History, presentation and investigations
A 35-year-old female civil servant with good past health was admitted to our centre on 28 April 2025 with a 6-month history of shortness of breath on exertion, wheeze, bilateral lower-limb oedema, 3 kg weight gain, and chest pain. She had no constitutional symptoms or palpitations, and no family history of rheumatologic disease or pulmonary arterial hypertension (PAH).
Before admission, the patient consulted a private doctor. She was misdiagnosed with bronchitis and treated with bronchodilators, but her symptoms subsequently worsened.
At presentation in April 2025, her blood pressure was 147/93 mm Hg, pulse rate was 98 bpm, and respiratory rate was 26 breaths per minute. Her peripheral oxygen saturation (SpO2) was 89 percent on room air, improving to 92 percent after receiving supplemental oxygen at 2 L/min via nasal cannula. The patient was admitted to the general medical ward, where she was treated as having heart failure with intravenous furosemide. She reported subjective improvement after treatment.
Chest X-ray showed hilar haziness. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was elevated at 1,215 pg/mL. (Table) Electrocardiography (ECG) demonstrated sinus arrhythmia and marked right axis deviation, while CT thorax showed right heart strain pattern. Ventilation perfusion (V/Q) scan excluded pulmonary embolism. Transoesophageal echo[1]cardiography (TEE) did not detect intracardiac shunt. Echocardiography showed enlarged right atrium and right ventricle (RA/RV), and significant tricuspid regurgitation. Investigations by pulmonologists ruled out lung disease. Cardiac MR (CMR) showed dilated, hypertrophied RV with leftward bowing of the interventricular septum, raising suspicion of pulmonary hypertension. The patient’s 6-minute walk distance (6MWD) was 106 m, and WHO functional class (FC) was IV. (Table)
Right heart catheterization (RHC) revealed elevated mean pulmonary arterial pressure (mPAP) of 90 mm Hg, mean RA pressure of 10 mm Hg, pulmonary vascular resistance (PVR) of 14.5 WU, and reduced cardiac output (Fick cardiac output, 3.11 L/min; Fick cardiac index, 1.82 L/min/m2). These findings confirmed idiopathic pulmonary arterial hypertension (PAH) with an intermediate risk classification based on the three-strata model (score, 2.6). (Table)
Treatment and response
Dual therapy with sildenafil 20 mg TID and macitentan 10 mg QD was started on 28 April 2025. Selexipag 200 mcg BID was added 2 days later, after which the patient was stabilized and discharged for early outpatient drug titration.
During follow-up at the PAH Day Centre in May 2025, the patient reported side effects of selexipag, including headache, nausea, vom[1]iting, and diarrhoea. Due to fair tolerance, selexipag dose was slowly uptitrated every 2 weeks, and alternative treatment options such as sotatercept or pulmonary artery denervation were discussed. In July 2025, after 3 months of triple therapy, the patient demonstrated clinical improvements in exercise tolerance, NT-proBNP level, FC, and risk status. (Table) However, she continued to experience significant side effects of selexipag.
On 4 July 2025, the patient received subcutaneous sotatercept Q3W through a named patient pro[1]gramme while receiving selexipag at 600 mcg BID (maximally tolerated dose). Sotatercept was started at 0.3 mg/kg and uptitrated to 0.7 mg/kg Q3W.
The patient tolerated sotatercept well. After 3 months of addon sotatercept, further clinical improvements were seen: WHO FC I–II, 6MWD 450 m, and NT-proBNP 146 pg/mL – consistent with a low-risk status based on the four-strata model (risk score, 1). (Table)
Discussion
The current treatment paradigm for PAH emphasizes early and aggressive therapy, with initial combination therapy as the standard of care. This approach focuses on multimodal treatment targeting three traditional pathways: the endothelin, nitric oxide, and prostacyclin signalling pathways.1
Sotatercept, the first US FDA–approved activin signalling inhibitor, holds potential for disease modification. Unlike traditional PAH therapies that mainly target vasoconstriction, sotatercept addresses the fundamental problem of excessive cellular proliferation in pulmonary arteries by improving the balance between proproliferative and antiproliferative signalling.1,2
The decision to add sotatercept to our patient’s triple therapy regimen was based on the results of the phase III STELLAR trial, in which 323 patients with PAH FC II or III who were on stable back[1]ground therapy (triple therapy, 61.3 percent; double therapy, 34.7 percent; monotherapy, 4.0 percent; prostacyclin infusion therapy, 39.9 percent) were randomized 1:1 to receive sotatercept or placebo.3
STELLAR met its primary endpoint, demonstrating a statistically and clinically significant improvement in 6MWD at week 24 vs placebo (difference, +40.8 m; p<0.001). The benefit was consistent across all prespecified subgroups.3
Notably, more patients on sotatercept vs placebo experienced improvement in their WHO FC at week 24 (29.4 vs 13.8 percent; p<0.001). Sotatercept also significantly improved biomarkers, including PVR (difference, -234.6 dyn·s/cm5; p<0.001) and NT-proBNP levels (difference, -441.6 pg/mL; p<0.001), vs placebo.3
Consistently, after 3-month treatment with sotatercept, our patient’s 6MWD increased by 80 m (from 370 to 450 m), her WHO FC improved from II to I–II, and NT-proBNP level decreased from 213 to 146 pg/mL. (Table)
According to STELLAR results, after a median of 32.7 weeks, treatment with sotatercept resulted in an 84 percent lower risk of a composite of death from any cause or nonfatal clinical worsening event vs placebo (hazard ratio [HR], 0.16; 95 percent confidence interval [CI], 0.08–0.35; p<0.001).3
An analysis of STELLAR and SOTERIA (an ongoing open-label extension study evaluating the long-term safety and efficacy of sotatercept) showed that sotatercept significantly reduced the risk of death by 83 percent vs placebo (HR, 0.17; 95 percent CI, 0.03–0.90; p=0.037).4
Rates of overall adverse events (AEs; 84.7 vs 87.5 percent), severe AEs (8.0 vs 13.1 percent), and serious AEs (14.1 vs 22.5 percent) at week 24 were numerically lower with sotatercept vs placebo. Fewer patients in the sotatercept vs placebo group discontinued the trial regimen owing to AEs (1.8 vs 6.2 percent).3
PAH is a rare, debilitating, rap[1]idly progressing, and ultimately life-threatening condition.5,6 In patients with FC II-III who are stable on background therapy, such as our patient and patients in the STELLAR trial, add-on sotatercept delays disease progression and improves NT-proBNP levels, exercise capacity, WHO FC and survival, with a favourable benefit–risk ratio.3,4
