Treatment Update For Gout The Future is Now

Treatment Update For Gout The Future is Now
Scott R. Burg, D.O. Orthopaedic and Rheumatologic Institute Cleveland Clinic

Gout…in 1799… 2

Flare: Classic Description
The victim goes to bed and sleeps in good health. About two o’clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. The pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them Now it is a violent stretching and tearing of the ligaments – now it is a gnawing pain, and now a pressure of tightening. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of the bedclothes nor the jar of a person walking in the room. The night is spent in torture. Sydenham, 1683 Sydenham, T: The Works of Thomas Sydenham, London, New Sydenham Soc (translation) 3

Gout Defined As… The deposition of monosodium urate crystals (MSU) in tissues at physiologic pH

What is Gout? Gout is a disorder of uric acid metabolism
This is NOT just a disease of the joints! Characterized by: Hyperuricemia Attacks of acute arthritis Tophi around joints Joint destruction Renal Disease (Glomerular, Interstitial, Tubular) Dz Uric Acid Urolithiasis

Untreated Gout May Lead to…
Tophaceous masses of MSU crystals in cartilage and joints Renal stones Urate nephropathy

Peripheral Structure Involvement vs Relative Sparing of Central Joints
Attacks due in part to temperatures <37 C peripherally Resulting in reduced solubility of urate

Total Population of Several Rheumatic Conditions in the United States
8.3 Million* 9 7.1 Million† 8 7 5.0 Million‡ 6 Total Population (Millions) 5 2.7 Million§ 4 3 1.3 Million‡ 2 Speaker Notes Gout is the most common form of inflammatory arthritis in men over 40, and its prevalence appears to be increasing5,7 Gout is caused by hyperuricemia, in which serum uric acid (sUA) is elevated. Hyperuricemia is defined as sUA >7.0 mg/dL in men and >6.0 mg/dL in women2,4 However, not all patients with hyperuricemia will develop gout1 Prevalence estimates, based on NHANES data, suggest it may affect as many as 8.3 million individuals in the US8 Prevalence of gout increases with age in both men and women4,6 Patient-reported data from NHANES and NHIS revealed gout is more prevalent or as prevalent as several other common rheumatic conditions, including rheumatoid arthritis, carpal tunnel syndrome, fibromyalgia, and activity-limiting back pain3,4,8 COLCRYS (colchicine, USP) and ULORIC (febuxostat) should only be used as indicated in the accompanying complete Prescribing Information NHANES = National Health and Nutrition Examination Survey NHIS = National Health Interview Survey Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987;82: Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999;59: Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part I. Arthritis Rheum. 2008;58:15-25. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum. 2008;58:26-35. McLean L. The pathogenesis of gout. In: Hochberg MC, Silman AJ, Smolen JS, et al, eds. Rheumatology. 3rd ed. Edinburgh: Mosby; 2003: Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology: Results from the UK General Practice Research Database, Ann Rheum Dis. 2005;64(2): Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Harris ED Jr, Budd RC, Genovese MC, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005: Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey Arthritis Rheum. 2011;63: 1 Gout Activity-limiting Fibromyalgia Carpal Tunnel Rheumatoid Back Pain Syndrome Arthritis *Based on patient-reported data from NHANES †Estimated from 1997 NHIS and 2005 US Census Bureau data. ‡Estimated from 2005 US Census Bureau data. §Based on 1988 NHIS data. 10

Who May Be the Patient With Hyperuricemia and Gout?
Comorbidities Demographics Advanced age Male Postmenopausal women Hypertension Cardiovascular disease Chronic kidney disease Diabetes mellitus Dyslipidemia Metabolic syndrome Lifestyle Speaker Notes Gout is associated with many comorbidities and risk factors that should be considered when identifying and managing your patients with gout5,6 Demographics Most common cause of inflammatory arthritis in men >40 years of age5 1 of every 10 men will be diagnosed with gout7 Both natural menopause and surgical menopause increase the risk for gout4 Estrogen therapy in postmenopausal women is associated with a reduced risk for gout; attributed to the uricosuric effects of estrogen4 Comorbidities Often Present Many patients with gout have impaired renal function and have reduced urate excretion related mainly to age and factors considered to increase the risk of vascular involvement such as hypertension, hyperlipidemia, and diabetes9 Commonly Used Medications Several common medications may increase the risk of gout by reducing net renal urate excretion8 Lifestyle Obesity is associated with increased sUA levels due to increased urate production and reduced urate excretion2 Excessive consumption of purine-rich foods (such as meat, seafood, and alcohol) and foods high in fructose are associated with elevated sUA levels, leading to an increased risk for developing gout or triggering acute flares1-3 High intake of dietary purines and fructose can induce urate overproduction1-3 ULORIC (febuxostat) is contraindicated in patients being treated with azathioprine or mercaptopurine Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2005;52: Choi HK, Mount DB, Reginato AM; American College of Physicians; American Physiological Society. Pathogenesis of gout. Ann Intern Med. 2005;143: Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ. 2008;336: Hak AE, Curhan GC, Grodstein F, Choi HK. Menopause, postmenopausal hormone use and risk of incident gout. Ann Rheum Dis. 2010;69(7): Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999;59: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10): Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum. 2008;58:26-35. McLean L. The pathogenesis of gout. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 3rd ed. Edinburgh: Mosby; 2003: Perez-Ruiz F, Calabozo M, Herrero-Beites AM, et al. Improvement of renal function in patients with chronic gout after proper control of hyperuricemia and gouty bouts. Nephron. 2000;86: Commonly Used Medications Obesity (high BMI) Diet rich in meat and seafood High alcohol intake Frequent consumption of high-fructose corn syrup Diuretics Low-dose aspirin (eg, <325 mg) Cyclosporine Niacin 11

Risk Factors for Gout (Continued)
Generic Overproducers Some patients have unusual shunt mechanism that converts glycine directly to uric acid HPRT deficiency Lesch-Nyhan Syndrome Gout and Mental Retardation in Children X-linked PRPP hyperactivity G6PD deficiency Autosomal recessive Von Gierke’s type-1 glycogen storage disease 12

Fructose Intake and Urate Excretion
HFCS Purine Catabolism Pyruvate Fructose AMP Uric Acid Lactate ATP Fructose 1-Phosphate Speaker Notes The principal “sweetener” for humans is high-fructose corn syrup (HFCS) rather than sucrose, or common table sugar2 Numerous studies have shown that the excessive consumption of fructose can contribute to the development of abnormally elevated levels of total urate1,3 There are at least 2 dominant mechanisms by which HFCS intake contributes to the development of an elevated serum uric acid4,6 Immediate phosphorylation of fructose leads to a rapid depletion of ATP and the accumulation of AMP4,6 AMP is catabolized through the purine pathway leading to an increase in uric acid production4,6 Fructose can be metabolized to lactate, which decreases urate excretion4,5 Increased levels of lactate production, secondary to excess fructose intake, leads to systemic urate retention4,5 Angelopoulos TJ, Lowndes J, Zukley L, et al. The effect of high-fructose corn syrup consumption on triglycerides and uric acid. J Nutr Jun;139(6):1242S-1245S. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr Apr;79(4): Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2008;59: Emmerson BT. Effect of oral fructose on urate production. Ann Rheum Dis May;33(3): Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology. 2005;20: Rho YH, et al. The epidemiology of uric acid and fructose. Semin Nephrol. 2011;31(5): Dominant dietary source – high-fructose corn syrup (HFCS) High concentration of fructose causes rapid accumulation of AMP Increases the body pool of purines Lactic acid is a by-product of fructose metabolism Lactate decreases urate excretion 13

Diagnosing Gout Abrupt onset of severe pain, swelling, and tenderness that reaches its maximum within just 6–12 hours, especially with overlying erythema, is suggestive of crystal inflammation though not specific for gout A presumptive diagnosis is reasonably accurate for typical presentations, such as recurrent podagra with hyperuricemia Demonstration of MSU crystals in synovial fluid or tophus provides definitive diagnosis Speaker Notes The EULAR guidelines offer the most current and practical recommendations on how to make a presumptive gout diagnosis The European League Against Rheumatism (EULAR), similar to the American College of Rheumatology (ACR) in the United States, represents the scientific societies of rheumatology of all the European nations3 The EULAR guidelines are the most current diagnostic guidelines utilized in the rheumatologic community (published in 2006)1,7,8 New clinical practice guidelines for gout management have been developed by the ACR; in addition, new diagnostic guidelines from ACR are currently in development5,6 Since synovial fluid analysis is not always a practical option, a presumptive diagnosis of gout can be made based on8: Complete patient history (risk factors, comorbidities, family history)1,4 Physical exam and labs (erythematous, swollen, painful joints; evidence of tophi; sUA measurement)2 Thorough identification of all current medications in use Dore RK. The gout diagnosis. Cleve Clin J Med. 2008;75(suppl 5):S17-S21. Eggebeen AT. Gout: an update. Am Fam Physician. 2007;76: European League Against Rheumatism (EULAR) Web site. Accessed November 27, 2012. Gibson T. Clinical features of gout. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 3rd ed. Edinburgh: Mosby; 2003: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10): Khanna D, Khanna PP, Fitzgerald JD, et al American College of Rheumatology guidelines for management of gout. Part 2: Therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10): Pascual E, Sivera F. Why is gout so poorly managed? Ann Rheum Dis. 2007;66: Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65: 14

Acute Flares Flares occur without warning and may:
Produce extreme pain Last hours to weeks Limit mobility Monoarticular in ~90% of initial presentations; ~50% are podagra Over time, flares may occur more often Temporary reduction in sUA levels can occur during a gout flare, making sUA measurements during a flare unreliable Courtesy of Theodore Fields, MD. Speaker Notes In some patients, abrupt changes in sUA levels allow for the release of crystals into the joint space and trigger an inflammatory response resulting in a flare.6 Flares occur without warning and can last from hours to weeks, producing extreme pain and potentially limiting mobility9 One possible way in which the inflammatory response occurs is through phagocytosis of MSU crystals3,5,8 Once the responding cell internalizes the MSU crystals, a complex called the inflammasome is activated and leads to the release of several inflammatory mediators, such as chemokines, prostaglandins, leukotrienes, and interleukins, such as IL-1β, which mediate gouty inflammation3,5,8 Gout can present in many areas, although one-half of patients with gout will initially present with podagra, in other words, pain in the first metatarsophalangeal joint1,7 The rapid onset of intense pain, swelling, and erythema is characteristic of acute gout7 Once a patient experiences a gout attack, it is highly likely they will experience another1,9,10 sUA may go down during a flare as a result of the uricosuric properties of IL-6, making sUA measurements during a flare unreliable8 The most accurate sUA measurements can be made after a flare has resolved, at least 2 weeks postflare2,4 An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC (febuxostat) Becker MA. Clinical gout and the pathogenesis of hyperuricemia in gout. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: Becker MA, Ruoff GE. What do I need to know about gout? J Fam Pract. 2010;59(6 Suppl):S1-S8. Chen CJ, Shi Y, Hearn A, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest. 2006;116: Logan JA, Morrison E, McGill PE. Serum uric acid in acute gout. Ann Rheum Dis. 1997;56(11): Martinon F, Glimcher LH. Gout: New insights into an old disease. J Clin Invest. 2006;116: Schumacher HR. The pathogenesis of gout. Clev Clin J Med. 2008;75(suppl 5):S2-S4. Terkeltaub RA. Gout. In: Klippel JH, Crofford LJ, Stone JH, Weyand CM, eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation; 2001: Urano W, Yamanaka H, Tsutani H, et al. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J Rheumatol. 2002;29: Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Harris ED Jr, Budd RC, Genovese MC, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005: Yu TF, Gutman AB. Efficacy of colchicine prophylaxis in gout. Ann Int Med. 1961;55: 15

Gout Radiograph 18

Intervals Between 1st & 2nd Acute Flares
Majority experience second acute flare within 1 year of first gout flare 1-2 yrs 16% A cohort study of 208 men with confirmed gout who used either daily colchicine alone or colchicine with uricosurics for 2 to 10 years found marked improvements in attack frequency in both groups, yet there was no difference between the intervention groups The risk of a second attack of gout after the first attack is 62% after 1 year, 78% after 2 years, and 93% after 10 years. The accompanying graphic addresses the segmented risk per year of the second attack as follows: within 1 year(62%), 1-2 years (16%), 2-3 years(6%), 3-5 years (5%), after 10 years (4%). Approximately 7% in the study experienced no second attack during the period of study. Yu T-F, Gutman AB. Ann Intern Med. 1961;55: 2-3 yrs- 6% 3-5 yrs - 5% Within 1 yr 62% After 10 yrs - 4% No 2nd in more than 10 yrs - 7% Yu et al. Ann Int Med ;55: 19

Chronic Gout Management
Recommendations From the 2012 American College of Rheumatology Guidelines for Management of Gout ACR recommends a comprehensive treatment plan for the management of gout, including both nonpharmacologic and pharmacologic approaches1,2 Patient education including diet and lifestyle modifications is recommended along with the following pharmacologic approaches for the management of gout1,2 Acute Gout Flares Gout Flare Prophylaxis Chronic Gout Management Treat an acute gout flare with pharmacologic therapy (NSAIDs, corticosteroids, or colchicine) within hours of onset2 For gout attack prophylaxis, initiate low-dose colchicine or low-dose NSAIDs when initiating urate-lowering therapy (ULT)2 Anti-inflammatory prophylaxis should be continued from initiation of ULT for the greater of2: At least 6 months, or Following achievement of target serum urate, for 3 months in patients without or 6 months in patients with tophi on physical exam When initiating ULT, begin anti-inflammatory gout flare prophylaxis1 Initiate first-line ULT, febuxostat or allopurinol, or if at least one of these is contraindicated or not tolerated, probenecid can be used to treat to sUA target of <6 mg/dL1 sUA should be monitored regularly (every 2-5 weeks) during ULT titration, then every 6 months once target sUA is achieved1 Speaker Notes New guidelines for gout management from the American College of Rheumatology (ACR) have been developed1,2 These guidelines are based on a review of current evidence and are aimed at helping clinicians manage acute and chronic gout1,2 Patient education including diet and lifestyle modifications is recommended along with the following pharmacologic approaches for the management of gout1,2 Acute Gout Flares Treat an acute gout flare with pharmacologic therapy (NSAIDs, corticosteroids, or colchicine) within 24 hours of onset2 Gout Flare Prophylaxis For gout attack prophylaxis, initiate low-dose colchicine or low-dose NSAIDs when initiating urate-lowering therapy (ULT)2 Anti-inflammatory prophylaxis should be continued from initiation of ULT for the greater of2: At least 6 months, or Following achievement of target serum urate, for 3 months in patients without or 6 months in patients with tophi on physical exam Chronic Gout Management When initiating ULT, begin anti-inflammatory gout flare prophylaxis1 Initiate first-line ULT, febuxostat or allopurinol, or if at least one of these is contraindicated or not tolerated, probenecid can be used to treat to sUA target of <6 mg/dL1 sUA should be monitored regularly (every 2-5 weeks) during ULT titration, then every 6 months once target sUA is achieved1 Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10): Khanna D, Khanna PP, Fitzgerald JD, et al American College of Rheumatology guidelines for management of gout. Part 2: Therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10): 22

Management of Gout RESOLVE Acute Flare INITIATE Urate-lowering Therapy
MAINTAIN Treatment to Control sUA Continue ULT to maintain sUA levels and reduce the risk of future flares Treat with anti-inflammatory agents Target sUA <6 mg/dL with ULT Speaker Notes Gout management goals are to: Resolve the painful acute attack3,8 Initiate urate-lowering therapy to target sUA levels <6 mg/dL3,8 Maintain treatment to control sUA levels and reduce the risk of future flares3,8 Acute flares should be resolved with anti-inflammatory agents2,3 Commonly used anti-inflammatory therapies include: Nonsteroidal anti-inflammatory drugs (NSAIDs)2,3 COLCRYS (colchicine, USP)2,3 Corticosteroids2,3 The choice of drug should be considered for each patient, keeping in mind the risks associated with use in patients with comorbidities, such as renal impairment, and the elderly2 For chronic management, initiate urate-lowering therapy to achieve sUA <6 mg/dL and provide concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Reduction of sUA concentrations to <6 mg/dL may eventually reduce recurrent gout attacks4,5,7 Initiation of urate-lowering therapy, including ULORIC (febuxostat), may result in a “mobilization” flare, which occurs when urate moves from tissue deposits6 In a clinical study, using colchicine with urate-lowering therapy for 6 months decreased the frequency of gout flares1 Track sUA levels to ensure target sUA is achieved and maintained2 Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31: Emmerson BT. The management of gout. N Engl J Med. 1996;334: Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999;59: Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol. 2001;28: Loebl WY, Scott JT. Withdrawal of allopurinol in patients with gout. Ann Rheum Dis. 1974;33: Schumacher HR, Chen LX. The practical management of gout. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. Shoji A,Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51: Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Harris ED Jr, Budd RC, Genovese MC, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005: Initiate concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Continuing prophylaxis for 6 months reduced the frequency of gout flares in a clinical study Track sUA levels 23

NSAIDS Indomethacin (Indocin) has usually been used
Lots of GI Toxicity / Renal Toxicity 25mg TID May use other NSAIDS Don’t use aspirin, competes with uric acid for excretion in the kidneys

Evidence for the Use of Concomitant Anti-Inflammatory Prophylaxis
Anti-inflammatories are used for both acute flares and prophylaxis Anti-inflammatory prophylactic therapy reduces the risk of mobilization flares, but is not a chronic treatment ACR guidelines, as well as medical consensus and clinical evidence, support the use of anti-inflammatory prophylaxis when initiating ULT In a clinical study, using colchicine with ULT for 6 months decreased the frequency of gout flares 2.0 * Colchicine 0.6 mg twice daily (n=21) 1.5 Placebo (n=22) † Mean Number of Flares1 1.0 Speaker Notes Anti-inflammatory prophylactic therapy for the prevention of mobilization flares is not a long-term treatment. It is used to prevent mobilization flares upon the initiation of urate-lowering therapy while sUA levels are normalizing1-3 Mobilization flares occur when sudden decreases in sUA trigger localized transient precipitation of monosodium urate (MSU) crystals in cartilage and soft tissues1 In this study, colchicine administration during initiation of allopurinol for chronic gouty arthritis reduced the frequency of mobilization flares1 Patients treated with colchicine experienced fewer total flares (0.52 vs 2.91, P=0.008), fewer flares from 0 to 3 months (0.57 vs 1.91, P=0.022), fewer flares from 3-6 months (0 vs 1.05, P=0.033)1 Patients should be educated that when initiating urate-lowering therapy, such as ULORIC (febuxostat), even with anti-inflammatory prophylaxis, gout flares are frequently observed and should be treated promptly2,3 Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31: Khanna D, , Khanna PP, Fitzgerald JD, et al American College of Rheumatology guidelines for management of gout. Part 2: Therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10): Schumacher HR, Chen LX. The practical management of gout. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. 0.5 0.0 0–3 3–6 Time Interval, Months *P=0.022; †P=0.033. 25

Corticosteroids Indications for Steroids in the Management of Acute Gouty Arthritis Co morbid medical illnesses CHF, HTN Renal Insufficiency Peptic Ulcer, GI Bleed Hepatic Insufficiency Chronic Alcoholism Bleeding diathesis Advanced Age Anticoagulant use Post Op NSAID Hypersensitivity Severe attacks refractory to NSAIDs/Colchicine

Corticosteroids Methods Prednisone Methylprednisolone Triamcinolone
Parenteral Oral Intra-articular Prednisone 1mg/kg PO as a single dose -OR- 20-40 mg PO QD taper by 5-10mg every 3 days until D/C Methylprednisolone 40 mg intra-articular single dose Triamcinolone 40 mg intra-articular as a single dose

Colchicine Alkaloid obtained from autumn crocus
Minimal effect on uric acid synthesis and excretion Prevents release of chemotactic factors and cytokines from neutrophils Binds to microtubules in neutrophils Major use is in acute gouty attacks 0.6mg - two initially, then one every 2 hours until pain is relieved, you have reached 6mg or diarrhea, nausea or vomiting develop IV Colchicine no longer available NSAIDS have largely replaced colchicine

Colchicine, USP Overview
Colchicine is approved for 2 gout indications: Treatment of gout flares Prophylaxis of gout flares Colchicine is not an analgesic medication and should not be used to treat pain from other causes Speaker Notes COLCRYS (colchicine, USP) is approved for 2 gout indications, including the treatment of gout flares and prophylaxis of gout flares. COLCRYS is not an analgesic medication and should not be used to treat pain from other causes. COLCRYS (colchicine, USP) full prescribing information, June 2012. 29

Colchicine, USP Dosing Considerations
Usage Dosing Renal or hepatic impairment ClCr ≥30 mL/min No dose adjustment Patients receiving dialysis Reduce dose Severe impairment Reduce dose Coadministration with CYP3A4 Reduce colchicine dose (eg, clarithromycin, ritonavir) or P-gp inhibitors (eg, cyclosporine) Renal or hepatic impairment AND Contraindicated, as Concurrent P-gp inhibitors or life-threatening or fatal strong inhibitors of CYP3A4 toxicity has been reported with colchicine in this setting Speaker Notes COLCRYS (colchicine, USP) dosing considerations for prophylaxis of gout flares: Patients with mild to moderate renal or hepatic impairment require no dose adjustment. Patients should be monitored closely for adverse effects of colchicine In patients with severe renal impairment, the starting dose for prophylaxis of gout flares should be reduced to 0.3 mg per day and any increase in dose should be done with close monitoring For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring Dose reduction should also be considered for the prophylaxis of gout flares in patients with severe hepatic impairment COLCRYS dosing considerations for the treatment of gout flares: In patients with severe impairment, while the dose for the treatment of gout flares does not need to be adjusted, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks Treatment of gout flares with COLCRYS (colchicine, USP) is not recommended in patients with renal or hepatic impairment who are receiving COLCRYS for prophylaxis Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted. For specific recommendations on coadministration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-gp, see the Dosage and Administration section of the complete Prescribing Information Examples of CYP3A4 inhibitors: clarithromycin, ritonavir, erythromycin, verapamil, diltiazem, ketoconazole, and itraconazole. Also note, grapefruit juice is a moderate CYP3A4 inhibitor. Grapefruit and grapefruit juice should not be consumed during COLCRYS treatment Example of a P-gp inhibitor: cyclosporine Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (including all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment See the Dosage and Administration section of the complete Prescribing Information for all dosing information, including dose adjustments and potential drug interactions COLCRYS (colchicine, USP) full prescribing information, June 2012. 30

Colchicine Pharmacokinetics in AGREE Trial
10 High-dose colchicine (4.8 mg total) Low-dose colchicine (1.8 mg total) Single-dose colchicine (0.6 mg total) 8 6 Concentration (ng/mL) 4 2 2 4 6 8 10 12 14 16 18 20 22 24 Hours

Colchicine, USP Dosing and Administration: Acute Flares
Usage Dosing Treatment of gout flares: 1.2 mg at first sign of flare, then 0.6 mg 1 hour later. Maximum dose 1.8 mg over a 1-hour period; higher doses have not been found to be more effective Speaker Notes Treatment of gout flares1: 1.2 mg, or 2 tablets, at the first sign of the flare followed by 0.6 mg, or 1 tablet, 1 hour later The maximum dose of COLCRYS (colchicine, USP) is 1.8 mg taken over a 1-hour period; higher doses have not been found to be more effective COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) 1 hour later Wait 12 hours and then resume the prophylactic dose Keep in mind, the dosing traditionally used for previously unapproved colchicine preparations to relieve or abort an attack was 0.6 to 1.2 mg followed by 0.6 mg every hour, or 1.2 mg every 2 hours until pain was relieved or until diarrhea arose. The usual dose was 4 to 8 mg per attack2-7 See the Dosage and Administration section of the complete Prescribing Information for all dosing information, including dose adjustments and potential drug interactions COLCRYS (colchicine, USP) full prescribing information, June 2012. Colchicine tablets, USP [package insert], Amneal Pharmaceutical Corp, January 2005. Colchicine tablets, USP [package insert], Excellium Pharmaceutical, Inc., February 1999. Colchicine tablets, USP [package insert], Vintage Pharmaceuticals, LLC, April 2005. Colchicine tablets, USP [package insert], Vision Pharma, LLC, October 2006. Colchicine tablets, USP [package insert], Watson Laboratories, Inc., June 2001. Colchicine tablets, USP [package insert], West-ward Pharmaceutical Corp., June 2007. 32

Colchicine, USP Dosing and Administration: Prophylaxis
Usage Dosing Prophylaxis of gout flares: For the prevention of mobilization flares, 0.6 mg once or twice daily; maximum dose 1.2 mg/day Speaker Notes Prophylaxis of gout flares1: For adults and adolescents older than 16 years of age, with a creatinine clearance greater than or equal to 30 mL/min and not taking P-glycoprotein or CYP3A4 inhibiting drugs1: 0.6 mg once or twice daily for the prevention of mobilization flares Maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day Twice-daily dosage can be reduced to 0.6 mg once daily based on tolerability2 Prophylaxis should be considered when initiating urate-lowering therapy1 See the Dosage and Administration section of the complete Prescribing Information for all dosing information, including dose adjustments and potential drug interactions COLCRYS (colchicine, USP) full prescribing information, June 2012. Hamburger M, et al; European League Against Rheumatism Recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad Med. 2011;123 (6 Suppl 1):3-36. 33

Colchicine, USP Effectively Reduced the Pain of Acute Gout Flares
Percentage of responders based on target joint pain score at 24 hours post first dose The primary endpoint was the proportion of patients who experienced at least 50% reduction in pain scores from baseline at 24 hours, without rescue medication 40 38%* † 30 33% Percentage of responders 20 16% Speaker Notes Multicenter, randomized, double-blind, placebo-controlled, parallel-group, 1-week, dose-comparison study Patients were randomly assigned to 1 of 3 groups: High-dose colchicine group: 1.2 mg, then 0.6 mg hourly for 6 hours for a total of 4.8 mg Low-dose colchicine group: 1.2 mg, then 0.6 mg in 1 hour for a total of 1.8 mg, followed by 5 placebo doses hourly Placebo group: 2 capsules, then 1 capsule hourly for 6 hours Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity, using the 11-point Likert scale, and adverse events over 72 hours Primary endpoint was the proportion of patients who experienced at least 50% reduction in pain scores from baseline at 24 hours, without rescue medication Measured based on response to treatment in the target joint, using patient self-assessment of pain at 24 hours following the time of first dose as recorded in the diary Depicted in this slide are the percentage of responders, or those patients who experienced at least a 50% reduction in pain scores from baseline at 24 hours, without rescue medication Response rates were similar for the recommended low-dose COLCRYS (colchicine, USP) group and the nonrecommended high-dose group 38% of patients in the recommended low-dose group and 33% in the nonrecommended high-dose group achieved the primary endpoint of the study compared to 16% of patients taking placebo COLCRYS tablets are indicated in adults for the prophylaxis of gout flares and treatment of acute gout flares when taken at the first sign of a flare. COLCRYS is not an analgesic medication and should not be used to treat pain from other causes Terkeltaub RA, et al. High versus low dosing of oral colchicine for early acute gout flare. Arthritis Rheum. 2010;62: COLCRYS (colchicine, USP) full prescribing information, June 2012. 10 Low-dose High-dose Placebo Colchicine, USP (n=74) colchicine (n=58) (n=52) * P=0.005 vs placebo; † P=0.034 vs placebo. 34

Colchicine, USP Had a Lower Incidence of Gastrointestinal Adverse Events
Treatment-emergent adverse events (AEs) occurring in ≥2% of patients in any treatment group 100 High-dose colchicine (n=52) † * Low-dose COLCRYS (n=74) 80 77 77 77 Placebo (n=59) 60 Percentage of patients 37 40 Speaker Notes Shown on this slide are treatment-emergent adverse events occurring in at least 2% of patients in any treatment group Low-dose COLCRYS (colchicine, USP) had a lower incidence of gastrointestinal adverse events than the high-dose colchicine group1 The most common adverse reactions reported in the clinical trial with COLCRYS for treatment of gout flares that were greater than placebo were diarrhea (23%) and pharyngolaryngeal pain (3%)1,2 Terkeltaub RA, et al. High versus low dosing of oral colchicine for early acute gout flare. Arthritis Rheum. 2010;62: COLCRYS (colchicine, USP) full prescribing information, June 2012. 27 26 23 20 17 17 19 20 14 8 4 5 1 2 Any AE Any gastrointestinal Diarrhea Nausea Vomiting General disorders Severe diarrhea disorder and administration- site conditions 35

Colchicine, USP Dose Adjustments for Coadministration With CYP3A4 Inhibitors
Speaker Notes Colchicine is a P-gp and CYP3A4 substrate Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given P-gp and strong CYP3A4 inhibitors If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted Use of COLCRYS (colchicine, USP) in conjunction with P-gp or strong CYP3A4 inhibitors (including all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment. In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses For specific recommendations on coadministration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-gp, see the Dosage and Administration section of the complete Prescribing Information COLCRYS (colchicine, USP) full prescribing information, June 2012. 36

Colchicine, USP Dose Adjustments for Coadministration With P-gp or Protease Inhibitors
Speaker Notes Colchicine is a P-gp and CYP3A4 substrate Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given P-gp and strong CYP3A4 inhibitors If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted Use of COLCRYS (colchicine, USP) in conjunction with P-gp or strong CYP3A4 inhibitors (including all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment. In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses For specific recommendations on coadministration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-gp, see the Dosage and Administration section of the complete Prescribing Information COLCRYS (colchicine, USP) full prescribing information, June 2012. 37

Principal Potential Adverse Events with Colchicine Used to Treat Acute Gout
Common with Excess Oral Colchicine GI Diarrhea (sometimes severe) Nausea Vomiting Abdominal cramps Dehydration Most common with Overdose of Oral Colchicine Bone marrow depression: nadir at 7 days Neuropathy-myopathy, elevated CK, and weakness: onset can be in weeks Less Common with Severe Overdose of Oral Colchicine CV Cardiac toxicity Arrhythmia Vascular collapse Hepatotoxicity Alopecia

Management of Gout RESOLVE Acute Flare INITIATE Urate-lowering Therapy
MAINTAIN Treatment to Control sUA Continue ULT to maintain sUA levels and reduce the risk of future flares Treat with anti-inflammatory agents Target sUA <6 mg/dL with ULT Speaker Notes Gout management goals are to: Resolve the painful acute attack3,8 Initiate urate-lowering therapy to target sUA levels <6 mg/dL3,8 Maintain treatment to control sUA levels and reduce the risk of future flares3,8 Acute flares should be resolved with anti-inflammatory agents2,3 Commonly used anti-inflammatory therapies include: Nonsteroidal anti-inflammatory drugs (NSAIDs)2,3 COLCRYS (colchicine, USP)2,3 Corticosteroids2,3 The choice of drug should be considered for each patient, keeping in mind the risks associated with use in patients with comorbidities, such as renal impairment, and the elderly2 For chronic management, initiate urate-lowering therapy to achieve sUA <6 mg/dL and provide concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Reduction of sUA concentrations to <6 mg/dL may eventually reduce recurrent gout attacks4,5,7 Initiation of urate-lowering therapy, including ULORIC (febuxostat), may result in a “mobilization” flare, which occurs when urate moves from tissue deposits6 In a clinical study, using colchicine with urate-lowering therapy for 6 months decreased the frequency of gout flares1 Track sUA levels to ensure target sUA is achieved and maintained2 Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31: Emmerson BT. The management of gout. N Engl J Med. 1996;334: Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999;59: Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol. 2001;28: Loebl WY, Scott JT. Withdrawal of allopurinol in patients with gout. Ann Rheum Dis. 1974;33: Schumacher HR, Chen LX. The practical management of gout. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. Shoji A,Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51: Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Harris ED Jr, Budd RC, Genovese MC, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005: Initiate concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Continuing prophylaxis for 6 months reduced the frequency of gout flares in a clinical study Track sUA levels 39

Gout Treatment Probenecid Indocin, Ibuprofen, Naproxen Sulfinpyrazone
Acute Treat the Pain! NSAIDS Indocin, Ibuprofen, Naproxen NOT Asprin! COX-2 Colchicine Corticosteroids Chronic/Ongoing Decreased production Probenecid Sulfinpyrazone Increase excretion Allopurinol Febuxostat Do not use these drugs during acute attack since these therapies may initially exacerbate the condition

FDA-Approved Urate-Lowering Agents
Drug Action Dose Range First-Line (Uricostatic) Allopurinol Xanthine Oxidase mg daily (decrease inhibitor dose in renal impairment) Febuxostat Xanthine Oxidase mg daily inhibitor Second-Line (Uricostatic) Probenecid URAT1 and GLUT mg daily (carefully inhibitor adjust dose to 3000 mg maximum) For Severe, Treatment-Refractory Disease (Uricostatic) Pregloticase IV Recombinant, 8 mg IV every 2 weeks PEGylated uricase

Allopurinol Historically the drug of choice in treatment of chronic tophaceous gout Competitive inhibitor of xanthine oxidase Xanthine and hypoxanthine are more soluble and better excreted renally Metabolized to oxypurinol Oxypurinol accumulates—may be responsible for antigout effects Oxypurinol is not well absorbed orally Decreases serum and urinary uric acid levels

Correlation Between Allopurinol Dose and Serum Urate
14 12 10 8 Serum Uric Acid Level (mg/dL) 6 4 2 2 4 6 8 Dose (mg/kg/day) Takada M, et al. J Clin Pharm Ther. 2005;30:

Velocity of reduction in Size of Index Tophus (mm/mo)
Velocity of Tophus Size Reduction Accelerates as Serum Urate Drops Below 4 mg/dL 8 6 Serum Urate (mg/dL) 4 Allopurinol Benzbromarone Combined 2 0.0 0.5 1.0 1.5 2.0 2.5 Velocity of reduction in Size of Index Tophus (mm/mo) Perez-Ruiz F, et al. Arthritis Rheum. 2002;47)4):

Gout Subject Achieving SUA <6.0 mg/dL (%)
Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients With Gout 100 80 P <0.01 60 Gout Subject Achieving SUA <6.0 mg/dL (%) 40 38 19.1 20 15 Lower than recommended Recommended Higher than recommended Dalbeth N, et al. J Rheumatol. 2006;33:

Drugs Potentially Affected by Allopurinol Therapy
Ampicillin/amoxicillin (~20% risk of ampicillin/amoxicillin-related rash) Azathiprine* Chlorpropamide Cyclophosphamide Dilantin Dilantin 6-Mercaptopurine* Probenecid Theophylline* Vidarabine Warfarin ACE inhibitors (suspected) *Potential for severe toxicity by impairment of drug clearance via suppression of xanthine oxidase. Potential for drug-drug interaction is also highly significant with the xanthine oxidase inhibitor febuxostat. Becker M, et al. Arthritis and Allied Conditions, 14th ed. Philadelphia, PA. Lippincott, Williams and Wilkins’ 2001:2323.

Allopurinol Hypersensitivity Syndrome (AHS), A Variant of Drug Reaction With Eosinophilla and Systemic Symptoms (DRESS) Symptoms Cutaneous rash 92% Fever 87% Renal dysfunction 85% Eosinophilia 73% Hepatitis 68% Leukocytosis 39% Death 21% Epidemiology Median dose 300 mg ( ) Median therapy duration 3 weeks (1-30) Prior renal dysfunction 81% Asymptomatic hyperuricemia 50% Concomitant thiazide diuretic 40% The DRESS syndrome usually commences symptomatically 1 to 8 weeks after exposure to the responsible drug. The symptom complex can be severe. The classic combination is rash, fever, and major internal organ involvement (most commonly hepatitis, but also can include nephritis and pneumonitis). The most common drugs inducing the DRESS syndrome include allopurinol, carbamazepine, phenobarbitol, phenytoin, minocycline, dapsoen, and sulfonamides. Hande KR, et al. Am J Med. 1984;769(1):47-56

Approximate Prevalance of the Human Leukocyte Antigen (HLA) Allele HLA-B*5801 in Various Geographic Regions of the World Unshaded areas represent regions where prevalence of the gene has not been determined. Middleton D, et al. Tissue Antigens. 2003;61(5):

Risk Factors for Allopurinol Hypersensitivity Reaction
Risk Factor Reference(s) Recent initiation of allopurinol 1,2,3,4 Renal impairment 1,2,4,5,6,7 Diurectic therapy 1,2,5,6,7 HLA-B*5801 4,8 Allopurinol dose (positive association) 1,2,5,9 Allopurinol dose (negative association) 4,10,11 Hande KR, et al. Am J Med. 1984;76:47-56 Lupton GP, et al. J Am Acad Dermatol. 1979,1: Singer JZ, et al. Arthritis Rheum. 1986;29:82-87 Hung SI, et al. Proc Nat Acad Sci USA. 2005,102: Arellano F, et al. Ann Pharmacother. 1993;27: Lang PG Jr, South Med J. 1979,72: Young JL Jr, et al. Arch Intern Med. 1974;134: Zinch I, et al. Pharmacogenomics. 2011,12: Perez-Ruiz F, et al. J Clin Rheumatol. 2005,11: Dalbeth N, et al. J Rheumatol. 2006;33: Vazquez-Mellado J, et al. Ann Rheum Dis. 2001;60: Dalbeth N, et al. Semin Dial. 2007;20: ; Zinch I, et al. Pharmacogenomics. 2011,12:

Febuxostat and Allopurinol
NC O S N CH3 CO2H H3C H Structure N N N HN O Tablet Formulation 40 mg or 80 mg 100 mg or 300 mg Dosing Range 40 mg-80 mg 100 mg-800 mg Dosing Frequency Once daily Once daily for ≤300 mg Divided doses for >300 mg Drug Elimination Primarily hepatic Primarily renal Dose adjustment in None Yes Patients with mild to moderate renal impairment Speaker Notes Dosing Allopurinol dosing may require a multistep titration process.2 The simple dosing of ULORIC (febuxostat) requires only one step to achieve the maximum recommended dosage1 The recommended starting dose of ULORIC is 40 mg; for patients who do not achieve an sUA level <6 mg/dL after 2 weeks, ULORIC 80 mg is recommended1 The recommended starting dose of allopurinol is 100 mg. The dose should be increased weekly in intervals of 100 mg until an sUA level of <6 mg/dL is attained but without exceeding the maximal recommended dosage (800 mg daily)2 Dose Adjustment ULORIC requires no dose adjustment in patients with mild to moderate renal impairment1 ULORIC is primarily eliminated by hepatic pathways and to a lesser extent renal pathways1 There are insufficient data in severe renal impairment (ClCr <30 mL/min). Caution should be exercised in those patients1 ULORIC (febuxostat) full prescribing information, November 2012. ZYLOPRIM (allopurinol) product information, October 2003. 50

Febuxostat Overview Febuxostat is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia Febuxostat may reduce elevated sUA in chronic gout patients who: Have sUA >6 mg/dL on existing therapy Are still flaring Have mild to moderate renal impairment* Speaker Notes ULORIC (febuxostat) is a xanthine oxidase inhibitor indicated for the chronic management of hyperuricemia in patients with gout3 ULORIC is the first branded drug in over 40 years for the treatment of hyperuricemia in patients with gout ULORIC is not recommended for the treatment of asymptomatic hyperuricemia3 ULORIC may reduce elevated serum uric acid in chronic gout patients who have a serum uric acid level greater than 6 mg/dL on existing therapy, are still flaring, those with mild to moderate renal impairment, and uric acid overproducers or underexcretors1-3 Mild to moderate renal impairment defined as estimated creatinine clearance greater than or equal to 30 mL/min and less than 90 mL/min3 ULORIC was shown to be an efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status1 153 patients with sUA ≥8.0 mg/dL at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo 118 (77%) were underexcretors (urinary uric acid [uUA] ≤800 mg/24 h) and 32 (21%) were overproducers (uUA >800 mg/24 h) Treatment with any dose of febuxostat led to the majority of patients achieved the primary endpoint of sUA <6.0 mg/dL at Day 28 in both overproducers and underexcretors There are insufficient data in severe renal impairment (ClCr <30 mL/min). Caution should be exercised in those patients ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine Goldfarb DS, MacDonald PA, Hunt B, Gunawardhana L. Febuxostat in gout: serum urate response in uric acid overproducers and underexcretors. J Rheumatol. 2011;38(7): Hamburger M, et al; European League Against Rheumatism Recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad Med. 2011;123 (6 Suppl 1):3-36. ULORIC (febuxostat) full prescribing information, November 2012. There are insufficient data in severe renal impairment (ClCr <30 mL/min). Caution should be exercised in those patients. Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine. 51

Febuxostat Dosing and Administration
Usage Dosing 40 mg is the recommended starting dose Once daily 80 mg is the recommended if sUA < 6 mg/dL is not achieved after 2 weeks with 40 mg dose Once daily Upon initiation of treatment, prophylaxis with and NSAID or colchicine may be beneficial Speaker Notes ULORIC (febuxostat) offers simple, once-daily dosing with 40 mg or 80 mg tablets3 The recommended starting dose of ULORIC is 40 mg; for patients who do not achieve a serum uric acid level less than 6 mg/dL after 2 weeks, ULORIC 80 mg is recommended Prophylaxis is recommended when initiating urate-lowering therapy with ULORIC (febuxostat)3 Gout flares may occur after initiation of ULORIC due to changing sUA levels resulting in mobilization of urate from tissue deposits3 Flare prophylaxis with a nonsteroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC to help prevent mobilization flares3 ULORIC should not be stopped if a gout flare occurs, and the flare should be managed while therapy with ULORIC continues3 ACR guidelines recommend that anti-inflammatory prophylaxis should be continued from initiation of ULT for the greater of at least 6 months, or following achievement of target serum urate for 3 months in patients without or 6 months in patients with tophi on physical exam.2 The ULORIC prescribing information states that prophylactic therapy may be beneficial for up to six months, and is based on data from a clinical study1,3 An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004;31: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10): ULORIC (febuxostat) full prescribing information, November 2012. Up to 6 months An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including Febuxostat. If a gout flare occurs during treatment, Febuxostat need not be discontinued. 52

Febuxostat Dosing Considerations
Special Considerations Dose Adjustment Febuxostat can be used in patients with mild to moderate renal or hepatic impairment Febuxostat can be used in patients receiving certain common medications Warfarin Hydrochlorothiazide Colchicine Naproxen Indomethacin Desipramine Speaker Notes ULORIC (febuxostat) can be used in patients with mild to moderate renal or hepatic impairment, the elderly, and those on certain common medications with no dose adjustments1 The specific drugs listed on this slide were studied because they interact with allopurinol (the anticoagulant dicumerol, the antihypertensive hydrochlorothiazide) or are given with allopurinol (colchicine, naproxen, indomethacin)1,2 ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine1 Patients should be instructed to inform their healthcare professional if they develop a rash or have any side effect that bothers them, or does not go away1 No studies have been conducted in patients with severe hepatic impairment, and there are insufficient data in severe renal impairment (ClCr <30 mL/min). Caution should be exercised in those patients1 ULORIC (febuxostat) full prescribing information, November 2012. ZYLOPRIM (allopurinol) product information, October 2003. 53

Febuxostat Efficacy: APEX, Fact, and Confirms
Proportion of Patients With sUA <6 mg/dL at Final Visit APEX (6 months) FACT (1 year) CONFIRMS (6 months) 80 70 60 50 40 30 20 10 72%* 74%* 67%*† Patients, % 45% 39% 42% 36% Speaker Notes Phase 2 Trials1,3 Study 004: 28-day, double-blind, multi-center, placebo-controlled, dose-response study. Patients randomized to placebo (n=38), ULORIC (febuxostat) 40 mg (n=37), ULORIC 80 mg (n=40), and ULORIC 120 mg (n=38). Patients who completed study 004 were eligible to enroll in FOCUS FOCUS: 5-year, open-label, long-term extension study. Patients (n=116) received ULORIC up to 5.5 years; 58 patients received treatment for a full 5.5 years Phase 3 Trials: Study Design1,3 APEX: 28-week, randomized, double-blind, allopurinol- and placebo-controlled, parallel group study Primary End Point: sUA <6 mg/dL at last 3 monthly visits Doses: ULORIC 80 mg, 120 mg, or 240 mg (240 mg included for safety assessment only), allopurinol 300 mg (100 mg in patients [n=10] with serum creatinine >1.5 and ≤2.0 mg/dL), or placebo Prophylaxis: 8 weeks of naproxen 250 mg twice daily or colchicine 0.6 mg daily; patients on previous urate-lowering therapy received prophylaxis for an additional 2 weeks before the study began FACT: 52-week, randomized, double-blind, multi-center study Doses: ULORIC 80 mg and 120 mg, allopurinol 300 mg CONFIRMS: 6-month, randomized, double-blind, multicenter, allopurinol-controlled study Primary End Point: sUA <6 mg/dL at final visit Doses: ULORIC 40 mg and 80 mg, allopurinol 300 mg (200 mg in patients [n=145] with estimated ClCr ≥30 mL/min and ClCr ≤59 mL/min) Prophylaxis: 6 months of colchicine 0.6 mg twice daily or naproxen 250 mg and lansoprazole 15 mg; patients on previous urate- lowering therapy received prophylaxis for an additional month before the study began EXCEL: 3-year, open-label, extension study of safety and efficacy, enrolling 1086 APEX and FACT participants. Analyses were performed using all available data from all patients receiving at least 1 dose of study drug Phase 3 Trials: Results1,3 APEX Baseline sUA: 9.9 mg/dL; 39% of patients had baseline sUA ≥10 mg/dL ULORIC 80 mg was superior to allopurinol in achieving sUA <6 mg/dL at the final visit (72% vs 39%) ULORIC 80 mg was superior to allopurinol in lowering sUA to <6 mg/dL at the last 3 monthly visits (48% vs 22%, respectively; P<0.001) 36% of patients with baseline sUA ≥10.0 mg/dL who received ULORIC 80 mg achieved sUA <6 mg/dL at the last 3 monthly visits FACT Baseline sUA: 9.8 mg/dL; 41% of patients had baseline sUA ≥10.0 mg/dL ULORIC 80 mg was superior to allopurinol in achieving sUA <6 mg/dL at the final visit (74% vs 36%) ULORIC 80 mg was superior to allopurinol in lowering sUA to <6 mg/dL at the last 3 monthly visits (53% vs 21%; P<0.001) CONFIRMS Baseline sUA: 9.6 mg/dL ULORIC 40 mg effectively lowered sUA to <6 mg/dL at the final visit ULORIC 80 mg was superior to allopurinol in achieving sUA <6 mg/dL at the final visit (67% vs 42%; P<0.001) Post-hoc Analysis2 ULORIC was shown to be highly efficacious in reducing sUA in patients with gout regardless of uric acid overproduction or underexcretion status ULORIC 40 mg effectively lowered sUA to <6 mg/dL in the CONFIRMS study1,3 ULORIC 80 mg was proven superior to allopurinol at lowering sUA to the target level of <6 mg/dL in the APEX, FACT, and CONFIRMS studies1,3 Individual results may vary based on factors such as baseline serum uric acid levels Data on file, Takeda Pharmaceuticals U.S.A, Inc. Goldfarb DS, MacDonald PA, Hunt B, Gunawardhana L. Febuxostat in gout: serum urate response in uric acid overproducers and underexcretors. J Rheumatol. 2011;38(7): ULORIC (febuxostat) full prescribing information, November 2012. (n=253) Febuxostat 80 mg (n=253/10) Allopurinol 300/100 mg (n=249) Febuxostat 80 mg (n=242) Allopurinol 300 mg (n=757) Febuxostat 40 mg (n=756) Febuxostat 80 mg (n=610/145) Allopurinol 300/200 mg *P<0.001 vs allopurinol; †P<0.001 vs Febuxostat 40 mg. 54

Confirms Efficacy in Patients With Mild to Moderate Renal Impairment
Proportion of Patients With Mild to Moderate Renal Impairment with sUA <6 mg/dL at Final Visit Confirms (6 months) 80 70 60 50 40 30 20 10 72%* 50%* Patients, % 42% Speaker Notes ULORIC (febuxostat) demonstrated greater efficacy in lowering sUA to <6 mg/dL at the final visit than allopurinol in patients with mild to moderate renal impairment2 A substantial proportion of patients in CONFIRMS (65%) had mild to moderate renal impairment (ClCr of mL/min)1 Mild: Defined as baseline estimated ClCr =60 mL/min to 89 mL/min Moderate: Defined as baseline estimated ClCr =30 mL/min to 59 mL/min Dose adjustment: Allopurinol was dosed 200 mg daily in patients with moderate renal impairment (n=145) and 300 mg daily in patients with mild renal impairment (n=356). ULORIC did not require dose adjustment in these patients2 Renal impairment was defined as baseline estimated ClCr ≥30 mL/min and <90 mL/min. There are insufficient data in severe renal impairment (ClCr <30 mL/min) and no data in patients with severe hepatic impairment. Caution should be exercised in these patients2 Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. ULORIC (febuxostat) full prescribing information, November 2012. (n=479) Febuxostat 40 mg (n=503) Febuxostat 80 mg (n=356/145) Allopurinol 300/200 mg *P≤0.05 vs allopurinol. Renal impairment was defined as baseline estimated ClCr ≥30 mL/min and <90 mL/min. 55

Adverse Reactions Summary: Physician-Reported
Placebo Febuxostat Febuxostat Allopurinol Adverse Reactions 40 mg 80 mg 300/200/100 mg (≥1% of Patients*) (n=134) (n=757) (n=1,279) (n=1,277) Liver Function 0.7% 6.6% 4.6% 4.2% Abnormalities Nausea 0.7% 1.1% 1.3% 0.8% Arthralgia 0% 1.1% 0.7% 0.7% Rash 0.7% 0.5% 1.6% 1.6% Speaker Notes ULORIC (febuxostat) has an extensively studied safety profile1,2 A treatment-emergent adverse reaction was defined as an adverse reaction occurring between the first dose and 30 days after the final dose of the study drug3 The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of the patients receiving ULORIC 40 mg, 1.2% of those receiving ULORIC 80 mg, and in 0.9% of allopurinol-treated patients1 Liver function abnormalities shown here were investigator reported and could be any elevation at all above normal1 ULORIC (febuxostat) full prescribing information, November 2012. Data on file, Takeda Pharmaceuticals U.S.A, Inc. Becker M, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23): *At a ≥0.5% greater rate than with placebo. 56

Probenecid ColBenemid
Inhibits tubular reabsorption of filtered urate in kidney Controls hyperuricemia and prevents tophus formation Salicylates interfere with action Use caution with decreased renal function Can impair renal secretion of : Sulfinpyrazone, Sulfonylureas Indomethacin Penicillin Sulfonamides

Drugs Potentially Affected by Probenecid Therapy
Ampicillin Penicillin Nafcillin Cephradine Cephaloridin Salicylates Indomethacin Heparin Dapsone Methotrexate Rifampicin

Uricase Enzymes Uricase Uricase H2O + O2 H2O2 + CO2 Uric acid
Allantoin Uricase (uric acid oxidase) catalyzes the eventual conversion of uric acid to allantoin, a more soluble, readily renally excreted form.

Uric Acid Production About two-thirds of uric acid is generated endogenously by the body, while one-third comes from purines in the diet Urate Oxidase (Uricase) Xanthine Oxidase Xanthine Oxidase Purine Catabolism2-5 Speaker Notes On this slide we see the final steps of purine catabolism as it occurs in the liver, which ultimately leads to the formation of uric acid2-5 Purines are derived from dietary sources such as red meats, as well as from endogenous synthesis of purine nucleotides, the building blocks in the formation of nucleic acids2 About two-thirds of the body’s uric acid is generated endogenously, while one-third comes from purines in the diet1 The enzyme xanthine oxidase is required for the metabolism of hypoxanthine to xanthine and xanthine to uric acid2 Inhibitors of xanthine oxidase can produce a systemic decrease in uric acid production5 Interestingly, we’re unable to further metabolize uric acid to allantoin like other mammals can2,6 The reason for this is we lack a functional key enzyme in the end metabolism of purines, namely uricase, which converts uric acid into the soluble metabolite allantoin This is a result of the mutations in the uricase (uric oxidase) gene that occurred some 8 to 24 million years ago (Miocene) As a result, we have higher levels of uric acid in cells, blood, and urine Uric acid is a weak organic acid with a pKa of This indicates that at a pH of 5.75, uric acid exists in equal amounts as the un-ionized and ionized forms of the molecule5 Since the pH of extracellular fluid is 7.4, uric acid is dominantly ionized in the body The abundant cation in extracellular fluid is sodium; hence, ionized uric acid exists primarily as monosodium urate (MSU) Fam AG. Gout, diet, and the insulin resistance syndrome. J Rheum. 2002;29: Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology. 2005;20: Johnson RJ, Sautin YY, Oliver WJ, et al. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? J Comp Physiol B. 2009;179:67-76. Terkeltaub RA. Gout. In: Klippel JH, Crofford LJ, Stone JH, Weyand CM, eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation;2001: Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther. 2006;8 (suppl 1):S4-S12. Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002;40: Hypoxanthine Xanthine Uric Acid Allantoin End product for humans, higher primates, reptiles, birds, and some mammals End product for the majority of mammals 60

Reduction in Plasma Urate Levels With IV Pegloticase in Phase 3 Trials
Mean PUA (All subjects) 14 Placebo Pegloticase 8 mg q 2wk 12 10 8 Mean PUA (mg/dL) (SE) 6 4 2 3 6 9 12 15 18 21 24 27 Week Replicate multicenter, phase 3, double-blind trials assigned to 128 patients with sever, refractory gout to receive either pegloticase 8 mg q2w, or a placebo infusion (n=43). The trials’ primary end point was a sustained plasma urate of <6.0 mg/dL in months 3 & 6. There is evidence for loss of efficacy overall overall over time in the treatment group.

Reduction in Plasma Urate Levels With IV Pegloticase in Phase 3 Trials
Mean PUA (Responders) 14 Placebo Nonresponders Responders Month 3 Month 6 12 10 8 Mean PUA (mg/dL) 6 4 2 1 3 5 7 9 11 13 15 17 19 21 23 25 Week Data are for those subjects in the q2w treatment arm of the phase 3 trials separating responders (ie, those who achieved the defined primary end point) vs nonresponders. Nonresponders were generally those subjects who developed high titers of pegloticase antibodies, and these antibodies correlated with infusion reactions.

Pegloticase-Associated Infusion Reaction Relationship to Pre-infusion Serum Urate Level
6 RCT OLE 5.5 4.8 5 4 IRs per 100 Infusions 3 2 1 0.8 0.5 <6 mg/dL >6 mg/dL Data from phase 3 randomized controlled trials (RCT) and open-label extensions (OLE) demonstrate a marked relationship between an increased frequency of infusion reactions (IR) and the loss of effectiveness of pegloticase. For all infusions after the initial pegloticase infusion, the likelihood of IRs depends greatly on whether the pre-infusion serum urate determination is above or below 6.0 mg/dL.

Most Common Signs and Symptoms of Infusion Reaction to Pegloticase*
Chest discomfort Flushing Dyspnea Nausea / vomiting Back / flank pain Erythema Blood pressure changes Muscle spasm / stiffness Hyperhidrosis *Data include all subjects in RCT and OLE in biweekly, monthly, and placebo arms.

Strategy for Lowering Uric Acid
Initiate prophylaxis with low dose Colchicine or NSAID 1-2 weeks prior to urate lowering agent Initiate uricostatic agent at low dose (100 mg/day Allopurinol or 40 mg/day for febuxostat) Escalate dose every 2-4 weeks while monitoring for toxicity until serum urate is < 6.0 mg/dL If treat to target goal achieved maintain anti-inflammatory prophylaxis for 3-6 months after last gouty flair or longer when tophi persist

Strategy for Lowering Uric Acid
Maintain urate-lowering agent indefinitely and check serum urate levels every 6-12 months If toxicity occurs with one uricostatic drug try the other agent. No evidence of cross-reactive toxicity. If target serum urate not achieved with uricostatic agent, a uricosuric can be added and titrated or Pegloticase can be tried No adjustment during gout flares

Study Showed Maintaining sUA <6 mg/dL Is Associated With Reduced Risk of Future Gout Attacks
Incidence of recurrent gout attacks more than 1 year after each patient visit* 80 86% of patients who achieved a serum uric acid level of <6 mg/dL (n=81) had no gout attacks during the observation period 60 Incidence of Recurrent Gout Attack, % 40 Observed Logistic regression (n=91) Speaker Notes Shoji et al demonstrated that maintaining sUA <6 mg/dL was associated with reduced risk of future gout flares Study Design: Retrospective analysis of 267 patients in Tokyo, Japan Inclusion criteria ≥1 gout attack before the initial visit and treatment at the clinic >1 year after the first visit at the clinic No patients received antihyperuricemic medication before their first visit 232 patients (medication group) received allopurinol (n=95), benzbromarone (n=136), or both (n=1; some patients were later switched from allopurinol to benzbromarone [n=2] or from benzbromarone to allopurinol [n=10], probenecid [n=2], or sulfinpyrazone [n=1] because of adverse reactions); 35 patients did not receive antihyperuricemic medication (no-medication group) 98% received allopurinol 300 mg daily or up to 50 mg of benzbromarone daily Data were collected for up to 3 years, and statistical analysis was performed on data from >1 year after study entry Results: Recurrence of acute gout attacks was associated with average sUA concentration during the whole investigation period (1-3 years) (OR 0.42 [P<0.001]) 91 of the patients analyzed experienced at least 1 recurrence of acute gouty arthritis a year or more after the initial visit (attack subgroup: average sUA 7.2 mg/dL [SE 0.09 mg/dL]) 176 patients had no recurrences a year or more after the initial visit (no-attack subgroup: average sUA mg/dL [SE 0.07 mg/dL]) Patients who received urate-lowering therapy and had at least 1 gout attack a year or more after the initial visit (n=69) had an average sUA level of 7.01 mg/dL (SE 0.10 mg/dL) COLCRYS (colchicine, USP) and ULORIC (febuxostat) should only be used as indicated in the accompanying complete Prescribing Information Shoji A,Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51: 20 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 Average Uric Acid Level During Investigation Period (mg/dL) Based on a retrospective analysis of 267 predominantly male gout patients for up to 3 years (Tokyo, Japan). Baseline mean sUA level >7.45 mg/dL. Urate-lowering therapies prescribed: allopurinol and benzbromarone. 67

Tracking sUA Levels sUA Levels Over Time sUA Level Intercritical Period Gout Attack Intercritical Period The best time to measure sUA is after a flare has resolved, at least 2 weeks postflare sUA levels may be artificially low ~50% of the time during a flare Evaluate sUA in patients on therapy to ensure that the target level is achieved and maintained ACR guidelines recommend monitoring sUA level every 2-5 weeks during urate-lowering therapy titration, then every 6 months once sUA target has been achieved Speaker Notes sUA levels are often artificially low during a flare; the most accurate measurements can be made after a flare has resolved, at least 2 weeks postflare1,3 In the Urano study, sUA levels during acute attacks were normal in 49% of patients. Mean levels of sUA during acute gout attacks ( mg/dL) were significantly lower than those in the intercritical phase ( mg/dL; P<0.0001)4 sUA levels may be reduced during a flare due to the potential uricosuric effects of IL-6 released during the acute flare4 The American College of Rheumatology (ACR) guidelines recommend regularly monitoring sUA level every 2-5 weeks during urate-lowering therapy titration, then every 6 months once sUA target goal is achieved2 Becker MA. Clinical gout and the pathogenesis of hyperuricemia in gout. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10): Logan JA, Morrison E, McGill PE. Serum uric acid in acute gout. Ann Rheum Dis. 1997;56(11): Urano W, Yamanaka H, Tsutani H, et al. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J Rheumatol. 2002;29: ACR=American College of Rheumatology. 68

Limitations of Lifestyle Modifications on Reaching Target sUA Levels
sUA levels may be reduced by making lifestyle changes including: Losing weight Limiting consumption of purine-rich meat and seafood Reducing alcohol intake, particularly beer Limiting high-fructose corn syrup intake Consuming dairy products Speaker Notes Patients should consider lifestyle and dietary changes to reduce their sUA In NHANES, higher levels of meat and seafood consumption are associated with higher levels of sUA due to high purine content2 In one study, acute high purine intake, especially from animal sources, increased the risk of recurrent gout attacks in gout patients almost 5-fold13 However, a purine-restricted diet can be unpalatable and can be difficult to adhere to in patients aiming to lose weight9 The effect of individual alcoholic beverages on sUA levels varies: beer confers a larger increase than liquor; moderate wine drinking does not increase sUA1,6 sUA increases with increased intake of fructose, such as high-fructose corn syrup found in sugar- sweetened soft drinks3 Studies have identified a link between milk consumption and reductions in sUA levels2,4 In addition, consumption of milk products was associated with a reduction in the incidence of gout5 Milk proteins have uricosuric properties in healthy individuals and may be the basis for this reduction2,4 Dietary restrictions may reduce sUA by about 1 mg/dL Reducing dietary purines typically results in reductions of sUA levels by about 1 mg/dL1-3,5,7 In 2 population studies using NHANES III data (n=14,809), Choi et al demonstrated the impact of purine-rich foods on sUA concentration. The difference in sUA levels between the lowest and highest consumer groups was 0.99 mg/dL for beer (95% CI, ), 0.58 mg/dL for liquor (95% CI, ), mg/dL for total meat (95% CI, ), and 0.16 mg/dL for seafood (95% CI, )1,2 Reducing purine intake should be a part of the clinical management plan in patients with gout who have excessive intake of purine-rich foods9,10 In addition to discussing diet and lifestyle modifications, educate patients about the root cause of gout and long-term treatment options. While discussing diet and lifestyle modifications should be a part of the gout management plan, it’s important that clinicians don’t blame their patients for their gout7,9-11 Genetics play a large role in the development of gout. Furthermore, low-purine diets are difficult to sustain over the long term, and only about 20% of patients are ready to commit to making changes to their lifestyle7,9 It’s important to remember that diet only contributes to one-third of the body’s purines; the remaining purines are endogenously produced7 Patients who believe gout is self-inflicted may be less likely to discuss long-term management options with their clinician for fear of being reprimanded for their dietary choices11 Choi HK, Curhan G. Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2004;51: Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2005;52: Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2008;59: Dalbeth N, Wong S, Gamble GD, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis Sep;69(9): Dalbeth N, Ames R, Gamble G, et al. Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial. Ann Rheum Dis. 2012;71: Emmerson BT. The management of gout. N Engl J Med. 1996;334: Fam AG. Gout, diet, and the insulin resistance syndrome. J Rheum. 2002;29: Gaffo AL, Roseman JM, Jacobs DR Jr, et al. Serum urate and its relationship with alcoholic beverage intake in men and women: findings from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Ann Rheum Dis Nov;69(11): Jordan KM, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) ;46: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10): Nicholls A, Scott JT. Effect of weight-loss on plasma and urinary levels of uric acid. Lancet. 1972;2: Spencer K, et al. Patient and provider barriers to effective management of gout in general practice: a qualitative study. Ann Rheum Dis. 2012;71(9): Zhang Y, Chen C, Choi H, et al. Purine-rich foods intake and recurrent gout attacks. Ann Rheum Dis. 2012;71(9): 70

Medication prescription and monitoring of SUA in patients with a diagnosis of gout
n/N % n/N % Continuous allopurinol prescription 297/643 46 SUA monitoring SUA checked and reached target 126/643 20 SUA checked but did not reach target 127/643 20 No SUA check 390/643 61 Colchicine/NSAID prophylaxis Colchicine Colchicine or NSAID ≥14 days before new allopurinol prescription 66/ /643 26 Before new allopurinol prescription 80/ /643 30 On or before new allopurinol prescription 169/ /643 48 ≤14 days after new allopurinol prescription 180/ /643 51 Singh JA, Jodges JS, Asch SM. Opportunities for improving medication use monitoring in gout. Ann Rheum Di. 2009;68:

Take-Away Messages The goal of therapy in subjects with multiple recurrent gout flares or tophaceous gout is to prevent disease progression by reducing the body urate burden. Any patient presenting with advanced gout, or simply demonstrating tophi on physical exam, should clearly be started on ULT. Both allopurinol and febuxostate are effective in gout patients whose hyperuricemia is caused by either uric acid overproduction or underexctetion. Uricosurics should not be used in overproducers of uric acid or as monotherapy in those with a history of urolithiasis.

Take-Away Messages The uricostatics can be administered as once-daily medications, which increases compliance. Probenecid requires 2 to 3 doses per day for optimal function. The uricostatic agents function well in the face of renal insufficiency, whereas probenecid requires a GFR of at least 50 mL/min to be most effective. In fact, febuxostat appears to function better than many other options in subjects with mild-to-moderate renal insufficiency.

Take-Away Messages Rash will develop in at least 2% of patients started on allopurinol. Most rashes are benign and dose related, but allopurinol is one of the more common drug causes of severe cutaneous reactions in the form of SJS or TEN and rashes as a component of the DRESS syndrome, which is more commonly known as AHS. HLA-B*5891, which is by far most common in those of Southeast Asian ancestry, is a marked risk factor for severe allopurinol cutaneous reaction particularly in Koreans with CKD, and those of Han Chinese and Thai descent.

Take-Away Messages In essence, the appropriate strategy for ULT is termed “treat to target,” with the evidence-based target to begin to achieve superior outcomes being achievement of a serum urate of <6.0 mg/dL, at a minimum. This requires checking the serum urate level regularly (eg, every 6 months once the target has been achieved). In patients with one or more tophi detected on physical exam, the authors prefer a serum urate target of <5.0 mg/dL and in certain patients with advanced disease and multiple tophaceous deposits, lowering the serum urate level to <4.0 mg/day is the preferred strategy by the authors to help optimize therapy outcome.

Take-Away Messages In certain patients with advance disease and multiple tophaceous deposits, lowering the serum urate level to well below 6.0 mg/dL, such as in the range of 4.0 mg/dL, appears to help optimize therapy by accelerating resolution of tophi. The recombinant PEGylated uricase pegloticase is FDA-approved as in approach for potent and rapid reduction of serum urate and achieves rapid debulking of tophi (within 6 months) in drug responders (which were between 40% to 50% of subjects in phase 3 clinical trials, using 8 mg IV every 14 days).

Take-Away Messages The therapeutic program of urate-lowering measures, once initiated, should keep the serum urate less than 6.0 mg/dL (at a minimum) for the remainder of the patient’s life, even after tophi and gouty arthritis attacks are no longer present. 77

Uric Acid Overproducers and Underexcretors
Uric Acid Underexcretion (~90%) Urate Overproduction (~10%) Primary Hyperuricemia Disordered urate transport Metabolic disorders Idiopathic Secondary Hyperuricemia Impaired renal function with urate transport Drug-induced renal toxicity Excessive purine intake Tumor lysis syndrome Speaker Notes Hyperuricemia is caused by urate overproduction, uric acid underexcretion, or both.3 Underexcretion of urate by the kidneys accounts for about 90% of individuals with hyperuricemia, leading to chronic elevation of systemic urate whereas overproduction of systemic urate accounts for only a small fraction of the metabolic mechanisms leading to gout4 Secondary elevation of serum uric acid can be caused by external factors, such as: A diet high in purines, for example, meat3 Excessive alcohol intake, particularly beer3 Acute lysis of tumor cells, for example, lymphomas1 Metabolic abnormalities in systemic urate metabolism3 In one study, febuxostat was shown to be an efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status2 Patients with sUA ≥8.0 mg/dL at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo The proportion of patients with sUA <6.0 mg/dL at Day 28 was observed (primary endpoint) as well as percentage reductions in sUA and urinary uric acid (uUA) from baseline to Day 28 (secondary endpoint) 153 patients were enrolled; 118 (77%) were underexcretors (uUA ≤800 mg/24 h) and 32 (21%) were overproducers (uUA >800 mg/24 h) Treatment with any dose of febuxostat led to the majority of patients achieving the primary endpoint of sUA <6.0 mg/dL at Day 28 in both overproducers and underexcretors Percentage change in sUA from baseline to Day 28 was similar between overproducers and underexcretors among all treatment groups; however, the mean percentage change was numerically greater for underexcretors in each treatment group and the difference between overproducers and underexcretors was greatest in the febuxostat 40 mg group Note that, in cases of asymptomatic hyperuricemia, pharmaceutical treatment is not recommended; however, associated risk factors should be monitored and/or addressed3 COLCRYS (colchicine, USP) and ULORIC (febuxostat) should only be used as indicated in the accompanying complete Prescribing Information Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004;116: Goldfarb DS, MacDonald PA, Hunt B, Gunawardhana L. Febuxostat in gout: serum urate response in uric acid overproducers and underexcretors. J Rheumatol. 2011;38(7): Sanders S, Wortmann RL. Gout. In: Imboden JB, Stone JH, Hellmann DB, eds. Current Rheumatology Diagnosis & Treatment. 2nd ed. New York, NY: McGraw-Hill; 2007: Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther. 2006;8(suppl 1):S4-S12. 79

Gout Flares Occur When Crystals Trigger an Acute Inflammatory Response
Hyperuricemia Acute flares may be triggered by fluctuations in sUA levels, which can mobilize crystals Crystals released into the joint space undergo phagocytosis Phagocytosis can initiate a proinflammatory response, resulting in gout flares Supersaturation Crystal Formation Microcrystal Release Speaker Notes In some patients, abrupt changes in sUA levels allow for the release of crystals into the joint space and trigger an inflammatory response resulting in a flare4 Other factors can trigger acute flares, including trauma, alcohol ingestion, and overindulgence in foods high in purine content1 A potential mechanism is that phagocytosis of MSU crystals may stimulate the production of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, which mediates gouty inflammation2 Evidence suggests that phagocytic cells, such as monocytes, internalize MSU crystals and activate the inflammasome, which alert the surrounding environment via the processing and release of active IL-1β3 Once a patient experiences a gout attack, it is likely they will experience another.1,5,6 A study showed that 62% of patients with a first attack of gout experienced a second gout attack within 1 year6 An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC (febuxostat) Becker MA. Clinical gout and the pathogenesis of hyperuricemia in gout. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: Chen CJ, Shi Y, Hearn A, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest. 2006;116: Martinon F, Glimcher LH. Gout: new insights into an old disease. J Clin Invest. 2006;116: Schumacher HR. The pathogenesis of gout. Clev Clin J Med. 2008;75(suppl 5):S2-S4. Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Harris ED Jr, Budd RC, Genovese MC, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005: Yu TF, Gutman AB. Efficacy of colchicine prophylaxis in gout. Ann Int Med. 1961;55: Inflammatory Cascade Recurrences Gout Flare 80

Treatment Update For Gout The Future is Now

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