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1</a>C&#41;&#46; Immunohistochemical techniques identified cells that were positive for CD1a &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41; and for S100&#44; as well as langerin in the histiocytes described&#44; all of which was consistent with Langerhans cell &#40;LC&#41; histiocytosis &#40;LCH&#41;&#46; At that time&#44; it was recommended that she quit smoking and the same immunosuppressive therapy was maintained&#46; During that entire period&#44; she had no joint or respiratory symptoms and underwent radiographic follow-up 6 months later&#46; The images showed residual pulmonary cysts and the nodules had disappeared &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; After 5 years of follow-up with no new incidences&#44; the patient continues to receive triple immunosuppressive therapy&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Discussion</span><p id="par0010" class="elsevierStylePara elsevierViewall">Histiocytes are cells of the immune system that include both macrophages and dendritic cells &#40;non-macrophage antigen-presenting cells&#41;&#46; Histiocytoses are rare diseases&#44; LCH being the most representative&#44; characterized by the infiltration of LC&#44; a type of dendritic cell found predominantly in the pulmonary alveoli and in the skin&#44; with its distinctive &#8220;racket&#8221;-shaped cytoplasmic Birbeck granules&#46; The term LCH was coined in the attempt to confer a better classification and identification of the patients&#44; as it combines previous entities &#40;eosinophilic granuloma&#44; histiocytosis X&#44; etc&#46;&#41; in which the lesions were due to a proliferation and infiltration of the same cell type&#44; the identification of LC being the diagnostic criteria called for since then&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> The pathogenesis is unknown&#44; there being either a reactive or clonal proliferative response&#44; with different degrees of phenotypic aggressiveness in the infiltrated organs or systems &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Pulmonary Langerhans cell histiocytosis &#40;PLCH&#41; is the most representative form in adults and is usually recognized as a separate entity&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">This disorder occurs in young adult smokers&#44; and smoking cessation can lead to partial or total remission of the pulmonary lesions&#46; In the early stages&#44; it is characterized by bronchoalveolar inflammatory changes and&#44; in the most advanced phases&#44; by cystic lung destruction&#46; The clinical manifestations vary widely&#58; dyspnea&#44; cough&#44; weakness&#44; fever&#44; weight loss&#44; pleuritic chest pain and&#44; occasionally&#44; spontaneous pneumothorax&#46; The incidence of hemoptysis is minor&#59; thus&#44; should it occur&#44; the cause should be looked for elsewhere &#40;mainly tumor-related&#41;&#46; The disease can be detected incidentally in radiological studies performed in asymptomatic patients&#44; occurring in around 15&#37; of the cases&#44; and the same proportion can be applied to those with extrapulmonary manifestations&#44; such as bone cysts&#44; diabetes insipidus or exanthema&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">2&#44;3</span></a> Computed tomography is the technique of choice to characterize pulmonary involvement&#46; The combination of multiple cysts and bilateral nodules distributed throughout the medium and upper lobes&#44; with or without interstitial thickening&#44; in a young smoker&#44; is considered to be a characteristic reason to strongly suspect PLCH&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a> This was not the case in our patient&#44; whose disorder had to do mainly with the nodules&#44; there being few cystic lesions and involvement of the lower lobes&#46; Bronchoalveolar lavage is useful for the diagnosis when more than 5&#37; of the LC are detected by electron microscopy or immunostaining&#44; but this technique is not available at every medical center&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> The combination of the typical radiological findings&#44; together with the positive results of bronchoalveolar lavage&#44; can be accepted as a sufficient diagnostic criteria&#44; without pathological confirmation&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> However&#44; should the latter be necessary&#44; the approach should be pulmonary biopsy&#44; since transbronchial biopsy has been found to have a very limited diagnostic yield&#46; The presence of LC is confirmed by immunohistochemical techniques with monoclonal antibodies against the CD1a membrane antigen&#44; the intracellular S100 protein and langerin&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The differential diagnosis should mainly include the formal screening for mycobacteria&#44; hematogenous infections&#44; other types of nodulosis such as sarcoidosis&#44; silicosis&#44; vasculitis&#44; metastases or primary pulmonary tumors&#44; and in our case&#44; obviously&#44; with pulmonary rheumatoid nodules &#40;RN&#41;&#46; With respect to the latter&#44; we must recall that pulmonary RN are classically related to tobacco use&#44; RF positivity&#44; coexistence of cutaneous RN and human leukocyte antigen &#40;HLA&#41; DRB1&#44; although there are also cases induced by treatment with synthetic disease-modifying antirheumatic drugs or biological therapy with anti-tumor necrosis factor &#40;TNF&#41; agents&#46; Rheumatoid nodulosis has long been known to be induced by MTX&#46; It is characterized by the rapid development of RN that are histopathologically similar to classic RN&#44; that stops once the drug is no longer being administered and reappears if the attempt is made to reintroduce it&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> It has been associated with the HLA DRB1&#42;0401 allele&#46; Pulmonary rheumatoid nodulosis of similar temporal characteristics as that induced by MTX is much less common&#46; In contrast&#44; in other situations in which the development of cutaneous or pulmonary RN during prolonged chronic treatment with MTX&#44; the causal association would be much more questionable&#46; Moreover&#44; on most occasions&#44; there is a characteristic disparity between the development of nodulosis and a good control of the joint disease&#46; Thus&#44; the strategy to be followed with respect to discontinuing treatment can also be debated&#44; and this all points to differences between the pathophysiological mechanisms that result in the formation of rheumatoid granulomas and those that lead to synovitis and synovial hypertrophy&#46; Similar problems with interpretation in the literature can be found with leflunomide and anti-TNF therapy as inducers of pulmonary rheumatoid nodulosis&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> Finally&#44; the differential diagnosis of purely cystic PLCH would include centrilobular emphysema&#44; cystic fibrosis&#44; tuberous sclerosis and&#44; specifically in women&#44; lymphangioleiomyomatosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The natural course of PLCH is unpredictable&#59; spontaneous remission can be estimated to occur in up to 50&#37; cases&#44; and severe progressive respiratory failure can develop in 10&#37;&#8211;20&#37; of the patients&#46; The major consideration for the treatment of PLCH is smoking cessation&#44; which may be achieved in up to one third of the cases&#46; This simultaneously eliminates an important risk factor for lung cancer&#44; chronic obstructive pulmonary disease and cardiovascular disease&#46; However&#44; it is estimated that the disease continues to progress in as many as one third of the patients who stop smoking&#46; Cases of recurrence have been reported in those who quit&#46; The use of corticosteroids as monotherapy or in combination with immunosuppressive agents &#40;methotrexate&#44; cyclophosphamide&#44; vinblastine and&#44; more recently&#44; cladribine&#41; is questioned because of the absence of controlled clinical trials and due to the uncertainty regarding the natural behavior of the disease&#46; It is usually reserved for cases of functional deterioration revealed by spirometry&#44; progressive interstitial disease or extrapulmonary multisystemic involvement&#46; Overall 5-year survival is estimated to be 75&#37;&#44; and the factors most widely associated with poor prognosis are advanced age and deterioration in respiratory function tests and its extension at the time of the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> Lung transplantation is an option for long-standing severe disease&#44; although recurrences have been reported in the transplanted organ&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient was in clinical remission for her joint disorder&#44; and was receiving triple therapy when the pulmonary manifestations were detected&#46; We maintained the same strategy&#44; especially after seeing the radiological improvement once she had achieved smoking cessation&#46; We found no cases in the literature on the previous coincidence of PLCH and RA&#46; There is a recently described case of PLCH in a patient with Sj&#246;gren&#39;s syndrome treated with oral steroids and azathioprine&#44; with a favorable radiological and functional response&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> Multicentric reticulohistiocytosis may be a cause of erosive arthritis and has been associated in patients with RA and Sj&#246;gren&#39;s syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> although clinically&#44; it is a differential diagnosis that was not considered in our case&#46; With respect to the attitude to take if at some time&#44; she were to need biological therapy&#44; we have only had access to the favorable communication of 2001 on the part of Henter et al&#46;&#44; in reference to a patient with very aggressive multifocal infantile LCH with a good response to etanercept&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> Since then&#44; communications along those lines have not been repeated&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In short&#44; PLCH is the most representative type of LCH in adulthood&#46; It is directly related to tobacco use&#44; and smoking cessation leads to a high percentage of cases in which the outcome proved to be the solution to the disease&#46; We have not found previous references in the literature to the simultaneous coexistence of RA and PLCH&#46; Our patient did not have a characteristic radiological pattern&#44; and triple immunosuppressive therapy does not appear to have influenced the favorable change in the symptoms after more than 5 years of follow-up after smoking cessation&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Ethical Disclosures</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Protection of human and animal subjects</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Confidentiality of data</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Right to privacy and informed consent</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflicts of Interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">We report the case of a 50-year-old female smoker with an 11-year history of seropositive rheumatoid arthritis &#40;rheumatoid factor and anti-cyclic citrullinated peptide antibodies&#41; receiving triple therapy&#46; She developed pulmonary nodules diagnosed as Langerhans cell histiocytosis by lung biopsy&#46; We found no reported cases of the coexistence of these two diseases&#46; Smoking abstinence led to radiologic resolution without modifying the immunosuppressive therapy&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se presenta el caso de una mujer de 50 a&#241;os&#44; fumadora&#44; con artritis reumatoide seropositiva &#40;FR y CCP&#41; de 11 a&#241;os de evoluci&#243;n en tratamiento con triple terapia&#44; y aparici&#243;n de n&#243;dulos pulmonares con diagn&#243;stico final de histiocitosis de c&#233;lulas de Langerhans por biopsia pulmonar&#46; No hemos encontrado casos descritos de la coexistencia de ambas enfermedades&#46; La abstinencia tab&#225;quica llev&#243; a la resoluci&#243;n radiol&#243;gica sin necesidad de modificar la terapia inmunosupresora&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as&#58; Zurita Prada PA&#44; Urrego Laur&#237;n CL&#44; Assyaaton Bobo S&#44; Far&#233; Garc&#237;a R&#44; Estrada Trigueros G&#44; Gallardo Romero JM&#44; et al&#46; Artritis reumatoide y n&#243;dulos pulmonares&#58; un diagn&#243;stico final inesperado&#46; 2017&#59;13&#58;167&#8211;170&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Pulmonary computed tomography &#40;CT&#41; at the time of diagnosis&#46; &#40;B&#41; Pulmonary CT 6 months after the patient had quit smoking&#46; &#40;C&#41; Langerhans cells &#40;hematoxylin&#8211;eosin&#41;&#46; &#40;D&#41; Positive immunohistochemical technique for CD1a &#40;100&#215;&#41;&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Simplified classification of histiocytosis<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&#46; <span class="elsevierStyleItalic">Langerhans cell histiocytosis &#40;LCH&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&#46; <span class="elsevierStyleItalic">Hemophagocytic lymphohistiocytosis &#40;HLH&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">3&#46; <span class="elsevierStyleItalic">The rare histiocytic disorders &#40;RHD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Juvenile xanthogranuloma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Erdheim-Chester disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Multicentric reticulohistiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rosai-Dorfman disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>The malignant histiocytosis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Classification of <span class="elsevierStyleItalic">Langerhans cell histiocytosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&#46; <span class="elsevierStyleItalic">Isolated disease in a single organ or system</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary LCH &#40;85&#37; of the cases of pulmonary LCH in adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Bone &#40;single or multiple&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Skin&#47;hypothalamus&#47;hypophysis&#47;lymph nodes&#47;liver&#44; spleen&#44; thyroid glands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&#46; <span class="elsevierStyleItalic">Multisystem disease</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&#58; <span class="elsevierStyleItalic">affecting two or more organs</span>&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Source&#58; <span class="elsevierStyleInterRef" id="intr0005" href="https://www.histiocytesociety.org/">https&#58;&#47;&#47;www&#46;histiocytesociety&#46;org</span>&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Previous nomenclature&#58; histiocytosis X&#44; eosinophilic granuloma&#46; Hashimoto Pritzker disease&#58; in the newborn&#44; skin lesions and self-healing course&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Previous nomenclature&#58; Letterer&#8211;Siwe disease&#58; aggressive infantile disorder with fever&#44; lymphadenopathy&#44; hepatosplenomegaly&#44; bone and lung involvement&#46; Hand&#8211;Schuller&#8211;Christian&#58; triad of exophthalmos&#44; diabetes insipidus and bone lesions&#44; typical infantile disease&#44; rare in adults&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Classification of Histiocytosis&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Differential diagnosis of the cystic pattern on radiology</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Respiratory bronchiolitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary Langerhans cell histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Amyloidosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lymphangioleiomyomatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary embolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cystic fibrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Congenital pulmonary airway malformation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tuberous sclerosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Case report
Rheumatoid Arthritis and Pulmonary Nodules: An Unexpected Final Diagnosis
Artritis reumatoide y nódulos pulmonares: un diagnóstico final inesperado
Pablo Antonio Zurita Pradaa,
Corresponding author
pzurita@salucastillayleon.es

Corresponding author.
, Claudia Lía Urrego Laurína, Sow Assyaaton Bobob, Regina Faré Garcíaa, Graciliano Estrada Triguerosc, José Manuel Gallardo Romeroc, Maria Henar Borrego Pintadod
a Área de Reumatología, Complejo Hospitalario de Segovia, Segovia, Spain
b Servicio de Geriatría, Complejo Hospitalario de Segovia, Segovia, Spain
c Área de Neumología, Complejo Hospitalario de Segovia, Segovia, Spain
d Servicio de Anatomía Patológica, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Case Report</span><p id="par0005" class="elsevierStylePara elsevierViewall">The patient was a 50-year-old woman who smoked 20 cigarettes&#47;day&#46; She had been diagnosed with seropositive &#40;rheumatoid factor &#91;RF&#93; and anti-cyclic citrullinated peptide antibodies &#91;anti-CCP&#93;&#41;&#44; erosive rheumatoid arthritis &#40;RA&#41; in 1999&#46; She was being treated with methotrexate &#40;MTX&#41; since 2000&#44; in combination with salazopyrin and hydroxychloroquine since February 2009&#44; at which time&#44; she had achieved complete remission&#46; In March 2010&#44; in relation to a self-limiting case of a cold&#44; her primary care physician had asked for a chest radiograph&#44; which showed possible images of nodules&#44; predominantly in the upper lobes&#46; The patient was asymptomatic and the physical examination was normal&#46; She had an immunological study in which she tested positive for RF and anti-CCP and negative for antinuclear antibodies and antineutrophil cytoplasmic antibodies&#59; the Mantoux text was positive&#44; and chest computed tomography revealed multiple bilateral pulmonary nodules measuring about 0&#46;5<span class="elsevierStyleHsp" style=""></span>cm&#44; some showing cavitation&#44; especially in images from the upper and middle lobes&#44; but the lower lobes were also involved &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; The bronchoscopy was normal&#44; with negative results in the smear&#44; bronchoalveolar lavage fluid culture and cytology of the bronchial aspirate for malignant cells&#46; The patient was referred to undergo lung biopsy&#46; Videothoracoscopy revealed that the lung parenchyma had small scattered subpleural lesions&#44; and the pathological study showed the presence of foamy histiocytes with grooved nuclei&#44; with other multinucleated and somewhat elongated histiocytes occupying the alveolar spaces &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46; Immunohistochemical techniques identified cells that were positive for CD1a &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41; and for S100&#44; as well as langerin in the histiocytes described&#44; all of which was consistent with Langerhans cell &#40;LC&#41; histiocytosis &#40;LCH&#41;&#46; At that time&#44; it was recommended that she quit smoking and the same immunosuppressive therapy was maintained&#46; During that entire period&#44; she had no joint or respiratory symptoms and underwent radiographic follow-up 6 months later&#46; The images showed residual pulmonary cysts and the nodules had disappeared &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; After 5 years of follow-up with no new incidences&#44; the patient continues to receive triple immunosuppressive therapy&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Discussion</span><p id="par0010" class="elsevierStylePara elsevierViewall">Histiocytes are cells of the immune system that include both macrophages and dendritic cells &#40;non-macrophage antigen-presenting cells&#41;&#46; Histiocytoses are rare diseases&#44; LCH being the most representative&#44; characterized by the infiltration of LC&#44; a type of dendritic cell found predominantly in the pulmonary alveoli and in the skin&#44; with its distinctive &#8220;racket&#8221;-shaped cytoplasmic Birbeck granules&#46; The term LCH was coined in the attempt to confer a better classification and identification of the patients&#44; as it combines previous entities &#40;eosinophilic granuloma&#44; histiocytosis X&#44; etc&#46;&#41; in which the lesions were due to a proliferation and infiltration of the same cell type&#44; the identification of LC being the diagnostic criteria called for since then&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> The pathogenesis is unknown&#44; there being either a reactive or clonal proliferative response&#44; with different degrees of phenotypic aggressiveness in the infiltrated organs or systems &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Pulmonary Langerhans cell histiocytosis &#40;PLCH&#41; is the most representative form in adults and is usually recognized as a separate entity&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">This disorder occurs in young adult smokers&#44; and smoking cessation can lead to partial or total remission of the pulmonary lesions&#46; In the early stages&#44; it is characterized by bronchoalveolar inflammatory changes and&#44; in the most advanced phases&#44; by cystic lung destruction&#46; The clinical manifestations vary widely&#58; dyspnea&#44; cough&#44; weakness&#44; fever&#44; weight loss&#44; pleuritic chest pain and&#44; occasionally&#44; spontaneous pneumothorax&#46; The incidence of hemoptysis is minor&#59; thus&#44; should it occur&#44; the cause should be looked for elsewhere &#40;mainly tumor-related&#41;&#46; The disease can be detected incidentally in radiological studies performed in asymptomatic patients&#44; occurring in around 15&#37; of the cases&#44; and the same proportion can be applied to those with extrapulmonary manifestations&#44; such as bone cysts&#44; diabetes insipidus or exanthema&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">2&#44;3</span></a> Computed tomography is the technique of choice to characterize pulmonary involvement&#46; The combination of multiple cysts and bilateral nodules distributed throughout the medium and upper lobes&#44; with or without interstitial thickening&#44; in a young smoker&#44; is considered to be a characteristic reason to strongly suspect PLCH&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a> This was not the case in our patient&#44; whose disorder had to do mainly with the nodules&#44; there being few cystic lesions and involvement of the lower lobes&#46; Bronchoalveolar lavage is useful for the diagnosis when more than 5&#37; of the LC are detected by electron microscopy or immunostaining&#44; but this technique is not available at every medical center&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> The combination of the typical radiological findings&#44; together with the positive results of bronchoalveolar lavage&#44; can be accepted as a sufficient diagnostic criteria&#44; without pathological confirmation&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> However&#44; should the latter be necessary&#44; the approach should be pulmonary biopsy&#44; since transbronchial biopsy has been found to have a very limited diagnostic yield&#46; The presence of LC is confirmed by immunohistochemical techniques with monoclonal antibodies against the CD1a membrane antigen&#44; the intracellular S100 protein and langerin&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The differential diagnosis should mainly include the formal screening for mycobacteria&#44; hematogenous infections&#44; other types of nodulosis such as sarcoidosis&#44; silicosis&#44; vasculitis&#44; metastases or primary pulmonary tumors&#44; and in our case&#44; obviously&#44; with pulmonary rheumatoid nodules &#40;RN&#41;&#46; With respect to the latter&#44; we must recall that pulmonary RN are classically related to tobacco use&#44; RF positivity&#44; coexistence of cutaneous RN and human leukocyte antigen &#40;HLA&#41; DRB1&#44; although there are also cases induced by treatment with synthetic disease-modifying antirheumatic drugs or biological therapy with anti-tumor necrosis factor &#40;TNF&#41; agents&#46; Rheumatoid nodulosis has long been known to be induced by MTX&#46; It is characterized by the rapid development of RN that are histopathologically similar to classic RN&#44; that stops once the drug is no longer being administered and reappears if the attempt is made to reintroduce it&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> It has been associated with the HLA DRB1&#42;0401 allele&#46; Pulmonary rheumatoid nodulosis of similar temporal characteristics as that induced by MTX is much less common&#46; In contrast&#44; in other situations in which the development of cutaneous or pulmonary RN during prolonged chronic treatment with MTX&#44; the causal association would be much more questionable&#46; Moreover&#44; on most occasions&#44; there is a characteristic disparity between the development of nodulosis and a good control of the joint disease&#46; Thus&#44; the strategy to be followed with respect to discontinuing treatment can also be debated&#44; and this all points to differences between the pathophysiological mechanisms that result in the formation of rheumatoid granulomas and those that lead to synovitis and synovial hypertrophy&#46; Similar problems with interpretation in the literature can be found with leflunomide and anti-TNF therapy as inducers of pulmonary rheumatoid nodulosis&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> Finally&#44; the differential diagnosis of purely cystic PLCH would include centrilobular emphysema&#44; cystic fibrosis&#44; tuberous sclerosis and&#44; specifically in women&#44; lymphangioleiomyomatosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The natural course of PLCH is unpredictable&#59; spontaneous remission can be estimated to occur in up to 50&#37; cases&#44; and severe progressive respiratory failure can develop in 10&#37;&#8211;20&#37; of the patients&#46; The major consideration for the treatment of PLCH is smoking cessation&#44; which may be achieved in up to one third of the cases&#46; This simultaneously eliminates an important risk factor for lung cancer&#44; chronic obstructive pulmonary disease and cardiovascular disease&#46; However&#44; it is estimated that the disease continues to progress in as many as one third of the patients who stop smoking&#46; Cases of recurrence have been reported in those who quit&#46; The use of corticosteroids as monotherapy or in combination with immunosuppressive agents &#40;methotrexate&#44; cyclophosphamide&#44; vinblastine and&#44; more recently&#44; cladribine&#41; is questioned because of the absence of controlled clinical trials and due to the uncertainty regarding the natural behavior of the disease&#46; It is usually reserved for cases of functional deterioration revealed by spirometry&#44; progressive interstitial disease or extrapulmonary multisystemic involvement&#46; Overall 5-year survival is estimated to be 75&#37;&#44; and the factors most widely associated with poor prognosis are advanced age and deterioration in respiratory function tests and its extension at the time of the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> Lung transplantation is an option for long-standing severe disease&#44; although recurrences have been reported in the transplanted organ&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient was in clinical remission for her joint disorder&#44; and was receiving triple therapy when the pulmonary manifestations were detected&#46; We maintained the same strategy&#44; especially after seeing the radiological improvement once she had achieved smoking cessation&#46; We found no cases in the literature on the previous coincidence of PLCH and RA&#46; There is a recently described case of PLCH in a patient with Sj&#246;gren&#39;s syndrome treated with oral steroids and azathioprine&#44; with a favorable radiological and functional response&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> Multicentric reticulohistiocytosis may be a cause of erosive arthritis and has been associated in patients with RA and Sj&#246;gren&#39;s syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> although clinically&#44; it is a differential diagnosis that was not considered in our case&#46; With respect to the attitude to take if at some time&#44; she were to need biological therapy&#44; we have only had access to the favorable communication of 2001 on the part of Henter et al&#46;&#44; in reference to a patient with very aggressive multifocal infantile LCH with a good response to etanercept&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> Since then&#44; communications along those lines have not been repeated&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In short&#44; PLCH is the most representative type of LCH in adulthood&#46; It is directly related to tobacco use&#44; and smoking cessation leads to a high percentage of cases in which the outcome proved to be the solution to the disease&#46; We have not found previous references in the literature to the simultaneous coexistence of RA and PLCH&#46; Our patient did not have a characteristic radiological pattern&#44; and triple immunosuppressive therapy does not appear to have influenced the favorable change in the symptoms after more than 5 years of follow-up after smoking cessation&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Ethical Disclosures</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Protection of human and animal subjects</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Confidentiality of data</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Right to privacy and informed consent</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflicts of Interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">We report the case of a 50-year-old female smoker with an 11-year history of seropositive rheumatoid arthritis &#40;rheumatoid factor and anti-cyclic citrullinated peptide antibodies&#41; receiving triple therapy&#46; She developed pulmonary nodules diagnosed as Langerhans cell histiocytosis by lung biopsy&#46; We found no reported cases of the coexistence of these two diseases&#46; Smoking abstinence led to radiologic resolution without modifying the immunosuppressive therapy&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se presenta el caso de una mujer de 50 a&#241;os&#44; fumadora&#44; con artritis reumatoide seropositiva &#40;FR y CCP&#41; de 11 a&#241;os de evoluci&#243;n en tratamiento con triple terapia&#44; y aparici&#243;n de n&#243;dulos pulmonares con diagn&#243;stico final de histiocitosis de c&#233;lulas de Langerhans por biopsia pulmonar&#46; No hemos encontrado casos descritos de la coexistencia de ambas enfermedades&#46; La abstinencia tab&#225;quica llev&#243; a la resoluci&#243;n radiol&#243;gica sin necesidad de modificar la terapia inmunosupresora&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as&#58; Zurita Prada PA&#44; Urrego Laur&#237;n CL&#44; Assyaaton Bobo S&#44; Far&#233; Garc&#237;a R&#44; Estrada Trigueros G&#44; Gallardo Romero JM&#44; et al&#46; Artritis reumatoide y n&#243;dulos pulmonares&#58; un diagn&#243;stico final inesperado&#46; 2017&#59;13&#58;167&#8211;170&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Pulmonary computed tomography &#40;CT&#41; at the time of diagnosis&#46; &#40;B&#41; Pulmonary CT 6 months after the patient had quit smoking&#46; &#40;C&#41; Langerhans cells &#40;hematoxylin&#8211;eosin&#41;&#46; &#40;D&#41; Positive immunohistochemical technique for CD1a &#40;100&#215;&#41;&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Simplified classification of histiocytosis<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&#46; <span class="elsevierStyleItalic">Langerhans cell histiocytosis &#40;LCH&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&#46; <span class="elsevierStyleItalic">Hemophagocytic lymphohistiocytosis &#40;HLH&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">3&#46; <span class="elsevierStyleItalic">The rare histiocytic disorders &#40;RHD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Juvenile xanthogranuloma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Erdheim-Chester disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Multicentric reticulohistiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rosai-Dorfman disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>The malignant histiocytosis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Classification of <span class="elsevierStyleItalic">Langerhans cell histiocytosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">1&#46; <span class="elsevierStyleItalic">Isolated disease in a single organ or system</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary LCH &#40;85&#37; of the cases of pulmonary LCH in adults&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Bone &#40;single or multiple&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Skin&#47;hypothalamus&#47;hypophysis&#47;lymph nodes&#47;liver&#44; spleen&#44; thyroid glands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">2&#46; <span class="elsevierStyleItalic">Multisystem disease</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&#58; <span class="elsevierStyleItalic">affecting two or more organs</span>&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Source&#58; <span class="elsevierStyleInterRef" id="intr0005" href="https://www.histiocytesociety.org/">https&#58;&#47;&#47;www&#46;histiocytesociety&#46;org</span>&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Previous nomenclature&#58; histiocytosis X&#44; eosinophilic granuloma&#46; Hashimoto Pritzker disease&#58; in the newborn&#44; skin lesions and self-healing course&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Previous nomenclature&#58; Letterer&#8211;Siwe disease&#58; aggressive infantile disorder with fever&#44; lymphadenopathy&#44; hepatosplenomegaly&#44; bone and lung involvement&#46; Hand&#8211;Schuller&#8211;Christian&#58; triad of exophthalmos&#44; diabetes insipidus and bone lesions&#44; typical infantile disease&#44; rare in adults&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Classification of Histiocytosis&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Differential diagnosis of the cystic pattern on radiology</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Respiratory bronchiolitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary Langerhans cell histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Amyloidosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lymphangioleiomyomatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary embolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cystic fibrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Congenital pulmonary airway malformation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tuberous sclerosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information
ISSN: 21735743
Original language: English
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Idiomas
Reumatología Clínica (English Edition)
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