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as well as the influence of adiposity on the RA inflammatory process&#46; However&#44; the association between adipocytokines with inflammatory cytokine levels is poorly understood&#46; Therefore&#44; the objective of this study is to describe the relationship between Leptin&#44; Adiponectin and Resistin with the disease activity of RA patients and the levels of several inflammatory cytokines&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patient selection</span><p id="par0015" class="elsevierStylePara elsevierViewall">Patients were recruited at the Rheumatology clinic of the Hospital General de Cuernavaca in Morelos&#44; Mexico between 2007 and 2009&#46; The study protocol was reviewed and approved by the Hospital ethics&#8217; committee&#46; All patients followed a similar treatment strategy&#58; methotrexate &#40;7&#46;5&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#41; in combination with cloroquine 150<span class="elsevierStyleHsp" style=""></span>mg&#47;d and prednisone &#8804;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; <span class="elsevierStyleItalic">Inclusion criteria&#58;</span> Patients included were seen consecutively and had Rheumatoid Arthritis&#44; classified according to the American College of Rheumatology 1987 criteria<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a>&#59; their ages ranged from 18 to 75 years&#59; signed informed consent was obtained from all of the patients and they all had a complete clinical file at the hospital&#46; Disease activity was measured using DAS28 based on the number of swollen and tender peripheral joints&#44; the patients&#8217; overall assessment by visual analog scale &#40;VAS&#41; and the erythrocyte sedimentation rate &#40;ESR&#41;&#46; The patients underwent a clinical evaluation performed by a single rheumatologist&#59; venous blood samples were withdrawn afterwards and plasma samples were separated on the same day of collection and frozen at &#8722;75<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; All patients received combination treatment with DMARDs &#40;mainly methotrexate and cloroquine&#41; and&#44; in some cases&#44; 10<span class="elsevierStyleHsp" style=""></span>mg or less per day of prednisone&#46; NSAID and analgesics were prescribed on demand&#46; No patients were treated with biologics due to health coverage limitations&#46; For the comparative analysis&#44; patients were stratified according to DAS28 into the following groups&#58; low disease activity &#40;DAS28 &#8804;3&#46;5&#41;&#44; moderate activity &#40;DAS28 &#62;3&#46;5 to &#8804;5&#46;1&#41; and high disease activity &#40;DAS28 &#62;5&#46;1&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Quantification of adipocytokine and cytokine blood levels</span><p id="par0020" class="elsevierStylePara elsevierViewall">Leptin&#44; Adiponectin&#44; Resistin&#44; IL-1&#946;&#44; IL-6&#44; IL-17 and TNF&#945; levels were determined from venous blood plasma by optimized ELISA employing specific monoclonal antibodies &#40;Santa Cruz Biotechnology&#44; eBioscience&#41;&#46; Calibrated curves were prepared in each plate employing a recombinant human standard for each metabolite &#40;Peprotech Inc&#46;&#41;&#46; All essays were performed by in triplicate for each sample&#46; Calibration curves fitted a linear regression with a correlation higher than 0&#46;85 and a <span class="elsevierStyleItalic">p</span> value &#60;0&#46;05&#37;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0025" class="elsevierStylePara elsevierViewall">Descriptive statistics were employed and results were expressed as means and standard deviations&#46; A one way ANOVA &#40;Kruskal&#8211;Wallis test&#41; was performed to compare DAS28-patients subgroups&#46; The comparison between groups was done using the Mann&#8211;Whitney test and correlation between variables was determined using Spearman&#39;s test &#40;PRISM v&#46;6&#46;0&#41;&#44; controlling for gender&#44; age&#44; years since onset of disease&#44; BMI and ESR &#40;STATA v&#46;13&#41;&#46; The level of statistical significance was set at 0&#46;05&#37;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0030" class="elsevierStylePara elsevierViewall">121 patients with RA were included in the study&#46; It is worth recognizing there were differences in the number of patients for each activity subgroup&#44; with only 22 patient in the low activity group&#44; while 56 patients had moderate activity &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; However&#44; the three subgroups were similar in gender&#44; age&#44; BMI&#44; time since onset of disease and RF or anti-CCP antibody titers&#46; Although most patients were overweight&#44; no differences were seen between the activity subgroups&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">There was a significant difference in Leptin&#44; Resistin&#44; IL-6 and IL-17 levels when comparing between activity subgroups using one-way ANOVA &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In the particular case of Leptin&#44; when comparing DAS28 subgroups&#44; all showed mutual statistical differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; suggesting a positive relation with the increase in the DAS28 score&#46; In a similar manner&#44; a significant mean difference for Resistin levels was observed by comparing the low vs&#46; high activity subgroups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0007&#41;&#59; however&#44; this was not the case when comparing the moderate vs&#46; high activity subgroups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;080&#41; or when comparing the low vs&#46; moderate activity subgroups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;107&#41;&#46; In contrast&#44; Adiponectin did not shown differences between clinical activity subgroups&#46; For its part&#44; the low activity subgroup showed lower IL-6 levels than the moderate &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41; or high activity subgroups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#46; Similarly&#44; the low activity subgroup also showed lower IL-17 levels compared to the moderate &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41; or high activity &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0003&#41; subgroups&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Leptin levels positively correlated with DAS28 &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;513&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; but not with age&#44; the time since onset of disease or BMI&#46; There was also an important correlation between Leptin and IL-1&#946; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;585&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#44; suggesting a relationship between this adipocytokine and activation of the immune response&#46; Significant correlations were also observed with Resistin &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;274&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and TNF&#945; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;277&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46; Likewise&#44; Resistin levels showed a positive relationship with DAS28 &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;403&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; but not with the other clinical parameters&#46; Additionally&#44; Resistin only showed a positive significant association with Leptin &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;277&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and IL-6 levels &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;256&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; For its part&#44; the same analysis confirmed the absence of an association of Adiponectin with disease activity &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;151&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; however it showed a negative correlation with TNF&#945; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;418&#41; and IL-17 &#40;&#8722;0&#46;283&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; and a positive correlation with IL-1&#946; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;596&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Both IL-6 and IL-17 showed a significant positive correlation with DAS28 &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;313&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;373&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001 for IL-6 and IL-17&#44; respectively&#41;&#46; On the other hand&#44; TNF&#945; levels were not associated with clinical activity &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; For its part&#44; a significant correlation between DAS28 and IL-1&#946; &#40;rho<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;213&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; was seen&#44; although it was not possible to differentiate by activity subgroups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0050" class="elsevierStylePara elsevierViewall">The present study supports previous ones suggesting that Leptin and Resistin are positively associated with RA disease activity&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">2&#44;3</span></a> but while Resistin showed a limited correlation with other inflammatory cytokines&#44; Leptin showed a positive association with IL-1&#946;&#46; It must be remembered though that in some studies&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> the observations have been longitudinal while this study made a single&#44; transversal measurement&#46; In contrast to other authors&#8217; publications&#44; we found no correlation between Leptin and IL-6<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> or IL-17&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> possibly because of differences in the origin of samples &#40;synovial fluid versus peripheral blood&#41; and design &#40;transversal versus longitudinal&#41;&#46; Otherwise&#44; in support of the present results&#44; studies with human pancreatic islet or cord blood T-cells showed that <span class="elsevierStyleItalic">in vitro</span> stimulation by Leptin was able to induce IL-1&#946; secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Conversely&#44; Adiponectin was not associated to clinical disease activity&#59; however&#44; it did show a differential association with IL-1&#946; and TNF&#945; levels&#58; a positive correlation with IL-1&#946; and a negative one with TNF&#945;&#46; Previous studies have confirmed the antagonistic relationship between TNF&#945; and Adiponectin<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> and have observed a synergistic effect of Adiponectin and IL-1&#946; in promoting pro-inflamatory cytokine secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> However there is still controversy regarding its exact role in RA inflammation and it has a major metabolic role in insulin sensitivity&#44; which might influence the characteristics of each patient depending on other factors such as adiposity&#46; Although Adipocytokines depend on white fat tissue for secretion&#44; in this study BMI did not play a significant role in cytokine&#47;adipocytokine levels when controlled for in the correlation analysis&#46; Gender&#44; age&#44; time since onset or ESR were also controlled for and changes in the cytokine or adipocytokine levels were also independent of them&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">As seen by other authors&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> circulating levels of IL-6 and IL-17 from moderate&#47;high activity &#40;DAS28 &#62;3&#46;5&#41; RA patients were significantly higher than those from patients in remission or with low disease activity&#46; Additionally&#44; there was a disparity in the circulating levels of TNF&#945;&#44; IL-1&#946;&#44; IL-6 and IL-17&#58; TNF&#945; was positively associated with IL-17&#44; but a negative correlation was observed with IL-1&#946; and no association was found with IL-6&#46; In support of our results&#44; previous studies have observed an antagonistic relation between TNF&#945; and IL-1&#946;&#44; a positive association between IL-1&#946; and IL-6 and a disparity between TNF&#945; and IL-6&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> probably reflecting a complex relationship between circulating cytokines in RA patients&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The present study&#44; however&#44; has several limitations&#44; including a small sample size&#44; the heterogeneity of DMARD treatment and the limitations in treatment&#46; Due to the fact that patients had no access to biologic therapy&#44; and that toxicity due to Methotrexate was frequently seen using doses over 15<span class="elsevierStyleHsp" style=""></span>mg&#47;week&#44; partial or complete remission was not achieved in many cases&#44; a factor that also plays a role in the results obtained&#46; However&#44; since all of the patients were followed and treated by only one clinician&#44; the clinical criteria employed for their evaluation was homogeneous&#46; Another limitation was that the C-reactive protein in our patients&#44; which has an important relationship to some of the evaluated cytokines&#44; was not heterogeneously measured and therefore was not included in the analysis&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion&#44; circulating Leptin&#44; Resistin&#44; IL-6 and IL-17 levels positively correlated with the clinical activity of RA patients in a BMI-independent way&#46; Due to the many inflammatory and metabolic pathways involved&#44; these complex relationships warrant further study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ethical disclosures</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Protection of human and animal subjects</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors state that the procedures conformed to the ethical standards of human experimentation committee responsible and according to the World Medical Association Declaration of Helsinki&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Confidentiality of data</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare that this article does not appear patient data&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Right to privacy and informed consent</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare they do not have any conflicts of interest&#46;</p></span></span>"
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    "fechaRecibido" => "2015-09-02"
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            0 => "Artrtitis reumatoide"
            1 => "Leptina"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To evaluate the association between the clinical activity of RA patients and serum adipocytokines &#40;Leptin&#44; Adiponectin and Resistin&#41; and inflammatory cytokines&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">All RA patients fulfilled ACR 1987 criteria and were treated with DMARDs&#46; Adipocytokine and inflammatory cytokine levels were evaluated using ELISA&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">121 patients were included in the study&#46; Stratifying according to DAS28 &#40;low&#44; moderate and high activity&#41;&#44; there were significant differences for Leptin&#44; Resistin&#44; IL-6 and IL-17&#44; however&#44; no differences were seen for Adiponectin&#44; TNF&#945; or IL-1&#946;&#46; Clinical activity positively correlated with Leptin&#44; Resistin&#44; IL-17 and IL-6 levels&#44; but not with Adiponectin&#44; TNF&#945; or IL-1&#946;&#46; Adiponectin levels negatively correlated with TNF&#945; and positively correlated with IL-1&#946;&#46; IL-1&#946; positively correlated with IL-6 and negatively correlated with TNF&#945; and IL-17&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Circulating Leptin&#44; Resistin&#44; IL-6 and IL-17 levels positively correlate with RA clinical activity in a manner independent of the subject&#39;s BMI&#46; Complex relationships between inflammatory cytokines were observed in RA patients suggesting that other metabolic or inflammatory factors could be involved&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Evaluar la asociaci&#243;n entre la actividad cl&#237;nica de pacientes con Artritis reumatoide y adipocitocinas s&#233;ricas &#40;Leptina&#44; Adiponectina y Resistina&#41;&#44; citocinas inflamatorias &#40;TNF&#945;&#44; IL-1&#946;&#44; IL-6&#44; IFN&#947; e IL-17A&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se seleccionaron pacientes con AR &#40;ACR 1987&#41; tratados con FARMEs&#46; Los niveles de adipocitocinas y citocinas inflamatorias fueron evaluados por ELISA&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">121 pacientes se incluyeron en el estudio&#46; La actividad cl&#237;nica correlacion&#243; positivamente con Leptina&#44; Resistina&#44; IL-6 e IL-17 pero no para Adiponectina&#44; TNF&#945; o IL-1&#946;&#46; Los niveles de Adiponectina se asociaron negativamente con TNF&#945; y positivamente con IL-1&#946;&#46; Por su parte&#44; IL-1&#946; se asoci&#243; de manera positiva con IL-6 y negativamente con TNF&#945; e IL-17&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los niveles circulantes de Leptina&#44; Resistina&#44; IL-6 e IL-17 se asociaron de manera positiva con la actividad cl&#237;nica de pacientes con AR&#44; independientemente del &#237;ndice de masa corporal &#40;IMC&#41;&#46; Asimismo&#44; en los pacientes con AR se observaron asociaciones complejas entre las adipocitocinas y citocinas&#44; sugiriendo que otros factores tanto metab&#243;licos como inflamatorios pudieran estar involucrados&#46;</p></span>"
        "secciones" => array:4 [
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          1 => array:2 [
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          2 => array:2 [
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          3 => array:2 [
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        ]
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                  <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="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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">Low disease activity<br>&#40;&#60;3&#46;5&#41;&nbsp;\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">Moderate disease activity<br>&#40;3&#46;5&#8211;5&#46;1&#41;&nbsp;\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">High disease activity<br>&#40;&#62;5&#46;1&#41;&nbsp;\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"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\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">Number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#8722;</span>&nbsp;\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">Gender&#44; Male&#47;Female &#40;&#37; F&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#47;21 &#40;95&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#47;54 &#40;96&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#47;41 &#40;95&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">Age&#44; Mean years &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&#46;5 &#40;12&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46&#46;3 &#40;10&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&#46;8 &#40;12&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">BMI&#44; Mean Kg&#47;m<span class="elsevierStyleSup">2</span> &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;5 &#40;10&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#46;7 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;9 &#40;4&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">Years since onset of RA&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;35 &#40;9&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;62 &#40;8&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;72 &#40;7&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">RF positive &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">88&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">aCCP positive &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">DAS28&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;83 &#40;0&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;33 &#40;0&#46;49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;22 &#40;0&#46;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\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">Leptin&#44; ng&#47;ml Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;228 &#40;0&#46;09&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;301 &#40;0&#46;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;368 &#40;0&#46;09&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\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">Adiponectin&#44; ng&#47;ml&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">178&#46;7 &#40;94&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">153&#46;0 &#40;74&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">151&#46;4 &#40;88&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">Resistin&#44; pg&#47;ml&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">271&#46;9 &#40;72&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">352&#46;8 &#40;162&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">441&#46;1 &#40;175&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;01&nbsp;\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">TNF&#945;&#44; ng&#47;ml&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;471 &#40;0&#46;94&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;570 &#40;1&#46;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;635 &#40;1&#46;222&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">IL-1&#946;&#44; pg&#47;ml&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">852&#46;5 &#40;535&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">973&#46;3 &#40;714&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">494&#46;6 &#40;263&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\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">IL-6&#44; pg&#47;ml&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">507&#46;2 &#40;145&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">601&#46;0 &#40;127&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">631&#46;8 &#40;132&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;01&nbsp;\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">IL-17&#44; pg&#47;ml&#44; Mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">65&#46;5 &#40;40&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">101&#46;6 &#40;47&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">121&#46;1 &#40;39&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Kruskal&#8211;Wallis test&#44; one-way&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">General and immunological data of the total of RA patients and according to their clinical activity subgroup&#46;</p>"
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      1 => array:7 [
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Spearman correlation coefficient&#44; <span class="elsevierStyleSup">&#42;</span>p&#60;0&#46;05&#59; <span class="elsevierStyleSup"><span class="elsevierStyleBold">&#42;&#42;</span></span><span class="elsevierStyleBold">p&#60;0&#46;01&#59;</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">&#42;&#42;&#42;</span></span><span class="elsevierStyleBold">p&#60;0&#46;001</span>&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Bold means P &#8804; 0&#46;01&#46;</p>"
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              "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="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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">Years since onset&nbsp;\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">BMI&nbsp;\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">DAS28&nbsp;\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">Leptin&nbsp;\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">Adiponectin&nbsp;\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">Resistin&nbsp;\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">TNF&#945;&nbsp;\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">IL-1&#946;&nbsp;\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">IL-6&nbsp;\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">IL-17&nbsp;\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">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;096&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;065&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;078&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;184&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;046&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;117&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;079&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;558&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;053&nbsp;\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">Years since onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;065&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;077&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;139&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;193&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;153&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;070&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;069&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;052&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;060&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;077&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;061&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;094&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;067&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;235<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;512</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;151&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;401</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;213<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;313</span><span class="elsevierStyleSup">&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;373</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\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">Leptin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;141&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;274<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;<span class="elsevierStyleBold">0&#46;277</span><span class="elsevierStyleSup">&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;585</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;221&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;159&nbsp;\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">Adiponectin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;058&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;<span class="elsevierStyleBold">0&#46;418</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;596</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;189&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;283<span class="elsevierStyleSup">&#42;</span>&nbsp;\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">Resistin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;061&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;106&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;256<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;004&nbsp;\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">TNF&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;<span class="elsevierStyleBold">0&#46;581</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;135&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;483</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\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">IL-1&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;459</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">&#8722;0&#46;427</span><span class="elsevierStyleSup">&#42;&#42;&#42;</span>&nbsp;\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">IL-6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "texto" => "<p id="par0095" class="elsevierStylePara elsevierViewall">The authors wish to thank MMM&#46; Jos&#233; Iv&#225;n Mart&#237;nez Rivera for performing the multivariable statistical analysis&#46; This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs1">Consejo Nacional de Ciencia y Tecnologia</span> &#40;CONACYT&#44; <span class="elsevierStyleGrantNumber" refid="gs1">CB2010-01-155392</span>&#41;&#46; C&#46;BR&#46;B received a stipend from CONACYT during the study&#46;</p>"
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Journal Information
Vol. 12. Issue 6.
Pages 323-326 (November - December 2016)
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Vol. 12. Issue 6.
Pages 323-326 (November - December 2016)
Brief Report
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Peripheral blood Leptin and Resistin levels as clinical activity biomarkers in Mexican Rheumatoid Arthritis patients
Niveles en sangre periférica de Leptina y Resistina como biomarcadores de la actividad clínica de pacientes mexicanos con Artritis reumatoide
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Carolina Bustos Rivera-Bahenaa,b, Daniel-Xavier Xibillé-Friedmanna,c, Judith González-Christena, Sandra Miriam Carrillo-Vázquezd, José Luis Montiel-Hernándeza,
Corresponding author
jlmontiel@uaem.mx

Corresponding author.
a Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Mexico
b Facultad de Ciencias, Universidad Autónoma del Estado de Morelos, Mexico
c Hospital General de Cuernavaca “José G. Parres”, SSM, Mexico
d Hospital Regional 1°. Octubre, ISSSTE, D.F. Mexico, Mexico
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Tables (2)
Table 1. General and immunological data of the total of RA patients and according to their clinical activity subgroup.
Table 2. Correlation between circulating adipocytokines and inflammatory cytokines.
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Abstract
Objective

To evaluate the association between the clinical activity of RA patients and serum adipocytokines (Leptin, Adiponectin and Resistin) and inflammatory cytokines.

Methods

All RA patients fulfilled ACR 1987 criteria and were treated with DMARDs. Adipocytokine and inflammatory cytokine levels were evaluated using ELISA.

Results

121 patients were included in the study. Stratifying according to DAS28 (low, moderate and high activity), there were significant differences for Leptin, Resistin, IL-6 and IL-17, however, no differences were seen for Adiponectin, TNFα or IL-1β. Clinical activity positively correlated with Leptin, Resistin, IL-17 and IL-6 levels, but not with Adiponectin, TNFα or IL-1β. Adiponectin levels negatively correlated with TNFα and positively correlated with IL-1β. IL-1β positively correlated with IL-6 and negatively correlated with TNFα and IL-17.

Conclusion

Circulating Leptin, Resistin, IL-6 and IL-17 levels positively correlate with RA clinical activity in a manner independent of the subject's BMI. Complex relationships between inflammatory cytokines were observed in RA patients suggesting that other metabolic or inflammatory factors could be involved.

Keywords:
Rheumatoid arthritis
Leptin
Resistin
Adiponectin
Pro-inflammatory cytokines
Clinical activity
Resumen
Objetivo

Evaluar la asociación entre la actividad clínica de pacientes con Artritis reumatoide y adipocitocinas séricas (Leptina, Adiponectina y Resistina), citocinas inflamatorias (TNFα, IL-1β, IL-6, IFNγ e IL-17A).

Métodos

Se seleccionaron pacientes con AR (ACR 1987) tratados con FARMEs. Los niveles de adipocitocinas y citocinas inflamatorias fueron evaluados por ELISA.

Resultados

121 pacientes se incluyeron en el estudio. La actividad clínica correlacionó positivamente con Leptina, Resistina, IL-6 e IL-17 pero no para Adiponectina, TNFα o IL-1β. Los niveles de Adiponectina se asociaron negativamente con TNFα y positivamente con IL-1β. Por su parte, IL-1β se asoció de manera positiva con IL-6 y negativamente con TNFα e IL-17.

Conclusión

Los niveles circulantes de Leptina, Resistina, IL-6 e IL-17 se asociaron de manera positiva con la actividad clínica de pacientes con AR, independientemente del índice de masa corporal (IMC). Asimismo, en los pacientes con AR se observaron asociaciones complejas entre las adipocitocinas y citocinas, sugiriendo que otros factores tanto metabólicos como inflamatorios pudieran estar involucrados.

Palabras clave:
Artrtitis reumatoide
Leptina
Resistina
Adiponectina
Citocinas pro-inflamatorias
Actividad clínica
Full Text
Introduction

In recent years there has been a lot of interest in studying the relationship between adipocytokines and disease activity in Rheumatoid Arthritis (RA), however results are heterogeneous. Several studies have observed higher peripheral blood concentrations of Leptin in RA than in healthy subjects,1 as well as an association with some inflammatory markers2 and disease activity.3 Additionally, other studies have observed an association with insulin-resistance4 and endothelial activation5 but not with radiographic progression.6 In a two-year-follow up study of patients with RA, a positive correlation between Leptin and IL-17 and a decrease in DAS28 was seen in patients treated with DMARDs.2 Similarly, high levels of Adiponectin have also been reported in RA1 and associated with radiographic progression.6

Resistin has been also studied in RA, with heterogeneous findings; some studies reported an association with inflammatory markers7 and clinical activity.8 Baseline Leptin levels predict clinical activity and response to DMARD treatment in non-overweigh/non-obese RA patients,9 suggesting both a role for Leptin in the systemic abnormalities seen during the course of the disease, as well as the influence of adiposity on the RA inflammatory process. However, the association between adipocytokines with inflammatory cytokine levels is poorly understood. Therefore, the objective of this study is to describe the relationship between Leptin, Adiponectin and Resistin with the disease activity of RA patients and the levels of several inflammatory cytokines.

Material and methodsPatient selection

Patients were recruited at the Rheumatology clinic of the Hospital General de Cuernavaca in Morelos, Mexico between 2007 and 2009. The study protocol was reviewed and approved by the Hospital ethics’ committee. All patients followed a similar treatment strategy: methotrexate (7.5–15mg/week) in combination with cloroquine 150mg/d and prednisone ≤10mg/day. Inclusion criteria: Patients included were seen consecutively and had Rheumatoid Arthritis, classified according to the American College of Rheumatology 1987 criteria10; their ages ranged from 18 to 75 years; signed informed consent was obtained from all of the patients and they all had a complete clinical file at the hospital. Disease activity was measured using DAS28 based on the number of swollen and tender peripheral joints, the patients’ overall assessment by visual analog scale (VAS) and the erythrocyte sedimentation rate (ESR). The patients underwent a clinical evaluation performed by a single rheumatologist; venous blood samples were withdrawn afterwards and plasma samples were separated on the same day of collection and frozen at −75°C. All patients received combination treatment with DMARDs (mainly methotrexate and cloroquine) and, in some cases, 10mg or less per day of prednisone. NSAID and analgesics were prescribed on demand. No patients were treated with biologics due to health coverage limitations. For the comparative analysis, patients were stratified according to DAS28 into the following groups: low disease activity (DAS28 ≤3.5), moderate activity (DAS28 >3.5 to ≤5.1) and high disease activity (DAS28 >5.1).

Quantification of adipocytokine and cytokine blood levels

Leptin, Adiponectin, Resistin, IL-1β, IL-6, IL-17 and TNFα levels were determined from venous blood plasma by optimized ELISA employing specific monoclonal antibodies (Santa Cruz Biotechnology, eBioscience). Calibrated curves were prepared in each plate employing a recombinant human standard for each metabolite (Peprotech Inc.). All essays were performed by in triplicate for each sample. Calibration curves fitted a linear regression with a correlation higher than 0.85 and a p value <0.05%.

Statistical analysis

Descriptive statistics were employed and results were expressed as means and standard deviations. A one way ANOVA (Kruskal–Wallis test) was performed to compare DAS28-patients subgroups. The comparison between groups was done using the Mann–Whitney test and correlation between variables was determined using Spearman's test (PRISM v.6.0), controlling for gender, age, years since onset of disease, BMI and ESR (STATA v.13). The level of statistical significance was set at 0.05%.

Results

121 patients with RA were included in the study. It is worth recognizing there were differences in the number of patients for each activity subgroup, with only 22 patient in the low activity group, while 56 patients had moderate activity (Table 1). However, the three subgroups were similar in gender, age, BMI, time since onset of disease and RF or anti-CCP antibody titers. Although most patients were overweight, no differences were seen between the activity subgroups.

Table 1.

General and immunological data of the total of RA patients and according to their clinical activity subgroup.

  Low disease activity
(<3.5) 
Moderate disease activity
(3.5–5.1) 
High disease activity
(>5.1) 
p* 
Number  22  56  43   
Gender, Male/Female (% F)  1/21 (95.5)  2/54 (96.4)  2/41 (95.2)  ns 
Age, Mean years (SD)  43.5 (12.5)  46.3 (10.7)  45.8 (12.2)  ns 
BMI, Mean Kg/m2 (SD)  29.5 (10.3)  27.7 (4.9)  26.9 (4.7)  ns 
Years since onset of RA, Mean (SD)  7.35 (9.3)  7.62 (8.4)  6.72 (7.9)  ns 
RF positive (%)  76.5  83.8  88.0  ns 
aCCP positive (%)  36.8  64.9  60.0  ns 
DAS28, Mean (SD)  2.83 (0.53)  4.33 (0.49)  6.22 (0.77)  <0.001 
Leptin, ng/ml Mean (SD)  0.228 (0.09)  0.301 (0.10)  0.368 (0.09)  <0.001 
Adiponectin, ng/ml, Mean (SD)  178.7 (94.4)  153.0 (74.3)  151.4 (88.4)  ns 
Resistin, pg/ml, Mean (SD)  271.9 (72)  352.8 (162)  441.1 (175)  0.01 
TNFα, ng/ml, Mean (SD)  1.471 (0.94)  1.570 (1.15)  1.635 (1.222)  ns 
IL-1β, pg/ml, Mean (SD)  852.5 (535)  973.3 (714)  494.6 (263)  ns 
IL-6, pg/ml, Mean (SD)  507.2 (145)  601.0 (127)  631.8 (132)  0.01 
IL-17, pg/ml, Mean (SD)  65.5 (40.1)  101.6 (47.8)  121.1 (39.4)  <0.01 
*

Kruskal–Wallis test, one-way.

There was a significant difference in Leptin, Resistin, IL-6 and IL-17 levels when comparing between activity subgroups using one-way ANOVA (Table 1). In the particular case of Leptin, when comparing DAS28 subgroups, all showed mutual statistical differences (p<0.001), suggesting a positive relation with the increase in the DAS28 score. In a similar manner, a significant mean difference for Resistin levels was observed by comparing the low vs. high activity subgroups (p<0.0007); however, this was not the case when comparing the moderate vs. high activity subgroups (p=0.080) or when comparing the low vs. moderate activity subgroups (p=0.107). In contrast, Adiponectin did not shown differences between clinical activity subgroups. For its part, the low activity subgroup showed lower IL-6 levels than the moderate (p=0.015) or high activity subgroups (p=0.004). Similarly, the low activity subgroup also showed lower IL-17 levels compared to the moderate (p=0.016) or high activity (p=0.0003) subgroups.

Leptin levels positively correlated with DAS28 (rho=0.513, p<0.0001, Table 2) but not with age, the time since onset of disease or BMI. There was also an important correlation between Leptin and IL-1β (rho=0.585, p<0.0001), suggesting a relationship between this adipocytokine and activation of the immune response. Significant correlations were also observed with Resistin (rho=0.274, p<0.05) and TNFα (rho=−0.277, p<0.005). Likewise, Resistin levels showed a positive relationship with DAS28 (rho=0.403, p<0.0001) but not with the other clinical parameters. Additionally, Resistin only showed a positive significant association with Leptin (rho=0.277, p<0.001) and IL-6 levels (rho=0.256, p<0.05). For its part, the same analysis confirmed the absence of an association of Adiponectin with disease activity (rho=−0.151, p>0.05, Table 2), however it showed a negative correlation with TNFα (rho=−0.418) and IL-17 (−0.283, p<0.05), and a positive correlation with IL-1β (rho=0.596).

Table 2.

Correlation between circulating adipocytokines and inflammatory cytokines.

  Years since onset  BMI  DAS28  Leptin  Adiponectin  Resistin  TNFα  IL-1β  IL-6  IL-17 
Age  0.096  −0.065  0.078  0.008  −0.184  −0.046  0.117  −0.079  0.558  0.053 
Years since onset    −0.014  −0.065  −0.077  −0.139  −0.193  −0.019  −0.153  0.070  −0.069 
BMI      0.052  −0.060  −0.077  −0.061  −0.016  −0.094  0.067  0.235* 
DAS28        0.512***  −0.151  0.401***  −0.014  0.213*  0.313**  0.373*** 
Leptin          −0.141  0.274*  0.277**  0.585***  0.221  0.159 
Adiponectin            0.058  0.418***  0.596***  0.189  −0.283* 
Resistin              −0.061  0.106  0.256*  0.004 
TNFα                0.581***  0.135  0.483*** 
IL-1β                  0.459***  −0.427*** 
IL-6                    0.104 

Spearman correlation coefficient, *p<0.05; **p<0.01;***p<0.001.

Bold means P ≤ 0.01.

Both IL-6 and IL-17 showed a significant positive correlation with DAS28 (rho=0.313, p<0.005; rho=0.373, p<0.0001 for IL-6 and IL-17, respectively). On the other hand, TNFα levels were not associated with clinical activity (Table 2). For its part, a significant correlation between DAS28 and IL-1β (rho=0.213, p<0.05) was seen, although it was not possible to differentiate by activity subgroups (Table 1).

Discussion

The present study supports previous ones suggesting that Leptin and Resistin are positively associated with RA disease activity,2,3 but while Resistin showed a limited correlation with other inflammatory cytokines, Leptin showed a positive association with IL-1β. It must be remembered though that in some studies,2 the observations have been longitudinal while this study made a single, transversal measurement. In contrast to other authors’ publications, we found no correlation between Leptin and IL-63 or IL-17,2 possibly because of differences in the origin of samples (synovial fluid versus peripheral blood) and design (transversal versus longitudinal). Otherwise, in support of the present results, studies with human pancreatic islet or cord blood T-cells showed that in vitro stimulation by Leptin was able to induce IL-1β secretion.11

Conversely, Adiponectin was not associated to clinical disease activity; however, it did show a differential association with IL-1β and TNFα levels: a positive correlation with IL-1β and a negative one with TNFα. Previous studies have confirmed the antagonistic relationship between TNFα and Adiponectin12 and have observed a synergistic effect of Adiponectin and IL-1β in promoting pro-inflamatory cytokine secretion.13 However there is still controversy regarding its exact role in RA inflammation and it has a major metabolic role in insulin sensitivity, which might influence the characteristics of each patient depending on other factors such as adiposity. Although Adipocytokines depend on white fat tissue for secretion, in this study BMI did not play a significant role in cytokine/adipocytokine levels when controlled for in the correlation analysis. Gender, age, time since onset or ESR were also controlled for and changes in the cytokine or adipocytokine levels were also independent of them.

As seen by other authors,14 circulating levels of IL-6 and IL-17 from moderate/high activity (DAS28 >3.5) RA patients were significantly higher than those from patients in remission or with low disease activity. Additionally, there was a disparity in the circulating levels of TNFα, IL-1β, IL-6 and IL-17: TNFα was positively associated with IL-17, but a negative correlation was observed with IL-1β and no association was found with IL-6. In support of our results, previous studies have observed an antagonistic relation between TNFα and IL-1β, a positive association between IL-1β and IL-6 and a disparity between TNFα and IL-6,15 probably reflecting a complex relationship between circulating cytokines in RA patients.

The present study, however, has several limitations, including a small sample size, the heterogeneity of DMARD treatment and the limitations in treatment. Due to the fact that patients had no access to biologic therapy, and that toxicity due to Methotrexate was frequently seen using doses over 15mg/week, partial or complete remission was not achieved in many cases, a factor that also plays a role in the results obtained. However, since all of the patients were followed and treated by only one clinician, the clinical criteria employed for their evaluation was homogeneous. Another limitation was that the C-reactive protein in our patients, which has an important relationship to some of the evaluated cytokines, was not heterogeneously measured and therefore was not included in the analysis.

In conclusion, circulating Leptin, Resistin, IL-6 and IL-17 levels positively correlated with the clinical activity of RA patients in a BMI-independent way. Due to the many inflammatory and metabolic pathways involved, these complex relationships warrant further study.

Ethical disclosuresProtection of human and animal subjects

The authors state that the procedures conformed to the ethical standards of human experimentation committee responsible and according to the World Medical Association Declaration of Helsinki.

Confidentiality of data

The authors declare that this article does not appear patient data.

Right to privacy and informed consent

The authors declare that no patient data appear in this article.

Conflicts of interest

The authors declare they do not have any conflicts of interest.

Acknowledgements

The authors wish to thank MMM. José Iván Martínez Rivera for performing the multivariable statistical analysis. This work was supported by the Consejo Nacional de Ciencia y Tecnologia (CONACYT, CB2010-01-155392). C.BR.B received a stipend from CONACYT during the study.

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