Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells

Abstract Background Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. Methods We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. Results Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. Conclusions BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias

BackgroundIn 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical "gold standard" of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs.PurposeThe objective of this statement is to update the 2002 ATS/ERS classification of IIPs.MethodsAn international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011.ResultsSubstantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis-interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment.ConclusionsThis update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation

Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis: Results of the INJOURNEY trial

Measurements and Main Results: On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were 213.3 (17.4) ml and 240.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. Conclusions: Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Rationale: Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. Objectives: To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. Methods: Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study

Background To evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease (DPLD). Methods Seven multidisciplinary meetings (MDTMs) consisting of at least one clinician, radiologist and pathologist, from 7 different countries evaluated 70 cases of diffuse lung disease in a two-stage process. First, the clinician, radiologist and pathologist (when lung biopsy was performed) evaluated each case and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. A full MDTM with review of all clinical, radiologic and pathologic data followed this. Interobserver agreement and inter-MDTM agreement for diagnosis was calculated using Cohen's kappa coefficient or weighted kappa coefficient where appropriate. Findings Inter-MDTM agreement for first choice diagnoses was acceptable (κ = 0.50). Idiopathic pulmonary fibrosis made up 18% of all MDTM first choice diagnoses. Diagnostic likelihoods for MDTM differential diagnoses were converted to a 5-point scale (0 = condition not included in the differential diagnosis, 1 = low probability (5-25%), 2 = intermediate probability (30-65%), 3 = high probability (70-95%), and 4 = pathognomonic (100%)). Inter-MDTM agreement on diagnostic likelihoods was good for idiopathic pulmonary fibrosis (IPF) (κw = 0.71) and connective tissue disease related interstitial lung disease (CTD-ILD) (κw = 0.73), only moderate for non-specific interstitial pneumonia (NSIP) (κw = 0.42) and poor for hypersensitivity pneumonitis (HP) (κw = 0.29). MDTMs, clinicians and radiologists respectively gave high confidence diagnoses of IPF (>65% likelihood) in 77.3%, 64.6% and 66.3% of cases. The prognostic significance of a first choice diagnosis of IPF versus not IPF was evaluated for MDTMs, clinicians and radiologists. Greater prognostic significance was demonstrated for an MDTM diagnosis of IPF as compared to individual clinician's diagnosis of IPF in 5/7 MDTMs, radiologist's diagnosis of IPF in 4/7 MDTMs. Interpretation Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF. This is validated by the greater prognostic significance of an IPF diagnosis made by MDTMs as compared to individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than clinicians or radiologists. MDTM agreement for diagnosis of NSIP and hypersensitivity pneumonitis is poor, indicating a need for international consensus on diagnostic criteria for these diseases