Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Lung Fibrosis Is Linked to Increased Endothelial Cell Activation and Dysfunctional Vascular Barrier Integrity.

Pulmonary fibrosis (PF) can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analyzed using transmission electron microscopy, immunohistochemistry, and single-cell RNA sequencing. Vascular barrier resistance, endothelial-immune cell adhesion, and sensitivity to an inflammatory milieu were studied in vitro. Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells (ECs) in fibrotic lungs compared with donors. A more intense CD31 and von Willebrand Factor (vWF) and patchy vascular endothelial (VE)-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin, and VEGFR-2 (vascular endothelial growth factor receptor-2) and activation marker vWF gene expression was increased in different endothelial subpopulations (e.g., arterial, venous, general capillary, aerocytes) in PF. This was associated with a heightened sensitivity of fibrotic ECs to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in ECs from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, whereas VE-Cadherin, Thrombomodulin, and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of patients with PF 6 months after the initial diagnosis. Our data demonstrate highly abnormal ECs in PF. The vascular compartment is characterized by hyperactivation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Reestablishing EC homeostasis and function might represent a new therapeutic option for fibrotic lung diseases.

SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.

The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases.

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis.

BACKGROUND: Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire. METHODS: Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on high-resolution computed tomography (HRCT) and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures. RESULTS: In total, 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8) and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (-1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (-0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT. CONCLUSION: Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and the impacts of ILD over 52 weeks in patients with PPF.

Is YouTube a sufficient source of information on Sarcoidosis?

BACKGROUND: The internet is a common source of health information for patients and caregivers. To date, content and information quality of YouTube videos on sarcoidosis has not been studied. The aim of our study was to investigate the content and quality of information on sarcoidosis provided by YouTube videos. METHODS: Of the first 200 results under the search term "sarcoidosis," all English-language videos with content directed at patients were included. Two independent investigators assessed the content of the videos based on 25 predefined key features (content score with 0-25 points), as well as reliability and quality (HONCode score with 0-8 points, DISCERN score with 1-5 points). Misinformation contained in the videos was described qualitatively. RESULTS: The majority of the 85 included videos were from an academic or governmental source (n = 63, 74%), and median time since upload was 33 months (IQR 10-55). Median video duration was 8 min (IQR 3-13) and had a median of 2,044 views (IQR 504 - 13,203). Quality assessment suggested partially sufficient information: mean HONCode score was 4.4 (SD 0.9) with 91% of videos having a medium quality HONCode evaluation. Mean DISCERN score was 2.3 (SD 0.5). Video content was generally poor with a mean of 10.5 points (SD 0.6). Frequently absent key features included information on the course of disease (6%), presence of substantial geographical variation (7%), and importance of screening for extrapulmonary manifestations (11%). HONCode scores were higher in videos from academic or governmental sources (p = 0.003), particularly regarding "transparency of sponsorship" (p < 0.001). DISCERN and content scores did not differ by video category. CONCLUSIONS: Most YouTube videos present incomplete information reflected in a poor content score, especially regarding screening for extrapulmonary manifestations. Quality was partially sufficient with higher scores in videos from academic or governmental sources, but often missing references and citing specific evidence. Improving patient access to trustworthy and up to date information is needed.

Hospitalisation patterns in interstitial lung diseases: data from the EXCITING-ILD registry.

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection. RESULTS: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005). CONCLUSION: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.

Disease trajectories in interstitial lung diseases - data from the EXCITING-ILD registry.

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5-10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression. RESULTS: Within the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001). CONCLUSION: Disease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.

Digital Smoking Cessation With a Comprehensive Guideline-Based App-Results of a Nationwide, Multicentric, Parallel, Randomized Controlled Trial in Germany.

BACKGROUND: Smoking tobacco implies significant health hazards. Digital cessation support can get more smokers in contact with guideline-based cessation. The objective was to test the efficacy of a guideline-based smoking cessation app (NichtraucherHelden®). The hypothesis was a significantly higher cessation rate in the intervention group. METHODS: The study was a nationwide, multicentric, prospective, parallel, randomized controlled trial in Germany from November 2021 to March 2023. Recruitment took place in medical practices and by telephone via study centers. Eligible participants were adult tobacco-dependent smokers according to ICD-10 (F17.2). Randomization (1:1) was operated by a computer-generated stratified 1:1 block procedure. Intervention (IG; n = 336) and control group (CG; n = 325) were briefly advised with regard to stop smoking, IG was additionally treated with the cessation app. The primary endpoint was the self-reported 7-day-point abstinence after 6 months with an intention to treat analysis. Secondary endpoints comprised prolonged abstinence and biochemically verified abstinence. The study was registered at the German Registry of Clinical Trials (DRKS00025933, UTN U1111-1268-2181) and was approved by the competent ethics committees (leading ethic committee Berlin #Eth-52/20). RESULTS: Three hundred thirty six participants (IG) and 325 (CG) were analyzed. Seven-day point prevalence was significantly higher in the app group (IG) (20% vs. 10%, OR 2.2 (1.4-3.4)). Additionally, the prolonged abstinence and the objective abstinence rates were significantly higher in the app group. CONCLUSIONS: The NichtraucherHelden app doubles the abstinence rate. Apps can bridge the gap between the small number of therapeutic offers and the need for modern evidence-based cessation support. IMPLICATIONS: The study is the first to provide evidence for the feasibility and efficacy of guideline-based digital smoking cessation provided by a smartphone app for the German statutory health insurance (SHI) system. Smoking cessation support by smartphone apps could be broadly distributed and thus bring more smokers in contact with guideline-based cessation support than to date and increase the number of successful quitters substantially.

Pharmacological Treatment of Idiopathic Pulmonary Fibrosis (Update) and Progressive Pulmonary Fibroses S2k Guideline of the German Respiratory Society.

Interstitial lung diseases (ILD) are characterized by a variable degree of inflammatory and fibrotic changes within the alveolar space and distal airways (bronchioles). An inverse correlation exists between the extent of fibrosis and the possibility that an ILD is reversible. While the acute (inflammatory) type of extrinsic allergic alveolitis may resolve without sequelae (restitutio ad integrum), IPF is the prototypic fibrotic ILD with a progressive course, leading to an irreversible and progressive fibrosis of the lung parenchyma. This guideline provides guidance on differnential pharmacological treatment approaches to different types of fibrotic interstitial lung diseases.

Development and initial validation of the ILD-Anxiety-Questionnaire (IAQ): A new instrument for assessing disease specific fears in interstitial lung disease.

INTRODUCTION: Multiple studies focusing on chronic lung diseases (i.e. COPD), have indicated that the quality of life (QoL) can be impacted by disease-related fears. In the context of Interstitial Lung Diseases (ILD), however, these have never been systematically examined. Therefore, the aim of the present study was to develop and evaluate an appropriate measuring tool, and to investigate the influence of disease-related anxieties on QoL in ILD. METHOD: N = 166 ILD patients participated in the study and completed an itempool on disease-related fears, based on the COPD-Anxiety-Questionnaire (CAF-R) and expert assessments. Further, demographic and psychological variables were assessed (anxiety: GAD-7, QoL: K-BILD; Beliefs about Health: KKG). Psychometric properties were analyzed (factor structure, reliability, validity). Regression analyses were used to calculate the differential predictive power of disease-related anxieties on QoL. RESULTS: The factor structure was confirmed (Scales: Fear-of-Dependence-and-Progression, Fear-of-Social-Exclusion-and-Isolation, Fear-of-Physical-Activity, Fear-of-Dyspnea, and Sleep-related- Complaints). The Scales showed satisfying reliabilities (α = 0.68 to 0.89) and good validity. Disease-related anxieties proved to be differential predictors for different scales of the K-BILD (ß = -0.15 to ß = -0.58, all ps < .01). CONCLUSIONS: The ILD-Anxiety-Questionnaire (IAQ) is an easy-to-use, valid measurement tool for assessing disease-related anxieties. These vary in their impact on different aspects of QoL. Therefore, it might aid in specifying the indication for potential psychological supplementary interventions. Additional long-term studies are required to investigate how specific anxieties affect both overall and condition-specific QoL in diverse situations.

[Pulmonary involvement in idiopathic inflammatory myopathies]. / Pulmonale Beteiligung bei idiopathischen inflammatorischen Myopathien.

Idiopathic inflammatory myopathies are rare systemic diseases with different types of pulmonary manifestations depending on the underlying aetiology; here, interstitial lung diseases (ILD) are the most frequently found patterns depending on the underlying disorder. There is a lack of sufficient prospective studies on this heterogeneous group of patients, particularly in case of ILD being involved. The diagnosis is based upon guideline recommendations for ILD and requires a multidisciplinary discussion within a team with specific expertise in this field. Myositis specific antibodies and myositis associated antibodies form an essential part of the diagnostic tools and may also be associated with a certain phenotype or disease progression. Anti-t-RNA-synthetase antibodies (Anti-ARS) and anti-melanoma differentiation-associated gene 5 antibodies (MDA5) play an important clinical role for treatment the estimation of response and prognosis. The most common ILD patterns are nonspecific interstitial pneumonia (NSIP) and organising pneumonia (OP) or a mixed pattern of both. Treatment is based on systemic steroids and early initiation of other immunosuppressant drugs. Evidence for this is, however, sparse, since most of the studies having investigated treatment modalities are of retrospective nature, even though some new prospective data may be useful for the establishment of treatment pathways in the future.

[Current status of lung cancer care in Germany in the context of treatment centralization and lack of personnel]. / Situation der Betreuung von Lungenkarzinompatienten im Hinblick auf Mindestmengenregelung und Personalmangel.

INTRODUCTION: Lung cancer is the malignancy with the highest mortality rate worldwide. In January 2025, the German public healthcare system will introduce a new regulation according to which a centre can offer surgery for lung cancer only if it carries out a minimum number of lung resections. The purpose of this directive is to reduce the number of centres offering surgical treatment for primary lung cancer, thus centralising and improving lung cancer care. It is expected that the introduction of this regulation will lead to a significant shift in the staffing of thoracic units. The purpose of this survey was to examine the current occupational structures behind the units of thoracic surgery and respiratory medicine. METHODS: We performed an online survey through the German Society for Thoracic Surgery and the Association of Respiratory Physicians. The responding centres were divided in two groups, centres that were certified by the German Cancer Society or the Society for Thoracic Surgery and centres which were not certified. RESULTS: The response rate was 29.3% (respiratory physicians) and 31.9% (thoracic surgeons); 67% of the participating colleagues answered that their unit was an independent department. The majority of the participants reported having to share the on-call duty of the trainees with other departments in order to be able to cover the required shifts. 35% of the respiratory physicians and 57% of the thoracic surgeons reported having vacant job posts in their units. DISCUSSION: The introduction of the minimum quantity regulation will have significant consequences for the treatment of lung cancer in Germany. The current staff shortage in healthcare will lead to both medical and nursing staff needing to be redistributed in order to meet the needs that will arise in 2025. Operating lists, theatre days, and operative equipment will need to be redistributed as well, not only within hospitals but probably on a nationwide level. A negative impact of the new regulation is to be expected on research and academic activities since most university hospitals are not expected to reach the minimum number of lung resections that is required in order keep performing lung cancer surgery.

[Diagnosis and Treatment of Hypersensitivity Pneumonitis - S2k Guideline of the German Respiratory Society and the German Society for Allergology and Clinical Immunology]. / Diagnostik und Therapie der exogen-allergischen Alveolitis.

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) in sensitized individuals caused by a large variety of inhaled antigens. The clinical form of acute HP is often misdiagnosed, while the chronic form, especially the chronic fibrotic HP, is difficult to differentiate from other fibrotic ILDs. The present guideline for the diagnosis and treatment of HP replaces the former German recommendations for the diagnosis of HP from 2007 and is amended explicitly by the issue of the chronic fibrotic form, as well as by treatment recommendations for the first time. The evidence was discussed by a multidisciplinary committee of experts. Then, recommendations were formulated for twelve questions on important issues of diagnosis and treatment strategies. Recently published national and international guidelines for ILDs and HP were considered. Detailed background information on HP is useful for a deeper insight into HP and the handling of the guideline.

[Therapeutic Pathways in Sarcoidosis. A Position Paper of the German Society of Respiratory Medicine (DGP)]. / Therapie der Sarkoidose. Ein Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis.

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. METHODS: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 µg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. RESULTS: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. CONCLUSIONS: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).

Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease.

OBJECTIVE: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with SSc-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. METHODS: Patient-reported outcome (PRO) measures [St. George's Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnoea, and HAQ-Disability Index (HAQ-DI), incorporating the Scleroderma HAQ visual analogue scale (SHAQ VAS)] at baseline and week 52 were assessed for associations to SSc-ILD severity. RESULTS: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted [week 52: SGRQ 45.1 vs 34.0 (P < 0.0001); FACIT-Dyspnoea 48.9 vs 44.5 (P < 0.0001); HAQ-DI 0.7 vs 0.6 (P < 0.0228); SHAQ VAS breathing problems 3.6 vs 2.6 (P < 0.0001)]. Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (P < 0.001). CONCLUSION: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933.

Anti-acid therapy in SSc-associated interstitial lung disease: long-term outcomes from the German Network for Systemic Sclerosis.

OBJECTIVES: Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). METHODS: We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan-Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. RESULTS: It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9-93.8); n = 290] and after 5 years [91.4% (89.2-93.8); n = 357 vs 70.9% (65.2-77.1); n = 106; P < 0.0001]. PPI use was also associated with improved PFS vs no PPI use after 1 year [95.9% (94.6-97.3); n = 745 vs 86.4% (82.9-90.1); n = 278] and after 5 years [66.8% (63.0-70.8); n = 286 vs 45.9% (39.6-53.2); n = 69; P < 0.0001]. CONCLUSION: GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.

Weight loss and outcomes in subjects with progressive pulmonary fibrosis: data from the INBUILD trial.

BACKGROUND: Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in subgroups by BMI at baseline and associations between weight change and outcomes in subjects with progressive pulmonary fibrosis (PPF) in the INBUILD trial. METHODS: Subjects with PPF other than idiopathic pulmonary fibrosis were randomized to receive nintedanib or placebo. In subgroups by BMI at baseline (< 25, ≥ 25 to < 30, ≥ 30 kg/m2), we analyzed the rate of decline in FVC (mL/year) over 52 weeks and time-to-event endpoints indicating disease progression over the whole trial. We used a joint modelling approach to assess associations between change in weight and the time-to-event endpoints. RESULTS: Among 662 subjects, 28.4%, 36.6% and 35.0% had BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively. The rate of decline in FVC over 52 weeks was numerically greater in subjects with baseline BMI < 25 than ≥ 25 to < 30 or ≥ 30 kg/m2 (nintedanib: - 123.4, - 83.3, - 46.9 mL/year, respectively; placebo: - 229.5; - 176.9; - 171.2 mL/year, respectively). No heterogeneity was detected in the effect of nintedanib on reducing the rate of FVC decline among these subgroups (interaction p = 0.83). In the placebo group, in subjects with baseline BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively, 24.5%, 21.4% and 14.0% of subjects had an acute exacerbation or died, and 60.2%, 54.5% and 50.4% of subjects had ILD progression (absolute decline in FVC % predicted ≥ 10%) or died over the whole trial. The proportions of subjects with these events were similar or lower in subjects who received nintedanib versus placebo across the subgroups. Based on a joint modelling approach, over the whole trial, a 4 kg weight decrease corresponded to a 1.38-fold (95% CI 1.13, 1.68) increase in the risk of acute exacerbation or death. No association was detected between weight loss and the risk of ILD progression or the risk of ILD progression or death. CONCLUSIONS: In patients with PPF, lower BMI at baseline and weight loss may be associated with worse outcomes and measures to prevent weight loss may be required. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02999178 .

Patients with worsening fibrosis (scarring) of the lungs may lose weight. This study suggests that the course of disease may be worse in patients who lose weight. Measures to prevent weight loss may be needed in these patients.

Immunomodulatory treatment in unclassifiable interstitial lung disease: A retrospective study of treatment response.

BACKGROUND AND OBJECTIVE: The optimal management of unclassifiable Interstitial lung disease (ILD) remains a challenge. The aim of this study was to describe pulmonary function trajectories for patients treated with immunomodulatory therapy and for untreated patients. METHODS: Clinical information and treatment data were obtained retrospectively at two ILD centres. Pulmonary function data were analysed using (1) mixed effects linear regression models with and without clinical covariates and (2) propensity score matching using gender, age, physiology (GAP) stage, smoking and presence of ground glass opacities. RESULTS: Sixty-five percent of the 249 patients included received corticosteroids and/or other immunomodulators. Treated patients had lower forced vital capacity (FVC) (72% vs. 83% predicted) and diffusing capacity for carbon monoxide (DLco) (44% vs. 60% predicted). In mixed effects linear regression, the adjusted change in FVC was -0.22%, [-0.34; -0.11], and -0.15% [-0.28;-0.012] for DLco. The difference in pulmonary function decline between treated and untreated patients was insignificant, -0.082% per month, [-0.28; 0.11], p = 0.10 for FVC and -0.14% per month, [-0.36; 0.079], p = 0.15, for DLco. In propensity score matched analysis, the difference in change in FVC was 0.039% per month, p = 0.12, and for DLco, 0.0085% per month, p = 0.7. CONCLUSION: The pulmonary function trajectories for treated and untreated patients were parallel, despite treated patients having more severe disease at baseline. The persisting differences between the groups suggest no overall effect, although improvement or stabilization may be seen in some patients. Prospective studies are needed to define subsets of patients with unclassifiable interstitial lung disease and their optimal management.