Unmet need in pulmonary hypertension-associated interstitial lung disease (PH-ILD): a clinician survey of real-world management of PH-ILD in Europe

Background With no approved therapies for pulmonary hypertension (PH) associated with interstitial lung disease (PH-ILD) in Europe, we surveyed clinician perceptions on PH-ILD management and unmet need to understand current real-world practices. Methods An online clinician survey on PH-ILD management was conducted in France, Germany, Italy, Spain and the UK. Results 55 clinicians (78% pulmonologists), each managing a median 20 PH-ILD patients (interquartile range (IQR) 10–50), participated. Upon PH suspicion, clinicians referred a median 50% (IQR 20–73%) of patients for echocardiography alone and 35% (IQR 20–78%) for echocardiography, followed by right heart catheterisation. Upon diagnosis, a median 20% (IQR 9–30%), 40% (IQR 20–50%) and 35% (IQR 20–55%) of patients fell under the pulmonary arterial pressure ranges of 21–24 mmHg, 25–34 mmHg and >35 mmHg, respectively. 50% of patients received off-label treatment for their PH and, of those, off-label phosphodiesterase-5 inhibitor (PDE-5i), endothelin receptor antagonist (ERA) and prostacyclin analogues were prescribed first-line by 78%, 9% and 7% of clinicians, respectively. Upon PDE-5i non-response, 35% of clinicians proceed with an ERA, 35% with no further therapy. 55% of clinicians used dual-therapy. Yearly median inpatient admissions and emergency visits were 2.0 (IQR 1.3–2.9) and 1.5 (IQR 1.0–2.0), respectively (n=31 responses). Most clinicians (69%) highlighted lack of efficacy or evidence for current therapies as a key gap in PH-ILD management. Conclusions This study gives insight into real-world European PH-ILD diagnosis and management. With significant use of off-label treatment, there is a large unmet need due to lack of approved therapies. Despite updated guidelines, more evidence is needed to standardise PH-ILD management.


Diagnostic pathway
In this section we would like to characterise the methods/rationale that were

Treatment pathway
In this section we would like to understand how PH-ILD patients are treated at your centre 28.How are your PH-ILD patients currently treated for their underlying ILD? Please select all therapies that apply:

Disease management and follow-up
In this section we would like to understand the methods used at your clinic for the follow up for PH-ILD patients

How frequently do you see your PH-ILD patients in a year?
1-2 times per year % of PH-ILD patients 3-4 times per year % of PH-ILD patients

ForFrequency
the following questions, please respond based on your experience in managing PH-ILD patients (confirmed interstitial lung disease and PH confirmed through right heart catheterisation (RHC) or those with a high probability of PH from echocardiography) 11.Approximately, what is the gender distribution of your PH-ILD patients?Male % of PH-ILD patients Female % of PH-ILD patients Total: % of PH-ILD patients 12. Approximately, what is the age distribution of your PH-ILD patients?≥60 years % of PH-ILD patients <60 years % of PH-ILD patients Total: % of PH-ILD patients 13.Approximately, what is the percentage distribution of your PH-ILD patients based on time since ILD diagnosis?≥2 years diagnosed with ILD % of PH-ILD patients <2 years diagnosed with ILD % of PH-ILD patients Total: % of PH-ILD patients Please state if not known due to specialisation: 14.Approximately, what is the percentage distribution of your PH-ILD patients based on time since PH diagnosis?not known due to specialisation: 15.Approximately, what is the distribution of your PH-ILD patients based on ILD type/cause?Idiopathic pulmonary fibrosis (IPF) % of PH-ILD patients Non-specific interstitial pneumonia (NSIP) % of PH-ILD patients Scleroderma associated connective tissue disease (CTD-ILD) % of PH-, what is the distribution of your PH-ILD patient based on WHO functional class at diagnosis of PH? WHO functional class 1-2 % of PH-ILD patients WHO functional class 3-4 % of PH-ILD patients Total: % of PH-ILD patients State if not known due to specialisation: 17.Approximately, what is the distribution of your PH-ILD patient based on predicted forced vital capacity (FVC) at diagnosis of PH? <50% forced vital capacity % of PH-ILD patients 50-70% forced vital capacity % of PH-ILD patients >70% forced vital capacity % of PH-ILD patients Total: % of PH-ILD patients State if not known due to specialisation: 18.On average, with what frequency are the following symptoms and signs seen in your PH-ILD patients?[The choices are: High (observed in >50% of patients), Medium (Observed in 25-50% of patients) and Low (observed in <25% of patients)]

.First
When are the above combinational therapies used to manage PH in PH-ILD patients?44.Based on your experience, what proportion (%) of your PH-ILD patients are receiving supplemental oxygen therapy?45.Based on your experience, are triple therapies also used to treat PH in your PH-ILD patients?If so, please elaborate on what combinations are used and when: 46.According to your experience, what are the primary PH treatment choices for PH-ILD patients?If the patient does not respond, what are the secondary treatment options?Please indicate an initial therapy and then a potential alternative therapy, if no other therapy would be given after non-response, leave "secondary therapy" blank on your experience, how relevant are the following factors when considering treatments for PH in PH-ILD patients?

58.
In your opinion, what are the key areas and actions needed to improve the disease management and follow-up in PH-ILD patients?59.Which of the following outcomes do you regularly capture/record in your PH-ILD patients?(Please select up to 6 options) ☐ Cardiopulmonary hospitalisation ☐ Diffusing capacity for carbon monoxide ☐ Echocardiographic measurements ☐ Episodes of acute exacerbations of ILD ☐ Exercise capacity (e.g., 6MWT, CPET) ☐ Haemodynamic parameters (i.e., mPAP, PVR) ☐ Number of lung disease exacerbations ☐ Oxygen saturation levels ☐ Pulmonary function (i.e., FVC) ☐ Quality of life (Patient Reported Outcomes) ☐ Serological Biomarkers (BNP, NT-ProBNP) ☐ Other (please specify): 60.Based on your experience, which are the key prognostic factors that could predict a positive outcome for PH treatment in PH-ILD patients?(please select up to 5 options) ☐ Absence of exacerbation of ILD ☐ Absence of right heart failure ☐ Age ☐ Baseline lung function ☐ Disease stage at diagnosis (WHO function classification) ☐ ILD type ☐ PH severity at diagnosis ☐ Other (please specify): 61.Based on your experience, please elaborate on how age is a key prognostic factor for positive response to PH treatment in PH-ILD patients 62.Based on your experience, please elaborate on how disease stage is a key prognostic factor for positive response to PH treatment in PH-ILD patients 63.Based on your experience, please elaborate on how ILD type is a key prognostic factor for positive response to PH treatment in PH-ILD patients 64.Based on your experience, please elaborate on how baseline lung function is a key prognostic factor for positive response to PH treatment in PH-ILD patients 65.Based on your experience, please elaborate on how PH severity at diagnosis is a key prognostic factor for positive response to PH treatment in PH-ILD patients 66.Based on your experience, please elaborate on how exacerbation of ILD is a key prognostic factor for positive response to PH treatment in PH-ILD patients 67.Based on your experience, please elaborate on how presence/absence of right heart failure is a key prognostic factor for positive response to PH treatment in PH-ILD patients 68.Based on your experience, please elaborate on how this "other" key factor predicts for a positive response to PH therapy in PH-ILD patients 69.According to your experience, which key outcomes/factors do you consider for PH treatment continuation in PH-ILD patients?(please select up to 5 options) ☐ Maintenance/improvement of haemodynamic parameters ☐ Maintenance/improvement of pulmonary parameters ☐ Maintenance/improvement of exercise capacity (6MWT, CPET) ☐ Maintenance/improvement in serological markers ☐ Maintenance/improvement of patient's quality of life ☐ Non-eligibility to lung transplant ☐ Other (please specify): 70.According to your experience, which key factors are considered to discontinue PAH treatment in PH-ILD patients?☐ Adverse response (eg: desaturation, tolerability, dyspnea) ☐ Comorbidity development ☐ ILD progression ☐ PH progression ☐ Other (please specify): 71.According to your experience, approximately what proportion of PH-ILD patients are hospitalised due to the following reasons?Acute exacerbation of ILD % of PH-ILD patients Comorbidity severity % of PH-ILD patients Right heart failure % of PH-ILD patients Severe symptom burden % of PH-ILD patients Other % of PH-ILD patients Total: % of PH-ILD patients

23. Approximately, what proportion of ILD patients with suspected PH are referred for the following procedures?
Echocardiography followed by right heart catheterisation (RHC) % of PH-ILD patients Right heart catheterisation (RHC) alone % of PH-ILD patients Other % of PH-ILD patients Total: % of PH-ILD patients If another procedure was used, please specify what it was:24.

Based on your experience, please elaborate in which cases you would or would not carry out a right heart catheterisation (RHC) in ILD patients 25. Given a suspicion of PH, approximately how long does it take to confirm a PH diagnosis through the use of right heart catheterisation
(RHC)? ☐ <2 weeks ☐ 2-4 weeks ☐ >4 weeks 26.What is the approximate relative distribution of mPAP outcomes at diagnosis of PH for your PH-ILD patients?*21-24mmHg % of PH-ILD patients 25-34mmHg % of PH-ILD patients 35mmHg+ % of PH-ILD patients Total: % of PH-ILD patients Comments:27.

29. Approximately, what % of your PH-ILD patients are receiving antifibrotics (nintedanib, pirfenidone) to treat their underlying ILD? 30. Approximately, what % of your PH-ILD patients are receiving anti-inflammatory therapy (prednisone, methylprednisolone) to treat their underlying ILD? 31. Approximately, what % of your PH-ILD patients are receiving immunosuppressant therapy (azathioprine, methotrexate, mycophenolate) to treat their underlying ILD? 32. Approximately, what % of your PH-ILD patients are receiving rituximab to treat their underlying ILD? 33. Approximately, what % of your PH-ILD patients are receiving TNF inhibitor therapy to treat their underlying ILD? 34. Do all of your PH-ILD patients receive specific treatment for PH?
Not known (ILD treatment outside of my specialisation)Others (please specify names and if known, the % of your PH-ILD patients that are receiving): inflammatory (prednisone, methylprednisolone) ☐ Immunosuppressants (azathioprine, methotrexate, mycophenolate) ☐ Rituximab ☐ TNF inhibitors ☐ ☐ Yes ☐ No (% of your PH-ILD patients not receiving treatment for PH):

According to your experience, which endothelin receptor antagonists (ERAs) are used as monotherapy to manage PH in your PH-ILD patients? If applicable, please select the proportion of your PH-ILD patients that receive this treatment.
were selected, please specify the drug: 39.