Gout in the 21st Century

JOAN M VON FELDT, MD, MSEd Professor of Medicine Division of Rheumatology University of Pennsylvania Philadelphia, PA GARY M. OWENS, MD President, Gary Owens Associates Medical Management and Pharmaceutical Consulting Glen Mills, PA Gout in the 21st Century Gout has markedly increased in prevalence and clinical complexity over the last 2 decades Prevalence rise is influenced by diet, aging, comorbidities, and the obesity epidemic Diagnostic criteria and imaging tools are evolving Treatment-refractory gouty arthritis and hyperuricemia are growing challenges New treatments are available Gout: Disease Definition Arthritis resulting from excess uric acid in body Can lead to: Gouty arthritis: Inflammation in joints; frequently occurs in big toe Tophi: Deposits of urate crystals that form subcutaneous nodules Renal disease: Kidney stones from uric acid crystals in the kidneys Chronic interstitial nephropathy (in severe cases) 1

Uric Acid, Hyperuricemia, and Gout Hyperuricemia: A serum urate concentration in excess of urate solubility (>6.8 mg/dl) Results from overproduction and/or underexcretion of uric acid The most common cause of hyperuricemia is renal insufficiency Does not always result in gout Gout: Results from deposition of monosodium urate crystals in the synovium, with subsequent release and resultant inflammation Becker MA. In Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. 2001:2281 2313. Gout: A Typical Case Middle-aged male Presentation with acute and excruciatingly painful arthritis associated with swelling and redness Big toe, midfoot, ankle involvement are classic Recurrent self-limited episodes of arthritis Kidney stones can occur Serum urate is elevated Source: American College of Rheumatology Slide Collection Gout Epidemiology Affects up to 6 million individuals in US 1% 2% prevalence in adult males Renal insufficiency is the most common cause of gout 9 times more common in young men (<40) than pre-menopausal women Metabolic syndrome is a significant risk factor and the prevalence of this disease is dramatically increasing in US population 2

Gout Epidemiology: Emerging Populations Renal insufficiency is growing more common in certain patient groups, increasing the risk of gout in: Elderly Heart failure patients Transplant patients Patients with metabolic syndrome Once patients are on dialysis, hyperuricemia eventually normalizes Commonly Underdiagnosed Groups Women Post-menopausal women have increasing risk of gout with advancing age Patients with tophi Asymptomatic patients can be proactively identified with a good musculoskeletal and skin exam Patients with hypertension (HTN) Diuretics, renal disease compounds hyperuricemia Patients with metabolic syndrome Insulin resistance and renal disease impair excretion of renal uric acid Schumacher HR. New Horizons. 2002;8:11 15. "Perfect Storm" Driving Increased Prevalence and Clinical Complexity Increased longevity Improved cardiovascular disease survival rates Iatrogenesis: Diuretics, low-dose ASA, niacin, major organ transplants Diet and alcohol use trends Increases in prevalence of comorbid conditions that promote hyperuricemia including: obesity, metabolic syndrome, DM, hypertension, CHF, CKD, and ESRD ASA aspirin DM diabetes mellitus CHF congestive heart failure CKD chronic kidney disease ESRD end-stage renal disease Terkeltaub R. Bull NYU Hosp Jt Dis. 2006;64:82 86. 3

Gout: Economic Burden Direct costs for new cases of acute gout: ~$27 million Care of chronic gout is approximately 6% of a patient's all-cause yearly health care costs Diagnosis of gout is independently associated with higher medical/arthritic comorbidity, higher utilization of health care Significant costs to employers: Patients with acute gouty arthritis miss an average of 3 5 days of work annually Estimated total annual cost of gout to employer per employee: Employee with gout >$6500 Employee without gout <$4000 Halpern R, et al. J Clin Rheumatol. 2009;15:3 7.; Kim KY, Schumacher HR. Clin Ther. 2003;25:1593 1617.; Wu EQ, Patel PA. J Manag Care Pharm. 2008;14:164 175.;Singh JA, Strand V. Ann Rheum Dis. 2008;67:1310 1316.; Kleinman NL, Brook RA. Value Health. 2007;10:231 237. Gout: Utilization National Ambulatory Medical Care and Hospital Ambulatory Care Surveys Total ambulatory visits/visits to primary care vs specialties 973 million ambulatory care visits, 3.9 million (0.4%) for gout 69% of gout visits to primary care 10% to cardiologists Up to 16% to other specialties or unknown <3% to rheumatologists Adapted from Terkeltaub R. Arthritis Res Ther. 2009;11:236. American College of Rheumatology (ACR) Criteria (1977) >1 attack of acute arthritis Maximum inflammation develops within 1 day Monoarthritis attack Redness over joints 1 st MTP joint painful or swollen Unilateral first MTP joint attack MTP: metatarsophalangeal Wallace SL, et al. Arthritis Rheum.1977;20:895 900. Unilateral tarsal joint attack Tophus Hyperuricemia Asymmetric swelling within a joint on x-ray Subcortical cysts without erosions on x-ray Synovial fluid cultures (-) for organisms When using 6 ACR criteria, diagnosis of gout is correct only in 80% 4

Netherlands Proposal: Diagnosis Without Joint Aspiration 7 variables "easily ascertainable in primary care": Male gender Previous patient-reported arthritis attack Onset within 1 day Joint redness Involvement of the 1 st MTP Hypertension or 1 or more cardiovascular diseases Serum uric acid level of more than 5.88 mg/dl Janssens HJ, et al. Arch Intern Med. 2010;170(13):1120-1126. Calibration Plot of the Final Diagnostic Rule OBSERVED PROBABILITY EXPECTED PROBABILITY Janssens HJ, et al. Arch Intern Med. 2010;170(13):1120-1126. WAITING FOR PERMISSION LANGUAGE Pitfalls in Gout Diagnosis Hyperuricemia is not a reliable marker for diagnosis Not all patients with elevated uric acid will develop gout Uric acid levels may be normal during an acute attack Other conditions that mimic gout should be ruled out: Septic arthritis Pseudogout due to calcium pyrophosphate crystals Inflammatory arthritis Cellulitis Osteoarthritis 5

The Role of Imaging in Diagnosis of Tophaceous Gout Plain x-rays are insensitive in early disease Although advanced imaging can identify soft tissue collections, there are no imaging modalities than can specifically diagnose tophi Diagnosis and Treatment Caveats Clinically significant hyperuricemia does not precisely predict which patients will develop gout Treatment of asymptomatic hyperuricemia is not currently recommended except for tumor lysis syndrome, or when serum uric acid exceeds 12.0 mg/dl (increased risk of nephrolithiasis); this may be changing Long-Term Management Goals in Gout Are Closely Linked Identify and manage comorbidities and causes of hyperuricemia Diagnose, treat, and prevent acute flares PATIENT EDUCATION AND TREATMENT ADHERENCE Urate-lowering drugs: Target SUA <6 mg/dl SUA serum uric acid 6

Principles of Gout Management Acute attack Therapeutic goal is to reduce pain and inflammation NSAIDs and colchicine can be used for acute gout attacks Colchicine works best in early flares (<24 hrs) Comorbidities and medications should guide choice Corticosteroids and IL-1 antagonists are alternatives NSAIDs non-steroidal anti-inflammatory drugs Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22 S25. Case 1 47-year-old man presents with first episode of gout No current medications Drinks 5 bottles of beer daily Physical exam: BMI 33; left 1 st MTP is swollen and tender Labs: Uric acid 6.9 mg/dl, Cr 1.0 What would you recommend? Case 1 Counsel patient to decrease alcohol intake and lose weight Prescribe indomethacin 50 mg TID for acute attack 7

Preventing Acute Attacks: Diet to Reduce Serum Urate Moderation of portion size is critical (including smaller meat and seafood portions) Diets tailored to insulin resistance and weight reduction are preferred Diet reduces serum urate up to 1 2 mg/dl Not enough to avoid urate-lowering therapy (ULT) in most Alcohol promotes hyperuricemia (and flares of arthritis in established gout) Dessein PH, et al. Ann Rheum Dis. 2000;59:539 543. Fam AG. J Rheumatol. 2005;32:773 777. Zhang Y, et al. Am J Med. 2006;119:800.e13 e18. Lee SJ, et al. Curr Rheum Rep. 2006;8:224 230. Case 2 65-year-old man with history of hypertension presents to your office after a recent admission for polyarticular arthritis of the right 1 st MTP, right ankle, and left knee Monosodium urate (MSU) crystals were identified on aspirate of the left knee Discharged on indomethacin 50 mg TID He had a previous episode of gout (pain and swelling of the 1 st MTP) about 1 year ago Case 2 Current medications: ASA 81 mg daily Metoprolol 50 mg daily Indomethacin 50 mg TID Physical exam: Remarkable for subcutaneous nodule within the left olecranon bursa Labs: Uric acid 8.1 mg/dl, Cr 1.4 How would you treat? 8

Case 2 Start colchicine 0.6 mg daily Start allopurinol or febuxostat and titrate until uric acid is <6 mg/dl Concise Explanation of Disease and Therapies to Patients: Gout is Like Matches Gout is like matches. Crystals of uric acid deposit in and around joints like matches. Gout flares happen when the matches catch on fire. A brief course of drugs such as naproxen, indomethacin, prednisone, or colchicine puts out the fire. A daily low dose of colchicine keeps the matches moist so they do not catch fire. Uric acid-lowering therapies like allopurinol and febuxostat shrink and ultimately get rid of the matches. Adapted from Wortmann RL. Am J Med. 1998;105:513 514. Treatment Options: Acute Attacks Cautions NSAIDs Colchicine Corticosteroids Heart Failure Hypertension Ulcer Disease Diabetes Infections Drug interactions Warfarin Cyclosporine, statins, clarithromycin and erythromycin, disulfiram ASA- or NSAID-induced asthma Renal impairment Liver impairment Avoid abrupt withdrawal Adapted from Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22 S25. 9

Gout: Acute Attack Prescriptions National Ambulatory Medical Care and Hospital Ambulatory Care Surveys Gout patient-specific anti-inflammatory prescriptions (2002) NSAIDs ~700 000 Colchicine ~381 000 Prednisone ~341 000 Adapted from Terkeltaub R. Arthritis Res Ther. 2009;11:236. Principles of Gout Management Preventing attacks: Therapeutic goal is to reduce serum urate and maintain serum uric acid <6.0 mg/dl Urate-lowering therapy (ULT) is life-long, as with other metabolic diseases Intermittent therapy can lead to recurrent flares Acute attack (gout flare) prophylaxis for 3 6 months is essential when starting ULT Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22 S25. Strategies to Lower Serum Urate to Complement Urate-Lowering Drugs Eliminate non-essential use of diuretics and niacin Optimally manage BP and renal function ARB s are mildly uricosuric Modify lifestyle: Reduction in dietary and alcohol excesses Weight/BMI reduction decreases serum urate Choi HK, et al. Rheumatology (Oxford). 2008;47:713 717. Eggebeen AT. Am Fam Physician. 2007;76:801 808. Cannella AC, et al. Am J Manag Care. 2005;11:S451 458. 10

Preventing Acute Attacks: Urate-Lowering Therapy (ULT) Goals of therapy Decrease total body burden of urate and monosodium urate crystals so that tophi resolve permanently Therapeutic goal: SUA <6.0 mg/dl Improved education for patients and PCPs Proposed slogans for patients* Keep gout away, check your SUA Do not let gout play tricks, keep your SUA below 6 *Ogdie AR, et al. Curr Opin Rheumatol. 2010;22(2):173-180. Preventing Gout Flares When Initiating ULT Start prophylaxis 1 week before initiating ULT Preferred regimen: oral colchicine 0.6 mg 1 2 times daily for 6 months Continue at least 6 months in patients with visible tophi Reduce colchicine dose in the following patient populations: >70 years, stage 3 CKD, potential drug-drug interactions Alternative regimen: Low-dose NSAID prophylaxis (eg, naproxen 250 mg BID) for same time frame as described for colchicine Avoid use of low-dose prednisone: fails to prevent gout flares and difficult to wean patients due to rebound flares Quality Gaps in ULT Delayed initiation of ULT Inadequate dosing of ULT Failure to document treatment response to ULT Failure to use gout flare prophylaxis during initiation of ULT Initiation of ULT during acute gout flares Sundy JS. Curr Opin Rheumatol. 2010;22(2):188-193. 11

Treatment Options: ULTs Cautions Allopurinol Febuxostat Probenecid Contraindicated in patients on azathioprine, mercaptopurine, or theophylline Other drug interactions NSAIDs, Certain Antibiotics Dose adjustment in CKD +/- +/- Potentially fatal hypersensitivity (rare) Monitor LFTs Ineffective in stage 3 or worse CKD Risk of nephrolithiasis Adapted from Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22 S25. Comparative Trials of Febuxostat and Allopurinol Study Febuxostat 40 mg daily CONFIRMS (6 months) APEX (6 months) FACT (12 months) % patients achieving SU <6.0 mg/dl Febuxostat 80 mg daily Allopurinol 300 mg daily Placebo 45% 67% 42% 72% 39% 1% 74% 36% Becker MA, et al. Arthritis Rheum. 2008;58:Late breaking abstract No: L11. Becker MA, et al. N Engl J Med. 2005;353:2450 2461. Schumacher HR Jr, et al. Arthritis Rheum. 2008;59:1540 1548. Sundy JS. Arthritis Rheum. 2008;59:1535 1537. SU: serum urate Treatment: Refractory Gout Classic features: Allopurinol-intolerant/resistant to appropriate doses CKD or urolithiasis ruling out uricosurics Abundant tophi Repeated flares or persistent gouty synovitis with joint erosion, deformity, and functional incapacity CHF Hypertension Diabetes Advanced age Potential drug-drug interactions and toxicities Edwards NL. Arthritis Rheum. 2008;58:2587 2590. 12

Results of two studies: Pegloticase 8 mg bimonthly: 47% and 38% of patients achieved plasma uric acid levels of <6 mg/dl for at least 80% of the time (months 3 and 6, respectively) vs 0% placebo (P <.001, both studies) Effects on tophi (present in 71% of patients at baseline) 45% of patients receiving bimonthly therapy achieved a complete response at month 6 vs placebo, 8% (P <.02) Most common adverse event was gout flare Premedication with antihistamines and corticosteroids is advised; colchicine prophylaxis Contraindicated in patients with G6PD deficiency Sundy JS, et al. Arthritis Rheum. 2008;58(9):2882-2891. Baraf HS, et al. Arthritis Rheum. 2008;58(11):3632-3634. Monitoring Patients With Gout Assess treatment efficacy Reduced gout flares Serum urate (SU) <6 mg/dl Monitor SU levels every 1 2 months when starting ULT, then at least 1 2 times per year For treatment-refractory disease: consider referral to rheumatologist Terkeltaub RA. N Engl J Med. 2003;349:1647 1655. Gout and Patient Nonadherence: Major Cause of ULT Failure % patients achieving adherence of 80% Hypertension 72.3% Hypothyroidism 68.4% Type 2 Diabetes 65.4% Seizure Disorders 60.8% Hypercholesterolemia 54.6% Osteoporosis 51.2% Gout 36.8% Decreased rates associated with patients <60 years Higher rates associated with increased visits, comorbidities Briesacher BA, et al. Pharmacotherapy. 2008;28:437 443. Healthcare claims data 706 032 adults >18 years 13

Adherence Tips for Healthcare Professionals Address patient's physical and financial barriers Provide education and assess the patient s understanding of prescribed treatment regimen Notify prescribers when a patient falls behind on refills Work with prescribers to simplify dosing regimens Explain risks and benefits of adherence Assess readiness to change and tailor medications to patient s goals and lifestyle Review medications to ensure contraindications do not exist Case 3 The complicated inpatient consult: 75-year-old s/p abdominal surgery 4 days ago presents with temperature 100.8 and polyarticular arthritis (knees, left ankle, right 1 st MTP and left wrist) of 2 days duration Arthrocentesis confirms urate crystals of both knees, with inflammatory synovial fluid Cr 2.4 mg/dl Surgeons resistant to treating patient with steroids What would you recommend? On the Horizon: IL-1 antagonists MSU crystals activate the NALP-3 inflammasome similar to cryopyrinassociated autoinflammatory syndromes for which IL-1 blockade is effective Anakinra, canakinumab, and rilonocept antagonists of IL-1 signaling have all be shown to be effective in acute gout (with only 1 dose) So A, et al. Arthritis Rheum.2010;62:3064-3076. So A, et al. Arthritis Res Ther. 2007;9:R28. Terkeltaub et al. Ann Rheum Dis. 2009;68:1613-1617. 14

Community Needs and Resources Arthritis Foundation - www.arthritis.org Patient Tutorials www.nlm.nih.gov/medlineplus/tutorials/gout/ htm/index.htm (interactive) http://nihseniorhealth.gov/gout/toc.html Medline Plus - www.nlm.nih.gov/medlineplus/gout.html Many resources in both English and Spanish Mayo Clinic Gout diet - www.mayoclinic.com/health/goutdiet/hq00765/method=print Summary Gout is costly; proper diagnosis and management can control costs Treat acute gout flares Identify/treat comorbidities and consider cause of hyperuricemia Initiate ULT (after first flare has passed) in those with: Frequent flares (>3 in 2 years) Tophi Uric acid overproduction Difficult to treat gout Do not stop ULT, or stop and start ULT, because of flares Initiate gout flare prophylaxis Monitor SU levels Educate patients on role of diet and importance of treatment adherence Refer poor responders to a rheumatologist 15