Abstract
Background Gouty arthritis is increasing in prevalence in men and women, particularly in older age groups.
Methods A PubMed search was conducted to identify common comorbidities associated with gouty arthritis, their impact on quality of life, and strategies to manage gouty arthritis and its associated comorbidities.
Results Gouty arthritis is associated with numerous comorbidities that are increasing in prevalence (chronic kidney disease [CKD], hypertension, obesity, diabetes, metabolic syndrome, and cardiovascular disease) and that negatively impact long-term prognosis and quality of life. Therefore, certain considerations and precautions are necessary when treating gouty arthritis in these patients. For example, nonsteroidal anti-inflammatory drugs can cause acute renal toxicity or worsen CKD and should be avoided in this population. Dosage adjustments are recommended when using colchicine and urate-lowering therapy in patients with CKD, which may limit efficacy. Febuxostat may be used in patients with mild to moderate renal impairment, but insufficient information is available for use in patients with creatinine clearance of less than 30 mL/min. Numerous drug-drug interactions in patients with gouty arthritis and comorbidities may alter serum uric acid levels. Several interleukin 1β inhibitors, which target the underlying inflammatory mechanism of gouty arthritis and many of its comorbidities, are in development and may provide an option for patients not adequately managed with other treatments.
Conclusions Gouty arthritis is associated with renal, metabolic, and cardiovascular comorbidities that negatively impact overall health. The management of gouty arthritis in the presence of comorbidities is particularly challenging because of contraindications, the need for dosage adjustments, and polypharmacy.
Gouty arthritis is an inflammatory condition caused by the crystallization of monosodium urate in joints. This crystallization occurs when the level of uric acid in bodily fluids exceeds its solubility limit of approximately 6.8 mg/dL.1,2The inflammatory process associated with gouty arthritis is triggered by interactions between monosodium urate crystals and tissue (Fig. 1).3–5When monosodium urate is deposited in tissue, macrophages and monocytes take up these crystals through phagocytosis, and phagocytes activate a molecular complex known as the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The inflammasome triggers the processing and secretion of proinflammatory cytokines. Release of these cytokines initiates a neutrophilic inflammatory response that is a key pathophysiologic feature of acute gouty arthritis.
The precursor of gouty arthritis is chronic hyperuricemia, which is usually caused by inefficient renal excretion of uric acid; however, in about 12% of patients, hyperuricemia is caused by urate overproduction due to genetic or dietary factors.6Gouty arthritis typically starts out as asymptomatic hyperuricemia and progresses to attacks of acute gouty arthritis followed by asymptomatic intercritical periods. During intercritical periods, crystals can persist in joint fluid, and tissue damage can occur. Eventually, the disease can progress to advanced gouty arthritis, which is characterized by continuous crystal formation and inflammation.6The progression of asymptomatic hyperuricemia to gouty arthritis is thought to be influenced by a combination of environmental and genetic factors, and more than 90% of patients with hyperuricemia will not develop gouty arthritis. Recent studies suggest that increased susceptibility to gouty arthritis may be related to mutations in genes that regulate the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin 1β (IL-1β).7
On average, patients with gouty arthritis have significantly more comorbidities than those without this condition.8In a recent survey of more than 500 patients with gouty arthritis, the average patient had approximately 4 comorbidities, and as many as 5% to 10% had 7 or more comorbidities.9The presence of these comorbid conditions (eg, chronic kidney disease [CKD], hypertension, obesity, diabetes, metabolic syndrome, and cardiovascular disease), coupled with their rising global prevalence,10,11has contributed to the increasing clinical complexity of managing gouty arthritis.9,12,13Indeed, the quality of care patients receive for gouty arthritis is often inadequate, in large part because of these comorbidities.9,14,15Other factors contributing to the difficulty in managing gouty arthritis include age-related complications due to the increasing prevalence of the condition in elderly patients, the potential for drug-drug interactions, and an increasing incidence of treatment-refractory disease.14
The purpose of this article was to review comorbidities associated with gouty arthritis, the impact comorbidities have on quality of life (QoL), and strategies to manage gouty arthritis and its associated comorbidities.
EPIDEMIOLOGY OF GOUTY ARTHRITIS
In developed countries, the prevalence of gouty arthritis is approximately 1% to 2% among adults, and it is the most common form of arthritis seen by general practitioners.16For comparison, rheumatoid arthritis has an estimated prevalence of 0.5% to 1%.1,16According to an analysis of the 2002 US National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, there were 3.9 million ambulatory care visits for gouty arthritis in 2002, and 69% of these visits were to primary care physicians.17
Gouty arthritis is predominantly a disease of middle-aged men.18In an analysis of an administrative claims database from 1990 to 1999, Wallace and colleagues19found that, in patients younger than 65 years, the prevalence of gouty arthritis was 4 times higher in men than in women. These findings are consistent with an earlier analysis of Framingham Study data in which the 2-year incidence was 3.2 per 1000 in men and 0.5 per 1000 in women.20The incidence of gouty arthritis increases with age, and in adults older than 65 years, it is as high as 8% in men and 3% in women.1Differences in the rates of gouty arthritis between men and women decrease with age, in part because after menopause women are no longer protected by the uricosuric effects of estrogens.16,21In elderly-onset gouty arthritis, which initially occurs at 65 years or older, the male-to-female incidence ratio is 2.4:1, and after age 80 years, elderly-onset gouty arthritis occurs almost exclusively in women.22
Over the past several decades, the prevalence of gouty arthritis has been steadily increasing in both men and women, especially in older age groups.18According to data from a US managed-care database, across all age groups, the prevalence of gouty arthritis increased from 2.9 cases per 1000 persons in 1990 to 5.2 cases per 1000 persons in 1999.19Over the same period, the prevalence of gouty arthritis increased from 24 cases to more than 31 cases per 1000 persons aged 65 to 74 years and from 21 cases to 41 cases per 1000 persons 75 years or older.19
COMORBIDITIES ASSOCIATED WITH GOUTY ARTHRITIS
As discussed in the following sections, gouty arthritis is associated with numerous comorbidities that are increasing in prevalence, including CKD, hypertension, metabolic disorders (eg, obesity, diabetes, and metabolic syndrome), and cardiovascular disease. By 2015, for example, it is estimated that 2.3 billion people globally will be overweight, and 700 million will be obese.11By 2025, 1.56 billion adults worldwide will have hypertension,10and by 2030, 366 million will have diabetes.11In line with the rising prevalence of these conditions is the increasing global burden of the metabolic syndrome and CKD.11,23The presence of these comorbidities further complicates the management of gouty arthritis, contributes to treatment-refractory disease, and negatively impacts long-term prognosis.9,14Indeed, the high prevalence of comorbidities is believed to be a major contributing factor to the significantly higher mortality rate observed in patients with versus those without gouty arthritis.8
Chronic Kidney Disease
For decades, it has been recognized that gouty arthritis significantly increases the risk of renal failure and end-stage renal disease.13Before the development of uricosuric therapies, renal failure was the cause of death in 18% to 25% of patients with gouty arthritis.13In an analysis of 259,209 patients receiving long-term dialysis treatment in the US Renal Data System, the presence of gouty arthritis significantly increased the risk of all-cause mortality (adjusted hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.43–1.55) and cardiovascular mortality (adjusted HR, 1.47; 95% CI, 1.26–1.59).24
In many cases, the development of renal disease in patients with primary forms of gouty arthritis is linked to the presence of nephrosclerosis caused by chronic glomerular hypertension.25Data from animal models and observational studies in humans suggest that hyperuricemia, through its effects on glomerular vessels, may play a direct pathogenic role in the development of renal disease and hypertension.13Evidence suggests that, in patients with chronic tophaceous gouty arthritis, hyperuricemia can promote renal disease because the deposition of urate crystals in the kidney can cause interstitial inflammation and tubular injury, which impairs renal function. Furthermore, recent clinical studies have shown that controlling uric acid levels with urate-lowering therapy (ULT) can slow the progression of CKD.9
Gouty arthritis is also an independent risk factor for development of kidney stones. According to an analysis of data from the Health Professionals’ Follow-up Study, the prevalence of renal stone disease is approximately 2-fold higher in men with versus those without gouty arthritis.26It is estimated that renal stones occur in 15% to 22% of patients with gouty arthritis, and most stones in these patients are composed of uric acid. However, gouty arthritis can also contribute to the formation of calcium oxalate stones. Patients with gouty arthritis often have persistently acidic urine, which creates an environment in the kidneys that is favorable for uric acid precipitation and development of uric acid stones. The precipitation of uric acid in acidic urine may also create heterogeneous nuclei for crystallization of calcium oxalate. Reducing urinary uric acid excretion with allopurinol has been shown to decrease the risk of calcium oxalate stones.27
Hypertension
Hypertension and gouty arthritis are overlapping diseases.28Hypertension is an independent risk factor for gouty arthritis,28,29and hyperuricemia is an independent risk factor for hypertension.9Recent studies have shown that functional mutations in chronic inflammatory factors involved in IL-1β–mediated inflammation play an important role in the development of both gouty arthritis and hypertension and may explain why these 2 conditions often occur together.7
Some antihypertensive drugs can increase the risk of gouty arthritis. Diuretic use is a significant risk factor because diuretics cause increased reabsorption of uric acid in the kidneys.12In a study by Lin and colleagues30that determined the prevalence of hyperuricemia in patients with hypertension, both diuretics and β-blockers were predictors of high serum uric acid levels. Hyperuricemia was observed in 44% of patients treated with thiazides, 56% of patients treated with loop diuretics, and 57% of patients treated with aldosterone-receptor blockers.30However, losartan, an angiotensin-receptor blocker, is known to reduce uric acid levels through inhibition of urate transporter 128,31and could have adjunctive benefits for the management or prevention of hyperuricemia in patients with hypertension.32
Metabolic Disorders
High body mass index (BMI) significantly increases the risk of developing gouty arthritis because obesity is associated with increased urate production and decreased renal urate excretion.12,29,33Conversely, weight loss has been shown to prevent development of gouty arthritis and to reduce serum urate levels.29,33In a study that evaluated the relationship between BMI and gouty arthritis, Choi and colleagues29found that, compared with men with a BMI of 21 to 22.9 kg/m2, men with a BMI of 30 to 34.9 kg/m2 had a relative risk (RR) of developing gouty arthritis of 2.33 (95% CI, 1.62–3.36), and men with a BMI of 35 kg/m2 or higher had a RR of 2.97 (95% CI, 1.73–5.10).
The link between gouty arthritis and type 2 diabetes may be due to shared metabolic factors, including abnormalities associated with the metabolic syndrome. Choi and colleagues34found that, in men with a high cardiovascular risk profile, the risk of developing diabetes was significantly higher for those with versus those without gouty arthritis (RR, 1.34; 95% CI, 1.09–1.64). After adjusting for serum uric acid levels, the risk of developing diabetes remained significantly higher in patients with gouty arthritis (RR, 1.26; 95% CI, 1.02–1.54), which suggests that hyperuricemia may not be the main driving factor in the risk of diabetes associated with gouty arthritis. The authors of this study concluded that the risk of diabetes may be related to chronic low-grade inflammation associated with gouty arthritis, and indeed others have identified gouty arthritis and type 2 diabetes as “inflammasome activation disorders” in which monosodium urate and glucose, respectively, trigger increased processing of IL-1β.35
Metabolic syndrome is remarkably common in patients with gouty arthritis, with estimates of the prevalence ranging from 30% to 82%.36–38Analysis of data from the Third National Health and Nutrition Examination Survey showed that the prevalence of metabolic syndrome was 62.8% in patients with gouty arthritis versus 25.4% in patients without gouty arthritis. The prevalence of individual metabolic abnormalities was also higher in patients with versus those without gouty arthritis (Table 1).38
Hypothyroidism is also more prevalent in patients with gouty arthritis than in the general population.39It is believed that hypothyroidism in patients with gouty arthritis or hyperuricemia is caused by reduced renal plasma flow and reduced glomerular filtration.40In patients with gouty arthritis and hypothyroidism, urate levels have been shown to decrease upon initiation of thyroid replacement therapy, probably through a renal mechanism.39
Cardiovascular Disease
Hyperuricemia is an independent risk factor for cardiovascular disease. Large epidemiological studies have shown that hyperuricemia is associated with an increased incidence of coronary heart disease and increased mortality in all patients, regardless of history of coronary heart disease.41Proposed mechanisms for this increased risk include development of hypertension and oxidative stress. It is unclear whether hyperuricemia has a causal effect in cardiovascular disease or, as has been more often suggested, is simply a marker for other risk factors, such as hypertension, dyslipidemia, and diabetes.13,42
Hyperuricemia has also been identified as a risk factor for mortality in patients with heart failure. In these patients, hyperuricemia is a marker for oxidative stress and endothelial dysfunction. In patients with heart failure, hyperuricemia and gouty arthritis are associated with elevated levels of serum markers for inflammation.43This inflammatory response plays an important role in the pathophysiology of gouty arthritis and cardiovascular disease. An increased level of circulating inflammatory IL-1 proteins has been identified as a cardiac risk factor in patients with hypertension, dyslipidemia, and diabetes.44Elevated IL-1 levels trigger secretion of chemokines and other inflammatory cytokines, expression of adhesion molecules, formation of reactive species, activation of endothelial and smooth muscle proliferation, activation of macrophages, and increased vascular permeability. The proinflammatory mechanisms of IL-1β have been implicated in promoting atherosclerosis, plaque destabilization, and atherogenesis, thereby contributing to the pathogenesis of heart failure and left ventricular dysfunction. Interleukin 1β is a particularly important cytokine in gouty arthritis because the inflammatory effects of monosodium urate can be blocked by IL-1β inhibitors.3,5
QUALITY OF LIFE
Numerous studies have shown that patients with gouty arthritis have significantly lower health-related QoL (HRQoL) than patients without gouty arthritis and that comorbidities are a primary contributor to overall HRQoL.6,8,45–48In a survey that evaluated HRQoL and health care utilization among US veterans, Singh and Strand8found that patients with gouty arthritis were significantly older; were more likely to be retired, unmarried, and nonsmokers; and had significantly more comorbidities than patients without gouty arthritis. The presence of medical comorbidities predicted significantly lower scores in all Short Form 36 (SF-36) domains, and arthritic comorbidities predicted significantly lower scores in the SF-36 physical domains and the physical component summary (Fig. 2). Compared with patients without gouty arthritis, patients with this condition had significantly more primary care visits per year (2.7 vs 3.5; P < 0.001) and significantly more hospital admissions (15.1% vs 18.3%; P < 0.01). Patients with gouty arthritis also had poorer functional ability and lower HRQoL; these differences were attributable to comorbidities and sociodemographic factors, rather than to the presence of gouty arthritis alone. Comorbidities associated with gouty arthritis also affected longevity. Patients with gouty arthritis had a 50% higher unadjusted 1-year mortality rate than those without this condition. Comorbidities and differences in sociodemographic factors also contributed to significantly higher primary and inpatient health care utilization costs among patients with gouty arthritis.
In a survey of patients registered with general practices, Roddy and colleagues46found that comorbidities associated with gouty arthritis (and not gouty arthritis itself) resulted in significantly poorer overall QoL and health satisfaction, whereas the physical burden of gouty arthritis caused significant impairments in physical HRQoL. In addition, QoL factors, including loss of work productivity and social participation, can be significantly affected in patients who are unable to manage their gouty arthritis with available ULTs.47
MANAGEMENT OF GOUTY ARTHRITIS
Lifestyle Modifications
Drug therapy is not indicated for patients with asymptomatic hyperuricemia.49These individuals should be monitored periodically for changes in serum uric acid levels and should receive counseling on lifestyle factors, such as weight loss and reduced alcohol consumption.49,50In addition, current gouty arthritis management guidelines49,50recommend that patients limit their consumption of purine-rich foods (eg, meat and shellfish) because these foods are known to adversely affect hyperuricemia. However, diets low in purine are often high in carbohydrate and saturated fat, which can increase the risk of developing insulin resistance.38A calorie-restricted, low-carbohydrate diet with a balance of protein, unsaturated fat, and dietary fiber has been shown to reduce serum urate and lipoprotein levels in patients with gouty arthritis, as well as to provide benefits for patients with insulin resistance.51
Pain Management
Patients experiencing an acute gouty arthritis attack can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), unless they are contraindicated; colchicine; low-dose steroids (eg, oral prednisone); or intra-articular steroid injections (eg, triamcinolone administration to the affected joint). However, before using intra-articular steroids, septic arthritis should be ruled out.
Urate-Lowering Therapy
Patients who have had 2 or more attacks of acute gouty arthritis should be treated with ULT, with the goal of maintaining serum uric acid at 6 mg/dL or less.50Urate-lowering therapy treatment options include allopurinol,52febuxostat,53pegloticase,54and probenecid.55
Allopurinol is usually prescribed at 200 to 300 mg/d for patients with mild gouty arthritis and at 400 to 600 mg/d for patients with moderately severe tophaceous gouty arthritis. Febuxostat should be given at a starting dose of 40 mg/d, and the dose can be escalated as needed to 80 mg/d to achieve a serum uric acid level of 6 mg/dL or less.53Pegloticase is a PEGylated uric acid–specific enzyme indicated for the treatment of chronic gouty arthritis that is refractory to standard ULT and in patients for whom standard ULT is contraindicated.54Probenecid is a uricosuric drug that lowers serum uric acid levels; however, the efficacy of probenecid is inferior to that of allopurinol.50In patients with gouty arthritis and hyperuricemia, febuxostat 80 mg/d has been shown to be more effective than allopurinol 300 mg/d for reduction of serum uric acid to the target level of 6 mg/dL or less.56,57
MANAGEMENT OF GOUTY ARTHRITIS IN THE PRESENCE OF COMORBIDITIES
Certain considerations and precautions are necessary when treating gouty arthritis in patients with comorbid conditions. These are summarized in Table 2. For example, patients with comorbid gouty arthritis and CKD are particularly difficult to treat. Nonsteroidal anti-inflammatory drugs or colchicine are generally used to treat joint pain and inflammation associated with acute gouty arthritis attacks; however, there are concerns associated with the use of these drugs in patients with CKD. Nonsteroidal anti-inflammatory drugs can cause acute renal toxicity or worsen CKD and thus should be avoided in this population.58Colchicine clearance is reduced in patients with CKD. Colchicine dosage adjustments are not required in patients with mild or moderate renal impairment but are recommended in patients with severe renal impairment, and all patients with decreased renal function should be monitored closely for adverse events including bone marrow suppression and myotoxicity.59Dosage reductions are also recommended when using ULT (eg, allopurinol, probenecid) in patients with CKD, and this may limit efficacy of these agents.21,50Febuxostat is metabolized mainly by glucuronide formation and oxidation in the liver,2whereas allopurinol is eliminated through the kidneys.52Thus, unlike allopurinol, the serum urate–lowering properties of febuxostat are not significantly altered in patients with mild to moderate renal impairment.60However, insufficient information is available on the use of febuxostat in patients with creatinine clearance of less than 30 mL/min or in severe hepatic impairment.
CHALLENGES AND UNMET NEEDS
There are several areas of concern and unmet needs that physicians should be aware of when gouty arthritis is managed in a primary care setting. In a study of physician adherence to quality indicators for the management of gouty arthritis, Mikuls and colleagues61found that allopurinol is often prescribed incorrectly and at inadequate doses, and it is often used inappropriately in patients with asymptomatic hyperuricemia. Treatment with ULT should be initiated early in patients with recurrent gouty arthritis attacks, tophi, or chronic persistent gouty arthritis, and once initiated, treatment should not be discontinued. Treatment response should be well documented, and gouty arthritis flare prophylaxis (eg, NSAIDs, low-dose prednisone, or colchicine) should be an integral component of treatment starting at the time of ULT initiation.32Urate-lowering therapy should not be initiated during acute gouty arthritis flares because rapid reduction in serum uric acid levels can induce or worsen acute gouty arthritis attacks; however, if patients were already being treated with ULT at the time of the attack, ULT should be continued.50,62
Therapeutic approaches to managing gouty arthritis in the presence of comorbid conditions can be complex because of the frequent need for polypharmacy. For example, in a recent clinical trial56that evaluated the efficacy and safety of ULT in 2269 patients with gouty arthritis and hyperuricemia, 87% of patients reported use of concomitant medications, including medications acting on the renin-angiotensin system (36%), lipid-modifying agents (31%), and anti-inflammatory and antirheumatic drugs (29%). Drugs prescribed for comorbid conditions may affect serum uric acid levels, and the need for several concomitant medications increases the risk of drug-drug interactions.63 Table 3 lists several drugs that affect serum uric acid levels and potential drug-drug interactions and contraindications for these agents.
Management of gouty arthritis is especially challenging in elderly patients, who are at an increased risk for drug interactions and have a higher prevalence of comorbidities, including CKD, peptic ulcers, cognitive impairment, and congestive heart failure. Therefore, the need for polypharmacy is particularly problematic in this population.6,21Furthermore, elderly patients are more likely to be taking medications that may affect serum uric acid levels (ie, diuretics and aspirin) and to have contraindications to drugs used to manage gouty arthritis (ie, colchicine and NSAIDs).21Low-dose and minidose (75–325 mg/d) aspirin as cardioprotective therapy should be used with caution in elderly patients with gouty arthritis because aspirin at low doses is associated with impaired renal function and uric acid retention.12,64,65
POTENTIAL FUTURE THERAPIES
Three new IL-1 inhibitors are currently in development for the treatment of gouty arthritis and other inflammatory and immune-mediated diseases.35Anakinra is a recombinant human IL-1–receptor antagonist that targets IL-1α and IL-1β. Anakinra is approved for the treatment of moderate to severe rheumatoid arthritis after failure of 1 or more disease-modifying antirheumatic drug.35In a pilot study of anakinra in patients with acute gouty arthritis who were unresponsive or intolerant to standard therapies, 10 of 10 patients who received anakinra 100 mg/d for 3 days showed improvement within 24 to 48 hours, and 9 of 10 patients had complete resolution of arthritic signs in affected joints after 3 days of treatment.66
Canakinumab is a humanized monoclonal anti–IL-1β antibody that is approved as an orphan drug for familial cold autoinflammatory syndrome and Muckle-Wells syndrome.35Canakinumab is highly specific for IL-1β and has a relatively long half-life, allowing for subcutaneous dosing every 8 weeks to suppress inflammation. Canakinumab is being investigated in several immune and inflammatory diseases, including gouty arthritis.67In a study in patients with acute gouty arthritis who had contraindications or whose disease was refractory to NSAIDs or colchicine, canakinumab 150 mg provided rapid, sustained pain relief and significantly reduced flare recurrence compared with triamcinolone acetate.68
Rilonacept is a dimeric fusion protein consisting of the extracellular portion of the IL-1 receptor and the Fc portion of human immunoglobulin G1. Rilonacept was approved in 2003 as an orphan drug for the treatment of cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome and Muckle-Wells syndrome; these are genetic disorders caused by mutations in the NLRP3 inflammasome.35In a 14-week, placebo-controlled, nonrandomized, single-blind clinical trial of rilonacept in patients with chronic active gouty arthritis, significant improvements were observed in median pain scores, symptom-adjusted joint scores, and severity-adjusted joint scores.69
CONCLUSIONS
Gouty arthritis is associated with renal, metabolic, and cardiovascular comorbidities that can have a significant negative impact on patients’ overall health and QoL. Indeed, guidelines for gouty arthritis emphasize the importance of identifying and treating comorbidities as part of the overall management of gouty arthritis.50In many cases, these comorbid conditions are potentially more life-threatening than gouty arthritis or hyperuricemia.38Thus, it is important to evaluate a patient’s overall health and monitor blood pressure and blood chemistry regularly, not just arthritic symptoms.50Management of gouty arthritis associated with comorbidities is complicated by the need for polypharmacy and the potential for drug-drug interactions. New drugs that reduce inflammation by targeting the IL-1β pathway may provide significant clinical benefits for patients with gouty arthritis that is not adequately managed with other treatments. In addition to improving the signs and symptoms of gouty arthritis, treatment with IL-1β inhibitors may also result in improvements in comorbid conditions associated with inflammation.