Pharmacologic Treatment of IPF

Abstract

The pathogenetic mechanisms leading to lung fibrosis in idiopathic pulmonary fibrosis (IPF) are mostly unknown. The old paradigm of inflammation has been substantially replaced by hypotheses of dysregulated wound healing with an excessive production of extracellular matrix. The lack of a complete comprehension of pathological mechanisms and the development of new hypotheses has led to a change in pharmacological approaches over the last two decades. The International Consensus Statement on IPF Diagnosis and Treatment published in 2000 established a standardized definition of IPF for the first time. This statement suggested possible benefit with a treatment regimen consisting of prednisone, azathioprine, or cyclophosphamide. However, the subsequent guideline published in 2011 stated that the use of aggressive immunosuppressive and cytotoxic treatment regimens has largely failed to reduce the death rate in patients with IPF. The 2015 American Thoracic Society (ATS)/European Respiratory Society (ERS)/ Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) clinical practice guideline that updated the 2011 guideline formulated a conditional recommendation for the use of either pirfenidone or nintedanib. This recommendation was based upon a new pathogenetic model where aberrant reparative mechanisms and fibrotic processes play a pivotal role in IPF pathogenesis. For the first time, an IPF-specific therapy was recommended, and new standards for therapy were established. The antifibrotic drugs, pirfenidone and nintedanib, can slow disease progression but have failed to arrest or reverse the disease course, which is probably related to the pathological heterogeneity of IPF. Many molecular pathways have been identified and could be potential targets for novel agents. The challenge of the next decade will be to develop targeted therapies against specific pathways. The aim of this chapter is to examine the evolution of IPF treatment during the last two decades, evaluate past treatments and the reasons why they were ineffective, present current approaches to disease management, and identify ongoing clinical trials with novel investigational drugs that target putative pathogenetic mechanisms of disease. Finally, current and potential strategies to treat and prevent acute exacerbations of IPF are reviewed.