特発性肺線維症

This study compares their safety profiles using real-world pharmacovigilance data and meta-analysis to guide clinical use. The gastrointestinal disorders and skin-related ADRs listed in the latest instructions for pirfenidone and nintedanib were systematically reviewed and subsequently analyzed using the FDA Adverse Event Reporting System (FAERS) database. Adverse drug event (ADE) reports for pirfenidone (2014-Q1 2025) and nintedanib (2014-Q1 2025) were extracted from the FAERS database via OpenVigil 2.1. ADE signals were analyzed using MedDRA's system organ class (SOC) and preferred terms (PT), with reporting odds ratio (ROR) for signal detection. Randomized controlled trials (RCTs) were retrieved from Cochrane, PubMed, Embase, and ClinicalTrials.gov, and meta-analysis was performed using RevMan 5.3. Pirfenidone and nintedanib were associated with 26,352 and 9,809 ADE reports, respectively, primarily in patients aged ≥ 65. Gastrointestinal disorders were common for both, but nintedanib showed fewer skin-related ADRs. Gender-based differences were observed: nintedanib's gastrointestinal ADRs varied by gender, while pirfenidone's skin-related ADRs differed significantly. Most reports originated from the U.S. Meta-analysis of 10 RCTs (6 pirfenidone, 4 nintedanib) showed both drugs slowed forced vital capacity (FVC) decline and reduced respiratory-related mortality. Nintedanib demonstrated superior efficacy in reducing acute exacerbations (RR = 0.57, 95%CI [0.34-0.98], I2 = 47%). Both drugs primarily caused gastrointestinal ADRs (e.g., nausea, vomiting), with pirfenidone linked to more photosensitivity reactions. Integrated pharmacovigilance and RCT analyses highlight the safety profiles of pirfenidone and nintedanib, offering evidence for clinical decision-making in idiopathic pulmonary fibrosis (IPF) treatment.

INTRODUCTION: While efficacy of antifibrotics (pirfenidone and nintedanib) in idiopathic pulmonary fibrosis (IPF) is well established, its effects on combined pulmonary fibrosis and emphysema (CPFE) remain unclear. We evaluated the therapeutic efficacy of antifibrotics in CPFE patients. METHODS: This multicentre study used the Korean IPF Cohort registry, identifying 966 CPFE patients. A 6-month landmark window controlled for immortal time bias. Propensity score matching (PSM) balanced baseline characteristics for age, sex, body mass index (BMI), lung cancer, and Composite Physiologic Index (CPI). Post-matching survival outcomes (N=584) were evaluated via 100-month truncated Restricted Mean Survival Time (RMST) to account for proportional hazards violation. Annual longitudinal lung function trajectories (n=310) were estimated via piecewise linear mixed models (LMM) handling missing data as missing at random. RESULTS: In the matched cohort, conventional Cox analysis exhibited a marginally significant risk in the treatment arm (HR=1.29; 95% CI: 1.01-1.65; p=0.045); however, a distinct trajectory cross-over occurred at ∼100 months. Truncated RMST confirmed that the net survival difference was statistically equivalent (-6.87 months; 95% CI: -14.64 to 0.90; p=0.264). Conversely, a significant physiological benefit was demonstrated in continuous lung function preservation, markedly attenuating the annual rate of diffusing capacity of the lung for carbon monoxide (DLCO) % predicted decline from -4.19±0.37%/year pre-treatment to -2.97±0.30%/year post-treatment (p<0.001). CONCLUSIONS: Although antifibrotic therapy does not demonstrate a long-term average survival advantage over a decade, it significantly attenuates the longitudinal physiological decline of lung function (DLCO) in patients with CPFE, providing a protective brake against disease progression.

INTRODUCTION: Progressive fibrosing interstitial lung diseases (PF-ILDs), including idiopathic pulmonary fibrosis (IPF), are characterised by irreversible fibrosis and poor prognosis. Despite the importance of timely identification, diagnostic delays remain common. This review aimed to summarise studies reporting time to diagnosis in PF-ILDs to identify reasons for diagnostic delays and the impact on several clinical and economic outcomes. METHODS: Database (Embase, MEDLINE, Cochrane Library, LILACS and grey literature) searches were conducted on 15 July 2024 and updated on 5 June 2026. Observational studies reporting time to diagnosis in PF-ILD published between 2002 and 2026 were identified. RESULTS: 34 studies representing 36 621 patients from 41 countries met the inclusion criteria. Dyspnoea, cough and fatigue were the most common presenting symptoms. Median time from symptom onset to diagnosis ranged between 6.0 and 25.2 months; mean estimates varied from 9.6 to 39.3 months in IPF and exceeded 30.2 months in non-IPF PF-ILD. Between 30% and 77% of patients experienced delays >12.0 months. An increased diagnostic time was associated with more advanced disease, worse survival, poorer quality of life and increased hospitalisation rate. Across included studies, between 21% and 87% of patients were misdiagnosed (often with cardiovascular or other respiratory diseases) and received treatment for other conditions. Predictors of delayed diagnosis included older age, comorbidities, misdiagnosis, previous therapy and absence of early imaging or multidisciplinary evaluation. CONCLUSIONS: Patients with PF-ILD, including IPF, face a long time to diagnosis, associated with unfavourable clinical and healthcare resource outcomes, with limited evidence on cost outcomes. Direct economic burden resulting from delayed diagnosis is currently poorly understood and needs further research.

ObjectiveTo evaluate the association between genetically predicted GLP-1R expression and idiopathic pulmonary fibrosis and to explore potential mediation through JAKMIP3 and pulmonary-function traits using Mendelian randomization.MethodsWe conducted a two-sample drug-target cis-Mendelian randomization study using Genotype-Tissue Expression lung cis-expression quantitative trait locus summary data as genetic proxies for GLP-1R expression and FinnGen R5 summary data (1028 cases and 196,986 controls; n = 198,014) for idiopathic pulmonary fibrosis. Type 2 diabetes mellitus served as a positive control, and a targeted panel of circulating molecular and pulmonary-function traits was evaluated using two-step Mendelian randomization. Primary estimates were obtained using inverse-variance weighting, with complementary estimators and sensitivity analyses. For the European-ancestry pulmonary function analyses, we used measured forced expiratory volume in 1 s (GCST90691840), forced vital capacity (GCST90691839), and peak expiratory flow (GCST90691841) genome-wide association studies, each including 383,471 participants.ResultsHigher genetically predicted GLP-1R expression was associated with a lower risk of idiopathic pulmonary fibrosis on inverse-variance weighted analysis (odds ratio = 0.740, 95% confidence interval: 0.632-0.866, p = 1.83 × 10-4). The positive-control analysis supported the biological coherence of the GLP1R expression proxy (type 2 diabetes mellitus, odds ratio = 0.630). JAKMIP3 was identified as a candidate circulating protein mediator, with a mediation proportion of 9.8%. In the European-ancestry pulmonary function analyses, forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow showed mediation proportions of 14.2%, 22.6%, and 11.8%, respectively, with the largest estimate observed for forced vital capacity.ConclusionsThe findings support an association between genetically predicted higher GLP-1R expression and lower risk of idiopathic pulmonary fibrosis and identify JAKMIP3 and pulmonary-function traits as candidate intermediates. These results provide a rationale for mechanistic and clinical studies evaluating glucagon-like peptide-1 receptor-related pathways in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) poses a health challenge with the destruction of lung architecture. It is featured by limited effective therapeutic options and a complex pathological mechanism. The molecular mechanism underlying the antifibrotic agent pirfenidone (PFD) remains to be fully determined. This study investigated the anti-inflammatory effects of pirfenidone in the treatment of IPF and explored its regulation of the C-X-C motif chemokine ligand 6 (CXCL6), a potent neutrophil chemoattractant. Using the murine model, pirfenidone has been identified to limit lung inflammation and neutrophil infiltration. Mice with pirfenidone administration expressed less CXCL6 than controls. Exogenous CXCL6 administration counteracted the anti-pulmonary fibrosis effect of pirfenidone in mice. Mechanistically, pirfenidone inhibited phosphorylation of NF-κB/p65, p38 MAPK, and Akt in IL-1β-stimulated macrophages, suggesting that pirfenidone modulated the inflammatory signaling pathways. Clinical analysis indicated that CXCL6 was upregulated in patients and decreased after pirfenidone treatment. Each unit increase in plasma CXCL6 concentration was linked to a 24% higher risk of death. This study identified the anti-inflammatory effects of pirfenidone and elucidated its novel mechanism by inhibiting CXCL6 secretion and neutrophil migration. Moreover, the identification of CXCL6 as a critical mediator of IPF may highlight a potential therapeutic target.