Phenotypes and treatment strategies for pulmonary hypertension in interstitial lung disease

A PH Group III webinar

The Pulmonary Hypertension Group III Workstream was founded in March 2021 and serves as a collaborative platform between industry, academic, regulatory, and patient representatives. Its aim is to strengthen our community’s understanding of pulmonary hypertension due to lung diseases.

Webinar summary

The recent PVRI webinar brought together global experts to address the challenges of pulmonary hypertension (PH) in interstitial lung disease (ILD). The session was moderated by Steve Nathan (Inova Fairfax Hospital, USA) and Sylvia Nikkho (Bayer AG, Clinical Development, Berlin), featuring insights from Lucilla Piccari (Hospital del Mar, Barcelona), Oksana Shlobin (Inova Fairfax Hospital), and John Wort (Royal Brompton Hospital, London).

Steve Nathan opened by giving a brief overview of the PH-Group 3 workstream of PVRI’s Innovative Drug Development Initiative (IDDI), highlighting their five articles published in the PVRI journal Pulmonary Circulation, which formed the scientific background of this webinar.^1-5

Steve outlined that the likelihood of developing PH increases as ILD progresses, with prevalence rates reaching up to 86% by the time of lung transplantation. The prognosis is poor in PH-Group 3 patients, having the worst prognosis in comparison to the other PH groups and IPF-PH has the worst prognosis in comparison to non-IPF-PH, CPFE and COPD-PH.⁶

In her presentation on phenotypes, Lucilla Piccari described distinct PH-ILD variants, including Combined Pulmonary Fibrosis and Emphysema (CPFE), Connective Tissue Disease (CTD)-associated PH, Post-tuberculosis PH, and Lymphangioleiomyomatosis with PH, emphasising the need for tailored management approaches based on specific disease characteristics.

The diagnostic challenges were addressed by Oksana Shlobin, who focused on distinguishing Group 1 from Group 3 PH. Oksana addressed the difficulty of distinguishing Group 1 (PAH) from Group 3 (PH associated with lung diseases) patients, particularly when ILD is mild. She underscored the value of advanced imaging, including high-resolution CT and Artificial Intelligence (AI) algorithms, to detect subtle fibrosis given recent registry findings that these patients represent a phenotype different from patients without any ILD. Early identification of these features using imaging methods, she argued, is critical for prognosis and therapeutic decisions. Incorporating imaging into patient selection for clinical trials may help avoid negative outcomes and learn more about patients with mild ILD.

John Wort elaborated on diagnostic tools, discussing the role of right heart catheterisation as the gold standard while highlighting the increasing importance of non-invasive methods, including biomarkers such as N-terminal pro b-type Natriuretic Peptide (NT-pro BNP) or B-type Natriuretic Peptide (BNP) and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO), exercise testing, advanced imaging with AI-enhanced detection, and echocardiography for monitoring.

Furthermore, John discussed the critical timing of intervention, presenting data from the INCREASE study as an example, which showed that patients with both mild and severe PH benefited from inhaled treprostinil. ^{7, 8}  He emphasised the importance of early intervention to preserve right ventricular function and improve clinical outcomes.

Steve concluded by reimagining clinical trial design, and emphasising that successful trials require appropriate patient phenotyping, optimal drug dosing, relevant endpoints, and pragmatic recruitment strategies.

Looking to the future, Steve proposed shifting the focus toward studies targeting the pulmonary vasculature rather than inclusion criteria based on rigid PH definitions. The panel discussed the potential of combining antifibrotics with PH therapies, the importance of refining patient stratification, and the need for validated biomarkers within adaptive research strategies. Sylvia Nikkho reinforced the need for collaborative, adaptive research to refine patient stratification and validate biomarkers.

Key Takeaways:

• Early Diagnosis Matters: Advanced imaging and phenotyping are essential to identify high-risk patients for close monitoring.
• Timely Intervention: Data supports that outcomes can be improved even in mild PH-ILD with early implementation of proven therapy
• Combination Therapies: Pairing antifibrotics with proven vasodilator therapy may offer synergistic benefits. This is an area warranting further study.
• Research Evolution: Trials should prioritize functional patient-centric endpoints, e.g., exercise capacity, quality of life, need for hospitalization and mortality over hemodynamic thresholds alone especially in late-stage studies.

The session closed with a consensus on the urgency of multidisciplinary collaboration within the PVRI to translate emerging insights into improved care for PH-ILD patients. 

For ongoing updates, stay tuned to PVRI’s newsletters and future webinars.

References:

1. Nikkho SM, Richter MJ, Shen E, et al. Clinical significance of pulmonary hypertension in interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's innovative drug development initiative—Group 3 pulmonary hypertension. Pulmonary Circulation 2022; 12: e12127. DOI: https://doi.org/10.1002/pul2.12127.

2. Shlobin OA, Shen E, Wort SJ, et al. Pulmonary hypertension in the setting of interstitial lung disease: Approach to management and treatment. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension. Pulm Circ 2024; 14: e12310. 2024/01/11. DOI: 10.1002/pul2.12310.

3. Vitulo P, Piccari L, Wort SJ, et al. Screening and diagnosis of pulmonary hypertension associated with chronic lung disease (PH-CLD): A consensus statement from the pulmonary vascular research institute's innovative drug development initiative—group 3 pulmonary hypertension. Pulmonary Circulation 2024; 14: e70005. DOI: https://doi.org/10.1002/pul2.70005.

4. Nathan SD, Fernandes P, Psotka M, et al. Pulmonary hypertension in interstitial lung disease: Clinical trial design and endpoints: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension. Pulm Circ 2022; 12: e12178. 2022/12/30. DOI: 10.1002/pul2.12178.

5. Piccari L, Allwood B, Antoniou K, et al. Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative - Group 3 Pulmonary Hypertension. Pulmonary Circulation 2023; 13: e12213. DOI: https://doi.org/10.1002/pul2.12213.

6. Chebib N, Mornex JF, Traclet J, et al. Pulmonary hypertension in chronic lung diseases: comparison to other pulmonary hypertension groups. Pulm Circ 2018; 8: 2045894018775056. 2018/04/20. DOI: 10.1177/2045894018775056.

7. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease. New England Journal of Medicine 2021; 384: 325-334. DOI: 10.1056/NEJMoa2008470.

8. Weatherald J, Nathan SD, El-Kersh K, et al. Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study. BMJ Open Respir Res 2024; 11 2024/03/23. DOI: 10.1136/bmjresp-2023-002116.