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BACKGROUND AND OBJECTIVE MicroRNA (miRNA) are transcriptional regulators implicated in pulmonary sarcoidosis and packaged in extracellular vesicles (EV) during cellular communication. We characterized EV and investigated miRNA expression in bronchoalveolar lavage (BAL) fluid from sarcoidosis patients. METHODS EV were characterized for size(s) using dynamic light scattering and transmission electron microscopy (TEM) analysis and protein markers by immunoblotting. Twelve extracellular and 5 cellular miRNA were investigated in BAL from 16 chest X-ray stage-I (CXR-I) and 17 CXR stage-II (CXR-II) sarcoidosis patients. Associations between miRNA and disease characteristics (extrapulmonary involvement, pulmonary function and BAL cell profile) were statistically analysed. RESULTS BAL from sarcoidosis patients contained exosomes and microvesicles (MV) as EV. In these EV, expression of miR-146a (P = 0.007), miR-150 (P = 0.003) and BAL cellular miR-21 (P = 0.01) was increased in CXR-II compared with CXR-I. Other detected EV (miR-21 and miR-26a) and cellular (miR-31, miR-129-3p, miR-146a and miR-452) miRNA were not differentially expressed. The investigated miRNA did not reflect extrapulmonary involvement, but EV miR-146a and miR-150 were negatively correlated with pulmonary function (miR-146a with vital capacity (VC; Spearman's correlation coefficient (rs ), P = -0.657, 0.007), percent predicted forced expiratory volume in 1 s (FEV1 ; -0.662, 0.006) and FEV1 /forced vital capacity (FVC) ratio (-0.649, 0.008); miR-150 correlated negatively with VC (-0.584, 0.019) and FEV1 /FVC ratio (-0.746, 0.001) in CXR-II cases). CONCLUSION Our data provide evidence that exosomes and microvesicles as extracellular vesicles are present in the bronchoalveolar space of sarcoidosis patients and they differentially express EV miRNA (miR-146a and miR-150), the expression of which correlates negatively with pulmonary function indices. The significance of these findings for disease pathophysiology and clinical course require further investigation.

Objective Anti-nuclear autoantibodies are known to occur in 85-99% of Systemic Sclerosis (SSc) patients, with each SSc autoantibody correlating with a distinct clinical subset of patients. The objective of this study was to investigate novel SSc autoantibodies in the remaining autoantibody negative patients and establish clinical associations. Methods Serum samples and clinical data were collected from 548 SSc patients. Sera were tested for known SSc autoantibodies by routine serological techniques, with negative samples being further investigated by radiolabelled protein immunoprecipitation (IPP). Sera that immunoprecipitated a novel 30 kDa band were analysed by indirect immunofluorescence and IPP using depleted cell extracts to establish a common reactivity. Mass spectrometry (MS) was used to identify the novel autoantigen and findings were confirmed using commercial antibodies. Sera from 426 patients with other forms of connective tissue disease, 103 patients with rheumatoid arthritis, 114 patients with idiopathic ILD and 150 healthy controls were serotyped as controls. Results A novel autoantigen with a molecular weight of ∼30 kDa was recognised by seven sera with SSc, six of whom had interstitial lung disease (ILD) and by no controls. Six of the patients had diffuse cutaneous involvement and four had overlap features with other autoimmune diseases. Immunodepletion experiments indicated that all samples targeted the same autoantigen and MS identified the novel autoantigen as eIF2B (Eukaryotic Initiation Factor 2B). Conclusion We report a novel autoantibody (anti-eIF2B) in a small number of patients with SSc (approximately 1%) that is closely associated with diffuse cutaneous manifestations and the presence of ILD. This article is protected by copyright. All rights reserved.

InterMune Inc. (Brisbane, California, USA) Background The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. Methods The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a >= 10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a >= 10% decline in FVC or death during the subsequent 6 months. Results A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, -0.146, p= 10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a >= 10% decline in FVC or death (5.9% vs 27.9% relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). Conclusions Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. Inova Fairfax Hosp, Heart & Lung Transplant Ctr, Falls Church, VA 22042 USA Univ Turin, Dept Clin & Biol Sci, Turin, Italy InterMune Inc, Brisbane, CA USA Ruhrlandklin, Dept Pneumol Allergy, Essen, Germany Univ London Imperial Coll Sci Technol & Med, London, England Alfred Hosp, Melbourne, Australia Monash Univ, Melbourne, Australia Univ Miami, Miller Sch Med, Miami, FL 33136 USA Univ Calif San Francisco, San Francisco, CA 94143 USA Vanderbilt Univ, Med Ctr, Nashville, TN USA Columbia Univ, Med Ctr, New York, NY USA Univ Fed Sao Paulo, Paulista Sch Med, Sao Paulo, Brazil Natl Jewish Hlth, Interstitial Lung Dis Program, Denver, CO USA Avicenne Univ Hosp, AP HP, Bobigny, France Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA Royal Brompton Hosp, London SW3 6LY, England Univ Fed Sao Paulo, Paulista Sch Med, Sao Paulo, Brazil| Web of Science

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort. The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity. The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features. A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort. ERS/ATS task force provides nomenclature and classification criteria for patients with IIP and autoimmune features

The Gender-Age-Physiology (GAP) model is a validated, baseline-risk prediction model for mortality in idiopathic pulmonary fibrosis. Longitudinal variables have been shown to contribute to risk prediction in idiopathic pulmonary fibrosis and may improve the predictive performance of the baseline GAP model. Our aims were to further validate the GAP model and evaluate whether the addition of longitudinal variables improves its predictive performance. The study population was derived from a large clinical trials cohort of patients with idiopathic pulmonary fibrosis (n=1109). Model performance was determined by improvement in the C-statistic, net reclassification improvement, clinical net reclassification improvement, and a goodness-of-fit test. The GAP model had good discriminative performance with a C-statistic of 0.757 (95% CI 0.750–0.764). However, the original GAP model tended to overestimate risk in this cohort. A novel, easy to use model, consisting of the original GAP predictors plus history of respiratory hospitalisation and 24-week change in forced vital capacity (the longitudinal GAP model) improved model performance with a C-statistic of 0.785 (95% CI 0.780–0.790), net reclassification improvement of 8.5%, clinical net reclassification improvement of 25%, and a goodness-of-fit test of 0.929. The Longitudinal GAP model, along with the original GAP model, may unify baseline and longitudinal mortality risk prediction in idiopathic pulmonary fibrosis. GAP and longitudinal GAP models may provide simple unified baseline and longitudinal mortality risk prediction in IPF http://ow.ly/FhYwZ

In pulmonary sarcoidosis, the optimal means of quantifying change is uncertain. The comparative usefulness of simple lung function trends and chest radiography remains unclear. We aimed to explore and contrast the disease-monitoring strategies of serial pulmonary function tests (PFTs) and chest radiography compared against morphologic change on high-resolution CT (HRCT) scan.Seventy-three patients with sarcoidosis were identified who had two HRCT scans with concurrent chest radiography and PFTs. Chest radiography and HRCT scans were assessed by two radiologists for change in disease extent. Concordance between the scoring systems, as well as agreement between PFT trends (% change from baseline in FEV, FVC, and diffusing capacity of the lung for carbon monoxide [Dlco]), chest radiography, and chest HRCT scan change, were examined using the weighted κ coefficient of variation (Kw).There was fair agreement between change in extent of disease on chest radiograph and significant PFT trends (Kw = 0.35, Plt; .001) and moderate agreement between change in extent of disease on serial HRCT scan and significant PFT trends (Kw = 0.64, Plt; .0001). The integration of Dlco trends did not improve concordance between change on HRCT scan and PFT change. Change in gas transfer coefficient (ie, Dlco/alveolar volume) displayed no overall linkage with change in disease extent on chest radiograph (Kw = 0.07, P = .27) and only poor agreement with change in disease extent on HRCT scan (Kw = 0.17, P = .07).Significant PFT trends correlate better with morphologic change as defined by serial HRCT scan than extent of disease on radiograph. Isolated change in gas transfer coefficient is more frequently discordant with change in disease extent on chest radiograph and HRCT scan and may suggest a pulmonary vascular component.

Background and objective A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA-ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers. Methods Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers. Results Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P

RationaleMortality prediction is well studied in idiopathic pulmonary fibrosis (IPF), but little is known about predictors of premortality disease progression. Identification of patients at risk for disease progression would be useful for clinical decision-making and designing clinical trials.ObjectivesTo develop prediction models for disease progression in IPF.MethodsIn a large clinical trial cohort of patients with IPF (n = 1,113), we comprehensively screened multivariate models of candidate baseline and past-change predictors for disease progression defined by 48-week worsening of FVC, dyspnea (University of California, San Diego Shortness of Breath Questionnaire [UCSD SOBQ]), 6-minute-walk distance (6MWD), and occurrence of respiratory hospitalization, or death. Progression outcomes were modeled as appropriate, by slope change using linear regression models and time to binary outcomes using Cox proportional hazards models.Measurements and main resultsThe overall cohort experienced considerable disease progression. Top-performing prediction models did not meaningfully predict most measures of disease progression. For example, prediction modeling explained less than or equal to 1% of the observed variation in 48-week slope change in FVC, UCSD SOBQ, and 6MWD. Models performed better for binary measures of time to disease progression but were still largely inaccurate (cross-validated C statistic ≤0.63 for ≥10% decline in FVC or death, ≤0.68 for ≥20-U increase in UCSD SOBQ or death, ≤0.70 for ≥100 m decline in 6MWD or death). Models for time to respiratory hospitalization or death (C statistic ≤0.77) or death alone (C statistic ≤0.81) demonstrated acceptable discriminative performance.ConclusionsClinical prediction models poorly predicted physiologic and functional disease progression in IPF. This is in contrast to respiratory hospitalization and mortality prediction.

Rationale There is no consensus as to when treatment for idiopathic pulmonary fibrosis (IPF) should be initiated. Some physicians prefer not to treat patients with preserved lung volume. Objective To investigate whether patients with IPF and preserved lung volume receive the same benefit from nintedanib as patients with more impaired lung volume. Methods Post hoc subgroup analyses of pooled data from the two replicate phase III INPULSIS trials by baseline FVC % predicted (≤90%, >90%). Results At baseline, 274 patients had FVC >90% predicted and 787 patients had FVC ≤90% predicted. In patients treated with placebo, the adjusted annual rate of decline in FVC was consistent between patients with FVC >90% predicted and FVC ≤90% predicted (−224.6 mL/year and −223.6 mL/year, respectively). There was no statistically significant difference between these subgroups in the effect of nintedanib on annual rate of decline in FVC, change from baseline in St George's Respiratory Questionnaire total score or time to first acute exacerbation. In patients with baseline FVC >90% predicted and ≤90% predicted, respectively, the adjusted annual rate of decline in FVC with nintedanib was −91.5 mL/year (difference vs placebo: 133.1 mL/year (95% CI 68.0 to 198.2)) and −121.5 mL/year (difference vs placebo: 102.1 mL/year (95% CI 61.9 to 142.3)). Adverse events associated with nintedanib were similar in both subgroups. Conclusions Patients with IPF and preserved lung volume (FVC >90% predicted) have the same rate of FVC decline and receive the same benefit from nintedanib as patients with more impaired lung volume. Trial registration number NCT01335464 and [NCT01335477][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01335477&atom=%2Fthoraxjnl%2Fearly%2F2016%2F09%2F26%2Fthoraxjnl-2016-208710.atom

The endothelins are a family of endothelium-derived peptides that possess a variety of biological activities, including potent vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and pulmonary fibrosis. Here, we use genome-wide expression array analysis to show that the addition of ET-1 (100 nm, 4 h) to normal lung fibroblasts directly induces expression of matrix and matrix-associated genes, including the profibrotic protein CCN2 (connective tissue growth factor, or CTGF). ET-1 induces the MEK/ERK MAP kinase pathway in fibroblasts. Blockade of the MEK/ERK kinase pathway with U0126 abrogates the ability of ET-1 to induce expression of matrix and matrix-associated mRNAs and the CCN2 protein. The CCN2 promoter possesses an ET-1 response element, which maps to the previously identified basal control element-1 (BCE-1) site. Our results suggest that ET-1 induces a program of matrix synthesis in lung fibroblasts and that ET-1 may play a key role in connective tissue deposition during wound repair and in pulmonary fibrosis.

Time to first investigator-reported acute exacerbation was a key secondary end-point in the INPULSIS trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF).We used the INPULSIS trial data to investigate risk factors for acute exacerbation of IPF and to explore the impact of nintedanib on risk and outcome of investigator-reported and adjudicated confirmed/suspected acute exacerbations. Mortality following these events and events adjudicated as not acute exacerbations was analysed using the log rank test.Risk of acute exacerbations was most strongly associated with the following variables: baseline forced vital capacity (higher risk with lower value), baseline supplemental oxygen (higher risk with use), baseline antacid medication (higher risk with use), treatment (higher risk with placebo), and for confirmed/suspected acute exacerbations, cigarette smoking. Mortality was similar following investigator-reported and adjudicated confirmed/suspected acute exacerbations. Nintedanib had no significant effect on risk of mortality post-exacerbation.Investigator-reported acute exacerbations of IPF are associated with similar risk factors and outcomes as adjudicated confirmed/suspected acute exacerbations.

Background Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. Results We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 Pmeta = 3.7 × 10−09). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10−7 and DQB1*06:02 P = 6.1 × 10−8). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q

Systemic lupus erythematosus (SLE) can affect all compartments of the thorax, either as part of the systemic disease or due to pulmonary infection as a consequence of the immunosuppressive effects of the disease itself or the drugs used to treat it. Infection must be rigorously excluded when lung disease is evident. This chapter focuses on all the pulmonary manifestations of SLE and provides the authors' views on best management while acknowledging that there is no true evidence base for any of the recommendations due to the absence of any controlled studies of pulmonary disease in SLE or its treatment.

Summary Some of the most pressing challenges associated with interstitial lung disease (ILD) are how best to define, diagnose, and treat connective tissue disease-associated ILD (CTD-ILD)—disorders with potentially substantial morbidity and mortality. In this focused review, we address aspects of prognosis for CTD-ILD and what indices might predict outcome, together with lessons that can be learnt from clinical trials of systemic sclerosis-associated ILD and idiopathic pulmonary fibrosis and how these lessons might be applied to future studies of CTD-ILD.

Summary Objective We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD). Methods The study sample included 74 subjects with respiratory symptoms, evaluated January 2008–January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation. Results The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity ( n =33), three developed the articular manifestations of RA during a median follow-up of 449 days. Conclusion We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation.

Pirfenidone has been shown in three recently published trials to slow down the progression of the devastating interstitial lung disease, idiopathic pulmonary fibrosis (IPF). The precise mechanisms that initiate and perpetuate the histopathological process leading to lung fibrosis in IPF are still uncertain, but increased concentrations of reactive oxidative species and fibrogenetic factors have been observed in the pulmonary tissue of patients. Although the exact mechanisms of its action are unknown, pirfenidone is a small molecule with antifibrotic and some hydroxyl scavenger properties that has recently been approved in Europe and elsewhere for the treatment of IPF. Along with the new ATS/ERS/JRS/ALAT 2011 statement for 'Evidence Based Guidelines for Diagnosis and Management', there is now a more profound basis for offering IPF patients an evidence-based evaluation and treatment. This review summarizes the background to the recommended use of pirfenidone for the treatment of IPF.

The American Thoracic Society and European Respiratory Society guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) have been published recently. However, the influence, practical application, and utility of the prior consensus statement for IPF have never been evaluated. Demographics, diagnostic criteria, pulmonary function data, and disposition of patients with IPF evaluated at an interstitial lung disease center between 2000 and 2009 were analyzed. Enrollment in clinical drug trials, lung transplantation, and mortality also were assessed. A total of 521 patients with IPF were evaluated, with pulmonary function testing available in 446. In the 64% of patients without surgical lung biopsy, the most common major criterion not fulfilled was bronchoscopy. Lung transplantation was performed in 16.1% of patients, whereas 27.4% of prescreened patients were enrolled in a prospective drug study. Patients with mild, moderate, and severe disease categorized by FVC % predicted had median survivals of 55.6, 38.7, and 27.4 months, respectively. The attrition rate of patients who survived beyond 5 years was attenuated in subsequent years. IPF remains a deadly disease with a poor prognosis. Bronchoscopy does not appear to be required for an accurate diagnosis. A minority of patients were accommodated within a clinical trial or with transplantation. Categorization by baseline FVC % predicted effectively discriminates groups with different long-term outcomes. Our analysis supports the view that the value of statements also can be realized in the subsequent demonstration of their impact on patient management, which might enable further refinements in a continuous, iterative rediscovery process.

A b s t r ac t Background The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. Methods Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. Results Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10 − 15 ; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10 − 37 ). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P

This commentary highlights the present dilemmas surrounding the classification of a patient with interstitial pneumonia who has clinical features suggesting an associated connective tissue disease but the features fall short of a clear diagnosis of connective tissue disease-associated interstitial lung disease under the current rheumatologic classification systems. This commentary illustrates what we perceive to be the limitations in the present approach to the classification of this group of patients and discusses problems with redefining the diagnosis of undifferentiated connective tissue disease to encompass patients with interstitial pneumonia. Finally, we advocate not only for a multidisciplinary approach to evaluation, but also disease classification and offer a proposal to define them as a distinct phenotype—lung-dominant CTD—for which prognostic, therapeutic, and pathobiologic implications can be tested in future, hopefully multiinstitutional, studies.

Summary Rationale Health-related quality of life (HRQL) is an important outcome in drug trials. Little is known about how the Short Form-36 (SF-36) and Saint George's Respiratory Questionnaire (SGRQ) perform in idiopathic pulmonary fibrosis (IPF). Objectives To examine the validity of the SF-36 and SGRQ and to determine scores from each that would constitute a minimum important difference (MID). Methods We analyzed data from a recently completed trial that enrolled subjects with well-defined IPF who completed the SF-36, SGRQ, and Baseline/Transition Dyspnea Index at baseline and six months. We compared mean changes in HRQL scores between groups of subjects whose disease severity changed over six months according to clinical anchors (FVC, DLCO, and dyspnea). We estimated the MID for each domain by using both anchor- and distribution-based approaches. Main results Results supported the validity of the SF-36 and SGRQ for use in longitudinal studies. Mean changes in domain scores differed significantly between subjects whose clinical status improved and those whose clinical status declined according to the anchors. MID estimates for the SF-36 ranged from 2–4 points and from 5–8 points for the SGRQ. Conclusion In IPF, the SF-36 and SGRQ possess reasonable validity for differentiating subjects whose disease severity changes over time. More studies are needed to continue the validation process, to refine estimates of the MIDs for the SF-36 or SGRQ, and to determine if a disease-specific instrument will perform better than either of these.

Rationale The response characteristics of the 6 minute walk test (6MWT) in studies of idiopathic pulmonary fibrosis (IPF) are only poorly understood, and the change in walk distance that constitutes the minimum important difference (MID) over time is unknown. Objectives To examine changes over time in distance walked (ie, 6MWD) during the 6MWT and to estimate the change in distance that constitutes the MID in patients with IPF. Methods Data from a recently completed trial that included subjects with IPF who completed the 6MWT, Saint George’s Respiratory Questionnaire (SGRQ) and forced vital capacity (FVC) at 6 and 12 months were used to examine longitudinal changes in 6MWD. Both anchorand distribution-based approaches as well as linear regression analyses were used to determine the MID for 6MWD. The SGRQ Total score and FVC were used as clinical anchors. Main results Among 123 subjects alive and able to complete the 6MWT at both follow-up time points, 6MWD did not change significantly over time (378.1 m at baseline vs 376.8 m at 6 months vs 361.3 m at 12 months, p¼0.5). The point estimate for the 6MWD MID was 28 m with a range of 10.8e58.5 m. Conclusion In a group of patients with IPF with moderate physiological impairment, for those alive and able to complete a 6MWT, 6MWD does not change over 12 months. At the population level, the MID for 6MWD appears to be w28 m. Further investigation using other anchors and derivation methods is required to refine estimates of the MID for 6MWD in this patient population.

Summary Objectives To describe the clinical features of patients presenting with “idiopathic” interstitial pneumonia that were diagnosed with anti-synthetase syndrome based on clinical features and positive anti-PL-7 or PL-12 antibodies. Methods Over a 24-month period, we evaluated 37 patients who presented with clinical features of anti-synthetase (AS) syndrome, negative anti-Jo-1 antibodies, and who were assessed for other anti-tRNA synthetase (anti-tRS) antibodies. All data were abstracted from the medical record. Results Nine (24%) were confirmed to have non-anti-Jo-1 positive AS syndrome based on clinical features and the presence of other anti-tRS antibodies (seven with anti-PL-7, two with anti-PL-12 antibodies). All presented with dyspnea as the initial symptom and with ILD as the first manifestation. Elevated CPK was identified in three patients but only two had muscle weakness. Pulmonary physiology revealed restriction (forced vital capacity 60% of predicted) and impaired gas transfer (diffusing capacity for carbon monoxide 40% of predicted). All had similar findings on thoracic HRCT scans, with basilar predominance of abnormalities and patterns suggestive of non-specific interstitial pneumonia and organizing pneumonia. Immunomodulatory therapies were used to treat the ILD—responses were variable, but some subjects clearly improved. Conclusion Anti-PL-7 and PL-12 antibodies may be more common among patients presenting with “idiopathic” interstitial pneumonia than formerly considered and should be checked in patients with features of AS syndrome despite a negative screen for anti-nuclear or anti-Jo-1 antibodies. Further research is needed to advance understanding of anti-PL-7 or anti-PL-12-positive AS syndrome, including its prognosis and optimal approaches to therapy.

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive, fibrosing interstitial lung disease without effective therapy and a poor prognosis. Median survival times have been observed to be as low as 2.5 years.1 Investigators2–8 have identified several prognostic variables in IPF, including age, gender, disease duration, symptom severity, radiologic features, functional capacity, and both baseline and serial changes in measures of pulmonary physiology and gas exchange. Despite the numerous prognostic variables that inform discussions about prognosis in IPF patients, heterogeneity in the disease course complicates making accurate survival predictions. Heart rate recovery (HRR), specifically the failure of the heart rate to decline at 1 or 2 min postexercise, is associated with increased mortality.9–11 Heart rates in patients with COPD recover less at 1 min than control subjects (mean [± SD] heart rates, 20 ± 9 vs 11 ± 9, respectively; p 14 beats 1 min after exercise is associated with a fivefold increased risk of death over a mean follow-up duration of 43 months.12 HRR after exertion has not been examined as a prognostic marker in patients with IPF. The 6-min walk test (6MWT) is a marker of functional exercise capacity that is increasingly used in the initial and longitudinal clinical assessments of patients with IPF. In these patients, the distance walked during the 6MWT is highly reproducible (test-retest reliability, 0.98) over short time intervals (eg, 1 to 2 weeks) and is highly correlated (r = 0.78) with peak oxygen uptake measured during a cardiopulmonary exercise test to volitional fatigue.13 Given the low cost and simplicity of the 6MWT and its apparent validity as an exercise challenge and measure of functional capacity in patients with IPF, we hypothesized that it would provide an ideal setting in which to measure HRR. The main objectives of this study were to define the cutoff values for abnormal HRR, to examine the predictors of an abnormal HRR, and to determine whether an abnormal HRR after a 6MWT carries prognostic value in patients with IPF.

Background: The best method to interpret the chest roentgenogram and its sensitivity to detect effect of treatment for sarcoidosis remains unclear. In a double-blind, randomized trial of infliximab for chronic pulmonary sarcoidosis, changes in serial chest roentgenograms were examined by radiologists, blinded to order or treatment. Methods: Chest roentgenograms were obtained at 0, 6, and 24 weeks of therapy with either placebo, 3 mg/kg infliximab, or 5 mg/kg infliximab. Films were reviewed in random order by two independent radiologists, unaware of treatment. The films were compared using two methods: the prespecified objective assessment, a scoring system previously proposed by Muers; and the post hoc assessment, a 5-point Likert scale global assessment between two films. Results: Of 138 patients enrolled in the study, chest roentgenograms for all studies were available on 130 patients. There was only fair agreement between the two radiologists in the original stage of the chest roentgenogram (weighted 0.43; 95% confidence interval [CI], 0.32 to 0.54). For the Likert scale of global assessment of change, there was good agreement between the two readers (weighted 0.61; 95% CI, 0.51 to 0.71). There was good correlation between the two readers for the various components of the Muers score, especially the reticulonodular (R) score (R 0.578; p < 0.05). The initial R score was positively correlated with improvement in FVC with infliximab therapy (R 0.239; p < 0.05). Conclusion: Global assessment and the Muers scoring system were associated with good agreement between two expert readers. Improvement in both scores correlated with improvement in FVC. Trial registration: ClinicalTrials.gov Identifier: NCT00073437 (CHEST 2009; 136:526–535)

To determine the type of ocular involvement in patients with neurosarcoidosis, and evaluate whether the type of eye involvement may help in the diagnosis of neurosarcoidosis.Retrospective, case history study. We reviewed the medical records of 46 patients who attended the sarcoidosis clinics at the Royal Brompton and Moorfields Eye Hospital over a 4-year period with a diagnosis of definite and probable neurosarcoidosis supported by laboratory investigations and exclusion of other causes for the neurological symptoms.Cranial nerve involvement was the most common neurological manifestation in this series. Among the 27 patients with cranial neuropathy, lower motor neurone facial palsy was the most frequently seen in 19 patients (70.4%). Diplopia was seen in four patients (14.9%). In three patients, this was because of common oculomotor nerve paresis. Uveitis was the most common intraocular manifestation in patients with neurosarcoidosis. The majority of these patients (9, 64.3%) suffered from anterior uveitis, but in 35.7% of them the inflammatory process involved the posterior segment.We found a higher incidence of ocular manifestations, including intraocular inflammation in neurosarcoidosis compared to that in systemic sarcoidosis elsewhere. The most common ocular complication seen in our series was anterior uveitis; however there were no associated clinical features of the uveitis in these series that could contribute to the differential diagnosis between neurosarcoidosis and other autoimmune disorders with neuro-ophthalmic features such as multiple sclerosis. Patients with neurological symptoms and associated intraocular inflammation should have a routine work-up for sarcoidosis. Investigations should include MRI scan of the brain and orbits and lumbar puncture in selected cases. Tissue biopsy should be attempted when clinically accessible lesions are available i.e., conjunctiva or lacrimal gland.

Assessment of disease activity in fibrosing alveolitis due to systemic sclerosis (FASSc) is difficult without using invasive investigation. A repeatable noninvasive method of assessing disease at a cellular level such as with positron emission tomography (PET) could be of great value in evaluating high-resolution changes in the pathological process.To investigate whether the level of inflammatory cell traffic and lung density in FASSc, imaged in vivo by PET, is different to controls and whether they are associated with changes in pulmonary function indices.We used PET to measure lung density and tissue uptake of (11)C-[R]-PK11195, a ligand that binds to receptors found in abundance in macrophages. Fifteen patients with FASSc were compared to seven controls.A trend of reduced uptake of (11)C-[R]-PK11195 was observed in FASSc patients (P=.09) and correlated inversely with lung density (r=-.62; P.05), which was significantly elevated in FASSc [0.35+/-0.02 vs. 0.23+/-0.02 g/cc (mean+/-S.E.M.); P.005].These results demonstrate that inflammatory cell traffic and lung density can be imaged in vivo in FASSc using PET, and that this approach might be of potential value in understanding, in situ, components of pathogenesis that may have value for prognosis.

Background Abnormal plasma and lung iron mobilization is associated with the onset and progression of ARDS and is detectable in specific at-risk populations. Patients with ARDS also have pronounced oxidative and nitrosative stress that can be catalyzed and thereby aggravated by the bioavailability of redox active iron. ARDS of pulmonary and extrapulmonary origin may differ pathophysiologically and require different ventilatory strategies. Evidence suggests that genetic predisposition is relevant to the pathogenesis of ARDS. We therefore explored the hypothesis that polymorphisms from a panel of genes encoding iron-metabolizing proteins determine susceptibility to ARDS. Methods Retrospective case-control study conducted at the adult ICUs of two university hospitals. Patients with ARDS (n = 122) and healthy control subjects (n = 193) were genotyped. Sequence-specific primer polymerase chain reaction was used to genotype selected biallelic single-nucleotide polymorphisms. An audit of the patient database was conducted, and 104 of the 122 ARDS patients were eligible for the final data analysis. Results Preliminary analysis indicated differences between ARDS and healthy control subjects in the incidence of polymorphism of the gene encoding ferritin light chain. Subgroup analysis indicated the prevalence of ferritin light-chain gene −3381GG homozygotes was increased in patients with ARDS of extrapulmonary origin compared to healthy control subjects. Secondly, a common haplotype in the heme oxygenase 2 gene was reduced in patients with ARDS compared to healthy control subjects and was more evident in those with ARDS of direct or pulmonary etiology. Conclusions These results provide preliminary evidence to suggest a distinction in the genetic background of the subpopulations studied, inferring that the ferritin light-chain gene genotype confers susceptibility to ARDS, while the heme oxygenase 2 haplotype is protective against the onset of the syndrome. Such data support further previous findings that suggest abnormalities in iron handling resulting in redox imbalance are implicated in the pathogenesis of ARDS.

Objective To explore increased susceptibility to fibrosis following experimental injury to alveolar epithelial cells (AECs) in a novel transgenic mouse model of scleroderma with fibroblast-specific perturbation of transforming growth factor β (TGFβ) signaling (TβRIIΔk-fib mice). Methods Wild-type (WT) and transgenic mice were injured with intratracheally administered saline or bleomycin, and the lungs were harvested for biochemical, histologic, and electron microscopic analysis. Results Electron microscopy revealed AEC abnormalities in the lungs of untreated transgenic mice and bleomycin-treated WT mice; the lungs of transgenic mice treated with bleomycin showed severe epithelial damage. Compared with lungs from bleomycin-treated WT mice, lungs from bleomycin-treated transgenic mice demonstrated increased fibroproliferation, myofibroblast persistence, and impaired hyperplasia and increased apoptosis of type II AECs. The lungs from saline-treated transgenic mice and those from bleomycin-treated WT mice had phenotypic similarities, suggesting enhanced susceptibility to minor epithelial injury in the transgenic strain. The level of collagen was increased in the lungs from transgenic mice compared with that in the lungs from WT mice after treatment with either bleomycin or saline. Persistent fibrosis in bleomycin-treated transgenic mice was independent of ongoing neutrophil inflammation but was associated with impaired alveolar epithelial repair. Conclusion These results suggest that in the context of fibroblast-specific perturbation of TGFβ signaling, even minor epithelial injury induces significant fibrosis. The model supports a central role for TGFβ in determining fibrosis and demonstrates that lung fibroblasts may regulate the response of AECs to injury. Our findings provide insight into likely pathogenic mechanisms in scleroderma-associated pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity, as measured by a modified six-minute-walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores, and quality of life (QOL) assessed using Short-Form 36 and St. George's Respiratory Questionnaire.A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-minute-walk distance (6MWD) up to Month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (hazard ratio [HR], 0.613; 95% confidence interval [CI], 0.328-1.144; P = 0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post hoc analysis; HR, 0.315; 95% CI, 0.126-0.789; P = 0.009). Changes from baseline up to Month 12 in assessments of dyspnea and QOL favored treatment with bosentan. No unexpected adverse events were reported.Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QOL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation. Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).

Objective Fibrosis is excessive scarring caused by the accumulation and contraction of extracellular matrix proteins and is a common end pathway in many chronic diseases, including scleroderma (systemic sclerosis [SSc]). Indeed, pulmonary fibrosis is a major cause of death in SSc. Transforming growth factor β (TGFβ) induces endothelin 1 (ET-1) in human lung fibroblasts by a Smad-independent, JNK-dependent mechanism. The goal of this study was to assess whether ET-1 is a downstream mediator of the profibrotic effects of TGFβ in lung fibroblasts. Methods We used a specific endothelin receptor antagonist to determine whether ET-1 is a downstream mediator of TGFβ responses in lung fibroblasts, using microarray technology, real-time polymerase chain reaction, and Western blot analyses. Results The ability of TGFβ to induce the expression of a cohort of profibrotic genes, including type I collagen, fibronectin, and CCN2, and to contract a collagen gel matrix, depends on ET-1. Conclusion ET-1 contributes to the ability of TGFβ to promote a profibrotic phenotype in human lung fibroblasts, consistent with the notion that endothelin receptor antagonism may be beneficial in controlling fibrogenic responses in lung fibroblasts.

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

Scleroderma (systemic sclerosis) is characterized by dermal thickening and is subclassified, on the basis of the pattern of skin involvement, as diffuse or limited cutaneous disease. The lung fibrosis associated with systemic sclerosis is histopathologically nonspecific interstitial pneumonia and occurs to various extents. A key determinant of the development of lung fibrosis is the carriage of the anti–DNA topoisomerase II autoantibody, which is driven by genotype, particularly major histocompatibility complex class II alleles. Epithelial and endothelial cell injury initiates lung pathology and the local milieu expresses all the expected components of an immune/inflammatory chronic process that has fibrosis as an associated feature. However, novel concepts of the pathogenesis include the role of epithelial mesenchymal transition as a source of myofibroblasts following epithelial cell triggering and the concept of fibroblast heterogeneity in terms of both origin and function. Focus on the poles of the pat...

PK11195 is a ligand with high affinity for peripheral benzodiazepine receptors (PBRs), which are present in large numbers in macrophages. PBRs play a role in antioxidant pathways and apoptosis, key factors in control of lung health. Intrapulmonary PBRs, assessed in vivo by positron emission tomography (PET), are decreased in interstitial lung disease (ILD) despite increased macrophage numbers. We wished to ascertain whether the observed decrease in in vivo expression of PBRs in the PET scans could be accounted for by a reduction in PBRs per cell by saturation-binding assays of R-PK11195 in cells obtained by bronchoalveolar lavage (BAL).We performed receptor saturation-binding assays with [(3)H]-R-PK11195 on a mixed population of cells recovered by BAL to quantify the number of R-PK11195 binding sites per macrophage in 10 subjects with ILD and 10 normal subjects.Receptor affinity [dissociation constant (Kd)] was similar in ILD patients and controls. However, R-PK11195 binding sites per cell [(maximal binding sites available (B(max))] were decreased in macrophages obtained by BAL from subjects with ILD compared to normal (P.0005). Microautoradiography confirmed localization of R-PK11195 to macrophages in a mixed inflammatory cell population obtained by BAL.These results demonstrate that in vitro PBR expression per cell on macrophages obtained by BAL is reduced in patients with ILD indicating a potentially functionally different macrophage phenotype. As PBRs are involved in the orchestration of lung inflammatory responses, this finding offers further insight into the role of macrophages in the pathogenesis of ILDs and offers a potential avenue for pharmacological strategy.

Among the idiopathic interstitial pneumonias, the two entities-idiopathic pulmonary fibrosis (IPF) characterised by the presence of the usual interstitial pneumonia pattern of histopathology (IPF/UIP) and non-specific interstitial pneumonia (NSIP; same nomenclature for the histopathological pattern and idiopathic disease) - have provoked considerable debate. IPF/UIP and NSIP closely mimic each other clinically but NSIP has a far better outcome. However, it remains unclear if NSIP is a truly separate and distinct entity. The histopathological pattern of NSIP can be found in a wide variety of clinical and radiological contexts. This review addresses these and other uncertainties regarding NSIP and UIP.

Aims and Methods: A review was undertaken of 19 patients diagnosed with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) between 1992 and 2006. Results: Most patients were women (n = 15) and non-smokers (n = 16). Clinical presentation was either with symptomatic pulmonary disease (group 1; n = 9) or as an incidental finding during investigation for another disorder, most frequently malignant disease (group 2; n = 10). In group 1, cough and dyspnoea were the most frequent symptoms, with an average duration of 8.6 years before diagnosis. Both groups showed mainly stable disease without treatment, although one patient progressed to severe airflow obstruction and one was diagnosed at single lung transplantation. Mosaicism with nodule(s) was the typical pattern of DIPNECH on high-resolution computed tomography, but one case had normal imaging despite airflow obstruction. Lung function tests showed obstructive (n = 8), mixed (n = 3) or normal (n = 5, all group 2) physiology. Two patients underwent a bronchoalveolar lavage and showed a lymphocytosis (30%) with mild chronic bronchiolitis being seen in all biopsies. Tumourlets and associated typical carcinoids (n = 9) showed weak positivity for thyroid transcription factor-1. Three patients had atypical carcinoids, one with multiple endocrine neoplasia type 1 syndrome. Conclusions: DIPNECH is being increasingly recognised, probably because of an increase in the usage and accuracy of investigative imaging and increased awareness of the entity. Most cases remain stable over many years independent of the mode of presentation, although a few patients progress to severe airflow obstruction.

Background Beryllium stimulates TNF-α from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells. Objective We sought to relate TNF polymorphisms to beryllium-stimulated TNF-α production, to the development of CBD, and to the risk of more severe CBD over time. Methods We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-α production from a subset of subjects. Results Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-α production was significantly increased in patients with CBD compared with that seen in those only sensitized ( P = .0002). Those subjects with the TNF –857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-α production compared with that seen in noncarriers ( P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-α levels ( P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pao 2 at maximum exercise was noted in patients with CBD with the −1031C allele ( P = .03) and with haplotypes other than the TNF haplotype 1 ( P = .01), 3 (from 5) of which contain the −1031C allele. Conclusions The −857T allele and haplotype 1 are associated with BAL cell TNF-α production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD. Clinical implications TNF promoter variants are not risk factors for CBD or sensitization.

Background: Pooled analysis of the ASCEND and CAPACITY studies showed a significant reduction in the risk of ACM over 52 weeks in patients with IPF treated with pirfenidone compared with placebo, and a non-significant trend favoring pirfenidone over the entire study period (up to week 120). Objective: To evaluate TE ACM over the full duration of observation in the pooled population from ASCEND and CAPACITY. Methods: TE ACM at last vital status assessment was evaluated in 1247 patients. TE deaths occurred after the first pirfenidone dose and within 28 days of the last dose. Kaplan-Meier estimates were used to summarize survival time. Results: At week 120, TE ACM occurred in 27/623 (4.3%) patients on pirfenidone compared with 44/624 (7.1%) on placebo. The most common cause of death in both treatment groups was IPF (1.6% and 3.4% for pirfenidone and placebo, respectively). The TE ACM rate was lower on pirfenidone, compared to placebo, with a 38% reduction in the risk of TE ACM over 120 weeks (HR=0.62; 95% CI, 0.39–1.01; P=0.0515; (Figure). Estimates of TE ACM after week 96 are associated with higher uncertainty since few patients remained thereafter in the study. Conclusions: Pooled outcome analysis of the ASCEND and CAPACITY studies showed a clear trend towards reduced risk of TE ACM in patients with IPF treated with pirfenidone.

Background: In the two replicate, 52-week, Phase III INPULSIS® trials, patients with idiopathic pulmonary fibrosis (IPF) were randomized 3:2 to receive treatment with nintedanib 150 mg twice daily (bid) or placebo. Concomitant treatment with prednisone ≤15 mg/day, or equivalent, was permitted if the dose had been stable for ≥8 weeks prior to screening. The primary endpoint was annual rate of decline in FVC. In both trials, nintedanib significantly reduced the annual rate of FVC decline vs placebo. Aim: To assess whether corticosteroid use at baseline affected the treatment effect of nintedanib. Methods: A pre-specified analysis of patients receiving vs not receiving systemic corticosteroids at baseline was conducted using pooled data from both INPULSIS® trials. Results: At baseline, 225 patients (21.2%) were receiving corticosteroids (136 nintedanib; 89 placebo) and 836 (78.8%) were not (502 nintedanib; 334 placebo). Demographics and baseline characteristics were balanced between treatment groups within each subgroup. The difference in the adjusted annual rate of decline in FVC was 98.5 mL/year (95% CI: 24.7, 172.3) and 113.1 mL/year (95% CI: 74.5, 151.6) in patients receiving and not receiving corticosteroids at baseline, respectively. The treatment-by-subgroup interaction was not significant for the primary endpoint (p=0.9379), i.e., the treatment effect of nintedanib vs placebo was similar in both subgroups. Conclusion: In a subgroup analysis of pooled data from the INPULSIS® trials, nintedanib reduced the annual decline in lung function in patients with IPF independent of corticosteroid use at baseline.

Background: The assessment of therapeutic response and the management of patients with IPF who experience progression during treatment represent distinct clinical challenges. Notably, there is limited evidence to inform clinicians on whether treatment should be continued or adjusted in patients following hospitalisation. Objective: To evaluate the effect of continued pirfenidone treatment after 6 months in patients with IPF who were hospitalised due to any cause within the first 6 months of study treatment. Methods: Source data included all patients randomised to pirfenidone 2403 mg/d or placebo in the ASCEND and CAPACITY studies (N = 1247). From these, we identified all patients who were hospitalised due to any cause within the first 6 months of study treatment and assessed FVC and mortality outcomes during the next 6 months of continued treatment. Results: A total of 44/623 (7.1%) and 49/624 (7.9%) patients in the pooled pirfenidone and placebo groups, respectively, were hospitalised due to any cause within the first 6 months of treatment. Outcomes after 6 months of continued treatment following hospitalisation are shown in the Table . ![Figure][1] Conclusions: These results suggest that continued treatment with pirfenidone may confer a benefit to patients with IPF who are hospitalised within the first 6 months of treatment. [1]: pending:yes

To investigate novel systemic sclerosis (SSc) autoantibodies in autoantibody-negative patients and establish clinical associations.Serum samples and clinical data for 548 patients with SSc were collected. Routine serologic techniques were used to test the serum samples for known SSc autoantibodies, and samples with negative results were further investigated by radiolabeled-protein immunoprecipitation assay. Sera that immunoprecipitated a novel 30-kd band were analyzed by indirect immunofluorescence and immunoprecipitation, using depleted cell extracts to establish a common reactivity. Mass spectrometry was performed to identify the novel autoantigen, and the results were confirmed using commercial antibodies. Sera from 426 patients with other forms of connective tissue disease, 103 with rheumatoid arthritis, 114 with idiopathic interstitial lung disease (ILD), and 150 healthy subjects were serotyped as controls.A novel autoantigen with a molecular weight of ∼30 kd was recognized by 7 sera from patients with SSc, 6 of whom had ILD, and by no controls. Six of the patients had diffuse cutaneous involvement, and 4 had overlap features with other autoimmune diseases. Immunodepletion experiments indicated that all samples targeted the same autoantigen, and mass spectrometry identified the novel autoantigen as eukaryotic initiation factor 2B (eIF2B).We report the identification of a novel autoantibody (anti-eIF2B) in a small number of patients with SSc (∼1%); this autoantibody is closely associated with diffuse cutaneous manifestations and the presence of ILD.

Pulmonary sarcoidosis is a multisystem granulomatous disease with various clinical phenotypes. So far, there has been little information on protein patterns (PPs) of bronchoalveolar lavage fluid (BALF) from patients with sarcoidosis and no data are available on PPs in clinical disease subtypes.To investigate the PP of BALF from patients with pulmonary sarcoidosis, to evaluate whether PPs reflect disease course as assessed by chest X-ray (CXR), and to compare PPs between patients with/without Löfgren's syndrome.Surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy was applied to investigate PPs in unconcentrated BALF from 65 patients (CXR stage I, n = 32; CXR stage II, n = 22, CXR stage III, n = 11) and 23 healthy control subjects. The Mann-Whitney U test was used to detect differentially expressed protein peaks. After reversed-phase fractionation, peptide fingerprint mapping and immunodepletion were used to identify deregulated (up-regulated or down-regulated) proteins.Forty differentially expressed protein entities (2.75-185.62 kD) were detected in patients with pulmonary sarcoidosis versus control subjects (p0.05). Whereas 13 peaks (33%) were present across all CXR stages, 27 (67%) were specific for particular CXR stages. Comparison of PPs between CXR stage I patients with or without Löfgren's syndrome revealed 25 differentially expressed peaks. The total number of deregulated peaks and also of those associated with sarcoidosis as a whole were markedly lower in patients with Löfgren's syndrome in comparison with other sarcoid phenotypes. Human serum albumin, alpha1-antitrypsin, and protocadherin-2 precursor were identified from sarcoidosis-associated PP.Surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy enables determination of protein patterns in sarcoid BALF and allows detection of protein patterns linked to a particular disease course.

The diagnosis of idiopathic pulmonary fibrosis (IPF) requires an integrated multidisciplinary approach involving pulmonologists, radiologists, and pathologists. Early recognition of IPF and of its differentiation from other interstitial lung diseases is important for directing patient management and predicting prognosis. Clinical suspicion of IPF should be raised when patients, particularly those over 50 years of age, present with dyspnea that is gradual in onset and progressive. A confident diagnosis of IPF can be made based on clinical assessment, pulmonary function test results, and radiographic and bronchoscopic evaluation. However, the definitive diagnosis of IPF requires a surgical lung biopsy to confirm the histopathologic pattern of usual interstitial pneumonia.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

Background: Chymase is released from mast cells following activation. Evidence suggests that chymase plays an important role in tissue injury and remodeling of the lungs, heart and skin. Objective: We postulated that chymase gene (CMA1) polymorphisms are associated with pulmonary fibrosis in Dutch and with cardiac and skin involvement in Japanese sarcoidosis patients. Patients and Methods: Dutch (n = 153) and Japanese (n = 122) sarcoidosis patients with controls (Dutch, n = 309; Japanese, n = 111) were studied. Pulmonary involvement in Dutch patients as well as clinical manifestations in Japanese patients was evaluated for association with five CMA1 polymorphisms. Results: The CMA1 polymorphisms were not associated with disease susceptibility in either population, or with radiographic evolution in the Dutch or with cardiac or skin involvement in the Japanese patients. The –526 T allele was associated with a lower iVC in Dutch patients. Conclusions: The CMA1 polymorphisms studied do not contribute to disease susceptibility in Japanese or Dutch sarcoidosis patients. CMA1 polymorphisms do not influence radiographic evolution in Dutch sarcoidosis patients, nor do they predispose to cardiac or skin involvement in Japanese patients. However, the association between CMA1 –526 C/T and iVC in the Dutch patients suggests that chymase may modify the functional outcome of pulmonary sarcoidosis.

RATIONALE: Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis. OBJECTIVES: To assess the efficacy of infliximab in sarcoidosis. METHODS: A phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis. Patients were randomized to receive intravenous infusions of infliximab (3 or 5 mg/kg) or placebo at Weeks 0, 2, 6, 12, 18, and 24 and were followed through Week 52. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the change from baseline to Week 24 in percent of predicted FVC. Major secondary efficacy parameters included Saint George's Respiratory Questionnaire, 6-min walk distance, Borg's CR10 dyspnea score, and the proportion of Lupus Pernio Physician's Global Assessment responders for patients with facial skin involvement. Patients in the combined infliximab groups (3 and 5 mg/kg) had a mean increase of 2.5% from baseline to Week 24 in the percent of predicted FVC, compared with no change in placebo-treated patients (p = 0.038). No significant differences between the treatment groups were observed for any of the major secondary endpoints at Week 24. Results of post hoc exploratory analyses suggested that patients with more severe disease tended to benefit more from infliximab treatment. CONCLUSIONS: Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24. The clinical importance of this finding is not clear. The results of this Phase 2 clinical study support further evaluation of anti-TNF-alpha therapy in severe, chronic, symptomatic sarcoidosis.