Uric Acid, Hyperuricemia, and Gout • Uric acid
Transcription
Uric Acid, Hyperuricemia, and Gout • Uric acid
Purdue University School of Pharmacy and Pharmaceutical Sciences and PharmCon Inc are accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE Universal Program Number assigned to the program by the accredited providers is: 798-999-08-075-L01-P. This activity is jointly sponsored by PharmCon, Purdue University School of Pharmacy and Pharmaceutical Sciences, and The TCL Institute. This activity is supported by an educational grant from Takeda Pharmaceuticals North America, Inc. Speaker : Dr. Randolph V. Fugit is an Internal Medicine Clinical Specialist at the Denver Veterans Affairs Medical Center as well as Adjoint Assistant Professor in the Department of Pharmacy Practice at the University of Colorado Health Sciences Center School of Pharmacy. Dr. Fugit received his Doctor of Pharmacy degree from the University of New Mexico College of Pharmacy. His areas of research include pharmacoeconomics and outcomes research (including clinical pathway development) involved in the management of both acute and chronic disease states in gastroenterology, rheumatology, infectious diseases, cardiology, and pulmonology. Speaker Disclosure: Dr. Fugit reported that he is a consultant to Takeda Pharmaceuticals North America, Inc. and Cubist Pharmaceuticals, Inc. He also reported that he is a speaker for Pfizer Inc.; Boehringer Ingelheim Corporation; Cubist Pharmaceuticals, Inc.; Astellas Pharma US, Inc.; and sanofi-aventis U.S. LLC. Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity This activity is supported by an educational grant from Takeda Pharmaceuticals North America, Inc. Accreditation: Pharmacist –798-999-08-075-L01-P Technicians- 798-999-08-075-L01-T Learning Objectives • Recognize the general clinical presentations of gout, differentiating between acute attacks and chronic underlying disease • Advise patients about lifestyle interventions for the prevention and management of gout, focusing on the importance of weight loss and dietary modifications • Implement a patient education program for gout to improve knowledge about the disease state, the importance of adherence to medications, and patient commitment to treatment • Counsel patients about the appropriate medications to be used for acute and chronic gout, with a special focus on comorbidities, medication contraindications, and drug interactions, and advise when a physician visit is necessary CE Credits: 1.0 Credit hour or 0.1 CEU for pharmacists/technicians Target Audience: Pharmacists & Technicians Program Overview: Gout is an enigma facing health care professionals today. Although it is an ancient disease with centuries of clinical experience, gout’s incidence and prevalence continues to rise owing to risk factors such as obesity from today’s more sedentary lifestyles. New epidemiological issues such as the association between hyperuricemia and cardiovascular disease also are now coming to the forefront in gout diagnosis and management. Objectives: • Recognize the general clinical presentations of gout, differentiating between acute attacks and chronic underlying disease • Advise patients about lifestyle interventions for the prevention and management of gout, focusing on the importance of weight loss and dietary modifications • Implement a patient education program for gout to improve knowledge about the disease state, the importance of adherence to medications, and patient commitment to treatment • Counsel patients about the appropriate medications to be used for acute and chronic gout, with a special focus on comorbidities, medication contraindications, and drug interactions and advise when a physician visit is necessary How Prevalent Is Gout Compared to Other Common Conditions? Uric Acid, Hyperuricemia, and Gout Lupus Rheumatoid arthritis Prostate cancer Gout affects 5 million adults in the United States1 Breast cancer Liver disease Kidney disease Fibromyalgia • Uric acid (urate) is the end product of purine degradation in humans1 • Hyperuricemia is a serum urate concentration in excess of urate solubility (≥ 6.8 mg/dL)2 – Results from underexcretion and/or overproduction of uric acid3 Gout Stroke 0 1 2 3 4 5 6 7 Adults in the United States (millions)1-6 • Gout is the disease state resulting from deposition of MSU crystals in tissues4 Gout is the most common inflammatory joint disease in men aged > 40 years7 1Kramer HM and Curhan G. Am J Kidney Dis. 2002;40:37-42. 2Lethbridge-Cejku M, et al. Vital Health Stat. 2006;10(228). RC, et al. Arthritis Rheum. 2008;58:26-35. 4Helmick CG, et al. Arthritis Rheum. 2008;58:15-25. 5Rahman A and Isenberg DA. N Engl J Med. 2008;358:929-939. 6American Heart Association Web site. http://www.americanheart.org/downloadable/heart/1200078608862HS_Stats%202008.final.pdf. Accessed November 19, 2008. 7Roubenoff R. Rheum Dis Clin North Am. 1990;16:539-550. 3Lawrence 1Hahn 3Becker PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355. 2Schumacher HR Jr. Cleve Clin J Med. 2008;75(suppl 5):S2-S4. MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339. 4Eggebeen AT. Am Fam Physician. 2007;76:801-808. Uric Acid: End Product of Purine Degradation in Humans Distribution of Serum Urate Values and Hyperuricemia 40 Solubility decreases OH N N Purine nucleosides Xanthine oxidase Xanthine oxidase OH OH N N N N HO N N H OH Hypoxanthine N H N OH N H N • Decreased solubility of urate (temperature) • Trauma or tissue injury Uric acid Xanthine Uricase O Uricase: Uricase: ▪ Humans lost enzyme during evolution O Development of MSU crystals associated with1 NH Men 30 Urate crystallizes at a level of 6.8 mg/dL3 25 20 15 10 5 O H2N N H 0 N H 0 1 2 Hahn PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355. Medications Altering Urate Levels Pyrazinamide Nicotinate Lactate, β-hydroxybutyrate, acetoacetate Salicylate (low dose) Ethambutol 3 4 5 6 7 8 9 10 11 12 13 Serum urate (mg/dL)* Allantoin Urate-Increasing Agent1 Laboratory range for population defined “normal”3,4 Women 35 Distribution (%)2 Purine nucleotides 1Dalbeth N, et al. Rheumatology. 2005;44:1090-1096. 2Lin K-C, et al. J Rheumatol. 2000;27:1045-1050. 3MedlinePlus Web site. http://www.nlm.nih.gov/medlineplus/ency/article/003468.htm. Accessed March 11, 2009. 4Mandell BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8. * Serum urate levels in 1515 men and 1670 women aged ≥ 30 years in Taiwan; 1991-1992 The Hyperuricemia Cascade Dietary purines Urate-Decreasing Agent1 Tissue nucleic acids Endogenous purine synthesis Uricosurics: Probenecid Losartan Salicylate (high dose) Fenofibrate Amlodipine Urate Overproduction 5%-10% of all gout patients Underexcretion 80%-90% of all gout patients! Hyperuricemia Most common cause of hyperuricemia Diuretics Cyclosporine Xanthine oxidase inhibitor: Tacrolimus Allopurinol Febuxostat β-blockers Uricase Silent tissue deposition Gout Other components may also affect uric acid clearance1-3 excessive alcohol intake, niacin, levodopa, cytotoxic drugs, and vitamin B12 2Quiceno • Male gender1 • Postmenopausal women2,3 • Longevity/improved survival of comorbidities2 • Diet: – High alcohol intake: • (Beer > hard liquor > wine)2,4,5 – Red/organ meats and seafood2,4,6 – High-fructose corn syrup7 • Drugs2 – Diuretics – Cyclosporine • Major organ transplantation2 • End-stage renal disease (ESRD)2 • Genetic influences4 Associated cardiovascular events and mortality Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339. Wortmann RL. In: Harrison’s Principles of Internal Medicine. 14th ed. 1998:2158-2165. Hahn PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355. Pittman JR and Bross MH. Am Fam Physician. 1999;59:1799-1806, 1810. 1Choi HK, et al. Ann Intern Med. 2005;143:499-516. GA and Cush JJ. Rheum Dis Clin North Am. 2007;33:123-134. 3Peronato G. Contrib Nephrol. 2005;147:1-21. Risk Factors for the Development of Gout Renal Renal manifestations manifestations Some Comorbidities Associated With Hyperuricemia Warrant Consideration • Obesity1,2 • Hyperlipidemia1-3 • Metabolic syndrome3 • Hypertension2,6-8 • Diabetes mellitus1,4 • Heart failure5,6 • Renal disease6,9 • Cardiovascular disease6,9 No reliable predictor that gout will develop in a given hyperuricemic patient10 Currently, asymptomatic hyperuricemia is not treated But, higher serum urate levels are more likely to lead to gout 1Kramer HM and Curhan G. Am J Kidney Dis. 2002;40:37-42. 2Bieber JD and Terkeltaub RA. Arthritis Rheum. 2004;50:2400-2414. 3Hak AE and Choi HK. Arthritis Res Ther. 2008;10:R116. 4Fam AG. J Rheumatol. 2005; 32:773-777. 5Choi HK, et al. Lancet. 2004;363:1277-1281. 6Choi HK, et al. N Engl J Med. 2004;350:1093-1103. 7Nakagawa T, et al. Am J Physiol Renal Physiol. 2006;290:F625-F631. 7Feig 1Fam AG. J Rheumatol. 2005;32:773-777. 2Campion EW, et al. Am J Med. 1987;82:421-426. 3Choi HK, et al. Am J Med. 2007;120:442-447. 4Choi HK, et al. Rheumatology. 2008;47:1567-1570. 5Anker SD, et al. Circulation. 2003;107:1991-1997. 6Baker JF, et al. Am J Med. 2005;118:816-826. DI and Johnson RJ. Hypertension. 2003;42:247-252. 8Alper AB Jr, et al. Hypertension. 2005;45:34-38. 9Zhou X, et al. Curr Hypertens Rep.2006;8:120-124. 10Lin KC, et al. J Rheumatol. 2000;27:1501-1505. Slide 8 M70 Add Schumacher Cleve Clin J Med 2008 to verify this. MOng, 10/6/2008 Hyperuricemia and Incidence of Hypertension Among Men Without Metabolic Syndrome Multiple Risk Factor Intervention Trial Control of Metabolic Syndrome Components Essential to Reduce Cardiovascular Disease Risk in Patients With Hyperuricemia and Gout Percent of patients with metabolic syndrome 100 Gout • No gout • 80 60 High prevalence of the metabolic syndrome in hyperuricemic patients1-3 Baseline hyperuricemia and risk of subsequent hypertension 1.00 Patients with gout have an approximately 30% elevated cardiovascular disease (CVD) risk3,4 40 Hyperuricemia3,4 20 0 20-39 40-59 Increases cardiovascular mortality in patients at high cardiovascular risk ≥ 60 Age (years) * NHANES III (1988-1994) Proportion of men without hypertension Higher prevalence of metabolic syndrome associated with gout across age groups*1,2 Adjusted for age Hyperuricemia increases the risk of developing hypertension by approximately 80% 0.75 SUA ≤ 7 mg/dL (n = 2270) SUA > 7 mg dL (n = 803) 0.50 0.25 0.00 0 1 AL. Cleve Clin J Med. 2008;75(suppl 5):S9-S12. HK, et al. Arthritis Rheum. 2007;57:109-115. 3Puig JG and Martínez MA. Curr Opin Rheumatol. 2008;20:187-191. 4Krishnan E, et al. Arch Intern Med. 2008;168:1104-1110. 2 3 4 5 6 7 8 Follow-up in years 1Weaver 2Choi Log rank P < 0.001 for both survivor functions Hyperuricemia Increases Risk of Renal Manifestations Increased risk of renal failure with hyperuricemia* † 8 P < 0.01 vs moderate SUA level † 6 4 2 0 Clinical Stages of Gout Hyperuricemia predicts ESRD‡ 10 Cumulative incidence of ESRD per 1000 screenees Relative risk of renal failure 10 Elevated serum urate with no clinical manifestations of gout Crystal deposition may be starting 1 Asymptomatic Hyperuricemia • Acute inflammation in the joint caused by urate crystallization and crystal phagocytosis 2 Acute Gouty Arthritis • • Intervals between acute flares Crystals persist in joints 3 Intercritical Periods • • 8 6 4 2 0 Low (0.3-4.9) Moderate (5.0-6.4) Slightly high (6.5-8.4) High (> 8.5) SUA (mg/dL) < 7.0 Screenees (n) 15,617 ESRD cases (n) 19 SUA level (mg/dL) * Prospective cohort study of 49,413 Japanese men ‡ Screened cohort of Japanese men and women ≥ 7.0 7332 34 < 6.0 21,795 19 Men ≥ 6.0 3433 31 Women • • Long-term complications of uncontrolled hyperuricemia Chronic arthritis and tophi Edwards NL. Cleve Clin J Med. 2008;75(suppl 5):S13-S16. Tomita M, et al. J Epidemiol. 2000;10:403-409. Iseki K, et al. Am J Kidney Dis. 2004;44:642-650. Lower extremities most often involved1 – Most common initial site (~90%): first metatarsophalangeal joint (podagra)1 – 80% of first attacks are monoarticular • • Fever in some patients1,4 • Can occur in bursae, tendons, and joints1 Feature Untreated, an initial acute gout attack resolves completely within 3 to 14 days4 – Majority of patients experience second acute flare within 1 year of first gout flare5 1Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339. HR Jr. Cleve Clin J Med. 2008;75(suppl 5):S2-S4. 3Terkeltaub R. Bull NYU Hosp Jt Dis. 2006;64:82-86. BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8. 5Yu TF and Gutman AB. Ann Intern Med. 1961;55:179-192. 2Schumacher 4Mandell Intercritical periods diminish Chronic pain and polyarticular gout Typical Gout Elderly Onset Gout Peak in mid-40s Over 65 Sex Distribution Men > women Men = women Presentation Acute monoarthritis Lower extremity (podagra 60%) More often: Polyarticular onset Upper extremity affected After years of attacks Elbows > fingers May occur early or without history of prior attacks Possibly more often over fingers Obesity Hyperlipidemia Hypertension Alcohol use, heavy Renal insufficiency Diuretic use, especially in women Alcohol use less common Age of Onset – Rarely affects shoulders, sternoclavicular joints, hips, spine, sacroiliac joints • Advanced Gout Flares are longer lasting and more severe Typical Clinical Features of Gout Differ With Age of Onset Pain and inflammation1-4 – Dramatic inflammatory response 4 Uncontrolled Hyperuricemia: Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339. Features of Acute Gouty Attacks • Krishnan E, et al. Hypertension. 2007;49:298-303. Tophi Associated Features Courtesy of the Clinical Slide Collection on the Rheumatic Diseases, American College of Rheumatology, 1996; with permission. Wise CM. Rheum Dis Clin North Am. 2007;33:33-55. Images courtesy of Charles Goldberg, MD. Diagnosing Gout: Why Aspirate the Joint? Diagnosing Gout: Aspirate the Joint Separate Septic Arthritis From Gout The Gold Standard • Does the patient have gout? • Are current inflammatory symptoms due to gout? Inflammatory Joint Fluids (> 4000-5000 white blood cells [WBCs] per Synovial fluid analysis1-4 • Examine for MSU crystals • Culture and Gram stain analysis mm3) Septic arthritis – Differential for septic arthritis Crystal-induced monoarthritis (eg, gout, pseudogout) Other potential causes: Rheumatoid arthritis Spondyloarthropathy Systemic lupus erythematosus Other inflammatory arthritides Adapted from Siva C, et al. Am Fam Physician. 2003;68:83-90. • Perform WBC count: This superolateral approach may be best when there is a large effusion5 Normal synovial fluid4 • – Viscous, straw-colored substance (small amounts in joints, bursae, tendon sheaths) – 1-2 mL of fluid sufficient for studies3 1Rott KT and Agudelo CA. JAMA. 2003;289:2857-2860. 2Schlesinger N. Drugs. 2004;64:2399-2416. 3Wheeless' Textbook of Orthopaedics. http://www.wheelessonline.com/ortho/synovial_fluid. Accessed November 20, 2008. 4MedlinePlus Web site. http://www.nlm.nih.gov/MEDLINEPLUS/ency/article/003629.htm. Accessed November 20, 2008. 5Zuber TJ. Am Fam Physician. 2002;66:1497-1500, 1503-1504, 1507. Differential Diagnosis: Advanced Gout MSU (Gout) or CPPD (“Pseudogout”) Crystals? • MSU crystals: strong negative birefringence: – Usually needle shaped under compensated polarized light1-3 MSU crystals3 • Calcium pyrophosphate dihydrate (CPPD) crystals: weak positive birefringence1,4,5 – Rhomboid, rods, squares, or irregular under compensated polarized light; frequently missed; consider septic arthritis5 CPPD crystals6 Direction of polarized light 1Schumacher HR and Reginato AJ. Atlas of Synovial Fluid Analysis and Crystal Identification. Philadelphia, PA: Lea & Febiger; 1991. 2Dore RK. Cleve Clin J Med. 2008;75(suppl 5):S17-S21. 3Reprinted with permission from ‘Gout and Hyperuricemia,’ February 151999, American Family Physician. Copyright © 1999 American Academy of Family Physicians. All Rights Reserved. 4Siva C, et al. Am Fam Physician. 2003;68:83-90. 5Pascual E and Jovaní V. Best Pract Res Clin Rheumatol. 2005;19:371-386. 6Image reprinted with permission from eMedicine.com, 2008. Available at: http://www.emedicine.com//med/topic1938.htm. Accessed November 20, 2008. Long-term Consequences of Chronic MSU-induced Inflammation Chronic Chronic synovitis synovitis Low-grade Low-grade synovitis synovitis in in involved involved joints joints can can persist persist after after acute acute attacks attacks Factors Factorsinvolved involvedin inacute acute attacks attacksalso alsocontribute contributeto to chronic inflammation: chronic inflammation: Cytokines Cytokines Chemokines Chemokines Proteases Proteases Oxidants Oxidants • Risk factors include1 – Long duration of hyperuricemia – High serum urate levels – Long periods of active, untreated gout • Subcutaneous gouty tophi occur frequently at sites of friction or trauma1 • Be careful: Chronic gout can mimic rheumatoid or psoriatic arthritis!2 Tophi Tophion oncartilage cartilagesurface surface may maycontribute contributeto tochondrolysis, chondrolysis, which whichcan canoccur occurdespite despite adequate adequatetreatment treatment Choi HK, et al. Ann Intern Med. 2005;143:499-516. Helices of the ear Olecranon bursae Extensor surface of the forearms Wrists Finger pads Principal Sites of Tophi Knees Achilles tendons 1Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339. 2Mandell BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8. Reproduced with permission from The Hand Center Web site. http://www.handcenter.org. Accessed November 20, 2008. Diagnosing Gout Common Challenges and Pitfalls History and Physical Examination Bone Bone erosion erosion Cartilage Cartilageloss loss – 5000 to 50,000/µL Serum Urate Level Some Patients Refuse Tapping the Joint 1Rott Acute versus chronic state, atypical joint involvement1 Elderly onset gout, (postmenopausal) women1,2 Not a definitive test; normal SUA levels common during acute attacks1 • Laboratory SUA level of population-defined “normal” often equivalent to significant hyperuricemia2 Alternative: presumptive clinical diagnosis3 • • History and physical examination for characteristic features4 Clinical diagnosis wrong in about 20% of the cases5 Sepsis may lead to joint destruction within 24-48 hours6,7 KT and Agudelo CA. JAMA. 2003;289:2857-2860. 2Mandell BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8. 3Harrold LR, et al. Arthritis Rheum. 2007;57:103-108. 4Dore RK. Cleve Clin J Med. 2008;75(suppl 5):S17-S21. 5Chen LX and Schumacher HR. J Clin Rheumatol. 2008;14(5 suppl):S55-S62. 6Siva C, et al. Am Fam Physician. 2003;68:83-90. 7Zhang W, et al. Ann Rheum Dis. 2006;65:1301-1311. What Is the Evidence for Gout Diagnosis? Question to Ask the Patient Ten Recommendations From EULAR Modified to US Standards Presumptive Diagnosis of Gout • When did the symptoms start? Was the onset sudden? 1 In acute attacks, rapid development of severe pain, swelling, and tenderness, reaching peak within 6-12 hours is highly suggestive of crystal inflammation, though not specific for gout • Was this the first time you experienced pain/swelling at this joint? If not, which other joints have been affected and how long ago has this been? 2 For typical gout presentations (eg, recurrent podagra), a clinical diagnosis of gout is reasonably accurate but not definitive unless crystal confirmed 3 Demonstration of MSU crystals in synovial fluid or tophus aspirates permits a definitive gout diagnosis 4 A routine search for MSU crystals is recommended in all synovial fluid aspirates from inflamed joints 5 Identification of MSU crystals from asymptomatic joints may allow gout diagnosis between attacks • Are you running a fever? • Do you have relatives with similar complaints? • Are you taking any medications, and which? • What have you been eating and/or drinking? Anything like red meat, shellfish, or beer? Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172. Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1301-1311. What Is the Evidence for Gout Diagnosis? Clinical Picture and Radiographic Evidence Ten Recommendations From EULAR Modified to US Standards (Cont.) 6 Gout and sepsis may coexist; if sepsis is suspected, Gram stain and culture of synovial fluid should be carried out even if MSU crystals are identified 7 Although the most important risk factor for gout, serum urate levels do not confirm or exclude gout 8 Renal uric acid excretion should be determined in selected gout patients (family history of young onset gout, onset of gout under age 25, or with renal calculi); hyperuricemia as a marker in acute gout 9 Radiographs may be useful for differential diagnosis and may show typical features in chronic gout; they are not useful in confirming a diagnosis of early or acute gout 10 Risk factors for gout and associated comorbidity should be assessed, including features of metabolic syndrome Polyarticular, tophaceous gout in a patient originally treated for rheumatoid arthritis for 8 years1 MetacarpalMetacarpalphalangeal joints of the hand with calcification of the tophus on the ulnar side2 1Image courtesy of N. Lawrence Edwards, MD. 2Images reprinted with permission from Ferguson M. http://uwmsk.org/residentprojects/gout.html. Accessed November 20, 2008. Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172. Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1301-1311. Considerations for the Treatment of Acute Gout Case Presentation Matthew, 66 Years Old • Matthew comes to the pharmacist for an over-the-counter (OTC) pain reliever: – He limps on the left foot using a cane • Questioning the patient reveals: – Swelling/erythema of first metatarsophalangeal joint on left foot started last night; patient runs a light fever – Patient cannot bear any weight on the painful toe – No other symptoms/recent injury, but similar episode in elbow a few months ago Matthew adheres to medication schedule: Hydrochlorothiazide 50 mg/day Glipizide 10 mg/day BMI 33 kg/m2 Enalapril 20 mg/day Difficulties with dietary changes: Aspirin 81 mg/day Consumption of red meat, alcohol, and caffeinated nondiet sodas Advanced gout: joint destruction from large erosions with “overhanging” overhanging” edges2 Agent Anti-inflammatory doses of NSAIDs Considerations and Cautions • • • • • Colchicine (oral) Corticosteroids (oral, intraarticular, intramuscular) 30 • • • • • All NSAIDs equally effective1-4 Caution with: older patients, renal insufficiency, heart failure, peptic ulcer disease, liver disease, anticoagulant therapy2,4 Taper off after attack has resolved3 Can be effective with early use1,4 Avoid in patients with severe renal or hepatic impairment1-4 Interacts with cyclosporine, statins, and macrolides5 Low-dose approach: similar efficacy without gastrointestinal concerns with higher dose*6 Useful when renal and/or gastrointestinal contraindications to other therapies3 Avoid in patients with joint sepsis1,4 Caution with diabetes patients1,4 * Unpublished or preliminary data 1Eggebeen AT. Am Fam Physician. 2007;76:801-808. 2Terkeltaub RA. N Engl J Med. 2003;349:1647-1655. 3Wortmann RL. Curr Rheumatol Rep. 2004;6:235-239. 4Schlesinger N. Drugs. 2004;64:2399-2416. 5Schumacher HR Jr and Chen LX. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. 6Terkeltaub R, et al. ACR Meeting 2008. Presentation 1944. Anti-inflammatory Prophylaxis Prior to Urate-lowering Therapy Urate-lowering Therapy to Prevent Disease Progression • Urate-lowering therapy (ULT) often started at week 2-4 with continuous prophylaxis, but no evidence from studies2-4 • Prophylactic agents1-3 Achieve/maintain SUA level < 6 mg/dL →Deplete serum urate pool and deposited crystals1-4 – NSAIDs, low-dose, oral colchicine – Useful for decreasing the frequency and severity of acute flares – Will not stop silent tissue deposition of crystals Reduce pain and inflammation Avoid hyperuricemia treatment during the acute attack • Initiate prophylaxis prior to starting urate-lowering therapy and continue for 6-12 months2,3 →Reduce frequency of acute attacks during ULT1-4 – Crystals often persist during intercritical periods3 – Risk for continued flares, low-grade persistent inflammation, and progressive disease3,4 →Maintain/improve quality of life (QOL)1-4 – Incidence of flares and SUA levels decline over time with treatment • Therapy should be lifelong3 – Do not discontinue if attack occurs during therapy initiation (flux in urate levels likely)2 – Uricosurics and xanthine oxidase inhibitors 1,2 • Weigh potential drug interactions/adverse events Patient dialogue and consistent follow-up Patient dialogue and consistent follow-up 1Terkeltaub 1Borstad 3Schumacher 2Schlesinger GC, et al. J Rheumatol. 2004;31:2429-2432. N. Drugs. 2004;64:2399-2416. HR, et al. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. 4Choi HK, et al. Ann Intern Med. 2005;143:499-516. What Is the Evidence for Gout Management? What Is the Evidence for Gout Management? Twelve Recommendations From EULAR Modified to US Standards (1) Twelve Recommendations From EULAR Modified to US Standards (2) Utilize both nonpharmacologic and pharmacologic modalities; tailor 1 to risk factors and clinical phase 8 Therapeutic goal of urate-lowering therapy: promote crystal dissolution and prevent crystal formation by maintaining the SUA level below the saturation point for MSU (6.8 mg/dL), target for SUA level < 6.0 mg/dL 9 Allopurinol: appropriate long-term urate-lowering drug; start at a low dose (eg, 100 mg daily) and increase by 100 mg every 2-4 weeks, if required; adjust dose in patients with renal impairment; options with allopurinol toxicity: other xanthine oxidase inhibitors, uricosuric agent, allopurinol desensitization (cases of mild rash) 10 Uricosuric agents (probenecid): alternative to allopurinol (with normal renal function); relatively contraindicated in patients with urolithiasis Stress patient education and lifestyle changes (eg, weight loss and 2 alcohol reduction) Address comorbidities like hyperlipidemia, hypertension, 3 hyperglycemia, obesity, and smoking Oral colchicine and/or NSAIDs are first-line agents for systemic 4 treatment of acute attacks 5 Side effects with high doses of colchicine; low doses (eg, 0.6 mg TID) may be sufficient for some patients with acute gout Prophylaxis against acute attacks during the first months of urate-lowering 11 therapy: colchicine (0.6-1.2 mg daily) and/or an NSAID (with gastro-protection, if indicated) Intra-articular aspiration and injection of long-acting steroid is 6 effective and safe for an acute attack Gout associated with diuretic therapy: stop diuretic, if possible; hypertension 12 and hyperlipidemia: consider use of losartan and fenofibrate, respectively (both have modest uricosuric effects) Urate-lowering therapy: patients with recurrent acute attacks, 7 arthropathy, tophi, or radiographic changes Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172. Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1312-1324. Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172. Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1312-1324. Adjunctive Therapy for Gout and Associated Comorbidities Urate-lowering Agents Uricosurics Dietary and Lifestyle Recommendations Control weight with daily exercise1,2 Limit red meat consumption1,2 Replace fish consumption with omega-3 fatty acids1 – Or supplements of docosahexaenoic acid and eicosapentaenoic acid Refrain from high-fructose–containing foods/drinks2,3 Consume 1-2 servings of dairy or calcium supplement daily1,2 Consume nuts and vegetables daily1,2 Supplementation with vitamin C 500 mg/day2,4 Some evidence for beneficial effect of coffee consumption2 • • • • • • • • RA. N Engl J Med. 2003;349:1647-1655. 2Schlesinger N. Drugs. 2004;64:2399-2416. 3Schumacher HR Jr and Chen LX. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. 4Becker MA, et al. Nucleosides Nucleotides Nucleic Acids. 2008;27:585-591. • Health benefits may extend beyond gout1,5 • Limited impact on SUA level (1-2 mg/dL) – Preventive strategies alone in patients with existing disorders may not be sufficient5 Uricosurics correct renal urate underexcretion by inhibiting postsecretory SUA reabsorption1 • Probenecid1,2 • • Mild uricosurics as adjunctive approach: – Losartan* and fenofibrate*2,3 – Lose effectiveness as renal function deteriorates 2-4 Other agents with urate-lowering properties: – Atorvastatin*5 – Amlodipine* (increased renal urate excretion)6 – Vitamin C (400-500 mg/day)6,7 – Less than 20% of patients make sustained lifestyle changes5 1Choi HK. Curr Rheum Rep. 2005;7:220-226. 2Hak AE and Choi HK. Curr Opin Rheumatol. 2008;20:179-186. 3Nakagawa T, et al. Am J Physiol Renal Physiol. 2006;290:F625-F631. 4Huang H-Y, et al. Arthritis Rheum. 2005;52:1843-1847. 5Levinson W, et al. Ann Intern Med. 2001;135:386-391. * Off-label Steps During Treatment2 Alkalinize urine Increase fluid consumption Multiple medication doses required Emphasize Compliance 1Terkeltaub RA. N Engl J Med. 2003;349:1647-1655. 2Daskalopoulou SS, et al. Curr Pharm Des. 2005;11:4161-4175. 3Bardin T. Ann Rheum Dis. 2003;62:497-498. 4Gaffo AL and Saag KG. Am J Kidney Dis. 2008;5:994-1009. 5Lee SJ, et al. Curr Rheumatol Rep. 2006;8:224-230. 6Choi HK, et al. Ann Intern Med. 2005;143:499-516. 7Gao X, et al. J Rheumatol. 2008;35:1853-1858. 37 Xanthine Oxidase Inhibitor Allopurinol Optimizing Allopurinol Dosing O • Effective in overproducers and underexcretors Allopurinol N NH • Maximal dose 800 mg/day N H N Limitations • Drug interactions • Rare but life-threatening hypersensitivity reaction possible • Dose adjustments required: • Allopurinol dose increase 3Perez-Ruiz Extremely rare, occurs in < 1% of patients on allopurinol Mild reactions usually subside with discontinuation of allopurinol • Progression to Stevens-Johnson syndrome or toxic epidermal necrolysis well reported: – Hepatomegaly, jaundice, and renal and hepatic dysfunction can accompany severe reactions – Risk factors include: renal dysfunction, hepatic disease, thiazide diuretics, and chronic alcohol abuse 50 32 30 24 17 20 10 0 – Unknown mechanism for this reaction < 200 mg/day n = 5942 Observational study of a managed care organization Typical Prescribing Errors With Available Xanthine Oxidase Inhibitor Percent of patients receiving incorrect prescription Interacting Drug 30 25.9 Warfarin 20 0 • 48/185 13/52 267/471 Incorrect dosing of allopurinol in renal failure Inadequate dose adjustment with concomitant allopurinol + AZA or 6-MP* Treatment of asymptomatic hyperuricemia Allopurinol is frequently prescribed inappropriately; more common with advancing age, male gender, and presence of polypharmacy Anecdotal reports of increased potential for bleeding Increased risk of allopurinol hypersensitivity Cyclophosphamide Increased risk of bone marrow suppression Adapted from Mikuls TR, et al. Rheumatology. 2005;44:1038-1042. Increased risk of rash Antacids/aluminum salts Chlorpropamide Cyclosporine Probenecid Phenytoin Theophylline * Allopurinol enhances effects of AZA and 6-MP W, et al. ACR Meeting 2005. Poster 362. CA, et al. J Clin Rheumatol. 2006;12:61-65. Angiotensin-converting enzyme inhibitors Ampicillin/amoxicillin 10 1Yang 2Sarawate Potential Effect Increased 6-MP serum concentration with increased risk of bone marrow suppression; reduce AZA dose to one-quarter AZA/6-MP 25.0 ≥ 300 to < 400 mg/day Potential Drug Interactions With Allopurinol 56.7 40 ≥ 200 to < 300 mg/day Majority of gout patients on varying doses of allopurinol therapy did not reach target SUA level of < 6.0 mg/dL1 Rechallenge with allopurinol should not be performed 50 1Dalbeth N and Stamp L. Semin Dial. 2007;20:391-395. 2Fels E and Sundy JS. Curr Opin Rheumatol. 2008;20:198-202. F, et al. J Clin Rheumatol. 2005;11:129-133. 4Hande KR, et al. Am J Med. 1984;76:47-56. Patients on pharmacotherapy with nontarget levels were 59% (allopurinol: 75%) more likely to flare than those at target level 40 However, reactions delayed by > 2 years have been reported: Fels E and Sundy JS. Curr Opin Rheumatol. 2008;20:198-202. Bohan KH, et al. In: Applied Therapeutics: The Clinical Use of Drugs. 9th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:42.1-42.14. 100 mg every 3 days 100 mg every 2 days 100 150 200 mg⁄day 250 300 350 400 Median SUA level with allopurinol treatment decreased from 8.7 to 7.1 mg/dL (P < 0.001)1,2 Percent of patients reaching target SUA1 • Data from United Kingdom General Practice research database 0 10 20 40 60 80 100 120 140 Maintenance Dose Allopurinol Target Serum Urate Levels Are Often Not Achieved Allopurinol Hypersensitivity Reaction 60 (mL⁄ minute) • Inform patients of the risks and benefits trade off: Hahn PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355. Perez-Ruiz F, et al. J Clin Rheumatol. 2005;11:129-133. Usually • appears within first 5 weeks of treatment Creatinine Clearance – Potential allopurinol toxicity versus gout progression1 – Concomitant azathioprine and 6-mercaptopurine – Renal function Can present as mild erythema and progress to fatal reactions with continued therapy Dosing Guidelines for Allopurinol Dosing1,4 – Prevent flare risk in all gout patients with gradual introduction1 – Monitor titration in patients with CKD, emphasize target SUA level of ≤ 6 mg/dL1-3 Decreased absorption of allopurinol Increased hypoglycemic effect Increased cyclosporine concentrations with potential for toxicity Increased renal elimination of oxypurinol; inhibition of probenecid metabolism Inhibited metabolism of phenytoin resulting in increased serum concentrations Increase in theophylline AUC, t½, and reduction in clearance Tatro DS. 2008 Drug Interaction Facts™. St Louis, MO: Lippincott Williams & Wilkins; 2008. Efficacy of Xanthine Oxidase Inhibitors in Patients With Normal Renal Function New Xanthine Oxidase Inhibitor Phase III, Randomized, Controlled, Multicenter, Double-blind Trial Febuxostat* • Nonpurine, selective • inhibitor of xanthine oxidase for the treatment of hyperuricemia associated • with gout CH 3 • H3 C N No dose adjustments in renal and mild/moderate hepatic insufficiency1,2 Different molecule, no crossreactions in allopurinolintolerant patients observed • CO2 H 45 • • – Concomitant use of azathioprine, 6-mercaptopurine and theophylline3 1Khosravan R, et al. J Clin Pharmacol. 2006;46:88-102. 2Swan S, et al. Arthritis Rheum. 2003;48:S529. Abstract 1348. US Food and Drug Administration Web site. http://www.fda.gov/cder/foi/label/2009/021856lbl.pdf. Accessed February 23, 2009. 20 0 • Mean changes in expected GFR after 5 years of treatment with febuxostat 40, 80, and 120 mg/day (baseline mean SUA: 9.7 mg/dL)* Mean changes in expected GFR (mL/min) Percent of patients with CKD 50 42 40 20 0 40 mg 80 mg 300 mg Allopurinol* Febuxostat • • • Becker M, et al. ACR Meeting 2008. Presentation L11. • OH HO N N H Uric acid Uricase O O NH O H2N N H N H Allantoin (Kidney excretion) 1Bomalaski Solubility increases N -1.5 -2.0 -5 Greater benefit on GFR with increased SUA reduction from baseline -10 -10.8 -15 ≤3 > 3 to ≤ 4 > 4 to ≤ 5 < 5 to ≤ 6 >6 *Preliminary or unpublished data n = 116; 91% male Comorbidities: 52% hypertension and 23% CVD Whelton A, et al. ACR Meeting 2008. Poster L7. Intravenous Uricase Enzyme: Treatment Response in Patients With TFG GOUT1/GOUT2 Phase III Randomized, Double-blind Efficacy and Safety Trials • Rapid and effective reduction in SUA levels and tophus burden1-4 – Reduced tophus burden in 40% of patients in phase III clinical trials (pegloticase 8 mg IV every 2 or 4 weeks)*4 – Short- and long-term effects? – Role of immunogenicity – Cardiac risk – Hemolysis risk * Investigational Unpublished or preliminary data Patients with plasma urate < 6.0 mg/dL after 6 months of intravenous pegloticase*1 100 • Investigations needed1,2,5 JS and Clark MA. Curr Rheumatol Rep. 2004;6:240-247. 2Sundy JS, et al. Arthritis Rheum. 2008;58:2882-2891. 3Sundy JS, et al. ACR Meeting 2008. Presentation 635. 4Baraf HS, et al. ACR Meeting 2008. Presentation 22. Today Web site. http://www.medpagetoday.com/MeetingCoverage/ACR/11470. Accessed January 23, 2009. 5Medpage 0.5 – 1.0 mL/min GFR improvement for each 1.0 mg/dL reduction in SUA (P = 0.02) – Normal expected annual reduction in GFR: 0.8 mL/min in healthy adults aged 30-80 years Percent of patients OH N 0.6 0 Significant relationship between GFR improvement and SUA reduction: Investigational Recombinant Pegylated Uricase Enzyme Polyethylene glycol (covalent uricase binding) 5 Average SUA decrease from baseline (mg/dL) CKD patients: efficacy of febuxostat 40 mg and 80 mg superior to allopurinol 300 mg/200 mg Febuxostat 80 mg efficacy superior to both febuxostat 40 mg and allopurinol 300 mg Comparable adverse event rates, including CV events, across study groups or by renal function n = 2269; randomized 1:1:1 to treatment groups * 145 subjects with moderate CKD in allopurinol group received 200 mg Comorbidities: mild/moderate CKD (65%; n = 1483), obesity (64%), hyperlipidemia (42%), hypertension (53%) Becker M, et al. ACR Meeting 2008. Presentation L11. SUA Reduction May Benefit Estimated Long-term GFR in Hyperuricemic Patients Patients achieving SUA levels < 6.0 mg/dL at final visit at 6 months P < 0.021 P < 0.001 P < 0.001 72 60 300 mg Allopurinol* n = 2269; randomized 1:1:1 to treatment groups * 145 subjects with moderate CKD in allopurinol group received 200 mg Comorbidities: mild/moderate CKD (65%; n = 1483), obesity (64%), hyperlipidemia (42%), hypertension (53%) Phase III, Randomized, Controlled, Multicenter, Double-blind Trial 80 80 mg Comparable efficacy of febuxostat 40 mg and allopurinol 300 mg/ 200 mg Febuxostat 80 mg efficacy superior to both febuxostat 40 mg and allopurinol 300 mg/200 mg Comparable adverse event rates, including CV events, across study groups or by renal function Efficacy of Xanthine Oxidase Inhibitors: Patients With Mild/Moderate CKD 100 42 40 Febuxostat Contraindication: * Approved by US Food and Drug Administration February 13, 2009 P < 0.001 67 60 40 mg – Gout flares, CV events, and elevated liver function tests3 3 S P < 0.001 80 Adverse events: CH NC Patients achieving SUA levels < 6.0 mg/dL at final visit at 6 months 100 – No safety studies available3 Febuxostat O Potent inhibition with significant urate reduction1 Percent of patients with normal renal function • Every 2 weeks Every 4 weeks Placebo 80 60 42.5 † 34.5 40 20 0 0 Every 2 weeks Every 4 weeks Placebo * Investigational; unpublished or preliminary data P value was significant versus placebo (mean values from GOUT1 and GOUT2 depicted) Treatment failure gout (TFG) was defined as: ≥ 3 flares in the previous 18 months, or ≥ 1 tophus, or gouty arthropathy; serum urate > 8.0 mg/dL; and prior failure of maximum medically appropriate dose of allopurinol or contraindication to allopurinol † 2Baraf 1Sundy JS, et al. ACR Meeting 2008. Presentation 635. HS, et al. ACR Meeting 2008. Presentation 22. 3Edwards NL, et al. ACR Meeting 2008. Presentation 27. Immunoreactivity and Clinical Response to Intravenous Uricase Enzyme Percent of patients on pegloticase 8 mg IV* Pooled Data From GOUT1 and GOUT2 Infusion reactions and high antipegloticase titers are increased with every 4 weeks in treatment group1 100 80 Every 2 weeks 67 Every 4 weeks 52 60 38 40 Managing Inflammatory Manifestations of Gout • Relative contraindications to symptomatic therapies frequent in refractory gout patients1,2 – eg, NSAIDs or corticosteroids • Potential benefit of biologic therapies*1 – Pain assessment, reduction of tender and swollen joint and creactive protein levels 24 20 • Use not established in large trials1 0 Infusion reactions High antipegloticase and infusion reactions • Main adverse events were gout flares and infusion reactions2 – Infusion reactions associated with anti–polyethylene glycol and high antipegloticase titers1 * Investigational; unpublished or preliminary data Response: plasma urate < 6 mg/dL for ≥ 80% of the time in months 3 and 6 1Becker MA, et al. ACR Meeting 2008. Presentation 1945. 2Sundy JS, et al. ACR Meeting 2008. Presentation 635. Case Discussion 1Fels E and Sundy JS. Curr Opin Rheumatol. 2008;20:198-202. MH, et al. Bull NYU Hosp Joint Dis. 2007;65:215-221. 3So A, et al. Arthritis Res Ther. 2007;9:R28. 4Terkeltaub R, et al. ACR meeting 2007. Poster 518. 5Fiehn C and Zeier M. Rheumatol Int. 2006;26:274-276. 6Tausche AK, et al. Ann Rheum Dis. 2004;63:1351-1352. 2Pillinger * Investigational; unpublished or preliminary data • Hyperuricemia is defined as an SUA level > 6.8 mg/dL • An acute gout attack has been confirmed by MSU crystal analysis: • The target goal of uric acid treatment is < 6.0 mg/dL – SUA levels can be normal, especially during the attack: Previous medications: Hydrochlorothiazide 50 mg/day Glipizide 10 mg/day Enalapril 20 mg/day Aspirin 81 mg/day Question to consider: • Should this patient be started on urate-lowering therapy at this point? Questions and Answers – Interleukin-1 inhibition (anakinra, rilonacept)1-4 – Tumor necrosis factor-α inhibition (etanercept, infliximab, and adalimumab)1,5,6 Conclusions Matthew, 66 Years Old – The patient returns to the pharmacist with new prescriptions • Small uncontrolled trials • Lifestyle modifications may benefit overall treatment • Proper timing, dosing, and adherence to pharmacotherapy important: – Anti-inflammatory treatment and when to initiate urate-lowering therapy – Counsel on potential adverse events with therapy – Ensure that contributory comorbidities are addressed • New therapies are available and may benefit patients