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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Gout&#44; a common inflammatory arthritis&#44; is induced by the local formation and deposition of monosodium urate crystals in joints due to excess serum uric acid in blood or tissue fluid&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">1&#44;2</span></a> The global burden of gout disease is rapidly growing&#44; and although the reported prevalence of gout varies from region to region and ranges from &#60;1&#37; to 6&#46;8&#37;&#44; poor medication adherence and failure to control diet are common phenomena in patients with gout&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The typical arthritis of gout is a monoarthritis attack of the lower extremities with severe pain&#44; localized swelling&#44; and reddened skin&#44; which usually resolves completely in 1&#8211;2 weeks&#44; even without treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">4&#44;5</span></a> However&#44; with the dual influence of disease duration continuation and irregular treatment&#44; the arthritic manifestations of gout become atypical or even refractory&#44; such as when the joint is no longer in complete remission within 2 weeks&#44; multiple joints have flares simultaneously&#44; and the frequency of flares markedly increases&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The persistence of joint pain after gout flares is likely to be a key turning point in the progression of gout from punctuated attacks to chronic arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;9</span></a> In-depth dissection of this clinical state can help clinicians judge a patient&#39;s condition and even provide clues to explore metabolic pathways or novel therapeutic targets associated with gout exacerbation&#46; Currently&#44; little is known about the clinical significance and associated factors of persistent joint pain after gout flares&#46; This study retrospectively collected detailed data on these patients and explored the associated clinical&#44; laboratory&#44; and imaging factors of this clinical condition from several aspects&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This was a cross-sectional study which included gout patients who visited Beijing Jishuitan Hospital from January 2016 to December 2022&#44; and those who met the inclusion and exclusion criteria were included in the analysis in the final study&#46; This study was approved by the ethics review of the Beijing Jishuitan Hospital &#40;approval of Ethics Committee&#58; Jilun&#91;K2023&#93;-&#91;125&#93;-00&#41;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0025" class="elsevierStylePara elsevierViewall">Data for patients with a diagnosis of gout were obtained in the electronic medical record system of Beijing Jishuitan Hospital&#46; Then&#44; the study subjects were included after screening with the inclusion and exclusion criteria&#46; The inclusion criteria were as follows&#58; &#40;1&#41; meeting the 2015 ACR&#47;EULAR classification criteria for gout &#40;&#8805;8 points&#41;&#59; &#40;2&#41; VAS score greater than or equal to 4 at gout flare&#59; &#40;3&#41; VAS scores recorded more than 2 times&#59; and &#40;4&#41; VAS score was recorded at least every 2 weeks after gout flare and the number of times documented was &#8805;3 times&#46; The exclusion criteria were as follows&#58; &#40;1&#41; other inflammatory arthritis&#44; such as rheumatoid arthritis&#44; ankylosing spondylitis&#44; psoriatic arthritis&#44; reactive arthritis and infectious arthritis&#44; among others&#59; &#40;2&#41; severe liver and kidney disease&#59; and &#40;3&#41; chronic infections&#44; such as tuberculosis&#44; viral hepatitis &#40;hepatitis B&#44; C&#44; <span class="elsevierStyleItalic">etc&#46;</span>&#41;&#44; and brucellosis&#46; The VAS &#40;Visual Analog Score&#41; ranges from 0 to 10 points&#46; Patients with VAS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>4 points after 4 weeks of gout flares were included in the persistent joint-pain group&#44; and patients with VAS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 points were included in the nonpersistent joint-pain group&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data collection and definition</span><p id="par0030" class="elsevierStylePara elsevierViewall">Demographic information&#44; present medical history and physical examination data&#44; laboratory tests&#44; and musculoskeletal ultrasound results were obtained from the electronic medical record system&#46; Detailed records of the involved joints with gout&#44; the number of gout flares in the last 1 year&#44; the joint sites with gout flares at the time of inclusion in the study&#44; and VAS scores were obtained&#46; History of alcohol consumption&#44; smoking&#44; family history&#44; hypertension&#44; diabetes&#44; CVD and medication after gout flare were recorded&#46; Disease duration was defined as the time from the first gout flare to the time of inclusion in the study&#46; A senior sonographer reviewed the musculoskeletal ultrasound findings and resolved four gout-related lesions based on international expert consensus<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a>&#58; tophus&#44; double contour&#44; aggregates&#44; and erosion&#46; Metabolic syndrome was defined as having at least 3 of the following<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a>&#58; &#40;1&#41; abdominal obesity&#58; waist circumference<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>90<span class="elsevierStyleHsp" style=""></span>cm for men and &#8805;85<span class="elsevierStyleHsp" style=""></span>cm for women&#59; &#40;2&#41; hyperglycemia&#58; fasting plasma glucose<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>6&#46;1<span class="elsevierStyleHsp" style=""></span>mmol&#47;L or a 2-h glucose load<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>7&#46;8<span class="elsevierStyleHsp" style=""></span>mmol&#47;L and&#47;or had been treated for established diabetes&#59; &#40;3&#41; hypertension&#58; blood pressure<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>130&#47;85<span class="elsevierStyleHsp" style=""></span>mmHg and&#47;or had confirmed hypertension and been treated&#59; &#40;4&#41; fasting TG<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;70<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#59; and &#40;5&#41; fasting HDL-C<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1&#46;04<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#46; The metabolic score equals the number of metabolic syndrome components&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">R &#40;version 4&#46;2&#46;2&#41; was used to analyze all data&#46; Measurements meeting a normal distribution are presented as the mean with standard deviation <span class="elsevierStyleItalic">&#40;mean</span><span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD&#41;</span>&#44; and measurements not meeting a normal distribution are presented as the median and interquartile range <span class="elsevierStyleItalic">&#91;M &#40;Q1&#44; Q3&#41;&#93;</span>&#46; The counting data were expressed as numbers and percentages&#46; Chi-square tests were used to compare differences in rates between two or more groups&#46; Contrasts of metered data between two groups were evaluated according to whether they conformed to a normal distribution using Student&#39;s <span class="elsevierStyleItalic">t</span> test or a nonparametric test &#40;Mann&#8211;Whitney&#41;&#46; Comparisons of multigroup metrology data that conformed to a normal distribution and were homogeneous in variance were performed by one-way ANOVA&#46; Multigroup metrology data that did not follow a normal distribution were compared by a nonparametric test &#40;Kruskal&#8211;Wallis <span class="elsevierStyleItalic">H</span>&#41;&#46; Logistic regression was used to correct for confounders between the independent variable and the dependent variable&#46; <span class="elsevierStyleItalic">P</span> values were corrected using the Bonferroni method after pairwise comparisons&#46; The Spearman correlation test was used to analyze the correlation between two variables&#44; and LOESS &#40;locally weighted regression&#41; was used to fit the curve between two variables&#46; Two-sided <span class="elsevierStyleItalic">P</span> values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 were considered to indicate statistical significance&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0040" class="elsevierStylePara elsevierViewall">A total of 1029 gout patients were included in the study&#59; 1007 &#40;97&#46;9&#37;&#41; were men&#44; and the mean age was 41&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;2 years&#46; There were 182 &#40;17&#46;7&#37;&#41; patients who developed persistent joint pain after gout flares&#44; and the duration of persistent joint pain was 8 weeks &#40;4 weeks&#44; 12 weeks&#41;&#46; The top three joints with persistent joint pain involvement were the knees &#40;93&#44; 51&#46;1&#37;&#41;&#44; ankles &#40;73&#44; 40&#46;1&#37;&#41;&#44; and metatarsophalangeal joints &#40;14&#44; 7&#46;7&#37;&#41;&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Demographic and basic clinical information</span><p id="par0045" class="elsevierStylePara elsevierViewall">Compared with patients with nonpersistent joint pain&#44; patients with persistent joint pain after gout flares were older&#44; had longer disease duration&#44; and had more patients with a history of smoking and drinking&#46; There were no significant differences in sex&#44; BMI&#44; waist circumference&#44; or family history between the two groups&#46; Patients with persistent joint pain used more anti-inflammatory drugs&#44; including colchicine&#44; NSAIDs&#44; and glucocorticoids&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Comparison of joint involvement</span><p id="par0050" class="elsevierStylePara elsevierViewall">Disease burden related to joints was significantly more severe in patients with persistent joint pain after gout flares than in those with nonpersistent joint pain&#46; Patients with persistent joint pain had more total involved joints &#91;5&#46;0 &#40;3&#46;0&#8211;7&#46;0&#41; <span class="elsevierStyleItalic">vs&#46;</span> 2&#46;0 &#40;1&#46;0&#8211;5&#46;0&#41;&#93;&#44; more gout flares in the past year &#91;4&#46;0 &#40;2&#46;0&#8211;8&#46;0&#41; <span class="elsevierStyleItalic">vs&#46;</span> 2&#46;0 &#40;1&#46;0&#8211;4&#46;0&#41;&#93;&#44; and more joints with simultaneous gout flares &#91;2&#46;0 &#40;1&#46;0&#8211;3&#46;0&#41; <span class="elsevierStyleItalic">vs&#46;</span> 1&#46;0 &#40;1&#46;0&#8211;2&#46;0&#41;&#93;&#44; all <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;01</span> after adjustment for age&#44; duration&#44; and drinking&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Musculoskeletal ultrasound was performed in 585 patients&#44; including 129 patients with persistent joint pain and 456 patients with nonpersistent joint pain&#46; Among the lesions explored by musculoskeletal ultrasound associated with gout&#44; patients with persistent joint pain had a higher incidence of tophus &#40;36&#46;4&#37; <span class="elsevierStyleItalic">vs&#46;</span> 21&#46;1&#37;&#41; and bone erosion &#40;18&#46;6&#37; <span class="elsevierStyleItalic">vs&#46;</span> 8&#46;6&#37;&#41;&#44; with all <span class="elsevierStyleItalic">P</span> values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 after adjustment for age&#44; duration&#44; and drinking&#46; Double contour was observed in 28&#46;7&#37; of patients with persistent joint pain and 19&#46;3&#37; of patients with nonpersistent joint pain&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;05</span> before adjustment for confounders and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;221</span> after adjustment&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Laboratory measures and comorbidities</span><p id="par0060" class="elsevierStylePara elsevierViewall">In terms of laboratory measures&#44; higher UA &#91;563&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>147&#46;8 <span class="elsevierStyleItalic">vs&#46;</span> 523&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>139&#46;1&#44; &#956;mol&#47;L&#93; and lower TBil &#91;12&#46;4 &#40;9&#46;3&#8211;16&#46;7&#41; <span class="elsevierStyleItalic">vs&#46;</span> 15&#46;4 &#40;11&#46;8&#8211;20&#46;5&#41;&#44; &#956;mol&#47;L&#93; were found in patients with persistent joint pain&#44; with all <span class="elsevierStyleItalic">P</span> values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001</span> after adjustment for age&#44; duration&#44; and drinking&#46; In terms of comorbidities&#44; hypertension &#91;54&#46;9&#37; <span class="elsevierStyleItalic">vs&#46;</span> 38&#46;7&#37;&#93; and metabolic syndrome &#40;58&#46;8&#37; <span class="elsevierStyleItalic">vs&#46;</span> 46&#46;4&#37;&#41; were both more frequent in patients with persistent joint pain&#44; with all <span class="elsevierStyleItalic">P</span> values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 after adjustment for age&#44; disease duration&#44; and drinking&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Association of TBIL with persistent joint pain&#44; uric acid and metabolic syndrome</span><p id="par0065" class="elsevierStylePara elsevierViewall">With increasing quartiles of TBil&#44; the incidence of persistent joint pain decreased &#40;<span class="elsevierStyleItalic">P for trend</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001</span>&#41;&#44; uric acid decreased progressively &#40;<span class="elsevierStyleItalic">P for trend</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001</span>&#41; and the incidence of metabolic syndrome decreased progressively &#40;<span class="elsevierStyleItalic">P for trend</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001</span>&#41;&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">LOESS &#40;locally weighted regression&#41; was used to fit the curve of TBil to the incidence of persistent joint pain&#44; uric acid values and metabolic syndrome scores&#46; TBil was negatively correlated with the incidence of persistent joint pain &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001&#44; r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#8722;0&#46;190</span>&#41;&#44; with UA values &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001&#44; r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#8722;0&#46;125</span>&#41;&#44; and with metabolic syndrome scores &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;001&#44; r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#8722;0&#46;192</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Chronic pain significantly affects people&#39;s quality of life and daily activities and has a multifaceted impact on patients&#8217; emotional and psychological well-being&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">12</span></a> Acute episodes of severe pain are typical at the onset of gout&#44; and such pain usually resolves within 2 weeks with a period of complete remission&#44; which can range from a few months to years&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">13</span></a> Chronic pain begins to appear in gout patients as the disease worsens&#46; Chronic pain is also one of the clinical manifestations in patients with gout&#44; as 182 &#40;17&#46;7&#37;&#41; patients in this study developed persistent pain for &#62;4 weeks after gout flares&#46; The reason for this persistent joint pain may be that as the condition continues to progress&#44; metabolic and immune interaction homeostasis is further imbalanced&#44; and monosodium urate crystals are no longer easily and completely dissolved&#44; which continually stimulates inflammatory production&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">14&#8211;16</span></a> The musculoskeletal ultrasound findings in this study could support this idea&#46; Higher incidences of tophi and double contour signs were detected by ultrasonography in patients with persistent joint pain after gout flares&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Joint involvement by gout can manifest as synovitis&#44; tendon inflammation&#44; excessive deposition of monosodium urate &#40;tophi or double contour sign&#41;&#44; bone erosion&#44; and ultimately destruction of joint architecture&#44; thereby limiting joint mobility&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">17&#8211;20</span></a> Arthritis represents a major disease burden in gout&#46; The results in this study demonstrate that patients with persistent joint pain after gout flares have a significantly greater joint disease burden&#44; including more affected joints&#44; more flares in the last year&#44; and a greater number of simultaneous flares&#46; These results suggest that persistent joint pain occurrence implies an aggravation of joint disease burden and that this symptom may be a turning point in the progression of gout to the chronic phase&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Tophi and bone erosion are closely associated with persistent monosodium urate deposition and are culprits for the destruction of joint architecture&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">21&#8211;23</span></a> Musculoskeletal ultrasound&#44; which enables earlier detection of tophi and bone erosion&#44; is a sensitive method of quantifying the progression of gout&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">24&#44;25</span></a> The results of this article showed a higher incidence of tophi and bone erosion detected by ultrasound in patients with persistent joint pain&#44; suggesting that the presence of this simple symptom is a marker of further worsening of gouty joint involvement&#46; Patients with persistent joint pain after gout flares require strict adherence to the treat-to-target &#40;T2T&#41; of serum urate &#40;SUA&#41; to reduce the risk of joint destruction&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The spectrum of comorbidities of gout is very broad&#44; including hypertension&#44; diabetes&#44; lipid metabolism abnormalities&#44; metabolic syndrome&#44; cardiovascular and cerebrovascular diseases&#44; venous thrombosis&#44; and even neurodegenerative diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a> The development of comorbidities is closely related to both hyperuricemia and monosodium urate-induced inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">27&#44;28</span></a> The results of this study show that patients with persistent joint pain after gout flares had higher rates of both hypertension &#40;54&#46;9&#37; <span class="elsevierStyleItalic">vs&#46;</span> 38&#46;7&#37;&#41; and metabolic syndrome &#40;58&#46;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 46&#46;4&#37;&#41;&#46; Hyperuricemia is a major metabolic abnormality in gout&#44; and the results of the present article also showed that patients with persistent joint pain had higher uric acid levels &#40;563&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>147&#46;8 <span class="elsevierStyleItalic">vs&#46;</span> 523&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>139&#46;1&#41;&#46; Hypertension&#44; metabolic syndrome&#44; and hyperuricemia are risk factors for cardiovascular disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">26&#44;29</span></a> Recent studies have also reported that gout flares are associated with a significant increase in cardiovascular events after flares&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a> Patients with persistent joint pain after gout flares deserve our attention because of the very high number of gout flares per year and because they have a more severe metabolic syndrome&#44; all of which are factors that predispose them to cardiovascular events&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Bilirubin is derived from the breakdown of heme&#44; which is decomposed to form biliverdin under the action of heme oxygenase and subsequently reduced to bilirubin under the action of biliverdin reductase&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a> Bilirubin was considered in the past as a marker of liver disease and jaundice&#44; especially when excessively high levels of bilirubin would affect cellular metabolic activity and even lead to neurological damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">32&#44;33</span></a> Currently&#44; there is increasing evidence that mild or physiological elevations in bilirubin are protective against a variety of diseases&#44; and bilirubin is an antioxidant that can directly scavenge reactive oxygen species and suppress oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">34&#44;35</span></a> Among the numerous oxidants&#44; bilirubin has the strongest activity of scavenging superoxide and peroxide radicals&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Studies have shown that higher bilirubin levels are inversely associated with risk factors for cardiovascular disease&#44; including obesity&#44; dyslipidemia&#44; and hypertension&#44; and have associations with inflammatory diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> Bilirubin plays antioxidant&#44; anti-inflammatory and antidipogenic roles in these diseases&#44; and bilirubin is a potentially valuable therapeutic target&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a> The results of the present study&#44; which showed a negative correlation between bilirubin levels and metabolic syndrome scores in patients with gout&#44; are in line with the above reports&#46; A large population cross-sectional study found an inverse association between bilirubin and new-onset hyperuricemia &#91;<span class="elsevierStyleItalic">OR &#40;95&#37; CI&#41;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;63 &#40;0&#46;50&#8211;0&#46;81&#41;&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> The present study provided further evidence of an inverse correlation between bilirubin levels and uric acid levels in patients with gout&#46; Encouragingly&#44; the results of the present study also showed an inverse correlation between bilirubin levels and the incidence of persistent joint pain after gout flares&#46; Taken together&#44; these results suggest that bilirubin may be a protective agent against the exacerbation of gout&#44; and we expect more future studies to confirm our inference and successfully use it in clinical practice&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The limitations of this article include the following&#46; First&#44; this was a retrospective study&#44; and some variables failed to be fully precisely controlled&#44; such as the specific details of the urate-lowering therapy of the patients&#46; Second&#44; the primary outcome measures of this study included VAS scores&#44; which were affected by some subjective factors&#46; However&#44; the pain triggered by a typical gout flare can typically be completely relieved within 2 weeks&#44; which also reduces the bias caused by subjectivity in pain assessment&#46; Third&#44; due to the limitations of this cross-sectional study&#44; it cannot show the follow-up development of patients with persistent joint pain after a gout flare&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; persistent joint pain after a gout flare predicts worsening of the disease burden of gout in both dimensions of arthritis and comorbidity&#44; and bilirubin has the potential to be a protective agent for gout exacerbation&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Authors&#8217; contributions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Wei Liu&#44; Peng Dong&#44; Chunyan Li&#44; Husheng Wu&#44; Hui Song conceived the project and designed the clinical study flow&#46; Wen Guo reviewed the ultrasound reports and Kaiping Zhao developed the statistical methods for this paper&#46; Wei Liu&#44; Peng Dong&#44; Siliang Man&#44; Liang Zhang collected the clinical data&#46; Wei Liu wrote the text of the article&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Data availability statement</span><p id="par0120" class="elsevierStylePara elsevierViewall">Data that support the findings of this study are available from the corresponding author&#44; Hui Song upon reasonable request&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Financial support</span><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs1">The capital health research and development of special</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">2018-4-2075</span>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare no competing interests&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A subset of gout patients developed persistent joint pain after flares&#46; Analysis of this clinical phenomenon may shed further light on the factors related to worsening gout and even provide clues to its pathogenesis&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We analyzed the clinical&#44; laboratory&#44; and ultrasound data of gout patients to explore the associations of these data with persistent joint pain after gout flares&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 1029 gout patients were included&#58; 182 &#40;17&#46;7&#37;&#41; patients with persistent joint pain and 847 &#40;82&#46;3&#37;&#41; patients with nonpersistent joint pain&#46; Patients with persistent joint pain had more total involved joints&#44; more gout flares in the past year&#44; and more joints with simultaneous gout flares &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Among the ultrasound-detected lesions&#44; patients with persistent joint pain had a higher incidence of tophus &#40;36&#46;4&#37; <span class="elsevierStyleItalic">vs&#46;</span> 21&#46;1&#37;&#41; and bone erosion &#40;18&#46;6&#37; <span class="elsevierStyleItalic">vs&#46;</span> 8&#46;6&#37;&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Higher UA and lower TBil were found in patients with persistent joint pain &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Hypertension &#40;54&#46;9&#37; <span class="elsevierStyleItalic">vs&#46;</span> 38&#46;7&#37;&#41; and metabolic syndrome &#40;58&#46;8&#37; <span class="elsevierStyleItalic">vs&#46;</span> 46&#46;4&#37;&#41; were both more frequent in patients with persistent joint pain &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; TBil was negatively correlated with the incidence of persistent joint pain &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;190&#41;&#44; UA values &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;125&#41;&#44; and metabolic syndrome scores &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;192&#41;&#46; A correlation curve was fitted using LOESS &#40;locally weighted region&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Persistent joint pain after gout flares is a marker of increased disease burden in gout&#46; The significance of the level of total bilirubin for the exacerbation of gout deserves further study&#46;</p></span>"
        "secciones" => array:4 [
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            "titulo" => "Objectives"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Un subgrupo de pacientes con gota desarroll&#243; dolor articular persistente tras los brotes&#46; El an&#225;lisis de este fen&#243;meno cl&#237;nico puede arrojar m&#225;s luz sobre los factores relacionados con el empeoramiento de la gota e incluso proporcionar pistas sobre su patogenia&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Analizamos los datos cl&#237;nicos&#44; de laboratorio y de ultrasonido de los pacientes para explorar la asociaci&#243;n de estos datos con el dolor articular persistente despu&#233;s de un ataque de gota&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 1029 pacientes en el estudio&#58; 182 &#40;17&#44;7&#37;&#41; con dolor articular persistente y 847 &#40;82&#44;3&#37;&#41; con dolor articular insostenible&#46; Los pacientes con dolor articular persistente ten&#237;an un mayor n&#250;mero total de articulaciones afectadas&#44; m&#225;s ataques gotosos en el &#250;ltimo a&#241;o y m&#225;s articulaciones con ataques gotosos simult&#225;neos &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#44; y los pacientes con dolor articular persistente ten&#237;an una mayor incidencia de c&#225;lculos gotosos &#40;36&#44;4&#37; frente a 21&#44;1&#37;&#41; y erosi&#243;n &#243;sea &#40;18&#44;6&#37; frente a 8&#44;6&#37;&#41; &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; Los pacientes con dolor articular persistente ten&#237;an un &#225;cido &#250;rico m&#225;s alto y una bilirrubina m&#225;s baja &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; La hipertensi&#243;n arterial &#40;54&#44;9&#37; frente al 38&#44;7&#37;&#41; y el s&#237;ndrome metab&#243;lico &#40;58&#44;8&#37; frente al 46&#44;4&#37;&#41; son m&#225;s frecuentes en pacientes con dolor articular persistente &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; La bilirrubina se asocia negativamente con la incidencia de dolor articular persistente&#44; &#225;cido &#250;rico y s&#237;ndrome metab&#243;lico&#46; Una curva de correlaci&#243;n fue ajustada con Loess &#40;regi&#243;n de peso local&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El dolor articular persistente despu&#233;s del ataque de gota es una marca de aumento de la carga de la enfermedad en la gota&#46; La importancia de los niveles de bilirrubina total en el empeoramiento de la gota merece un estudio m&#225;s detallado&#46;</p></span>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Trends in persistent joint pain&#44; uric acid&#44; and metabolic syndrome grouped by TBil quartiles&#46; &#40;a&#41; Incidence of persistent joint pain&#46; &#40;b&#41; Uric acid values&#46; &#40;c&#41; Incidence of metabolic syndrome&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Correlation curves between TBil and persistent joint pain&#44; UA and metabolic score&#46; &#40;e&#41; Probability of persistent joint pain&#46; &#40;f&#41; Uric acid values&#46; &#40;g&#41; Metabolic score&#46;</p>"
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                  \t\t\t\t">GLU &#40;&#956;mol&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">CHOL &#40;mmol&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">TRIG &#40;mmol&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">HDL-C &#40;mmol&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">LDL-C &#40;mmol&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#947;-GT &#40;IU&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">TBil &#40;&#956;mol&#47;L&#41;&#44; <span class="elsevierStyleItalic">M &#40;Q1&#44; Q3&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Hypertension&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;930 &#40;1&#46;397&#8211;2&#46;666&#41;&nbsp;\t\t\t\t\t\t\n
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