This program is made possible through an

1. Enhanced Subspecialist Deck: Recommendations for the Diagnosis and Management of Gout and Hyperuricemia

2. This CME activity is intended for practicing physicians, and other health care providers who may treat patients who have Gout and Hyperuricemia. • There is no fee for participation in this CME activity. This program is made possible through an educational grant from Savient Pharmaceuticals, Inc. and URL Pharma, Inc.

3. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of UHS-PEP of Virginia Commonwealth University Health System and Miller Professional Group. UHS-PEP is accredited by the ACCME to provide continuing medical education for physicians. Accreditation

4. Disclosure of Significant Relationships with Relevant Commercial Interests • Neither VCU nor Miller Professional Group has any commercial interests relevant to the content of this activity. The content of this CME activity will not contain discussion of off-label uses. Please consult the product prescribing information for full disclosure of labeled uses.

5. DISCLOSURES of FACULTY CONFLICTS OF INTEREST • These members of the faculty and /or VCU UHS-PEP faculty and staff disclose the following relevant relationships to commercial interests: • Thomas Adamson, III, MD is a member of the Speaker’s Bureau for Warner Chilcott and Pfizer; and participated in a one-time speaking even for Interpace BioPharma. • Herb Baraf, MD is a member of the Speaker’s Bureau for Savient and Takeda and is an Investigator for Savient, Takeda, Ardea, Metabollix and Regeneron; and is a Consultant for Savient. • Howard Blumstein, MD is a member of the Speaker’s Bureau for Abbott, UCB, Warner Chilcott and Genentech. • Alan Brown, MD is a member of the Speaker’s Bureau for Takeda. • Paul Doghramji, MD is a member of the Speaker’s Bureau and a Consultant for URL. • N. Lawrence Edwards, MD is a Consultant for Takeda, Savient, Novartis, Ardea and Regeneron. • Alan Epstein, MD is a member of the Speaker’s Bureau for Takeda and HGS. • Madelaine Feldman, MD has no relationships to report. • Germano Guadagnoli, MD is a member of the Speaker’s Bureau for Pfizer, Amgen, Takeda, URL and Savient. • Max Hamburger, MD is a member of the Speaker’s Bureau for Amgen, BMS, Genentech and UCB; is a Consultant for Amgen and BMS; and has obtained Med Ed grants on behalf of 3rd parties from Abbott, Amgen, BMS, Centocor, Genentech and UCB. Miller Professional Group (MPG), a medical education and communications company, owned by a family member; has been the recipient of CME grants from Abbott, Amgen, BMS, Centocor, Crescendo, Genentech, Biogen Idec, Roche, and URL. • Joseph Huffstutter, MD is a member of the Speaker’s Bureau for Takeda, HGSI and Savient. • Richard Jimenez, MD is a member of the Speaker’s Bureau for Takeda. • Joseph Lieberman III, MD has no relationships to report. • Kenneth Miller, MD has no relationships to report. • Eric Mizuno, MD has no relationships to report.

6. DISCLOSURES of FACULTY CONFLICTS OF INTEREST • Alan Morton, DO is a member of the Speaker’s Bureau for Pfizer, Amgen, UCB, URL, BMS, Takeda, Genentech, Abbott, Warner Lambert and Savient; and is a Consultant for Pfizer, Amgen, URL, BMS, Savient and Novartis. • David Mount, MD has no relationships to report. • Richard Pope, PA-C is a member of the Speaker’s Bureau for Takeda and URL. • Gregory Schimizzi, MD has no relationships to report. • Paul Schulman, MD has no relationships to report. • Katy Setoodeh, MD is a member of the Speaker’s Bureau for Amgen and HGS. • Evan Siegel, MD is a member of the Speaker’s Bureau for Amgen and Abbott. • John Skosey, MD is a Stockholder in Amgen and TheraTest Laboratories and is a Director of TheraTest Laboratories. • Michael Weitz, MD is a member of the Speaker’s Bureau for Savient. All conflicts of interest due to reported relationships above have been resolved according to VCU’s Policy on Conflict of Interest and the Standards for Commercial Support of the ACCME. All presenting faculty affirm that they will employ the best available evidence from all sources to support any clinical recommendations made in their presentations.

7. After Participating in the Educational Activity, Attendees should be able to: • Describe the patho-physiology of hyperuricemia and gout • Describe recent advances in the understanding of the epidemiology of gout and hyperuricemia, and the relationship between hyperuricemia, risk factors and co-morbidities • Apply recommended guidelines for correctly diagnosing gout and hyperuricemia • Manage gout and hyperuricemia in accordance with recommended guidelines and incorporate data on efficacy and safety • Manage the acute attack • Implement prophylaxis and urate lowering therapy • Management of chronic hyperuricemia • Manage the refractory or challenging patient

9. Updating the EULAR 2006 Guidelines-Methods • A multidisciplinary team with members specializing in rheumatology, nephrology, cardiology, primary care, and allied health reviewed the diagnostic and management recommendations published by EULAR in 2006.11, 12 • The EULAR evidence hierarchy for diagnosis and management of gout was based primarily on study design. • The revised recommendations are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach13 as an evidence-based strategy for rating quality of evidence and grading the strength of recommendations formulated for use in clinical practice.

10. Strength of Recommendation • Strength-of-recommendation scores express expert experience and consensus. • Each team member rated the strength of each agreed-on recommendation on 2 scales: • a categorical scale (as fully, strongly, moderately, weakly, or not recommended) • a visual analog scale (VAS) ranging from 60 (weak recommendation) to 100 (strong recommendation). • Based on categorical data, the percentage of strongly and fully recommended scores was calculated for each recommendation. • Analysis of continuous data resulted in a mean VAS score with 95% confidence intervals for each recommendation.

11. The numbered recommendations in this presentation were taken with permission from: 2011 Recommendations for the Diagnosis and Management of Gout and Hyperuricemia Postgraduate Medicine Volume 123 Issue 6 Supplement 1 Hamburger et al

12. Sir Thomas Sydenham: Description of Acute Gout: 1848 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. This pain is like that of a dislocation. ... Then it is a violent stretching and tearing of the ligaments. … now it is a gnawing pain and now a pressure and tightening. … He cannot bear the weight of bedclothes nor the jar of a person walking in the room. The night is passed in torture, and perpetual change of posture; the tossing about of the body being as incessant as the pain of the tortured joint. Sydenham T. The Works of Thomas Sydenham, MD Translated by RG Latham. Vol II London: Sydenham Society; 1848:1224.

13. A Renaissance for Uric Acid? Increasing incidence of gout Mapping/characterization of genes associated with hereditary hyperuricemic nephropathy, uric acid stones, hyperuricemia, and gout Evolving associations with hyperuricemia: Kidney stones Insulin resistance syndrome / metabolic syndrome Hypertension, renal disease Prognosis of vascular disease, heart failure, stroke Protection from Parkinson’s, multiple sclerosis, AD

14. Gout Gout: Acute arthritis, typically very severe Most common form of inflammatory joint disease. Disease Process Urate: End product of purine metabolism Blood level of urate > physiologic limit of solubility (6.8mg/dL): Tissue crystallization Sodium in tissues: Conversion of urate to monosodium urate (MSU) Inflammatory response to the presence of MSU crystals: Acute Gout Terkeltaub RA. N Eng J Med 2003; 349:1647-1655

15. Gout - a Progressive and Disabling DiseaseOne Chronic Disease - 4 Stages Asymptomatic hyperuricemia1 asymptomatic Gout2 Gout hyperuricemia sUA ≥ 7 mg/dl Chronic Arthropathy and Tophi Persistent or Progressive gout Acute flares Intercritical Period ~5 million ~300-800k ~32million in US ~8 million Intermittent inflammatory arthritis First MTP Joint Chronic synovitis Visible tophi Increasing frequency and duration of attacks Polyarticular presentation Progression togout: 20 – 30% Necessary butnot sufficient for gout Disease Progression 1. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S566 2. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S901-2

16. Stages of Gout Pain Level Years Acute Gout with Intercritical Periods Asymptomatic Hyperuricemia Advanced Gout

17. Classification of Patients with Gout and Hyperuricemia • >90% are Under-excretors • Enhanced net proximal tubular reabsorption of urate • Renal insufficiency • Medications impairing renal urate clearance • <10% are Over-producers: de novo increased purine biosynthetic rate • Scott JT, Pollard AC Ann Rheum Dis 1970:29:397-400

18. Pathogenesis of Hyperuricemia Choi, H. K. et. al. Ann Intern Med 2005;143:499-516 (reprinted with permission)

19. Purine Sources Total Body Uric Acid Pool Purine Elimination Endogenous purine synthesis Miscible urate pool Renal excretion 500 mg 600 mg Tissue nucleic acids 1200 mg SUA x Blood Volume Intestinal uricolysis 200 mg Dietary purines 100 mg Sources and distribution of uric acid

20. Purine Sources Total Body Uric Acid Pool Purine Elimination Endogenous purine synthesis Miscible urate pool Miscible urate pool Renal excretion 500 mg 300 mg 600 mg Tissue nucleic acids 1200 mg 2000 mg Intestinal uricolysis 200 mg Dietary purines 300 mg 100 mg Insoluble urate pool 1 to >100 grams

21. Consequences of Expanded Urate Pools Asymptomatic hyperuricemia Miscible urate pool Miscible urate pool Hypertension, kidney & heart disease 1200 mg ? 2000 mg Renal Manifestations Gouty arthritis Insoluble urate pool Urate tophi 1 to >40 grams

22. URIC ACID AND THE KIDNEY

23. Overview • Pathways for proximal tubular urate absorption and secretion; relevance to hyperuricemia • Genetics of renal urate transport • Renal hypouricemia • Hyperuricemia and gout – new genetic factors • Hyperuricemia and renal disease • Familial hyperuricemic nephropathy • Nephrolithiasis and gout • Progression of CKD • Management issues for gout in CKD

24. Pathophysiology of Renal Urate Transport Renal under-excretion is the dominant mechanism for hyperuricemia in gout. Genetic syndromes of renal hyper/hypouricemia. Renal hypouricemia – deficiency in the absorptive transporters URAT1 and GLUT9 Familial hyperuricemic nephropathy – mutations in uromodulin Genetic variation in urate transporters and associated proteins are the dominant contributor to genetic risk of hyperuricemia and gout Strong correlation between proximal tubular reabsorption of Na+-Cl- and urate  hyperuricemia in volume depletion, hypouricemia in SIADH. Indirect evidence for regulation of renal urate reabsorption by: Insulin Angiotensin-II PTH

25. Renal Processes

26. Renal Transport of Urate Proximal Tubule Peritubular Interstitium Renal Proximal Tubular Epithelium Nephron Lumen Urate MRP4 UAT Urate OAT1 OAT3 Urate Anions ABCG2 Urate NTP1 SECRETION Na+ OAT4 OAT10 Anions REABSORPTION Urate Anions URAT1 L-GLUT9 Urate Urate S-GLUT9 Urate To Blood To Urine Edwards NL, ACP Medicine, 2012

27. Proximal Urate Absorption

28. Proximal Urate SECRETION

29. Inhibition AND Activation of Urate Exchange by the Same Anions

30. TAKE HOME MESSAGES:Proximal Tubular Apical Absorption • URAT1, OAT4, and OAT10 function as apical, absorptive urate:anion exchangers • The Na+-anion transporters SLC5A8 and SLC5A12 activate urate absorption via “trans-stimulation” of apical urate exchange. • Many of the “trans-activating” anions can also “cis-inhibit”. • The four-component model is imperfect • Anti-uricosurics  absorption, versus  secretion

31. Genome-Wide Association Studies Have Revealed Multiple Genetic Contributors to Variation in Urate • SLC2A9 – encodes GLUT9, involved in urate absorption • ABCG2 – apical urate secretory transporter: loss of function  hyperuricemia • SLC17A1/A3 – apical urate secretory transporters: loss of function  hyperuricemia • SLC16A9 – MCT9 – solute transporter, mechanism of hyperuricemia unknown • GCKR – regulator of glucokinase – contributes to risk of metabolic syndrome • SLC22A11 – encodes OAT4, absorptive urate transporter • SLC22A12 – encodes URAT1, absorptive urate transporter • PDZK1 – scaffolding protein for URAT1, OAT4, SLC5A8/A12, etc. Most of this genetic variation affects net renal urate excretion

32. Gout and Chronic Kidney Disease CKD complicates the management of acute gout and urate-lowering therapy. Gout is much less common in ESRD/dialysis, but can resume or emerge after transplant. Lowering urate in gout patients can  GFR, ? partially secondary to  in NSAID use. Evolving interest in the role of urate in CKD and hypertension Inhibition of xanthine oxidase (XO) also exerts urate-independent effects on kidney and vasculature.

33. Gout and Transplantation 2-13% of renal transplants may develop new-onset gout; ~1/3 asymptomatic hyperuricemia. New-onset gout is associated with graft loss. Treatment issues Post transplant gout tends to be highly tophaceous. Risk of gout with CsA >>> than with tacrolimus. Allopurinol  effect of azathioprine, but has less effect on MMF. Xanthine Oxidase inhibitors are contraindicated with allopurinol CsA  risk of myoneurotoxicity from colchicine.

34. Diagnostic Recommendations

35. Diagnostic Recommendation:Assess for Risk Factors Risk factors for gout should be assessed, including features of the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, and hypertension), chronic kidney disease (CKD), medications, family history, and lifestyle. (#10) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Moderate, grade 2 recommendation

36. Risk Factors & Co-Morbid Conditions • Risk Factors • Modifiable1-6 • Obesity • Serum urate • High-fructose corn syrup • Purine-rich diets • Meats (organ meats), Seafood • Alcohol consumption • Medications • Diuretics, Low-dose aspirin, Cyclosporine, Ethambutol • Non-modifiable • Age • Gender • Male • Postmenopausal females • Co-Morbid Conditions • Metabolic Syndrome7(63%) • Hypertension • Diabetes Mellitus • Obesity • Cardiovascular Disease • Myocardial Infarction • Peripheral artery disease • Congestive heart failure • Impaired Renal Function8-11(10 -50%) Choi et al. Arthritis Rheum. 2007;57:109 Keenan RT, et al. Am. J. Med. 2010:Article in Press. KRYSTEXXA™ (pegloticase) for intravenous infusion, Briefing Document for Arthritis Advisory Committee. Becker MA, et al. New Engl. J. Med. 2005;353(23):2450-2461. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S365 Bieber JD, Terkeltaub RA. Arthritis & Rheumatism. 2004;50(8):2400-2414 Wallace KL et al. J Rheumatol. 2004;31:1582-1587. Weaver AL. Cleveland Clinic Journal of Medicine. 2008;75(Sup 5):S9-S12. Choi HK et al. Arch Intern Med. 2005;165:742-748. Williams. Am J Clin Nutr. 2008;87:1480. Smith RG. US Pharm. 2009;34(5):40-47.

37. Risk Factors for Development of Gout: Diet • Risk from caffeine : 5+ caffeinated beverages/day  risk of gout • Risk from alcohol intake: Beer>liquor>wine • High meat consumption:  risk of gout • High seafood consumption:  risk of gout • High dairy consumption:  risk of gout • High consumption of purine-rich vegetables or total protein: no association Choi HK, Willett W, Curhan G. Arthritis Rheum 2007;56(6):2049-2055 Choi HK, Atkinson K, Karlson EW, Willet W Curhan G. Lancet 2004:363:1277-1281.Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. NEJM 2004;350:1093-1101. .

38. Dietary Purine Intake and Serum Uric Acid Levels • Severe reduction in dietary purine intake can accomplish no more than a 1 mg/dl decrease in serum uric acid. • Exception: Reduction of dietary fructose • Only carbohydrate that influences purine metabolism • Implicated in insulin resistance, metabolic syndrome and obesity • An apple a day? Ingestion of 5 apples=35% increase in serum uric acid within 6 hours Choi HK, Atkinson K, Karlson WE, Willett W, Curhan G. NEJM 2004;350:1093-1101 Choi HK, Atkinson, K, Karlson WE, Willett W, Curhan G. Lancet 2004;353: 1277-1281 Lotito SB, Frei B Free Radic Biol Med. 2004;37:251-8

39. Medications Affecting Urate Excretion Thiazides and loop diuretics Low dose aspirin Cyclosporin A Anti-tuberculous medications pyrazinamide and ethambutol Niacin PTH therapy Gonzalez EB, Miller ST, Agudelo CA. Drugs Aging 1994;4:128-134.

40. Secondary Causes of Gout and Hyperuricemia Due to Uric Acid Overproduction Myeloproliferative syndromes Lymphoproliferative disorders Malignancy Hemolytic anemias Exfoliative psoriasis Tumor lysis syndrome Hyperparathyroidism Genetic disorders Deficient hypoxanthine-guanine phosphoribosyl transferase Glycogen storage diseases

41. Hyperuricemia: Cardiovascular Risk Factor? Chronic inflammation associated with chronic gout Stronger risk factor in those already at high risk for cardiovascular disease Bickel C, et al. Am J Cardiol 2002; 29:12-17. Niskanen LK, et al. Arch Int Med 2004;164:1546-1551. Culleton BF, et al. Ann Int Med 1999;131:7-13. Fang J, Alderman M. JAMA 2000;283:2404-2410.

42. Hyperuricemia and Hypertension Co-occurrence of hypertension with hyperuricemia Hyperuricemia predicts development of hypertension, in many but not all studies ULT of hypertensive hyperuricemia in adolescents   bp Animal models – uricase inhibition   bp/renin In vitro effects of uric acid on endothelial and VSM cells; intracellular pro-oxidant effect

43. Acute Gout • Acute arthritis, typically monoarticular and very severe • Inflammatory response to the presence of monosodium urate (MSU) crystals • Urate: end product of purine metabolism • Most common form of inflammatory joint disease in men* • Crystallization occurs when the blood level of urate> physiologic limit of solubility: 6.8mg/dl • * Terkeltaub RA. N Eng J Med 2003; 349:1647-1655

44. Diagnostic Recommendation:Know the Clinical Picture of Gout In acute monoarticular attacks of the lower extremities, the rapid development of severe pain, swelling, and tenderness that reaches its maximum within 6 to 12 hours, especially with overlying erythema, is highly suggestive of crystal inflammation, though not specific for gout. (#1) • Strength of recommendation: 93 (95% CI, 91–94) • Highly or strongly recommend: 96% • Quality of evidence: Moderate, grade 1 recommendation

45. Diagnostic Recommendation:Normal Serum Uric Acid Levels Don’t Confirm or Exclude Gout While being the most important risk factor for gout, serum uric acid (SUA) levels do not confirm or exclude gout, as many people with hyperuricemia do not develop gout, and SUA levels may be normal during acute attacks. (#3) Elevated IL-6 levels are uricosuric, contributing to a drop in SUA during acute attack • Strength of recommendation: 80 (95% CI, 79–81) • Highly or strongly recommend: 47% • Quality of evidence: Low, Grade 2 recommendation

46. CommonSites ofAcute GoutAttacks OlecranonBursa Elbow Gout flares or attacks can occur in bursae, tendons, and joints Wrist Fingers Knee 1st MTP (eventually affected in ~ 90% of individuals with gout) Ankle Subtalar Midfoot

47. Precipitating Factors • Trauma, including surgery • Diuretics-other medications • Dehydration or volume depletion for any reason • Sudden rise or fall in SUA • Dietary indiscretion • Low temperature of affected limb • Alcohol: Beer > Liquor > Wine • Systemic illness

48. Special Considerations for Diagnosing Gout • Look for gout, even if • Serum uric acid levels are normal • The symptoms present in a woman • The attack is polyarticular and chronic • The involved joint is atypical • Don’t diagnose based on response to treatment: • Other types of acute arthritis may also respond to colchicine

49. Differential Diagnosis of Gout • Septic Joint • Trauma, Hemarthrosis • Pseudogout (CPPD/chondrocalcinosis) • Rheumatoid or psoriatic arthritis • Acute bursitis, tendonitis

50. Diagnostic Recommendation:Gout and Infection May Coexist Gout and sepsis may coexist; therefore, when septic arthritis is suspected, Gram staining and culture of synovial fluid should still be performed, even if MSU crystals are identified. (#6) • Strength of recommendation: 92 (95% CI, 91–93) • Highly or strongly recommend: 95% • Quality of evidence: Very low, grade 1 recommendation