Medical Management of Acute Gout

IN BRIEF

Medical Management of Acute Gout Peter C. Chimenti, MD, Warren C. Hammert, MD by acute episodes of inflammatory arthritis caused by deposition of uric acid crystals in the joints and soft tissues. Gout affects an estimated 6.1 million people in the United States, and the prevalence is rising.1 It is divided into 3 clinical stages: acute, intercritical, and chronic.2 Hand surgeons can assist in the management of any stage but are typically involved with the evaluation of an acute gout flare. Acute gout typically presents as a monoarticular arthritis that most commonly affects the first metatarsophalangeal joint (termed podagra) but can involve the midfoot, ankle, or knee joint in 85%–90% of initial presentations.3 Initial presentation in the upper extremity is appears to be less likely, but it can involve the elbow, wrist, and fingers. Elderly women might be more likely to present with polyarticular involvement involving the fingers.4 The shoulder is rarely affected by acute attacks, but chronic gout of the shoulder has been described in case reports.5,6 Gout can cause an acute carpal tunnel syndrome caused by accumulation of uric acid crystals and subsequent inflammatory response within the soft tissues of the wrist. The most common complaint is one of rapidly progressive joint pain over a short time course, usually less than 24 hours. The affected joint is erythematous, warm, swollen, and tender to palpation. Left untreated, an acute gout flare resolves over 3 to 10 days, followed by an asymptomatic phase known as the intercritical period. As the disease progresses, these pain-free intervals become shorter, and episodes of acute flares become more frequent. Although the definition of the chronic stage of the disease remains unclear,7 patients

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OUT IS CHARACTERIZED

In Brief

From the Department of Orthopaedic Surgery, University of Rochester Medical Center, Rochester, NY. Received for publication December 20, 2011; accepted in revised form April 30, 2012. W.C.H. has consulted with Synthes. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Warren C. Hammert, MD, University of Rochester Medical Center, Department of Orthopaedic Surgery, 601 Elmwood Ave., Box 665, Rochester, NY 14642; e-mail: [email protected]. 0363-5023/12/37A10-0034$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2012.04.041

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FIGURE 1: Posteroanterior radiograph of the left hand of a patient with chronic gout (⬎ 1 y). Findings include extensive erosions of the interphalangeal joints with overlying soft tissue swelling, consistent with tophaceous gout.

with chronic gout can have radiographic changes of a destructive arthropathy and clinically have tophi overlying affected joints (Fig. 1). DIAGNOSIS OF ACUTE GOUT Hyperuricemia is an important risk factor for the development of gout; however, elevated serum urate (SU) alone is not sufficient to make the diagnosis or develop the disease. Uric acid crystals begin to form with an SU concentration greater than 6.8 mg/dL; however, the threshold for hyperuricemia is generally defined as a SU ⬎ 7.0 mg/dL (0.42 mmol/L) in men and 6.0 mg/dL (0.36 mmol/L) in women.8,9 The risk of developing gout rises with the SU. The 5-year cumulative incidence10 of gout for patients with SU ⬎ 10 mg/dL is 30%, whereas those with ⬍ 7 mg/dL is 0.6%. The majority of patients with hyperuricemia are asymptom-

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tive protein; and a swollen, tender wrist—joint atic and do not develop gout; nearly half of patients 11 fluid is typically obtained. Patients who do not with acute flares can have normal SU levels. Other have joint aspirations performed are followed clinrisk factors for acute flares include dehydration and ically by the orthopedic hand service to ensure consumption of foods high in purines—particularly liimprovement and resolution of symptoms with quor, beer, red meat, and seafood. systemic antibiotics or anti-inflammatories, as inThe gold standard for diagnosis remains joint fluid dicated. Although rare, the possibility of a coexanalysis, specifically the identification of negatively biistent gout flare and septic refringent, needle-shaped EDUCATIONAL OBJECTIVES arthritis has been reurate crystals under polarized ● ported.15 Discuss the role of serum urate levels and the development of gout. light microscopy. Clinical criteria to establish the diag- ● State the risk factor(s) for the development of an acute flare of gout. nosis without joint fluid were ● Summarize the clinical criteria to establish the diagnosis without joint fluid TREATMENT OF ACUTE GOUT proposed by the American proposed by the American College of Rheumatology. College of Rheumatology ● Discuss the first-line medications available for an acute flare of gout. Treatment for an acute gout and by the European League ● flare consists of fluid resusciDescribe the role of interleukin-1 inhibitors in the management of gout. Against Rheumatism in tation; avoidance of risk fac● List the medications available for the treatment of chronic gout. 12 2006. Their diagnostic valtors, including alcohol conues were examined and Earn up to 2 hours of CME credit per JHS issue when you read the related sumption and diuretic use; found to have a sensitivity of articles and take the online test. To pay the $20 fee and take this month’s and treatment with nonsteroi97.3% and specificity of test, visit http://www.jhandsurg.org/CME/home. dal anti-inflammatory drugs 95.6% when 4 of the follow(NSAIDs), colchicine, cortiing 8 criteria were positive: costeroids, or interleukin 1 inhibitors. The choice of (1) monoarthritis or oligoarthritis, (2) more than 1 atmedications depends on the patient’s medical comortack of acute arthritis, (3) rapid progression of pain and bitities, specifically diabetes, chronic renal insuffiswelling in less than 24 hours, (4) podagra, (5) eryciency, severity of the gout flare, and age. The currently thema, (6) tophi, (7) unilateral tarsitis, and (8) hyperrecommended, evidence-based treatment regimens are uricemia (⬎ 7 mg/dL in men; ⬎ 6 mg/dL in women).13 listed in Table 1. Although these criteria are helpful, especially in the Nonsteroidal anti-inflammatory drugs are traditional clinical setting, they do not rule out other serious causes first-line agents for acute gout, especially in patients of swollen and painful joints, such as septic arthritis. with normal renal function. Evidence suggests that they Skeete et al examined 104 patients presenting to might be primarily effective within the first several days the emergency department with concern for septic of an acute gout flare; however, no clinically significant arthritis of the wrist. They found that the most differences in outcome or adverse effects among differcommon diagnosis was cellulitis (42%) followed ent NSAIDs have been reported.16 The incidence of by gout (15%), whereas septic arthritis was idengout flares is higher among elderly patients and, given tified in only 5% of patients.14 Four of the 5 the concern of cardiovascular adverse events with cypatients with a diagnosis of septic wrist were imclooxygenase-2 inhibitors, they must be used with caumunocompromised and did not demonstrate eletion. A recent systematic review examining NSAIDs vated laboratory markers of infection, such as demonstrated that etoricoxib (Arcoxia, Merck & Co., erythrocyte sedimentation rate, C-reactive protein, Inc, Whitehouse Station, NJ) provides equivalent pain or white blood cell count. This finding suggests relief to indomethacin, although etoricoxib is not apthat relying on these values alone can be misleadproved for treatment of acute gout in the United ing, demonstrating the importance of arthrocenteStates.17 A randomized, double-blind study of sis for fluid analysis, especially in immunocomnaproxen (Aleve, Bayer Healthcare LLC, Morrispromised patients. At our institution, we base the town, NJ) 500 mg twice daily compared with oral decision to perform an arthrocentesis on the hisprednisolone (35 mg daily) demonstrated equivatory, physical examination, and laboratory marklent outcomes for pain relief, with similar rates of ers. Radiographs are often obtained by the emeradverse effects.18 A comparison of indomethacin gency department before orthopedic consultation. and prednisolone demonstrated equivalent pain reIf the overall clinical picture suggests infection— lief, but indomethacin had a higher rate of gastroincluding systemic symptoms of fevers or chills; intestinal bleeding (11% vs 0%) and higher overall elevated erythrocyte sedimentation rate or C-reacrate of adverse effects.19 Based on the current JHS 䉬 Vol A, October 

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MEDICAL MANAGEMENT OF ACUTE GOUT

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MEDICAL MANAGEMENT OF ACUTE GOUT

TABLE 1.

Typical Regimens for Management of Acute Gout Flares and Chronic Gout Management of Acute Gout Flares

Drug

Regimen

Adverse Effects

Avoid In Patients With

Naproxen (Aleve)

500 mg orally, twice a day for 7–10 days

GI bleeding, renal impairment

CRI, GI bleed, NSAID allergy

Indomethacin

50 mg orally, 3 times a day for 3 days

GI bleeding, headache, renal impairment, peripheral edema

CRI, GI bleed, NSAID allergy, currently taking lithium (due to decreased lithium excretion)

Colchicine (Colcrys)

1.2 mg orally once, 0.6 mg orally 1 hour later

Severe diarrhea, nausea, vomiting

Cardiovascular disease, patients on NSAID therapy already, those on CYP3A4 inhibitors

Prednisolone

30 mg orally every day for 5 days

Elevation of blood glucose

Diabetes mellitus

Triamcinolone

40 mg intra-articular injection once

Risks associated with injection

Any concern for septic arthritis, polyarticular involvement

Anakinra (Kineret)

100 mg subcutaneously for 3 days

GI upset, upper respiratory infections

Neutropenia, CRI, asthma

Management of Chronic Gout Allopurinol (Lopurin)

100 mg orally every day, up to 800 mg orally every day, titrate to serum urate ⬍ 6.0 mg/dL

Worsening of symptoms if started during acute attack; rash, hypersensitivity

CRI (dose adjustment necessary), pregnancy

Probenecid (Benemid)

250 mg orally twice a day for 1 week, then 500 mg orally twice a day

Worsening of symptoms if started during acute attack; hypersensitivity

Urolithiasis, decreased creatinine clearance, blood dyscrasias

Febuxostat (Uloric)

40–80 mg orally every day, titrate to serum urate level

Nausea, diarrhea, elevation of liver enzymes

Patients taking azathioprine or mercaptopurine

In Brief

CRI, chronic renal insufficiency; GI, gastrointestinal.

literature, patients without renal impairment or history of gastrointestinal bleeding should begin NSAID therapy as soon as possible after diagnosis and continue for 7 to 10 days or until symptoms resolve. In patients with coexistent cardiovascular disease, a history of gastrointestinal bleeding, or already on NSAID therapy, colchicine is an alternative medication for use in acute gout flares. Traditionally, colchicine was prescribed at doses of 0.5 mg every hour or 2 and continued until symptom relief or severe gastrointestinal disturbances—most commonly diarrhea, nausea, and vomiting—were experienced. A recent study by Terkeltaub et al compared a low-dose regimen consisting of 1.2 mg followed by 0.6 mg 1 hour later to a high-dose regimen of 1.2 mg followed by 0.6 mg every hour for 6 hours. They found that rates of adverse effects were significantly lower in the low-dose group (36.5% vs 76.9%) with equivalent efficacy in providing

greater than or equal to 50% pain relief in 24 hours.20 Colchicine should be used cautiously in patients with renal impairment or those taking medications that interfere with cytochrome P450, including cyclosporine, clarithromycin, ketoconazole, diltiazem or verapamil, statins, and certain anti-retroviral drugs. Another option for management of acute gout is systemic or intra-articular glucocorticoids. Although there are no randomized trials to support their use, an intra-articular corticosteroid injection seems to be effective for single joint involvement when there is no clinical concern for infection.21 A 2008 Cochrane review examined the data for systemic glucocorticoids and concluded that there was insufficient evidence for the efficacy of steroids in the management of acute gout but that no serious adverse events attributable to steroid use were noted.22 In addition, prednisolone is more cost effective than indomethacin, associated with an average savings of $158 per patient treated.23

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TREATMENT OF CHRONIC GOUT Although no clear consensus exists on what defines the chronic stage of the disease,7 it is generally recommended to start urate-lowering therapy after the patient experiences more than 2 acute gout attacks in a year. Allopurinol is the first-line medication, but it must be used with caution in patients with renal impairment. It is not begun during acute attacks but can be used when the pain from an acute flare has resolved. Alternative medications include uricosuric (probenecid) for patients with normal renal function and febuxostat, a xanthine oxidase inhibitor. Although it is not a first-line therapy for chronic gout, febuxostat might be a good option for patients with hypersensitivity to allopurinol or with chronic kidney disease. As with allopurinol, it is necessary to continue NSAID or colchicine prophylaxis during initiation of treatment with febuxostat to reduce the incidence of acute flares.2 Management of acute gout flares begins with proper diagnosis, which can include arthrocentesis, especially in the setting of immunocompromise. Consideration of the patient’s medical comorbidities is important in the selection of the proper initial therapy. In our practice, recommendations for initial medial management in the emergency department or outpatient setting are typically made, followed by referral to the primary care physician for further management of medications. Given that the natural history of a gout flare is to resolve spontaneously over 3 to 10 days and that all the current therapies have an adverse effect profile that carries some risk, the earliest possible initiation of therapy

maximizes the benefit-to-risk ratio and clinically justifies therapy. REFERENCES 1. Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009;11:229. 2. Smith HS, Bracken D, Smith JM. Gout: current insights and future perspectives. J Pain 2011;12:1113–1129. 3. Richette P, Bardin T. Gout. Lancet 2010;375:318 –328. 4. ter Borg EJ, Rasker JJ. Gout in the elderly, a separate entity? Ann Rheum Dis 1987;46:72–76. 5. Chang CH, Lu CH, Yu CW, Wu MZ, Hsu CY, Shih TT. Tophaceous gout of the rotator cuff. A case report. J Bone Joint Surg 2008;90A: 178 –182. 6. O’leary ST, Goldberg JA, Walsh WR. Tophaceous gout of the rotator cuff: a case report. J Shoulder Elbow Surg 2003;12:200 –201. 7. Wijnands JM, Boonen A, Arts IC, Dagnelie PC, Stehouwer CD, van der Linden S. Large epidemiologic studies of gout: challenges in diagnosis and diagnostic criteria. Curr Rheumatol Rep 2011;13:167– 174. 8. Schlesinger N. Diagnosis of gout: clinical, laboratory, and radiologic findings. Am J Manag Care 2005;11:S443– 450; quiz S465– 468. 9. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 2000;283:2404 – 2410. 10. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 1987;82:421– 426. 11. Schlesinger N, Baker DG, Schumacher HR Jr. Serum urate during bouts of acute gouty arthritis. J Rheumatol 1997;24:2265–2266. 12. Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, 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. 13. Vázquez-Mellado J, Hernández-Cuevas CB, Alvarez-Hernández E, Ventura-Rios L, Peláez-Ballestas I, Casasola-Vargas J, et al. The diagnostic value of the proposal for clinical gout diagnosis (CGD). Clin Rheumatol 2012;31:429 – 434. 14. Skeete K, Hess EP, Clark T, Moran S, Kakar S, Rizzo M. Epidemiology of suspected wrist joint infection versus inflammation. J Hand Surg 2011;36A:469 – 474. 15. Schuind FA, Remmelink M, Pasteels JL. Co-existent gout and septic arthritis at the wrist: a case report. Hand Surg 2003;8:107–109. 16. Sutaria S, Katbamna R, Underwood M. Effectiveness of interventions for the treatment of acute and prevention of recurrent gout—a systematic review. Rheumatology (Oxford) 2006;45:1422–1431. 17. Schumacher HR Jr, Boice JA, Daikh DI, Mukhopadhyay S, Malmstrom K, Ng J, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002;324: 1488 –1492. 18. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet 2008; 371:1854 –1860. 19. 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 doubleblind, randomized, controlled trial. Ann Emerg Med 2007;49:670 – 677. 20. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. 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.

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Anakinra, an interleukin-1␤ inhibitor, recently was shown to be a target for further research in a study of 10 patients with refractory gout.24 When treated with 100 mg subcutaneously for 3 days, all 10 patients reported improvement in pain with no significant adverse events during the follow-up period of 1 to 2 months. For patients who cannot tolerate NSAIDS, colchicine, or corticosteroids, the interleukin-1 inhibitors appear to be an alternative. In our practice, after a patient is diagnosed with an acute gout flare in the emergency department setting, the orthopedic service can suggest appropriate initial medical management; however, subsequent referral to the primary care physician for management of the chronic stages of the disease is generally recommended. For a new diagnosis of gout as an outpatient, patients are typically referred to the primary care physician or a rheumatologist unless arthritic changes are present that might warrant surgical intervention (Fig. 1).

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21. Fernandez C, Noguera R, Gonzalez JA, Pascual E. Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone acetonide. J Rheumatol 1999;26:2285–2286. 22. Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev 2008;2:CD005521.

23. Cattermole GN, Man CY, Cheng CH, Graham CA, Rainer TH. Oral prednisolone is more cost-effective than oral indomethacin for treating patients with acute gout-like arthritis. Eur J Emerg Med 2009; 16:261–266. 24. 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.

JOURNAL CME QUESTIONS Medical Management of Acute Gout What is the risk factor(s) for the development of an acute flare of gout? a. Dehydration b. Drinking alcohol c. Eating red meat d. Consuming seafood e. All of the above

What nonsteroidal anti-inflammatory drug is most efficacious for acute gout if administered within the first several days of an acute flare? a. Indomethacin b. Naproxen (Aleve, Bayer Healthcare LLC, Morristown, NJ) c. Etoricoxib (Arcoxia, Merck & Co., Inc, Whitehouse Station, NJ) d. Colchicine e. None is superior

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