Agent For Idiopathic Pulmonary Fibrosis Research Articles

Prognostic significance of antifibrotic agents in idiopathic pulmonary fibrosis after initiation of long-term oxygen therapy.

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive interstitial lung disease with varying degrees of hypoxemia. Long-term oxygen therapy (LTOT) is frequently used to treat hypoxemia, however the prognostic factors for better survival in IPF patients after initiation of LTOT remain unknown. We retrospectively investigated favorable factors of survival in consecutive 55 IPF patients with chronic respiratory failure who were introduced LTOT. The 6-, 12-, 18-, and 24-month survival rates in IPF patients after introduction of LTOT were 70.9%, 49.0%, 45.2%, and 32.3%, respectively. Univariate analysis demonstrated that low Glasgow Prognostic Score (GPS) (hazard ratio [HR] 0.482, p=0.043) and treatment with antifibrotic agents (HR 0.401, p=0.013) were associated with favorable survival, while multivariate analysis revealed that treatment with antifibrotic agents was the independent predictor (HR 0.449, p=0.032). Moreover, IPF patients treated with antifibrotic agents with LTOT had significantly longer survival than those without antifibrotic agents (p = 0.0106). In IPF patients who were introduced LTOT, treatment with antifibrotic agents was the independent factor for favorable survival. Treatment with antifibrotic agents may improve prognosis of IPF even after initiation of LTOT.

Nintedanib Mitigates Radiation-Induced Pulmonary Fibrosis by Suppressing Epithelial Cell Inflammatory Response and Inhibiting Fibroblast-to-Myofibroblast Transition.

Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-β/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.

AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling

Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1+/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1+/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.

P16‐88: Real world multicenter prospective study of combination therapy of anti‐fibrotic agents in idiopathic pulmonary fibrosis (J‐avengers): An interim analysis

P16‐88: Real world multicenter prospective study of combination therapy of anti‐fibrotic agents in idiopathic pulmonary fibrosis (J‐avengers): An interim analysis

Efficacy and tolerability of antifibrotic agents in idiopathic pulmonary fibrosis: An experience from Turkey

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with poor prognosis. Antifibrotic drugs have come into use in the treatment of IPF, for which no effective therapeutic option existed until recently. This study makes an evaluation of IPF patients receiving pirfenidone or nintedanib as treatment. MATERIALS AND METHODS: This retrospective study included IPF patients who received antifibrotic therapy in our outpatient clinic between 2017 and 2020. The demographics, clinical symptoms, spirometric results, modified Medical Research Council (mMRC) and Leicester Cough Questionnaire (LCQ) scores, drug-related side effects, and treatment responses (at 6 months) were recorded. RESULTS: There were 52 patients (32:male-61.5% and 20:female-38.5%) with mean age of 70.65 ± 9.18. The most common presenting symptoms were dyspnea (86.5%) and cough (61.5%). The patients received pirfenidone (n = 31) and nintedanib (n = 21) therapies. The rate of side effects was 53.1%. At the 6-month control examination, 66% of the patients reported symptom relief. No significant difference was found in clinical symptoms, mMRC, respiratory parameters, or occurrence of side effects between the two treatment groups (P = 0.936, 0.393, 0.124, and 0.962, respectively). There was a stastistically significant improvement at LCQ score in patients treated with pirfenidone (P CONCLUSION: The outcomes of antifibrotic therapy in IPF are particularly promising in terms of relieving clinical symptoms and the preservation of lung capacity. IPF patients receiving pirfenidone as a treatment seems to have a significant improvement in cough-related health quality.

Effects of pirfenidone targeting the tumor microenvironment and tumor-stroma interaction as a novel treatment for non-small cell lung cancer

Targeting cancer-associated fibroblasts (CAFs), as well as the crosstalk between stroma and cancer cells, could be of value in managing cancers. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of fibroblast activation and the tumor-stroma interaction in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. PFD significantly inhibited myofibroblast differentiation and activation of both primary cultured normal human lung fibroblasts and CAFs. Cocultivation of NSCLC cells with conditioned media (CM) of fibroblasts changed the morphology or epithelial to mesenchymal transition (EMT) status, and PFD suppressed these changes. Cocultivation of CAFs with CM of NSCLC cells also induced activation of CAFs, and these changes were suppressed by PFD. On in vivo examination, CAFs promoted tumor progression, and PFD suppressed tumor progression with an inhibitory effect on tumor-stroma crosstalk. PFD might inhibit not only fibroblast activity, but also the crosstalk between cancer cells and fibroblasts. PFD may have great potential as a novel treatment for NSCLC from multiple perspectives.

The Clinical Efficacy of Pulmonary Hypertension-Specific Agents in Idiopathic Pulmonary Fibrosis: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials

BackgroundPulmonary hypertension (PH) is common in patients with idiopathic pulmonary fibrosis (IPF) and is associated with poor outcomes. This study was performed to determine the clinical efficacy of PH-specific therapeutic agents for IPF patients.MethodsWe performed a systematic review and meta-analysis using MEDLINE, EMBASE, and the Cochrane Central Register. We searched randomized controlled trials (RCTs) without language restriction until November 2018. The primary outcome was all-cause mortality to end of study.ResultsWe analyzed 10 RCTs involving 2,124 patients, 1,274 of whom received PH-specific agents. In pooled estimates, the use of PH-specific agents was not significantly associated with reduced all-cause mortality to end of study compared with controls (hazard ratio, 0.99; 95% confidence interval [CI], 0.92, 1.06; P = 0.71; I2 = 30%). When we performed subgroup analyses according to the type of PH-specific agent, sample size, age, forced vital capacity, diffusion lung capacity, and the extent of honeycombing, PH-specific agents also showed no significant association with a reduction in all-cause mortality. A small but significant improvement in quality of life, measured using the St. George Respiratory Questionnaire total score, was found in the PH-specific agent group (mean difference, −3.16 points; 95% CI, −5.34, −0.97; P = 0.005; I2 = 0%). We found no significant changes from baseline in lung function, dyspnea, or exercise capacity. Serious adverse events were similar between the two groups.ConclusionAlthough PH-specific agents provided small health-related quality-of-life benefits, our meta-analysis provides insufficient evidence to support their use in IPF patients.

1545 Drug-Induced Colitis With Nintedanib Therapy

INTRODUCTION: Nintedanib has emerged as an important treatment agent for Idiopathic Pulmonary Fibrosis (IPF). Gastrointestinal side effects, such as diarrhea and nausea, have been reported. However, Nintedanib-Induced Colitis, as described in the following cases, is a rare finding. CASE DESCRIPTION/METHODS: Case 1: 65 year-old man with a history of IPF on Nintedanib for three years presented with diarrhea. He reported two watery, non-bloody bowel movements daily with urgency, despite taking four tablets of loperamide daily. He had lower abdominal pain and an eighty-pound weight loss. A colonoscopy revealed mild edema, loss of vascular markings throughout the colon, and significant patches of submucosal hemorrhage/petechiae in the right colon. Biopsies revealed subepithelial deposition of amorphous eosinophilic material, prominently filling the subepithelial capillaries (Figure 1). Masson trichrome stain highlights dense blue staining, indicating collagen. The patient's symptoms resolved within a few days of discontinuing Nintedanib, and returned with rechallenge. Case 2: 76 year-old man with IPF on Nintedanib for three years presented with four loose, non-bloody bowel movements daily. He had bowel urgency, abdominal pain, and ten-pound weight loss despite loperamide use. Colonoscopy showed diffuse villous clubbing and erythema in the ileum. The entire colon revealed erythema and loss of vascular markings without ulcers (Figure 2). Histopathology revealed a paucicellular area of eosinophilic change in the lamina propria of the colon (Figure 3). There was no definite collagen deposition in this case. Nintedanib was discontinued and the patient's diarrhea resolved within two days; it returned with rechallenge. DISCUSSION: Nintedanib is a tyrosine kinase inhibitor, which is associated with diarrhea in about half of patients. Diarrhea is usually reported in the first three months of treatment and is generally adequately treated with anti-diarrheal medications. However, the specific entity of Nintedanib-induced colitis is a rare finding. There have only been two cases reported in the literature, neither of which described any particular pathologic findings. Our two cases demonstrate that symptoms resolve rapidly with drug withdrawal, recur rapidly upon rechallenge, and resolve again on withdrawal, suggesting a hypersensitivity reaction. Both cases demonstrate deposition of subepithelial eosinophilic material, which may offer a diagnostic clue to this drug induced diarrhea.

Protective effect of cysteinyl leukotriene receptor antagonist montelukast in bleomycin-induced pulmonary fibrosis.

This study aims to investigate the early- and late-term effects of pharmacological inhibition of cysteinyl leukotriene activity by using montelukast in bleomycin-induced inflammatory and oxidative lung injury in an animal model. The study included 48 male Wistar albino rats (weighing 250 g to 300 g). Rats were administered intratracheal bleomycin or saline and assigned into groups to receive montelukast or saline. Bronchoalveolar lavage fluid and lung tissue samples were collected four and 15 days after bleomycin administration. Bleomycin resulted in significant increases in tumor necrosis factor-alpha levels (4.0±1.4 pg/mL in controls vs. 44.1±14.5 pg/mL in early-term vs. 30.3±5.7 pg/mL in late-term, p<0.001 and p<0.001, respectively), transforming growth factor beta 1 levels (28.6±6.6 pg/mL vs. 82.3±14.1 pg/mL in early-term vs. 60.1±2.9 pg/mL in late-term, p<0.001 and p<0.001, respectively), and fibrosis score (1.85±0.89 in early-term vs. 5.60±1.14 in late-term, p<0.001 and p<0.01, respectively). In bleomycin exposed rats, collagen content increased only in the late-term (15.3±3.0 ?g/mg in controls vs. 29.6±9.1 ?g/mg in late-term, p<0.001). Montelukast treatment reversed all these biochemical indices as well as histopathological alterations induced by bleomycin. Montelukast attenuates bleomycin-induced inflammatory and oxidative lung injury and prevents lung collagen deposition and fibrotic response. Thus, cysteinyl leukotriene receptor antagonists might be regarded as new therapeutic agents for idiopathic pulmonary fibrosis.

P1.02-068 Effects of Pirfenidone Targeting EMT and Tumor-Stroma Interaction as Novel Treatment for Non-Small Cell Lung Cancer

Epithelial-to-mesenchymal transition (EMT) is related to the malignant behavior of cancer. Interaction between cancer-associated fibroblasts (CAFs) and tumor cells has been shown to increase tumor cell survival via several pathways including EMT. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis and one of its functions may be to inhibit fibrotic EMT. We evaluated the effects of PFD on EMT using non-small cell lung cancer (NSCLC) cells, as well as interactions between CAFs and NSCLC cells in vitro and in vivo.

Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia.

Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took ≥1085 mg/m2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP.

Idiopathic pulmonary fibrosis in the era of antifibrotic therapy: Searching for new opportunities grounded in evidence

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that up to now has been associated with a poor prognosis. However, the results of the INPULSIS and ASCEND trials and the approval of nintedanib and pirfenidone have marked the beginning of a new era for IPF patients. Questions remain, however. Should these drugs be used earlier? What effect will they have on more severe disease? Will their effects last beyond the trial period? This manuscript is the outcome of a multidisciplinary meeting between pulmonology, radiology, and pathology clinicians on the use of antifibrotic agents in IPF. In our opinion, the existing data show that pirfenidone and nintedanib slow functional decline in early stages of disease. These drugs also appear to result in therapeutic benefits when administered to patients with advanced disease at diagnosis and maintain effective over time. The data also suggest that continuing antifibrotic therapy after disease progression may confer benefits, but more evidence is needed. Early diagnosis and treatment are crucial for reducing functional decline, slowing disease progression, and improving quality of life.

(1242) - Short-Term Outcomes in Patients Taking Antifibrotic Agents for Idiopathic Pulmonary Fibrosis (IPF) After Lung Transplantation

(1242) - Short-Term Outcomes in Patients Taking Antifibrotic Agents for Idiopathic Pulmonary Fibrosis (IPF) After Lung Transplantation

Pirfenidone plays a biphasic role in inhibition of epithelial-mesenchymal transition in non-small cell lung cancer

IntroductionEpithelial to mesenchymal transition (EMT) relates to both organ fibrosis and malignant behavior of cancer. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis and one of its functions may be to inhibit fibrotic EMT. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of EMT in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. MethodsNSCLC cells (A549, NCI-H358) were used to evaluate PFD effects on TGF-β1 induced phenotypic changes. Possible TGF-β1 signaling pathways modulated by PFD were evaluated. The effects of PFD on EMT induced by an anti-cancer drug was also analyzed. The impact of PFD on tumor growth in nude mice as well as on EMT change in vivo was also determined. ResultsPFD significantly inhibited TGF-β1-induced EMT. Smad2 phosphorylation and TGF-β1 receptor I expression were also inhibited as was translocation of Smad2 from the cytoplasm into the nucleus. Carboplatin induced elevation of TGF-β1 production from cancer cells together with induction of EMT, which were suppressed by co-treatment with PFD. In in vivo examination, PFD alone did not inhibit tumor progression whereas its combination with carboplatin significantly decreased tumor growth. Immunohistological analysis showed that PFD suppressed EMT change induced by carboplatin. ConclusionsPFD could attenuate the EMT process induced not only by exogenous TGF-β1 but also by paracrine TGF-β produced from NSCLC cells. PFD may be a promising new therapeutic agent for the treatment of NSCLC through the regulation of EMT.

Newer insights into the management of interstitial lung disease in systemic sclerosis

Interstitial lung disease (ILD) is a debilitating complication of systemic sclerosis (SSc) and now the leading cause of death in SSc patients, largely from progressive respiratory failure or advanced pulmonary hypertension. Despite significant advances in our understanding of the epidemiology and pathogenesis of SSc-ILD, there are significant uncertainties in the approach to managing these patients given the heterogeneity of presentation, substantial variability in progression, and presence of comorbid cardiopulmonary conditions, particularly pulmonary hypertension and esophageal dilation with recurrent aspiration pneumonitis that portend poor prognosis. Early detection of progressive lung involvement based on worsening pulmonary physiology and quantification of fibrosing alveolitis severity on high-resolution computed tomography is critical as response to immunomodulatory agents is usually best when initiated earlier in the disease course. A selected group of patients may benefit from early referral for hematopoietic stem cell transplantation or lung/heart–lung transplant. The last decade has seen a significant advance in evidence-based approaches to treatment of SSc-ILD with immune suppressants, and there are several ongoing treatment trials with recent advances in understanding of the role of pro-inflammatory and profibrotic cytokines in SSc-ILD. The efficacy of antifibrotic agents in idiopathic pulmonary fibrosis has also provided another promising avenue for utilization in these patients. In this review, we will provide an up-to-date review of the treatment options for SSc-ILD, the ongoing studies moving this field forward, emerging treatments for SSc-ILD, and propose a management algorithm for SSc-ILD, based on the available evidence in the literature and our experience.

Assessing the Therapeutic Response to Pirfenidone in Idiopathic Pulmonary Fibrosis: Can We Do Better than with Forced Vital Capacity Alone?

New anti-fibrotic agents for idiopathic pulmonary fibrosis (IPF) were approved based on the results of forced vital capacity (FVC) trends, although concerns were raised about the reliability of FVC as the only endpoint parameter. We hypothesized that IPF-specific multi-dimensional scores (Composite Physiologic Index-CPI; gender-age-physiology-GAP; risk stratification score-RISE) would better capture response to therapy. In this pilot study, treated and untreated cohorts of IPF patients, matched for demographic and functional characteristics were prospectively followed for 1year, at 4-month intervals. Progression-free survival was significantly improved in treated patients (p=0.0093). While no difference in FVC longitudinal trends was observed, MRC dyspnea score (p=0.0347), diffusing lung capacity (p=0.0015), 6-min walk distance (p=0.0007), CPI (p=0.0457) and RISE (p=0.0005) were significantly stabilized in treated patients, compared to steady worsening in untreated subjects. Multi-dimensional scores provide broader spectrum of prognostic information and may facilitate the assessment of efficacy of new drugs for IPF.

Pirfenidone exerts a suppressive effect on CCL18 expression in U937-derived macrophages partly by inhibiting STAT6 phosphorylation

Context: CC chemokine ligand 18 (CCL18) is suggested to play a role in the development of pulmonary fibrosis. Macrophages are thought to be the main source of CCL18, and the effect of pirfenidone, an anti-fibrotic agent for idiopathic pulmonary fibrosis, on the expression of CCL18 in macrophages warrants investigation.Objective: The purpose of this study was to investigate the effect of pirfenidone on the expression of CCL18 in macrophages.Materials and methods: U937 cells were differentiated into macrophages by phorbol myristate acetate and then stimulated with recombinant IL-4 to induce the production of CCL18. The cells were treated with pirfenidone, and the mRNA and protein levels for CCL18 were measured by a reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The effects of pirfenidone on the IL-4 receptor (IL-4R) expression and STAT6 activation were investigated and on the JAK kinase activity were measured using the Z′-LYTE™ kinase assay.Results: Pirfenidone significantly suppressed the expression of CCL18 when the cells were treated with concentrations of 50–250 μg/mL. Pirfenidone did not affect the expression of the IL-4R components. The selective STAT6 inhibitor AS1517499 suppressed CCL18 expression. Both AS1517499 and pirfenidone suppressed STAT6 phosphorylation (p < .05), although the effect of pirfenidone was less marked than that of AS1517499. The Z′-LYTE™ kinase assay showed a reduction in the activities of JAK1, JAK3 and TYK2 by pirfenidone.Conclusion: Pirfenidone suppresses CCL18 expression in macrophages and this effect is thought to be attributed partly to the inhibition of STAT6 phosphorylation.

Development of Novel Agents for Idiopathic Pulmonary Fibrosis: Progress in Target Selection and Clinical Trial Design

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Until recently, the standard therapy for this disease has been essentially supportive, with the exception of a minority of patients who were eligible for lung transplantation. The development pathway for novel medications for IPF has been complicated. There have been several challenges, including an incomplete understanding of the pathogenesis, unpredictable clinical course, lack of validated biomarkers, the low clinical predictive value of animal models of lung injury, and the need to commit to large clinical trials of long duration to obtain initial evidence of clinical efficacy. Despite these challenges, the combination of recent advances in translational medicine and the unprecedented increase in clinical data accumulated from recent large clinical trials has stimulated an increase in the number of clinical development programs for IPF. Clinical programs are increasingly characterized by rational target selection, preclinical optimization of therapeutic molecules, and an emphasis on efficient clinical trial design. A lower rate of functional decline in patients treated with pirfenidone and nintedanib was demonstrated in large clinical trials. In October 2014, these two drugs became the first agents to be approved by the US Food and Drug Administration for the treatment of IPF. (Pirfenidone had already been approved in several countries outside the United States.) In November 2014, the European Medicines Agency approved the use of nintedanib for IPF. The landscape for management of IPF has markedly changed with the advent of approved therapeutic options for IPF. In this article, we review the strategies that are being used to increase the likelihood of success in clinical development programs of novel disease-modifying agents in IPF.

Do all patients with idiopathic pulmonary fibrosis warrant a trial of therapeutic intervention? A pro-con perspective.

Idiopathic pulmonary fibrosis (IPF) is an incurable condition that is characterized by progressive pulmonary fibrosis, architectural distortion of the lung and loss of gas exchange units. Until recently, there was no effective treatment for this condition. However, there were two landmark trials published earlier this year, which have changed the management of this condition. Pirfenidone (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis trial) and nintedanib (Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis-1 and -2 trials) have both demonstrated positive outcomes in patients with IPF. In this perspective, we critically discuss the role of these agents in IPF and in the broader pulmonary fibrosis population.

Non-steroid agents for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a chronic progressive lung disease with poor outcome and no effective treatment to date. This is an update of a Cochrane Review first published in 2003. To assess the efficacy of non-steroid agents in adults with idiopathic pulmonary fibrosis. We searched the Cochrane Airways Group Register (30 March 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2010), Ovid MEDLINE to March week 5, 2010, EMBASE to week 13, 2010 and PubMed to April 2010, with additional handsearching, including abstracts of international conferences. We also contacted pharmaceutical companies and researchers in the field. Randomised studies comparing non-steroid drugs with placebo or steroids in adults with idiopathic pulmonary fibrosis. Two authors independently assessed trial quality, extracted data and assessed risk of bias. We contacted pharmaceutical companies to obtain missing information, if any. We combined survival outcomes using Peto odds ratios or hazard ratios (HR). Fifteen trials involving 10 different drugs were included. Two trials enrolling 1156 patients compared interferon gamma-1beta with placebo: interferon gamma-1beta did not significantly improve survival (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68). Four trials involving 1155 patients compared pirfenidone with placebo. Three trials, conducted in 1046 patients, provided data on progression-free survival: pirfenidone significantly reduced the risk of disease progression by 30% (HR 0.70, 95% CI 0.56 to 0.88, P = 0.002). Data on the effect of pirfenidone on pulmonary function could only be assessed for two studies analysing 314 patients. Forced vital capacity or vital capacity was significantly improved by pirfenidone (mean difference 0.08 L, 95% CI 0.03 to 0.13, P = 0.0006). Based on available data, partly still unpublished, pirfenidone appears to improve progression-free survival and, to a lesser extent, pulmonary function in patients with idiopathic pulmonary fibrosis. More data are needed on overall survival and quality of life on treatment. From the studies in this review, interferon gamma-1beta has not been shown to affect survival. Other agents evaluated in single studies either failed to provide evidence for a benefit or need to be assessed in larger randomised controlled trials.