Roberto Tonelli

Acute exacerbation of systemic autoimmune rheumatic disease-associated interstitial lung disease (AE-SARD-ILD) is an uncommon but severe cause of acute respiratory failure, frequently requiring intensive care. Although commonly managed according to paradigms derived from acute exacerbation of idiopathic pulmonary fibrosis or acute respiratory distress syndrome, AE-SARD-ILD encompasses heterogeneous pathological processes with distinct respiratory mechanics, pulmonary vascular involvement, reversibility, and treatment response. Management based solely on the underlying rheumatic disease or radiological pattern may therefore be inadequate. This Perspective reviews current evidence on the diagnosis and critical care management of AE-SARD-ILD and proposes an integrated clinical–radiological–mechanical framework for physiology-guided decision-making. Moving beyond conventional disease- and imaging-based fibrotic classifications, the framework identifies four dominant, potentially overlapping physiological phenotypes arising from the interaction between the chronic pulmonary substrate and the superimposed acute insult: fibrotic/UIP-like, inflammatory/ARDS-like, pulmonary hypertension-dominant, and diffuse alveolar haemorrhage-dominant. These phenotypes provide a physiological rationale for selecting, titrating, and escalating non-invasive and invasive respiratory support, controlling excessive respiratory drive, and integrating immunomodulatory, pulmonary vascular, and extracorporeal strategies. Although prospective validation is required, physiological phenotype-based assessment may support individualized respiratory management, dynamic prognostication, and time-limited intensive care trials in AE-SARD-ILD.

Background: Generic formulations of pirfenidone are increasingly adopted in idiopathic pulmonary fibrosis (IPF), yet real-world evidence supporting their clinical equivalence to the originator remains limited. We aimed to evaluate whether switching from branded pirfenidone (Esbriet ^® ) to a generic formulation affects treatment efficacy or tolerability. Methods: We conducted a retrospective, within-patient observational study including consecutive patients with IPF treated with Esbriet ^® for ≥ 6 months before switching to generic pirfenidone. Pulmonary function was assessed at three time points: 6 months before the switch (T − 6), at switch (T0), and 6 months after (T + 6). The primary endpoint was the within-patient percentage change in FVC over two consecutive 6-month periods (T − 6 → T0 vs T0 → T + 6), analysed within a pre-specified equivalence framework (± 5 percentage points). Secondary endpoints included DLCO changes and treatment-related adverse events (AEs), analysed at the patient level using paired comparisons. Results: Sixty-five patients (median age 77.0 years [72.3–80.0] years, 78% male) had complete functional follow-up. The mean percentage decline in FVC was − 1.9% before the switch and − 1.7% after the switch. The estimated between-period difference in FVC change was 0.2 percentage points (95% CI − 1.1 to 1.5), fully contained within the pre-specified equivalence margins. Similar findings were observed for DLCO, with no significant difference between periods. Overall, 43% of patients experienced at least one AE during treatment. Gastrointestinal AEs were the most frequent, but paired analyses showed no significant difference in patient-level AE occurrence between branded and generic periods. No severe AEs or treatment discontinuations were observed. Conclusions: In this real-world cohort of patients with IPF, switching from branded to generic pirfenidone was not associated with clinically meaningful differences in lung function decline or treatment tolerability.

In recent years, several studies have examined the impact of sleep-disordered breathing (SBD) on the quality of life and prognosis of patients with idiopathic pulmonary fibrosis (IPF). Among these disorders, obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are the most prevalent and extensively studied, whereas central sleep apnea (CSA) has only been documented in recent research. The mechanisms underlying the relationship between IPF and SBDs are complex and remain an area of active investigation. Despite growing recognition of SBDs in IPF, no standardized guidelines exist for their management and treatment, particularly in a population characterized by distinct structural pulmonary abnormalities. This review outlines the pathophysiological connections between sleep-breathing disorders (SBDs) and idiopathic pulmonary fibrosis (IPF), as well as current therapeutic options. A comprehensive literature search using PubMed identified relevant studies, confirming the efficacy of CPAP in treating severe OSA and CSA. While high-flow oxygen therapy has not been validated in this patient cohort, it may offer a potential solution for select patients, particularly the elderly and those with low compliance. Conventional oxygen therapy, however, is limited to cases of isolated nocturnal hypoxemia or mild central sleep apnea.

Recent advances in genetics and epigenetics have provided critical insights into the pathogenesis of both idiopathic and non-idiopathic interstitial lung diseases (ILDs). Mutations in telomere-related genes and surfactant proteins have been linked to familial pulmonary fibrosis, while variants in MUC5B and TOLLIP increase the risk of ILD, including idiopathic pulmonary fibrosis and rheumatoid arthritis-associated ILD. Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs such as miR-21 and miR-29, regulate fibrotic pathways, influencing disease onset and progression. Although no standardized genetic panel for ILD exists, understanding the interplay of genetic mutations and epigenetic alterations could aid in the development of personalized therapeutic approaches. This review highlights the genetic and epigenetic factors driving ILD, emphasizing their potential for refining diagnosis and treatment.