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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 systemic inflammatory disease that primarily affects the joints and causes joint destruction&#44; impaired functional capacity&#44; and quality of life&#44; and may even reduce life expectancy&#46; It is the most prevalent form of chronic polyarthritis in Spain with the greatest social and health impact&#46; According to data from the EPISER study&#44; RA has an estimated prevalence of &#46;82&#37; in the Spanish adult population&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In addition to joint damage&#44; in a variable percentage of cases the disease presents with different extra-articular manifestations&#44; including pulmonary manifestations&#46; The spectrum of respiratory complications caused by RA is very broad and includes pleural involvement&#44; rheumatoid pulmonary nodules &#40;including Caplan syndrome&#41;&#44; interstitial lung disease &#40;ILD&#41; and follicular or obliterative bronchiolitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Bronchiectasis&#44; primary pulmonary hypertension&#44; secondary amyloidosis&#44; thromboembolic disease&#44; and cricoarytenoid arthritis have been reported more rarely&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">ILD is one of the most frequent and severe pulmonary complications of RA&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> The risk of RA patients developing this complication is almost 9 times higher than in the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Furthermore&#44; although there has been a significant improvement in prognosis in the last 25 years&#44; <span class="elsevierStyleSup">7</span> ILD is still the second leading cause of death from the disease&#44; accounting for 10&#37;&#8211;20&#37; of deaths&#46; This clinical fact warrants a common strategy between rheumatologists and pneumologists to improve the prognosis and quality of life of patients with this complication&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">For this reason&#44; the Spanish Societies of Rheumatology &#40;SER&#41; and Pneumology and Thoracic Surgery &#40;SEPAR&#41; promoted the drafting of a joint document of recommendations for the management of RA-ILD based on the best available evidence&#44; with the aim of answering most of the common clinical questions&#44; reducing the variability in medical care and facilitating decision-making for clinicians directly involved in the care of the condition&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">A qualitative synthesis of the scientific evidence and consensus techniques was used in the drafting of these recommendations&#44; which reflect the agreement of experts based on the available evidence and their clinical experience&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The procedure for developing the project was as follows&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Creation of the working group</span>&#46; An interdisciplinary working group was formed by 5 rheumatologists from SER &#40;JN&#44; GB&#44; IC&#44; NMV&#44; and AMO&#41; and 5 pneumologists from SEPAR &#40;MA&#44; ECJ&#44; MAN&#44; CV&#44; and JARP&#41;&#46; The participants were endorsed by their society to participate in this document&#46; The clinical and methodological aspects were coordinated&#44; respectively&#44; by one of the rheumatologists &#40;JN&#41; and a pneumologist &#40;JARP&#41;&#44; as principal investigators &#40;PI&#41;&#44; and two methodology specialists from the SER Research Unit&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Identification of key areas</span>&#46; The content and key aspects of the document were defined&#44; and the clinical research questions with the greatest impact on clinical practice were formulated&#46; The questions were reformulated in patient&#44; intervention&#44; comparison&#44; and outcome &#40;PICO&#41; format&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Literature search</span>&#46; A search for published scientific evidence was conducted and progressively expanded until October 2020&#46; The databases PubMed &#40;MEDLINE&#41;&#44; EMBASE&#44; and Cochrane Library &#40;Wiley Online&#41; were used for this purpose&#46; The process was completed with a manual search of the references of the studies identified&#44; as well as posters and conference abstracts that the reviewers and experts considered to be of interest&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4</span><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Analysis and synthesis of the scientific evidence</span>&#46; Rheumatologists from SER who are experts in evidence review conducted the systematic reviews and synthesis of the scientific evidence&#46; The level of scientific evidence was assessed using Scottish Intercollegiate Guidelines Network &#40;SIGN&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> criteria &#40;Appendix B Annex&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5</span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Formulation of recommendations</span>&#46; Once the critical reading had been completed&#44; the PIs&#44; together with the members of the expert group reviewing the evidence for each of the PICO questions&#44; formulated the recommendations&#44; based on formal evaluation or &#34;reasoned judgement&#34; of the evidence for each of the questions&#46; The quality&#44; quantity&#44; and consistency of the scientific evidence&#44; the generalisability&#44; applicability&#44; and clinical impact of the results were considered&#46; The strength of the recommendations was graded using the SIGN<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> system&#46; For questions where the evidence was insufficient&#44; recommendations were formulated based on consensus of the expert group&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The recommendations have been divided into five main areas&#58; incidence and prevalence of ILD in RA&#44; risk factors for the onset of ILD in RA&#44; prognostic factors for mortality and pulmonary progression&#44; as well as the safety of drug treatment in patients with RA-ILD&#44; and its efficacy in managing this complication&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">External review&#46;</span> The draft document was subjected to external review to ensure the validity and accuracy of the recommendations and&#44; subsequently&#44; to public exposure so that other SER and SEPAR members&#44; as well as different groups and potentially interested entities&#44; could evaluate the document&#44; and offer criticism or suggestions&#46;</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">General preliminary considerations</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Identification of the type of RA-associated ILD</span><p id="par0070" class="elsevierStylePara elsevierViewall">The most common histological types of RA-ILD are usual interstitial pneumonia &#40;UIP&#41; and non-specific interstitial pneumonia &#40;NSIP&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;7</span></a> The UIP pattern is as frequent or more frequent than NSIP&#46; Other patterns described are organising pneumonia &#40;OP&#41;&#44; lymphoid interstitial pneumonia &#40;LIP&#41;&#44; diffuse alveolar damage &#40;DAD&#41;&#44; acute fibrinous and organising pneumonia &#40;AFOP&#41;&#44; desquamative interstitial pneumonia &#40;DIP&#41;&#44; respiratory bronchiolitis associated with interstitial lung disease and the combined pulmonary fibrosis&#160;&#43;&#160;emphysema &#40;CPFE&#41; pattern&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;7&#44;10</span></a> These last three patterns are included in the spectrum of smoking-related lung lesions&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> although they have also been described in patients with RA who are non-smokers&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The ILD pattern must be correctly identified because of its therapeutic and prognostic implications&#44; since the more inflammatory patterns &#40;cellular NSIP&#44; OP&#44; LIP&#41; will respond better to anti-inflammatory and immunosuppressive treatment than UIP&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Diagnosis of RA-ILD</span><p id="par0080" class="elsevierStylePara elsevierViewall">If ILD is suspected &#40;presence of cough and&#47;or dyspnoea of more than 3 months duration or velcro-like crackles on respiratory auscultation&#41;&#44; a chest X-ray and lung function test &#40;LFT&#41; including spirometry and diffusing capacity of the lungs for carbon monoxide &#40;DLCO&#41; are usually performed for initial screening&#46; In general&#44; chest X-ray is a very insensitive technique in the early stages&#46; In ILD&#44; spirometry shows restrictive ventilatory impairment together with decreased DLCO&#46; However&#44; in early stages&#44; it is not uncommon for decreased DLCO to be the only abnormality present&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">High-resolution computed tomography &#40;HRCT&#41; of the chest to confirm ILD is the gold standard for the diagnosis of this complication&#46; The radiological pattern on HRCT correlates well with the histological pattern in most cases&#44; and therefore a lung biopsy is usually not necessary&#46; HRCT is also useful to quantify the extent of parenchymal involvement &#40;alveolitis&#47;fibrosis&#41;&#44; to determine the potential reversibility of the lesions &#40;alveolitis&#47;fibrosis&#41;&#44; to establish a prognosis &#40;UIP vs&#46; non-UIP&#41; and to assess response to treatment&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Disease activity and response to treatment is monitored with LFTs &#40;spirometry and plethysmography to assess forced vital capacity &#91;FVC&#93;&#44; DLCO and total lung capacity&#41;&#44; the 6-minute walk test and assessment of dyspnoea with one of the different clinical scales&#46; Chest HRCT is usually only repeated in cases where it is necessary to assess functional deterioration&#44; treatment readjustments or if exacerbation&#44; infection&#44; or other respiratory complications&#44; such as lung cancer&#44; are suspected&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In advanced stages&#44; Doppler echocardiography is also useful to detect onset of secondary pulmonary arterial hypertension&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Bronchoalveolar lavage is not routinely performed&#46; It is only indicated if it helps in the differential diagnosis&#44; primarily with infections&#46; Lung biopsy is only performed if there is suspicion of non-RA-ILD&#44; doubts about the presence of other entities such as neoplasms or infection&#44; or to establish a histo-specific diagnosis in atypical cases&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The differential diagnosis of ILD is mainly infection&#44; pulmonary drug toxicity&#44; thromboembolic disease&#44; heart failure&#44; or lung cancer &#40;fundamentally in smokers&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Definition of progressive fibrosing ILD</span><p id="par0110" class="elsevierStylePara elsevierViewall">A variable percentage of patients with RA-ILD &#40;around 40&#37; at 5 years after ILD diagnosis&#41;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a> develop progressive pulmonary fibrosis with severe deterioration of lung function&#44; rapid progression to chronic respiratory failure&#44; and high mortality&#46; There is no standard or agreed definition of what is considered progressive fibrosing ILD&#46; The randomised clinical trial INBUILD<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> used the following four criteria to define progression in patients with fibrosing ILD&#58; 1&#41; a decrease in baseline FVC&#160;&#62;&#160;10&#37; of the percentage of the estimated theoretical value&#59; 2&#41; a decrease in FVC of between 5&#37;&#8211;10&#37; with evidence of progressive fibrosing on chest HRCT&#59; 3&#41; a decrease in FVC of between 5&#37;&#8211;10&#37; with worsening respiratory symptoms &#40;dyspnoea and dry cough&#41;&#44; or 4&#41; a worsening of dyspnoea with progressive fibrosing on HRCT in the previous 24 months despite treatment&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Some experts also define progression as a decrease in FVC between 5&#37;&#8211;10&#37; with a worsening of DLCO greater than 15&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">According to the INBUILD study&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> fibrosing ILD is defined as fibrosis changes affecting more than 10&#37; of the lung parenchyma&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">However&#44; and according to the classic definitions of the American Society of Pulmonology&#44; worsening of any type of ILD &#40;fibrosing or non-fibrosing&#41; is defined as a decrease in FVC &#40;expressed as a percentage of the predicted value&#41; greater than 10&#37; or a decrease in DLCO greater than 15&#37; during follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0130" class="elsevierStylePara elsevierViewall">A total of 18 recommendations have been formulated&#46; This article contextualises the six recommendations made following the systematic literature review &#40;SLR&#41; of the epidemiology&#44; risk factors&#44; and prognosis of RA-ILD &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">For further information on any of the sections summarised in this article&#44; the full content of the document can be accessed on the SER website &#40;<a href="http://www.ser.es">www&#46;ser&#46;es</a>&#41;&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Epidemiology of RA-ILD</span><p id="par0140" class="elsevierStylePara elsevierViewall">&#8212; <span class="elsevierStyleItalic">What is the incidence and prevalence of RA-IDP in patients with RA&#63;</span><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#9633;</span><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendation</span>&#46; Based on its incidence and prevalence&#44; it is recommended that the possibility of ILD should always be considered in the initial assessment and follow-up of patients with RA &#40;recommendation grade &#8730;&#41;&#46;</p></li></ul></p><p id="par0150" class="elsevierStylePara elsevierViewall">It is vital to establish the prevalence and incidence of ILD in RA&#46; Knowing the magnitude of this complication is essential to define strategies for early diagnosis and treatment&#44; and good health planning&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The scientific evidence for this recommendation was based on an SLR in which the population was adult subjects&#44; the intervention was a diagnosis of RA according to ACR 1987 or ACR&#47;EULAR 2010 criteria&#44; and the outcome was the incidence or prevalence of ILD diagnosed by chest HRCT scan and&#47;or lung biopsy&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Incidence of RA-associated ILD</span><p id="par0160" class="elsevierStylePara elsevierViewall">The incidence of RA-associated ILD is 1&#46;056 cases per 1000 patients &#40;1&#46;452 in males and &#46;677 in females&#41; according to a study conducted in a Japanese population &#40;IORRA cohort&#41; between 2004 and 2007&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Outside the body of evidence&#44; two other studies have been identified that evaluate the incidence in the Caucasian population&#44; although the condition was not diagnosed with HRCT in all cases&#46; In the study by Koduri et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> conducted in an English cohort of patients with RA onset&#44; this complication was only investigated in the presence of respiratory symptoms or signs as part of routine clinical care practice&#46; After a follow-up of 3 years&#44; the incidence of ILD was 4&#46;1 per 1000 patients&#46; In another prospective population-based cohort study &#40;Rochester&#44; Minnesota&#41; the cumulative incidence of ILD at 10&#44; 20&#44; and 30 years was 3&#46;5&#44; 6&#46;3&#44; and 7&#46;7&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In this study&#44; the risk of RA patients developing this complication was much higher than that of the general population &#40;HR&#58; 8&#46;96&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Prevalence&#47;frequency of RA-ILD</span><p id="par0170" class="elsevierStylePara elsevierViewall">Eleven articles have been identified in which all patients diagnosed with RA &#40;consecutive unselected patients&#41; were screened for ILD&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;33</span></a> The main results of these studies are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; The frequency of this complication shows great variability&#44; ranging from 11&#46;9&#37; to 55&#46;7&#37;&#46; This variability can be explained by the differences between the populations studied &#40;great heterogeneity in demographic characteristics&#44; time since onset&#44; and degree of disease activity&#44; frequency of smoking and percentage of patients with respiratory symptoms&#41; and by the lack of uniformity in the HRCT findings used to establish a diagnosis of ILD&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">Of the eleven articles identified&#44; three included patients with RA of less than two years&#39; duration&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#8211;27</span></a>In these studies&#44; the variability of the prevalence of ILD is lower and ranges from 27&#46;5&#37; to 41&#46;8&#37;&#44; with higher figures in populations with a higher frequency of smoking&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In the eight studies conducted in patients with established RA &#40;more than two years since onset&#41;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24&#44;28&#8211;33</span></a> there is wide disparity in the frequency figures&#44; even between the two studies that investigated this question prospectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> Thus&#44; Bilgici et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> in a cohort of 52 unselected RA patients from a single centre in Turkey&#44; found chest CT changes consistent with ILD in 55&#46;7&#37;&#46; Dawson et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> in a cohort of 150 consecutive RA patients in two hospitals in the North of England&#44; describe findings of &#34;fibrosing alveolitis&#34;&#44; a term comparable to UIP and fibrosing NSIP patterns&#44; in 19&#37; of cases&#46; In general&#44; and predictably&#44; in these eight studies&#44; the higher the percentage of patients included with respiratory symptoms&#44; the higher the frequency of ILD&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Outside the body of evidence&#44; in a prospective study conducted in Spain in patients with RA onset without respiratory symptoms in which only those with radiographic or LFT abnormalities underwent chest HRCT&#44; the prevalence of confirmed ILD at disease diagnosis was 5&#37;&#44; increasing to 7&#46;5&#37; at 5 years since onset&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> These figures are lower than those reported in a Chinese cohort in which the frequency of ILD at diagnosis was 9&#46;76&#37;&#44; increasing to 30&#46;9&#37; at 5-year follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">However&#44; if we only consider the frequency of symptomatic or clinically significant RA-ILD &#40;which is not the issue raised in the research question&#41;&#44; the prevalence by HRCT in several landmark studies is between 10&#37; and 29&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#8211;39</span></a> Finally&#44; the prevalence of ILD in the only autopsy study to investigate this complication is 35&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Risk factors for onset of ILD in RA</span><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">&#8212; In patients with RA&#44; what are the risk factors for onset of ILD&#63;</span><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#9633;</span><p id="par0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendation&#46;</span> Patients with RA should be systematically screened for ILD in cases with respiratory symptoms or if velcro-like crackles are heard &#40;recommendation grade &#8730;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#9633;</span><p id="par0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendation&#46;</span> In cases without respiratory symptoms and with normal auscultation&#44; the need for screening should be assessed individually according to the number of risk factors for onset of this complication&#44; regardless of the time since onset of RA &#40;recommendation grade &#8730;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#9633;</span><p id="par0210" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendation&#46;</span> The presence of ILD should always be considered when deciding on treatment&#44; given the potential risk of pneumonitis described with some of the drugs commonly used in RA &#40;recommendation grade &#8730;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#9633;</span><p id="par0215" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendation&#46;</span> In patients with RA&#44; none of the investigational serum biomarkers tested so far has been shown to have better predictive value for the onset of ILD than ACPA antibodies&#46; Based on the current evidence&#44; the drafting group does not recommend the use of other serum biomarkers in routine clinical practice &#40;recommendation grade D&#41;&#46;</p></li></ul></p><p id="par0220" class="elsevierStylePara elsevierViewall">Despite its frequency and severity&#44; to date there are no recommendations on screening for this complication&#44; in either the initial assessment or in the follow-up of RA patients&#46; However&#44; as mentioned above&#44; when the entire RA population was screened for ILD by HRCT&#44; a non-negligible percentage of subclinical disease was detected &#40;between 11&#46;9&#37; and 55&#46;7&#37;&#41;&#44; confirming that it is underdiagnosed&#46; In fact&#44; in clinical practice&#44; it is not uncommon for ILD to be diagnosed late&#44; as it is often asymptomatic or pseudo-symptomatic in its early stages&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Therefore&#44; knowing the main risk factors associated with the onset of RA-ILD will help us identify the subgroup of patients at greatest risk of developing this complication who may benefit from specific screening to diagnose them early &#40;even if they do not have respiratory symptoms or signs&#41;&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">According to the results of the SLR&#44; the main risk factors for the onset of RA-ILD are&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">1</span><p id="par0235" class="elsevierStylePara elsevierViewall">Male sex<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;41</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">2</span><p id="par0240" class="elsevierStylePara elsevierViewall">Advanced age and late onset of the disease &#40;level of evidence 2&#43;&#43;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;35&#44;36&#44;42</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> No cut-off point is established in most studies&#44; except two&#58; &#62;60 years &#40;OR&#58; 1&#46;48&#59; 95&#37; CI&#58; 1&#46;01&#8211;2&#46;18&#41;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and &#8805;65 years &#40;RR&#58; 4&#46;58&#59; 95&#37; CI&#58; 1&#46;67&#8211;12&#46;53&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">3</span><p id="par0245" class="elsevierStylePara elsevierViewall">Duration of the disease&#44; onset of ILD being more frequent during the first 5&#8211;10 years of RA progression<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;32&#44;35</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">4</span><p id="par0250" class="elsevierStylePara elsevierViewall">Smoking<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;36&#44;44&#44;45</span></a> &#40;level of evidence 2&#43;&#43;&#41;&#46; Smoking and smoking rate are strongly associated with onset of ILD&#44; with an OR&#58; 3&#46;76 &#40;95&#37; CI&#58; 1&#46;59&#8211;8&#46;88&#41; in the case of having smoked &#8805;25 pack-years and 1&#46;9 &#40;95&#37; CI&#58; &#46;68&#8211;5&#46;24&#41; if less than 25 pack&#47;years&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Several studies indicate that smokers&#8217; increased risk of developing ILD is associated with the presence of the shared epitope&#44; showing that there is an important gene-environment interaction between the shared epitope alleles and smoking&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;42&#44;44</span></a></p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">5</span><p id="par0255" class="elsevierStylePara elsevierViewall">Moderate or high sustained RA activity<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> &#40;level of evidence 2&#43;&#43;&#41;&#46; Patients with moderate&#47;high maintained disease activity according to DAS28-CRP scores are at twice the risk of developing ILD than patients in remission or with low disease activity &#40;results adjusted for sex&#44; smoking&#44; RA duration&#44; and serostatus&#58; HR&#58; 2&#46;22&#59; 95&#37; CI&#58; 1&#46;28&#8211;3&#46;82&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> The risk of ILD in the different disease activity statuses is as follows&#58; low disease activity &#40;DAS28&#160;&#62;&#160;2&#46;6&#8211;3&#46;2&#41; 1&#46;41 &#40;95&#37; CI&#58; &#46;61&#8211;3&#46;28&#41;&#44; moderate disease activity &#40;&#62;3&#46;2-5&#46;1&#41; 2&#46;08 &#40;95&#37; CI&#58; 1&#46;06&#8211;4&#46;05&#41;&#44; and high disease activity &#40;&#62;5&#46;1&#41; 3&#46;48 &#40;95&#37; CI&#58; 1&#46;64&#8211;7&#46;38&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">6</span><p id="par0260" class="elsevierStylePara elsevierViewall">RF positivity &#40;level of evidence 2&#43;&#43;&#41; and&#44; especially&#44; ACPA positivity &#40;level of evidence 1&#43;&#41;&#44; especially at high titres&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;32&#44;35&#44;46&#8211;48</span></a> In a meta-analysis &#40;which included 7 studies with 1685 patients&#59; I<span class="elsevierStyleSup">2</span>&#58; 0&#37;&#41;&#44; the risk of ILD and pulmonary fibrosis in the presence of ACPA was almost 5 times higher &#40;OR&#58; 4&#46;68&#59; 95&#37; CI&#58; 2&#46;07&#8211;10&#46;57&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p></li></ul></p><p id="par0265" class="elsevierStylePara elsevierViewall">In addition to RF and ACPA&#44; the usefulness of other potential biomarkers predictive of the onset of ILD is being investigated&#44; most notably antibodies directed against carbamylated proteins &#40;anti-CarP&#41;&#46; A correlation has been demonstrated between levels of all anti-CarP specificities &#40;foetal calf serum&#44; fibrinogen&#44; and chimeric fibrine&#47;filagrine homocitrullinated peptide&#41; and the presence of ILD&#44; after adjustment for other known risk factors<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> &#40;level of evidence 3&#41;&#46; Promising preliminary results have also been obtained with serum levels of extracellular matrix metalloproteinase 7 &#40;MMP-7&#41;&#44; interferon gamma-inducible protein-10 &#91;IP-10&#93; or CXCL10&#44; interleukin-18&#44; and 90- and 70-KDa heat shock proteins &#40;HSP90&#47;70&#41;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#8211;53</span></a> &#40;level of evidence 2&#41;&#46; None of these are yet available in clinical practice&#44; nor have they as yet been shown to have greater predictive value for the development of this complication than ACPAs&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Likewise&#44; some genetic biomarkers have been identified&#44; including mutations in the MUC5B gene<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> &#40;which encodes one of the proteins of the mucin family&#41; &#40;level of evidence 2&#43;&#41; and mutations in the telomerase genes that cause accelerated telomere shortening<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#44;56</span></a> &#40;in cases with a family history of ILD&#41; &#40;level of evidence 2&#43;&#41;&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Finally&#44; onset of ILD has also been linked to some of the drugs commonly used in the treatment of this disease&#46; This issue is reviewed in depth in the second part of the recommendations&#44; also published in this journal&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">To avoid late diagnosis of ILD in RA patients&#44; the drafting group recommends regular questioning about the presence of respiratory symptoms and auscultation at least once a year for dry velcro-like crackles&#46; The presence of velcro-like crackles correlates well with the presence of pulmonary fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> In addition&#44; two studies have shown that conventional respiratory auscultation is acceptably diagnostically accurate to detect ILD compared to digital stethoscope&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">The group also considers that patients with respiratory symptoms &#40;cough and&#47;or dyspnoea of more than 3 months&#39; duration in the absence of known underlying pulmonary disease or pre-existing heart disease&#41; should be routinely screened&#44; and all those with velcro-like crackles detected on auscultation&#44; even if asymptomatic&#46; In asymptomatic patients with normal auscultation&#44; the need for ILD screening will be assessed on an individual basis according to the number of risk factors for onset of the complication&#44; regardless of time since onset of RA&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Risk factors for onset of RA-ILD</span><p id="par0290" class="elsevierStylePara elsevierViewall">&#8212; <span class="elsevierStyleItalic">What are the prognostic factors for mortality and progression of Lund disease in patients with RA-ILD&#63;</span><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#9633;</span><p id="par0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Recommendation&#58;</span> In patients with RA and ILD&#44; it is recommended that the presence of prognostic factors associated with progression and mortality be considered when planning follow-up &#40;frequency of check-ups&#41; and treatment strategy &#40;recommendation grade B&#41;&#46;</p></li></ul></p><p id="par0300" class="elsevierStylePara elsevierViewall">ILD remains the second leading cause of premature death in RA&#44; after cardiovascular complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;7</span></a> Approximately half of patients have stable or very slowly progressive ILD&#44; whereas in the other half lung function deteriorates more or less rapidly&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a> This heterogeneity in the course of the disease makes it essential to identify prognostic factors for severe disease and mortality&#46; The SLR identified factors associated with progression of ILD and factors associated with increased mortality in patients with RA-ILD&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Predictors of RA-ILD progression</span><p id="par0305" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#9633;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Radiological pattern of UIP&#58; the risk of progression in patients with UIP is approximately three times higher than in patients with NINE<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;35</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#9633;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Elevated ACPA titres &#40;3 times above the upper limit of normal&#41; with an OR of 4&#46;03 &#40;95&#37; CI&#58; 1&#46;04&#8211;15&#46;6&#41;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#9633;</span><p id="par0320" class="elsevierStylePara elsevierViewall">The degree of baseline DLCO deterioration&#44;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;62&#44;63</span></a> having been demonstrated with two cut-off points&#58; DLCO&#160;&#60;&#160;45&#37; &#40;percentage of predicted value&#41; &#40;OR&#58; 3&#46;02&#59; 95&#37; CI&#58; 1&#46;13&#8211;8&#46;03&#41;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and&#44; only in patients with a progressive fibrosing phenotype&#44; DLCO&#160;&#60;&#160;54&#37;&#58; &#40;OR&#58; &#46;85&#59; 95&#37; CI&#58; &#46;74&#8211;&#46;98&#41;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#9633;</span><p id="par0325" class="elsevierStylePara elsevierViewall">In patients with UIP pattern&#44; a drop &#8805;10&#37; in FVC during follow-up &#40;OR&#58; &#46;89&#59; 95&#37; CI&#58; &#46;82&#8211;&#46;97&#41; &#40;level of evidence 2&#43;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a></p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#9633;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Overall&#44; the risk of progression of ILD increases the lower the baseline DLCO values&#44; and the greater the worsening of FVC and&#47;or DLCO during follow-up<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#9633;</span><p id="par0335" class="elsevierStylePara elsevierViewall">Extensive distribution on fibrotic changes on HRCT&#44; principally traction bronchiectasis &#40;&#8805; 4 lung areas affected with &#62; 50&#37; of the subpleural total&#41;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> &#40;level of evidence 2&#43;&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#9633;</span><p id="par0340" class="elsevierStylePara elsevierViewall">Elevated serum levels of IL-6 and KL-6 &#40;level of evidence 2&#43;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#44;66</span></a></p></li></ul></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Prognostic factors for mortality in RA-ILD</span><p id="par0345" class="elsevierStylePara elsevierViewall">Patients with RA-ILD have a 3- to 10-fold higher adjusted mortality risk than RA patients without the complication&#44; regardless of the follow-up period and the presence of comorbidities<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;67&#44;68</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">The main prognostic factors for mortality identified in the SLR are&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#9633;</span><p id="par0355" class="elsevierStylePara elsevierViewall">Advanced age at diagnosis of ILD<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;35&#44;60&#44;62</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#44;67&#44;69&#8211;72</span></a>&#58; no cut-off point is established in most of the studies found&#44; except three&#58; &#62;60 years &#40;HR&#58; 3&#46;18&#59; 95&#37; CI&#58; 1&#46;27 to 7&#46;94<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and HR&#58; 2&#46;32&#59; 95&#37; CI&#58; 1&#46;27 to 4&#46;25<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&#41; and &#8805;65 years &#40;OR&#58; 1&#46;08&#59; 95&#37; CI&#58; 1&#46;02&#8211;1&#46;15&#41;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#9633;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Male gender<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">67&#44;73&#44;74</span></a>&#58; men have 3&#46;6- to 14&#46;5-fold higher mortality than women with this complication<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#9633;</span><p id="par0365" class="elsevierStylePara elsevierViewall">Duration of RA<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;75</span></a>&#58; the longer the duration of disease at diagnosis of ILD&#44; the higher the mortality &#40;HR per decade&#58; 1&#46;81&#59; 95&#37; CI&#58; 1&#46;16&#8211;2&#46;83&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#9633;</span><p id="par0370" class="elsevierStylePara elsevierViewall">Moderate or high disease activity &#40;DAS28-VSG &#62;3&#46;2&#41; is also associated with increased mortality &#40;OR&#58; 1&#46;6&#59; 95&#37; CI 1&#46;0&#8211;2&#46;5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a></p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#9633;</span><p id="par0375" class="elsevierStylePara elsevierViewall">Radiological pattern of UIP<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;70&#44;73&#44;74</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76&#44;77</span></a>&#58; according to the conclusions of a recent meta-analysis that included 10 retrospective studies with 1&#46;256 patients with RA-ILD &#40;I<span class="elsevierStyleSup">2</span>&#58; 76&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> the UIP pattern has a mortality risk almost 2 times higher than non-UIP patterns &#40;RR&#58; 1&#46;66&#59; 95&#37; CI&#58; 1&#46;07&#8211;2&#46;76&#41; &#40;level of evidence 1&#43;&#43;&#41;&#46; In analysis by subgroups&#44; when the UIP pattern was compared with the NSIP pattern the RR was 2&#46;39 &#40;95&#37; CI&#58; &#46;86&#8211;6&#46;68&#41; and 1&#46;45 &#40;95&#37; CI&#58; &#46;89 to 2&#46;37&#41; when the UIP was compared with other non-NSIP patterns&#46; Increased mortality has also been described with a probable UIP pattern<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> &#40;level of evidence 2&#43;&#41; and&#44; in general&#44; with all the forms of fibrosing RA-ILD &#40;HR&#58; 2&#46;1&#59; 95&#37; CI&#58; 1&#46;11&#8211;4&#46;26&#41;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li></ul></p><p id="par0380" class="elsevierStylePara elsevierViewall">It is important to highlight that in two studies<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;78</span></a> the radiological pattern is no longer a predictor of mortality after adjustment for confounding variables in multivariate analysis&#44; the main prognostic factors being the degree of baseline deterioration in respiratory function tests &#40;FVC and DLCO&#41; and the magnitude of their worsening during follow-up&#46;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#9633;</span><p id="par0385" class="elsevierStylePara elsevierViewall">A low baseline DLCO or a decrease in DLCO&#160;&#62;&#160;15&#37; during follow-up &#40;level of evidence 2&#43;&#43;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61&#44;71&#8211;73&#44;76&#44;79</span></a> Only the study by Zamora-Legoff et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> establishes a cut-off point for baseline DLCO&#44; setting it at less than 40&#37; &#40;HR&#58; 2&#46;48&#59; 95&#37; CI&#58; 1&#46;55&#8211;3&#46;95&#41; &#40;level of evidence 2&#43;&#41;&#46; The prognostic value of baseline DLCO is independent of the presence or absence of emphysema due to smoking<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> &#40;level of evidence 1&#43;&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#9633;</span><p id="par0390" class="elsevierStylePara elsevierViewall">A low baseline FVC during follow-up &#40;HR&#58; 2&#46;57&#59; 95&#37; CI&#58; 1&#46;79&#8211;3&#46;70&#41; &#40;level of evidence 1&#43;&#43;&#41; or a decrease in FVC&#160;&#62;&#160;10&#37;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;71&#44;76</span></a> &#40;level of evidence 2&#43;&#41;&#46; These studies do not establish a cut-off point for baseline FVC&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">&#9633;</span><p id="par0395" class="elsevierStylePara elsevierViewall">Extensive lung involvement on thoracic HRCT has been demonstrated when more than 20&#37; of the lung parenchyma is involved<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;80&#44;81</span></a> &#40;level of evidence 2&#43;&#43;&#41;&#44; and when more than 30&#37; is involved 30&#37;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;71</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">&#9633;</span><p id="par0400" class="elsevierStylePara elsevierViewall">Elevated serum levels of KL-6&#44; which are associated with higher mortality &#40;3&#8211;4 times higher&#41;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#44;74</span></a> &#40;level of evidence 2&#43;&#41;&#46;</p></li></ul></p><p id="par0405" class="elsevierStylePara elsevierViewall">Finally&#44; the usefulness of the GAP index &#40;calculated with gender&#44; age&#44; and FVC and DLCO values&#41; to predict the risk of mortality at 1&#44; 2 and 3 years in patients with RA-ILD has been demonstrated<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;82</span></a> &#40;level of evidence 2&#43;&#41;&#46; The CPI score<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> &#40;level of evidence 2&#43;&#41; also appears to be useful for this purpose&#46;</p></span></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0410" class="elsevierStylePara elsevierViewall">RA-ILD is a complex clinical situation&#44; both because of its frequency and potential severity&#44; and because of the difficulty in its therapeutic management&#46; There is little published evidence on the subject&#44; most is of low methodological quality&#44; and with contradictory results in some aspects&#46; There are also no recommendations yet agreed upon by scientific societies&#46;</p><p id="par0415" class="elsevierStylePara elsevierViewall">This why we present the first official document drawn up by the SER and SEPAR with specific recommendations for the management of RA-ILD&#44; which aims to serve as a guide for professionals caring for these patients and to bring clinical practice in line with the best possible evidence&#46; These recommendations have been reached through a strict and validated methodology of systemic reviews of the scientific literature and expert consensus techniques&#46;</p><p id="par0420" class="elsevierStylePara elsevierViewall">Epidemiological information is essential to measure the socio-health importance of diseases and to contribute to proper health planning&#46; Therefore&#44; one of the main objectives of the paper was to determine the prevalence and incidence of ILD in RA patients&#46; However&#44; the SLR revealed great variability in the studies that have investigated this issue&#44; and therefore its actual frequency could not be reliably established&#46; As a guideline&#44; the prevalence of symptomatic ILD diagnosed by chest HRCT varies between 10&#37; and 29&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#8211;39</span></a> whereas its incidence varies between 1&#46;05 and 4&#46;1 cases per 1000 patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> and the risk of developing this complication in RA patients is much higher than in the general population&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;84</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">In more than three-quarters of patients&#44; ILD develops after RA has been diagnosed&#44; usually in the first 5&#8211;10 years of disease progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;7&#44;21&#44;22&#44;28</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;35&#44;85</span></a> In these cases&#44; it is not uncommon for it to be diagnosed late&#44; since it is often asymptomatic in its initial stages or presents with few symptoms&#44; and goes unnoticed until advanced stages&#44; when the extent of fibrotic changes limits therapeutic possibilities and survival &#40;UIP is the most frequent histopathological pattern in RA&#41;&#46; Less frequently&#44; ILD occurs at onset of RA or precedes the joint manifestations by months or years&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;7</span></a> This circumstance has been reported in up to 10&#37;&#8211;14&#37; of patients with RA and ILD and is not always present and is often confused with idiopathic forms&#44; despite their different prognosis and treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68&#44;86&#44;87</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">Although a significant improvement in prognosis has been observed over the last 25 years&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> RA-ILD is still the second leading cause of premature death in RA&#44; after cardiovascular complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;7</span></a> Patients with RA-ILD have an adjusted mortality risk 3&#8211;10 times higher than RA patients without this complication<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;67</span></a> and their median survival from diagnosis of ILS varies from 2&#46;6 to 8&#46;1 years&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">Although ILD is a frequent and under-diagnosed complication with high morbidity and mortality&#44; there are as yet no recommendations for screening&#46; In the absence of studies supporting the cost-effectiveness of universal screening&#44; a reasonable strategy would be to design a selective screening proposal based on patients&#8217; clinical risk&#46; This clinical risk would be defined by the presence of respiratory symptoms &#40;cough and&#47;or dyspnoea of an unrelated cause of more than 3 months&#39; duration&#41;&#44; by the presence of dry velcro-like crackles on respiratory auscultation&#44; or by the number of risk factors for the patient developing this complication&#46; This initiative towards a multidisciplinary approach to selective screening criteria to identify patients with RA and ILD early was launched as a joint collaboration between the SER and SEPAR as part of the RA-EPIDSER project&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> A tool to enable early identification of these patients with good sensitivity will help improve their survival and quality of life&#46;</p><p id="par0440" class="elsevierStylePara elsevierViewall">Another important point is that RA-ILD behaves heterogeneously in terms of its clinical course and prognosis&#46; ILD will be stable or progress very slowly in approximately half of patients&#44; while in the other half lung function deteriorates rapidly&#44; especially in patients with fibrosing ILD&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a> This heterogeneity in progression makes it essential to identify prognostic factors for pulmonary progression and mortality to detect patients with a more severe profile early&#44; who will be candidates for specific treatment as soon as the diagnosis of ILD is confirmed and for close clinical follow-up&#46; The main prognostic factors include UIP pattern&#44; extensive lung involvement on chest HRCT&#44; the severity of deterioration of FVC and DLCO at diagnosis of RA-ILD&#44; and the extent that these parameters have worsened during follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;60&#44;61&#44;69&#8211;74&#44;76&#44;77&#44;79&#8211;81</span></a> Apart from the clinical and functional variables already in use&#44; it remains to be seen how useful some of the biomarkers under investigation are&#44; mainly IL-6 and KL-6&#44; will be as tools to help predict progression and mortality in the short and medium term&#46; Although the prognostic predictive capacity of these biomarkers has been validated in some studies &#40;most with a small sample size&#41;&#44; their use in daily clinical practice is limited and international guidelines are reluctant to recommend their use<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> mainly due to the lack of efficiency studies demonstrating the cost-benefit compared to other currently used clinical and functional variables&#44; the absence of consensus on the measurements that could be most useful&#44; and the need for additional validation studies with a large number of patients&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Ethical responsibilities</span><p id="par0445" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Protection of humans and animals&#46;</span> The authors declare that no experiments on humans or animals have been conducted for this research&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Data confidentiality&#46;</span> The authors declare that no patient data appear in this article&#46;</p><p id="par0455" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Right to privacy and informed consent&#46;</span> The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Funding</span><p id="par0460" class="elsevierStylePara elsevierViewall">This project was funded by the <span class="elsevierStyleGrantSponsor" id="gs0005">Spanish Society of Rheumatology</span> &#40;SER&#41; and the <span class="elsevierStyleGrantSponsor" id="gs0010">Spanish Society of Pneumology and Thoracic Surgery</span> &#40;SEPAR&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Authorship</span><p id="par0465" class="elsevierStylePara elsevierViewall">All the authors made substantial contributions to a&#41; the conception and design of the study and the data analysis&#44; b&#41; drafting of the article or critical review of the intellectual content&#44; and c&#41; final approval of the version presented&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interests</span><p id="par0470" class="elsevierStylePara elsevierViewall">Jos&#233; Antonio Rodr&#237;guez Portal has received funding from Roche and Sanofi for attendance at courses&#47;congresses&#59; honoraria from Roche&#44; Boehringer and Janssen for presentations&#59; financial support from Bristol&#44; Janssen&#44; Roche&#44; and Boehringer for consultancy for pharmaceutical companies and other technologies&#59; and has participated in clinical trials funded by Gilead&#44; Roche and Boehringer&#46;</p><p id="par0475" class="elsevierStylePara elsevierViewall">No&#233; Brito Garc&#237;a has no conflict of interests to declare&#46;</p><p id="par0480" class="elsevierStylePara elsevierViewall">Petra D&#237;az del Campo Fontecha has no conflict of interests to declare&#46;</p><p id="par0485" class="elsevierStylePara elsevierViewall">Claudia Valenzuela has received funding from Boehringer and Roche for attendance at courses&#47;congresses&#59; honoraria from Roche for presentations&#59; and has received financial support from Boehringer&#44; Galapagos&#44; and Roche for consultancy for pharmaceutical companies and other technologies&#46;</p><p id="par0490" class="elsevierStylePara elsevierViewall">Ana Mar&#237;a Ortiz has received funding from Lilly&#44; Novartis&#44; Pfizer&#44; Roche&#44; Sandoz&#44; Sanofi&#44; and UCB for attending courses&#47;congresses&#59; honoraria from Abbvie&#44; Lilly&#44; MSD&#44; and Roche for presentations&#59; funding from Bristol&#44; Gilead&#44; MSD&#44; and Roche for participating in research&#44; and has received financial support from Abbvie&#44; Gilead&#44; Janssen&#44; Lilly&#44; and Pfizer for consultancy for pharmaceutical companies and other technologies&#46; She has also participated in clinical trials for MSD&#47;Amgen and Bristol&#46;</p><p id="par0495" class="elsevierStylePara elsevierViewall">Mar&#237;a Asunci&#243;n Nieto has received funding from Boehringer&#44; MSD&#44; Roche&#44; and TEVA for attending courses&#47;congresses&#59; honoraria from Boehringer&#44; BMS&#44; and Roche for presentations and for educational programmes or courses&#59; funding from Boehringer and Roche for participating in research&#59; and has received financial support from Roche&#44; Boehringer&#44; and Astra for consultancy for pharmaceutical companies and other technologies&#46;</p><p id="par0500" class="elsevierStylePara elsevierViewall">Natalia Mena V&#225;zquez has received funding from Abbvie&#44; Novartis&#44; Pfizer&#44; and Roche for attending courses&#47;congresses&#59; honoraria from Abbvie&#44; MSD&#44; Pfizer&#44; and Roche for presentations&#59; and has received funding from Abbvie and MSD for educational programmes and courses&#46;</p><p id="par0505" class="elsevierStylePara elsevierViewall">Esteban Cano Jim&#233;nez has received funding from Boehringer and Roche for attendance at courses&#47;congresses&#59; honoraria from Boehringer&#44; Chiesi&#44; Roche&#44; and Rovi for presentations&#59; and has received financial support from Galapagos for consultancy for pharmaceutical companies and other technologies&#46;</p><p id="par0510" class="elsevierStylePara elsevierViewall">Iv&#225;n Castellv&#237; has received funding from Actelion&#44; BMS&#44; Boheringer&#44; Kern&#44; Lilly&#44; Novartis&#44; Pfizer&#44; and Sanofi for attendance at courses&#47;congresses&#59; honoraria from Actelion&#44; BMS Boehringer&#44; Nordic&#44; Pfizer&#44; and Roche for presentations&#59; funding from Actelion for educational programmes and courses&#44; and has received financial support from Actelion&#44; Boehringer&#44; Gebro&#44; and Kern for consultancy for pharmaceutical companies and other technologies&#46;</p><p id="par0515" class="elsevierStylePara elsevierViewall">Myriam Aburto has received funding from Boehringer and Roche for attendance at courses&#47;congresses&#59; honoraria from BMS&#44; Boehringer&#44; and Roche for presentations&#59; and financial support from Boehringer for consultancy for pharmaceutical companies and other technologies&#46; She has also participated in a Boehringer clinical trial&#46;</p><p id="par0520" class="elsevierStylePara elsevierViewall">Gema Bonilla has received funding from Abbvie and Janssen for attendance at courses&#47;congresses and honoraria from Abbvie&#44; BMS&#44; Boehringer&#44; Novartis&#44; Roche&#44; and UCB for presentations&#46;</p><p id="par0525" class="elsevierStylePara elsevierViewall">Mar&#237;a Vanesa Hern&#225;ndez has no conflict of interests to declare&#46;</p><p id="par0530" class="elsevierStylePara elsevierViewall">F&#233;lix Manuel Francisco Hern&#225;ndez has no conflict of interests to declare&#46;</p><p id="par0535" class="elsevierStylePara elsevierViewall">Mar&#237;a Correyero Plaza has no conflict of interests to declare&#46;</p><p id="par0540" class="elsevierStylePara elsevierViewall">Isabel Castrej&#243;n has no conflict of interests to declare&#46;</p><p id="par0545" class="elsevierStylePara elsevierViewall">Miguel &#193;ngel Abad Hern&#225;ndez has no conflict of interests to declare&#46;</p><p id="par0550" class="elsevierStylePara elsevierViewall">Javier Narv&#225;ez has received funding from Bristol&#44; Kern&#44; Lilly&#44; Pfizer&#44; Roche&#44; and Sanofi for attendance at courses&#47;congresses&#59; honoraria from Abbvie&#44; Bristol&#44; Boehringer&#44; Gebro pharma&#44; GSK&#44; Kern&#44; Lilly&#44; Pfizer&#44; Sanofi&#44; and Sobi for presentations and consultancies for pharmaceutical companies and other technologies&#44; and has participated in clinical trials funded by Boehringer&#44; GSK&#44; Janssen&#44; Roche&#44; and Vorso&#46;</p></span></span>"
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          "titulo" => "General preliminary considerations"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Identification of the type of RA-associated ILD"
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              "titulo" => "Diagnosis of RA-ILD"
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              "titulo" => "Definition of progressive fibrosing ILD"
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              "titulo" => "Epidemiology of RA-ILD"
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                  "titulo" => "Incidence of RA-associated ILD"
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                  "titulo" => "Prevalence&#47;frequency of RA-ILD"
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              "titulo" => "Risk factors for onset of ILD in RA"
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              "titulo" => "Risk factors for onset of RA-ILD"
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                  "titulo" => "Predictors of RA-ILD progression"
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                  "titulo" => "Prognostic factors for mortality in RA-ILD"
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          "titulo" => "Discussion"
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          "titulo" => "Acknowledgements"
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          "titulo" => "References"
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    "fechaRecibido" => "2021-12-22"
    "fechaAceptado" => "2022-02-07"
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          "clase" => "keyword"
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            0 => "Rheumatoid arthritis"
            1 => "Diffuse interstitial lung disease"
            2 => "Incidence"
            3 => "Prevalence"
            4 => "Risk factors"
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            0 => "Artritis reumatoide"
            1 => "Enfermedad pulmonar intersticial difusa"
            2 => "Incidencia"
            3 => "Prevalencia"
            4 => "Factores de riesgo"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease &#40;RA-ILD&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field&#46; Systematic reviews of the available evidence were conducted&#44; and evidence was graded according to the Scottish Intercollegiate Guidelines Network &#40;SIGN&#41; criteria&#46; Specific recommendations were made&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Six PICO questions were selected&#44; three of which analysed the incidence and prevalence of RA-ILD&#44; associated risk factors&#44; and predictors of progression and mortality&#46; A total of 6 specific recommendations on these topics&#44; structured by question&#44; were formulated based on the evidence found and&#47;or expert consensus&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions and facilitate decision-making for patients&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Elaborar unas recomendaciones multidisciplinares para mejorar el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide &#40;EPID-AR&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Un panel de reumat&#243;logos y neum&#243;logos expertos identific&#243; preguntas cl&#237;nicas de investigaci&#243;n relevantes para el objetivo del documento&#46; Se realizaron revisiones sistem&#225;ticas de la evidencia&#44; que se gradu&#243; de acuerdo con los criterios del <span class="elsevierStyleItalic">Scottish Intercollegiate Guidelines Network</span> &#40;SIGN&#41;&#46; Tras ello&#44; se formularon las recomendaciones&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Se seleccionaron seis preguntas PICO&#44; tres de las cuales espec&#237;ficamente evaluaron la incidencia y prevalencia de esta complicaci&#243;n&#44; los factores de riesgo para su desarrollo&#44; y los factores pron&#243;sticos de mortalidad y de progresi&#243;n de la EPID-AR&#46; Se formularon un total de 6 recomendaciones espec&#237;ficas sobre estos aspectos&#44; estructuradas por pregunta&#44; con base en la evidencia encontrada y&#47;o consenso de expertos&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Se presenta el primer documento oficial SER-SEPAR de recomendaciones espec&#237;ficas para el abordaje la EPID-AR&#44; con el fin de ayudar en la toma de decisiones a los cl&#237;nicos directamente implicados en su manejo y aproximar la pr&#225;ctica asistencial a la mejor evidencia posible&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar2005">Please cite this article as&#58; Rodr&#237;guez Portal JA&#44; Brito Garc&#237;a N&#44; D&#237;az del Campo Fontecha P&#44; Valenzuela C&#44; Mar&#237;a Ortiz A&#44; Nieto MA&#44; et al&#46; Recomendaciones SER-SEPAR para el manejo de la enfermedad pulmonar intersticial difusa asociada a la artritis reumatoide&#46; Parte 1&#58; epidemiolog&#237;a&#44; factores de riesgo y pron&#243;stico&#46; Reumatol Cl&#237;n&#46; 2022&#59;18&#58;443&#8211;452&#46;</p>"
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                  \t\t\t\t">Based on its incidence and prevalence&#44; it is recommended that the possibility of interstitial lung disease should always be considered in the initial assessment and follow-up of patients with rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \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">Patients with rheumatoid arthritis should be systematically screened for interstitial lung disease in cases with respiratory symptoms or if velcro-like crackles are heard&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8730;&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">In cases without respiratory symptoms and with normal auscultation&#44; the need for screening should be assessed individually according to the number of risk factors<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> for onset of this complication&#44; regardless of the time since onset of rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8730;&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">The presence of interstitial lung disease should always be considered when deciding on treatment&#44; given the potential risk of pneumonitis described with some of the drugs commonly used in rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8730;&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">In patients with rheumatoid arthritis&#44; none of the investigational serum biomarkers tested so far has been shown to have better predictive value for the onset of interstitial lung disease than anti-citrullinated protein&#47;peptide antibodies&#46; Based on the current evidence&#44; the drafting group does not recommend the use of other serum biomarkers in routine clinical practice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D&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">In patients with rheumatoid arthritis and interstitial lung disease it is recommended that the presence of prognostic factors associated with progression<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> and mortality<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> be considered when planning follow-up &#40;frequency of check-ups&#41; and treatment strategy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The main risk factors for the development of interstitial lung disease&#44; easily identifiable in the clinic&#44; are male sex&#44; older age&#44; late disease onset&#44; duration of rheumatoid arthritis&#44; history of smoking&#44; sustained moderate&#44; or high disease activity&#44; and rheumatoid factor and anti-citrullinated protein&#47;peptide antibody positivity&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The main predictors of progression of interstitial lung disease are the radiological pattern of usual interstitial pneumonia&#44; elevated anti-citrullinated protein&#47;peptide antibody titres&#44; degree of baseline DLCO impairment&#44; a &#8805;10&#37; decrease &#40;percentage of estimated theoretical value&#41; in FVC during follow-up&#44; extensive lung involvement on chest HRCT&#44; and elevated serum levels of interleukin-6 and Krebs von den Lungen-6 glycoprotein&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">The main prognostic factors associated with increased mortality are advanced age at diagnosis of interstitial lung disease&#44; male sex&#44; duration of rheumatoid arthritis&#44; moderate or high disease activity&#44; the usual radiological pattern of interstitial pneumonia&#44; low baseline FVC and&#47;or DLCO&#44; a decrease in FVC&#160;&#62;&#160;10&#37; or DLCO&#160;&#62;&#160;15&#37; during follow-up&#44; extensive lung involvement on chest HRCT&#44; GAP and CPI &#40;composite physiologic index&#41; indices&#44; and elevated serum levels of Krebs von den Lungen-6 glycoprotein&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">SER-SEPAR recommendations for the management of rheumatoid arthritis-associated interstitial lung disease&#58; epidemiology&#44; epidemiology&#44; risk factors and prognosis of RA-ILD&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0010"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ACPA&#58; Anti-citrullinated Protein&#47;peptide Antibodies&#59; ILD&#58; Interstitial Lung Disease&#59; NS&#58; Not specified&#59; RF&#58; Rheumatoid Factor&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#176; of centres&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Time since onset &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Smoking &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">RF &#40;&#43;&#41;&#47;ACPA &#40;&#43;&#41; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Respiratory symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency of ILD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bilgici et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> &#40;2005&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Turkey&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;6&#160;&#177;&#160;11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;37&#160;&#177;&#160;8&#46;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">67&#46;3&#37;&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic 59&#46;6&#37; &#40;31&#47;52&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#46;76&#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symptomatic 21&#37; &#40;11&#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
                  \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">Dawson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> &#40;2001&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">150&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#46;9&#160;&#177;&#160;10&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;7&#160;&#177;&#160;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77&#37;&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic&#59; 15 had crackles on respiratory auscultation &#40;10&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;6&#37;&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">Mohd Noor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> &#40;2009&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Malaysia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;7&#160;&#177;&#160;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#160;&#177;&#160;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#46;7&#37;&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic 67&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#46;4&#37;&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">Mori et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> &#40;2008&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">126&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#160;&#177;&#160;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61 patients with established RA &#40;Time since onset&#58; 11&#46;8&#160;&#177;&#160;9&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&#37;&#47;93&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with established RA&#58; Asymptomatic 68&#46;8&#37; &#40;42&#47;61&#41; Symptomatic 31&#46;2&#37; &#40;19&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total&#58; 11&#46;9&#37; &#40;15&#47;126&#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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 patients with time since onset&#58; 2&#46;6&#160;&#177;&#160;4&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic patients 83&#46;1&#37; &#40;54&#47;65&#41; Symptomatic 16&#46;9&#37; &#40;11&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;1&#37; &#40;8&#47;61&#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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;7&#37; &#40;7&#47;65&#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">Skare et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> &#40;2011&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brazil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#46;7&#160;&#177;&#160;10&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;8&#160;&#177;&#160;6&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">704&#37;&#47;38&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic 44&#46;75&#37; &#40;30&#47;71&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54&#46;92&#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symptomatic 55&#46;25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">Wang y Du<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> &#40;2015&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">China&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">544&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;6&#160;&#177;&#160;6&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;26&#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Crackles on auscultation&#58; 52 &#40;9&#46;5&#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="left" 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">Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> &#40;2017&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">China&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#160;&#177;&#160;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#160;&#177;&#160;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&#46;5&#37;&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic 59&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;1&#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symptomatic 41&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">Zrour et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> &#40;2005&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tunisia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#160;&#177;&#160;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96&#160;&#177;&#160;88&#160;m &#40;8 years&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;6&#37;&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic 74&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symptomatic 25&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">Gabbay et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> &#40;1997&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Australia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;8&#160;&#177;&#160;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#37;&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#37;&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">Gochuico et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> &#40;2008&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">United States&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&#46;89&#37;&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">Habib et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> &#40;2011&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Saudi Arabia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;6&#160;&#177;&#160;10&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&#37; &#47;NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main characteristics of the 11 studies that have analysed the prevalence of RA-ILD included in the systematic review of the literature&#46;</p>"
        ]
      ]
      2 => array:5 [
        "identificador" => "upi0005"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.docx"
          "ficheroTamanyo" => 28978
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
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        "texto" => "<p id="par0555" class="elsevierStylePara elsevierViewall">The group of experts in this study would like to thank Mercedes Guerra Rodr&#237;guez&#44; documentalist at the SER&#44; for her collaboration in the evidence search strategies&#46;</p><p id="par0560" class="elsevierStylePara elsevierViewall">They would also expressly like to thank Dr&#46; Raimon Sanmart&#237; Sala and Dr&#46; Gustavo Enrique Zabert as expert reviewers of the document&#44; for their critical review and contributions to it&#46;</p><p id="par0565" class="elsevierStylePara elsevierViewall">They would also like to thank Dr&#46; Federico D&#237;az Gonz&#225;lez&#44; Director of the SER Research Unit&#44; for his participation in the review of the final manuscript and for his help in preserving the independence of this document&#46;</p>"
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