Meeting Clinical Challenges in Gout - Global Academy for Medical ...

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All of these scenarios require some imaginativethinking when it comes to managing gout.Newer drugs currently in the research pipelineand existing drugs approved for other indicationsare being studied and used to treat goutin these patient populations, and offer usefulalternatives to the standard treatments. •References1. Vázquez-Mellado J, García CG, Vázquez SC, et al.Metabolic syndrome and ischemic heart disease ingout. J Clin Rheumatol. 2004;10:105-109.2. Stamp LK, Taylor WJ, Jones PB, et al. Starting doseis a risk factor for allopurinol hypersensitivity syndrome:A proposed safe starting dose of allopurinol.Arthritis Rheum. 2012;64:2529-2536.3. Schlesinger N. Management of acute and chronicgouty arthritis: Present state-of-the-art. Drugs.2004;64:2399-2416.4. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascularrisk. N Engl J Med. 2008;359:1811-1821.5. Choi HK, Atkinson K, Karlson EW, Curhan G.Obesity, weight change, hypertension, diuretic use,and risk of gout in men: The Health ProfessionalsFollow-Up Study. Arch Intern Med. 2005;165:742-748.6. Reyes AJ. Cardiovascular drugs and serum uric acid.Cardiovasc Drugs Ther. 2003;17:397-414.7. Choi HK, Soriano LC, Zhang Y, Rodriguez LA.Antihypertensive drugs and risk of incident goutamong patients with hypertension: Populationbased case-control study. BMJ. 2012;344:d8190.8. Edwards NL. Quality of care in patients with gout:Why is management suboptimal and what can be doneabout it? Curr Rheumatol Rep. 2011;13:154-159.9. Sarawate CA, Brewer KK, Yang W, et al. Goutmedication treatment patterns and adherence tostandards of care from a managed care perspective.Mayo Clin Proc. 2006;81:925-934.10. McCarthy GM, Barthelemy CR, Veum JA,Wortmann RL. Influence of antihyperuricemictherapy on clinical and radiographic progressionof gout. Arthritis Rheum. 1991;34:1489-1494.11. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012American College of Rheumatology guidelines formanagement of gout. Part 1: Systematic nonpharmacologicand pharmacologic therapeutic approaches tohyperuricemia. Arthritis Care Res (Hoboken).2012;64:1431-1446.12. Stamp L, Searle M, O’Donnell J, Chapman P. Goutin solid organ transplantation: A challenging clinicalproblem. Drugs. 2005;65:2593-2611.13. Pegloticase (Krystexxa) [package insert].Bridgewater, NJ: Savient Pharmaceuticals, Inc; 2012.14. Reinders MK, Jansen TL. New advances in thetreatment of gout: Review of pegloticase. Ther ClinRisk Manag. 2010;6:543-550.Acute Gouty Arthritis: Issues and Recommendations for Prophylaxis and Treatment continued from page 5Prophylaxis DuringUrate-Lowering TherapyAs noted, the goal of prophylaxis is to lowerserum uric acid levels to the point at whichgouty attacks will not occur over the longterm. For most patients, this means loweringlevels to below the threshold of 6 mg/dL.Initially, many patients experience acuteattacks as the body’s stores of urate are pulledinto the circulation—a process that someclinicians refer to as “crystal stripping” or“mobilization attacks.”Because patients are so much more likely toexperience acute gout attacks during hyperuricemictherapy, the 2012 ACR guidelinesrecommend initiating and maintaining prophylacticanti-inflammatory therapy while loweringserum uric acid levels. The medications used forthis purpose are the same as those used for acuteattacks, although at lower doses than those usedto treat acute gout. 2The guidelines recommend colchicine oran NSAID as the first line of therapy forchronic use and using low-dose prednisoneonly if colchicine, an NSAID, or a combinationof the two fails to adequately keepinflammation controlled or in cases in whichpatients cannot tolerate these two drugs. Aconsensus was not reached about whetheranti–IL-1 therapy should be used prophylactically,although several prospective, blindedtrials suggest that such a strategy is effective. 2Failure to Reach TargetSerum Uric Acid LevelsWhen patients are taking urate-lowering medications(ie, allopurinol or febuxostat) and havenot reached target serum uric acid levels, givenan adequate trial, medication dosages shouldbe titrated upward to the maximal appropriatedosage. If this approach is still not adequate,addition of a uricosuric agent is recommendedin patients with adequate renal function;probenecid or, alternatively, the antihypertensivelosartan—or the lipid-lowering agentfenofibrate—may be added. If these do notresult in achievement of the target urate leveland the disease remains active, consideration ofpegloticase therapy is appropriate.SummaryTreatment approaches to acute gouty arthritis(commonly referred to as acute gout)target two areas: (1) managing the inflammationthat results from spontaneouslyprecipitated or mobilized predeposited tissuestores of MSU crystals and (2) reducing theconditions permitting future attacks bymanaging hyperuricemia.New understanding regarding the pathogenesisof acute gout and mechanisms ofaction of traditional therapies for acute goutand hyperuricemia has allowed the developmentby the ACR of the first US evidence-basedtreatment recommendations. The standardanti-inflammatory medications for the managementof acute gout—colchicine andNSAIDs—are still the mainstay of therapy.ACTH, once FDA approved for gout, is nowan off-label therapy that may be considered inselected cases. IL-1–directed therapies, severalof which are approved for other indications,currently are being investigated for the treatmentof acute gout; according to the ACRguidelines, these agents also may be consideredfor off-label use in selected patients.The mainstay of treatment for urate loweringin patients with hyperuricemia isallopurinol, starting at 100 mg/day and slowlytitrating upward to a level sufficient to lowerserum urate to less than 6.0 mg/dL. Febuxostatand pegloticase are important, more recentlyavailable agents that may be considered inappropriately selected patients.The guidelines also provide specific recommendationsfor anti-inflammatory therapyto be used prophylactically during urate-lowering treatment, as the reduction of serumurate levels commonly causes attacks of acutegouty arthritis. •References1. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012American College of Rheumatology guidelines formanagement of gout. Part 1: Systematic nonpharmacologicand pharmacologic therapeutic approaches tohyperuricemia. Arthritis Care Res (Hoboken).2012;64:1431-1446.2. Khanna D, Khanna PP , Fitzgerald JD, et al. 2012American College of Rheumatology guidelines formanagement of gout. Part 2: Therapy and antiinflammatoryprophylaxis of acute gouty arthritis.Arthritis Care Res (Hoboken). 2012;64:1447-1461.3. Giclas PC, Ginsberg MH, Cooper NR.Immunoglobulin G independent activation of theclassical complement pathway by monosodium uratecrystals. J Clin Invest. 1979;63:759-764.4. Busso N, So A. Mechanisms of inflammation ingout. Arthritis Res Ther. 2010;12:206.5. Malawista SE, de Boisfleury AC, Naccache PH.Inflammatory gout: Observations over a half-century.FASEB J. 2011;25:4073-4078.6. Martinon F, Petrilli V, Mayor A, Tardivel A,Tschopp J. Gout-associated uric acid crystals activatethe NALP3 inflammasome. Nature. 2006;440:237-241.7. Getting SJ, Lam CW, Chen AS, Grieco P, PerrettiM. Melanocortin 3 receptors control crystal-inducedinflammation. FASEB J. 2006;20:2234-2241.8. So A, De Smedt T, Revaz S, Tschopp J. A pilot studyof IL-1 inhibition by anakinra in acute gout.Arthritis Res Ther. 2007;9:R28.9. Terkeltaub RA, Schumacher HR, Carter JD, et al.Rilonacept in the treatment of acute gouty arthritis:A randomized, controlled clinical trial using indomethacinas the active comparator. Arthritis ResTher. 2013;15:R25.10. So A, De Meulemeester M, Pikhlak A, et al.Canakinumab for the treatment of acute flares indifficult-to-treat gouty arthritis: Results of a multicenter,phase II, dose-ranging study. ArthritisRheum. 2010;62:3064-3076.11. Dalbeth N, House ME, Horne A, Petrie KJ,McQueen FM, Taylor WJ. Prescription and dosingof urate-lowering therapy, rather than patientbehaviours, are the key modifiable factors associatedwith targeting serum urate in gout. BMCMusculoskelet Disord. 2012;13:174.10 www.globalacademycme.com/rheumatology • Meeting Clinical Challenges in Gout
Gout: Demographics, Diagnosis, and Description continued from page 3disease, in whom gout is sometimes misdiagnosedand mistreated because gout or othercrystal-associated arthritis—such as calciumpyrophosphate crystal deposition disease(pseudogout) or apatite arthritis—has not beenconsidered in the differential diagnosis.Emerging approaches in diagnosticimaging—ultrasonography and dual-energycomputed tomography (DECT) scan—may provide tools that are less invasive andyield more rapid results. Rheumatologistsin the United States are beginning to usehigh-resolution ultrasonography to diagnosegout. Ultrasonography may be almost asspecific as microscopic detection of crystals ina synovial aspirate; however, the sensitivityand accuracy of results—primarily, demonstrationof the “double contour” sign—ishighly dependent on operator skill. 12Improvements in equipment and skills maymake this modality more widely useful.Conventional computed tomographic scanningdoes not have a significant current role inthe diagnosis of gout. It does demonstrate theextent of bone damage, a finding that can behelpful in persuading patients of the need tocomply with their prescribed treatmentregimen, but plain films usually suffice for thispurpose. 12 DECT is an emerging techniquethat can produce striking images. 13 However,its use to date has been primarily in patientswith chronic tophaceous disease, in whomdiagnosis is rarely a problem. 12SummaryThe prevalence of gout in the United Stateshas increased markedly in recent years. Thischange has been linked to lifestyle changes,especially to excessive dietary intake of fructose.The demonstration of MSU crystals inaspirates of synovial fluid or other tissueremains the pathognomonic and most specificfinding in gouty arthritis. Ultrasonographicand computed tomographic technologiesshow promise in diagnosing gout but are notyet widely used in the United States. •References1. Lawrence RC, Felson DT, Helmick CG, et al, forthe National Arthritis Data Workgroup. Estimatesof the prevalence of arthritis and other rheumaticconditions in the United States: Part II. ArthritisRheum. 2008;58:26-35.2. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout andhyperuricemia in the US general population: TheNational Health and Nutrition Examination Survey2007-2008. Arthritis Rheum. 2011;63:3136-3141.3. Hak AE, Choi HK. Menopause, postmenopausalhormone use and serum uric acid levels in US women—the Third National Health and Nutrition ExaminationSurvey. Arthritis Res Ther. 2008;10:R116.4. Choi HK, Willett W, Curhan G. Fructose-richbeverages and risk of gout in women. JAMA.2010;304:2270-2278.5. Johnson RJ, Sautin YY, Oliver WJ. Lessons fromcomparative physiology: Could uric acid represent aphysiologic alarm signal gone awry in western society?J Comp Physiol B. 2009;179:67-76.6. Rho YH, Zhu Y, Choi HK. The epidemiology of uricacid and fructose. Semin Nephrol. 2011;31:410-419.7. Zgaga L, Theodoratou E, Kyle J, et al. The associationof dietary intake of purine-rich vegetables, sugarsweetenedbeverages and dairy with plasma urate, in across-sectional study. PLoS One. 2012;7:e38123.8. Forbess LJ, Fields TR. The broad spectrum of uratecrystal deposition: Unusual presentations of goutytophi. Semin Arthritis Rheum. 2012;42:146-154.9. Pillinger MH, Goldfarb DS, Keenan RT. Gout andits comorbidities. Bull NYU Hosp Jt Dis. 2010;68:199-203.10. Schlesinger N. Diagnosis of gout. Minerva Med.2007;98:759-767.11. Malik A, Schumacher HR, Dinnella JE, ClayburneGM. Clinical diagnostic criteria for gout:Comparison with the gold standard of synovial fluidcrystal analysis. J Clin Rheumatol. 2009;15:22-24.12. Perez-Ruiz F, Dalbeth N, Urresola A, de Miguel E,Schlesinger N. Imaging of gout: Findings andutility. Arthritis Res Ther. 2009;11:232.13. Choi HK, Al-Arfaj AM, Eftekhari A, et al. Dualenergy computed tomography in tophaceous gout.Ann Rheum Dis. 2009;68:1609-1612.Current Options for Managing Hyperuricemia continued from page 7In addition to reducing consumption ofthese sugars, dietary supplementation withmore dairy products and nutriceuticals suchas cherry juice extract may exert some benefit.These measures have not been shown to reduceserum urate to levels low enough to permit thedissolution of urate deposits in tissue, butfollowing a heart-healthy diet, avoidingfructose and extremely high purine-contentfoods (such as organ meats and beer), consuminglow-fat dairy foods, and maintaining areasonable weight may all be helpful in controllingthe serum urate level. Binge drinkingor drinking several “cocktails” followed byperiods of low food ingestion has been shownto elicit gout attacks. Ingestion of ascorbicacid supplementation likely has a minimaleffect at lowering the urate level.Medication EffectsPatients with gout have an extremely high prevalenceof coexistent metabolic syndrome. Thus,they are frequently on medications for treatmentor prevention of cardiovascular diseases includingcoronary syndromes (aspirin, statins) andhypertension (thiazides), which can raise theserum urate level. However, neither cardioprotective(low-dose) aspirin or thiazide diureticswill significantly elevate the serum urate level;the increases that occur are usually much lessthan 1 mg/dL, certainly not above what caneasily be managed by a slight increase in thedosage of a xanthine oxidase inhibitor. Giventhe proven value of aspirin prophylaxis andgood control of hypertension, I do not stopthese medications in patients with gout.SummaryIn patients with known gouty arthritis, thecurrently recommended target rate of serumurate is below 6 mg/dL. The xanthine oxidaseinhibitor allopurinol, used at an appropriatelyhigh enough dosage, is a cost-effective and clinicallyefficacious agent and remains a mainstayof urate-lowering therapy. The newer xanthineoxidase inhibitor febuxostat is an alternativeand is particularly useful in patients with tolerance,hypersensitivity, or allergic reactions toallopurinol. The newest addition to the rosterof treatment options is pegloticase, which isappropriate for patients who are refractory toantihyperuricemic treatment with conventionalagents or in whom the conventionalagents are contraindicated. Pegloticase is especiallyuseful for patients with macrotophaceousgout, in whom rapid lowering of serum urate tovery low levels is desirable. The goal of loweringserum urate is to decrease the burden of uricacid deposition over the long term. •References1. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012American College of Rheumatology guidelines formanagement of gout. Part 1: Systematic nonpharmacologicand pharmacologic therapeutic approaches tohyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1431-1446.2. Burns CM, Wortmann RL. Latest evidence on goutmanagement: What the clinician needs to know.Ther Adv Chronic Dis. 2012;3:271-286.3. Becker MA, Schumacher HR Jr, Wortmann RL, et al.Febuxostat compared with allopurinol in patientswith hyperuricemia and gout. N Engl J Med. 2005;353:2450-2461.4. Becker MA, Schumacher HR, Espinoza LR, et al.The urate-lowering efficacy and safety of febuxostatin the treatment of the hyperuricemia of gout: TheCONFIRMS trial. Arthritis Res Ther. 2010;12:R63.5. Pegloticase (Krystexxa) [package insert].Bridgewater, NJ: Savient Pharmaceuticals, Inc; 2012.6. Reinders MK, Jansen TL. New advances in thetreatment of gout: Review of pegloticase. Ther ClinRisk Manag. 2010;6:543-550.7. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M,Herrero-Beites A, Garcia-Erauskin G, Ruiz-LuceaE. Efficacy of allopurinol and benzbromarone forthe control of hyperuricaemia: A pathogenicapproach to the treatment of primary chronic gout.Ann Rheum Dis. 1998;57:545-549.8. Stamp LK, Taylor WJ, Jones PB, et al. Starting doseis a risk factor for allopurinol hypersensitivity syndrome:A proposed safe starting dose of allopurinol.Arthritis Rheum. 2012;64:2529-2536.9. Taylor TH, Mecchella JN, Larson RJ, Kerin KD,Mackenzie TA. Initiation of allopurinol at firstmedical contact for acute attacks of gout: A randomizedclinical trial. Am J Med. 2012;125:1126-1134.10. Choi HK, Willett W, Curhan G. Fructose-richbeverages and risk of gout in women. JAMA.2010;304:2270-2278.11. Johnson RJ, Sautin YY, Oliver WJ. Lessons fromcomparative physiology: Could uric acid representa physiologic alarm signal gone awry in westernsociety? J Comp Physiol B. 2009;179:67-76.12. Zgaga L, Theodoratou E, Kyle J, et al. The associationof dietary intake of purine-rich vegetables, sugarsweetenedbeverages and dairy with plasma urate, in across-sectional study. PLoS One. 2012;7:e38123.www.globalacademycme.com/rheumatology • Meeting Clinical Challenges in Gout 11
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