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Background
Gout is a condition caused by the over-production or under-excretion of uric acid, resulting in the deposition of monosodium urate crystals in the joints or soft tissue. The disease is often, but not always, associated with increased blood uric acid levels. The four phases of gout are (i) asymptomatic hyperuricemia, (ii) acute gouty arthritis, (iii) inter-critical gout, and (iv) chronic tophaceous gout. The peak incidence of gout occurs in patients 30 to 50 years old, and the condition is much more common in men than in women. Individuals with asymptomatic hyperuricemia do not require specific treatment; however, attempts should be made to decrease their urate levels by encouraging them to make dietary and lifestyle modifications (e.g., a low carbohydrate, high protein and unsaturated fat diet). Acute gout most commonly affects the first metatarsal joint of the foot, but the small joints of the hands, wrists and elbows may also be involved. Gout rarely occurs in the shoulders, hips, sacroiliac joints or spine. Gout in the elderly differs from classical gout found in middle-aged men in several respects: it has a more equal gender distribution, frequent polyarticular presentation with involvement of the joints of the upper extremities, fewer acute gouty episodes, a more indolent chronic clinical course, and an increased incidence of tophi, which are deposits of monosodium urate crystals in people with longstanding high levels of uric acid in the blood and are commonly seen in conjunction with gout. Long-term diuretic use in patients with hypertension or congestive cardiac failure, renal insufficiency, prophylactic low-dose aspirin, and alcohol abuse (particularly by men) are factors associated with the development of hyperuricemia and gout in the elderly (Pittman and Bross, 1999; Harris et al, 1999; Agudelo and Wise, 2000; Agudelo and Wise, 2001).
Segal and Albert (1999) stated that diagnosis of the crystal-induced arthritides is primarily based on microscopic identification of crystals in synovial fluid. Harris and colleagues (1999) noted that definitive diagnosis requires joint aspiration with demonstration of birefringent crystals in the synovial fluid under a polarized light microscope.
While blood level of uric acid has been commonly used as a diagnostic indicator of hyperuricemia and gout, the value of salivary level, scalp hair level, as well as 24-hour urine level of uric acid in diagnosing gout has not been established. Microscopic analysis by means of compensated polarized light and culture of synovial fluid helps differentiate gouty arthritis from other arthropathies, and the presence of monosodium urate crystals establishes the diagnosis of gout. When gout is suspected, yet the initial examination does not reveal the telltale crystals, re-examination of synovial fluid is warranted. It is important to note that diagnosis of gout does not rule out the possibility of concurrent arthritic conditions (Uy et al, 1996; Owen-Smith et al, 1998; Kobayashi et al, 1998; Pittman and Bross, 1999; Schlesinger et al, 1999).
Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics on the diagnosis of gout (Zhang et al, 2006a) stated that radiographs have little role in diagnosis, though in late or severe gout radiographical changes of asymmetrical swelling and subcortical cysts without erosion may be useful to differentiate chronic gout from other joint conditions.
Treatment goals include termination of the acute attack, prevention of recurrent attacks and prevention of complications associated with the deposition of urate crystals in tissues. Pharmacotherapy remains the mainstay of treatment. Acute attacks may be terminated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine or intra-articular injections of corticosteroids. Probenecid, sulfinpyrazone and allopurinol can be used to prevent recurrent attacks. In patients with peptic ulcer disease, selective cyclo-oxygenase-2 (COX-2) inhibitors provide another treatment option. In the presence of renal impairment, allopurinol is the treatment of choice for urate-lowering therapy, but doses of allopurinol and colchicine must be adjusted. Urate-lowering therapy should only be used if recurrent episodes of gout occur despite aggressive attempts to reverse or control the underlying causes. It should not be introduced or discontinued during an acute episode of gout. Obesity, alcohol consumption and certain foods and medications can contribute to hyperuricemia. These risk factors should be identified and modified (Pittman and Bross, 1999; McGill, 2000; van Doornum and Ryan, 2000; Zhang et al, 2006b).
Caution should be exercised when prescribing NSAIDs for the treatment of acute gouty arthritis in the elderly. Short-acting NSAIDs (e.g., diclofenac and ketoprofen) are preferred, but these drugs are not recommended in patients with peptic ulcer disease, renal failure, uncontrolled hypertension or cardiac failure. Colchicine is poorly tolerated in the elderly and is best avoided. Intra-articular and systemic corticosteroids are increasingly being used for treating acute gouty flares in elderly patients with medical disorders contraindicating NSAID therapy. Urate-lowering drugs are poorly tolerated and the frequent presence of renal impairment in the elderly renders these drugs ineffective. Allopurinol is the urate-lowering drug of choice, but its use in the elderly is associated with an increased incidence of both cutaneous and severe hypersensitivity reactions. To minimize this risk, the dosage of allopurinol must be kept low (Fam, 1998).
Cronstein and Terkeltaub (2006) stated that despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many NSAIDs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the 1st-line of anti-inflammatory therapy for acute gout is NSAIDs, and the selective COX-2 inhibitor, celecoxib, can be used where appropriate. The 2nd-line of treatment is glucocorticoids, given systemically (intramuscular, intravenous, or oral) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The 3rd-line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects.
The task force of the Standing Committee for International Clinical Studies Including Therapeutics on the management of gout (Zhang et al, 2006b) noted that recommended drugs for acute gout attacks were oral NSAIDs, oral colchicine, or joint aspiration and injection of corticosteroid. Urate-lowering therapy is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographical changes of gout. Allopurinol was confirmed as effective long-term urate-lowering therapy. If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol de-sensitization, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol and can be used in patients with mild-to-moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5 to 1 mg daily or an NSAID (with gastro-protection if indicated) is recommended.
The clinical guideline on the management of initial gout in adults by the University of Texas at Austin (2009) included pharmacolotherapies (e.g., colchicine, corticosteroids [intra-articular or systemic], NSAIDs, and vitamin C), as well as non-pharmacological management (e.g., avoidance of heat therapy, co-morbidity management, diet including coffee [2 cups of coffee daily], low alcohol diet, low-fat dairy diet, low fructose diet [especially avoiding sugar-sweetened soft drinks], and low purine diet [avoidance of red meats, seafood], ice therapy, and rest of affected joint).
In April 2009, the U.S. Food and Drug Administration (FDA) approved febuxostat (Uloric), a non-purine analog xanthine oxidase inhibitor and is the first new urate-lowering gout drug in more than 40 years. In August 2009, the FDA approved colchicine (Condylon) for the treatment of acute gout. Several other pharmaceutical companies are also conducting clinical trials to test new drugs for the treatment of acute and chronic gout; one of them is pegloticase, a pegylated recombinant uricase that converts urate into the easily excretable allantoin (Schlesinger 2010).
Yue and associates (2008) described the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4- and 8-mg doses, or every 4 weeks at 8- or 12-mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and co-variates were examined (age, antibody response, body weight, gender, ideal body weight, and race). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1-compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (E(max)) function. Pegloticase suppressed uric acid levels up to 83 %. Weight only affected clearance and volume of distribution. No co-variates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2-hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.
In a phase II, randomized study, Sundy et al (2008) evaluated the effectiveness of pegloticase in achieving and maintaining plasma urate levels of less than 6 mg/dl in gout patients in whom other treatments have failed, and assessed the pharmacokinetics and safety of pegloticase. A total of 41 patients were randomized to undergo 12 to 14 weeks of treatment with pegloticase at 1 of 4 dosage levels: (i) 4 mg every 2 weeks, (ii) 8 mg every 2 weeks, (iii) 8 mg every 4 weeks, or (iv) 12 mg every 4 weeks. Plasma uricase activity, plasma urate, and anti-pegloticase antibodies were measured, pharmacokinetic parameters were assessed, and adverse events were recorded. The mean plasma urate level was reduced to less than or equal to 6 mg/dl within 6 hours in all dosage groups, and this was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups. The most effective dosage was 8 mg every 2 weeks. Twenty-six patients received all protocol doses. The percentage of the patients in whom the primary efficacy end point (plasma urate less than 6 mg/dl for 80 % of the study period) was achieved ranged from 50 % to 88 %. Gout flares occurred in 88 % of the patients. The majority of adverse events (excluding gout flare) were unrelated to treatment and were mild or moderate in severity. Infusion-day adverse events were the most common reason for study withdrawal (12 of 15 withdrawals). There were no anaphylactic reactions. Anti-pegloticase antibody, present in 31 of 41 patients, was associated with reduced circulating half-life of pegloticase in some patients. The authors concluded that pegloticase, administered in multiple doses, was effective in rapidly reducing and maintaining plasma urate levels at less than or equal to 6 mg/dl in most patients in whom conventional therapy had been unsuccessful due to lack of response, intolerability, or contraindication.
Hershfield et al (2010) noted that a high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support rests largely on in vitro data and epidemiologic associations. Pegloticase therapy generates H(2)O(2) while depleting urate, offering an in vivo test of the antioxidant hypothesis. These researchers showed that erythrocytes can efficiently eliminate H(2)O(2) derived from urate oxidation to prevent cell injury in vitro; during therapy, disulfide-linked peroxiredoxin 2 dimer did not accumulate in red blood cells, indicating that their peroxidase capacity was not exceeded. To assess oxidative stress, these researchers monitored F2-isoprostanes (F2-isoPs) and protein carbonyls (PC), products of arachidonic acid and protein oxidation, in plasma of 26 refractory gout patients receiving up to 5 infusions of pegloticase at 3-week intervals. At baseline, PUA was markedly elevated in all patients, and plasma F2-isoP concentration was elevated in most. Pegloticase infusion rapidly lowered mean PUA to less than or equal to 1 mg/dL in all patients, and PUA remained low in 16 of 21 patients who completed treatment. F2-isoP levels did not correlate with PUA and did not increase during 15 weeks of sustained urate depletion. There also was no significant change in the levels of plasma PC. Because refractory gout is associated with high oxidative stress in spite of high PUA, and profoundly depleting uric acid did not increase lipid or protein oxidation, the authors concluded that urate is not a major factor controlling oxidative stress in vivo.
On September 14, the FDA approved pegloticase (Krystexxa) for the treatment of gout in adults who do not respond to or who can not tolerate conventional therapy. Patients who have failed to normalize serum uric acid (to less than 6 mg/dL) with xanthine oxidase inhibitors at the maximum medically appropriate dose for at least 3 months are deemed refractory. The maximum recommended dosages of allopurinol [Zyloprim] and febuxostat [Uloric] for gout are 800 mg/day and 80 mg/day, respectively. The approval was based on 2 replicate, multi-center, randomized, double-blind, placebo-controlled clinical studies of 6 months duration (a total of 212 patients). Patients were randomized to receive pegloticase every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio. The primary endpoint in both trials was the proportion of patients who achieved PUA less than 6 mg/dL for at least 80 % of the time during month 3 and month 6. The data in both clinical studies demonstrated that a greater proportion of patients treated with pegloticase every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. During the first 6 months of treatment, 47 % (p < 0.001) and 38 % (p < 0.001) of patients in the pegloticase arms of the 2 clinical studies achieved the primary efficacy endpoint, compared with 0 % of patients in the placebo arm.
The effect of treatment with pegloticase on tophi was a secondary efficacy endpoint of the clinical studies and was assessed using standardized digital photography, image analysis and a central reader blinded to treatment assignment. Baseline tophi was found in 71 % of patients. A pooled analysis of data from both clinical studies at month 6 demonstrated that 45 % (p < 0.02) of patients with tophi treated with pegloticase every 2 weeks achieved a complete response, defined as 100 % resolution of at least one target tophus, no new tophus appearing and no single tophus showing progression, compared to 8 % of patients receiving placebo.
Since 25 % of patients in the clinical trials experienced a severe allergic reaction when receiving an infusion of Krystexxa, health care providers should dispense an anti-histamine and a corticosteroid to their patients beforehand to minimize the risk of such a reaction. Other reactions included chest pain, constipation, gout flare, injection site bruising, irritation of the nasal passages, nausea and vomiting. The drug is administered to patients every 2 weeks as an intravenous infusion; it should not be administered as an intravenous push or bolus.
Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of methemoglobinemia and hemolysis. It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened for G6PD deficiency before starting pegloticase.
Several pipeline drugs for the treatment of gout include the selective uricosuric drug RDEA594 and various interleukin-1 (IL-1) inhibitors (anakinra, rilonacept, and canakinumab) (Burns and Wortmann, 2011). So et al (2007) stated that monosodium urate crystals stimulate monocytes and macrophages to release IL-1 beta via the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in patients with hereditary auto-inflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. Inhibition of IL-1 prevented peritoneal neutrophil accumulation but tumor necrosis factor blockade had no effect. Based on these findings, these investigators performed a pilot, open-labeled study in 10 patients with gout who could not tolerate or had failed standard anti-inflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. Blockade of IL-1 appears to be an effective therapy for acute gouty arthritis. The authors stated that these findings need to be confirmed in a controlled study.
In an observational study, Krishnan and colleagues (2012) examined if blood lead levels (BLLs) within the range currently considered acceptable are associated with gout. A total of 6,153 civilians aged 40 years or older with an estimated glomerular filtration rate greater than 10 ml/min per 1.73 m2 were included in this study. Outcome variables were self-reported physician diagnosis of gout and serum urate level. Blood lead level was the principal exposure variable. Additional data collected were anthropometric measures, blood pressure, dietary purine intake, medication use, medical history, and serum creatinine concentration. The prevalence of gout was 6.05% (95 % confidence interval [CI]: 4.49 % to 7.62 %) among patients in the highest BLL quartile (mean of 0.19 µmol/L [3.95 µg/dL]) compared with 1.76 % (CI: 1.10 % to 2.42 %) among those in the lowest quartile (mean of 0.04 µmol/L [0.89 µg/dL]). Each doubling of BLL was associated with an unadjusted odds ratio of 1.74 (CI: 1.47 to 2.05) for gout and 1.25 (CI: 1.12 to 1.40) for hyperuricemia. After adjustment for renal function, diabetes, diuretic use, hypertension, race, body mass index, income, and education level, the highest BLL quartile was associated with a 3.6-fold higher risk for gout and a 1.9-fold higher risk for hyperuricemia compared with the lowest quartile. The authors concluded that blood lead levels in the range currently considered acceptable are associated with increased prevalence of gout and hyperuricemia. The main drawback of this study was that blood lead level does not necessarily reflect the total body lead burden.
The updated European League Against Rheumatism (EULAR) guideline for the diagnosis and management of gout and hyperuricemia (Hamburger et al, 2011) did not mention testing for BLL. Furthermore, an UpToDate review on "Clinical manifestations and diagnosis of gout" (Becker, 2012) as well as an University of Texas at Austin School of Nursing's clinical practice guideline on "Management of chronic gout in adults" (2012) do not mention measurement of BLL as a diagnostic tool.
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