Tatum Mead, PharmD; Kavitha Arabindoo, MD, Managing : FAAFP; Brianna Smith, PharmD Research Family Medicine There’s more we can do Residency Program (Drs. Mead and Arabindoo); School of Pharmacy (Drs. Acute and chronic gout arthritis are increasingly prevalent, Mead and Smith), University of Missouri- but often poorly managed. This review, based largely Kansas City on the American College of Rheumatology’s gout [email protected] guidelines, details the components of high-quality care. The authors reported no potential conflict of interest relevant to this article.

rom the 1960s to the ’90s, the prevalence of gout more Practice 1 recommendations than doubled among US residents. In the years since, gout has become increasingly prevalent worldwide.1-5 › Prescribe an anti- F The key causes—an aging population, poor diet, widespread inflammatory drug whenever use of diuretics to treat cardiovascular disease, and comorbidi- you initiate urate-lowering ties that promote —have made the presentation therapy (ULT). A of gout more complex and harder to manage, as well.4-6 › Do not initiate ULT during In fact, gout is frequently poorly managed. Initiation and an acute gout attack; if a maintenance of urate-lowering therapy (ULT)—as well as patient on an established monitoring of serum urate—is not done often enough, and ULT regimen has an acute there is significant variation in medications used to treat gout. attack, however, therapy should not be stopped. C As a result, recommended serum urate targets commonly re- main unattained.7-9 › Increase the dosage of We can do better. Enhanced understanding of risk factors ULT to achieve a lower for gout, augmented by recent research and the approval of target if gout symptoms 10 persist despite a serum 2 new pharmacologic agents ( in 2009 and pegloti- 11 urate level <6 mg/dL. B case in 2010 ), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.12,13 Strength of recommendation (SOR) The key components of gout management—patient education, A Good-quality patient-oriented lifestyle modifications, and pharmacologic therapy—are de- evidence tailed in the text and tables that follow. B Inconsistent or limited-quality patient-oriented evidence C Consensus, usual practice, opinion, disease-oriented evidence, case series Understanding gout Gout is actually a heterogeneous spectrum of diseases. It is char- acterized by an elevated serum urate concentration, with recur- rent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crys- tals in tissues in and around the joints—interstitial renal disease, and nephrolithiasis.14 Symptoms occur when the excess uric acid, the result of inefficient rather than overpro- duction,2,12,14,15 is deposited in restricted joint spaces. continued

jfponline.com Vol 63, No 12 | DECemBER 2014 | The Journal of Family Practice 707 TABLE 1 Dietary recommendations for patients with gout: What the guidelines call for12

Avoid Limit Encourage Organ meats high in purine content Serving sizes of purine-rich meats (beef, lamb, Low-fat or nonfat dairy (sweetbreads, liver, ) pork) and seafood (sardines, shellfish) products High fructose corn syrup-sweetened sodas Serving sizes of fruit juice, table sugar, Vegetables and other beverages and foods sweetened beverages and desserts, and table salt, including salt in sauces and gravies Alcohol overuse (>2 drinks/d for men and Alcohol (particularly beer, but also wine and >1 drink/d for women). Refrain from all spirits) alcohol during periods of frequent gout attacks or advanced, poorly controlled gout

Who’s at risk? aging studies are not recommended for the Risk factors include numerous cardiovascular evaluation of gout because therapy is guided Asymptomatic and metabolic conditions, such as increased by symptoms.14 hyperuricemia adiposity, hypertension, dyslipidemia, heart z Asymptomatic hyperuricemia alone alone does not failure, insulin resistance, hyperglycemia, does not establish a diagnosis of gout, and establish and renal disease.3,6,12 Older age, genetics, there is no evidence to support ULT for isolat- a diagnosis of poor diet, alcohol consumption, and medica- ed hyperuricemia. However, advice regarding gout and there tions associated with hyperuricemia, such as lifestyle modifications and treatment of asso- is no evidence loop and thiazide diuretics and low-dose ace- ciated comorbidities may be warranted for to support tylsalicylic acid, are risk factors, as well. such patients.18 urate-lowering Defined as a serum urate level ≥6.8 mg/dL therapy —the point at which urate becomes insoluble for isolated in extracellular fluids12,16,17—hyperuricemia is How best to manage gout hyperuricemia. the most important modifiable risk factor for Optimal gout management encompasses the development of gout. It can precipitate nonpharmacologic therapy, symptom man- painful episodic attacks and complications agement of acute attacks, and combination such as chronic arthritis, urolithiasis, and anti-inflammatory and ULT prophylaxis for tophi.12 patients with chronic gout.12,13 It is important to work with patients to track and document What you’ll see both the number and the severity of acute Patients often present with acute onset of attacks occurring over a 12-month period pain and inflammation of a single joint, usu- so that those who qualify for ULT can begin ally the first metatarsophalangeal. Other it without delay.12 It is important to discuss joints and soft tissues that may be involved to treatment objectives and management of co- a lesser extent include (in order of frequency) morbidities, as well. the insteps, ankles, heels, knees, fingers, and Review the medications the patient is elbows.14 Polyarticular attacks are an atypical taking, and consider eliminating prescription manifestation and are sometimes confused drugs associated with hyperuricemia if the with rheumatoid arthritis or osteoarthritis, risks outweigh the benefits.19-21 In many cas- particularly in the elderly. es, however, lifestyle modification—ie, eating Clinical evaluation should include a his- a heart-healthy diet, exercising regularly, and tory of symptom severity, disease burden, losing weight—may do more to prevent gout and comorbidities, and a thorough physi- attacks and manage complications than stop- cal examination focused on findings such as ping medications that provide cardioprotec- tophi and acute and chronic synovitis.12 Im- tion.6 The ACR divides food and beverages

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TABLE 2 Pharmacologic agents for acute gout attacks8,13,14

Type of agent Drugs Dosing Common adverse Considerations effects* NSAIDs • Indomethacin Use FDA-approved Headache, GI (pain, Caution required for patients (first-line) anti-inflammatory or dyspepsia, heartburn, with PUD, active bleeding, • analgesic doses nausea) anticoagulation or antiplatelet • Sulindac therapy, renal dysfunction, CKD, HTN, fluid retention, CHF, or hepatic disease Anti-gout agent 1.2 mg loading dose GI (cramping, Do not initiate >36 hrs after (first-line) and 0.6 mg 1 hr later, abdominal pain, symptom onset then 0.6 mg after nausea, vomiting, If patient has received colchicine 12 hrs, as needed, diarrhea) therapy within 14 days, use an 1-2 times/d until NSAID or corticosteroid instead symptoms resolve Caution required for patients with renal dysfunction, CKD, or hepatic disease Contraindicated with concurrent use of P-glycoprotein or CYP3A4 inhibitors Systemic • Prednisone 0.5 mg/kg/d for GI (abdominal Caution required for patients corticosteroids 5-10 days distension, ulcers), with DM, fluid retention, (first-line) hypertension, ongoing infection or increased OR headache, insomnia infection risk, or PUD 2-5 days at full dose, IA, IV, or IM administration then taper for possible for patients who are 7-10 days NPO • Methyl- Methylprednisolone prednisolone dose pack: Taper according to package instructions Hormone (stimulates ACTH 25-40 IU SC Musculoskeletal, Option for patients who are NPO corticosteroid endocrine, metabolic, GI, Less effective in patients on production) cardiovascular, nervous long-term oral corticosteroid system, dermatological therapy effects, hypersensitivity reactions Short duration of action ACTH, adrenocorticotropic hormone; CHF, congestive heart failure; CKD, chronic kidney disease; DM, diabetes mellitus; FDA, US Food and Drug Administration; GI, gastrointestinal; HTN, hypertension; IA, intra-articular; IM, intramuscular; IU, international unit; IV, intravenous; NPO, nothing by mouth; NSAID, nonsteroidal anti- inflammatory drug; PUD, peptic ulcer disease; SC, subcutaneous. * Partial listing.

into 3 simple categories—avoid, limit, or en- mined by both a pain score on a visual analog courage (TABLE 1.)12 scale (VAS) and the number of affected joints; patient preference, prior response, and asso- Responding to an acute attack ciated comorbidities are also important con- Whenever possible, initiate pharmacologic siderations (TABLE 28,13,14). When medications therapy within 24 hours of symptom on- are prescribed for acute attacks or chronic set, because this has been associated with gout, a discussion of adverse effects, drug decreased pain and shorter duration of an interactions, contraindications, cost, and the acute attack.8,13 The choice of drug should be importance of adherence is needed, as well. guided by the severity of the attack, as deter- For mild to moderate pain (≤6 out of

jfponline.com Vol 63, No 12 | DECemBER 2014 | The Journal of Family Practice 709 10 on a VAS) involving a few small joints or one Both ULT and anti-inflammatory therapy or 2 large joints, monotherapy with a nonste- should be started after an acute gout attack roidal anti-inflammatory drug (NSAID), a cor- resolves, but patients already on prophy- ticosteroid, or colchicine is recommended. For lactic therapy should continue the regimen severe pain (>6 out of 10) and/or polyarticular both during and after acute attacks to avoid involvement (≥4 joints in more than one region more frequent exacerbations.9,12 If gout symp- of the body), combination therapy is recom- toms persist despite a serum urate level of mended (eg, colchicine and either an NSAID or <6.0 mg/dL, increase the dose of ULT to a corticosteroid).13 Prednisone, methylprednis- achieve a target of <5 mg/dL to reduce the olone, and adrenocorticotropic hormone are frequency of flares and the size and number options for patients who are NPO. Acute gout of tophi.12,26 therapy should be continued until the attack , a xanthine oxidase inhibi- resolves, which can range from 5 to 14 days.13 tor, is typically used as first-line ULT due to z Colchicine considerations. The dose efficacy and low cost.13 Febuxostat, also a of colchicine recommended by the ACR for xanthine oxidase inhibitor, is an additional an acute gout attack (1.2 mg loading dose, first-line option, although the US Food and followed by 0.6 mg one hour later, then fol- Drug Administration issued a warning based lowed after 12 hours, as needed, by up to on postmarketing reports of hepatic failure.25 0.6 mg once or twice a day) is substantially In the case of a xanthine oxidase allergy or Allopurinol lower than the dosing schedule used histori- intolerance, probenecid may be used as an hypersensitivity cally (1.0 mg loading dose, followed by 0.5 mg alternative first-line therapy. First-line agents syndrome every 2-3 hours). Higher doses have not prov- for anti-inflammatory prophylaxis include is rare, but en to be more effective, however, and typi- low-dose colchicine (0.6 mg once or twice potentially fatal. cally led to gastrointestinal toxicity, causing daily) and low-dose NSAIDs. Oral corticoste- patients to stop taking the drug before acute roids (<10 mg/d) are considered second-line symptoms resolved.8,13,22 therapy.13 Keep in mind, too, that colchicine z Allopurinol hypersensitivity. Although therapy should not be initiated more than allopurinol is generally well tolerated, about 36 hours after symptom onset, as therapy is 2% of patients develop a mild rash and up to less effective beyond this time frame.8,13 In ad- 5% of patients stop taking it because of an dition, concurrent use with P-glycoprotein and adverse effect.25 More importantly, allopuri- CYP3A4 inhibitors—eg, clarithromycin and nol hypersensitivity syndrome (AHS) is rare erythromycin and some antifungals, antiretro- but potentially fatal; in the United States, virals, calcium-channel blockers, immunosup- it is estimated that one in every 1000 pa- pressants, and statins—may increase the risk of tients treated with allopurinol will develop colchicine toxicity and should be avoided. AHS.12,27 AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epider- Treating chronic gout mal necrolysis), eosinophilia, leukocytosis, Management of recurrent or progressive fever, hepatitis, and renal failure.12,25 There gout is aimed at reducing and maintaining is no cure; the mainstay of treatment is early serum urate levels <6.0 mg/dL, using ULT diagnosis, withdrawal of allopurinol, and (TABLE 312,23-25) combined with anti-inflam- supportive care.25 Because of the high mor- matory prophylaxis to reduce the frequency tality rate (20%-25%),12,27 genetic screening of gout flares and the size and number of to- for allele HLA-B*5801 prior to starting al- phi.12,23 Patients who meet one or more of the lopurinol therapy is recommended for pa- following criteria qualify for ULT: tients in high-risk groups: Koreans with CKD • the presence of tophi (stage 3 or worse) and all Han Chinese and • ≥2 acute attacks per year Thai patients, regardless of kidney func- • chronic kidney disease (CKD) tion.12 Alternative therapies should be stages 2 through 5 used for patients who test positive for the • a history of urolithiasis.12 allele.

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TABLE 3 Urate-lowering therapy: Which agent is best for your patient?*12,23-25

Type of Drug Dosing Considerations agent Xanthine Allopurinol Initiate at 100 mg/d; titrate Requires renal dosing: Initiate at oxidase upward by 100 mg every 50 mg/d for patients with CKD inhibitor 2-5 wks to reach target serum (stage 4 or worse); potentially (first-line) urate acid level; maximum fatal hypersensitivity syndrome dose: 800 mg/d (testing recommended for high- risk groups†)

Febuxostat Initiate at 40 mg/d; titrate to May cause liver enzyme maximum dose (80 mg/d) after elevation, arthralgia, or rash 2 wks if serum uric acid level is Liver tests needed in patients not achieved who develop fatigue, anorexia, right upper abdominal discomfort, dark , or jaundice Probenecid 250 mg twice daily for 1 wk, Avoid in patients with history Studies have agent then 500 mg twice daily; titrate of urolithiasis and those with found that less in 500 mg increments every creatinine clearance <50 mL/min 4 wks until target serum uric than half acid level is reached; maximum of patients dose: 2 g/d started on ‡ (ARB) No FDA-approved dosing Useful for patients with HTN urate-lowering therapy take ‡ No FDA-approved dosing Useful for patients with dyslipidemia their medication (fibric acid as prescribed for derivative) the entire first Urate 8 mg IV every 2 wks IV infusion over ≥120 min year of therapy. oxidase Severe infusion and allergic enzyme reactions possible May exacerbate CHF High cost

ARB, angiotensin receptor blocker; CHF, congestive heart failure; CKD, chronic kidney disease; FDA, US Food and Drug Adminis- tration; HTN, hypertension; IV, intravenous. * Patients receiving urate-lowering therapy should be started on an anti-inflammatory agent, as well. † Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients. ‡ Not FDA-approved for the treatment of gout.

Duration of therapy achieved and previously detected tophi have Pharmacologic treatment of an acute gout at- resolved.13 tack should continue until the attack resolves, z ULT should continue indefinitely,12 which can range from 5 to 14 days. The dura- with monitoring of serum urate levels every tion of treatment for chronic gout is far longer. 2 to 5 weeks until the target is achieved and z Anti-inflammatory prophylaxis should every 6 months thereafter. continue for whichever is greater: 3 months after the target serum urate level is achieved Not responding to therapy? for patients with no evidence of tophi; or Consider nonadherence, refractory gout 6 months after the target serum urate level is If a patient is not responding as expected,

jfponline.com Vol 63, No 12 | DECemBER 2014 | The Journal of Family Practice 711 consider whether he or she is taking the med- uric acid to allantoin31 (a water-soluble me- ication as prescribed. Gout therapy has one tabolite of uric acid), is a possible therapeu- of the lowest adherence rates of any chronic tic option for patients who do not achieve disorder.7,8,12,28-30 Studies have found that less adequate serum urate levels and continue than half of patients started on ULT take their to have symptoms of gout.12 Candidates for medication as prescribed for the entire first pegloticase therapy, which is administered year of therapy.9,28 intravenously, include adult patients with Evidence suggests that nonadherence is gout refractory to conventional ULT or exces- especially likely among younger and health- sive uric acid accumulation due to chemo- ier individuals, possibly because they have therapy and those with contraindications to little experience managing chronic condi- conventional ULT. tions or needing ongoing care.28-30 Such pa- Pegloticase is associated with anaphylac- tients may also be unsure of when and how tic and infusion reactions, requires extensive to take their medication. To promote adher- monitoring, and costs thousands of dollars per ence, physicians should schedule more fre- month, however. Thus, it is important to care- quent follow-up appointments after initiating fully evaluate the extent of disease burden (ie, ULT to assess management of the disease and gout symptoms and effect on quality of life) stress the importance of following the medi- and determine whether the patient has taken cation regimen as prescribed.9,28 ULT and uricosuric drugs as prescribed before To promote Not all patients who don’t respond to considering this option. Pegloticase requires adherence, ULT are nonadherent, of course. Some have the same anti-inflammatory prophylaxis as schedule more refractory gout. If uric acid levels do not reach other forms of ULT, but there is no consensus frequent the goal of <6 mg/dL (or <5 mg/dL) at the on the duration of use.12 JFP follow-up maximum dose of a first-line xanthine oxi- dase inhibitor, add a uricosuric agent such as appointments Correspondence after initiating probenecid, fenofibrate, or losartan.12 Tatum Mead, PharmD, University of Missouri-Kansas City z Pegloticase, School of Pharmacy, Health Sciences Building, Room 2243, urate-lowering a pegylated recombinant 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@ therapy. form of enzyme that converts umkc.edu

References 1. Lawrence RC, Felson DT, Helmick CG, et al; National Arthritis management of hyperuricemia in patients with gout [press re- Data Workgroup. Estimates of the prevalence of arthritis and lease]. February 13, 2009. Drugs.com Web site. Available at: other rheumatic conditions in the United States. Part II. Arthritis http://www.drugs.com/newdrugs/fda-approves-uloric-febux- Rheum. 2008;58:26-35. ostat-chronic-management-hyperuricemia-patients-gout-1266. 2. Brook RA, Forsythe A, Smeeding JE, et al. Chronic gout: epidemi- html. Accessed October 29, 2014. ology, disease progression, treatment and disease burden. Curr 11. US Food and Drug Administration. FDA approves new drug for Med Res Opin. 2010;26:2813-2821. gout [press release]. September 14, 2010. US Food and Drug Ad- minstration Web site. Available at: http://www.fda.gov/News- 3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperurice- Events/Newsroom/PressAnnouncements/ucm225810.htm. Ac- mia in the US general population: the National Health and Nu- cessed October 29, 2014. trition Examination Survey 2007-2008. Arthritis Rheum. 2011;63: 3136-3141. 12. Khanna D, Fitzgerald JD, Khanna PP, et al; American College of Rheumatology. 2012 American College of Rheumatology guide- 4. Wallace KL, Riedel AA, Joseph-Ridge N, et al. Increasing preva- lines for management of gout. Part 1: systematic nonpharmaco- lence of gout and hyperuricemia over 10 years among older logic and pharmacologic therapeutic approaches to hyperurice- adults in a managed care population. J Rheumatol. 2004;31: mia. Arthritis Care Res (Hoboken). 2012;64:1431-1446. 1582-1587. 13. Khanna D, Khanna PP, Fitzgerald JD, et al; American College of 5. Roddy E, Zhang W, Doherty M. The changing epidemiology of Rheumatology. 2012 American College of Rheumatology guide- gout. Nat Clin Pract Rheumatol. 2007;3:443-449. lines for management of gout. Part 2: therapy and antiinflamma- 6. Choi HK. A prescription for lifestyle change in patients with tory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hobo- hyperuricemia and gout. Curr Opin Rheumatol. 2010;22: ken). 2012;64:1447-1461. 165-172. 14. Fravel MA, Ernst ME, Clark EC. Gout and hyperuricemia. In: 7. Dalbeth N, Lindsay K. The patient’s experience of gout: new DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Patho- insights to optimize management. Curr Rheumatol Rep. physiologic Approach. 9th ed. New York, NY: McGraw Hill; 2014: 2012;14:173-178. 1505-1523. 8. Edwards NL. Quality of care in patients with gout: why is manage- 15. Neogi T. Clinical practice. Gout. N Engl J Med. 2011;364:443-452. ment suboptimal and what can be done about it? Curr Rheumatol 16. Loeb JN. The influence of temperature on the solubility of mono- Rep. 2011;13:154-159. sodium urate. Arthritis Rheum. 1972;15:189-192. 9. Singh JA, Hodges JS, Asch SM. Opportunities for improving 17. Terkeltaub R. Update on gout: new therapeutic strategies and op- medication use and monitoring in gout. Ann Rheum Dis. 2009;68: tions. Nat Rev Rheumatol. 2010;6:30-38. 1265-1270. 18. Zhang W, Doherty M, Bardin T, et al; EULAR Standing Committee 10. Drugs.com. FDA approves Uloric (febuxostat) for the chronic for International Clinical Studies Including Therapeutics. EULAR

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evidence based recommendations for gout. Part II: Management. US Food and Drug Administration Web site. Available at: http:// Report of a task force of the EULAR Standing Committee for Inter- www.fda.gov/Safety/MedWatch/SafetyInformation/ucm243770. national Clinical Studies Including Therapeutics (ESCISIT). Ann htm. Accessed October 29, 2014. Rheum Dis. 2006;65:1312-1324. 25. Stamp LK, Taylor WJ, Jones PB, et al. Starting dose is a risk factor 19. Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther. for allopurinol hypersensitivity syndrome: a proposed safe start- 2010;12:223. ing dose of allopurinol. Arthritis Rheum. 2012;64:2529-2536. 20. McAdams DeMarco MA, Maynard JW, Baer AN, et al. Diuretic 26. Becker MA, Schumacher HR, Benjamin KL, et al; Gout National use, increased serum urate levels, and risk of incident gout in a Study Group. Quality of life and disability in patients with treat- population-based study of adults with hypertension: the Ath- ment-failure gout. J Rheumatol. 2009;36:1041-1048. erosclerosis Risk in Communities cohort study. Arthritis Rheum. 2012;64:121-129. 27. Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol. 1979;1:365-374. 21. Caspi D, Lubart E, Graff E, et al. The effect of mini-dose on renal function and uric acid handling in elderly patients. Arthritis 28. Harrold LR, Andrade SE, Briesacher BA, et al. Adherence with Rheum. 2000;43:103-108. urate-lowering therapies for the treatment of gout. Arthritis Res Ther. 2009;11:R46. 22. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dos- ing of oral colchicine for early acute gout flare: Twenty-four-hour 29. Reach G. Treatment adherence in patients with gout. Joint Bone outcome of the first multicenter, randomized, double-blind, Spine. 2011;78:456-459. placebo-controlled, parallel-group, dose-comparison colchicine 30. Briesacher BA, Andrade SE, Fouayzi H, et al. Comparison of drug study. Arthritis Rheum. 2010;62:1060-1068. adherence rates among patients with seven different medical 23. Wortmann RL, Macdonald PA, Hunt B, et al. Effect of prophylaxis conditions. Pharmacotherapy. 2008;28:437-443. on gout flares after the initiation of urate-lowering therapy: analy- 31. Lexicomp. News from the world of pharmacology. Lexicomp Web sis of data from three phase III trials. Clin Ther. 2010;32:2386-2397. site. Available at: https://www.lexi.com/individuals/pharma- 24. US Food and Drug Administration. Uloric (febuxostat tablets). cists/newsletters.jsp?id=october_10. Accessed January 13, 2014.

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