Interferon Gamma-1b Therapy for Advanced Idiopathic Pulmonary Fibrosis

doi:10.4065/78.9.1082

Mayo Clinic Proceedings

Volume 78, Issue 9, September 2003, Pages 1082-1087

https://doi.org/10.4065/78.9.1082 Get rights and content

OBJECTIVE

To report on observations made in a group of patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) who were treated with interferon gamma-1b.

Patients and Methods

We reviewed the clinical records, radiological studies, and pulmonary function data of all patients treated with interferon gamma-1b between January 2000 and March 2002 at the Mayo Clinic in Rochester, Minn.

Results

Twenty-one patients (mean age, 68 years; range, 52-80 years) were treated with interferon gamma-1b for a mean duration of 8.2 months (range, 3-21 months). All patients had been diagnosed previously as having IPF/UIP based on clinical, pulmonary function, and chest highresolution computed tomographic scan criteria; 12 patients had also undergone video-assisted thoracoscopic surgical lung biopsy. Baseline pulmonary function data (mean ± SEM percent predicted) were as follows: total lung capacity, 57.3±2.5; vital capacity, 55.0±3.3; diffusing capacity of lung for carbon monoxide, 39.7±2.8; and forced expiratory volume in 1 second, 58.1±3.6. Only 1 patient showed symptomatic and functional improvement, and 7 discontinued treatment because of a perceived lack of benefit. Eleven patients (52%) died after a mean of 6.4 months of treatment, and follow-up pulmonary function data suggested continued worsening in all but 1 patient.

Conclusion

These observations do not support the use of interferon gamma-1b therapy for patients with advanced IPF/UIP.

Section snippets

PATIENTS AND METHODS

Patients treated between January 2000 and March 2002 were identified from the records of the Interstitial Lung Disease Clinic at the Mayo Clinic in Rochester, Minn. All had been diagnosed with IPF by using current American Thoracic Society/European Respiratory Society criteria, including compatible clinical, chest high-resolution computed tomographic (HRCT), and histological abnormalities.² In keeping with our usual practice, all biopsies and CT scans had been evaluated by a pulmonary core

RESULTS

The 18 men and 3 women who had been treated with interferon gamma-1b had a mean age of 68 years (range, 52-80 years). The median time from definitive diagnosis to initiation of treatment with interferon gamma-1b was 12 months (range, 0-72 months). In 12 patients (57%), the diagnosis was based on a compatible clinical picture combined with typical or compatible radiological findings on chest HRCT² and consistent findings on biopsy obtained through video-assisted thorascopic surgery or at

DISCUSSION

The treatment of IPF remains frustrating. No known cure exists, and all agents that have been tried thus far have unpredictable efficacy, with most patients failing to respond.1, 2 Instead there is a progressive, usually fatal decline,3, 4 often accompanied by pronounced adverse effects from the drugs. Because of the impression that fibroblast proliferation and extracellular matrix deposition are involved in the pathogenesis of this condition,⁵ the central role of TGF-β1 in this process,6, 7, 8

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Cited by (34)

Novel therapy for idiopathic pulmonary fibrosis-How to evaluate the efficacy?
2008, Respiratory Medicine CME
As disease concepts have changed, the treatment of idiopathic interstitial pneumonias (IIPs) has become focused on idiopathic pulmonary fibrosis (IPF), which has the most adverse prognosis. Since 1998, large-scale multicenter trials have evolved, and clinical trials using novel therapeutic drugs such as interferon-γ in US and N-acetylcysteine in Europe and pirfenidone in Japan, have been organized. Most of these trials were evaluated using 1-year FVC or VC changes as the therapy endpoint, with significant differences obtained for non-progressive stage IPF. However, no significant differences were obtained in the progressive stages for any of the trials, and whether or not they contribute to improvement in life prognosis has been left to the post-market evaluation. A debate has begun in Europe and the US as to the value of assessment evaluation indicator done during activity since constant speed treadmill walking tests were introduced in the pirfenidone clinical trials carried out in Japan. Until now, therapy evaluations for IIPs have been compared using diagnostic imaging, pulmonary function tests, and pathology. In the future, therapeutic efficacy and prognosis will be discussed in terms not only of resting respiratory function evaluation, but also of systemic evaluation using exercise endurance, which is also recognized as an ADL evaluation indicator. In recent years, acute exacerbation of IPF has been the focus of global concern. A joint perspective by ATS/ERS was published, and standardized diagnosis and treatment have been provided. Acute exacerbation is an adverse prognosis factor, as are lung cancer complications, and treatments for improving life prognosis are being explored. This paper presents therapeutic drugs and treatments whose introduction is awaited, and discusses the relationship between indicators of therapy evaluation and disease concepts.
Effects of antifibrotic agents on TGF-β1, CTGF and IFN-γ expression in patients with idiopathic pulmonary fibrosis
2007, Respiratory Medicine
Citation Excerpt :
However, smaller studies of IFN-γ therapy in IPF have shown controversial results. Kalra et al.29 observed symptomatic and functional improvement only in one of the 21 patients treated. Similarly, Prasse et al.30 found improvement in PFTs only in one among five patients.
Idiopathic pulmonary fibrosis (IPF) is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of IFN-γ-1b and colchicine, on biomarkers expression associated with fibrosis (TGF-β, CTGF) and immunomodulatory/antimicrobial activity (IFN-γ), in the lungs of patients with IPF.
Fourteen (14) patients with an established diagnosis of IPF received either 200 μg of IFN-γ-1b subcutaneously three times per week, or 1 mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor β1 (TGF-β1), connective-tissue growth factor (CTGF), and interferon-γ (IFN-γ) genes in lung tissue before and after treatment with IFN-γ-1b or colchicine.
Marked mRNA expression of TGF-β1 and CTGF, but complete lack of interferon-γ was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of IFN-γ gene at 6 months that was sustained at 24 months. The expression of CTGF and TGF-β1 remained almost stable before and after treatment, in the IFN-γ-1b group, while TGF-β1 was statistically decreased after therapy, in the colchicine group (p=0.0002). Significant difference in DLCO (% pred), was found between the two treatment groups in favor of IFN-γ-1b group (p=0.04). In addition, the IFN-γ-1b group showed stability in arterial PO₂ while the colchicine group significantly deteriorated (p=0.02).
In conclusion, we report the effect of antifibrotic agents (IFN-γ-1b and colchicine) in TGF-β, CTGF, and endogenous IFN-γ gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings.
Interferon-γ1b therapy in idiopathic pulmonary fibrosis: A metaanalysis
2005, Chest
Citation Excerpt :
Questions have been raised about whether the patients included in the trial were truly representative of a general population of patients with IPF. For example, other studies420 that included patients with lower FVC have not demonstrated a similar benefit. This also raises the possibility that IFN-γ1b treatment may be most beneficial in patients with less advanced disease, as suggested by a subgroup analysis of the largest trial to date.14
Despite the investigation of multiple therapeutic options, idiopathic pulmonary fibrosis (IPF) remains a devastating, progressively fatal disease. Much interest has focused on the use of interferon (IFN)-γ1b therapy, but the efficacy of this treatment has not been proven.
To determine whether IFN treatment reduces mortality in patients with IPF.
A metaanalysis of randomized controlled trials evaluating the use of IFN-γ1b as treatment for IPF.
Mortality in patients treated with IFN-γ1b was compared to mortality in patients treated with control therapies.
A total of three studies involving 390 patients was included in the analysis. IFN-γ1b therapy was associated with reduced mortality (hazard ratio [HR], 0.418; 95% confidence interval [CI], 0.253 to 0.690; p = 0.0003). A comparison of mortality at different time points revealed that IFN-γ1b therapy was associated with significantly reduced mortality at 1 year (0.0861; 95% CI, 0.0244 to 0.1478; p = 0.0063), 18 months (0.1682; 95% CI, 0.1065 to 0.2299; p < 0.0001), 650 days (0.1939; 95% CI, 0.1386 to 0.2492; p < 0.0001), and 2 years (0.2652; 95% CI, 0.1652 to 0.3652; p < 0.0001).
When the results of multiple studies are combined in a metaanalysis, IFN-γ1b therapy is associated with reduced mortality.
Drug treatments for idiopathic pulmonary fibrosis
2005, Revue de Pneumologie Clinique
La fibrose pulmonaire idiopathique est une maladie de cause inconnue, caractérisée par une toux, une dyspnée progressive, un trouble ventilatoire restrictif aux épreuves fonctionnelles respiratoires, un aspect « en nid d’abeille » sur le scanner thoracique en haute résolution, et une pneumopathie interstitielle commune sur la biopsie pulmonaire. La plupart des patients décèdent dans les 3 à 8 ans qui suivent le diagnostic.
Les traitements actuels sont fondés sur l’association de corticoïdes et d’immunosuppresseurs, mais leur efficacité demeure discutée. De nouvelles perspectives thérapeutiques s’ouvrent maintenant aux patients. De nouveaux traitements sont actuellement en cours d’évaluation dans le cadre d’essais cliniques : interféron-γ, pirfénidone, N-acétylcystéine, etanercept (anti-TNFα), bosentan (antagoniste des récepteurs de l’endothéline), imatinib (inhibiteur de la tyrosine-kinase du récepteur du PDGF), etc. Dans le même temps, de nouvelles molécules démontrent leur efficacité dans des modèles expérimentaux de fibrose, et de nouveaux concepts physiopathologiques voient le jour, venant renouveler pensées et pratiques.
Idiopathic pulmonary fibrosis is a disease of unknown cause characterized by cough, progressive dyspnea, restrictive respiratory disorder, a typical honeycomb aspect on the high-resolution CT-scan, and usual interstitial pneumonia at histological examination of the lung biopsy. Most patients die 3 to 8 years after diagnosis.
Current treatment is based on a combination of corticosteroids and immunosuppressants, but the efficacy of treatment remains a matter of debate. New therapeutics currently under evaluation in controlled clinical trials include interferon-γ, pirfenidone, N-acetylcysteine, etanercept (anti-TNFα), bosentan (endothelin receptor antagonist), imatinib (tyrosine-kinases inhibitor of the PDGF receptor), etc. At the same time, new compounds showing efficacy in experimental models of fibrosis and the development of new pathophysiological concepts open new perspectives both in terms of concept and clinical practice.
Medical treatment for pulmonary fibrosis: Current trends, concepts, and prospects
2004, Clinics in Chest Medicine
Interstitial lung disease guideline: The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society
2008, Thorax

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: This study was supported in part by the Robert N. Brewer Family Foundation.

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Original ArticleInterferon Gamma-1b Therapy for Advanced Idiopathic Pulmonary Fibrosis

OBJECTIVE

Patients and Methods

Results

Conclusion

Section snippets

PATIENTS AND METHODS

RESULTS

DISCUSSION

Mayo Clin Proc

Chest

Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement

Am J Respir Crit Care Med

Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis

Am J Respir Crit Care Med

Increased expression of type VI collagen in lung fibrosis

Am J Respir Crit Care Med

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann Intern Med

Idiopathic pulmonary fibrosis

N Engl J Med

Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung

J Clin Invest

Original Article
Interferon Gamma-1b Therapy for Advanced Idiopathic Pulmonary Fibrosis