Gout, “the king of diseases and the disease of kings,” was one of the earliest disorders to be recognized as a clinical entity.1 No longer discriminating among socioeconomic classes, it has more than doubled in prevalence over the past 2 decades.2 A disorder of purine metabolism, gout now is the most common inflammatory arthropathy. It occurs in men more than in women (ratio, about 3 or 4:1).2
Even in this setting of a rising prevalence, primary care management of gout does not always adhere to evidence-based best practice.3 In addition, a significant number of patients do not respond to appropriate therapy or do not achieve optimal response to treatment, even in the hands of experienced rheumatologists (R. T. Keenan, M. H. Pillinger, unpublished data).
Recently, after almost 50 years of dormancy, new therapeutic agents for the management of gout have entered the market or are in clinical development. In this article, we review current guidelines for the diagnosis and management of gout.
The diagnosis of gout is not always easy to make. The original American College of Rheumatology criteria4 have been shown to have limited validity (sensitivity, 0.80; specificity, 0.64; positive predictive value, 0.80; and negative predictive value, 0.65).5 More recently, the European League Against Rheumatism (EULAR) also developed recommendations.6
Visualization of crystals
The gold standard for making a diagnosis of gouty arthropathy is visualization of negatively birefringent, needle-shaped crystals. This is done with arthrocentesis and analysis of synovial fluid (SF) or tophus aspirate and identification of monosodium urate (MSU) crystals, particularly intracellular crystals in neutrophils.6,7 MSU crystals also may be identified in SF obtained from asymptomatic joints, especially the knees and the first metatarsophalangeal (MTP) joints.7,8
Of note, acute gouty arthritis may coexist with another joint disease, such as septic arthritis or pseudogout. Therefore, arthrocentesis should be performed in almost all circumstances.
Serum uric acid (SUA) levels may be obtained during an acute attack (a high SUA level supports the possibility that a patient has gout). However, SUA levels may be paradoxically low during an acute attack (because of an increase in renal excretion); they typically are highest about 2 weeks after.
1. Choi H. Epidemiology of crystal arthropathy. Rheum Dis Clin North Am. 2006;32:255-273, v.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States, part II. Arthritis Rheum. 2008;58:26-35.
3. Pal B, Foxall M, Dysart T, et al. How is gout managed in primary care? A review of current practice and proposed guidelines. Clin Rheumatol. 2000;19:21-25.
4. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895-900.
5. Janssens HJ, Janssen M, van de Lisdonk EH, et al. Limited validity of the American College of Rheumatology criteria for classifying patients with gout in primary care. Ann Rheum Dis. 2010;69:1255-1256.
6. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout, part I: diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-1311.
7. Pascual E, Doherty M. Aspiration of normal or asymptomatic pathological joints for diagnosis and research: indications, technique and success rate. Ann Rheum Dis. 2009;68:3-7.
8. Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout. Arthritis Rheum. 1991;34:141-145.
9. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;(8 suppl 1):S2.
10. Liebman SE, Taylor JG, Bushinsky DA. Uric acid nephrolithiasis. Curr Rheumatol Rep. 2007;9:251-257.
11. Schumacher HR Jr, Becker MA, Palo WA, et al. Tophaceous gout: quantitative evaluation by direct physical measurement. J Rheumatol. 2005;32:2368-2372.
12. Dalbeth N, Clark B, Gregory K, et al. Computed tomography measurement of tophus volume: comparison with physical measurement. Arthritis Rheum. 2007;57:461-465.
13. Konatalapalli RM, Demarco PJ, Jelinek JS, et al. Gout in the axial skeleton. J Rheumatol. 2009;36:609-613.
14. Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237-241.
15. Janssens HJ, Janssen M, van de Lisdonk EH, et al. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008;371:1854-1860.
16. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med. 2007;49:670-677.
17. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2009;38:411-419.
18. Schumacher HR Jr, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ. 2002;324:1488-1492.
19. Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Res Ther. 2006;(8 suppl 1):S1.
20. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010;62:1060-1068.
21. Getting SJ, Lam CW, Chen AS, et al. Melanocortin 3 receptors control crystal-induced inflammation. FASEB J. 2006;20:2234-2241.
22. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9:R28.
23. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis. 2009;68:1613-1617.
24. So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis. Arthritis Rheum. 2010 Jun 8; [Epub ahead of print].
25. Schumacher HR Jr, Chen LX. Newer therapeutic approaches: gout. Rheum Dis Clin North Am. 2006;32:235-244, xii.
26. Stein HB, Hasan A, Fox IH. Ascorbic acid-induced uricosuria: a consequency of megavitamin therapy. Ann Intern Med. 1976;84:385-388.
27. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143:499-516.
28. Hunter DJ, York M, Chaisson CE, et al. Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study [published correction appears in J Rheumatol. 2006;33:1714]. J Rheumatol. 2006;33:1341-1345.
29. Riedel AA, Nelson M, Joseph-Ridge N, et al. Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol. 2004;31:1575-1581.
30. Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc. 2006;81:925-934.
31. Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009;11:135-140.
32. Okamoto K, Eger BT, Nishino T, et al. An extremely potent inhibitor of xanthine oxidoreductase: crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003;278:1848-1855.
33. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63.
34. Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002;40:355-360.
35. Kissel P, Lamarche M, Royer R. Modification of uricaemia and the excretion of uric acid nitrogen by an enzyme of fungal origin. Nature. 1968;217:72-74.
36. Terkeltaub R. Learning how and when to employ uricase as bridge therapy in refractory gout. J Rheumatol. 2007;34:1955-1958.
37. Richette P, Briére C, Hoenen-Clavert V, et al. Rasburicase for tophaceous gout not treatable with allopurinol: an exploratory study. J Rheumatol. 2007;34:2093-2098.
38. Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008;58:2882-2891.
39. Study Utilizing Rilonacept in Gout Exacerbations (SURGE). ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00855920. Accessed September 9, 2010.
40. RDEA594, a novel uricosuric agent, significantly reduced serum urate levels and was well tolerated in a phase 2a pilot study in hyperuricemic gout patients. Rheumatology Aco. http://acr.confex.com/acr/2009/webprogram/Paper15506.html. Accessed September 9, 2010.
41. Study of tranilast alone or in combination with allopurinol in subjects with hyperuricemia. ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01052987?term=tranilast&rank=2. Accessed September 9, 2010.
42. Study to evaluate the urate-lowering activity and safety of oral BCX4208 administered in subjects with gout. ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00985127?term=BCX4208&rank=2. Accessed September 9, 2010.
43. Eggebeen AT. Gout: an update. Am Fam Physician. 2007;76:801-808.