Gout

in Clinical Prac.ce
16/06/54 KIATTISAK K. MD. PORNANAN D. MD.

Case 1

A 65 year-old man presented with severe right knee arthri:s for 1 day, he had HT and was treated with amlodipine 10 mg/d and HCTZ 25 mg/day. PE: BT 39 degree C, BP 148/68 mmHg Marked swelling, tender of right knee. No tophi What s next management ?

Inves:ga:on
MSU crystals in PMN, G/S : nega:ve BUN 14 / Cr 1.0 Uric acid : 9.2 Hb 13.7 gm/dl, WBC 14,500/cu.mm (PMN 99%) adequate platelet smear Chol 120 LDL 80 HDL 32 TG 110 FBS 80 HbA1C 6

 Diagnosis ?

Management ?

Acute Gouty Arthri:s

gouty arthri:s tophi uric nephropathy joint kidney sob :ssue Hyperuricemia monosodium urate , MSU deposi.on

Hyperuricemia
Serum urate level > 6.8 mg/dL When uric acid levels are high enough, needle shaped monosodium urate crystals form The crystals commonly deposit in .ssues with limited blood ow, such as tendons, car:lage, ligaments, bursa, and the skin in areas that are cooler or around distal joints

UA overproduc.on UA underexcre.on Primary Idiopathic Idiopathic hyperuricemia Inherited enz. (HGPRT,PRPP) def.
Common gene:c variants

Secondary meat,seafood, hyperuricemia EtOH intake MPNs, lymPD

Chronic Hemoly:c anemia

dehydra:on renal impairment drugs ***

Psoriasis , cytotoxic drug

Drugs and Uric acid

Increase produc.on Didanosine, ethanol Glucocor:coid Ribavarin /interferon Nico:nic acid > 3gm/day Decrease renal excre.on ACEI (except losartan) Cyclosporin/tacrolimus Diure:cs (except aldactone) Ethambutol/Pyrazinamide Levodopa Probenacid ASA < 2 gm/day

CANT LEAP : cyclosporin, alcohol, nico:nic, thiazides, loop diure:cs

ethambutol, ASA low dose , PZA

Risk of gout
Age and sex (estrogen = uricosuric agent) Serum uric acid : degree and dura:on
Serum urate mg%

annual incidence Cumula.ve 0.08 % 0.09% 0.41% 0.84% 4.32% 7.02%

incidence 5 yrs

< 6 6.0 6.9 7.0 7.9 8.0 8.9 9.0 9.9 > 10

0.5 % 0.6% 2.0% 4.1% 19.8% 30%

Risk of gout
BMI : BMI risk Alcohol : acetate acetyl coA adenosine nucelo:de + uric acid produc:on Beer : most potent risk (guanosine uric )

MSU deposi:on
Urate conc. > 6.8 mg/dL

Environment .ssue (nega.ve charge) Collagen, chondroi:n sulfate , proteoglycan

Temperature

Mechanism of arthri:c are

TLR2,4
MyD88 PAMP

NF-KB

IL6 TNF a

Caspase I

Endothelial ac:va:on

Apopto:c bodies

TGF-beta, (NO, IL-10) Endothelial inac:va:on Inhibi:on of inammatory response to MSU crystals

Mature macrophage

Mechanism of arthri:c remission

Progression of Gout
4 stage 1. Asymptoma:c hyperuricemia 2. Acute gouty arthri:s 3. Intercri:cal or interval gout 4. Chronic tophaceous gout

Management
5 steps 1. Educa:on and advise 2. Treat acute inamma:on 3. Prevent recurrent 4. Long term uric acid lowering 5. Treat complica:on and co-morbid diseases

Diets
Low purine diet rela:vely ineec:ve (reduces urinary urate but liqle eect on serum level) Calorie restricted diet reduced saturated fat-complex carbohydrate Dairy products rather than meat protein

Rx of Acute inamma:on
Colchicine NSAIDs Steroids and ACTH

Limita:on of drugs used in acute gout

S/E NSAIDs colchicine steroids gastropathy Fluid reten.on Renal risk CNS dys. PLT dys. BM sup. (IV) Sudden death (IV) Wound healing hyperglycemia Short-lived eect
ACTH

Acute gouty aWack

Oligo-poly joints
Renal and liver disease Normal : renal and liver

Single joint

Intra-ar:cular steroid or NSAIDs or colchicine

Renal or liver disease

Oral
Prednisolone 30-60 mg/day then taper o in 2 wks

IV
ACTH sc or IM
40 iu q 12 hrs 1-3 days Solumedrol IM,IV 100-150 mg/d x 1-2 days

Normal renal and liver

High risk cardiac and GI toxicity Dura:on of onset Colchicine 0.6 mg :d
Prednisolone 30-60 mg/day taper o in 2 week

Low risk cardiac and GI toxicity

NSAIDs

Colchicine prophylac:c dosage

GFR (ml/min) 50 35 - 49 10 34 Colchicine oral dosage (mg/day) 0.6 mg bid 0.6 mg OD 0.6 mg q 2-3 days

< 10 or HD Ovoid Or signicant hepatobiliary dysfunc:on aged 70 yrs 50% of usual dose

Management of Hyperuricemia
Indica.on 1. acute aqack 3 :mes/yr 2. tophi + 3. uric acid > 9 mg/dL 4. 24 hr urine for uric acid > 800 mg/day or renal stone Goal : uric acid 5.5 6.8 mg/dL If tophi < 5 mg/dL dura:on?

Urate lowering agents

3 groups 1. uricosta.c drugs allopurinol, oxypurinol and febuxostat 2. uricoly.c drugs uricase ; rasburicase , puricase 3. uricosuric drugs probenacid, benzpromarone and sulnpyrazole

Uricosta:c drugs
Allopurinol Xanthine oxidase inhibitor Use in increase synthesis and low excre:on OD dose Renal adjustment Metabolism : CYPs (P450) oxypurinol Ini:al : 100 mg/d increase dose 100mg/ 2wk

Maintenance Dose of allopurinol (adjust as renal fuc:on)

CCr (ml/min) > 100 80 99 60 79 40 59 20 39 < 20 Allopurinol dose (mg/d) 300 250 200 150 100 50

100 mg AD or 300-400 mg biweekly: immediately aber HD Maintain plasma oxypurinol levels < 100 mmol/L (15.2mg/L)

Uricosta:c drugs
Oxypurinol Ac:ve metabolite of allopurinol Cross reac:on : allopurinol 30% Renal adjustment

Uricosta:c drugs
Febuxostat Xanthine oxidase inhibitor (another pathway) Not inhibit other enzymes Metabolism : liver excre:on in renal and fecal route (50%) avoid in CCr < 30 DI : 6MP, azathioprine and theophilline Initail : 40 mg/day OD dose S/E : hepa::s, diarrhea, arthralgia and headache

Uricoly:c drugs
Uricase Uric allantoin Use in tumor lysis syndrome Rapid ac:on and very potent drug Metabolism : non CPYs S/E : 1. hemoly:c anemia in G6PD def. 2. acute aqack

Uricoly:c drugs
1. Rasburicase : IV con:nuous infusion anaphylatoid reac:on , alloan:body (recombinant unmodied aspergillus avus uricase ) 2. Peglo.case (Krystexxa) IM,IV and SC 8mg q 2 wk FDA approved in severe gout and poor response with conven:onal treatment

Uricosuric drugs
1. Probenicid(500 mg-2g/d) 2. Sulphinpyrazone 3. Benzbromarone(50-200 mg/d) combina:on therapy with allopurinol rela:vely ineec:ve Contraindicate hyperexcretors & renal stone formers

Uricosuric drugs
Probenecid Dose 250 mg rising to 500- 1000 mg 2-3 :mes daily(max 3g/d) Increases urinary calcium excre:on Numerous drug interac:on esp. ASA (block) Indicate in allopurinol allergy with CCr > 60 ml/min S/E : nephro:c, N/V

Uricosuric drugs
Sulphinpyrazone Dose 50 mg bid rising to 100-200 mg 3-4 :me daily(max 800 mg/d) CCr > 30 ml/min Potent than probenacid : 5x

Uricosuric drugs
Benzbromarone 50-200 mg/days Liver metabolism, urinary excre:on8% Contraindicate : liver disease renal stones low GFR (<30ml/min) hyperexcretor>700 mg/d DI : an:-TB and ASA (block) , coumadin (1/2) S/E : diarrhea, skin rash and hepa::s

Other drugs
Increase urine uric excre.on losartan, fenobrate* and atorvasta:n IL-1 inhibitor (anakinra) IL-1B an:body (canakinumab) *** Etanercept , iniximab Study drugs PDE4-TNF-a inhibitor, BCX-4208 (purine nucleoside phosphorylase inhibitor )

Co-morbids
Dyslipidemia HT T2DM Obese CKD Atherosclerosis Metabolic syndrome

Complica:ons
Renal disease acute uric acid nephropathy chronic urate nephropathy uric acid nephrolithiasis (nidus) Hypertension Insulin resistance Cardiovascular risk Musculoskeletal complica:on

Case 2

An elderly male 70 yrs old with crystal- proven gout has a history of 4 aqacks during the previous year and uric acid level 10 mg/dL Cr 0.7 GFR 90 Now he was prescribed allopurinol 200 mg/day for 1 week He comes to hospital today for evalua:on about skin lesion

Diagnosis ? Management ? And futhur management Gout?

 5% of severe cutaneous adverse reac.ons (SCARs) HSS, SJS, TEN

Allopurinol

Severe cutaneous adverse reac.on= HSS, SJS, TEN

PNAS 2005;4134-39

High frequencies of HLA-B*5801

HLA-B*58:01 Odd ra.o =580.3

PNAS 2005;4134-39

Ethics
Africans Caucasian Asian Indians Chinese

Prevalence (%)
2-4 1-6 3-15 8.8-10.9

Allele frequency of HLA-B*58:01

Pharmacogene.cs and Genomics 2009, 19:704709

Pharmacogene:cs and Genomics 2009, 19:704 709

Associa:on of individual HLA-B allele with allopurinol induce SJS/TEN

HLA-B allele
5801 1301 1502 1802 3802 4001 4601 5101

Allopurinol induce SJS/TEN (n=27)

27 (100.0) 4 (14.8) 2 (7.4) 3 (11.1) 1 (3.7) 1 (3.7) 3 (11.1) 1 (3.7)

Allopurinol tolerant (n=54)

7 (13.0) 10 (18.5) 10 (18.5) 2 (3.7) 5 (9.3) 7 (13.0) 16 (29.6) 8 (14.8)

OR
348.3 0.8 0.4 3.3 0.4 0.3 0.3 0.2

95% CI
19.2-6336.9 0.2-2.7 0.1-1.7 0.5-20.7 0.04-3.4 0.03-2.2 0.06-1.1 0.03-1.9

P value
1.61x10-13 0.68 0.18 0.19 0.37 0.19 0.06 0.13

EJ Phillips. J ALLERGY CLIN IMMUNOL 2011

http://pharmacology.md.kku.ac.th/

Case 3

A 54-year-old KT man with gout his serum urate level is 11 mg/dL , has a history of 6 aqacks during the previous year current medica,on cyclosporin A, prednisolone 15 mg/day amlodipine 10 mg, enalapril 20 mg Cr = 1.4 mg/dL How should his gout be managed?

organ transplant pa.ents

Treatment of gout in

INCIDENCE
Hyperuricemia in organ transplant pa:ent with cyclosporine about 30-80% Developed gout about 3.5-25% Cyclosporine decrease renal excre:on hyperuricemia

Gout in KT pa.ents
Post KT about 5 years develop gouty arthri:s Cyclosporine use with diure:cs increase incidence <thiazide, loop diure:cs> Oligo to polyarthri:s more common typical presenta:on Early develop tophi Hip, shoulder, sacroiliac joint arthri:s

Gout in KT pa.ents
Check baseline renal func:on before treatment Cau:on with NSAIDs usage Kidney, heart, lung transplanta:on

Management in acute aWack

First line drug aqack colchicine Cau:on cyclosporine VS colchicine because increase colchicine toxicity Dosage 0.6 mg bid *2 days then 0.6 mg OD If renal impairment choice = cor.costeroid 20-30 mg/day IA cor:costeroid if mono-oligoarthri:s

Prophylaxis & Rx hyperuricemia

Drug of choice prophylaxis 1.low dose steroid 5-10 mg/day 2.colchicine < 0.6 mg/day Uric acid lowering agents allopurinol Drug interac:on allopurinol VS azathioprine because allopurinol inhibit xanthine oxidase increase azathioprine toxicity

Prophylaxis & Rx hyperuricemia

Star:ng with low dose of allopurinol Adjust decrease azathioprine dose at least 50% Switch to other immunosuppressive drug change to mycophenolate

Prophylaxis & Rx hyperuricemia

If good renal func:on, CrCl > 30 ml/min can be use uricosuric drugs Benzbromarone cau:on HEPATITIS Sulnpyrazone decrease cyclosporine toxicity BUT probenecid not eec:ve in cyclosporine induce hyperuricemia

Non-pharmacological treatment
Advice and educa:on about Lifestyle , nutri.on, adjunc.ve therapies Find out atherosclero:c risk and treatment if indicated DM, insulin resistance, hypertension, metabolic syndrome, dyslipidemia

Reference hyperuricemia Clive DM. renal transplant associated

and gout. J Am Soc Nephrol 2000;11:974-9. Mazzali M. uric acid and trasplanta:on.Semin Nephrol 2005;25:50-5. .management in complicated gout 2552:34-66