Arata Azuma

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. Georges Respiratory Questionnaire, both assessed over a 52-week period. RESULTS A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline

BACKGROUND This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment. METHODS 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. RESULTS 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. CONCLUSIONS The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.

Epidemiology of sarcoidosis in Japan

The present study was designed to identify recent clinical phenotypes using the National Epidemiological Survey and to compare findings with those of previous surveys in Japan. Pathologically confirmed sarcoidosis cases newly diagnosed in 2004 were eligible for the present study. Disease parameters were recorded and compared. A total of 1,027 patients were enrolled from a cluster encompassing 79.4% of the entire Japanese population. The study participants consisted of 364 males and 663 females, providing an average incidence rate of 1.01 per 100,000 inhabitants (0.73 for males and 1.28 for females). The age-specific incidence rate displayed a biphasic pattern in the whole patient population and in the females. The male incidence rates peaked in the 20–34-yr-old group. A second peak for 50–60-yr-old females showed a higher incidence than the first younger peak. Patients with abnormalities in eyes, skin and cardiac laboratory findings accounted for 54.8, 35.4 and 23.0% of cases, respectively. The female/male incidence ratio was increased, and the frequency of eye and skin involvement and cardiac abnormality was higher than in previous surveys conducted in Japan. In conclusion, the data obtained in the present study differ from those of other countries and showed changes in sarcoidosis clinical phenotypes compared with previous studies in Japan.

Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS

RATIONALE 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. OBJECTIVES To investigate the potential association of demographic and clinical variables with the effect of nintedanib in subjects with IPF. METHODS 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. Georges Respiratory Questionnaire (SGRQ) total score (≤40, >40), smoking status (never, ex/current), systemic corticosteroid use (yes/no), and bronchodilator use (yes/no). MEASUREMENTS AND MAIN RESULTS 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. CONCLUSIONS 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.

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. Nintedanib had acceptable safety and tolerability in Japanese patients with IPF http://ow.ly/DNG4k

Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment

BackgroundA phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial.MethodsThe patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO2), and the lowest oxygen saturation by pulse oximetry (SpO2) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52.ResultsSignificant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO2 < 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea.ConclusionsIPF patients having %VC ≥ 70% and SpO2 < 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment.Trial RegistrationThis clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (Registration Number: JAPICCTI-050121).

The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias

BACKGROUND Idiopathic interstitial pneumonias (IIPs) are one of the most common complications in patients with lung cancer. In lung cancer patients with IIP, the most serious toxicity is acute exacerbation of IIP caused by anticancer treatment in Japan. However, there has been no consensus and no evidence presented, regarding optimal treatment for advanced lung cancer with IIP. PATIENTS AND METHODS Chemotherapy-naïve patients of inoperable stage, or post-operative recurrent non-small cell lung cancer (NSCLC) with IIPs were enrolled. Patients received paclitaxel at a dose of 100mg/m(2) on Days 1, 8, 15, and carboplatin every 28 days at a target dose of area under the curve (AUC) 5.0 on Day 1. RESULTS Between May 2004 and October 2008, 18 patients, including 6 with idiopathic pulmonary fibrosis (IPF), were enrolled and treated for a median of four cycles (range, 1-6). One patient (5.6%; 95% confidence interval (CI), 0-17%) with histologically confirmed IPF had acute exacerbation of IIPs associated with the treatment. The overall response rate was 61% (95% CI, 36-86%). The median progression-free survival, median survival time, and 1-year survival rate were 5.3 months, 10.6 months, and 22%, respectively. CONCLUSION This is the first report indicating that advanced NSCLC patients with IIP may benefit from chemotherapy. Weekly paclitaxel and carboplatin combination chemotherapy was as effective as conventional regimens in advanced NSCLC patients without IIP and was safer than previously reported for NSCLC patients with IIP. The results from this study would support, on ethical grounds, the conduct of a large-scale study to confirm the feasibility of this regimen.

EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-β signaling in lung fibroblasts

BackgroundFourteen-membered ring macrolides have been effective in reducing chronic airway inflammation and also preventing lung injury and fibrosis in bleomycin-challenged mice via anti-inflammatory effects. EM703 is a new derivative of erythromycin (EM) without the bactericidal effects. We investigated the anti-inflammatory and antifibrotic effects of EM703 in an experimental model of bleomycin-induced lung injury and subsequent fibrosis in mice.MethodsSeven-week-old male ICR mice were used. All experiments used eight mice/group, unless otherwise noted in the figure legends. Bleomycin was administered intravenously to the mice on day 0. EM703 was orally administered daily to mice. All groups were examined for cell populations in the bronchoalveolar lavage (BAL) fluid and for induction of messenger RNA (mRNA) of Smad3 and Smad4 in the lung tissues by reverse transcriptase (RT)-polymerase chainreaction (PCR) on day 7. Fibroblastic foci were assessed histologically, and the hydroxyproline content was chemically determined in the lung tissues on day 28. We performed assay of proliferation and soluble collagen production, and examined the induction of mRNA of Smad3 and Smad4 by RT-PCR in murine lung fibroblast cell line MLg2908. We also examined Smad3, Smad4 and phosphorylated Smad2/3 (p-Smad2/3) protein assay by western blotting in MLg2908.ResultsBleomycin-induced lung fibrosis, and the infiltration of macrophages and neutrophils into the airspace were inhibited by EM703. The expression of Smad3 and Smad4 mRNA was clearly attenuated by bleomycin, but was recovered by EM703. EM703 also inhibited fibroblast proliferation and the collagen production in lung fibroblasts induced by Transforming growth factor-beta (TGF-β). The expression of Smad3 and Smad4 mRNA in murine lung fibroblasts disappeared due to TGF-β, but was recovered by EM703. EM703 inhibited the expression of p-Smad2/3 and Smad4 protein in murine lung fibroblasts induced by TGF-β.ConclusionThese findings suggest that EM703 improves bleomycin-induced pulmonary fibrosis in mice by actions of anti-inflammation and regulation of TGF-β signaling in lung fibroblasts.

Consensus statement for the diagnosis and treatment of drug-induced lung injuries.

Keishi Kubo, Arata Azuma, Minoru Kanazawa, Hideto Kameda, Masahiko Kusumoto, Akihiko Genma, Yasuo Saijo, Fumikazu Sakai, Yukihiko Sugiyama, Koichiro Tatsumi, Makoto Dohi, Hitoshi Tokuda, Shu Hashimoto, Noboru Hattori, Masayuki Hanaoka, Yuh Fukuda, the Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries Nagano Prefectural Hospital Organization, Japan Division of Pulmonary Medicine, Infections Diseases, and Oncology, Department of Internal Medicine, Nippon Medical School, Japan Department of Respiratory Medicine, Saitama Medical University, Japan Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Japan Department of Diagnostic Radiology, National Cancer Center Hospital, Japan Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Japan Department of Diagnostic Radiology, Saitama International Medical Center, Saitama Medical University, Japan Division of Pulmonary Medicine, Department of Internal Medicine, Jichi Medical University, Japan Department of Respirology, Chiba University Graduate School of Medicine, Japan Department of Allergy and Rheumatology, Tokyo University Graduate School of Medicine, Japan Department of Respiratory Medicine, Social Insurance Central General Hospital, Japan Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Japan Department of Molecular and Internal Medicine, Hiroshima University Graduate School of Biomedical & Health Sciences, Japan Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Japan

Leflunomide-related lung injury in patients with rheumatoid arthritis: imaging features

Imaging findings of 26 cases of leflunomide (Arava)-related acute lung injury were analyzed. Thirteen cases had pre-existing interstitial pulmonary disease on chest X-ray or computed tomography. The main features of clinically determined leflunomide-induced acute lung injury were similar to those caused by other drugs: diffuse or widespread patchy ground-glass opacities and/or consolidation, frequently accompanied by septal thickening and intralobular reticular opacities. We categorized these findings into four patterns: diffuse alveolar damage (DAD), acute eosinophilic pneumonia, hyperreaction, and cryptogenic organizing pneumonia. The DAD group had a higher mortality rate, but statistically not a significant one. It is impossible to exclude infectious disease such as pneumocystis carinii pneumonia based on imaging findings, and detailed correlation of imaging findings with clinical and laboratory findings is essential in order to make a correct diagnosis.