Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial pneumonia characterised by relentlessly progressive restrictive-ventilatory limitation, hypoxia, dyspnoea, and cough, and is associated with a poor prognosis.1 Although rare, its incidence is increasing with our aging population and it represents a growing challenge for public health worldwide.2 The 28th European Respiratory Society (ERS) International Congress, which was held in Paris, France on 15–19 September, 2018, featured a number of presentations highlighting the latest advances in IPF.
In 2014, two treatments, nintedanib (Ofev®, Boehringer Ingelheim) and pirfenidone (Esbriet®, Roche), were approved by the US Food and Drug Administration (FDA) for the treatment of patients of IPF and are, to date, the only approved therapies that can slow disease progression in patients with mild-to-moderate IPF. Final data from IMPULSIS-ON, an open-label extension of the two IMPULSIS phase III studies of nintedanib, involving 734 patients, showed that long-term treatment with nintedanib (up to 68 months) is effective in reducing disease progression and has an acceptable safety and tolerability profile.3 However, as the results of a survey conducted in 41 countries have shown, many patients have restricted access to these therapies. Among 24,643 IPF patients seen in a 12-month period, across centres where both nintedanib and pirfenidone are available, on average only 30.92% were taking pirfenidone, 26.33% nintedanib, and 42.75% were not taking either of the two.4 There is a need for more education to address poor understanding of IPF and its treatments, and issues of treatment access. We also need to increase physician awareness of the benefits associated with antifibrotic treatment across the spectrum of IPF severity.
Boehringer Ingelheim presented the results of the INSTAGE trial, which evaluated the efficacy and safety of nintedanib plus sildenafil compared with nintedanib monotherapy in patients with IPF and severely impaired gas exchange (DLCO ≤35% predicted), a patient population that has largely been excluded from previous trials. While results showed that the addition of sildenafil to nintedanib did not significantly improve the primary endpoint (St George’s Respiratory Questionnaire [SGRQ] total score at week 12) compared to nintedanib therapy alone, these findings are important because they have demonstrated that nintedanib is effective in reducing lung function decline in patients with more advanced IPF, with safety and tolerability comparable to that in mild-to-moderate disease.5,6
While these antithrombotic therapies delay the loss of lung function, they do not stabilise or reverse fibrosis. Other approaches are, therefore, being investigated in the treatment of IPF. A phase I study of OATD-01 (OncoArendi Therapeutics, Poland), a small molecule inhibitor of acidic mammalian chitinase and chitotriosidase, found that this agent was well tolerated in healthy males, had a favourable pharmacokinetic profile and demonstrated sustainable inhibition of chitinolytic activity, supporting its further clinical development.7
The significance of circulating autoantibodies in patients with IPF has been of clinical interest for many years. A study presented at ERS evaluated the prevalence and clinical significance of antinuclear antibody (ANA) in 325 participants from the recently completed ESTAIR study (Efficacy and Safety of SAR156597 in the Treatment of Idiopathic Pulmonary Fibrosis). Patients with high levels of ANA were more likely to be female (35.4% versus 23.4%) and white (100% versus 91.8%), have an earlier diagnosis of IPF (1.68 versus 1.82 years) and symptoms of IPF, have never smoked (56.3% versus 32.3%), have greater history of acute exacerbations (12.5% versus 4.7%) and require supplemental oxygen (22.9% versus 11.7%), and show more definite features of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT; 41.7% versus. 31.0%) compared to those who were ANA negative. The clinical significance of these findings remains to be determined.8
While body mass index (BMI) is known to compound chronic obstructive pulmonary disease and asthma, little is known about how BMI influences the survival of patients with IPF. Although further study is required, initial data from 2,003 in the Boehringer Ingelheim-sponsored EMPIRE registry suggests that greater BMI is associated with longer survival. Using normal weight as the reference, the hazard ratios for death were: underweight; 1.53, overweight; 0.90, obese; 0.81.9
In 2011, the American Thoracic Society (ATS), ERS, Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) collaborated to develop the first clinical practice guideline for the diagnosis and management of IPF on the basis of radiologic and histologic findings.10 However, the 2011 diagnostic criteria have since been shown to have important limitations in clinical practice. Recently, the ATS, ERS, JRS, and ATAT have updated the diagnostic criteria for IPF to address these limitations. Previously defined patterns of UIP have been refined and are now subdivided into patterns of UIP, probable UIP, indeterminate for UIP, and alternate diagnosis.11 A presentation at ERS described the use of a new algorithm that can provide automated, low-cost and reproducible classification of fibrotic lung disease based on these criteria. Among a cohort of 150 HRCT studies with fibrotic lung disease, the diagnostic accuracy of the algorithm was 73.3%, compared with 70.7% based on the majority vote of 91 specialist thoracic radiologists from international thoracic imaging societies.12
While data presented at this year’s ERS revealed no therapeutic breakthroughs, they reflect improvement in our understanding of the otherwise incurable condition that will hopefully lead to further advances in the coming years.
1. Raghu G, Rochwerg B, Zhang Y, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015;192:e3–19.
2. Diamantopoulos A, Wright E, Vlahopoulou K, et al. The burden of illness of idiopathic pulmonary fibrosis: a comprehensive evidence review. Pharmacoeconomics. 2018;36:779–807.
3. Crestani B, Quaresma M, Kaye M, et al. Long-term nintedanib treatment in idiopathic pulmonary fibrosis (IPF): final data from INPULSIS-ON. Presented at the 28th European Respiratory Society International Congress, 15–19 September, 2018, Paris, France. Abstract PA5230.
4. Wijsenbeek MS, Floricel F, Thonnard J, et al. Idiopathic Pulmonary Fibrosis – a worldwide review of ‘real’ life’ practice: experience from a treatment feasibility review in 41 countries. Presented at the 28th European Respiratory Society International Congress, 15–19 September, 2018, Paris, France. Abstract OA263.
5. Kolb M, Raghu G, Wells AU, et al. Nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2018.379:1722–31.
6. Boehringer Ingelheim. Clinical trial data for nintedanib in patients with advanced IPF published. Available at: www.boehringer-ingelheim.com/press-release/instage-data-nintedanib-advanced-ipf-published (accessed 4 October 2018).
7. Lipner J, Lissy M, Dymek B, et al. Phase 1, first-in-human study of OATD-01, a dual chitinase inhibitor for the treatment of respiratory diseases. Presented at the 28th European Respiratory Society International Congress, 15–19 September, 2018, Paris, France. Abstract PA5228.
8. Wung P, Raghu G, Crestani B, et al. Prevalence and clinical significance of antinuclear antibody (ANA) in IPF: analysis from ESTAIR study. Presented at the 28th European Respiratory Society International Congress, 15–19 September, 2018, Paris, France. Abstract OA540.
9. Mogulkok N, Sterclova M, Müller V, et al. Does body mass index have prognostic significance for patients with idiopathic pulmonary fibrosis? Presented at the 28th European Respiratory Society International Congress, 15–19 September, 2018, Paris, France. Abstract PA2210.
10. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824.
11. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198:e44–68.
12. Walsh S, Calandriellom L, Silva M, et al. A Deep Learning Algorithm for Classifying Fibrotic Lung Disease on High Resolution Computed Tomography. Presented at the 28th European Respiratory Society International Congress, 15–19 September, 2018, Paris, France. Abstract OA263.