Our results show that the burden of non-IPF PPF and SSc-ILD on society is significant in Europe. It was estimated that 86,794 patients with non-IPF PPF and 13,221 patients with SSc-ILD were living in Europe. While the prognosis of patients with non-IPF PPF and patients with SSc-ILD is poor, comorbidities, sick leaves, permanent disability, and early retirement contribute to the disease burden, not only for the healthcare systems but also on society overall. We estimated the aggregated income loss to be €1433 million for non-IPF PPF and €220 million for SSc-ILD. Permanent disability and early retirement were the most important source of aggregate income loss, representing around half and 43% of costs for non-IPF PPF and SSc-ILD, respectively. Additionally, job losses resulting from the diseases were estimated to cost €194 million for non-IPF PPF and €26 million for SSc-ILD.

There are very few economic studies around the burden of PPF and SSc-ILD. A cost-effectiveness analysis about non-IPF PPF was conducted in the Netherlands by Westerink and colleagues [22], whose model was based on data coming from the INBUILD trial [23]. It showed that the societal costs per patient, including round trip to hospital, general practitioner, and specialist, healthcare worker/domestic support at home, and sick days, were in the range €1627–2403, with the lowest cost associated with patients treated with nintedanib. These figures are much lower than those calculated in our study, as we found that the estimated annual cost per patient was €16,506. However, it is difficult to compare such costs since the methodologies used are different, as were the nature of costs. In the Westerink study, costs related to early retirements, permanent disability, and job losses were not included.

Another study conducted in France assessed the disease burden associated with progressive fibrosing. In this study, total median annual costs per patient were €18,362, including all hospitalizations, specific laboratory tests, imagery and treatment, and specific medical and paramedical costs but excluding sick leave, daily allowances, and transport costs [19]. While these costs are similar to those in Westerink et al.’s study, as our study focuses on productivity losses, comparison with the two aforementioned studies is irrelevant.

SSc is generally diagnosed during working age (mean 46 years) [24] and associated ILD arises within the first 5 years after diagnosis [25]. Therefore, in addition to increased direct costs, a huge economic burden is expected due to the loss of productivity. A small US claims data analysis performed by Zhou et al. [26] evaluated sick days and the relevant costs of 52 insured and employed patients with SSc-ILD compared with healthy controls. In the 6 months immediately following the diagnosis, they found that the sick days per patient were 23.2. Hypothesizing a comparison with our results by doubling the aforementioned figures to convert to 12-month values, we obtain that 46.4 annual sick days per patient. These data are very similar to the assumptions of our study (50.8 annual sick days). Nonetheless, comparing US to EEA productivity loss costs is irrelevant, as the median income in the USA [27] is 3-fold than that found in the EEA [17, 18].

The first follow-up European study to evaluate indirect costs associated with SSc-ILD was the study by Knarborg and colleagues [12] based on a Danish national patients registry. They evaluated the excess direct healthcare costs and indirect costs associated with SSc in patients with and without ILD 5 years before and 4 years after the diagnosis, finding reduced mean annual income per case of €9763 in SSc-ILD cohort compared with €6604 in the non-ILD SSc cohort. Foregone earnings were calculated not only for working cases but also for the entire Danish SSc population. Disability pension was the key driver of excess public transfer income in both cohorts after diagnosis. In our SSc-ILD study cohort, around one-third of annual income loss was due to permanent disabled patients’ loss, which is a lower proportion than that found in our non-IPF PPF cohort, maybe as a result of the slow progression rate of fibrosis in SSc-ILD [1].

Antifibrotics were already used in IPF when the INBUILD trial [23], which reported its efficacy also in non-IPF PPF, was published, thus resulting in a paradigm shift toward an en bloc approach to antifibrotic therapy [6]. Pirfenidone is also an antifibrotic agent, with anti-inflammatory, antioxidative, and antiproliferative properties. It was recommended for treatment of IPF in prior guidelines. However, the official ATS/ERS/JRS/ALAT Clinical Practice Guideline [6] found that data about the use of pirfenidone were insufficient to give a recommendation for its use in non-IPF PPF, as two randomized clinical trials with small sample sizes were analyzed [28, 29], one of which was terminated early as a result of futility triggered by slow recruitment [28].

Dyspnea, cough, and fatigue are the most common symptoms of non-IPF PPF and heavily affect health-related quality of life (HRQoL) [30]. Nintedanib proved to be able to significantly reduce the worsening of cough and dyspnea in patients with non-IPF PPF [31]. In fact, nintedanib had a statistically [32] and clinically [33] meaningful impact on HRQoL on the cough domain score of Living with Pulmonary Fibrosis (L-PF) questionnaire administered to patients with non-IPF PPF recruited in the INBUILD trial [15].

In addition to the disease-modifying drugs, a supportive care program should also be offered to patients in order to meet their needs and relieve the disease burden [34, 35]. The early diagnosis and management of the progressive behavior of the disease is particularly important as it may be able to prevent the worsening of the quality of life, thus reducing the burden of the disease [34].

These measures are underused in Europe and generally accessed only at the final stages of the disease, despite carrying the potential to reduce symptom burden [36]. One of the reasons is that they are too often called “palliative care” and such terms often make patients perceive themselves as “doomed” [35]. Therefore, a comprehensive support strategy, generally indicated as “holistic care”, able not only to slow down the progression of the disease but also to offer supportive measures, symptom relief, and end-of-life care [34], has emerged in the last decade as an unmet need for patients affected by non-IPF PPF.

In particular, supportive measures include support groups, both nurse-led and among peers, pulmonary rehabilitation, and supplemental oxygen. Also education programs, where attended, have received the appreciation of patients [34]. In the BUILDup study [4], most panelists agreed that progressive fibrosing ILDs affect caregivers’ quality of life in terms of sleep and health, daily activities, emotional well-being, social life, and finances. As a result of substantial psychological burden carried by caregivers, the need for emotional and educational support is apparent [35]. However, both for emotional and educational support groups, the impact in the long-term on well-being is still to be demonstrated. Pulmonary rehabilitation proved to be able to significantly increase exercise capacity, quality of life, and dyspnea in the short term, but again data about the long term are lacking, even though the gains in quality of life seem to be preserved [34]. Supplemental oxygen is recommended by the official ATS/ERS/JRS/ALAT Clinical Practice Guideline [6] in patients with hypoxia, but few data support these recommendations [34].

Finally, end-of-life care means facing the conversation about end-of life decisions, in accordance with patient’s preference and religious beliefs. As a result of the frequent avoidance of such a conversation, even though the majority of patients prefer to die at home, most of them actually die in the hospital [34].

In a review by van Manen and colleagues about IPF [37], a comprehensive program was summarized as the “ABCDE of IPF care”, and then adapted by Kreuter et al. [35] to ILD care in general, i.e., “Assessing patients’ needs; Backing patients by giving information and support; delivering Comfort care by focusing on treating symptoms and taking into account Comorbidities; striving to prolong life by Disease modification; helping and preparing patients and their caregivers for the eventual End-of-life events that are likely to occur”. Besides, our study shows a significant proportion of patients with SSc-ILD and patients with non-IPF PPF were estimated to have fatigue or depression. A Greek study reported that depression was indirectly associated with disease severity, symptom burden, and quality of life in patients with IPF, reinforcing the need for mental support for patients with ILD [38].

In Europe, surveys conducted in European countries among healthcare professionals (HCPs) and patients with IPF and non-IPF PPF showed that less than 50% of patients had access to pulmonary rehabilitation, maybe as a result of incomplete reimbursements, unawareness, and physical distance issues [36]. In addition, as already reported in the literature, patients and their caregivers feel the need for better emotional and psychological support [36], but reimbursement and access to psychologists for this type of patients are still restricted. Therefore, the support groups mentioned above are the best alternative and have been shown to be appreciated by patients. In addition, the need for educational activities and active involvement of patients in the development of treatment plans emerged from these surveys [36].

Even though the course of non-IPF PPF is unpredictable, supportive care should be offered early, as it is able to partly relieve the disease burden [35]. Brereton and colleagues, who analyzed several models of palliative care life-limiting illnesses, found that models of palliative care show several benefits for patients and caregivers and just few disadvantages, but the final conclusion about the cost-effectiveness of palliative care cannot be drawn because of the heterogeneity of diseases and strategies of palliative care considered [39]. We speculate that an improved state of health may reduce sick days and the relevant productivity loss.

In the future, novel approaches should be taken to diagnose ILDs early on or to prevent or limit their progression, ultimately limiting the burden on healthcare systems and societies. In the field of precision medicine, biomarkers at an acceptable cost could provide actionable information to clinicians for instance regarding disease activity or the need for treatment modification [40].

Our study has some limitations. First of all, as evidenced by Hilberg and colleagues [2], prevalence and incidence estimates about ILDs are highly variable, both according to the type of ILD considered and among European countries. Besides, in our study we used the mean of several countries and therefore did not reflect country variations or any potential fluctuation in prevalence with age. The uncertainty about the economic impact is the direct consequence of the uncertainty about epidemiological data. In our sensitivity analysis, disease prevalence is the factor that impacts aggregate income loss estimates the most. Given the large range of prevalence used in the sensitivity analysis based on a multicountry epidemiology study, it is likely that the actual aggregate income loss falls within that range.

Similarly, we applied data from BUILDup studies, which were based on opinions of European experts gathered and elaborated thanks to the DELPHI methods, by using averages [4, 14]. However, it is very likely that differences among countries exist, as reported about another respiratory disease, i.e., chronic obstructive pulmonary disease (COPD). In fact, in a systematic review conducted in some European countries [41], indirect costs varied greatly, as costs of work productivity loss ranged from €5735 (Germany) to €998 (Greece) and early retirement cost varied €19,031 (Germany) to €3695 (Sweden). Besides, as BUILDup was based on expert opinions and not from patients themselves, productivity loss data should be taken with caution, and more research on this topic should be done.

We used the comorbidity data from BUILDup studies and not an average of different real-world evidence studies, which presents limitations. In the BUILDup study on PPF, the most prevalent comorbidities were fatigue (45.6%), pulmonary infection (29.3%), gastroesophageal reflux disease (29.2%), depression (27.2%), osteoporosis (20.3%), and pulmonary hypertension (19.8%) [4]. In Nasser et al.’s study in France, the most prevalent diseases were arterial hypertension (63.8%), gastroesophageal reflux disease (55.4%), cardiac arrythmias (21.9%), depression (20.5%), and congestive heart failure (20.0%) [19]. While there is variability between studies, it seems our assumptions do not overestimate the high level of comorbidities in patients with ILD.

Our study excluded direct costs. Direct costs typically include hospitalizations such as for exacerbations, visits to health professionals, or medication. This type of information is not available in a several European countries and costs do not always follow the level of citizens income, making estimations difficult. Besides, some country healthcare systems can be composed of multiple financing systems and calculations of direct costs can differ across countries, some including value-added tax and others not.

We assumed in our model that patients with non-progressive SSc-ILD do not present exacerbations. As exacerbations are characterized by acute, clinically significant respiratory deteriorations, our assumption is valid for modeling disease burden and at worse underestimate the burden of disease. Besides, we assumed that 37% of patients with SSc-ILD are progressive, which was based on patient file review [2]. This is comparable to Wijsenbeek et al.’s study that shows that 31% of patients with SSc-ILD have progressive disease [3].

Other limitations include the fact that exacerbation rates and mortality with or without treatment are based on clinical trial data and not based on European real-world evidence over a longer follow-up period. While this might affect our results overall, we assumed this approach to be appropriate enough for modelling purposes.

Finally, our study relies on few articles assessing the epidemiology and the societal burden of ILD. Although we conducted a sensitivity analysis to reflect potential variations in assumptions, more investigation is needed on productivity loss for patients with ILD.