Pulmonary veno-occlusive disease (PVOD) represents a rare form of pulmonary arterial hypertension (PAH), distinguished by its impact on the entire pulmonary vascular bed, including pulmonary veins, capillaries, and arteries.1 The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines currently classify PVOD as group 1.5, titled ‘PAH with features of venous/capillary involvement’.1 PVOD is noted for its specific phenotype, reflecting venular and capillary damage, with radiological abnormalities such as septal lines, ground-glass opacities, lymph node enlargement, severe hypoxaemia, and a significantly reduced diffusing capacity for carbon monoxide (DLco).2 PVOD can be hereditary, linked to biallelic mutations in the EIF2AK4 gene, associated with exposure to toxic substances (e.g., alkylating agents or organic solvents), or occur sporadically.2 The most defining characteristic of PVOD is its particularly guarded prognosis, with survival rates without transplantation around 30–35% at three years.3 This is attributed to a limited response to PAH-approved drugs, compounded by the risk of pulmonary oedema.3 Currently, there is a lack of data on the benefit/risk ratio of PAH-approved drugs in PVOD, which invariably is an exclusion criterion in clinical trials conducted for PAH. Thus, lung transplantation remains the standard treatment for eligible patients.2

In PAH, it has been clearly demonstrated that risk stratification plays a crucial role in the therapeutic approach. It enables the assessment of initial severity and guides the choice of PAH-approved drugs (mono, dual, or triple therapy), and their mode of administration, especially for treatments targeting the prostacyclin pathway (oral or parenteral).1 Risk stratification also facilitates evaluating treatment response during follow-up and guiding treatment adjustments. In recent years, numerous risk stratification tools have been validated in large registries, notably the 4-strata and 3-strata ESC/ERS models and scores from the US REVEAL Registry.4–7 The current treatment objective is to achieve a low mortality risk status for patients, correlating with improved outcomes. However, until recently, these risk classifications had not been applied to PVOD.

In the current issue of Archivos de Bronconeumologia, Cruz-Utrilla et al. have examined the relevance of risk stratification in a cohort of 54 PVOD patients from the Spanish Registry of PAH (REHAP) between 2011 and 2022.8 First, this study corroborates the grim prognosis for these patients, with observed mortality rates of 22.9% at 3 years and 50.5% at 5 years. The authors demonstrated the prognostic efficacy of both the ESC/ERS risk score and the REVEAL Lite 2 model in PVOD at the time of diagnosis, in defining the risk of death or transplantation. These findings are consistent with a study our team conducted on a large population of 327 patients with PVOD, including baseline and follow-up assessments.9 Indeed, Boucly et al. compared six risk assessment methods (number of four low-risk and three non-invasive low-risk variables, ESC/ERS guidelines 3-strata and 4-strata models, and REVEAL 2.0 and Lite 2 models) at baseline and early follow-up.9 All methods were able to discriminate mortality risk, with the ESC/ERS 4-strata model proving the most accurate both at baseline and during follow-up. However, only a small fraction of PVOD patients (14%) achieved a low-risk status within a year according to the ESC/ERS 4-strata method; and contrary to PAH, the prognosis for patients achieving low- or intermediate-low-risk status at first follow-up remained poor, with 5-year survival rates of only 68% and 29%, respectively. Of note, no significant differences based on the initial PAH treatment strategy (no treatment, mono-, or dual therapy) were observed.

The question arises: What is the value of assessing the risk in a population for which no treatment has demonstrated a satisfactory benefit/risk ratio? Consequently, we cannot rely on risk stratification to guide therapeutic strategies as it is recommended for other forms of PAH. Nonetheless, these two studies have shown that prognosis can be estimated by risk stratification. This enables the optimization of timing for lung transplantation listing and prioritization of high-risk patients, who could benefit from urgent listing transplantation programmes when such options are feasible. The evaluation of risk also holds significance for PVOD in the context of future therapeutic trials. The PAH-approved drugs currently available primarily exert a pulmonary arterial vasodilatory effect, likely offering little or no impact on the capillary and venular components of PVOD and promoting pulmonary oedema. However, innovative PAH therapies targeting preferentially vascular remodelling without a major vasodilatory effect could offer promising therapeutic options for PVOD. Among these, sotatercept, targeting the activin pathway and restoring the balance of the TGF-beta pathway, demonstrated in phase 2 and 3 studies a significant effect in PAH.10,11 Additionally, the phase 2 study with inhaled seralutinib, a small-molecule inhibitor of PDGFRα/PDGFRβ, CSF1R, and c-KIT kinase, in PAH (TORREY, NCT04456998) met its primary endpoint of reducing pulmonary vascular resistance after 24 weeks.12 Interestingly, dysfunction in the BMPRII and PDGF pathways has been observed in human and experimental PVOD, which may justify evaluating such treatments in PVOD.13,14

The setting-up of clinical trials dedicated to PVOD has become an urgent goal given the severity of the disease's prognosis and the current therapeutic impasse. It is challenging to envision that the endpoints for these phase 2 studies could be directly comparable to those used for PAH, especially pulmonary vascular resistance. These recent studies8,9 demonstrating the applicability and relevance of risk stratification in PVOD open up the possibility of using this criterion as an endpoint for future dedicated clinical trials.