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Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?
Respiratory Medicine xxx (2016) 1e4
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy? Steven D. Nathan a, *, Jürgen Behr b, Vincent Cottin c, Harold R. Collard d, Marius M. Hoeper e, Fernando J. Martinez f, Athol U. Wells g a
Inova Fairfax Hospital, Vienna, VA, USA Department of Internal Medicine V, University of Munich, Member of the German Center for Lung Research, Munich, Germany National Reference Center for Rare Pulmonary Diseases, Regional Center for Pulmonary Hypertension, Louis Pradel Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France d University of California San Francisco, San Francisco, CA, USA e Hannover Medical School and Hannover and German Centre for Lung Research, Hannover, Germany f Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical School, New York, NY, USA g Royal Brompton & Harefield, NHS Foundation, London, England, United Kingdom b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 June 2016 Received in revised form 28 September 2016 Accepted 2 November 2016 Available online xxx
Advances in the treatment of idiopathic interstitial pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results. © 2016 Published by Elsevier Ltd.
Keywords: Idiopathic interstitial pneumonia Interstitial lung disease Pulmonary hypertension Idiopathic pulmonary fibrosis
1. Background The idiopathic interstitial pneumonias (IIP) represent a distinct group of conditions with no known cause and are characterized by variable amounts of fibrosis and inflammation [1]. The inflammatory component is felt to be mostly responsive to corticosteroids with or without additional immunosuppressive therapy. Unfortunately, steroid-responsive disease is the exception and is generally limited to patients with cellular nonspecific interstitial pneumonitis (NSIP) and cryptogenic organizing pneumonia. The IIPs can be categorized into chronic fibrosing IP, smoking-related IP, and acute/ subacute IP. The chronic fibrosing IPs (idiopathic pulmonary fibrosis [IPF] and fibrotic NSIP) are largely irreversible and tend to be progressive over time, especially IPF [1]. Recently, two medications, pirfenidone and nintedanib, were approved in the United States and other countries for the treatment of IPF. Both agents have
* Corresponding author. E-mail address: [email protected] (S.D. Nathan).
been shown to slow the rate of progression of disease in IPF; however, whether these drugs have a role in any of the other fibrosing IIPs remains to be determined [2e5]. An additional pathophysiologic event that may complicate the chronic fibrosing IIPs is pulmonary hypertension (IIP-PH). IIP-PH is associated with increased oxygen needs, greater functional limitation, and increased mortality [6]. Most studies defining the prevalence and consequences of IIP-PH have been derived from cohorts of IPF patients. However, there are data to suggest that PH can complicate any of the other IIPs with similar consequences [7,8]. There are factors other than the extent of the fibrosis that play a role in the genesis of IIP-PH. These may result in PH that appears “disproportionate” to the extent of the parenchymal disease. It is noteworthy that in the pirfenidone (ASCEND/CAPACITY) and the nintedanib (INPULSIS) trials [2,3], patients with a diffusing capacity of the lungs for carbon monoxide (DLco) <30% of predicted were excluded; therefore, the subset of patients who might have had IPFPH were poorly represented. Although both drugs have pleiotropic effects, including decreasing fibroblast proliferation and extracellular matrix production, there are no data to suggest they may
http://dx.doi.org/10.1016/j.rmed.2016.11.003 0954-6111/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: S.D. Nathan, et al., Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?, Respiratory Medicine (2016), http://dx.doi.org/10.1016/j.rmed.2016.11.003
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S.D. Nathan et al. / Respiratory Medicine xxx (2016) 1e4
protect against the development of PH. 2. Clinical trials in IIP The brevity of this section is a testimony to the lack of such studies. Indeed, all drug development from phase 1 through phase 3 have only included IPF patients. The difficulty of recruiting into many of these prior studies has been due to their very specific inclusion and exclusion criteria, necessary to ensure a homogenous population of IPF patients. The result is that both pirfenidone and nintedanib are approved only for IPF [2e4]. This precision approach to drug development is in contrast to the pulmonary arterial hypertension (PAH) field in which the majority of studies have been inclusive of most group 1 PAH patients. By virtue of the prevalence of the respective subtypes, a consistent breakdown of patients enrolled into these studies has been about 60% with idiopathic PAH, 30% with connective-tissue disease PH (mostly scleroderma), and 10% with one of the less common group 1 PAH conditions (congenital heart disease, portopulmonary, and HIV-associated) [9]. The approach has not only boosted study enrollment but has resulted in these drugs being approved and available to treat the less common group 1 PAH conditions. Indeed, it is extremely unlikely that drug development programs would have been initiated for these other group 1 PAH subtypes. It is noteworthy that numerous PAH trials have been undertaken and successfully completed despite the very different prognoses among the various group 1 PAH entities [10]. Perhaps this approach can provide a blueprint for future studies of the IIPs as a group (or possibly all fibrosing lung conditions), despite their differing etiologies and outcomes. 3. Clinical trials in IIP-PH While most major clinical trials of treatment for PH have enrolled patients with group 1 PAH, a number of smaller prospective clinical trials have targeted patients who have PH associated with IPF and other fibrosing IIPs. The ARTEMIS-PH trial of ambrisentan for patients with IPF and PH was stopped early due to a lack of efficacy and potential harm seen in the parallel ARTEMISIPF clinical trial [11]. Interestingly, all three available endothelin receptor antagonists have been studied for their antifibrotic effects in IPF, with not only ARTEMIS-IPF but also BUILD 3 (bosentan) and MUSIC (macitentan), being negative [12,13]. In the STEP-IPF study of patients with advanced IPF (a population presumably with a high prevalence of PH), the phosphodiesterase-5 inhibitor (PDE-5i) sildenafil did not meet the primary endpoint of a 20% improvement in 6-min walk distance (6MWD), but it did show modest but statistically significant effects on health status, symptoms, single-breath DLco, and arterial oxygenation [14]. A positive impact on 6MWD was noted in the subgroup of patients with echocardiographic evidence of right ventricular dysfunction [15]. A prospective study of bosentan in patients with fibrosing lung conditions was unequivocally negative, whereas an open-label study of parenteral treprostinil in patients with pulmonary fibrosis and severe PH showed promising results with improvements in 6MWD, echocardiographic indices, and hemodynamics [8,16]. A recent review of a large registry database also attested to improvements in 6MWD associated with PH medications for patients with IIP-PH. The noted improvements were almost equivalent to those seen in patients with PAH from the same registry [7]. Therefore, while it is well recognized that PH occurs frequently in IIP and is associated with worsening of clinical symptoms and increased morbidity and mortality, there are equivocal data about the use of PAH medications in these patients. Nonetheless, there is tantalizing evidence that a positive treatment benefit might be seen
in a phenotype of these patients. None of the available PAH drugs are approved for IIP-PH; given the universal poor prognosis of disease, there remains a dire need for large, well-designed, prospective, randomized clinical trials to definitively address this question. 4. Studies in IIP-PH: building the case The two drugs available for IPF both serve to slow the rate of progression of disease and have only been studied in patients with mild to moderate disease. Patients with more advanced IPF therefore join other IIP patients in a therapeutic void. There are data suggesting that once IIP patients without IPF develop more advanced disease, their prognosis is equally dismal to those with advanced IPF [17]. The final common course in all these patients might be heralded by the onset of PH, which then drives outcomes in a similar fashion, no matter the initial cause or pattern of fibrosis. This has led to great interest in treating IIP-PH. In which patients such a treatment approach might be of benefit is unknown; specifically, what pressure threshold and how much parenchymal lung disease is permissible to warrant therapy remain unanswered questions. By grouping all IIP and PH patients together, the onus of determining a specific diagnosis is removed and broadens the base of patients who might derive benefit. In any event, categorizing patients into one of the nine categories or subcategories of IIP might be semantic, because when PH does supervene, invariably there is a component of either UIP or NSIP, no matter the initial clinical or histopathologic presentation [8]. A precise diagnosis of ILD can be difficult to obtain, as approximately 10% of patients ultimately have unclassifiable disease [18]. Such patients are a recognized subcategory that can be studied under the broad umbrella of the IIPs. It is likely that these patients also had one of the two fibrosing IIPs at inception of disease. As evidenced in earlier studies [8], we therefore support the identification of IIP-PH as a singular condition that warrants study and management. 5. Riociguat for IIP-PH: is there a case? Riociguat is an agent that acts on the nitric oxide pathway. It has a dual mode of action: it sensitizes soluble guanylate cyclase (sGC) to the body's own nitric oxide (NO), and it can also increase sGC activity in the absence of NO, causing vasorelaxation [19e23]. Positive results have been observed in clinical trials of riociguat in patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) [22,23]. PAH patients receiving riociguat in the phase 3 PATENT-1 trial exhibited a statistically significant placeboadjusted mean increase in 6MWD from baseline to week 12 of 36 m. There were also significant improvements in pulmonary vascular resistance (P < 0.001), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P < 0.001), World Health Organization (WHO) functional class (P ¼ 0.003), time to clinical worsening (P ¼ 0.005), and Borg dyspnea score (P ¼ 0.002). On the strength of those findings, riociguat was approved for the treatment of adults with PAH to improve exercise capacity and WHO functional class and to delay time to clinical worsening. The phase 3 CHEST-1 trial in patients with chronic thromboembolic pulmonary hypertension (CTEPH) demonstrated similar efficacy, with a placebo-adjusted mean increase in 6MWD of 46 m (P < 0.001) and significant improvements in secondary endpoints (pulmonary vascular resistance [PVR; P < 0.001]; NT-proBNP [P < 0.001]; WHO functional class [P ¼ 0.003]) [23]. Riociguat was also approved for the treatment of adults with either inoperable or postoperative persistent/recurrent CTEPH to improve exercise capacity and WHO functional class. Riociguat has proven effects in group 1 and group 4 PH. Will it
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S.D. Nathan et al. / Respiratory Medicine xxx (2016) 1e4
have similar salutary effects in IIP-PH patients, the subgroup with the worst prognosis among group 3 PH? There is evidence to suggest benefit from a phase 2a study of riociguat performed in patients with various types of ILD [24]. The majority of this cohort had either IPF (n ¼ 13) or NSIP (n ¼ 5). The mean age of the cohort was 60.5, and all the patients were either WHO functional class III or IV. The baseline mean 6MWD of the group was 316 m, the forced vital capacity (FVC) 67% of predicted, and the mean pulmonary artery pressure (mPAP) 40 mmHg. After 12 weeks of riociguat therapy, there were improvements in hemodynamic parameters, including an increase in cardiac output from 4.4 L/min to 5.5 L/min and a decrease in PVR from 648 to 528 dyn s cm5. These hemodynamic changes were associated with an increase in 6MWD of 25 m. Among the concerns with pulmonary vasoactive therapies in the context of parenchymal lung disease is that there might be increased ventilation perfusion mismatching and worsened oxygenation. Indeed, in this small series, the partial pressure of oxygen did decrease on average by 7 mmHg at 12 weeks. However, this appeared to be compensated for by the increase in cardiac output, as the mixed venous oxygen saturation increased slightly on therapy from 65% to 67%. Therefore, this phase 2 study in ILD provides safety information with regard to the effects of riociguat on ventilation perfusion mismatching, oxygenation, and tissue oxygen delivery [24]. Based on these data, there does appear to be a strong rationale and supportive evidence for further investigation of riociguat as a therapy for IIP-PH. Whether riociguat has effects in patients with group 3 PH beyond its vasodilatory properties is uncertain. Similarly, whether riociguat may be more or possibly less effective than any of the other pulmonary vasodilators is open to speculation. 6. IIP-PH study with riociguat: closing the case A randomized, placebo-controlled trial of riociguat targeting PH in IIPs appears to represent a viable approach to address many looming questions. Is PH a worthwhile therapeutic target in IIP? Who should be treated and at what stage of disease? Is there benefit and, most importantly, can this be harmful in patients in whom the development of PH might be an adaptive rather than a maladaptive phenomenon? It is a commonly accepted notion that the effective treatment of fibrosing lung conditions will ultimately include some form of multimodality therapy [25]. Therapies directed against fibrosis, residual inflammation, and other aspects of disease pathogenesis, including PH, makes intuitive sense. Targeting the latter has tremendous appeal given its association with functional impairment and mortality. The approval of the two antifibrotic agents has been a significant breakthrough in the management of IPF; however, these are not approved for use in other IIPs. It is also very unlikely that any other new agents for IPF, or any of the other IIPs, will be available for some years given the deliberate pace of drug development. Therefore, successful targeting of IIP-PH represents the next potential breakthrough finding and should be vigorously explored through robust clinical trials. 7. The RISE-IIP clinical trial The basis for the RISE-IIP phase 2 clinical trial was to validate the benefit of riociguat in patients with IIP-PH in a randomized, doubleblind, clinical trial. The study was the first study to include all the IIPs. Two of the more perplexing inclusion criteria addressed by the steering committee pertained to the balance of permissible fibrosis versus level of PH needed to demonstrate a treatment response. The chosen thresholds are purposefully broad (FVC 45% predicted, mPAP 25 mmHg) so as not to deny this potential treatment
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approach to patients with mild PH or more severe fibrosis and also to enable robust recruitment into the study. The primary endpoint of this study is change in 6MWD over 26 weeks, with close scrutiny of a key secondary endpoint of time to clinical worsening (either a 15% decrease in 6MWD, cardiopulmonary hospitalization, change in WHO functional class, or death) [26]. The RISE-IIP trial was discontinued in May 2016. 8. Implications for future clinical trial design Implementation of the RISE-IIP study may raise additional questions for future clinical trial designs. For example, should this all-encompassing concept be extended beyond the IIPs to include other ILD patients with complicating PH? Chronic hypersensitivity pneumonitis (CHP), another common fibrosing lung disease, can be very difficult to differentiate from IIP, and there are data to suggest CHP patients have a similar incidence and outcome once PH supervenes [27]. The ability to identify a specific etiology for a patient's progressive fibrosis might not preclude the possibility of a treatment response to PH therapy. Including these patients in future studies might diminish the need to make this differentiation as well as increase the base of patients who might benefit from this treatment approach. Perhaps this inclusive strategy can be extended beyond just those patients with complicating PH. The concept of targeting specific common pathogenic aspects of disease may in the future be extended to fibrosis itself, thereby enabling patients with any fibrosing lung condition to be studied as a group. Conflict of interest Steven D. Nathan, MD has served as a consultant and speaker for Bayer HealthCare and is principal investigator for the RISE-IIP study. His institution has received research funding from Bayer HealthCare. He is also a consultant and is on the speakers bureau for Boerhringer Ingelheim and Roche-Genentech. Jürgen Behr, MD has served as a consultant and speaker for Actelion, Bayer HealthCare, and Boehringer Ingelheim and on the steering committee for Bayer and Boehringer Ingelheim. Vincent Cottin, MD, PhD has served as a consultant and speaker for Actelion, Bayer HealthCare, Biogen Idec, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Intermune, MSD, Novartis, Pfizer, Roche and Sanofi; and has received foundation grants from Actelion, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Roche. Harold R. Collard, MD has served as an advisor or consultant for Aeolue, Alkermes, aTyr Pharmaceuticals, Bayer HealthCare, Boehringer Ingelheim, Five Prime, GBT, Genoa, Gilead, GlaxoSmithKline, MedImmune, Mesoblast, Moerae Matrix, Patara, Pfizer, PharmAkea, Promedior, Prometic, Pulmatrix, Pulmonary Fibrosis Foundation, Samumed, Takeda, UCB Celltech, Unity, Veracyte, and Xfibra. Marius M. Hoeper, MD, PhD has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, and Pfizer. Fernando Martinez, MD has received support from Forest, Janssen, GSK, Nycomed/Takeda, Amgen, Astra Zeneca, Boehringer Ingelheim, Carden Jennings, CSA Medical, Ikaria/Bellerophon, Genentech, Merck, Novartis, Pearl, Pfizer, Roche, Sunovion, Theravance, Axon, CME Incite, the California Society for Allergy and Immunology, Annenberg, Inova Health System, Integritas, InThought, Miller Medical, the National Association for Continuing Education, Paradigm, Peer Voice, UpToDate, Haymarket Communications, St John's Hospital, St Mary's Hospital, the Western Society of Allergy and Immunology, Informa, Bioscale, Unity Biotechnology, Centocor, Gilead, Promedior, Ikaria, Kadmon, Vertex, Veracyte, the American Thoracic Society, Academic CME, Falco, MedScape, Axon Communication, Genzyme, Johnson & Johnson, Spectrum Health System, University of Texas Southwestern and
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Biogen, and grants from the National Institutes of Health and National Heart, Lung and Blood Institute. Athol Wells, MD has received personal fees from Bayer, Roche and Boehringer Ingelheim. Acknowledgments The authors would like to thank Dr. Nathan for development of the manuscript. Additional writing assistance was provided by Ken Kauffman, BSc. Editorial support and formatting assistance were provided by Wendy Kopf, Adelphi Communications, LLC, New York, NY. Writing assistance, editorial support, and article processing fees were funded by Bayer HealthCare, Whippany, NJ. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. References [1] W.D. Travis, U. Costabel, D.M. Hansell, et al., An official American thoracic society/European respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 188 (6) (2013) 733e748. [2] T.E. King Jr., W.Z. Bradford, S. Castro-Bernardini, et al., ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis, 29, N. Engl. J. Med. 370 (22) (2014) 2083e2092. [3] P.W. Noble, C. Albera, W.Z. Bradford, et al., Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Lancet 377 (9779) (2011) 1760e1769. [4] L. Richeldi, R.M. du Bois, G. Raghu, et al., INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis, N. Engl. J. Med. 370 (22) (2014) 2071e2082. [5] G. Raghu, B. Rochwerg, Y. Zhang, 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. 192 (2015) e3ee19. [6] S.D. Nathan, P. Noble, R. Tuder, Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots, Am. J. Respir. Crit. Care Med. 175 (2007) 875e880. [7] M.M. Hoeper, J. Behr, M. Held, et al., Pulmonary hypertension in patients with chronic fibrosing idiopathic interstitial pneumonias, PLoS ONE 10 (12) (2015) e0141911, http://dx.doi.org/10.1371/journal.pone.0141911. [8] T.J. Corte, G.J. Keir, K. Dimopoulos, et al., Bosentan inpulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia, Am. J. Respir. Crit. Care Med. 190 (2014) 208e217. [9] M.M. Hoeper, J.S. Gibbs, The changing landscape of pulmonary arterial hypertension and implications for patient care, Eur. Respir. Rev. 23 (2014) 450e457.
, P.A. Corris, A. Frost, et al., Updated treatment algorithm of pulmonary [10] N. Galie arterial hypertension, J. Am. Coll. Cardiol. 62 (2013) D60eD72. [11] G. Raghu, J. Behr, K.K. Brown, et al., Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial, Ann. Intern Med. 158 (9) (2013) 641e649. [12] T.E. King Jr., K.K. Brown, G. Raghu, et al., BUILD-3: a randomized, controlled trial of bosentan in idiopthic pulomonary fibrosis, Am. J. Respir. Crit. Care. Med. 184 (2011) 92e99. [13] G. Raghu, Rachel Million-Rousseau, A. Morganti, L. Perchenet, J. Behr, Macitentan for the treatment of idiopathic pulmonary dibrosis: the randomised controlled MUSIC trial, MUSIC Study Group, Eur. Respir. J. 42 (2013) 1622e1632. [14] The Idiopathic Pulmonary Fibrosis Clinical Research Network, A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis, N. Engl. J. Med. 363 (7) (2010) 620e628. [15] M.K. Han, D.S. Bach, P.G. Hagan, et al., Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction, Chest 143 (6) (2013) 1699e1708. [16] R. Saggar, D. Khanna, A. Vaidya, et al., Changes in right heart haemodynamics andechocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis, Thorax 69 (2014) 123e129. [17] P.I. Latsi, R.M. du Bois, A.G. Nicholson, et al., Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends, Am. J. Respir. Crit. Care Med. 168 (2003) 531e537. [18] C.J. Ryerson, T.H. Urbania, L. Richeldi, et al., Prevalence and prognosis of unclassifiable interstitial lung disease, Eur. Respir. J. 42 (2013) 750e757. [19] R.T. Schermuly, J.P. Stasch, S.S. Pullamsetti, et al., Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension, Eur. Respir. J. 32 (4) (2008) 881e891. [20] F. Grimminger, G. Weimann, R. Frey, et al., First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension, Eur. Respir. J. 33 (4) (2009) 785e792. [21] H.A. Ghofrani, F. Grimminger, Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy, Eur. Respir. Rev. 18 (111) (2009) 35e41. [22] H.A. Ghofrani, N. Galie, F. Grimminger, et al., Riociguat for the treatment of pulmonary arterial hypertension, N. Engl. J. Med. 369 (4) (2013) 330e340. [23] H.-A. Ghofrani, A.M. D'Armini, F. Grimminger, et al., Riociguat for the treatment of chronic thromboembolic pulmonary hypertension, N. Engl. J. Med. 369 (2013) 319e329. [24] M.M. Hoeper, M. Halank, H. Wilkens, et al., Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial, Eur. Respir. J. 41 (4) (2013) 853e860. [25] W.A. Wuyts, K.M. Antoniou, K. Borensztajn, et al., Combination therapy: the future of management for idiopathic pulmonary fibrosis? Lancet Respir. Med. 2 (2014) 933e942. [26] Bayer HealthCare. In: Clinicaltrials.gov. Bethesda (MD): National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT02138825? term¼RISE-IIP&rank¼1. NCT02138825. [27] R.K.F. Oliveira, C.A.C. Pereira, R.P. Ramos, et al., A haemodynamic study of pulmonary hypertension in chronic hypersensitivity pneumonitis, Eur. Respir. J. 44 (2014) 415e424.
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Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy? Steven D. Nathan a, *, Jürgen Behr b, Vincent Cottin c, Harold R. Collard d, Marius M. Hoeper e, Fernando J. Martinez f, Athol U. Wells g a
Inova Fairfax Hospital, Vienna, VA, USA Department of Internal Medicine V, University of Munich, Member of the German Center for Lung Research, Munich, Germany National Reference Center for Rare Pulmonary Diseases, Regional Center for Pulmonary Hypertension, Louis Pradel Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France d University of California San Francisco, San Francisco, CA, USA e Hannover Medical School and Hannover and German Centre for Lung Research, Hannover, Germany f Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical School, New York, NY, USA g Royal Brompton & Harefield, NHS Foundation, London, England, United Kingdom b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 June 2016 Received in revised form 28 September 2016 Accepted 2 November 2016 Available online xxx
Advances in the treatment of idiopathic interstitial pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results. © 2016 Published by Elsevier Ltd.
Keywords: Idiopathic interstitial pneumonia Interstitial lung disease Pulmonary hypertension Idiopathic pulmonary fibrosis
1. Background The idiopathic interstitial pneumonias (IIP) represent a distinct group of conditions with no known cause and are characterized by variable amounts of fibrosis and inflammation [1]. The inflammatory component is felt to be mostly responsive to corticosteroids with or without additional immunosuppressive therapy. Unfortunately, steroid-responsive disease is the exception and is generally limited to patients with cellular nonspecific interstitial pneumonitis (NSIP) and cryptogenic organizing pneumonia. The IIPs can be categorized into chronic fibrosing IP, smoking-related IP, and acute/ subacute IP. The chronic fibrosing IPs (idiopathic pulmonary fibrosis [IPF] and fibrotic NSIP) are largely irreversible and tend to be progressive over time, especially IPF [1]. Recently, two medications, pirfenidone and nintedanib, were approved in the United States and other countries for the treatment of IPF. Both agents have
* Corresponding author. E-mail address: [email protected] (S.D. Nathan).
been shown to slow the rate of progression of disease in IPF; however, whether these drugs have a role in any of the other fibrosing IIPs remains to be determined [2e5]. An additional pathophysiologic event that may complicate the chronic fibrosing IIPs is pulmonary hypertension (IIP-PH). IIP-PH is associated with increased oxygen needs, greater functional limitation, and increased mortality [6]. Most studies defining the prevalence and consequences of IIP-PH have been derived from cohorts of IPF patients. However, there are data to suggest that PH can complicate any of the other IIPs with similar consequences [7,8]. There are factors other than the extent of the fibrosis that play a role in the genesis of IIP-PH. These may result in PH that appears “disproportionate” to the extent of the parenchymal disease. It is noteworthy that in the pirfenidone (ASCEND/CAPACITY) and the nintedanib (INPULSIS) trials [2,3], patients with a diffusing capacity of the lungs for carbon monoxide (DLco) <30% of predicted were excluded; therefore, the subset of patients who might have had IPFPH were poorly represented. Although both drugs have pleiotropic effects, including decreasing fibroblast proliferation and extracellular matrix production, there are no data to suggest they may
http://dx.doi.org/10.1016/j.rmed.2016.11.003 0954-6111/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: S.D. Nathan, et al., Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?, Respiratory Medicine (2016), http://dx.doi.org/10.1016/j.rmed.2016.11.003
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protect against the development of PH. 2. Clinical trials in IIP The brevity of this section is a testimony to the lack of such studies. Indeed, all drug development from phase 1 through phase 3 have only included IPF patients. The difficulty of recruiting into many of these prior studies has been due to their very specific inclusion and exclusion criteria, necessary to ensure a homogenous population of IPF patients. The result is that both pirfenidone and nintedanib are approved only for IPF [2e4]. This precision approach to drug development is in contrast to the pulmonary arterial hypertension (PAH) field in which the majority of studies have been inclusive of most group 1 PAH patients. By virtue of the prevalence of the respective subtypes, a consistent breakdown of patients enrolled into these studies has been about 60% with idiopathic PAH, 30% with connective-tissue disease PH (mostly scleroderma), and 10% with one of the less common group 1 PAH conditions (congenital heart disease, portopulmonary, and HIV-associated) [9]. The approach has not only boosted study enrollment but has resulted in these drugs being approved and available to treat the less common group 1 PAH conditions. Indeed, it is extremely unlikely that drug development programs would have been initiated for these other group 1 PAH subtypes. It is noteworthy that numerous PAH trials have been undertaken and successfully completed despite the very different prognoses among the various group 1 PAH entities [10]. Perhaps this approach can provide a blueprint for future studies of the IIPs as a group (or possibly all fibrosing lung conditions), despite their differing etiologies and outcomes. 3. Clinical trials in IIP-PH While most major clinical trials of treatment for PH have enrolled patients with group 1 PAH, a number of smaller prospective clinical trials have targeted patients who have PH associated with IPF and other fibrosing IIPs. The ARTEMIS-PH trial of ambrisentan for patients with IPF and PH was stopped early due to a lack of efficacy and potential harm seen in the parallel ARTEMISIPF clinical trial [11]. Interestingly, all three available endothelin receptor antagonists have been studied for their antifibrotic effects in IPF, with not only ARTEMIS-IPF but also BUILD 3 (bosentan) and MUSIC (macitentan), being negative [12,13]. In the STEP-IPF study of patients with advanced IPF (a population presumably with a high prevalence of PH), the phosphodiesterase-5 inhibitor (PDE-5i) sildenafil did not meet the primary endpoint of a 20% improvement in 6-min walk distance (6MWD), but it did show modest but statistically significant effects on health status, symptoms, single-breath DLco, and arterial oxygenation [14]. A positive impact on 6MWD was noted in the subgroup of patients with echocardiographic evidence of right ventricular dysfunction [15]. A prospective study of bosentan in patients with fibrosing lung conditions was unequivocally negative, whereas an open-label study of parenteral treprostinil in patients with pulmonary fibrosis and severe PH showed promising results with improvements in 6MWD, echocardiographic indices, and hemodynamics [8,16]. A recent review of a large registry database also attested to improvements in 6MWD associated with PH medications for patients with IIP-PH. The noted improvements were almost equivalent to those seen in patients with PAH from the same registry [7]. Therefore, while it is well recognized that PH occurs frequently in IIP and is associated with worsening of clinical symptoms and increased morbidity and mortality, there are equivocal data about the use of PAH medications in these patients. Nonetheless, there is tantalizing evidence that a positive treatment benefit might be seen
in a phenotype of these patients. None of the available PAH drugs are approved for IIP-PH; given the universal poor prognosis of disease, there remains a dire need for large, well-designed, prospective, randomized clinical trials to definitively address this question. 4. Studies in IIP-PH: building the case The two drugs available for IPF both serve to slow the rate of progression of disease and have only been studied in patients with mild to moderate disease. Patients with more advanced IPF therefore join other IIP patients in a therapeutic void. There are data suggesting that once IIP patients without IPF develop more advanced disease, their prognosis is equally dismal to those with advanced IPF [17]. The final common course in all these patients might be heralded by the onset of PH, which then drives outcomes in a similar fashion, no matter the initial cause or pattern of fibrosis. This has led to great interest in treating IIP-PH. In which patients such a treatment approach might be of benefit is unknown; specifically, what pressure threshold and how much parenchymal lung disease is permissible to warrant therapy remain unanswered questions. By grouping all IIP and PH patients together, the onus of determining a specific diagnosis is removed and broadens the base of patients who might derive benefit. In any event, categorizing patients into one of the nine categories or subcategories of IIP might be semantic, because when PH does supervene, invariably there is a component of either UIP or NSIP, no matter the initial clinical or histopathologic presentation [8]. A precise diagnosis of ILD can be difficult to obtain, as approximately 10% of patients ultimately have unclassifiable disease [18]. Such patients are a recognized subcategory that can be studied under the broad umbrella of the IIPs. It is likely that these patients also had one of the two fibrosing IIPs at inception of disease. As evidenced in earlier studies [8], we therefore support the identification of IIP-PH as a singular condition that warrants study and management. 5. Riociguat for IIP-PH: is there a case? Riociguat is an agent that acts on the nitric oxide pathway. It has a dual mode of action: it sensitizes soluble guanylate cyclase (sGC) to the body's own nitric oxide (NO), and it can also increase sGC activity in the absence of NO, causing vasorelaxation [19e23]. Positive results have been observed in clinical trials of riociguat in patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) [22,23]. PAH patients receiving riociguat in the phase 3 PATENT-1 trial exhibited a statistically significant placeboadjusted mean increase in 6MWD from baseline to week 12 of 36 m. There were also significant improvements in pulmonary vascular resistance (P < 0.001), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P < 0.001), World Health Organization (WHO) functional class (P ¼ 0.003), time to clinical worsening (P ¼ 0.005), and Borg dyspnea score (P ¼ 0.002). On the strength of those findings, riociguat was approved for the treatment of adults with PAH to improve exercise capacity and WHO functional class and to delay time to clinical worsening. The phase 3 CHEST-1 trial in patients with chronic thromboembolic pulmonary hypertension (CTEPH) demonstrated similar efficacy, with a placebo-adjusted mean increase in 6MWD of 46 m (P < 0.001) and significant improvements in secondary endpoints (pulmonary vascular resistance [PVR; P < 0.001]; NT-proBNP [P < 0.001]; WHO functional class [P ¼ 0.003]) [23]. Riociguat was also approved for the treatment of adults with either inoperable or postoperative persistent/recurrent CTEPH to improve exercise capacity and WHO functional class. Riociguat has proven effects in group 1 and group 4 PH. Will it
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have similar salutary effects in IIP-PH patients, the subgroup with the worst prognosis among group 3 PH? There is evidence to suggest benefit from a phase 2a study of riociguat performed in patients with various types of ILD [24]. The majority of this cohort had either IPF (n ¼ 13) or NSIP (n ¼ 5). The mean age of the cohort was 60.5, and all the patients were either WHO functional class III or IV. The baseline mean 6MWD of the group was 316 m, the forced vital capacity (FVC) 67% of predicted, and the mean pulmonary artery pressure (mPAP) 40 mmHg. After 12 weeks of riociguat therapy, there were improvements in hemodynamic parameters, including an increase in cardiac output from 4.4 L/min to 5.5 L/min and a decrease in PVR from 648 to 528 dyn s cm5. These hemodynamic changes were associated with an increase in 6MWD of 25 m. Among the concerns with pulmonary vasoactive therapies in the context of parenchymal lung disease is that there might be increased ventilation perfusion mismatching and worsened oxygenation. Indeed, in this small series, the partial pressure of oxygen did decrease on average by 7 mmHg at 12 weeks. However, this appeared to be compensated for by the increase in cardiac output, as the mixed venous oxygen saturation increased slightly on therapy from 65% to 67%. Therefore, this phase 2 study in ILD provides safety information with regard to the effects of riociguat on ventilation perfusion mismatching, oxygenation, and tissue oxygen delivery [24]. Based on these data, there does appear to be a strong rationale and supportive evidence for further investigation of riociguat as a therapy for IIP-PH. Whether riociguat has effects in patients with group 3 PH beyond its vasodilatory properties is uncertain. Similarly, whether riociguat may be more or possibly less effective than any of the other pulmonary vasodilators is open to speculation. 6. IIP-PH study with riociguat: closing the case A randomized, placebo-controlled trial of riociguat targeting PH in IIPs appears to represent a viable approach to address many looming questions. Is PH a worthwhile therapeutic target in IIP? Who should be treated and at what stage of disease? Is there benefit and, most importantly, can this be harmful in patients in whom the development of PH might be an adaptive rather than a maladaptive phenomenon? It is a commonly accepted notion that the effective treatment of fibrosing lung conditions will ultimately include some form of multimodality therapy [25]. Therapies directed against fibrosis, residual inflammation, and other aspects of disease pathogenesis, including PH, makes intuitive sense. Targeting the latter has tremendous appeal given its association with functional impairment and mortality. The approval of the two antifibrotic agents has been a significant breakthrough in the management of IPF; however, these are not approved for use in other IIPs. It is also very unlikely that any other new agents for IPF, or any of the other IIPs, will be available for some years given the deliberate pace of drug development. Therefore, successful targeting of IIP-PH represents the next potential breakthrough finding and should be vigorously explored through robust clinical trials. 7. The RISE-IIP clinical trial The basis for the RISE-IIP phase 2 clinical trial was to validate the benefit of riociguat in patients with IIP-PH in a randomized, doubleblind, clinical trial. The study was the first study to include all the IIPs. Two of the more perplexing inclusion criteria addressed by the steering committee pertained to the balance of permissible fibrosis versus level of PH needed to demonstrate a treatment response. The chosen thresholds are purposefully broad (FVC 45% predicted, mPAP 25 mmHg) so as not to deny this potential treatment
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approach to patients with mild PH or more severe fibrosis and also to enable robust recruitment into the study. The primary endpoint of this study is change in 6MWD over 26 weeks, with close scrutiny of a key secondary endpoint of time to clinical worsening (either a 15% decrease in 6MWD, cardiopulmonary hospitalization, change in WHO functional class, or death) [26]. The RISE-IIP trial was discontinued in May 2016. 8. Implications for future clinical trial design Implementation of the RISE-IIP study may raise additional questions for future clinical trial designs. For example, should this all-encompassing concept be extended beyond the IIPs to include other ILD patients with complicating PH? Chronic hypersensitivity pneumonitis (CHP), another common fibrosing lung disease, can be very difficult to differentiate from IIP, and there are data to suggest CHP patients have a similar incidence and outcome once PH supervenes [27]. The ability to identify a specific etiology for a patient's progressive fibrosis might not preclude the possibility of a treatment response to PH therapy. Including these patients in future studies might diminish the need to make this differentiation as well as increase the base of patients who might benefit from this treatment approach. Perhaps this inclusive strategy can be extended beyond just those patients with complicating PH. The concept of targeting specific common pathogenic aspects of disease may in the future be extended to fibrosis itself, thereby enabling patients with any fibrosing lung condition to be studied as a group. Conflict of interest Steven D. Nathan, MD has served as a consultant and speaker for Bayer HealthCare and is principal investigator for the RISE-IIP study. His institution has received research funding from Bayer HealthCare. He is also a consultant and is on the speakers bureau for Boerhringer Ingelheim and Roche-Genentech. Jürgen Behr, MD has served as a consultant and speaker for Actelion, Bayer HealthCare, and Boehringer Ingelheim and on the steering committee for Bayer and Boehringer Ingelheim. Vincent Cottin, MD, PhD has served as a consultant and speaker for Actelion, Bayer HealthCare, Biogen Idec, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Intermune, MSD, Novartis, Pfizer, Roche and Sanofi; and has received foundation grants from Actelion, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Roche. Harold R. Collard, MD has served as an advisor or consultant for Aeolue, Alkermes, aTyr Pharmaceuticals, Bayer HealthCare, Boehringer Ingelheim, Five Prime, GBT, Genoa, Gilead, GlaxoSmithKline, MedImmune, Mesoblast, Moerae Matrix, Patara, Pfizer, PharmAkea, Promedior, Prometic, Pulmatrix, Pulmonary Fibrosis Foundation, Samumed, Takeda, UCB Celltech, Unity, Veracyte, and Xfibra. Marius M. Hoeper, MD, PhD has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, and Pfizer. Fernando Martinez, MD has received support from Forest, Janssen, GSK, Nycomed/Takeda, Amgen, Astra Zeneca, Boehringer Ingelheim, Carden Jennings, CSA Medical, Ikaria/Bellerophon, Genentech, Merck, Novartis, Pearl, Pfizer, Roche, Sunovion, Theravance, Axon, CME Incite, the California Society for Allergy and Immunology, Annenberg, Inova Health System, Integritas, InThought, Miller Medical, the National Association for Continuing Education, Paradigm, Peer Voice, UpToDate, Haymarket Communications, St John's Hospital, St Mary's Hospital, the Western Society of Allergy and Immunology, Informa, Bioscale, Unity Biotechnology, Centocor, Gilead, Promedior, Ikaria, Kadmon, Vertex, Veracyte, the American Thoracic Society, Academic CME, Falco, MedScape, Axon Communication, Genzyme, Johnson & Johnson, Spectrum Health System, University of Texas Southwestern and
Please cite this article in press as: S.D. Nathan, et al., Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?, Respiratory Medicine (2016), http://dx.doi.org/10.1016/j.rmed.2016.11.003
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Biogen, and grants from the National Institutes of Health and National Heart, Lung and Blood Institute. Athol Wells, MD has received personal fees from Bayer, Roche and Boehringer Ingelheim. Acknowledgments The authors would like to thank Dr. Nathan for development of the manuscript. Additional writing assistance was provided by Ken Kauffman, BSc. Editorial support and formatting assistance were provided by Wendy Kopf, Adelphi Communications, LLC, New York, NY. Writing assistance, editorial support, and article processing fees were funded by Bayer HealthCare, Whippany, NJ. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. References [1] W.D. Travis, U. Costabel, D.M. Hansell, et al., An official American thoracic society/European respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 188 (6) (2013) 733e748. [2] T.E. King Jr., W.Z. Bradford, S. Castro-Bernardini, et al., ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis, 29, N. Engl. J. Med. 370 (22) (2014) 2083e2092. [3] P.W. Noble, C. Albera, W.Z. Bradford, et al., Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Lancet 377 (9779) (2011) 1760e1769. [4] L. Richeldi, R.M. du Bois, G. Raghu, et al., INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis, N. Engl. J. Med. 370 (22) (2014) 2071e2082. [5] G. Raghu, B. Rochwerg, Y. Zhang, 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. 192 (2015) e3ee19. [6] S.D. Nathan, P. Noble, R. Tuder, Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots, Am. J. Respir. Crit. Care Med. 175 (2007) 875e880. [7] M.M. Hoeper, J. Behr, M. Held, et al., Pulmonary hypertension in patients with chronic fibrosing idiopathic interstitial pneumonias, PLoS ONE 10 (12) (2015) e0141911, http://dx.doi.org/10.1371/journal.pone.0141911. [8] T.J. Corte, G.J. Keir, K. Dimopoulos, et al., Bosentan inpulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia, Am. J. Respir. Crit. Care Med. 190 (2014) 208e217. [9] M.M. Hoeper, J.S. Gibbs, The changing landscape of pulmonary arterial hypertension and implications for patient care, Eur. Respir. Rev. 23 (2014) 450e457.
, P.A. Corris, A. Frost, et al., Updated treatment algorithm of pulmonary [10] N. Galie arterial hypertension, J. Am. Coll. Cardiol. 62 (2013) D60eD72. [11] G. Raghu, J. Behr, K.K. Brown, et al., Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial, Ann. Intern Med. 158 (9) (2013) 641e649. [12] T.E. King Jr., K.K. Brown, G. Raghu, et al., BUILD-3: a randomized, controlled trial of bosentan in idiopthic pulomonary fibrosis, Am. J. Respir. Crit. Care. Med. 184 (2011) 92e99. [13] G. Raghu, Rachel Million-Rousseau, A. Morganti, L. Perchenet, J. Behr, Macitentan for the treatment of idiopathic pulmonary dibrosis: the randomised controlled MUSIC trial, MUSIC Study Group, Eur. Respir. J. 42 (2013) 1622e1632. [14] The Idiopathic Pulmonary Fibrosis Clinical Research Network, A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis, N. Engl. J. Med. 363 (7) (2010) 620e628. [15] M.K. Han, D.S. Bach, P.G. Hagan, et al., Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction, Chest 143 (6) (2013) 1699e1708. [16] R. Saggar, D. Khanna, A. Vaidya, et al., Changes in right heart haemodynamics andechocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis, Thorax 69 (2014) 123e129. [17] P.I. Latsi, R.M. du Bois, A.G. Nicholson, et al., Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends, Am. J. Respir. Crit. Care Med. 168 (2003) 531e537. [18] C.J. Ryerson, T.H. Urbania, L. Richeldi, et al., Prevalence and prognosis of unclassifiable interstitial lung disease, Eur. Respir. J. 42 (2013) 750e757. [19] R.T. Schermuly, J.P. Stasch, S.S. Pullamsetti, et al., Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension, Eur. Respir. J. 32 (4) (2008) 881e891. [20] F. Grimminger, G. Weimann, R. Frey, et al., First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension, Eur. Respir. J. 33 (4) (2009) 785e792. [21] H.A. Ghofrani, F. Grimminger, Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy, Eur. Respir. Rev. 18 (111) (2009) 35e41. [22] H.A. Ghofrani, N. Galie, F. Grimminger, et al., Riociguat for the treatment of pulmonary arterial hypertension, N. Engl. J. Med. 369 (4) (2013) 330e340. [23] H.-A. Ghofrani, A.M. D'Armini, F. Grimminger, et al., Riociguat for the treatment of chronic thromboembolic pulmonary hypertension, N. Engl. J. Med. 369 (2013) 319e329. [24] M.M. Hoeper, M. Halank, H. Wilkens, et al., Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial, Eur. Respir. J. 41 (4) (2013) 853e860. [25] W.A. Wuyts, K.M. Antoniou, K. Borensztajn, et al., Combination therapy: the future of management for idiopathic pulmonary fibrosis? Lancet Respir. Med. 2 (2014) 933e942. [26] Bayer HealthCare. In: Clinicaltrials.gov. Bethesda (MD): National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT02138825? term¼RISE-IIP&rank¼1. NCT02138825. [27] R.K.F. Oliveira, C.A.C. Pereira, R.P. Ramos, et al., A haemodynamic study of pulmonary hypertension in chronic hypersensitivity pneumonitis, Eur. Respir. J. 44 (2014) 415e424.
Please cite this article in press as: S.D. Nathan, et al., Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?, Respiratory Medicine (2016), http://dx.doi.org/10.1016/j.rmed.2016.11.003