CME

Gout: A comprehensive review Eric Rymal, PA-C; Denise Rizzolo, PA-C, PhD

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ABSTRACT The prevalence of gout in the US population is steadily increasing. Genome-wide research has found several variants of DNA sequences that predispose patients to irregular uric acid metabolism. Comorbidities linked to gout include obesity and cardiovascular disease. Though the formal diagnosis is made with arthrocentesis and subsequent analysis, CT and ultrasound findings supplement the diagnosis and monitor disease management. Newer immunologic agents are available for patients whose disease is refractory to standard therapy. Keywords: gout, arthritis, genetics, purine-rich foods, IL-1b inhibitors, uric acid

Learning objectives Identify the clinical presentation of the four stages of gout. Apply appropriate diagnostic and imaging tests for patients with symptoms consistent with gout. Develop treatment plans for patients with gout.

G

out is an ancient disease that is on the rise in the United States. Podagra was first documented in ancient Egypt.1 Hippocrates described it as an “unwalkable disease.” In keeping with Hippocratic medicine, medieval people associated gout with an imbalance of one of the four humors that maintained a person’s health.1 Advances in medicine eventually identified the actual excess “humor” in gout to be uric acid. Historically, the imbalance has been linked to excesses that could only be afforded by the wealthy.1 However, the Western diet has developed into one that is purine-rich, regardless of income levels, contributing to the rise in gout in the United States.1,2

Eric Rymal practices physical medicine in Hampton Roads, Va., managing acute and chronic musculoskeletal conditions. Denise Rizzolo is an associate professor in the PA program at Seton Hall University in South Orange, N.J., an assistant clinical professor in the PA program at Pace University in New York City, and practices urgent care in Springfield, N.J.The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000453233.24754.ec Copyright © 2014 American Academy of Physician Assistants

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Understanding the disease process is critical to effective management. Advances and developments in genetics, imaging, and medications have been emerging rapidly. This article reviews the pathophysiology and general management of gout, advances in genetics, usefulness of diagnostic imaging, and new therapies. EPIDEMIOLOGY About 8.3 million people in the United States (about 3.9% of the population) have gout, compared with about 2.7% of the population in the early 1990s.2 Hyperuricemia, defined as a serum uric acid level greater than 6 mg/dL, is reported in 21% of the US population, correlating with a substantial rise in obesity and hypertension.2 Recent epidemiologic data suggest that the risk of developing gout is age-related, with the typical age range between 40 and 69 years at diagnosis.2 More men than women in this age group are affected.2 The sex discrepancy equalizes after women undergo menopause, suggesting that estrogen Volume 27 • Number 9 • September 2014

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Gout: A comprehensive review

Key points The prevalence of gout in the United States has increased to 3.9% of the population, from 2.7% in the early 1990s. The purine-rich Western diet is a contributing factor. Needle-shaped, negatively green birefringent crystals seen with polarized light microscopes are pathognomic for gout. Serum uric acid level is used to monitor treatment efficacy but is not clinically used in the diagnosis of gout because some patients with hyperuricemia (defined as serum uric acid over 6 mg/dL) never develop gout. NSAIDs and colchicine or intra-articular injections are used to manage acute gout episodes; urate-lowering therapy is indicated for patients with repeated episodes, tophi, or renal urate stones. Refractory chronic gout can be treated with new IL-1b inhibitors and uricases.

(specifically estradiol) plays a role in uric acid regulation.3 Although gout may affect all ethnicities equally, higher prevalence is well documented in some Asian, Maori, and Pacific Islander populations.2,4,5 GENETICS In the past, gout was thought to be a monogenic trait; however, recent studies suggest a polygenic mode of inheritance. Genome-wide association studies have identified several variants that increase a patient’s relative risk of developing hyperuricemia and gout.4-6 These studies have discovered eight DNA sequence variations associated with varying degrees of increased serum uric acid; the SLC2A9, SLC22A11, and SLC22A12 genes, which correspond with the Glut-9, OAT1, and URAT1 transporters, respectively, have been highly associated with hyperuricemia.4,5 Glut-9 plays a role in urate reabsorption at the proximal tubules of the kidney and may account for up to 3.7% of a patient’s serum uric acid variance.5 The same hyperuricemia-associated DNA sequence variations found in people of European ancestry are associated with hyperuricemia in some Asian and black populations. In total, genetic variances may only account for up to 6% of serum uric acid variations associated with hyperuricemia.4,5 Genetic variances are of little clinical significance at present; however, they may provide an explanation for cases refractory to usual therapies.4,5 Clinically, genetics research has been able to identify an association between allopurinol, a common treatment for gout, and the HLA-B*5801 allele, which is found more commonly in patients of Japanese, Korean, Han Chinese, Thai, and some of European descent. The HLA-B*5801 allele is strongly associated with an 80 to 97 times increased likelihood of developing allopurinol hypersensitivity syndrome; with this development in mind, biomarker testing is now available and may be used in at-risk populations.4-6 JAAPA Journal of the American Academy of Physician Assistants

Test patients of Japanese, Han Chinese, Thai, or Korean ancestry before starting allopurinol. If testing is not available, consider an alternative therapeutic agent. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme deficiencies are X-linked disorders that are very rare causes of hyperuricemia. The prevalence of HPRT enzyme disorders is estimated to be 1 in 380,000 births, and usually presents in young adulthood.7,8 LeschNyhan syndrome is a complete HPRT deficiency disorder characterized by the presence of gout, nephropathy, motor and cognitive impairment, self-injurious behavior, and megaloblastic anemia.7 Partial HPRT deficiencies may produce HPRT-associated gout and a varying degree of neurologic symptoms; these are referred to as Lesch-Nyhan variants. Kelley-Seegmiller syndrome, another HPRT variant, only causes HPRT-associated gout but does not typically have any of the neurologic involvement of LeschNyhan syndrome.7 Enzymatic testing of HPRT and adenine phosphoribosyltransferase (APRT) activity can confirm an HPRT deficiency diagnosis.7 PATHOPHYSIOLOGY Hyperuricemia can be relatively benign; only 22% of men with a serum uric acid greater than 9 mg/dL develop gout over a 5-year period.9 Sudden fluctuations in serum uric acid have been associated with acute gout flares, and monosodium urate crystals begin to form and deposit at serum uric acid levels greater than 6.8 mg/dL.10 Monosodium urate crystals may deposit into bursas, joints, and tendons. On a cellular level, synovial cells phagocytize the monosodium urate crystals, which then form an inflammasome. The inflammasome releases interleukin-1 beta (IL-1b), which, in turn, releases chemokines and inflammatory mediators to attract neutrophils. This cascade leads to a very potent inflammatory state in the joint or synovial tissues.10 Repetitive accumulation of monosodium urate crystals forms tophi, and is referred to as tophaceous gout. Temperature, mechanical trauma, previous disease, and underlying osteoarthritis make a joint susceptible to monosodium urate crystal and tophi deposition.10,11 GOUT, DIET, AND COMORBIDITIES Role of diet Early understandings of gout primarily associated the disease with a rich or heavy diet consisting of excess proteins and alcohol.1 Production of uric acid is associated with certain meats, seafood, and vegetables (Table 1). Data show that an increased intake of purinerich meats and seafood are associated with increases in serum uric acid; however, intake of purine-rich vegetables is not associated with increased risk of gout.12,13 Dietary alcohol intake is associated with gout in varied degrees. Beer consumption is associated with a high risk of developing gout; liquor and wine consumption are associated with moderate and low risks, respectively.10,12,13 Cherry consumption has been linked to lower serum uric acid levels.14 www.JAAPA.com

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Studies have observed an inverse relationship between dairy intake and serum uric acid.12,13 Tell patients to restrict consumption of purine-rich meats and alcohol, and increase their intake of low-fat dairy, because current data support low-fat dairy as beneficial in reducing serum uric acid. Comorbidities Hyperuricemia and gout are highly associated with hypertension, kidney disease, and cardiovascular disease, which are common among patients in the United States.3,6,15-17 On a microscopic level, uric acid is linked to renin-angiotensin system stimulation, vascular constriction, and renal inflammation and injury.15 Administering allopurinol to patients with hyperuricemia and hypertension has demonstrated a mild BP-lowering effect when serum uric acid levels were lowered; this effect reversed when allopurinol was discontinued.16 Lowering serum uric acid also is associated with a slower progression of renal disease.6,15 Further, the Multiple Risk Factor Investigative Trial (MRFIT) observed gout as being an independent risk factor for myocardial infarction.17 Losartan and fenofibrate have modest uric acid–lowering effects and may be considered in patients with gout and hypertension and hypercholesterolemia, respectively.18 In an attempt to avoid needless polypharmacy, clinicians must identify these conditions and consider them while managing patients with symptomatic gout. STAGES OF GOUT Asymptomatic hyperuricemia is a preliminary stage of gout and many hyperuricemic patients never develop clinical manifestations of gout. Acute gout commonly presents as an abrupt onset of an erythematous, warm, swollen, and exquisitely sensitive joint, classically the first metatarsophalangeal joint.19 Suspect gout if the patient has acute onset of monoarticular joint pain with the maximum intensity occurring within 12 hours.19,20 In some cases, acute gout may be self-limiting. Intercritical or interval gout occurs after acute symptoms have resolved, and low-grade inflammation may remain within the joint, causing unnoticed damage.19 During this intercritical stage, persistent hyperuricemia drives monosodium urate crystal deposition and aggregation into tophi development, causing erosive changes to the bone, which may be seen radiographically in patients with chronic gout. Chronic gout is persistent arthralgia or repeated episodes of acute gout, usually complicated by tophi formation. Although the time frame for tophi development has varied TABLE 1.

Examples of purine-rich foods10,12,13

• Meats: beef, pork, lamb, veal • Organ meats: spleen, liver, lung, heart • Fish: tuna, redfish, halibut, herring, sardines • Other seafood: shrimp, lobster, scallops • Brewer’s yeast products: beer, wine • Vegetables: asparagus, cauliflower, beans, lentils, spinach

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across studies, without urate-lowering therapy, about 30% of patients develop chronic gout within 5 years.21 Acute gout symptoms often are not well recognized in patients with chronic gout because of a lack of intensity or soft tissue swelling; in these cases, the patient presentation may simply mimic osteoarthritis.8,10,11 DIAGNOSIS AND IMAGING While acute gout is typically monoarticular and can be diagnosed clinically, clinicians must take a full patient history regarding the onset, timeline, location, previous joint trauma or injury, other arthralgias, dietary intake, alcohol consumption, and medications. Perform a thorough review of medications: acute gout can be caused by recently implemented or chronic use of loop diuretics (and to a lesser degree, thiazide diuretics), niacin, or lowdose aspirin.22,23 In patients who have had transplants, cyclosporine and tacrolimus have been strongly associated with precipitating gout.8 Patient presentations of gout are not limited to metatarsophalangeal arthralgia: reported atypical presentations include dermatologic manifestation secondary to tophi eruption, ocular involvement, spinal gout, and visceral manifestations mimicking a tumor or infection.8 The varied presentation of atypical gout is beyond the scope of this article. The diagnostic gold standard for gout is joint aspiration and fluid analysis during acute gout; needle-shaped, negatively green birefringent crystals seen with polarized light microscopies are pathognomic for gout.10,19,20 Aspiration may be considered during the intercritical or asymptomatic period, but may only show positive microscopy in about 70% of patients with diagnosed gout; therefore, the optimal time to make the definitive diagnosis by aspiration is during the acute stage.10,19,20 In addition to crystal examination, aspirated fluid should be sent for gram stain and culture because simultaneous septic arthritis may occur in 4% of patients.20 The usefulness of serum uric acid level in diagnosing gout remains poor. Although a serum uric acid level greater than 6 mg/dL indicates hyperuricemia, an elevated serum uric acid level alone is not diagnostic—many patients with hyperuricemia remain asymptomatic and never develop gout.2,4,9,19,20 Imaging studies during acute gout episodes are useful only for ruling out trauma. Other than nonspecific soft tissue swelling, plain film radiographic abnormalities rarely occur in acute gout.20 In chronic gout, the hallmark signs are punched-out erosions and interosseous tophi.24 In patients with chronic gout, CT, MRI, and ultrasound have proven clinically useful in evaluating joints for tophi. MRI is particularly useful because of its ability to identify the surrounding deep soft tissues and ease the clinician’s concern for malignancy or tumor. CT does not image bursae, tendons, or synovium, and is less used for these reasons. Advanced imaging methods are more typically used to monitor the success of disease treatment rather than for diagnosis.20,21,24-27 Volume 27 • Number 9 • September 2014

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Gout: A comprehensive review

Imaging in monitoring disease Imaging modalities can measure the efficacy of urate-lowering therapy in patients with gout by evaluating the extent of tophi and their regression. CT has been shown to be highly specific for identifying and fully visualizing tophi, especially with the evolution of three-dimensional reconstruction techniques. Dual-energy CT (DECT) shows promising clinical utility in monitoring gout because of its high specificity in identifying monosodium urate crystal deposits and detecting subclinical tophi (monosodium urate deposits are seen as color changes); this study also may estimate tophi volume.25,27 As always, consider the risks and benefits of radiation exposure when choosing imaging studies. MRI provides the ability to visualize soft tissue and inflammatory bone changes such as marrow edema that may not be fully seen on plain radiographs and CT studies. On T2-weighted images, tophi are seen as medium-high signal changes and calcifications are seen as low signal changes.24,25,27 However, MRI may be somewhat costprohibitive in most cases and its findings typically require confirmation via guided aspiration.25 Musculoskeletal ultrasound technology has become increasingly popular as a diagnostic tool for painful joints. Findings that are highly suspicious for gout are tophi and the double-contour sign. Tophi are seen as a heterogeneous, hyperechoic signal with poorly defined contours surrounded by an anechoic signal.28 The double-contour sign is defined as a hyperechoic signal overlying an anechoic signal; this sign is more than 96% specific, although the exact rate varies widely among joints.24-26 Musculoskeletal ultrasound also may double as a medium for guided aspiration of a tophus or the involved joint. The application of enhanced imaging modalities in diagnosing gout needs further study. The American College of Rheumatology (ACR) recommends using CT, DECT, MRI, musculoskeletal ultrasound, and plain film radiographs to evaluate disease burden by detection of tophi and bony erosions.27 Musculoskeletal ultrasound is recommended to identify nontophaceous disease; however, no guidelines specify an interval in which these tests should be performed.27 MANAGING ACUTE GOUT Nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated for initial management of acute gout. NSAIDs indicated for acute gout are naproxen, indomethacin, and sulindac; the similar pharmacokinetics of other NSAIDs suggest comparable efficacy at their respective recommended doses.27 Consider celecoxib in patients with intolerance to traditional NSAIDs. Start with a loading dose of 800 mg of celecoxib, followed by a daily dose of 200 to 400 mg.27,29 Consider the risks and benefits of NSAIDs in each patient—adverse reactions to these drugs include an increased risk of bleeding, gastrointestinal (GI) distress, fluid retention, and increased BP.27,29,30 In some patients, a proton-pump inhibitor may be indicated to prevent GI complications.27,30 JAAPA Journal of the American Academy of Physician Assistants

Colchicine is an anti-inflammatory drug indicated for managing acute gout, and should be started within the first 24 to 36 hours from symptom onset.27,30,31 GI adverse reactions are very common with higher dosages and often are the primary reason for patients discontinuing therapy. Studies comparing low-dose regimens with high-dose regimens have found similar efficacy, and fewer adverse reactions with low-dose regimens.30,31 Initiate colchicine therapy with a 1.2-mg loading dose and 0.6-mg an hour later. Administer 0.6 mg every 12 hours thereafter until symptoms resolve.27,29,31 A combination of NSAIDs and colchicine is a common oral regimen in managing acute gout.27,29,30 Corticosteroid injection is an effective alternative first-line therapy, and should be considered in patients who are intolerant to or have contraindications to NSAIDs and colchicine. If the disease is isolated to fewer than three joints, consider an intra-articular approach with triamcinolone acetonide.27,30 If more than three joints are affected by acute gout, consider an IM injection with triamcinolone acetonide.27,30 For patients whose gout is refractory to initial management, or patients whose treatment options are limited because of underlying conditions, consider subcutaneous injections of canakinumab, a human monoclonal antiinterleukin-1 beta (IL-1b) antibody.29,32-34 Educate the patient about dietary modifications and discuss the patient’s risk factors and whether they can be modified. Restricting dietary purine alone has shown a modest reduction in serum uric acid equivalent to about 1 mg/dL.12-14 URATE-LOWERING THERAPY Before starting urate-lowering therapy, thoroughly review the patient’s modifiable risk factors and obtain a joint fluid analysis during an acute attack to confirm the diagnosis of gout. Also obtain baseline serum uric acid levels before starting therapy; these levels provide an objective measurement to monitor the effectiveness of therapy. Although dietary modifications can reduce serum uric acid, these changes alone usually are not enough to reach target levels.6,12,13 A target serum uric acid level of 6 mg/dL has been the norm, but lower targets may actually reverse the disease process, because tophi resolution increases as serum uric acid levels fall.21,29,35 One study evaluated varied levels of serum urate in relation to tophi regression, and the group whose serum urate level was reduced to less than 4 mg/dL achieved a 0.9 to 2.1 mm regression per month.21 Levels as low as 2 mg/dL have been pursued safely with newer immunologic therapies, but these drugs carry the risk of hypouricemia, which may be linked to neurodegenerative processes.35 Consider urate-lowering therapy for patients who have had three or more episodes of acute gout, have tophi on physical examination, or have renal urate stones.29 For the initial 6 months of urate-lowering therapy, the patient also should take prophylactic colchicine and NSAIDs to prevent acute gout related to the shift in serum uric acid level.10,27,29,31 www.JAAPA.com

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Xanthine oxidase inhibitors Allopurinol, oxypurinol, and febuxostat prevent the breakdown and conversion of dietary purines into uric acid. Allopurinol is a precursor to oxypurinol, which directly inhibits the conversion of hypoxanthines and xanthine to uric acid.29 Febuxostat is a selective xanthine oxidase inhibitor; 80-mg dosages have been found superior to 300-mg dosages of allopurinol in reducing serum uric acid; however, recent ACR recommendations suggest increased efficacy for allopurinol at doses up to 800 mg daily in healthy patients.27 Therefore, a higher dose of allopurinol may be considered before switching to febuxostat to achieve target serum uric acid. When xanthine oxidase inhibitors are used for renal hyperuricemia and urate stones, febuxostat may be considered over allopurinol.36 Both xanthine oxidase inhibitors require dose modifications in patients with renal disease; however, recent literature suggests allopurinol may be safely titrated above the previous 300-mg dose threshold to target lower serum uric acid, as long as the patient’s renal function is monitored closely.6,19,27,29,30 When considering urate-lowering therapy with allopurinol, monitor patients for allopurinol hypersensitivity syndrome, which occurs in about 0.2% of patients.4-6,27,29 This deadly reaction has symptoms of a pseudo-StevensJohnson-like rash, fever, eosinophilia, hepatitis, renal failure, and end-organ vasculitis.6,27,29 Patients at highest risk for developing allopurinol hypersensitivity syndrome are those of Han Chinese, Thai, and Korean descent who have stage 3 renal disease, and patients with the HLAB*5801 allele; rapid polymerase chain reaction testing for biomarker rs9263726 is available for use in these at-risk populations before starting allopurinol.5,6,27,29 Regardless of which xanthine oxidase inhibitor is chosen, avoid starting therapy during acute gout because of the potential to precipitate another acute episode. After symptoms resolve, a xanthine oxidase inhibitor can be started at a low dose, and concomitantly prescribed with prophylactic colchicine and/or NSAIDs.27,29,35 More aggressive proponents of urate-lowering therapy have discovered that starting allopurinol during acute gout improved patient compliance with therapy without any significant increase in precipitating acute episodes.37 Uricosurics Probenecid is the only available uricosuric in the United States; benzbromarone is available in Europe. These drugs competitively bind the transporters of the renal tubule brush border, effectively increasing the renal excretion of uric acid. Aspirin interferes with this mechanism and patients should avoid using it while taking probenecid. Uricosurics also pose a high risk of renal calculi, especially in patients who overproduce urate. A 24-hour urinary uric acid test should be performed before starting uricosuric therapy, and uricosurics should be avoided in patients with a urinary uric acid level above 800 mg.38 These drugs also are contraindicated in patients with a history of nephrolithiasis and renal disease.29,30 Tell patients to drink the 30

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recommended 64 oz of water daily to reduce the risk of developing urate stones. Drug-to-drug interactions are very common, so uricosurics should be used cautiously.27,29,38 NEW DRUGS FOR AN OLD DISEASE IL-1b inhibitors and uricases have been developed to treat refractory chronic and acute gout. These medications are fairly new, expensive, and likely are beyond the scope of the general practitioner. For patients with refractory chronic gout, consider referral to a rheumatologist earlier in the disease course rather than later. Pegloticase, a PEGylated recombinant mammalian uricase, has been proven to be very effective in lowering serum uric acid levels below the target 6 mg/dL. This drug is indicated for patients with refractory chronic gout that does not respond to usual urate-lowering therapy. Pegloticase catalyzes uric acid into 5-hydroxyisourate, which spontaneously converts into allantoin and is cleared via the kidneys. Studies have found the drug improves quality of life, function, and pain visual analog score, and reduces tophi size in patients with refractory chronic gout.29,39 The drug rapidly lowers serum uric acid levels to below 6 mg/ dL within the first 6 hours of infusion and is approved for biweekly infusions. However, the drug’s rapid onset of action means that nearly 80% of patients in the drug trials suffered an acute gout episode during therapy initiation, probably due to the rapid shift in serum uric acid levels.29,39,40 Also, a subset of patients undergoing pegloticase therapy during drug trials developed an antibody to the drug that hindered serum uric acid reduction; in these patients the medication was discontinued.40 Canakinumab is a human monoclonal IL-1b antibody, administered via subcutaneous injection that limits activation of the IL-1b cytokine.33,34 The drug has been studied comparatively against IM triamcinolone acetonide, NSAIDs, and colchicine in managing acute gout. In these studies it was proven to be superior in improving pain visual analog scale ratings during the initial 72 hours and lowering the risk of a repeat acute gout episode during initiation of urate-lowering therapy.29,32-34 The risk of infection is increased with canakinumab as with any other immunologic agent; other adverse reactions include headache, lumbago, neutropenia, and thrombocytopenia.34 CONCLUSION The prevalence of gout has been increasing in the US population. Genetic variations account for rare cases of gout, but more commonly gout is the result of multiple risk factors. Clinicians should be aware of the comorbidity association gout has with obesity, hypertension, renal, and heart disease. Although the gold standard of diagnosis remains the discovery of needle-shaped, negatively green birefringent crystals on polarized light microscopy from joint aspirate, imaging modalities such as CT and musculoskeletal ultrasound are proving useful in monitoring Volume 27 • Number 9 • September 2014

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Gout: A comprehensive review

treatment efficacy. A target serum uric acid level well below 6 mg/dL can facilitate disease regression. Referral to rheumatology should be considered early in the disease course. For patients with refractory chronic gout, new targeted therapies are available. JAAPA Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa. org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of September 2014.

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Gout: a comprehensive review.

The prevalence of gout in the US population is steadily increasing. Genome-wide research has found several variants of DNA sequences that predispose p...
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