GOUT. Dr Krishnan Baburaj West herts NHS Trust

Transcription

1 GOUT Dr Krishnan Baburaj West herts NHS Trust

2 podagra

3 Gout A disease of kings, the king of diseases

4 History Louis XIV Emperor Augustus Henry VIII

5 Introduction Gout an inflammatory arthritic condition that occurs when urate crystals accumulate in joints and other tissues

6 Epidemiology Common medical problem affecting 1-2% of adults in the industrialised world 1-3 Overall prevalence of 1.39% in UK general practices 2 Most common inflammatory arthritis in men More common in men male:female ratio 4:1 to 9:1 Prevalence increases with age >7% in men > 65 years and almost 3% in women >85 years (UK data) 2 For comparison, the prevalence of rheumatoid arthritis is 0.5-1% in the general adult population 4

7 Epidemiology incidence of gout increases with age Incidence, per 100,000 people Males ( ) Males ( ) Females ( ) Females ( ) Age at diagnosis of gout Arromdee E, et al. J Rheumatol 2002; 29(11):

8 Comorbidities are common in gout patients Renal impairment Metabolic syndrome Coronary heart disease Obesity Dyslipidaemia Hypertension Type 2 diabetes Rott KT, Agudelo CA. JAMA 2003; 289(21):

9 Risk factors for gout Non-modifiable Age Male gender Race Genetic factors Impaired renal function Modifiable Hyperuricaemia High-purine diet Alcohol consumption Obesity Certain medications diuretics Roddy E, et al. Nat Clin Pract Rheumatol 2007; 3:

10 Pathophysiology of gout Urate Urate crystals O HN N H O O N H N H Image courtesy of Dr Anne Kathrin Tausche

11 Uric acid formation: purine metabolic pathway Adenosine adenosine deaminase Inosine nucleoside phosphorylases Guanine guanine deaminase Hypoxanthine Xanthine xanthine oxidase Yasuhiro T et al. Life Sci 2005; 76: In vitro animal studies xanthine oxidase Urate

12 Gout: overproduction and/or underexcretion of urate HN O N O Kidneys remove uric acid from the blood for excretion out of the body O N Urate N H Serum urate 6.8 mg/dl (0.4 mmol/l) threshold for solubility at 37 C

13 Clinical features of gout Natural history Clinical picture Diagnosis Diagnostic imaging Tophi Nephrolithiasis

14 Progression of gout Adapted from Gout. Risk Factors, Diagnosis and Treatment. Available on Internet:

15 Known triggers of gouty attacks Presence of crystals Mobilisation of urate due to changes in serum urate level Direct trauma Intercurrent illness/surgery that triggers the acute phase response Dehydration/acidosis (including alcoholic binge) Medications (including initiation of urate lowering therapy) Rapid weight loss

16 Clinical picture (I) Recurrent attacks of acute, very painful, monoarticular inflammation Podagra is the classic symptom (gout affecting the big toe) Other common sites are foot, ankle, knee, finger, wrist and elbow Typical rapid development of severe pain, swelling and tenderness Attacks often start at night or in the early morning Attacks usually resolve within 7-10 days without specific treatment Image courtesy of Dr Anne Kathrin Tausche

17 Common sites of acute attacks Common order of progression in untreated primary gout: Metatarso phalangeal joint of the first toe (~50% of initial attacks; known as podagra) Midfoot, ankle, knee Wrist Finger joints (in the elderly and people who have had primary gout for a long period of time) Olecranon bursae (elbow) Usually monoarticular (~90% of first attacks) but can be polyarticular in higher risk patients (e.g., alcoholics, postmenopausal women) and as disease progresses Harris MD, et al. Am Fam Physician 1999; 59(4):

18 Differential diagnosis Crystal arthropathies Acute pseudogout Primary oxalosis Other arthropathies Calcium pyrophosphate dihydrate (CPPD) crystals positively birefringent, blue rhomboid crystals Most commonly seen in the knee, wrist, and shoulder Calcium oxalate crystals positively birefringent, bipyramidal crystals Septic arthritis Psoriatic arthritis Ruled out with Gram stain and culture, and sensitivity of synovial aspirate May be associated with fever, elevated white blood cell count, C-reactive protein, procalcitonin; can co-exist with gout Can affect finger, wrist, toe, knee, ankle, elbow, shoulder joint, the spine, and sacroiliac joint; not usually as acute as gout Images courtesy of Dr Tim Jansen

19 dactylitis

20 Erythema nodosum

21 sarcoidosis

22 Stress fracture

23 Diagnostic aspiration? Necessary Skills

24 Alternative diagnostic approaches A presumptive diagnosis of gout may be made in the absence of synovial fluid aspiration if the patient has a Typical presentation of podagra History of gout flares or hyperuricaemia Other supportive information sua measurement 2-3 weeks postflare Physical examination X-ray/scan of affected joint

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26 Gout diagnosis for rheumatologists Demonstration of monosodium urate crystals by microscopic examination for negatively birefringent crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout Urate crystals are intra- or extracellular Long needles, typically μm der a polarizing filter will be: the axis of the red compensator to the direction of polarization Image courtesy of Dr Tim Jansen

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29 Role of sua in gout diagnosis sua measurement sua measurement by itself is not diagnostic sua concentrations during gouty attack may be near normal ~50% of time Best time to measure sua: 2 weeks postflare High sua measurements during inter-critical periods may be predictive of future gout attacks Best time to measure sua 0 Days (Start of flare) 4 Days 8 Days 14 Days 20 Days Urano W, et al. J Rheumatol 2002; 29(9):

30 Tophaceous deposits Images 1 2 courtesy of Dr Tim Jansen/Images 3 5 Dr Anne Kathrin Tausche

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36 Gout Current management strategies

37 Goals of treatment Acute attacks: Relieve pain rapidly and reduce inflammation Long-term treatment (gout is curable by dissolving all crystals and preventing further crystal formation): Prevent further acute attacks Prevent joint damage Eliminate tophi

38 Tophus resolution sua 3.7 mg/dl (0.22 mmol/l) for one year Treatment with benzbromarone 100 mg/day Photographs courtesy of Dr F Perez Ruiz

39 Treatment strategies Treat acute attacks 4 6 weeks review Life style changes Urate lowering therapy Gout prophylaxis

40 Acute attack Rest/analgesics NSAIDs PPI if required Colchicine Allopurinol avoid Steroids Diuretics stop if possible

41 NSAIDs 1 2 weeks Maximum dose Naproxen, indomethacin or etoricoxib 120mg PPI if at risk of bleeding Avoid renal failure, warfarin, CHF

42 colchicine Slow Diarrhoea 0.5 mg bd qds

43 steroids Safe in renal failure /warfarin Intra articular/ oral/ I.m Prednisolone 30 40mg and taper over 1 3 weeks

44 4week review Serum urate/ renal function Glucose Life style factors Blood pressure Stop diuretics if possible

45 Lifestyle changes Optimize weight avoid crash dieting and Atkins Diet encourage skimmed milk,youghurt,vegetable source of proteins Restrict high purine foods red meat, liver, shellfish etc Avoid dehydration If urolithiasis, >2L /day and consider alkalanization of urine

46 Lifestyle (cont d) Restrict alcohol Atleast 3 alcohol free days per week Avoid beer, stout, port etc Avoid intense physical exercise

47 Gout prophylaxis To prevent flare ups during urate lowering therapy Colchicine 0.5 mg bd for 6 months or NSAIDs /coxib for 6 weeks or Rarely prednisolone

48 Indications for ULT 2 attacks within 1 year or Tophi Renal failure Uric acid stones CHF on diuretics

49 Start ULT about 2 weeks after inflammation has settled Target plasma urate level < 0.30 mmol/l

50 Current long-term urate-lowering treatment options Agent Allopurinol Sulphinpyrazone Benzbromarone (named patient basis) Probenecid (not available in UK) Considerations Extra caution needed if renal function poor Multiple drug interactions Target sua not always achieved Skin rashes common; serious hypersensitivity reactions rare (can, very rarely, be fatal; can be a latent period) Non-selective inhibition of xanthine oxidase Avoid in hypersensitivity to NSAIDs; reduced renal function Liver toxicity Risk of nephrolithiasis Renal function Multiple drug interactions Target sua not always achieved Multiple daily dosing required

51 allopurinol mg daily mg increments every 3 4 weeks Till target SUA level reached Max dose 900mg Dose adjustment for renal failure (maximum 100mg)

52 Second line ULT Febuxostat ( avoid in cardiac failure) Sulfinpyrazone and probenecid (avoid if GFR < 30) Benzbromarone avoid in liver failure

53 NICE Febuxostat is an option in Allopurinol intolerance Contraindications for allopurinol Unable to titrate to maximum dose

54 Febuxostat Non-purine, selective inhibitor of xanthine oxidase (XO) Once-daily chronic medication for the management of hyperuricaemia in patients with gout 80 mg and 120 mg tablets Extensive clinical trial programme 31 clinical studies: 25 phase I studies, 1 phase II study, 3 phase III studies, 2 open-label extension studies Over 4,000 subjects have received at least one dose of febuxostat ( mg/day) New Drug Application N Febuxostat. November Available at: EU SmPC Adenuric.

55 Febuxostat significantly lowers sua compared to allopurinol (I) APEX study (6 months): proportion of subjects with last 3 sua levels <6.0 mg/dl (<0.36 mmol/l) % of patients % * 48% * 65% *p<0.001 vs placebo and allopurinol 22% Placebo Febuxostat Febuxostat Allopurinol (n=134) 80 mg (n=262) 120 mg (n=269) 300/100 mg ** (n=258/10) ** Within combined allopurinol 300/100 group, allopurinol 100 mg efficacy: 0%; allopurinol 300 mg efficacy: 23%. ITT population: subjects with serum urate level 8.0 mg/dl on day 2. Adapted from Schumacher HR, et al. Arthritis Rheum 2008; 59:

56 Febuxostat significantly lowers sua compared to allopurinol (II) % of patients FACT study (1 year): proportion of subjects with last 3 sua levels <6.0 mg/dl (<0.36 mmol/l) * 53% * 62% 21% *p<0.001 vs allopurinol 10 0 Febuxostat 80 mg (n=255) Febuxostat 120 mg (n=250) Allopurinol 300 mg (n=251) ITT population: subjects with serum urate level 8.0 mg/dl on day 2. Becker MA, et al. NEnglJ Med 2005; 353:

57 Dosage and administration* The recommended dose of febuxostat is 80 mg od Dose can be titrated up to 120 mg if sua is 6.0 mg/dl ( 0.36 mmol/l) at week 2-4 Testing for the target sua level of <6.0 mg/dl (<0.36 mmol/l) may be performed as early as 2 weeks after initiating febuxostat therapy Subsequent sua levels may be measured every 6 months or yearly as indicated for the individual patient *Based on FACT and APEX studies.

58 Special precautions with the use of Adenuric Adenuric is not recommended in: Patients with ischaemic heart disease or congestive heart failure Patients being treated with mercaptopurine or azathioprine Patients with xanthine deposition Organ transplant recipients Caution is required when Adenuric is used in: Patients being treated with theophylline Patients with thyroid disorders SmPC Adenuric. ADENURIC is a registered trademark of Teijin Pharma Ltd. Tokyo, Japan.

59 THANK YOU