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Patients with interstitial lung disease associated with systemic sclerosis were treated with usual care plus placebo or nintedanib. The annual rate of change in forced vital capacity assessed over a 52-week period was −52.4 ml per year with nintedanib and −93.3 ml per year with placebo. There were no differences in other measures of systemic sclerosis.

In the two replicate, placebo-controlled, 52-week, phase III INPULSIS trials, nintedanib 150 mg twice daily significantly reduced the annual rate of decline in FVC, the primary endpoint, in subjects with idiopathic pulmonary fibrosis (IPF). It is unknown if this effect was uniform across all subjects treated with nintedanib. To investigate the potential association of demographic and clinical variables with the effect of nintedanib in subjects with IPF. Subgroup analyses of pooled data from the INPULSIS trials were prespecified. Subgroups were analyzed by sex, age (<65, ≥65 yr), race (white, Asian), baseline FVC percentage predicted (≤70%, >70%), baseline St. George's Respiratory Questionnaire (SGRQ) total score (≤40, >40), smoking status (never, ex/current), systemic corticosteroid use (yes/no), and bronchodilator use (yes/no). A total of 1,061 subjects were treated (nintedanib n = 638, placebo n = 423). There was no statistically significant difference in the effect of nintedanib for the primary endpoint or the key secondary endpoints of change from baseline in SGRQ total score or time to first acute exacerbation in any subgroup. Treatment effects for the key secondary endpoints seemed more pronounced in subjects with baseline FVC ≤70% predicted, because the majority of acute exacerbations and a greater deterioration in SGRQ total score occurred in placebo-treated subjects in this subgroup. Pooled data from the INPULSIS trials support a consistent effect of nintedanib across a range of IPF phenotypes by slowing disease progression across a number of prespecified subgroups.

This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment. Systematic reviews and, when appropriate, meta-analyses were performed to summarize all available evidence pertinent to our questions. The evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and then discussed by a multidisciplinary panel. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity, recommendations were made for or against specific treatment interventions. The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.

In this randomized, placebo-controlled trial, treatment with nintedanib, an intracellular inhibitor of multiple tyrosine kinases, led to a reduced rate of loss of forced vital capacity in patients with idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. 1 A decline in forced vital capacity (FVC) is consistent with disease progression and is predictive of reduced survival time. 1 – 6 Idiopathic pulmonary fibrosis is believed to arise from an aberrant proliferation of fibrous tissue and tissue remodeling due to the abnormal function and signaling of alveolar epithelial cells and interstitial fibroblasts. 7 The activation of cell-signaling pathways through tyrosine kinases such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of . . .

Pirfenidone is the first antifibrotic agent to be approved for the treatment of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is one of the idiopathic interstitial pneumonias with the worst prognoses; approximately half of patients die within 3–5 years, and the need for an effective treatment has been unmet until recently. The etiology of IPF is still unknown and its pathogenesis is poorly understood. Anti-inflammatory drugs, such as corticosteroids and some immunosuppressants, have been empirically used to treat IPF, although they have not been objectively proven to be effective by large-scale randomized, controlled trials. Pirfenidone is an agent that can inhibit the decline of forced vital capacity (FVC)/vital capacity (VC) and that thereby can be hoped to decrease the mortality rate. The number of clinical trials of pirfenidone completed, ongoing, or planned is growing, and the present status of pirfenidone as treatment for IPF is summarized in this review.

We used data from the SENSCIS and SENSCIS-ON trials to assess decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) who received long-term treatment with nintedanib and the effect of switching patients from placebo to nintedanib. In the SENSCIS trial, patients were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤ 100 weeks. In SENSCIS-ON, the extension to SENSCIS, all patients received open-label nintedanib. Per protocol, the off-treatment period between these trials was ≤ 12 weeks. We assessed the trajectory of FVC in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON ( n  = 197) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON ( n  = 231). The last on-treatment measurement in SENSCIS and the baseline measurement of SENSCIS-ON were considered anchor measurements. In patients who received nintedanib in SENSCIS, the mean decline in FVC in the 52 weeks prior to the last on-treatment measurement in SENSCIS was − 41.5 mL and the mean decline in FVC from baseline to week 52 of SENSCIS-ON was − 58.3 mL. In patients who received placebo in SENSCIS, the mean decline in FVC in the 52 weeks prior to the last on-treatment measurement in SENSCIS was − 96.8 mL and the mean decline in FVC from baseline to week 52 of SENSCIS-ON (when patients received nintedanib) was − 42.8 mL. These findings illustrate the progressive nature of SSc-ILD and support the efficacy of nintedanib in slowing decline in lung function over the long term.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with rare incidence but high mortality, and the pathogenesis of which is still poorly understood. Available treatment options have been empirically applied but evidence-based benefits have not yet been confirmed. Pirfenidone is an antifibrotic agent that is potentially effective for IPF treatment. Preclinical studies have been reported using experimental animal models, which revealed inhibitory effects pn profibrotic and proinflammatory cytokines. Several clinical studies provided promising and reproducible effects for inhibition of IPF disease progression in different nations. The efficacy is demonstrated in patients with mild-to-moderate impairment of pulmonary functions, but not confirmed for patients with severe impairment. Major adverse events are photosensitivity and anorexia, but the treatment was generally safe and well tolerated. In this article, the usefulness and limitations of pirfenidone in IPF treatment are discussed to determine its potential for the management of IPF progression.

Background Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. Methods Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non–AE-IPF rate during postoperative days 0–30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. Results From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7–99.4 %, p  = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5–99.9 %, p  = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3–5 adverse events were observed. Conclusions Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients. Trial registration This clinical trial was registered with the University Hospital Medical Information Network (UMIN) on April 16th, 2012 (Registration Number: UMIN000007774 ).

Background Bone marrow-derived fibrocytes reportedly play important roles in the pathogenesis of idiopathic pulmonary fibrosis. Pirfenidone is an anti-fibrotic agent; however, its effects on fibrocytes have not been investigated. The aim of this study was to investigate whether pirfenidone inhibits fibrocyte pool size in the lungs of bleomycin-treated mice. Methods Bleomycin (100 mg/kg) was infused with osmotic pumps into C57BL/6 mice, and pirfenidone (300 mg/kg/day) was orally administered daily for 2 wk. The lungs were removed, and single-cell suspensions were subjected to fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes, which were defined as CD45 and collagen-I double-positive cells. Immunohistochemistry was performed on the lung specimens to quantify fibrocytes. Chemokines in the lung digests were measured with enzyme-linked immunosorbent assay. The effect of pirfenidone on alveolar macrophages was evaluated with bronchoalveolar lavage (BAL). In a therapeutic setting, pirfenidone administration was initiated 10 days after bleomycin treatment. For chemotaxis assay, lung fibrocytes were isolated with immunomagnetic selection (CD45-positive mesenchymal cells) after culture and allowed to migrate toward chemokines in the presence or absence of pirfenidone. Moreover, the effect of pirfenidone on the expression of chemokine receptors on fibrocytes was evaluated. Results Pirfenidone significantly ameliorated bleomycin-induced pulmonary fibrosis as assessed with quantitative histology and collagen measurement. Fibrocyte pool size in bleomycin-treated mice lungs was attenuated from 26.5% to 13.7% by pirfenidone on FACS analysis. This outcome was also observed in a therapeutic setting. Immunohistochemistry revealed that fibrocytes were significantly decreased by pirfenidone administration compared with those in bleomycin-treated mice ( P = 0.0097). Increased chemokine (CC motif) ligand-2 (CCL2) and CCL12 production in bleomycin-treated mouse lungs was significantly attenuated by pirfenidone ( P = 0.0003 and P < 0.0001, respectively). Pirfenidone also attenuated macrophage counts stimulated by bleomycin in BAL fluid. Fibrocyte migration toward CCL2 and chemokine (CC motif) receptor-2 expression on fibrocytes was significantly inhibited by pirfenidone in vitro . Conclusions Pirfenidone attenuated the fibrocyte pool size in bleomycin-treated mouse lungs via attenuation of CCL2 and CCL12 production in vivo , and fibrocyte migration was inhibited by pirfenidone in vitro . Fibrocyte inhibition is considered a mechanism of anti-fibrotic action of pirfenidone.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a prognosis that can be worse than for many cancers. The initial stages of the condition were thought to mainly involve chronic inflammation; therefore, corticosteroids and other drugs that have anti-inflammatory and immunosuppressive actions were used. However, recently, agents targeting persistent fibrosis resulting from aberrant repair of alveolar epithelial injury have been in the spotlight. There has also been an increase in the number of available antifibrotic treatment options, starting with pirfenidone and nintedanib. These drugs prevent deterioration but do not improve IPF. Therefore, nonpharmacologic approaches such as long-term oxygen therapy, pulmonary rehabilitation, and lung transplantation must be considered as additional treatment modalities.