Introduction
Gout is one of the most common of the inflammatory arthritides. It is a metabolic disorder manifested by an inflammatory arthritis associated with monosodium urate (MSU) crystal deposition within joints, tophus formation, uric acid urolithiasis, and in all patients, underlying hyperuricemia.
Although the term "gout" was not used until the 12th century, the condition has been recorded since antiquity, with the ancient Egyptians first describing it in 2500 BC, and Hippocrates calling it "the unwalkable disease" around 600 BC.[1] There have been many further reports of gout through the ages, possibly due to its occurrence in many well-known historical figures, including Charles Darwin, Theodore Roosevelt, Martin Luther King, Benjamin Franklin, Thomas Jefferson, Karl Marx, and Sir Isaac Newton.
Today, data suggest that in the United States gout is the most common inflammatory arthritis in men over 40 years of age, and its prevalence and incidence continue to increase. A descriptive study from a US managed-care database suggested the prevalence of gout increased from 2.9 cases per 1000 population in 1990 to 5.2 cases per 1000 population in 1999.[2]
The incidence of gout shows a similar increase over the past decades. The Rochester Epidemiology Project showed the age- and sex-adjusted annual incidence of gout increased from 45.0 new cases per 100,000 population in 1977 to 1978 to 62.3 new cases per 100,000 population in 1995 to 1996.[3]
This increase in cases over the last 10 to 15 years has been driven by a number of factors, including increasing longevity and the concurrent rises in disorders such as obesity, hypertension, diabetes, and the metabolic syndrome. Despite this, there has until very recently been little in the way of new treatments for gout to help counter its increasing prevalence.[4]
Consultation 1
A 48-year-old man presents to his primary care physician (PCP) with severe pain in his right big toe. He describes the pain as starting suddenly 3 nights previously, and being of such intensity that it woke him up from sleep. He has no history of trauma. He noticed the joint was swollen and warm to the touch, and he immediately took an over-the-counter pain medication, which only had a limited analgesic effect. The pain has now been present for 3 days. The patient has a slight fever, and has had little sleep since the pain started, as even the touch of a bed sheet on the affected joint produces significant pain. The patient has suffered 2 less-painful attacks in the past, although the toe affected has been different each time. Given this recurrence, he has decided to consult a physician.
Continuation of Consultation 1
On further examination, the patient is found to be modestly overweight (body mass index [BMI] 31) with mid-abdomen adiposity. The patient has a sedentary job, takes little exercise, and admits to eating a poor diet high in red meat, white breads, rice, pasta, and potatoes. On further questioning, he also admits to often drinking significant amounts of beer with his colleagues after work and non-diet sodas during the day. He suffered from asthma as a child, and this occasionally leaves him breathless and wheezing. Although he did not make the connection himself, when prompted, he remembers his father suffered from gout after he retired from work at age 65 years.
What are the Risk Factors for Gout?
Genetic Factors
In Caucasians, there is a genetic variation within SLC2A9 that takes part in the control of serum urate levels,[5-7] and susceptibility to gout.[7] In addition, twin studies show renal clearance and fractional excretion of urate both have a hereditary component.[8] Suggested sites for susceptibility loci include the 1q21 region of chromosome 1,[9] the 4q25 region of chromosome 4,[10] and an estrogen receptor gene thymine-adenine repeat polymorphism at chromosome 6q25.1.[11]
Hyperuricemia
Hyperuricemia is considered to be the primary risk factor for the development of gout, with prospective studies showing a positive correlation between serum urate levels and the risk of developing the disease[12,13] (Figure 1).[14-17]
Figure 1.
Gout occurs when MSU crystals form in and around joints.[18] These crystals form when tissues become saturated with urate, due to over-production or under excretion.[19] The latter is more common, with urate overproduction accounting for only 12% of cases, mainly due to genetic or dietary causes.[19]
There is a growing consensus that the definition of hyperuricemia is the point at which supersaturation of plasma and other body fluids are reached. Urate crystal precipitation occurs in vitro at ~6.8 mg/dL, although lower temperatures lead to precipitation at lower concentrations.[20] Although hyperuricemia is one of the most important underlying risk factors for the development of gout, it is not a disease in itself, and individuals can have high levels of serum urate while remaining asymptomatic. In a study of 2,046 men, only 22% of those with serum urate levels ≤9 mg/dL developed gout during a 5-year period.[12]
Medications
A number of concomitant medications may affect the development of gout. Aspirin is known to have a bimodal effect on the renal handling of uric acid. High doses (>3 g/day) are uricosuric, while low doses (1-2 g/day) cause retention of uric acid. A study of low-dose aspirin, commonly used as a platelet aggregation inhibitor, showed 75 mg/day was associated with a 15% decrease in the rate of uric acid excretion and a commensurate increase in serum levels of uric acid.[21]
The use of diuretics, such as a thiazide, which is often used as first-line treatment for hypertension, has also been associated with an increased risk of gout.[13]
Metabolic Syndrome
The metabolic syndrome is a group of interrelated atherosclerotic risk factors (including obesity, insulin resistance, and hypertension) that affects more than 50 million Americans.[22] There is a close association between the presence of the metabolic syndrome and gout; a total of 63% of gout patients fulfill the criteria for metabolic syndrome, compared with only 25% of people without gout.[23] This pattern increases with aging.
Mean serum urate levels in patients with the metabolic syndrome are approximately 0.5-1.0 mg/dL higher than in controls,[24] and levels increase with the number of components of the metabolic syndrome present, even when adjusted for age, gender, creatinine clearance, alcohol intake, and diuretic use.[25]
Patients with the metabolic syndrome are known to have a reduced ability to excrete uric acid,[24] through hyperinsulinemia-enhanced proximal tubular sodium reabsorption.[26] Reduced uric acid excretion due to enhanced sodium reabsorption has also been reported in 2 of the most common metabolic syndrome-related conditions: obesity and hypertension.[27]
As well as reduced excretion, some evidence suggests an increase in uric acid production in metabolic syndrome through increased fructose intake. Fructose-based products have been widely used over the past decades as a cheap alternative to sucrose in food, which may account for the increased prevalence of the metabolic syndrome (and hence gout) in recent years.[28]
One of the main contributing factors to the metabolic syndrome is obesity. Many patients with gout are overweight or obese, and there is a strong association between the risk of gout and increasing BMI scores.[29] Obesity is also linked with increases in serum urate through increased uric acid production and a decrease in renal excretion.[30] Given that approximately 60% of Americans are overweight and one-third are obese (as measured by BMI), it is important for physicians and patients to understand this increased risk. Fortunately the increased risk of gout due to obesity is reversible, with men who lose 10lb of weight showing a risk ratio of 0.61.[29]
Higher insulin levels in the circulation (a consequence of insulin resistance) reduce the renal excretion of uric acid[31] and may enhance renal urate reabsorption through stimulation of the urate-anion exchanger (URAT1),[32] or the Na+-dependent anion co-transporter in brush border membranes of the renal proximal tubule.[18]
Hypertension is also associated with an increased incidence of gout. Increased blood pressure leads to a decrease in renal blood flow, which in turn increases the rate of renal urate reabsorption.[18]
In summary, all the contributing factors of the metabolic syndrome drive an increase in gout. However, each of these factors can also be a complication of gout.
Diet and Alcohol
Gout was once called "the disease of kings" because of the association with rich foods and excessive alcohol consumption. Although diet is no longer considered the main causative factor, there is still evidence that certain foods increase the risk of developing gout (Figure 2).[23,33,34]
Figure 2.
A large prospective survey of 47,150 men showed the development of gout was associated with alcohol consumption (with beer drinkers most at risk),[33] and meat and seafood intake.[35] These foods are all rich in purines, which are eventually metabolized to uric acid, and this may be the reason for their association with the incidence of gout.
Dietary advice to patients suffering from gout should take into account the potential complication of metabolic syndrome. Consumption of meat, seafood, and alcoholic beverages plays a role in the management of gout; a high intake of alcohol can result in refractoriness to urate-lowering drugs. Patients with hyperuricemia need to pay attention to weight management, including moderation in the intake of meat and seafood rich in cholesterol and saturated fatty acids and restraint in consumption of foods and drinks with non-complex carbohydrates. In the obese, controlled weight management and reduction in alcohol consumption have the potential to lower serum urate in a quantitatively similar way to relatively unpalatable "low purine" diets.[36]
Decreasing serum urate levels can best be achieved with a low purine diet, but if followed strictly, the result is a diet high in saturated fats and carbohydrates. This increases the risk of insulin resistance and high serum insulin levels, which in turn reduces the excretion rate of urate through the kidneys and hence increases serum urate levels (Figure 3).[37]
Figure 3.
What are the Initial Symptoms of Gout?
Acute gout often occurs at night. The patient may be woken with an intense joint pain, accompanied by redness, swelling, and heat. In men, the initial gouty attacks are usually monoarticular, but occasionally multiple joints may be involved, especially as the disease progresses. Often it is the first MTP joint that is affected. Lower-extremity joints are commonly affected but any joint may be involved.
The pain tends to increase in intensity over several hours and is described by patients as the worst pain they have ever endured. Often the pain is so intense, that even the lightest touch can be agony. Some patients may experience a low-level fever, but in other cases, particularly those where multiple joints are involved, fever may be more severe.
What Diagnostic Steps Should Be Considered?
Laboratory and non-laboratory investigations can be helpful in further confirming the diagnosis of gout. For example, a full blood count can exclude myeloproliferative disorders, causing hyperuricemia and increasing the risk of gout
A number of potential investigations/evaluations can be performed in a patient presenting with what appears to be gout[38] (Figure 4).[39]
Figure 4.
Identification of monosodium urate (MSU) crystals in joints and tophi is used to definitively establish the diagnosis of gout. This can be done by aspirating fluid from the affected joint and examining it under compensated polarized light microscopy. The MSU crystals will appear as needle shaped and between 2 to 20 microns in length (Figures 5 and 6).[38,40-42] However, the majority of gout diagnosis is not based on joint aspiration,[43] instead it's based on the established preliminary diagnostic criteria (American College of Rheumatology [ACR] or the more recent European League Against Rheumatism [EULAR])[41,42] based on clinical, laboratory, and radiology findings.
Figure 5.
Figure 6.
According to the preliminary ACR criteria, gout is present if MSU crystals are seen, a tophi suspected, or if at least 6 of the criteria listed in Figure 7 are met.[41,43]
Figure 7.
The EULAR criteria are similar but are presented as a "ladder of evidence" (Figure 8).[42] With the addition of each symptom to the clinical presentation, the confidence in an accurate diagnosis of gout increases.
Figure 8.
If there is reasonable doubt about the diagnosis of gout, joint aspiration should be performed. Likely reasons for not performing joint aspiration as standard practice include (lack of) access to compensated polarized light microscopy, inexperience in joint aspiration, and patient reluctance to consider the procedure on a highly tender and inflamed joint.
Laboratory and Non-laboratory Tests for Gout
A number of laboratory and non-laboratory tests may assist with the diagnosis and/or differential diagnosis of gout.[43, 44] Serum urate levels are important, but 50% of patients suffering an acute attack will have normal serum urate levels. Renal function is important, since many gout treatments are either contraindicated, require dose alteration in renally impaired patients, or require more stringent follow-up. A full blood count can exclude myeloproliferative disorders or confirm septic arthritis, and metabolic markers (such as fasting lipids and glucose levels) may identify co-morbidities associated with gout (Figure 9).[43] Radiographic or ultrasound imaging can detect and quantify the presence of tophi, which are seen in patients who have had long-standing gout (Figure 10).[44]
Figure 9.
Figure 10.
Differential Diagnosis of Gout
There are a number of differential diagnoses to be aware of when examining the patient (Figure 11), [45] the most important of which is septic arthritis.
Figure 11.
Septic arthritis is an infection in a joint, and presents with symptoms very similar to gout, ie, pain, erythema, redness, etc. Septic arthritis is a medical emergency and unless appropriate treatment is initiated within 24 to 48 hours, permanent joint damage may occur.
Pseudogout is an inflammation of joints caused by the deposition of calcium pyrophosphate crystals in articular and periarticular tissues. It is most common in patients, mostly women, over the age of 50 years, and often occurs in the knees or wrists. Unlike gout, synovial fluid analysis will show calcium pyrophosphate dihydrate (CPPD) crystals, and plain film radiography of the affected joint may reveal chrondrocalcinosis.
Other differential diagnoses for gout include other categories of arthritis, such as reactive arthritis, rheumatoid arthritis, psoriatic arthritis, and osteoarthritis. These can be excluded by an effective review of the patient's clinical history and physical examination coupled with blood and radiologic findings.[45]
Treatment of Acute Gout
The initial objective when presented with a patient suffering from acute gout is the rapid resolution of symptoms. Most gout symptoms will resolve within a week or two, but a number of options exist that may reduce the time to resolution (Figure 12).[46, 47]
Figure 12.
NSAIDs are the mainstay of acute gout treatment. High doses should be used for the first 24 hours, and then gradually tapered until symptoms subside. Example regimens include naproxen 500 mg twice daily for 5 days, tapering to 500 mg daily for a further 5-7 days, or indomethacin 150-200 mg daily, tapering to 100 mg daily for a further 7 days. Although NSAIDs may reduce pain in as little as 4 hours, a more common outcome is a gradual reduction in pain over 6-7 days. NSAIDs have well-documented side effects, and they should be used cautiously, or not at all, in patients with chronic heart failure or kidney disease.
Colchicine has the smallest benefit to toxicity ratio of the drugs that are used in the management of gout.[48] It should therefore be used only as a second line therapy when oral NSAIDs or corticosteroids are contraindicated or ineffective. Colchicine (0.5 mg 3 times daily for 1 to 2 days) is used but the therapeutic window is small, and colchicine has a number of drug-drug interactions, therefore care must be taken to avoid toxicities and/or drug interactions.
Corticosteroids (CS) may be effective if given systemically (eg, prednisone 20-60 mg daily for up to 7-10 days usually in a tapered fashion, tapering by 10 mg per day every 2-3 days to discontinuation), or intra-articularly, usually used for flares in a single large joint, although caution needs to be taken to make sure the joint is not a septic joint.
ACTH has been used in a number of open studies, but more than one injection may be required to have a discernable effect. There is some evidence that as well as stimulating the release of corticosteroids, ACTH may also have a direct anti-inflammatory effect on the melanocortin 3 receptor of inflammatory cells.[49] Its high cost limits its use.
Consultation 2
When the patient returns several weeks after first presenting, he says the pain and swelling reduced with the NSAID treatment within a couple of days. Meanwhile, the laboratory results show the patient has a slightly raised white blood cell count (WBC) and CRP levels. LFTs and TFTs are normal, but he has an elevated serum urate level of 7.5 mg/dL. Plain film X-ray shows diffuse soft tissue swelling.
What are the Options for the Long-term Management of Gout?
After the complete resolution of an acute gout attack, the physician and patient should discuss the options available to reduce the likelihood of recurrence. The main treatment goal is the reduction of serum uric acid to ≤ 6.0 mg/dL. This can be achieved by a combination of pharmacologic and non-pharmacologic interventions.
Although lifestyle changes often prove difficult for patients to maintain, reducing the intake of meat, seafood, and alcohol (particularly beer) are of help in reaching the serum urate target. As the majority of gout patients are overweight, encouraging the patient to lose weight can provide significant advantages too. It is however important to understand that changes in lifestyle produce only minor changes in serum urate.
In a small study of 13 men with gout, a low calorie diet with moderate carbohydrate restriction, and an increased proportional intake of protein and unsaturated fats tailored to insulin resistance, produced a 17% decrease in serum urate concentration, as well as decreases in serum lipid levels, weight, and the frequency of acute gout attacks.[46]
Since lifestyle changes produce only small changes in serum urate, use of urate-lowering drugs such as allopurinol is usually needed. Pharmacologic management usually starts with allopurinol, a xanthine oxidase inhibitor that blocks the conversion of hypoxanthine to uric acid. The recommended starting dose is 100 mg/day, stepping up by 100 mg/day every 1 to 4 weeks to a maximum of 800 mg/day, or to the point where the serum urate target is reached.[42,50]
What are the Options for the Long-term Management of Gout?
Allopurinol (Figure 13)[42,50,51] is associated with several limitations, not the least of which is patient compliance. A recent study estimated compliance at only around 50%, with the poorest compliance in younger patients who had fewer visits and fewer co-morbidities.[52] This may be due to the fact that 20% of allopurinol patients experience side effects, and up to 5% discontinue treatment completely.[53]
Figure 13.
Allopurinol is also associated with hypersensitivity reactions. Although the incidence is low, around 2% can be severe or even life-threatening.[54] Risk factors for hypersensitivity reactions include thiazide diuretic therapy, the presence of the HLA-B58 genotype,[55] high doses of allopurinol, and the presence of CKD.[56]
Allopurinol has been associated with a number of drug-drug interactions, including with azathioprine, 6-mercaptopurine, theophylline, warfarin, and amoxicillin.[57]
Consultation 3
The patient is prescribed allopurinol to try to normalize and then maintain his serum urate levels at ≤ 6.0 mg/dL. Initial dose is 100 mg once daily, titrated up to 300 mg once daily over the course of 4 months. The concurrent use of NSAIDs is also recommended as prophylaxis management, since gout flares may occur as the uric acid is mobilized.
The patient returns to his physician after 4 months of allopurinol therapy. He has suffered further gout attacks and does not feel allopurinol is working for him. Furthermore, he is complaining of a rash on the lower extremities. Further laboratory analysis confirms his serum urate level has not dropped below 6.0 mg/dL and that his creatinine clearance is decreased at 56 mg/day.
Alternatives to Allopurinol Treatment
Allopurinol is not appropriate for all patients. Even in those patients who can tolerate it well, only 20% to 50% of patients achieve a serum urate level of ≤ 6.0 mg/dL.[62] For these patients, there are a number of other treatment options.
Uricosurics
The uricosuric agents, such as probenecid and benzbromarone, lower serum urate by increasing renal uric acid excretion. A EULAR evidence-based review showed probenecid 2 g/day was effective in reducing serum urate, but less so than allopurinol.[58]
Probenecid at doses of 1 to 3 g/day can be effective in patients with normal renal function and underexcretion of uric acid. Its efficacy reduces as renal function worsens, becoming ineffective when creatinine clearance levels are below 60 mL/min.[63]
An additional potential complication of uricosuric agents is the deposition of uric acid crystals within the kidney, which can result in urate nephropathy and/or the formation of kidney stones. Patients should be advised to drink at least 8 glasses of water per day to avoid these complications.
PEG-Uricase
Most mammals eliminate urate by oxidation to allantoin, which is more soluble than urate and undergoes more efficient renal clearance. Humans, however, do not have the functional uricase enzyme, which leads to an increased likelihood of hyperuricemia.
A recombinant preparation of this enzyme has been developed to treat hyperuricemia and gout. Rasburicase is purified uricase produced from the Aspergillus flavus fungus. Administered intravenously daily or every other day for a single treatment course of <>[59,60]
However, the need for parenteral administration and concerns over immunogenicity have limited its use. Subsequently, a PEGylated bacterial uricase (PEG-uricase, pegloticase) has been developed to try to overcome these problems (Figure 14).[64]
Figure 14.
Pegloticase was studied in a 12-week, Phase II, randomized, open-label, multicenter, parallel group trial.[65] A total of 41 patients with treatment-failure gout were dosed with 1 of 4 regimens: 4 mg or 8 mg IV every 2 weeks for a total of 6 doses, and 8 mg or 12 mg IV every 4 weeks for a total of 3 doses. All groups showed a rapid and sustained reduction in serum urate levels, most pronounced in the cohort receiving 8 mg every 2 weeks. In this group, serum urate levels were maintained at or below 2 mg/dL throughout the study.
Building on these data, a 6-month Phase III trial was undertaken comparing PEG-uricase 8 mg every 2 weeks or 8 mg every 4 weeks vs placebo. The primary endpoint of reduction of serum urate to ≤ 6.0 mg/dL was achieved in 42% of those taking 8 mg every 2 weeks and 0% of those taking placebo (p <>[66]
Febuxostat
Febuxostat is an orally administered, nonpurine, selective inhibitor of xanthine oxidase recently approved for use in the management of chronic hyperuricemia in patients with gout (Figure 15).[61,67,68]
Figure 15.
The efficacy of febuxostat relative to allopurinol was assessed in the pivotal Phase III trial FACT (Febuxostat versus Allopurinol Controlled Trial).[69] Febuxostat 80 mg (n=255) or 120 mg once daily (n=250) or allopurinol 300 mg once daily (n=251) were administered for 52 weeks. Prophylaxis against gout flares with naproxen or colchicine was provided for the first 8 weeks of the trial.
The primary endpoint was the percentage of patients with serum urate ≤ 6.0 mg/dL at each of the final 3 monthly measurements. Both doses of febuxostat were significantly superior to allopurinol on this measure (Figure 16).[69]
Figure 16.
Significantly more febuxostat than allopurinol treated patients achieved a serum urate ≤ 6.0 mg/dL at all patient visits (p <>p <>
Febuxostat has been extensively studied in clinical trials. The FOCUS study (Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety) was an open-label, 5-year extension study from an earlier dose-response trial.[69] A total of 116 patients were enrolled, with all receiving febuxostat 80 mg once daily through weeks 0-4. Between weeks 4 and 24, patients could receive dose adjustment to febuxostat 40, 80, or 120 mg once daily to maintain serum urate levels between 3.0 to ≤ 6.0 mg/dL. From week 28, a stable dose was maintained. As with other serum urate-lowering agents, there is a risk of gout flares as the MSU crystals come out of solution; therefore, all patients were provided prophylaxis treatment with colchicine, NSAIDs, analgesics, or corticosteroids.
The primary endpoint of the trial, reduction of serum urate levels to ≤ 6.0 mg/dL, was achieved in 82% of patients by week 28, with similar levels of success maintained throughout the 5-year period (79%, 77%, 84%, 90%, and 93% at years 1, 2, 3, 4, and 5 respectively).
A secondary endpoint was reduction from baseline serum urate at the final visit. The 59 patients who completed the 5-year study period showed approximately a 50% fall, regardless of febuxostat dose (Figure 17).[70]
Figure 17.
The incidence of gout flares requiring treatment declined over time, with the greatest reductions seen in the 80 mg/day group. The overall incidence of gout flares during years 1, 2, 3, 4, and 5 for febuxostat 80 mg/day were 1.67, 0.22, 0.002, 0.009, and zero flares per subject-year.
The APEX study (Allopurinol and Placebo-controlled Efficacy study of febuXostat) was a 28-week, randomized, double-blind trial that included patients with renal impairment (defined as a serum creatinine level of 1.6-2.0 mg/dL). The overall percentage of patients who achieved a serum urate level ≤ 6.0 mg/dL is shown in Figure 18, and all active treatment groups were superior to placebo.[71]
Figure 18.
In those patients with moderate renal impairment, this same endpoint was achieved in 44%, 45%, and 60% of recipients of febuxostat 80, 120, or 240 mg/day compared with 10% of allopurinol 100 mg/day, and no placebo patients. No statistical analysis was performed because of the small sample size.[71]
Febuxostat has proven effective in reducing and maintaining serum urate concentrations ≤ 6.0 mg/dL in gout patients. It appears to be well tolerated with a similar spectrum and frequency of adverse events as allopurinol, but no severe hypersensitivity reactions and subsequently the FDA has approved febuxostat at doses of 40 and 80 mg. Febuxostat can also be used in patients with mild-moderate renal impairment, as it is primarily metabolized by the liver with renal function accounting for <10%>[67,68] As with all serum urate-lowering agents, low-dose colchicine or NSAIDs should initially be co-administered to avoid flares of acute gout.
Conclusion
Gout is a disease that is increasing in prevalence across the western world. Patients have elevated serum urate levels strongly associated with other comorbidities, particularly those seen with metabolic syndrome.
The hyperuricemia leads to urate supersaturation, urate crystal formation, and ultimately clinical gout, which if left untreated can lead to permanent joint damage. Acute attacks commonly present as severe pain in a single joint, most often the first MTP joint. NSAIDs or other anti-inflammatory drugs may reduce the time to resolution of the acute attack, but long-term intervention with urate-lowering drugs is needed to minimize the chance of recurrence.
The clinical goal in managing chronic or refractory gout is reducing the frequency and severity of attacks. This can best be achieved by reducing serum urate levels to ≤ 6.0 mg/dL. Lifestyle and dietary changes are useful, but pharmacologic intervention is usually required. Current treatments such as allopurinol are effective, but have several limitations including patient non-compliance and dose limitations in patients with renal disease. A number of emerging therapies such as febuxostat and pegloticase may help overcome these problems in the future.
Source : http://cme.medscape.com/viewarticle/701583_14
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