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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Frequency of antibody positivity in patients with early stage and established RA&#44; in healthy controls and in controls with other diseases&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Differences were found between the titres of antibodies in all of the patients with RA compared to the total of patients with other diseases and healthy individuals&#46; This was so for anti-CFP antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41;&#44; anti-MCV antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41;&#44; anti-CCP2 antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41; and RF antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0027&#41;&#46; Differences were found in the titres of RF antibodies in patients with early stage and established RA &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0121&#41;&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; CCP2&#58; second generation citrullinated peptides&#59; RF&#58; rheumatoid factor&#59; MCV&#58; mutated citrullinated vimentin&#59; <span class="elsevierStyleItalic">n</span>&#58; total number of patients&#59; CFP&#58; citrullinated fibrinogen peptide&#59; RCI&#58; interquartile ranges&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is a disease that is characterised by chronic inflammation and the presence of auto-antibodies&#46; It affects the small peripheral joints with a high degree of morbidity and disability&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although the aetiopathogenesis of RA has not been completely elucidated&#44; there is evidence that indicates that influenced by complex environmental and genetic interactions&#44; the organisms own antigens with posttranslational modifications such as citrullination are presented to the immune system&#44; leading to breakdown of the processes involved in immunological tolerance&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">3&#8211;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The disease was diagnosed using the 1987 criteria of the American College of Rheumatology&#46; This sets 6 clinical criteria and rheumatoid factor &#40;RF&#41; as the sole serological criterion&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">7</span></a> As protein citrullination has been implicated in the pathogenic mechanisms of RA&#44; antibodies against citrullinated peptides have been included in the latest criteria of the American College of Rheumatology and the European League against Rheumatism for diagnosis of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The first antibodies against citrullinated peptides described were perinuclear factor and anti-keratin antibodies&#46; These react with profilaggrin protein&#44; identified by indirect immunofluorescence&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">9</span></a> The insertion of cyclical changes into lineal filaggrin peptides gave rise to the first generation of assays for the determination of antibodies against citrullinated peptides&#44; which are more sensitive for diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">One of the most widely-used assays is the determination of antibodies against second generation citrullinated peptides &#40;anti-CCP2&#41;&#44; which as well as being highly specific&#44; are also present in early stages of the disease and are predictive of joint erosion in patients with RA&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">8&#44;10&#44;11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The third generation of immunoanalysis &#40;anti-CCP3&#41; was designed using peptide engineering&#46; Several authors have shown that there is no major difference between these and the anti-CCP2 assay&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">11&#44;12</span></a> Other authors state that they have higher diagnostic value than anti-CCP2 antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">On the other hand&#44; citrullinated proteins which are highly specific for diagnosis have been detected in the synovial tissue of the inflamed joints of patients with RA &#40;fibrinogen&#44; vimentin&#44; enolase&#44; fibronectin and type II collagen&#41;&#46; These proteins are thought to be relevant candidates for triggering autoimmunity in genetically susceptible individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Our aim in this work was to determine the diagnostic value of antibodies against a citrullinated fibrinogen peptide in Cuban patients with early stage and established RA&#44; by means of enzymatic immunoanalysis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">A transversal study was performed&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0050" class="elsevierStylePara elsevierViewall">The sample was composed of 162 patients included consecutively in the study &#40;81 patients with early stage RA diagnosed less than one year beforehand and 81 patients with established RA&#41;&#46; They were of both sexes and older than 18 years old&#46; They were treated in the National Centre of Rheumatology of Cuba&#44; and they fulfilled the criteria of the American College of Rheumatology and the European League against Rheumatism&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">8</span></a> Patients with neoplasias and pregnant patients were excluded&#46; 25 healthy individuals from the provincial blood bank of La Habana also took part&#44; together with 56 individuals with other autoimmune or autoinflammatory diseases or chronic infections &#40;13 patients with symptoms but with no definitive diagnosis of RA&#44; 10 with mixed disease of connective tissue&#44; 10 with chronic viral hepatitis&#44; 9 with systemic lupus erythematosus&#44; 4 with scleroderma&#44; 3 with psoriatic arthritis&#44; 3 with spondyloarthropathies&#44; 3 with autoimmune myositis and one with Sj&#246;gren&#39;s syndrome&#41; from the National Genetic Medicine Centre&#44; Cuba&#46; This study was approved by the Ethics Committee of the National Genetic Medicine Centre and all of the participants gave their informed consent&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Determination of disease activity indicators</span><p id="par0055" class="elsevierStylePara elsevierViewall">The erythrocyte sedimentation rate &#40;ESR&#41; was determined in 2<span class="elsevierStyleHsp" style=""></span>ml of blood anticoagulated with 0&#46;5<span class="elsevierStyleHsp" style=""></span>ml sodium citrate &#40;3&#46;8&#37;&#41;&#44; in 1<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a> Reactive C protein was determined by the qualitative technique of agglutination in latex &#40;Diagnostic Automation&#47;Cortez Diagnostics&#44; USA&#41;&#44; by adding a drop of patient serum in the latex sheets and observing the presence of turbidity in 2<span class="elsevierStyleHsp" style=""></span>min reaction&#46; The health assessment questionnaire &#40;HAQ&#41; was applied and the clinical indicator of disease activity based on the ESR &#40;DAS 28&#41; was calculated&#46; DAS 28 was considered to show remission &#40;DAS 28 &#60;2&#46;6&#41;&#44; DAS 28 low activity &#40;DAS 28 &#8805;2&#46;6 and &#8804;3&#46;2&#41;&#44; moderate activity &#40;DAS 28 &#62;3&#46;2 and &#8804;5&#46;1&#41; and high activity &#40;DAS 28 &#62;5&#46;1&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">8&#44;17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Design and obtaining citrullinated fibrinogen peptide</span><p id="par0060" class="elsevierStylePara elsevierViewall">Antigenic determinants of the &#945; and &#946; fibrinogen chains were predicted&#44; in the three-dimensional structure of the protein obtained from the RSCB-PDB-101 data bank&#44; using the computer programs BepiPred 1&#46;0 &#40;DTU Bioinformatics&#44; Technical University of Denmark&#44; Lyngby&#44; Denmark&#41;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">18</span></a> and Discotope 1&#46;2 &#40;DTU Bioinformatics&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">19</span></a> 2 fibrinogen peptides were selected&#46; The covalent bond was formed of both peptides with an intermediate cysteine amino acid between a peptidic chain of &#945; fibrinogen and a chain of &#946; fibrinogen&#44; with the location of a final cysteine and the substitution of the terminal carboxylic termination by terminal carboxamide&#46; Both peptidic subunits were citrullinated in 2 arginine residues&#46; Solid phase synthesis was performed using Fmoc&#47;tBu &#40;9-fluoerenylmethyloxycarbonyl&#47;tert-butyl&#41; methodology&#46; Purification was carried out using preparative reverse phase high performance liquid chromatography &#40;HPLC-RP&#41; in LabChrom equipment &#40;Merck LaChrom&#44; Hitachi High-Technologies Corporation&#44; Germany&#41;&#46; Degree of purity was determined by analytic HPLC-RP in AKTA 100 equipment &#40;GE Healthcare&#44; Groton&#44; CT&#44; USA&#41;&#46; Molecular mass determination was performed using electronebulisation ionisation mass spectrometry in a Q-Tof spectrometer &#40;Micromass&#44; Ltd&#46;&#44; Manchester&#44; United Kingdom&#41;&#46; The peptide was synthesised in its native &#40;uncitrullinated&#41; form to compare reactivity with the citrullinated fibrinogen peptide&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Determination of antibodies</span><p id="par0065" class="elsevierStylePara elsevierViewall">The determination of IgG type designed antipeptide citrullinated fibrinogen antibodies &#40;anti-CFP&#41; was performed by an indirect type enzyme-linked immunoabsorbent assay &#40;ELISA&#41;&#46; 96 well maximum absorption plates were sensitised &#40;Thermo Ficher Scientific&#44; NUNC&#44; Roskilde&#44; Denmark&#41; with fibrinogen peptide at a concentration of 10<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml in buffered saline phosphate solution 0&#46;15<span class="elsevierStyleHsp" style=""></span>M&#44; pH<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;2 &#40;PBS&#41;&#46; It was incubated for 16<span class="elsevierStyleHsp" style=""></span>h in a humidity chamber at 20&#8211;25<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; It was washed 3 times with PBS and Tween 20 at 0&#46;05&#37; in a micro ELISA washer &#40;SUMA&#44; MW-2001 Centro de Inmunoensayos&#44; La Habana&#44; Cuba&#41;&#44; adding 200<span class="elsevierStyleHsp" style=""></span>&#956;l in each well&#46; Bovine serum albumin &#40;BSA&#41; was added &#40;SIGMA&#44; Aldrich&#44; St Louis&#44; MO&#44; USA&#41; diluted at 2&#37; in PBS&#44; it was incubated for 1<span class="elsevierStyleHsp" style=""></span>h in a humidity chamber at 20&#8211;25<span class="elsevierStyleHsp" style=""></span>&#176;C before being washed again&#46; Positive and negative controls were prepared from patients with RA and healthy individuals&#44; respectively&#44; and in the same way as the dilute samples 1&#47;100 in PBS&#44; BSA 2&#37; and Tween 20 at 0&#46;05&#37; were added to them&#46; Standard serum was added&#44; from 120<span class="elsevierStyleHsp" style=""></span>U&#47;ml to 6&#46;2<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#44; prepared using serum from patients with RA&#44; the concentration of which was evaluated in comparison with standard assay serum anti-CCP2 &#40;IBL&#44; International GmbH&#44; Hamburg&#44; Germany&#41;&#46; It was incubated at 20&#8211;25<span class="elsevierStyleHsp" style=""></span>&#176;C during 1<span class="elsevierStyleHsp" style=""></span>h in a humidity chamber&#46; After another step of washing the conjugated anti-IgG with peroxidase was added &#40;Dako cytomation&#44; Dako&#44; Glostrup&#44; Denmark&#41; 100<span class="elsevierStyleHsp" style=""></span>&#956;l in each well at the dilution suggested for the reagent &#40;1&#47;6000&#41;&#44; in PBS&#44; Tween 20 at 0&#46;05&#37;&#46; It was incubated for 1<span class="elsevierStyleHsp" style=""></span>h at 20&#8211;25<span class="elsevierStyleHsp" style=""></span>&#176;C and the plate was washed&#46; The dihydrochloric ortho-phenylendiamine substrate wad added &#40;SIGMA&#44; USA&#41; 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml diluted in the buffered solution sodium citrate 0&#46;1<span class="elsevierStyleHsp" style=""></span>mol&#47;l&#44; pH 5&#46;5 with hydrogen peroxide 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml &#40;Merck&#44; Germany&#41;&#46; It was incubated for 30<span class="elsevierStyleHsp" style=""></span>min at a temperature of 20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The reaction was halted by the addition of 50<span class="elsevierStyleHsp" style=""></span>&#956;l sulphuric acid 3<span class="elsevierStyleHsp" style=""></span>mol&#47;l &#40;Merck&#44; Germany&#41; in water&#44; and absorbency was measured at 492<span class="elsevierStyleHsp" style=""></span>nm in an ELISA PR-521 reader &#40;SUMA&#44; Cuba&#41;&#46; A logarithmic adjustment was used for the calibration curve&#46; The determination of type IgG anti-CCP2 antibodies was performed by ELISA &#40;IBL International&#44; Germany&#41;&#44; with a suggested cut-off point of 30<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#46; The determinations of mutated citrullinated antivimentin antibodies &#40;anti-MCV&#41; and IgM type RF were performed by ELISA &#40;Orgentec&#44; Diagnostika GmbH&#44; Mainz&#44; Germany&#41;&#44; with a suggested cut-off point of 20<span class="elsevierStyleHsp" style=""></span>U&#47;ml for each assay&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The Statistica 7&#46;0 &#40;StatSoft&#44; Inc&#46;&#44; Tulsa&#44; OK&#44; USA&#41; and EPIDAT 3&#46;1 &#40;Direcci&#243;n General de Salud P&#250;blica&#44; Junta de Galicia&#44; PanAmerican Health Organisation PHO&#47;WHO&#41; programs were used&#46; Qualitative variables were expressed as frequencies and percentages&#46; <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> was calculated with Fisher&#39;s exact test for expected values below 5&#44; and the odds ratio &#40;OR&#41; was estimated as a magnitude of association&#46; The differences between the optical densities of the controls were determined by Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#46; Quantitative variables with a distribution other than normal were expressed as a median with interquartile ranges&#46; Quantitative variables were compared between groups using the Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Spearman&#39;s coefficient was determined for correlation&#46; To determine diagnostic value contingency tables were created for all of the patients with RA&#44; in comparison with the healthy individuals and patients with other autoimmune or autoinflammatory diseases or chronic infections&#46; The same procedure was followed separately for the patients with early stage RA and the group of patients with established RA&#46; Diagnostic sensitivity and specificity were calculated&#44; as well as the positive and negative predictive values&#46; The Youden index &#40;YI&#41; was calculated as was the area under the receiver operating characteristic &#40;ROC&#41; curve&#46; The level of statistical significance used was 0&#46;05&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">The patients included in early stage RA group had a mean age of 48 years old &#40;39&#8211;53 years old&#41;&#46; 60 of these patients were recently diagnosed and in 21 patients the median duration of the disease was 7 months &#40;5&#8211;12 months&#41; after diagnosis&#46; The median age of the patients with established RA was 51 years old &#40;44&#8211;61 years old&#41;&#44; with a median duration of the disease of 5 years &#40;2&#8211;10 years&#41;&#46; There was a high proportion of female patients in the early stage RA group &#40;76&#46;5&#37;&#41; and in the established RA group &#40;82&#46;7&#37;&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The prediction of antigenic determinants with the &#945; and &#946; chains of fibrinogen protein made it possible to obtain different epitopes with probable antigenicity to react with ACPC in patients with RA&#46; The regions with the largest amount of amino acids obtained in the predictions with fibrinogen were amino acid regions from 210 to 232 of the &#945; chain and from 16 to 69 of the &#946; chain &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The sequence of amino acids selected was Lys Asp Ile Ile Pro Ser citrulline Asp Arg Gln His citrulline Pro Leu Asp Lys Lys Arg Glu Glu Cys &#40;KDLLPS citrulline DRQHCGH citrulline PLDKKREEC&#41;&#44; covering 1&#46;9&#37; of the &#945; chain of fibrinogen &#40;11&#47;560 amino acids&#41; and 2&#46;4&#37; of the &#946; chain of fibrinogen &#40;11&#47;461&#41;&#46; The designed peptide had a net positive charge &#40;2&#43;&#41;&#44; an arginine&#47;citrulline balance of 1&#44; a molecular mass of 2916&#46;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;02<span class="elsevierStyleHsp" style=""></span>Da&#44; which coincides with the theoretical molecular mass of 2916&#46;46<span class="elsevierStyleHsp" style=""></span>Da&#44; and a purity of 98&#46;3&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">When ELISA was performed with the designed citrullinated fibrinogen peptide and the uncitrullinated peptide&#44; no differences were found between the positive and negative controls &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;6644&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the patients with early stage RA the antibodies detected the most were anti-CFP antibodies &#40;84&#46;0&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The frequency of positivity of all the antibodies studies was higher in the patients with RA than it was in the controls&#46; In the total of patients with RA&#44; titres were higher for anti-CFP antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41;&#44; anti-MCV antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41;&#44; anti-CCP2 antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41; and RF &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0027&#41;&#44; in comparison with the total of patients with other diseases and healthy individuals&#46; Differences were observed between the titres of RF antibodies in patients with early stage RA and established RA &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0121&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">The most frequent antibodies in patients who had no anti-CFP antibodies were anti-MCV antibodies in early stage RA &#40;84&#46;6&#37;&#41; and anti-CCP2 antibodies in established &#40;68&#46;8&#37;&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Analysis of YI &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; and the ROC curves &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; anti-CFP antibodies performed the best in diagnosing early stage RA&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">All of the patients with early stage RA had moderate or high DAS 28 scores&#44; as did 80&#46;2&#37; of patients with established RA &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; with a higher median of 5&#46;1&#46; The highest rate of positivity for reactive C protein was observed in patients with early stage RA&#46; Reactive protein C positivity was shown to be associated with the presence of anti-CFP antibodies &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;8&#59; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;7&#59; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;2&#8211;17&#46;9&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0163&#41; in early stage RA and established RA &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;3&#59; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;9&#59; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;2&#8211;7&#46;4&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0217&#41;&#46; Additionally&#44; in early stage RA a positive correlation was observed between anti-CFP antibodies and the DAS 28&#44; as well as higher DAS 28 scores in patients positive for anti-CFP antibodies in comparison with seronegative patients &#40;<span class="elsevierStyleItalic">U</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>244&#46;0&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0108&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">The most important finding of this study was the capacity of designed citrullinated fibrinogen peptide to recognise the antibodies present in Cuban patients with RA in a high number of cases&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Several studies have analysed the utility of fibrin-derived peptides in the diagnosis of this disease&#46; The designed peptide had similarities to the peptides evaluated previously in these patients&#44; in terms of coincidence with certain amino acid regions&#44; net positive charge and the arginine&#47;citrulline balance&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">20&#8211;22</span></a> According to these researchers&#44; a net positive charge and a suitable balance of arginine&#47;citrulline residues in the peptides may favour a formation that has greater capacity to bind with the autoantibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Previous studies have shown that not all citrulline peptides have the same reactivity&#46; This shows the importance of the surrounding non-citrullinated amino acid residues in amplifying antigenicity&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a> It has been observed that the amino acid residues which surround the citrulline intervene in the affinity of the peptide for the antibodies&#44; where the amino acids found the most often are glycine&#44; serine&#44; histidine&#44; threonine and glutamine&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">22&#8211;24</span></a> In the designed peptide the amino acids serine and histidine are found surrounding the citrulline&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The diagnostic value of anti-CFP antibodies was superior to the commercial immunoanalysis methods used habitually &#40;anti-MCV&#44; anti-CCP2 and RF&#41; in Cuban patients with early stage RA&#44; while in the patients with established RA it was only superior to anti-CCP2 and RF assays&#46; The capacity which the modified antigens present in joints such as fibrinogen to trigger the production of antibodies in the early stages of the disease is therefore important&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">14&#44;15</span></a> Previous studies in Cuban patients with RA have shown that the antibodies against modified vimentin antigens have superior diagnostic value than anti-CCP2 antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">25</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Immunoanalysis to determine the anti-CFP antibodies evaluated showed superior values of sensitivity and lower values of specificity in the diagnosis of early stage RA in comparison with those obtained by other authors&#44; who evaluated citrullinated peptides against other epitopes of fibrin and fibrinogen proteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">21&#44;22&#44;26</span></a> In 2009&#44; Sanmarti et al&#46; found a sensitivity of 72&#46;1&#37; and a specificity of 98&#37; for a peptide in the &#945; chain of citrullinated fibrin &#40;617&#8211;631&#44; citrullination 630&#41; bonded to filagrine and a sensitivity of 73&#46;9&#37; in the determination of anti-CCP2 antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">21</span></a> In 2014&#44; Cornillet et al&#46; evaluated a &#946; chain peptide of citrullinated fibrin &#40;60&#8211;74&#44; citrullination 60&#44; 72&#44; 74&#41; that had been reported the previous decade&#44; obtaining a sensitivity &#40;71&#37;&#41; and specificity &#40;95&#37;&#41; similar to those obtained using determination of anti-CCP2 antibodies &#40;74&#37; sensitivity and 95&#37; specificity&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">26</span></a> They demonstrated that these fibrin epitopes are recognised by antibodies against citrullinated fibrinogen&#44; and they also studied the reactivity of an &#945; chain citrullinated fibrin peptide &#40;36&#8211;50&#41; combined with a &#946; chain peptide &#40;60&#8211;74&#41;&#44; finding a sensitivity of 47&#37; when specificity was set to 98&#37; &#40;26&#41;&#46; Cabrera-Villalba et al&#46;&#44; in 2017&#44; found a frequency of 68&#46;5&#37; for an &#945; citrullinated fibrinogen peptide &#40;617&#8211;631&#44; citrullination 630&#41; in patients with RA&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">27</span></a> This is less than the frequency of appearance of the antibodies that recognise the designed peptide in early stage RA&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In the Cuban population there may be different antigenic specificities recognised by other antibodies against citrullinated peptides not detected by anti-CCP2 antibodies&#46; The variations in different populations of the frequency of antibodies to recognise citrullinated proteins may be due to genetic and environmental factors&#44; as well as demographic characteristics&#44; patient selection and disease classification&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">4&#44;11</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The presence of anti-CFP antibodies was associated with greater disease severity&#44; so that they are therefore a useful tool for the clinical evaluation of Cuban patients with RA&#46; These antibodies may it possible to differentiate 2 clearly defined patient populations with different clinical characteristics&#46; In early stage RA&#44; the group of seropositive patients is characterised by greater disease activity&#44; with a higher DAS 28 score than seronegative patients&#46; The treatment objectives and strategies for RA may therefore differ in patients who are seropositive for anti-CFP antibodies&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">One limitation of this work was that the association of anti-CFP antibodies with radiological studies was not examined&#44; and this may form a part of future clinical research in Cuban patients with RA&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">The immunoanalysis designed with a new citrullinated fibrinogen peptide is able to detect specific antibodies in Cuban patients with early stage and established RA&#46; It has high diagnostic value and may be used to identify patients with greater disease severity&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Financing</span><p id="par0160" class="elsevierStylePara elsevierViewall">This research was financed by the <span class="elsevierStyleGrantSponsor" id="gs1">Public Health Ministry&#44; La Habana&#44; Cuba</span>&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interests</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Material and methods"
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              "titulo" => "Patients"
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              "identificador" => "sec0020"
              "titulo" => "Determination of disease activity indicators"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Design and obtaining citrullinated fibrinogen peptide"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Determination of antibodies"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Conclusions"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2018-06-18"
    "fechaAceptado" => "2018-11-06"
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        0 => array:4 [
          "clase" => "keyword"
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          "identificador" => "xpalclavsec1299084"
          "palabras" => array:4 [
            0 => "Rheumatoid arthritis"
            1 => "Antibodies against citrullinated peptides"
            2 => "Fibrinogen"
            3 => "Diagnostic value"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Artritis reumatoide"
            1 => "Anticuerpos contra p&#233;ptidos citrulinados"
            2 => "Fibrin&#243;geno"
            3 => "Valor diagn&#243;stico"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determinate the diagnostic value of an antibody against a citrullinated fibrinogen peptide in Cuban patients with rheumatoid arthritis&#44; using an enzyme immunoassay&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A citrullinated peptide of fibrinogen designed by informatics prediction was synthesised and used in an enzyme immunoassay&#46; The participants were 81 patients with early disease&#44; 81 patients with established disease&#44; 58 patients with other rheumatic and inflammatory diseases&#44; and 43 healthy individuals&#46; Anti-citrullinated fibrinogen peptide&#44; anti-mutated citrullinated vimentin&#44; anti second generation citrullinated peptides and rheumatoid factor antibodies were determined by enzyme-linked immunosorbent assay&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Determination of anti-citrullinated peptide of fibrinogen antibodies by the designed enzyme immunoassay showed the best diagnostic value in early rheumatoid arthritis patients&#44; with the highest value sensitivity &#40;84&#37;&#41;&#44; negative predictive value &#40;85&#37;&#41;&#44; Youden index &#40;0&#46;73&#37;&#41; and area under the receiver operating curve &#40;0&#46;9192&#41;&#46; Specificity &#40;89&#37;&#41; and positive predictive value &#40;88&#37;&#41; were higher than rheumatoid factor&#44; similar to anti-mutated citrullinated vimentin&#44; but lower than second generation anti-citrullinated peptides assay&#46; The positivity of C-reactive protein was associated with the presence of anti-citrullinated fibrinogen peptide antibodies and the titres of these antibodies correlated with clinical activity in early disease&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The immunoassay designed with a citrullinated fibrinogen peptide has a high diagnostic value and can identify patients with greater clinical activity in early rheumatoid arthritis&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Materials and methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Determinar el valor diagn&#243;stico de los anticuerpos contra un p&#233;ptido del fibrin&#243;geno citrulinado&#44; en pacientes cubanos con artritis reumatoide &#40;AR&#41;&#44; mediante un inmunoan&#225;lisis enzim&#225;tico&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se sintetiz&#243; un p&#233;ptido del fibrin&#243;geno citrulinado dise&#241;ado por predicci&#243;n inform&#225;tica y se utiliz&#243; en un inmunoan&#225;lisis enzim&#225;tico&#46; Participaron 81 pacientes con AR temprana&#44; 81 pacientes con AR establecida&#44; 58 pacientes con otras enfermedades reum&#225;ticas e inflamatorias y 43 individuos sanos&#46; Se determinaron los anticuerpos contra el p&#233;ptido citrulinado del fibrin&#243;geno&#44; antivimentina citrulinada mutada&#44; antip&#233;ptidos citrulinados de segunda generaci&#243;n y factor reumatoide mediante el ensayo de inmunoabsorci&#243;n ligaado a enzimas &#40;ELISA&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La determinaci&#243;n de anticuerpos contra el p&#233;ptido citrulinado del fibrin&#243;geno mediante el inmunoan&#225;lisis enzim&#225;tico dise&#241;ado mostr&#243; el mejor desempe&#241;o diagn&#243;stico en pacientes con enfermedad temprana&#44; con el valor m&#225;s elevado de sensibilidad &#40;84&#37;&#41;&#44; valor predictivo negativo &#40;85&#37;&#41;&#44; &#237;ndice de Youden &#40;0&#44;73&#37;&#41; y &#225;rea bajo la curva operativa del receptor &#40;0&#44;9192&#41;&#46; La especificidad &#40;89&#37;&#41; y el valor predictivo positivo &#40;88&#37;&#41; fueron superiores al factor reumatoide&#44; similar al ensayo antivimentina citrulinada mutada&#44; pero inferiores al ensayo antip&#233;ptidos citrulinados de segunda generaci&#243;n&#46; La positividad de prote&#237;na C reactiva se asoci&#243; a la presencia de anticuerpos contra el p&#233;ptido citrulinado del fibrin&#243;geno y los t&#237;tulos de estos anticuerpos tuvieron correlaci&#243;n con la actividad cl&#237;nica en la enfermedad temprana&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El inmunoan&#225;lisis dise&#241;ado con un p&#233;ptido citrulinado del fibrin&#243;geno tiene un alto valor diagn&#243;stico y permite la identificaci&#243;n de pacientes con mayor actividad cl&#237;nica en la AR temprana&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Mart&#237;nez T&#233;llez G&#44; Torres Rives B&#44; G&#243;mez Morej&#243;n JA&#44; P&#233;rez Garay H&#44; Rodr&#237;guez AM&#44; Portal Miranda J&#193;&#46; Valor diagn&#243;stico de anticuerpos antip&#233;ptido citrulinado del fibrin&#243;geno en la artritis reumatoide&#46; Reumatol Clin&#46; 2020&#59;16&#58;455&#8211;461&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Frequency of antibody positivity in patients with early stage and established RA&#44; in healthy controls and in controls with other diseases&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Differences were found between the titres of antibodies in all of the patients with RA compared to the total of patients with other diseases and healthy individuals&#46; This was so for anti-CFP antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41;&#44; anti-MCV antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41;&#44; anti-CCP2 antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0000&#41; and RF antibodies &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0027&#41;&#46; Differences were found in the titres of RF antibodies in patients with early stage and established RA &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0121&#41;&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; CCP2&#58; second generation citrullinated peptides&#59; RF&#58; rheumatoid factor&#59; MCV&#58; mutated citrullinated vimentin&#59; <span class="elsevierStyleItalic">n</span>&#58; total number of patients&#59; CFP&#58; citrullinated fibrinogen peptide&#59; RCI&#58; interquartile ranges&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Analysis of the ROC curves obtained in evaluation of the diagnostic performance of the immunoanalysis&#46; &#40;A&#41; Early stage RA&#46; &#40;B&#41; Established RA&#46; &#40;C&#41; Total number of RA patients&#46;</p> <p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">The area homogeneity test showed differences between all of the curves &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;000&#41;&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; CCP2&#58; second generation citrullinated peptides&#59; RF&#58; rheumatoid factor&#59; CI&#58; confidence interval&#59; MCV&#58; mutated citrullinated vimentin&#59; CFP&#58; citrullinated fibrinogen peptide&#59; ROC curve&#58; receiver operative curve&#46;</p>"
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                  \t\t\t\t">&#946; fibrinogen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#8211;69&#44; 91&#8211;102&#44; 105&#8211;113&#44; 129&#8211;141&#44; 143&#8211;146&#44; 156&#8211;162&#44; 216&#8211;222&#44; 230&#8211;234&#44; 243&#8211;250&#44; 254&#8211;288&#44; 304&#8211;305&#44; 316&#8211;324&#44; 330&#8211;337&#44; 345&#8211;354&#44; 359&#8211;362&#44; 378&#8211;402&#44; 408&#8211;419&#44; 427&#8211;434&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#44; 90&#8211;99&#44; 110&#44; 123&#8211;142&#44; 144&#8211;149&#44; 158&#8211;159&#44; 221&#44; 231&#8211;234&#44; 243&#8211;246&#44; 256&#8211;257&#44; 304&#8211;306&#44; 315&#8211;322&#44; 332&#8211;337&#44; 348&#44; 359&#8211;364&#44; 377&#8211;381&#44; 384&#8211;392&#44; 396&#8211;397&#44; 417&#8211;425&#44; 429&#8211;431&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2436677.png"
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Amino acid regions of the epitopes obtained in the prediction of fibrinogen &#945; and &#946; chains&#44; where both computer programs agree&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; CCP2&#58; second generation citrullinated peptides&#59; RF&#58; rheumatoid factor&#59; CI&#58; confidence interval&#59; YI&#58; Youden index&#59; MCV&#58; mutated citrullinated vimentin&#59; <span class="elsevierStyleItalic">n</span>&#58; number of patients&#59; CFP&#58; citrullinated fibrinogen peptide&#59; CP&#58; cut-off point&#59; NPV&#58; negative predictive value&#59; PPV&#58; positive predictive value&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Method&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sensitivity &#40;&#37;&#41;&#59; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Specificity &#40;&#37;&#41;&#59; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PPV &#40;&#37;&#41;&#59; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NPV &#40;&#37;&#41;&#59; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">YI&#59; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Early stage RA &#40;n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">81&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CFP&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#46;0&#59; 75&#46;3&#8211;92&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;4&#8211;96&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;3&#59; 80&#46;5&#8211;96&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#46;7&#59; 76&#46;5&#8211;93&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;73&#59; 0&#46;62&#8211;0&#46;83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-MCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#46;3&#59; 71&#46;0&#8211;89&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;4&#8211;96&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;8&#59; 79&#46;7&#8211;96&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&#46;8&#59; 73&#46;2&#8211;90&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;69&#59; 0&#46;6&#8211;0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CCP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#46;4&#59; 37&#46;9&#8211;60&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&#46;8&#59; 95&#46;7&#8211;100&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#46;6&#59; 91&#46;6&#8211;100&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#46;1&#59; 57&#46;3&#8211;75&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;48&#59; 0&#46;37&#8211;0&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#46;4&#59; 33&#46;0&#8211;55&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85&#46;2&#59; 76&#46;8&#8211;93&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75&#46;0&#59; 61&#46;7&#8211;88&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;5&#59; 51&#46;1&#8211;69&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;30&#59; 0&#46;2&#8211;0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Established RA &#40;n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">81&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CFP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;5&#59; 49&#46;2&#8211;71&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;4&#8211;96&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#46;5&#59; 74&#46;3&#8211;94&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&#46;2&#46; 59&#46;9&#8211;78&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;49&#59; 0&#46;37&#8211;0&#46;62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-MCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;7&#59; 79&#46;8&#8211;95&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;4&#8211;96&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;2&#8211;96&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;8&#59; 80&#46;1&#8211;95&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;77&#59; 0&#46;67&#8211;0&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CCP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;1&#59; 41&#46;6&#8211;64&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&#46;8&#59; 95&#46;7&#8211;100&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#46;7 92&#46;2&#8211;100&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">67&#46;8 58&#46;9&#8211;76&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;52 0&#46;41&#8211;0&#46;63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#46;2&#59; 53&#46;1&#8211;75&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85&#46;2&#59; 76&#46;8&#8211;93&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&#46;3&#59; 70&#46;9&#8211;91&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#46;4&#59; 60&#46;9&#8211;80&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;49&#59; 0&#46;36&#8211;0&#46;62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Total RA &#40;n</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">162&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CFP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;2&#59; 65&#46;0&#8211;79&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;4&#8211;96&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;9&#59; 88&#46;0&#8211;97&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#46;5&#59; 52&#46;3&#8211;70&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;61&#59; 0&#46;51&#8211;0&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-MCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#46;0&#59; 78&#46;0&#8211;89&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#46;9&#59; 81&#46;4&#8211;96&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&#46;8&#59; 89&#46;5&#8211;98&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&#46;5&#59; 64&#46;2&#8211;82&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;73&#59; 0&#46;64&#8211;0&#46;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-CCP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;2&#59; 43&#46;2&#8211;59&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&#46;8&#59; 95&#46;7&#8211;100&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98&#46;8&#59; 95&#46;9&#8211;100&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#46;3&#59; 42&#46;2&#8211;58&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;50&#59; 0&#46;42&#8211;0&#46;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>RF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;9&#59; 43&#46;9&#8211;59&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85&#46;2&#59; 76&#46;8&#8211;93&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;5&#59; 80&#46;4&#8211;94&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&#46;9&#59; 38&#46;5&#8211;55&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;37&#59; 0&#46;26&#8211;0&#46;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">RA&#58; rheumatoid arthritis&#59; DAS 28&#58; disease activity index based on the count of 28 joints&#59; HAQ&#58; health assessment questionnaire&#59; <span class="elsevierStyleItalic">m</span>&#58; median&#59; <span class="elsevierStyleItalic">n</span>&#58; number of patients&#59; CFP&#58; citrullinated fibrinogen peptide&#59; RCI&#58; interquartile range&#59; ESR&#58; erythrocyte sedimentation rate&#46;</p>"
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                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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indicators&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Early stage RA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Established RA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DAS 28&#44; m &#40;RCI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;2 &#40;4&#46;3&#8211;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;1 &#40;3&#46;9&#8211;5&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Remission&#58; DAS 28 &#60;2&#46;6&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;8&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Low activity&#58; DAS 28 &#8805;2&#46;6 and &#8804;3&#46;2&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Moderate&#58; DAS 28 &#62;3&#46;2 and &#8804;5&#46;1&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;43&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26 &#40;32&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>High&#58; DAS 28 &#62;5&#46;1&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43 &#40;53&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 &#40;48&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DAS 28 in anti-CFP positives&#44; m &#40;RCI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;4 &#40;4&#46;5&#8211;6&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;3 &#40;4&#46;8&#8211;5&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DAS 28 in anti-CFP negatives&#44; m &#40;RCI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;5 &#40;3&#46;7&#8211;5&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;5 &#40;2&#46;9&#8211;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HAQ&#44; m &#40;RCI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;62 &#40;0&#46;25&#8211;0&#46;75&#41;&nbsp;\t\t\t\t\t\t\n
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