통풍 진단 및 치료의 최신지견 분당서울대학교병원 류마티스내과 하유정

Gout (통풍, 痛風) A clinical disease associated with hyperuricemia Inflammatory reaction caused by the deposition of monosodium urate (MSU) crystals in and around the tissues of joints Also non-articular (soft tissue): tophi, urolithiasis “Punch cures the gout, the colic, and the ‘tisick” (anonymous). Historical sterotypes of gout persist and can act as barriers to adequate care.

Uric acid pool Metabolism of uric acid and risk factors for gout Nat Rev Rheumatol. 2014;10:271-62

Hyperuricemia Definition : serum uric acid (SUA) ≥ 7.0 mg/dL Exogenous 1/3 GI excretion Purine rich diet Alcohol (Beer) 2/3 Uric acid Renal excretion 체내 urate pool 1200 mg/day Glomerular filtration Endogenous (purine metabolism) Proximal tubules 100% S1 98-100%, Reabsorption Enzyme deficiency Hematologic disease Tissue hypoxia Drugs S2 50%, Secretion 50% S3 40-45%, Reabsorption 5-10%

MSU crystal formation About 6.8 mg/dL in serum at 37ºC Temperature (◦C) 20 28 36 5.0 10.0 Uric acid concentration (mg/dL) Temperature in the ankle joint Ann Rheum Dis. 1983;42 Suppl 1:12-5 Curr Rheumatol Rep. 2014;16:400

Clinical features of gout Podagra Chronic tophaceous gout Rapid onset Excruciating pain Resolve in 1-2 weeks Site: lower limb - 1st MTP (m/c) - midfoot, ankle, knee - wrist, elbow, bursa (less common) Mono-articular (esp. early course) ~ Oligo-articular A through F, Radiographs of damage to joints due to gout. A, Erosions at the third proximal interphalangeal and fourth distal interphalangeal joints of the hand. B, Discrete punched-out lesion at the first metatarsophalangeal (MTP) joint. C, More advanced disease at the first MTP joint with periarticular tophaceous material. D, Erosion at the fifth MTP joint. E and F, Severe destruction with malalignment. Radiograph of joint damage

Prevalence Nat Rev Rheumatol. 2015;11:649-62

Change in gout prevalence according to the age and gender group Gout in Korea Prevalence per 100,000 persons Gout prevalence in the NHIC database Year Change in gout prevalence according to the age and gender group Age group Prevalence ratio from 2001 to 2008 대한류마티스학회지. 2011;18:94

The Normative Aging Study Annual incidence of gout Hyperuricemia & gout High levels of uric acid increase the risk of clinically apparent gout Serum UA level could be normal during acute attack The Normative Aging Study (2046 previously healthy men [initial average age 42] followed for 14.9 years) Initial U.A level Annual incidence of gout ≥ 9 mg/dL (n=141) 4.9% 7 – 8.9 mg/dL (n=1642) 0.5% < 7 mg/dL (n=5249) 0.1% Ame J Med 1987;82:421-6 Normal serum UA level in 43% during acute episode Arthritis Rheum. 1977;20:895-900 Ann Rheum Dis. 1997;56:696-7

Natural history of gout ~ 1 yr: 62% 1 ~ 2 yr: 16% 2 ~ 5 yr: 11% 5 yr ~ : 13% Asymptomatic hyperuricemia Asymptomatic MSU deposits Intermittent flares Chronic gout Curr Opin Rheumatol 2014;26:181-91 Primer on the Rheumatic Diseases. 12th ed.

Gold standard in diagnosis of gout Definitive Dx.: demonstration of MSU crystal in synovial fluid or tophus aspirate Needle-shaped negative birefringence on compensated polarized microscopy (yellow, when parallel to the axis of compensator) ◈ Limitations Poorly accessible to joint aspiration or polarizing microscope – small joints or non-expertise MSU crystal identification is dependent on an operator (requires adequate training). SF MSU crystals are present in some patients with asymptomatic hyperuricemia without over clinical features of gout. MSU crystals may be present in patients presenting with joint inflammation due to concomitant rheumatic conditions such as septic arthritis. Compensator axis http://images.rheumatology.org/ Nat Rev Rheumatol. 2014;10:271-62

Diagnostic criteria for gout 1963 Rome 1966 New York 1977 ACR 2010 Mexico 2010 Netherland MSU crystal sUA > 7 (M) or >6 (F) Hyperuricemia sUA > 5.88 (3.5) Tophus Tophus (13) Attacks of painful joint swelling with abrupt onset and resolution within 2 wks ≥ 2 attacks of painful joint swelling with complete resolution within 2 wks ≥ 2 attacks of acute arthritis Previous patient-reported arthritis attack (2) Maximum inflammation within 1 day Rapid onset of pain and swelling (less than 24 h) Onset within 1 day (0.5) Redness over joints Joint erythema Joint redness (1) Complete termination of attack H/O or observation of podagra 1st MTP joint pain or swelling Podagra 1st MTP involvement (2.5) Unilateral 1st MTP attack Unilateral tarsal attack Oligoarthritis attack Mono and/or oligoarticular attacks Asymmetrical swelling in a joint (x-ray) Subcortical cysts without erosions (x-ray) Rapid response to CCC (within 48 h) Male sex (2) HTN or ≥ 2 CVD (1.5) ≥ 2 criteria ≥ 2/4 criteria or MSU ≥ 6/12 criteria or MSU ≥ 4/8 criteria or MSU Score > 8

Limitation of previous criteria Lack of Specificity Classifiability Robust validation Ann Rheum Dis 2016;75:178-82

Advances in imaging modalities Ultrasound Dual-energy CT (DECT) Rheumatology (Oxford) 2007;46:1116-21 Ann Rheum Dis 2012;71:1466-71

2015 ACR/EULAR Gout Classification Criteria Categories score CLINICA Pattern of joint/bursa involvement Ankle OR midfoot (mono-/oligo-) 1 1st MTP (mono-/oligo-) 2 Characteristics of episode(s) ever One characteristic Two characteristic Three characteristics 3 Time-course of episode(S) ever One typical episode Recurrent typical episodes Clinical evidence of tophus Present 4 LAB Serum Urate 6 - <8 mg/dL 8 - <10 mg/dL ≥ 10 mg/dL IMAGE Imaging evidence of urate deposition Present (U/S DCS or DECT) Imaging evidence of gout-related joint damage Present (X-ray gouty erosion) SUA<4: -4 / MSU-ve: -2 Maximum Total Score 23 Score ≥ 8 ⇒ High sensitivity (92%) and specificity (89%) Arthritis Rheumatol. 2015;67:2257-68

Management of Gout General management Acute gouty arthritis Urate-lowering therapy (ULT) Prophylaxis → Based on ‘2012 ACR recommendations’ ‘2016 EULAR recommendations’ Arthritis Care Res. 2012;75:1431-46 Ann Rheum Dis. 2017;76:29-42

Baseline recommendations Patient education: appropriate diet & lifestyle Weight loss Avoidance of alcohol (esp. beer and spirits), sugar-sweetened drinks, heavy meals, and excessive intake of meat and seafood Regular exercise Consider secondary causes of hyperuricemia (“Co-morbidity Checklist”) Consider elimination of non-essential prescription medications that induce hyperuricemia Clinically evaluate gout disease burden (palpable tophi, frequency & severity of acute/chronic sx & signs) Comorbidity checklist Obesity, dietary factors Excessive alcohol intake Metabolic syndrome, Type 2 DM Hypertension Hyperlipidemia Serum urate-elevating medications History of urolithiasis Chronic kidney, glomerular, or interstitial renal disease In selected cases, potential genetic or acquired cause of UA overproduction Arthritis Care Res. 2012;75:1431-46 Ann Rheum Dis. 2017;76:29-42

General health, diet and lifestyle measures Arthritis Care Res. 2012;75:1431-46

Management of an acute gout attack <2012 ACR recommendation> Acute gouty arthritis attacks should be treated with pharmacologic therapy To provide optimal care, pharmacologic treatment should be initiated within 24 hrs of acute gout attack onset Ongoing pharmacological ULT should not be interrupted during an attack

Management of an acute gout attack <2016 EULAR recommendation> Acute flares of gout should be treated as early as possible. Fully informed patients should be educated to self-medicate at the first warning symptoms. The choice of drugs should be based on the presence of contraindications, the patient’s previous experience with treatments, time of initiation after flare onset and the number and type of joint(s) involved. Recommended first-line options for acute flares are colchicine (within 12 hours of flare onset) at a loading dose of 1 mg followed 1 hour later by 0.5 mg on day 1 and/or an NSAID (plus PPI if appropriate), oral corticosteroid (30–35 mg/day of equivalent prednisolone for 3–5 days) or articular aspiration and injection of corticosteroids. Colchicine and NSAIDs should be avoided in patients with severe renal impairment. Colchicine should not be given to patients receiving strong P-glycoprotein and/or CYP3A4 inhibitors such as cyclosporin or clarithromycin. Ann Rheum Dis 2017;76:29-42

Ann Rheum Dis 2017;76:29-42 Cyclosporin Clarithromycin Verapamil Ketoconazole Canakinumab rilonacept Ann Rheum Dis 2017;76:29-42

Choice of drugs for attack Agents Advantages NSAIDs Any NSAID is effective at the appropriate dose Colchicine (CCC) Fast-acting control when used early (within 6-12 h) Synergism with other agents Able to abort flares during prodromal phase Steroids Useful with renal and/or GI contraindications to other therapies Available via multiple routes (oral, IA, IM, IV) Limitation NSAIDs CCC Steroids Gastropathy ○ Renal dysfunction △ (GFR< 30mg/min) CNS dysfunction Fluid retention Platelet inhibition Impaired wound healing Hyperglycemia Flares after discontinuing

IL-1 blockade Anakinra Rilonacept Canakinumab (approved in Europe) Ann Rheum Dis 2012;71:1839-48

Urate-lowering therapy (ULT) Indications [2012 ACR] Tophus by clinical exam or imaging study Frequent acute gout attacks (≥2/yr) CKD stage 2-5 or ESRD Past urolithiasis [2016 EULAR] + Young age (<40yrs) Very high SUA level (>8 mg/dL) Comorbidities ⇒ ULT should be started at a low dose and the titrated upwards the SUA target is reached. SUA target should be maintained lifelong. Renal impairment, HTN, Ischemic HD, HF

Xanthine oxidase (XO) inhibitors Mechanisms of ULT Hypoxanthine Allopurinol Oxypurinol Febuxostat Xanthine oxidase (XO) inhibitors Xanthine Allopurinol Oxypurinol Febuxostat Uricolytics Uric acid Probenecid Benzbromrone Losartan Fenofibrate Rasburicase Pegloticase Uricase URAT1 Uricosuric agents Allantoin Renal excretion Urinary excretion URAT1, urate transporter 1 (SLC22A12)

XO inhibitors Characteristic Allopurinol Febuxostat Action Elimination Nonspecific XOI Specific XOI Elimination Renal Hepatic Daily dose (50mg), 100~300 (900) mg 40mg, 80mg, (120mg) DRESS/SCAR Rare, but serious (RF: Asian population, HLA-B*5801, renal impairment) Extremely rare Cautions Severe renal impairment Heart failure (NYHA class III or IV), hepatic failure, eGFR <30ml/min/1.73m2 Interactions Cytotoxic drugs metabolized by XO (eg. azathioprine, mercaptopurine) Warfarin Cytotoxic drugs metabolized by XO (eg. azathioprine, mercaptopurine) Cost (1 tablet) KW 26 KW 221

Adopting dose of allopurinol British J Clin Pharmacol 2016;81:277-89

Febuxostat Greater efficacy than allopurinol 300mg/day  more gout attacks during treatment Extensive hepatic metabolism and renal function does not affect elimination. Hepatotoxicity, diarrhea, nausea, headache

Uricosuric agent Probenecid Benzbromarone Typical maintenance dose 500-2000 mg 50-200 mg Route and schedule Orally twice daily Orally once daily Half-life 3-8 hrs (500mg); 6-12 hrs (larger doses) 3 hrs (~30 hours for the active metabolite) Primary site of metabolism Liver Liver (CYP2C9) Primary sites of elimination Liver and kidney Limitations Drug-drug interactions; limited efficacy in renal insufficiency Safety concerns (several liver toxicity)

Benzbromarone A potent inhibitor of URAT1 in proximal tubules  inhibits post-secretory reabsorption 100mg benzbromarone vs. 300mg allopurinol Effective in moderate renal impairment (Ccr > 30 mL/min) Contraindicated with tophi, stone hx, severe renal impairment, or in overproducers. May cause urinary stone or hepatotoxicity

Pegloticase Mammalian recombinant uricase 2010 FDA approved RCT 42% 8mg biweekly infusion group achieved plasma UA < 6mg/dL vs. 0% in placebo 40% biweekly infusion group had complete resolution of ≥1 tophus vs 7% in PBO Considered ‘3rd line’ in 2012 ACR & 2016 EULAR treatment guidelines JAMA. 2011 ;306:711-20 Arthritis Rheumatol. 2002;47:356-60

Other agent with uricosuric or anti-uricosuric effects Estrogen Losartan Fenofibrates Amlodipine Statins Diuretics Salicylates Cyclosporine Pyrazinamide Ethambutol Substitute loop or thiazide diuretics if possible HTN: losartan, CCBs Hyperlipidemia: statin or fenofibrate

Tophi, chronic arthropathy, frequent attacks SUA target 2016 EULAR 2012 ACR 2010 Japan 2007 BSR 6 mg/dL or 5 mg/dL Tophi, chronic arthropathy, frequent attacks 요산 수치를 많이 낮추면 낮출수록 좋은가요? Uric acid might protect against various neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis) Does not recommend lowering continuously the SUA level to <3 mg/dL for several years Am J Epidemiol. 2009 ;169:1064-9 Am J Epidemiol. 2007 ;166:561-7 Int J Geriatric Psychiatry. 2006;21:344-8

Ann Rheum Dis 2017;76:29-42

Prophylaxis Anti-inflammatory prophylaxis against gout attcks is recommended when ULT is initiated (up to 6 months) Low dose colchicine : colchin 0.6mg qd or bid Interaction with strong P-glycoprotein and/or CYP3A4 inhibitors Awareness of potential neurotoxicity and/or muscular toxicity in case of renal impairment or statin treatment Low dose NSAIDs : NSAIDs half-dose or one-dose eg.; naproxen 250mg bid Low dose prednisolone : prednisolone 2.5~5mg/d

Prophylaxis Arthritis Care Res. 2012;75:1431-46

How can we treat gout better? Suboptimal treatment Poor adherence Not at target

Are we doing enough treatment? Cumulative Probability of Eligibility and Receipt of Prescription for ULT At 5 years 87% indication for ULT 57% had ever received 30% were on ULT JAMA. 2014 ;312:2684-6

Poor adherence Drug adherence rates across 7 medical conditions from 2001 to 2004 in USA. Medication possession ratio 80~100% 60~79% 40~59% 20~39% 0~19% Pharmacotherapy. 2008;28:437-43

Poor adherence Continuing suboptimal management of gout in UK Partially adherent At 6 months Adherent Standardized % of patients on ULT Adherence of ULT treated patients At 12 months Non-adherent Ann Rheum Dis. 2015;74:661-7

Emerging therapeutics ULT Lesinurad: uricosuric (inhibits URAT1 and OAT4) Ulodesine: PNP (purine nucleoside phosphorylase) inhibitor Topiroxostat: novel XOI Dual-acting: anti-inflammatory + ULT Arhalofenate (PPARγ modulator) : uricosuric (inhibits URAT1, OAT4, OAT10), IL-1β inhibition Anti-inflammatory therapies Caspase inhibitors Ther Adv Musculoskel Dis. 2016;8:145-59

Topiroxostat Novel XO inhibitor RCT, 120mg/d is non-inferior to allopurinol 200mg in UA lowering 160mg/d effectively reduced SUA level in the hyperuricemic stage 3 CKD pt w or wo gout Clin Exp Nephrol. 2014;18:876-84 J Clin Pharm Ther. 2016;41:290-7

Lesinurad Selectively inhibits renal UA resoption via URAT1 and OAT4 With allopurinol, lesinurad 200-600mg/d reduced sign and UA in gout FDA licensed in Dec 2015 At dose 200mg in combination with XOI Ann Rheum Dis. 2016;75:1074-80 Arthritis Rheumatol. 2017;69:203-12

Arhalofenate Uricosuric (block UA reabsorption by inhibition of URAT1 & OAT) + anti-inflammatory (suppress local release of IL-1β) Decrease sUA level Decrease gout flares Arthritis Rheumatol. 2016;68:2027-34

Summary Diagnosis Treatment Not dependent only on serum UA levels MSU crystal detection (but consider a false negativity) or based on clinical features ⇒ 2015 ACR classification criteria Treatment Management of comorbid conditions, Wt control, hydration Avoid organ meats, high fructose beverages, and alcohol Acute gout attack : NSAIDs, CCC, steroid ULT + prophylaxis Indication: tophi, frequent attacks, CKD, or urolithiasis (+ young age, very high SUA level, comorbidities) Target: SUA levels < 5~6 mg/dL with long-term ULT Curable disease, but inappropriately treated