purines

Uric acid

Elimination

Intestinalexcretion

Renal excretion

Urate crystal formation

• Urate more soluable in plasma, synovial fluid and urine

• At a concentration above 0.42 plasma is supersaturated with urate

• Urate and uric acid soluability fall with decreasing temperatures

Factors affecting urate crystal formation

• Concentration of urate at site of crystal formation (dehydration)

• Local temperature (? Why big toe affected)

• Presence or absence of substances maintaining urate in solution

What causes the inflammation

• MSU crystals recognised by innate immune system

• Uptake of MSU by phagocytic cells• MSU activates NALP3 inflammation• IL 1ß released which mediates the

autoinflammatory response

Acquired causes of hyperuricaemia

Overproduction

Nutritional Purine consumptionAlcoholFructose administration

Haemopoeitic Myeloproliferative disordersPolycythaemia, leukamia and infectious mononucleosis

Systemic disease psoriasis

Under excretion

Nutritional Alcohol

Renal disease

Drugs

Metabolites / hormones Vasopressin, lactic acidosis, ketosis, angiotensin

Misc Myxodema, respiratory acidosis, toxaemia of pregnancy, myocardial infarct, hyperparathyroidism

Drugs mondifying renal excretion of urate

Increased excretion Decreased excretion

High dose aspirinPhenylbutazoneProbenicidSulfinpyrazoneBenzbromaroneDiflunisalAzapropazoneRadiographic contrast mediaOral anticoagulantsAdrenal corticosteroidsAllopurinolFeboxustatlosartan

Low dose aspirinLow dose phenylbutazoneThiazide diureticsFurosemideEthambutolPyrazinamide nicotinic acid

Case 1

• 40 year old male• Normal BMI• No significant past history apart

from 2 previous episodes of gout in 10 months

• Family history of gout• Presents with inflamed big toe• Currently on no medication

Management

• NSAIDs- Assess risk factors• Colchicine 500mcg bd

Review at 4-6 weeks

• Bloods for urate, U&E, glucose and lipids

• BP• Lifestyle advice• Cardiovascular risk profile

Allopurinol ?

• Yes recurrent acute gout (3 attacks in 12 months)

• Also start if – Tophi– GFR <80– Uric acid stones – Need to continue diuretics

Tips• Wait until acute attack has settled at least 2

weeks and bring urate levels down slowly

• Rapid lowering of urate may disrupt surface of crystals and trigger IL1 induced inflammation

• Initial allopurinol dose 100mg daily• Titrate by 100mg every 3-4 weeks• Don’t stop during acute flares• Aim for urate less than 0.3

Tips 2

• Colchicine prophylaxis signficantly reduces flares at 6months

• Serum urate levels fall within 2 days and are in steady state at 2 weeks therefore repeating level at 3-4 weeks appropriate

• Lowering serum urate to less than 0.36 eliminates recurrent attacks in 86% of patients.

• BSR suggest lower than 0.30 as urate less likely to come out of solution and tophi shrink faster.

Neil StanleyGPST3

Patient information and Resources in Gout

1. Key points for patient education / advice

2. Resources for patients

3. Cardiovascular risk

Aims

1) Eat less high urate containing foods • Beef• Pork • Seafood• Offal• Liver• Kidney• Oily fish• Yeast containing food (bovril, marmite) • Lamb

• Avoid sugary fizzy drinks (fructose containing)• -metabolism can lead to urate production

Key points for Patient education

2) Alcohol consumption• Drink within recommended government levels–but may be advisable to cut down

even within these levels• All alcoholic drinks implicated except low to moderate wine consumption

3) Lose weight• If overweight• (?referral to weight management courses)

4) Medication issues• Complaince

–Concept of preventer vs. reliever medication

–Take your preventer medication every day

• Allopurinol can trigger a flare up of gout when started or dose increased– Explain importance and role of taking

nsaid/steroid/colchicine at these times– Who to contact how and why

• DO NOT STOP DURING FLARE UP

• Continue to take after acute symptoms resolve – they may recur if withdrawn

• Take every day (preventer)

Allopurinol

Resources for patient information

• The Gateshead gout guideline PIL

Information leaflets

• Arthritis research council Gout PIL

• (Downloadable or can order from www.arthritisresearchuk.org.uk)

Information leaflets

• www.arthritisresearchuk.org.uk

• www.patient.co.uk

• www.arthritiscare.org.uk–(call 0808 800 4050 - free)

Websites

Cardiovascular risk

• Gout is associated with lifestyle factors that can increase vascular risk

• Hyperuricaemia is associated with cardiovascular disease (does lowering urate reduce risk??)

• All patients with gout should be risk stratified using standard assessment - BP, Bloods, history and JBS calculation - and appropriate interventions considered (lifestyle and medication)

Primary prevention

Pharmacology and Evidence base

Anne- Marie Bailey

Colchicine

• Alkaloid• Interferes with neutrophil migration via

action on microtubules• Inhibits tyrosine phosphorylation in

neutrophils in response to MSU• Inhibits NALP 3 inflammation in

moncytes• Reduces IL1 production (key

proinflammatory cytokine)

Evidence Base

ColchicineAcute flare • NNT of 3 to reduce pain after 48 hours• NNT of 2 to reduce symptoms after 48

hoursProphylaxis • Reduction in number of acute flares from 2.91 to

0.52 (n= 43 p=0.008) over 3 month period• Much larger study (n= 540 over 20yrs)

demonstrated excellent results in 82% of patients with only 5% unsatisfactory

Risk factors for colchicine toxicity

• Renal or hepatic impairment– avoid if possible or if no alternative therapy

exists for patients with creatinine clearance < 30mL/minute, extend the interval between colchicine treatment courses to 2 weeks during an acute gout flare

• Increasing age • Gastrointestinal or cardiac disease • High doses of colchicine (> 1.5mg daily)• Prescribing colchicine concurrently with

drugs that inhibit CYP3A4 or P-gp

Strong inhibitors of CYP3A4

May need to stop colchicine or reduce dose if on following drugs:-

• Antiarrhythmics - digoxin• Antibiotics - clarithromycin, erythromycin• Antifungals - fluconazole, itraconazole

ketoconazole• Antiretrovirals - amprenavir, atazanavir,

fosamprenavir, indinavir, ritonavir, saquinavir• Calcium-channel blockers - diltiazem,

verapamil • Fibrates - fenofibrate, gemfibrozil• Grapefruit juice• Immunosuppressants - cyclosporin, tacrolimus• Statins - atorvastatin, fluvastatin, pravastatin,

simvastatin

Mechanism of action of allopurinol

adenosine inosine hypoxanthine xanthine Uric acid

Allopurinol

XO XO

Contraindications to allopurinol

• Previous hypersensitivity• Azathioprine (extreme caution

metabolism of aza and 6MPU decreased leading to increased risk of toxicity)

• Reduced dose but not contraindicated in patients with renal impairment

Case continued……

Progress

• Started on allopurinol 100mg with colchicine 500mcg bd

• Phones 2 weeks later acute pain and swelling right knee

• Options?

Management

• Check for signs of sepsis

• Pyrexia• Systemic upset• Can be very difficult to differentiate between sepsis and gout

• If in doubt discuss with on call rheumatologist

• Bloods• Aspirate joint and send for

polarised microscopy (best done in secondary care)

• Inject kenalog 40mg• Urate > 0.3 increase allopurinol

Progress 2

• Phones 1 week later• Rash widespread

Options

• Feboxustat 80mg increasing to 120mg after 2-4 weeks if urate remains up

• Non purine inhibitor of xanthine oxidase

• Can be used in allopurinol hypersensitivity

Feboxustat adverse effects

• Liver enzyme elevation• Increased risk of GI adverse effects

compared to allopurinol• ? Increased risk of vascular events

– Placebo 0, feboxustat 40mg 0, feboxustat 80 1.09, allopurinol 0.97 events per hundred patient years

Interactions

• Azathioprine• 6 Mercaptopurine• Increases theophylline

concentration

• NICE guidance not currently recommended for patients with significant renal and cardiovascular disease.

52 year old man10 week history of pain and swelling in forefeetSpreading to involve MCP, PIP joints elbows and wristsPast history of hypertension

Examination

Bilateral swellings over KnucklesNodular swelling over right ulna and dorsum of feet

Beware other presentations

Investigations ESR 87mm/hrRF 1/40Erosions on radiographs

Case 2 (Cont)

Case 2 (Cont)

White tophaceous fluid aspirated from small jointMonosodium urate crystals in synovial fluid

Urate: 0.63mmol/l

Progress

Gout starts in first MTP in 50%Polyarticular at onset in 10%Tophi may have similar distribution to RA nodules

Case 1 (Cont)

No clinical critera have a positive predictive value greater than 70%

In patients where fluid unavailable for microscopySuggestive features include

• Classic history of monoarticular attacks, asymptomatic• Between• Maximum inflammation within 24 hours• Unilateral first MTP joint• Hyperuricaemia• Typical tophi• Erosions consistent with gout

JG Age 78

Case 3

History

Rheumatic Heart diseaseCCF on high dose diureticsRenal failure- creatinine 200, Urea 35NSAIDs contraindicatedColchicine in low dose led to diarrhoea

What to do?

Case 2 (Cont)

Is treatment required?

Are there any contributing factors that can be removed?

DiureticsLow dose AspirinObesityAlcohol

Lesions usually trouble freeSevere attacks uncommon but at high risk of complications

Case 2 (Cont)

Options for treatment?

Low dose colchicineCorticosteroids- Oral IA, IMAllopurinol

Case 2 (Cont)

In one GP practice

• 31 patients presented over a 3 month period

• 12 patients were seen more than once-only 1 of whom was on allopurinol

• Only 10 patients were on or were started on prophylaxis

• Only 6/25 patients with known gout were on allopurinol

• None referred to secondary care

In secondary care over 6 monthsNo of samples No of patients

Crystals not seen

215

Pyrophosphate 44

Uric acid 30 27

Mixed pyrophos/ urate

2 2

Cholesterol 2 2

Unidentifiable 1 1

Total 294

Cost of treatment vs Activity costs

Cost of 6 months treatment (Based on Drug Tariff costs at Jan 2012)

• Allopurinol 300mg 1 daily £8.00• Colchicine 500micrograms twice daily

£107• Febuxostat 80mg daily for 2-4 weeks then

120mg daily £159Activity costs

• Attendance at out patient clinic with procedure (joint aspiration) £400

• Same procedure with 48hr or less hospital stay £1400

Febuxostat and NICE

• Recommended as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant of allopurinol or for whom allopurinol is contraindicated within licensed indication

• Expected incidence of Allopurinol intolerance or hypersensensitivity is 5%

• 43 patients in Gateshead estimated to require Febuxostat but only 2 patients started to date since NICE guidance (September 2008)

Other options

• Probenicid• Sulphinpyrazone• Benzbromarone• Uricase• New IL1B inhibitors in development• Pegloticase (uric acid specific

enzyme)

Challenges

• Compliance• Organising regular review for

titration• Presentations out of hours and

minimising A&E attendance

Conclusion

• Gout is undertreated• The majority of patients will

respond to inexpensive drugs• Optimal treatment will lead to long

term benefits to health community and individual patients both in terms of improved health and reduction in utilisation of resources