Loading...
 

April - June 2018: 
Volume 31, Issue 2

Click on the image to download the Issue in PDF format.

ARCHIVE

Pneumon 2018, 31(2):71-80, Review
Idiopathic Pulmonary Fibrosis. Time to get personal
Authors Information
15th Department of Pneumonology, General Hospital for Thoracic Diseases “SOTIRIA”, Athens, Greece
2First Academic Department  of Pneumonology, General Hospital  for Thoracic Diseases “SOTIRIA”,  Medical School, National and Kapodistrian University of Athens, Athens, Greece
3Division of Immunology, Biomedical Sciences Research Center “Alexander Fleming”, Athens, Greece
Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and debilitating disease of unknown etiology. Median survival after diagnosis ranges from 3 to 5 years. The clinical course of the disease is highly heterogeneous and unpredictable. Despite this heterogeneity, the two novel compounds, pirfenidone and nintedanib, are administered uniformly to patients with IPF with little correlation to inter-individual differences. Personalized medicine refers to a medical model aiming to determine disease susceptibility, tailor the ideal treatment, predict and improve outcome according to individuals’ molecular and environmental profile. The conceptualization of precision medicine dates back to the era of Hippocrates, the father of western medicine, who first coined out the term “idiosyncrasy” to describe the individuality in the clinical course of the disease. Compared to oncology, precision medicine approaches in IPF have significantly lagged behind. Disease management and prognostication is still based on functional and physiological parameters, which present with several caveats and provide no mechanistic insights. This short review article summarizes the current state of knowledge in the prognostic and therapeutic field of IPF, highlights the most recent findings and addresses the pressing need to integrate molecular biomarkers in the everyday clinical practice.

Pneumon 2018, 31(2):71-80.

Full text

Introduction

Idiopathic pulmonary fibrosis (IPF) represents a devastating chronic lung disease of unknown origin, characterized by the complex interaction of environmental, immunologic, genetic and epigenetic factors1-6. Median survival after diagnosis ranges from 3 to 5 years7. The clinical course of the disease is highly unpredictable and heterogeneous8. Based on current functional and physiological indices, patients are categorized into three distinct patterns of disease progression: slow progressors, rapid progressors and patients with relative stability interposed by periods of rapid acceleration named acute exacerbations8-10. Until recently, lung transplantation was the only approach that could prolong patients’ survival. To this end, two novel compounds (pirfenidone and nintedanib), able to reduce the rate of progression, represent the pharmaceutical treatment approved for the disease11,12. These  compounds are administered uniformly to patients with IPF based on diagnosis and with little correlation to inter-individual differences13.

Personalized medicine dates back to the times of Hippocrates who stated that ‘’It’s far more important to know what person the disease has than what disease the person has’’  and refers to a medical model aiming to determine disease susceptibility, tailor the ideal treatment, predict and improve outcome according to patients’ molecular and environmental profile14,15. However, it was not until the 19th century that significant progress has been achieved, as Reuben Ottenberg reported the first known blood compatibility test in 1907. The past 2 years precision medicine initiatives have drugged much of attention13. Unfortunately, personalized medicine approaches in IPF have significantly lagged behind16,17. In the past few years, several conventional therapeutic regimens led to fatal-side effects18. To this end, there is an amenable need for the identification of distinct endotypes and application of targeted therapeutic approaches on a pathway-specific basis. This short review article summarizes the current state of knowledge in the prognostic and therapeutic field of IPF and presents ways to optimize the use of precision medicine in the everyday clinical practice by providing realistic answers to fundamental questions.

Which is the current status used in the everyday clinical practice for treatment stratification and prognostication?

Despite disease heterogeneity and complexity, pirfenidone and nintedanib are currently administered uniformly to patients irrespective of endotypes13,19-21. Clinicians usually choose the compound that is theoretically best tailored to the individual patient, according to comorbidities and risk of adverse events. With regards to comorbid conditions including lung cancer, pulmonary hypertension and gastroesophageal reflux, the ideal approach remains to be elucidated and consensus task forces are greatly anticipated16,22-26.

Prognostication is solely based on functional and physiological parameters. Currently, forced vital capacity (FVC), diffusion capacity for carbon monoxide (DLCO) and 6-minute walking test( 6MWT) are the main prognosticators used in the real life setting6,27-29. GAP (Gender, Age and Physiology variables) score and composite physiologic index (CPI) are the two most reliable risk-stratification algorithms30,31. However, these parameters present with significant caveats including technical variabilities, overestimation of FVC in patients with combined pulmonary fibrosis and emphysema (CPFE) and erroneous interpretations of 6MWT due to myoskeletal and heart related comorbities28,32-34. Finally, all these parameters provide no mechanistic insights.

Why personalized medicine approaches for IPF had significantly lagged behind in the past?

IPF is a relatively ‘newly introduced’ disease. Wiliam Osler first coined out the term ‘’chronic interstitial pneumonia’’ almost a century ago; yet, in this case fibrosis was unilateral35. The pathologic term ‘’usual interstitial pneumonia (UIP)’’ was introduced by Averill Liebow in 196836. Until the past few years, IPF was an underecognized entity and considered as an end stage lung disease with no effective treatment. Thus, precision medicine approaches have focused on identification of compounds for more common diseases, including anti-IL-5 (mepolizumab), anti-IgE (omalizumab), anti-IL-13 (lebrkizumab and tralokinumab) treatment for asthma and  PD-1/PD-L1 inhibitors (nivolumab and pembrolizumab)  and compounds targeting EGFR mutations (erlotinib, gefitinib, afatinib) for non-small cell lung cancer17,37-39.

Could genetics and epigenetics contribute to personalized medicine approaches? (Table 1)

Common or rare variants have been associated with nearly half of IPF cases40-42. Intriguingly, a common variant located in the putative promoter region of the MUC5B gene (rs35705950) conferred risk for pulmonary fibrosis development, but has also been associated with better prognosis43-57. Similarly, a toll interacting protein (TOLLIP) functional variant (rs5743890) was found protective against fibrosis development but was also associated with increased mortality among individuals affected16,46. Another single nucleotide polymorphism (SNP) within TOLLIP (rs3750920) was able to stratify patients with IPF based on treatment response to N-acetylcysteine58,59. A functional variant (Leu412Phe, TLR3 L412F) of toll-like receptor 3 (TLR3) has been also reported as a marker of rapidly progressive disease in patients with IPF60. Furthermore, loss of-function mutations in a TLR3 agonist (ELMOD2) have been associated with familial IPF susceptibility61,62. Short leucocyte telomere length has been also associated with worse survival in IPF63-66, while patients with telomerase mutations were more prone to complications due to nephrotoxic immunosuppressants and to post-transplantation hematologic complications, maybe owing to reduced bone marrow reserves67-74. Several other mutations in genes have been suggested as biomarkers including mutations associated with surfactant proteins15,75. Interestingly, patients carrying SFTPA2 mutations had also an increased risk of developing lung cancer22,76,77.

Table 1. Main biomarkers investigated in IPF and their potential clinical utility in the context of personalized medicine
 

With regards to epigenetics,  application of high-throughput screening methods identified differentially methylated and expressed genes including TOLLIP, NOTCH1, Thy-1, CDKN2Ap14ARF and SHOX2 homeobox family gene in patients with IPF78-86. Histone demethylase and deacetylase inhibitors have been suggested as novel therapeutic targets for a subset of patients22,87. Finally, both downregulated and so called “anti-fibrotic” (let-7d, miR-29) and upregulated (miR-21, miR-154) have been considered major orchestrators of pulmonary fibrosis88-93. Interestingly, mir-29 has exhibited in vivo therapeutic benefits in several models of pulmonary fibrosis and is currently entering the pipeline of clinical trials; yet, caution is demanded as such trials exhibit several risks including the risk of carcinogenesis94-97.

Figure 1. Figure 1 depicts main applications of personalized medicine in patients with IPF. A single nucleotide polymorphism (SNP) within TOLLIP (rs3750920) was able to stratify patients with IPF based on treatment response to N-acetylcysteine. Patients with specific SNPs (MUC5B rs35705950, TOLLIP, rs3750920) present with a survival benefit. Several other biomarkers depicted in the figure have been associated with poor prognosis. Finally, combination of a genomic risk scoring system (Scoring Algorithm for Molecular Subphenotypes; SAMS) and GAP score after adjustment for several parameters, was able to discriminate patients into two risk groups with regards to mortality and transplant free survival.
 

Time to get personal? Main lessons from personal ‘’omics’’ profiling (Table 1)

Kaminski and Selman distinguished patients with IPF into rapid progressors and slow progressors based on genomics2,98-100. In a follow-up study, a 52-gene outcome-predictive signature including genes involved in "The costimulatory signal during T cell activation" Biocarta pathway (CD28, ICOS, LCK, and ITK) discriminated patients into two groups with significant difference in transplant-free survival (TFS)101.

Proteomics technology led to the identification of several novel therapeutic compounds, currently used in clinical trials including inhibitors of LOXL2, CTGF, IL-13, galectin, NOX1/NOX4, and SHP96,102-110. Moreover, several biomarkers validated in independent cohorts, including MMP-7, CCL-18, CXCL13 and MMP-degraded extracellular matrix proteins, have been identified through proteomics9,111-113. In particular, increased MMP-7 values have been associated with poor prognosis77,114-116. Increased levels of circulating chemokine ligand 18 (CCL18) and chemokine (C-X-C motif) ligand 13 (CXCL13) were also likewise predictive of IPF progression101,117,118.

What has been recently added to the field?

Significant progress has been achieved in the context of personalized medicine during the last year. A genomic risk scoring system (Scoring Algorithm for Molecular Subphenotypes; SAMS) ,able to discriminate patients into two risk groups with regards to mortality and transplant free survival, has been recently published119. These findings provide evidence that integration of genomic data into prognostic algorithms encompassing demographic and functional data significantly improves the prediction of outcome compared to GAP index alone and address the need for more complex criteria than conventional demographic and physiologic parameters in studies investigating therapeutic effect15,120-126.

Moreover, the recently published PROFILE study is the largest prospective analysis of serum biomarkers in IPF. Three epithelium derived biomarkers (CA19-9, CA-125 and surfactant protein D) were able both to discriminate stable from progressive IPF and identify patients at increased risk of mortality127. No studies had previously identified CA19-9 as a biomarker of IPF progression or CA-125 as a dynamic IPF biomarker, in the past. Furthermore, this study validated that high concentrations of baseline surfactant protein D and MMP 7 can be used to distinguish individuals with disease from controls and predict outcome. These results are of paramount importance, as they could demonstrate a crucial role in an effort to streamline clinical trial designs and even assess treatment response based on biomarkers.

Towards the direction of assessment of treatment response, another recent study reported that 3D pulmospheres (spheroids composed of cells from primary lung biopsy) predicted responsiveness in antifibrotic compounds and thus the most beneficial anti-fibrotic drug for every patient as individual. However, a major caveat is the fact that pulmospheres were obtained via video-assisted thoracic surgery (VATS)128. Obtaining tissue to form 3D pulmospheres with less invasive methods such as cryobiopsy could play a cardinal role in personalized medicine approaches in the future.

Future perspectives and concluding remarks

Despite recent discoveries on disease pathogenesis and treatment, IPF still represents an incurable disease. Application of precision medicine could predict responsiveness in available compounds and lead to efficacious treatments for specific IPF endotypes, like mepolizumab and omalizumab in asthma and novel regimens in lung cancer. Ideal application of personalized medicine involves a ‘’ two-way process’’. This process includes 1) extremely precise diagnostic tests and biomarkers able to determine whether patient may benefit from an intervention or not and 2) the therapeutic intervention itself. Several future challenges remain to be addressed for the successful application of this ‘’two-way process’’ including the following:

Diagnostic tests: Advances in computational power and medical imaging (i.e. microCT) are paving the way for personalized medical approaches considering and combining patient’s anatomical profile along with physiological and genetic features129,130.

Pharmacogenetic approach: Implementation of biomarkers and pharmacogenetic approach into future clinical trials is crucial, given the robust information we have gained during the past years from biomarkers including MUC5B, TOLLIP, MMP-3, MMP-7, CXCL13, lysyl oxidase homolog 2, periostin, heat shock protein 70 and type V collagen9,40,129,130. A number of such studies (PROFILE, COMET, LGRC, the European IPF network registry) have already been organized111,131-133.

Therapeutic interventions: Studies using lung-targeted therapies including clinical studies for the role of aerosolized thyroid hormone administration in patients with IPF are greatly anticipated134.

Targeted approach for comorbidities: Clinical trials targeting comorbid conditions including gastroesophageal reflux, lung cancer and pulmonary hypertension are also of paramount importance. Το this end, studies for proton pump inhibitors in IPF present with conflicting results and there is caution for their use mainly due to the subsequent alteration of lung microbiome. The role of lung-gut axis in this context deserves further investigation135,136. The results of a phase II clinical trial for laparoscopic anti-reflux therapy in IPF will address whether this intervention is only a trigger for acute exacerbation or beneficial for a subgroup of patients137. Furthermore, there is a pressing need for Consensus Task Force addressing the ideal diagnostic algorithm and chemotherapeutic regimen in patients with IPF and lung cancer138,139. Finally, studies for antifibrotics plus a vasodilator or even tyrosine kinase inhibitors alone for patients with IPF and pulmonary hypertension are anticipated.

Collectively, from FDA’s vantage point, the era of precision medicine has already arrived. In 2010, FDA announced the “Regulatory Science Initiative” highlighting personalized medicine as a key priority area and since 2011, approximately one-third of files, submitted for compounds waiting for approval, included some type of genetic or other biomarker data. However, personalized medicine in IPF had lagged behind. Thus, there is a pressing need to enrich former president’s Obama precision medicine initiative with diseases including IPF, which accounts for the same number of deaths with breast cancer in the USA and is the non-cancer lung disease with the gravest prognosis22,140. It’s upon clinicians’ and researchers’ hands to persuade the scientific and political community that IPF should be launched into the same trajectory as many types of cancer.

References

1.  Martinez FJ, Chisholm A, Collard HR, et al. The diagnosis of idiopathic pulmonary fibrosis: current and future approaches. The Lancet Respiratory medicine 2017; 5:61-71.

2. Herazo-Maya JD, Kaminski N. Personalized medicine: applying 'omics' to lung fibrosis. Biomark Med 2012; 6:529-40.

3.  Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 1997; 155:242-8.

4.  Karampitsakos T, Woolard T, Bouros D, Tzouvelekis A. Toll-like receptors in the pathogenesis of pulmonary fibrosis. European journal of pharmacology 2016.

5.  Tzouvelekis A, Kaminski N. Epigenetics in idiopathic pulmonary fibrosis. Biochemistry and cell biology = Biochimie et biologie cellulaire 2015; 93:159-70. 

6.  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. American journal of respiratory and critical care medicine 2011; 183:788-824.

7.  Tzouvelekis A, Tzilas V, Papiris S, Aidinis V, Bouros D. Diagnostic and prognostic challenges in Idiopathic Pulmonary Fibrosis: A patient's "Q and A" approach. Pulmonary pharmacology & therapeutics 2017; 42:21-4.

8.  Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Annals of internal medicine 2005; 142:963-7.

9.  Tzouvelekis A, Herazo-Maya J, Sakamoto K, Bouros D. Biomarkers in the evaluation and management of idiopathic pulmonary fibrosis. Current topics in medicinal chemistry 2016; 16:1587-98.

10.  Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An International Working Group Report. American journal of respiratory and critical care medicine 2016; 194:265-75.

11.  Fletcher S, Jones MG, Spinks K, et al. The safety of new drug treatments for idiopathic pulmonary fibrosis. Expert opinion on drug safety 2016; 15:1483-9.

12.  Spagnolo P, Tzouvelekis A, Bonella F. The management of patients with idiopathic pulmonary fibrosis. Frontiers in medicine 2018; 5:148.

13.  Maher TM. Precision medicine in idiopathic pulmonary fibrosis. QJM: monthly journal of the Association of Physicians 2016; 109:585-7.

14.  Karagiannis TC. The timeless influence of Hippocratic ideals on diet, salicytates and personalized medicine. Hellenic journal of nuclear medicine 2014; 17:2-6.

15.  Spagnolo P, Tzouvelekis A, Maher TM. Personalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current opinion in pulmonary medicine 2015; 21:470-8.

16.  Spagnolo P, Oldham JM, Jones MG, Lee JS. Personalized medicine in interstitial lung diseases. Current opinion in pulmonary medicine 2017; 23:231-6.

17.  Brownell R, Kaminski N, Woodruff PG, et al. Precision Medicine: The new frontier in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2016; 193:1213-8.

18.  Network TIPFCR. Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis. New England Journal of Medicine 2012; 366: 1968-77.

19.  Raghu G, Wells AU, Nicholson AG, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. American journal of respiratory and critical care medicine 2017; 195:78-85.

20.  Kolb M, Richeldi L, Behr J, Maher TM. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax 2017; 72:340-6.

21.  George PM, Wells AU. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert review of clinical pharmacology 2017; 10:483-91.

22.  Karampitsakos T, Tzilas V, Tringidou R, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Pulmonary pharmacology & therapeutics 2017.

23.  Nathan SD, Behr J, Cottin V, et al. Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy? Respir Med 2017; 122 Suppl 1: S10-s13.

24.  Kreuter M, Wuyts W, Renzoni E, et al. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. The Lancet Respiratory medicine 2016; 4:381-9.

25.  Margaritopoulos GA, Antoniou KM, Wells AU. Comorbidities in interstitial lung diseases. European respiratory review: an official journal of the European Respiratory Society 2017;26.

26.  Karampitsakos T, Tzouvelekis A, Chrysikos S, Bouros D, Tsangaris I, Fares WH. Pulmonary hypertension in patients with interstitial lung disease. Pulmonary pharmacology & therapeutics 2018.

27.  Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet (London, England) 2017.

28.  du Bois RM, Albera C, Bradford WZ, et al. 6-minute walk test distance is an independent predictor of mortality in patients with idiopathic pulmonary fibrosis. The European respiratory journal 2013.

29.  du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. American journal of respiratory and critical care medicine 2011; 183:1231-7.

30.  Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Annals of internal medicine 2012; 156: 684-91.

31.  Wells AU, Desai SR, Rubens MB, et al. Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography. American journal of respiratory and critical care medicine 2003; 167: 962-9.

32.  Ward K, Spurr L, Goldman NR, et al. Patient eligibility for anti-fibrotic therapy in idiopathic pulmonary fibrosis can be altered by use of different sets of reference values for calculation of FVC percent predicted. Respir Med 2016; 120:131-3.

33.  Cortes-Telles A, Forkert L, O’Donnell DE, Morán-Mendoza O. Idiopathic pulmonary fibrosis: New insights to functional characteristics at diagnosis. Canadian Respiratory Journal: Journal of the Canadian Thoracic Society 2014; 21:e55-60.

34.  Wells AU. Forced vital capacity as a primary end point in idiopathic pulmonary fibrosis treatment trials: making a silk purse from a sow's ear. Thorax 2013; 68:309-10.

35.  Osler W. The principles and practice of medicine. New York, D Appleton and Company 1982.

36.  Liebow A. New concepts and entities in pulmonary disease. The Lung Baltimore, The Williams and Wilkins Company 1968: 332-65.

37.  Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. The Lancet Respiratory medicine 2016; 4:549-56.

38.  Strunk RC, Bloomberg GR. Omalizumab for Asthma. New England Journal of Medicine 2006; 354:2689-95.

39.  Bradley CJ, Yabroff KR, Mariotto AB, Zeruto C, Tran Q, Warren JL. Antineoplastic treatment of Advanced-Stage Non-Small-Cell lung cancer: Treatment, survival, and spending (2000 to 2011). Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2017: Jco2016694166.

40.  Blackwell TS, Tager AM, Borok Z, et al. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. American journal of respiratory and critical care medicine 2014; 189:214-22.

41.  Spagnolo P, Cottin V. Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine. Journal of medical genetics 2017; 54:93-9.

42.  Kropski JA, Blackwell TS, Loyd JE. The genetic basis of idiopathic pulmonary fibrosis. The European respiratory journal 2015; 45:1717-27.

43.  Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. The New England journal of medicine 2011; 364:1576-7.

44.  Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. The New England journal of medicine 2013; 368:2192-200.

45.  Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. The New England journal of medicine 2011; 364:1503-12.

46.  Noth I, Zhang Y, Ma SF, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. The Lancet Respiratory medicine 2013; 1:309-17.

47.  Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. Jama 2013; 309:2232-9.

48.  Borie R, Crestani B, Dieude P, et al. The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the European Caucasian population. PloS one 2013; 8:e70621.

49.  Stock CJ, Sato H, Fonseca C, et al. Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis. Thorax 2013; 68:436-41.

50.  Horimasu Y, Ohshimo S, Bonella F, et al. MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis. Respirology (Carlton, Vic) 2015; 20:439-44.

51.  Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annual review of pathology 2014; 9:157-79.

52.  Wang C, Zhuang Y, Guo W, et al. Mucin 5B promoter polymorphism is associated with susceptibility to interstitial lung diseases in Chinese males. PloS one 2014; 9:e104919.

53.  Nakano Y, Yang IV, Walts AD, et al. MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine 2016; 193:464-6.

54.  Roy MG, Livraghi-Butrico A, Fletcher AA, et al. Muc5b is required for airway defence. Nature 2014; 505:412-6.

55.  Kolb M, White ES, Gauldie J. Mucking around in the Genome: MUC5B in Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine 2016; 193: 355-7.

56.  Araki T, Putman RK, Hatabu H, et al. Development and progression of interstitial lung abnormalities in the framingham heart study. American journal of respiratory and critical care medicine 2016; 194:1514-22.

57.  Chung JH, Peljto AL, Chawla A, et al. CT Imaging phenotypes of pulmonary fibrosis in the muc5b promoter site polymorphism. Chest 2016; 149:1215-22.

58.  Oldham JM, Ma SF, Martinez FJ, et al. TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine 2015; 192:1475-82.

59.  Oldham JM, Noth I, Martinez FJ. Pharmacogenetics and interstitial lung disease. Current opinion in pulmonary medicine 2016; 22:456-65.

60.  O'Dwyer DN, Armstrong ME, Trujillo G, et al. The Toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2013; 188:1442-50.

61.  Pulkkinen V, Bruce S, Rintahaka J, et al. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2010; 24:1167-77.

62.  Fingerlin TE, Zhang W, Yang IV, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC genetics 2016; 17:74.

63.  Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proceedings of the National Academy of Sciences of the United States of America 2008; 105:13051-6.

64.  Kropski JA, Mitchell DB, Markin C, et al. A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. Chest 2014; 146:e1-7.

65.  Cronkhite JT, Xing C, Raghu G, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. American journal of respiratory and critical care medicine 2008; 178:729-37.

66.  Stuart BD, Lee JS, Kozlitina J, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. The Lancet Respiratory medicine 2014; 2:557-65.

67.  Armanios M. Telomerase mutations and the pulmonary fibrosis-bone marrow failure syndrome complex. The New England journal of medicine 2012; 367: 384; author reply 384.

68.  Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proceedings of the National Academy of Sciences of the United States of America 2007; 104:7552-7.

69.  Stuart BD, Choi J, Zaidi S, et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nature genetics 2015; 47:512-7.

70.  Cogan JD, Kropski JA, Zhao M, et al. Rare variants in RTEL1 are associated with familial interstitial pneumonia. American journal of respiratory and critical care medicine 2015; 191:646-55.

71.  Wei R, Li C, Zhang M, et al. Association between MUC5B and TERT polymorphisms and different interstitial lung disease phenotypes. Translational research: the journal of laboratory and clinical medicine 2014; 163:494-502.

72.  Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. The New England journal of medicine 2007; 356:1317-26.

73.  Silhan LL, Shah PD, Chambers DC, et al. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. The European respiratory journal 2014; 44:178-87.

74.  Borie R, Kannengiesser C, Hirschi S, et al. Severe hematologic complications after lung transplantation in patients with telomerase complex mutations. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 2015; 34:538-46.

75.  Ley B, Brown KK, Collard HR. Molecular biomarkers in idiopathic pulmonary fibrosis. American journal of physiology Lung cellular and molecular physiology 2014; 307:L681-91.

76.  Maitra M, Cano CA, Garcia CK. Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-beta1 secretion. Proceedings of the National Academy of Sciences of the United States of America 2012; 109:21064-9.

77. Song JW, Do KH, Jang SJ, et al. Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis. Chest 2013; 143:1422-9.

78.  Sanders YY, Liu H, Liu G, Thannickal VJ. Epigenetic mechanisms regulate NADPH oxidase-4 expression in cellular senescence. Free radical biology & medicine 2015; 79:197-205.

79.  Sanders YY, Hagood JS, Liu H, Zhang W, Ambalavanan N, Thannickal VJ. Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice. The European respiratory journal 2014; 43:1448-58.

80. Sanders YY, Ambalavanan N, Halloran B, et al. Altered DNA methylation profile in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2012; 186:525-35.

81. Selman M, Lopez-Otin C, Pardo A. Age-driven developmental drift in the pathogenesis of idiopathic pulmonary fibrosis. The European respiratory journal 2016; 48:538-52.

82. Yang IV, Pedersen BS, Rabinovich E, et al. Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2014; 190:1263-72 

83.  Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. American journal of respiratory cell and molecular biology 2007; 36:226-35.

84. Sanders YY, Pardo A, Selman M, et al. Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. American journal of respiratory cell and molecular biology 2008; 39:610-8.

85.  Cisneros J, Hagood J, Checa M, et al. Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. American journal of physiology Lung cellular and molecular physiology 2012; 303:L295-303.

86.  Huang SK, Scruggs AM, McEachin RC, White ES, Peters-Golden M. Lung fibroblasts from patients with idiopathic pulmonary fibrosis exhibit genome-wide differences in DNA methylation compared to fibroblasts from nonfibrotic lung. PloS one 2014; 9:e107055.

87.  Huang SK, Scruggs AM, Donaghy J, et al. Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. Cell Death Dis 2013; 4:e621.

88.  Milosevic J, Pandit K, Magister M, et al. Profibrotic role of miR-154 in pulmonary fibrosis. American journal of respiratory cell and molecular biology 2012; 47:879-87.

89.  Pandit KV, Corcoran D, Yousef H, et al. Inhibition and role of let-7d in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2010; 182:220-9.

90.  Huleihel L, Ben-Yehudah A, Milosevic J, et al. Let-7d microRNA affects mesenchymal phenotypic properties of lung fibroblasts. American journal of physiology Lung cellular and molecular physiology 2014; 306:L534-42.

91.  Parker MW, Rossi D, Peterson M, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. The Journal of clinical investigation 2014.

 92.  Liu G, Friggeri A, Yang Y, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. The Journal of experimental medicine 2010; 207:1589-97.

 93.  Pandit KV, Milosevic J, Kaminski N. MicroRNAs in idiopathic pulmonary fibrosis. Translational research: the journal of laboratory and clinical medicine 2011; 157:191-9.

94.  Montgomery RL, Yu G, Latimer PA, et al. MicroRNA mimicry blocks pulmonary fibrosis. EMBO molecular medicine 2014; 6:1347-56.

95.  Xiao J, Meng XM, Huang XR, et al. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Molecular therapy: the journal of the American Society of Gene Therapy 2012; 20:1251-60.

96.  Tomos IP, Tzouvelekis A, Aidinis V, et al. Extracellular matrix remodeling in idiopathic pulmonary fibrosis. It is the 'bed' that counts and not 'the sleepers'. Expert review of respiratory medicine 2017; 11:299-309.

97.  Cushing L, Kuang PP, Qian J, et al. miR-29 is a major regulator of genes associated with pulmonary fibrosis. American journal of respiratory cell and molecular biology 2011; 45:287-94.

98.  Tzouvelekis A, Patlakas G, Bouros D. Application of microarray technology in pulmonary diseases. Respiratory research 2004; 5:26.

99.  Campbell JD, Spira A, Lenburg ME. Applying gene expression microarrays to pulmonary disease. Respirology (Carlton, Vic) 2011; 16:407-18.

100.  Selman M, Carrillo G, Estrada A, et al. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern. PloS one 2007; 2:e482.

101.  Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Science translational medicine 2013; 5:205ra136.

102.  Tzouvelekis A, Yu G, Lacks Lino Cardenas C, et al. SH2 Domain-containing Phosphatase-SHP-2 is a Novel Anti-fibrotic regulator in pulmonary fibrosis. American journal of respiratory and critical care medicine 2016.

103.  Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nature medicine 2010; 16:1009-17.

104.  Liu F, Mih JD, Shea BS, et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. The Journal of cell biology 2010; 190: 693-706.

105.  Cheng T, Liu Q, Zhang R, et al. Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation. Journal of molecular cell biology 2014; 6:506-15.

106.  Raghu G, Scholand MB, de Andrade J, et al. FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis. The European respiratory journal 2016; 47:1481-91.

107.  Murray LA, Argentieri RL, Farrell FX, et al. Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2. The international journal of biochemistry & cell biology 2008; 40:2174-82.

108.  Kathiriya JJ, Nakra N, Nixon J, et al. Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis. Cell Death Discovery 2017; 3:17010.

109.  Nishi Y, Sano H, Kawashima T, et al. Role of galectin-3 in human pulmonary fibrosis. Allergology international: official journal of the Japanese Society of Allergology 2007; 56:57-65.

110.  Gaggini F, Laleu B, Orchard M, et al. Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. Bioorg Med Chem 2011; 19:6989-99.

111.  Maher TM. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery. European respiratory review: an official journal of the European Respiratory Society 2013; 22:148-52.

112.  Korthagen NM, van Moorsel CH, Barlo NP, et al. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respir Med 2011; 105:106-13.

113.  Tajiri M, Okamoto M, Fujimoto K, et al. Serum level of periostin can predict long-term outcome of idiopathic pulmonary fibrosis. Respiratory investigation 2015; 53:73-81.

114.  Tzouvelekis A, Herazo-Maya JD, Slade M, et al. Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology (Carlton, Vic) 2017; 22:486-93.

115.  Richards TJ, Kaminski N, Baribaud F, et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2012; 185:67-76.

116.  Rosas IO, Richards TJ, Konishi K, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS medicine 2008; 5:e93.

117.  Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 2009; 179:717-23.

118.  DePianto DJ, Chandriani S, Abbas AR, et al. Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax 2015; 70:48-56.

119.  Herazo-Maya JD, Sun J, Molyneaux PL, et al. Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study. The Lancet Respiratory Medicine 2017; 5:857-68.

120.  Spagnolo P, Sverzellati N, Rossi G, et al. Idiopathic pulmonary fibrosis: an update. Annals of medicine 2015; 47:15-27.

121.  Tzouvelekis A, Bonella F, Spagnolo P. Update on therapeutic management of idiopathic pulmonary fibrosis. Therapeutics and clinical risk management 2015; 11:359-70.

122.  Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. The New England journal of medicine 2012; 366:1968-77.

123.  King TE, Jr., Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England journal of medicine 2014; 370:2083-92.

124.  Richeldi L, Cottin V, Flaherty KR, et al. Design of the INPULSIS trials: Two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med 2014; 108:1023-30.

125.  Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. The New England journal of medicine 2014; 370:2071-82.

126.  Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet (London, England) 2011; 377:1760-9.

127.  Maher TM, Oballa E, Simpson JK, et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. The Lancet Respiratory medicine 2017; 5:946-55.

128.  Surolia R, Li FJ, Wang Z, et al. 3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs. 2017; 2:e91377.

129.  Kolb M, Jenkins G, Richeldi L. Study the past to divine the future. Confucius' wisdom doesn't work for idiopathic pulmonary fibrosis. Thorax 2016; 71:399-400.

130.  Richeldi L. How we will diagnose IPF in the future. QJM: monthly journal of the Association of Physicians 2016; 109:581-3.

131.  Naik PK, Bozyk PD, Bentley JK, et al. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. American journal of physiology Lung cellular and molecular physiology 2012; 303:L1046-56.

132.  Kusko RL, Brothers J, Liu G, et al. Comprehensive genomic profiling of the lung transcriptome in emphysema and idiopathic pulmonary fibrosis using RNA-Seq. BMC Proceedings 2012; 6:P21-P21.

133.  Guenther A, European IPFN. The European IPF Network: towards better care for a dreadful disease. The European respiratory journal 2011; 37:747-8.

134.  Yu G, Tzouvelekis A, Wang R, et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. 2017.

135.  Huang Y, Mao K, Chen X, et al. S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science (New York, NY) 2018; 359:114-9.

136.  Mjösberg J, Rao A. Lung inflammation originating in the gut. Science (New York, NY) 2018; 359:36-37.

137.  Ghebre YT, Raghu G. Idiopathic Pulmonary Fibrosis: Novel concepts of proton pump inhibitors as antifibrotic drugs. American journal of respiratory and critical care medicine 2016; 193:1345-52.

138.  Karampitsakos T, Tzilas V, Tringidou R, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Pulmonary pharmacology & therapeutics 2017; 45:1-10.

139.  Tzouvelekis A, Spagnolo P, Bonella F, et al. Patients with IPF and lung cancer: diagnosis and management. The Lancet Respiratory medicine 2017.

140.  Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. The New England journal of medicine 2016; 375:717-29.