Gout in the Elderly
Even though gout is often thought of as a middle-age malady, it is the most common inflammatory arthritis seen in the elderly.1 Epidemiologic studies of aging populations have shown rises in the incidence and prevalence of gout in both sexes.2,3 History has portrayed gout as a relatively benign, painful disease, but severe gout can cause significant morbidity and functional decline.4 The majority of patients with gout are treated by their primary care providers.5 While acute, intercritical, and chronic gout can be difficult to treat in any patient, in older individuals, there are also the physiological changes that occur with aging to contend with.6 Implications from this perspective require additional vigilance in the management of medications, the lifestyle, and the environment of the older patient. In addition, because gout and hyperuricemia may be independent risk factors for cardiovascular disease,5,7,8 the accurate diagnosis and treatment are even more essential.
Cost of Gout in the Elderly
Because the prevalence of gout has been increasing in the older population, several studies have examined not only the incidence and prevalence of the disease, but also the healthcare utilization and the burdens of care in this patient population. A 5-year retrospective study conducted in Nova Scotia, Canada, focused on the healthcare burden of gout in the elderly.9 Patients over the age of 65 years were included in this study, and the data were obtained from the Population Health Research Units in the Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada. Variables such as hospitalizations and physician visits were statistically elevated in patients who had a diagnosis of gout. The additional healthcare cost in patients with gout was also found to be more than $8000 over a 5-year course as compared with their matched controls.9
A similar study was conducted in the United States, in which data extracted from the Integrated Healthcare Information Services claims database were used to compare the all-cause healthcare utilization and costs in elderly patients with gout versus matched patients without gout.10 After adjusting costs based on other comorbidities, the subjects with gout had, on average, costs that were $3038 more than their counterparts without gout over a 12-month course. In addition, this study compared a subset of patients with gout with and without tophi. Patients with gout who had tophi had an average healthcare cost that was $5501 more than their tophi-free counterparts with gout over a 12-month period.10
Pathology of Gout
Gout is an inflammatory arthritis that is primarily defined by the presence of uric acid crystals. In humans, hyperuricemia is caused by a difference in the way that uric acid is metabolized. The uricase gene in humans is associated with the presence of two mutations that introduce stop codons prematurely, which prevents the production of the uricase enzyme.11 This gene defect, coupled with the increased reabsorption rate of urate, leads to much higher levels of uric acid in humans as compared with other mammals.
Uric acid crystal formation is directly correlated with serum urate levels. There are, however, other factors, including temperature, pH levels, and cation concentrations, that have an association with the solubility of uric acid in the serum. Once the uric acid crystals form, they serve to stimulate the release of numerous inflammatory mediators that include interleukin-1 (IL-1) and tumor necrosis factor-alpha.
Classic Presentation of Gout
The classic flare of gout usually presents itself after years of asymptomatic hyperuricemia. With the first attack, a sudden and rapid monoarticular involvement of severe pain, erythema, and edema occurs. The attack escalates over a period o 6 to 12 hours, and the pain can be very debilitating. The first presentation of acute gout involves the first metatarsophalangeal joint more than 50% of the time, but also can involve the knees, ankles, wrists, and elbows.12 The initial gout attack usually presents in men during the estrogen-protective effects. Premenopausal levels of estrogen may promote more efficient clearance of urate.13 There can also be systemic manifestations of an acute gout flare, including fevers, malaise, and chills. Although acute gout flares vary in length, attacks typically resolve within 7 to 10 days.
Gout Presentation in the Elderly
As reported in a study by Fam,14 gout flares in the elderly can present differently from a classic gout flare in middle-aged men in various aspects. First, gout flares in the elderly tend to be more polyarticular, as gout in these patients has become more chronic and indolent. Second, given the chronicity of gout, elderly patients tend to have an increased incidence of tophi, especially of the elbows and hands. From an epidemiologic standpoint, gout in the elderly tends to have a more equal gender distribution, and there is a stronger association with hypertension, diuretic use, and renal impairment.14
Diagnosis of Gout
The gold standard for diagnosing gout is the demonstration of monosodium urate (MSU) crystals in the synovial fluid in the setting of an acutely inflamed joint. The presence of such crystals, particularly when seen intracellularly, confirms the diagnosis of an acute attack and helps to distinguish gout from septic arthritis, pseudogout, and other crystal arthropathies, as well as other causes of inflammatory joint disease. The sensitivity and specificity of synovial fluid analysis for demonstrating negative birefringent crystals in patients with acute gouty arthritis is approximately 90% and 100%, respectively.15 In contrast, the specificity of a clinical diagnosis of gout will be significantly lower, and may result in the misinterpretation of another joint disease, such as septic arthritis or pseudogout. Therefore, in almost all circumstances, arthrocentesis should be performed. Synovial fluid should be sent for Gram stain and culture given that the presence of MSU crystals does not exclude infection, and acute gout and concurrent septic arthritis can occur.16 Erythrocyte sedimentation rate and/or C-reactive protein can support the presence of an inflammatory process, but will not provide further distinction between one type of inflammatory arthropathy or another.
In the elderly, diagnosing gout can be more challenging than in younger persons. In addition to mimicking septic arthritis, acute gout flares can present quite similarly to nodular rheumatoid arthritis. The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules. Also, tophi can supervene on Heberden’s and Bouchard’s nodes.17 As a result, gout can be mistaken for changes that are usually attributed to osteoarthritis. However, some of the distinguishing features of gouty arthritis are the presence of MSU crystals in the synovial fluid, the asymmetrical distribution of the tophaceous joint swelling, and the presence of typical radiographic findings of tophaceous gout. These findings include “overhanging margins” and “punched-out” cortical lesions seen on hand films in patients with tophaceous gout. Musculoskeletal ultrasound has the capacity to visualize intra-articular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage, known as the “double contour sign.” Again, limitations include the inability to differentiate between the type of crystal deposition and the presence or absence of infection.
Acute Treatment of Gout
Although the guidelines of gout treatment are the same in the elderly as in the general population, recognition of the physiological changes that affect medication metabolism, drug interactions, and medical comorbities in older individuals is paramount (Table I). For the acute treatment of gout, the benefits must be weighed against the risks, especially in the elderly. Given the higher rates of chronic renal insufficiency, polypharmacy, and other comorbid conditions, the use of certain medications for acute gout must be individually tailored to each elderly patient. One must consider that an acute gout flare is self-limited, and that the acute flare should resolve on its own without intervention. If there are any questions or concerns regarding care, a referral to a rheumatologist would be prudent (Table II).
Nonsteroidal Anti-Inflammatory Drugs
For the management of an acute gout flare, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is a convenient and effective option for treatment. Traditionally, indomethacin has been the NSAID of choice for acute gout, but head-to-head studies of NSAIDs in patients with acute gout have revealed that just about any NSAID will suffice.18-21 In fact, selective cyclooxygenase-2 (COX-2) inhibitors may work as well as typical NSAIDs with less gastrointestinal (GI) toxicity.22 In the elderly population, there is a higher risk of upper GI bleeding (especially with concomitant use of even low-dose salicylates) and the concern of concurrent renal insufficiency with NSAID use.23 NSAIDs are not recommended in patients who use anticoagulants or have comorbidities such as heart failure, uncontrolled hypertension, alcoholism, and bleeding diathesis. In the elderly, chronic use of NSAIDs is not recommended, and short-term use should be closely monitored. Recognized side effects of NSAID use in the geriatric population include GI upset, confusion, headaches, and psychosis, which may limit the therapeutic effects that are gained with gout control. Indomethacin and ketorolac have both been associated with increased adverse effects in the elderly.24 In addition to NSAID-induced events such as renal impairment, hypertension, and GI bleeding, indomethacin has also been associated with increased central nervous system adverse effects. Even metabolic clearance of naproxen has been shown to be decreased in the elderly.25 This decreased clearance has incited some authors to recommend a 50% dose reduction of this common NSAID in elderly patients. As a result, it may be prudent to select an NSAID with a short half-life (eg, ibuprofen), given how NSAID use can trend toward renal failure. Other NSAIDs such as nabumetone and meloxicam have longer half-lives, but may be dosed accordingly in persons with mild-to-moderate renal impairment if use is unavoidable.
Corticosteroids can be used systemically or intra-articularly in the treatment of an acute gout flare. One of the main advantages of corticosteroids is that they do not need to be renally dosed. In our experience, the use of methylprednisolone 40 mg to 80 mg intra-articularly is helpful and effective in treating an acute gout flare. Prior to corticosteroid injection, however, great care is needed to rule out concurrent septic arthritis. For patients who have a polyarticular joint flare, the use of oral prednisone is effective starting at a 40- to 60-mg dose and tapering the dose over the course of 7 to 10 days. The most common side effects of short-term corticosteroid use include hyperglycemia, psychosis, increased risk of infection, and exacerbation of heart failure. The risk of developing side effects can be decreased by administering corticosteroids over a short, contained course.
Although colchicine has been used to treat acute gout for decades, it has recently gone through clinical trials and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute gout flares. The limiting side effects include severe GI manifestations, which can include nausea, vomiting, diarrhea, and abdominal pain. In addition, patients who take colchicine can develop a painful axonal neuromyopathy. The toxic effects of colchicine are potentiated in patients with renal and hepatic insufficiency.26 In addition, as colchicine and certain statins are metabolized through the cytochrome P450 system, the combination of both has been shown to increase the risk of the development of a neuromyopathy and rhabdomyolysis.27 Given this side-effect profile, caution should be used when prescribing this medication in the elderly.
In the past, colchicine has been prescribed as often as 0.6 mg every 1 to 2 hours, with the rate-limiting effect determined by either (1) joint relief, (2) development of GI side effects, or (3) after taking 10 pills without relief. There has been recent evidence that the use of low-dose colchicine may be as efficacious as high-dose colchicine with much less toxicity. In a study done by Terkeltaub et al,28 the use of colchicine 1.8 mg given over 1 hour was shown to be as efficacious as colchicine 4.8 mg over 6 hours. However, the subject mean age in this trial was 51.9 + 10 years, and there is no mention of octogenarians being included in the study.28 In 2009, consensus guidelines for the dosing of several renally cleared medications in older patients was published; colchicine was recommended not to be used in patients with a creatinine clearance of less than 10 mL/min/1.73m2.29
Chronic Treatment of Gout
The decision to initiate uric acid–lowering therapy depends on the presence of subcutaneous tophi or an unacceptably high rate of gout flares over 1 year. The presence of tophi is especially a concern in the elderly, in whom years of chronic gout have led to subcutaneous deposition of uric acid crystals. If left unchecked, tophi act as a nidus of inflammation. The chronicity of inflammation from tophi can lead to destruction of bone and cartilage, which has a significant impact on a patient’s ability to perform activities of daily living.
When treating gout and initiating uric acid–lowering therapy, the target serum urate level should be lower than 6.0 mg/dL. As the solubility of uric acid has been demonstrated to be at 6.8 mg/dL, lowering the uric acid level below this threshold will prevent further attacks from reoccurring. It is critical that this level is achieved, as crystal deposition can occur at any concentration above this. There are a few instances when lowering uric acid levels even further may be more beneficial. In fact, a study published in 2002 found that achieving and maintaining a lower uric acid level led to faster resolution of tophi (baseline mean serum urate level was 8.78 mg/dL versus the mean follow-up urate level of 5.37 mg/dL, resulting in a velocity of reduction of 0.57 mm/month over a 29-month period).30 It is also important to remember that initiation of uric acid–lowering agents should not be started or discontinued during an acute gout flare.31 When starting a uric acid–lowering agent, initiation of low-dose colchicine or NSAIDs should be used for gout prophylaxis. At this time, there are several agents that lower serum urate, including allopurinol, probenecid, and the relatively newly FDA-approved febuxostat (Table I).
Allopurinol is a xanthine oxidase inhibitor. Xanthine oxidase is the enzyme that is directly responsible for the oxidation of xanthine and the eventual production of uric acid. Allopurinol is the most frequently prescribed medication for the purpose of lowering uric acid.32 Once-daily dosing, as well as the demonstrated efficacy in lowering uric acid, make it an attractive first-line therapy. Allopurinol is metabolized in the liver to its active metabolite, oxypurinol. Oxypurinol, however, is secreted primarily through the kidneys, with a half-life of approximately 16 to 18 hours. In the elderly, the use of allopurinol can be hampered by several aspects. First, polypharmacy remains a big challenge in these patients. Since allopurinol is metabolized in the liver, it can reduce the activity of hepatically processed medications such as warfarin and prolong their respective half-lives. Second, the side effects of allopurinol primarily include GI upset and skin rashes. A more serious reaction can include allopurinol hypersensitivity syndrome, which consists of fever, hepatitis, skin rash, vasculitis, and renal dysfunction. In historical reports, associated factors for the development of this syndrome include renal insufficiency, hypertension, and, possibly, the use of thiazide diuretics. 33 In the growing geriatric population, the prevalence of declining renal function and the risk of polypharmacy are factors that a clinician must be aware of when prescribing allopurinol. In addition, adjusting allopurinol doses based on creatinine clearance may not be sufficient to achieve a goal serum urate level of less than 6.0 mg/dL. There have been several reports illustrating that allopurinol can be used safely and efficaciously in the setting of renal impairment.34,35
Uricosuric medications work by competing with urate in the proximal tubule of the kidney, thereby increasing urate excretion and decreasing serum uric acid. Uricosuric medications include probenecid, sulfinpyrazone, and benzbromarone. Although benzbromarone has been shown to be superior to both allopurinol and probenecid,36 it was taken off the market in the United States due to potential hepatotoxicity. Probenecid is currently the only uricosuric that is readily available for use in the United States. Uricosurics are primarily used in patients who have been found to have undersecretion of uric acid, evidenced by secretion of less than 800 mg of uric acid in a 24-hour urine collection. There are several limitations to using uricosuric medications. The patient must have a creatinine clearance of over 60 mL/min/1.73m2 and no history of nephrolithiasis. The medication has a risk of urolithiasis, so patients must be able to drink at least 2 liters of fluid per day to prevent this from happening.
Febuxostat is a new xanthine oxidase inhibitor that has shown clinical and laboratory efficacy in patients with gout. There are several benefits to the use of this new medication. First, febuxostat can be given without concurrent food intake or antacid use.37 Second, at this time, there are no dosage adjustments that are recommended in patients with mild-to-moderate renal insufficiency.38 It has been shown that, although the metabolites of febuxostat are generally higher in patients with renal impairment, an 80-mg once-daily dose seems to be well tolerated in patients of differing renal function.38 Third, when comparing the pharmacokinetics and dynamics of febuxostat in elderly subjects (≥ 65 years) with those who are age 18 to 40 years, researchers found no statistically significant differences.39 Finally—and most importantly—there have been phase III trials that have documented the efficacy of febuxostat when compared with allopurinol. The Febuxostat versus Allopurinol Control Trial (FACT) compared patients who received febuxostat (80 mg or 120 mg) with patients who received allopurinol 300 mg.40 At the end the study, it was concluded that the use of febuxostat in either 80-mg or 120-mg increments was more effective than allopurinol 300 mg in lowering serum urate levels. For the elderly patient who has an intolerance to allopurinol due to allergy and side effects, febuxostat would be a good alternative; it is approved by the FDA at 40-mg and 80-mg doses. In addition, it can also be used in elderly patients with mild-to-moderate renal insufficiency. Febuxostat should be avoided in patients taking azathioprine, mercaptopurine, and theophylline.
There are novel medications that are being evaluated for their efficacy in gout. For example, some of the newer pharmocologic modalities for treatment of acute gout focus on inhibiting IL-1, while other medications that seek to promote control of chronic gout focus on purine nucleoside phosphorylase inhibition. It will be interesting to see how these new agents will influence our approach to treating gout.
Adjunctive Therapies for Gout in the Elderly
In addition to pharmacologic interventions for acute and chronic gout, there are other adjunctive therapies that can be used in the treatment of gout. It has been well known since ancient times that gout is associated with excessive alcohol intake and with certain foods. In a study published in 2004, Choi et al41 examined the incidence of gout and alcohol consumption. The results of the study revealed that alcohol intake was indeed strongly associated with gout, with a larger intake of alcohol having a stronger association. In addition, it was concluded that beer increased the risk of gout more than spirits or wine. In fact, it was shown that a moderate intake of wine (≥ two 4-oz glasses) was not associated with an increased risk.41
There has been further insight on the epidemiology of certain diet components in the relationship to uric acid levels. In a study that prospectively examined dietary risk factors for the development of gout, it was shown that higher levels of seafood and meat consumption are associated with a higher risk of gout.42 Conversely, consumption of a higher amount of dairy products was associated with a lower risk of gout. Purine-rich vegetables and total protein intake were not associated with an increased risk of gout.42
With proper education on specific lifestyle modifications, gout risk can be decreased. This can be especially helpful in the elderly. It needs to be kept in mind, however, that many patients have difficulty adjusting to dietary changes and that even compliance to a low-purine diet only yields a limited reduction in serum urate levels.43
There are differences in the clinical features and approaches to the treatment of gout in the elderly as compared with the general population. While the common theme involves an acute inflammatory monoarticular arthritis, the presentation of gout in the elderly is more indolent. As a result, an index of suspicion for gout must be high even if an elderly patient presents with a polyarticular, progressive arthritis. From the treatment standpoint, although the same pharmacologic agents are used in the elderly, they must be administered with great caution, as there are many comorbidities that can affect medication management. By diagnosing gout correctly and achieving a therapeutic level of control with the appropriate medicinal adjustments in the elderly patient, a better quality of life can be attained without unnecessarily increasing morbidity from gout or medication adverse effects.
Dr. Keenan has received speaker honoraria from Novartis. Dr. Ning reports no relevant financial relationships.
From the Division of Rheumatology and Immunology, Duke University School of Medicine, Durham, NC.
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