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My Treatment Approach to Gout

      Abstract

      Gout is the most common form of inflammatory arthritis in the United States. Nevertheless, gout remains misunderstood, misdiagnosed, underdiagnosed, and undertreated. Several new recommendation and guideline documents regarding the management of gout have been published in the past few years. New diagnostic modalities, such as ultrasound and dual-energy computed tomography, are now available. Newer treatment options exist, and older agents and their interactions are now better understood. This review addresses these recent diagnostic and therapeutic developments and describes our management protocol with the aim of providing the clinician with a pragmatic approach to gout management.

      Abbreviations and Acronyms:

      ACR (American College of Rheumatology), CAD (coronary artery disease), CKD (chronic kidney disease), CVD (cardiovascular disease), DECT (dual-energy computed tomography), EULAR (European League Against Rheumatism), GFR (glomerular filtration rate), IL-1 (interleukin-1), MSU (monosodium urate), MTP (metatarsophalangeal), NSAID (nonsteroidal anti-inflammatory drug), ULT (urate-lowering therapy), US (ultrasound), XOI (xanthine oxidase inhibitor)
      Gout is the most common form of inflammatory arthritis in the United States, affecting 4% of the population,
      • Zhu Y.
      • Pandya B.J.
      • Choi H.K.
      Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008.
      and its prevalence has been increasing.
      • Roddy E.
      • Doherty M.
      Epidemiology of gout.
      Its prevalence has also increased in other countries, which has been attributed to a westernized lifestyle, more comorbidities, and improved life expectancy.
      • Choi H.K.
      • Mount D.B.
      • Reginato A.M.
      American College of Physicians, American Physiological Society
      Pathogenesis of gout.
      Most patients with gout are obese and have coexisting hypertension and renal disease.
      • Zhu Y.
      • Pandya B.J.
      • Choi H.K.
      Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008.
      Unfortunately, gout remains misdiagnosed, underdiagnosed, and undertreated.
      • Doherty M.
      • Jansen T.L.
      • Nuki G.
      • et al.
      Gout: why is this curable disease so seldom cured?.
      • Kuo C.F.
      • Grainge M.J.
      • Mallen C.
      • Zhang W.
      • Doherty M.
      Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study.
      • Roddy E.
      • Zhang W.
      • Doherty M.
      Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations.
      • Kuo C.F.
      • Grainge M.J.
      • Mallen C.
      • Zhang W.
      • Doherty M.
      Eligibility for and prescription of urate-lowering treatment in patients with incident gout in England.
      New guidelines and recommendations have addressed the diagnosis and treatment of gout.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      Advances have been made in the diagnostic imaging of gout with ultrasound (US) and dual-energy computed tomography (DECT). More data on older medications are now available, and new medications have been approved to treat gout.
      • Hoy S.M.
      Lesinurad: first global approval.
      The care of most patients with gout is managed by primary care providers; less than 10% of patients are referred to rheumatologists.
      • Pal B.
      • Foxall M.
      • Dysart T.
      • Carey F.
      • Whittaker M.
      How is gout managed in primary care? a review of current practice and proposed guidelines.
      This review addresses the recent diagnostic and therapeutic developments, guidelines, and recommendations, along with our management protocol. We aim to provide the clinician with a pragmatic approach to gout management.

      Making a Diagnosis

      Confirmation of monosodium urate (MSU) crystals on polarized microscopy is the gold standard for diagnosis of gout. The presence of intracellular crystals is diagnostic of an acute flare, although extracellular crystals can exist in the synovial fluid between attacks. A red, hot, and swollen great toe may be the most common presentation of acute gout; however, gout does not always present in this manner. The possibility of gout in nonmetatarsophalangeal joints and a polyarticular presentation must always be considered.

       Diagnosis by Criteria

      Gout is usually diagnosed clinically because most patients are seen in primary care practices, where lack of facilities and time hamper synovial fluid aspiration. For example, arthrocentesis was performed in only 8% of patients with suspected gout first seen in an emergency department,
      • Schlesinger N.
      • Radvanski D.C.
      • Young T.C.
      • McCoy J.V.
      • Eisenstein R.
      • Moore D.F.
      Diagnosis and treatment of acute gout at a university hospital emergency department.
      and it is unlikely that the use of arthrocentesis will increase substantially in the immediate future. Because of these real-world limitations, a diagnostic rule for acute gout was proposed and then validated for primary care settings.
      • Janssens H.J.
      • Fransen J.
      • van de Lisdonk E.H.
      • van Riel P.L.
      • van Weel C.
      • Janssen M.
      A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis.
      • Kienhorst L.B.
      • Janssens H.J.
      • Fransen J.
      • Janssen M.
      The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study.
      Seven clinical variables were used in the calculation (Table 1). Caveats to note are that the study included only monoarticular arthritis, and the diagnoses were dependent on the evaluating physician's expertise. Therefore, atypical presentations may have been missed.
      Table 1Diagnostic Rule in Patients With Monoarthritis
      a CVD = cardiovascular disease; MTP = metatarsophalangeal.
      ,
      b SI conversion factor: To convert serum uric acid values to μmol/L, multiply by 59.485.
      VariablePoints
      Male sex2
      Previous arthritis attack2
      Onset within 1 d0.5
      Joint erythema1
      First MTP joint involved2.5
      Hypertension or ≥1 CVD variable1.5
      Serum uric acid >5.88 mg/dL3.5
      CategoryTotal points
      95% of patients do not have gout. Consider alternative diagnoses.≤4
      Insufficient basis for diagnosis. Consider arthrocentesis if possible; otherwise, careful follow-up.5-7
      85% of patients have gout.≥8
      a CVD = cardiovascular disease; MTP = metatarsophalangeal.
      b SI conversion factor: To convert serum uric acid values to μmol/L, multiply by 59.485.
      The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have also proposed clinical classification criteria for gout because of the low utilization of synovial analysis (these classification criteria are not intended to be diagnostic criteria).
      • Neogi T.
      • Jansen T.L.
      • Dalbeth N.
      • et al.
      2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
      The ACR/EULAR criteria have as an entry criterion the occurrence of acute arthritis in a peripheral joint or bursa, such as the metatarsophalangeal (MTP), ankle, or olecranon bursa. The presence of MSU crystals in synovial fluid was determined by ACR/EULAR to be a sufficient criterion to establish a diagnosis without further scoring. When synovial fluid is not available, clinical features, serum uric acid level, and imaging findings (US and DECT) are used to make the diagnosis. The ACR/EULAR calculator has sensitivity of 92% and specificity of 89% and is accessible at http://goutclassificationcalculator.auckland.ac.nz.
      When time, resources, or both are limited, these criteria (ACR/EULAR and the diagnostic rule) may be useful to identify gout. Atypical presentations or lack of response to treatment should trigger comprehensive testing, including synovial fluid aspiration, use of US or DECT, closer patient follow-up, or referral to a rheumatologist, or a combination. If an infection is considered, whether alone or concomitantly with gout, synovial fluid aspiration must be performed by a qualified individual, and appropriate referrals must be made. A diagnosis of gout should always be considered in any person with an atypical, seronegative inflammatory arthritis. Examining the synovial fluid for crystals should be an essential step in the evaluation of any inflammatory arthritis.

       Hyperuricemia and Gout

      Not all patients with hyperuricemia develop gout. In the United States, 21% of the population have hyperuricemia, and 4% have gout.
      • Zhu Y.
      • Pandya B.J.
      • Choi H.K.
      Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008.
      The 5-year cumulative incidence of gout was 0.5% in men with uric acid levels of 6 mg/dL or less (to convert to μmol/L, multiply by 59.485) and 30.5% in those with levels of 10 mg/dL or higher.
      • Campion E.W.
      • Glynn R.J.
      • DeLabry L.O.
      Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study.
      Uric acid levels may fluctuate and possibly decrease during an acute episode, but if normal, measuring uric acid 2 to 3 weeks after an acute attack has resolved will provide an accurate baseline and may aid in establishment of the diagnosis.
      • Logan J.A.
      • Morrison E.
      • McGill P.E.
      Serum uric acid in acute gout.
      • Schlesinger N.
      • Norquist J.M.
      • Watson D.J.
      Serum urate during acute gout.
      Acute gout cannot be excluded by the presence of a normal serum urate level.

       Gout in Women and Young Persons

      Estrogen protects women from gout because of its association with enhanced renal excretion of uric acid,
      • Nicholls A.
      • Snaith M.L.
      • Scott J.T.
      Effect of oestrogen therapy on plasma and urinary levels of uric acid.
      and estrogen in hormone replacement therapy has a similar effect.
      • Sumino H.
      • Ichikawa S.
      • Kanda T.
      • Nakamura T.
      • Sakamaki T.
      Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia.
      Gout occurs in only 0.2 per 1000 cases of women younger than 45 years.
      Centers for Disease Control and Prevention, National Center for Health Statistics
      Vital and health statistics: current estimates from the National Health Interview Survey, 1996.
      Women with gout tend to be older and have more comorbidities, such as obesity and kidney disease, compared with men. Diuretic use as opposed to dietary triggers is more common in women than in men with gout.
      • Harrold L.R.
      • Etzel C.J.
      • Gibofsky A.
      • et al.
      Sex differences in gout characteristics: tailoring care for women and men.
      Elderly women, particularly those taking diuretic agents, may have an initial polyarticular presentation, upper extremity–dominant disease, or tophi that may be confused with rheumatoid nodules.
      • De Souza A.
      • Fernandes V.
      • Ferrari A.J.
      Female gout: clinical and laboratory features.
      • Neogi T.
      Gout.
      Tophi may also be present in Heberden nodes.
      Approximately 25% of patients with gout have a family history. However, in patients with early-onset gout (age <25 years), 80% have a family member with gout.
      • Edwards N.L.
      Clinical gout.
      These patients should be referred to a rheumatologist for further evaluation and management.

      Role of Imaging

       Radiography and Computed Tomography

      Radiographs usually have negative findings but can be used to rule out fractures. Disease 5 to 10 years
      • Bloch C.
      • Hermann G.
      • Yu T.F.
      A radiologic reevaluation of gout: a study of 2,000 patients.
      after onset may show tophi and typical erosions, called rat bite erosions, which have overhanging edges.
      • McQueen F.M.
      • Doyle A.
      • Dalbeth N.
      Imaging in the crystal arthropathies.
      Joint space is preserved until later in the course of the disease. Conventional computed tomography is not used in the routine diagnosis of gout, but it is excellent for identifying erosions.
      • Parathithasan N.
      • Lee W.K.
      • Pianta M.
      • Oon S.
      • Perera W.
      Gouty arthropathy: review of clinico-pathologic and imaging features.

       Ultrasonography

      Ultrasound is a well-accepted, safe, noninvasive, nonionizing, portable, and relatively inexpensive imaging modality. Typical sonographic findings in gout are the double-contour sign, tophi, and the snowstorm sign. Ultrasound is more sensitive than radiography for identifying erosions.
      • Chowalloor P.V.
      • Keen H.I.
      A systematic review of ultrasonography in gout and asymptomatic hyperuricaemia.
      A meta-analysis showed that pooled sensitivity and specificity for the double-contour sign on US were 83% and 76%, respectively, and for tophi, 65% and 80%, respectively.
      • Ogdie A.
      • Taylor W.J.
      • Weatherall M.
      • et al.
      Imaging modalities for the classification of gout: systematic literature review and meta-analysis.
      Results of a large multicenter study showed more than 90% specificity for US in clinically symptomatic joints, and specificity remained high in cases without tophi, MTP swelling, or tenderness.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      Ultrasound is useful in the evaluation of acute monoarticular or oligoarticular disease. In 1 long-term study of arthritis in the first MTP, the initial impression was gout in 98% of the patients, but only 77% were confirmed to have gout. Thus, although the MTP is the most common joint involved and may appear to have gout, gout is not always the correct diagnosis.
      • Kienhorst L.B.
      • Janssens H.J.
      • Fransen J.
      • van de Lisdonk E.H.
      • Janssen M.
      Arthritis of the first metatarsophalangeal joint is not always gout: a prospective cohort study in primary care patients.
      Ultrasound also facilitates assessing the effectiveness of urate-lowering therapy (ULT) because the tophi and double-contour sign regress with successful treatment.
      • Ottaviani S.
      • Gill G.
      • Aubrun A.
      • Palazzo E.
      • Meyer O.
      • Dieude P.
      Ultrasound in gout: a useful tool for following urate-lowering therapy.
      Ultrasound is a valuable tool for guiding arthrocentesis of synovial fluid. In 1 study of primary care internists, US-guided aspiration was successful in 93% vs 52% of patients when palpation was used.
      • Greenlund L.J.
      • Ward W.J.
      Use of ultrasound by internists to improve diagnostic small joint aspiration.
      Ultrasound also facilitates local corticosteroid injections into an affected joint. Also, US guidance can be used for dry needling, a technique used for aspirating MSU crystals in an asymptomatic joint in a patient without a synovial effusion but with suspected gout.
      • Slot O.
      • Terslev L.
      Ultrasound-guided dry-needle synovial tissue aspiration for diagnostic microscopy in gout patients presenting without synovial effusion or clinically detectable tophi.
      The double-contour sign should be differentiated from a cartilage-interface sign, which is dependent on the angle of insonation. In 1 study, 29% of patients with asymptomatic hyperuricemia had evidence of MSU deposition.
      • Howard R.G.
      • Pillinger M.H.
      • Gyftopoulos S.
      • Thiele R.G.
      • Swearingen C.J.
      • Samuels J.
      Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: concordance between readers.
      However, patients with gout tend to have more erosions and synovitis than asymptomatic patients with hyperuricemia and MSU deposition.
      • Stewart S.
      • Dalbeth N.
      • Vandal A.C.
      • Allen B.
      • Miranda R.
      • Rome K.
      Ultrasound features of the first metatarsophalangeal joint in gout and asymptomatic hyperuricaemia: comparison with normouricaemic individuals.
      Some concern has been expressed about differentiating gout from calcium pyrophosphate deposition disease; however, recent findings showed that the double-contour sign and tophi retain high specificity and allow for differentiation between the 2 diagnoses.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      Although US is a convenient tool for assessing gout, it does not replace arthrocentesis as the test of choice.
      • Zufferey P.
      • Valcov R.
      • Fabreguet I.
      • Dumusc A.
      • Omoumi P.
      • So A.
      A prospective evaluation of ultrasound as a diagnostic tool in acute microcrystalline arthritis.
      It also does not exclude a diagnosis of infection, which requires clinical judgment and arthrocentesis. The use of US should increase because more programs now offer training in US as a part of graduate medical education.
      • Berko N.S.
      • Goldberg-Stein S.
      • Thornhill B.A.
      • Koenigsberg M.
      Survey of current trends in postgraduate musculoskeletal ultrasound education in the United States.
      However, its point-of-care availability, time constraints for the provider performing the procedure, availability of US-trained providers or radiologists, and a sonographer's skill may be limiting factors in a general community practice.

       Dual-Energy Computed Tomography

      DECT is based on the principle of different attenuation of substances being dependent on their density, atomic number, and photon beam energy. Exposure to 2 different photon beam energies allows differentiation of substances.
      • Omoumi P.
      • Becce F.
      • Racine D.
      • Ott J.G.
      • Andreisek G.
      • Verdun F.R.
      Dual-energy CT: basic principles, technical approaches, and applications in musculoskeletal imaging (part 1).
      Regarding MSU deposition, DECT is as sensitive as US for the lower extremity and more sensitive than US for the upper extremity, the latter perhaps due to more complex anatomy that may not be easily accessible by US.
      • Zhu L.
      • Wu H.
      • Wu X.
      • et al.
      Comparison between dual-energy computed tomography and ultrasound in the diagnosis of gout of various joints.
      DECT can image MSU deposits in anatomically inaccessible areas, such as tendons, which are not easily amenable to aspiration. DECT identified gout in 30% of patients who had negative results for crystals in synovial fluid because the MSU deposition was not intra-articular.
      • Bongartz T.
      • Glazebrook K.N.
      • Kavros S.J.
      • et al.
      Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study.
      Also, DECT will identify any underlying erosions but not any coexisting synovitis.
      DECT and US compare well. In 1 study, DECT and US were comparable, but some false-negative results were associated with DECT. In this study, there was 85.7% concordance between synovial fluid analysis and DECT findings.
      • Gruber M.
      • Bodner G.
      • Rath E.
      • Supp G.
      • Weber M.
      • Schueller-Weidekamm C.
      Dual-energy computed tomography compared with ultrasound in the diagnosis of gout.
      Another study reported DECT to be more specific than US, although small deposits were not always identified.
      • Huppertz A.
      • Hermann K.G.
      • Diekhoff T.
      • Wagner M.
      • Hamm B.
      • Schmidt W.A.
      Systemic staging for urate crystal deposits with dual-energy CT and ultrasound in patients with suspected gout.
      DECT was also not useful for diagnosing acute, new-onset disease or for diagnosing gout when advanced osteoarthritis was present in knee joints.
      • Bongartz T.
      • Glazebrook K.N.
      • Kavros S.J.
      • et al.
      Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study.
      DECT was found to have 64% sensitivity for detecting nontophaceous gout and 100% for overt tophi.
      • Baer A.N.
      • Kurano T.
      • Thakur U.J.
      • et al.
      Dual-energy computed tomography has limited sensitivity for non-tophaceous gout: a comparison study with tophaceous gout.
      However, artifacts mimicking MSU crystals may occur around nail deposits with DECT.
      • Glazebrook K.N.
      • Guimaraes L.S.
      • Murthy N.S.
      • et al.
      Identification of intraarticular and periarticular uric acid crystals with dual-energy CT: initial evaluation.
      In addition, the sensitivity was lower when DECT was used solely for clinically symptomatic joints. DECT may also miss tophi that lack density,
      • Melzer R.
      • Pauli C.
      • Treumann T.
      • Krauss B.
      Gout tophus detection: a comparison of dual-energy CT (DECT) and histology.
      and machine parameter settings can produce false-negative results.

       Advanced Imaging: Summary

      No perfect imaging modality exists for diagnosing gout.
      • Durcan L.
      • Grainger R.
      • Keen H.I.
      • Taylor W.J.
      • Dalbeth N.
      Imaging as a potential outcome measure in gout studies: a systematic literature review.
      The choice of imaging type may be governed by availability and experience of available operators and the clinical context. Both US and DECT are considered in the ACR/EULAR classification criteria for gout diagnosis. However, they provide evidence of MSU deposition only (unless coexisting synovitis and erosions seen on US and erosions seen on DECT suggest more active disease), and this finding must be interpreted in the context of the clinical situation to make a diagnosis of gout. It is not our practice or recommendation to image every patient with suspected gout with US or DECT to detect MSU deposition but to use it when there is diagnostic uncertainty or lack of treatment response. Initially, when used, US may be the preferred method because of its lower cost, better availability, and lack of associated radiation.
      • Parathithasan N.
      • Lee W.K.
      • Pianta M.
      • Oon S.
      • Perera W.
      Gouty arthropathy: review of clinico-pathologic and imaging features.
      • Zhu L.
      • Wu H.
      • Wu X.
      • et al.
      Comparison between dual-energy computed tomography and ultrasound in the diagnosis of gout of various joints.
      In contrast, DECT is limited by higher cost, radiation, restricted availability, and lack of portability. Also, US and DECT can be used synergistically to identify patients with hydroxyapatite deposition.
      • Aslam F.
      • Matteson E.L.
      Polyarthritis as a rare presentation of hydroxyapatite deposition disease.
      Table 2 gives suggestions for choosing DECT vs US.
      Table 2Choice of Advanced Imaging Technique
      a Choices are not mutually exclusive.
      UltrasoundDual-energy computed tomography
      Recent-onset acute diseaseNonacute disease
      Easily accessible anatomical locationInaccessible anatomical areas/complex anatomy
      Single-joint diseaseMulti-joint disease/assessment of disease burden
      Guidance for diagnostic aspirationNo identifiable target for aspiration
      Dry needling guidance for diagnosisUnsuccessful aspiration
      Guidance for therapeutic injectionResistant disease and unconfirmed diagnosis or atypical disease
      Differentiation between soft-tissue masses (eg, tophus vs rheumatoid nodule)Women with Bouchard and Heberden nodes with suspicion of underlying gout
      Patient wants to avoid exposure to radiationPatient has chronic inflammatory arthritis. Concern for underlying or coexisting gout
      a Choices are not mutually exclusive.

       Some Thoughts on Diagnosing Gout

      Ideally, a diagnosis of gout should be confirmed by synovial fluid analysis. Realistically, this may not be possible in many practices, and we encourage using the ACR/EULAR approach for making a clinical diagnosis. In our practice, we strive to obtain a synovial analysis whenever possible by using US guidance, if necessary. If not, we ask the patient to contact us during an acute flare for an evaluation and arthrocentesis.

      Indications for Treatment

      Patients who have 2 or more acute attacks per year, the presence of palpable tophi or tophi confirmed by radiography, stage 2 or greater chronic kidney disease (CKD), or a history of urolithiasis merit treatment for hyperuricemia according to the ACR guidelines.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      Also, ULT could be considered in patients who have gout at a younger age (<40 years), uric acid levels higher than 8 mg/dL, or coexisting diseases such as hypertension, cardiovascular disease (CVD), or heart failure according to the EULAR recomendations.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      This recommendation was based on evidence-based studies reporting gout-related increases in CVD mortality and kidney impairment. In contrast, recent guidelines from the American College of Physicians recommended against initiating ULT for patients with fewer than 2 attacks per year or in patients after their first gout attack and suggest a treat-to-avoid-symptoms strategy.
      • Qaseem A.
      • Harris R.P.
      • Forciea M.A.
      Clinical Guidelines Committee of the American College of Physicians
      Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians.
      However, evidence does not exist to support the latter, and these recommendations have been opposed by the rheumatology community.
      • Neogi T.
      • Mikuls T.R.
      To treat or not to treat (to target) in gout.
      We do not advocate a treat-to-avoid-symptoms strategy unless a patient declines ULT or it is contraindicated because this strategy ignores the consequences of ongoing urate deposition, negates an understanding of pathophysiology, and discounts years of clinical experience. The patient should be involved in deciding the level of treatment aggressiveness. Treatment for asymptomatic hyperuricemia is not currently recommended, pending further evidence, although Japanese guidelines recommend treating such patients.
      • Yamanaka H.
      Japanese Society of Gout and Nucleic Acid Metabolism
      Japanese guideline for the management of hyperuricemia and gout: second edition.

      Principles of Management

      Gout management has 3 principles: treatment of acute attacks, prevention of gout flares, and treatment of hyperuricemia. The choice of medication is dictated by the coexisting medical conditions.

       Acute Attack Management

      Medications for managing an acute attack include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids. For most patients, these medications relieve 50% of symptoms.
      • Terkeltaub R.
      Clinical gout.
      For maximal effectiveness, therapy should be initiated early, preferably within 24 hours of an acute attack onset. Ice, applied topically, is a useful adjunct. Ongoing ULT should not be interrupted. Figure 1 gives a general overview of our protocol of acute gout management.
      Figure thumbnail gr1
      Figure 1Acute gout management. CAD = coronary artery disease; CKD = chronic kidney disease; CYP 3A4 = cytochrome P450 3A4; IL-1 = interleukin-1; NSAID = nonsteroidal anti-inflammatory drug; ULT = urate-lowering therapy.
      No particular NSAID or cyclooxygenase inhibitor is preferred over another. Naproxen, indomethacin, and sulindac have been approved for treatment of acute episodes of gout.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      In resistant or severe cases, a drug from a different class should be added. Combination therapy with 2 different classes of agents should be initiated in the case of a severe attack or for polyarticular disease (≥4 joints).
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      Combinations of an NSAID and an oral corticosteroid should be avoided owing to the additive adverse effects. However, intra-articular corticosteroids may be used in combination with any class of drugs. Typically, NSAIDs are given at the full dose for the first 3 days of the acute attack and then at a lower dose over 4 to 7 days, tailored as per the clinical response (eg, naproxen, 750-1000 mg daily for 3 days and then 500-750 mg for 4-7 days).
      • Terkeltaub R.
      Clinical gout.
      Studies have found that indomethacin and naproxen have equivalent efficacy to prednisone (35 mg/d) over a short course, although NSAIDs may have more adverse effects.
      • Janssens H.J.
      • Janssen M.
      • van de Lisdonk E.H.
      • van Riel P.L.
      • van Weel C.
      Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial.
      • Man C.Y.
      • Cheung I.T.
      • Cameron P.A.
      • Rainer T.H.
      Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial.
      A recent randomized controlled trial comparing prednisone with indomethacin in the emergency department reported similar clinical effectiveness for the treatment of acute gout.
      • Rainer T.H.
      • Cheng C.H.
      • Janssens H.J.
      • et al.
      Oral prednisolone in the treatment of acute gout: a pragmatic, multicenter, double-blind, randomized trial.
      This finding supports the use of prednisone as a first-line agent when adverse effects concerns or contraindications preclude the use of NSAIDs. NSAIDs should be avoided in patients with CKD, coronary artery disease, or gastroesophageal reflux disease and in those taking oral anticoagulants. Prophylaxis with a proton pump inhibitor may be needed. Cyclooxygenase inhibitor therapy may be used in carefully selected patients. When any of these medications are prescribed, a patient's blood cell count and renal and hepatic function should be assessed periodically.
      Prednisone is the prototypical corticosteroid used for acute gout management. It can be administered in several ways. One schedule is 30 to 35 mg daily for 5 days.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      For severe cases, a dose of 0.5 mg/kg for 5 to 10 days may be used and then stopped without tapering.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      This higher dose may also be used for individuals with a high body mass index. Another regimen is 30 to 60 mg daily for 2 days and then tapering by 5 to 10 mg every 2 days, for a total of 10 to 14 days.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      Methylprednisolone dose packs may also be prescribed. When 1 or 2 joints are involved, intra-articular corticosteroids may be considered. We use methylprednisolone for injection of small or superficial joints and triamcinolone for larger joints, such as the knee or ankle. Clinical judgment should be exercised with respect to the possibility of septic arthritis in a joint, and fluid should be sent for analysis as well as a Gram stain and bacterial culture. If the findings are equivocal, an arthrocentesis should be performed to exclude infection, and a corticosteroid should be injected 48 hours later provided that the cultures show negative findings. Patients with a nothing-by-mouth instruction can be given intra-articular injections, intramuscular triamcinolone (60 mg), intravenous methylprednisolone (0.5-2 mg/kg), or subcutaneous adrenocorticotropic hormone (25-40 IU), with dosing repeated as clinically indicated.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      Glucocorticoids must be used with caution for patients with congestive heart failure, diabetes mellitus, and hypertension. Reflux prophylaxis should be considered, and if it is used long-term, osteoporosis prevention should be pursued. For patients with heart failure (particularly symptomatic or decompensated), dexamethasone may be used because of its lower mineralocorticoid effect.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      Colchicine for an acute gout episode is given at a dose of 1.2 mg, followed by another dose of 0.6 mg in 1 hour. After 12 hours, 0.6 mg can be given once or twice daily until the flare resolves.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      This regimen is as effective as the former, standard high-dose regimen and has fewer associated adverse effects.
      • Terkeltaub R.A.
      • Furst D.E.
      • Bennett K.
      • Kook K.A.
      • Crockett R.S.
      • Davis M.W.
      High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study.
      This newer regimen is most effective if used within 36 hours of the onset of the acute attack.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      It may not be effective if the flare has been ongoing for 72 hours or more, and it should be continued for the duration of the flare. Patients with established gout who are educated about their disease can use the pill-in-the-pocket strategy, where they self-administer colchicine at the earliest sign of a flare.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      It is imperative to look for comorbid conditions and concomitant medications in gout management in general and with colchicine use in particular. One study reported that one-third of patients taking colchicine had 1 contraindication to it, and more than 90% had at least 1 contraindication to NSAIDs.
      • Keenan R.T.
      • O'Brien W.R.
      • Lee K.H.
      • et al.
      Prevalence of contraindications and prescription of pharmacologic therapies for gout.
      The safety of colchicine in patients with a glomerular filtration rate (GFR) less than 30 mL/min has not been established; thus, for those patients, colchicine is best avoided.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      The most commonly reported adverse effect is gastrointestinal toxicity. Bone marrow suppression, cardiac toxicity, and arrhythmias can also occur. Myotoxicity is rare but a particular problem in patients undergoing transplant and taking colchicine. Periodic creatine kinase monitoring should be considered for patients whose GFR is less than 50 mL/min.
      • Mikuls T.R.
      • MacLean C.H.
      • Olivieri J.
      • et al.
      Quality of care indicators for gout management.
      Enhanced myotoxicity can occur with concomitant statin use.
      • Finkelstein Y.
      • Aks S.E.
      • Hutson J.R.
      • et al.
      Colchicine poisoning: the dark side of an ancient drug.
      Recent recommendations from the American Heart Association suggested careful monitoring for muscle-related toxicity when statins and colchicine are given together, and dose reductions of simvastatin, atorvastatin, and lovastatin may need to be considered.
      • Wiggins B.S.
      • Saseen J.J.
      • Page II, R.L.
      • et al.
      Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association.
      A patient with renal insufficiency taking a statin drug may be at higher risk for such toxicity. Vigilance should also be exercised in patients with underlying hepatic disease.
      Several drugs interact with colchicine. Colchicine should not be given or should have the dosage reduced in patients taking a concomitant P-glycoprotein or a moderate to strong inhibitor of cytochrome P450 3A4. These agents include cyclosporine, tacrolimus, clarithromycin, erythromycin, verapamil, diltiazem, and ketoconazole. Cyclosporine, for example, can cause neuromyopathy within weeks of its use with colchicine.
      • Terkeltaub R.A.
      Colchicine update: 2008.
      In contrast, azithromycin, a macrolide, is safe to use.
      • Terkeltaub R.A.
      • Furst D.E.
      • Digiacinto J.L.
      • Kook K.A.
      • Davis M.W.
      Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors.
      Modified colchicine dosing regimens have been addressed elsewhere.
      • Terkeltaub R.A.
      • Furst D.E.
      • Digiacinto J.L.
      • Kook K.A.
      • Davis M.W.
      Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors.
      The blood cell count and renal and hepatic function should be assessed periodically.
      The interleukin-1 (IL-1) inhibitors anakinra (100 mg for 3 days) and canakinumab (a single 150-mg dose) may be used subcutaneously when the typically prescribed agents are contraindicated.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      Infection is a contraindication to the use of IL-1 inhibitors. The IL-1 inhibitors are safe in renal disease, although anakinra should be given every other day if the patient's creatinine clearance is less than 30 mL/min/1.73 m2 (to convert to mL/s/m2, multiply by 0.0167). However, in clinical practice, the cost and required insurance approvals limit their use. The best use for IL-1 inhibitors currently is for hospitalized patients with acute polyarticular gout where multiple comorbidities contraindicate the use of NSAIDs or systemic corticosteroids.

       Acute Attack Prophylaxis

      Anti-inflammatory prophylaxis is always indicated when initiating ULT because flares are increased during the initial phase of urate lowering. Educating patients about flares and about adequate treatment methods is important for patient compliance and successful long-term gout management. Prophylaxis should be started along with or just before initiating ULT. Our practice is to start prophylaxis a week before ULT is begun. This decision should be made in consultation with the patient, considering the potential adverse effects of these medications. In a study undertaken in a gout clinic, patients were found to do well without prophylaxis for gout flare when they were thoroughly educated about the disease and when allopurinol use was started at lower doses and titrated slowly.
      • Rees F.
      • Jenkins W.
      • Doherty M.
      Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study.
      This regimen may not be applicable in routine care settings or in patients with a high urate level. Prophylaxis should be continued as long as there is a recent (within the past 3 months) gout flare, chronic gouty synovitis (within the past 3 months), or the presence of tophi. If no recent gout flare or gouty synovitis is present, prophylaxis can be continued for 6 months or, alternatively, for 3 months after a sustained target uric acid level is achieved in a patient who never had tophi; or for 6 months in patients who had tophi that resolved and whose target uric acid level was achieved and sustained.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      Colchicine or a low-dose NSAID is the preferred prophylactic agent.
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      In clinical practice, colchicine may be preferred over NSAIDs to minimize adverse effects. Colchicine prevents or lowers the frequency of flares in 80% to 85% of patients.
      • Finger D.R.
      Hypouricemic agents and colchicine.
      We use a dose of 0.6 mg daily, but a twice-daily dose may also be used. Low-dose NSAIDs, such as naproxen (250 mg twice daily) should be used with concomitant gastrointestinal prophylaxis. If these 2 classes of drugs cannot be used, low-dose prednisone (≤10 mg) may be given,
      • Khanna D.
      • Khanna P.P.
      • Fitzgerald J.D.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
      with appropriate consideration for the possible adverse effects on the gastrointestinal system and bones. The colchicine dose should be reduced to 0.3 mg daily if the patient's GFR is less than 30 mL/min. The dosage for patients undergoing dialysis is 0.3 mg twice weekly, but this dosage needs to be monitored carefully because colchicine is essentially nondialyzable.

      UpToDate. Colchicine. Vol 2017.

      The IL-1 antagonists (eg, canakinumab or rilonacept) may be used for prophylaxis if standard agents cannot be used.

       Hyperuricemia Treatment

      Lowering the uric acid level is important to prevent long-term joint damage and tophus development. Figure 2 provides a general overview of our protocol for managing chronic gout. Treatment of hyperuricemia is lifelong because recurrence eventually occurs once ULT is stopped.
      • Perez-Ruiz F.
      • Atxotegi J.
      • Hernando I.
      • Calabozo M.
      • Nolla J.M.
      Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study.
      Recent data suggest that ULT may be started during an acute flare.
      • Hill E.M.
      • Sky K.
      • Sit M.
      • Collamer A.
      • Higgs J.
      Does starting allopurinol prolong acute treated gout? a randomized clinical trial.
      • Taylor T.H.
      • Mecchella J.N.
      • Larson R.J.
      • Kerin K.D.
      • Mackenzie T.A.
      Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial.
      However, until more data are available regarding initiating ULT during a flare, the strategy remains to wait for the flare to resolve.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      • Terkeltaub R.
      Clinical gout.
      Discussing the potential for lifelong treatment with a patient may also be more fruitful when the patient is pain free. In general, the target uric acid level should be less than 6 mg/dL; for patients with tophi, the level should be less than 5 mg/dL.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      Sustained uric acid levels lower than 3 mg/dL should be avoided because some evidence suggests that uric acid may be neuroprotective.
      • Chen H.
      • Mosley T.H.
      • Alonso A.
      • Huang X.
      Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study.
      • Weisskopf M.G.
      • O'Reilly E.
      • Chen H.
      • Schwarzschild M.A.
      • Ascherio A.
      Plasma urate and risk of Parkinson's disease.
      In our consulting practices, we have found that the most common error in managing gout is not lowering the level of serum uric acid adequately—to a level below the crystallization threshold. Therefore, we support treating to target urate levels as an effective clinical strategy.
      Figure thumbnail gr2
      Figure 2Chronic gout management. ULT = urate-lowering therapy; XOI = xanthine oxidase inhibitor.

       Xanthine Oxidase Inhibitors

      Xanthine oxidase inhibitors (XOIs), including allopurinol and febuxostat, are the mainstays of ULT. When XOIs are used, periodic monitoring of blood cell counts and renal and hepatic function is necessary. Uric acid should be monitored every 4 weeks until the target urate level is reached and then every 6 months. Xanthine oxidase inhibitors are contraindicated in patients taking azathioprine or its metabolites. The concomitant use of allopurinol and febuxostat is not recommended.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      It is thought that no additive benefit is gained because both agents compete for the same receptor.
      • Mandell B.F.
      • El-Zawawy H.
      Gout and chronic kidney disease.
      With combination therapy, xanthinuria could also occur. However, 1 case report described successful combination of the 2 XOIs.
      • Maekawa M.
      • Tomida H.
      • Aoki T.
      • Hishida M.
      • Morinaga T.
      • Tamai H.
      Successful treatment of refractory gout using combined therapy consisting of febuxostat and allopurinol in a patient with chronic renal failure.
      No single XOI is preferred, although allopurinol is more cost-effective. Patients should be informed about the possibility of increased flares with the initiation of ULT.
      Allopurinol remains the principal treatment for ULT but is underused. We hope that the ensuing discussion will make prescribers more comfortable with appropriate allopurinol use. With allopurinol dosing, the approach should be to start low and go slow. For normal renal function, the starting dose is 100 mg daily, increasing by 100 mg every 4 weeks depending on the urate level.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      Patients with chronic stage IV renal disease or worse should start by taking 50 mg daily. A common error in gout management is to stop the dosing increase at 300 mg even if the target serum urate level has not been achieved. Commonly, the average dose required to reach a target uric acid level is 400 mg.
      • Stamp L.K.
      • O'Donnell J.L.
      • Zhang M.
      • et al.
      Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment.
      However, dosages can be increased to 800 mg daily even in patients with renal disease.
      • Stamp L.K.
      • O'Donnell J.L.
      • Zhang M.
      • et al.
      Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment.
      Some physicians may feel uncomfortable doing so in patients with CKD, especially when febuxostat is available.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • Bardin T.
      Response: renal dosing of allopurinol results in suboptimal gout care by T Neogi et al.
      Because of genetic polymorphisms, some people may be allopurinol resistant.
      • Roberts R.L.
      • Wallace M.C.
      • Phipps-Green A.J.
      • et al.
      ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.
      Attempts to safely maximize allopurinol dosing should not be abandoned, especially if cost or intolerance issues limit the use of febuxostat. Careful monitoring, however, is necessary.
      Allopurinol hypersensitivity syndrome, which is rare, typically occurs within 60 days of a patient starting therapy
      • Ramasamy S.N.
      • Korb-Wells C.S.
      • Kannangara D.R.
      • et al.
      Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012.
      and has a mortality rate of approximately 25%.
      • Arellano F.
      • Sacristan J.A.
      Allopurinol hypersensitivity syndrome: a review.
      Renal dysfunction and thiazide diuretic agents are risk factors for allopurinol hypersensitivity. The syndrome is more likely in persons of Korean descent with CKD of stage III or higher or those of Thai or Han Chinese ethnicity. Before being prescribed allopurinol, a patient of these ethnic origins should have baseline genetic screening for HLA-B*5801.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      Approximately 20% of patients develop a rash if they take amoxicillin or ampicillin along with allopurinol. Monitoring should include laboratory evaluations, including for eosinophilia, and clinical evaluations, including for rash. Patients should be educated to stop taking the medicine if they develop pruritus, which can indicate an impending reaction. When doses are higher than 300 mg daily, they should be split to mitigate gastrointestinal adverse effects.
      Febuxostat is given in 40 and 80 mg doses, although doses up to 120 mg have been approved in Europe. The dose of febuxostat may be increased in 2 weeks if uric acid levels do not decline.
      • Terkeltaub R.
      Clinical gout.
      New data suggest that febuxostat is safe for patients with moderate to severe renal disease.
      • Saag K.G.
      • Whelton A.
      • Becker M.A.
      • MacDonald P.
      • Hunt B.
      • Gunawardhana L.
      Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment.
      • Quilis N.
      • Andres M.
      • Gil S.
      • Ranieri L.
      • Vela P.
      • Pascual E.
      Febuxostat for patients with gout and severe chronic kidney disease: which is the appropriate dosage? comment on the article by Saag et al.
      Febuxostat is not cross-reactive with allopurinol, although vigilance is still recommended.
      • Bardin T.
      • Chales G.
      • Pascart T.
      • et al.
      Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol: a retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment.
      • Chohan S.
      Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions.
      Approximately 2% to 4% of users may develop a rash from febuxostat.
      • Ogdie A.
      • Taylor W.J.
      • Neogi T.
      • et al.
      Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
      Transaminitis, diarrhea, and nausea may occur. Some concern has been expressed about the cardiovascular safety of febuxostat, but this is an area of ongoing research.
      • Frampton J.E.
      Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout.
      Of note, the European Union recommends against using febuxostat in patients with CVD or heart failure.
      Menarini International Operations Luxembourg
      Adenuric 80 mg film-coated tablets: EU summary of product characteristics.
      Our practice has been to use it carefully in such patients.

       Uricosuric Medications

      The underexcretion of uric acid is the cause of hyperuricemia in most patients, and probenecid is the standard uricosuric agent used to treat hyperuricemia.
      • Perez-Ruiz F.
      • Calabozo M.
      • Erauskin G.G.
      • Ruibal A.
      • Herrero-Beites A.M.
      Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output.
      However, probenecid is underused compared with XOIs, and its required twice-daily doses may cause compliance issues for patients. Probenecid is contraindicated in patients with nephrolithiasis or a creatinine clearance less than 30 mL/min/1.73 m2; it is also contraindicated in those who excrete excess urate (determined by 24-hour urinalysis for uric acid). Adequate hydration is important for patients taking probenecid because the risk of kidney stones is 9% to 11%.
      • Terkeltaub R.
      Clinical gout.
      For patients who require probenecid in the setting of a history of renal stones, alkalization of the urine should be considered with sodium bicarbonate or potassium citrate. A typical starting dose for probenecid is 250 mg twice daily, which can be increased to 2000 to 3000 mg daily. Probenecid can be used in combination with XOIs or as an alternative first-line agent.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      Its ability to alter the serum levels of many medications, including NSAIDs, β-lactam antibiotics, methotrexate, and heparin, must be considered when it is prescribed.
      Lesinurad, another uricosuric agent, was approved recently for use in combination with any XOI; the dose (200 mg/d) should be given in the morning. Lesinurad should not be used as monotherapy because of possible adverse effects on the kidneys.
      • Hoy S.M.
      Lesinurad: first global approval.
      If the XOI is withheld, so should lesinurad. Renal function requires careful monitoring, but lesinurad can be used in patients with a history of nephrolithiasis. One review reported that patients enrolled in various trials had increased levels of creatinine, although the increased levels resolved in most patients by their final follow-up visit.
      • Sattui S.E.
      • Gaffo A.L.
      Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications.
      It should not be started if the creatinine clearance is less than 45 mL/min/1.73 m2 and should be halted if the creatinine level rises to more than 2 times the pretreatment value. Common adverse effects are headaches, influenza, and gastroesophageal reflux. Clinical experience is lacking at present.

       Pegloticase

      Pegloticase is a powerful pegylated uricase that converts uric acid to the more soluble allantoin and is recommended for gout that is refractory to other ULTs, as well as to combination therapy with a uricosuric agent.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      Pegloticase is highly effective at reducing uric acid levels and the tophaceous burden. Glucose-6-phosphate dehydrogenase deficiency is a contraindication to its use. It is given intravenously at a dose of 8 mg every 2 weeks. During treatment with pegloticase, multiple gout flares are common because of the rapid decline in uric acid levels. Prophylaxis should be maintained and started for an acute gout attack a week before the pegloticase infusions. Patients should be premedicated to prevent infusion reactions. Infusion reactions due to antibody formation result from pegloticase in 40% of patients and are preceded by loss of the urate-lowering response.
      • Sundy J.S.
      • Baraf H.S.
      • Yood R.A.
      • et al.
      Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials.
      • Becker M.A.
      • Baraf H.S.
      • Yood R.A.
      • et al.
      Long-term safety of pegloticase in chronic gout refractory to conventional treatment.
      Therefore, preinfusion uric acid levels should be evaluated, and if they are increasing or at or above 6 mg/dL, further infusions should be withheld. To help prevent masking of an increase in uric acid level, concomitant ULT cannot be given to patients taking pegloticase. Long-term management and the duration of treatment with pegloticase are unclear. An open-label extension study with mean follow-up of 25 months did not report any new safety signals, and the target uric acid level was achieved in 55% of the patients.
      • Becker M.A.
      • Baraf H.S.
      • Yood R.A.
      • et al.
      Long-term safety of pegloticase in chronic gout refractory to conventional treatment.
      Switching to an oral ULT has been suggested once the tophi resolve.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2016 updated EULAR evidence-based recommendations for the management of gout.
      Pegloticase has a narrow indication and is used essentially as a debulking therapy in persons with severe tophaceous gout. The care approach to a patient with refractory gout is given in Table 3.
      Table 3Approach to Resistant Gout
      Confirm diagnosis by aspiration of crystals.
      Always consider alternative and coexisting diagnoses.
      Ensure that patients are educated regarding gout and understand that gout is a chronic disease.
      Emphasize weight reduction, diet moderation, and avoidance of acute flare triggers (eg, beer).
      Account for comorbidities in choosing medications.
      Ensure proper flare prophylaxis.
      Provide acute, prompt, and appropriately dosed treatment of acute flares.
      Withdraw, if feasible, medicines that contribute to hyperuricemia (eg, loop diuretics).
      Add medications with hypouricemic properties to replace the hyperuricemic ones (eg, losartan to treat hypertension instead of hydrochlorothiazide).
      Use the maximal permissible dosage for urate-lowering therapy. Be aware of potential allopurinol resistance.
      Add an appropriate uricosuric agent, if possible.
      Verify compliance with the patient and consider checking oxypurinol levels for allopurinol compliance.
      Involve rheumatology consultants to manage care for patients with complex disease (eg, advanced kidney disease, previous transplant, unconfirmed diagnosis, intolerance to therapy, and refractory disease) and for consideration of treatment with pegloticase.

       Supplementary Medicines

      Losartan is a mild uricosuric agent, but other angiotensin receptor blockers and angiotensin-converting enzyme inhibitors are not. β-Blockers confer an increased gout risk.
      • Choi H.K.
      • Soriano L.C.
      • Zhang Y.
      • Rodriguez L.A.
      Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study.
      Fenofibrate lowers the uric acid level on average by 1.5 mg/dL.
      • Derosa G.
      • Maffioli P.
      • Sahebkar A.
      Plasma uric acid concentrations are reduced by fenofibrate: a systematic review and meta-analysis of randomized placebo-controlled trials.
      Atorvastatin and simvastatin also lower uric acid levels, but hypouricemia was not found to be a class effect of statin therapies.
      • Derosa G.
      • Maffioli P.
      • Reiner Z.
      • Simental-Mendia L.E.
      • Sahebkar A.
      Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis.

       Nonpharmacologic Measures

      Patients should be educated about gout. The provider should emphasize that gout is a lifelong condition, and the goal of treatment is to prevent flares and joint damage. Convincing patients to commit to lifelong pharmacologic therapy is not easy. In 1 study, the authors reported that 40% of the respondents preferred nonpharmacologic treatments.
      • Singh J.A.
      • Shah N.
      • Edwards N.L.
      A cross-sectional internet-based patient survey of the management strategies for gout.
      The target levels for uric acid need to be set with the patient and reinforced at every visit. In 1 survey, only 14% of patients knew their target uric acid level.
      • Coburn B.W.
      • Bendlin K.A.
      • Sayles H.
      • Hentzen K.S.
      • Hrdy M.M.
      • Mikuls T.R.
      Target serum urate: do gout patients know their goal?.
      In a report of a systematic review, adherence to treatment ranged from 10% to 46%.
      • De Vera M.A.
      • Marcotte G.
      • Rai S.
      • Galo J.S.
      • Bhole V.
      Medication adherence in gout: a systematic review.
      Patients also need to be educated about the importance of maintaining an acceptable weight and in avoiding certain foods, which can help control gout. Weight loss is important because adiposity contributes to hyperuricemia. Organ meat, red meat, and seafood with a high purine content, such as shellfish, anchovies, and sardines, cause hyperuricemia.
      • Khanna D.
      • Fitzgerald J.D.
      • Khanna P.P.
      • et al.
      2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
      Consuming most forms of alcohol, particularly beer, increases uric acid levels in a dose-dependent manner; moderate wine consumption does not.
      • Choi H.K.
      • Atkinson K.
      • Karlson E.W.
      • Willett W.
      • Curhan G.
      Alcohol intake and risk of incident gout in men: a prospective study.
      Fructose-containing drinks and soft drinks increase uric acid levels, but diet drinks do not.
      • Choi J.W.
      • Ford E.S.
      • Gao X.
      • Choi H.K.
      Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey.
      Dairy proteins lower uric acid levels. Coffee consumption also reduces uric acid and the risk of incident gout.
      • Choi H.K.
      • Willett W.
      • Curhan G.
      Coffee consumption and risk of incident gout in men: a prospective study.
      • Choi H.K.
      • Curhan G.
      Coffee, tea, and caffeine consumption and serum uric acid level: the third National Health and Nutrition Examination Survey.
      Purine-rich vegetables do not substantially increase uric acid levels,
      • Choi H.K.
      • Atkinson K.
      • Karlson E.W.
      • Willett W.
      • Curhan G.
      Purine-rich foods, dairy and protein intake, and the risk of gout in men.
      and eating cherries can reduce gout attacks.
      • Zhang Y.
      • Neogi T.
      • Chen C.
      • Chaisson C.
      • Hunter D.J.
      • Choi H.K.
      Cherry consumption and decreased risk of recurrent gout attacks.
      However, patients with gout should understand that diet and lifestyle changes do not obviate ULT. Data from 1 study of 30 patients reported that dietary interventions did not have a profound effect on uric acid levels.
      • Holland R.
      • McGill N.W.
      Comprehensive dietary education in treated gout patients does not further improve serum urate.
      However, they are certainly important from an overall health perspective, considering the risk associated with the typical metabolic profile of patients with gout.

       Specific Situations

      Approximately 40% of patients with gout have CKD (at least stage II) and a reduced GFR,
      • Gaffo A.L.
      • Saag K.G.
      Management of hyperuricemia and gout in CKD.
      which limits the use of medications such as NSAIDs and uricosuric agents. In this situation, colchicine, in renal-adjusted dosing, may be used for prophylaxis and treatment, but clinical judgment regarding risks and benefits should be individualized to the patient. Great caution must be exercised when using colchicine in patients undergoing dialysis because of its nondialyzable nature, although gout flare frequency typically declines in these patients because of hemodialysis.
      • Gaffo A.L.
      • Saag K.G.
      Management of hyperuricemia and gout in CKD.
      Sevelamer, commonly used for patients with CKD to manage phosphate load, is hypouricemic.
      • Ohno I.
      • Yamaguchi Y.
      • Saikawa H.
      • et al.
      Sevelamer decreases serum uric acid concentration through adsorption of uric acid in maintenance hemodialysis patients.
      Calcium pyrophosphate deposition disease arthropathy should remain part of the differential diagnosis for patients with CKD because of its association with hyperparathyroidism.
      An increase in organ transplant has resulted in a concomitant increase in hyperuricemia and gout, primarily from the renal effects of immunosuppressive medications such as cyclosporine
      • Cea Soriano L.
      • Rothenbacher D.
      • Choi H.K.
      • Garcia Rodriguez L.A.
      Contemporary epidemiology of gout in the UK general population.
      and tacrolimus. Transplant patients with gout may develop tophi early after their transplant and in unusual sites, such as the spine and sacroiliac joints.
      • Stamp L.K.
      • Chapman P.T.
      Gout and organ transplantation.
      Surgical management can be considered when there is infection, joint instability, or an entrapment neuropathy.
      • Poratt D.
      • Rome K.
      Surgical management of gout in the foot and ankle: a systematic review.
      Without ULT, the tophi tend to recur.

      Conclusion

      Effective management of gout requires a complete understanding of the disease process and its chronicity, as well as treatment by the providers, compliance by the patients, and support by their caregivers. With the present patients, we must emphasize the lifelong nature of the disease and its negative health consequences if the disease is untreated. In this review, we provided suggestions based on the current literature and from our practice to help guide the practicing clinician in managing this challenging disease.

      References

        • Zhu Y.
        • Pandya B.J.
        • Choi H.K.
        Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008.
        Arthritis Rheum. 2011; 63: 3136-3141
        • Roddy E.
        • Doherty M.
        Epidemiology of gout.
        Arthritis Res Ther. 2010; 12: 223
        • Choi H.K.
        • Mount D.B.
        • Reginato A.M.
        • American College of Physicians, American Physiological Society
        Pathogenesis of gout.
        Ann Intern Med. 2005; 143: 499-516
        • Zhu Y.
        • Pandya B.J.
        • Choi H.K.
        Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008.
        Am J Med. 2012; 125: 679-687
        • Doherty M.
        • Jansen T.L.
        • Nuki G.
        • et al.
        Gout: why is this curable disease so seldom cured?.
        Ann Rheum Dis. 2012; 71: 1765-1770
        • Kuo C.F.
        • Grainge M.J.
        • Mallen C.
        • Zhang W.
        • Doherty M.
        Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study.
        Ann Rheum Dis. 2015; 74: 661-667
        • Roddy E.
        • Zhang W.
        • Doherty M.
        Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations.
        Ann Rheum Dis. 2007; 66: 1311-1315
        • Kuo C.F.
        • Grainge M.J.
        • Mallen C.
        • Zhang W.
        • Doherty M.
        Eligibility for and prescription of urate-lowering treatment in patients with incident gout in England.
        JAMA. 2014; 312: 2684-2686
        • Khanna D.
        • Fitzgerald J.D.
        • Khanna P.P.
        • et al.
        2012 American College of Rheumatology guidelines for management of gout, part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
        Arthritis Care Res (Hoboken). 2012; 64: 1431-1446
        • Khanna D.
        • Khanna P.P.
        • Fitzgerald J.D.
        • et al.
        2012 American College of Rheumatology guidelines for management of gout, part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis.
        Arthritis Care Res (Hoboken). 2012; 64: 1447-1461
        • Richette P.
        • Doherty M.
        • Pascual E.
        • et al.
        2016 updated EULAR evidence-based recommendations for the management of gout.
        Ann Rheum Dis. 2017; 76: 29-42
        • Hoy S.M.
        Lesinurad: first global approval.
        Drugs. 2016; 76: 509-516
        • Pal B.
        • Foxall M.
        • Dysart T.
        • Carey F.
        • Whittaker M.
        How is gout managed in primary care? a review of current practice and proposed guidelines.
        Clin Rheumatol. 2000; 19: 21-25
        • Schlesinger N.
        • Radvanski D.C.
        • Young T.C.
        • McCoy J.V.
        • Eisenstein R.
        • Moore D.F.
        Diagnosis and treatment of acute gout at a university hospital emergency department.
        Open Rheumatol J. 2015; 9: 21-26
        • Janssens H.J.
        • Fransen J.
        • van de Lisdonk E.H.
        • van Riel P.L.
        • van Weel C.
        • Janssen M.
        A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis.
        Arch Intern Med. 2010; 170: 1120-1126
        • Kienhorst L.B.
        • Janssens H.J.
        • Fransen J.
        • Janssen M.
        The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study.
        Rheumatology (Oxford). 2015; 54: 609-614
        • Neogi T.
        • Jansen T.L.
        • Dalbeth N.
        • et al.
        2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
        Ann Rheum Dis. 2015; 74: 1789-1798
        • Campion E.W.
        • Glynn R.J.
        • DeLabry L.O.
        Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study.
        Am J Med. 1987; 82: 421-426
        • Logan J.A.
        • Morrison E.
        • McGill P.E.
        Serum uric acid in acute gout.
        Ann Rheum Dis. 1997; 56: 696-697
        • Schlesinger N.
        • Norquist J.M.
        • Watson D.J.
        Serum urate during acute gout.
        J Rheumatol. 2009; 36: 1287-1289
        • Nicholls A.
        • Snaith M.L.
        • Scott J.T.
        Effect of oestrogen therapy on plasma and urinary levels of uric acid.
        Br Med J. 1973; 1: 449-451
        • Sumino H.
        • Ichikawa S.
        • Kanda T.
        • Nakamura T.
        • Sakamaki T.
        Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia.
        Lancet. 1999; 354: 650
        • Centers for Disease Control and Prevention, National Center for Health Statistics
        Vital and health statistics: current estimates from the National Health Interview Survey, 1996.
        (Accessed February 8, 2017)
        • Harrold L.R.
        • Etzel C.J.
        • Gibofsky A.
        • et al.
        Sex differences in gout characteristics: tailoring care for women and men.
        BMC Musculoskelet Disord. 2017; 18: 108
        • De Souza A.
        • Fernandes V.
        • Ferrari A.J.
        Female gout: clinical and laboratory features.
        J Rheumatol. 2005; 32: 2186-2188
        • Neogi T.
        Gout.
        Ann Intern Med. 2016; 165: ITC1-ITC16
        • Edwards N.L.
        Clinical gout.
        in: 6th ed. Rheumatology. Vol. 2. Elsevier, Philadelphia, PA2015: 1569-1574
        • Bloch C.
        • Hermann G.
        • Yu T.F.
        A radiologic reevaluation of gout: a study of 2,000 patients.
        AJR Am J Roentgenol. 1980; 134: 781-787
        • McQueen F.M.
        • Doyle A.
        • Dalbeth N.
        Imaging in the crystal arthropathies.
        Rheum Dis Clin North Am. 2014; 40: 231-249
        • Parathithasan N.
        • Lee W.K.
        • Pianta M.
        • Oon S.
        • Perera W.
        Gouty arthropathy: review of clinico-pathologic and imaging features.
        J Med Imaging Radiat Oncol. 2016; 60: 9-20
        • Chowalloor P.V.
        • Keen H.I.
        A systematic review of ultrasonography in gout and asymptomatic hyperuricaemia.
        Ann Rheum Dis. 2013; 72: 638-645
        • Ogdie A.
        • Taylor W.J.
        • Weatherall M.
        • et al.
        Imaging modalities for the classification of gout: systematic literature review and meta-analysis.
        Ann Rheum Dis. 2015; 74: 1868-1874
        • Ogdie A.
        • Taylor W.J.
        • Neogi T.
        • et al.
        Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard.
        Arthritis Rheumatol. 2017; 69: 429-438
        • Kienhorst L.B.
        • Janssens H.J.
        • Fransen J.
        • van de Lisdonk E.H.
        • Janssen M.
        Arthritis of the first metatarsophalangeal joint is not always gout: a prospective cohort study in primary care patients.
        Joint Bone Spine. 2014; 81: 342-346
        • Ottaviani S.
        • Gill G.
        • Aubrun A.
        • Palazzo E.
        • Meyer O.
        • Dieude P.
        Ultrasound in gout: a useful tool for following urate-lowering therapy.
        Joint Bone Spine. 2015; 82: 42-44
        • Greenlund L.J.
        • Ward W.J.
        Use of ultrasound by internists to improve diagnostic small joint aspiration.
        Am J Med. 2017; 130: 234-236
        • Slot O.
        • Terslev L.
        Ultrasound-guided dry-needle synovial tissue aspiration for diagnostic microscopy in gout patients presenting without synovial effusion or clinically detectable tophi.
        J Clin Rheumatol. 2015; 21: 167-168
        • Howard R.G.
        • Pillinger M.H.
        • Gyftopoulos S.
        • Thiele R.G.
        • Swearingen C.J.
        • Samuels J.
        Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: concordance between readers.
        Arthritis Care Res (Hoboken). 2011; 63: 1456-1462
        • Stewart S.
        • Dalbeth N.
        • Vandal A.C.
        • Allen B.
        • Miranda R.
        • Rome K.
        Ultrasound features of the first metatarsophalangeal joint in gout and asymptomatic hyperuricaemia: comparison with normouricaemic individuals.
        Arthritis Care Res (Hoboken). 2017; 69: 875-883
        • Zufferey P.
        • Valcov R.
        • Fabreguet I.
        • Dumusc A.
        • Omoumi P.
        • So A.
        A prospective evaluation of ultrasound as a diagnostic tool in acute microcrystalline arthritis.
        Arthritis Res Ther. 2015; 17: 188
        • Berko N.S.
        • Goldberg-Stein S.
        • Thornhill B.A.
        • Koenigsberg M.
        Survey of current trends in postgraduate musculoskeletal ultrasound education in the United States.
        Skeletal Radiol. 2016; 45: 475-482
        • Omoumi P.
        • Becce F.
        • Racine D.
        • Ott J.G.
        • Andreisek G.
        • Verdun F.R.
        Dual-energy CT: basic principles, technical approaches, and applications in musculoskeletal imaging (part 1).
        Semin Musculoskelet Radiol. 2015; 19: 431-437
        • Zhu L.
        • Wu H.
        • Wu X.
        • et al.
        Comparison between dual-energy computed tomography and ultrasound in the diagnosis of gout of various joints.
        Acad Radiol. 2015; 22: 1497-1502
        • Bongartz T.
        • Glazebrook K.N.
        • Kavros S.J.
        • et al.
        Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study.
        Ann Rheum Dis. 2015; 74: 1072-1077
        • Gruber M.
        • Bodner G.
        • Rath E.
        • Supp G.
        • Weber M.
        • Schueller-Weidekamm C.
        Dual-energy computed tomography compared with ultrasound in the diagnosis of gout.
        Rheumatology (Oxford). 2014; 53: 173-179
        • Huppertz A.
        • Hermann K.G.
        • Diekhoff T.
        • Wagner M.
        • Hamm B.
        • Schmidt W.A.
        Systemic staging for urate crystal deposits with dual-energy CT and ultrasound in patients with suspected gout.
        Rheumatol Int. 2014; 34: 763-771
        • Baer A.N.
        • Kurano T.
        • Thakur U.J.
        • et al.
        Dual-energy computed tomography has limited sensitivity for non-tophaceous gout: a comparison study with tophaceous gout.
        BMC Musculoskelet Disord. 2016; 17: 91
        • Glazebrook K.N.
        • Guimaraes L.S.
        • Murthy N.S.
        • et al.
        Identification of intraarticular and periarticular uric acid crystals with dual-energy CT: initial evaluation.
        Radiology. 2011; 261: 516-524
        • Melzer R.
        • Pauli C.
        • Treumann T.
        • Krauss B.
        Gout tophus detection: a comparison of dual-energy CT (DECT) and histology.
        Semin Arthritis Rheum. 2014; 43: 662-665
        • Durcan L.
        • Grainger R.
        • Keen H.I.
        • Taylor W.J.
        • Dalbeth N.
        Imaging as a potential outcome measure in gout studies: a systematic literature review.
        Semin Arthritis Rheum. 2016; 45: 570-579
        • Aslam F.
        • Matteson E.L.
        Polyarthritis as a rare presentation of hydroxyapatite deposition disease.
        Arthritis Rheumatol. 2016; 68: 2056
        • Qaseem A.
        • Harris R.P.
        • Forciea M.A.
        • Clinical Guidelines Committee of the American College of Physicians
        Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians.
        Ann Intern Med. 2017; 166: 58-68
        • Neogi T.
        • Mikuls T.R.
        To treat or not to treat (to target) in gout.
        Ann Intern Med. 2017; 166: 71-72
        • Yamanaka H.
        • Japanese Society of Gout and Nucleic Acid Metabolism
        Japanese guideline for the management of hyperuricemia and gout: second edition.
        Nucleosides Nucleotides Nucleic Acids. 2011; 30: 1018-1029
        • Terkeltaub R.
        Clinical gout.
        in: 6th ed. Rheumatology. Vol. 2. Elsevier, Philadelphia, PA2015: 1575-1582
        • Janssens H.J.
        • Janssen M.
        • van de Lisdonk E.H.
        • van Riel P.L.
        • van Weel C.
        Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial.
        Lancet. 2008; 371: 1854-1860
        • Man C.Y.
        • Cheung I.T.
        • Cameron P.A.
        • Rainer T.H.
        Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial.
        Ann Emerg Med. 2007; 49: 670-677
        • Rainer T.H.
        • Cheng C.H.
        • Janssens H.J.
        • et al.
        Oral prednisolone in the treatment of acute gout: a pragmatic, multicenter, double-blind, randomized trial.
        Ann Intern Med. 2016; 164: 464-471
        • Terkeltaub R.A.
        • Furst D.E.
        • Bennett K.
        • Kook K.A.
        • Crockett R.S.
        • Davis M.W.
        High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study.
        Arthritis Rheum. 2010; 62: 1060-1068
        • Keenan R.T.
        • O'Brien W.R.
        • Lee K.H.
        • et al.
        Prevalence of contraindications and prescription of pharmacologic therapies for gout.
        Am J Med. 2011; 124: 155-163
        • Mikuls T.R.
        • MacLean C.H.
        • Olivieri J.
        • et al.
        Quality of care indicators for gout management.
        Arthritis Rheum. 2004; 50: 937-943
        • Finkelstein Y.
        • Aks S.E.
        • Hutson J.R.
        • et al.
        Colchicine poisoning: the dark side of an ancient drug.
        Clin Toxicol (Phila). 2010; 48: 407-414
        • Wiggins B.S.
        • Saseen J.J.
        • Page II, R.L.
        • et al.
        Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association.
        Circulation. 2016; 134: e468-e495
        • Terkeltaub R.A.
        Colchicine update: 2008.
        Semin Arthritis Rheum. 2009; 38: 411-419
        • Terkeltaub R.A.
        • Furst D.E.
        • Digiacinto J.L.
        • Kook K.A.
        • Davis M.W.
        Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors.
        Arthritis Rheum. 2011; 63: 2226-2237
        • Rees F.
        • Jenkins W.
        • Doherty M.
        Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study.
        Ann Rheum Dis. 2013; 72: 826-830
        • Finger D.R.
        Hypouricemic agents and colchicine.
        in: West S.G. Rheumatology Secrets. 3rd ed. Elsevier, Philadelphia, PA2015: 645-651
      1. UpToDate. Colchicine. Vol 2017.

        • Perez-Ruiz F.
        • Atxotegi J.
        • Hernando I.
        • Calabozo M.
        • Nolla J.M.
        Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study.
        Arthritis Rheum. 2006; 55: 786-790
        • Hill E.M.
        • Sky K.
        • Sit M.
        • Collamer A.
        • Higgs J.
        Does starting allopurinol prolong acute treated gout? a randomized clinical trial.
        J Clin Rheumatol. 2015; 21: 120-125
        • Taylor T.H.
        • Mecchella J.N.
        • Larson R.J.
        • Kerin K.D.
        • Mackenzie T.A.
        Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial.
        Am J Med. 2012; 125: 1126-1134
        • Chen H.
        • Mosley T.H.
        • Alonso A.
        • Huang X.
        Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study.
        Am J Epidemiol. 2009; 169: 1064-1069
        • Weisskopf M.G.
        • O'Reilly E.
        • Chen H.
        • Schwarzschild M.A.
        • Ascherio A.
        Plasma urate and risk of Parkinson's disease.
        Am J Epidemiol. 2007; 166: 561-567
        • Mandell B.F.
        • El-Zawawy H.
        Gout and chronic kidney disease.
        Cleve Clin J Med. 2011; 78 ([letter]): 81-82
        • Maekawa M.
        • Tomida H.
        • Aoki T.
        • Hishida M.
        • Morinaga T.
        • Tamai H.
        Successful treatment of refractory gout using combined therapy consisting of febuxostat and allopurinol in a patient with chronic renal failure.
        Intern Med. 2014; 53: 609-612
        • Stamp L.K.
        • O'Donnell J.L.
        • Zhang M.
        • et al.
        Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment.
        Arthritis Rheum. 2011; 63: 412-421
        • Richette P.
        • Doherty M.
        • Pascual E.
        • Bardin T.
        Response: renal dosing of allopurinol results in suboptimal gout care by T Neogi et al.
        Ann Rheum Dis. 2017; 76: e2
        • Roberts R.L.
        • Wallace M.C.
        • Phipps-Green A.J.
        • et al.
        ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.
        Pharmacogenomics J. 2017; 17: 201-203
        • Ramasamy S.N.
        • Korb-Wells C.S.
        • Kannangara D.R.
        • et al.
        Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012.
        Drug Saf. 2013; 36: 953-980
        • Arellano F.
        • Sacristan J.A.
        Allopurinol hypersensitivity syndrome: a review.
        Ann Pharmacother. 1993; 27: 337-343
        • Saag K.G.
        • Whelton A.
        • Becker M.A.
        • MacDonald P.
        • Hunt B.
        • Gunawardhana L.
        Impact of febuxostat on renal function in gout patients with moderate-to-severe renal impairment.
        Arthritis Rheumatol. 2016; 68: 2035-2043
        • Quilis N.
        • Andres M.
        • Gil S.
        • Ranieri L.
        • Vela P.
        • Pascual E.
        Febuxostat for patients with gout and severe chronic kidney disease: which is the appropriate dosage? comment on the article by Saag et al.
        Arthritis Rheumatol. 2016; 68: 2563-2564
        • Bardin T.
        • Chales G.
        • Pascart T.
        • et al.
        Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol: a retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment.
        Joint Bone Spine. 2016; 83: 314-317
        • Chohan S.
        Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions.
        J Rheumatol. 2011; 38: 1957-1959
        • Frampton J.E.
        Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout.
        Drugs. 2015; 75: 427-438
        • Menarini International Operations Luxembourg
        Adenuric 80 mg film-coated tablets: EU summary of product characteristics.
        (Accessed February 8, 2017)
        • Perez-Ruiz F.
        • Calabozo M.
        • Erauskin G.G.
        • Ruibal A.
        • Herrero-Beites A.M.
        Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output.
        Arthritis Rheum. 2002; 47: 610-613
        • Sattui S.E.
        • Gaffo A.L.
        Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications.
        Ther Adv Musculoskelet Dis. 2016; 8: 145-159
        • Sundy J.S.
        • Baraf H.S.
        • Yood R.A.
        • et al.
        Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials.
        JAMA. 2011; 306: 711-720
        • Becker M.A.
        • Baraf H.S.
        • Yood R.A.
        • et al.
        Long-term safety of pegloticase in chronic gout refractory to conventional treatment.
        Ann Rheum Dis. 2013; 72: 1469-1474
        • Choi H.K.
        • Soriano L.C.
        • Zhang Y.
        • Rodriguez L.A.
        Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study.
        BMJ. 2012; 344: d8190
        • Derosa G.
        • Maffioli P.
        • Sahebkar A.
        Plasma uric acid concentrations are reduced by fenofibrate: a systematic review and meta-analysis of randomized placebo-controlled trials.
        Pharmacol Res. 2015; 102: 163-170
        • Derosa G.
        • Maffioli P.
        • Reiner Z.
        • Simental-Mendia L.E.
        • Sahebkar A.
        Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis.
        Drugs. 2016; 76: 947-956
        • Singh J.A.
        • Shah N.
        • Edwards N.L.
        A cross-sectional internet-based patient survey of the management strategies for gout.
        BMC Complement Altern Med. 2016; 16: 90
        • Coburn B.W.
        • Bendlin K.A.
        • Sayles H.
        • Hentzen K.S.
        • Hrdy M.M.
        • Mikuls T.R.
        Target serum urate: do gout patients know their goal?.
        Arthritis Care Res (Hoboken). 2016; 68: 1028-1035
        • De Vera M.A.
        • Marcotte G.
        • Rai S.
        • Galo J.S.
        • Bhole V.
        Medication adherence in gout: a systematic review.
        Arthritis Care Res (Hoboken). 2014; 66: 1551-1559
        • Choi H.K.
        • Atkinson K.
        • Karlson E.W.
        • Willett W.
        • Curhan G.
        Alcohol intake and risk of incident gout in men: a prospective study.
        Lancet. 2004; 363: 1277-1281
        • Choi J.W.
        • Ford E.S.
        • Gao X.
        • Choi H.K.
        Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey.
        Arthritis Rheum. 2008; 59: 109-116
        • Choi H.K.
        • Willett W.
        • Curhan G.
        Coffee consumption and risk of incident gout in men: a prospective study.
        Arthritis Rheum. 2007; 56: 2049-2055
        • Choi H.K.
        • Curhan G.
        Coffee, tea, and caffeine consumption and serum uric acid level: the third National Health and Nutrition Examination Survey.
        Arthritis Rheum. 2007; 57: 816-821
        • Choi H.K.
        • Atkinson K.
        • Karlson E.W.
        • Willett W.
        • Curhan G.
        Purine-rich foods, dairy and protein intake, and the risk of gout in men.
        N Engl J Med. 2004; 350: 1093-1103
        • Zhang Y.
        • Neogi T.
        • Chen C.
        • Chaisson C.
        • Hunter D.J.
        • Choi H.K.
        Cherry consumption and decreased risk of recurrent gout attacks.
        Arthritis Rheum. 2012; 64: 4004-4011
        • Holland R.
        • McGill N.W.
        Comprehensive dietary education in treated gout patients does not further improve serum urate.
        Intern Med J. 2015; 45: 189-194
        • Gaffo A.L.
        • Saag K.G.
        Management of hyperuricemia and gout in CKD.
        Am J Kidney Dis. 2008; 52: 994-1009
        • Ohno I.
        • Yamaguchi Y.
        • Saikawa H.
        • et al.
        Sevelamer decreases serum uric acid concentration through adsorption of uric acid in maintenance hemodialysis patients.
        Intern Med. 2009; 48: 415-420
        • Cea Soriano L.
        • Rothenbacher D.
        • Choi H.K.
        • Garcia Rodriguez L.A.
        Contemporary epidemiology of gout in the UK general population.
        Arthritis Res Ther. 2011; 13: R39
        • Stamp L.K.
        • Chapman P.T.
        Gout and organ transplantation.
        Curr Rheumatol Rep. 2012; 14: 165-172
        • Poratt D.
        • Rome K.
        Surgical management of gout in the foot and ankle: a systematic review.
        J Am Podiatr Med Assoc. 2016; 106: 182-188