Antifibrotic therapy for idiopathic pulmonary fibrosis: time to treat
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a dismal prognosis. The average life expectancy of untreated patients with IPF is only 3 to 4 years. Decline in forced vital capacity (FVC) in patients with IPF appears to be almost linear, with patients with well-preserved FVC at baseline experiencing the same rate of decline in FVC as patients with more advanced disease. Two antifibrotic therapies have been approved for the treatment of IPF: nintedanib and pirfenidone. These drugs slow decline in lung function and reduce the risk of acute respiratory deteriorations, which are associated with very high morbidity and mortality. Individual clinical trials have not been powered to show reductions in mortality, but analyses of pooled data from clinical trials, as well as observational studies, suggest that antifibrotic therapies improve life expectancy. Despite this, many individuals with IPF remain untreated. In many cases, this is because the physician perceives that the disease is stable and so does not warrant therapy, or has concerns over the potential side-effects of antifibrotic drugs. There remains a need to educate pulmonologists that IPF is a progressive, irreversible and fatal disease and that prompt treatment is critical to preserving patients’ lung function and improving outcomes. Most individuals can tolerate antifibrotic therapy, and dose adjustment has been shown to be effective at reducing side effects without compromising efficacy. In addition to anti-fibrotic therapies, individuals with IPF benefit from a holistic approach to their care that includes symptom management and supportive care tailored to the needs of the individual. An animation illustrating the themes covered in this article will be available at: http://www.usscicomms.com/respiratory/maher/treatment-of-IPF.
KeywordsNintedanib Pirfenidone Interstitial lung disease Therapeutics Treatment Mortality
Cough and Sputum Assessment Questionnaire
Chronic obstructive pulmonary disease
Forced vital capacity
Gastroesophageal reflux disease
High-resolution computed tomography
Interstitial lung disease
Idiopathic pulmonary fibrosis
National Institute for Health and Care Excellence
St George’s Respiratory Questionnaire
University of California San Diego Shortness of Breath Questionnaire
Clinical course of IPF
Benefits of antifibrotic therapies
In the US, Europe and many other countries, two drugs are approved for the treatment of IPF: nintedanib and pirfenidone. In vitro studies have shown that by inhibiting signaling mediated via tyrosine kinases, nintedanib inhibits fundamental processes of fibrosis, such as the recruitment, proliferation and differentiation of fibroblasts and fibrocytes and the deposition of extracellular matrix . Data from animal models of fibrosis suggest that nintedanib may also act to normalize the distorted microvascular architecture in the lungs . The mechanism of action of pirfenidone is less well defined, as its target remains unknown, but non-clinical studies suggest that it inhibits pro-fibrotic behaviors in fibroblasts and fibrocytes [17, 18].
Importance of prompt treatment of IPF
Diagnosis of IPF is often delayed due to misdiagnosis, with symptoms frequently being ascribed to more common conditions such as COPD, asthma, or cardiac disease, resulting in late referral to specialist centers [6, 36, 44, 45]. This means that by the time a patient receives a diagnosis of IPF, their lung function will have been in decline for some time. It is worth noting that because of the way that predicted values for FVC are calculated (based on a patient’s age, height, and weight), some patients will have an FVC of more than 100% predicted before their lung function begins to decline. Thus it cannot be assumed that a patient with, for example, an FVC of 90% predicted at diagnosis has not already suffered significant loss of lung volume. The presence of comorbid emphysema may also result in FVC being artificially higher than it would have been if the patient had IPF alone .
Prompt treatment of IPF is critical to preserving patients’ lung function, reducing the risk of acute exacerbations and improving outcomes. Arguably, antifibrotic therapy should be initiated in all patients with IPF given that the course of disease for an individual cannot be predicted at diagnosis and the overall prognosis of untreated IPF is dismal. Physicians have a key role to play in explaining to patients that the aim of drug therapy is to slow the progression of their disease and that decline in FVC while taking a drug may not indicate a failure of treatment. While a small proportion of patients may make an informed decision not to proceed with treatment, physicians need to ensure that patients are making that decision based on an understanding that IPF is a progressive, irreversible and fatal disease for which early intervention can improve outcomes.
Managing side-effects of antifibrotic therapies
Antifibrotic therapies are associated with gastrointestinal adverse events [26, 53, 54, 55]. The most common side-effect of nintedanib is diarrhea, which was reported in 62.4% of subjects treated with nintedanib compared with 18.4% of subjects given placebo, in the INPULSIS trials, but led to permanent treatment discontinuation in only 4.4% of the nintedanib group . Pirfenidone is more commonly associated with nausea and decreased appetite than with diarrhea [54, 55] and is recommended to be taken during or after a meal to minimize gastrointestinal issues. Pirfenidone is also associated with rash and photosensitivity, so patients should be advised to minimize exposure to the sun and use high-factor sun block. Both nintedanib and pirfenidone have been associated with elevations in liver enzymes. Few data are available on the tolerability of combination therapy with nintedanib and pirfenidone, but it appears to have an adverse event profile consistent with those of the individual drugs [56, 57].
Management of the side-effects that may occur when they take antifibrotic therapy is important to helping patients stay on treatment. Dose adjustment, through treatment interruption and dose reduction, and symptomatic relief of gastrointestinal adverse events using adequate hydration and medications such as loperamide, are recommended to manage side-effects. Importantly, the dose adjustments made to manage side-effects in clinical trials did not reduce the benefits of treatment in decreasing lung function decline [58, 59]. Most patients are able to tolerate antifibrotic therapy, and discontinuations due to adverse events decrease over time [59, 60]. Education is key to patients understanding the role of antifibrotic therapies in reducing disease progression, so that they can make an informed assessment of the benefits of therapy in the context of side effects that may occur.
Other therapies used in patients with IPF
The latest international treatment guideline gave a conditional recommendation for the use of anti-acid medications in patients with IPF and asymptomatic gastroesophageal reflux disease (GERD) . However, there is no evidence from randomized controlled trials to support this recommendation and the value of anti-acid medications in the treatment for IPF remains the subject of debate . Post-hoc analyses of data from large randomized controlled trials have shown no benefit of anti-acid medications in reducing FVC decline in subjects with IPF, and suggest that the use of such medications may be associated with an increased risk of infections and acute exacerbations [25, 28, 62]. Whether this increased risk is caused by anti-acid medication permitting translocation of bacteria from the upper gastrointestinal tract into the lungs, or is simply a reflection of greater disease severity in patients with IPF who take these medications remains unclear. Sildenafil has been investigated as a treatment for IPF in individuals with severely impaired gas exchange in two clinical trials: versus placebo in STEP-IPF  and in combination with nintedanib versus nintedanib alone in the INSTAGE trial . In both these trials, the primary endpoint was not met, but exploratory analyses of secondary endpoints suggested potential benefits of sildenafil; a further trial of sildenafil in combination with pirfenidone in patients with IPF and severely impaired gas exchange (NCT02951429) is ongoing. Other therapies commonly used in the treatment of IPF (e.g. N-Acetylcysteine, steroids, bronchodilators) have not been demonstrated to have efficacy in slowing the progression of IPF. Triple therapy with prednisone, azathioprine and N-Acetylcysteine (but not N-Acetylcysteine alone) was shown in the PANTHER-IPF trial to be harmful to patients with IPF [64, 65].
A holistic approach to the management of IPF
In addition to anti-fibrotic therapies, patients with IPF benefit from a holistic approach to care that may include pulmonary rehabilitation, symptom management, education and support, vaccinations, management of comorbidities, supplemental oxygen for those with hypoxemia, and palliative care tailored to the needs of the patient and their caregivers [66, 67, 68]. Lung transplant is an option for a minority of patients with IPF and patients should be referred for transplant evaluation at an early stage of disease to maximize their chances of meeting eligibility criteria. The possibility of enrolling patients into clinical trials of investigational therapies should also be considered at an early stage.
Although the course of disease for an individual cannot be predicted at diagnosis, IPF is an inevitably progressive disease with a very poor prognosis. Prompt treatment of IPF is critical to preserving individuals’ lung function, reducing the risk of acute exacerbations and improving outcomes. Pulmonologists may be reluctant to initiate antifibrotic therapy in individuals with IPF whose lung function appears to be stable; nonetheless they have an obligation to explain to patients that their disease is progressive and that therapies are available that slow progression but that cannot reverse fibrosis or improve breathlessness once progression has occurred. Physicians also have a key role to play in helping patients manage side-effects of antifibrotic therapies through education and dose adjustment, thus enabling them to gain the advantages of long-term treatment.
Writing support was provided by Wendy Morris, MSc, of FleishmanHillard Fishburn, London, UK, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
Both authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Both authors were involved in the drafting of the article and have read and approved the final version.
The page processing charges for this article have been covered by Boehringer Ingelheim Pharmaceuticals, Inc. The authors received no direct compensation related to the development of this manuscript.
Ethics approval and consent to participate
Consent for publication
Outside the submitted work, TMM reports receiving grant funding to his institution and personal fees for service on a clinical trial advisory board from GlaxoSmithKline; personal fees from Boehringer Ingelheim, InterMune/Roche, Sanofi Aventis, AstraZeneca, Biogen Idec, Cipla, Prometic and Sanumed; research fees to his institution; personal fees and non-financial support from UCB; he holds stock options in Apellis. Outside the submitted work, MES reports grants from Boehringer Ingelheim, Novartis, Roche and the National Institutes of Health, and personal fees from Boehringer Ingelheim.
- 9.Behr J, Kreuter M, Prasse A, Wirtz HR, Pittrow D, Klotsche J, et al. Exacerbations, hospitalisations and mortality in patients with idiopathic pulmonary fibrosis: 5-year follow-up of the INSIGHTS-IPF registry. Am J Respir Crit Care Med. 2018;197:A4525 [abstract].Google Scholar
- 12.Nathan SD, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, et al. Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax. 2016;71:429–35.CrossRefGoogle Scholar
- 35.Lancaster L, Hernandez P, Inoue Y, Wachtlin D, Loaiza L, Conoscenti CS, et al. Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF): pooled data from six clinical trials. In: Poster presented at the American Thoracic Society International Conference; 2018. Available at: http://ILDPosters2018.com/pdf/ATSLancaster.pdf.Google Scholar
- 37.Vašáková M, Sterclova M, Mogulkoc N, Kus J, Müller V, Hajkova M, et al. Real world idiopathic pulmonary fibrosis in the EMPIRE registry. In: Poster presented at the European Respiratory Society International Congress; 2018.Google Scholar
- 40.Kreuter M, Stansen W, Stowasser S, Schoof N. Impact of lung function decline on health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). In: Poster presented at the American Thoracic Society International Conference; 2018. Available at: http://ILDPosters2018.com/pdf/ATSKreuter.pdf.Google Scholar
- 45.Hewson T, et al. Timing of onset of symptoms in people with idiopathic pulmonary fibrosis. Thorax. 2017. https://doi.org/10.1136/thoraxjnl-2017-210177 epub ahead of print.
- 49.Flaherty KR, de Andrade J, Lancaster L, Limb S, Lindell K, Nathan S, et al. Baseline characteristics of the initial 1461 participants in the Pulmonary Fibrosis Foundation patient registry. In: Poster presented at the European Respiratory Society International Congress; 2018.Google Scholar
- 50.Lodhi T, Leonard C, Rivera Ortega P, Morris H, Marshall T, Zakis K, et al. What can we learn from idiopathic pulmonary fibrosis registries? In: Poster presented at the European Respiratory Society International Congress; 2018.Google Scholar
- 58.Maher TM, Inoue Y, Harai Case A, Sakamoto W, Stowasser S, Wuyts WA. Effect of dose reductions and/or interruptions on the efficacy of nintedanib in patients with idiopathic pulmonary fibrosis (IPF): subgroup analysis of the INPULSIS trials. In: Poster presented at the American Thoracic Society International Conference; 2017. Available at: http://www.ildposters2017.com/pdf/INPULSIS_Maher.pdf.Google Scholar
- 60.Costabel U, Kreuter M, Song JW, Huggins JT, Wallaert B, Stansen W, et al. Patterns of discontinuation in patients with IPF treated with open-label nintedanib: data from INPULSIS®-ON. In: Poster presented at the European Respiratory Society International Congress; 2018. Available at: http://ILDPosters2018.com/pdf/ERSCostabel.pdf.Google Scholar
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