• Humans
• Lung Diseases, Interstitial/etiology
• Scleroderma, Systemic/complications
• Immunosuppressive Agents/therapeutic use
• Randomized Controlled Trials as Topic
• Practice Guidelines as Topic
• Indoles

• Cryobiopsy
• Interstitial lung disease
• Lung biopsy
• Systemic sclerosis

• Humans
• Scleroderma, Systemic/diagnosis
• Scleroderma, Systemic/complications
• Scleroderma, Systemic/pathology
• Lung Diseases, Interstitial/diagnosis
• Lung Diseases, Interstitial/pathology
• Biopsy/methods
• Prognosis
• Lung/pathology
• Female

Pulmonary involvement complicates the various aspects of care in patients suffering from autoimmune disorders. The epidemiological data generated over the last 10 to 15 years have improved the overall understanding of the risk factors and pathophysiological mechanisms involved in pulmonary involvement in rheumatological conditions. Recent advances in genetics have provided superior insight into the pathogenesis of autoimmune diseases and the underlying pulmonary involvement. This review article provides a concise overview of the four most common rheumatological conditions associated with pulmonary involvement: systemic lupus erythematosus (SLE), dermatomyositis/polymyositis, rheumatoid arthritis (RA), and systemic sclerosis (SSc). The clinical, epidemiological, and genetic aspects of these diseases are summarized in this article with particular emphasis on the characteristic patterns of pulmonary involvement in radiological imaging and various treatment options for each of these autoimmune diseases and their lung manifestations.

To investigate the correlation of HRCT findings with pulmonary metabolic activity in the corresponding regions using ¹⁸F-FDG PET/CT and inflammatory markers in patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD).

This was a cross-sectional study involving 23 adult patients with SSc-associated ILD without other connective tissue diseases. The study also involved ¹⁸F-FDG PET/CT, HRCT, determination of serum chemokine levels, clinical data, and pulmonary function testing.

In this cohort of patients with long-term disease (disease duration, 11.8 ± 8.7 years), a nonspecific interstitial pneumonia pattern was found in 19 (82.6%). Honeycombing areas had higher median standardized uptake values (1.95; p = 0.85). Serum levels of soluble tumor necrosis factor receptor 1, soluble tumor necrosis factor receptor 2, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 10 were higher in SSc patients than in controls. Serum levels of CCL2-a marker of fibroblast activity-were correlated with pure ground-glass opacity (GGO) areas on HRCT scans (p = 0.007). ¹⁸F-FDG PET/CT showed significant metabolic activity for all HRCT patterns. The correlation between serum CCL2 levels and GGO on HRCT scans suggests a central role of fibroblasts in these areas, adding new information towards the understanding of the mechanisms surrounding cellular and molecular elements and their expression on HRCT scans in patients with SSc-associated ILD.

¹⁸F-FDG PET/CT appears to be unable to differentiate the intensity of metabolic activity across HRCT patterns in chronic SSc patients. The association between CCL2 and GGO might be related to fibroblast activity in these areas; however, upregulated CCL2 expression in the lung tissue of SSc patients should be investigated in order to gain a better understanding of this association.

• Gastroprotective agents
• Interstitial lung disease
• Observational study
• Prevention
• Systemic sclerosis

• Adult
• Aged
• Canada/epidemiology
• Female
• Follow-Up Studies
• Gastrointestinal Agents/administration & dosage
• Humans
• Incidence
• Lung Diseases, Interstitial/etiology
• Lung Diseases, Interstitial/prevention & control
• Male
• Middle Aged
• Registries
• Retrospective Studies
• Risk
• Scleroderma, Systemic/complications

• FRN 83518 CIHR

• evidence-based medicine
• guidelines
• hypersensitivity pneumonitis
• interstitial lung disease

• S100A12
• epithelial cells
• interstitial lung disease
• skin fibrosis
• systemic sclerosis

Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung. To better understand SSc pathogenesis and develop new disease-modifying therapies, it is quite important to understand the complex pathogenesis of SSc from the two distinct perspectives, namely the common pathologic cascade and additional organ-specific pathologies.

• a common pathologic cascade across multiple organs
• additional organ-specific pathologies
• systemic sclerosis

• bronchiolitis
• hypersensitivity pneumonitis
• interstitial lung diseases
• lung sounds

• Auscultation/methods
• Bronchioles/pathology
• Bronchioles/physiopathology
• Cohort Studies
• Female
• Humans
• Lung Diseases, Interstitial/complications
• Lung Diseases, Interstitial/diagnosis
• Lung Diseases, Interstitial/physiopathology
• Male
• Middle Aged
• Pulmonary Fibrosis/diagnostic imaging
• Pulmonary Fibrosis/etiology
• Pulmonary Fibrosis/physiopathology
• Respiratory Sounds/diagnosis
• Respiratory Sounds/physiopathology
• Retrospective Studies
• Tomography, X-Ray Computed/methods

• Barrett’s esophagus
• GERD
• interstitial lung disease
• laryngopharyngeal reflux
• microaspiration
• silent reflux
• systemic sclerosis

International experts recently characterized interstitial pneumonia with autoimmune features (IPAF) as a provisional diagnosis for patients with interstitial lung disease who have characteristics of autoimmune disease but do not meet criteria for a specific autoimmune disease. We describe clinical characteristics of IPAF patients and examine responses to mycophenolate as a therapy for IPAF.

This retrospective cohort included adult patients meeting European Respiratory Society/American Thoracic Society classification criteria for IPAF. Sociodemographic, clinical, and pulmonary function test data were abstracted for patients with and without mycophenolate treatment and followed longitudinally from interstitial lung disease diagnosis for change in pulmonary function test results.

We identified 52 patients who met criteria for IPAF. Of 52 IPAF patients, 24 did not receive mycophenolate and 28 did, with median time to mycophenolate treatment 22 months. Changes in FVC% and percentage predicted lung diffusion capacity for carbon monoxide (D_LCO%) between the mycophenolate-treated and untreated groups were not significantly different (FVC% change P=0.08, D_LCO% change P=0.17). However, there was a trend toward more rapid baseline decline of both FVC% and D_LCO% in the mycophenolate-treated cohort before vs after mycophenolate therapy. The slope of both FVC% and D_LCO% values improved after onset of mycophenolate exposure for the treated group, although this finding was not statistically significant.

Patients with IPAF might benefit from mycophenolate therapy. Larger prospective clinical trials are needed to evaluate the efficacy of mycophenolate for patients who meet criteria for IPAF.

• autoimmune disease
• connective tissue disease
• interstitial lung disease
• mycophenolate

• Biopsy
• Disease Progression
• Humans
• Lung/diagnostic imaging
• Lung/pathology
• Lung/physiopathology
• Lung Diseases, Interstitial/diagnosis
• Lung Diseases, Interstitial/etiology
• Lung Diseases, Interstitial/physiopathology
• Lung Diseases, Interstitial/therapy
• Predictive Value of Tests
• Prognosis
• Pulmonary Diffusing Capacity
• Reproducibility of Results
• Respiratory Function Tests
• Scleroderma, Systemic/complications
• Scleroderma, Systemic/diagnosis
• Scleroderma, Systemic/physiopathology
• Scleroderma, Systemic/therapy
• Time Factors
• Tomography, X-Ray Computed
• Total Lung Capacity
• Vital Capacity

• diagnostic criteria
• guidelines
• severity classification
• systemic sclerosis
• treatment

• Dermatologic Agents/therapeutic use
• Evidence-Based Medicine/methods
• Evidence-Based Medicine/standards
• Fingers
• Gastrointestinal Tract/diagnostic imaging
• Gastrointestinal Tract/pathology
• Heart/diagnostic imaging
• Humans
• Kidney/pathology
• Lung/diagnostic imaging
• Lung/pathology
• Myocardium/pathology
• Rheumatology/methods
• Rheumatology/standards
• Scleroderma, Systemic/classification
• Scleroderma, Systemic/diagnosis
• Scleroderma, Systemic/drug therapy
• Scleroderma, Systemic/pathology
• Severity of Illness Index
• Skin/pathology
• Time Factors
• Tomography, X-Ray Computed

Lung illness encountered in patients with rheumatic diseases bears clinical significance in terms of increased morbidity and mortality as well as potential challenges placed on patient care. Although our understanding of natural history of this important illness is still limited, epidemiologic knowledge has been accumulated during the past decade to provide useful information on the risk factors and prognosis of lung involvements in rheumatic diseases. Moreover, the pathogenesis particularly in the context of genetics has been greatly updated for both the underlying rheumatic disease and associated lung involvement. This review will focus on the current update on the epidemiologic and genetics features and treatment options of the lung involvements associated with four major rheumatic diseases (rheumatoid arthritis, systemic sclerosis, myositis, and systemic lupus erythematosus), with more attention to a specific form of involvement or interstitial lung disease.

• bronchiolitis obliterans
• hypersensitivity pneumonitis
• non specific interstitial pneumonia
• organizing pneumonia
• respiratory bronchiolitis
• usual interstitial pneumonia

• Pathology
• Pulmonary involvement
• Radiology
• Systemic sclerosis
• Tomography
• X-ray computed

Systemic sclerosis (SSc) is a disorder characterized by immune dysfunction, microvascular injury, and fibrosis. Organ involvement in patients with SSc is variable; however, pulmonary involvement occurs in up to 90% of patients with SSc. Interstitial lung disease (ILD) is a major cause of mortality and, thus, a major determinant in the prognosis of patients with SSc. This review summarizes current findings about the characteristics of ILD in patients with SSc, selection of patients with SSc-ILD who are candidates for the treatment, and current treatment options.

• interstitial lung disease
• pulmonary hypertension
• systemic sclerosis

Interstitial lung disease (ILD) is an important manifestation of collagen vascular diseases. It is a common feature of scleroderma, and also occurs in dermatomyositis and polymyositis, mixed connective tissue disease, Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, and Antineutrophil cytoplasmic antibody-associated vasculitis. When present, it is associated with increased morbidity and mortality, thus making early diagnosis important. In fact, in many patients, ILD may be the first manifestation of a collagen vascular disease. The most common symptoms are cough and dyspnea. The diagnosis is made based on pulmonary function tests showing restrictive lung disease and impaired oxygen diffusion and chest imaging showing ground glass infiltrates, interstitial thickening, and/or fibrosis. The most common histologic finding on lung biopsy is non-specific interstitial pneumonia, though organizing pneumonia and usual interstitial pneumonia may also be seen. Treatment is focused on addressing the underlying collagen vascular disease with immunosuppression, either with corticosteroids or a steroid-sparing agent such as cyclophosphamide, azathioprine, or mycophenolate, although the optimal agent and duration of therapy is not known. There are few clinical trials to guide therapy that focus specifically on the progression of ILD. The exception is in the case of scleroderma-associated ILD, where cyclophosphamide has been shown to be effective.

• Interstitial lung disease
• Collagen vascular disease
• Connective tissue disease
• Rheumatoid arthritis
• Scleroderma
• Myositis
• Sjogren’s syndrome
• Systemic lupus erythematosus
• Antineutrophil cytoplasmic antibody-associated vasculitis
• Mixed connective tissue disease

• Constipation
• Dysmotility
• Esophagus
• Fecal incontinence
• Gastroesophageal reflux
• Gastroparesis
• Pseudo-obstruction
• Systemic sclerosis

Airway-centered Interstitial Fibrosis (ACIF) is a common pathologic pattern observed in our practice.

The objectives of this study are to describe the causes associated with ACIF in a large sample of patients and its effect on survival.

A retrospective study in three centers of interstitial lung disease in São Paulo, between January of 1995 and December of 2012. The surgical lung biopsy specimens were reviewed by three pathologists. The clinical, functional and tomographic findings were analyzed by a standardized protocol.

There were 68 cases of ACIF, most of them women. The mean age was 57 ± 12 yr. Dyspnea, cough, restrictive pattern at spirometry and oxygen desaturation at exercise were common. A reticular pattern with peribronchovascular infiltrates was found in 79% of the cases. The etiologies of ACIF were hypersensitivity pneumonitis in 29 (42.6%), gastroesophageal reflux disease in 17 (25.0%), collagen vascular disease in 4 (5.9%), a combination of them in 15 cases and idiopathic in 3 (4.4%). The median survival was 116 months (95% CI = 58.5 – 173.5). Lower values of oxygen saturation at rest, presence of cough and some histological findings - organizing tissue in the airways, fibroblastic foci and microscopic honeycombing - were predictors of worse survival.

ACIF is an interstitial lung disease with a better survival when compared with IPF. The main etiologies are HP and GERD. The oxygen saturation at rest, the presence of cough and some histological findings are predictors of survival.

• systemic sclerosis
• idiopathic pulmonary fibrosis
• immunohistochemistry
• angiotensin
• survival

• Aged
• Analysis of Variance
• Biopsy
• Female
• Fibrosis
• Humans
• Idiopathic Pulmonary Fibrosis/pathology
• Immunohistochemistry
• Lung/pathology
• Lymphatic Vessels/pathology
• Male
• Middle Aged
• Proportional Hazards Models
• Receptor, Angiotensin, Type 1/analysis
• Receptor, Angiotensin, Type 2/analysis
• Respiratory Function Tests
• Risk Factors
• Scleroderma, Systemic/pathology
• Statistics, Nonparametric

Because histopathological changes in the lungs of patients with systemic sclerosis (SSc) are consistent with alveolar and vessel cell damage, we presume that this interaction can be characterized by analyzing the expression of proteins regulating nitric oxide (NO) and plasminogen activator inhibitor-1 (PAI-1) synthesis. To validate the importance of alveolar-vascular interactions and to explore the quantitative relationship between these factors and other clinical data, we studied these markers in 23 cases of SSc nonspecific interstitial pneumonia (SSc-NSIP). We used immunohistochemistry and morphometry to evaluate the amount of cells in alveolar septa and vessels staining for NO synthase (NOS) and PAI-1, and the outcomes of our study were cellular and fibrotic NSIP, pulmonary function tests, and survival time until death. General linear model analysis demonstrated that staining for septal inducible NOS (iNOS) related significantly to staining of septal cells for interleukin (IL)-4 and to septal IL-13. In univariate analysis, higher levels of septal and vascular cells staining for iNOS were associated with a smaller percentage of septal and vascular cells expressing fibroblast growth factor and myofibroblast proliferation, respectively. Multivariate Cox model analysis demonstrated that, after controlling for SSc-NSIP histological patterns, just three variables were significantly associated with survival time: septal iNOS (P=0.04), septal IL-13 (P=0.03), and septal basic fibroblast growth factor (bFGF; P=0.02). Augmented NOS, IL-13, and bFGF in SSc-NSIP histological patterns suggest a possible functional role for iNOS in SSc. In addition, the extent of iNOS, PAI-1, and IL-4 staining in alveolar septa and vessels provides a possible independent diagnostic measure for the degree of pulmonary dysfunction and fibrosis with an impact on the survival of patients with SSc.

• DYSPHAGIA
• GASTROESOPHAGEAL REFLUX DISEASE
• INTERSTITIAL LUNG DISEASE
• PULMONARY FIBROSIS
• SCLERODERMA
• SYSTEMIC SCLEROSIS

• Gastrointestinal Diseases/diagnosis
• Gastrointestinal Diseases/etiology
• Gastrointestinal Diseases/physiopathology
• Gastrointestinal Diseases/therapy
• Humans
• Scleroderma, Systemic/complications

The histological counterpart of idiopathic pulmonary fibrosis is usual interstitial pneumonia, in which areas of fibrosis of various ages are interspersed with normal lung. This pattern could be explained by repeated episodes of lung injury followed by abnormal wound healing responses. The cause of the initiating alveolar epithelial injury is unknown, but postulated mechanisms include immunological, microbial, or chemical injury, including aspirated gastric refluxate. Reflux is promoted by low basal pressure in the lower oesophageal sphincter and frequent relaxations, potentiated by hiatus hernia or oesophageal dysmotility. In susceptible individuals, repeated microaspiration of gastric refluxate may contribute to the pathogenesis of IPF. Microaspiration of nonacid or gaseous refluxate is poorly detected by current tests for gastroesophageal reflux which were developed for investigating oesophageal symptoms. Further studies using pharyngeal pH probes, high-resolution impedance manometry, and measurement of pepsin in the lung should clarify the impact of reflux and microaspiration in the pathogenesis of IPF.