The combined OPUS/OrPHeUS dataset is the largest new-users database for macitentan in the US, and includes a large proportion of patients with CTD-PAH. Data collection spanned the years 2013–2020, providing contemporary, real-world data on the management and outcomes of patients with CTD-PAH, albeit limited to those receiving macitentan. Here, we show that macitentan is used in newly diagnosed and prevalent patients with CTD-PAH, including in those with SSc-PAH, SLE-PAH, and MCTD-PAH, as part of a combination therapy regimen in the majority of patients, and tolerability and safety are comparable to the I/HPAH patient population and consistent with previous safety reports [10, 20].

In OPUS/OrPHeUS, patients with CTD-PAH comprised approximately a quarter of the PAH follow-up cohort. This is similar to previous reports where patients with CTD-PAH represented 24–34% of patients with PAH [5, 7]. In our analyses, the median ages for the overall CTD-PAH group and I/HPAH group were similar (62 vs. 64 years), while the median ages differed between the CTD subgroups: patients with SLE-PAH and MCTD-PAH were younger compared to patients with SSc-PAH (49, 57, and 64 years, respectively). This similarity in age between the overall CTD-PAH and I/HPAH groups in OPUS/OrPHeUS contrasts with earlier registries where patients with CTD-PAH were older than patients with IPAH (mean age 57 for patients with CTD-PAH versus 50 years for IPAH)[7], and older than other patients with PAH (mean age 56 for patients with CTD-PAH versus 51 years for PAH) [12]. This may reflect the changing demographics of patients with PAH, however, as OPUS and OrPHeUS were macitentan drug registries, there was the potential for bias in patient selection and therefore the study population may not be directly comparable with disease registries. In OPUS/OrPHeUS, patients with CTD-PAH were less likely to be obese and diabetic than patients with I/HPAH and the proportion of Black or African-American patients in the SLE-PAH group and the proportion of White patients in the SSc-PAH group were consistent with previous reports [21]. Additionally, the demographics and characteristics of patients with SSc-PAH and SLE-PAH were similar to previous reports from disease registries [22, 23], despite OPUS/OrPHeUS being a drug registry.

The current 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) PH treatment guidelines, as well as those effective at the time of study conduct, recommend that patients with CTD-PAH be treated according to the same algorithm as patients with IPAH [24,25,26,27,28,29]. Compared to patients with I/HPAH, a higher proportion of patients with CTD-PAH initiated macitentan as part of combination therapy and were more likely to escalate therapy up to 2 years after macitentan initiation. Overall, the MCTD-PAH group had the highest proportion of patients who escalated treatment up to 2 years after macitentan initiation. The MCTD-PAH group had the worst clinical presentation at macitentan initiation among the other subgroups; with a high proportion of patients with a low baseline 6MWD (a quarter of patients with a 6MWD < 152 m), and the highest proportion of patients in WHO FC III/IV at macitentan initiation (82.4%). Additionally, the MCTD-PAH group had a high proportion of patients with hospitalizations (50.8%). These factors could have contributed to the urgency to escalate therapy in these patients.

Exposure to macitentan was similar in patients with I/HPAH and CTD-PAH, with comparable proportions of patients discontinuing treatment due to an AE/HAE. AE profiles in OPUS were similar across the groups, and comparable to observations in previous RCTs assessing PAH therapies [1, 9], including ERAs. The incidence of HAEs, HAESIs, and liver abnormalities were low, and in line with the known safety profile of macitentan [10, 20]. Overall, these data show that the administration of macitentan, including as part of a combination therapy regimen, is well tolerated in newly diagnosed and prevalent patients with CTD-PAH and subgroups with varying characteristics.

We found the overall rates of first hospitalization and survival were similar between patients with I/HPAH and CTD-PAH in OPUS/OrPHeUS, in contrast to the REVEAL registry that enrolled patients from 2006 to 2009, and the recent COMPERA PAH-disease registry [8, 30]. Several recent studies have shown that survival has improved in patients with CTD-PAH in the last 10 years, which may be related to improved screening of patients with CTD for PAH, leading to earlier detection and initiation of initial combination treatment [12, 22, 30,31,32]. In REVEAL, only 39.5% of patients with CTD-PAH were on combination therapy at enrollment [7], whereas 65.2% were on combination therapy in OPUS/OrPHeUS. The differences in outcomes might also be due to the type of registry (disease versus drug), where patients may enroll in a disease registry at different times along their PAH journey; the time from diagnosis to enrollment for patients with CTD-PAH in REVEAL was mean (standard deviation) 27 (30) months [7], whereas in OPUS/OrPHeUS median (Q1, Q3) time from diagnosis to enrollment for patients with CTD-PAH was 6 (1, 35) months. The outcomes of patients with CTD-PAH in our study indicate progress has been made for early diagnosis and improved treatment options, however, outcomes could be further enhanced with increased use of initial combination therapy, as per the 2015 and recent 2022 ESC/ERS guidelines [26,27,28,29].

The OPUS and OrPHeUS studies provide valuable insights into the real-world management of patients with PAH newly treated with macitentan, including in patients with CTD-PAH, although their observational nature is associated with limitations. Firstly, as OPUS and OrPHeUS were drug registries, there is the possibility of bias with respect to the type of patients enrolled, and results may not be directly comparable with disease registries. In both studies, follow-up data were collected according to routine clinical practice without protocol-mandated rules or assessments. As such, data on patient baseline and disease characteristics are incomplete, particularly for WHO FC and 6MWD, which may indicate that for a large proportion of patients accurate risk assessment was not performed as recommended in the 2015 ESC/ERS guidelines, relevant at the time of the study [17, 26, 27]. Many parameters reported here (e.g., CTD-PAH diagnosis and deaths) were investigator-assessed and were not adjudicated. The sample sizes of the CTD-PAH subgroups are small (with corresponding wide 95% confidence limits), and the results from the time-to-event analysis should be interpreted with caution due to the small number of events. It should also be noted that the comparisons between the populations are descriptive. Finally, there are differences in the data between both studies [17], with decreased robustness in the data from OrPHeUS due to the retrospective nature of a medical chart review.