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Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis

Treatment

Read time: 20 mins
Last updated:30th Oct 2023
Published:29th Jan 2020

Treatment pathways

In this section, learn about the current advice on the management of patients with idiopathic pulmonary fibrosis (IPF), including patient monitoring and interventions, as well therapies in development.

Monitoring the clinical course of disease

Monitoring patients with idiopathic pulmonary fibrosis (IPF) is important to identify patients with disease progression and/or potential treatment complications.2

Monitoring should be done every four to six months or sooner as clinically indicated.2

In the absence of another identifiable cause, the presence of any of the following indicates progressive disease:2

  • progressive dyspnoea (objectively assessed)
  • progressive, sustained decrease from baseline in absolute forced vital capacity
  • progressive, sustained decrease from baseline in absolute DLCO (corrected for haemoglobin)
  • progression of fibrosis from baseline on high-resolution computed tomography
  • acute exacerbation
  • death from respiratory failure

Pulmonary function testing provides the most standardised approach to monitoring and quantification of disease progression.2

Interventions

In this section about interventions for patients with idiopathic pulmonary fibrosis (IPF), find out about current therapies, including their mode of action and side effects, non-pharmaceutical interventions and the importance of early treatment and managing exacerbations.

Therapies

In the absence of a cure for idiopathic pulmonary fibrosis (IPF), the goals of patient care are:23

  • to slow the progression of the disease
  • preserve quality of life 
  • improve survival


Nintedanib and pirfenidone

Two anti-fibrotic drugs, nintedanib and pirfenidone, have both proven to be effective in significantly reducing lung functional decline in patients with IPF compared to placebo (see Figures 8 and 9).24,25

BI_IPF_Fig8__9B617299-5453-4970-A89E22B6CF9CCA08.png

Figure 8. Adjusted annual rate of change in forced vital capacity (FVC) in two randomised, double-blind, phase III clinical trials (and open-label extension) of nintedanib in patients with IPF.25,26

BI_IPF_Fig9__908A0F4C-DFB1-4FEA-A2B5F61F72AE88C4.png

Figure 9. Percentage of patients with a meaningful decrease in % FVC (change ≥10% decline) at Week 52 in a phase III clinical trial of pirfenidone in patients with IPF.24

Nintedanib and pirfenidone have also been shown to potentially reduce mortality in patients with IPF.27,28 In a prespecified pooled analysis of clinical trials in patients with IPF.27,28

  • pirfenidone compared with placebo significantly reduced all-cause mortality (3.5% versus 6.7%, respectively; P=0.01, hazard ratio (HR): 0.52)
  • nintedanib compared with placebo numerically reduced all-cause mortality (5.5% versus 7.8%, respectively; P=0.14, HR: 0.70)

The US FDA approved both pirfenidone and nintedanib in 2014 with no prescription limitations and with no restrictions to lung function impairment severity.10 However, so far clinical trials have been limited to patients with mild-to-moderate IPF and more information on effectiveness in patients with IPF with greater impairment are needed.13

Anti-fibrotics such as nintedanib have also been evaluated in other forms of interstitial lung disease. View why Professor Elisabeth Bendstrup thought that this data was groundbreaking at the ERS Congress 2019 in the video 'What has been your highlight of the ERS Congress 2019?'.

Antacid treatment 

Antacid treatments, including proton pump inhibitors (PPIs) or histamine-2 blocker receptor antagonists (H2RAs), may decrease the risk of microaspiration-associated lung injury or damage potentially caused by GER/GOR and are recommended (with low confidence in estimates of effect) by international guidelines for regular use by patients with IPF.13

Treatment mode of action

Nintedanib

Nintedanib binds to the intracellular ATP-binding pocket of vascular endothelial growth factor receptors (VEGFR) 1–3, fibroblast growth factor receptors (FGFR) 1–3 and platelet-derived growth factor receptors (PDGFR) α and β (see Figure 10).29

VEGF, FGF and PDGF mediate a number of processes including fibrogenesis and angiogenesis and have been implicated in the pathogenesis of IPF.29

Nintedanib inhibits:29

  • fibroblast proliferation and migration
  • fibroblast-to-myofibroblast transformation.

BI_IPF_Fig10__715642CA-4D7F-4519-9FAFB82461805239.png

Figure 10. Polypharmacology of nintedanib. 

Pirfenidone

The precise mode of action of pirfenidone remains unknown; however, it is thought to regulate of the expression of TGF-β and TNF-α and has either direct or indirect action on other molecules including collagen I, PDGF, IL-6, IL-1β, IL-13, IL-12p40, fibronectin, HSP47 and ICAM-1.30

Pirfenidone has been shown to have anti-fibrotic properties (Figure 11).31

BI_IPF_Fig11__31264215-5F9C-4E3A-8A5DA32AE83C6AFA.png

Figure 11. Potential mechanisms of fibrogenesis suppression by pirfenidone.31

Pirfenidone potentially inhibits the production of pro-fibrotic cytokines, inflammatory cytokines, collagen-specific chaperone HSP-47 and reactive oxygen species and stimulates the production of IFN-γ and IL-10. It has, however, little suppressive activity for immunity.31

Management of treatment side effects

Nintedanib

The five highest adverse events reported in patients treated with nintedanib include:32

  • diarrhoea (62%)
  • nausea (24%)
  • abdominal pain (15%)
  • vomiting (12%)
  • liver enzyme elevations (14%)

These adverse events can be managed in most patients through dose reduction and treatment interruption.33

Nintedanib efficacy does not appear to be affected by dose reductions or treatment interruptions (that have been made to manage adverse events): nintedanib reduced forced vital capacity (FVC) decline to a similar amount in both patients with a dose intensity of ≤90% and in patients with a dose intensity >90% (mean 112.7 and 72.7 mL/year, respectively).33

A recent study found that poor general condition, low body mass index (BMI) and full dosage of nintedanib at treatment initiation were risk factors gastrointestinal adverse effects during nintedanib treatment.34 Addition of prednisolone to the nintedanib treatment regimen may prevent the development of diarrhoea during treatment.34

Pirfenidone

The five highest adverse events reported patients treated with pirfenidone include:35

  • nausea (36%)
  • rash (30%)
  • abdominal pain (24%)
  • upper respiratory tract infection (27%)
  • diarrhoea (26%)

However, long-term treatment with pirfenidone is generally well tolerated, with most adverse events being mild or moderate in severity and responsive to dose modification.23

Early treatment

The irreversible lung damage caused by disease progression underlines the importance of early treatment.16

Once the diagnosis of IPF has been established, treatment should begin as early as possible with the aim of preserving pulmonary function, improving patients’ quality of life and prolonging survival.23

As the IPF disease course is unpredictable, even in patients with apparent slow disease progression events such as acute exacerbations can appear and cause irreparable lung damage.19

A post-hoc subgroup analyses of pooled data from the nintedanib phase III clinical trials demonstrate that patients with relatively well-preserved lung function (FVC >90% predicted) benefit from anti-fibrotic treatment, supporting the advantages of early treatment in patients with ‘mild’ disease.36

Accredited CME: Recognising and optimising care of IPF

Non-pharmaceutical interventions

International guidelines for the treatment of idiopathic pulmonary fibrosis (IPF) include recommendations on several non-pharmacological treatments in appropriate patients, such as pulmonary rehabilitation, long-term oxygen therapy and lung transplantation.2

Pulmonary rehabilitation

International guidelines include a weak recommendation for pulmonary rehabilitation in the majority of patients with IPF.2

Pulmonary rehabilitation programs involve aerobic conditioning, strength and flexibility training, educational lectures, nutritional interventions and psychosocial support.2

Studies of pulmonary rehabilitation in patients with IPF have shown improvements in walk distance, symptoms and quality of life.2,37

Supplemental oxygen 

Guidelines recommend that patients with IPF and clinically significant resting hypoxaemia should be treated with long-term oxygen therapy.2 Although there are no studies on the use of long-term oxygen therapy in patients with IPF, the recommendation was driven by a physiological rationale, ethical concern over withholding supplemental oxygen in a patient demonstrating clinically significant resting hypoxaemia (commonly defined by a resting oxygen saturation [SpO2] of < 88%), and extrapolation from data in chronic obstructive pulmonary disease.2

Lung transplants

Discussion of lung transplantation is encouraged with appropriate patients at the time of their diagnosis and detailed evaluation for lung transplantation should occur in a timely manner at the first sign of pulmonary deterioration.2

Studies suggest that patients with pulmonary fibrosis undergoing lung transplantation have favourable long-term survival compared with other disease indications.2 Five-year survival rates after lung transplantation in patients with IPF are estimated to be 50–56%.2

However, not all patients with IPF are eligible for a transplant – the most appropriate candidates for transplant are selected based on their probability of survival with and without a transplant.23

Managing exacerbations

Currently, there are no proven treatments for acute exacerbations and supportive management aims at alleviating symptoms and correcting hypoxia. Patients hospitalised with an acute exacerbation of inflammatory pulmonary fibrosis (IPF) may require supplemental oxygen and broad-spectrum antibiotics.20,21

No controlled clinical studies support the efficacy or safety of high-dose systemic corticosteroids in the management of acute exacerbations, but may be appropriate given anecdotal reports of benefit and the high-mortality associated with exacerbations.21,38

Mechanical ventilation is not generally used to manage acute exacerbations; however, mechanical ventilation may have a role in some patients, such as bridging to lung transplant.38

Therapies in development

Although the standard of care for patients with idiopathic pulmonary fibrosis (IPF) has greatly improved in recent years, current treatment does not completely stop disease progression.23 Novel therapeutic strategies such as combining drugs and the development of new anti-fibrotic agents are therefore in progress.

Nintedanib and pirfenidone in combination

Two recent open-label, exploratory safety studies of nintedanib and pirfenidone in combination show promising tolerability and safety profiles in patients with IPF, supporting further efficacy studies.39,40

Novel anti-fibrotic agents

Table 5. Novel anti-fibrotic agents in development for the treatment of IPF.

BI_IPF_Table 5__61C9C00E-8989-4EEA-8265037A3B5EC039.png

We asked Professor Elisabeth Bendstrup why she thought that drugs targeting plausible biological mechanisms have not translated into recommended treatments. See how she responded in these two videos 'Why do you feel drugs targeting several biologically plausible mechanisms have not translated into recommended treatments?' and 'Is it a poor understanding of the disease or poorly designed studies?

Welcome:

Guidelines

The 2015 international guidelines on treatment of idiopathic pulmonary fibrosis (IPF) by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and Latin American Thoracic Association recommend two anti-fibrotic treatments and anti-acid therapy for patients with IPF (Table 6).13

Table 6. Current recommendations for the treatment of IPF.13

BI_IPF_Table 6__EF5B1834-916B-4838-8BCBB7F00EBA3995.png

aStrong recommendation: most patients would want the suggested course of action. Conditional recommendation: the majority of patients would want the suggested course of action. Different choices will be appropriate for different patients depending on individual values and preferences.

Welcome:

IPF References

1. King J, Costabel U, Cordier JF, DoPico GA, DuBois RM, Lynch D, et al. Idiopathic pulmonary fibrosis: diagnosis and treatment: International Consensus Statement. American Journal of Respiratory and Critical Care Medicine. 2000;161(2 I):646–664.

2. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, 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(6):788–824.

3. Sauleda J, Núñez B, Sala E, Soriano JB. Idiopathic Pulmonary Fibrosis: Epidemiology, natural history, phenotypes. Med Sci (Basel, Switzerland). 2018;6(4). 

4. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795–806.

5. Ley B, Collard HR. Epidemiology of idiopathic pulmonary fibrosis. Clinical Epidemiology. 2013. doi:10.2147/CLEP.S54815.

6. Collard HR, Chen SY, Yeh WS, Li Q, Lee YC, Wang A, et al. Health care utilization and costs of idiopathic pulmonary fibrosis in U.S. medicare beneficiaries aged 65 years and older. Ann Am Thorac Soc. 2015;12(7):981–987.

7. Van Manen MJG, Geelhoed JJM, Tak NC, Wijsenbeek MS. Optimizing quality of life in patients with idiopathic pulmonary fibrosis. Therapeutic advances in respiratory disease. 2017;11(3):157–169.

8. Glaspole IN, Chapman SA, Cooper WA, Ellis SJ, Goh NS, Hopkins PM, et al. Health-related quality of life in idiopathic pulmonary fibrosis: Data from the Australian IPF Registry. Respirology. 2017;22(5):950–956.

9. Swigris JJ, Kuschner WG, Jacobs SS, Wilson SR, Gould MK. Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review. Thorax. 2005;60:588–594.

10. Kreuter M, Bonella F, Wijsenbeek M, Maher TM, Spagnolo P. Pharmacological treatment of idiopathic pulmonary fibrosis: Current approaches, unsolved issues, and future perspectives. 2015. doi:10.1155/2015/329481.

11. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: Pathogenesis and management. Respiratory Research. 2018;19(1). doi:10.1186/s12931-018-0730-2.

12. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157–79.

13. Raghu G, Rochwerg B, Zhang Y, Garcia CAC, Azuma A, Behr J, et al. AMERICAN THORACIC SOCIETY An official ATS / ERS / JRS / ALAT clinical practice guideline: Treatment of idiopathic pulmonary fibrosis an update of the 2011 clinical practice guideline. 2015;192:3–19.

14. Kim HJ, Perlman D, Tomic R. Natural history of idiopathic pulmonary fibrosis. Respir Med. 2015;109(6):661–670.

15. de Boer K, Lee JS. Under-recognised co-morbidities in idiopathic pulmonary fibrosis: A review. Respirology. 2016;21(6):995–1004.

16. Molina-Molina M, Aburto M, Acosta O, Ancochea J, Rodríguez-Portal JA, Sauleda J, et al. Importance of early diagnosis and treatment in idiopathic pulmonary fibrosis. Expert Review of Respiratory Medicine. 2018;12(7):537–539.

17. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis An Official ATS/ERS/JRS/ALAT Clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–e68.

18. Cottin V, Cordier JF. Velcro crackles: The key for early diagnosis of idiopathic pulmonary fibrosis? European Respiratory Journal. 2012. doi:10.1183/09031936.00001612.

19. Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431–440.

20. Glassberg MK. Overview of idiopathic pulmonary fibrosis, evidence-based guidelines, and recent developments in the treatment landscape. Am J Manag Care. 2019;25(11 Suppl):S195–S203.

21. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. 2016;194(3):265–275.

22. Kreuter M, Ehlers-Tenenbaum S, Palmowski K, Bruhwyler J, Oltmanns U, Muley T, et al. Impact of comorbidities on mortality in patients with idiopathic pulmonary fibrosis. PLoS One. 2016;11(3):e0151425.

23. Raghu G, Richeldi L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir Med. 2017;129. doi:10.1016/j.rmed.2017.05.017.

24. King, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic Pulmonary Fibrosis. N Engl J Med. 2014;22:2083–92.

25. Richeldi L, Du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;22:2071–82.

26. Crestani B, Huggins JT, Kaye M, Costabel U, Glaspole I, Ogura T, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60–68.

27. Nathan SD, Albera C, Bradford WZ, Costabel U, Glaspole I, Glassberg MK, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med. 2017;5(1):33–41.

28. Richeldi L, Cottin V, Du Bois RM, Es Selman M, Kimura T, Bailes Z, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS trials. Respir Med. 2016;113:74–79.

29. Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. European Respiratory Journal. 2015;45(5):1434–1445.

30. Lopez-de la Mora DA, Sanchez-Roque C, Montoya-Buelna M, Sanchez-Enriquez S, Lucano-Landeros S, Macias-Barragan J, et al. Role and new insights of pirfenidone in fibrotic diseases. International journal of medical sciences. 2015;12(11):840–847.

31. Takeda Y, Tsujino K, Kijima T, Kumanogoh A. Efficacy and safety of pirfenidone for idiopathic pulmonary fibrosis. Patient Preference and Adherence. 2014;8:361–370.

32. Ofev Prescribing Information. 2014. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205832s000lbl.pdf (accessed September 2019).

33. Corte T, Bonella F, Crestani B, Demedts MG, Richeldi L, Coeck C, et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. 2012. doi:10.1186/s12931-015-0276-5.

34. Kato M, Sasaki S, Nakamura T, Kurokawa K, Yamada T, Ochi Y, et al. Gastrointestinal adverse effects of nintedanib and the associated risk factors in patients with idiopathic pulmonary fibrosis. Sci Rep. 2019;9(1):12062.

35. Esbriet PI. Esbriet Prescribing Information. 2014. 

36. Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2017;72:340–346.

37. Vainshelboim B, Oliveira J, Yehoshua L, Weiss I, Fox BD, Fruchter O, et al. Exercise training-based pulmonary rehabilitation program is clinically beneficial for idiopathic pulmonary fibrosis. Respiration. 2014;88(5):378–388.

38. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017;389(10082):1941–1952.

39. Flaherty KR, Fell CD, Huggins JT, Nunes H, Sussman R, Valenzuela C, et al. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis. Eur Respir J. 2018;52(2). doi:10.1183/13993003.00230-2018.

40. Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC, et al. Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis: Results of the INJOURNEY trial. Am J Respir Crit Care Med. 2018;197(3):356–363.

41. Maher TM, van der Aar EM, Van de Steen O, Allamassey L, Desrivot J, Dupont S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med. 2018;6(8):627–635.

42. Maher TM, Kreuter M, Lederer DJ, Brown KK, Wuyts W, Verbruggen N, et al. Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2). BMJ Open Respir Res. 2019;6(1). doi:10.1136/bmjresp-2019-000422.

43. Raghu G, Scholand MB, De Andrade J, Lancaster L, Mageto Y, Goldin J, et al. FG-3019 anti-connective tissue growth factor monoclonal antibody: Results of an open-label clinical trial in idiopathic pulmonary fibrosis. Eur Respir J. 2016;47(5):1481–1491.

44. NCT03955146. Evaluation of Efficacy and Safety of Pamrevlumab in Patients With Idiopathic Pulmonary Fibrosis. 2019. Available at https://clinicaltrials.gov/ct2/show/NCT03955146?term=FG-3019&cond=Pulmonary+Fibrosis&rank=4 (accessed Septemer 2019).

45. Khalil N, Manganas H, Ryerson CJ, Shapera S, Cantin AM, Hernandez P, et al. Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2019;53(3). 

46. Raghu G, Van Den Blink B, Hamblin MJ, Whitney Brown A, Golden JA, Ho LA, et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial. JAMA - J Am Med Assoc. 2018;319(22):2299–2307.

47. Raghu G, van den Blink B, Hamblin MJ, Brown AW, Golden JA, Ho LA, et al. Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study. Lancet Respir Med. 2019;7(8):657–664.