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Artritis gotosa


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© Springer Healthcare 2011
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Artritis gotosa

  1. 1. Prashanth Sunkureddi () The University of Texas Medical Branch (UTMB), 2060 Space Park Drive, Suite 208, Nassau Bay, TX 77058, USA. Email: Adv Ther (2011) 28(9):748-760. DOI 10.1007/s12325-011-0058-5 REVIEW Gouty Arthritis: Understanding the Disease State and Management Options in Primary Care Prashanth Sunkureddi Received: July 12, 2011 / Published online: August 31, 2011 © Springer Healthcare 2011 ABSTRACT Acute gouty arthritis is an inflammatory response triggered by the release of monosodium urate crystal deposits into the joint space. The disease is associated with debilitating clinical symptoms and functional impairments as well as adverse economic and quality-of-life burdens. Because gouty arthritis is typically diagnosed and managed in the primary care setting, clinicians require a thorough knowledge of the presenting clinical features, risk factors, differential diagnoses, and treatment options for appropriate management. Although generally effective, the use of currently available therapies to control gouty arthritis is challenging because many medications used to treat comorbidities can exacerbate gouty arthritis and because current agents are associated with a number of adverse events, contraindications, or both. Based on an understanding of the underlying inflammatory pathogenesis of gouty arthritis, several new agents are being developed that may provide improved efficacy. Keywords: diagnosis; emerging therapy; gouty arthritis; tophi; uric acid; uric acid lowering therapy INTRODUCTION Gouty arthritis is a metabolic disorder in which circulating uric acid can accumulate and form monosodium urate crystals in both synovial fluid and cartilage, resulting in arthritic inflammation.1 It is one of the earliest documented diseases, first identified by the ancient Egyptians and later described by Hippocrates in the fifth century BC.2 Because the disease is associated with eating and drinking certain foods and beverages that once could be afforded only by the affluent, it was termed the “disease of kings.”2 For a long time, acute gouty attacks were also erroneously considered to prevent other illnesses and were thus considered desirable.2 Acute gouty arthritis is triggered when sufficient monosodium urate crystal deposits around the joint are released into the joint space.3 Triggering factors include infection,
  2. 2. Adv Ther (2011) 28(9):748-760. 749 intravenous contrast media, acidosis, traumas, surgery, chemotherapy, diuretic therapy, or any condition that leads to a rapid increase/decrease in serum uric acid (sUA) levels, such as a purine- rich meal or a disruption of dietary habits caused by hospitalization.4 Clinical symptoms are characterized by a rapid onset of pain that is often too intense to bear weight, and, in some cases, even a bed sheet over the affected joint. Other signs and symptoms include swelling, redness, warmth of the affected joint, and sometimes fever, flu-like symptoms, or both. Attacks of gouty arthritis typically affect only one joint, and in 50% of initial gouty attacks, the metatarsophalangeal joint of the great toe is involved. The attack in the first metatarsophalangeal joint is known as podagra. These attacks are often self-limiting, lasting 3-14 days.3,4 Over a period of years, the time between attacks become less defined, and chronic gouty arthritis often develops as urate deposits slowly increase. Although the attacks become less painful, they last longer and tend to involve more joints and tendons.1,3 Large deposits of crystals damage joints, tophi (ie, urate crystal deposits in tissues) appear, and the joints become chronically stiff and swollen.1 Chronic, erosive gouty arthritis can resemble rheumatoid arthritis and is characterized by the presence of: intense inflammation; chronic, deforming, persistent joint abnormalities; monosodium urate crystals in joint fluid; tophi; chronic arthropathy; renal stone formation; renal insufficiency; and nephrolithiasis.5,6 Gouty arthritis is the most common form of inflammatory arthritis in Western countries.1 In a recent analysis of the National Health and Nutrition Examination Survey (NHANES 2007- 2008), gouty arthritis was found to affect 3.9% of US adults (8.3 million).7 The prevalence was significantly higher than that seen in NHANES III (2.7%; 1988-1994). The increase in prevalence was primarily observed among men and the elderly.7 It is thought that increased rates of obesity and metabolic syndrome may contribute to this increased prevalence.8 Gouty arthritis accounted for almost 4 million outpatient office visits in the USA in 2002.4 Gouty arthritis has a substantial clinical and economic burden and adversely affects health- related quality of life. Gouty arthritis-associated pain restricts function and significantly lowers quality of life compared with age-matched US norms.9 Gouty arthritis interferes with activities of daily living such as work and recreation.9 In addition, gouty arthritis may result in comorbidities that have a significant impact on morbidity and mortality.10 In the Health Professionals Follow-Up Study, a history of gouty arthritis was associated with a 28% increased risk of death, 38% increased risk of cardiovascular disease-related death, and 55% increased risk of coronary heart disease-related death.10 In addition, gouty arthritis-related medications can result in many adverse events, interfere with the treatment of comorbidities, or both.11 PATHOPHYSIOLOGY OF GOUTY ARTHRITIS The inflammatory response associated with gouty arthritis is initiated by the formation and deposition of monosodium urate crystals.5 When the solubility threshold of monosodium urate in plasma is exceeded, monosodium urate crystals are deposited in tissues, causing the subsequent release of inflammatory mediators (ie, tumor necrosis factor-alpha, interleukin [IL]-1, IL-6), which create the joint-related and systemic effects (ie, fever, leukocytosis) of a gouty arthritis attack.12 Although monosodium urate acid crystal-induced inflammation is initially episodic, chronic synovitis can occur over time, resulting in chronic pain, as well as damage to bone and cartilage.3
  3. 3. 750 Adv Ther (2011) 28(9):748-760. DIAGNOSIS AND CLINICAL FEATURES Because gouty arthritis is mostly diagnosed (usually without synovial fluid analysis for monosodium urate crystals) and managed by primary care physicians, they require a thorough understanding of the clinical presentation.6 Numerous risk factors have been identified for the development of gouty arthritis (Table 1).5,8,13,14 The incidence of gouty arthritis increases with age and is more common in men than women.8 Premenopausal women rarely develop attacks; however, a more equal distribution between the sexes occurs in the elderly population, likely related to the loss of the uricosuric effect of estrogen in postmenopausal women.8 Other risk factors include lifestyle (eg, diet/alcohol intake), medications, and comorbidities.8 The stages of gouty arthritis range from asymptomatic hyperuricemia to advanced/ chronic tophaceous gouty arthritis. Early in the course of the disease, patients with sUA >6.8 mg/dL may develop urate crystal formation and deposits in joints and tissues and acute/painful arthritic flares, although many individuals remain asymptomatic and do not develop gouty arthritis.1,3 It is difficult to determine who will develop gouty arthritis symptoms, although higher serum urate levels substantially increase the risk of an attack.8 Once sufficient urate deposits have developed around joints, patients will have intermittent attacks of gouty arthritis in response to trauma- or local milieu-related release of crystals into the joint space.3 During intervals between attacks (termed intercritical periods) crystals are still present at a low level in periarticular and synovial tissue, causing further deposition that may lead to future attacks, chronic pain, and joint damage.3 As the crystallization of uric acid and deposition of monosodium urate in joints increases, extended asymptomatic intervals decrease. Advanced/chronic tophaceous gouty arthritis is characterized by constant pain, stiffness, swelling of joints, tophi, and urate kidney deposits/renal stones.3,5 Large crystal deposits cause joint damage and chronic deforming arthritis.5 Table 1. Risk factors for the development of gouty arthritis.5,8,13,14 Age • Increases with age • Usually >50 years at onset Race • African American > White Sex • Male > female Genetics • Amount of uric acid excreted by kidneys influenced by genetics Lifestyle factors • Heavy consumption of alcohol (especially beer) • Red meat, seafood • High-fructose corn syrup • Purine-rich foods • Certain vegetables • Obesity • Low consumption of dairy products Medications • Diuretics (thiazides, loop diuretics) • Low-dose aspirin • Ciclosporin • Niacin • Pyrazinamide • Ethambutol Comorbidities • Metabolic syndrome • Hypertension • Cardiovascular disease – Thromboembolic disorders (myocardial infarction, peripheral artery disease) – Heart failure • Chronic kidney disease • Hyperuricemia without gouty arthritis
  4. 4. Adv Ther (2011) 28(9):748-760. 751 Diagnosis involves a thorough examination. Typical presenting symptoms include the rapid development of pain, swelling, and tenderness in a single joint with complete resolution of flares in a few days to 2 weeks.5 Patients can also develop erythema of the surrounding tissue; alternately, acute gouty arthritis can present as bursitis or tenosynovitis. The joint is red, hot, swollen, and very tender to touch or move.5 As gouty arthritis progresses, the hands and more proximal joints may become involved.5 Although only a single joint is usually affected in patients with early disease, polyarticular involvement becomes increasingly prevalent as the disease progresses. Women present differently than men and are more likely to have involvement in multiple joints in the upper extremities and in distal interphalangeal joints, potentially as a result of pre-existing joint damage caused by osteoarthritis.5,15 Overall, the most common sites involved are the first metatarsophalangeal joint, foot, ankle, knee, wrist, and elbow. Joint examination at these sites should look for the cardinal signs of inflammation such as erythema, warmth, swelling, tenderness, and for presence of tophus. The diagnostic standard for gouty arthritis is the presence of intracellular monosodium urate crystals in synovial fluid or in the aspirate of a tophus.13 The exclusion of infection or other crystal types in the synovial fluid of an affected joint is also important.15 Several diagnostic/ clinical variables can help to determine whether joint fluid aspiration is necessary. These include male sex, previous patient-reported arthritis attack, onset within 1 day, joint redness, metatarsophalangeal involvement, hypertension or ≥1 cardiovascular diseases, and an sUA level >5.88 mg/dL.14 In an analysis of 328 patients presenting to a family physician with monoarthritis, the presence of ≤4 of these variables ruled out gouty arthritis in almost 100% of cases. The presence of ≥8 variables confirmed gouty arthritis in more than 80% of cases.14 These diagnostic criteria allow family physicians to treat empirically without waiting for laboratory results. American College of Rheumatology (ACR) guidelines for the diagnosis of acute arthritis of primary gout were developed in 1977.16 According to these guidelines, gouty arthritis may be diagnosed if monosodium urate crystals are present in synovial fluid, or tophi are confirmed with crystal examination.16 Alternatively, the presence of ≥6 of the 12 criteria (Table 2) satisfies the criteria for the diagnosis of acute gouty arthritis.16 The sensitivity of these criteria was 84.8%, but the specificity was lower because 7.3% of patients with pseudogout, 2.5% with septic arthritis, and 1.7% with rheumatoid arthritis also met the criteria.16 Thus, if infection is possible or suspected (ie, septic arthritis), aspiration is recommended.15 The patient work-up should include a patient history and assessment of risk factors. A history of multiple arthritic attacks of rapid onset in the Table 2. ACR criteria* for the diagnosis of acute gouty arthritis.16 Maximal inflammation developed within 1 day History of more than one arthritis attack Monoarticular arthritis Redness observed over the joint(s) First metatarsophalangeal joint painful or swollen Unilateral first metatarsophalangeal joint affected Unilateral tarsal joint affected Suspected tophus or tophi Hyperuricemia Asymmetric swelling Subcortical cysts without erosions on radiograph Synovial fluid culture negative for organisms during an attack *Presence of ≥6 items fulfills the criteria for acute gouty arthritis. ACR=American College of Rheumatology.
  5. 5. 752 Adv Ther (2011) 28(9):748-760. same joint with complete resolution within a few days to 2 weeks is suggestive of gouty arthritis.5 Male sex, presence of obesity, family history of gouty arthritis, patient history of urolithiasis, use of urate-elevating medications (eg, thiazide, loop diuretics, low-dose aspirin, ciclosporin, niacin, pyrazinamide, and ethambutol), recent joint trauma or surgery, alcohol consumption (particularly beer), diet high in purine-rich foods (eg, red meat, seafood, certain vegetables), soft drinks containing high-fructose corn syrup, or low consumption of dairy also increase the likelihood of the diagnosis.5,14 The patient history also should include questions regarding comorbidities commonly associated with gouty arthritis (eg, hypertension, hypertriglyceridemia, diabetes, metabolic syndrome, coronary heart disease, kidney disease).15 Evaluation of gouty arthritis- associated cardiovascular and renal diseases is particularly important.14 Laboratory tests that should be performed include sUA level, glomerular filtration rate, erythrocyte sedimentation rate, and C-reactive protein level given that elevations in these markers are associated with monosodium urate crystals.14 The presence of persistent hyperuricemia (ie, sUA >6.8 mg/dL) can be indicative of gouty arthritis in a patient who reports a history of previous monoarticular arthritic attacks.5,14 However, it should be noted that measurement of sUA during an acute flare of gouty arthritis might not accurately reflect chronic hyperuricemia.13 Studies have shown that patients with gout can have significantly lower sUA levels during an acute flare compared with levels observed during the intercritical phase because of an increase in the urinary excretion of uric acid that accompanies the acute inflammatory events associated with flare.17 Imaging techniques for diagnosis and assessment of treatment response include conventional radiography, ultrasound, computed tomography, and magnetic resonance imaging (MRI).18 Similar to what is seen in rheumatoid arthritis, advanced imaging techniques (eg, MRI and ultrasound) appear to be more sensitive for destructive arthropathy.18 However, there is concern regarding the risk of nephrogenic systemic fibrosis in patients with reduced renal function after exposure to a gadolinium-based contrast agent.19 The differential diagnosis for gouty arthritis includes pseudogout, septic arthritis, psoriatic arthritis, nodal osteoarthritis, and reactive arthritis. Early stages of the disease rarely resemble rheumatoid arthritis, but gouty arthropathy in multiple joints, when accompanied by tophi, can resemble rheumatoid nodules.3-5 However, radiographically prominent, proliferative bony reaction in gouty arthritis is not seen in rheumatoid arthritis. Unlike rheumatoid arthritis, gouty arthritis- related tophi also can cause bone destruction away from a joint.3 Furthermore, gouty arthritis is less likely than rheumatoid arthritis to cause joint space narrowing. Erosions can be more central rather than marginal, as in rheumatoid arthritis, and there can be overhanging edges and less peri-articular osteopenia in gouty arthritis.3 Gouty arthritis can also resemble stress or silent traumatic bone fracture, and in the setting of an arthritic attack, it is particularly important to rule out septic arthritis.5,15 In ruling out septic arthritis, it is important to keep in mind that patients with early gouty arthritis usually have no fever or leukocytosis.5 When these features are present, gram stain and culture of synovial fluid or blood are needed to exclude infection.5 Pseudogout can have a presentation very similar to an attack of gouty arthritis, but the differences can be seen upon microscopy.15 Using a polarizing microscope, pseudogout
  6. 6. Adv Ther (2011) 28(9):748-760. 753 crystals are positively birefringent and rhomboid shaped, while urate crystals are negatively birefringent and needle-like in appearance.15 Also, pseudogout attacks often occur in the wrist (at the base of the thumb), knee, and shoulder, with radiographic examination often showing chondrocalcinosis.5,15 MANAGEMENT AND TREATMENT Decisions about intervention with agents for gouty arthritis attacks and those that lower serum urate levels should be individualized, taking into consideration comorbidities, likelihood of continued attacks, potential impact on lifestyle, and complications of continued medication.3 Treatment also may be challenging because of potential issues associated with drugs often used to manage comorbidities. For example, diuretics, used to treat hypertension, induce hyperuricemia and are associated with an increased risk of gouty arthritis.8 Other medications that cause hyperuricemia because of decreased excretion of urate include ciclosporin, nicotinic acid, ethambutol, pyrazinamide, and aspirin.6 Treating Gouty Arthritis Attacks The immediate goals for management of patients with gouty arthritis attacks are to treat the pain of acute flares aggressively (with a nonsteroidal anti-inflammatory drug [NSAID] of choice, colchicine, and/or corticosteroids), to reduce pain intensity and duration, and to improve function.5 Ice, rest, and elevation are useful nonpharmacologic adjunctive therapies.5 Treatment of gouty arthritis attacks has no impact on crystal formation or deposition, so it does not affect progression of gouty arthritis. Importantly, patients should not be initiated on uric acid-lowering therapy (ULT) during an attack, as it can further propagate the attack; however, because sUA is the most important modifiable risk factor, patients already on ULT should continue it.5,20 Current pharmacologic agents for the treatment of acute gouty arthritis are effective for reducing inflammation, although all currently available agents have limitations in use.11 Early initiation of anti-inflammatory treatment is effective for reducing the cascade of inflammatory events initiated by urate crystals.21 The first-line treatment of acute gout is symptomatic pain relief with colchicine or a NSAID.22 There is no evidence for superior clinical efficacy among drugs within the NSAID class, and both conventional NSAIDS such as sulindac or naproxen, and cyclo-oxyenase-2 (COX-2) inhibitors have demonstrated effective pain relief in clinical trials.22 COX-2 inhibitors, such as rofecoxib and valdecoxib, have shown efficacy in treating acute flares; however, these agents are no longer available in the USA, and celecoxib, the only currently available COX-2 inhibitor available in the USA, is not approved for use in this indication.23 Naproxen is approved for the treatment of acute gout at a dose of 1000-1500 mg on day 1, followed by 1000 mg/day thereafter until the attack has subsided.24 Both celecoxib and naproxen should be used with care in patients with risk factors for cardiovascular disease and are contraindicated in certain high-risk patient groups.23,24 Both drugs also carry a black box warning regarding serious gastrointestinal adverse events, including bleeding, ulceration, and perforation, and particular care should be exercised when considering use of these drugs in elderly patients.23,24 Colchicine is approved for the prophylaxis (0.6 mg once or twice daily) and treatment (1.2 mg followed by 0.6 mg 1 hour later) of gout flares.25 Recently, the randomized AGREE (Acute
  7. 7. 754 Adv Ther (2011) 28(9):748-760. Gout Flare Receiving Colchicine Evaluation) trial demonstrated equivalent efficacy between low-dose (1.8 mg total over 1 hour) and high- dose (4.8 mg total over 6 hours) colchicine (and significantly superior efficacy versus placebo) for the treatment of acute gouty arthritis.26 Based on the results of this study, colchicine was granted marketing approval by the US Food and Drug Administration (FDA), with maximum recommended daily doses of 1.2 mg for prophylaxis and 1.8 mg for treatment of flare.25 Until recently, intravenous colchicine was available; however, given toxicity concerns, this formulation is no longer recommended. In the AGREE trial, gastrointestinal adverse events were the most frequently reported toxicity associated with colchicine administration: diarrhea was reported in 23% of patients in the low-dose arm, although none of these cases were considered severe.26 Colchicine is contraindicated in patients with renal or hepatic impairment who also are receiving P-glycoprotein or strong cytochrome P450 3A4 (CYP3A4) inhibitors because of the potential for life-threatening toxicity. Overdose in excess of 0.8 mg/kg is associated with 100% mortality.25 In addition, dose adjustments are required for all patients (regardless of renal or hepatic dysfunction) who are taking or have recently completed treatment with a moderate or strong CYP3A4 inhibitor, P-glycoprotein inhibitor, or protease inhibitor, and for those patients considering prophylactic therapy who have severe renal impairment.25 Systemic corticosteroids also are approved as an adjunctive therapy for short-term administration in patients with acute gouty arthritis flares,27 although a recent Cochrane analysis found inconclusive evidence for their effectiveness over other anti-inflammatory treatments.28 However, there are limited data from large, controlled trials. Corticosteroids should be used for short-term therapy, with the dose tapered as symptoms improve to avoid rebound flares on withdrawal.5 Starting doses of prednisone vary from 5 to 60 mg/day with lower doses often effective in patients with less severe disease.27 Doses should be individualized for each patient, to achieve a satisfactory response, and once symptoms are controlled, maintenance therapy should be based on the minimum dose and shortest duration necessary to maintain symptom control.27 Adrenocorticotropic hormone (ACTH) is also used in a proportion of patients with gouty arthritis, with doses of 40-80 IU being administered intramuscularly every 8-12 hours as needed.6 While originally presumed to treat acute gout by stimulating cortisol synthesis, it has since been discovered that ACTH acts through melanocyte-stimulating hormone receptors to influence inflammation.11 ACTH provides a potential option for patients who cannot receive NSAIDs or colchicine, especially patients with congestive heart failure, renal impairment, or a history of gastrointestinal bleeding.22 Narcotic analgesics (eg, morphine) are effective for short-term relief of severe pain but should only be used as adjunctive therapy because they do not address the inflammation that characterizes a gouty arthritis attack.29 Lowering Uric Acid ULT is indicated for patients with intolerable or debilitating symptoms, signs of progressive gouty arthritis, gouty arthritis in the presence of renal function impairment, or tophaceous gouty arthritis and it is the mainstay of treatment to reduce risk of recurrent attacks, uric acid accumulation, and tophus formation.5,22 The initiation of ULT requires appropriate dose titration and monitoring of sUA.
  8. 8. Adv Ther (2011) 28(9):748-760. 755 The overall goal for the prophylaxis of flares is a target sUA level <6 mg/dL to allow urate crystal dissolution, prevent crystal formation, and consequently reduce the recurrence of flares.22 However, there are often gaps in therapy and nonadherence issues with current medications because the benefits of therapy are not immediately apparent.5 Indirect evidence suggests a causal association between noncompliance with ULT and increasing frequency of flares.30 Thus, patient education about the disease and goals of pharmacologic and nonpharmacologic (ie, diet and lifestyle) treatments are important components of patient management.5 Xanthine oxidase inhibitors, such as allopurinol and febuxostat, reduce the production of uric acid by inhibiting the enzyme that catalyzes the final steps in uric acid synthesis. Allopurinol is indicated for the treatment of patients with gout, including those with acute attacks, tophi, and joint destruction.31 It is not, however, approved for treatment of patients with asymptomatic hyperuricemia. Allopurinol should be initiated at a dose of 100 mg/day then increased in 100 mg increments every week until an sUA goal of 6 mg/dL is reached, without exceeding the maximum daily dose of 800 mg/day.31 In practical terms, dose titration is slower (4-6 weeks) to lower the incidence of flares. Dose reductions are required in patients with renal dysfunction. An increase in the frequency of gout flares during the early stages of allopurinol therapy has been reported and it is consequently advised that prophylactic colchicine be administered concurrently. These attacks generally become less frequent with time; however, it can require up to several months of therapy before uric acid levels are reduced to an extent where attacks are adequately controlled.31 The most common adverse reaction is skin rash.31 Potentially severe, life-threatening reactions, including hypersensitivity, Stevens-Johnson syndrome, generalized vasculitis, irreversible hepatotoxicity, and death, are rare but have been reported; therefore, allopurinol therapy should be immediately discontinued at the first sign of skin rash.31 Drug-drug interactions with allopurinol include mercaptopurine, theophylline, and azathioprine, and doses of these agents should therefore be reduced when considering coadministration with allopurinol.31 Febuxostat is a nonpurine xanthine oxidase inhibitor that is highly selective for xanthine oxidase, sparing other enzymes involved in purine and pyrimidine metabolism.32 It is approved for the management of hyperuricemia in patients with gout, but not for use in those with asymptomatic hyperuricemia.32 Febuxostat should be initiated at a dose of 40 mg once daily, increasing to a maximum of 80 mg once daily if an sUA goal of 6 mg/dL is not achieved within 2 weeks of treatment at the lower dose.32 Given the hepatic metabolism of the drug, dose adjustment is not necessary in patients with mild to moderate renal impairment (ie, creatinine clearance [CrCl] 30-89 mL/min).32 In the CONfirmation of Febuxostat In Reducing and Maintaining Serum urate (CONFIRMS) study,33 significantly more patients receiving febuxostat 80 mg/day achieved an sUA goal <6.0 mg/ dL at their final clinic visit (treatment duration was a maximum of 6 months) compared with patients receiving febuxostat 40 mg/day or allopurinol 200-300 mg/day (67.1% vs 45.2% or 42.1%, respectively, P<0.001). Overall, tolerability between treatment arms was similar with 3.7% of patients receiving febuxostat 80 mg/day experiencing a serious adverse event compared with 2.5% and
  9. 9. 756 Adv Ther (2011) 28(9):748-760. 4.1% of those receiving febuxostat 40 mg/day or allopurinol 200-300 mg/day, respectively.33 In general, febuxostat has a relatively benign toxicity profile with abnormal liver function tests, nausea, and arthralgia representing the most frequently reported adverse events.32,33 Febuxostat is contraindicated in patients undergoing treatment with azathioprine or mercaptopurine, and its efficacy in patients with severe renal or hepatic impairment has yet to be established.32 Similar to other ULTs, prophylactic colchicine or NSAID treatment is recommended with febuxostat for the first 6 months to reduce incidence of flares.32 Probenecid is a potent uricosuric drug indicated for the treatment of hyperuricemia associated with gout and gouty arthritis,34 and it is largely considered as an alternative to allopurinol.22,34 Treatment with probenecid should not be started in patients while they are experiencing a gouty attack, but therapy may be continued in those receiving probenecid before the onset of an attack.34 Prophylactic colchicine or alternative symptomatic therapy also is advised because of the risk of exacerbation during the early stages of therapy.34 Overall, probenecid is considered less effective than allopurinol.22 The recommended dose is 250 mg twice daily for 1 week and 500 mg twice daily thereafter. In patients with renal impairment and uncontrolled symptoms or 24 hour uric acid excretion <700 mg, doses can be increased in 500 mg/day increments every 4 weeks to a maximum of 2000 mg/day. Probenecid may not be effective in patients with CrCl ≤30 mL/min.34 Hydration is recommended, and sodium bicarbonate (3-7.5 g/day) or potassium citrate (7.5 g/day) should also be administered to maintain urine alkalization and mitigate the risk for uric acid stone formation, hematuria, renal colic, or costovertebral pain arising due to increased uric acid clearance. Other adverse events associated with probenecid therapy include headache, dizziness, hepatic necrosis, nausea, and vomiting.34 Pegloticase is a pegylated uricase uric acid- lowering enzyme that was recently approved by the FDA for the treatment of chronic gout in adult patients refractory to conventional therapy (ie, those who have failed to normalize sUA and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated).35 The recommended dosing of pegloticase in adults is 8 mg administered as an intravenous infusion every 2 weeks, although optimal treatment duration has not yet been established. Randomized, controlled trials have demonstrated that pegloticase can substantially reduce plasma uric acid levels below 6 mg/dL35 and resolve tophi.36 For example, in the phase 3 clinical trials (GOUT1 and GOUT2) for pegloticase, complete tophus resolution (defined as a complete resolution of ≥1 tophus and no increase in size of any other tophus or appearance of new ones) was significantly higher in patients receiving an 8 mg infusion of pegloticase every 2 weeks compared with placebo (41% vs. 7%, respectively, P=0.002).36 The most common adverse events are infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis, and vomiting.35 In addition, it should be noted that the risk of infusion reactions and anaphylaxis is significant enough to warrant the inclusion of a black box warning on the pegloticase prescribing information. It is also a requirement for patients to be medicated with antihistamines and corticosteroids before treatment.35 A significant portion of patients developed antibodies to pegloticase and this was associated with a higher rate of treatment failure and infusion reactions.35
  10. 10. Adv Ther (2011) 28(9):748-760. 757 NEWLY EMERGING THERAPIES AND NEW AREAS OF DEVELOPMENT IN THE MANAGEMENT OF GOUTY ARTHRITIS Given the currently available therapies, there is a continuing need for new treatment options in gouty arthritis. Several novel agents are in various stages of clinical development, driven by our increased understanding about the role of proinflammatory mediators in gouty arthritis. For example, it is known that the phagocytosis of urate crystals by monocytes and macrophages in the synovial lining can result in the formation/ activation of the inflammasome, a cytosolic complex that drives the activation of IL-1beta, an important mediator of inflammatory response (Figure 1).1,12 IL-1beta then drives the generation of other proinflammatory cytokines such as IL-8, tumor necrosis factor, and IL-6.1 These various inflammatory mediators recruit inflammatory cells, mainly neutrophils and monocytes, to the synovium, where they release other factors that may further the inflammatory cascade.1 Anakinra, a recombinant, synthetic IL-1 receptor antagonist that has been reported in case series to be effective in patients with acute gouty arthritis or acute urate crystal-induced arthritis and who are failing conventional therapy.37,38 However, the data for anakinra are limited, the efficacy is variable, and relapse is common.38 Further, the short half-life of the drug means that daily injections are required. Rilonacept is a soluble receptor-Fc fusion protein inhibitor of IL-1alpha and IL-1beta that has also been studied in gouty arthritis.39 A proof-of- concept study conducted in 10 patients with gouty arthritis suggested benefit in reducing pain in patients with chronic refractory gouty arthritis.39 Canakinumab is a fully human anti- IL-1beta monoclonal antibody with a half-life of 21-28 days.40 In a phase 2 dose-ranging study, canakinumab was associated with significantly greater pain relief and a greater reduction in the risk of recurrent flares compared with triamcinolone acetonide in patients with acute gouty arthritis.40 Although IL-1beta appears to be an important target in gouty arthritis, agents that interfere with IL-1beta have been associated with an increased risk of infection. Data from additional randomized controlled trials will help provide a Figure 1. Model of the gouty arthritis inflammatory process.1 MSU=monosodium urate crystals; PR3=proteinase-3; ROS=reactive oxygen species; TRX=thioredoxin; TXNIP=thioredoxin-interacting protein. Reprinted with kind permission from Springer Science+Business Media: Curr Rheumatol Rep. 2010:12(2):135-141, Martinon F, Figure 1, © Springer Science+Business Media, LLC 2010.
  11. 11. 758 Adv Ther (2011) 28(9):748-760. better understanding regarding the benefit-risk profile of these agents in gouty arthritis. Caspase-1 inhibitors have been investigated in clinical trials for possible use in auto- inflammatory syndromes.11 Caspase-1 is involved in the conversion of pro-IL-1beta to active IL-1beta within the core of the inflammasome.11 Melanocyte-stimulating hormone receptor agonists (eg, adrenocorticotropic hormone [ACTH]) have long been presumed to be a treatment approach for acute gouty arthritis by stimulating cortisol synthesis and modulating inflammation.11 Therefore, selective melanocyte- stimulating hormone receptor agonists might be useful in treating gouty arthritis while avoiding glucocorticoid effects. Recent studies have identified the urate transporter 1, an organic ion transporter, as a major uric acid reuptake engine in the renal tubule.11 RDEA594, the most recent inhibitor of urate transporter 1 to be investigated, appears to be well tolerated, has no serious adverse events, and is effective in lowering sUA.11 Other approaches to be pursued include inhibition of other targets in the macrophage IL-1beta-generating pathway.11 CONCLUSION Gouty arthritis is a metabolic disorder that produces arthritic inflammation and is associated with substantial clinical, functional, economic, and quality-of-life burdens. Management of the disease is complicated by comorbidities and the adverse events, drug interactions, and contraindications associated with various therapeutic modalities. Numerous treatment options are available, with several more under development. A thorough understanding of the pathogenesis, diagnosis, and treatment of acute gouty arthritis will enable primary care practitioners to individualize management regimens so that patient outcomes are optimized. ACKNOWLEDGMENTS Editorial assistance for this manuscript was funded by Novartis Pharmaceuticals Corporation and provided by Santo D’Angelo, PhD, MS, of ApotheCom. The author had full control of the contents, and the opinions expressed here are those of the author and not of Novartis Pharmaceuticals Corporation. Prashanth Sunkreddi is a Speaker/Consultant for Novartis, UCB, Bristol-Myers Squibb, and Pfizer. Prashanth Sunkureddi is the guarantor for this article, and takes responsibility for the integrity of the work as a whole. REFERENCES 1. Martinon F. Update on biology: uric acid and the activation of immune and inflammatory cells. Curr Rheumatol Rep. 2010;12:135-141. 2. Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Res Ther. 2006;8(suppl. 1):S1. 3. Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008;75(suppl. 5):S5-S8. 4. Eggebeen AT. Gout: an update. Am Fam Physician. 2007;76:801-808. 5. Becker MA, Ruoff GE. What do I need to know about gout? J Fam Pract. 2010;59(suppl. 6):S1-S8. 6. Keith MP, Gilliland WR. Updates in the management of gout. Am J Med. 2007;120:221-224. 7. Zhu Y, Pandya B, Choi H. Increasing gout prevalence in the US over the last two decades: The National Health and Nutrition Examination Survey (NHANES). Arthritis Rheum. 2010;62:S901-S902. 8. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;8(suppl. 1):S2. 9. Lee SJ, Hirsch JD, Terkeltaub R, et al. Perceptions of disease and health-related quality of life among patients with gout. Rheumatology (Oxford). 2009;48:582-586.
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