Idiopathic Pulmonary Fibrosis: Biomarkers and New Treatment Options

The molecular heterogeneity of idiopathic pulmonary fibrosis (IPF) may be important when selecting treatment strategies, including 2 new medications for delaying the progression of IPF-pirfenidone and nintedanib. In a featured lecture, Steven K. Huang, MD, an expert in IPF and an assistant professor of internal medicine at the University of Michigan, discussed characterization of the disease from the perspective of genetics.

Steven K. Huang, MD, an expert in idiopathic pulmonary fibrosis (IPF) and an assistant professor of internal medicine at the University of Michigan, discussed characterization of the disease from the perspective of genetics during a featured lecture at the 2014 American College of Chest Physicians conference in Austin, Texas. IPF is known to have substantial variability in its natural history among different patients. In addition, patients respond to treatments in different ways. The molecular heterogeneity of IPF may be important when selecting treatment strategies, including 2 new medications for delaying the progression of IPF—pirfenidone and nintedanib.

The classification and understanding of IPF has evolved over time. For instance, in 1975, Liebow and colleagues separated IPF into several different distinct pathologies. Later on, computed tomography (CT) imaging enabled further distinction of IPF. Ultimately, this led to 7 different names for IPF in the literature, which led to some confusion.1

Current evidence-based diagnostic criteria for IPF require exclusion of other known causes of pulmonary fibrosis, including usual interstitial pneumonia, through high-resolution CT scoring of pulmonary fibrosis and a surgical lung biopsy.2 Even with these guidelines, community physicians often disagree on the diagnosis of IPF. In a study of differences between academic and community-based physicians, there was substantial disagreement on which cases were IPF and which cases could be attributed to another diffuse parenchymal lung disease.3 Ultimately, Dr Huang noted, it is important to have “dynamic interaction between clinicians, radiologists, and pathologists for a final diagnosis of IPF.”

Part of the reason for disagreement between specialists on the diagnosis of IPF may be its heterogeneous pathology—even in a single patient. In 2001, Flaherty et al found that 26% of patients who had biopsies from the upper and lower lobes of the lung had very different pathologies between the 2 lobes.4

The heterogeneity within a single patient in IPF is accompanied by variability in clinical course between patients. Dr Huang noted that, often, academic review papers will make a statement about IPF, such as, “IPF is a chronic, progressive, scarring disease with a median survival of 3 to 5 years.” This statement belies the complexity of the disease. According to Dr Huang, “It can be quite variable and you can have people who are stable for a long time and acutely deteriorate...there are others with a stepwise decline.” This variability in patients is evident in results from the trials of nintedanib and pirfenidone in IPF.5

Richeldi et al published results of the INPULSIS trials (INPULSIS-1 and INPULSIS-2) in 2014 in the New England Journal of Medicine. In 2 replicate phase 3 trials of nintedanib for IPF, a total of 1066 patients were randomized in a 3:2 ratio to receive 150 mg nintedanib twice daily or placebo twice daily for 52 weeks. Change in forced vital capacity (FVC) was measured, as were changes on the St. George’s Respiratory Questionnaire. After 52 weeks, in INPULSIS-1, investigators observed less annual decline in FVC over 1 year (—114.7 mL with nintedanib vs –239.9 mL with placebo; P <.001). Similar results were observed in INPULSIS-2 (-113.6 mL with nintedanib vs —203.7 mL with placebo; P <.001).6

However, the 2 trials found different results in the time to occurrence of the first acute exacerbation. Results of INPULSIS-1 suggested no significant effect (P = .67), but results of INPULSIS-2 showed a significant effect (hazard ratio of exacerbation: 0.38; P = .005). The most common adverse event with nintedanib was diarrhea, which occurred in more than half (61.5%) of patients receiving nintedanib versus 18.6% of those receiving placebo.6 According to Dr Huang, the differences in time to first acute exacerbation between these 2 parallel phase 3 trials (which provided evidence for the approval of nintedanib) may be due to heterogeneity in patients with IPF.

The same issue initially occurred with studies of pirfenidone, although the ASCEND trial showed a clear benefit with pirfenidone. In this study, which was published in 2014 in the New England Journal of Medicine, investigators studied pirfenidone versus placebo in patents with IPF. A total of 555 patients with IPF were randomized in a 1:1 ratio to receive once-daily oral pirfenidone at a dosage of 2403 mg daily or placebo over 52 weeks.7

Investigators measured the primary end points of changes in FVC and rates of death after 1 year. Other end points included changes in 6-minute walk distance and progression-free survival. Use of pirfenidone daily significantly reduced the percentage of patients with a 10% or greater reduction in FVC over the study period (relative risk reduction: 47.9%; P <.001). Skin-related adverse events and gastrointestinal adverse events were the most common adverse events with pirfenidone.7

According to Dr Huang, “Cearly there was a benefit...change in FVC was clearly better in the pirfenidone arm versus the placebo arm.” These studies cannot be directly compared, however, because the populations were different.

Heterogeneity is common in many diseases, including asthma, chronic obstructive pulmonary disease, and lung cancer. For instance, asthma is separated into exercise-induced asthma, allergic asthma, and eosinophilic asthma. Unfortunately, there is not yet any way to make these determinations for patients with IPF.

Not all cases of IPF are genetic. Familial cases make up only 1.5% to 2.2% of all diagnoses of IPF. The high rate of sporadic cases in IPF suggests a possible epigenetic mechanism in IPF pathophysiology. Intriguingly, methylation levels at a site known as EP2 are related to the total lung capacity of patients with IPF, and they are correlated with long-term survival. Variations in a gene known as TLR9 may also predict the course of the disease.8

Ultimately, although many questions remain, a more intimate understanding of the genetic and epigenetic factors in IPF will ultimately lead to improved diagnosis techniques and markers to predict the course of IPF.


  1. Smith GJ. Averill Abraham Liebow: contributions to pulmonary pathology. Yale J Biol Med. 1981;54(2):139-146.
  2. Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. 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. Flaherty KR, Andrei AC, King TE Jr, et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med. 2007;175(10):1054-1060.
  4. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164(9):1722-1727.
  5. Martinez FJ, Safrin S, Weycker D, et al; IPF Study Group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142(12, pt 1):963-967.
  6. Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
  7. King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092.
  8. Selman M, Carrillo G, Estrada A, et al. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern. PLoS One. 2007;2(5):e482.
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