Michelle A. Fravel, Michael E. Ernst, and Elizabeth C. Clark
In the absence of a history of gout, asymptomatic hyperuricemia may not require treatment.
Acute gouty arthritis may be treated effectively with short courses of high-dose nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or colchicine.
Low-dose colchicine is highly effective at relieving acute attacks of gout; dose titration leads to more adverse effects but does not improve efficacy.
Treatment with urate-lowering drugs to reduce risk of recurrent attacks of gouty arthritis is considered cost-effective for patients having two or more attacks of gout per year.
Xanthine oxidase inhibitors are efficacious for the prophylaxis of recurrent gout attacks in both underexcreters and overproducers of uric acid. Either allopurinol or febuxostat should be initiated in patients with one of the following indications for urate-lowering therapy: (a) two or more gout attacks per year, (b) the presence of one or more tophus, (c) chronic kidney disease (stage 2 or worse), or (d) a history of urolithiasis. The dose of the xanthine oxidase inhibitor should be titrated to a goal serum urate concentration of <6 mg/dL (or <5 mg/dL if signs of gout persist at a level of 6 mg/dL).
Uricosuric agents should be avoided for patients with renal impairment [a creatinine clearance below 50 mL/min (0.84 mL/s)], a history of renal calculi, or overproduction of uric acid.
Low-dose colchicine, NSAID, or corticosteroid therapy should be administered during the first 3 to 6 months of urate-lowering therapy to minimize the risk of acute gout attacks that may occur during this initiation period.
Uric acid nephrolithiasis should be treated with adequate hydration (2 to 3 L/day), a daytime urine-alkalinizing agent, and 60 to 80 mEq/day (60 to 80 mmol/L) of potassium bicarbonate or potassium citrate.
Patients with hyperuricemia or gout should undergo comprehensive evaluation for signs and symptoms of cardiovascular disease, and aggressive management of cardiovascular risk factors (i.e., weight loss, reduction of alcohol intake, control of blood pressure, glucose, and lipids) should be undertaken as indicated.
The term gout describes a heterogeneous clinical spectrum of diseases including elevated serum urate concentration (hyperuricemia), recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, deposits of monosodium urate crystals (tophi) in tissues in and around joints, interstitial renal disease, and uric acid nephrolithiasis.1
The underlying metabolic disorder of gout is hyperuricemia, defined physiochemically as serum that is supersaturated with monosodium urate. At 37°C (98.6°F), serum urate concentrations above (or around) 7 mg/dL (416 μmol/L) begin to exceed the limit of solubility for monosodium urate.1 For determination of the risk of gout, hyperuricemia is defined statistically as serum urate concentrations greater than two standard deviations above the population means for age- and sex-matched healthy populations, usually 7 mg/dL (416 μmol/L) for men and 6 mg/dL (357 μmol/L) for women.1,2 Although hyperuricemia is fundamental to the development of gout, the mere presence of hyperuricemia itself is often an asymptomatic condition.
Historically, gout has been referred to as the “disease of kings” since it was often associated with affluent societies and lifestyles of overindulgence, gluttony, and intemperance.1 Gout continues to occur more commonly in developed countries (e.g., United States, Japan, United Kingdom, and Australia) as compared to developing countries (e.g., China).3 In the United States, the prevalence of gout is increasing. According to data from the 2007 to 2008 National Health and Nutrition Examination Survey (NHANES), the prevalence of gout in US adults is 3.9%, which corresponds to an estimated 8.3 million people. This represents a 1.2% increase in prevalence compared with NHANES-III survey data from 1988 to 1994.4
Elevated serum urate levels are the single most important risk factor for the development of gout, and the relationship between the risk of an attack of acute gouty arthritis and serum urate levels is linearly correlated. The 5-year cumulative risk of gout for patients with serum urate concentrations <7 mg/dL (<416 μmol/L) is 0.6%, compared with a risk of 30.5% for those with urate levels >10 mg/dL (>595 μmol/L).5 Sustained elevation of serum urate is virtually essential for the development of gout; however, hyperuricemia does not always lead to gout, and many patients with hyperuricemia remain asymptomatic.2 Although unusual, acute gouty arthritis has been reported to occur in the presence of normal serum uric acid concentrations.6 The prevalence of hyperuricemia in the United States mirrors the trend seen with gout, affecting 21.4% of adults (43.3 million people) in 2007 to 2008 compared to just 18.2% in 1998 to 1994.4
The increased prevalence of gout and hyperuricemia may be partly explained by the aging of the population. Gout and hyperuricemia occur more commonly in the older adult with the highest prevalence, 12.6%, in those 80 years of age and older compared with just 0.4% in those ages 20 to 29 years.4 Another major contributor to the increased prevalence of gout in the United States is the obesity epidemic. Obese persons are twice as likely to have gout as nonobese counterparts.7 Dietary and lifestyle factors linked to obesity have also been independently associated with gout. These include consumption of alcohol, sugary beverages, and red meat along with a sedentary lifestyle.8
Regarding sex distribution, gout affects men about three times more often than women.4 The lowest rates of gout are observed in women younger than 45 years, approximately 0.6 cases per 1,000 person-years.9 Serum uric acid levels in women approach those of men once menopause has occurred; thus, in older age groups the gender gap narrows, and approximately half of newly diagnosed cases of gout are found in women.10,11 Gout in men younger than 30 years of age or in premenopausal women may indicate an inherited enzyme defect or the presence of renal disease. Although no genetic marker has been isolated for gout, the familial nature of gout strongly suggests an interaction between genetic and environmental factors.
ETIOLOGY AND PATHOPHYSIOLOGY
In humans, the production of uric acid is the terminal step in the degradation of purines. Uric acid serves no known physiologic purpose and is regarded as a waste product. Normal uric acid levels are near the limits of urate solubility, because of the delicate balance that exists between the amount of urate produced and excreted.2 Humans have higher uric acid levels than other mammals because they do not express the enzyme uricase, which converts uric acid into the more soluble allantoin.10
Gout occurs exclusively in humans in whom a miscible pool of uric acid exists. Under normal conditions, the amount of accumulated uric acid is about 1,200 mg in men and about 600 mg in women. The size of the urate pool is increased severalfold in individuals with gout. This excess accumulation may result from either overproduction or underexcretion of uric acid. Several conditions are associated with either decreased renal clearance or an overproduction of uric acid, leading to hyperuricemia. Table 74–1 lists some of these conditions.
TABLE 74-1 Conditions Associated with Hyperuricemia
Overproduction of Uric Acid
The purines from which uric acid is produced originate from three sources: dietary purine, conversion of tissue nucleic acid into purine nucleotides, and de novo synthesis of purine bases. The purines derived from these three sources enter a common metabolic pathway leading to the production of either nucleic acid or uric acid. Under normal circumstances, uric acid may accumulate excessively if production exceeds excretion. The average human produces about 600 to 800 mg of uric acid each day. Dietary purines play an unimportant role in the generation of hyperuricemia in the absence of some derangement in purine metabolism or elimination. However, diet modifications are important for patients with such problems who develop symptomatic hyperuricemia.
Several enzyme systems regulate purine metabolism. Abnormalities in these regulatory systems can result in overproduction of uric acid. Uric acid may also be overproduced as a consequence of increased breakdown of tissue nucleic acids and excessive rates of cell turnover, as observed with myeloproliferative and lymphoproliferative disorders, polycythemia vera, psoriasis, and some types of anemias. Cytotoxic medications used to treat these disorders can result in overproduction of uric acid secondary to lysis and breakdown of cellular matter.
Two enzyme abnormalities resulting in an overproduction of uric acid have been well described (Fig. 74–1). The first is an increase in the activity of phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased concentration of PRPP. PRPP is a key determinant of purine synthesis and uric acid production. The second is a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT is responsible for the conversion of guanine to guanylic acid and hypoxanthine to inosinic acid. These two conversions require PRPP as the cosubstrate and are important reactions involved in the synthesis of nucleic acids. A deficiency in the HGPRT enzyme leads to increased metabolism of guanine and hypoxanthine to uric acid and to more PRPP to interact with glutamine in the first step of the purine pathway.12 Complete absence of HGPRT results in the childhood Lesch–Nyhan syndrome, characterized by choreoathetosis, spasticity, intellectual disability, and markedly excessive production of uric acid. A partial deficiency of the enzyme may be responsible for marked hyperuricemia in otherwise normal, healthy individuals.
FIGURE 74-1 Purine metabolism. (HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate.)
CLINICAL PRESENTATION Acute Gouty Arthritis
• Gout classically presents as an acute inflammatory monoarthritis. The first metatarsophalangeal joint is often involved (“podagra”), but any joint of the lower extremity can be affected and occasionally gout will present as a monoarthritis of the wrist or finger. The spectrum of gout also includes nephrolithiasis, gouty nephropathy, and aggregated deposits of sodium urate (tophi) in cartilage, tendons, synovial membranes, and elsewhere
Signs and Symptoms
• Fever, intense pain, erythema, warmth, swelling, and inflammation of involved joints
• Elevated serum uric acid levels; leukocytosis
Other Diagnostic Tests
• Observation of monosodium urate crystals in synovial fluid or a tophus
• For patients with long-standing gout, radiographs may show asymmetric swelling within a joint on or subcortical cysts without erosions
Underexcretion of Uric Acid
Normally, uric acid does not accumulate as long as production is balanced with elimination. About two thirds of the daily uric acid production is excreted in the urine and the remainder is eliminated through the GI tract after enzymatic degradation by colonic bacteria. The vast majority of patients (90%) with gout have a relative decrease in the renal excretion of uric acid for an unknown reason (primary idiopathic hyperuricemia).2
A decline in the urinary excretion of uric acid to a level below the rate of production leads to hyperuricemia and an increased miscible pool of sodium urate. Almost all the urate in plasma is freely filtered across the glomerulus. The concentration of uric acid appearing in the urine is determined by multiple renal tubular transport processes in addition to the filtered load. Evidence favors a four-component model including glomerular filtration, tubular reabsorption, tubular secretion, and postsecretory reabsorption.
Approximately 90% of filtered uric acid is reabsorbed in the proximal tubule, probably by both active and passive transport mechanisms. There is a close linkage between proximal tubular sodium reabsorption and uric acid reabsorption, so conditions that enhance sodium reabsorption (e.g., dehydration) also lead to increased uric acid reabsorption. The exact site of tubular secretion of uric acid has not been determined; this too appears to involve an active transport process. Postsecretory reabsorption occurs somewhere distal to the secretory site. Table 74–2 lists the drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes. By enhancing renal urate reabsorption, insulin resistance is also associated with gout.
TABLE 74-2 Drugs Capable of Inducing Hyperuricemia and Gout
The pathophysiologic approach to the evaluation of hyperuricemia requires determining whether the patient is overproducing or underexcreting uric acid. This can be accomplished by placing the patient on a purine-free diet for 3 to 5 days and then measuring the amount of uric acid excreted in the urine in 24 hours. As it is very difficult to maintain a purine-free diet for several days, this test is done infrequently in clinical practice. Nevertheless, when it is performed, individuals who excrete more than 600 mg on a purine-free diet may be considered overproducers. Hyperuricemic individuals who excrete less than 600 mg of uric acid per 24 hours on a purine-free diet may be classified as underexcreters of uric acid. On a regular diet, excretion of more than 1,000 mg per 24 hours reflects overproduction; less than this is probably normal.
Gout is diagnosed clinically by symptoms rather than laboratory tests of uric acid. In fact, asymptomatic hyperuricemia discovered incidentally generally requires no therapy because many individuals with hyperuricemia will never experience an attack of gout. These patients should still be encouraged to implement lifestyle measures to reduce serum urate concentrations.
Acute Gouty Arthritis
A classic acute attack of gouty arthritis is characterized by rapid and localized onset of excruciating pain, swelling, and inflammation. The attack is typically monoarticular at first, most often affecting the first metatarsophalangeal joint (great toe) and then, in order of frequency, the insteps, ankles, heels, knees, wrists, fingers, and elbows. In one half of initial attacks, the first metatarsophalangeal joint is affected, a condition commonly referred to as podagra(see Fig. 74–2). Up to 90% of patients with gout will experience podagra at some point in the course of their disease.2
FIGURE 74-2 Acute gout attack of the first metatarsophalangeal joint. (From Imboden J, Hellmann DB, Stone JH. Current Rheumatology Diagnosis and Treatment, 2nd ed. New York: McGraw-Hill, 2004:316.)
Atypical presentations of gout also occur. For elderly patients, gout can present as a chronic polyarticular arthritis that can be confused with rheumatoid arthritis or osteoarthritis. Additionally, the onset of gout may be less dramatic than the typical acute attack and have fewer clinical findings.13 Multiple small joints in the hands may be involved, especially in elderly women.10 Table 74–3 summarizes the different clinical manifestations of gout.
TABLE 74-3 Clinical Manifestations of Gout
The predilection of acute gout for peripheral joints of the lower extremity is probably related to the low temperature of these joints combined with high intraarticular urate concentration. Synovial effusions are likely to occur transiently in weight-bearing joints during the course of a day with routine activity. At night, water is reabsorbed from the joint space, leaving behind a supersaturated solution of monosodium urate, which can precipitate attacks of acute arthritis. Attacks generally begin at night with the patient awakened from sleep by excruciating pain.
The development of crystal-induced inflammation involves a number of chemical mediators causing vasodilation, increased vascular permeability, complement activation, and chemotactic activity for polymorphonuclear leukocytes.14 Phagocytosis of urate crystals by the leukocytes results in rapid lysis of cells and a discharge of lysosomal and proteolytic enzymes into the cytoplasm. The ensuing inflammatory reaction is associated with intense joint pain, erythema, warmth, and swelling. Fever is common, as is leukocytosis. Untreated attacks may last from 3 to 14 days before spontaneous recovery.
Although acute attacks of gouty arthritis may occur without apparent provocation, a number of conditions may precipitate an attack. These include stress, trauma, alcohol ingestion, infection, surgery, rapid lowering of serum uric acid by ingestion of uric acid-lowering agents, and ingestion of certain drugs known to elevate serum uric acid concentrations (see Table 74–2). Other crystal-induced arthropathies that may resemble gout on clinical presentation are caused by calcium pyrophosphate dihydrate crystals (pseudogout) and calcium hydroxyapatite crystals, which are associated with calcific periarthritis, tendinitis, and arthritis.14–17 Acute flares of gouty arthritis may occur infrequently, but over time the interval between attacks may shorten if appropriate measures to correct hyperuricemia are not undertaken. Later in the disease, tophaceous deposits of monosodium urate crystals in the skin or subcutaneous tissues may be found. These tophi can be anywhere but are often found on the hands, wrists, elbows, or knees. It is estimated to take 10 or more years for tophi to develop.
Table 74–4 lists the differential diagnosis of an acute monoarthritis.18,19 A definitive diagnosis of gout requires aspiration of synovial fluid from the affected joint and identification of intracellular crystals of monosodium urate monohydrate in synovial fluid leukocytes.2 Identification of monosodium urate crystals is highly dependent on the experience of the observer. Crystals are needle shaped, and when examined under polarizing light microscopy, they are strongly negatively birefringent (see Fig. 74–3). Crystals can be observed in synovial fluid during asymptomatic periods.20 If an affected joint is tapped, the resulting synovial fluid may have white cells and appear purulent. Such findings should always raise the question of infection. If any clinical features of infection are present, such as high fever, elevated white blood cell count, multiple joints affected, or an identified source of infection, proper diagnosis and treatment are critical. Patients with gout can have septic arthritis. Diabetes, alcohol abuse, and advanced age increase the likelihood of septic arthritis.
TABLE 74-4 Differential Diagnosis of Acute Monoarthritis
FIGURE 74-3 Urate crystal ingested by a polymorphonuclear leukocyte in synovial fluid. (From Imboden J, Hellmann DB, Stone JH. Current Rheumatology Diagnosis and Treatment, 2nd ed. New York: McGraw-Hill, 2004:317.)
In lieu of obtaining a synovial fluid sample from an affected joint to inspect for urate crystals, the clinical triad of inflammatory monoarthritis, elevated serum uric acid level, and response to colchicine can be used to diagnose gout. However, this approach has limitations, including a failure to recognize atypical gout presentations and the fact that serum uric acid levels can be normal or even low during an acute gout attack.2,5,21 In addition, use of colchicine as a diagnostic tool for gout is limited by lack of sensitivity and specificity for the disease. Other conditions such as psoriatic arthritis, sarcoidosis, and Mediterranean fever can respond to colchicine therapy. For patients with long-standing gout, radiographs may show punched-out marginal erosions and secondary osteoarthritic changes; however, in an acute first attack radiographs will be unremarkable.19,22 The presence of chondrocalcinosis on radiographs may indicate pseudogout. Some studies have recently examined the use of magnetic resonance imaging and computed tomography to obtain images for patients with gout; however, this is not currently considered part of normal practice. Table 74–5 shows the European League Against Rheumatism (EULAR) evidence-based diagnostic principles.22
TABLE 74-5 EULAR Evidence-Based Recommendations for Gout: Diagnostic Principles
Uric Acid Nephrolithiasis
Clinicians should be suspicious of hyperuricemic states for patients who present with kidney stones, as nephrolithiasis occurs in approximately 15% of patients with gout.23 The frequency of urolithiasis depends on serum uric acid concentrations, acidity of the urine, and urinary uric acid concentration. Typically, patients with uric acid nephrolithiasis have a urinary pH of less than 6. Uric acid has a negative logarithm of the acid ionization constant of 5.5. Therefore, when the urine is acidic, uric acid exists primarily in the unionized, less soluble form. At a urine pH of 5, urine is saturated at a uric acid level of 15 mg/dL (0.89 mmol/L). When the urine pH is 7, the solubility of uric acid in urine is increased to 200 mg/dL (11.9 mmol/L).1 For patients with uric acid nephrolithiasis, urinary pH typically is less than 6 and frequently less than 5.5. When acidic urine is saturated with uric acid, spontaneous precipitation of stones may occur.
Other factors that predispose individuals to uric acid nephrolithiasis include excessive urinary excretion of uric acid and highly concentrated urine. The risk of renal calculi approaches 50% in individuals whose renal excretion of uric acid exceeds 1,100 mg/day (6.5 mmol/day). In addition to pure uric acid stones, hyperuricosuric individuals are at increased risk for mixed uric acid–calcium oxalate stones and pure calcium oxalate stones. Uric acid stones are usually small, round, and radiolucent. Uric acid stones containing calcium are radiopaque.24
There are two types of gouty nephropathy: acute uric acid nephropathy and chronic urate nephropathy.2 In acute uric acid nephropathy, acute renal failure occurs as a result of blockage of urine flow secondary to massive precipitation of uric acid crystals in the collecting ducts and ureters. This syndrome is a well-recognized complication for patients with myeloproliferative or lymphoproliferative disorders and is a result of massive malignant cell turnover, particularly after initiation of chemotherapy.
Chronic urate nephropathy is caused by the long-term deposition of urate crystals in the renal parenchyma. Microtophi may form, with a surrounding giant-cell inflammatory reaction. A decrease in the kidneys’ ability to concentrate urine and the presence of proteinuria may be the earliest pathophysiologic disturbances. Hypertension and nephrosclerosis are common associated findings. Although renal failure occurs in a higher percentage of gouty patients than expected, it is not clear if hyperuricemia per se has a harmful effect on the kidneys. The chronic renal impairment seen in individuals with gout may result largely from the coexistence of hypertension, diabetes mellitus, and atherosclerosis.
Tophi (urate deposits) are uncommon in the general population of gouty subjects and are a late complication of hyperuricemia. The most common sites of tophaceous deposits for patients with recurrent acute gouty arthritis are the base of the fingers, olecranon bursae, ulnar aspect of the forearm, Achilles tendon, knees, wrists, and hands (Fig. 74–4).2 Eventually, even the hips, shoulders, and spine may be affected. In addition to causing obvious deformities, tophi may damage surrounding soft tissue, cause joint destruction and pain, and even lead to nerve compression syndromes including carpal tunnel syndrome.
FIGURE 74-4 Tophaceous gout with subcutaneous nodule almost breaking through the skin. (From South-Paul JE, Matheny SC, Lewis EL. Current Diagnosis and Treatment in Family Medicine. New York: McGraw-Hill, 2004:275.)
The goals in the treatment of gout are to terminate the acute attack, prevent recurrent attacks of gouty arthritis, and prevent complications associated with chronic deposition of urate crystals in tissues. These can be accomplished through a combination of pharmacologic and nonpharmacologic methods, including focused patient education efforts. The first-ever American College of Rheumatology (ACR) evidence- and consensus-based guidelines for the management of gout were published in 2012.25,26 These guidelines provide specific recommendations for treatment of acute gout attacks, management of hyperuricemia in gout, and antiinflammatory prophylaxis of acute gout during initiation of urate-lowering therapy. These guidelines will be discussed throughout the remainder of the treatment section of this chapter. Tables 74–6 and 74-7 summarize dosing and monitoring information for available pharmacotherapy used in management and prevention of gout.
TABLE 74-6 Pharmacotherapy of Acute Gout, Antiinflammatory Prophylaxis During Initiation of Urate-Lowering Therapy and Hyperuricemia in Gouta
TABLE 74-7 Drug Monitoring
Acute Gouty Arthritis
There are limited effective nonpharmacologic therapies for an acute gout attack; therefore, they are recommended strictly as adjunctive treatment.
Local ice application is the most effective.26 In one small study, adjunctive ice application resulted in significantly greater pain reduction in those receiving the therapy compared with those not treated with ice (difference of 3.33 cm on a 10-cm visual analog pain scale, P = 0.021).27 Complementary and alternative medicines, including flaxseed and celery root, are not recommended in ACR guidelines.26
For most patients, acute attacks of gouty arthritis may be treated successfully with nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or colchicine. The ACR guidelines recognize these three modalities as first-line monotherapy for the treatment of acute gout. Treatment should commence within 24 hours of the onset of an attack. In more severe cases, those affecting multiple joints or causing higher intensity pain, combination or investigational drug therapy may be indicated (Fig. 74–5).26
FIGURE 74-5 Algorithm for management of an acute gout attack.
Nonsteroidal Antiinflammatory Drug
NSAIDs are a mainstay of therapy for acute attacks of gouty arthritis because of their excellent efficacy and minimal toxicity with short-term use. Indomethacin has been historically favored as the NSAID of choice for acute gout flares, but there is little evidence to support one NSAID as being more efficacious than another. Three agents (indomethacin, naproxen, and sulindac) have U.S. Food and Drug Administration (FDA)-approved labeling for the treatment of gout, although several others are likely to be effective.26 Although choice of NSAID is not an important determinant of therapeutic success, timing of pharmacotherapy is. It is critical that therapy is initiated within 24 hours of acute gout attack onset and continued until complete resolution.26 Following resolution of the attack, tapering of NSAID therapy may be considered, especially in patients with comorbidities such as hepatic or renal insufficiency where prolonged therapy would be undesirable.26 Resolution of an acute attack for most patients generally occurs within 5 to 8 days after initiating therapy.
All NSAIDs have the potential to cause similar adverse effects. The most common areas affected include the GI system (gastritis, bleeding, perforation), kidneys (renal papillary necrosis, reduced creatinine clearance), cardiovascular system (sodium and fluid retention, increased blood pressure), and CNS (impaired cognitive function, headache, dizziness). Caution should be exercised when using NSAIDs for individuals with a history of peptic ulcer disease, congestive heart failure, uncontrolled hypertension, renal insufficiency, coronary artery disease, or who are concurrently receiving anticoagulants or antiplatelets. Patients with active peptic ulcer disease, uncompensated congestive heart failure, severe renal impairment, or a history of hypersensitivity to aspirin or other NSAIDs should not be prescribed an NSAID.
Selective cyclooxygenase-2 (COX-2) inhibitors present a potentially better tolerated alternative to nonselective NSAIDs in patients with GI issues. Specific COX-2 inhibitors, etoricoxib and lumiracoxib, have demonstrated efficacy in the treatment of acute gout in numerous controlled trials; however, these agents are not available in the United States. One study has established effectiveness of high-dose celecoxib (1200 mg on day 1 followed by 400 mg twice daily thereafter) in the treatment of acute gout, but concerns regarding the cardiovascular risk of COX-2 inhibitors must be considered when using these agents (see Chap. 71, Osteoarthritis, for further discussion of COX-2 inhibitors).28,29 The ACR guidelines recommend celecoxib as an option for patients unable to take NSAIDs but note that the risk-to-benefit ratio of celecoxib use in acute gout is unclear.26
Corticosteroids have historically been reserved for treatment of acute gout flares when contraindications to other therapies exist, largely due to lack of evidence from controlled clinical trials. However, more recent evidence indicates that corticosteroids are equivalent to NSAIDs in the treatment of acute gout flares.30 They can be used either systemically or by intraarticular injection. The ACR guidelines recommend that the number of joints involved be considered when choosing the route of corticosteroid administration. If only one or two joints are involved, either intraarticular or oral corticosteroids are recommended. If an attack is polyarticular, systemic therapy is necessary.26 A hypothetical risk for a rebound attack upon steroid withdrawal exists; therefore, gradual tapering is often employed when discontinuing steroid therapy. The ACR guidelines suggest two different dosing strategies for oral corticosteroid therapy (prednisone or prednisolone) in the treatment of acute gout: (a) 0.5 mg/kg daily for 5 to 10 days followed by abrupt discontinuation or (b) 0.5 mg/kg daily for 2 to 5 days followed by tapering for 7 to 10 days. The guidelines also support the use of a methylprednisolone dose pack for acute treatment of gout, a 6-day regimen that starts with 24 mg on day 1 and decreases by 4 mg each day.26 Intraarticular administration of triamcinolone acetonide in a dose of 20 to 40 mg may be useful in treating acute gout limited to one or two joints. Injection should be done under an aseptic technique in a joint determined not to be infected. Per ACR guideline recommendations, intraarticular corticosteroid therapy should be used in conjunction with either an NSAID, colchicine, or oral corticosteroid therapy; however, case reports suggest that this therapeutic approach may be as effective as monotherapy.26,31A single intramuscular injection of a long-acting corticosteroid, such as methylprednisolone, followed by oral corticosteroid therapy is recognized as a reasonable therapeutic approach to the treatment of acute gout by the ACR guidelines.26 Alternatively, intramuscular corticosteroid monotherapy may be considered in patients with multiple affected joints who are unable to take oral therapy.
The adverse effects of corticosteroids are generally dose and duration dependent. Short-term use for treatment of acute attacks is generally well tolerated. Corticosteroids should be used with caution for patients with diabetes as they can increase blood sugar. In addition, patients with a history of GI problems, bleeding disorders, cardiovascular disease, and psychiatric disorders should be monitored closely. Long-term corticosteroid use should be avoided because of the risk for osteoporosis, hypothalamic–pituitary axis suppression, cataracts, and muscle deconditioning that can occur with their use.
Corticotropin, or adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex to produce cortisol and corticosterone, can be administered in acute gout. Doses of 40 to 80 United States Pharmacopeia (USP) units are given intramuscularly every 6 to 8 hours for 2 to 3 days, and then discontinued. Studies with ACTH are limited, but it appears to provide similar efficacy to systemic antiinflammatory doses of corticosteroids.32 When administered alone or in combination with colchicine, ACTH may provide earlier efficacy compared with indomethacin but with fewer adverse effects.33Because the studies have several limitations, the regimen should be considered only as an alternative, especially for patients with comorbidities where other regimens are contraindicated.34 Examples of patients where ACTH has been used safely when other first-line gout therapies were contraindicated include those with congestive heart failure, chronic renal failure, and history of GI bleeding.35 The ACR guidelines support the use of ACTH in the treatment of acute gout in patients unable to take oral medications.26
Colchicine is an antimitotic drug that is highly effective at relieving acute attacks of gout.36 When begun within the first 24 hours of an acute attack, colchicine produces a response in two thirds of patients within hours of administration.37 If the initiation of colchicine is delayed; however, the probability of success with the drug diminishes substantially. For this reason, the ACR guidelines advocate use of colchicine for treatment of acute gout only if started within 36 hours of attack onset.26
Although it is a highly effective therapy, oral colchicine can cause dose-dependent GI adverse effects, including nausea, vomiting, and diarrhea. Other important non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened for patients taking other myopathic drugs such as β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitors (statins) or for those with renal insufficiency.
Colchicine was used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings. More recently, the FDA approved a 0.6-mg tablet of colchicine (Colcrys®) for oral use. Data submitted in support of the safety and efficacy of colchicine in acute gout flares demonstrated that a substantially lower dose of colchicine (1.2 mg initially, followed by 0.6 mg 1 hour later) was as effective as higher doses traditionally used (continued hourly dosing until symptoms subside or GI symptoms become intolerable).38 These findings suggest that prior use of high-dose colchicine regimens, may unnecessarily expose patients to increased toxicity with no additional efficacy. In addition to the new low-dose regimen, the ACR guidelines also suggest that colchicine 0.6 mg once or twice daily can be started 12 hours following the initial 1.2 mg dose and continued until the acute attack resolves.26 This off-label dosing recommendation is based upon pharmacokinetic data that suggests that colchicine levels begin to decline 12 hours after administration.38
Comprehensive review of postmarketing safety data revealed an increased risk of adverse events for patients receiving colchicine administered concurrently with P-glycoprotein or cytochrome P450 3A4 inhibitors (e.g., clarithromycin or cyclosporine) (Table 74–8).39–42 These interactions are thought to result in an increased colchicine concentration. Colchicine should also be used carefully for patients with renal and hepatic insufficiency. Refer to Table 74–8 for colchicine dosing recommendations in these special situations.
TABLE 74-8 Colchicine Dosing in Special Situations/Colchicine Drug Interactions
IV colchicine has resulted in fatalities and is no longer available.43
During acute gout attacks, urate crystals elicit an inflammatory response that triggers the production of interleukin-1 (IL-1).44 This finding has led to the investigational use of IL-1 inhibitors in the treatment of acute gout.
In small trials, two IL-1 inhibitors, anakinra and canakinumab, have demonstrated efficacy in the treatment of acute gout.45–48 Neither is approved for treatment of acute gout by the FDA, and their use remains off-label.44 The ACR guidelines suggest that anakinra 100 mg subcutaneously daily for 3 days or single-dose canakinumab 150 mg subcutaneously can be considered for treatment of severe acute gout attacks refractory to other treatments. However, due to a lack of randomized controlled trials and an uncertain risk-to-benefit ratio, the guidelines note that the role of IL-1 inhibitors in the treatment of acute gout is unclear.26
Hyperuricemia in Gout
Following treatment and resolution of the intense pain associated with an acute gout attack, the focus shifts to the prevention of future episodes. Recurrent gout attacks can be prevented by maintaining low uric acid levels. Although both nonpharmacologic and pharmacologic efforts to maintain low uric acid levels are critical in the management of gout, trials have shown high rates of nonadherence with urate-lowering therapies.49 A likely explanation for this lack in patient adherence is the silent nature of intercritical gout (the period of time between two gout attacks). Patient education, therefore, is a critical first step in the management of hyperuricemia.25,50 Education should address the recurrent nature of the disease and reinforce the objective of each lifestyle/dietary modification and medication therapy recommended.
Weight loss through caloric restriction and exercise should be promoted in all patients with gout and hyperuricemia, as this may enhance renal excretion of urate.51 Restriction of alcohol intake is of great importance, as this is closely correlated with gout attacks.52,53 Acute ingestions of alcohol cause lactic acidemia, which reduces renal urate excretion, and long-term alcohol intake promotes production of purines as a by-product of the conversion of acetate to acetyl coenzyme A in the metabolism of alcohol.54 The ACR guidelines recommend limiting alcohol use in all gout patients and avoidance of any alcohol during periods of frequent gout attacks and in those with advanced gout under poor control.25 The ACR guidelines also recommend limiting consumption of high-fructose corn syrup and purine-rich foods (organ meats and some seafood), which have been linked to uric acid elevation, and encourage the consumption of vegetables and low-fat dairy products, which have been shown to have urate-lowering effects.25,55–60
Another strategy to lower uric acid before initiating urate-lowering pharmacotherapy is to evaluate a patient’s medication list for potentially unnecessary drugs that may elevate uric acid levels (Table 74–2). These include thiazide and loop diuretics, calcineurin inhibitors, niacin, and low-dose aspirin. The ACR guidelines consider the potential elimination of uric acid-elevating medications as a baseline recommendation for all gout patients with hyperuricemia; however, the benefit of thiazide diuretics in the treatment of hypertension and of low-dose aspirin in cardiovascular disease prevention is specifically noted.25
The presence of gout should not be a contraindication to the use of thiazide diuretics in hypertensive patients, although clinicians should be aware that diuretics are independent risk factors for gout and can increase serum uric acid levels.9 It may be important to avoid using diuretics if other agents can be used to control blood pressure, particularly if the patient has had frequent gout attacks or continues to have an elevated serum uric acid level despite appropriate therapy for gout. The ACR guidelines specifically recommend against discontinuing low-dose aspirin used for cardiovascular prevention in patients with gout, since aspirin’s effect on elevating serum uric acid is negligible.25
After the first attack of acute gouty arthritis, a decision to institute prophylactic urate-lowering pharmacotherapy must be considered. This decision should carefully balance risk and benefit. Prophylactic pharmacotherapy has been found to be cost-effective if patients have two or more attacks per year, even if the serum uric acid concentration is normal or only minimally elevated.61,62
Consistent with this finding, the ACR guidelines recognize the occurrence of two or more gout attacks per year as an indication for pharmacologic urate-lowering therapy.25 Other indications include the presence of one or more tophus, chronic kidney disease (stage 2 or worse), and a history of urolithiasis.25
Pharmacologic urate-lowering therapy can be started during an acute gout attack if appropriate antiinflammatory prophylaxis has been initiated25 (see Antiinflammatory Gout Prophylaxis During Initiation of Pharmacologic Urate-lowering Therapy section and Fig. 74–6 for more detail). The goal of initiating urate-lowering therapies is to achieve and maintain a serum uric acid concentration of less than 6 mg/dL (357 μmol/L), and preferably below 5 mg/dL (297 μmol/L) if signs and symptoms of gout persist.25,63 Urate lowering should be prescribed for long-term use, as intermittent administration has been less effective in controlling gouty attacks.25,64 Reduction of serum urate concentrations can be accomplished pharmacologically by decreasing the synthesis of uric acid (xanthine oxidase inhibitors) or by increasing the renal excretion of uric acid (uricosurics).
FIGURE 74-6 Algorithm for management of hyperuricemia in gout.
The ACR guidelines provide a step-wise approach in the treatment of hyperuricemia in gout25 (Fig. 74–6). Within this strategy, xanthine oxidase inhibitors are recommended as first-line therapy. Probenecid, a potent uricosuric therapy, is recommended as an alternative first-line therapy in patients with a contraindication or intolerance to xanthine oxidase inhibitor therapy. In refractory cases, combination therapy including a xanthine oxidase inhibitor plus an agent with uricosuric properties (probenecid, losartan, or fenofibrate) is suggested. Finally, in severe cases in which the patient cannot tolerate or is not responding to other therapies, pegloticase is recommended.
Xanthine Oxidase Inhibitors
Xanthine oxidase inhibitors reduce uric acid by impairing the ability of xanthine oxidase to convert hypoxanthine to xanthine and xanthine to uric acid. Because they are efficacious for prophylaxis in both underexcreters and overproducers of uric acid, xanthine oxidase inhibitors are the most widely prescribed agents for the long-term prevention of recurrent attacks of gout. For nearly 40 years, allopurinol was the only agent available in the United States; a second xanthine oxidase inhibitor (febuxostat; Uloric) reached the US market in 2009.
Allopurinol is an effective urate-lowering agent, but up to 5% of patients are unable to tolerate it because of adverse effects, and long-term adherence with allopurinol is low.49,65 Mild adverse effects such as skin rash, leukopenia, GI problems, headache, and urticaria can occur with allopurinol administration. More severe adverse reactions including severe rash (toxic epidermal necrolysis, erythema multiforme, or exfoliative dermatitis), hepatitis, interstitial nephritis, and eosinophilia reportedly occur in approximately 1:1,000 patients and are associated with a 20% to 25% mortality.25 Although direct evidence is lacking, the presence of renal insufficiency and thiazide diuretic use is believed to predispose patients to this “allopurinol hypersensitivity syndrome.”25,66
Evidence has also linked higher starting doses of allopurinol with an increased incidence of allopurinol hypersensitivity syndrome; therefore, conservative initial dosing is important.67 ACR guidelines recommended that allopurinol be started at a dose no greater than 100 mg daily and then gradually titrated every 2 to 5 weeks up to a maximum dose of 800 mg/day until the serum urate target is achieved. Patients with chronic kidney disease (stage 4 or worse) should start at a dose no greater than 50 mg per day.25 This conservative dosing strategy is intended to avoid allopurinol hypersensitivity syndrome and also prevent acute gout attacks common during initiation of urate-lowering therapy.
Traditionally, the maximum daily dose of allopurinol has been reduced for patients with renal insufficiency; however, this recommendation comes from a non-evidence-based algorithm and is therefore not supported by the ACR guidelines.25,66 It is critical, however, to educate patients with renal impairment taking allopurinol about the signs and symptoms of a serious reaction, including pruritus and rash. These patients should also undergo routine monitoring for elevation of hepatic enzymes and signs of eosinophilia.25
Similar to allopurinol, febuxostat lowers serum urate concentrations in a dose-dependent manner.68,69 In clinical trials, 40 mg/day of febuxostat was noninferior to conventionally dosed allopurinol (300 mg/day) in achieving the primary endpoint of serum urate concentration <6 mg/dL (<357 μmol/L), while 80 mg/day of febuxostat was more effective. The incidence of gout flares occurring during the initial months of administration was similar for both drugs. Febuxostat is well tolerated, with adverse events mostly limited to nausea, arthralgias, and minor liver transaminase elevations.
One criticism of the studies comparing allopurinol and febuxostat is that a fixed dose of allopurinol was used, rather than titrating the dose to achieve the targeted serum urate level. However, the 300 mg/day dosing of allopurinol reflects what has typically been used in the majority of clinical practice.70 An advantage of febuxostat is that it has been studied in patients with mild-to-moderate hepatic and renal impairment [creatinine clearances of 30 to 89 mL/min (0.50 to 1.49 mL/s)] and does not require dose adjustment in these patients.
Uricosuric drugs increase the renal clearance of uric acid by inhibiting postsecretory renal proximal tubular reabsorption of uric acid. The drug used most widely to increase uric acid excretion is probenecid. Several other uricosuric drugs are available in Europe, but not in the United States.
Uricosuric therapies, through their action to increase the elimination of uric acid, cause marked uricosuria and may cause stone formation. Probenecid, specifically, has been associated with a 9% to 11% risk of urolithiasis.25,71,72For this reason, patients with a history or urolithiasis should not use potent uricosuric drugs, such as probenecid.25 The maintenance of adequate urine flow and alkalinization of the urine during the first several days of uricosuric therapy may help to diminish the possibility of uric acid stone formation.25
Probenecid is given initially at a dose of 250 mg twice a day for 1 to 2 weeks and then 500 mg twice a day for 2 weeks. Thereafter, the daily dose is increased by 500 mg increments every 1 to 2 weeks until satisfactory control is achieved or a maximum dose of 2 g is reached. In addition to urolithiasis, major adverse effects associated with uricosuric therapy include GI irritation, rash and hypersensitivity, and precipitation of acute gouty arthritis. A disadvantage of uricosurics is that salicylates may interfere with this mechanism and result in treatment failure; however, low doses (325 mg/day or less) of enteric-coated aspirin may be used cautiously. In addition, probenecid can inhibit the tubular secretion of other organic acids; thus, increased plasma concentrations of penicillins, cephalosporins, sulfonamides, and indomethacin can occur.
Uricosuric drugs are contraindicated for patients who are allergic to them, for patients with impaired renal function [a creatinine clearance <50 mL/min (<0.84 mL/s)], and for patients who are overproducers of uric acid; for such patients, a xanthine oxidase inhibitor should be used.
Gout and hyperuricemia are highly prevalent in patients with renal impairment. Selection of uric acid-lowering therapy in this population is complicated, given the lack of safety and efficacy data. Renal impairment is a risk factor for allopurinol hypersensitivity syndrome. Reducing the maximum daily dose of allopurinol in patients with renal impairment does not necessarily reduce the risk of allopurinol hypersensitivity syndrome but does compromise efficacy. Normal daily doses of allopurinol may be used in patients with reduced renal function, but slow titration and careful monitoring for symptoms of allopurinol hypersensitivity are necessary.
An alternative uric acid-lowering therapy, febuxostat, is approved for use in patients with creatinine clearance 30 to 60 mL/min (0.5 to 1 mL/s) but has not been studied in those with lower creatinine clearance rates. Uricosuric therapy is not recommended in this population due to lack of evidence for safety and efficacy. It is unclear which uric acid-lowering therapy is the safest, most efficacious, and most cost-effective in patients with renal impairment.
Pegloticase (Krystexxa) is a pegylated recombinant uricase that works to reduce serum uric acid by converting uric acid to allantoin, a water-soluble and easily excreted substance.
In two 6-month randomized controlled trials, biweekly pegloticase therapy demonstrated efficacy in reducing serum uric acid and resolving tophi in patients with severe gout and hyperuricemia (uric acid ≥8 mg/dL [≥476 μmol/L]) who failed or had a contraindication to allopurinol therapy.73 Severe gout referred to patients who met at least one of the following criteria: (a) three or more gout flares within the most recent 18 months, (b) one or more tophi, or (c) joint damage due to gout. Far more patients receiving pegloticase therapy compared with placebo achieved the primary outcome, maintenance of uric acid <6 mg/dL (<357 μmol/L) for at least 80% of the time during months 3 and 6 of the trial (42% vs. 0%; P < 0.001).
Although clearly efficacious, pegloticase has several drawbacks that limit widespread use. One is the route of administration. The biweekly IV infusions of pegloticase must be given over no less than 2 hours, a potential inconvenience to many patients. Furthermore, given potential infusion-related allergic reactions, patients must be treated with antihistamines and corticosteroids before therapy. Cost is another major consideration. Pegloticase is estimated to cost more than $5,000 per month, not including administration costs associated with an IV infusion.74 This represents a significantly greater cost burden compared with other urate-lowering therapies.74
The ideal duration of pegloticase therapy is currently unknown. Other urate-lowering therapies, xanthine oxidase inhibitors for example, are typically used indefinitely in patients with gout and hyperuricemia. Immunogenicity issues associated with pegloticase therapy may limit the duration with which pegloticase therapy may be used effectively. In the previously cited 6-month pegloticase trials, 134 of 150 patients developed pegloticase antibodies that, for most patients, resulted in a loss of efficacy by month 4.73
Given these many limitations and the narrow patient population in which the drug has been studied, pegloticase is an agent of last resort that should be reserved for patients with refractory gout who are unable to take or have failed all other urate-lowering therapies.
Pegloticase is a new recombinant uricase approved for use in chronic refractory gout. Evidence supports its efficacy in maintaining target serum uric acid levels, but little is known about its ability to reduce the frequency of recurrent gout attacks. Also unclear is the optimal duration of pegloticase therapy. Use of pegloticase in special populations at high risk of gout, including those with renal impairment and older patients, has not yet been studied. Given the many unknowns, a clear role for pegloticase in gout therapy is not yet established.
Lipid-lowering agents, in particular fenofibrate, can also be prescribed for patients with gout. Although dyslipidemia is common in gout patients, the fibrates are believed to exert their effects as an ancillary benefit by increasing the clearance of hypoxanthine and xanthine, leading to a sustained reduction in serum urate concentrations. Reductions of 20% to 30% in urate levels are observed with fenofibrate use.75,76 Importantly, fenofibrate does not appear to not cause an acute gout flare when initiated and is well tolerated overall.77,78
Losartan, an angiotensin II receptor antagonist, has also demonstrated benefit in reducing serum urate concentrations independent of angiotensin receptor antagonism.79 Losartan inhibits renal tubular reabsorption of uric acid and increases urinary excretion, and this effect seems to be a unique property of losartan that is not shared with other angiotensin II receptor antagonists.80 In addition, it alkalinizes the urine, which helps reduce the risk for stone formation.
The ACR guidelines support the use of fenofibrate or losartan in combination with a xanthine oxidase inhibitor in patients with refractory disease.25
Antiinflammatory Gout Prophylaxis During Initiation of Pharmacologic Urate-Lowering Therapy
Initiation of urate-lowering therapy can prompt an acute attack of gout due to remodeling of urate crystal deposits in joints as a result of rapid lowering of urate concentrations.26 As such, prophylactic antiinflammatory pharmacotherapy should be employed to prevent gout attacks and, secondarily, to assist in ensuring patient acceptance of and adherence with urate-lowering therapy. The ACR guidelines recommend low-dose oral colchicine (0.6 mg twice daily) and low-dose NSAIDs (e.g., naproxen 250 mg twice/day) as first-line prophylactic therapies, with stronger evidence supporting use of colchicine.26
Low-dose corticosteroid therapy (e.g., ≤10 mg/day prednisone) is recommended as an alternative in patients with intolerance, contraindication, or lack of response to first-line therapy.26 Limited evidence suggests efficacy of IL-1 inhibitors in the prevention of acute gout during the first 16 weeks of urate-lowering therapy initiation [subcutaneous rilonacept 320 mg loading dose followed by 160 mg weekly and subcutaneous canakinumab single dose (50 to 300 mg) or four times weekly dosing (50 mg—50 mg—25 mg—25 mg)].81,82 Given the limited evidence and lack of FDA approval for this indication, the ACR guidelines do not provide a recommendation for the use of IL-1 inhibitors in this setting.
Pharmacologic prophylaxis should be continued for at least 3 months after achieving target serum uric acid or 6 months total, whichever is longer. For patients with one or more tophi, prophylactic therapy should be continued for 6 months following achievement of serum urate target26 (Fig. 74–6).
Given the considerable duration of therapy required for acute gout prophylaxis during initiation of urate-lowering therapy, adverse effects of the pharmacologic agents employed must be seriously considered. Although the risk for gastric ulceration and bleeding is relatively small with short-term NASID therapy normally employed when treating acute gout flares, administration of a proton-pump inhibitor or other acid-suppressing therapy is indicated to protect from NSAID-induced gastric problems for patients on long-term prophylactic therapy.26 Prolonged corticosteroid therapy is clearly linked to many severe adverse effects (i.e., hyperglycemia, Cushing’s syndrome, fluid retention, hypertension, osteoporosis, glaucoma, depression/euphoria) and, as suggested above, is not appropriate for first-line therapy for this reason.
Cost is another major consideration when selecting prophylactic pharmacotherapy given the need for an extended duration of therapy (6 months of therapy compared to approximately 1 week for acute gout treatment). While improved dosing recommendations resulted from the recent availability of an FDA-approved colchicine product, the research efforts that provided this additional information have come with a price. Market exclusivity rights were granted to the manufacturer of Colcrys and the resulting lack of competition has caused the price of the medication to increase from approximately $0.09 per tablet to almost $5 per tablet.83 The cost of this brand name colchicine, if not covered by insurance, is a potential challenge to therapy for certain patients. To date there have been no formal pharmacoeconomic studies evaluating colchicine in comparison to other therapies for antiinflammatory prophylaxis during urate-lowering therapy initiation; however, NSAIDs and corticosteroids may present more affordable options for patients.
The medical management of uric acid nephrolithiasis includes hydration sufficient to maintain a urine volume of 2 to 3 L/day, alkalinization of urine, avoidance of purine-rich foods, moderation of protein intake, and reduction of urinary uric acid excretion.
Maintenance of a 24-hour urine volume of 2 to 3 L with an adequate intake of fluids is desirable for all gout patients, but especially for those with excessive uric acid excretion [>1 g/day (>6 mmol/day)]. Alkalinizing agents should be used with the objective of making the urine less acidic. Urine pH should be maintained at 6 to 6.5. In this pH range, up to 85% of uric acid will be in the form of the soluble urate ion.
Reduction of urine acidity is usually accomplished by the administration of potassium bicarbonate or potassium citrate 60 to 80 mEq/day (60 to 80 mmol/day).84,85 Administration of alkali via sodium salts is a less desirable option for two reasons. First, the sodium-induced volume expansion will increase sodium excretion and can secondarily cause hypercalcemia because calcium passively follows the reabsorption of sodium in the proximal tubule and loop of Henle. In the presence of uric acid, the resultant hypercalcemia can lead to calcium oxalate stone formation. Second, older patients with uric acid kidney stones may also have hypertension, congestive heart failure, or renal insufficiency. Because of these conditions, they should not be overloaded with alkalinizing sodium salts or unlimited fluid intake, as these can worsen these conditions.
Acetazolamide, a carbonic anhydrase inhibitor, produces rapid and effective urinary alkalinization and sometimes is used in conjunction with alkali therapy. When a 250 mg dose of acetazolamide is given at bedtime, the excretion of acidic urine in the early morning hours is avoided. The usual tachyphylaxis (rapid tolerance) to this drug is obviated by a daily repletion dose of bicarbonate.
Since the advent of xanthine oxidase inhibitors, a low-purine, low-protein diet for the patient with uric acid nephrolithiasis is no longer as critical as it once was; however, it is still advisable to instruct the patient to avoid foods rich in purine and to limit protein to no more than 90 g/day. Such a diet is still palatable and reduces appreciably the amount of uric acid in the urine.
The mainstay of drug therapy for recurrent uric acid nephrolithiasis is xanthine oxidase inhibitors. They are effective in reducing both serum and urinary uric acid levels, thus preventing the formation of calculi. Xanthine oxidase inhibitors are recommended as prophylactic treatment for patients who will receive cytotoxic agents for the treatment of lymphoma or leukemia. The marked increase in uric acid production associated with cytolysis of a neoplasm predisposes a patient to the development of uric acid nephrolithiasis.
Questions are often raised regarding the indication for drug therapy for asymptomatic hyperuricemia. The purported benefits include prevention of acute gouty arthritis, tophi formation, nephrolithiasis, and chronic urate nephropathy. The first three complications are easily controlled should they develop; therefore, antihyperuricemic therapy is not warranted to prevent these conditions. The prevention of urate nephropathy might be a stronger indication because it is irreversible even with proper treatment. Available data indicate, however, that gouty nephropathy is extremely rare in the absence of clinical gout, and evidence that elevation of uric acid by itself may cause renal disease is weak and inconclusive. As discussed previously, renal impairment associated with hyperuricemia is very rare in the absence of concurrent hypertension and atherosclerosis. In addition, it is unclear whether uric acid-lowering therapy protects renal function in such individuals. Thus, the routine treatment of asymptomatic hyperuricemia on the grounds of reducing renal complications is presently not recommended.
The relationship between elevated serum urate concentrations and cardiovascular disease is controversial. In observational studies, hyperuricemia has been shown to be a risk factor for ischemic heart disease.86–89 However, hyperuricemia is also associated with other known risk factors for cardiovascular disease, such as diabetes mellitus, dyslipidemia, and hypertension, and the individual contribution of hyperuricemia on the risk for cardiovascular disease is difficult to separate from these associated factors. Recently, a 12-year follow-up of the Health Professionals Study revealed a 28% higher risk of death from all causes, 38% higher risk of cardiovascular disease death, 55% higher risk of death from coronary heart disease, and a 59% higher risk of nonfatal myocardial infarction for men with a self-reported history of gout compared with those without this reported history.90 These associations remained significant even after adjusting for age, body mass index, smoking, family history of myocardial infarction, and comorbidities such as diabetes and hypertension. To date, this study is the only one providing prospective data that implicate gout as an independent risk for coronary heart disease. No studies have examined whether drug treatment of asymptomatic hyperuricemia or gout is protective against coronary artery disease. At this time, it is premature to implement therapy for patients with asymptomatic hyperuricemia in the absence of a history of gout. Instead, efforts should be directed toward aggressive management of cardiovascular risk factors.
While asymptomatic hyperuricemia is not generally treated, some clinicians do recommend treatment to reduce the risks of vascular disease, including hypertension, cerebrovascular disease, and kidney disease. Although the link between hyperuricemia and vascular disease has been demonstrated in epidemiologic studies, a direct association has not been established due to the lack of prospective, randomized controlled trials. Furthermore, the impact of normalizing uric acid levels with the use of urate-lowering pharmacotherapy on vascular outcomes is unknown.
While the ACR guidelines provide clear recommendations regarding use of pharmacotherapy in the management of gout and hyperuricemia, application of these recommendations requires personalization to fit the needs of a specific patient. When making therapeutic choices for an individual, it is critical to evaluate the adverse effect profile of a particular pharmacotherapeutic agent while considering a patient’s baseline risk for those unwanted effects. This involves an analysis of patient demographics and comorbidities.13
Allopurinol hypersensitivity syndrome is perhaps the most concerning adverse effect of all potential side effects associated with gout therapies, given the high mortality rate associated with this reaction. As such, it would be ideal if patients at high risk for developing this syndrome could be screened for and, consequently, guided to alternative therapy. Recent research has identified a genetic link in certain populations that increases risk for the development of allopurinol hypersensitivity syndrome. Korean patients with chronic kidney disease (stage 3 or worse), Han Chinese patients, and Thai patients have been identified as being at increased risk for allopurinol hypersensitivity syndrome if found to have a specific genotype (HLA-B*5801 positive).91–93 The ACR guidelines recommend that HLA-B*5801 testing be considered before allopurinol initiation in these specific subpopulations; for those found to be positive, alternative therapy should be used.25
Certain comorbidities may warrant dose adjustment of some gout therapies or, in certain instances, complete avoidance of certain medications. For example, patients with renal impairment should, in general, avoid NSAID therapy and must receive colchicine at reduced doses. Patients with GI disease should also avoid NSAID therapy and may not be able to tolerate colchicine therapy and, therefore, may find most success with corticosteroid therapy. In addition to comorbidities, polypharmacy and cost considerations may affect treatment decisions in an individual patient. Refer to Table 74–9 for an overview of important factors to consider when personalizing pharmacotherapy for an individual patient with gout.
TABLE 74-9 Personalized Pharmacotherapy in Gout
Evaluation of Therapeutic Outcomes
Follow-up of patients with gout depends on the frequency of attacks and on the medications used to treat symptoms. For a patient who is experiencing a first attack of gout, long-term therapy is generally not indicated. As previously mentioned, the ACR guidelines recommend that urate-lowering pharmacotherapy be started only after two or more attacks of gout in one year, because the treatment is long term and relatively expensive, the drugs used are potentially toxic, and adherence for patients without symptoms is generally poor.25,62,65 Patients having a first attack should be educated about the likelihood of recurrence and what to do if another attack occurs. Approximately 60% of patients have a second attack within the first year, and 78% have a second attack within 2 years. Only 7% of patients do not have a recurrence within a 10-year period.94
Baseline blood work for patients receiving hypouricemic medications chronically should include renal function (serum creatinine, blood urea nitrogen), liver enzymes (aspartate aminotransferase, alanine aminotransferase), complete blood count, and electrolytes. There is generally no need to recheck these laboratory parameters for patients undergoing acute therapy with an NSAID or colchicine of limited duration. However, for patients requiring long-term therapy or prophylaxis, they should be rechecked every 6 to 12 months or as clinically indicated. For patients suspected of having an acute attack of gouty arthritis, it is reasonable to check a serum uric acid level, particularly if it is not the first attack and a decision is to be made regarding initiation of prophylactic therapy. However, clinicians should be mindful that acute gouty arthritis can occur in the presence of normal serum uric acid concentrations.6During titration of urate-lowering therapy, uric acid should be monitored every 2 to 5 weeks; once the urate target is achieved, uric acid should be monitored every 6 months.25 This monitoring regimen is recommended not only to ensure appropriate dosing of urate-lowering therapy, but also to serve as an assessment of patient adherence given the known adherence issues with urate-lowering therapies. Because of the high rates of comorbidities associated with gout, including diabetes mellitus, chronic kidney disease, hypertension, obesity, myocardial infarction, heart failure, and stroke, elevated uric acid levels or gout should prompt evaluations for signs of cardiovascular disease and the need for appropriate risk reduction measures.95 Additionally, clinicians should look for a possible correctable cause of hyperuricemia, such as medications (e.g., thiazide and loop diuretics, niacin, calcineurin inhibitors), obesity, malignancy, and alcohol abuse. Patients should be encouraged to exercise, lose weight, reduce alcohol intake, reduce consumption of syrup-sweetened sodas and increase consumption of low-fat dairy foods and vegetables, and have periodic follow-up to address progress on these goals.
Hyperuricemia may lead to acute arthritis, chronic gout, or kidney stones or to no sequelae at all. Asymptomatic hyperuricemia may not need to be treated, although lifestyle modifications (e.g., weight loss, reduction of alcohol intake, control of blood pressure) should be encouraged to help reduce serum urate and overall cardiovascular health.
Acute gouty arthritis responds well to short courses of NSAIDs, colchicine, or corticosteroids to treat the underlying inflammatory condition. The management of uric acid nephrolithiasis includes hydration and alkalinization of the urine. Prevention of recurrent gouty arthritis or recurrent nephrolithiasis and treatment of chronic gout require hypouricemic therapy with either a uricosuric drug or xanthine oxidase inhibitor. Xanthine oxidase inhibitors are effective in both underexcreters and overproducers of uric acid, making them the hypouricemic drugs of choice for most patients with gout. Finally, antiinflammatory prophylaxis with low-dose colchicine or NSAID therapy is indicated during the initiation of urate-lowering therapy to prevent the development of acute gout due to rapid mobilization or urate.
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