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Management of Gout Dr Jennifer Hamilton Consultant Rheumatologist

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1 Management of Gout Dr Jennifer Hamilton Consultant Rheumatologist
Queen Elizabeth Hospital Gateshead

2 Overview Background Pathophysiology of gout Gateshead Gout Guideline
Patient information Costings

3 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

4 Treatment options Cheap Tried and tested
Opportunity to reduce utilisation of health resources Reduce costs as can be largely managed in primary care

5

6 Synthesis Metabolism Elimination Dietary purine Body purine nucleotides Intestinal excretion Purine synthesis Purines Tissue nucleic acids Renal excretion Uric acid

7 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

8 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

9 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

10 Acquired causes of hyperuricaemia
Overproduction Nutritional Purine consumption Alcohol Fructose administration Haemopoeitic Myeloproliferative disorders Polycythaemia, leukamia and infectious mononucleosis Systemic disease psoriasis Under excretion Renal disease Drugs Metabolites / hormones Vasopressin, lactic acidosis, ketosis, angiotensin Misc Myxodema, respiratory acidosis, toxaemia of pregnancy, myocardial infarct, hyperparathyroidism

11 Drugs mondifying renal excretion of urate
Increased excretion Decreased excretion High dose aspirin Phenylbutazone Probenicid Sulfinpyrazone Benzbromarone Diflunisal Azapropazone Radiographic contrast media Oral anticoagulants Adrenal corticosteroids Allopurinol Feboxustat losartan Low dose aspirin Low dose phenylbutazone Thiazide diuretics Furosemide Ethambutol Pyrazinamide nicotinic acid

12 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

13

14 Management NSAIDs- Assess risk factors Colchicine 500mcg bd

15 Review at 4-6 weeks Bloods for urate, U&E, glucose and lipids BP
Lifestyle advice Cardiovascular risk profile

16 Allopurinol ? Yes recurrent acute gout (3 attacks in 12 months)
Also start if Tophi GFR <80 Uric acid stones Need to continue diuretics

17 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

18 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.

19 Patient information and Resources in Gout
Neil Stanley GPST3

20 Aims Key points for patient education / advice Resources for patients
Cardiovascular risk

21 Key points for Patient education
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

22 Drink within recommended government levels
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

23 (?referral to weight management courses) 4) Medication issues
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

24 Allopurinol 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)

25 Resources for patient information

26 Information leaflets The Gateshead gout guideline PIL

27 Information leaflets Arthritis research council Gout PIL
(Downloadable or can order from

28 Websites www.arthritisresearchuk.org.uk www.patient.co.uk
(call free)

29 Cardiovascular risk

30 Primary prevention 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)

31 Pharmacology and Evidence base
Anne- Marie Bailey

32 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)

33 Evidence Base Colchicine Acute flare
NNT of 3 to reduce pain after 48 hours NNT of 2 to reduce symptoms after 48 hours Prophylaxis 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

34 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

35 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

36 Mechanism of action of allopurinol
adenosine inosine hypoxanthine xanthine Uric acid Allopurinol XO

37 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

38 Case continued……

39 Progress Started on allopurinol 100mg with colchicine 500mcg bd
Phones 2 weeks later acute pain and swelling right knee Options?

40 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

41 Bloods Aspirate joint and send for polarised microscopy (best done in secondary care) Inject kenalog 40mg Urate > 0.3 increase allopurinol

42 Progress 2 Phones 1 week later Rash widespread

43 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

44 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 , allopurinol 0.97 events per hundred patient years

45 Interactions Azathioprine 6 Mercaptopurine
Increases theophylline concentration NICE guidance not currently recommended for patients with significant renal and cardiovascular disease.

46 Beware other presentations
52 year old man 10 week history of pain and swelling in forefeet Spreading to involve MCP, PIP joints elbows and wrists Past history of hypertension Examination Bilateral swellings over Knuckles Nodular swelling over right ulna and dorsum of feet

47 Case 2 (Cont) Investigations ESR 87mm/hr RF 1/40 Erosions on radiographs

48 Case 2 (Cont) Progress White tophaceous fluid aspirated from small joint Monosodium urate crystals in synovial fluid Urate: 0.63mmol/l

49 Case 1 (Cont) Gout starts in first MTP in 50% Polyarticular at onset in 10% Tophi may have similar distribution to RA nodules

50 No clinical critera have a positive predictive value greater than 70%
In patients where fluid unavailable for microscopy Suggestive 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

51 Case 3 JG Age 78

52 Case 2 (Cont) History Rheumatic Heart disease CCF on high dose diuretics Renal failure- creatinine 200, Urea 35 NSAIDs contraindicated Colchicine in low dose led to diarrhoea What to do?

53 Case 2 (Cont) Is treatment required? Lesions usually trouble free Severe attacks uncommon but at high risk of complications Are there any contributing factors that can be removed? Diuretics Low dose Aspirin Obesity Alcohol

54 Case 2 (Cont) Options for treatment? Low dose colchicine Corticosteroids- Oral IA, IM Allopurinol

55 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

56 In secondary care over 6 months
No of samples No of patients Crystals not seen 215 Pyrophosphate 44 Uric acid 30 27 Mixed pyrophos/ urate 2 Cholesterol Unidentifiable 1 Total 294

57 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 £159 Activity costs Attendance at out patient clinic with procedure (joint aspiration) £400 Same procedure with 48hr or less hospital stay £1400

58 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)

59 Other options Probenicid Sulphinpyrazone Benzbromarone Uricase
New IL1B inhibitors in development Pegloticase (uric acid specific enzyme)

60 Challenges Compliance Organising regular review for titration
Presentations out of hours and minimising A&E attendance

61 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


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