U. Costabel

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias

BACKGROUNDnIn 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical gold standard of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs.nnnPURPOSEnThe objective of this statement is to update the 2002 ATS/ERS classification of IIPs.nnnMETHODSnAn international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011.nnnRESULTSnSubstantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis-interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment.nnnCONCLUSIONSnThis update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.

Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial

The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5u2005mg·kg−1 body weight administered over 24u2005weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24u2005weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24u2005weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.

All-Cause Mortality Rate in Patients with Idiopathic Pulmonary Fibrosis. Implications for the Design and Execution of Clinical Trials

RATIONALEnFVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials.nnnOBJECTIVESnTo conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF.nnnMETHODSnThe study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design.nnnMEASUREMENTS AND MAIN RESULTSnA total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients.nnnCONCLUSIONSnThe all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.

Triple therapy in idiopathic pulmonary fibrosis: an alarming press release

On October 21, 2011, the National Heart, Lung, and Blood Institute (NHLBI), announced by press release that the prednisolone/azathioprine/ N -acetylcysteine (triple therapy) arm of the PANTHER study (Prednisone, Azathioprine and N -acetylcysteine: a Study That Evaluates Response in IPF) had been discontinued [1]. Compared with patients receiving placebo, patients with idiopathic pulmonary fibrosis (IPF) treated with triple therapy had excess deaths (11% versus 1%), more hospitalisations (29% versus 8%) and a higher prevalence of serious adverse events (31% versus 9%). The study is continuing with the N -acetylcysteine and placebo arms only. No concerns have been raised as a result of preliminary analysis of the N -acetylcysteine monotherapy arm of the PANTHER study. The preliminary announcement by the NHLBI has no immediate implications with regard to the introduction or continuation of N -acetylcysteine in IPF.nnIt is hardly surprising that this announcement has caused widespread alarm amongst medical practitioners and patients with IPF currently taking triple therapy, especially in Europe, where this therapy is largely used. In isolation, the small absolute number of excess deaths in the triple therapy arm, although statistically significant, could not be viewed as conclusive. In earlier IPF studies, the supposed efficacy of interferon-γ [2] and the protective effect of pirfenidone against acute exacerbations [3] were based on similarly low numbers of events and neither …

Idiopathic pulmonary fibrosis in 2011: key updates on guidelines and therapeutics

This first Advancing in Idiopathic pulmonary fibrosis Research (AIR) meeting took place in Berlin, on the 4th and 5th of November 2011, bringing leading experts in the field of Idiopathic Pulmonary Fibrosis (IPF) and European clinicians together to share knowledge on recent advances and practical experience in the management of this devastating disease. n nIt is widely recognised that although IPF is a rare fibrosing lung disease it is associated with a tremendous burden. The estimated median survival of patients with IPF is 2–5 years following diagnosis, and the mortality rate is greater than that associated with numerous malignancies [1,2]. n nThis has presented significant challenges in patient management and until recently there were no pharmacological treatments approved for patients with IPF in Europe. n nThe timing of this meeting was therefore particularly relevant as there were a number of important advances and new findings during 2011, which included the publication of the updated guidelines from the ATS/ERS/JRS/ALAT Committee and the approval of pirfenidone for the treatment of mild-to-moderate IPF in Europe [3,4]. n nIn addition, a press release from the National Institutes of Health reported that one arm of an ongoing trial, PANTHER-IPF, had been stopped because patients with IPF receiving a currently used triple-drug therapy consisting of prednisone, azathioprine, and N-acetylcysteine (NAC) had worse outcomes than those who received matching placebo. The interim results from PANTHER-IPF have since been published [5]. n nThis supplement to Respiratory Research reported the proceedings from this first European IPF meeting, with key articles selected by the AIR Scientific Committee, which were considered essential reading for all clinicians managing patients with IPF in Europe. n nArticles in this supplement included a review of the recently updated ATS/ERS/JRS ALAT diagnostic criteria by Professor Athol Wells, and discussion on how these can facilitate early diagnosis of IPF. It also considered issues that may remain unclear despite the updated guidance. Linked to the diagnosis of IPF, Nicola Sverzellati gave a master class on HRCT imaging and practical requirements for optimising CT scanning techniques. n nPresentations then focused on the management of IPF. Professor Luca Richeldi discussed the Cochrane Collaboration approach to analysing clinical trial data and the findings of Cochrane meta-analyses that have been performed to determine the effect of treatments used in the management of IPF. This was followed by Professor Vincent Cottin, who summarised the outcomes from prior clinical trials in IPF and the recently published Phase III studies of pirfenidone that led to its approval in Europe. Following these updates, Professor Jurgen Behr and Luca Richeldi discussed how these data can be interpreted in light of the updated recommendations of the ATS/ERS/JRS/ALAT Committee regarding treatment of IPF. Professor Carlo Albera outlined the implications of the press release from the NIH regarding the PANTHER-IPF study. n nHopefully the selected proceedings from this meeting will provide IPF clinicians with new insights and support in the management of their patients. The intention is for the AIR meeting to become a fixed date in the calendar for respiratory physicians and researchers dedicated to improving knowledge and bringing new hope for IPF patients.

Effect of baseline FVC on decline in lung function with nintedanib: results from the INPULSIS™ trials

Background: Nintedanib, an intracellular inhibitor of tyrosine kinases, is in development for the treatment of idiopathic pulmonary fibrosis (IPF). The INPULSIS™ trials were two replicate randomized, double-blind, placebo-controlled, 52-week Phase III trials that assessed the efficacy and safety of nintedanib 150 mg twice daily in patients with IPF. The primary endpoint was the annual rate of decline in forced vital capacity (FVC), which was significantly reduced in the nintedanib group compared with placebo in both trials. Aim: To assess the impact of baseline FVC on the effect of nintedanib on rate of decline in FVC. Methods: A pre-specified subgroup analysis of patients with baseline FVC >70% versus ≤70% of predicted value was undertaken using pooled data from both trials. Results: 700 patients (nintedanib 431, placebo 269) had baseline FVC >70% predicted and 361 patients (nintedanib 207, placebo 154) had baseline FVC ≤70% predicted. For patients with a baseline FVC >70% predicted, mean age was 67.4 years, 76.9% were male, 55.7% were White and mean carbon monoxide diffusion capacity (DL CO ) was 4.0 mmol/min/kPa. For patients with a baseline FVC ≤70% predicted, mean age was 65.5 years, 83.9% were male, 60.4% were White and mean DL CO was 3.6 mmol/min/kPa. There was no significant treatment by subgroup interaction: the difference in adjusted annual rate of decline in FVC between the nintedanib and placebo groups was comparable in both subgroups. Conclusion: A subgroup analysis of pooled data from the INPULSIS™ trials showed that nintedanib 150 mg twice daily slowed the decline in lung function in patients with IPF, independent of severity of lung function impairment at baseline.