Sotatercept in Pulmonary Langerhans Cell Histiocytosis‐Associated Pulmonary Hypertension: A Case Series and Systematic Review

ABSTRACT

Pulmonary Langerhans cell histiocytosis (PLCH) frequently complicated by pulmonary hypertension (PH), which markedly worsens prognosis. We retrospectively reviewed three institutional PLCH‐PH cases treated with off‐label Sotatercept added to background triple therapy and performed a systematic review of published PLCH‐PH reports (PubMed/Embase through May 2025). Our three patients (ages 69, 62, 49; all female) had progressive vascular disease despite optimized vasodilator therapy. Following Sotatercept, all experienced ≥ 3‐fold increases in 6‐min walk distance and improved functional class. Hemodynamics improved substantially: right‐atrial pressure −78.6%, pulmonary vascular resistance −75.5%, pulmonary artery systolic pressure −58.5%, mean PAP − 56.0%, PA diastolic pressure −51.0%, PAWP − 47.1%; cardiac output and index rose +75.9% and +73.8%, respectively. BNP/NT‐proBNP normalized. Systematic review identified 34 published cases (2010–2025): mean age 37.2 ± 13.7 years, 44.1% female, 45.7% current/former smokers. Reported management strategies included targeted vasodilators, cytotoxic PLCH therapies (e.g., cladribine), smoking cessation, and selective surgery/transplant. In this small series, Sotatercept added to background therapy produced marked clinical and hemodynamic gains in refractory PLCH‐PH. These effects of Sotatercept in Group 5 PH—are encouraging but limited by sample size and retrospective design. Prospective, collaborative studies are needed to define safety, efficacy, and optimal patient selection.

1. Introduction

Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon interstitial lung disorder characterized by bronchiolocentric nodular infiltration of CD1a‐ and Langerin‐positive dendritic cells, evolving into cystic lesions predominantly in upper and mid‐lung zones. The adult incidence approximates 1–2 cases per million, with > 90% of patients reporting tobacco exposure and ~30% cannabis use. While some patients improve after smoking cessation, a subset progresses to respiratory failure or multisystem involvement [1, 2, 3].

Pulmonary hypertension (PH) is a recognized complication of PLCH, though its exact frequency and incidence under reported due to the rarity of PLCH. Available data suggest that PH occurs in a significant proportion of advanced PLCH cases. Studies indicate that PH is present in approximately 90% of patients with severe PLCH, highlighting its prevalence in end‐stage disease. Additionally, PH has been observed in 15%–35% of patients with advanced PLCH, with some reports noting its presence in up to 92% of cases when assessed by right heart catheterization or echocardiography in symptomatic patients. The incidence increases with disease progression, correlating with cystic lung destruction and pulmonary vascular remodeling. However, precise population‐based incidence rates are lacking due to the disease's rarity and the need for specialized diagnostic evaluation [2, 3, 4, 5, 6].

PLCH‐PH is a rare and under‐recognized form of pulmonary hypertension, often excluded from clinical trials, resulting in limited evidence in medical management. To address this gap, we conducted a systematic review of published cases and literature. Additionally, the therapeutic role of novel agents such as activin signaling inhibitors remains unexplored in this population. Here, we present a case series of three patients with PLCH‐PH who were treated with Sotatercept, highlighting its potential utility in this complex and understudied subtype of PH.

2. Methods

2.1. Institutional Case Series

We retrospectively identified patients with pulmonary Langerhans cell histiocytosis (PLCH) and right heart catheterization (RHC)‐confirmed pulmonary hypertension (PH) who were treated across several medical centers. For each patient, we collected clinical data, radiographic imaging, invasive hemodynamic measurements, therapeutic regimens, and follow‐up outcomes.

2.2. Literature Review

A systematic literature review was conducted through PubMed, MEDLINE and Embase databases, covering all records from inception through May 2025. We included only English‐language publications reporting PLCH with confirmed precapillary PH. Search terms for PLCH‐related reports included “Langerhans cell histiocytosis,” “pulmonary hypertension,” and “case report.” For studies involving Sotatercept, we used a combination of “systematic review,” “pulmonary hypertension,” and “Sotatercept.” Two independent reviewers screened all titles and abstracts for eligibility and subsequently assessed the full texts of potentially relevant articles. Data extracted included demographic characteristics, diagnostic modalities such as high‐resolution computed tomography (HRCT) and RHC, treatment approaches, and clinical outcomes. Discrepancies between reviewers were resolved through consensus. Case reports or series with missing essential data were excluded from the analysis.

2.3. Selection Criteria

Studies were included if they met all the following criteria. The study cohort were adult patients aged 18 years or older with a confirmed diagnosis of PLCH who received any form of treatment. No specific treatment modality was required for inclusion; instead, we aimed to capture a broad spectrum of management strategies employed for PLCH with PH. Eligible studies had to report on at least one relevant clinical outcome, such as mortality, improvement in functional status, or enhancement in laboratory, echocardiographic, pulmonary function, or invasive hemodynamic parameters. Studies were excluded if they were review articles, editorials, or conference abstracts without available full‐text data. Additionally, non‐English language publications were excluded unless a complete English translation was accessible.

2.4. Data Extraction

Following deduplication, all titles and abstracts were screened according to the predefined inclusion criteria. Full‐text articles that met initial screening criteria were independently reviewed by two investigators to confirm eligibility. From each eligible study, we extracted data using a standardized Excel spreadsheet. Extracted information included study identification details such as first author, year of publication, and country of origin; study design (e.g., case report, case series, randomized controlled trial, or systematic review); and patient characteristics, including total number of patients, gender distribution (both count and percentage), and reported mean or median age with corresponding standard deviation or interquartile range. We also collected information on the therapeutic approach used for PLCH. Outcome data included all‐cause mortality, treatment‐related side effects, and improvement in clinical or diagnostic parameters such as the 6‐min walk test (6MWT), RHC measurements, and laboratory biomarkers like BNP or pro‐BNP levels. Follow‐up duration was extracted when available, although no minimum time threshold was applied. Discrepancies during the extraction process were resolved by consensus between reviewers.

3. Clinical Summaries of Three PLCH‐Associated Pulmonary Hypertension Patients

3.1. Patient 1

A 69‐year‐old former smoker female with longstanding pulmonary Langerhans cell histiocytosis (PLCH), chronic hypoxic respiratory failure (O₂‐dependent since 2006), ongoing evaluation for lung transplant, and severe COPD, NYHA class IV functional condition despite maximally tolerated triple therapy, including parenteral Prostacyclin. Baseline echocardiography showed a preserved ejection fraction of 50%–55%, moderate right ventricular dilatation, septal flattening, and an estimated RVSP of 97 mmHg, with an RA pressure of 3 mmHg and TAPSE of 2.0 cm. Pulmonary function test progression is shown in Table 2. She required 10–12 L O₂ at rest and up to 15 L on exertion. 6‐min walk distance was 240 m. Right‐heart catheterization confirmed severe precapillary PH (Supporting Information Table 1 & Figure 1). In May 2024, subcutaneous Sotatercept was initiated (0.3 mg/kg with a goal of 0.7 mg/kg). Over the following months, she noted markedly improved energy levels, stair‐climbing capacity, and decreased resting O₂ requirement (down to 8 L) and exertional O₂ (10–12 L). On‐treatment echocardiography showed stable EF, resolution of septal flattening, normal RV size, and normalized TAPSE. Repeat PFTs on therapy improved (Supporting Information Table 2), and the 6‐min walk peaked around 300 m. RHC on treatment demonstrated dramatic hemodynamic relief Supporting Information Table 1. Unfortunately, after four Sotatercept doses, she developed thrombocytopenia and recurrent worsening nosebleeds during following additional Sotatercept doses, which prompted discontinuation of Sotatercept. Following cessation, her PFTs (Supporting Information Table 2) and 6‐min walk distance declined (6MWD → 180 m), O₂ requirements rose back to 10–15 L, and she reported increased dyspnea and fatigue.

3.2. Patient 2

A 62‐year‐old female with PLCH–related chronic hypoxic respiratory failure (requiring 8–10 L O₂), former smoker, hypothyroidism, adrenal insufficiency, hypertensive heart disease, and stage III CKD was referred for refractory dyspnea and right‐heart failure. Prior to Sotatercept, she was on maximally tolerated triple therapy. Subcutaneous Sotatercept was initiated (0.3 mg/kg with a goal of 0.7 mg/kg). Baseline echocardiography estimated an RVSP of 113 mmHg, severe RV enlargement with septal flattening, markedly reduced TAPSE, and preserved LV size with normal EF. Pre Sotatercept treatment RHC revealed near systemic pulmonary arterial pressures (mPAP ~65 mmHg), with mildly elevated PCWP ( ~ 19 mmHg), and RAP 8 mmHg, CO/CI of 6.8/4.4 and PVR of 6.6 WU (Supporting Information Table 3). Notably, baseline initial hemodynamics prior to PH therapy, had multiple normal left atrial pressure assessments with PCWP and LVEDP. With shared decision making, Sotatercept was added to her regimen; within 1 year, her functional status improved to NYHA II, RV size was nearly normalized on echo, and septal flattening improved. Repeat hemodynamics demonstrated a mean pulmonary artery pressure of 45 mmHg, CO/CI of 3.4/2.1, and PVR of 8.2 WU. Oxygen requirement improved to 6 L.

3.3. Patient 3

A 48‐year‐old female with fibrotic interstitial lung disease phenotyped as PLCH with lung biopsy, heavy tobacco and methamphetamine exposure, and obesity, was initially hospitalized due to refractory dyspnea at rest on high‐flow nasal cannula (100% FiO₂). The patient was an active drug user, due to which the patient was deemed not to be a candidate for transplant evaluation. HRCT showed diffuse centrilobular emphysema, upper‐lobe cystic PLCH, and pulmonary fibrosis. Echocardiogram demonstrated severe RV enlargement with interventricular septal flattening, severe RV systolic dysfunction, hyperdynamic LV, and estimated sPAP ≈ 110 mmHg. Baseline PFTs were not reported, but RHC confirmed near‐suprasystemic precapillary PH (Supporting Information Table 4), with no acute vasoreactivity to inhaled nitric oxide. NT‐BNP was markedly elevated. Initial management with maximally tolerated triple therapy, along 15 L oxygen requirment. Although shock and systemic congestion improved, she remained NYHA IV. Five‐month follow‐up RHC demonstrated a significant drop in mPAP (to ~66 mmHg) and PVR, but CI remained low. With shared decision‐making, Sotatercept was added (0.3 mg/kg with a goal of 0.7 mg/kg). Within weeks, her dyspnea improved to NYHA II, her stamina increased, NT‐BNP normalized, and repeat imaging showed reduced RV size and better RV function. After 1 year of Sotatercept, RHC revealed near‐normalization of CI, further PVR reduction and oxygen requirement down to 10 L. She tolerated therapy with only mild headaches and flushing and reported sustained improvement in quality of life.

3.4. Overall Takeaways

All three patients had advanced PLCH with severe precapillary pulmonary hypertension unresponsive to initial maximally tolerated triple therapies. In each case, adding Sotatercept to background PH treatments at least for 12 months (Supporting Information Table 6), produced rapid and durable improvements in hemodynamics (mPAP drops of 30%–50%), right‐ventricular remodeling, BNP/Pro‐BNP normalized, and functional capacity (6‐min walk distance increases of 100–200 m). Sotatercept‐associated side effects (thrombocytopenia, epistaxis, headaches) were generally manageable but led to discontinuation in one patient due to severity at 14 months of treatment initiation, while rest of the patients tolerated. Collectively, these experiences highlight that early escalation to Sotatercept in PLCH‐PH may reverse right‐heart failure and significantly reduce O₂ requirements, even when other therapies have plateaued (Supporting Information Table 5). RHC showed that Patient 3 experienced a decrease in both CO and CI after treatment, with CO dropping from 4.0 to 3.2 L/min and CI from 2.0 to 1.7 L/min/m². This could be explained using vasodilators, such as Sildenafil and Treprostinil along NSTEMI event. In addition, the significant PVR decrease (from 6.0 to 3.5 WU) might have caused excessive unloading of the right ventricle, potentially leading to decreased preload and subsequent lower CO and CI. Despite worsening in CO and CI, clinically patient was clinically better and did not have any sign of hypoperfusion or functional capacity worsening (Supporting Information Figure 1).

4. Literature Review

Between 2010 and 2025, 34 PLCH‐PH cases were reported, involving patients aged 18–65 (average late thirties), half female, and 75% current or former smokers, often with cannabis use. Symptom duration varied: some had progressive dyspnea for years, others presented acutely with pneumothorax or right‐heart failure. Most (80%) reported chronic dyspnea, often with cough, fatigue, or weight loss. Some younger patients with multisystem involvement had prior diabetes insipidus or hypogonadism, hinting at Langerhans cell disease. Physical exams showed tachycardia or right‐ventricular enlargement, but misdiagnoses (e.g., COPD, asthma) were common until imaging or biopsy established PLCH.

Diagnosis relied on high‐resolution chest CT (HRCT) and biopsy. HRCT typically revealed upper‐lobe cysts or nodules, sparing the lung bases. In two‐thirds of cases, video‐assisted thoracoscopic surgery (VATS) or pleurectomy provided tissue for CD1a/S100 immunostaining, confirming Langerhans cells. Bronchoalveolar lavage occasionally supported the diagnosis. PH evaluation followed, with echocardiography detecting elevated right‐ventricular pressures (sPAP > 40 mmHg) and right‐heart catheterization confirming precapillary PH (mPAP 40–50 mmHg, high PVR, often right‐atrial hypertension).

Treatment varied by PLCH stage and PH severity. Smoking cessation was universal, but most patients needed more. Mild‐to‐moderate PH patients often improved with single‐agent vasodilators (bosentan, sildenafil). Adding prostanoids (iloprost, treprostinil) enhanced outcomes. Severe PH cases received upfront combination therapy (ERA + PDE5 inhibitor ± prostanoid), yielding significant mPAP drops (10–20 mmHg) and improved 6‐min walk distance. Multisystem LCH patients got cladribine, sometimes with prednisone, but severe PH still required vasodilators. Supplemental oxygen, diuretics, and anticoagulation supported right‐ventricular function. Recurrent pneumothoraces often needed chest tubes, pleurodesis, or bullectomy. Endocrine replacement was vital for multisystem cases.

Most patients saw significant hemodynamic improvements: mPAP dropped by about 12 mmHg, PVR fell by nearly half, and right‐atrial pressure decreased by 40%. Functional capacity, measured by 6‐min walk distance, often more than doubled, with many on triple‐therapy regimens walking over 250 m within a month. NT‐proBNP levels, when rechecked, fell by roughly 75%, reflecting substantial right‐ventricular relief. Clinically, about 70% of patients improved by at least one NYHA functional class, and six initially listed for lung transplantation stabilized on medical therapy, avoiding the procedure. Three others successfully underwent transplantation after pulmonary vasodilator bridging.

Despite these gains, about 20% of patients died, typically those with delayed diagnosis or rapidly progressive disease unresponsive to therapy. Causes included refractory right‐heart failure, acute respiratory failure, or complications from advanced pulmonary vascular remodeling. Adverse events, such as liver dysfunction from bosentan, hypotension from prostanoids, or neutropenia from cladribine, were uncommon and rarely led to stopping treatment. Recurrent pneumothoraces, however, posed a persistent challenge, sometimes requiring repeated surgical interventions.

In summary, PLCH‐PH typically presents in smokers aged 30–40 years, often after years of insidious respiratory symptoms. Early recognition of characteristic HRCT features and prompt RHC confirms the diagnosis. Smoking cessation alone is insufficient once PH develops; targeted vasodilator therapy—especially combination regimens—achieves the greatest hemodynamic and functional benefits, with cladribine serving as an important adjunct in multisystem LCH. With a comprehensive, personalized approach, most patients experience durable improvement, although delayed treatment and aggressive disease correlate with poorer survival. Continued collaborative research is needed to refine optimal treatment sequencing and evaluate novel agents in this challenging population (Supporting Information Table 7).

5. Discussion

PH is a devastating condition marked by uncontrolled proliferation and resistance to apoptosis in the cells lining the pulmonary vasculature. Over time, these changes lead to narrowing and stiffening of the small pulmonary arteries, raising PVR and placing increasing strain on the right ventricle. Current therapies—targeting the endothelin, nitric oxide, and prostacyclin pathways—can improve symptoms and delay disease progression, but they don't directly address the deeper biological disturbances driving the disease [7, 8, 9, 10]. One key player in that biology is the transforming growth factor‐β (TGF‐β) superfamily signaling network, which becomes dysregulated in PH and drives pathological vascular remodeling [11, 12, 13, 14, 15].

Sotatercept offers a new way forward. It's a fusion protein designed to restore balance to the TGF‐β pathway by binding and neutralizing pro‐proliferative ligands like activin A and GDF11. This shifts the signaling environment back toward an anti‐proliferative state—specifically, activating SMAD1/5/8 pathways while dampening the SMAD2/3 axis. In doing so, Sotatercept targets the vascular remodeling process more directly than traditional vasodilators [7, 8, 16, 17].

Though classified as WHO Group 5 PH, PLCH‐PH shares striking pathobiological features with Group 1 PH—including aberrant TGF‐β signaling and smooth muscle hyperplasia. Yet, unlike idiopathic PH, PLCH‐PH stems from a distinct inflammatory and fibrotic process driven by Langerhans cells, often leading to cystic and granulomatous changes in the lungs. These differences make conventional PH therapies only modestly effective in this setting. The mechanistic overlap with TGF‐β dysregulation, suggests Sotatercept might offer therapeutic value even here—where few options exist [1, 5, 7, 13, 18, 19].

The initial promise of Sotatercept was demonstrated in the PULSAR and STELLAR trials specifically enrolled patients with WHO Group 1 pulmonary arterial hypertension, which showed meaningful gains in 6‐min walk distance (6MWD), NT‐proBNP levels, and PVR among patients with WHO functional class II–III PAH already on background therapy. More recently, the ZENITH trial (2025) took these findings a step further, enrolling 172 patients with more severe disease—functional class III–IV and high‐risk status based on REVEAL Lite 2 scores (≥ 9). Even in this vulnerable cohort, Sotatercept delivered striking benefits. Over 24 weeks, it reduced the risk of death, lung transplantation, or prolonged hospitalization for PH by 76% (HR 0.24; 95% CI 0.13–0.43; p < 0.001), and cut hospitalization for worsening PH fivefold (9.3% vs. 50.0%) [7, 8, 9, 10].

Improvements weren't limited to clinical outcomes. Hemodynamic and biomarker responses were equally impressive: NT‐proBNP fell by over 2300 pg/mL, mean pulmonary artery pressure dropped by 21 mmHg, PVR fell by 339.6 dyn·s·cm⁻⁵, and 6MWD rose by 63 meters. Perhaps most notably, nearly half the patients in the Sotatercept arm improved to a lower REVEAL risk category—even though most were already receiving triple therapy, including prostacyclin infusion. These results speak to Sotatercept potential as a true disease‐modifying agent, not simply an adjunct vasodilator [9, 10, 17].

As for safety, the ZENITH trial enrolling WHO Group 1 PH patients, confirmed the profile seen in earlier studies. While adverse events like epistaxis (44.2%), telangiectasia (25.6%), and gingival bleeding (10.5%) were more common with Sotatercept, serious adverse events, drug discontinuations, and mortality were all less frequent. Laboratory abnormalities such as elevated hemoglobin and thrombocytopenia (both ~12.8%) were observed but were manageable. Importantly, there was no excess of serious bleeding events [7, 9, 17].

These findings have been echoed in several independent meta‐analyses, which help place the drug's effects into a broader perspective. Jaiswal et al., pooling data from PULSAR and STELLAR, found that Sotatercept led to significant reductions in PVR (SMD –1.00), mean PAP, right atrial pressure, and NT‐proBNP, with lower mortality and higher thrombocytopenia compared to placebo. Nasrollahzadeh et al. extended these conclusions across additional trials, confirming consistent gains in functional class and PVR. Uddin et al. reported a nearly 35‐meter improvement in 6MWD and a 2.5‐fold increase in the odds of WHO class improvement, though the NT‐proBNP change narrowly missed significance [7, 8, 20, 21, 22].

Looking to the long term, McLaughlin et al. modeled the potential population‐level impact of adding Sotatercept to standard care. Their projections were compelling: an average 11.5‐year gain in life expectancy, 683 hospitalizations prevented, and fewer lung transplants and prostacyclin infusions required across a patient's lifetime. While such models depend on assumptions, the magnitude of potential benefit underscores Sotatercept potential in PH management [8, 9, 23].

In the SPECTRA trial, 21 patients with WHO group 1 PH on background therapy underwent cardiopulmonary exercise testing and cardiac MRI before and after treatment. Peak oxygen uptake (VO₂) increased significantly, and many patients experienced a > 50% drop in PVR. But more than that—imaging revealed reverse right ventricular remodeling: reduced RV mass and end‐diastolic volume, and improved ejection fraction. In short, Sotatercept didn't just reduce afterload—it may be changing the structure and function of the RV itself in a beneficial way [24].

For rare and understudied entities like PLCH‐PH, these mechanistic insights and clinical outcomes offer a framework for cautious optimism. While formal trials in Group 5 PH are lacking, anecdotal use and emerging case series suggest that Sotatercept could offer real benefit by targeting the fibrotic, inflammatory pathways central to PLCH pathology. As evidence continues to accumulate, Sotatercept stands out not only as an innovation in PH—but as a candidate for redefining treatment paradigms in complex, fibrotic forms of PH like PLCH [1, 2, 5, 9, 13, 17].

PLCH‐PH remains one of the most challenging and understudied forms of Group 5 pulmonary hypertension, frequently excluded from clinical trials, leaving limited evidence to guide therapy [25, 26, 27, 28]. As outlined in the 2022 ESC/ERS guidelines, PLCH‐PH arises through a convergence of mechanisms: on one hand, a PH‐like vasculopathy driven by granulomatous inflammation and vascular remodeling; and on the other, hypoxia‐induced vasoconstriction from cystic parenchymal destruction and ventilation–perfusion mismatch. This mixed pathophysiology often produces pulmonary pressures out of proportion to traditional lung function markers, making clinical recognition and treatment complex [29, 30, 31].

The landmark French cohort by Le Pavec et al., published in CHEST journal, described 29 well‐characterized patients with PLCH‐PH confirmed by right heart catheterization, the burden of disease was substantial: mPAP 45  ±  14 mmHg, PVR 555  ±  253 dyn·s·cm⁵, and 83% in WHO functional class III or IV at presentation. Importantly, targeted PH therapies—used in 12 patients—were not only well tolerated but also led to sustained hemodynamic improvement (mPAP reduced from 56 to 45 mmHg, PVR from 701 to 469 dyn·s·cm⁵) without compromising oxygenation or triggering pulmonary edema. The study underscored that meaningful hemodynamic responses in PLCH‐PH are possible, even in the setting of advanced cystic disease, and that WHO class remained the strongest predictor of survival [5].

Importantly, our decision to proceed with Sotatercept was guided by the same caution voiced in the CHEST series: that vasodilators—particularly in diseases with postcapillary involvement—could pose risks of worsening V/Q mismatch or pulmonary edema. Yet, like the French group, we observed none of these complications. This may reflect the underlying histopathology, which often includes plexiform‐like lesions and diffuse intimal and medial thickening even in areas remote from nodular disease, suggesting a systemic, rather than localized, vascular process [5]. Our three institutional patients reflect the severe end of that same spectrum. All were symptomatic despite being on dual or triple PH‐targeted therapy, had no option for transplantation due to comorbidity or frailty, and were progressively declining. In this context, and after careful multidisciplinary discussion, we opted for off‐label use of Sotatercept—an investigational agent targeting the TGF‐β superfamily pathway, which holds the promise of not just vasodilation, but vascular remodeling reversal [24, 32, 33, 34, 35].

Taken together, our experience affirms and builds upon the Le Pavec et al. findings. In patients with advanced PLCH‐PH who are no longer responding to standard therapy and are ineligible for transplant, Sotatercept may offer a life‐altering option, especially if introduced early, before right‐heart failure becomes irreversible. However, we caution that its use in cystic lung disease must be accompanied by close surveillance for bleeding and hypoxemia. Moving forward, we need prospective trials that include PLCH‐PH and other rare Group 5 diseases, explore genotype‐based response predictors (e.g., BMPR2, GDF2), and assess long‐term outcomes such as transplant‐free survival [5].

Most patients experience meaningful improvements, but a subset does not. Langleben et al. described a 41‐year‐old man with heritable PH linked to a BMP9 (GDF2) missense variant (c.1276 T > C; p. Cys426Arg). Despite 15 months of Sotatercept, his symptoms, hemodynamics and labs remained unchanged, and he never developed telangiectasias. The authors hypothesized that without functional BMP9, the ligand‐trap mechanism failed to shift signaling back to the SMAD1/5/8 side—there simply wasn't enough BMP9 around to activate anti‐proliferative signals. This case underscores the potential benefit of genetic screening (for BMP9/GDF2 or BMPR2 variants) to identify patients who may not derive benefit and to avoid exposing them to cost and side effects [36].

Ultimately, PLCH‐PH is a disease where destruction and proliferation having devastating effect of patient's daily life, therapies like Sotatercept may offer a path not just to palliation, but to reversal.

6. Conclusion

PH is a devastating complication of pulmonary Langerhans cell histiocytosis in which parenchymal cystic destruction and granulomatous vascular remodeling synergize to drive severe precapillary hypertension. While combination PH therapies and cytotoxic agents (cladribine) can produce meaningful hemodynamic and functional improvements, a subset of patients remains refractory and faces high mortality. Sotatercept, by reestablishing TGF‐β superfamily signaling balance, offers a novel, disease‐modifying approach that can rapidly reverse severe vascular remodeling, improve right‐heart function, and enhance exercise capacity. These promising preliminary findings warrant initiation of clinical trials.

7. Limitations

Our conclusions derive from a limited number of heterogeneous case reports and three multi‐center patients, precluding definitive causal inference; the retrospective nature and publication bias inherent in case series further constrain generalizability. Variability in timing of hemodynamic assessments across reports complicates direct comparison. Moreover, long‐term outcomes—such as sustained transplant avoidance, overall survival, and durability of Sotatercept response—remain unknown absent prospective follow‐up. Adverse event reporting in case narratives may understate the true incidence of hematologic and hemorrhagic complications within cystic lungs.

Author Contributions

All authors contributed substantially to the conception and design of the study, acquisition and interpretation of data, and drafting or critical revision of the manuscript. Parth Rali was responsible for study conception and design. Giorgi Chilingarashvili, Ruben Joseph Mylvaganam, and Roberto J. Bernardo collected and analyzed the data. Giorgi Chilingarashvili drafted the initial manuscript. All authors reviewed, revised, and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

The authors received no specific funding for this work.

Ethics Statement

Written informed consent was obtained from all patients prior to inclusion in the study. Patient confidentiality was maintained throughout the research process, and all data were de‐identified prior to analysis.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table 1: Patient 1 RHC parameters before and after treatment. After treatment, the patient demonstrated marked hemodynamic improvement. Table 2: Patient 1, pulmonary function test results represented with treatment regimen. Table 3: Patient 2 RHC parameters. Treatment reduced mean PA pressure (−28 mmHg), PAWP (−9 mmHg), and RAP (−9 mmHg), showing improved filling pressures. Table 4: Patient 3 RHC parameters. In Patient 3, treatment led to striking hemodynamic improvement. Table 5: Summarizes prostacyclin dosing and oxygenation changes during treatment across three patients. Table 6: Treatment length by patient by the time of manuscript submission. Table 7: Overview of published case reports.

Chilingarashvili G, Mylvaganam RJ, Bernardo RJ, Shah A, Cuttica M, Roberts T, Marchetti N, Rali P, “Sotatercept in Pulmonary Langerhans Cell Histiocytosis‐Associated Pulmonary Hypertension: A Case Series and Systematic Review,” Pulmonary Circulation 16 (2026): 1‐7. 10.1002/pul2.70239.