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.
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. George's Respiratory Questionnaire, both assessed over a 52-week period.
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.
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.).
Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in ...lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.
In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 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). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire SGRQ), and total lung capacity.
A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.
In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).
Sarcoidosis is a systemic inflammatory disorder of unknown etiology characterized by tissue infiltration with macrophages and lymphocytes and associated non-caseating granuloma formation. The disease ...primarily affects the lungs. Patients suffering from sarcoidosis show a wide range of clinical symptoms, natural history and disease outcomes. Originally described as a Th1-driven disease, sarcoidosis involves a complex interplay among diverse immune cells. This review highlights recent advances in the pathogenesis of sarcoidosis, with emphasis on the role of different immune cells. Accumulative evidence suggests Th17 cells, IFN-γ-producing Th17 cells or Th17.1 cells, and regulatory T (Treg) cells play a critical role. However, their specific actions, whether protective or pathogenic, remain to be clarified. Macrophages are also involved in granuloma formation, and M2 polarization may be predictive of fibrosis. Previously neglected cells including B cells, dendritic cells (DCs), natural killer (NK) cells and natural killer T (NKT) cells were studied more recently for their contribution to sarcoid granuloma formation. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with hope to open up new therapeutic avenues and if possible, to develop preventive measures.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible fibrotic disease of the lung that has greatly frustrated clinicians for a long time. The prognosis of IPF (median ...survival 2-5 years following diagnosis) is poorer than that of some cancers and for many years no significant advances were made in its management. However, between 2011 and 2014 a number of pivotal developments were made that have improved the outlook for patients with IPF. Herein, we review this rapidly changing landscape, discussing key events whilst still acknowledging that IPF remains a challenging disease to diagnose and manage.
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.
Granulomatous lung diseases are a heterogeneous group of disorders that have a wide spectrum of pathologies with variable clinical manifestations and outcomes. Precise clinical evaluation, laboratory ...testing, pulmonary function testing, radiological imaging including high-resolution computed tomography and often histopathological assessment contribute to make a confident diagnosis of granulomatous lung diseases. Differential diagnosis is challenging, and includes both infectious (mycobacteria and fungi) and noninfectious lung diseases (sarcoidosis, necrotising sarcoid granulomatosis, hypersensitivity pneumonitis, hot tub lung, berylliosis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, rheumatoid nodules, talc granulomatosis, Langerhans cell histiocytosis and bronchocentric granulomatosis). Bronchoalveolar lavage, endobronchial ultrasound-guided transbronchial needle aspiration, transbronchial cryobiopsy, positron emission tomography and genetic evaluation are potential candidates to improve the diagnostic accuracy for granulomatous lung diseases. As granuloma alone is a nonspecific histopathological finding, the multidisciplinary approach is important for a confident diagnosis.
Gastro-oesophageal reflux disease is a potential risk factor for the development and progression of idiopathic pulmonary fibrosis (IPF). We aimed to investigate the effect of antacid therapy on ...disease progression in patients randomly assigned to placebo through analysis of three large, phase 3 trials of pirfenidone in IPF.
Patients with IPF from the placebo groups of three trials of pirfenidone (CAPACITY 004, CAPACITY 006, and ASCEND) were included in this post-hoc analysis. We analysed effects of antacid therapy use from baseline for pulmonary function, exercise tolerance, survival, hospital admission, and adverse events for 52 weeks with and without adjustment for potential confounders. The primary endpoint, disease progression by 1 year, was defined as a decrease in predicted forced vital capacity (FVC) by 10% or more, a decrease in 6 min walk distance (6MWD) by 50 m or more, or death. We did survival analyses with the Kaplan-Meier estimator and evaluated using the log-rank test.
Of 624 patients, 291 (47%) received antacid therapy and 333 (53%) did not. At 52 weeks, we noted no significant difference between groups for disease progression (114 39% for antacid therapy vs 141 42% for no antacid therapy, p=0·4844). Rates also did not differ for all-cause mortality (20 7% vs 22 7%, p=0·8947), IPF-related mortality (11 4% vs 17 5%; p=0·4251), absolute FVC decrease by 10% or more (49 17% vs 64 19%; p=0·4411), or mean observed change in FVC (% predicted -4·9% SD 6·4 vs -5·5% 7·2, p=0·3355; observed volume -0·2 L 0·3 vs -0·2 L 0·3, p=0·4238). The rate of hospital admission was non-significantly higher in the antacid therapy group (65 22% vs 54 16%; p=0·0522). When stratified by baseline FVC (<70% or ≥70%), disease progression, mortality, FVC, 6MWD, and hospital admission did not differ between groups. Adverse events were similar between treatment and no treatment groups; however, overall infections (107 74% vs 101 62%; p=0·0174) and pulmonary infections (20 14% vs 10 6%; p=0·0214) were higher in patients with advanced IPF (ie, FVC <70%) who were treated with antacids than not treated with antacids.
Antacid therapy did not improve outcomes in patients with IPF and might potentially be associated with an increased risk of infection in those with advanced disease.
F Hoffmann-La Roche.
There have been no recent comprehensive studies of the epidemiology of sarcoidosis in the United States. Changes in health care use have made available access to data on large numbers of patients ...with sarcoidosis.
To use a U.S. national health care database to gather data on patients with sarcoidosis identified over a 3-year period who were 18 years of age and older, and to determine health care costs for these patients.
The Optum health care database was queried for a 3-year period (2010-2013). This database includes approximately 15% of U.S. residents. The incidence rate of sarcoidosis was calculated for new cases identified in each year. Calculation of prevalence was based on any patient with sarcoidosis seen during the year. Incidence and prevalence rates are reported per 100,000 patients.
A total of 29,372 adult patients with sarcoidosis were identified. Of these, 14,700 (55%) were over 55 years of age at the time of diagnosis. The incidence and prevalence rates were higher for African Americans (17.8 and 141.4 per 100,000, respectively) than for white individuals (8.1 and 49.8), Hispanics (4.3 and 21.7), or Asians (3.2 and 18.9). Women were two times more likely to have sarcoidosis, with the highest prevalence for sarcoidosis noted in African American women (178.5). Overall, the yearly health care cost reported for patients with sarcoidosis was low, with a median of $18,663 per year. However, the yearly cost for the top 5% was $93,201.
For patients 18 years of age and older enrolled in a U.S. national administrative database, sarcoidosis was more common among African Americans, but it was reported for all four of the major ethnic groups studied. While health care costs were relatively small for most patients, the cost of care for some patients was considerable.
Surgical lung biopsy is often required for a confident multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF). Alternative, less-invasive biopsy methods, such as bronchoscopic lung ...cryobiopsy (BLC), are highly desirable.
To address the impact of BLC on diagnostic confidence in the multidisciplinary diagnosis of IPF.
In this cross-sectional study we selected 117 patients with fibrotic interstitial lung disease without a typical usual interstitial pneumonia pattern on high-resolution computed tomography. All cases underwent lung biopsies: 58 were BLC, and 59 were surgical lung biopsy (SLB). Two clinicians, two radiologists, and two pathologists sequentially reviewed clinical-radiologic findings and biopsy results, recording at each step in the process their diagnostic impressions and confidence levels.
We observed a major increase in diagnostic confidence after the addition of BLC, similar to SLB (from 29 to 63%, P = 0.0003 and from 30 to 65%, P = 0.0016 of high confidence IPF diagnosis, in the BLC group and SLB group, respectively). The overall interobserver agreement in IPF diagnosis was similar for both approaches (BLC overall kappa, 0.96; SLB overall kappa, 0.93). IPF was the most frequent diagnosis (50 and 39% in the BLC and SLB group, respectively; P = 0.23). After the addition of histopathologic information, 17% of cases in the BLC group and 19% of cases in the SLB group, mostly idiopathic nonspecific interstitial pneumonia and hypersensitivity pneumonitis, were reclassified as IPF.
BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of interstitial lung disease and may prove useful in the diagnosis of IPF. This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared with SLB.
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