BACKGROUND:Sarcoidosis is a multisystemic granulomatous disease that can involve the skeletal system, although bone manifestations are considered relatively uncommon and often underdiagnosed. OBJECTIVES:To describe the prevalence, clinical characteristics, and treatment outcomes of bone involvement in a large multicenter Italian cohort of patients with sarcoidosis. METHODS:This retrospective, two-center observational study included 867 patients with histologically confirmed sarcoidosis followed at two Italian referral centers (2018-2025). Bone localization was identified by imaging (PET/CT, MRI, X-ray) and/or biopsy. Clinical, functional, laboratory, and therapeutic data were collected. RESULTS:Bone involvement was found in 46 patients (5.3%), predominantly women (58.7%), with mean age at diagnosis of 49.7 ± 12.2 years. Osseous lesions were most frequently localized in the axial skeleton, particularly pelvis (54.3%) and vertebrae (52.2%). Bone sarcoidosis was significantly associated with extra-thoracic lymphadenopathy, hepatic, and splenic involvement (p < 0.001), reflecting a pattern of clustered multi-organ disease. Osteoporosis and osteopenia were present in 15.2% and 13.0% of cases, respectively. Corticosteroid monotherapy was the most common initial treatment (56.5%), while 30.4% received combination therapy with csDMARDs or biologics. At one-year PET/CT re-evaluation, 56.5% showed a reduction of SUV at bone sites, with no significant correlation between therapeutic regimen and metabolic response. CONCLUSIONS:Bone involvement in sarcoidosis, though relatively rare, represents a clinically relevant phenotype strongly associated with hepatosplenic and lymphatic disease and characterized by a preferential axial skeleton localization. Recognition of this pattern is essential for diagnosis and management. Given the retrospective design and the limited follow-up sample, these findings should be interpreted with caution. Close radiological monitoring and tailored therapeutic strategies are warranted to improve outcomes.

INTRODUCTION:Airway secretion retention represents a major clinical challenge in critically ill patients, promoting gas exchange impairment and atelectasis, precipitating failure of noninvasive respiratory support, and prolonging invasive mechanical ventilation, with an associated increase in respiratory-related complications and mortality. High-frequency chest wall oscillation (HFCWO) is a noninvasive airway clearance technique widely used in chronic respiratory diseases, but its role in the intensive care unit (ICU) remains unclear. This systematic review aimed to evaluate the available evidence on the efficacy and safety of HFCWO in adult ICU patients. METHODS:A systematic literature search was conducted in PubMed/MEDLINE, Embase, and Cochrane Library from inception to December 2025 in accordance with PRISMA guidelines. Studies evaluating HFCWO in adult ICU patients, including those receiving invasive or noninvasive respiratory support, were eligible. Primary outcomes included duration of mechanical ventilation, ICU length of stay, and mortality. Secondary outcomes included impact on secretion airway clearance and its radiographic/functional surrogates as well as safety and treatment tolerance. RESULTS:A limited number of studies met the inclusion criteria, mainly small randomized controlled trials and observational studies, characterized by substantial heterogeneity in patient populations, intervention protocols, and assessed outcomes. HFCWO effects on clinically meaningful primary endpoints, including duration of mechanical ventilation, length of ICU stay, and mortality, remain variable and inconclusive. Overall, HFCWO was well tolerated and appeared to enhance secretion clearance, with some studies reporting modest improvements in oxygenation and respiratory mechanics. CONCLUSIONS:Current evidence suggests that HFCWO is a safe and feasible airway clearance strategy in selected ICU patients with secretion burden and without proved effects on the main clinical outcomes. Lack of physiopathologically driven criteria for selection of patients more likely to respond to HFCWO either alone or integrated with other cough-assisting techniques may partially explain these scanty findings from the overall published studies. This precludes its routine use in clinical practice. Well-designed, adequately powered randomized trials are needed to define patient selection criteria, optimal timing, and the true clinical impact of HFCWO in the ICU setting.

RATIONALE:Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES:To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS:We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS:We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS:We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

Multidisciplinary discussion remains the cornerstone of ILD diagnosis and management, with recent advances further strengthening the integration of clinical, radiological, pathological, and molecular information. Updated ILD nomenclature and classification better align disease terminology with underlying morphology and pathobiology. Growing emphasis is being placed on the early detection of ILD and on identifying individuals at high risk of progression among those with interstitial lung abnormalities (ILAs). Emerging multi-omic biomarkers and quantitative imaging techniques are enhancing prognostic stratification and may support future precision medicine approaches. Novel antifibrotic therapies and targeted treatments are expanding therapeutic options beyond IPF, although important unmet needs remain regarding patient selection, treatment response, and disease modification. The integration of clinical, radiological, functional, and molecular information will be fundamental to optimize individualized management and improve long-term outcomes in patients with ILDs.

BACKGROUND:In the FIBRONEER-ILD trial in patients with progressive pulmonary fibrosis (PPF), nerandomilast 9 mg twice daily and 18 mg twice daily (hereafter nerandomilast 9 mg and 18 mg, respectively) reduced the decline in forced vital capacity at week 52 compared with placebo (primary end-point). We assessed the effects of nerandomilast up to the final database lock. METHODS:Time to first acute exacerbation of interstitial lung disease, hospitalisation for respiratory cause or death (key secondary end-point) and other time-to-event end-points were assessed. RESULTS:1176 patients, of whom 512 were taking background nintedanib, received nerandomilast or placebo. At the final database lock, the mean±sd exposure to trial medication was 15.1±5.7 months and the mean±sd observation period was 17.0±4.1 months. Compared with placebo, the hazard ratio for the key secondary end-point was 0.78 (95% CI 0.61-1.00) for nerandomilast 9 mg and 0.77 (95% CI 0.60-0.99) for nerandomilast 18 mg; hazard ratios were lower among patients not taking nintedanib (0.69 (95% CI 0.49-0.97) and 0.65 (95% CI 0.46-0.92), respectively) than among those taking background nintedanib (0.90 (95% CI 0.63-1.30) and 0.93 (95% CI 0.65-1.34), respectively). For death, the hazard ratio versus placebo was 0.51 (95% CI 0.34-0.78) for both nerandomilast doses. Adverse events led to discontinuation of trial medication in 12.5%, 12.0% and 12.3% of the placebo, nerandomilast 9 mg and nerandomilast 18 mg groups, respectively. CONCLUSIONS:In the FIBRONEER-ILD trial in patients with PPF, nerandomilast reduced the risk of clinically important outcomes, including death, over the whole trial. Nerandomilast had a favourable safety and tolerability profile.

Acute exacerbations (AEs) occur both in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung disease (fILD). These events confer high morbidity and mortality, with a lack of proven effective therapeutic interventions. The objective of this state-of-the-art document is to summarize latest evidence since the 2016 international working group report on AE-IPF, expanding it across the spectrum of all fILDs. A comprehensive literature review on the epidemiology, associated and risk factors, prognosis, and management of AE-fILD is summarized. In addition to revising the AE definition and diagnostic criteria for broad application across different fILDs, a conceptual framework for acute respiratory worsening (ARW) has been proposed to encompass a variety of acute respiratory deteriorations, both related and unrelated to AE. This allows structured evaluation in both clinical and research settings. The proposed revised definition for AE-fILD is an acute respiratory event characterized by increased respiratory symptoms or signs and associated with radiologic or histologic features consistent with diffuse alveolar damage (with or without superimposed organizing pneumonia) in a patient with known or newly diagnosed fILD. On the other hand, ARW refers to a heterogeneous group of clinical events with acute symptom worsening not attributable to DAD in patients with fILD, such as pulmonary edema, bronchitis, and pneumonia, although severe pneumonia can trigger AE-fILD. Additionally, we discuss considerations for inclusion of AE as a clinical trial endpoint, as well as research priorities for advancing knowledge on the pathogenic mechanisms, event prediction, risk stratification, and development of drugs and supportive treatments.

BACKGROUND:In the placebo-controlled FIBRONEER-IPF and FIBRONEER-ILD trials in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), the key secondary endpoint was not met but numerical benefits of nerandomilast on time to death (a secondary endpoint) were observed. We further investigated the robustness of the effect of nerandomilast on survival. METHODS:In both trials, the primary analysis of time to death was based on all deaths except those after lung transplant, using a Cox proportional hazards model. We performed sensitivity analyses of the impact of covariates, tipping point analyses, and supplementary analyses of deaths during and shortly after treatment and the impact of intercurrent events. We assessed time to death by exposure to nerandomilast (trough concentration at steady state). RESULTS:Based on pooled data from both trials, over the whole follow-up period (mean:16.7 months), the risk of death versus placebo was reduced by 33% (hazard ratio: 0.67 [95% CI: 0.49, 0.90]; p=0.009) with nerandomilast 9 mg bid and by 43% (hazard ratio: 0.57 [95% CI: 0.41, 0.78]; p<0.001) with nerandomilast 18 mg bid. Sensitivity analyses and supplementary analyses were consistent with the primary analysis of time to death. Tipping point analyses demonstrated a very low likelihood that the benefit of nerandomilast on mortality was due to missing data. Exposure-response analyses indicated that a higher plasma exposure to nerandomilast was associated with a lower risk of death. CONCLUSION:These analyses support the use of nerandomilast 18 mg bid to improve survival in patients with IPF and PPF.

The therapeutic goals related to chronic airway diseases are evolving from short-term symptom control toward sustained suppression of disease activity and prevention of future risk. In severe asthma, this shift has been captured by the concept of clinical remission, generally defined by absence of exacerbations, no need for oral corticosteroids, symptom control, and stable or improved lung function. In chronic obstructive pulmonary disease (COPD), the analogous concept has more often been described as disease stability. Although remission in asthma and stability in COPD have developed within different biological and clinical frameworks, they may reflect disease-specific expressions of the same therapeutic ambition. Recent studies support COPD stability as a measurable and clinically meaningful state, associated with reduced exacerbation risk and mortality. Evidence from optimized inhaled triple therapy, particularly with fluticasone furoate/umeclidinium/vilanterol, indicates that multidimensional stability can be achieved and maintained in a proportion of patients, while real-world studies reinforce its applicability beyond randomized trials. The emergence of biologic therapies for selected patients with eosinophilic or type 2 COPD further strengthens the rationale for considering stability as an ambitious treatment target. In this narrative review, informed by a structured literature search, we discuss the conceptual relationship between asthma remission and COPD stability, and summarize the evidence supporting disease stability as an attainable and prognostically relevant outcome. In addition, we propose a pragmatic multidimensional definition based on symptom stability, absence of moderate or severe exacerbations, no systemic corticosteroid use, and maintained lung function over 12 months. COPD stability should not be viewed as a weaker goal than asthma remission, but rather as the most appropriate COPD-specific expression of sustained low disease activity.

Interstitial lung diseases (ILDs) encompass a heterogeneous group of disorders characterized by varying degrees of inflammation and fibrosis. Despite advances in understanding the pathogenesis, therapeutic options remain limited, particularly for patients with progressive phenotypes. Current international guidelines for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) emphasize the need for antifibrotic strategies and call for novel pharmacological interventions targeting key molecular pathways involved in fibrogenesis. This review provides a comprehensive overview of the most promising emerging pharmacological agents for ILDs, with particular attention to their mechanisms of action, efficacy, and safety profiles as reported in recent preclinical and clinical studies. The recent approval of Nerandomilast and the ongoing phase III trials of other agents mark a pivotal transition toward a new generation of antifibrotic therapies, aiming to achieve more effective disease control and improved patient outcomes. In view of an enlargement of active drugs aiming at controlling the disease with different mechanisms, the Authors underline the need for a "precision medicine" model to be applied to each ILD phenotyped patient, mirroring what already happens for other respiratory diseases.

Small-airway disease (SAD) is a key feature of severe asthma and is associated with poor symptom control and frequent exacerbations. Dupilumab has demonstrated efficacy in improving lung function and reducing exacerbations, but real-world evidence on its effects in SAD remains limited. The aim of this study is to evaluate the impact of 12 months of dupilumab treatment on SAD, clinical outcomes, and type 2 inflammation. We included 21 patients. Small-airway function was assessed by impulse oscillometry (R5-R20) and spirometry FEF25-75% predicted at baseline (T0) and after 3 (T3), 6 (T6), and 12 (T12) months of treatment. Additional assessments included FEV1, the Asthma Control Test (ACT), exacerbation frequency, oral corticosteroid (OCS) use, the blood eosinophil count (BEC), and fractional exhaled nitric oxide (FeNO). At baseline, 62% of patients exhibited SAD (R5-R20 > 0.07 kPa/L/s). Dupilumab treatment led to a significant and sustained improvement in small-airway function: mean R5-R20 decreased from 0.18 ± 0.17 kPa/L/s to 0.09 ± 0.07 at T12 (p = 0.04), while predicted FEF25-75% increased from 29.5 ± 20.8% to 47.0 ± 21.1% (p < 0.001). ACT scores improved from 13.1 ± 4.9 to 19.6 ± 3.8 (p < 0.001). FeNO levels declined from 64.1 ± 50.7 ppb to 24.8 ± 20.9 ppb (p = 0.01). Improvements in R5-R20 correlated with better ACT and FeNO reductions. In this real-world cohort, dupilumab significantly improved SAD, lung function, and asthma control, while reducing exacerbations, OCS dependence, and type 2 inflammation over 12 months.

For patients with idiopathic pulmonary fibrosis (IPF), cough impairs quality of life; effective treatments for IPF-associated cough are needed. To determine if nalbuphine extended release (ER), a κ opioid receptor agonist and μ-opioid receptor antagonist, decreases cough compared with placebo in patients with IPF-associated cough. In this randomized, double-blind, placebo-controlled phase 2b trial conducted at 52 sites in 10 countries, patients with IPF, chronic cough for at least 8 weeks, and a Cough Severity Numerical Rating Scale (0, no cough; 10, worst possible cough) score of 4 or higher were enrolled from February 2024 to February 2025, with last follow-up in April 2025. Statistical analyses were conducted from May to August 2025. Patients were randomized 1:1:1:1 to receive nalbuphine ER at doses of 27 mg, 54 mg, or 108 mg or placebo twice daily for 6 weeks. The primary outcome was the relative change from baseline in 24-hour cough frequency (coughs/h), measured with a digital cough monitor, for nalbuphine ER compared with placebo at week 6. The key secondary outcome was the relative change from baseline in the patient-reported cough frequency (Evaluating Respiratory Symptoms in IPF cough subscale; scores range from 0-4, lower scores indicate lesser cough frequency) at week 6. Of the 223 patients screened, 165 were randomized (42, 43, 40, and 40 to receive nalbuphine ER 27 mg, 54 mg, and 108 mg, and placebo, respectively) and 160 were included in the primary analysis (median age, 71 [range, 51-85] years; 28.5% female). The baseline mean (SD) cough count was 28.3 (27.4) coughs/h. In the nalbuphine ER 27 mg, 54 mg, and 108 mg twice-daily groups, the mean relative decrease in the cough count and the absolute decrease in coughs/h were 47.9% (from 24.6 to 11.9; P = .008), 53.4% (from 28.0 to 14.9; P < .001), and 60.2% (from 31.5 to 11.9; P < .001), respectively, compared with placebo (16.9%; from 29.4 to 28.1 coughs/h). For the key secondary outcome of patient-reported cough frequency at week 6, the relative and absolute changes were −31.4% (from 2.3 to 1.5; P = .14), −40.6% (from 2.6 to 1.4; P = .004), and −40.2% (from 2.4 to 1.4; P < .005) in the 27-mg, 54-mg, and 108-mg groups, respectively, compared with –21.9% (from 2.6 to 1.9) with placebo. For patients with IPF-associated chronic cough, all 3 doses of nalbuphine ER reduced objective cough frequency and the 2 higher doses improved patient-reported cough frequency at 6 weeks. ClinicalTrials.gov Identifier: NCT05964335

Fibrosis is a severe pathological outcome of many chronic diseases, yet the therapeutic potential of targeting the altered major histocompatibility complex (MHC) class I immunopeptidome remains largely unexplored. Here we characterized the MHC class I immunopeptidomes from both fibrotic foci of human idiopathic pulmonary fibrosis lung explants and bleomycin-treated mice, identifying a diverse repertoire of fibrosis-associated peptides. Parallel profiling of bleomycin-induced pulmonary fibrosis in mice enabled the computational prioritization of therapeutic targets. In vivo, therapeutic vaccination with three candidate peptides (MAF116-124, APBB270-78 and TNS3119-127) effectively mitigated fibrosis progression in bleomycin-treated mice. Furthermore, leveraging its evolutionary conservation, we found that MAF116-124 elicited specific human cytotoxic T lymphocytes that lysed human idiopathic pulmonary fibrosis-derived myofibroblasts and M2-like macrophages. This study indicates that immunopeptidome profiling provides a robust platform for discovering translatable antifibrotic immunotherapies.

RATIONALE:In the randomized placebo-controlled FIBRONEER-IPF trial in patients with idiopathic pulmonary fibrosis, both nerandomilast 9 mg bid and 18 mg bid met the primary endpoint of reducing decline in forced vital capacity at week 52. Patients continued to receive randomized treatment after week 52, until the last patient had completed an end-of-treatment visit. OBJECTIVES:To assess the effects of nerandomilast over the full duration of follow-up in the FIBRONEER-IPF trial. METHODS:Time to first acute exacerbation of IPF, hospitalization for respiratory cause, or death (key secondary endpoint) and other time-to-event endpoints were assessed at final database lock. MEASUREMENTS AND MAIN RESULTS:1177 patients were treated. Mean (SD) exposure to trial medication was 14.8 (5.0), 14.9 (5.0) and 14.7 (5.3) months in the placebo, nerandomilast 9 mg bid and nerandomilast 18 mg bid groups, respectively. Compared with placebo, the hazard ratio (95% CI) for the key secondary endpoint was 0.92 (0.69, 1.22) for nerandomilast 9 mg bid and 0.99 (0.75, 1.31) for nerandomilast 18 mg bid and the hazard ratio (95% CI) for death was 0.95 (0.61, 1.49) for nerandomilast 9 mg bid and 0.66 (0.41, 1.08) for nerandomilast 18 mg bid. Adverse events led to treatment discontinuation in 13.0%, 13.5% and 16.1% of the placebo, nerandomilast 9 mg bid and nerandomilast 18 mg bid groups, respectively. CONCLUSIONS:In the FIBRONEER-IPF trial, nerandomilast had no effect on the composite endpoint of time to first acute exacerbation of IPF, hospitalization for respiratory cause, or death, but nerandomilast 18 mg bid was associated with a numerically lower risk of death. Nerandomilast had a favorable safety profile, with a low rate of discontinuation due to adverse events.

Introduction Bexotegrast is an oral, once-daily, dual-selective inhibitor of integrins αvβ6 and αvβ1 in development for idiopathic pulmonary fibrosis (IPF). In the phase 2a study INTEGRIS-IPF study (NCT04396756), bexotegrast was well tolerated and showed antifibrotic activity.Methods and analysis BEACON-IPF (NCT06097260) is a randomised, double-blind, placebo-controlled, dose-finding, operationally seamless, adaptive phase 2b/3 study evaluating the efficacy and safety of bexotegrast over 52 weeks in participants with IPF. The phase 2b dose selection cohort will enrol 360 participants randomised 1:1:1 to once-daily bexotegrast 160 mg, 320 mg or placebo. After enrolling the last participant in the phase 2b cohort and while conduct is ongoing, the phase 3 cohort will immediately begin enrolment with a ‘seamless group’ using the same 1:1:1 randomisation. Once the phase 2b cohort has completed and a dose has been selected, the remainder of the phase 3 cohort will be enrolled. Participants in the phase 2b cohort receiving the non-selected dose will be eligible for an open-label study at the selected phase 3 dose. Background therapy with pirfenidone or nintedanib is permitted in ≤70% of the study population. Participants must be adults (≥40 years), have an IPF diagnosis ≤7 years per 2018 international guidelines, per cent predicted forced vital capacity (FVCpp) ≥45% and diffusing capacity for carbon monoxide (haemoglobin adjusted) ≥30%. The primary endpoint is change from baseline in absolute FVC at week 52. Additional endpoints include safety and tolerability, time to disease progression, participant-reported symptom assessments and quantitative lung fibrosis extent.Ethics and dissemination This study was approved by Advarra institutional review board (IRB; OHRP and Food and Drug Administration registration 00000971) and at each participating site by IRBs and local ethics review committees. Participants will provide written informed consent before taking part. Study results will be disseminated in peer-reviewed journals and international conferences targeted to medical, academic and patient communities.Trial registration number NCT06097260.

The neutrophil-to-lymphocyte ratio (NLR) is a simple, inexpensive and easily accessible inflammatory biomarker that reflects the balance between innate and adaptive immunity. In recent years, NLR has emerged as a potential prognostic and disease severity marker for different diseases, including idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease with a highly variable course and poor prognosis. Several studies have highlighted that NLR can be associated with several clinical outcomes such as lung function decline, increased risk of hospitalization, acute exacerbation of IPF, and mortality over time. It might also correlate with overall survival in the course of antifibrotic therapy and validated prognostic score as a gender–age–physiology score. Despite these findings, the clinical use of NLR remains limited due to its non-specific nature, the lack of standardized cut-off values, and high variability related to demographic factors, comorbidities and medications. Hence, NLR may display the underlying immune dysregulation in IPF and could be exploited as a non-invasive tool for risk stratification and disease monitoring. Further studies are needed to confirm and validate its use in IPF and to establish reliable cut-off values in clinical applications.

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of conditions that can cause fibrosis of the lung interstitium, resulting in respiratory failure and death. Patients with an ILD, particularly idiopathic pulmonary fibrosis (IPF) or connective tissue disease-associated ILDs (CTD-ILDs), are prone to develop chronic pulmonary infections such as tuberculosis (TB) and non-tuberculous mycobacterial pulmonary disease (NTM-PD). Methods: This case series examines the management of three ILD patients with a usual interstitial pneumonia (UIP) pattern and concomitant NTM-PD or TB at National Institute for Infectious Diseases “Lazzaro Spallanzani” in Rome, Italy, over three years (2019–2022). Results and Conclusions: Multi-disciplinary discussion (MDD) was crucial to define the therapeutic approach due to the increased risk of side effects and drug interactions. Our work underscored how a comprehensive diagnostic evaluation, enriched by MDD, is useful for optimizing the management and reducing drug-related adverse effects and interactions in ILD patients with cavitary lesions.