Editorial in New England Journal of Medicine Regarding Fibrosis Study

Thought the below was interesting. It is an editorial also in the NEJM regarding the study in yesterday's blog. Hope you, dear reader, find it interesting.

EDITORIAL

Resolving the Scar of Pulmonary Fibrosis

Gregory P. Downey, M.D.

N Engl J Med 2011; 365:1140-1141September 22, 2011

Article

References

Fibrosis, or scarring, of the lung is a common consequence of certain types of pneumonias, and in such cases it is a localized and self-limited process. However, in conditions such as the complex group of disorders termed the idiopathic interstitial pneumonias, pulmonary fibrosis may be a progressive and diffuse process.1 The current classification scheme for idiopathic interstitial pneumonias is based on a combination of clinical, histopathological, and radiographic features.1The idiopathic interstitial pneumonias may be related to an underlying connective-tissue disease, such as rheumatoid arthritis or scleroderma, or they may be caused by unknown factors, in which case the disease is denoted idiopathic pulmonary fibrosis. The most common histopathological pattern seen in lung-biopsy specimens from patients with idiopathic pulmonary fibrosis is termed usual interstitial pneumonia and is characterized by heterogeneous areas of dense fibrosis, the presence of fibroblastic foci, and honeycombing with architectural distortion.1 Clinically, idiopathic pulmonary fibrosis affects more than 50,000 people in the United States alone. It is a relentlessly progressive and ultimately fatal disorder with a dismal median survival of 2 to 3 years from the time of diagnosis.1,2

Both genetic and environmental factors have been implicated in the pathogenesis of idiopathic pulmonary fibrosis. Genes associated with pulmonary fibrosis include those encoding transforming growth factor β (TGF-β),3 surfactant protein C (SFTPC),4 mucin 5B (MUC5B),5 and human telomerase reverse transcriptase (hTERT).6 Environmental factors involved in disease pathogenesis may include viral infection and exposure to cigarette smoke or other inhaled irritants. Interestingly, idiopathic pulmonary fibrosis appears to be a disease of aging,7 perhaps reflecting the cumulative effect of age-related genetic alterations that may impair the ability of the lung to repair itself after repeated injury. Mounting evidence from experimental models and observations in humans has led to the notion that in persons with a permissive genetic background, nonresolving injury to lung epithelial cells consequent to environmental exposures leads to the release of cytokines and growth factors that induce myofibroblast accumulation in the lung and tissue fibrosis.8 Surprisingly, the origin of the myofibroblasts remains uncertain; possibilities include differentiation of resident fibroblasts, recruitment of progenitor cells from bone marrow (fibrocytes), and transformation of lung epithelial cells, endothelial cells, and pericytes to mesenchymal cells (termed mesenchymal transition).9 Despite considerable progress in our understanding of the mechanisms that drive this progressive fibrosis, there is to date no effective treatment for it.1

Recent studies have elucidated the role of a group of fibrogenic growth factors — including TGF-β, platelet-derived growth factor (PDGF), connective-tissue growth factor (CTGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) — in driving tissue fibrosis. Importantly, these growth factors produce signals through tyrosine kinase receptors or are linked to pathways controlled by tyrosine kinases. On the basis of this knowledge, investigators have developed selective tyrosine kinase inhibitors that target these fibrogenic pathways.

The study by Richeldi et al. in this issue of the Journal 10 tested the efficacy of a potent intracellular tyrosine kinase inhibitor, BIBF 1120, in the treatment of patients with idiopathic pulmonary fibrosis. BIBF 1120 inhibits a variety of growth-factor receptors (including PDGF-Rα and PDGF-Rβ, VEGF-R1, R2, and R3, and FGF-R1, R2, and R3) that have been shown to regulate fibrogenic pathways. In addition, preclinical testing showed that inhibiting each of these receptor tyrosine kinases prevented the development of pulmonary fibrosis in animal models, thus providing a solid foundation for human studies. In the current study, patients underwent randomization to receive placebo or one of four doses of BIBF 1120. The primary end point was decline in forced vital capacity, a well-accepted means of tracking lung function. Secondary end points included the frequency of acute exacerbations, quality of life, and total lung capacity. Patients treated with the highest dose of the inhibitor showed a trend toward reduction in the rate of decline of lung function, fewer acute exacerbations, and better quality of life. Notably, the highest dose was associated with significant side effects including gastrointestinal symptoms and hepatotoxicity.

Although the differences in primary end point among the study groups were not statistically significant, the benefits observed in the study were indeed clinically relevant. This study represents an important advance in the treatment of this devastating disease. As compared with other treatment approaches,1 including the administration of antioxidants such as N-acetylcysteine and of pirfenidone, the nonspecific suppression of the inflammatory response with systemic glucocorticoids and potent immunosuppressive agents such as azathioprine and cyclophosphamide, and the use of antifibrotic cytokines such as interferon-γ-1b, phosphodiesterase-5 inhibitors, or endothelin receptor antagonists, the beneficial effects of BIBF 1120 shine like a beacon over a turbulent sea of unfulfilled promises and failed clinical trials. Newer inhibitors of fibrogenic pathways now being developed have the potential to produce even more effective treatments that selectively target fibrogenic pathways without affecting the immune and inflammatory responses.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

SOURCE INFORMATION

From the Division of Pulmonary and Critical Care Medicine, National Jewish Health, and the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado — both in Denver.