Update on Gout for GPs Dr Patrick Kiely PhD FRCP Consultant Physician and Rheumatologist St George s, London
2/3 1/3 Gut bacteria have uricase
Chronic erosive arthropathy Clinical spectrum
Making the diagnosis Needle shaped crystals in joint fluid Negative birefringence Classic podagra Tophaceous deposits NOT hyperuricaemia with aches/pains
Brief overview UK prevalence 1.5%, M 2.5 : 1 F rises exponentially with age Prevalence rising Nation: living older, increasing BMI, richer diet Classic risk factors Under excretors: genetic, CKD, alcohol, drugs Over producers: genetic, alcohol, diet/obesity Metabolic syndrome: hypertension, insulin resistance, hyperlipidaemia Only a minority ever get gout
Acute attacks Diagnosis Triggers: trauma, illness/surgery, dehydration, initiation of urate lowering therapy Usually mono articular: 1 st MTP, wrist, knee, ankle Classic presentation: intense pain, swelling, erythema Rapid evolution: 6-12 hours Self limiting: 5 14 days, can be longer Serum uric acid may not be raised (increased excretion, acute phase oxidation to allantoin) Synovial fluid analysis compulsory main differential is sepsis, or other crystal US has an emerging role crystals on cartilage surface
US appearances: gout and pseudo-gout Urate crystals on surface of cartilage CPP crystals in mid-cartilage
Treatment of acute attacks Rest and elevation, cold packs NSAIDs/Coxibs + PPI needs to be potent: Indomethacin, high dose Etoricoxib Avoid: ulcer disease, GI bleeds, CKD, asthma, warfarin Colchicine Ignore BNF: 500 mg tds or bd Can still cause diarrhoea, vomiting, more so if > 70 yrs Corticsteroids Oral or intra-articular (aspirating for crystals) Often safest in elderly Avoid in diabetics, or alter glycaemic control No effect on underlying hyperuricaemia
Resistant acute attacks: IL-1 cytokine inhibition Monosodium urate crystals stimulate monocytes and macrophages to release IL-1
Gout metabolic syndrome
Indications for long term urate-lowering therapy (ULT): The vast majority of people with hyperuricaemia never get gout; this is not a diagnostic test Asymptomatic hyperuricaemia is not an indication for ULT It is a trigger to think about the metabolic syndrome Commence urate lowering measures if: 1. Recurrent troublesome acute attacks (eg 3 or more per year) 2. Tophaceous deposits 3. Gout with evidence of erosive change 4. Gout associated with interstitial nephropathy 5. Uric acid stone formation 6. Acute uric acid nephropathy 7. Prophylaxis against tumour lysis syndrome in patients receiving chemotherapy
Urate lowering options Dietary modification only a modest effect on sua e.g. 10-15% reduction with a low-purine diet Consult the UK gout society diet sheet Stop beer and fructose rich drinks wine is neutral Cherries are good cherry active Stop/switch therapies which elevate sua Urate Lowering Therapies
Effects of different types of alcohol on sua Results similar in men and women, and at lower and higher levels of BMI.
Fructose Only CHO known to SUA Men who drink two or more sugary soft drinks a day have an 85% higher risk of gout than those who drink less than one a month. US sales: soft drinks 1977 1997 61% Single largest food source of calories Diet drinks OK
Cheers
Urate lowering options Discontinue any medication causing hyperuricaemia Main culprits: Diuretics Ciclosporin Tacrolimus Minor effect: pyrazinamide, ethambutol, low dose aspirin, omeprazole, L-Dopa, nicotinic acid
Urate lowering therapies Treat to target T2T If serum uric acid lowered to 300 mmol/l the risk of recurring acute attacks of gout will be virtually abolished, and tophi will dissolve sua 300 360 420 480 540 % with attack in 1 yr 10 20 40 55 75 No. attacks/yr 1 6 Rate of dissolution of tophi correlates with absolute serum uric acid concentration
Drug Treatments for Gout Xanthine Oxidase Inhibitors Allopurinol Febuxostat Uricosurics Benzbromarone Fenofibrate Losartan Atorvastatin Vitamin C Cytokine Inhibition Uricase IL-1 Holloways ointment, 1854
Xanthine oxidase inhibition XO catalyzes the oxidation of hypoxanthine to xanthine, and the oxidation of xanthine to uric acid Hypoxanthine xanthine uric acid Allopurinol competitive XO inhibitor Start low 100mg, titrate to target SUA <350mmol/ Co-prescribe colchicine for first 6 months 500mg daily Keep going if they flare Interactions: azathioprine, 6MP, warfarin
Febuxostat Non-purine selective XO inhibitor Effective in moderate renal impairment Oral admin: 40, 80, 120mg daily
Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout Patients with gout and serum urate of > 8.0 mg/dl (480 µmol/liter) Primary end point: sua < 6.0 mg/dl (0.36 mmol/l) Febuxostat 80mg n=256 53% Febuxostat 120mg n=251 62% Allopurinol n=253 21% * p<0.001 for each Febuxostat group vs. Allopurinol group At all ranges of initial urate levels tested *lower than expected: no titration and high baseline uric acid Becker MA et al, NEJM 2005; 353: 2450-61
Febuxostat - summary Xanthine oxidase inhibitor Effective in moderate renal impairment Hepatic metabolism Compared to fixed dose Allopurinol 300mg more potent, but not effective at 120mg in all higher rate of gout flares elevated LFTs & rash may be a problem NICE guidance 2008 recommended for the management of chronic hyperuricaemia in gout for people who are intolerant of allopurinol or for whom allopurinol is contraindicated
URICOSURICS Increase renal excretion of uric acid Logical for vast majority of patients who are under-excretors, but effects on sua may be modest, and influenced by renal function Sulfinpyrazone only effective with good renal function *Benzbromarone can be used in renal impairment, Fenofibrate Losartan weak effect Contra-indicated in patients with nephrolithiasis Risk of precipitating crystalluria and stones formation Increase in fluid intake recommended * Not licensed in UK
BENZBROMARONE (DESURIC ) Not licensed in UK - available on special purchase Increases urinary uric acid excretion by inhibiting proximal tubular urate reabsorption Can be used down to egfr 20ml/min Reduces serum urate by 33-59% 6 males, crossover study, 7 days, mean reduction SUA Benzbromarone 100mg od 0.25mmol/l Probenecid 1g od 0.11mmol/l Allopurinol 300mg od 0.07mmol/ Schepers et al 1981 J Int Med Res
BENZBROMARONE Adverse effects nausea, diarrhoea, rash, erectile dysfunction, conjunctivitis Hepatotoxicity raised enzymes, fulminant hepatic failure allergic response to or cytotoxic action of intermediate metabolites must monitor LFTs Interactions: inhibits metabolism of warfarin
FENOFIBRATE Specific urate-lowering effect amongst fibrates Lowers serum urate by 46% Increases uric acid excretion by 101% in healthy men Yamamoto T et al 2001 J Rheumatol
FENOFIBRATE: STUDIES IN PATIENTS WITH GOUT Fenofibrate 267mg od given to 10 male patients with gout established on allopurinol 300-900mg od in 3 week crossover design 19% reduction in serum urate with fenofibrate (p<0.004) and 36% increase in uric acid excretion (p<0.006) Feher M et al 2003 Rheumatol
FENOFIBRATE
OTHER NOVEL URICOSURIC DRUGS Losartan Lowers serum urate by 7-15% in patients with hyperuricaemia treated with thiazide diuretics Shahinfar et al 1999 Kidney Int Efficacy may fall with time Raises urinary ph: low risk of stones
Uricase (urate oxidase) Catalyzes the final path of purine metabolism: Uric acid + H20 + O2 Allantoin + CO2 + H2O2 Absent in man, birds, cold water reptiles, dalmatian dogs and apes humans do have the gene for UO, but it is nonfunctional, a consequence purported to be due to an occurrence of a sudden mutational event early in primate evolution proposed that the loss of UO protein expression has been advantageous to hominoids, since uric acid is a powerful antioxidant
PEG-Uricase PEG-modified recombinant mammalian urate oxidase primarily porcine, C-terminal sequence from baboon uricase in trials s.c. or i.v. for patients intolerant or refractory to available therapies profound rapid fall in serum uric acid i.v. < 2mg/dl in 24 72 hours s.c. < 6mg/dl in 2 6 days duration of uric acid suppression variable 4 12mg i.v. repeat infusion every 2-4 weeks maintenance Gout flares common Uricase s.c. : Ganson NJ et al, Arthritis Res Ther 2006; 8: R12 i.v. : Sundy JS et al, Arthritis Rheum 2007; 56: 1021-8
Kinetics of plasma uric acid and uricase following PEG-uricase 8mg s.c. in 4 patients Ganson et al. Arthritis Research & Therapy 2006 8:R12
GOUT: take home key points - 1 Hyperuricaemia is very common and rising The majority never get gout Not a diagnostic test for gout Think metabolic syndrome Falls during an acute attack Recognise an acute attack If uncertain must aspirate to exclude septic arthritis Rapid onset Self limiting Treat with strong anti-inflammatories
GOUT: take home key points - 2 Urate lowering strategies Diet Beer is worst, see UK gout society diet sheet Wine is neutral, cherry juice is uricosuric Co-therapies Stop diuretics if possible, also ciclosporin, tacrolimus Urate Lowering Therapies (ULT) More than 3 attacks a year, tophi or erosive arthropathy
ULT treat to target: SuA 300-350 mmol/l Acute attack NSAIDs Colchicine Prednisolone Anakinra Chronic uric acid suppression XO inhibitors Allopurinol Febuxostat Uricosurics: Benzbromarone Fenofibrate Losartan Uricases