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Optimal treatment for idiopathic pulmonary fibrosis
  1. T M Maher,
  2. A U Wells
  1. Interstitial Lung Disease Unit, Department of Respiratory Medicine, Royal Brompton Hospital, London, UK
  1. Dr T M Maher, Interstitial Lung Disease Unit, Department of Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK; t.maher{at}

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The recent review series on interstitial lung disease has created a great deal of interest. However, the review by Williams and Wilson of novel treatments and lung transplantation in pulmonary fibrosis1 does not reflect recent developments in clinical and translational research in idiopathic pulmonary fibrosis (IPF).

The belief that inflammation is the primary driver of fibrosis in IPF has been superseded by newer pathogenetic paradigms that emphasise the role of aberrant wound healing in the evolution of fibrosis.2 The pathogenetic importance of inflammation has been downgraded. Furthermore, greater diagnostic accuracy has led to a better understanding of IPF disease behaviour. It is now appreciated that patients with IPF may have periods of remarkable disease stability interspersed by acute exacerbations, during which time fibrosis progresses rapidly, often with fatal consequences.3 Better understanding of the pathogenesis of IPF has led to the development of treatments directed at various elements of the wound healing cascade.2 Additionally, treatment strategies that aim to modify IPF disease behaviour and prevent acute exacerbations have been investigated. Consequently, there has been a recent striking increase in clinical trials in IPF. Among these trials, a number of key results not covered by the review of Williams and Wilson stand out.

In a 9-month study of 107 patients, Azuma and colleagues found that the pluripotent antifibrotic agent pirfenidone improved vital capacity and reduced the incidence of acute exacerbations compared with placebo.4 Kubo et al in a relatively small group of patients, all of whom were initially hospitalised with acute exacerbations of IPF, found that treatment with warfarin and prednisolone improved survival and reduced subsequent exacerbations compared with prednisolone alone.5 In the recently reported placebo controlled BUILD-1 study, no treatment effect was demonstrated for bosentan in the whole cohort, although a statistically significant effect was evident in the subgroup of biopsied patients.6

In the most important recent trial, the IFIGENIA study, Demedts et al demonstrated that the addition of N-acetylcysteine (NAC) 600 mg three times daily to standard therapy of prednisolone and azathioprine significantly slowed disease progression in IPF compared with prednisolone and azathioprine alone.7 While questions have been raised concerning both the clinical significance of this finding and the mechanism by which NAC exerts a beneficial effect, this paper represents a landmark in the treatment of IPF. For the first time, primary end points have been clearly met in this relentless disease in a well-performed placebo controlled study.

In contrast to these trials, a large phase III study of interferon-γ1b, a compound that had previously shown promise as a treatment for IPF, was definitively negative with mortality (the primary end point) minimally higher in the treatment arm.8

The ongoing expansion in the number of new drugs being trialled in IPF offers the realistic hope that effective disease-modifying therapy may become available in the foreseeable future. Given the rapid development of novel therapies, we would urge that patients with IPF should be enrolled in clinical trials whenever possible. When this is not possible, we believe that the results of the IFIGENIA study provide a rationale for treatment in IPF.7 NAC is non-toxic and the benefits of treatment, although uncertain in magnitude, exceed the negligible risk. In a lethal disease it does not appear logical to withhold a cheap non-toxic treatment shown to have a beneficial functional effect, even if the exact clinical significance of this effect remains uncertain.


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  • Competing interests: None.

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