in the clinic - Tripod.comenotes.tripod.com/gout2010.pdf · tion of uric acid. In particular, binge drinking increases urate lev-els. The risk differs by the type of alcohol, with

inthe

clinicin the clinic

GoutPrevention and Screening page ITC2-2

Diagnosis page ITC2-6

Treatment page ITC2-9

Practice Improvement page ITC2-13

CME Questions page ITC2-16

Section EditorsChristine Laine, MD, MPHBarbara J. Turner, MD, MSEDSankey Williams, MD

Science WriterJennifer F. Wilson

The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), includingPIER (Physicians’ Information and Education Resource) and MKSAP (MedicalKnowledge and Self-Assessment Program). Annals of Internal Medicineeditors develop In the Clinic from these primary sources in collaborationwith the ACP’s Medical Education and Publishing Division and with the assistance of science writers and physician writers. Editorial consultants fromPIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consulthttp://pier.acponline.org, http://www.acponline.org/products_services/mksap/15/?pr31, and other resources referenced in each issue of In the Clinic.

CME Objective: To review current evidence for the prevention, diagnosis, andtreatment of gout.

The information contained herein should never be used as a substitute forclinical judgment.

© 2010 American College of Physicians

What are the risk factors forgout?In 2280 prospectively followedhealthy men in the Boston VeteransAdministration Normative AgingStudy, the serum urate level was thestrongest predictor of gout (3).However, in that study, only 22% ofthe participants with serum uratelevels greater than 535.4 µmol/L (9 mg/dL) developed gout over a5-year period. Overall, about 10%of persons with hyperuricemia de-velop gout (4). Gout usually occursonly after many years of hyper-uricemia. It is not currently recom-mended to treat asymptomatic hyperuricemia to prevent the disease.However, once gout develops, theurate level is predictive of flares.

Among 2237 elderly patients with knowngout, those with high serum urate concen-trations (356.91 to 534.8 μmol/L [6 to 8.99mg/dL]) were 2 times more likely to have aflare in 12 months than patients with nor-mal levels (<356.91 μmol/L [<6 mg/dL]),and those with very high serum urate con-centrations (>535.4 μmol/L [>9 mg/dL])were 3 times more likely. Moreover, thehighest uric acid levels were associatedwith higher total and gout-related directhealth care costs per episode (2)

Age and sexMen have higher serum urate levelsand a higher risk for gout thanwomen, in part because estrogenstimulates renal excretion of uric acid.In persons younger than 30 years, the

prevalence of gout is far greater inmen than in women, but the gendergap narrows such that men andwomen older than 60 years haveequal risk for gout and women intheir eighties have greater risk forgout than men in their eighties. Especially among elderly persons, theprevalence of gout is increasing.

In a managed-care population of patientsolder than 75 years, the prevalence of goutroughly doubled from 21 to 41 cases per 1000in 1990 to 1999 but changed little in personsyounger than 65 years during that decade (1).

WeightObesity is also an important risk fac-tor for gout. Observational studiessuggest that weight control may beeffective in reducing the risk for gout,but this has not been evaluated in aclinical trial.

In the Health Professionals Follow-upStudy, which included more than 47 000men, the risk for gout over 12 years in-creased linearly with increasing body massindex (BMI). Multivariate relative risks (RRs)for gout rose from 1.95 (95% CI, 1.44 to2.65) for a BMI of 25 to 29.9 kg/m2 to 2.97(CI, 1.73 to 5.10) for a BMI of 35 kg/m2 orgreater versus a BMI of 21 to 22.9 kg/m2

(P < 0.001 for trend). A loss of more than 10lbs since study entry was associated with a30% reduction in risk for gout (RR, 0.61 [CI,0.40 to 0.92]) (5).

DietUric acid is produced from the metabolism of purines that come

© 2010 American College of Physicians ITC2-2 In the Clinic Annals of Internal Medicine 2 February 2010

For several thousand years, gout has been recognized as a very painfulform of acute and frequently recurrent arthritis. Gout is increasing inprevalence because of the higher prevalence of obesity, a high-caloric

Western diet, diuretic use, and an aging population (1). Gout currently af-fects more than 5 million persons in the United States alone (2). It is themost common cause of inflammatory arthritis in men, with the highest inci-dence in men in their forties. Gout is caused by monosodium urate (MSU)crystals formed in joints and tissues when serum urate levels exceed 404.5µmol/L (6.8 mg/dL), the approximate saturation point in human biologicalfluids. Gout causes acute mono- or polyarticular arthritis as well as chronicinflammation, which leads to joint destruction. Treatment is aimed at lower-ing serum urate levels and reducing the inflammatory response to the MSUcrystals. After few advances in treatment for several decades, several newdrugs for prevention of gout are now available.

Prevention andScreening

Risk Factors for Gout• Hyperuricemia• Male sex if younger than 60 years• Obesity• Diet high in purines (for example,

red meat, shellfish)• Consumption of alcohol (especial-

ly beer and spirits) and high-fructose drinks (for example, sodas, some juices)

• Medications (especially thiazidediuretics or cyclosporine)

• Renal insufficiency• Lead exposure• Organ transplantation• Specific diseases (for example,

hypertension, diabetes, hyperlipi-demia, the metabolic syndrome,hematologic malignant conditions)

• Genetic risk factors

1. Wallace KL, Riedel AA,Joseph-Ridge N, et al.Increasing prevalenceof gout and hyper-uricemia over 10years among olderadults in a managedcare population. J Rheumatol.2004;31:1582-7.[PMID: 15290739]

2. Wu EQ, Patel PA,Mody RR, et al. Fre-quency, risk, and costof gout-relatedepisodes among theelderly: does serumuric acid level mat-ter? J Rheumatol.2009;36:1032-40.[PMID: 19369467]

© 2010 American College of PhysiciansITC2-3In the ClinicAnnals of Internal Medicine2 February 2010

exogenously from specific foods andendogenously from cellular metabo-lism (Box). Persons with gout maybenefit from limiting dietary purines.

In an observational study of 47 150 men,the risk for gout increased by 21% foreach additional portion of meat per dayand by 7% for each additional portion ofseafood per week. On the other hand,moderate consumption of purine-richvegetables, such as mushrooms, was notassociated with an increased risk forgout. Furthermore, the incidence of goutdecreased with increasing intake of dairyproducts. Protein from dairy productsdoes not seem to carry the same risk asprotein from meat or fish sources (6).

Consumption of high-fructose foodsand drinks has recently been recog-nized as a risk factor for gout.

In an observational study of 46 393 malehealth professionals, the adjusted RR forgout for 5 to 6 servings of sugar-sweetenedsoft drinks per week was 1.29 (CI, 1.00 to1.68), for 1 serving per day was 1.45 (CI,1.02 to 2.08), and for 2 or more servings perday was 1.85 (CI, 1.08 to 3.16) versus lessthan 1 serving per month (P = 0.002 fortrend). Intake of fruit juice or fructose-richfruits, such as apples and oranges, wasalso associated with a higher risk for gout(P < 0.05 for trend). Diet soft drinks werenot associated with risk for gout (7).

AlcoholAlcohol increases serum urate levelsand even moderate levels of alcoholuse can precipitate an attack in per-sons predisposed to gout. Alcoholmay also interfere with renal excre-tion of uric acid. In particular,binge drinking increases urate lev-els. The risk differs by the type ofalcohol, with beer and spirits beingthe more risky and wine less so.

An analysis of the National Health and Nutrition Examination Survey III revealedthat serum urate level increased with con-sumption of beer and liquor and that per-sons with the highest intake (≥1 servingper day) had serum urate levels that were58.9 μmol/L (CI, 48.8 to 69.6) higher (forbeer) and 34.5 μmol/L (CI, 21.4 to 47.6)higher (for liquor) than in nondrinkers. Thiseffect was greater for women and personswith BMIs less than 25 kg/m2. On the other

hand, wine consumption had an oppositeeffect: 1 or more servings per day was asso-ciated with a lower serum urate level (−13.7 μmol/L [CI, −28.6 to −1.8]) (8).

Similarly, among 47 150 men, the adjustedRR of gout was 1.32 (CI, 0.99 to 1.75) for al-cohol consumption of 10.0 to 14.9 g/d(about 1 drink), 1.49 (CI, 1.14 to 1.94) for15.0 to 29.9 g/d, 1.96 (CI, 1.48 to 2.60) for30.0 to 49.9 g/d, and 2.53 (CI, 1.73 to 3.70)for 50 g or more per day (P <0.001 fortrend) versus men who did not drink alco-hol. Beer had the strongest associationwith gout, followed by spirits (9).

MedicationsDiuretics, especially thiazides, arestrongly linked to the developmentof gout. Diuretics increase renal re-sorption of uric acid, leading to hyperuricemia. Diuretic use is acommon factor contributing togout in older persons. Low-to-moderate levels of aspirin also in-crease the risk for gout. Otherdrugs that decrease renal urateclearance include pyrazinamide,ethambutol, and pyrazinoate. Inaddition, nicotinic acid, vitamin B12,cancer chemo-therapy, and lev-odopa increase serum urate levels.Cyclosporine increases tubular re-sorption of uric acid and can causepolyarticular gout.

Lead exposureChronic occupational lead exposurehas been associated with an in-creased incidence of gout becauseof reduced uric acid excretion,which leads to higher serum uratelevels. Even low-level exposure hasbeen reported to increase the riskfor gout (10).

Organ transplantationPersons who have received a renaltransplant have an especially in-creased risk for gout, because of thecombination of renal insufficiencyand treatment with cyclosporine toprevent rejection. Other types oforgan transplantation are also asso-ciated with an increased risk forgout. However, tacrolimus has lessof an effect on urate levels and isnow used more often.

3. Campion EW, GlynnRJ, DeLabry LO.Asymptomatic hyper-uricemia. Risks andconsequences in theNormative AgingStudy. Am J Med.1987;82:421-6.[PMID: 3826098]

4. Vitart V, Rudan I, Hay-ward C, et al. SLC2A9is a newly identifiedurate transporter in-fluencing serumurate concentration,urate excretion andgout. Nat Genet.2008;40:437-42.[PMID: 18327257]

5. Choi HK, Atkinson K,Karlson EW, et al.Obesity, weightchange, hyperten-sion, diuretic use, andrisk of gout in men:the health profes-sionals follow-upstudy. Arch InternMed. 2005;165:742-8.[PMID: 15824292]

6. Choi HK, Atkinson K,Karlson EW, et al.Purine-rich foods,dairy and protein in-take, and the risk ofgout in men. N Engl JMed. 2004;350:1093-103. [PMID: 15014182]

7. Choi HK, Curhan G.Soft drinks, fructoseconsumption, andthe risk of gout inmen: prospective co-hort study. BMJ.2008;336:309-12.[PMID: 18244959]

8. Choi HK, Curhan G.Beer, liquor, and wineconsumption andserum uric acid level:the Third NationalHealth and NutritionExamination Survey.Arthritis Rheum.2004;51:1023-9.[PMID: 15593346]

9. Choi HK, Atkinson K,Karlson EW, et al. Al-cohol intake and riskof incident gout inmen: a prospectivestudy. Lancet.2004;363:1277-81.[PMID: 15094272]

High-Purine Animal and Fish Sources• Red meat (beef, pork, lamb)• Meat extracts (broth, gravy)• Organ meats (such as sweet-

breads, liver, and kidney)• Seafood (shrimp, anchovies, mus-

sels, scallops, sardines, herring,fish roe, canned tuna, shrimp, andlobster)

• Yeast products (beer and bakedgoods)

10. Lin JL, Tan DT, HoHH, et al. Environ-mental lead expo-sure and urate ex-cretion in thegeneral population.Am J Med.2002;113:563-8.[PMID: 12459402]

11. Suppiah R, Dis-sanayake A, DalbethN. High prevalenceof gout in patientswith Type 2 dia-betes: male sex, re-nal impairment, anddiuretic use are ma-jor risk factors. N ZMed J. 2008;121:43-50. [PMID: 18841184]

12. Davidson MB,Thakkar S, Hix JK, etal. Pathophysiology,clinical conse-quences, and treat-ment of tumor lysissyndrome. Am JMed. 2004;116:546-54. [PMID: 15063817]

13. Giordano N, San-tacroce C, Mattii G,et al. Hyperuricemiaand gout in thyroidendocrine disorders.Clin Exp Rheumatol.2001;19:661-5.[PMID: 11791637]

14. Dehghan A, KöttgenA, Yang Q, et al. Association of threegenetic loci with uricacid concentrationand risk of gout: agenome-wide asso-ciation study. Lancet.2008;372:1953-61.[PMID: 18834626]

15. Chen SY, Chen CL,Shen ML, et al. Clini-cal features of famil-ial gout and effectsof probable geneticassociation betweengout and its relateddisorders. Metabo-lism. 2001;50:1203-7.[PMID: 11586494]

16. Coiffier B, Altman A,Pui CH, et al. Guide-lines for the man-agement of pedi-atric and adulttumor lysis syn-drome: an evidence-based review. J ClinOncol. 2008;26:2767-78. [PMID: 18509186]

17. Bosly A, Sonet A,Pinkerton CR, et al.Rasburicase (recom-binant urate oxi-dase) for the man-agement ofhyperuricemia in pa-tients with cancer:report of an interna-tional compassion-ate use study. Can-cer. 2003;98:1048-54.[PMID: 12942574]


Diseases associated with an increasedrisk for goutPatients with renal insufficiencyhave an increased risk for gout be-cause, as renal function decreases, sodoes renal clearance of uric acid(11). Hypertension, diabetes, hyper-lipidemia, and the metabolic syn-drome are also associated with in-creased risk for gout. Hematologicmalignant conditions predispose togout because of increased produc-tion of uric acid from rapid cellularturnover (12). Patients with hypo-thyroidism also have an increasedincidence of gout due to decreasedrenal plasma flow and impairedglomerular filtration of uric acid(13). To a lesser extent, patientswith hyperthyroidism may also havean increased risk due to increaseduric acid production. Psoriasis hasalso been associated with an in-creased risk for gout, probably fromincreased cell turnover in plaques.

Genetic risk factorsSeveral genetic variants have beenassociated with gout. One variantreduces the efficiency of uric acidtransport across the membranes ofthe kidney (4), whereas 2 othergene mutations are associated withhigh levels of uric acid (14, 15).

Inherited metabolic disorders, suchas hypoxanthine-guanine phospho-ribosyl transferase deficiency, phosphoribosyl pyrophosphate syn-thetase overactivity, and glucose-6-phosphatase deficiency, can leadto purine overproduction that pre-disposes a person to gout. Geneticdisorders, such as the Bartter syn-drome, polycystic kidney disease,and the Down syndrome, can alsolead to hyperuricemia via decreasedrenal clearance of urate.

Are there effective strategies forpreventing gout?Primary prevention of gout involveslifestyle changes to reduce risk fac-tors and lower serum urate levels, butprospective studies of the effective-ness of lifestyle changes are lacking.

Pharmacologic therapy of asymp-tomatic hyperuricemia is not recommended, because of the potential toxicity of long-termprophylactic treatment.

Drugs are required to preventgout in patients receivingchemotherapy for hematologicmalignant conditions. Uricacid–lowering drugs and hydra-tion reduce the risk for second-ary gout due to tumor lysis inthese persons. Without thistreatment, uric acid nephropathywith tubular obstruction can de-velop. Allopurinol, which pre-vents formation of uric acid fromproducts of purine breakdown ofnuclear material, must be initiat-ed 1 to 3 days before chemother-apy and, therefore, can delaytreatment. Because of allopuri-nol’s limitations for the preven-tion of the tumor lysis syndrome(16), rasburicase, a recombinantform of urate oxidase, recentlyapproved by the U.S. Food andDrug Administration (FDA), hasbecome a widely used alternative(17). The drug promotes conver-sion of uric acid to the more sol-uble allantoin. Table 1 showsstandard dosing. Patients whoare glucose-6-phosphatase defi-cient or allergic should not takerasburicase. There is a 10% inci-dence of developing antibodiesto this drug.

Is gout associated with increasedrisk for cardiovascular disease,and can this be prevented?High serum urate levels have beenassociated with serum markers ofinflammation, including C-reactiveprotein, fibrinogen, interleukin(IL)-6, and elevated neutrophilcounts (18–20). Cardiovasculardisease has also been associatedwith markers of inflammation (21).This shared association with chronicinflammation may explain why therisk for cardiovascular disease is increased in persons with gout orhyperuricemia.


Table 1. Drugs to Prevent or Treat GoutDrug (Mechanism of Action) Dose Benefits Side Effects and Notes

Prevention of Gout

Allopurinol (Xanthine Start at 100–200 mg/d, increase by 100 Most effective in long-term GI effects (nausea, diarrhea). Rash, headache, oxidase inhibitor; mg/d every 1–4 wk to serum urate prevention if urate level below urticaria, interstitial nephritis. Rare but inhibits uric acid goal. Average dose 400–600 mg/d, <365.9 mmol/L (6 mg/dL)*. devastating hypersensitivity reactions. Do not synthesis) maximum dose 800 mg/d. Modify use in acute attack; use colchicine to reduce

initial dose for elevated creatinine, acute flare when starting drug; not preferred divide doses to reduce GI toxicity. for prevention of the tumor lysis syndrome†.

Febuxostat (Xanthine Start 40–80 mg/d; increase dose to 80–120 Most effective in long-term Liver function abnormalities, diarrhea, oxidase inhibitor; inhi- mg/d to achieve goal urate level. Steady treatment if urate level headache, nausea, rash. No dose adjustment bits uric acid synthesis) state uric acid level after 2 wk of use. <365.9 mmol/L (6 mg/dL). for mild-to-moderate renal insufficiency.

Rasburicase 0.1 to 0.2 mg/kg Use for prevention of the Do not use if glucose-6 phosphatase deficient. (Recombinant form or intravenously for 1 to 7 d. tumor lysis syndrome. 10% incidence of autoantibodies. Start 4–24 h urate oxidase; promotes before chemotherapy.conversion of uric acidto allantoin)

Probenicid (Uricosuric) 0.5–2 g/d, divided twice per d and Most effective in long-term Do not use with aspirin. Increases methotrexate dose adjusted until serum urate prevention if urate level toxicity. Rare anaphylaxis. Use only if level normalizes. <365.9 mmol/L (6 mg/dL). underexcrete urate; twice-daily dosing required;

not effective in patients with renal disease. Colchicine, oral (Multiple 0.6 mg twice per d for CrCl ≥50 mL/min To prevent gout, combine GI intolerance with nausea, vomiting, or dia-

anti-inflammatory per 1.73 m2, 0.6 mg once per day for with allopurinol or probenicid rrhea. Bone marrow suppression. Myopathy or effects‡) CrCl 35 to 49 mL/min per 1.73 m2, or when starting therapy. neuropathy may be increased with renal disease

0.6 mg every 2 to 3 d for CrCL or statin use. Dermatitis, urticaria, alopecia,10 to 34 mL/min per 1.73 m2. Continue purpura. CYP3A4 inhibitor, so may need dosefor 6 mo after serum urate level adjustment with other inhbitors (clarithromycin<365.9 mmol/L (6 mg/dL) or until cyclosporine). May need to reduce dose withtophi disappear. calcium channel blockers. Avoid if CrCl <10

mL/min per 1.73 m2or if severe liver disease§.Acute Gout

Nonsteroidal anti- Varies by type of NSAID (e.g., naproxen, Effective in acute gout, GI bleeding, renal toxicity, hepatotoxicity. inflammatory drugs 750 mg initial dose then 250 mg within 12–24 h of onset. Risk for fluid overload especially if history of (Block formation of every 8 h, taper over 2–10 d to 1 wk)||. CHF. Increases blood pressure. Reversible inflammatory platelet dysfunction. Do not use if anticoagu-prostaglandins and lated. Avoid in elderly patients. Start quickly at analgesic effects) high dose, then rapidly taper. Do not use aspirin,

because it can increase urate levels. Use proton-pump inhibitor if history of GI bleeding¶.

Colchicine, oral (Multiple 0.6 mg 2 or 3 times per d until Relatively short time to GI intolerance with nausea, vomiting, or anti-inflammatory symptoms subside or GI intolerance therapeutic onset. diarrhea. Bone marrow suppression, effects‡) occurs. Alternatively, 1.2 mg myopathy, neuropathy, dermatitis, urticaria,

followed 1 h later by 0.6 mg. alopecia, purpura. Note: intravenouscolchicine no longer available. Start rapidly.Reduce dose for liver or renal disease andavoid if on dialysis. Avoid in elderly patients. GItoxicity dose-related. Bone marrow effects canbe severe at high doses. Myopathy and neuro -pathy occur at any dose. CYP3A4 interactions.

Corticosteroids, oral Prednisolone, 35 mg/d, or prednisone, Useful when NSAIDs are GI bleeding, especially in elderly patients. Do (Multiple anti- 40–60 mg/d (in divided doses) until contraindicated (e.g., renal not use if active peptic ulcer disease. Increases inflammatory effects) symptoms begin to subside, insufficiency). Preferred for blood glucose. Fluid retention. Impaired wound

then rapidly taper over several d. polyarticular gout. healing. Optimal steroid regimen still not clear.Corticosteroids, intra- Triamcinolone hexacetonide, 40 mg for Especially useful if only 1 Risk for damage to nerve, tendon, or vascular

articular (Multiple large joints, 5–20 mg for small joints. joint is inflamed and patient structures if administered improperly. Risk for anti-inflammatory Methylprednisolone acetate, 40–80 mg has contraindications to joint infection. Other side effects same aseffects) for large joints, 20–40 mg for other agents. those with oral formulation. Must be per-

small joints. Betamethasone acetate, formed by using sterile technique. Rule out 3–6 mg for large joints, infectious cause before injecting cortico-0.75–1.5 mg for small joints. steroid into joint.

CrCl = creatinine clearance; GI = gastrointestinal; NSAID = nonsteroidal anti-inflammatory drug.* Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009;11:135-40. [PMID: 19296886]† Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004;116:546-54. [PMID: 15063817]‡ Terkeltaub RA. Colchicine udate: 2008. Semin Arthritis Rheum. 2009;38:411-9. [PMID: 18973929]§ Terkeltab RA. Clinical practice. Gout. N Eng J Med. 2003; 349:1647–55. [PMID: 14573737]|| Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999;59:925-34. [PMID: 10068714]

Wallace SL, Singer JZ. Therapy in gout. Rheum Dis Clin North Am. 1988;14:441-57. [PMID: 3051159]¶ Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002:CD002296. [PMID: 12519573]

18. Coutinho Tde A,Turner ST, Peyser PA,et al. Associations ofserum uric acid withmarkers of inflam-mation, metabolicsyndrome, and sub-clinical coronary ath-erosclerosis. Am JHypertens.2007;20:83-9.[PMID: 17198917]

19. Kanellis J, Kang DH.Uric acid as a media-tor of endothelialdysfunction, inflam-mation, and vasculardisease. SeminNephrol. 2005;25:39-42. [PMID: 15660333]

20. Fröhlich M, Imhof A,Berg G, et al. Associ-ation between C-reactive protein andfeatures of the meta-bolic syndrome: apopulation-basedstudy. Diabetes Care.2000;23:1835-9.[PMID: 11128362]

21. Cao JJ, Arnold AM,Manolio TA, et al. As-sociation of carotidartery intima-mediathickness, plaques,and C-reactive pro-tein with future car-diovascular diseaseand all-cause mor-tality: the Cardiovas-cular Health Study.Circulation.2007;116:32-8.[PMID: 17576871]

22. Krishnan E, Baker JF,Furst DE, et al. Goutand the risk of acutemyocardial infarc-tion. ArthritisRheum.2006;54:2688-96.[PMID: 16871533]

23. Choi HK. Diet, alco-hol, and gout: howdo we advise pa-tients given recentdevelopments? CurrRheumatol Rep.2005;7:220-6.[PMID: 15918999]

24. Niskanen LK, Laakso-nen DE, NyyssönenK, et al. Uric acid lev-el as a risk factor forcardiovascular andall-cause mortality inmiddle-aged men: aprospective cohortstudy. Arch InternMed. 2004;164:1546-51. [PMID: 15277287]

25. Malik A, Schumach-er HR, Dinnella JE, et al. Clinical diag-nostic criteria forgout: comparisonwith the gold stan-dard of synovial fluidcrystal analysis. J ClinRheumatol.2009;15:22-4.[PMID: 19125136]

26. Mandell BF. Clinicalmanifestations of hy-peruricemia andgout. Cleve Clin JMed. 2008;75 Suppl5:S5-8.[PMID: 18822469]


Prevention and Screening…... Hyperuricemia is the most important risk factor forgout. However, other factors also affect this risk, because only 1 of 10 personswith hyperuricemia develops gout. Important predictors of gout in patients withhyperuricemia include age less than 60 years in men, diet high in nonvegetablepurines, alcohol consumption (especially beer and liquor), diuretic use, and obesi-ty. Several genetic variants place some families at increased risk for gout. Com-mon diseases that increase risk for gout include diabetes, the metabolic syn-drome, hyperlipidemia, hypothyroidism, and hypertension. Pharmacologic therapyof asymptomatic hyperuricemia is not recommended to prevent gout except whentreating hematologic malignant conditions. In patients with at least 1 gout at-tack, risk for recurrence needs to be reduced through lifestyle modifications, suchas dietary changes and gradual weight loss. In addition, patients should avoidmedications that increase serum urate levels.

CLINICAL BOTTOM LINE

In the Multiple Risk Factor InterventionTrial, the risk for nonfatal acute myocar-dial infarction (MI) was increased for per-sons with gout (adjusted odds ratio [OR],1.26 [CI, 1.14 to 1.40]; P < 0.001) and forpersons with hyperuricemia (adjustedOR, 1.11 [CI, 1.08 to 1.15]), but fatal acuteMI was not associated. In persons withincident diabetes mellitus, a history ofgout was associated with a more than 2-fold increase in the adjusted OR of acuteMI (2.49 [CI, 1.97 to 3.13]) (22).

Because of these associations, somehave recommended identifying per-sons with hyperuricemia beforethey develop gout to avert associat-ed diseases (23), whereas othershave reported that the increasedrisk for cardiovascular disease andall-cause mortality associated withan elevated serum urate level is notmodifiable (24). Studies to clarifythis issue are underway.

DiagnosisAssociated fever and constitutionalfeatures are sequelae of the releaseof cytokines. Because lower temper-atures favor crystal deposition, thehelix of the ear and lower extremi-ties (that is, midfoot, first metatar-sophalangeal joint, ankle, or knee)are often sites of crystal depositionand tophus development. Crystalsare also more likely to form in pre-viously diseased joints; persons withother forms of arthritis have in-creased risk for gout. Acute flaresalso occur in periarticular structures,including bursae and tendons (suchas the olecranon bursa and bursaearound the knee).

Gout attacks initially subside in 3to 14 days without treatment, inpart because crystals dissolve, arephagocytized, or are resequesteredin the synovial tissue. Althoughthe symptoms may resolve, crystalsare still present in the joint and

What symptoms and physicalexamination findings suggestgout?A patient report of episodic self-limited joint pain, swelling, and ery-thema is highly sensitive but notspecific for gout. Specificity is in-creased to about 80% to 90% by ahistory of podagra (attack in thefirst metatarsophalangeal joint) andthe finding of a possible tophus(chalky deposits of MSU in soft tis-sues around joints and helix of ear)(25). Patients often report recenttrauma, which can trigger the re-lease of crystals into the joint space,resulting in an attack of gout. At-tacks often begin in the middle ofthe night or early morning.

On examination, gout is character-ized by warmth, swelling, redness,and is usually accompanied by se-vere joint pain. An estimated 90%of first attacks are monoarticular.

27. Schlesinger N,Norquist JM, WatsonDJ. Serum urate dur-ing acute gout. J Rheumatol.2009;36:1287-9.[PMID: 19369457]

28. Wallace SL, Robin-son H, Masi AT, et al.Preliminary criteriafor the classificationof the acute arthritisof primary gout.Arthritis Rheum.1977;20:895-900.[PMID: 856219]


attacks are likely to recur. The es-timated flare recurrence rate is60% in 1 year after the initial at-tack, 78% in 2 years, and 84% in 3years (26). Crystalline deposits of-ten grow if untreated, resulting inchronically stiff and swollen joints.Subsequent attacks tend to lastlonger and may involve morejoints or tendons. Chronic goutcan involve multiple joints andmimic rheumatoid arthritis.

Tophi are collections of MSU crys-tals that incite a chronic granuloma-tous inflammatory response, formingcool lumps in the tissues around af-fected joints and the helix of the ear.Some patients have tophi as the pre-senting physical finding. Tophi in-volving Heberden nodes (osteo-arthritis of distal interphalangealjoint) or the finger pads are partic-ularly characteristic of gout in eld-erly women taking diuretics.

What tests can diagnose gout?Many patients do not have a suffi-ciently high probability of gout todiagnose the first attack definitelyby clinical and laboratory testsalone. Serum urate levels are help-ful but may be normal during anacute flare (Box). Conversely,hyper uricemia can occur in asymp-tomatic persons (27). The diagnosisis best established by documentingthe presence of MSU crystals ob-tained by aspirating the fluid froman inflamed joint or a suspected tophus. Crystals of needle or rod-shaped MSU in polymorpho-nuclear leukocytes are seen in thesynovial fluid and confirmed by us-ing polarized microscopy. In mate-rial aspirated from a tophus, thecrystals tend to be seen alone, be-cause the material is usually acellular.Birefringent crystals are also typicalof pseudogout, which is caused bycalcium pyrophosphate dihydratecrystals (Table 2) but can be distin-guished from MSU crystals becausethey diffract polarized light moreweakly and more often have arhomboid or shorter rod shape.

When gout is suspected, order acell count with differential and cul-ture as part of the synovial fluid examination to help define the di-agnosis. Accumulations of joint flu-id due to acute or chronic gout arealmost always inflammatory in na-ture, with leukocyte counts between2 to 75 × 109 cells/L. If the leuko-cyte count is very high (>75 × 109

cells/L), septic arthritis should beconsidered, even in the presence ofMSU crystals. Be aware of substan-tial overlap between the leukocytecell counts in gout and septicarthritis. For example, most episodesof joint sepsis occur in joints thatare already diseased, including jointsthat have been affected by gout. Anadequate examination of synovialfluid can avert unnecessary jointlavage, arthroscopy, or arthrotomy.

Joint aspiration sometimes fails toestablish the diagnosis, such aswhen no crystals are seen or no flu-id is obtained. Patients may declinethe procedure or have contraindica-tions. The preliminary AmericanCollege of Rheumatology criteriafor the definition of gout offers al-ternatives to establish the diagnosis(Box) (28). However, the purelyclinical aspects of these criteriawithout examination of joint fluidmay not have adequate accuracy fordistinguishing gout from rheuma-toid arthritis or other inflammatoryjoint diseases (25).

What is the value of radiographyor ultrasonography in thediagnosis of gout?In acute gout attacks early in thecourse of disease, radiographymay occasionally help rule outother causes of joint pain andswelling, such as fractures or cal-cium pyrophosphate depositiondisease (pseudogout). Later in thecourse of disease, radiography canshow more long-term changesdue to gout. However, gout is lesslikely to cause joint space–narrowing than is either psoriaticarthritis or rheumatoid arthritis

Tests Useful in Gout Diagnosis• Serum urate level• Complete blood count with differ-

ential (if considering septicarthritis)

• Serum creatinine• Examination of synovial fluid or

tophus aspirate (polarized mi-croscopy, cell count, culture)

• Radiography (especially rule outother causes)

American College ofRheumatology PreliminaryCriteria for Diagnosis of GoutThe presence of characteristic urate

crystals in the joint fluid duringattack, or

A tophus proved to contain uratecrystals by chemical or polarizedlight microscopic means, or

6 of the following criteria:• More than 1 attack of acute

arthritis• Maximum joint inflammation

developed within 1 day• Monoarticular arthritis (although

gout can be polyarticular)• Redness of joint• First metatarsophalangeal joint

pain or swelling• Unilateral first metatarsopha-

langeal joint attack• Unilateral tarsal joint attack• Suspected tophus• Hyperuricemia• Asymmetrical swelling within the

joint on radiography• Subcortical cysts without erosions

on radiography• Joint fluid culture negative during

attack


(Table 2). Unlike radiographicfindings in rheumatoid arthritis,chronic gout shows a prominent,proliferative bony reaction, andtophi can cause bone destructionaway from the joint.

What conditions are in thedifferential diagnosis of gout?Gout is commonly confused withother conditions. Key features ofdiseases that can be confused withgout are shown in Table 2.

Table 2. Differential Diagnosis of GoutDisease Characteristics Notes

Rheumatoid arthritis Symmetrical polyarthritis preferentially in small joints of hands Acute rheumatoid arthritis synovitis and feet. Affects about 1% of the population. Subcutaneous sometimes mimics gout. Involvement of many rheumatoid nodules in about 20% of patients with rheumatoid joints makes rheumatoid arthritis the more arthritis. Radiographic changes include soft-tissue swelling, likely diagnosis. Hands more likely to be diffuse joint-space narrowing (within a joint), marginal erosions of involved in rheumatoid arthritis than in gout.small joints, and symmetrical multiple joint involvement. Usually osteopenic and without signs of repair (osteophytes).

Calcium pyrophosphate Can mimic osteoarthritis or gout. Resembles osteoarthritis or Diagnosed by CPPD crystals in synovial fluid deposition disease rheumatoid arthritis on radiography, but some evidence of bony and by chondrocalcinosis on radiography (pseudogout) repair (osteophytes or lack of osteopenia) is usually present. (most commonly in fibrocartilage)

Cartilage calcification, especially in fibrocartilage of knee meniscus, Concomitant crystal disease (calcium symphysis pubis, glenoid and acetabular labrum, and triangular pyrophosphate dihydrate deposition, cartilage of wrist, is pathognomonic for CPPD. Osteoarthritis in hydroxyapatite) is increasingly common with unusual places (wrist, elbow, metacarpophalangeal joints, or age in a hallux valgus (bunion), causing shoulder) without a history of trauma should suggest CPPD. potential confusion with gout.Affects 10% to 15% of persons older than 65 years.

Septic arthritis Fever, arthritis, great tenderness. Joint sepsis may occur in Must be diagnosed early to avoid joint previously abnormal joints, and up to one half have concomitant destruction.rheumatoid arthritis. The source (skin, lungs) is often evident. Radiography generally shows swelling and effusion. If not treated promptly, damage occurs, with diffuse joint-space narrowing.

Cellulitis Patient has erythema and swelling of extremity that is very tender Infection often due to Staphylococcus or and is often febrile. Soft-tissue lymphatic drainage often abnormal Streptococcus infection. Joint examination because of peripheral venous insufficiency, previous surgery, or may be difficult, but if painful to move joint, previous infection in the area. Radiography shows soft-tissue aspiration is recommended.swelling but no joint changes.

Reactive arthritis Inflammatory oligoarthritis, weight-bearing joints often affected Patient usually has had infection with an and may have tendon insertion inflammation. Fingers and toes may appropriate organism (Salmonella, Shigella, resemble sausages (dactylitis). Extraarticular manifestations include Yersinia, Campylobacter, or Chlamydia species conjunctivitis, urethritis, stomatitis, and psoriaform skin changes. or intravesicular bacilli Calmette–Guérin) Soft-tissue swelling on radiography. The only acute bony change within 3 weeks before onset of initial attack.is dactylitis.

Fracture or trauma Tenderness along the affected bony surface. History of trauma, Radiography should show fracture (more than except stress fractures. Radiography should show disruption of the 1 view may be required).cortex related to the fracture.

Osteoarthritis Bony enlargement, no acute signs of inflammation (erosive changes Hallux valgus (bunion) is very common and is can be seen in Heberden nodes and confused with gout) but acute the most commonly affected joint (as in gout).exacerbations of joint symptoms, especially after use. Radiography may show focal joint-space loss, bony repair with osteophytes, subchondral sclerosis. Central erosions sometimes in finger joints.

Psoriatic arthritis Joint distribution and appearance similar to reactive arthritis. Patients with psoriasis may have elevated uric Predilection for distal interphalangeal joints of fingers, often with acid levels proportional to proliferative state concomitant nail changes. Radiography similar to reactive arthritis, of skin.with soft-tissue swelling and possible dactylitis. If long-standing, the patient may have diffuse joint-space narrowing. Small joints of hands may also have central erosions. Some tendency to have subchondral sclerosis and other signs of bony repair.

Sarcoidosis Acute disease (the Lofgren syndrome) generally involves ankles, Parotitis, uveitis, hilar adenopathy, or lung sometimes with erythema nodosum or subcutaneous nodules. involvement are features of sarcoidosis but Radiography may show subcutaneous nodules and soft-tissue swelling. not of gout.

CPPD = calcium pyrophosphate dihydrate.


Diagnosis…... Misdiagnosis of gout is common, and joint pain and hyperuricemiaalone will not establish the diagnosis. It is established by documenting the pres-ence of MSU crystals or is strongly suggested by fulfilling the clinical criteriafrom the American College of Rheumatology preliminary definition. In patientsnot known to have gout, clinicians should order tests to measure serum urate andserum creatinine levels and aspirate synovial fluid from an involved joint or asuspected tophus. Joint fluid from gout can resemble fluid obtained from a jointwith pseudogout or septic arthritis, but the former can be distinguished by askilled examination of the type of crystals, and the latter can be distinguished byconstitutional symptoms and cultures. Radiography and ultrasonography may alsobe useful in distinguishing other forms of inflammatory joint disease from gout.


Treatmentdrinking plenty of water may re-duce the risk for recurrence.

Diets high in fiber, vitamin C, fo-late (for example, fruits and vegeta-bles), and dairy products seem tobe protective.

Clinicians should review the med-ications that their patients are tak-ing and identify any that may impair uric acid secretion. Thiazidediuretics and low-dose aspirin arethe most common drugs to inter-fere with handling of uric acid bythe kidney. When possible, substi-tute another drug that does not ad-versely affect uric acid excretion.

What is the role of drug therapyin the acute treatment of gout?Acute attacks of gout often have arapid onset and last 1 week withouttreatment. Optimum managementof acute gout requires pain relief andcontrol of inflammation. The choiceof agents depends largely on patientcharacteristics and especially on co-morbid conditions (Table 1).

NSAIDsFor mild-to-moderate pain,NSAIDs are usually the first-linetherapy because of combined anal-gesic and anti-inflammatory effects.Two to 10 days of NSAIDS is usu-ally enough to treat a gout attack.Ibuprofen and naproxen seem to beas effective as indomethacin but bet-ter tolerated.

When should clinicians considerhospitalizing a patient with gout?Because acute gout can be difficultto distinguish from septic arthritiswithout careful joint fluid analysis,it may be necessary to hospitalizethe patient and administer empiri-cal antibiotics until a definite diag-nosis can be established. Promptantibiotic treatment for septicarthritis is needed to prevent severejoint destruction and disability. Re-peated synovial fluid analysis maybe warranted for cell count, bacteri-al culture, and the presence or ab-sence of MSU crystals to establisha definitive diagnosis.

Gout is one of the most painfulconditions known. Effective painmanagement is essential. Patientswhose pain cannot be controlled byoutpatient analgesics, such as non-steroidal anti-inflammatory drugs(NSAIDs) or oral narcotics, mayalso need to be hospitalized. Aspi-ration of the joint may improvepain if sufficient fluid is removed todecrease intra-articular pressure.

What is the role of nondrugtherapy in managing patients whoalready have gout?Long-term management of gout canbe improved by lifestyle changes,such as reducing consumption offoods high in purines, alcohol, andhigh-fructose and sugary drinks.Weight loss may decrease serumurate levels. Staying hydrated by


Aspirin should not be used, becauselow-to-moderate doses increase therisk for gout and high doses are tootoxic. Initiating treatment quickly isessential. To hasten the anti-inflammatory action, start theNSAID at a higher dose and taperover about 1 week (29, 30). Gastro -intestinal toxicity from NSAIDs isan important concern. Proton-pump inhibitors can reduceNSAID ulcers by more than 50%versus no treatment (31).

ColchicineColchicine has long been a mainstayfor the treatment of acute gout be-cause it has many anti-inflammatoryeffects (32). However, colchicine hasa narrow therapeutic window due tocommon side effects. Doses shouldbe reduced for renal or hepatic dys-function. It should be avoided inelderly persons, and should not beadministered with other strongCYP3A4 inhibitors.

The FDA recently withdrew ap-proval for all intravenous prepara-tions of colchicine. Oral colchicinetreatment is most effective when ini-tiated 12 to 36 hours after the startof an acute gouty attack. Only 1small randomized trial has been con-ducted of a higher-dose regimen(that is, oral colchicine, 1 mg, andthen 0.5 mg every 2 hours until acomplete response or toxicity devel-oped) (33). Although colchicine re-duced pain by 50% in nearly threequarters of treated patients, all treat-ed patients developed diarrhea orvomiting after a median of 24 hoursof treatment or a mean dose of 6.7mg. Currently, experts recommendtreating with lower doses of oralcolchicine (0.6 mg 2 to 3 times perday), but the efficacy of this regimenhas not been evaluated in random-ized, controlled trials (34). A recentpresentation reported that colchicine,1.2 mg, followed 1 hour later with0.6 mg, was effective in treating acutegout (35). Myopathic effects andmyelosuppression are rare with short-term treatment.

CorticosteroidsCorticosteroids are the preferredtreatment for acute gout in patientswith renal insufficiency or other con-traindications to NSAIDs. Formonoarticular gout, an intra-articularcorticosteroid injection can be veryeffective. Oral corticosteroids are pre-ferred for polyarticular gout. In a ran-domized trial, prednisolone, 35 mg/d,was similar in effectiveness tonaproxen, 500 mg twice per day (36).Patients with diabetes may developincreasing hyperglycemia while tak-ing corticosteroids.

NarcoticsWhen pain is severe, narcotic anal-gesics can be used on a short-termbasis until the inflammatory processstarts to resolve, but this has notbeen rigorously studied. Combina-tions of oxycodone, hydrocodone, orcodeine may be given orally. In se-vere cases, morphine may be givenintravenously or subcutaneously, ormeperidine may be given intra-venously or intramuscularly.

What is the role of drug therapyto prevent gout and complicationsof hyperuricemia?For patients who have had severalgout attacks, long-term pharma-cotherapy should be started duringan intercritical period when thedisease is quiescent, with the goal ofdecreasing and maintaining serumurate levels in the normal range(Box). Treatment is also warrantedfor patients with tophi or jointdamage seen on radiography (37).Patients who have had just 1 attackor an unusually high serum uratelevel may prefer to be treated afterdiscussing the pros and cons of me-diations. In addition, it is also im-portant to prevent nephrolithiasisdue to uric acid stones, which occurin 10% to 40% of patients with gout.

Tophi can be dissolved by decreasingthe serum urate level to low levels,such as 237.9 to 297.4 µmol/L (4 to5 mg/dL), that seem to promotemore-rapid dissolution of crystals and

29. Harris MD, Siegel LB,Alloway JA. Goutand hyperuricemia.Am Fam Physician.1999;59:925-34.[PMID: 10068714]

30. Wallace SL, SingerJZ. Therapy in gout.Rheum Dis ClinNorth Am.1988;14:441-57.[PMID: 3051159]

31. Rostom A, Dube C,Wells G, et al. Pre-vention of NSAID-in-duced gastroduode-nal ulcers. CochraneDatabase Syst Rev.2002:CD002296.[PMID: 12519573]

32. Terkeltaub RA.Colchicine update:2008. Semin ArthritisRheum. 2009;38:411-9. [PMID: 18973929]

33. Ahern MJ, Reid C,Gordon TP, et al.Does colchicinework? The results ofthe first controlledstudy in acute gout.Aust N Z J Med.1987;17:301-4.[PMID: 3314832]

34. Baker JF, Schumach-er HR. Update ongout and hyper-uricemia. Int J ClinPract. 2009.[PMID: 19909378]

35. Terkeltaub R, FurstDE, Bennett K, et al.Colchicine efficacyassessed by time to50% reduction ofpain is comparablein low dose andhigh dose regimens:secondary analysesof the AGREE trial(poster). AmericanCollege of Rheuma-tology Annual Scien-tific Meeting; 19 October 2009;Philadelphia. Accessed at http://acr.confex.com/acr/2009/webprogram/Paper15030.html on18 December 2009.

Long-Term Treatment ofHyperuricemia Is RecommendedAfter Discussion With thePatient Who Has:• At least 2 or 3 acute attacks of

gout• Tophaceous gout• Severe attacks or polyarticular at-

tacks• Radiographic evidence of joint

damage from gout• Identifiable inborn metabolic defi-

ciency causing hyperuricemia• Nephrolithiasis


tophi (38). Patients with tophi almostalways require lifelong therapy.

In a trial of stopping of urate-loweringmedications in patients treated for 5 yearswho had no palpable tophi and mean uricacid levels during that time of less than416.4 μmol/L (<7 mg/dL), nearly half had arecurrence of gout attacks from 6 to 60months after therapy had been discontin-ued (39). Uric acid levels returned to thelevel before urate-lowering therapy wasused (mean of 535.4 μmol/L [9 mg/dL]).

Hyperuricemia is related to diminished re-nal function. A systematic review of 9prospective cohort studies reported that 8identified an independent association be-tween hyperuricemia and development ofrenal insufficiency (40). Research is current-ly being conducted to evaluate whethertreating hyperuricemia can prevent or re-duce a decline in renal function.

UricosuricsTissue MSU deposits can be elimi-nated only if the concentration gradi-ent between the tissues and serum isadequate. Hyperuricemia results fromeither overproduction/overconsump-tion or low renal excretion. To distin-guish these when uricosuric therapy isbeing considered, a 24-hour urine col-lection for uric acid and creatinineshould be performed. The urine is col-lected during an intercritical period.Renal excretion is low if the level ofuric acid in the urine collection is lessthan 600 to 700 mg/d while consum-ing a low-purine diet. Treatment witha uricosuric drug is warranted forunder excretion of uric acid.Probenecid is the only uricosuricavailable in the United States. A uri-cosuric drug should not be used in pa-tients with nephrolithiasis because itcan promote the formation of stones.

Xanthine oxidase inhibitorsAllopurinol and a recently FDA-approved drug, febuxostat, are xanthineoxidase inhibitors that inhibit the ac-tivity of an enzyme involved in purinemetabolism, thus decreasing uric acidproduction and lowering serum uratelevels. When starting treatment withthese drugs, it is important to wait un-til an acute attack of gout has resolved,

because these drugs mobilize uric acidfrom tissue deposits, prolonging at-tacks. To decrease the likelihood of agout flare while starting treatment, allopurinol should be started at theminimal effective dose and the doseincreased until the goal of a serumurate level less than 356.9 µmol/L (6 mg/dL) has been achieved (41)(Table 1). Concurrent colchicine pro-phylaxis may help decrease flares.Gastrointestinal side effects of allop-urinol are dose-dependent but gener-ally mild with doses under 300 mg/d.At higher doses, side effects may bereduced by giving the drug in divideddoses. Allopurinol may be combinedwith uricosurics, such as probenecid, ifallopurinol is ineffective; however, thismay compromise the uric acid–lower-ing effect of allopurinol by promotingexcretion of this drug and its majoractive metabolite, oxypurinol.

While patients are taking allopurinol,it is important to monitor the liverpanel, chemistry profile, and completeblood count regularly in conjunctionwith the serum urate level before andafter starting allopurinol treatment.Asymptomatic increases in liver en-zymes can occur in up to 5% of pa-tients, and serious hepatotoxicity canoccasionally occur (41).

It is recommended to reduce the doseof allopurinol in patients with renal in-sufficiency and to warn patients to im-mediately report side effects, such as arash. The rash is typically macu-lopapular with pruritus and occurs inabout 2% of patients. A rash is morecommon when the patient is alsotreated with ampicillin or amoxicillin.The allopurinol hypersensitivity syn-drome is a serious complication, occur-ring in 1 to 4 patients per 1000, withdeath occurring in up to one quarter ofcases (42). This hypersensitivity syn-drome has multiple manifestations, in-cluding a severe cutaneous reactions,such as the Stevens–Johnson syn-drome, eosinophilia, leukocytosis, fever,hepatitis, or renal failure. It is probablydue to cell-mediated immunity to al-lopurinol and oxypurinol (43).

36. Janssens HJ, JanssenM, van de LisdonkEH, et al. Use of oralprednisolone ornaproxen for thetreatment of goutarthritis: a double-blind, randomisedequivalence trial.Lancet.2008;371:1854-60.[PMID: 18514729]

37. EULAR StandingCommittee for Inter-national ClinicalStudies IncludingTherapeutics. EULARevidence based rec-ommendations forgout. Part II: Man-agement. Report ofa task force of theEULAR StandingCommittee for Inter-national ClinicalStudies IncludingTherapeutics (ES-CISIT). Ann RheumDis. 2006;65:1312-24.[PMID: 16707532]

38. Perez-Ruiz F, Calabo-zo M, Pijoan JI, et al.Effect of urate-low-ering therapy on thevelocity of size re-duction of tophi inchronic gout. Arthritis Rheum.2002;47:356-60.[PMID: 12209479]

39. Perez-Ruiz F, Atxote-gi J, Hernando I, etal. Using serumurate levels to deter-mine the period freeof gouty symptomsafter withdrawal oflong-term urate-lowering therapy: aprospective study.Arthritis Rheum.2006;55:786-90.[PMID: 17013833]

40. Avram Z, Krishnan E.Hyperuricaemia—where nephrologymeets rheumatol-ogy. Rheumatology(Oxford).2008;47:960-4.[PMID: 18443007]

41. Chao J, Terkeltaub R.A critical reappraisalof allopurinol dos-ing, safety, and effi-cacy for hyper-uricemia in gout.Curr Rheumatol Rep.2009;11:135-40.[PMID: 19296886]

42. Hande KR, NooneRM, Stone WJ. Se-vere allopurinol toxi-city. Description andguidelines for pre-vention in patientswith renal insuffi-ciency. Am J Med.1984;76:47-56.[PMID: 6691361]

43. Braden GL, Warzyns-ki MJ, Golightly M, etal. Cell-mediated im-munity in allopuri-nol-induced hyper-sensitivity. ClinImmunol Im-munopathol.1994;70:145-51.[PMID: 8299230]

44. Becker MA, Schu-macher HR Jr, Wort-mann RL, et al.Febuxostat com-pared with allopuri-nol in patients withhyperuricemia andgout. N Engl J Med.2005;353:2450-61.[PMID: 16339094]

45. Schumacher HR Jr,Becker MA, Lloyd E,et al. Febuxostat inthe treatment ofgout: 5-yr findings ofthe FOCUS efficacyand safety study.Rheumatology (Ox-ford). 2009;48:188-94. [PMID: 19141576]

46. Edwards NL. Febux-ostat: a new treat-ment for hyperuri-caemia in gout.Rheumatology (Ox-ford). 2009;48 Suppl2:ii15-ii19.[PMID: 19447778]

47. Borstad GC, BryantLR, Abel MP, et al.Colchicine for pro-phylaxis of acuteflares when initiatingallopurinol forchronic gouty arthri-tis. J Rheumatol.2004;31:2429-32.[PMID: 15570646]

48. Justiniano M, Dold S,Espinoza LR. Rapidonset of muscleweakness (rhab-domyolysis) associ-ated with the com-bined use ofsimvastatin andcolchicine. J ClinRheumatol.2007;13:266-8.[PMID: 17921794]

49. So A, De Smedt T,Revaz S, et al. A pilotstudy of IL-1 inhibi-tion by anakinra inacute gout. ArthritisRes Ther. 2007;9:R28.[PMID: 17352828]


Febuxostat has recently been approvedby the FDA for treatment of hyper-uricemia and gout. In a randomizedtrial, febuxostat was more effective (ata dose of either 80 or 120 mg/d) thanlower-dose allopurinol (300 mg/d) inreducing uric acid to less than 356.9µmol/L (6 mg/dL) (44). A 5-yearstudy of using febuxostat showed thatit nearly eliminated gout flares (45).Febuxostat does not require dose ad-justment for mild-to-moderate renalimpairment. A recent review reportedthat allopurinol and febuxostat had asimilar incidence of minor side effects,but it is not clear whether febuxostatwas associated with greater cardiovas-cular side effects (46).

ColchicineTo prevent gout flares, colchicinecan be combined with allopurinolor probenecid. Dosing of colchicineis based on renal function. It shouldnot be used in patients with severerenal insufficiency or hepatobiliarydysfunction (47) (Table 1).

A small randomized trial in patients start-ing allopurinol found that low-dosecolchicine (0.6 mg twice per day) signifi-cantly reduced the frequency and severityof gout flares (47). If diarrhea developed, itwas generally managed by reducing thedose to 0.6 mg once per day.

Colchicine treatment is generallycontinued for 6 months after theserum urate level is less than 356.9µmol/L (6 mg/dL) or until tophidisappear. Emerging research indi-cates that the dose of colchicineshould be reduced in patients re-ceiving calcium-channel blockers toreduce adverse effects (37). Cautionwhen used with other strongCYP3A4 inhibitors. Long-termcolchicine in patients with renaldisease or statin use can cause neu-romyopathy (48).

NSAIDsNSAIDs have not been specificallystudied as anti-inflammatory prophy-lactic agents, but they may be prefer-able when there is pain from jointdamage, such as from osteoarthritis.

New medications under investigationResearch has indicated that IL-1inhibition might be effective in re-lieving inflammation associatedwith acute gout, because via activa-tion of the inflammasome, MSUcrystals stimulate monocytes andmacrophages to release IL-1 β. AnIL-1 inhibitor called anakinra isbeing investigated off-label to treatgout flares not responsive to usualtreatment. Other IL-1 antagonistsare also under study.

In a small, open-label trial of 10 patientswith gout who were intolerant of or did notrespond to standard anti-inflammatorytherapies, anakinra (100 mg/d subcuta-neous for 3 d) resulted in 100% responserate in 48 hours or less and 79% mean painimprovement with no adverse effects (49).

In addition, pegloticase is a recom-binant, pegylated formulation of amodified mammalian urate oxidasein late-stage development for treat-ment-failure gout to control hyper-uricemia as well as treat gout.

When should clinicians considerspecialty consultation for patientswith gout?Misdiagnosis of gout is common(50). Consultation with a rheuma-tologist or orthopedist should beconsidered for suspicion of jointsepsis, poorly controlled gout, un-usual features of possible gout, orgout along with other forms ofarthritis. A specialist in rheumatol-ogy or inherited metabolic diseasesshould be asked to consult foryoung patients with gout (for ex-ample, younger than 20 years)

Recent evidence suggests that manyprimary-care physicians do not man-age gout well.

In an analysis of 10 British primary-carepractices, 60% of patients with acute gouttook high-dose regimens of colchicine thatare not recommended. Only 23% of pa-tients had treatment for hyperuricemiawithin 1 year after a gout attack (51).

In a retrospective, case–control study of138 consecutive in-patients with gout,57% had a rheumatology consultation.

50. Wolfe F, Cathey MA.The misdiagnosis ofgout and hyper-uricemia. J Rheuma-tol. 1991;18:1232-4.[PMID: 1941830]

51. Roddy E, Mallen CD,Hider SL, et al. Pre-scription and co-morbidity screeningfollowing consulta-tion for acute goutin primary care.Rheumatology (Ox-ford). 2010;49:105-11. [PMID: 19920095]

52. Barber C, ThompsonK, Hanly JG. Impactof a rheumatologyconsultation serviceon the diagnosticaccuracy and man-agement of gout inhospitalized pa-tients. J Rheumatol.2009;36:1699-704.[PMID: 19567626]


Patients with a consultation were morelikely to have had a synovial fluid analysis(P < 0.001) and to have fulfilled preliminaryAmerican College of Rheumatology criteriafor gout than those without a consultation(65% vs. 37%; P = 0.002). Rheumatologycare was associated with more treatmentwith intra-articular corticosteroids (44% vs.12%; P < 0.001) and more care consistentwith European League Against Rheuma-tism (EULAR) recommendations (52).

In addition, consultation with anephrologist can help in manag-ing patients with renal insuffi-ciency or urate nephropathy andits implications for drug therapy.A consultant may aid in investi-gation of drug interactions, tim-ing of uric acid–lowering thera-pies, and assessment forunderlying causes of gout.

Treatment…... Differentiating acute gout from other forms of inflammatoryarthritis, especially septic arthritis and pseudogout, is challenging. When septicarthritis is a possibility, aspirate and analyze joint fluid promptly. If infection is aconcern, hospitalize patients and administer empirical antibiotics until a definitediagnosis is established. Patients whose gout-related pain cannot be controlledwith outpatient analgesics may need to be hospitalized. Optimum managementof acute gout requires control of inflammation as well as pain relief, usually withNSAIDs, colchicine, or corticosteroids. For patients with chronic gout, long-termpharmacotherapy is advised to reduce and maintain serum uric acid levels at lessthan 356.9 µmol/L (6 mg/dL). Medication and lifestyle changes, including dietarymodifications, weight loss, and reducing alcohol consumption, may reduce recur-rence. Consultation with a rheumatologist is warranted for guidance in diagnosisand management of unusual or complex cases.


Practice Improvementother treatments. Colchicine offers

an effective alternative but may beslower to work than NSAIDs. Inregard to prevention, the guidelinewith the strongest evidence was toco-administer colchicine with allop-urinol or a uricosuric drug for up to6 months.

The European League AgainstRheumatism (EULAR) issued aguideline regarding evidence-basedrecommendations for the diagnosisof gout (www.ard.bmj.com/cgi/content/abstract/65/10/1301?siteid=bmjjournals&ijkey=7jOEXurujRa0k&keytype=ref ). They de-veloped 10 key recommendations,with the primary points being:MSU crystals are very likely to beidentified from joint fluid duringacute gout; classic podagra andpresence of tophi have the highestclinical diagnostic value for gout;hyperuricemia may be a useful di-agnostic marker; radiography haslittle role in diagnosis except in late

Are there practice guidelinesrelevant to gout prevention andmanagement?In 2007, the British Society forRheumatology/British Health Pro-fessionals in Rheumatology releaseda guideline on management of gout(www.rheumatology.oxfordjournals.org/cgi/content/full/kem056av1).The recommendations on acute goutattack management with thestrongest evidence base include start-ing analgesic, anti-inflammatorydrug therapy immediately and con-tinuing it for 1 to 2 weeks; treatingwith fast-acting oral NSAIDs atmaximum doses when patients haveno contraindications; prescribingconcurrent gastroprotective agentswhen patients have an increased riskfor peptic ulcers, bleeding, or perfo-ration; continuing allopurinol duringan attack in patients already takingthis drug; and using corticosteroidsin patients who cannot tolerateNSAIDs or who are refractory to

inthe

c linicTool Kit

in the clinic

Gout

PIER Modulehttp://pier.acponline.orgAccess the PIER modules on gout and arthrocentesis. PIER modules provide evidence-based, updated information on current diagnosis and treatment in an electronic format de-signed for rapid access at the point of care.

Patient Informationwww.rheumatology.org/public/factsheets/diseases_and_conditions/gout.asp?aud=patwww.rheumatology.org/publications/classification/gout.aspPatient-oriented information about gout from the American College of Rheumatology.http://pier.acponline.org/physicians/public/d160/pt.educ/d160-s8.htmlInformation for patients from the ACPs PIER module on gout.www.arthritis.org/foods-for-gout.phpInformation about safe foods for persons with gout.www.niams.nih.gov/Health_Info/Gout/gout_ff.asp (English)www.niams.nih.gov/Portal_en_espanol/Informacion_de_salud/Gota/default.asp (Spanish)Information about gout in English and Spanish for patients by the National Institute ofAllergy and Infectious Diseases.www.niams.nih.gov/Health_Info/Gout/default.aspAnswers to questions about gout from the National Institutes of Health.www.nlm.nih.gov/medlineplus/gout.htmlAccess MEDLINE Plus information about gout for patients, including an interactive tu-torial available in both English and Spanish.http://pier.acponline.org/physicians/public/d160/figures/d160-figures.htmlAccess figures showing tophaceous material viewed under light microscopy and polarizedmicroscopy and gout-related photos and information on joint aspiration.

2 February 2010Annals of Internal MedicineIn the ClinicITC2-14© 2010 American College of Physicians

or severe gout; and risk factors (forexample, diet or diuretics) and co-morbid conditions (for example,chronic renal failure or diabetes) areassociated with gout (37).

The EULAR also issued a guide-line regarding management ofgouts (ww.ard.bmj.com/cgi/content/abstract/65/10/1312?siteid=bmjjournals&ijkey=uZK1Nk6Uq8MCs&keytype=ref ). Recommenda-tions address patient educationabout modifying lifestyle risk fac-tors and appropriate treatment ofassociated comorbid conditions andother risk factors (for example,stopping diuretics). They also rec-ommended managing acute attackswith NSAIDs, intra-articular corti-costeroids, or colchicine. Urate-lowering therapy was recommendedfor patients with recurrent attacks,tophi, arthropathy, or radiographicchanges of gout. Allopurinol waspreferred for attack prevention. Al-ternatives included a uricosuric, al-lopurinol desensitization for thosewith an allergy, or other xanthineoxidase inhibitors. For prophylaxisagainst acute attacks, eithercolchicine or an NSAID are rec-ommended.

Are there quality measuresrelevant to the prevention andmanagement of gout?The National Quality MeasuresClearinghouse lists 4 measures relat-ed to gout (www.qualitymeasures.ahrq.gov/search/searchresults.aspx?Type=3&txtSearch=gout&num=20):1) the proportion of patients withhyperuricemia and gouty arthritiswho were offered treatment with aurate-lowering drug; 2) the propor-tion of patients with tophaceousgout who were given an initial pre-scription for urate-lowering med-ication and who concurrently re-ceived a prophylactic anti-inflammatory agent (excludingthose with renal impairment orpeptic ulcer disease); 3) the per-centage of patients with renal im-pairment and gout who are pre-scribed allopurinol at a dose lessthan 300 mg/d; and 4) the percent-age of patients with history ofnephrolithiasis or significant renalinsufficiency and gout who werestarted on urate-lowering therapyand prescribed a xanthine oxidaseinhibitor rather than a uricosuric.

In the ClinicAnnals of Internal Medicine

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THINGS YOU SHOULDKNOW ABOUT GOUT

What is gout?• Gout is a very painful type of arthritis caused whencrystals form in joints or soft tissues.

• Gout causes sudden joint swelling, redness, heat,and pain, often in the big toe.

• Acute attacks often start at night and last about 1 week.

• A build-up of uric acid known as tophi can formlumps around joints and tissues and damage joints.

Who is most likely to develop gout?• Middle-aged men

• Women after menopause

• People with high uric acid levels

• Overweight people

• Certain foods increase the risk for gout (red meats,organ meats [liver], shellfish, some fish [anchovies],alcohol, and sugary soft drinks).

• Some medications, such as diuretics (water pills),and some diseases, such as diabetes and kidneyproblems, increase the risk for gout.

How is gout diagnosed?• The best way to diagnose gout is to have the doctordraw some fluid from the joint with a needle and haveit examined under a microscope for urate crystals.

What should I do if I think I have gout?• Contact your doctor to treat the pain and shortenthe attack.

• The pain and inflammation can be treated bynonsteroidal anti-inflammatory drugs (such asnaproxen or ibuprofen), colchicine, or corticosteroids(either by mouth or as an injection into the joint).

• After more than 1 gout attack, you need to takemedicine long-term to lower the uric acid level and toprevent gout and other complications. You need totake the medicine just as the doctor prescribed it inorder for it to work.

• Lifestyle changes and switching some medicationsthat can raise the level of uric acid can also help.

For More Information

Web Sites With Good Information About Goutwww.rheumatology.org/public/factsheets/diseases_and_conditions/gout.asp?aud=patAmerican College of Rheumatology: Goutwww.arthritis.org/disease-center.php?disease_id=42Arthritis Foundation: Goutwww.niams.nih.gov/Health_Info/Gout/default.aspNational Institute of Arthritis and Musculoskeletal andSkin Diseases: Questions and Answers About Goutwww.gouteducation.org/Gout and Uric Acid Education Society

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Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP, accessed athttp://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/

to obtain up to 1.5 CME credits, to view explanations for correct answers, or to purchase the complete MKSAP program.

CME Questions

2 February 2010Annals of Internal MedicineIn the ClinicITC2-16© 2010 American College of Physicians

A 68-year-old woman has had 4 or 5episodes of joint pain and swelling, last-ing 3 to 8 days, that involved the rightknee and left elbow. She is asymptomaticbetween attacks, and sulindac, 200 mgtwice per day, has usually relieved thesymptoms. Her most recent episode was4 months ago.

On physical examination, none of herjoints is swollen or tender, but there ismarked crepitus on extension of theknee. She also has a positive bulge signover the left knee and pain on full ex-tension of the left elbow.

Which of the following tests would con-firm the diagnosis?

A. Arthrocentesis of the knee andlaboratory analysis of the synovialfluid by an expert in crystalidentification

B. Measurement of serum uric acidC. Measurement of serum rheumatoid

factorD. Radiography of the kneeE. MRI of the knee with gadolinium

contrast

A 62-year-old man is evaluated for leftanterior hip pain that started 3 days ear-lier. He was recently hospitalized for kid-ney stone extraction and was discharged4 days ago. The pain is worse with activ-ity and disturbs his sleep. He has chillsbut no rash, palpitations, or back pain.He has history of degenerative joint dis-ease in his hips and knees and has goutattacks in his first metatarsophalangealjoints about 3 times per year. There is nohistory of tick exposure.

On physical examination, temperature is38.7°C (101.7°F), pulse rate is 110/min,and blood pressure is 142/72 mm Hg.The patient has markedly decreasedrange of motion and pain in his left hipand some warmth over the anterior andlateral aspect. All other joints are normalon palpation.

Which of the following tests is most ap-propriate?

A. Serology for Borrelia burgdorferiB. Urethral swab for Neisseria

gonorrhoeaeC. Antinuclear antibody and

rheumatoid factor titersD. Hip joint aspirationE. Bone scan

A 55-year-old woman who has hadrheumatoid arthritis for 10 years is eval-uated because of severe pain in the leftshoulder that developed during the pre-vious day. In recent months, her diseasehas been poorly controlled on a regimenof methotrexate, hydroxychloroquine,and low-dose prednisone. She has ap-proximately 90 minutes of morning stiffness.

On physical examination, her tempera-ture is 36.8°C (98.2°F), her pulse rate is82/min, and her blood pressure is 110/70mm Hg. She has moderate tenderness ofthe small joints of her hands and of bothwrists. Her left shoulder is warm andvery tender; she can move it only slightlybefore being limited by pain.

What is the best next step in this pa-tient’s management?

A. Orthopedic consultation forpossible shoulder arthroplasty

B. Aspiration of the shoulderC. Radiography of the shoulderD. MRI contrast arthrography of the

shoulderE. Physical therapy for the shoulder

A 38-year-old man with a history of id-iopathic focal and segmental glomeru-losclerosis developed end-stage renaldisease and subsequently underwent acadaveric renal transplantation 28months ago. He presents to your officefor a routine follow-up visit. His trans-plantation was uncomplicated, withoutdelayed graft function or clinically

apparent acute rejection episodes. Hisimmunosuppression regimen consisted ofprednisone, cyclosporine, and azathio-prine. His serum creatinine concentrationon discharge was 123.76 µmol/L (1.4 mg/dL). He was given colchicine for a suspected gouty attack 4 monthsago and continues to take the drug once a day.

At a follow-up clinic appointment 3months ago, his blood pressure was ele-vated and his serum creatinine concen-tration was 150.28 µmol/L (1.7 mg/dL).The urinary protein-to-creatinine ratiowas less than 0.3. He was given dilti-azem for better control of blood pres-sure. His immunosuppressive regimen re-mained unchanged.

At the current visit, physical examinationreveals a mild tremor and blood pressureof 150/90 mm Hg. Cardiac, pulmonary,and abdominal examinations are unre-markable. There is no tenderness at thetransplant site, and the patient has tracebilateral edema.

Laboratory studies found the followingresults: Serum creatinine level, 194.48µmol/L (2.2 mg/dL); serum uric acid level,713.82 µmol/L; urinalysis, specific gravityof 1.010, trace proteinuria, and no gluco-suria, hematuria, or ketonuria; urine mi-croscopy, few broad casts, scattered re-nal epithelial cells; urineprotein-to-creatinine ratio, 0.4; andurine uric acid–to-creatinine ratio of 0.6.

What is the most likely cause of this pa-tient’s current renal dysfunction?

A. Transplantation renal arterystenosis

B. Recurrent focal and segmentalglomerulosclerosis

C. Cyclosporine toxicityD. Uric acid nephropathyE. Polyoma virus nephropathy

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Documents

in the clinic - Tripod.comenotes.tripod.com/gout2010.pdf · tion of uric acid. In particular, binge drinking increases urate lev-els. The risk differs by the type of alcohol, with