Diagnosis and treatment
Gout: Diagnosis and treatment
Diagnóstico y tratamiento de la gota
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Bajo luz polarizada simple (imagen central), el cristal muestra una birrefringencia intensa que, al aplicar el compensador rojo de primer orden (imagen inferior), se confirma como birrefringencia negativa –al ser de color amarillo y estar situado de forma paralela al eje del compensador (flecha)–. 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SPAHC, strategic plan for addressing hepatitis C.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María Buti, Jose Luis Calleja, Javier García-Samaniego, Miguel Ángel Serra, Javier Crespo, Manuel Romero, Miguel Ángel Simón, Juan Turnes, Antonio Javier Blasco, Pablo Lázaro, Sarah Robbins, Homie Razavi" "autores" => array:13 [ 0 => array:2 [ "nombre" => "María" "apellidos" => "Buti" ] 1 => array:2 [ "nombre" => "Jose Luis" "apellidos" => "Calleja" ] 2 => array:2 [ "nombre" => "Javier" "apellidos" => "García-Samaniego" ] 3 => array:2 [ "nombre" => "Miguel Ángel" "apellidos" => "Serra" ] 4 => array:2 [ "nombre" => "Javier" "apellidos" => "Crespo" ] 5 => array:2 [ "nombre" => "Manuel" "apellidos" => "Romero" ] 6 => array:2 [ "nombre" => "Miguel Ángel" "apellidos" => "Simón" ] 7 => array:2 [ "nombre" => "Juan" "apellidos" => "Turnes" ] 8 => array:2 [ "nombre" => "Antonio Javier" "apellidos" => "Blasco" ] 9 => array:2 [ "nombre" => "Pablo" "apellidos" => "Lázaro" ] 10 => array:2 [ "nombre" => "Sarah" "apellidos" => "Robbins" ] 11 => array:2 [ "nombre" => "Homie" "apellidos" => "Razavi" ] 12 => array:1 [ "colaborador" => "on behalf of the Grupo para el Estudio y Modelización Epidemiológica de la Hepatitis C en España (GEMEHCE)" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316307102" "doi" => "10.1016/j.medcli.2016.12.018" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316307102?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301882?idApp=UINPBA00004N" "url" => "/23870206/0000014800000006/v1_201704120030/S2387020617301882/v1_201704120030/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020617301869" "issn" => "23870206" "doi" => "10.1016/j.medcle.2017.03.011" "estado" => "S300" "fechaPublicacion" => "2017-03-22" "aid" => "3892" "copyright" => "Elsevier España, S.L.U." 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(A) Mediastinal lymph nodes (red arrows). (B) Pulmonary window showing septal thickening.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Carlos Ortiz-Bautista, Ignacio Hernández-González, Pilar Escribano-Subías" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Carlos" "apellidos" => "Ortiz-Bautista" ] 1 => array:2 [ "nombre" => "Ignacio" "apellidos" => "Hernández-González" ] 2 => array:2 [ "nombre" => "Pilar" "apellidos" => "Escribano-Subías" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316306777" "doi" => "10.1016/j.medcli.2016.11.031" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316306777?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617301869?idApp=UINPBA00004N" "url" => "/23870206/0000014800000006/v1_201704120030/S2387020617301869/v1_201704120030/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Diagnosis and treatment</span>" "titulo" => "Gout: Diagnosis and treatment" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "271" "paginaFinal" => "276" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Francisca Sivera, Mariano Andrés, Neus Quilis" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Francisca" "apellidos" => "Sivera" "email" => array:1 [ 0 => "fransimas@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Mariano" "apellidos" => "Andrés" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Neus" "apellidos" => "Quilis" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Sección de Reumatología, Hospital General Universitario de Elda, Elda, Alicante, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Sección de Reumatología, Hospital General Universitario de Alicante, Departamento de Medicina Clínica, Universidad Miguel Hernández, Elche, Alicante, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diagnóstico y tratamiento de la gota" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3307 "Ancho" => 1500 "Tamanyo" => 474726 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Synovial fluid microscopy at 600-magnification with ordinary light (top image), where a needle-shape crystal is shown inside a leucocyte. Under simple polarized light (middle image), the glass shows strong birefringence which, after applying the first order red compensator (below), is confirmed as negative birefringence–as it is yellow in colour and is positioned parallel to the compensator's axis (arrow)–. Photographs courtesy of Prof. Eliseo Pascual.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Gout is a disease caused by the deposition of monosodium urate (MSU) crystals in and around the joints as a result of persistent hyperuricemia. It is a chronic process, although its clinical manifestations may occur intermittently at onset (episodes of acute inflammation). Without a uric acid lowering treatment, the frequency of episodes and the number of joints affected increase. Any gout that does not receive adequate treatment is associated with significant morbidity, disability and reduced quality of life. However, despite numerous guidelines and recommendations, treatment of these patients is often poor.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Diagnosis</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Identification of crystals (gold standard)</span><p id="par0010" class="elsevierStylePara elsevierViewall">The identification of MSU crystals in synovial fluid or tophi aspirate remains the gold standard for the diagnosis of gout, as specified by the recommendations and clinical practice guidelines<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1–3</span></a>; this also comes from understanding gout as a MSU crystal deposition disease.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Their identification is simple and reliable after a short training. An optical microscope equipped with 400–600 magnification is required. This allows adequate visualization of crystals both under ordinary light as well as with single polarization. The MSU crystals are acicular, variable in size and can be located both in the cytoplasm of leukocytes and extracellularly (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). A very intense birefringence is observed with polarized light, which facilitates identification even in very cellular samples, mixed with blood or with few crystals. Its negative birefringence can be determined using a first order red compensator, a fact seldom necessary in clinical practice. In the absence of a uric acid lowering treatment, the crystals remain in the synovial fluid of previously inflamed joints, which allows diagnosis during the intercritical stage.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">MSU crystal deposition precedes the first attack of gout, over a not-well-defined period of time, but presumably long. In subjects with asymptomatic hyperuricemia (AHU), – i.e., without gout attacks or other manifestation attributable to the disease – crystals may be occasionally found in the synovial fluid of joints evaluated for another reason. Using techniques such as ultrasound<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> or <span class="elsevierStyleItalic">dual-energy computed tomography</span> (DECT),<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> it has been estimated that such silent MSU crystal deposition occurs in about 25–30% of subjects with AHU, although not all patients with AHU develop gout. The possible impact of such deposition in those who do not develop clinical inflammation is unknown; recent data show a possible detrimental cardiovascular effect.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The use of Raman spectroscopy for the detection of the crystals, both as synovial fluid and <span class="elsevierStyleItalic">in vivo</span>,<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> has been proposed, but only very recently. The results look very promising, but so far, they are preliminary and must be properly substantiated in the future.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Diagnosis without crystal identification</span><p id="par0030" class="elsevierStylePara elsevierViewall">To date, no technique can replace the synovial fluid analysis to diagnose gout. However, in clinical practice, it is common to establish the diagnosis when compatible clinical symptoms occur in a hyperuricaemic subject, disregarding microscopy as a diagnostic method. This occurs even in specialized care consultations.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> The clinical diagnosis is wrong in one out of every 4 patients.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Given the simplicity and reliability of synovial fluid microscopy, this should not be disregarded even in situations of high probability (e.g., recurrent podagra in a hyperuricaemic patient). Incorporating arthrocentesis and synovial fluid analysis to the evaluation of all patients with arthritis or joint effusion in clinical practice–something that has been, in fact, formally recommended<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a>–allows, on one hand, to maintain proper caution in cases of just a clinical diagnosis, and on the other, diagnose cases of less typical forms of disease presentation.</p><p id="par0035" class="elsevierStylePara elsevierViewall">A new set of classification criteria for gout has been recently validated. It has shown excellent sensitivity and specificity using clinical, laboratory and imaging data.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> However, they are mean to be classification criteria and, as specified by the authors themselves, their aim is to select patients for clinical trials, and therefore should not be used for diagnosis in clinical practice.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Ultrasound and DECT (the latter with limited availability) are imaging techniques that can be helpful to diagnose and evaluate patients with gout, while others such as plain radiography, conventional CT or MRI have a more marginal and specific use. MSU crystal deposition is hyperechogenic, resulting in lines parallel to the cortical bone <span class="elsevierStyleItalic">(double contour sign)</span> given its deposition on the cartilage surface, or aggregates in joints, tendon or periarticular areas, occasionally surrounded by a hypoechoic halo<span class="elsevierStyleItalic">(Tophi).</span> These findings show remarkable results in experienced operators, but, for the moment, they should not replace the synovial fluid analysis, and they do not show sufficient sensitivity, probably because a remarkable crystal load is required for proper ultrasound visualization. An advantage of ultrasound is that it serves as a guide for conducting arthrocentesis on deep joints or punctures of possible deposition areas. On the other hand, DECT allows to characterize almost unequivocally the presence of urate crystals, but needs a crystal load even higher than ultrasound for their visualization, which hampers its sensitivity.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Differential diagnosis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Gout should be included in the differential diagnosis of all patients with acute arthritis, along with arthritis caused by calcium pyrophosphate crystals, septic arthritis and other less common, such as reactive arthritis or psoriatic arthritis. Mechanical joint problems (e.g., arthritis, hemarthrosis) may be occasionally considered as gout attacks. Sometimes, especially in long-progression patients that are not being adequately treated and with extensive deposition, gout can affect several joints (oligo or polyarthritis) and more in a more persistent way, therefore, it should be distinguished from other forms of chronic arthritis, such as rheumatoid arthritis or spondyloarthritis. As mentioned above, the systematic analysis of all synovial fluid extracted greatly facilitates diagnosis of the less typical cases.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Comorbidities</span><p id="par0050" class="elsevierStylePara elsevierViewall">Patients with gout have a high frequency of cardiovascular and renal type comorbidities, linked to the very pathogenesis of the disease: hyperuricemia associated with metabolic syndrome, renal hypoexcretion of uric acid caused by chronic kidney disease and/or use of diuretics, etc. These comorbidities, whose prevalence is significantly higher than in the general population, affect patient prognosis and treatment, therefore, their adequate care is necessary when evaluating patients with gout.</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Cardiovascular risk</span><p id="par0055" class="elsevierStylePara elsevierViewall">The association of gout with atherosclerosis and its complications is jointly related to the metabolic syndrome and the disease itself, which is a proven independent risk factor for all forms of cardiovascular disease.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> This has been associated with MSU crystal-induced inflammation, both the acute form related to the attacks as well as the subclinical form which persists during intercritical stages, as evident in the fact that patients with tophaceous gout–with greater deposition extension and inflammatory state–have an increased risk of developing Q wave infarction and increased mortality. Other factors, such as a hyperuricaemic state or taking anti-inflammatories, could also contribute to increased cardiovascular risk in gout.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Nephropathy</span><p id="par0060" class="elsevierStylePara elsevierViewall">The presence of renal failure in patients with gout is common in clinical practice, although figures vary widely in different published series (3–72%). Kidney disease is primarily due to prevalent processes like nephroangiosclerosis or diabetic nephropathy, although microtophi have been described in the renal medulla which, in long-term untreated patients, could contribute to renal failure.</p></span></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Gout treatment</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objectives</span><p id="par0065" class="elsevierStylePara elsevierViewall">MSU crystal deposition in patients with gout is reversible. Therefore, the treatment strategy objective (non-negotiable) is to remove MSU deposition (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Without crystals, there is no inflammation (or acute attacks, or maintained subclinical inflammation), therefore, gout can be considered cured. The only known method to dissolve deposition is to reduce uric acid levels below their saturation point in a sustained manner. Uric acid reduction in gouty patients determines the decrease in tophi volume until their complete disappearance<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> and the absence of crystals in synovial fluid samples examined microscopically.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> The crystal dissolution rate is slow–usually, years–and is conditioned by the magnitude of existing deposition and by the uric acid level reached with treatment.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">While crystals persist in the joints, the patient may have episodes of acute inflammation, mainly articular, but also in bursae or tendons. Hypouricemic treatment initiation contributes to the appearance of inflammatory episodes, therefore, patients should receive prophylactic treatment (e.g., colchicine). If, despite prophylaxis, inflammatory episodes occur, the patient should receive early and appropriate anti-inflammatory treatment, often self-initiated.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Finally, gout is associated with comorbidities such as cardiovascular risk factors or kidney failure. A gout related medical visit is an opportunity to detect and treat these comorbidities.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Reducing uricemia</span><p id="par0080" class="elsevierStylePara elsevierViewall">To be effective, uric acid must be reduced below the saturation point, although the optimal threshold is still under discussion. Most guidelines recommend reducing uric acid levels below 6<span class="elsevierStyleHsp" style=""></span>mg/dl.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">12,16</span></a> Under certain circumstances (e.g., tophi, structural damage, etc.) a stricter target is usually recommended (<5<span class="elsevierStyleHsp" style=""></span>mg/dl). It is worth mentioning that lower uric acid levels equal faster deposition dissolution. Therefore, the uric acid target will also determine the speed with which the patient will dissolve tophi and deposition. There is no solid evidence to link the reduction of uric acid with unwanted side effects. The proportion of gouty patients who can benefit from tighter uric acid controls can therefore be greater than that expressed in the recommendations (e.g., patients with cardiovascular risk factors).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Treatment initiation should be considered in all patients with a clear diagnosis of gout from the outset.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> In patients with recurrent episodes of inflammation, tophi, nephrolithiasis or structural damage, the hypouricemic treatment is clearly indicated. Since the magnitude of the deposition is directly linked to gout progression time, early treatment allows for a speedier recovery.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> Also, if the presence of crystals–and its associated subclinical inflammation–proves to be an independent risk factor for cardiovascular events and mortality, early treatment may be advisable.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Currently there are different treatment options for reducing uricemia: allopurinol, febuxostat or benzbromarone, among others (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The incorporation of a new drug is expected soon: lesinurad. However, knowing the treatment objective is more important than the choice of drug itself: reducing uric acid below the saturation point. Some drugs can increase serum uric acid levels (such as diuretics) and should be avoided as far as possible; others may offer some uricosuric effect (losartan, fenofibrate).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Xanthine oxidase inhibitors</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Allopurinol</span><p id="par0095" class="elsevierStylePara elsevierViewall">Allopurinol is the most widely used hypouricemic treatment<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> and enjoys an extensive experience. The emergence of new molecules has increased the number of studies on allopurinol. In clinical trials, allopurinol at fixed-doses of 300<span class="elsevierStyleHsp" style=""></span>mg (100–200<span class="elsevierStyleHsp" style=""></span>mg in patients with mild to moderate renal insufficiency) gets uric acid concentration levels <6<span class="elsevierStyleHsp" style=""></span>mg/dl in only 20–40% of patients.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17,18</span></a> However, the use of a fixed and relatively low but frequent dose of allopurinol makes the interpretation of these data difficult. In Spain, allopurinol is authorized to maximum doses of 900<span class="elsevierStyleHsp" style=""></span>mg daily with normal renal function. A study in patients who did not achieve an adequate control of uric acid with 300<span class="elsevierStyleHsp" style=""></span>mg daily of allopurinol showed that increasing the dose to 600<span class="elsevierStyleHsp" style=""></span>mg daily was effective<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a>; doses higher than 600<span class="elsevierStyleHsp" style=""></span>mg daily did not received critical attention.</p><p id="par0100" class="elsevierStylePara elsevierViewall">The main limitation with allopurinol is the potential occurrence of adverse effects. Most are mild and reversible (such as elevated transaminases), but occasionally they may be severe and even fatal (as some hypersensitivity reactions). The occurrence of allergic reactions is associated with the initial dose of allopurinol and the coexistence of renal failure. Therefore, starting with small doses (<1.25<span class="elsevierStyleHsp" style=""></span>mg/day per ml/min of estimated glomerular filtration rate) is recommended.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> Gradual dose increases until reaching the therapeutic goal seems safe. This strategy is known as <span class="elsevierStyleItalic">start low</span>, <span class="elsevierStyleItalic">go slow</span>. Despite these recommendations, most patients never receive doses higher than 300<span class="elsevierStyleHsp" style=""></span>mg daily, especially in primary care. Desensitization regimens have been tested in patients with allergic reactions to allopurinol, but given the availability of alternatives, their use is limited.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Febuxostat</span><p id="par0105" class="elsevierStylePara elsevierViewall">Febuxostat is a non-purine xanthine oxidase inhibitor and is administered in a single daily dose of 80–120<span class="elsevierStyleHsp" style=""></span>mg. In its pivotal studies–where gouty patients with uric acid concentrations above 8<span class="elsevierStyleHsp" style=""></span>mg/dl were included–it achieved the therapeutic target in 45–70% of patients,<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17,18</span></a> a substantially greater percentage than that obtained with a fixed dose of allopurinol. Usually, the starting dose is 80<span class="elsevierStyleHsp" style=""></span>mg (40<span class="elsevierStyleHsp" style=""></span>mg dose is not sold in Europe) and is increased to 120<span class="elsevierStyleHsp" style=""></span>mg after 2–4 weeks if the therapeutic goal is not achieved. In addition, febuxostat is effective and safe in patients with mild and moderate renal impairment, not requiring dose adjustment; there is anecdotal evidence on the use of febuxostat in patients with severe renal impairment (creatinine clearance <30<span class="elsevierStyleHsp" style=""></span>ml/min).</p><p id="par0110" class="elsevierStylePara elsevierViewall">The safety profile is similar to that of allopurinol, with diarrhoea as the main side effect in controlled studies. Transaminase elevation occurs in one out of 10 patients and may require dose adjustment. In case of hypersensitivity reaction to allopurinol, febuxostat has emerged as a safe alternative. However, several studies (retrospective) show that a small proportion of patients with reaction to allopurinol may develop a further reaction when exposed to febuxostat<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a>; more data are needed to substantiate the safety of subsequent treatment with febuxostat after a severe reaction to allopurinol. Currently, caution is recommended in patients with ischaemic heart disease or congestive heart failure, given the increase in adverse events in pivotal studies; there are studies underway to test the drug's safety in this patient group.</p><p id="par0115" class="elsevierStylePara elsevierViewall">At present, febuxostat is an effective alternative in patients intolerant or refractory to allopurinol. In addition, it is a first-line drug in patients with renal impairment or with very high uric acid concentrations.</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Uricosurics</span><p id="par0120" class="elsevierStylePara elsevierViewall">The pathogenesis of most patients with gout is based on decreased renal excretion of uric acid, so increasing its renal clearance is conceptually appealing. Benzbromarone, probenecid and sulfinpyrazone are uricosuric drugs, with different accessibility in each country. In Spain, benzbromarone is accessible but restricted to certain indications and subject to prescription by a rheumatologist or nephrologist. Benzbromarone inhibits tubular reabsorption of uric acid by the URAT-1 transporter and produces a significant reduction in uric acid levels at least as important as that achieved with allopurinol.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">19,22</span></a> Although there is risk of hepatotoxicity–severe in some cases–, this seems very limited in patients of European descent<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a>; the most common side effect is gastrointestinal intolerance. Since it is a drug that facilitates renal excretion of uric acid, benzbromarone should be avoided in previous cases of uric acid nephrolithiasis or excessive renal excretion of uric acid (>700<span class="elsevierStyleHsp" style=""></span>mg/d). Hydration and urine alkalinization hinder the appearance of uric acid lithiasis. As with other potent uric-acid-lowering drugs, it is advisable to start at low doses (e.g., 50<span class="elsevierStyleHsp" style=""></span>mg daily) and then increase the dose gradually until achieving the therapeutic goal, with a maximum of 200<span class="elsevierStyleHsp" style=""></span>mg daily. Given its different mechanism of action, adding moderate doses of benzbromarone to standard doses of allopurinol or febuxostat has demonstrated an additive effect in reducing uric acid levels and can be a strategy in refractory patients.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Lesinurad is a selective inhibitor of uric acid absorption, inhibiting the URAT-1 transporter. It has been approved at doses of 200<span class="elsevierStyleHsp" style=""></span>mg daily in combination with a xanthine oxidase inhibitor. Clinical trials in combination with allopurinol or febuxostat show an increase in the proportion of patients achieving the therapeutic goal.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> There has been a creatinine increase in patients receiving lesinurad, sometimes significant, and more studies are needed to determine its relevance.</p><p id="par0130" class="elsevierStylePara elsevierViewall">There are several drugs used in other diseases with small or moderate uricosuric properties (fenofibrate, losartan, atorvastatin, leflunomide). Although not indicated in gout, they can help control uric acid levels, provided that the patient has comorbidities for which they are approved.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Uricases</span><p id="par0135" class="elsevierStylePara elsevierViewall">Uricase (or urate oxidase) catalyses the degradation of uric acid to allantoin, an easy renal excretion molecule. As a result of these mutations, humans and some primates have no active uricase. The development of recombinant techniques has enabled the production of uricases for human treatment (rasburicase, pegloticase). Rasburicase is marketed for the prevention of tumour lysis syndrome and there are anecdotal cases of its use for refractory gout.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> Pegloticase (a PEGylated uricase) is not currently marketed in Spain, although it has been approved by the FDA.</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of acute episodes</span><p id="par0140" class="elsevierStylePara elsevierViewall">Gouty inflammatory episodes occur with acute arthritis in one or more joints; tend to be self-limiting, but in the absence of treatment last for days or even weeks. Non-pharmacological measures are not usually sufficient for their resolution. NSAIDs (including COX-2 selective inhibitors), glucocorticoids, colchicine and interleukin (IL)-1 inhibitors have proven effective for treatment. The choice of one or the other will be individualized according to their associated comorbidities and preferences. In any case, the chosen treatment effectiveness depends on its early establishment, since this is associated with a faster resolution of the attack.</p><p id="par0145" class="elsevierStylePara elsevierViewall">NSAIDs are widely used in the absence of contraindications. Available studies do not show an anti-inflammatory superiority over others. The use of maximum doses is recommended. Both classic NSAIDs as well as COX-2 are effective in treating acute episodes, the latter with better digestive tolerance.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Glucocorticoids can be used orally, parenterally or intra-articularly. Although there is little published data, intra-articular injection (e.g., triamcinolone acetonide) is a quick and effective option for patients with monoarthritis. The infiltration should be performed after having reasonably ruled out an infectious aetiology. Orally, a brief treatment with glucocorticoids (prednisone 30–35<span class="elsevierStyleHsp" style=""></span>mg for 5–7 days) may be as effective as NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> These guidelines may be accompanied by a rebound effect after suspension, so colchicine should be started simultaneously. Available data regarding intramuscular administration of corticosteroids are rare.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Colchicine at low doses (1.8<span class="elsevierStyleHsp" style=""></span>mg over one hour), established early, is effective and well tolerated.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> High doses should be avoided as gastrointestinal adverse effects are common, with no improvement in efficacy. The dose of colchicine should be reduced in patients with impaired renal or hepatic function.</p><p id="par0160" class="elsevierStylePara elsevierViewall">Inflammation is mediated by IL-1β in gouty arthritis, therefore, blocking the same has therapeutic implications both for the treatment of acute attack as well as for prophylaxis, especially in patients where traditional options are contraindicated. IL-1β inhibitors are well tolerated, although we must pay attention to the potential risk of infection resulting from their use. Canakinumab was approved by the EMA in 2013 for the treatment of acute attacks in patients with recurrent attacks (3 or more in the previous year) and with contraindication or intolerance to NSAIDs, colchicine and glucocorticoids. Two randomized, parallel, double-blind, compared with intramuscular triamcinolone acetonide trials show that the control of acute attacks is achieved faster with canakinumab.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Prophylaxis of acute attack</span><p id="par0165" class="elsevierStylePara elsevierViewall">When the hypouricemic treatment begins, patients maintain–and even transiently increase–the risk of acute attacks. The appearance of inflammatory episodes can negatively affect the confidence and adherence of patients, so the implementation of an appropriate attack prophylaxis is important.</p><p id="par0170" class="elsevierStylePara elsevierViewall">The only drug approved for prophylaxis is colchicine (0.5–1.5<span class="elsevierStyleHsp" style=""></span>mg/d with dose reduction in case of renal failure). In refractory cases or where colchicine is contraindicated, anti-inflammatories may be used (e.g., indomethacin 25<span class="elsevierStyleHsp" style=""></span>mg/d or naproxen 250–500<span class="elsevierStyleHsp" style=""></span>mg/d), low-dose prednisone (<7.5<span class="elsevierStyleHsp" style=""></span>mg/d) or new anti-IL-1 drugs. There is no clear time limit in which prophylaxis should be maintained; one option is to establish it 1–2 weeks prior to hypouricemic treatment initiation, and hold it for 6 months. However, it is not recommended to suspend it in case of recurrent or persistent inflammation, evidence of tophi or if the desired levels of uric acid have not been reached.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Lifestyle</span><p id="par0175" class="elsevierStylePara elsevierViewall">Numerous studies have evaluated the relationship between different foods and uric acid levels. Alcoholic beverages, mainly beer and spirits, are related to increased uric acid.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> Foods rich in animal proteins as well as sugary drinks (soft drinks) and foods rich in fructose have been linked to increased uric acid levels, while foods such as dairy products, vegetable proteins (legumes, nuts) coffee and low-fat products are associated with lower levels of uric acid.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> It is advisable to minimize the intake of alcohol (especially beer); however, the impact that restrictive diets could have has not been critically evaluated.</p><p id="par0180" class="elsevierStylePara elsevierViewall">The coexistence of cardiovascular risk factors such as obesity, hypertension, dyslipidaemia, etc., is common in patients with gout. Therefore, recommendations for a heart-healthy diet, regular exercise, weight control and smoking cessation should be incorporated into medical consultations of patients with gout.</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusions</span><p id="par0185" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0190" class="elsevierStylePara elsevierViewall">The diagnosis of gout should be performed based on the identification of MSU crystals in a sample of synovial fluid or tophus aspirate.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0195" class="elsevierStylePara elsevierViewall">The therapeutic goal in gout is the dissolution of crystal deposition. To achieve this, we must reduce uric acid levels <6<span class="elsevierStyleHsp" style=""></span>mg/dl. In selected patients, more stringent treatment goals should be considered (<5<span class="elsevierStyleHsp" style=""></span>mg/dl), as a lower uricemia means quicker crystal dissolution.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0200" class="elsevierStylePara elsevierViewall">Initial treatment options include xanthine oxidase inhibitors: allopurinol and febuxostat.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">•</span><p id="par0205" class="elsevierStylePara elsevierViewall">If the therapeutic goal is not achieved, the dose can be increased or combined with a uricosuric drug.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">•</span><p id="par0210" class="elsevierStylePara elsevierViewall">Cardiovascular risk factor screening should be conducted in all patients diagnosed with gout.</p></li></ul></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of interests</span><p id="par0215" class="elsevierStylePara elsevierViewall">FS has received fees from Menarini regarding educational programmes and presentations and has participated in AstraZeneca's <span class="elsevierStyleItalic">advisory board</span>. MA has received fees from Menarinin associated with presentations and has participated in AstraZeneca's <span class="elsevierStyleItalic">advisory board</span>. NQ declares no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Diagnosis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Identification of crystals (gold standard)" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnosis without crystal identification" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Differential diagnosis" ] 3 => array:3 [ "identificador" => "sec0025" "titulo" => "Comorbidities" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Cardiovascular risk" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Nephropathy" ] ] ] ] ] 1 => array:3 [ "identificador" => "sec0040" "titulo" => "Gout treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Objectives" ] 1 => array:3 [ "identificador" => "sec0050" "titulo" => "Reducing uricemia" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0055" "titulo" => "Xanthine oxidase inhibitors" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Allopurinol" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Febuxostat" ] ] ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Uricosurics" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Uricases" ] ] ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Treatment of acute episodes" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Prophylaxis of acute attack" ] 4 => array:2 [ "identificador" => "sec0090" "titulo" => "Lifestyle" ] ] ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Conclusions" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Conflict of interests" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-04" "fechaAceptado" => "2016-10-20" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Sivera F, Andrés M, Quilis N. Diagnóstico y tratamiento de la gota. Med Clin (Barc). 2017;148:271–276.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3307 "Ancho" => 1500 "Tamanyo" => 474726 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Synovial fluid microscopy at 600-magnification with ordinary light (top image), where a needle-shape crystal is shown inside a leucocyte. Under simple polarized light (middle image), the glass shows strong birefringence which, after applying the first order red compensator (below), is confirmed as negative birefringence–as it is yellow in colour and is positioned parallel to the compensator's axis (arrow)–. Photographs courtesy of Prof. Eliseo Pascual.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">MSU, monosodium urate.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Primary objective \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Elimination of MSU crystal deposition<br>Surrogate marker: serum uric acid levels<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>5–6<span class="elsevierStyleHsp" style=""></span>mg/dl \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Secondary objectives \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1. Treatment of acute inflammatory episodes<br>2. Prevention of acute inflammatory episodes<br>3. Detection and treatment of comorbidities \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1391573.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Objectives in the treatment of gout.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">NSAIDs, non-steroidal anti-inflammatory drugs; COX, cyclooxygenase.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reduce uric acid \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment and prevention of acute episodes \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Xanthine oxidase inhibitors</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="7" align="left" valign="top">NSAIDs (traditional and COX-2 inhibitors)<br>Colchicine<br>Corticosteroids (intraarticular or systemic)<br>Inhibitors of interleukin-1</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Allopurinol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Febuxostat \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Uricosurics</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Benzbromarone \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lesinurad \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Uricases</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1391574.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Summary of treatments in gout by objectives.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multinational evidence-based recommendations for the diagnosis and management of gout: Integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. 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