The lung as a target and as an initiator of rheumatoid arthritis-associated immunity: Implications for interstitial lung disease

array:22 ["pii" => "S0121812323000889" "issn" => "01218123" "doi" => "10.1016/j.rcreu.2023.09.006" "estado" => "S300" "fechaPublicacion" => "2024-04-01" "aid" => "2084" "copyrightAnyo" => "2023" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Rev Colomb Reumatol. 2024;31 Supl 1:S74-S81" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S0121812323000877" "issn" => "01218123" "doi" => "10.1016/j.rcreu.2023.09.007" "estado" => "S300" "fechaPublicacion" => "2024-04-01" "aid" => "2085" "copyright" => "Asociación Colombiana de Reumatología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Rev Colomb Reumatol. 2024;31 Supl 1:S82-S93" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review Article" "titulo" => "Progressive pulmonary fibrosis associated autoimmune diseases: Systematic review of the literature" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "S82" "paginaFinal" => "S93" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fibrosis pulmonar progresiva asociada a enfermedad autoinmune: revisión sistemática de la literatura" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1129 "Ancho" => 3000 "Tamanyo" => 170183 ] ] "descripcion" => array:1 [ "en" => "Mortality risk of PPF-ILD across studies." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luis Javier Cajas Santana, Diana Rocío Gil Calderón, Manuela Rubio Rivera, José Alex Yate, Javier Leonardo Galindo" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Luis Javier" "apellidos" => "Cajas Santana" ] 1 => array:2 [ "nombre" => "Diana Rocío" "apellidos" => "Gil Calderón" ] 2 => array:2 [ "nombre" => "Manuela" "apellidos" => "Rubio Rivera" ] 3 => array:2 [ "nombre" => "José" "apellidos" => "Alex Yate" ] 4 => array:2 [ "nombre" => "Javier" "apellidos" => "Leonardo Galindo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0121812323000877?idApp=UINPBA00004N" "url" => "/01218123/00000031000000S1/v5_202405200140/S0121812323000877/v5_202405200140/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0121812323000816" "issn" => "01218123" "doi" => "10.1016/j.rcreu.2023.08.005" "estado" => "S300" "fechaPublicacion" => "2024-04-01" "aid" => "2078" "copyright" => "Asociación Colombiana de Reumatología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Rev Colomb Reumatol. 2024;31 Supl 1:S67-S73" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Review article" "titulo" => "Measurement of health-related quality of life in patients with interstitial lung disease and autoimmune diseases" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "S67" "paginaFinal" => "S73" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Medición de calidad de vida relacionada con la salud en pacientes con enfermedad pulmonar intersticial y enfermedades autoinmunes" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Claudia Mora, Alirio Rodrigo Bastidas Goyes, Lina Paola Fajardo Muriel, Cristian Felipe Rodríguez Yasno" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Claudia" "apellidos" => "Mora" ] 1 => array:2 [ "nombre" => "Alirio Rodrigo" "apellidos" => "Bastidas Goyes" ] 2 => array:2 [ "nombre" => "Lina Paola" "apellidos" => "Fajardo Muriel" ] 3 => array:2 [ "nombre" => "Cristian Felipe" "apellidos" => "Rodríguez Yasno" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0121812323000816?idApp=UINPBA00004N" "url" => "/01218123/00000031000000S1/v5_202405200140/S0121812323000816/v5_202405200140/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review Article" "titulo" => "The lung as a target and as an initiator of rheumatoid arthritis-associated immunity: Implications for interstitial lung disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "S74" "paginaFinal" => "S81" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Malena Loberg Haarhaus, Lars Klareskog" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Malena Loberg" "apellidos" => "Haarhaus" ] 1 => array:4 [ "nombre" => "Lars" "apellidos" => "Klareskog" "email" => array:1 [ 0 => "lars.klareskog@ki.se" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Rheumatology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El pulmón como diana y como iniciador de la inmunidad asociada a la artritis reumatoide; implicaciones para la enfermedad pulmonar intersticial" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 971 "Ancho" => 2515 "Tamanyo" => 169434 ] ] "descripcion" => array:1 [ "en" => "The figure illustrates the bi-directional interplay between immune and inflammatory events in the lungs and the longitudinal evolution of seropositive RA. Immunity triggered in the lungs is assumed to contribute to the development of seropositive RA and inflammation in RA is assumed to contribute to inflammation and fibrosis in the lungs." ] ] ] "textoCompleto" => "IntroductionLungs are essential immune organs where immune defense against the many hostile agents in the environment are handled, i.e. microbes as well as many hazardous environmental agents. Lungs are also the place in the body where environment meets immune system without other protective layers or environments such as the epidermis in the skin or the acidity in the stomach. The lungs are therefore vulnerable for many types of immune-dependent events, both concerning too limited immunity resulting in bacterial or viral airway infections or concerning too vigorous immune responses resulting in autoimmune disease. Research over recent years has demonstrated that the lungs are not only organs where immunity may result in local pulmonary inflammation and subsequent fibrosis but may also be sites where immunity is triggered that results in autoimmune disease elsewhere. A prime example of this is rheumatoid arthritis<a class="elsevierStyleCrossRefs" href="#bib0330">1,2</a> which will be further discussed in this review, but similar relationships have been demonstrated for multiple sclerosis<a class="elsevierStyleCrossRef" href="#bib0340">3</a> and certain variants of myositis.<a class="elsevierStyleCrossRef" href="#bib0345">4</a>In order to understand, prevent, and treat pulmonary inflammation as potential trigger of systemic inflammatory disease and pulmonary fibrosis as a co-morbidity to other inflammatory diseases such as RA, there is thus a need to understand the functional relationships between immunity in the lungs and immune-mediated disease affecting other organs such as the joints. This will be the perspective in this review.Lung-associated morbidity and mortality in RA: take-homes from epidemiologyLung complications, i.e. mainly interstitial pulmonary fibrosis resulting from chronic inflammation in lungs, are major reasons for increased mortality and long-term morbidity in RA, and in contrast to other co-morbidities such as infections and cardiovascular disease, the frequency of pulmonary complications have remained high in RA.<a class="elsevierStyleCrossRefs" href="#bib0350">5,6</a> Similar to other extra-articular manifestations of RA, lung complications and interstitial pulmonary fibrosis are most common in RA patients who are positive for antibodies to citrullinated protein antigens (ACPA) and/or rheumatoid factors (RF).<a class="elsevierStyleCrossRefs" href="#bib0360">7,8</a> These observations indicate that we should search at least part of the explanation to the occurrence of long-term lung inflammation and interstitial pulmonary fibrosis in factors that trigger the production of these antibodies and are involved in their effector mechanisms.Epidemiological studies on risk factors for development of RA have demonstrated that exposure of airways to noxious agents such as smoke, silica dust, and several other occupational airways are the major environmental risk factors for RA, and that these risk factors are mainly restricted to the ACPA and/or RF positive subset of disease.<a class="elsevierStyleCrossRefs" href="#bib0370">9–13</a> Major gene–environment interactions were also demonstrated between these airway exposures and presence of the major genetic risk factors for RA, i.e. certain alleles within the MHC class II.<a class="elsevierStyleCrossRefs" href="#bib0330">1,11,13</a> Taken together, these data suggested that lungs might be sites where these immune reactions are triggered in a MHC class II restricted way.<a class="elsevierStyleCrossRefs" href="#bib0395">14,15</a>The lung as a site for triggering of RA-associated immunitySeveral molecular and cellular studies have further supported that immunity to citrullinated antigens might be triggered in the lungs and that such triggering may occur before onset of clinically defined arthritis. Such evidence comes from the demonstration of higher levels of ACPA in BAL fluids as compared to serum suggesting local production of the antibodies.<a class="elsevierStyleCrossRef" href="#bib0405">16</a> Similar results have come from sputum analysis if taken already before onset of arthritis.<a class="elsevierStyleCrossRef" href="#bib0410">17</a> A recent addition to these data, giving further evidence for the contribution of T cell-driven antibody production was the finding of ACPA-producing B cells/plasma cells obtained from bronchoalveolar lavage obtained both at early stages of RA and from ACPA-positive individuals at high risk for RA.<a class="elsevierStyleCrossRef" href="#bib0415">18</a> Notably, the Ig genes coding for these antibodies and derived from single ACPA-producing B cells/plasma cells were highly somatically mutated indicating local T cell help.<a class="elsevierStyleCrossRef" href="#bib0415">18</a> These and other cellular and molecular studies have substantiated the concept of a mucosal origin of at least part of the RA-associated autoantibodies and most probably also of the seropositive RA itself<a class="elsevierStyleCrossRefs" href="#bib0330">1,2,14,15</a>; the concept has sometimes been denoted the “mucosal hypothesis” for an origin of seropositive RA.<a class="elsevierStyleCrossRef" href="#bib0335">2</a>Inflammation in lungs as a consequence of RA-associated immunityAn obvious question is whether the lung immune systems is not only involved in triggering of RA-associated immunity but whether the same immunity is also involved in effector functions, i.e. contributing to pulmonary inflammation and subsequent fibrosis. Some evidence supports such a scenario: one is observations from HRCT investigations of lungs at early diagnosis of RA, where signs of inflammation were observed in the ACPA/RF positive subset of the disease as compared to control and ACPA/RF negative RA.<a class="elsevierStyleCrossRef" href="#bib0405">16</a> Additional studies have demonstrated the presence of certain lung abnormalities in ACPA and/or RF positive individuals already before onset of clinically diagnosed RA.<a class="elsevierStyleCrossRef" href="#bib0420">19</a> It is still not clear, however, how ACPA and RF and associated T cell immunity can activate pro-inflammatory events. Thus, some in vitro studies have demonstrated that ACPA may be involved both in activation of macrophages in a Fc receptor and often immune complex mediated way.<a class="elsevierStyleCrossRef" href="#bib0425">20</a> Pro-inflammatory in vitro effects of ACPA have also been demonstrated in neutrophil assays where some ACPA may recognized activated neutrophils and contribute to pro-inflammatory effects of NET-osis.<a class="elsevierStyleCrossRef" href="#bib0430">21</a> To which extent such immune-mediated effects from ACPA/RF contribute to the long- term inflammation and fibrosis is so far less known.Long-term effects of lung inflammation in RA: development of interstitial lung diseaseAs stated in the introduction, chronic inflammation and subsequent fibrosis constitute major reasons for long-term morbidity and also mortality in RA, and lung involvement can be found in as many as 70% of RA patients, where RA interstitial lung disease (ILD) is the most common finding.<a class="elsevierStyleCrossRef" href="#bib0435">22</a> Approximately 2–10% of RA patients will develop symptomatic RA ILD during the course of the disease as seen in cohort-based studies and as many as 20% will develop asymptomatic disease.<a class="elsevierStyleCrossRefs" href="#bib0440">23–27</a> The median survival in patients with RA ILD ranges between 3 and 10 years in historic cohorts.<a class="elsevierStyleCrossRefs" href="#bib0450">25,28,29</a> RA ILD is strongly related to the presence of relatively well characterized risk factors. Such risk factors contributing to interstitial lung fibrosis in RA are presence of ACPA and/or RF, and exposure to noxious airways agent, and inflammatory activity over time.<a class="elsevierStyleCrossRef" href="#bib0440">23</a> The genetic risk factor most distinctly related to the fibrotic phenotype in RA ILD is an allelic form of the mucoprotein MUC5B.<a class="elsevierStyleCrossRef" href="#bib0475">30</a> This protein is secreted by submucosal mucinous gland cells and is involved in mucosal ciliary function and may also be involved in the regulation of local immune responses and alveolar regeneration following injury.<a class="elsevierStyleCrossRef" href="#bib0440">23</a> Genetics, in particular the RA-associated MHC class II alleles also contribute, mainly related to presence of ACPA.<a class="elsevierStyleCrossRefs" href="#bib0330">1,31</a> Additional risk factors are long-standing disease and long-term inflammatory load as well as age and male gender.<a class="elsevierStyleCrossRef" href="#bib0660">32</a>The subtype of ILD most common in RA is the “Usual Interstitial Pneumonia” (UIP).<a class="elsevierStyleCrossRef" href="#bib0660">32</a> The histopathological and radiological pattern of UIP is similar to findings in idiopathic pulmonary fibrosis (IPF) which is characterized by a progressive fibrosis of the lungs and is also associated with the highest mortality as compared to other ILD subtypes.<a class="elsevierStyleCrossRefs" href="#bib0660">32,33</a> On imaging, typical features of UIP include basal predominant reticular opacities, traction bronchiectasis, and honeycombing. Non-specific interstitial pneumonia (NSIP) is the second most common HRCT pattern characterized by ground glass opacities without honeycombing.<a class="elsevierStyleCrossRef" href="#bib0495">34</a> The distinct disease phenotypes of RA ILD impact differently on clinical outcomes. When comparing patients with IPF to patients with RA ILD, Kim et al.<a class="elsevierStyleCrossRef" href="#bib0500">35</a> described a median survival of 3.2 years in RA ILD with UIP pattern, which was similar to those with IPF and significantly shorter than the median survival of 6.6 years in patients without UIP pattern (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Mechanisms that are involved in the mediation of lung fibrosis from the presence of the described risk factors, are not yet well understood. Descriptive studies have shown increase of macrophage and fibroblast activation as well as increased presence of B and T cells at sites of chronic pulmonary inflammation and fibrosis in RA as compared to ILD in individuals without RA,<a class="elsevierStyleCrossRef" href="#bib0440">23</a> and it appears that fibrosis development occurs as a result of inflammation that may involve all these cells.<a class="elsevierStyleCrossRef" href="#bib0500">35</a> Notably, noxious agents like smoking being risk factors for RA as well as RA-ILD are able to cause increased production and activation of enzymes, peptidyl-arginine deiminases (PADs) that cause citrullination.<a class="elsevierStyleCrossRef" href="#bib0505">36</a> Citrullinated molecules in the lungs may then be involved both in triggering autoimmunity towards these post-translationally modified molecules in the context of certain genotypes<a class="elsevierStyleCrossRefs" href="#bib0505">36–38</a> but may also directly be involved in activation of macrophages<a class="elsevierStyleCrossRef" href="#bib0425">20</a> and neutrophils via binding to pattern recognition molecules such as toll-like receptors,<a class="elsevierStyleCrossRef" href="#bib0430">21</a> often in immune-complex-dependent contexts – thereby potentially explaining an additive role of rheumatoid factors in addition to the ACPAs. Whether presence of ACPA and/or RF have independent effects on fibrosis development in addition to having effects on inflammation and macrophage activation is presently now known. It is feasible, however, that specific interactions may occur between T cells and fibroblasts in the lung tissue similar to what has recently been described for these cells in the synovial tissue in RA.<a class="elsevierStyleCrossRef" href="#bib0520">39</a> It is also possible that ACPA and ACPA-containing immune complexes are involved in the activation of neutrophils and subsequent NETosis, which may also be directly involved in activation and proliferation of fibroblasts and subsequent fibrosis.<a class="elsevierStyleCrossRef" href="#bib0525">40</a> The overall conclusion from what is specifically known about inflammation and fibrosis in the lung of RA patients, suggest that largely similar risk factors and mechanism as for seropositive RA are involved in the pathogenesis of RA ILD. Nevertheless, the relationship between development of RA-ILD and inflammation in RA is far from linear, and thus additional lung-specific mechanisms should therefore be possible to identify. Pathways associated with mutations in MUC5B represent one such option to follow.<a class="elsevierStyleCrossRef" href="#bib0475">30</a> Investigations of the lung microbiome, which is different in RA patients as compared to otherwise healthy individuals<a class="elsevierStyleCrossRef" href="#bib0530">41</a> indicate that that better understanding of the interplay between lung microbiome and lung inflammation and fibrosis may be another way forward.Options for prevention and treatment of pulmonary morbidity in RAAs the major known risk factors and pathways involved in the development of RA-ILD are the same as those involved in the development and perpetuation of seropositive RA, the same options for prevention and treatment that exists for RA should be used to prevent and treat RA ILD. As extensively reviewed and discussed elsewhere,<a class="elsevierStyleCrossRef" href="#bib0535">42</a> such options involve very early diagnosis, rapid reduction of inflammation with appropriate pharmaceuticals as well as targeting of modifiable lifestyle and environmental factors, in particular those that include airway noxious substances.<a class="elsevierStyleCrossRef" href="#bib0375">10</a> The most important of these options remain smoking cessation, which has been shown to reduce risk for RA, reduce inflammation in ongoing RA and improve effects of anti-rheumatic treatments.<a class="elsevierStyleCrossRefs" href="#bib0540">43,44</a>The importance of detecting RA ILD in an early stage cannot be stressed enough due to its large impact on mortality and morbidity. A clinical obstacle is that most patients are asymptomatic and the prevalence of RA ILD is relatively low compared to ILD in other connective tissue diseases such as systemic sclerosis (SSc). HRCT is the preferred imaging technique for the diagnosis of ILD and in all patients with SSc, HRCT is used as the screening method according to guidelines for SSc ILD. In RA it is not justifiable to screen all patients with HRCT since most patients will show no signs of ILD. International guidelines for screening and monitoring RA ILD are lacking.<a class="elsevierStyleCrossRef" href="#bib0460">27</a> One group has recently suggested a screening algorithm that involves lung auscultation, history of respiratory symptoms and assessment of risk factors for ILD. They have also suggested a risk score to better identify the patients that benefit from HRCT.<a class="elsevierStyleCrossRef" href="#bib0550">45</a> Another group has suggested a slightly different algorithm for screening for RA ILD.<a class="elsevierStyleCrossRef" href="#bib0435">22</a> Further clinical studies are needed and ongoing for justification of these and other algorithms and risk scores. Ideally, the management of RA ILD should involve multidisciplinary collaboration, including rheumatologists, pulmonologists, radiologists, and pathologists.<a class="elsevierStyleCrossRefs" href="#bib0450">25,33</a>Prevention of RA-ILD should be considered already from the diagnosis of RA and involve careful monitoring of risk factors for RA ILD and efforts to reduce modifiable risk factors.RA disease activity has been associated with an increased risk of developing RA-ILD<a class="elsevierStyleCrossRefs" href="#bib0450">25,29,46</a> and therapies targeting RA can thus potentially reduce the risk to develop RA ILD. Post hoc analyses of existing trials and observational studies have demonstrated mixed results. Rituximab was associated with improved lung function<a class="elsevierStyleCrossRef" href="#bib0560">47</a> and better survival in RA ILD patients than other DMARDs.<a class="elsevierStyleCrossRefs" href="#bib0565">48,49</a> Promising results have also been shown for Abatacept with respect to improvement of lung function in RA ILD,<a class="elsevierStyleCrossRef" href="#bib0575">50</a> but a large registry study could only demonstrate stabilization of lung function.<a class="elsevierStyleCrossRef" href="#bib0580">51</a> Tocilizumab showed no progression of ILD in three-fourth of the RA ILD cases in a small retrospective study but demonstrated a good safety profile.<a class="elsevierStyleCrossRef" href="#bib0585">52</a> TNF-inhibitors may even have a negative effect on RA ILD, however, this is still a matter of debate.<a class="elsevierStyleCrossRef" href="#bib0590">53</a> Evidence from randomized controlled trials targeting RA ILD is still lacking.Recent progress in reducing fibrosis development in individuals with existing ILD has provided a completely novel way to reduced morbidity in ILD,<a class="elsevierStyleCrossRefs" href="#bib0595">54,55</a> and this is described elsewhere in this theme issue of inflammatory diseases and ILD. The INBUILD study included patients with progressive fibrosing ILD and compared tyrosine kinase inhibitor nintedanib with placebo. In a subgroup analysis of 170 patients with connective tissue disease, 89 patients had RA ILD. There was a reduction in the rate of decline in FVC over 52 weeks by 60% in the RA ILD subgroup which were similar results as seen in the overall population. There was no difference in the RA ILD subgroup in patients who were or were not taking DMARDs or glucocorticoids in the nintedanib or placebo group.<a class="elsevierStyleCrossRef" href="#bib0605">56</a> In an animal model of RA ILD, nintedanib was demonstrated to reduce pulmonary collagen levels while reducing arthritis.<a class="elsevierStyleCrossRef" href="#bib0610">57</a> Another possible mechanism of action is the suppression of M2 macrophage polarization and hyperplasia of Type 2 alveolar epithelial cells.<a class="elsevierStyleCrossRef" href="#bib0615">58</a> One notable progress of large importance for everyday clinical practice in RA treatment is that methotrexate, the anchor drug in RA treatment is not associated with increased risk or worse prognosis of ILD, contrary to some earlier assumptions.<a class="elsevierStyleCrossRefs" href="#bib0620">59–61</a> In fact, use of methotrexate was associated with improved survival in patients with acute exacerbation of RA ILD.<a class="elsevierStyleCrossRef" href="#bib0635">62</a> Thus, methotrexate remains the anchor drug for reduction of inflammation also in individuals at increased risk of ILD.Options for the future are plentiful and involve both improved and earlier use of therapies used for RA today and more specific options, for example inhibition of PAD enzyme activity that has shown promise in experimental animal models.<a class="elsevierStyleCrossRef" href="#bib0640">63</a> Also enhanced B cell depletion, for example with CAR T cell therapy that has shown remarkable effects also on pulmonary symptoms in case reports of myositis with severe ILD<a class="elsevierStyleCrossRefs" href="#bib0645">64,65</a> may be an option for patients with severe and treatment-resistant RA-ILD already today.FundingThe work from our research unit that is described in this review was supported by grants from the Swedish Research Council and from the Knut and Alice Wallenberg Foundation to late professor Anca Catrina who initiated several of the investigations of RA, lungs and ILD at Karolinska and elsewhere.Conflict of interestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2149721" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1824879" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2149722" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1824880" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Lung-associated morbidity and mortality in RA: take-homes from epidemiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "The lung as a site for triggering of RA-associated immunity" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Inflammation in lungs as a consequence of RA-associated immunity" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Long-term effects of lung inflammation in RA: development of interstitial lung disease" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Options for prevention and treatment of pulmonary morbidity in RA" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-08-23" "fechaAceptado" => "2023-09-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1824879" "palabras" => array:4 [ 0 => "Rheumatoid arthritis" 1 => "Interstitial lung disease" 2 => "Interstitial pulmonary fibrosis" 3 => "Pathogenesis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1824880" "palabras" => array:4 [ 0 => "Artritis reumatoide" 1 => "Enfermedad pulmonar intersticial" 2 => "Fibrosis pulmonar intersticial" 3 => "Patogénesis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Interstitial lung disease (ILD) is a serious extra-articular co-morbidity in rheumatoid arthritis (RA) patients and accounts for a substantial part of the increased mortality in RA. In this review, we describe how environmental and lifestyle factors interact with genetic variants in the HLA genetic locus in triggering RA-specific antibodies against post-translationally modified, mainly citrullinated proteins (ACPA), which are associated with an increased risk of ILD. The same environmental risk factors, i.e. exposure to noxious agents such as smoke to the lungs contribute additionally to the emergence of RA ILD as does long-lasting high disease activity and an additional ILD-specific genetic risk variant related to mucus formation (MUC5B). Options for prevention and therapy of RA ILD resulting from this so far incomplete knowledge of its pathophysiology are expanding. The most obvious option is to address modifiable environmental risk factors, such as smoking and exposure to other noxious agents affecting the lungs. The second option is to reduce the inflammatory activity of RA; here different anti-rheumatic therapies appear to have differential effects on ILD development. The third and novel option is to use anti-fibrotic therapy which may reduce the development of RA ILD but has not yet been shown to revert existing fibrosis. The main conclusion concerning the clinical handling of RA ILD is therefore an early awareness of the risk for RA ILD combined with active measures to reduce modifiable environmental/lifestyle factors and use optimal anti-rheumatic therapies for early and sustained reduction of disease activity. These actions should be combined with a preparedness to use anti-fibrotic therapy for patients at high risk for ILD despite previous risk reduction efforts." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La enfermedad pulmonar intersticial (EPI) es una comorbilidad extraarticular grave en pacientes con artritis reumatoide y representa una parte sustancial del aumento de la mortalidad en esta última. En esta revisión describimos cómo los factores ambientales y de estilo de vida interactúan con variantes genéticas en el locus genético HLA para desencadenar anticuerpos específicos de AR contra proteínas, principalmente citrulinadas, modificadas de forma postraduccional (Ac anti-PCC), que están asociadas con un mayor riesgo de EPI. Los mismos factores de riesgo ambientales, es decir, la exposición a agentes nocivos como el humo en los pulmones, contribuyen adicionalmente a la aparición de EPI con AR, al igual que la alta actividad prolongada de la enfermedad y una variante de riesgo genético adicional específica de la EPI relacionada con la formación de mucoso (MUC5B). Las opciones para la prevención y el tratamiento de la EPI con AR resultantes de este conocimiento hasta ahora incompleto de su fisiopatología se están ampliando: la opción más obvia es abordar los factores de riesgo ambientales modificables, como el tabaquismo y la exposición a otros agentes nocivos que afectan los pulmones. La segunda opción es reducir la actividad inflamatoria de la AR; aquí las diferentes terapias antirreumáticas parecen tener efectos diferenciales en el desarrollo de la EPI. La tercera y novedosa opción es utilizar una terapia antifibrótica que puede reducir el desarrollo de EPI con AR, pero aún no se ha demostrado que revierta la fibrosis existente. La conclusión principal sobre el manejo clínico de la EPI con AR es, en consecuencia, una conciencia temprana del riesgo de EPI con AR, combinada con medidas activas para reducir los factores ambientales y de estilo de vida modificables y utilizar terapias antirreumáticas óptimas para una reducción temprana y sostenida de la actividad de la enfermedad. Estas acciones deben combinarse con una preparación para usar la terapia antifibrótica en pacientes con alto riesgo de EPI, a pesar de los esfuerzos previos de reducción del riesgo." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary material to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary material" "identificador" => "sec0085" ] ] ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 971 "Ancho" => 2515 "Tamanyo" => 169434 ] ] "descripcion" => array:1 [ "en" => "The figure illustrates the bi-directional interplay between immune and inflammatory events in the lungs and the longitudinal evolution of seropositive RA. Immunity triggered in the lungs is assumed to contribute to the development of seropositive RA and inflammation in RA is assumed to contribute to inflammation and fibrosis in the lungs." ] ] 1 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 227216 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:65 [ 0 => array:3 [ "identificador" => "bib0330" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Klareskog" 1 => "P. Stolt" 2 => "K. Lundberg" 3 => "H. Källberg" 4 => "C. Bengtsson" 5 => "J. Grunewald" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.215752" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2006" "volumen" => "54" "paginaInicial" => "38" "paginaFinal" => "46" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16385494" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0335" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "V.M. Holers" 1 => "M.K. Demoruelle" 2 => "K.A. Kuhn" 3 => "J.H. Buckner" 4 => "W.H. Robinson" 5 => "Y. Okamoto" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41584-018-0070-0" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Rheumatol" "fecha" => "2018" "volumen" => "14" "paginaInicial" => "542" "paginaFinal" => "557" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30111803" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0340" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "T. Olsson" 1 => "L.F. Barcellos" 2 => "L. Alfredsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrneurol.2016.187" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Neurol" "fecha" => "2017" "volumen" => "13" "paginaInicial" => "25" "paginaFinal" => "36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27934854" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0345" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Chinoy" 1 => "S. Adimulam" 2 => "F. Marriage" 3 => "P. New" 4 => "M. Vincze" 5 => "E. Zilahi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/annrheumdis-2011-200182" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2012" "volumen" => "71" "paginaInicial" => "961" "paginaFinal" => "965" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22186711" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0350" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Factors associated with interstitial lung disease in patients with rheumatoid arthritis: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M. Zhang" 1 => "J. Yin" 2 => "X. Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0286191" "Revista" => array:5 [ "tituloSerie" => "PLoS One" "fecha" => "2023" "volumen" => "18" "paginaInicial" => "e0286191" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37352174" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0355" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Survival of adults with rheumatoid arthritis associated interstitial lung disease – a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.J. Farquhar" 1 => "N. Beckert" 2 => "L. Beckert" 3 => "A.L. Edwards" 4 => "E.L. Matteson" 5 => "C. Frampton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.semarthrit.2023.152187" "Revista" => array:5 [ "tituloSerie" => "Semin Arthritis Rheum" "fecha" => "2023" "volumen" => "60" "paginaInicial" => "152187" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36933302" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0360" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: a nested case–control study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V.L. Kronzer" 1 => "K. Hayashi" 2 => "K. Yoshida" 3 => "J.M.3rd. Davis" 4 => "G.C. McDermott" 5 => "W. Huang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s2665-9913(22)00380-0" "Revista" => array:6 [ "tituloSerie" => "Lancet Rheumatol" "fecha" => "2023" "volumen" => "5" "paginaInicial" => "e77" "paginaFinal" => "e87" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36874209" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0365" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms of lung disease development in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D. Wang" 1 => "J. Zhang" 2 => "J. Lau" 3 => "S. Wang" 4 => "V. Taneja" 5 => "E.L. Matteson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41584-019-0275-x" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Rheumatol" "fecha" => "2019" "volumen" => "15" "paginaInicial" => "581" "paginaFinal" => "596" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31455869" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0370" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. Källberg" 1 => "B. Ding" 2 => "L. Padyukov" 3 => "C. Bengtsson" 4 => "J. Rönnelid" 5 => "L. Klareskog" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2009.120899" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2011" "volumen" => "70" "paginaInicial" => "508" "paginaFinal" => "511" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21149499" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0375" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The importance of differences: on environment and its interactions with genes and immunity in the causation of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L. Klareskog" 1 => "J. Rönnelid" 2 => "S. Saevarsdottir" 3 => "L. Padyukov" 4 => "L. Alfredsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/joim.13058" "Revista" => array:6 [ "tituloSerie" => "J Intern Med" "fecha" => "2020" "volumen" => "287" "paginaInicial" => "514" "paginaFinal" => "533" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32176395" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0380" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Tang" 1 => "Q. Liu" 2 => "A. Ilar" 3 => "P. Wiebert" 4 => "S. Hägg" 5 => "L. Padyukov" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard-2022-223134" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2023" "volumen" => "82" "paginaInicial" => "316" "paginaFinal" => "323" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36600175" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0385" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is male rheumatoid arthritis an occupational disease? A review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D. Murphy" 1 => "D. Hutchinson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2174/1874312901711010088" "Revista" => array:6 [ "tituloSerie" => "Open Rheumatol J" "fecha" => "2017" "volumen" => "11" "paginaInicial" => "88" "paginaFinal" => "105" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28932330" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0390" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.S. Lee" 1 => "P. Irigoyen" 2 => "M. Kern" 3 => "A. Lee" 4 => "F. Batliwalla" 5 => "H. Khalili" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.22703" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2007" "volumen" => "56" "paginaInicial" => "1745" "paginaFinal" => "1753" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17530703" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0395" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Klareskog" 1 => "A.I. Catrina" 2 => "S. Paget" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(09)60008-8" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2009" "volumen" => "373" "paginaInicial" => "659" "paginaFinal" => "672" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19157532" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0400" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The pathogenesis of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "I.B. McInnes" 1 => "G. Schett" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra1004965" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2011" "volumen" => "365" "paginaInicial" => "2205" "paginaFinal" => "2219" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22150039" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0405" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Reynisdottir" 1 => "R. Karimi" 2 => "V. Joshua" 3 => "H. Olsen" 4 => "A.H. Hensvold" 5 => "A. Harju" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.38201" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheumatol" "fecha" => "2014" "volumen" => "66" "paginaInicial" => "31" "paginaFinal" => "39" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24449573" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0410" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The complex role of the lung in the pathogenesis and clinical outcomes of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L.B. Kelmenson" 1 => "M.K. Demoruelle" 2 => "K.D. Deane" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11926-016-0618-4" "Revista" => array:5 [ "tituloSerie" => "Curr Rheumatol Rep" "fecha" => "2016" "volumen" => "18" "paginaInicial" => "69" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27796844" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0415" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis specific autoimmunity in the lung before and at the onset of disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Joshua" 1 => "M. Loberg Haarhaus" 2 => "A. Hensvold" 3 => "H. Wähämaa" 4 => "C. Gerstner" 5 => "M. Hansson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.42549" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheumatol" "fecha" => "2023" "volumen" => "75" "paginaInicial" => "1910" "paginaFinal" => "1922" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37192126" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0420" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of sputum neutrophil extracellular trap subsets with IgA anti-citrullinated protein antibodies in subjects at risk for rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Okamoto" 1 => "S. Devoe" 2 => "N. Seto" 3 => "V. Minarchick" 4 => "T. Wilson" 5 => "H.M. Rothfuss" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.41948" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheumatol" "fecha" => "2022" "volumen" => "74" "paginaInicial" => "38" "paginaFinal" => "48" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34369110" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0425" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J. Sokolove" 1 => "X. Zhao" 2 => "P.E. Chandra" 3 => "W.H. Robinson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.30081" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2011" "volumen" => "63" "paginaInicial" => "53" "paginaFinal" => "62" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20954191" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0430" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Khandpur" 1 => "C. Carmona-Rivera" 2 => "A. Vivekanandan-Giri" 3 => "A. Gizinski" 4 => "S. Yalavarthi" 5 => "J.S. Knight" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/scitranslmed.3005580" "Revista" => array:5 [ "tituloSerie" => "Sci Transl Med" "fecha" => "2013" "volumen" => "5" "paginaInicial" => "178ra40" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23536012" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0435" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thoracic manifestations of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.J. Esposito" 1 => "S.G. Chu" 2 => "R. Madan" 3 => "T.J. Doyle" 4 => "P.F. Dellaripa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ccm.2019.05.003" "Revista" => array:6 [ "tituloSerie" => "Clin Chest Med" "fecha" => "2019" "volumen" => "40" "paginaInicial" => "545" "paginaFinal" => "560" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31376890" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0440" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Spagnolo" 1 => "O. Distler" 2 => "C.J. Ryerson" 3 => "A. Tzouvelekis" 4 => "J.S. Lee" 5 => "F. Bonella" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/annrheumdis-2020-217230" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2021" "volumen" => "80" "paginaInicial" => "143" "paginaFinal" => "150" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33037004" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0445" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Hyldgaard" 1 => "O. Hilberg" 2 => "A.B. Pedersen" 3 => "S.P. Ulrichsen" 4 => "A. Løkke" 5 => "E. Bendstrup" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/annrheumdis-2017-211138" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2017" "volumen" => "76" "paginaInicial" => "1700" "paginaFinal" => "1706" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28611082" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0450" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Bongartz" 1 => "C. Nannini" 2 => "Y.F. Medina-Velasquez" 3 => "S.J. Achenbach" 4 => "C.S. Crowson" 5 => "J.H. Ryu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.27405" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2010" "volumen" => "62" "paginaInicial" => "1583" "paginaFinal" => "1591" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20155830" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0455" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C. Turesson" 1 => "W.M. O’Fallon" 2 => "C.S. Crowson" 3 => "S.E. Gabriel" 4 => "E.L. Matteson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.62.8.722" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2003" "volumen" => "62" "paginaInicial" => "722" "paginaFinal" => "727" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12860726" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0460" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Proceedings of the American College of Rheumatology/Association of Physicians of Great Britain and Ireland Connective Tissue Disease: Associated interstitial lung disease summit: a multidisciplinary approach to address challenges and opportunities" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Fischer" 1 => "M.E. Strek" 2 => "V. Cottin" 3 => "P.F. Dellaripa" 4 => "E.J. Bernstein" 5 => "K.K. Brown" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/qjmed/hcy272" "Revista" => array:6 [ "tituloSerie" => "QJM" "fecha" => "2019" "volumen" => "112" "paginaInicial" => "81" "paginaFinal" => "93" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30605544" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0465" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.J. Solomon" 1 => "J.H. Chung" 2 => "G.P. Cosgrove" 3 => "M.K. Demoruelle" 4 => "E.R. Fernandez-Perez" 5 => "A. Fischer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.00357-2015" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2016" "volumen" => "47" "paginaInicial" => "588" "paginaFinal" => "596" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26585429" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0470" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ERAS (Early Rheumatoid Arthritis Study). Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Koduri" 1 => "S. Norton" 2 => "A. Young" 3 => "N. Cox" 4 => "P. Davies" 5 => "J. Devlin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/keq035" "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2010" "volumen" => "49" "paginaInicial" => "1483" "paginaFinal" => "1489" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20223814" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0475" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.A. Juge" 1 => "J.S. Lee" 2 => "E. Ebstein" 3 => "H. Furukawa" 4 => "E. Dobrinskikh" 5 => "S. Gazal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1801562" "Revista" => array:5 [ "tituloSerie" => "N Engl J Med" "fecha" => "2018" "volumen" => "79" "paginaInicial" => "2209" "paginaFinal" => "2219" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0655" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Sokolove" 1 => "D.S. Johnson" 2 => "L.J. Lahey" 3 => "C.A. Wagner" 4 => "D. Cheng" 5 => "G.M. Thiele" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.38307" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheumatol" "fecha" => "2014" "volumen" => "66" "paginaInicial" => "813" "paginaFinal" => "821" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24757134" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0660" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulmonary complications of rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H. Farquhar" 1 => "R. Vassallo" 2 => "A.L. Edwards" 3 => "E.L. Matteson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0039-1683995" "Revista" => array:6 [ "tituloSerie" => "Semin Respir Crit Care Med" "fecha" => "2019" "volumen" => "40" "paginaInicial" => "194" "paginaFinal" => "207" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31137060" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0490" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "American Thoracic Society, European Respiratory Society Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Raghu" 1 => "M. Remy-Jardin" 2 => "J.L. Myers" 3 => "L. Richeldi" 4 => "C.J. Ryerson" 5 => "D.J. Lederer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.201807-1255ST" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2018" "volumen" => "198" "paginaInicial" => "e44" "paginaFinal" => "e68" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30168753" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0495" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R. Diesler" 1 => "V. Cottin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/17476348.2022.2089116" "Revista" => array:6 [ "tituloSerie" => "Expert Rev Respir Med" "fecha" => "2022" "volumen" => "16" "paginaInicial" => "541" "paginaFinal" => "553" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35695895" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0500" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.J. Kim" 1 => "B.M. Elicker" 2 => "F. Maldonado" 3 => "W.R. Webb" 4 => "J.H. Ryu" 5 => "J.H. Van Uden" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.00092309" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2010" "volumen" => "35" "paginaInicial" => "1322" "paginaFinal" => "1328" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19996193" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0505" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The lung in rheumatoid arthritis, cause or consequence?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Chatzidionisyou" 1 => "A.I. Catrina" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/BOR. 0000000000000238" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Rheumatol" "fecha" => "2016" "volumen" => "28" "paginaInicial" => "76" "paginaFinal" => "82" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26599384" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0510" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.P. Linn-Rasker" 1 => "A.H. van der Helm-van Mil" 2 => "F.A. van Gaalen" 3 => "M. Kloppenburg" 4 => "R.R. de Vries" 5 => "S. le Cessie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2005.041079" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2006" "volumen" => "65" "paginaInicial" => "366" "paginaFinal" => "371" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16014670" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0515" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.L. Too" 1 => "A. Yahya" 2 => "S. Murad" 3 => "J.S. Dhaliwal" 4 => "P.T. Larsson" 5 => "N.A. Muhamad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/ar3813" "Revista" => array:5 [ "tituloSerie" => "Arthritis Res Ther" "fecha" => "2012" "volumen" => "14" "paginaInicial" => "R89" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22537824" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0520" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibroblasts as immune regulators in infection, inflammation and cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Davidson" 1 => "M. Coles" 2 => "T. Thomas" 3 => "G. Kollias" 4 => "B. Ludewig" 5 => "S. Turley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41577-021-00540-z" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Immunol" "fecha" => "2021" "volumen" => "21" "paginaInicial" => "704" "paginaFinal" => "717" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33911232" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0525" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Carmona-Rivera" 1 => "P.M. Carlucci" 2 => "E. Moore" 3 => "N. Lingampalli" 4 => "H. Uchtenhagen" 5 => "E. James" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/sciimmunol.aag3358" "Revista" => array:5 [ "tituloSerie" => "Sci Immunol" "fecha" => "2017" "volumen" => "2" "paginaInicial" => "eaag3358" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28649674" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0530" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The lung microbiota in early rheumatoid arthritis and autoimmunity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.U. Scher" 1 => "V. Joshua" 2 => "A. Artacho" 3 => "S. Abdollahi-Roodsaz" 4 => "J. Öckinger" 5 => "S. Kullberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s40168-016-0206-x" "Revista" => array:5 [ "tituloSerie" => "Microbiome" "fecha" => "2016" "volumen" => "4" "paginaInicial" => "60" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27855721" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0535" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.S. Smolen" 1 => "R.B.M. Landewé" 2 => "S.A. Bergstra" 3 => "A. Kerschbaumer" 4 => "A. Sepriano" 5 => "D. Aletaha" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard-2022-223356" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2023" "volumen" => "82" "paginaInicial" => "3" "paginaFinal" => "18" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36357155" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0540" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Saevarsdottir" 1 => "S. Wedrén" 2 => "M. Seddighzadeh" 3 => "C. Bengtsson" 4 => "A. Wesley" 5 => "S. Lindblad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.27758" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2011" "volumen" => "63" "paginaInicial" => "26" "paginaFinal" => "36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20862678" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0545" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Saevarsdottir" 1 => "H. Rezaei" 2 => "P. Geborek" 3 => "I. Petersson" 4 => "S. Ernestam" 5 => "K. Albertsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.27758" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2011" "volumen" => "74" "paginaInicial" => "1509" "paginaFinal" => "1514" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24706006" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0550" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 2: Treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Narváez" 1 => "P. Díaz Del Campo Fontecha" 2 => "N. Brito García" 3 => "G. Bonilla" 4 => "M. Aburto" 5 => "I. Castellví" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.reumae.2022.03.004" "Revista" => array:6 [ "tituloSerie" => "Reumatol Clin (Engl Ed)" "fecha" => "2022" "volumen" => "18" "paginaInicial" => "501" "paginaFinal" => "512" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36064885" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0555" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis disease activity predicting incident clinically apparent rheumatoid arthritis-associated interstitial lung disease: a prospective cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.A. Sparks" 1 => "X. He" 2 => "J. Huang" 3 => "E.A. Fletcher" 4 => "A. Zaccardelli" 5 => "H.M. Friedlander" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.40904" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheumatol" "fecha" => "2019" "volumen" => "71" "paginaInicial" => "1472" "paginaFinal" => "1482" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30951251" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0560" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of rituximab in slowing down progression of rheumatoid arthritis-related interstitial lung disease: data from the NEREA Registry" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Vadillo" 1 => "M.A. Nieto" 2 => "F. Romero-Bueno" 3 => "L. Leon" 4 => "O. Sanchez-Pernaute" 5 => "Rodriguez-Nieto." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/kez673" "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2020" "volumen" => "59" "paginaInicial" => "2099" "paginaFinal" => "2108" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31990338" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0565" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.Y. Md Yosof" 1 => "A. Kabia" 2 => "M. Darby" 3 => "G. Lettieri" 4 => "P. Beirne" 5 => "E.M. Vital" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/kex072" "Revista" => array:5 [ "tituloSerie" => "Rheumatology" "fecha" => "2017" "volumen" => "56" "paginaInicial" => "348" "paginaFinal" => "357" ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0570" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis related interstitial lung disease – improving outcomes over 25 years: a large multicentre UK study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.A. Kelly" 1 => "M. Nisar" 2 => "S. Arthanari" 3 => "S. Carty" 4 => "F.A. Woodhead" 5 => "A. Price-Forbes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/keaa577" "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2021" "volumen" => "60" "paginaInicial" => "1882" "paginaFinal" => "1890" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33150434" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0575" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abatacept in patients with rheumatoid arthritis and interstitial lung disease: a national multicenter study of 63 patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Fernández-Díaz" 1 => "J. Loricera" 2 => "S. Castañeda" 3 => "R. López-Mejías" 4 => "C. Ojeda-García" 5 => "A. Olivé" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.semarthrit.2017.12.012" "Revista" => array:6 [ "tituloSerie" => "Semin Arthritis Rheum" "fecha" => "2018" "volumen" => "48" "paginaInicial" => "22" "paginaFinal" => "27" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29422324" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0580" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Fernández-Díaz" 1 => "S. Castañeda" 2 => "R.B. Melero-González" 3 => "F. Ortiz-Sanjuán" 4 => "A. Juan-Mas" 5 => "C. Carrasco-Cubero" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/keaa621" "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2020" "volumen" => "59" "paginaInicial" => "3906" "paginaFinal" => "3916" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33068439" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0585" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicentre retrospective study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Manfredi" 1 => "G. Cassone" 2 => "F. Furini" 3 => "E. Gremese" 4 => "V. Venerito" 5 => "F. Atzeni" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/imj.14670" "Revista" => array:6 [ "tituloSerie" => "Intern Med J" "fecha" => "2020" "volumen" => "50" "paginaInicial" => "1085" "paginaFinal" => "1090" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31661185" "web" => "Medline" ] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0590" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathogenesis, clinical features, and treatment strategy for rheumatoid arthritis-associated interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Akiyama" 1 => "Y. Kaneko" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2022.103056" "Revista" => array:5 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2022" "volumen" => "21" "paginaInicial" => "103056" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35121155" "web" => "Medline" ] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0595" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of nintedanib in patients with progressive pulmonary fibrosis associated with rheumatoid arthritis: data from the INBUILD trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E.L. Matteson" 1 => "M. Aringer" 2 => "G.R. Burmester" 3 => "H. Mueller" 4 => "L. Moros" 5 => "M. Kolb" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10067-023-06623-7" "Revista" => array:6 [ "tituloSerie" => "Clin Rheumatol" "fecha" => "2023" "volumen" => "42" "paginaInicial" => "2311" "paginaFinal" => "2319" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37209188" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0600" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "INBUILD trial investigators nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.U. Wells" 1 => "K.R. Flaherty" 2 => "K.K. Brown" 3 => "Y. Inoue" 4 => "A. Devaraj" 5 => "L. Richeldi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-2600(20)30036-9" "Revista" => array:6 [ "tituloSerie" => "Lancet Respir Med" "fecha" => "2020" "volumen" => "8" "paginaInicial" => "453" "paginaFinal" => "460" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32145830" "web" => "Medline" ] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0605" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of antifibrotics in the treatment of rheumatoid arthritis-associated interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Liang" 1 => "E.L. Matteson" 2 => "A. Abril" 3 => "J.H.W. Distler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1759720X221074457" "Revista" => array:3 [ "tituloSerie" => "Ther Adv Musculoskelet Dis" "fecha" => "2022" "volumen" => "14" ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0610" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.F. Redente" 1 => "M.A. Aguilar" 2 => "B.P. Black" 3 => "B.L. Edelman" 4 => "A.N. Bahadur" 5 => "S.M. Humphries" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajplung.00304.2017" "Revista" => array:6 [ "tituloSerie" => "Am J Physiol Lung Cell Mol Physiol" "fecha" => "2018" "volumen" => "314" "paginaInicial" => "L998" "paginaFinal" => "L1009" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29543042" "web" => "Medline" ] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0615" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Y. Miura" 1 => "H. Ohkubo" 2 => "A. Niimi" 3 => "S. Kanazawa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/23120541.00345-2021" "Revista" => array:3 [ "tituloSerie" => "ERJ Open Res" "fecha" => "2021" "volumen" => "7" ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0620" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate and rheumatoid arthritis associated interstitial lung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.A. Juge" 1 => "J.S. Lee" 2 => "J. Lau" 3 => "L. Kawano-Dourado" 4 => "J. Rojas Serrano" 5 => "M. Sebastiani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.00337-2020" "Revista" => array:5 [ "tituloSerie" => "Eur Respir J" "fecha" => "2021" "volumen" => "57" "paginaInicial" => "2000337" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32646919" "web" => "Medline" ] ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0625" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the severity of lung disease are associated to prognosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. Rojas-Serrano" 1 => "D. Herrera-Bringas" 2 => "D.I. Pérez-Román" 3 => "R. Pérez-Dorame" 4 => "H. Mateos-Toledo" 5 => "M. Mejía" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10067-017-3707-5" "Revista" => array:6 [ "tituloSerie" => "Clin Rheumatol" "fecha" => "2017" "volumen" => "36" "paginaInicial" => "1493" "paginaFinal" => "1500" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28585060" "web" => "Medline" ] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0630" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The case of methotrexate and the lung: Dr Jekyll and Mr Hyde" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Cottin" 1 => "E. Bendstrup" 2 => "P. Bonniaud" 3 => "M. Nasser" 4 => "P. Spagnolo" 5 => "C. Valenzuela" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/13993003.00079-2021" "Revista" => array:5 [ "tituloSerie" => "Eur Respir J" "fecha" => "2021" "volumen" => "57" "paginaInicial" => "2100079" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33574052" "web" => "Medline" ] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0635" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: clinical features and prognosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Izuka" 1 => "H. Yamashita" 2 => "A. Iba" 3 => "Y. Takahashi" 4 => "H. Kaneko" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/keaa608" "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2021" "volumen" => "60" "paginaInicial" => "2348" "paginaFinal" => "2354" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33241299" "web" => "Medline" ] ] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0640" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Applicability of small-molecule inhibitors in the study of peptidyl arginine deiminase 2 (PAD2) and PAD4" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.T. Martín Monreal" 1 => "A.S. Rebak" 2 => "L. Massarenti" 3 => "S. Mondal" 4 => "L. Šenolt" 5 => "N. Ødum" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2021.716250" "Revista" => array:5 [ "tituloSerie" => "Front Immunol" "fecha" => "2021" "volumen" => "12" "paginaInicial" => "716250" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34737738" "web" => "Medline" ] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0645" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CD19-targeted CAR T cells in refractory antisynthetase syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Müller" 1 => "S. Boeltz" 2 => "J. Knitza" 3 => "M. Aigner" 4 => "S. Völkl" 5 => "S. Kharboutli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(23)00023-5" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2023" "volumen" => "401" "paginaInicial" => "815" "paginaFinal" => "818" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36930673" "web" => "Medline" ] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0650" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CD19-targeting CAR T-cell therapy for antisynthetase syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I.E. Lundberg" 1 => "A.S. Galindo-Feria" 2 => "B. Horuluoglu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2023.7240" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2023" "volumen" => "329" "paginaInicial" => "2130" "paginaFinal" => "2131" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37367988" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/01218123/00000031000000S1/v5_202405200140/S0121812323000889/v5_202405200140/en/main.assets" "Apartado" => array:4 [ "identificador" => "95645" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/01218123/00000031000000S1/v5_202405200140/S0121812323000889/v5_202405200140/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0121812323000889?idApp=UINPBA00004N"]

Statistics

Review Article

El pulmón como diana y como iniciador de la inmunidad asociada a la artritis reumatoide; implicaciones para la enfermedad pulmonar intersticial

Malena Loberg Haarhaus, Lars Klareskog

Corresponding author

lars.klareskog@ki.se

Corresponding author.

Rheumatology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Read

131

Times
was read the article

Total PDF

Total HTML

Share statistics

 array:22 [
  "pii" => "S0121812323000889"
  "issn" => "01218123"
  "doi" => "10.1016/j.rcreu.2023.09.006"
  "estado" => "S300"
  "fechaPublicacion" => "2024-04-01"
  "aid" => "2084"
  "copyrightAnyo" => "2023"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "rev"
  "cita" => "Rev Colomb Reumatol. 2024;31 Supl 1:S74-S81"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:18 [
    "pii" => "S0121812323000877"
    "issn" => "01218123"
    "doi" => "10.1016/j.rcreu.2023.09.007"
    "estado" => "S300"
    "fechaPublicacion" => "2024-04-01"
    "aid" => "2085"
    "copyright" => "Asociaci&#243;n Colombiana de Reumatolog&#237;a"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "rev"
    "cita" => "Rev Colomb Reumatol. 2024;31 Supl 1:S82-S93"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Review Article</span>"
      "titulo" => "Progressive pulmonary fibrosis associated autoimmune diseases&#58; Systematic review of the literature"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "S82"
          "paginaFinal" => "S93"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Fibrosis pulmonar progresiva asociada a enfermedad autoinmune&#58; revisi&#243;n sistem&#225;tica de la literatura"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0015"
          "etiqueta" => "Fig&#46; 3"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr3.jpeg"
              "Alto" => 1129
              "Ancho" => 3000
              "Tamanyo" => 170183
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Mortality risk of PPF-ILD across studies&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Luis Javier Cajas Santana, Diana Roc&#237;o Gil Calder&#243;n, Manuela Rubio Rivera, Jos&#233; Alex Yate, Javier Leonardo Galindo"
          "autores" => array:5 [
            0 => array:2 [
              "nombre" => "Luis Javier"
              "apellidos" => "Cajas Santana"
            ]
            1 => array:2 [
              "nombre" => "Diana Roc&#237;o"
              "apellidos" => "Gil Calder&#243;n"
            ]
            2 => array:2 [
              "nombre" => "Manuela"
              "apellidos" => "Rubio Rivera"
            ]
            3 => array:2 [
              "nombre" => "Jos&#233;"
              "apellidos" => "Alex Yate"
            ]
            4 => array:2 [
              "nombre" => "Javier"
              "apellidos" => "Leonardo Galindo"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0121812323000877?idApp=UINPBA00004N"
    "url" => "/01218123/00000031000000S1/v5_202405200140/S0121812323000877/v5_202405200140/en/main.assets"
  ]
  "itemAnterior" => array:18 [
    "pii" => "S0121812323000816"
    "issn" => "01218123"
    "doi" => "10.1016/j.rcreu.2023.08.005"
    "estado" => "S300"
    "fechaPublicacion" => "2024-04-01"
    "aid" => "2078"
    "copyright" => "Asociaci&#243;n Colombiana de Reumatolog&#237;a"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "rev"
    "cita" => "Rev Colomb Reumatol. 2024;31 Supl 1:S67-S73"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>"
      "titulo" => "Measurement of health-related quality of life in patients with interstitial lung disease and autoimmune diseases"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "S67"
          "paginaFinal" => "S73"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Medici&#243;n de calidad de vida relacionada con la salud en pacientes con enfermedad pulmonar intersticial y enfermedades autoinmunes"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Claudia Mora, Alirio Rodrigo Bastidas Goyes, Lina Paola Fajardo Muriel, Cristian Felipe Rodr&#237;guez Yasno"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "Claudia"
              "apellidos" => "Mora"
            ]
            1 => array:2 [
              "nombre" => "Alirio Rodrigo"
              "apellidos" => "Bastidas Goyes"
            ]
            2 => array:2 [
              "nombre" => "Lina Paola"
              "apellidos" => "Fajardo Muriel"
            ]
            3 => array:2 [
              "nombre" => "Cristian Felipe"
              "apellidos" => "Rodr&#237;guez Yasno"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0121812323000816?idApp=UINPBA00004N"
    "url" => "/01218123/00000031000000S1/v5_202405200140/S0121812323000816/v5_202405200140/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Review Article</span>"
    "titulo" => "The lung as a target and as an initiator of rheumatoid arthritis-associated immunity&#58; Implications for interstitial lung disease"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "S74"
        "paginaFinal" => "S81"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Malena Loberg Haarhaus, Lars Klareskog"
        "autores" => array:2 [
          0 => array:2 [
            "nombre" => "Malena Loberg"
            "apellidos" => "Haarhaus"
          ]
          1 => array:4 [
            "nombre" => "Lars"
            "apellidos" => "Klareskog"
            "email" => array:1 [
              0 => "lars.klareskog@ki.se"
            ]
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:2 [
            "entidad" => "Rheumatology Division&#44; Department of Medicine&#44; Karolinska Institutet&#44; Stockholm&#44; Sweden"
            "identificador" => "aff0005"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "El pulm&#243;n como diana y como iniciador de la inmunidad asociada a la artritis reumatoide&#59; implicaciones para la enfermedad pulmonar intersticial"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 971
            "Ancho" => 2515
            "Tamanyo" => 169434
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The figure illustrates the bi-directional interplay between immune and inflammatory events in the lungs and the longitudinal evolution of seropositive RA&#46; Immunity triggered in the lungs is assumed to contribute to the development of seropositive RA and inflammation in RA is assumed to contribute to inflammation and fibrosis in the lungs&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Lungs are essential immune organs where immune defense against the many hostile agents in the environment are handled&#44; i&#46;e&#46; microbes as well as many hazardous environmental agents&#46; Lungs are also the place in the body where environment meets immune system without other protective layers or environments such as the epidermis in the skin or the acidity in the stomach&#46; The lungs are therefore vulnerable for many types of immune-dependent events&#44; both concerning too limited immunity resulting in bacterial or viral airway infections or concerning too vigorous immune responses resulting in autoimmune disease&#46; Research over recent years has demonstrated that the lungs are not only organs where immunity may result in local pulmonary inflammation and subsequent fibrosis but may also be sites where immunity is triggered that results in autoimmune disease elsewhere&#46; A prime example of this is rheumatoid arthritis<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1&#44;2</span></a> which will be further discussed in this review&#44; but similar relationships have been demonstrated for multiple sclerosis<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">3</span></a> and certain variants of myositis&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In order to understand&#44; prevent&#44; and treat pulmonary inflammation as potential trigger of systemic inflammatory disease and pulmonary fibrosis as a co-morbidity to other inflammatory diseases such as RA&#44; there is thus a need to understand the functional relationships between immunity in the lungs and immune-mediated disease affecting other organs such as the joints&#46; This will be the perspective in this review&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Lung-associated morbidity and mortality in RA&#58; take-homes from epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Lung complications&#44; i&#46;e&#46; mainly interstitial pulmonary fibrosis resulting from chronic inflammation in lungs&#44; are major reasons for increased mortality and long-term morbidity in RA&#44; and in contrast to other co-morbidities such as infections and cardiovascular disease&#44; the frequency of pulmonary complications have remained high in RA&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">5&#44;6</span></a> Similar to other extra-articular manifestations of RA&#44; lung complications and interstitial pulmonary fibrosis are most common in RA patients who are positive for antibodies to citrullinated protein antigens &#40;ACPA&#41; and&#47;or rheumatoid factors &#40;RF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">7&#44;8</span></a> These observations indicate that we should search at least part of the explanation to the occurrence of long-term lung inflammation and interstitial pulmonary fibrosis in factors that trigger the production of these antibodies and are involved in their effector mechanisms&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Epidemiological studies on risk factors for development of RA have demonstrated that exposure of airways to noxious agents such as smoke&#44; silica dust&#44; and several other occupational airways are the major environmental risk factors for RA&#44; and that these risk factors are mainly restricted to the ACPA and&#47;or RF positive subset of disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">9&#8211;13</span></a> Major gene&#8211;environment interactions were also demonstrated between these airway exposures and presence of the major genetic risk factors for RA&#44; i&#46;e&#46; certain alleles within the MHC class II&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1&#44;11&#44;13</span></a> Taken together&#44; these data suggested that lungs might be sites where these immune reactions are triggered in a MHC class II restricted way&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">14&#44;15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The lung as a site for triggering of RA-associated immunity</span><p id="par0025" class="elsevierStylePara elsevierViewall">Several molecular and cellular studies have further supported that immunity to citrullinated antigens might be triggered in the lungs and that such triggering may occur before onset of clinically defined arthritis&#46; Such evidence comes from the demonstration of higher levels of ACPA in BAL fluids as compared to serum suggesting local production of the antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">16</span></a> Similar results have come from sputum analysis if taken already before onset of arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">17</span></a> A recent addition to these data&#44; giving further evidence for the contribution of T cell-driven antibody production was the finding of ACPA-producing B cells&#47;plasma cells obtained from bronchoalveolar lavage obtained both at early stages of RA and from ACPA-positive individuals at high risk for RA&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> Notably&#44; the Ig genes coding for these antibodies and derived from single ACPA-producing B cells&#47;plasma cells were highly somatically mutated indicating local T cell help&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">18</span></a> These and other cellular and molecular studies have substantiated the concept of a mucosal origin of at least part of the RA-associated autoantibodies and most probably also of the seropositive RA itself<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1&#44;2&#44;14&#44;15</span></a>&#59; the concept has sometimes been denoted the &#8220;mucosal hypothesis&#8221; for an origin of seropositive RA&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Inflammation in lungs as a consequence of RA-associated immunity</span><p id="par0030" class="elsevierStylePara elsevierViewall">An obvious question is whether the lung immune systems is not only involved in triggering of RA-associated immunity but whether the same immunity is also involved in effector functions&#44; i&#46;e&#46; contributing to pulmonary inflammation and subsequent fibrosis&#46; Some evidence supports such a scenario&#58; one is observations from HRCT investigations of lungs at early diagnosis of RA&#44; where signs of inflammation were observed in the ACPA&#47;RF positive subset of the disease as compared to control and ACPA&#47;RF negative RA&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">16</span></a> Additional studies have demonstrated the presence of certain lung abnormalities in ACPA and&#47;or RF positive individuals already before onset of clinically diagnosed RA&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">19</span></a> It is still not clear&#44; however&#44; how ACPA and RF and associated T cell immunity can activate pro-inflammatory events&#46; Thus&#44; some in vitro studies have demonstrated that ACPA may be involved both in activation of macrophages in a Fc receptor and often immune complex mediated way&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">20</span></a> Pro-inflammatory in vitro effects of ACPA have also been demonstrated in neutrophil assays where some ACPA may recognized activated neutrophils and contribute to pro-inflammatory effects of NET-osis&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">21</span></a> To which extent such immune-mediated effects from ACPA&#47;RF contribute to the long- term inflammation and fibrosis is so far less known&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Long-term effects of lung inflammation in RA&#58; development of interstitial lung disease</span><p id="par0035" class="elsevierStylePara elsevierViewall">As stated in the introduction&#44; chronic inflammation and subsequent fibrosis constitute major reasons for long-term morbidity and also mortality in RA&#44; and lung involvement can be found in as many as 70&#37; of RA patients&#44; where RA interstitial lung disease &#40;ILD&#41; is the most common finding&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Approximately 2&#8211;10&#37; of RA patients will develop symptomatic RA ILD during the course of the disease as seen in cohort-based studies and as many as 20&#37; will develop asymptomatic disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">23&#8211;27</span></a> The median survival in patients with RA ILD ranges between 3 and 10 years in historic cohorts&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">25&#44;28&#44;29</span></a> RA ILD is strongly related to the presence of relatively well characterized risk factors&#46; Such risk factors contributing to interstitial lung fibrosis in RA are presence of ACPA and&#47;or RF&#44; and exposure to noxious airways agent&#44; and inflammatory activity over time&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">23</span></a> The genetic risk factor most distinctly related to the fibrotic phenotype in RA ILD is an allelic form of the mucoprotein MUC5B&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">30</span></a> This protein is secreted by submucosal mucinous gland cells and is involved in mucosal ciliary function and may also be involved in the regulation of local immune responses and alveolar regeneration following injury&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">23</span></a> Genetics&#44; in particular the RA-associated MHC class II alleles also contribute&#44; mainly related to presence of ACPA&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">1&#44;31</span></a> Additional risk factors are long-standing disease and long-term inflammatory load as well as age and male gender&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">32</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The subtype of ILD most common in RA is the &#8220;Usual Interstitial Pneumonia&#8221; &#40;UIP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">32</span></a> The histopathological and radiological pattern of UIP is similar to findings in idiopathic pulmonary fibrosis &#40;IPF&#41; which is characterized by a progressive fibrosis of the lungs and is also associated with the highest mortality as compared to other ILD subtypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">32&#44;33</span></a> On imaging&#44; typical features of UIP include basal predominant reticular opacities&#44; traction bronchiectasis&#44; and honeycombing&#46; Non-specific interstitial pneumonia &#40;NSIP&#41; is the second most common HRCT pattern characterized by ground glass opacities without honeycombing&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">34</span></a> The distinct disease phenotypes of RA ILD impact differently on clinical outcomes&#46; When comparing patients with IPF to patients with RA ILD&#44; Kim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">35</span></a> described a median survival of 3&#46;2 years in RA ILD with UIP pattern&#44; which was similar to those with IPF and significantly shorter than the median survival of 6&#46;6 years in patients without UIP pattern &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Mechanisms that are involved in the mediation of lung fibrosis from the presence of the described risk factors&#44; are not yet well understood&#46; Descriptive studies have shown increase of macrophage and fibroblast activation as well as increased presence of B and T cells at sites of chronic pulmonary inflammation and fibrosis in RA as compared to ILD in individuals without RA&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">23</span></a> and it appears that fibrosis development occurs as a result of inflammation that may involve all these cells&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">35</span></a> Notably&#44; noxious agents like smoking being risk factors for RA as well as RA-ILD are able to cause increased production and activation of enzymes&#44; peptidyl-arginine deiminases &#40;PADs&#41; that cause citrullination&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">36</span></a> Citrullinated molecules in the lungs may then be involved both in triggering autoimmunity towards these post-translationally modified molecules in the context of certain genotypes<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">36&#8211;38</span></a> but may also directly be involved in activation of macrophages<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">20</span></a> and neutrophils via binding to pattern recognition molecules such as toll-like receptors&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">21</span></a> often in immune-complex-dependent contexts &#8211; thereby potentially explaining an additive role of rheumatoid factors in addition to the ACPAs&#46; Whether presence of ACPA and&#47;or RF have independent effects on fibrosis development in addition to having effects on inflammation and macrophage activation is presently now known&#46; It is feasible&#44; however&#44; that specific interactions may occur between T cells and fibroblasts in the lung tissue similar to what has recently been described for these cells in the synovial tissue in RA&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">39</span></a> It is also possible that ACPA and ACPA-containing immune complexes are involved in the activation of neutrophils and subsequent NETosis&#44; which may also be directly involved in activation and proliferation of fibroblasts and subsequent fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">40</span></a> The overall conclusion from what is specifically known about inflammation and fibrosis in the lung of RA patients&#44; suggest that largely similar risk factors and mechanism as for seropositive RA are involved in the pathogenesis of RA ILD&#46; Nevertheless&#44; the relationship between development of RA-ILD and inflammation in RA is far from linear&#44; and thus additional lung-specific mechanisms should therefore be possible to identify&#46; Pathways associated with mutations in MUC5B represent one such option to follow&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">30</span></a> Investigations of the lung microbiome&#44; which is different in RA patients as compared to otherwise healthy individuals<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">41</span></a> indicate that that better understanding of the interplay between lung microbiome and lung inflammation and fibrosis may be another way forward&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Options for prevention and treatment of pulmonary morbidity in RA</span><p id="par0050" class="elsevierStylePara elsevierViewall">As the major known risk factors and pathways involved in the development of RA-ILD are the same as those involved in the development and perpetuation of seropositive RA&#44; the same options for prevention and treatment that exists for RA should be used to prevent and treat RA ILD&#46; As extensively reviewed and discussed elsewhere&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">42</span></a> such options involve very early diagnosis&#44; rapid reduction of inflammation with appropriate pharmaceuticals as well as targeting of modifiable lifestyle and environmental factors&#44; in particular those that include airway noxious substances&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">10</span></a> The most important of these options remain smoking cessation&#44; which has been shown to reduce risk for RA&#44; reduce inflammation in ongoing RA and improve effects of anti-rheumatic treatments&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">43&#44;44</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The importance of detecting RA ILD in an early stage cannot be stressed enough due to its large impact on mortality and morbidity&#46; A clinical obstacle is that most patients are asymptomatic and the prevalence of RA ILD is relatively low compared to ILD in other connective tissue diseases such as systemic sclerosis &#40;SSc&#41;&#46; HRCT is the preferred imaging technique for the diagnosis of ILD and in all patients with SSc&#44; HRCT is used as the screening method according to guidelines for SSc ILD&#46; In RA it is not justifiable to screen all patients with HRCT since most patients will show no signs of ILD&#46; International guidelines for screening and monitoring RA ILD are lacking&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">27</span></a> One group has recently suggested a screening algorithm that involves lung auscultation&#44; history of respiratory symptoms and assessment of risk factors for ILD&#46; They have also suggested a risk score to better identify the patients that benefit from HRCT&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">45</span></a> Another group has suggested a slightly different algorithm for screening for RA ILD&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">22</span></a> Further clinical studies are needed and ongoing for justification of these and other algorithms and risk scores&#46; Ideally&#44; the management of RA ILD should involve multidisciplinary collaboration&#44; including rheumatologists&#44; pulmonologists&#44; radiologists&#44; and pathologists&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">25&#44;33</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Prevention of RA-ILD should be considered already from the diagnosis of RA and involve careful monitoring of risk factors for RA ILD and efforts to reduce modifiable risk factors&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">RA disease activity has been associated with an increased risk of developing RA-ILD<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">25&#44;29&#44;46</span></a> and therapies targeting RA can thus potentially reduce the risk to develop RA ILD&#46; Post hoc analyses of existing trials and observational studies have demonstrated mixed results&#46; Rituximab was associated with improved lung function<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">47</span></a> and better survival in RA ILD patients than other DMARDs&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">48&#44;49</span></a> Promising results have also been shown for Abatacept with respect to improvement of lung function in RA ILD&#44;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">50</span></a> but a large registry study could only demonstrate stabilization of lung function&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">51</span></a> Tocilizumab showed no progression of ILD in three-fourth of the RA ILD cases in a small retrospective study but demonstrated a good safety profile&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">52</span></a> TNF-inhibitors may even have a negative effect on RA ILD&#44; however&#44; this is still a matter of debate&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">53</span></a> Evidence from randomized controlled trials targeting RA ILD is still lacking&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Recent progress in reducing fibrosis development in individuals with existing ILD has provided a completely novel way to reduced morbidity in ILD&#44;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">54&#44;55</span></a> and this is described elsewhere in this theme issue of inflammatory diseases and ILD&#46; The INBUILD study included patients with progressive fibrosing ILD and compared tyrosine kinase inhibitor nintedanib with placebo&#46; In a subgroup analysis of 170 patients with connective tissue disease&#44; 89 patients had RA ILD&#46; There was a reduction in the rate of decline in FVC over 52 weeks by 60&#37; in the RA ILD subgroup which were similar results as seen in the overall population&#46; There was no difference in the RA ILD subgroup in patients who were or were not taking DMARDs or glucocorticoids in the nintedanib or placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">56</span></a> In an animal model of RA ILD&#44; nintedanib was demonstrated to reduce pulmonary collagen levels while reducing arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">57</span></a> Another possible mechanism of action is the suppression of M2 macrophage polarization and hyperplasia of Type 2 alveolar epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">58</span></a> One notable progress of large importance for everyday clinical practice in RA treatment is that methotrexate&#44; the anchor drug in RA treatment is not associated with increased risk or worse prognosis of ILD&#44; contrary to some earlier assumptions&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">59&#8211;61</span></a> In fact&#44; use of methotrexate was associated with improved survival in patients with acute exacerbation of RA ILD&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">62</span></a> Thus&#44; methotrexate remains the anchor drug for reduction of inflammation also in individuals at increased risk of ILD&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Options for the future are plentiful and involve both improved and earlier use of therapies used for RA today and more specific options&#44; for example inhibition of PAD enzyme activity that has shown promise in experimental animal models&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">63</span></a> Also enhanced B cell depletion&#44; for example with CAR T cell therapy that has shown remarkable effects also on pulmonary symptoms in case reports of myositis with severe ILD<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">64&#44;65</span></a> may be an option for patients with severe and treatment-resistant RA-ILD already today&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Funding</span><p id="par0080" class="elsevierStylePara elsevierViewall">The work from our research unit that is described in this review was supported by grants from the <span class="elsevierStyleGrantSponsor" id="gs1">Swedish Research Council</span> and from the <span class="elsevierStyleGrantSponsor" id="gs2">Knut and Alice Wallenberg Foundation</span> to late professor Anca Catrina who initiated several of the investigations of RA&#44; lungs and ILD at Karolinska and elsewhere&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:13 [
        0 => array:3 [
          "identificador" => "xres2149721"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0005"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1824879"
          "titulo" => "Keywords"
        ]
        2 => array:3 [
          "identificador" => "xres2149722"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec1824880"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Lung-associated morbidity and mortality in RA&#58; take-homes from epidemiology"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "The lung as a site for triggering of RA-associated immunity"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Inflammation in lungs as a consequence of RA-associated immunity"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Long-term effects of lung inflammation in RA&#58; development of interstitial lung disease"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Options for prevention and treatment of pulmonary morbidity in RA"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Funding"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conflict of interest"
        ]
        12 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-08-23"
    "fechaAceptado" => "2023-09-13"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1824879"
          "palabras" => array:4 [
            0 => "Rheumatoid arthritis"
            1 => "Interstitial lung disease"
            2 => "Interstitial pulmonary fibrosis"
            3 => "Pathogenesis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1824880"
          "palabras" => array:4 [
            0 => "Artritis reumatoide"
            1 => "Enfermedad pulmonar intersticial"
            2 => "Fibrosis pulmonar intersticial"
            3 => "Patog&#233;nesis"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Interstitial lung disease &#40;ILD&#41; is a serious extra-articular co-morbidity in rheumatoid arthritis &#40;RA&#41; patients and accounts for a substantial part of the increased mortality in RA&#46; In this review&#44; we describe how environmental and lifestyle factors interact with genetic variants in the HLA genetic locus in triggering RA-specific antibodies against post-translationally modified&#44; mainly citrullinated proteins &#40;ACPA&#41;&#44; which are associated with an increased risk of ILD&#46; The same environmental risk factors&#44; i&#46;e&#46; exposure to noxious agents such as smoke to the lungs contribute additionally to the emergence of RA ILD as does long-lasting high disease activity and an additional ILD-specific genetic risk variant related to mucus formation &#40;MUC5B&#41;&#46; Options for prevention and therapy of RA ILD resulting from this so far incomplete knowledge of its pathophysiology are expanding&#46; The most obvious option is to address modifiable environmental risk factors&#44; such as smoking and exposure to other noxious agents affecting the lungs&#46; The second option is to reduce the inflammatory activity of RA&#59; here different anti-rheumatic therapies appear to have differential effects on ILD development&#46; The third and novel option is to use anti-fibrotic therapy which may reduce the development of RA ILD but has not yet been shown to revert existing fibrosis&#46; The main conclusion concerning the clinical handling of RA ILD is therefore an early awareness of the risk for RA ILD combined with active measures to reduce modifiable environmental&#47;lifestyle factors and use optimal anti-rheumatic therapies for early and sustained reduction of disease activity&#46; These actions should be combined with a preparedness to use anti-fibrotic therapy for patients at high risk for ILD despite previous risk reduction efforts&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad pulmonar intersticial &#40;EPI&#41; es una comorbilidad extraarticular grave en pacientes con artritis reumatoide y representa una parte sustancial del aumento de la mortalidad en esta &#250;ltima&#46; En esta revisi&#243;n describimos c&#243;mo los factores ambientales y de estilo de vida interact&#250;an con variantes gen&#233;ticas en el locus gen&#233;tico HLA para desencadenar anticuerpos espec&#237;ficos de AR contra prote&#237;nas&#44; principalmente citrulinadas&#44; modificadas de forma postraduccional &#40;Ac anti-PCC&#41;&#44; que est&#225;n asociadas con un mayor riesgo de EPI&#46; Los mismos factores de riesgo ambientales&#44; es decir&#44; la exposici&#243;n a agentes nocivos como el humo en los pulmones&#44; contribuyen adicionalmente a la aparici&#243;n de EPI con AR&#44; al igual que la alta actividad prolongada de la enfermedad y una variante de riesgo gen&#233;tico adicional espec&#237;fica de la EPI relacionada con la formaci&#243;n de mucoso &#40;MUC5B&#41;&#46; Las opciones para la prevenci&#243;n y el tratamiento de la EPI con AR resultantes de este conocimiento hasta ahora incompleto de su fisiopatolog&#237;a se est&#225;n ampliando&#58; la opci&#243;n m&#225;s obvia es abordar los factores de riesgo ambientales modificables&#44; como el tabaquismo y la exposici&#243;n a otros agentes nocivos que afectan los pulmones&#46; La segunda opci&#243;n es reducir la actividad inflamatoria de la AR&#59; aqu&#237; las diferentes terapias antirreum&#225;ticas parecen tener efectos diferenciales en el desarrollo de la EPI&#46; La tercera y novedosa opci&#243;n es utilizar una terapia antifibr&#243;tica que puede reducir el desarrollo de EPI con AR&#44; pero a&#250;n no se ha demostrado que revierta la fibrosis existente&#46; La conclusi&#243;n principal sobre el manejo cl&#237;nico de la EPI con AR es&#44; en consecuencia&#44; una conciencia temprana del riesgo de EPI con AR&#44; combinada con medidas activas para reducir los factores ambientales y de estilo de vida modificables y utilizar terapias antirreum&#225;ticas &#243;ptimas para una reducci&#243;n temprana y sostenida de la actividad de la enfermedad&#46; Estas acciones deben combinarse con una preparaci&#243;n para usar la terapia antifibr&#243;tica en pacientes con alto riesgo de EPI&#44; a pesar de los esfuerzos previos de reducci&#243;n del riesgo&#46;</p></span>"
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0195" class="elsevierStylePara elsevierViewall">The following are the supplementary material to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary material"
            "identificador" => "sec0085"
          ]
        ]
      ]
    ]
    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 971
            "Ancho" => 2515
            "Tamanyo" => 169434
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The figure illustrates the bi-directional interplay between immune and inflammatory events in the lungs and the longitudinal evolution of seropositive RA&#46; Immunity triggered in the lungs is assumed to contribute to the development of seropositive RA and inflammation in RA is assumed to contribute to inflammation and fibrosis in the lungs&#46;</p>"
        ]
      ]
      1 => array:5 [
        "identificador" => "upi0005"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.pdf"
          "ficheroTamanyo" => 227216
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:65 [
            0 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A new model for an etiology of rheumatoid arthritis&#58; smoking may trigger HLA-DR &#40;shared epitope&#41;-restricted immune reactions to autoantigens modified by citrullination"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Klareskog"
                            1 => "P&#46; Stolt"
                            2 => "K&#46; Lundberg"
                            3 => "H&#46; K&#228;llberg"
                            4 => "C&#46; Bengtsson"
                            5 => "J&#46; Grunewald"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.215752"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2006"
                        "volumen" => "54"
                        "paginaInicial" => "38"
                        "paginaFinal" => "46"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16385494"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis and the mucosal origins hypothesis&#58; protection turns to destruction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "V&#46;M&#46; Holers"
                            1 => "M&#46;K&#46; Demoruelle"
                            2 => "K&#46;A&#46; Kuhn"
                            3 => "J&#46;H&#46; Buckner"
                            4 => "W&#46;H&#46; Robinson"
                            5 => "Y&#46; Okamoto"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41584-018-0070-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol"
                        "fecha" => "2018"
                        "volumen" => "14"
                        "paginaInicial" => "542"
                        "paginaFinal" => "557"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30111803"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interactions between genetic&#44; lifestyle and environmental risk factors for multiple sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "T&#46; Olsson"
                            1 => "L&#46;F&#46; Barcellos"
                            2 => "L&#46; Alfredsson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrneurol.2016.187"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Neurol"
                        "fecha" => "2017"
                        "volumen" => "13"
                        "paginaInicial" => "25"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27934854"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interaction of HLA-DRB1&#42;03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies&#58; a European-wide case study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Chinoy"
                            1 => "S&#46; Adimulam"
                            2 => "F&#46; Marriage"
                            3 => "P&#46; New"
                            4 => "M&#46; Vincze"
                            5 => "E&#46; Zilahi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/annrheumdis-2011-200182"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2012"
                        "volumen" => "71"
                        "paginaInicial" => "961"
                        "paginaFinal" => "965"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22186711"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Factors associated with interstitial lung disease in patients with rheumatoid arthritis&#58; a systematic review and meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46; Zhang"
                            1 => "J&#46; Yin"
                            2 => "X&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0286191"
                      "Revista" => array:5 [
                        "tituloSerie" => "PLoS One"
                        "fecha" => "2023"
                        "volumen" => "18"
                        "paginaInicial" => "e0286191"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37352174"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Survival of adults with rheumatoid arthritis associated interstitial lung disease &#8211; a systematic review and meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;J&#46; Farquhar"
                            1 => "N&#46; Beckert"
                            2 => "L&#46; Beckert"
                            3 => "A&#46;L&#46; Edwards"
                            4 => "E&#46;L&#46; Matteson"
                            5 => "C&#46; Frampton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.semarthrit.2023.152187"
                      "Revista" => array:5 [
                        "tituloSerie" => "Semin Arthritis Rheum"
                        "fecha" => "2023"
                        "volumen" => "60"
                        "paginaInicial" => "152187"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36933302"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease&#58; a nested case&#8211;control study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46;L&#46; Kronzer"
                            1 => "K&#46; Hayashi"
                            2 => "K&#46; Yoshida"
                            3 => "J&#46;M&#46;3rd&#46; Davis"
                            4 => "G&#46;C&#46; McDermott"
                            5 => "W&#46; Huang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s2665-9913(22)00380-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Rheumatol"
                        "fecha" => "2023"
                        "volumen" => "5"
                        "paginaInicial" => "e77"
                        "paginaFinal" => "e87"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36874209"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms of lung disease development in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "D&#46; Wang"
                            1 => "J&#46; Zhang"
                            2 => "J&#46; Lau"
                            3 => "S&#46; Wang"
                            4 => "V&#46; Taneja"
                            5 => "E&#46;L&#46; Matteson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41584-019-0275-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol"
                        "fecha" => "2019"
                        "volumen" => "15"
                        "paginaInicial" => "581"
                        "paginaFinal" => "596"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31455869"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smoking is a major preventable risk factor for rheumatoid arthritis&#58; estimations of risks after various exposures to cigarette smoke"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "H&#46; K&#228;llberg"
                            1 => "B&#46; Ding"
                            2 => "L&#46; Padyukov"
                            3 => "C&#46; Bengtsson"
                            4 => "J&#46; R&#246;nnelid"
                            5 => "L&#46; Klareskog"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2009.120899"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2011"
                        "volumen" => "70"
                        "paginaInicial" => "508"
                        "paginaFinal" => "511"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21149499"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The importance of differences&#58; on environment and its interactions with genes and immunity in the causation of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "L&#46; Klareskog"
                            1 => "J&#46; R&#246;nnelid"
                            2 => "S&#46; Saevarsdottir"
                            3 => "L&#46; Padyukov"
                            4 => "L&#46; Alfredsson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/joim.13058"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Intern Med"
                        "fecha" => "2020"
                        "volumen" => "287"
                        "paginaInicial" => "514"
                        "paginaFinal" => "533"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32176395"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Occupational inhalable agents constitute major risk factors for rheumatoid arthritis&#44; particularly in the context of genetic predisposition and smoking"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Tang"
                            1 => "Q&#46; Liu"
                            2 => "A&#46; Ilar"
                            3 => "P&#46; Wiebert"
                            4 => "S&#46; H&#228;gg"
                            5 => "L&#46; Padyukov"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard-2022-223134"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2023"
                        "volumen" => "82"
                        "paginaInicial" => "316"
                        "paginaFinal" => "323"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36600175"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is male rheumatoid arthritis an occupational disease&#63; A review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46; Murphy"
                            1 => "D&#46; Hutchinson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2174/1874312901711010088"
                      "Revista" => array:6 [
                        "tituloSerie" => "Open Rheumatol J"
                        "fecha" => "2017"
                        "volumen" => "11"
                        "paginaInicial" => "88"
                        "paginaFinal" => "105"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28932330"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interaction between smoking&#44; the shared epitope&#44; and anti-cyclic citrullinated peptide&#58; a mixed picture in three large North American rheumatoid arthritis cohorts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;S&#46; Lee"
                            1 => "P&#46; Irigoyen"
                            2 => "M&#46; Kern"
                            3 => "A&#46; Lee"
                            4 => "F&#46; Batliwalla"
                            5 => "H&#46; Khalili"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.22703"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2007"
                        "volumen" => "56"
                        "paginaInicial" => "1745"
                        "paginaFinal" => "1753"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17530703"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Klareskog"
                            1 => "A&#46;I&#46; Catrina"
                            2 => "S&#46; Paget"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(09)60008-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2009"
                        "volumen" => "373"
                        "paginaInicial" => "659"
                        "paginaFinal" => "672"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19157532"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pathogenesis of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "I&#46;B&#46; McInnes"
                            1 => "G&#46; Schett"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1004965"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2011"
                        "volumen" => "365"
                        "paginaInicial" => "2205"
                        "paginaFinal" => "2219"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22150039"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Reynisdottir"
                            1 => "R&#46; Karimi"
                            2 => "V&#46; Joshua"
                            3 => "H&#46; Olsen"
                            4 => "A&#46;H&#46; Hensvold"
                            5 => "A&#46; Harju"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.38201"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2014"
                        "volumen" => "66"
                        "paginaInicial" => "31"
                        "paginaFinal" => "39"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24449573"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The complex role of the lung in the pathogenesis and clinical outcomes of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46;B&#46; Kelmenson"
                            1 => "M&#46;K&#46; Demoruelle"
                            2 => "K&#46;D&#46; Deane"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s11926-016-0618-4"
                      "Revista" => array:5 [
                        "tituloSerie" => "Curr Rheumatol Rep"
                        "fecha" => "2016"
                        "volumen" => "18"
                        "paginaInicial" => "69"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27796844"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis specific autoimmunity in the lung before and at the onset of disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Joshua"
                            1 => "M&#46; Loberg Haarhaus"
                            2 => "A&#46; Hensvold"
                            3 => "H&#46; W&#228;h&#228;maa"
                            4 => "C&#46; Gerstner"
                            5 => "M&#46; Hansson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.42549"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2023"
                        "volumen" => "75"
                        "paginaInicial" => "1910"
                        "paginaFinal" => "1922"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37192126"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of sputum neutrophil extracellular trap subsets with IgA anti-citrullinated protein antibodies in subjects at risk for rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Okamoto"
                            1 => "S&#46; Devoe"
                            2 => "N&#46; Seto"
                            3 => "V&#46; Minarchick"
                            4 => "T&#46; Wilson"
                            5 => "H&#46;M&#46; Rothfuss"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.41948"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2022"
                        "volumen" => "74"
                        "paginaInicial" => "38"
                        "paginaFinal" => "48"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34369110"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fc&#947; receptor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46; Sokolove"
                            1 => "X&#46; Zhao"
                            2 => "P&#46;E&#46; Chandra"
                            3 => "W&#46;H&#46; Robinson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.30081"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2011"
                        "volumen" => "63"
                        "paginaInicial" => "53"
                        "paginaFinal" => "62"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20954191"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46; Khandpur"
                            1 => "C&#46; Carmona-Rivera"
                            2 => "A&#46; Vivekanandan-Giri"
                            3 => "A&#46; Gizinski"
                            4 => "S&#46; Yalavarthi"
                            5 => "J&#46;S&#46; Knight"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/scitranslmed.3005580"
                      "Revista" => array:5 [
                        "tituloSerie" => "Sci Transl Med"
                        "fecha" => "2013"
                        "volumen" => "5"
                        "paginaInicial" => "178ra40"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23536012"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thoracic manifestations of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;J&#46; Esposito"
                            1 => "S&#46;G&#46; Chu"
                            2 => "R&#46; Madan"
                            3 => "T&#46;J&#46; Doyle"
                            4 => "P&#46;F&#46; Dellaripa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ccm.2019.05.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Chest Med"
                        "fecha" => "2019"
                        "volumen" => "40"
                        "paginaInicial" => "545"
                        "paginaFinal" => "560"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31376890"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms of progressive fibrosis in connective tissue disease &#40;CTD&#41;-associated interstitial lung diseases &#40;ILDs&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Spagnolo"
                            1 => "O&#46; Distler"
                            2 => "C&#46;J&#46; Ryerson"
                            3 => "A&#46; Tzouvelekis"
                            4 => "J&#46;S&#46; Lee"
                            5 => "F&#46; Bonella"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/annrheumdis-2020-217230"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2021"
                        "volumen" => "80"
                        "paginaInicial" => "143"
                        "paginaFinal" => "150"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33037004"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease&#58; comorbidity and mortality"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Hyldgaard"
                            1 => "O&#46; Hilberg"
                            2 => "A&#46;B&#46; Pedersen"
                            3 => "S&#46;P&#46; Ulrichsen"
                            4 => "A&#46; L&#248;kke"
                            5 => "E&#46; Bendstrup"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/annrheumdis-2017-211138"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2017"
                        "volumen" => "76"
                        "paginaInicial" => "1700"
                        "paginaFinal" => "1706"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28611082"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0450"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence and mortality of interstitial lung disease in rheumatoid arthritis&#58; a population-based study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Bongartz"
                            1 => "C&#46; Nannini"
                            2 => "Y&#46;F&#46; Medina-Velasquez"
                            3 => "S&#46;J&#46; Achenbach"
                            4 => "C&#46;S&#46; Crowson"
                            5 => "J&#46;H&#46; Ryu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.27405"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2010"
                        "volumen" => "62"
                        "paginaInicial" => "1583"
                        "paginaFinal" => "1591"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20155830"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0455"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Extra-articular disease manifestations in rheumatoid arthritis&#58; incidence trends and risk factors over 46 years"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46; Turesson"
                            1 => "W&#46;M&#46; O&#8217;Fallon"
                            2 => "C&#46;S&#46; Crowson"
                            3 => "S&#46;E&#46; Gabriel"
                            4 => "E&#46;L&#46; Matteson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.62.8.722"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2003"
                        "volumen" => "62"
                        "paginaInicial" => "722"
                        "paginaFinal" => "727"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12860726"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0460"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Proceedings of the American College of Rheumatology&#47;Association of Physicians of Great Britain and Ireland Connective Tissue Disease&#58; Associated interstitial lung disease summit&#58; a multidisciplinary approach to address challenges and opportunities"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Fischer"
                            1 => "M&#46;E&#46; Strek"
                            2 => "V&#46; Cottin"
                            3 => "P&#46;F&#46; Dellaripa"
                            4 => "E&#46;J&#46; Bernstein"
                            5 => "K&#46;K&#46; Brown"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/qjmed/hcy272"
                      "Revista" => array:6 [
                        "tituloSerie" => "QJM"
                        "fecha" => "2019"
                        "volumen" => "112"
                        "paginaInicial" => "81"
                        "paginaFinal" => "93"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30605544"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;J&#46; Solomon"
                            1 => "J&#46;H&#46; Chung"
                            2 => "G&#46;P&#46; Cosgrove"
                            3 => "M&#46;K&#46; Demoruelle"
                            4 => "E&#46;R&#46; Fernandez-Perez"
                            5 => "A&#46; Fischer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/13993003.00357-2015"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2016"
                        "volumen" => "47"
                        "paginaInicial" => "588"
                        "paginaFinal" => "596"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26585429"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0470"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "ERAS &#40;Early Rheumatoid Arthritis Study&#41;&#46; Interstitial lung disease has a poor prognosis in rheumatoid arthritis&#58; results from an inception cohort"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Koduri"
                            1 => "S&#46; Norton"
                            2 => "A&#46; Young"
                            3 => "N&#46; Cox"
                            4 => "P&#46; Davies"
                            5 => "J&#46; Devlin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/keq035"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2010"
                        "volumen" => "49"
                        "paginaInicial" => "1483"
                        "paginaFinal" => "1489"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20223814"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0475"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;A&#46; Juge"
                            1 => "J&#46;S&#46; Lee"
                            2 => "E&#46; Ebstein"
                            3 => "H&#46; Furukawa"
                            4 => "E&#46; Dobrinskikh"
                            5 => "S&#46; Gazal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1801562"
                      "Revista" => array:5 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2018"
                        "volumen" => "79"
                        "paginaInicial" => "2209"
                        "paginaFinal" => "2219"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0655"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Sokolove"
                            1 => "D&#46;S&#46; Johnson"
                            2 => "L&#46;J&#46; Lahey"
                            3 => "C&#46;A&#46; Wagner"
                            4 => "D&#46; Cheng"
                            5 => "G&#46;M&#46; Thiele"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.38307"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2014"
                        "volumen" => "66"
                        "paginaInicial" => "813"
                        "paginaFinal" => "821"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24757134"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0660"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary complications of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "H&#46; Farquhar"
                            1 => "R&#46; Vassallo"
                            2 => "A&#46;L&#46; Edwards"
                            3 => "E&#46;L&#46; Matteson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-0039-1683995"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Respir Crit Care Med"
                        "fecha" => "2019"
                        "volumen" => "40"
                        "paginaInicial" => "194"
                        "paginaFinal" => "207"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31137060"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0490"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "American Thoracic Society&#44; European Respiratory Society Japanese Respiratory Society&#44; and Latin American Thoracic Society&#46; Diagnosis of idiopathic pulmonary fibrosis&#46; An official ATS&#47;ERS&#47;JRS&#47;ALAT clinical practice guideline"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Raghu"
                            1 => "M&#46; Remy-Jardin"
                            2 => "J&#46;L&#46; Myers"
                            3 => "L&#46; Richeldi"
                            4 => "C&#46;J&#46; Ryerson"
                            5 => "D&#46;J&#46; Lederer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.201807-1255ST"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2018"
                        "volumen" => "198"
                        "paginaInicial" => "e44"
                        "paginaFinal" => "e68"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30168753"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0495"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary fibrosis associated with rheumatoid arthritis&#58; from pathophysiology to treatment strategies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Diesler"
                            1 => "V&#46; Cottin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/17476348.2022.2089116"
                      "Revista" => array:6 [
                        "tituloSerie" => "Expert Rev Respir Med"
                        "fecha" => "2022"
                        "volumen" => "16"
                        "paginaInicial" => "541"
                        "paginaFinal" => "553"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35695895"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0500"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;J&#46; Kim"
                            1 => "B&#46;M&#46; Elicker"
                            2 => "F&#46; Maldonado"
                            3 => "W&#46;R&#46; Webb"
                            4 => "J&#46;H&#46; Ryu"
                            5 => "J&#46;H&#46; Van Uden"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.00092309"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2010"
                        "volumen" => "35"
                        "paginaInicial" => "1322"
                        "paginaFinal" => "1328"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19996193"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0505"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The lung in rheumatoid arthritis&#44; cause or consequence&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Chatzidionisyou"
                            1 => "A&#46;I&#46; Catrina"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/BOR. 0000000000000238"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Rheumatol"
                        "fecha" => "2016"
                        "volumen" => "28"
                        "paginaInicial" => "76"
                        "paginaFinal" => "82"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26599384"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0510"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;P&#46; Linn-Rasker"
                            1 => "A&#46;H&#46; van der Helm-van Mil"
                            2 => "F&#46;A&#46; van Gaalen"
                            3 => "M&#46; Kloppenburg"
                            4 => "R&#46;R&#46; de Vries"
                            5 => "S&#46; le Cessie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2005.041079"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2006"
                        "volumen" => "65"
                        "paginaInicial" => "366"
                        "paginaFinal" => "371"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16014670"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0515"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis&#58; results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis &#40;MyEIRA&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;L&#46; Too"
                            1 => "A&#46; Yahya"
                            2 => "S&#46; Murad"
                            3 => "J&#46;S&#46; Dhaliwal"
                            4 => "P&#46;T&#46; Larsson"
                            5 => "N&#46;A&#46; Muhamad"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/ar3813"
                      "Revista" => array:5 [
                        "tituloSerie" => "Arthritis Res Ther"
                        "fecha" => "2012"
                        "volumen" => "14"
                        "paginaInicial" => "R89"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22537824"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0520"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibroblasts as immune regulators in infection&#44; inflammation and cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Davidson"
                            1 => "M&#46; Coles"
                            2 => "T&#46; Thomas"
                            3 => "G&#46; Kollias"
                            4 => "B&#46; Ludewig"
                            5 => "S&#46; Turley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41577-021-00540-z"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Immunol"
                        "fecha" => "2021"
                        "volumen" => "21"
                        "paginaInicial" => "704"
                        "paginaFinal" => "717"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33911232"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0525"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Carmona-Rivera"
                            1 => "P&#46;M&#46; Carlucci"
                            2 => "E&#46; Moore"
                            3 => "N&#46; Lingampalli"
                            4 => "H&#46; Uchtenhagen"
                            5 => "E&#46; James"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/sciimmunol.aag3358"
                      "Revista" => array:5 [
                        "tituloSerie" => "Sci Immunol"
                        "fecha" => "2017"
                        "volumen" => "2"
                        "paginaInicial" => "eaag3358"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28649674"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0530"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The lung microbiota in early rheumatoid arthritis and autoimmunity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;U&#46; Scher"
                            1 => "V&#46; Joshua"
                            2 => "A&#46; Artacho"
                            3 => "S&#46; Abdollahi-Roodsaz"
                            4 => "J&#46; &#214;ckinger"
                            5 => "S&#46; Kullberg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s40168-016-0206-x"
                      "Revista" => array:5 [
                        "tituloSerie" => "Microbiome"
                        "fecha" => "2016"
                        "volumen" => "4"
                        "paginaInicial" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27855721"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs&#58; 2022 update"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;S&#46; Smolen"
                            1 => "R&#46;B&#46;M&#46; Landew&#233;"
                            2 => "S&#46;A&#46; Bergstra"
                            3 => "A&#46; Kerschbaumer"
                            4 => "A&#46; Sepriano"
                            5 => "D&#46; Aletaha"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard-2022-223356"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2023"
                        "volumen" => "82"
                        "paginaInicial" => "3"
                        "paginaFinal" => "18"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36357155"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors&#58; observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Saevarsdottir"
                            1 => "S&#46; Wedr&#233;n"
                            2 => "M&#46; Seddighzadeh"
                            3 => "C&#46; Bengtsson"
                            4 => "A&#46; Wesley"
                            5 => "S&#46; Lindblad"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.27758"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2011"
                        "volumen" => "63"
                        "paginaInicial" => "26"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20862678"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis&#58; results from the SWEFOT trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Saevarsdottir"
                            1 => "H&#46; Rezaei"
                            2 => "P&#46; Geborek"
                            3 => "I&#46; Petersson"
                            4 => "S&#46; Ernestam"
                            5 => "K&#46; Albertsson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.27758"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2011"
                        "volumen" => "74"
                        "paginaInicial" => "1509"
                        "paginaFinal" => "1514"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24706006"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease&#46; Part 2&#58; Treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Narv&#225;ez"
                            1 => "P&#46; D&#237;az Del Campo Fontecha"
                            2 => "N&#46; Brito Garc&#237;a"
                            3 => "G&#46; Bonilla"
                            4 => "M&#46; Aburto"
                            5 => "I&#46; Castellv&#237;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.reumae.2022.03.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Reumatol Clin &#40;Engl Ed&#41;"
                        "fecha" => "2022"
                        "volumen" => "18"
                        "paginaInicial" => "501"
                        "paginaFinal" => "512"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36064885"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis disease activity predicting incident clinically apparent rheumatoid arthritis-associated interstitial lung disease&#58; a prospective cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;A&#46; Sparks"
                            1 => "X&#46; He"
                            2 => "J&#46; Huang"
                            3 => "E&#46;A&#46; Fletcher"
                            4 => "A&#46; Zaccardelli"
                            5 => "H&#46;M&#46; Friedlander"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.40904"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2019"
                        "volumen" => "71"
                        "paginaInicial" => "1472"
                        "paginaFinal" => "1482"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30951251"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy of rituximab in slowing down progression of rheumatoid arthritis-related interstitial lung disease&#58; data from the NEREA Registry"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Vadillo"
                            1 => "M&#46;A&#46; Nieto"
                            2 => "F&#46; Romero-Bueno"
                            3 => "L&#46; Leon"
                            4 => "O&#46; Sanchez-Pernaute"
                            5 => "Rodriguez-Nieto&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/kez673"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2020"
                        "volumen" => "59"
                        "paginaInicial" => "2099"
                        "paginaFinal" => "2108"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31990338"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease&#58; 10 years&#8217; experience at a single centre"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;Y&#46; Md Yosof"
                            1 => "A&#46; Kabia"
                            2 => "M&#46; Darby"
                            3 => "G&#46; Lettieri"
                            4 => "P&#46; Beirne"
                            5 => "E&#46;M&#46; Vital"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/kex072"
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatology"
                        "fecha" => "2017"
                        "volumen" => "56"
                        "paginaInicial" => "348"
                        "paginaFinal" => "357"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis related interstitial lung disease &#8211; improving outcomes over 25 years&#58; a large multicentre UK study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;A&#46; Kelly"
                            1 => "M&#46; Nisar"
                            2 => "S&#46; Arthanari"
                            3 => "S&#46; Carty"
                            4 => "F&#46;A&#46; Woodhead"
                            5 => "A&#46; Price-Forbes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/keaa577"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2021"
                        "volumen" => "60"
                        "paginaInicial" => "1882"
                        "paginaFinal" => "1890"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33150434"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Abatacept in patients with rheumatoid arthritis and interstitial lung disease&#58; a national multicenter study of 63 patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Fern&#225;ndez-D&#237;az"
                            1 => "J&#46; Loricera"
                            2 => "S&#46; Casta&#241;eda"
                            3 => "R&#46; L&#243;pez-Mej&#237;as"
                            4 => "C&#46; Ojeda-Garc&#237;a"
                            5 => "A&#46; Oliv&#233;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.semarthrit.2017.12.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Arthritis Rheum"
                        "fecha" => "2018"
                        "volumen" => "48"
                        "paginaInicial" => "22"
                        "paginaFinal" => "27"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29422324"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Abatacept in interstitial lung disease associated with rheumatoid arthritis&#58; national multicenter study of 263 patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Fern&#225;ndez-D&#237;az"
                            1 => "S&#46; Casta&#241;eda"
                            2 => "R&#46;B&#46; Melero-Gonz&#225;lez"
                            3 => "F&#46; Ortiz-Sanju&#225;n"
                            4 => "A&#46; Juan-Mas"
                            5 => "C&#46; Carrasco-Cubero"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/keaa621"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2020"
                        "volumen" => "59"
                        "paginaInicial" => "3906"
                        "paginaFinal" => "3916"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33068439"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease&#58; a multicentre retrospective study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Manfredi"
                            1 => "G&#46; Cassone"
                            2 => "F&#46; Furini"
                            3 => "E&#46; Gremese"
                            4 => "V&#46; Venerito"
                            5 => "F&#46; Atzeni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/imj.14670"
                      "Revista" => array:6 [
                        "tituloSerie" => "Intern Med J"
                        "fecha" => "2020"
                        "volumen" => "50"
                        "paginaInicial" => "1085"
                        "paginaFinal" => "1090"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31661185"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathogenesis&#44; clinical features&#44; and treatment strategy for rheumatoid arthritis-associated interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Akiyama"
                            1 => "Y&#46; Kaneko"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.autrev.2022.103056"
                      "Revista" => array:5 [
                        "tituloSerie" => "Autoimmun Rev"
                        "fecha" => "2022"
                        "volumen" => "21"
                        "paginaInicial" => "103056"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35121155"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of nintedanib in patients with progressive pulmonary fibrosis associated with rheumatoid arthritis&#58; data from the INBUILD trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46;L&#46; Matteson"
                            1 => "M&#46; Aringer"
                            2 => "G&#46;R&#46; Burmester"
                            3 => "H&#46; Mueller"
                            4 => "L&#46; Moros"
                            5 => "M&#46; Kolb"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10067-023-06623-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Rheumatol"
                        "fecha" => "2023"
                        "volumen" => "42"
                        "paginaInicial" => "2311"
                        "paginaFinal" => "2319"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37209188"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "INBUILD trial investigators nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial&#58; a randomised&#44; double-blind&#44; placebo-controlled&#44; parallel-group trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;U&#46; Wells"
                            1 => "K&#46;R&#46; Flaherty"
                            2 => "K&#46;K&#46; Brown"
                            3 => "Y&#46; Inoue"
                            4 => "A&#46; Devaraj"
                            5 => "L&#46; Richeldi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-2600(20)30036-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Respir Med"
                        "fecha" => "2020"
                        "volumen" => "8"
                        "paginaInicial" => "453"
                        "paginaFinal" => "460"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32145830"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of antifibrotics in the treatment of rheumatoid arthritis-associated interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Liang"
                            1 => "E&#46;L&#46; Matteson"
                            2 => "A&#46; Abril"
                            3 => "J&#46;H&#46;W&#46; Distler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/1759720X221074457"
                      "Revista" => array:3 [
                        "tituloSerie" => "Ther Adv Musculoskelet Dis"
                        "fecha" => "2022"
                        "volumen" => "14"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0610"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;F&#46; Redente"
                            1 => "M&#46;A&#46; Aguilar"
                            2 => "B&#46;P&#46; Black"
                            3 => "B&#46;L&#46; Edelman"
                            4 => "A&#46;N&#46; Bahadur"
                            5 => "S&#46;M&#46; Humphries"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajplung.00304.2017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol Lung Cell Mol Physiol"
                        "fecha" => "2018"
                        "volumen" => "314"
                        "paginaInicial" => "L998"
                        "paginaFinal" => "L1009"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29543042"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0615"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-associated interstitial lung disease mouse model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Y&#46; Miura"
                            1 => "H&#46; Ohkubo"
                            2 => "A&#46; Niimi"
                            3 => "S&#46; Kanazawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/23120541.00345-2021"
                      "Revista" => array:3 [
                        "tituloSerie" => "ERJ Open Res"
                        "fecha" => "2021"
                        "volumen" => "7"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0620"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methotrexate and rheumatoid arthritis associated interstitial lung disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;A&#46; Juge"
                            1 => "J&#46;S&#46; Lee"
                            2 => "J&#46; Lau"
                            3 => "L&#46; Kawano-Dourado"
                            4 => "J&#46; Rojas Serrano"
                            5 => "M&#46; Sebastiani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/13993003.00337-2020"
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2021"
                        "volumen" => "57"
                        "paginaInicial" => "2000337"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32646919"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0625"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rheumatoid arthritis-related interstitial lung disease &#40;RA-ILD&#41;&#58; methotrexate and the severity of lung disease are associated to prognosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46; Rojas-Serrano"
                            1 => "D&#46; Herrera-Bringas"
                            2 => "D&#46;I&#46; P&#233;rez-Rom&#225;n"
                            3 => "R&#46; P&#233;rez-Dorame"
                            4 => "H&#46; Mateos-Toledo"
                            5 => "M&#46; Mej&#237;a"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10067-017-3707-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Rheumatol"
                        "fecha" => "2017"
                        "volumen" => "36"
                        "paginaInicial" => "1493"
                        "paginaFinal" => "1500"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28585060"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0630"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The case of methotrexate and the lung&#58; Dr Jekyll and Mr Hyde"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Cottin"
                            1 => "E&#46; Bendstrup"
                            2 => "P&#46; Bonniaud"
                            3 => "M&#46; Nasser"
                            4 => "P&#46; Spagnolo"
                            5 => "C&#46; Valenzuela"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/13993003.00079-2021"
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2021"
                        "volumen" => "57"
                        "paginaInicial" => "2100079"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33574052"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0635"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease&#58; clinical features and prognosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; Izuka"
                            1 => "H&#46; Yamashita"
                            2 => "A&#46; Iba"
                            3 => "Y&#46; Takahashi"
                            4 => "H&#46; Kaneko"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/rheumatology/keaa608"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
                        "fecha" => "2021"
                        "volumen" => "60"
                        "paginaInicial" => "2348"
                        "paginaFinal" => "2354"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33241299"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0640"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Applicability of small-molecule inhibitors in the study of peptidyl arginine deiminase 2 &#40;PAD2&#41; and PAD4"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;T&#46; Mart&#237;n Monreal"
                            1 => "A&#46;S&#46; Rebak"
                            2 => "L&#46; Massarenti"
                            3 => "S&#46; Mondal"
                            4 => "L&#46; &#352;enolt"
                            5 => "N&#46; &#216;dum"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2021.716250"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol"
                        "fecha" => "2021"
                        "volumen" => "12"
                        "paginaInicial" => "716250"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34737738"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0645"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CD19-targeted CAR T cells in refractory antisynthetase syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; M&#252;ller"
                            1 => "S&#46; Boeltz"
                            2 => "J&#46; Knitza"
                            3 => "M&#46; Aigner"
                            4 => "S&#46; V&#246;lkl"
                            5 => "S&#46; Kharboutli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(23)00023-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2023"
                        "volumen" => "401"
                        "paginaInicial" => "815"
                        "paginaFinal" => "818"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36930673"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0650"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CD19-targeting CAR T-cell therapy for antisynthetase syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "I&#46;E&#46; Lundberg"
                            1 => "A&#46;S&#46; Galindo-Feria"
                            2 => "B&#46; Horuluoglu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.2023.7240"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2023"
                        "volumen" => "329"
                        "paginaInicial" => "2130"
                        "paginaFinal" => "2131"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37367988"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/01218123/00000031000000S1/v5_202405200140/S0121812323000889/v5_202405200140/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "95645"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Review articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/01218123/00000031000000S1/v5_202405200140/S0121812323000889/v5_202405200140/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0121812323000889?idApp=UINPBA00004N"
]

Article information

ISSN: 01218123
Original language: English

DOI:10.1016/j.rcreu.2023.09.006

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 August	1	2	3
2024 June	1	0	1
2024 April	5	0	5
2024 March	21	4	25
2024 February	24	6	30
2024 January	43	24	67

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter