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smoking may be a preventable risk factor for susceptibility to RA&#44; RA-associated ILD and idiopathic pulmonary fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Synthetic &#40;sDMARD&#41; and biological &#40;bDMARD&#41; disease modifying drugs are the primary treatment for RA&#44; although glucocorticoids&#44; non-steroidal anti-inflammatory drugs &#40;NSAIDs&#41; and analgesics are also used as symptomatic treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> Studies in RA and ILD patients treated with DMARDs are few and contradictory&#46; In addition&#44; these patients are usually excluded from clinical trials due to the condition&#46; All this has led to a restriction of their use and remains a challenge for clinicians&#46; Therefore&#44; there is a need to better understand the characteristics of patients treated with DMARDs in routine clinical practice&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">12&#44;13</span></a> The objectives of this study are&#58; &#40;1&#41; to describe the clinical&#44; radiological&#44; respiratory functional and echocardiographic characteristics of a prospective cohort of RA and clinical ILD patients treated with DMARDs in routine clinical practice and &#40;2&#41; to study the possible association of severity factors &#40;e&#46;g&#46;&#44; ACPA positivity&#44; erosions&#41; with RA-associated lung disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">Multicentre cross-sectional study conducted in a cohort of RA and ILD patients from different hospitals in Andalusia&#44; Spain&#44; and a control group of RA subjects without IDL&#44; matched by sex and age&#46; The recruitment period was from January 2015 to January 2017&#46; The study was approved by the medical ethics committee&#44; and all subjects provided written their informed consent prior to enrolment&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Subjects</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0025" class="elsevierStylePara elsevierViewall">All the patients with RA and ILD treated with DMARDs were recruited consecutively from rheumatology clinics of different centres in Andalusia&#58; Hospital Regional Universitario de M&#225;laga&#44; Hospital Virgen de la Victoria de M&#225;laga&#44; Hospital de Valme de Sevilla and Hospital Virgen de las Nieves de Granada&#46; The inclusion criteria were age &#8805;16 years&#44; diagnosis of RA according to the classification criteria of the American College of Rheumatology&#47;European League Against Rheumatism 2010 &#40;ACR&#47;EULAR criteria 2010&#41;&#44; ILD &#40;American Thoracic Society&#47;European Respiratory Criteria&#41; and treated with DMARDs at the last visit&#46; The exclusion criteria were the presence of any inflammatory or rheumatic disease other than RA &#40;except secondary Sj&#246;gren&#39;s syndrome&#41; and pregnancy&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Controls</span><p id="par0030" class="elsevierStylePara elsevierViewall">Patients with RA without ILD were selected consecutively from a prospective cohort at the Hospital Regional Universitario de M&#225;laga&#46; Controls were paired by sex&#44; age and time of disease progression&#46; The inclusion criteria were age &#8805;16 years&#44; diagnosis of RA according to the classification criteria of the American College of Rheumatology&#47;European League Against Rheumatism 2010 &#40;ACR&#47;EULAR 2010 criteria&#41; and treated at the last visit with DMARDs&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protocol</span><p id="par0035" class="elsevierStylePara elsevierViewall">Patients with RA and ILD who attended rheumatology consultations from January 2015 to December 2017 and met the selection criteria were treated according to a pre-established protocol for data collection&#46; The date of this visit was used as the index date&#44; and this visit was marked as V0&#46; High resolution computed tomography &#40;HRCT&#41;&#44; respiratory functional tests &#40;PFTs&#41; and echocardiography were requested for all patients who had not undergone these tests in the past year&#46; The controls were also treated using a pre-established protocol for data collection&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Variables and operational variables</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Principal variable</span><p id="par0045" class="elsevierStylePara elsevierViewall">The main variables analysed were&#58; &#40;1&#41; description of the radiological type of ILD in RA patients and &#40;2&#41; difference in markers of disease severity and activity in cases and controls at the date of inclusion&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Other variables</span><p id="par0050" class="elsevierStylePara elsevierViewall">ILD variables included description of radiological type by high resolution computerised tomography &#40;nonspecific interstitial pneumonia &#91;NSIP&#93;&#44; usual interstitial pneumonia &#91;UIP&#93;&#41; and lung function by RFT &#40;DLCO&#44; FEV1&#44; FV&#44; FEV1&#47;CVF&#41;&#59; presence of pulmonary hypertension &#40;PHT&#41; by echocardiogram&#44; and presence and degree of dyspnoea&#46; HRCT was performed in the baseline assessment with a 1&#46;5 axial section or 2<span class="elsevierStyleHsp" style=""></span>mm thickness taken at intervals of 1<span class="elsevierStyleHsp" style=""></span>cm along the chest and reconstructed using a high spatial frequency algorithm&#44; taking 20&#8211;25 slices for each patient&#46; The CT scans were evaluated by two chest radiology experts blinded to the clinical data&#46; They were graded according to the Kazerooni score on the fibrotic component and the extent of ground glass opacities&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;9</span></a> ILD patterns were classified according to the criteria of the American Thoracic Society&#47;European Respiratory Criteria&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The variables of RA included the duration of symptoms&#44; extra-articular manifestations and history of smoking&#58; current or past&#46; In addition&#44; the following parameters were collected at the date of inclusion&#58; count of painful and inflamed joints&#44; visual analogue scale of 0&#8211;10<span class="elsevierStyleHsp" style=""></span>cm&#59; disease activity measured by DAS28 &#40;Disease Activity Score&#41;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> and physical function by a health assessment questionnaire &#40;HAQ&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> Severity variables were also collected at the date of inclusion&#58; RF&#44; measured in U&#47;ml&#44; was considered high when the titres were above the upper cut-off point used in our laboratory &#40;&#62;20<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41; and high titre &#40;&#62;60<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#59; presence of ACPA&#44; measured in U&#47;ml&#58; were considered positive with titres above 10<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#44; and high titre &#40;&#62;340<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#59; as well as the presence of radiological erosion&#46; Treatments&#58; sDMARD&#44; bDMARD&#44; other immunosuppressants or glucocorticoids that the patient was taking at the date of inclusion&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">First&#44; a descriptive analysis of the characteristics in both groups of patients was performed&#46; The qualitative variables were expressed as absolute numbers and their percentages&#59; the quantitative variables&#44; as mean and standard deviation when their distribution was normal&#44; and as median and interquartile range when not normal&#46; The goodness of fit of the continuous variables was confirmed with the Kolmogorov&#8211;Smirnov test&#46; The <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> or Fisher&#39;s test was performed as appropriate&#44; and for quantitative variables&#44; the Student&#39;s <span class="elsevierStyleItalic">t</span>-test for independent samples or Mann&#8211;Whitney in cases of non-normality&#46; Finally&#44; a binary logistic regression analysis was performed in patients with RA and ILD &#40;DV&#58; ILD&#41; to check which variables were independently associated with the presence of ILD&#46; The sample size was calculated assuming an alpha risk of &#46;10 and a beta risk of &#46;2 in a bilateral contrast&#44; and 40 subjects in each group were required to detect the difference between two proportions as statistically significant&#44; which for group 1 was expected to be &#46;53 and for group 2 &#46;26&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> The analysis was performed using the Rcomander statistical programme&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Result</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Baseline characteristics</span><p id="par0065" class="elsevierStylePara elsevierViewall">The study population comprised 82 RA patients&#58; 41 RA patients with ILD and 41 RA patients without ILD&#46; All the patient with IDL had been previously diagnosed by CT&#46; The baseline characteristics of both patient groups are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Although there were no differences between either group in most clinical and epidemiological parameters&#44; a higher percentage of patients with ILD were ex-smokers &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;013&#41;&#44; with erosive disease &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41; and double or single seropositive&#46; The group of patients with ILD had a higher percentage of RF-positive &#40;P&#61;<span class="elsevierStyleHsp" style=""></span>&#46;077&#41;&#44; ACPA-positive &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;023&#41;&#44; and RF- and high-titre ACPA-positive &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;040&#41; patients&#46; The patients with RA and ILD also had a higher frequency of serositis &#40;P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;033&#41; and osteoporosis &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Treatments&#44; disease activity and physical function</span><p id="par0070" class="elsevierStylePara elsevierViewall">All the patients were under treatment with DMARDs&#46; Among the patients with RA and ILD&#58; 9 &#40;21&#46;9&#37;&#41; were taking a bDMARD with an sDMARD&#44; the most common combination being DMARD &#43;RTX &#40;12&#46;1&#37;&#41;&#59; 25 patients &#40;60&#46;9&#37;&#41; were receiving sDMARDs in monotherapy&#44; most commonly methotrexate &#40;MTX&#41; &#40;48&#37;&#41;&#44; and 7 &#40;17&#46;0&#41; monotherapy with a bDMARD &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Among the RA patients without ILD&#44; bDMARD monotherapy was also the most frequent in 26 patients &#40;63&#46;4&#37;&#41;&#44; with MTX also the most frequent&#44; followed by combination therapy in 13 patients &#40;31&#46;7&#37;&#41;&#59; only 2 patients were on bDMARD monotherapy &#40;4&#46;8&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">With regard to disease activity parameters&#44; no differences in the median were observed in either of the patient groups &#40;p75&#8211;p25&#41; in TJC &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;590&#41;&#44; NIA &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;834&#41;&#44; CRP &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;338&#41;&#44; ESR &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;320&#41; or DAS28 &#40;2&#46;7 &#91;2&#46;3&#8211;3&#46;3&#93; vs&#46; 2&#46;29 &#91;1&#46;9&#8211;3&#46;2&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;145&#41;&#46; Quality of life was shown to be worse in the patients with ILD measured by HAQ &#40;1&#46;20 &#91;&#46;5&#8211;1&#46;7&#93; vs&#46; &#46;75 &#91;&#46;0&#8211;&#46;0&#93;&#59; P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;006&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Lung characteristics of the patients with rheumatoid arthritis and interstitial lung disease</span><p id="par0080" class="elsevierStylePara elsevierViewall">With regard to the patients&#8217; respiratory symptoms&#44; at the assessment date most described moderate effort dyspnoea &#40;25&#59; 61&#46;0&#37;&#41;&#44; 14 patients &#40;34&#46;1&#37;&#41; has no dyspnoea and only 2 patients &#40;4&#46;9&#37;&#41; had minimal effort dyspnoea with home oxygen therapy&#46; The patients without dyspnoea had better mean &#40;SD&#41; O<span class="elsevierStyleInf">2</span>Sat than the patients with moderate and minimal effort dyspnoea &#40;97&#46;15 &#91;2&#46;5&#93; vs&#46; 95&#46;12 &#91;2&#46;2&#93; vs&#46; 95&#46;0 &#91;&#46;7&#93;&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The PFT alterations included a reduction in DLCO diffusing capacity in most of the patients&#46; Forced vital capacity &#40;FVC&#41; and forced expiratory volume in 1 second &#40;FEV1&#41; were below 80 in slightly more than half the patients&#44; but the FEV1&#47;FVC ratio was mostly normal &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; DLCO &#60;70 was associated with erosions &#40;&#60;&#46;001&#41;&#44; elevated RF &#40;&#46;038&#41; and positive ACPA &#40;&#46;039&#41;&#46; Four patients &#40;9&#46;8&#37;&#41; had PHT on the echocardiogram&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The most common histopathological types described by HRCT were usual interstitial pneumonia in 27 patients &#40;65&#46;9&#37;&#41; and nonspecific interstitial pneumonia in 13 &#40;31&#46;7&#37;&#41;&#46; Only one patient &#40;2&#46;3&#37;&#41; had an organising pneumonia&#46; Three patients had a combination of NSIP and UIP&#44; but eventually described as dominant type&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Factors associated with interstitial lung disease</span><p id="par0095" class="elsevierStylePara elsevierViewall">The multivariate analysis showed that patients with a history of smoking of at least 6 months and erosive arthritis tripled the risk of ILD&#46; The variable most independently associated with ILD was the presence of ACPA &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;91&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; This model would explain 36&#37; of the variability of the presence of ILD &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;36&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">The RA patients treated with DMARDs and ILD in our cohort show a predominant histopathological pattern on HRCT of UIP &#40;65&#46;9&#37;&#41; or NSIP &#40;31&#46;7&#37;&#41;&#44; similar percentages to those described in the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">14&#44;15</span></a> We should also highlight that almost 90&#37; of our patients had a reduced DLCO&#46; These figures coincide with other studies&#44; such as that of Zhang et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> who found a reduced DLCO in 92&#37; of patients with RA and ILD and describe it as the most common and sensitive physiopathological change in ILD&#46; This is of diagnostic interest and could also be a result of screening from the onset of the disease&#46; In fact&#44; a recent study of RA patients highlights DLCO as a good method for preclinically identifying patients with ILD and RA&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> The latter study also describes an inverse correlation between DLCO levels and ACPA titre &#40;&#8722;&#46;45&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> In our cohort the patients with ILD with a DLCO&#60;80 were associated with erosion &#40;&#60;&#46;001&#41;&#44; elevated RF &#40;&#46;038&#41; and positive ACPA &#40;&#46;039&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The patients with RA and ILD in our cohort had more severe disease in the form of greater association with erosive disease and presence of ACPA&#46; We also identified more patients with a history of smoking in the patients with ILD&#46; The higher prevalence of ACPA detected in our RA-ILD patients compared to the RA patients without ILD is in line with most studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">5&#44;18&#8211;20</span></a> although there are some in whom this association was not seen&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">21&#44;22</span></a> These differences could be explained by the type of population&#44; the definition of the disease or the methodology for detecting clinical parameters&#46; The varying sensitivity and specificity of the methods for detecting ACPA may also affect their value when assessing the association with ILD&#46; The significantly higher positivity in the patients with RA and ILD could indicate that the presence of ACPA could be a good biomarker for diagnosing ILD in patients with RA&#46; It is believed that lung injury from smoking and other stimuli could contribute to protein citrullination modification&#44; which later creates new epitopes and subsequent autoimmune responses&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> In this regard&#44; a previous history of smoking &#40;for at least 6 months&#41; is associated with ILD in RA&#44; and multiple studies have demonstrated this association&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In terms of the treatment used&#44; the patients with RA and ILD took more sDMARDs than those without ILD&#44; mainly at the expense of MTX&#59; this could be due to the contradictory data described with this DMARD&#58; a meta-analysis of randomised controlled trials describing an increased risk of pneumonitis associated with MTX &#40;RR&#58; 7&#46;81&#44; 95&#37; CI&#58; 1&#46;76&#8211;34&#46;72&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> Subsequently a group of experts expressed their disagreement with this&#44; among other reasons because of the non-specific definition of the term pneumonitis&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> They described the course of lung function in a cohort of patients with RA and ILD and observed improved lung function tests after treatment with corticosteroids plus DMARDs &#40;MTX&#44; LFN or AZA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> With regard to treatment with bDMARDs&#44; in these patients the evidence is even more uncertain&#46; The few studies carried out describe abatacept and rituximab as drugs that could be effective and safe in the treatment of RA with IDL&#44; both at joint level and in stabilisation&#44; even with improvement in respiratory parameters&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28&#44;29</span></a> In line with the data described&#44; the distribution of the use of biological therapy in our patients was consistent&#58; higher use of rituximab and abatacept in patients with ILD versus anti-TNF and tocilizumab in the group without ILD&#46; The fact that both patient groups are under treatment could explain why there was no difference in inflammatory activity measured by DAS28 and APR &#40;CRP and ESR&#41; in both groups of patients&#46; The study by Restrepo et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> like ours&#44; also presents a lower percentage of patients treated with MTX due to contradictory data regarding its pulmonary toxicity&#46; However&#44; they associate this under-treatment with a higher DAS28 in these patients&#46; This might be due to the fact that the patients with ILD in their study were older and had a longer disease duration than those without ILD&#44; which was not the case in our study&#44; because we matched them by sex&#44; age and time since onset&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Among this study&#39;s limitations&#44; since it was performed in routine clinical practice&#44; were that no PFT or HRCT were performed in the group of RA patients without a diagnosis of ILD because they had no associated symptoms and unaltered chest X-rays&#46; Although according to various studies<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> there could already be alterations in PFT and on HRCT in the preclinical phase&#44; in these routine practice patients these tests were requested due to suspected pulmonary involvement&#46; This study is an observational analysis of a cohort of patients with RA and ILD&#44; in whom we prospectively analyse the parameters of respiratory function over time&#44; and a cohort of patients with RA without clinical respiratory symptoms&#46; The study was conducted under routine clinical practice conditions and its results could be extrapolated to situations in this field&#44; although longitudinal studies with a larger number of patients would be necessary to confirm the findings of our study and to establish causality&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">To conclude&#44; the results of our study support the higher frequency of the NIU and NINE histopathological patterns in patients with RA and ILD&#44; as well as impaired DLCO as the most important parameter&#46; Patients with RA and ILD are associated with more severe disease &#40;erosions and presence of ACPA&#41; as well as the smoking exposure factor&#46; Treatment with DMARDs in both patient groups controls inflammatory activity&#44; with increased use of the synthetic DMARDS HQC and leflunomide&#44; and the bDMARDs rituximab and abatacept&#44; in patients with ILD&#46; We need to wait for the prospective assessment of these patients to see any association of the treatment with the course of the lung disease&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs1">Andalusian Public Foundation for Health and Biomedicine Research in M&#225;laga &#40;FIMABIS&#41;</span>&#46; <span class="elsevierStyleGrantSponsor" id="gs2">Spanish Rheumatology Foundation &#40;FER&#41;</span>&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">Natalia Mena-V&#225;zquez&#58; talks for MSD&#44; UCB and Roche&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Lorena P&#233;rez-Albaladejo&#58; no conflict of interest&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Sara Manrique-Arija&#58; talks&#47;presentations for Abbvie&#44; Pzifer and MSD&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Carmen Mar&#237;a Romero-Barco&#58; talks&#47;speeches for Abbvie&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Carmen G&#243;mez Cano&#58; no conflict of interest to declare&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Inmaculada Ure&#241;a-Garnica&#58; no conflict of interest to declare&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Antonio Fern&#225;ndez-Nebro&#58; talks&#47;presentations for Roche&#44; MSD and BMS&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Patients and methods"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
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            3 => array:3 [
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              "titulo" => "Variables and operational variables"
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                0 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "Principal variable"
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                  "titulo" => "Other variables"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Result"
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            0 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Baseline characteristics"
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            1 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Treatments&#44; disease activity and physical function"
            ]
            2 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Lung characteristics of the patients with rheumatoid arthritis and interstitial lung disease"
            ]
            3 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Factors associated with interstitial lung disease"
            ]
          ]
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          "titulo" => "Discussion"
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          "titulo" => "Funding"
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        9 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Conflict of interests"
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        10 => array:2 [
          "identificador" => "xack521619"
          "titulo" => "Acknowledgements"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2019-02-26"
    "fechaAceptado" => "2019-06-03"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1352813"
          "palabras" => array:4 [
            0 => "Rheumatoid arthritis"
            1 => "Comorbidities"
            2 => "Interstitial lung disease"
            3 => "Disease modifying antirheumatic drugs"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1352812"
          "palabras" => array:4 [
            0 => "Artritis reumatoide"
            1 => "Comorbilidades"
            2 => "Enfermedad pulmonar intersticial"
            3 => "F&#225;rmacos modificadores de la enfermedad"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To study the differences between rheumatoid arthritis &#40;RA&#41;-interstitial lung disease &#40;ILD&#41; patients and RA patients without ILD in severity markers and disease activity and to identify factors associated with the presence of ILD in RA patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Patients&#58; RA-ILD patients selected from a multicentre cohort in Andalusia&#44; Spain&#46; Controls&#58; RA-patients without ILD paired by sex&#44; age and disease duration&#46; Protocol&#58; RA patients are reviewed every 3&#8211;6 months in rheumatology consultation&#46; All patients are reviewed according to a predetermined protocol with systematic data collection&#46; Outcomes&#58; description of ILD type&#44; differences in severity markers and disease activity in both groups&#46; Other variables&#58; ILD type by imaging technique &#40;HRCT&#41;&#58; nonspecific interstitial pneumonia &#40;NSIP&#41;&#47;usual interstitial pneumonia &#40;UIP&#41;&#46; Lung function by PTF&#46; Activity and severity markers of arthritis by DAS28-ESR&#44; HAQ&#44; RF&#44; ACPA and erosions&#46; Treatment with DMARD&#46; Statistical analysis&#58; descriptive and paired <span class="elsevierStyleItalic">T</span>-test or Chi-square test followed by binary logistic regression &#40;DV&#58; ILD in patients with RA&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Eighty-two patients were included&#44; 41 RA-ILD and 41 RA controls&#46; RF and ACPA positivity&#44; serositis and osteoporosis were more frequent in RA-ILD patients&#46; No significant differences in DAS28 were observed &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;145&#41; between RA-ILD and RA control patients&#46; RA-ILD patients presented worse HAQ scores &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;006&#41;&#46; All patients were treated with disease modifying antirheumatic drugs &#40;DMARDs&#41;&#46; The risk of developing ILD in RA patients is tripled by a history of smoking or the presence of erosive arthritis &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;36&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The results of our study support the higher frequency of UIP and NSIP in RA patients&#46; DLCO is the most sensitive parameter to detect ILD in RA patients&#46; Our study showed that ILD in RA patients was associated with RA severity &#40;presence of erosions and ACPA&#41; and with a history of smoking&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Patients and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudiar las diferencias en pacientes con artritis reumatoide &#40;AR&#41; y enfermedad pulmonar intersticial &#40;EPID&#41; y pacientes con AR sin EPID&#44; e identificar factores asociados con la EPID en pacientes con AR&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional de casos y controles&#46; Pacientes&#58; se seleccionaron pacientes de una cohorte con AR y EPID de diferentes centros de Andaluc&#237;a&#46; Controles&#58; pacientes con AR sin EPID pareados por edad&#44; g&#233;nero y tiempo de evoluci&#243;n&#46; Protocolo&#58; los pacientes con AR se revisan cada 3-6 meses en consulta&#46; Todos los pacientes son revisados de acuerdo con un protocolo predeterminado con recogida de datos sistem&#225;tica&#46; Desenlaces&#58; descripci&#243;n del tipo radiol&#243;gico de EPID&#44; diferencias en los marcadores de gravedad en casos y controles y en la actividad de la enfermedad&#46; Otras variables&#58; descripci&#243;n del tipo de EPID por TACAR&#58; neumon&#237;a intersticial usual &#40;NIU&#41;&#44; neumon&#237;a intersticial no espec&#237;fica &#40;NINE&#41; y de la funci&#243;n pulmonar por PFR&#59; marcadores de actividad y gravedad de artritis&#58; DAS28&#44; HAQ&#44; FR&#44; ACPA&#44; erosiones&#46; Tratamiento con FAME&#46; An&#225;lisis&#58; descriptivo&#44; &#967;<span class="elsevierStyleSup">2</span> o t de Student&#44; seguida de regresi&#243;n log&#237;stica binaria &#40;Vd&#58;EPID en pacientes con AR&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 82 pacientes&#58; 41 con AR y EPID y 41 controles AR sin EPID&#46; Los pacientes con EPID presentaron un mayor porcentaje de pacientes con FR y ACPA positivos y una mayor frecuencia de serositis y osteoporosis&#46; No hubo diferencias significativas en DAS28 en casos y controles&#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;145&#41;&#44; pero los pacientes de AR con EPID presentaron peor HAQ &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;006&#41;&#46; Todos los pacientes estaban en tratamiento con FAME&#46; El an&#225;lisis multivariante mostr&#243; que los pacientes con AR exfumadores y con artritis erosiva triplicaron el riesgo de presentar EPID &#40;R<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;36&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados de nuestro estudio apoyan la mayor frecuencia de NIU y NINE en pacientes con AR&#44; as&#237; como la alteraci&#243;n de DLCO como el par&#225;metro m&#225;s importante&#46; Los pacientes con AR y EPID se asociaron con una enfermedad m&#225;s grave &#40;erosiones y ACPA&#41; y con el tabaco&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Objetivos"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mena-V&#225;zquez N&#44; P&#233;rez Albaladejo L&#44; Manrique-Arija S&#44; Romero Barco CM&#44; G&#243;mez Cano C&#44; Ure&#241;a Garnica I&#44; et al&#46; An&#225;lisis de las caracter&#237;sticas cl&#237;nico-anal&#237;ticas de pacientes con artritis reumatoide y enfermedad pulmonar intersticial&#58; casos y controles&#46; Reumatol Clin&#46; 2021&#59;17&#58;197&#8211;202&#46;</p>"
      ]
    ]
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      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:1 [
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            0 => array:2 [
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                0 => """
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RA with ILD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Age in years&#44; mean &#40;&#177;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">67&#46;9 &#40;7&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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><span class="elsevierStyleItalic">Smoking history</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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">&#46;013&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><span class="elsevierStyleHsp" style=""></span>Never smoked&#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">11 &#40;26&#46;8&#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">22 &#40;53&#46;7&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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><span class="elsevierStyleHsp" style=""></span>Occasionally&#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">30 &#40;73&#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">19 &#40;46&#46;3&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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><span class="elsevierStyleItalic">Time since onset of RA&#44; months&#44; median &#40;p75&#8211;p25&#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">116&#46;4 &#40;75&#46;5&#8211;193&#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">102&#46;1 &#40;71&#46;1&#8211;132&#46;7&#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">&#46;230&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><span class="elsevierStyleItalic">Diagnostic delay&#44; months&#44; median &#40;p75&#8211;p25&#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">12&#46;1 &#40;7&#46;6&#8211;15&#46;7&#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">8&#46;1 &#40;4&#46;9&#8211;13&#46;7&#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">&#46;050&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><span class="elsevierStyleItalic">RF&#43; &#40;&#62;10&#41;&#44; n &#40;&#37;&#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">39 &#40;95&#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">34 &#40;82&#46;9&#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">&#46;077&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><span class="elsevierStyleItalic">Elevated RF &#40;&#62;60&#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">29 &#40;70&#46;7&#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">20 &#40;48&#46;8&#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">&#46;043&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><span class="elsevierStyleItalic">ACPA&#43; &#40;&#62;20&#41;&#44; n &#40;&#37;&#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">35 &#40;85&#46;4&#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;63&#46;4&#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">&#46;023&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><span class="elsevierStyleItalic">Elevated ACPA &#40;&#62;340&#41;&#44; n &#40;&#37;&#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">25 &#40;61&#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">16 &#40;39&#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">&#46;040&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><span class="elsevierStyleItalic">Double seropositivity &#40;RF&#43; and ACPA&#43;&#41;&#44; n &#40;&#37;&#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">34 &#40;82&#46;9&#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">27 &#40;65&#46;9&#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">&#46;077&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><span class="elsevierStyleItalic">Erosion&#44; n &#40;&#37;&#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">34 &#40;82&#46;9&#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">22 &#40;53&#46;7&#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">&#46;004&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="4" 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="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Other extra-articular manifestations</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><span class="elsevierStyleItalic">Serositis &#40;pleuritis or pericarditis&#41;&#44; n &#40;&#37;&#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">13 &#40;31&#46;7&#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 &#40;12&#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">&#46;033&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><span class="elsevierStyleItalic">Vasculitis&#44; n &#40;&#37;&#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">2 &#40;4&#46;9&#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 &#40;&#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">&#46;151&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><span class="elsevierStyleItalic">Rheumatoid nodules&#44; n &#40;&#37;&#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">11 &#40;26&#46;8&#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">8 &#40;19&#46;5&#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">&#46;432&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><span class="elsevierStyleItalic">Anaemia of chronic disorder&#44; n &#40;&#37;&#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">12 &#40;29&#46;3&#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">6 &#40;14&#46;6&#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">&#46;109&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><span class="elsevierStyleItalic">Sj&#246;gren&#39;s syndrome&#44; n &#40;&#37;&#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
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;7&#46;3&#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
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                  \t\t\t\t">4 &#40;9&#46;8&#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="" valign="\n
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                  \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>Infliximab&#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
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                  \t\t\t\t">1 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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>Adalimumab&#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
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DLCO &#60;80&#37;&#44; n &#40;&#37;&#41;</span>&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
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                  \t\t\t\t">62&#46;1 &#40;10&#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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>DLCO&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CVF &#60;80&#37;&#44; n &#40;&#37;&#41;</span>&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
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                  \t\t\t\t">27 &#40;65&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>CVF&#44; mean &#40;SD&#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="left" valign="\n
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                  \t\t\t\t">72&#46;1 &#40;20&#46;7&#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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">FEV1 &#60;80&#37;&#44; n &#40;&#37;&#41;</span>&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
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                  \t\t\t\t">20 &#40;48&#44;8&#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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>FEV1&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">76&#46;6 &#40;20&#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><span class="elsevierStyleItalic">FEV1&#47;CVF &#60;70&#44; n &#40;&#37;&#41;</span>&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
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                  \t\t\t\t">4 &#40;10&#46;5&#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><span class="elsevierStyleHsp" style=""></span>FEV1&#47;CVF&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">83&#46;8 &#40;14&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Respiratory function tests in patients with RA with ILD&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Nagelkerke&#39;s <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;371&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Predictor variables&#58; sex&#44; age&#44; history of smoking &#40;&#8805;6 months&#41;&#44; erosions&#44; ACPA positive&#44; disease duration&#44; DAS28&#44; HAQ&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Predictor variables&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OR&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CI &#40;95&#37;&#41;&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">History of smoking &#40;&#8805;6 months&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;94&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;02&#8211;8&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#46;046&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">ACPA positive&nbsp;\t\t\t\t\t\t\n
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                  \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">1&#46;07&#8211;12&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;040&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">Erosions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;20&#8211;12&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#46;046&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Binary multivariate logistic regression using the presence of ILD as a dependent variable&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
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            0 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;S&#46; Smolen"
                            1 => "D&#46; Aletaha"
                            2 => "I&#46;B&#46; McInnes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2016"
                        "volumen" => "388"
                        "paginaInicial" => "2023"
                        "paginaFinal" => "2038"
                      ]
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              "identificador" => "bib0155"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interstitial lung disease in patients with rheumatoid arthritis&#58; spontaneous and drug induced"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;W&#46; Hallowell"
                            1 => "M&#46;R&#46; Horton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40265-014-0190-z"
                      "Revista" => array:6 [
                        "tituloSerie" => "Drugs"
                        "fecha" => "2014"
                        "volumen" => "74"
                        "paginaInicial" => "443"
                        "paginaFinal" => "450"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24570384"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interstitial lung disease in recent onset rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Gabbay"
                            1 => "R&#46; Tarala"
                            2 => "R&#46; Will"
                            3 => "G&#46; Carroll"
                            4 => "B&#46; Adler"
                            5 => "D&#46; Cameron"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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Original Article
Analysis of clinical–analytical characteristics in patients with rheumatoid arthritis and interstitial lung disease: Case–control study
Análisis de las características clínico-analíticas de pacientes con artritis reumatoide y enfermedad pulmonar intersticial: casos y controles
Natalia Mena-Vázqueza, Lorena Pérez Albaladejob, Sara Manrique-Arijaa,
Corresponding author
Sarama_82@hotmail.com

Corresponding author.
, Carmen María Romero Barcoc, Carmen Gómez Canod, Inmaculada Ureña Garnicaa, Antonio Fernández-Nebroa
a UGC de Reumatología, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
b Hospital Universitario Virgen de las Nieves, Granada, Spain
c Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain
d Hospital Universitario Virgen de Valme, Sevilla, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is an immune-mediated inflammatory disease of unknown cause and chronic course&#46; It primarily affects the joints&#44; but extra-articular clinical manifestations are common&#46; The lung is one of the most frequently affected organs and causes significant morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1&#44;2</span></a> Interstitial lung disease &#40;ILD&#41; is the most common non-plural lung manifestation in RA&#46; Between 8&#37; and 10&#37; of patients develop clinically significant ILD&#44; while subclinical ILD&#44; detected by systematic screening&#44; occurs in 22&#37;&#8211;33&#37; of patients with established RA&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> This condition has been associated with a poor prognosis&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> and therefore greater knowledge of its characteristics &#40;e&#46;g&#46;&#44; histopathological type&#41; and the discovery of risk factors associated with its development are of great importance in its diagnosis and treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Variables associated with RA with ILD include male sex&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> elevated levels of rheumatoid factor &#40;RF&#41;&#44; erythrocyte sedimentation rate &#40;ESR&#41; and smoking&#46; The most recent studies also involve anticitrullinated peptide antibodies &#40;ACPA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> Because of the connection between tobacco smoke and the development of ACPA&#44; it is believed that this toxic substance may influence both the pathogenesis of RA and its complications&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a> Therefore&#44; smoking may be a preventable risk factor for susceptibility to RA&#44; RA-associated ILD and idiopathic pulmonary fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Synthetic &#40;sDMARD&#41; and biological &#40;bDMARD&#41; disease modifying drugs are the primary treatment for RA&#44; although glucocorticoids&#44; non-steroidal anti-inflammatory drugs &#40;NSAIDs&#41; and analgesics are also used as symptomatic treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> Studies in RA and ILD patients treated with DMARDs are few and contradictory&#46; In addition&#44; these patients are usually excluded from clinical trials due to the condition&#46; All this has led to a restriction of their use and remains a challenge for clinicians&#46; Therefore&#44; there is a need to better understand the characteristics of patients treated with DMARDs in routine clinical practice&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">12&#44;13</span></a> The objectives of this study are&#58; &#40;1&#41; to describe the clinical&#44; radiological&#44; respiratory functional and echocardiographic characteristics of a prospective cohort of RA and clinical ILD patients treated with DMARDs in routine clinical practice and &#40;2&#41; to study the possible association of severity factors &#40;e&#46;g&#46;&#44; ACPA positivity&#44; erosions&#41; with RA-associated lung disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">Multicentre cross-sectional study conducted in a cohort of RA and ILD patients from different hospitals in Andalusia&#44; Spain&#44; and a control group of RA subjects without IDL&#44; matched by sex and age&#46; The recruitment period was from January 2015 to January 2017&#46; The study was approved by the medical ethics committee&#44; and all subjects provided written their informed consent prior to enrolment&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Subjects</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0025" class="elsevierStylePara elsevierViewall">All the patients with RA and ILD treated with DMARDs were recruited consecutively from rheumatology clinics of different centres in Andalusia&#58; Hospital Regional Universitario de M&#225;laga&#44; Hospital Virgen de la Victoria de M&#225;laga&#44; Hospital de Valme de Sevilla and Hospital Virgen de las Nieves de Granada&#46; The inclusion criteria were age &#8805;16 years&#44; diagnosis of RA according to the classification criteria of the American College of Rheumatology&#47;European League Against Rheumatism 2010 &#40;ACR&#47;EULAR criteria 2010&#41;&#44; ILD &#40;American Thoracic Society&#47;European Respiratory Criteria&#41; and treated with DMARDs at the last visit&#46; The exclusion criteria were the presence of any inflammatory or rheumatic disease other than RA &#40;except secondary Sj&#246;gren&#39;s syndrome&#41; and pregnancy&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Controls</span><p id="par0030" class="elsevierStylePara elsevierViewall">Patients with RA without ILD were selected consecutively from a prospective cohort at the Hospital Regional Universitario de M&#225;laga&#46; Controls were paired by sex&#44; age and time of disease progression&#46; The inclusion criteria were age &#8805;16 years&#44; diagnosis of RA according to the classification criteria of the American College of Rheumatology&#47;European League Against Rheumatism 2010 &#40;ACR&#47;EULAR 2010 criteria&#41; and treated at the last visit with DMARDs&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protocol</span><p id="par0035" class="elsevierStylePara elsevierViewall">Patients with RA and ILD who attended rheumatology consultations from January 2015 to December 2017 and met the selection criteria were treated according to a pre-established protocol for data collection&#46; The date of this visit was used as the index date&#44; and this visit was marked as V0&#46; High resolution computed tomography &#40;HRCT&#41;&#44; respiratory functional tests &#40;PFTs&#41; and echocardiography were requested for all patients who had not undergone these tests in the past year&#46; The controls were also treated using a pre-established protocol for data collection&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Variables and operational variables</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Principal variable</span><p id="par0045" class="elsevierStylePara elsevierViewall">The main variables analysed were&#58; &#40;1&#41; description of the radiological type of ILD in RA patients and &#40;2&#41; difference in markers of disease severity and activity in cases and controls at the date of inclusion&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Other variables</span><p id="par0050" class="elsevierStylePara elsevierViewall">ILD variables included description of radiological type by high resolution computerised tomography &#40;nonspecific interstitial pneumonia &#91;NSIP&#93;&#44; usual interstitial pneumonia &#91;UIP&#93;&#41; and lung function by RFT &#40;DLCO&#44; FEV1&#44; FV&#44; FEV1&#47;CVF&#41;&#59; presence of pulmonary hypertension &#40;PHT&#41; by echocardiogram&#44; and presence and degree of dyspnoea&#46; HRCT was performed in the baseline assessment with a 1&#46;5 axial section or 2<span class="elsevierStyleHsp" style=""></span>mm thickness taken at intervals of 1<span class="elsevierStyleHsp" style=""></span>cm along the chest and reconstructed using a high spatial frequency algorithm&#44; taking 20&#8211;25 slices for each patient&#46; The CT scans were evaluated by two chest radiology experts blinded to the clinical data&#46; They were graded according to the Kazerooni score on the fibrotic component and the extent of ground glass opacities&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;9</span></a> ILD patterns were classified according to the criteria of the American Thoracic Society&#47;European Respiratory Criteria&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The variables of RA included the duration of symptoms&#44; extra-articular manifestations and history of smoking&#58; current or past&#46; In addition&#44; the following parameters were collected at the date of inclusion&#58; count of painful and inflamed joints&#44; visual analogue scale of 0&#8211;10<span class="elsevierStyleHsp" style=""></span>cm&#59; disease activity measured by DAS28 &#40;Disease Activity Score&#41;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> and physical function by a health assessment questionnaire &#40;HAQ&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> Severity variables were also collected at the date of inclusion&#58; RF&#44; measured in U&#47;ml&#44; was considered high when the titres were above the upper cut-off point used in our laboratory &#40;&#62;20<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41; and high titre &#40;&#62;60<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#59; presence of ACPA&#44; measured in U&#47;ml&#58; were considered positive with titres above 10<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#44; and high titre &#40;&#62;340<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#59; as well as the presence of radiological erosion&#46; Treatments&#58; sDMARD&#44; bDMARD&#44; other immunosuppressants or glucocorticoids that the patient was taking at the date of inclusion&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">First&#44; a descriptive analysis of the characteristics in both groups of patients was performed&#46; The qualitative variables were expressed as absolute numbers and their percentages&#59; the quantitative variables&#44; as mean and standard deviation when their distribution was normal&#44; and as median and interquartile range when not normal&#46; The goodness of fit of the continuous variables was confirmed with the Kolmogorov&#8211;Smirnov test&#46; The <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> or Fisher&#39;s test was performed as appropriate&#44; and for quantitative variables&#44; the Student&#39;s <span class="elsevierStyleItalic">t</span>-test for independent samples or Mann&#8211;Whitney in cases of non-normality&#46; Finally&#44; a binary logistic regression analysis was performed in patients with RA and ILD &#40;DV&#58; ILD&#41; to check which variables were independently associated with the presence of ILD&#46; The sample size was calculated assuming an alpha risk of &#46;10 and a beta risk of &#46;2 in a bilateral contrast&#44; and 40 subjects in each group were required to detect the difference between two proportions as statistically significant&#44; which for group 1 was expected to be &#46;53 and for group 2 &#46;26&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> The analysis was performed using the Rcomander statistical programme&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Result</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Baseline characteristics</span><p id="par0065" class="elsevierStylePara elsevierViewall">The study population comprised 82 RA patients&#58; 41 RA patients with ILD and 41 RA patients without ILD&#46; All the patient with IDL had been previously diagnosed by CT&#46; The baseline characteristics of both patient groups are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Although there were no differences between either group in most clinical and epidemiological parameters&#44; a higher percentage of patients with ILD were ex-smokers &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;013&#41;&#44; with erosive disease &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41; and double or single seropositive&#46; The group of patients with ILD had a higher percentage of RF-positive &#40;P&#61;<span class="elsevierStyleHsp" style=""></span>&#46;077&#41;&#44; ACPA-positive &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;023&#41;&#44; and RF- and high-titre ACPA-positive &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;040&#41; patients&#46; The patients with RA and ILD also had a higher frequency of serositis &#40;P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;033&#41; and osteoporosis &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Treatments&#44; disease activity and physical function</span><p id="par0070" class="elsevierStylePara elsevierViewall">All the patients were under treatment with DMARDs&#46; Among the patients with RA and ILD&#58; 9 &#40;21&#46;9&#37;&#41; were taking a bDMARD with an sDMARD&#44; the most common combination being DMARD &#43;RTX &#40;12&#46;1&#37;&#41;&#59; 25 patients &#40;60&#46;9&#37;&#41; were receiving sDMARDs in monotherapy&#44; most commonly methotrexate &#40;MTX&#41; &#40;48&#37;&#41;&#44; and 7 &#40;17&#46;0&#41; monotherapy with a bDMARD &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Among the RA patients without ILD&#44; bDMARD monotherapy was also the most frequent in 26 patients &#40;63&#46;4&#37;&#41;&#44; with MTX also the most frequent&#44; followed by combination therapy in 13 patients &#40;31&#46;7&#37;&#41;&#59; only 2 patients were on bDMARD monotherapy &#40;4&#46;8&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">With regard to disease activity parameters&#44; no differences in the median were observed in either of the patient groups &#40;p75&#8211;p25&#41; in TJC &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;590&#41;&#44; NIA &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;834&#41;&#44; CRP &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;338&#41;&#44; ESR &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;320&#41; or DAS28 &#40;2&#46;7 &#91;2&#46;3&#8211;3&#46;3&#93; vs&#46; 2&#46;29 &#91;1&#46;9&#8211;3&#46;2&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;145&#41;&#46; Quality of life was shown to be worse in the patients with ILD measured by HAQ &#40;1&#46;20 &#91;&#46;5&#8211;1&#46;7&#93; vs&#46; &#46;75 &#91;&#46;0&#8211;&#46;0&#93;&#59; P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;006&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Lung characteristics of the patients with rheumatoid arthritis and interstitial lung disease</span><p id="par0080" class="elsevierStylePara elsevierViewall">With regard to the patients&#8217; respiratory symptoms&#44; at the assessment date most described moderate effort dyspnoea &#40;25&#59; 61&#46;0&#37;&#41;&#44; 14 patients &#40;34&#46;1&#37;&#41; has no dyspnoea and only 2 patients &#40;4&#46;9&#37;&#41; had minimal effort dyspnoea with home oxygen therapy&#46; The patients without dyspnoea had better mean &#40;SD&#41; O<span class="elsevierStyleInf">2</span>Sat than the patients with moderate and minimal effort dyspnoea &#40;97&#46;15 &#91;2&#46;5&#93; vs&#46; 95&#46;12 &#91;2&#46;2&#93; vs&#46; 95&#46;0 &#91;&#46;7&#93;&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The PFT alterations included a reduction in DLCO diffusing capacity in most of the patients&#46; Forced vital capacity &#40;FVC&#41; and forced expiratory volume in 1 second &#40;FEV1&#41; were below 80 in slightly more than half the patients&#44; but the FEV1&#47;FVC ratio was mostly normal &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; DLCO &#60;70 was associated with erosions &#40;&#60;&#46;001&#41;&#44; elevated RF &#40;&#46;038&#41; and positive ACPA &#40;&#46;039&#41;&#46; Four patients &#40;9&#46;8&#37;&#41; had PHT on the echocardiogram&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The most common histopathological types described by HRCT were usual interstitial pneumonia in 27 patients &#40;65&#46;9&#37;&#41; and nonspecific interstitial pneumonia in 13 &#40;31&#46;7&#37;&#41;&#46; Only one patient &#40;2&#46;3&#37;&#41; had an organising pneumonia&#46; Three patients had a combination of NSIP and UIP&#44; but eventually described as dominant type&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Factors associated with interstitial lung disease</span><p id="par0095" class="elsevierStylePara elsevierViewall">The multivariate analysis showed that patients with a history of smoking of at least 6 months and erosive arthritis tripled the risk of ILD&#46; The variable most independently associated with ILD was the presence of ACPA &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;91&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; This model would explain 36&#37; of the variability of the presence of ILD &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;36&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">The RA patients treated with DMARDs and ILD in our cohort show a predominant histopathological pattern on HRCT of UIP &#40;65&#46;9&#37;&#41; or NSIP &#40;31&#46;7&#37;&#41;&#44; similar percentages to those described in the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">14&#44;15</span></a> We should also highlight that almost 90&#37; of our patients had a reduced DLCO&#46; These figures coincide with other studies&#44; such as that of Zhang et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> who found a reduced DLCO in 92&#37; of patients with RA and ILD and describe it as the most common and sensitive physiopathological change in ILD&#46; This is of diagnostic interest and could also be a result of screening from the onset of the disease&#46; In fact&#44; a recent study of RA patients highlights DLCO as a good method for preclinically identifying patients with ILD and RA&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> The latter study also describes an inverse correlation between DLCO levels and ACPA titre &#40;&#8722;&#46;45&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> In our cohort the patients with ILD with a DLCO&#60;80 were associated with erosion &#40;&#60;&#46;001&#41;&#44; elevated RF &#40;&#46;038&#41; and positive ACPA &#40;&#46;039&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The patients with RA and ILD in our cohort had more severe disease in the form of greater association with erosive disease and presence of ACPA&#46; We also identified more patients with a history of smoking in the patients with ILD&#46; The higher prevalence of ACPA detected in our RA-ILD patients compared to the RA patients without ILD is in line with most studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">5&#44;18&#8211;20</span></a> although there are some in whom this association was not seen&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">21&#44;22</span></a> These differences could be explained by the type of population&#44; the definition of the disease or the methodology for detecting clinical parameters&#46; The varying sensitivity and specificity of the methods for detecting ACPA may also affect their value when assessing the association with ILD&#46; The significantly higher positivity in the patients with RA and ILD could indicate that the presence of ACPA could be a good biomarker for diagnosing ILD in patients with RA&#46; It is believed that lung injury from smoking and other stimuli could contribute to protein citrullination modification&#44; which later creates new epitopes and subsequent autoimmune responses&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> In this regard&#44; a previous history of smoking &#40;for at least 6 months&#41; is associated with ILD in RA&#44; and multiple studies have demonstrated this association&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In terms of the treatment used&#44; the patients with RA and ILD took more sDMARDs than those without ILD&#44; mainly at the expense of MTX&#59; this could be due to the contradictory data described with this DMARD&#58; a meta-analysis of randomised controlled trials describing an increased risk of pneumonitis associated with MTX &#40;RR&#58; 7&#46;81&#44; 95&#37; CI&#58; 1&#46;76&#8211;34&#46;72&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> Subsequently a group of experts expressed their disagreement with this&#44; among other reasons because of the non-specific definition of the term pneumonitis&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> They described the course of lung function in a cohort of patients with RA and ILD and observed improved lung function tests after treatment with corticosteroids plus DMARDs &#40;MTX&#44; LFN or AZA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> With regard to treatment with bDMARDs&#44; in these patients the evidence is even more uncertain&#46; The few studies carried out describe abatacept and rituximab as drugs that could be effective and safe in the treatment of RA with IDL&#44; both at joint level and in stabilisation&#44; even with improvement in respiratory parameters&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28&#44;29</span></a> In line with the data described&#44; the distribution of the use of biological therapy in our patients was consistent&#58; higher use of rituximab and abatacept in patients with ILD versus anti-TNF and tocilizumab in the group without ILD&#46; The fact that both patient groups are under treatment could explain why there was no difference in inflammatory activity measured by DAS28 and APR &#40;CRP and ESR&#41; in both groups of patients&#46; The study by Restrepo et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> like ours&#44; also presents a lower percentage of patients treated with MTX due to contradictory data regarding its pulmonary toxicity&#46; However&#44; they associate this under-treatment with a higher DAS28 in these patients&#46; This might be due to the fact that the patients with ILD in their study were older and had a longer disease duration than those without ILD&#44; which was not the case in our study&#44; because we matched them by sex&#44; age and time since onset&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Among this study&#39;s limitations&#44; since it was performed in routine clinical practice&#44; were that no PFT or HRCT were performed in the group of RA patients without a diagnosis of ILD because they had no associated symptoms and unaltered chest X-rays&#46; Although according to various studies<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> there could already be alterations in PFT and on HRCT in the preclinical phase&#44; in these routine practice patients these tests were requested due to suspected pulmonary involvement&#46; This study is an observational analysis of a cohort of patients with RA and ILD&#44; in whom we prospectively analyse the parameters of respiratory function over time&#44; and a cohort of patients with RA without clinical respiratory symptoms&#46; The study was conducted under routine clinical practice conditions and its results could be extrapolated to situations in this field&#44; although longitudinal studies with a larger number of patients would be necessary to confirm the findings of our study and to establish causality&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">To conclude&#44; the results of our study support the higher frequency of the NIU and NINE histopathological patterns in patients with RA and ILD&#44; as well as impaired DLCO as the most important parameter&#46; Patients with RA and ILD are associated with more severe disease &#40;erosions and presence of ACPA&#41; as well as the smoking exposure factor&#46; Treatment with DMARDs in both patient groups controls inflammatory activity&#44; with increased use of the synthetic DMARDS HQC and leflunomide&#44; and the bDMARDs rituximab and abatacept&#44; in patients with ILD&#46; We need to wait for the prospective assessment of these patients to see any association of the treatment with the course of the lung disease&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs1">Andalusian Public Foundation for Health and Biomedicine Research in M&#225;laga &#40;FIMABIS&#41;</span>&#46; <span class="elsevierStyleGrantSponsor" id="gs2">Spanish Rheumatology Foundation &#40;FER&#41;</span>&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">Natalia Mena-V&#225;zquez&#58; talks for MSD&#44; UCB and Roche&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Lorena P&#233;rez-Albaladejo&#58; no conflict of interest&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Sara Manrique-Arija&#58; talks&#47;presentations for Abbvie&#44; Pzifer and MSD&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Carmen Mar&#237;a Romero-Barco&#58; talks&#47;speeches for Abbvie&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Carmen G&#243;mez Cano&#58; no conflict of interest to declare&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Inmaculada Ure&#241;a-Garnica&#58; no conflict of interest to declare&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Antonio Fern&#225;ndez-Nebro&#58; talks&#47;presentations for Roche&#44; MSD and BMS&#46;</p></span></span>"
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              "titulo" => "Treatments&#44; disease activity and physical function"
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              "titulo" => "Lung characteristics of the patients with rheumatoid arthritis and interstitial lung disease"
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    "fechaRecibido" => "2019-02-26"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To study the differences between rheumatoid arthritis &#40;RA&#41;-interstitial lung disease &#40;ILD&#41; patients and RA patients without ILD in severity markers and disease activity and to identify factors associated with the presence of ILD in RA patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Patients&#58; RA-ILD patients selected from a multicentre cohort in Andalusia&#44; Spain&#46; Controls&#58; RA-patients without ILD paired by sex&#44; age and disease duration&#46; Protocol&#58; RA patients are reviewed every 3&#8211;6 months in rheumatology consultation&#46; All patients are reviewed according to a predetermined protocol with systematic data collection&#46; Outcomes&#58; description of ILD type&#44; differences in severity markers and disease activity in both groups&#46; Other variables&#58; ILD type by imaging technique &#40;HRCT&#41;&#58; nonspecific interstitial pneumonia &#40;NSIP&#41;&#47;usual interstitial pneumonia &#40;UIP&#41;&#46; Lung function by PTF&#46; Activity and severity markers of arthritis by DAS28-ESR&#44; HAQ&#44; RF&#44; ACPA and erosions&#46; Treatment with DMARD&#46; Statistical analysis&#58; descriptive and paired <span class="elsevierStyleItalic">T</span>-test or Chi-square test followed by binary logistic regression &#40;DV&#58; ILD in patients with RA&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Eighty-two patients were included&#44; 41 RA-ILD and 41 RA controls&#46; RF and ACPA positivity&#44; serositis and osteoporosis were more frequent in RA-ILD patients&#46; No significant differences in DAS28 were observed &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;145&#41; between RA-ILD and RA control patients&#46; RA-ILD patients presented worse HAQ scores &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;006&#41;&#46; All patients were treated with disease modifying antirheumatic drugs &#40;DMARDs&#41;&#46; The risk of developing ILD in RA patients is tripled by a history of smoking or the presence of erosive arthritis &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;36&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The results of our study support the higher frequency of UIP and NSIP in RA patients&#46; DLCO is the most sensitive parameter to detect ILD in RA patients&#46; Our study showed that ILD in RA patients was associated with RA severity &#40;presence of erosions and ACPA&#41; and with a history of smoking&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudiar las diferencias en pacientes con artritis reumatoide &#40;AR&#41; y enfermedad pulmonar intersticial &#40;EPID&#41; y pacientes con AR sin EPID&#44; e identificar factores asociados con la EPID en pacientes con AR&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional de casos y controles&#46; Pacientes&#58; se seleccionaron pacientes de una cohorte con AR y EPID de diferentes centros de Andaluc&#237;a&#46; Controles&#58; pacientes con AR sin EPID pareados por edad&#44; g&#233;nero y tiempo de evoluci&#243;n&#46; Protocolo&#58; los pacientes con AR se revisan cada 3-6 meses en consulta&#46; Todos los pacientes son revisados de acuerdo con un protocolo predeterminado con recogida de datos sistem&#225;tica&#46; Desenlaces&#58; descripci&#243;n del tipo radiol&#243;gico de EPID&#44; diferencias en los marcadores de gravedad en casos y controles y en la actividad de la enfermedad&#46; Otras variables&#58; descripci&#243;n del tipo de EPID por TACAR&#58; neumon&#237;a intersticial usual &#40;NIU&#41;&#44; neumon&#237;a intersticial no espec&#237;fica &#40;NINE&#41; y de la funci&#243;n pulmonar por PFR&#59; marcadores de actividad y gravedad de artritis&#58; DAS28&#44; HAQ&#44; FR&#44; ACPA&#44; erosiones&#46; Tratamiento con FAME&#46; An&#225;lisis&#58; descriptivo&#44; &#967;<span class="elsevierStyleSup">2</span> o t de Student&#44; seguida de regresi&#243;n log&#237;stica binaria &#40;Vd&#58;EPID en pacientes con AR&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 82 pacientes&#58; 41 con AR y EPID y 41 controles AR sin EPID&#46; Los pacientes con EPID presentaron un mayor porcentaje de pacientes con FR y ACPA positivos y una mayor frecuencia de serositis y osteoporosis&#46; No hubo diferencias significativas en DAS28 en casos y controles&#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;145&#41;&#44; pero los pacientes de AR con EPID presentaron peor HAQ &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;006&#41;&#46; Todos los pacientes estaban en tratamiento con FAME&#46; El an&#225;lisis multivariante mostr&#243; que los pacientes con AR exfumadores y con artritis erosiva triplicaron el riesgo de presentar EPID &#40;R<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;36&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados de nuestro estudio apoyan la mayor frecuencia de NIU y NINE en pacientes con AR&#44; as&#237; como la alteraci&#243;n de DLCO como el par&#225;metro m&#225;s importante&#46; Los pacientes con AR y EPID se asociaron con una enfermedad m&#225;s grave &#40;erosiones y ACPA&#41; y con el tabaco&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
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            "titulo" => "Pacientes y m&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mena-V&#225;zquez N&#44; P&#233;rez Albaladejo L&#44; Manrique-Arija S&#44; Romero Barco CM&#44; G&#243;mez Cano C&#44; Ure&#241;a Garnica I&#44; et al&#46; An&#225;lisis de las caracter&#237;sticas cl&#237;nico-anal&#237;ticas de pacientes con artritis reumatoide y enfermedad pulmonar intersticial&#58; casos y controles&#46; Reumatol Clin&#46; 2021&#59;17&#58;197&#8211;202&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RA with ILD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RA &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Age in years&#44; mean &#40;&#177;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">67&#46;9 &#40;7&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">67&#46;6 &#40;8&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;898&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sex&#44; female&#59; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20 &#40;48&#46;&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">19 &#40;46&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;825&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sex&#44; male&#59; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">21 &#40;51&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">22 &#40;53&#46;7&#41;&#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="" valign="\n
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                  \t\t\t\t">&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="4" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Clinical&#8211;analytical characteristics</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Current smoking</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;105&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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Non-smokers&#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
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                  \t\t\t\t">33 &#40;80&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">38 &#40;92&#46;7&#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="" valign="\n
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                  \t\t\t\t">&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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Smokers&#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
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                  \t\t\t\t">8 &#40;19&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">3 &#40;7&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Smoking history</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">&#46;013&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><span class="elsevierStyleHsp" style=""></span>Never smoked&#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">11 &#40;26&#46;8&#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">22 &#40;53&#46;7&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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><span class="elsevierStyleHsp" style=""></span>Occasionally&#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">30 &#40;73&#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">19 &#40;46&#46;3&#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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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><span class="elsevierStyleItalic">Time since onset of RA&#44; months&#44; median &#40;p75&#8211;p25&#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">116&#46;4 &#40;75&#46;5&#8211;193&#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">102&#46;1 &#40;71&#46;1&#8211;132&#46;7&#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
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                  \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><span class="elsevierStyleItalic">Diagnostic delay&#44; months&#44; median &#40;p75&#8211;p25&#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">12&#46;1 &#40;7&#46;6&#8211;15&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">34 &#40;82&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
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                  \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
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;61&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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">16 &#40;39&#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
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                  \t\t\t\t">&#46;040&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \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
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                  \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><span class="elsevierStyleItalic">Erosion&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;53&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Vasculitis&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">0 &#40;&#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">&#46;151&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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Rheumatoid nodules&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">8 &#40;19&#46;5&#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">&#46;432&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><span class="elsevierStyleItalic">Anaemia of chronic disorder&#44; n &#40;&#37;&#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">12 &#40;29&#46;3&#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">6 &#40;14&#46;6&#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">&#46;109&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><span class="elsevierStyleItalic">Sj&#246;gren&#39;s syndrome&#44; n &#40;&#37;&#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
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                  \t\t\t\t">8 &#40;19&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">9 &#40;22&#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
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                  \t\t\t\t">&#46;785&nbsp;\t\t\t\t\t\t\n
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                  \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><span class="elsevierStyleItalic">Osteoporosis&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \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">20 &#40;48&#46;8&#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">6 &#40;14&#46;6&#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">&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RA with ILD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RA without ILD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Synthetic DMARD&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39 &#40;95&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t">28 &#40;67&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sulfasalazine&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&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
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methotrexate<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>hydroxychloroquine&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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">Biological DMARD&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Rituximab&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6 &#40;14&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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>Abatacept&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;4&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Tocilizumab&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Adalimumab&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>DLCO&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CVF &#60;80&#37;&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>CVF&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20 &#40;48&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4 &#40;10&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>FEV1&#47;CVF&#44; mean &#40;SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">83&#46;8 &#40;14&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
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                      "autores" => array:1 [
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                            1 => "D&#46; Aletaha"
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                          "etal" => false
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                            2 => "J&#46; Sokolove"
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                        0 => array:2 [
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                          "autores" => array:6 [
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                            3 => "C&#46; Bengtsson"
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                    0 => array:2 [
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Article information
ISSN: 21735743
Original language: English
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