Monoclonal antibodies (mAb) play a central role in modern medicine; however, several of them have been associated with the development of drug-induced interstitial lung diseases (ILD). We present a case of a patient affected by psoriatic arthritis (PsA) treated with secukinumab, an anti-IL17 mAb, who developed a histological organising pneumonia pattern with microgranulomas. After resolution, the patient relapsed when exposed to guselkumab, an anti-IL23 mAb, with further histological confirmation. Treatment withdrawal and steroids resolved the ILD in both cases. To evaluate the risk of developing ILD in the context of those two drugs, we also performed a review of the literature and the clinical trials for the drugs in PsA. Papers presenting drug-induced ILD in patients treated with secukinumab and/or guselkumab in PubMed and Embase were searched and summarised. Respiratory-related adverse events reported in secukinumab and guselkumab clinical trials for PsA were summarised. We summarised seven papers, finding a rare presentation (between 0.1

Introduction:Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism (OCA), ocular nystagmus, bleeding diathesis and, in certain forms, pulmonary fibrosis (PF). We report a case of genetically confirmed HPS type 1 (HPS-1) with pulmonary involvement in a patient with rheumatoid arthritis (RA). Patient concerns and clinical findings:A 62-year-old Caucasian woman, former smoker, was referred for progressive pulmonary fibrosis (PPF) documented since 2019. History included chronic kidney disease and RA diagnosed in 2022, treated with hydroxychloroquine, prednisone, and abatacept. On presentation, she exhibited exertional dyspnea. Distinctive features included OCA, ocular nystagmus, and recurrent non-traumatic bruises, consistent with a bleeding tendency. Diagnostic assessment:Between 2021 and 2024, spirometry documented a decline in forced vital capacity - percent of predicted (FVC%) from 86% to 61% and a reduction in diffusing capacity of carbon monoxide - percent of predicted (DLCO%) from 60% to 37%. The six-minute walking test (6MWT) revealed exertional desaturation. High-resolution computed tomography (HRCT) showed PPF characterized by reticular thickening, ground-glass opacities (GGO), honeycombing, and traction bronchiectasis. Platelet aggregation study revealed impaired function with reduced CD41a expression, while transmission electron microscopy (TEM) confirmed rarefaction-to-absence of platelet dense granules. Genetic analysis identified a homozygous c.355del p.(His119ThrfsTer5) pathogenic variant in HPS1, confirming HPS-1. Interventions and outcomes:Abatacept was discontinued and rituximab initiated for RA management. Antifibrotic therapy was not pursued due to renal impairment and limited supporting evidence. Supportive measures included supplemental oxygen during exertion, pulmonary rehabilitation, and vaccination. Lung transplantation was deemed infeasible owing to renal failure and active autoimmune disease. The patient remains under follow-up. Conclusion:In patients presenting with PF, OCA, and bleeding diathesis, HPS should be suspected. Diagnostic workup begins with platelet aggregation study and TEM of platelets, and the diagnosis is confirmed by molecular genetic testing. No disease-modifying therapies exist for HPS-associated PF (HPS-PF); pirfenidone has uncertain benefit, while lung transplantation remains the only option for end-stage disease. This case underscores the need for early suspicion of HPS to guide investigations, counseling, and referral to specialized care. Moreover, the unusual association with RA is emphasized, as it may have contributed to PF.

Chronic eosinophilic pneumonia is a rare inflammatory lung disease that typically responds to systemic glucocorticoids but is frequently complicated by relapses and treatment-related toxicity. In recent years, monoclonal antibodies targeting the interleukin-5 (IL-5) pathway have emerged as effective glucocorticoid-sparing therapies in relapsing or glucocorticoid-dependent chronic eosinophilic pneumonia. Alongside these advances, a substantial proportion of patients develops progressive fibrotic changes over time, challenging the traditional view of chronic eosinophilic pneumonia as a fully reversible condition. This narrative review summarises current clinical evidence on the use of anti-IL-5/IL-5 receptor subunit α biologicals in chronic eosinophilic pneumonia, examines the emerging phenotype of fibrotic chronic eosinophilic pneumonia, and discusses the mechanistic links between eosinophilic inflammation and pulmonary fibrosis. We also review experimental and clinical data implicating eosinophils, type 2 cytokines, epithelial alarmins and extracellular traps in fibroblast activation and extracellular matrix deposition, providing a biological rationale for a continuum from inflammation to irreversible lung remodelling. Available data on the use of IL-5-targeted therapies in fibrotic disease are limited, and no prospective studies have specifically addressed this patient population. Conversely, antifibrotic agents such as nintedanib have demonstrated efficacy in progressive fibrosing interstitial lung diseases but have been rarely studied in eosinophilic lung disorders. We propose a phenotype-adapted therapeutic framework in which sustained control of eosinophilic inflammation aims to prevent fibrotic progression in early disease, while antifibrotic therapy may be considered in patients with established or progressive fibrosis. Fibrotic chronic eosinophilic pneumonia thus represents a clinical entity at the crossroads between inflammation and fibrosis, requiring individualised management strategies and dedicated future studies.

The natural history of IPF remains unpredictable despite antifibrotic treatment. In addition, some patients discontinue treatment due to the occurrence of adverse events. To date, no data exist on either the effect of long-term treatment or predictors of treatment response. In the present study, we aim to evaluate the functional trajectory of IPF patients treated with antifibrotics for at least three years and to establish predictors of treatment response. This multicenter study enrolled long-term survivors IPF patients provided they had stopped treatment for no longer than one month during at least three-year study period. Based on the absolute decline of FVC

INTRODUCTION:Loss of muscle mass and sarcopenia are associated with poor prognosis in chronic respiratory illnesses and are currently emerging as coexisting conditions that deserve attention in patients with idiopathic pulmonary fibrosis (IPF). However, the exact impact of muscle changes in this deadly disease is not entirely understood. Our study aimed to investigate the role of muscle loss/myosteatosis assessed by computed tomography in the short- and long-term survival of patients with IPF treated with antifibrotics. METHODS:Ninety-six patients with IPF (16 females, 80 males) were retrospectively enrolled between March 2014 and December 2022. Demographic, functional, and radiological data were collected at diagnosis. Area and density of the paravertebral muscle at the level of the 12th thoracic vertebra were collected, and myosteatosis was defined as Hounsfield Unit (Hu) value <30; moreover, using the same segmentation, 54 radiomic variables were extracted. RESULTS:Forty-four out of 96 patients (46%) had myosteatosis. Patients with myosteatosis were older (74.6 vs. 67.4 years; p < 0.001) with lower GERD comorbidities (25% vs. 54%; p = 0.006) compared with patients with preserved muscle density. Patients with myosteatosis had lower 2-year survival (p = 0.03), but no significant differences occurred for the overall survival. In the multivariable Cox regression analysis, myosteatosis was an independent predictor of 2-year mortality [HR 6.13, 95% CI (1.62-23.12); p = 0.007]. CONCLUSION:Myosteatosis is already present in half of the IPF population at diagnosis and impacts short-term survival after 2 years. Our findings highlight the importance of a fully comprehensive assessment of IPF patients to address early nutritional intervention and/or rehabilitation programs.

Background/Objectives: Up to one third of pleural biopsies performed during medical thoracoscopy (MT) are labelled as non-specific pleuritis (NSP). The histological diagnosis of NSP has long been worrisome for pulmonologists, with the potential to evolve into a life-threatening condition. The aim of this study was to identify clinical and biological predictors for patients with a diagnosis of NSP to guide clinical decisions. Methods: Baseline, procedural and follow-up data of NSP patients were retrospectively analysed to identify potential outcome predictors. Results: Of the 272 patients who underwent MT, 192 (71%) were diagnosed with malignancies, 9 (3%) with benign diseases and 71 (26%) with NSP. At follow-up, 17% were diagnosed with malignant disease and 21% with a benign condition and 62% remained idiopathic. A thoracoscopist’s evaluation of the pleural appearance reported a PPV of 28% and an NPV of 91% to predict malignancy. Patients with a subsequent diagnosis of malignancy tended to have a higher volume of fluid drained than those with persistently idiopathic NSP [2.7 litres (L) vs. 1.6 L p = 0.06]. A lymphocytic pleural effusion was more common in the malignant and idiopathic groups (63% and 60%, respectively) than the benign group (16%; p = 0.06 and p = 0.01). The three groups had a similar rate of effusion recurrence. Overall survival was higher in patients with idiopathic pleural effusion than in those with malignant (p = 0.04) or benign disease (p = 0.008). Conclusions: NSP diagnosis hides a malignancy in one in five cases, underlying the importance of closely following up these patients. The volume of drained pleural fluid, cell count and thoracoscopist’s impression may guide clinicians in the challenging management of patients with NSP.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects millions of people worldwide and is characterized by persistent inflammation, pain, and joint destruction. In RA, the dysregulation of the immune system is well documented. However, the genetic basis of the disease is not fully understood, especially when extra-articular organs are involved. Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with RA. Notably, RA-ILD shares several risk factors with idiopathic pulmonary fibrosis (IPF), namely male gender, smoking history, usual interstitial pneumonia (UIP) pattern of fibrosis, and association with the MUC5B rs35705950 polymorphism. In addition, other genetic susceptibilities are reported in RA-ILD for some HLA alleles and other less studied polymorphisms. However, the pathobiology of RA-ILD, particularly whether and to what extent genetic and environmental factors interact to determine the disease, remains elusive. In this review, we summarize and critically discuss the most recent literature on the genetics and pathogenesis of RA-ILD. The main clinical aspects of RA-ILD are also discussed.

Extracellular Vesicles (EVs), released by all cell types and detectable in biological samples, carry a variety of biological molecules. These molecules mediate communication and signaling with both local and distant cells, potentially playing a role in the pathogenesis of diseases, including Interstitial Lung Diseases and, more specifically, Idiopathic Pulmonary Fibrosis. To better understand the role of EVs in IPF, a systematic search was performed in PubMed, Scopus, and Ovid databases. These searches were conducted from January 1st, 2019, the period during which the MISEV 2018 guidelines were published, to August 31st, 2024. The SANRA scale was used for quality assessment. A total of 691 papers were screened, and 16, in the end, were definitively enrolled for our evaluation. The studies were reviewed in the following steps: 1) the nomenclature used to define EVs; 2) conformity with the MISEV 2018 guidelines; 3) the biological samples used to isolate EVs; 4) the main conclusion of each manuscript. There was significant heterogeneity among the publications in all the aforementioned steps, such as the type and source of EVs and the analysis of EVs content, primarily a wide array of different miRNAs in the various publications. Despite these differences, the emerging role of EVs and their potential usefulness both in therapies and clinical practice is of growing interest.

ObjectiveThe term progressive pulmonary fibrosis (PPF) refers to a specific disorder that becomes worse despite optimal treatment. The pathogenic explanation of this progressive worsening is still to be found. In this study, we explored whether any histological, molecular, radiological, or clinical features could predict a progressive phenotype in patients with fibrotic interstitial lung diseases.MethodsTwo hundred and fifteen patients with PPF other than idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD) were followed in our ILD clinic between January 2016 and May 2023. Based on tissue block availability, 48 patients were definitively enrolled. Progression was defined according to the most recent guidelines. Clinical, radiological, and functional data were also collected retrospectively and correlated with tissue morphological and molecular cytokine profiles.ResultsFifteen patients were classified as progressors (PPF) and 33 as non-progressors (nPPF) with similar age at diagnosis and gender. PPF showed a higher prevalence of traction bronchiectasis (80% vs. 27%; p=<0.001) at CT scan and lower functional parameters [FVC: 2.42 L vs. 3.37 L; p=0.004; TLC: 3.83 L vs. 4.65 L; p=0.027] at diagnosis. Lung specimens revealed a significant overexpression of IL9 in the PPF compared to the nPPF group (p=0.049). Boruta algorithm analysis showed that lymphoid aggregates and traction bronchiectasis at diagnosis are the most important variables in determining the PPF status.ConclusionsThe present results increase the understanding of the pathological mechanisms of PPF, offering potential avenues for improved prognostication and therapeutic intervention.

Background: Chronic eosinophilic pneumonia (CEP) is a rare inflammatory lung disease typically responsive to glucocorticoids, but is prone to relapse and, in some cases, progressive deterioration. A subset of patients develops fibrosing CEP, a distinct phenotype characterized by irreversible parenchymal remodeling and declining lung function, for which no standard treatment exists. Although biologic therapies targeting interleukin-5 (IL-5) are effective in relapsing CEP, their role in fibrosing forms remains unclear. Case Presentation: We report the case of a 43-year-old man with idiopathic CEP initially treated with systemic glucocorticoids, which were discontinued due to severe adverse effects. Despite subsequent therapy with inhaled steroids and azathioprine, the disease relapsed and progressed to a fibrosing phenotype, as confirmed by radiologic and functional assessments. An off-label treatment with subcutaneous mepolizumab, 100 mg, every 4 weeks was started. After eight months of therapy, the patient achieved clinical stability, improved lung function, and the radiologic stabilization of fibrotic changes, without the need for any further treatment with a corticosteroid. Conclusions: This is, to the best of our knowledge, the first documented case of fibrosing CEP treated with an anti-IL-5 monoclonal antibody, highlighting its potential role as a steroid-sparing agent and immunomodulator even in the fibrotic phase of disease. Further research is warranted to define the place of biologics in the management of CEP with a fibrosing evolution and possible combinations with antifibrotic drugs.

Interstitial lung disease (ILD) prevalence and survival are increasing due to improvement in scientific research together with clinical complications typical of advanced disease. Lung cancer (LC) is described as a possible event occurring in lung parenchyma in the context of fibrotic abnormalities that worsen patients’ prognosis. This growth of malignant cells on a fibrotic background has also been called scar-cinoma. For this reason, not only an early diagnosis but also personalized decisions on the best treatment approach should be considered for each patient in a multidisciplinary discussion, since in some cases chemotherapy or surgery could be detrimental for patients with pulmonary fibrosis. LC and lung fibrosis may share common pathogenetic mechanisms like an altered healing process in response to repeated tissue damage from environmental exposure in genetically susceptible individuals. Smoking history and air pollution together with mutations in telomere and surfactant protein genes lead to the production of cytokines and nitro derivatives in the microenvironment that facilitate the carcinomatous transformation during fibrogenesis. The evolution of LC therapy and the implementation of immunotherapy acting on targetable immune checkpoints have raised interest in evaluating ILD-LC actionable mutations. The main pathogenetic mechanisms, clinical presentations and treatment implications are presented in this review.

Idiopathic pulmonary fibrosis (IPF) represents a clinical and therapeutic challenge characterized by progressive fibrosis and destruction of the lung architecture. The pathogenesis of IPF has been long debated; while it is generally believed that repeated lung injury and abnormal wound repair are the main pathogenetic mechanisms, clear understanding of disease development and efficacious treatment remain important unmet needs. Indeed, current standard of care (i.e., the antifibrotic drugs pirfenidone and nintedanib) can slow down lung function decline and disease progression without halting the disease. In the last 2 decades, several clinical trials in IPF have been completed mostly with negative results. Yet, unprecedented numbers of clinical trials of pharmacological interventions are currently being conducted. In this review, we summarize and critically discuss the current and future treatment landscape of IPF, with emphasis on the most promising developmental molecules.

OBJECTIVES:Body composition plays a significant role in various rheumatic and autoinflammatory diseases. The aim of our study was to assess the impact of muscle mass and subcutaneous adipose tissue quality and quantity in patients with SSc. METHODS:Adults with SSc referring to our tertiary centre who underwent high-resolution chest CT (HRCT) to assess pulmonary involvement were included. A semi-automatic segmentation of the subcutaneous fat and paravertebral muscle was performed at the level of the 12th dorsal vertebra, and body composition metrics were collected (subcutaneous fat and paravertebral muscle area and density). Stepwise linear regression analysis was applied to evaluate if body composition, demographics and pulmonary function tests acted as predictors of mortality. Considering patients with muscle Hu values <30 as affected by myosteatosis, we used the odds-risk ratio to assess if it is associated with a higher risk of mortality. RESULTS:Eighty-seven SSc patients (77 females, age 60 ± 15 years, 61% affected by limited cutaneous SSc) were included. The linear model demonstrated that lower DLCO (P = 0.047), higher BMI (P = 0.013), higher density of the subcutaneous fat (P = 0.005) and lower skeletal muscle index (P < 0.001) acted as predictors of mortality. Overall, 63 patients (72%) were affected by myosteatosis (i.e. Hu <30 Hu) and patients affected by muscle fat infiltration at CT showed a 3.345 times higher mortality risk (95% CI 0.396-28.295). CONCLUSION:Patients with SSc are affected by myosteatosis and pre-sarcopenia and body composition seems to influence the overall outcome.