Collagen-Vascular Disease Associated With Interstitial Lung

Article Author:
Steven Lange
Article Editor:
Maansi Parekh
Updated:
6/21/2020 8:38:59 PM
PubMed Link:
Collagen-Vascular Disease Associated With Interstitial Lung

Introduction

Collagen vascular disease encompasses a diverse group of immunologically-mediated entities which share overlapping clinical and histopathologic features as well as manifest in characteristic patterns of interstitial lung disease. The collagen vascular diseases which commonly affect the pulmonary system include rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), polymyositis (PM), dermatomyositis (DM), mixed connective tissue disease (MCTD), and Sjogren’s syndrome (SS). The degree of lung involvement and spectrum of thoracic findings vary among the disorders, may be seen with clinically early or late disease, and portends certain patient outcomes. Identification of pulmonary involvement has important therapeutic and prognostic implications. Collagen vascular disease may be associated with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), diffuse alveolar damage (DAD), and lymphocytic interstitial pneumonia (LIP).[1]

Etiology

The collagen vascular diseases are immunologically-mediated diseases that may be idiopathic or influenced by genetic and environmental factors, such as medications, smoking, and sex hormones. The causes of connective diseases are mostly unknown, though the role of autoimmunity is well-established.[2] Rheumatoid arthritis is theorized to be instigated by an infectious agent with tissue damage mediated by tumor necrosis factor. Various cytokines have been identified as contributory in the inflammatory response. Systemic lupus erythematosus is thought to be caused by an interaction between gene susceptibility and environmental agents and inflammation-mediated by deposition of auto-antibodies in certain tissues. Various viruses, such as Ebstein-Barr, and Mycoplasma and Borrelia species, have also been implicated as causes of systemic lupus erythematosus. Vascular injury is believed to be the initial pathologic event in scleroderma, while similar mechanisms of inflammation are implicated in Sjogren's syndrome, polymyositis, and dermatomyositis.

Epidemiology

Approximately 15 percent of patients with interstitial lung disease have underlying collagen vascular disease, although the exact frequency of collagen vascular disease-associated interstitial lung disease is unknown.[3] Up to 90% of patients with collagen vascular disease will have pulmonary involvement. Interstitial lung disease prevalence on high-resolution computed tomography (CT) is 70%-90% in systemic sclerosis, 4%-68% in rheumatoid arthritis, 20%-85% in mixed connective tissue disease, 10%-30% in Sjogren's syndrome, and up to 30% in systemic lupus erythematosus.[4] 

Rheumatoid arthritis affects up to two percent of the population, most of whom are women, although rheumatoid arthritis-related interstitial lung disease is more common in middle-aged men. The highest incidence occurs between the ages of 25 and 50 years. Extra-articular involvement is seen in up to half of patients with rheumatoid arthritis, with the pulmonary disease as the second most common cause of death.[5] Clinically significant interstitial lung disease in the form of usual interstitial pneumonia (most common), nonspecific interstitial pneumonia, or cryptogenic organizing pneumonia is seen in approximately five percent of patients.[6] Acute interstitial pneumonia is a rare entity that presents with a rapidly fatal course.[7]

Progressive systemic sclerosis (SSc), or scleroderma, is a multisystem disease occurring predominantly in women. The highest incidence occurs between the ages of 45 and 64 years.[8] Patterns of interstitial lung disease include nonspecific interstitial pneumonia and less commonly usual interstitial pneumonia. Of patients with collagen vascular disease, those with systemic sclerosis suffer the highest mortality, mostly secondary to pulmonary arterial hypertension (10%-16% prevalence).[9] 

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease that predominantly affects women (>90% of cases) and non-Whites. Interstitial lung disease is a rare yet insidious complication, affecting 1 in 1000 individuals, with the most common manifestation being nonspecific interstitial pneumonia.[10]

Polymyositis (PM) and dermatomyositis (DM) are inflammatory myopathies, which occur most commonly in women between the ages of 40 and 50 years. The frequency of ILD is purported to be between 5% and 30%, presenting most commonly as nonspecific interstitial pneumonia or cryptogenic organizing pneumonia, which may precede the development of clinical myositis.[10] 

Mixed connective tissue disease (MCTD), as the name suggests, manifests as a combination of the above etiologies. Ninety percent of patients are female, with incidence highest in the second and third decades. Interstitial lung disease is the most common pulmonary manifestation, occurring in up to 66% of patients.[11][12] The most common pattern of interstitial lung disease is nonspecific interstitial pneumonia, followed by usual interstitial pneumonia and lymphocytic interstitial pneumonia, with ground glass opacities the most frequent parenchymal abnormality.[6][13]

Sjogren's syndrome (SS) is an autoimmune disease characterized by T-cell infiltration of various organs, most often the lacrimal and salivary glands. It affects up to 3% of adults, most of whom are women aged 30 to 40 years. Interstitial lung disease is more common in primary Sjogren's syndrome, manifesting as lymphocytic interstitial pneumonia, nonspecific interstitial pneumonia, usual interstitial pneumonia, or cryptogenic organizing pneumonia.[14][15]

Pathophysiology

Interstitial lung disease is characterized by a combination of chronic inflammation and a pro-inflammatory cascade with varying degrees of fibrosis.

Histopathology

On histopathologic examination, interstitial lung disease associated with collagen vascular disease includes usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), diffuse alveolar damage (DAD), lymphocytic interstitial pneumonia (LIP), and apical fibrosis.[16] Although nonspecific, suggestive findings include lymphoid hyperplasia and prominent plasma cell inflammation with interstitial inflammation.[17] There are varying degrees of inflammation and fibrosis, which often correspond to reticular or ground glass opacification on CT.[18]

Usual interstitial pneumonia appears as architectural distortion, fibrosis with honeycombing, and fibroblastic foci. There are heterogeneous areas of fibrosis interspersed with normal lung parenchyma.[19]

Nonspecific interstitial pneumonia can be classified as the cellular or fibrotic type, depending on the degree of interstitial inflammation and fibrosis. There is diffuse cellular inflammation in a homogenous pattern with patchy intervening lung tissue and preservation of lung architecture.[19]

Cryptogenic organizing pneumonia appears as intraluminal organizing fibrosis in the distal airspaces with patchy preservation of lung architecture and mild chronic interstitial inflammation.

Diffuse alveolar damage appears as alveolar edema, hyaline membranes, and fibroelastic proliferation with little mature collagen.

Lymphocytic interstitial pneumonia appears as infiltration of T-lymphocytes, plasma cells, and macrophages with lymphoid hyperplasia.

Acute lupus pneumonitis may appear as alveolar damage and necrosis, leading to inflammatory cell infiltration, edema, and hyaline membrane formation. Histopathologic findings are commonly those of usual interstitial pneumonia or nonspecific interstitial pneumonia.[20]

In rheumatoid arthritis, interstitial pneumonitis and fibrosis are the most common manifestations.[21] Most patients with interstitial fibrosis have usual interstitial pneumonia or nonspecific interstitial pneumonia. Follicular bronchiolitis may be present. The spectrum of histologic patterns includes pulmonary rheumatoid nodules, usual interstitial pneumonia, cryptogenic organizing pneumonia, lymphoid hyperplasia, and cellular interstitial infiltrates in an NSIP-type pattern.[22]

Systemic sclerosis frequently involves pulmonary fibrosis in both limited and diffuse forms of the disease, secondary to nonspecific interstitial pneumonia or usual interstitial pneumonia, and follicular bronchiolitis or cryptogenic organizing pneumonia is occasionally seen.[23]

Although diffuse interstitial pneumonitis is uncommon in systemic lupus erythematosus, histopathologic findings are those of nonspecific interstitial pneumonia or usual interstitial pneumonia.[16]

Interstitial lung disease associated with polymyositis or dermatomyositis may manifest as cryptogenic organizing pneumonia, usual interstitial pneumonia, nonspecific interstitial pneumonia, or diffuse alveolar damage, each of which determines a different prognosis. Diffuse alveolar damage and usual interstitial pneumonia portend a worse prognosis (30% survival at 5 years), contrary to those with cryptogenic organizing pneumonia or nonspecific interstitial pneumonia.[24]

Mixed connective tissue disease may demonstrate interstitial fibrosis secondary to usual interstitial pneumonia or nonspecific interstitial pneumonia.[16]

Sjogren’s syndrome most commonly presents with lymphocytic interstitial pneumonia, characterized by diffuse interstitial infiltration of lymphoplasma cells, often with mild fibrosis.[25] Overinflation of the secondary pulmonary lobule may represent cyst formation and/or air-trapping.[26]

History and Physical

Patients with interstitial lung disease typically present with exertional dyspnea and nonproductive cough. Extrapulmonary symptoms such as arthralgia, myalgia, fatigue, or malaise may also be present and suggest an underlying collagen vascular disease. Family history may suggest a particular diagnosis, as some collagen vascular diseases have a genetic basis. Smoking, drug use, employment history, and occupational exposure are important to ascertain.[27]

Pulmonary auscultation may reveal rales or crackles. Skin findings may include skin thickening and telangiectasias (systemic sclerosis), Raynaud's phenomenon (systemic sclerosis and systemic lupus erythematosus), discoid, or butterfly rash (systemic lupus erythematosus), heliotrope rash (polymyositis and dermatomyositis), and Gottron papules (polymyositis and dermatomyositis). Xerostomia, xerophthalmia, and parotid swelling may be seen in patients with Sjogren's syndrome.[28]

Evaluation

The diagnosis of interstitial lung disease can be made with pulmonary function testing (PFT) demonstrating restrictive lung disease with diminished total lung capacity (TLC), decreased forced vital capacity (FVC), and impaired diffusion of oxygen and carbon dioxide. Reduction in forced vital capacity determines the severity of restrictive physiology. PFT is predominantly a guide of the severity of disease and response to treatment, and should not be used alone to diagnose interstitial lung disease as it is nonspecific.[19] Autoimmune serologic testing may detect antibodies and other markers specific to certain subtypes of collagen vascular disease. Surgical lung biopsy remains the gold standard for determining the subtype of interstitial lung disease.[4]

A chest radiograph is often the first radiologic modality used in the investigation of interstitial lung disease, though it is insufficient in making a diagnosis. The X-ray may detect basilar reticulonodular infiltrates or cystic changes in various subtypes of interstitial lung disease, though many patients with interstitial lung disease may have an unremarkable study.

High-resolution computed tomography (HRCT) of the chest shows a variety of patterns in different interstitial lung diseases.

In nonspecific interstitial pneumonia, there are bilateral and generally symmetric ground-glass opacities and subpleural reticulation, occasionally with microcystic honeycombing, with subpleural sparing. Traction bronchiectasis or bronchiolectasis is a nearly universal feature in fibrotic nonspecific interstitial pneumonia, as is lower-lobe architectural distortion. Cellular and fibrotic nonspecific interstitial pneumonia are ultimately distinguished only by histology.[16]

Usual interstitial pneumonia may be indistinguishable from nonspecific interstitial pneumonia, with ground glass opacities and subpleural reticulation in an apicobasal gradient. Consolidation and honeycombing, however, are more common in usual interstitial pneumonia.[6] Findings in usual interstitial pneumonia include intralobular septal thickening, honeycombing, traction bronchiectasis, and subpleural reticular opacities in a peripheral, subpleural, or basal distribution. The presence of macrocystic honeycombing is typical for UIP.

Lymphocytic interstitial pneumonia is characterized by diffuse ground-glass opacities with thin-walled central or perivascular cysts. There may be centrilobular nodules, bronchovascular bundle thickening, and interlobular septal thickening.

Organizing pneumonia appears as patchy bilateral and peripheral consolidations and ground-glass opacities. Alveolar opacities may appear triangular, polygonal, or wedge-shaped in appearance, range in size from small nodules to mass-like consolidations, and expand or migrate over time. The atoll or reverse halo sign may be appreciated.[29] 

Diffuse alveolar damage demonstrates diffuse consolidation and ground-glass opacification, often with lobular sparing as well as traction bronchiectasis in later stages.[16] Crazy paving (a linear pattern superimposed on a background of ground-glass opacity) may be appreciated.

Acute or chronic aspiration, such as from esophageal dysmotility in systemic sclerosis or respiratory muscle weakness in polymyositis/dermatomyositis, may appear as centrilobular nodules, tree-in-bud opacities, and/or bronchial wall thickening.[30]

In rheumatoid arthritis, irregular hyperattenuating areas represent intralobular lines and interlobular septal thickening. Honeycombing may be seen at the lung bases. CT patterns include subpleural reticulation or ground-glass opacities with or without honeycombing (nonspecific interstitial pneumonia, usual interstitial pneumonia, cryptogenic organizing pneumonia), centrilobular branching structures with or without bronchial dilatation or traction bronchiectasis (usual interstitial pneumonia, cryptogenic organizing pneumonia), and consolidation (cryptogenic organizing pneumonia). The reticular pattern predominates in early disease, whereas honeycombing and consolidation typically appear in progressive disease.[6][31]

In systemic sclerosis, there may be evidence of interstitial pneumonitis and fibrosis involving the lower lobes in a peripheral and posterior distribution.[32] Findings on CT have been shown to correlate with pulmonary function tests, and the extent of honeycombing significantly correlates with a decrease in diffusing capacity for carbon monoxide.[13]

In systemic lupus erythematosus, ground-glass opacities and consolidations may reflect interstitial pneumonitis and fibrosis. Interstitial abnormalities, including interlobular septal thickening, irregular linear hyperattenuating areas, and architectural distortion may be seen in up to one-third of patients, and are commonly mild and focal[33].

In polymyositis and dermatomyositis, there may be prominent interlobular septa, ground-glass opacities, patchy consolidation, parenchymal bands, bronchial thickening, and subpleural lines. Consolidation with or without ground-glass opacification corresponds to cryptogenic organizing pneumonia or diffuse alveolar damage. Patchy consolidations, parenchymal bands, and bronchial thickening are reversible, while ground-glass opacities with subpleural lines representing usual interstitial pneumonia may progress to honeycombing.[34]

In mixed connective tissue disease, abnormalities may include irregular linear hyperattenuating areas with reticulation at the lung bases. In later stages of the disease, there may be honeycombing with fibrosis extending apically, as well as areas of consolidation that may be related to cryptogenic organizing pneumonia.[16]

In Sjogren's syndrome, the most common findings on CT are bronchiolectasis and centrilobular nodular or branching linear hyperattenuating areas, ground-glass opacities, and honeycombing. The characteristic pattern of lymphocytic interstitial pneumonia with extensive ground-glass opacification and thin-walled cysts may be seen. Poorly defined centrilobular nodules and bronchovascular thickening represent lymphoplasma cell infiltration of interstitial tissue.[26]

Treatment / Management

Treatment of collagen vascular disease-associated interstitial lung disease is geared towards the underlying connective tissue disease. Corticosteroids, immunomodulators, and antifibrosis medications have been employed with variable efficacy. Oxygen therapy improves breathing, facilitates exercise, prevents complications of hypoxia and pulmonary arterial hypertension, and fosters well-being. Physical rehabilitation may help improve mobility and achieve activities of daily living. Lung transplantation may be an option for patients with advanced and irreversible disease.

Differential Diagnosis

Other entities that cause interstitial lung diseases, such as sarcoidosis and occupational disorders, must be considered. Acute viral pneumonia, including COVID-19 pneumonia, may also appear clinically and radiologically similar to acute exacerbation of interstitial lung disease. Cardiogenic and non-cardiogenic pulmonary edema may cause diffuse alveolar and interstitial opacities with interlobular septal thickening that may simulate interstitial lung disease.[35]

Prognosis

Collagen vascular disease-associated interstitial lung disease is associated with significant morbidity and mortality. Collagen vascular disease-associated interstitial lung disease typically bears a better prognosis than idiopathic interstitial lung disease and a slower progression than idiopathic pulmonary fibrosis. Mortality is highest in those who develop pulmonary hypertension, have higher oxygen requirements, and require mechanical ventilation.[27][36] Nearly 20% of patients with nonspecific interstitial pneumonia die within five years of diagnosis.[37] More extensive disease, as determined by a higher volume of lung burden on high-resolution CT and diminished forced vital capacity on pulmonary function testing, correlates with future mortality in many patients.[4]

Complications

Interstitial lung disease and pulmonary arterial hypertension are the main causes of mortality and morbidity in patients with collagen vascular disease.[6] Drug toxicity and infection are also common complications affecting this patient population.

Drugs used to treat rheumatoid arthritis, such as gold salts and penicillamine, may cause diffuse alveolar damage or obliterative bronchiolitis.[5] Methotrexate therapy, on the other hand, has been associated with pneumonitis.[38]

Consultations

An interprofessional team involving rheumatologists and pulmonologists is often necessary to treat patients with collagen vascular disease-associated interstitial lung disease. A consensus approach by a team with expertise in interstitial lung disease is considered the gold standard.[1]

Deterrence and Patient Education

Patients with a personal or family history of collagen vascular disease who present with salient physical exam findings or symptomatology should consult with a rheumatologist and/or pulmonologist in order to be evaluated for collagen vascular disease-associated interstitial lung disease, which may include a physical exam, pulmonary function testing, and radiologic imaging.

Enhancing Healthcare Team Outcomes

The diagnosis of collagen vascular disease-associated interstitial lung disease and its distinction from infectious disease, hypersensitivity or drug-associated pneumonitis, and malignancy is often difficult, requiring collaboration among a team of healthcare professionals. Treatment and management are improved using an interprofessional approach with clinical, radiological, and pathological models for decision-making. A comprehensive management approach also takes into consideration comorbid conditions such as gastroesophageal reflux disease, obstructive sleep apnea, and pulmonary hypertension, as well as adjunctive therapeutic modalities such as oxygen use, exercise, and cardiopulmonary rehabilitation.[39][40]


References

[1] Mikolasch TA,Garthwaite HS,Porter JC, Update in diagnosis and management of interstitial lung disease . Clinical medicine (London, England). 2017 Apr;     [PubMed PMID: 28365626]
[2] Jindal SK,Agarwal R, Autoimmunity and interstitial lung disease. Current opinion in pulmonary medicine. 2005 Sep;     [PubMed PMID: 16093819]
[3] Koo SM,Uh ST, Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist's point of view. The Korean journal of internal medicine. 2017 Jul;     [PubMed PMID: 28704913]
[4] Wallace B,Vummidi D,Khanna D, Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Current opinion in rheumatology. 2016 May;     [PubMed PMID: 27027811]
[5] Kim DS, Interstitial lung disease in rheumatoid arthritis: recent advances. Current opinion in pulmonary medicine. 2006 Sep;     [PubMed PMID: 16926650]
[6] Capobianco J,Grimberg A,Thompson BM,Antunes VB,Jasinowodolinski D,Meirelles GS, Thoracic manifestations of collagen vascular diseases. Radiographics : a review publication of the Radiological Society of North America, Inc. 2012 Jan-Feb;     [PubMed PMID: 22236892]
[7] Brown KK, Rheumatoid lung disease. Proceedings of the American Thoracic Society. 2007 Aug 15;     [PubMed PMID: 17684286]
[8] Coral-Alvarado P,Pardo AL,Castaño-Rodriguez N,Rojas-Villarraga A,Anaya JM, Systemic sclerosis: a world wide global analysis. Clinical rheumatology. 2009 Jul;     [PubMed PMID: 19277816]
[9] McLaughlin V,Humbert M,Coghlan G,Nash P,Steen V, Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford, England). 2009 Jun;     [PubMed PMID: 19487219]
[10] Tansey D,Wells AU,Colby TV,Ip S,Nikolakoupolou A,du Bois RM,Hansell DM,Nicholson AG, Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004 Jun;     [PubMed PMID: 15186274]
[11] Burdt MA,Hoffman RW,Deutscher SL,Wang GS,Johnson JC,Sharp GC, Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis and rheumatism. 1999 May;     [PubMed PMID: 10323445]
[12] Bodolay E,Szekanecz Z,Dévényi K,Galuska L,Csípo I,Vègh J,Garai I,Szegedi G, Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford, England). 2005 May;     [PubMed PMID: 15716315]
[13] Kim EA,Johkoh T,Lee KS,Ichikado K,Koh EM,Kim TS,Kim EY, Interstitial pneumonia in progressive systemic sclerosis: serial high-resolution CT findings with functional correlation. Journal of computer assisted tomography. 2001 Sep-Oct;     [PubMed PMID: 11584237]
[14] Cain HC,Noble PW,Matthay RA, Pulmonary manifestations of Sjögren's syndrome. Clinics in chest medicine. 1998 Dec;     [PubMed PMID: 9917960]
[15] Parambil JG,Myers JL,Lindell RM,Matteson EL,Ryu JH, Interstitial lung disease in primary Sjögren syndrome. Chest. 2006 Nov;     [PubMed PMID: 17099028]
[16] Kim EA,Lee KS,Johkoh T,Kim TS,Suh GY,Kwon OJ,Han J, Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. Radiographics : a review publication of the Radiological Society of North America, Inc. 2002 Oct;     [PubMed PMID: 12376608]
[17] American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. American journal of respiratory and critical care medicine. 2002 Jan 15;     [PubMed PMID: 11790668]
[18] Wells AU,Hansell DM,Corrin B,Harrison NK,Goldstraw P,Black CM,du Bois RM, High resolution computed tomography as a predictor of lung histology in systemic sclerosis. Thorax. 1992 Sep;     [PubMed PMID: 1440471]
[19] Kalchiem-Dekel O,Galvin JR,Burke AP,Atamas SP,Todd NW, Interstitial Lung Disease and Pulmonary Fibrosis: A Practical Approach for General Medicine Physicians with Focus on the Medical History. Journal of clinical medicine. 2018 Nov 24;     [PubMed PMID: 30477216]
[20] Colby TV, Pulmonary pathology in patients with systemic autoimmune diseases. Clinics in chest medicine. 1998 Dec;     [PubMed PMID: 9917955]
[21] Tanoue LT, Pulmonary manifestations of rheumatoid arthritis. Clinics in chest medicine. 1998 Dec;     [PubMed PMID: 9917959]
[22] Yousem SA,Colby TV,Carrington CB, Lung biopsy in rheumatoid arthritis. The American review of respiratory disease. 1985 May;     [PubMed PMID: 3873887]
[23] Minai OA,Dweik RA,Arroliga AC, Manifestations of scleroderma pulmonary disease. Clinics in chest medicine. 1998 Dec;     [PubMed PMID: 9917962]
[24] Tazelaar HD,Viggiano RW,Pickersgill J,Colby TV, Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. The American review of respiratory disease. 1990 Mar;     [PubMed PMID: 2310101]
[25] Deheinzelin D,Capelozzi VL,Kairalla RA,Barbas Filho JV,Saldiva PH,de Carvalho CR, Interstitial lung disease in primary Sjögren's syndrome. Clinical-pathological evaluation and response to treatment. American journal of respiratory and critical care medicine. 1996 Sep;     [PubMed PMID: 8810621]
[26] Johkoh T,Müller NL,Pickford HA,Hartman TE,Ichikado K,Akira M,Honda O,Nakamura H, Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1999 Aug;     [PubMed PMID: 10429719]
[27] Singh P,Thakur B,Mohapatra AK,Padhan P, Clinical features and outcome of acute exacerbation in connective tissue disease-associated interstitial lung disease: A single-center study from India. International journal of rheumatic diseases. 2019 Sep;     [PubMed PMID: 31328423]
[28] Kadoya K,Togo S,Tulafu M,Namba Y,Iwai M,Watanabe J,Okabe T,Jin J,Kodama Y,Kitamura H,Ogura T,Kitamura N,Ikeo K,Takeda T,Kondo N,Takahashi K, Specific Features of Fibrotic Lung Fibroblasts Highly Sensitive to Fibrotic Processes Mediated via TGF-β-ERK5 Interaction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2019     [PubMed PMID: 30946557]
[29] Polverosi R,Maffesanti M,Dalpiaz G, Organizing pneumonia: typical and atypical HRCT patterns. La Radiologia medica. 2006 Mar;     [PubMed PMID: 16671378]
[30] Argiriadi PA,Mendelson DS, High resolution computed tomography in idiopathic interstitial pneumonias. The Mount Sinai journal of medicine, New York. 2009 Feb;     [PubMed PMID: 19170217]
[31] Akira M,Sakatani M,Hara H, Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and their courses. Journal of computer assisted tomography. 1999 Nov-Dec;     [PubMed PMID: 10589572]
[32] Remy-Jardin M,Remy J,Wallaert B,Bataille D,Hatron PY, Pulmonary involvement in progressive systemic sclerosis: sequential evaluation with CT, pulmonary function tests, and bronchoalveolar lavage. Radiology. 1993 Aug;     [PubMed PMID: 8327704]
[33] Fenlon HM,Doran M,Sant SM,Breatnach E, High-resolution chest CT in systemic lupus erythematosus. AJR. American journal of roentgenology. 1996 Feb;     [PubMed PMID: 8553934]
[34] Akira M,Hara H,Sakatani M, Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology. 1999 Feb;     [PubMed PMID: 10207411]
[35] Atzeni F,Gerardi MC,Barilaro G,Masala IF,Benucci M,Sarzi-Puttini P, Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review. Expert review of clinical immunology. 2018 Jan     [PubMed PMID: 29202589]
[36] Takizawa H,Suzuki N,Yanagawa T,Okazaki H,Satoh M,Akiyama N,Kohyama T,Ito K,Oka T, [Importance of interstitial lung disease in collagen vascular disease: analysis of outcome]. Nihon Kyobu Shikkan Gakkai zasshi. 1996 Nov;     [PubMed PMID: 8976070]
[37] Travis WD,Hunninghake G,King TE Jr,Lynch DA,Colby TV,Galvin JR,Brown KK,Chung MP,Cordier JF,du Bois RM,Flaherty KR,Franks TJ,Hansell DM,Hartman TE,Kazerooni EA,Kim DS,Kitaichi M,Koyama T,Martinez FJ,Nagai S,Midthun DE,Müller NL,Nicholson AG,Raghu G,Selman M,Wells A, Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. American journal of respiratory and critical care medicine. 2008 Jun 15;     [PubMed PMID: 18388353]
[38] Imokawa S,Colby TV,Leslie KO,Helmers RA, Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. The European respiratory journal. 2000 Feb;     [PubMed PMID: 10706507]
[39] Solomon JJ,Chartrand S,Fischer A, Current approach to connective tissue disease-associated interstitial lung disease. Current opinion in pulmonary medicine. 2014 Sep;     [PubMed PMID: 25022317]
[40] Fischer A,du Bois R, Interstitial lung disease in connective tissue disorders. Lancet (London, England). 2012 Aug 18;     [PubMed PMID: 22901890]