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Adjuvant Molecular Hydrogen Therapy in SLE-associated Pulmonary Arterial Hypertension: A Case Report on Immunomodulatory Effects on Regulatory and Effector Lymphocytes

CHIN LIU, JENG-WEI LU, CHUN-HSIEN WU, YI-JUNG HO, SHAN-WEN LUI, TING-YU HSIEH, KUANG-YIH WANG and FENG-CHENG LIU
In Vivo January 2026, 40 (1) 551-560; DOI: https://doi.org/10.21873/invivo.14220

Abstract

Background/Aim: Pulmonary arterial hypertension (PAH) is a significant and challenging complication for patients with systemic lupus erythematosus (SLE). It is thought to arise from immune dysregulation and vascular remodeling, ultimately leading to progressive right heart failure. Molecular hydrogen therapy, a selective antioxidant and anti-inflammatory agent, may modulate the immune responses seen in autoimmune diseases. This case report details the use of adjuvant hydrogen capsule therapy in a patient with SLE with PAH, suggesting its potential as a novel approach for this difficult clinical condition.

Case Report: A 42-year-old Taiwanese woman with SLE-PAH received hydrogen capsule therapy, during which serial immunophenotyping revealed dynamic changes in suppressive markers including programmed cell death protein 1 (PD1) and Fas cell surface death receptor (FAS), as well as regulatory T- and B-cell subsets. Notably, the populations of double negative and class-switched memory B-cells decreased during therapy, suggesting durable immune suppression. These results support the effect of hydrogen capsule therapy in achieving immune tolerance and inflammation modulation.

Conclusion: This case study suggests that molecular hydrogen therapy may be a promising treatment for patients with SLE-PAH, particularly due to its immunomodulatory effects.

Keywords:

Introduction

Pulmonary arterial hypertension (PAH) is a progressive, debilitating vascular disease marked by remodeling of the small pulmonary arteries. This leads to increased pulmonary vascular resistance and, eventually, right ventricular failure (1). The exact cause is complex and multifactorial, involving genetics, endothelial dysfunction, smooth muscle cell proliferation, and an imbalance of factors that constrict and dilate blood vessels. Key pathological features include vascular remodeling, thrombosis formation, and inflammation (2). Because symptoms such as fatigue, dyspnea on exertion, palpitations, and hemoptysis can be subtle, PAH is often missed in clinical practice at an early stage.

PAH can stem from various causes, and includes idiopathic types, genetic types, and its association with other medical conditions. Among these, PAH is a significant complication of several systemic autoimmune diseases, most commonly systemic lupus erythematosus (SLE), systemic sclerosis, and mixed connective tissue disease (3, 4). For patients with SLE, risk factors for developing PAH include Raynaud’s phenomenon, Anti-U1-RNP antibodies, disease duration, and severity (3, 5). The underlying mechanisms that connect autoimmune diseases to PAH are chronic inflammation, a buildup of circulating immune complexes within pulmonary vessels, pathological autoantibody production, and widespread damage to the endothelium. These factors collectively cause the characteristic remodeling of pulmonary blood vessels (6).

Accurate diagnosis and prognosis are vital for managing PAH. And there are several key indicators that help evaluate a patient’s condition. Functional capacity, measured by the 6-minute walk distance (6MWD), is a crucial prognostic tool that reflects exercise tolerance. Additionally, biomarkers such as B-type natriuretic peptide (BNP) or N-terminal pro-BNP are elevated in heart failure and PAH, correlating with disease severity. Patients are also classified into different functional classes using the World Health Organization (WHO) functional classification, which is a strong predictor of clinical outcomes (1).

Current treatment strategies for PAH aim to improve symptoms, quality of life, and survival by targeting the pulmonary vasculature. Calcium channel blockers (e.g., Nifedipine) are used for those who are vasoreactive responders. PAH-specific drugs aim at three main pathways: the endothelin pathway (e.g., endothelin receptor antagonists such as bosentan), the nitric oxide pathway (e.g., phosphodiesterase-5 inhibitors such as sildenafil), and the prostacyclin pathway (e.g., prostacyclin analogs such as epoprostenol) (1, 2). Despite current therapeutic advancements, many patients with PAH, especially those associated with autoimmune diseases, still face disease progression and high mortality. Although some investigations on immunosuppressive drugs or biological agents are undergoing, there remains a gap in treatment (7). This highlights the critical need for new, effective, and well-tolerated treatment options.

Molecular hydrogen therapy is gaining attention as a new treatment because it works across a wide range of diseases (8, 9). Its appeal lies in its unique ability to act as a selective antioxidant. Unlike traditional antioxidants that neutralize many reactive oxygen species, hydrogen specifically acts on cytotoxic radicals, including hydroxyl radicals and peroxynitrite anions (10). Importantly, it leaves beneficial reactive oxygen species, which are crucial for cell signaling, untouched, avoiding the potential side-effects of non-selective antioxidants. This targeted approach is key to therapeutic effectiveness (10).

Aside from its strong antioxidant effects, hydrogen also has significant anti-inflammatory and anti-apoptotic properties. It modulates key inflammatory pathways, including the most notably nuclear factor kappa (NF-κB) light-chain enhancer of activated B-cells pathway, and pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL1), and IL6 (11). Additionally, hydrogen helps maintain cellular homeostasis by preserving mitochondria integrity and function of anti-inflammatory. Owing to its small size and lipophilic nature, hydrogen molecular is easily able to cross biological membranes and directly act on mitochondria and other intracellular targets (12). This property prevents excessive or inappropriate apoptosis, thereby limiting tissue damage and inflammation (13). Research also shows its role in regulating autophagy, and its anti-shock effects, which further help reduce organ damage in severe conditions (12). Collectively, these effects explain its benefits across a wide range of conditions, from ischemia-reperfusion injury, cardiovascular diseases, respiratory diseases, neurodegenerative disorders, to cancer and chronic inflammatory diseases such as chronic kidney disease (10, 14-18).

Case reports also support the potential benefits of hydrogen therapy in connective tissue disease-associated PAH (19, 20). Considering the characteristics of oxidative stress, chronic inflammation, and cellular dysfunction in SLE and its related pulmonary hypertension, we believe that molecular hydrogen therapy may represent a promising adjunctive approach in this context.

Here, we present our observations from patients with SLE-associated PAH who received molecular hydrogen therapy, to provide preliminary clinical insight into its potential therapeutic role. Approval for this study was granted by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical University, Taiwan (no. B202105106; November 27, 2024). The patient gave written informed consent for the publication of this case report. All research procedures were carried out in accordance with institutional ethical guidelines and the principles of the Declaration of Helsinki (1964) and its subsequent updates.

Case Report

A 42-year-old Taiwanese woman was diagnosed with SLE-associated PAH with right-sided heart failure in February 2017. Her echocardiogram at that time reported an extremely high level of pulmonary artery pressure (PAP=169 mmHg), dilated right atrium and ventricle with systolic and diastolic D-shape of left ventricle, severe tricuspid regurgitation, and normal systolic function of left ventricle with the ejection fraction estimated at 66%. Right heart catheterization was performed immediately and revealed that the mean PAP was 59 mmHg, the pulmonary capillary wedge pressure was 8 mmHg, and the pulmonary vascular resistance was 22.3 Wood units.

Over the years, her disease has stayed relatively stable with regular treatment. She underwent repeated right heart catheterization in June 2019; mean PAP was 49 mmHg, pulmonary capillary wedge pressure was 9 mmHg, and pulmonary vascular resistance was 11.76 Wood units. The time course of changes in PAP measured by echocardiogram, 6MWD, and the level of pro-BNP are shown in Figure 1. Hydrogen capsule therapy (PURE HYDROGEN capsules (HoHo Biotech Co., Ltd., Taipei, Taiwan, ROC), each containing 170 mg of hydrogen-enriched coral calcium, equivalent to approximately 1.7 × 1021 molecules of molecular hydrogen) with one capsule a day was initiated as an adjunctive treatment since November 2024.

Figure 1.
Figure 1.

Trends of pulmonary artery pressure (PAP), 6-Minute Walk Distance (6MWD), and pro-B-type natriuretic peptide (pro-BNP) of this case over time.

Flow-cytometry uses blood samples which were prepared using standard fluorescent dye preparation methods and fluorescent antibody reagent kits with dried reagents (Beckman Coulter, Brea, CA, USA). The methods, steps, immunophenotypic analysis, and cell gating were conducted following previously described procedures (21). Flow-cytometric analysis of T-cells revealed dynamic immunophenotypic changes after the hydrogen capsule therapy. As shown in Figure 2, detection of programmed cell death protein 1 (PD1) positivity showed hydrogen capsule therapy tended to increase effector T-helper, effector memory T-helper, effector cytotoxic, and effector memory cytotoxic T-cells. Regarding cells with FAS expression, there were declines among B-cells, naïve B-cells, class-switched memory B-cells, and double-negative (DN) (CD27-IgD-) B-cells after hydrogen therapy (Figure 3).

Figure 2.
Figure 2.

Immunophenotypic changes in T-cells. Time course of changes in programmed cell death protein 1 (PD1)-positive effector T-helper (Th) (A), effector memory (EM) Th (B), effector cytotoxic T (Tc) (C), and EM Tc (D) cells: pre-treatment (up to October 27, 2022) and post-treatment to hydrogen capsule therapy (February 6, 2025). HC: Healthy controls; data obtained from healthy volunteers.

Figure 3.
Figure 3.

Immunophenotypic changes in B-cells. Time course of changes in Fas cell surface death receptor (FAS)-positive (A), naïve B-cells (B), class-switched memory (SM) B-cells (C), and double-negative (DN) B-cells (D): pre-treatment (up to October 27, 2022) and post-treatment to hydrogen capsule therapy (February 6, 2025). HC: Healthy controls; data obtained from healthy volunteers.

Class-switched memory B-cells, which are derived from germinal centers (22), decreased in percentage after hydrogen therapy (Figure 4A). Similarly, a drop in plasmablasts after hydrogen therapy was observed (Figure 4B). Their changes may reflect a downregulation of B-cell activation and differentiation (23, 24). Moreover, regulatory cells, including regulatory B-cells (Bregs) and T-cells (Tregs), both showed a sharp surge after hydrogen therapy (Figure 5A and B), indicating possible inflammatory suppression mediation or tolerance (23, 25). Moreover, type 1 regulatory (Tr1) cells, another interleukin-10 (IL-10) producing cell type, were attenuated during the therapy (Figure 5C).

Figure 4.
Figure 4.

Immunophenotypic changes in class-switched memory B-cells (CD27+CD38−/dim) and plasmablasts (CD27+CD38high). Time course of class-switched memory B-cells (CD27+CD38−/dim) (A) and plasmablasts (CD27+CD38high) (B): pre-treatment (up to October 27, 2022) and post-treatment to hydrogen capsule therapy (February 6, 2025). HC: Healthy controls; data obtained from healthy volunteers.

Figure 5.
Figure 5.

Immunophenotypic changes in regulatory B-cells (Breg) (A) and regulatory T-cells (Tregs) (B), and type 1 regulatory (Tr1). Time course demonstrating the Breg (A) and Tregs (B), and Tr1 cells (C): pre-treatment (up to October 27, 2022) and post-treatment to hydrogen capsule therapy (February 6, 2025). HC: Healthy controls; data obtained from healthy volunteers.

Discussion

Since the case’s clinical disease severity according to European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk stratification became stable over the years (1), we focused on immunological profiling, which revealed dynamic shifts in both effector and regulatory immune cell subsets across the course of hydrogen capsule therapy. As shown in Figure 2, the immunophenotypic changes of PD1+ expressing T-cells in this case are consistent with the feature of PD1 as regulator of immune response and peripheral tolerance, especially in effecter cells (26). The elevated level in these PD1+ T-cells may suggest a hydrogen therapy-mediated shift toward a more regulated or exhausted T-cell state (27, 28). This aligns with the known immunomodulatory effects of hydrogen, including the attenuation of oxidative stress and inflammatory pathways (13, 18), potentially contributing to immune rebalancing in autoimmune conditions.

B-Cells expressing FAS (also known as CD95 or APO1; (Figure 3) diminished during the therapy. These results are consistent with the characteristic of FAS as a trigger of NF-κB and mitogen-activated protein kinase pathways (29, 30), and with the known ability of hydrogen therapy to inhibit NF-κB activation by reducing oxidative stress and suppressing upstream signaling. Firstly, the observed downregulation of FAS+ B-cells may reflect a general dampening of the death-inducing signaling complex in response to hydrogen therapy (31). Furthermore, naïve FAS+ B-cells are thought to be primed under inflammatory cues and may serve as precursors for autoreactive clones in SLE (32, 33). Their decline suggests a suppression of early-stage B-cell activation. Moreover, FAS+ switched memory B-cells, which are antigen-experienced and capable of mounting rapid, high-affinity antibody responses, have been implicated in chronic autoantibody production in SLE (34). The reduction of these cells may contribute to reduced humoral autoimmune activity (35). Furthermore, FAS+ DN B-cells, particularly the DN2 phenotype, are recognized as pathogenic B-cells in lupus, enriched in inflammatory settings and likely to escape tolerance (35, 36). Their suppression during molecular hydrogen therapy supports the notion that hydrogen may combat the expansion of self-reactive B-cells. At the same time, these DN B-cells have a role in producing plasmablasts (35). As shown in Figure 4B, the percentage of plasmablasts in this case went straight down during hydrogen capsule therapy. Given their role in autoantibody production and association with disease flares in SLE (37, 38), this reduction suggests that hydrogen therapy may suppress pathogenic B-cell activation and extrafollicular plasmablast differentiation. This effect may be related to the downregulation of inflammatory signaling pathways [e.g., NF-κB and mitogen-activated protein kinase (MAPK)] by hydrogen, as well as the potential enhancement of regulatory immune components such as Tregs and Bregs, which may suppress B-cell differentiation. These mechanisms of regulatory cells will be further discussed below.

In addition, the decline in class-switched memory B-cells (IgD−CD27+CD21+CD38−) following hydrogen capsule therapy (Figure 4A) may reflect a relatively durable suppression of the germinal center-derived, antigen-experienced memory B-cell population (36). Along with the previously mentioned DN B-cells, these changes indicated that the prolonged regulatory effect of hydrogen therapy is not only found in extrafollicular sites but also inside the germinal center (36).

The surge in both Bregs and Tregs found during the hydrogen therapy suggests a shift toward an immunoregulatory phenotype (Figure 5A and B). Bregs, especially IL10-producing, regulate immune responses by inhibiting proinflammatory type 1 T-helper cells and type 17 T-helper cells, and supporting Treg stability (23, 24). The observed Breg increase in our patient matches the potential of hydrogen to help IL10 production and Breg proliferation under autoimmune conditions (18). Tregs, which keep peripheral tolerance and prevent autoimmunity, suppress autoreactive T- and B-cells via cell–cell contact and immunosuppressive cytokines such as IL10, transforming growth factor-β and IL35 (23, 25, 39). Similar to Bregs, hydrogen has been shown to enhance expansion of Tregs and their suppressive function by attenuating oxidative stress and modulating pathways such as NF-κB. Changes in Tregs and Bregs during hydrogen therapy in our case may suggest a trend of suppressing pathogenic autoimmunity and maintaining peripheral tolerance in SLE.

On the other hand, the type 1 regulatory T-cells, known to produce cytokines including IL10 and transforming growth factor-β (40), decreased after hydrogen therapy (Figure 5C). Corresponding with the trends in regulatory cells, molecular hydrogen contributed to maintaining immune tolerance, preventing autoimmunity, and modulating inflammatory response in our case.

Conclusion

This case study shows that molecular hydrogen therapy might help patients with SLE-PAH. The results are promising in the immunomodulatory aspect. To ensure its clinical value, larger-scale and long-term studies are needed.

Acknowledgements

This study was supported by the National Science and Technology Council, Taiwan (grants NSTC 112-2314-B-016-033, NSTC 113-2314-B-016-052 and NSTC 114-2314-B-016-052-MY3), and Tri-Service General Hospital, Taiwan (grants TSGH-E-112218 and TSGH-E-113238).

Footnotes

  • Authors’ Contributions

    CL: Conceptualization, methodology, writing original draft, writing review and editing. JWL: Conceptualization, methodology, writing original draft, writing review and editing. CHW: Conceptualization, methodology, writing review and editing. YJH: Conceptualization, methodology, writing, review and editing. SWL: Conceptualization, methodology, writing, review and editing. TYH: Conceptualization, methodology, writing, review and editing. KYW: Conceptualization, methodology, writing, review and editing. FCL: Conceptualization, investigation, supervision, writing, review and editing.

  • Conflicts of Interest

    The Authors declare no conflicts of interest associated with this study.

  • Artificial Intelligence (AI) Disclosure

    During the preparation of this manuscript, a large language model (ChatGPT, by OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning–based image enhancement tools.

  • Received September 20, 2025.
  • Revision received October 25, 2025.
  • Accepted November 13, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Adjuvant Molecular Hydrogen Therapy in SLE-associated Pulmonary Arterial Hypertension: A Case Report on Immunomodulatory Effects on Regulatory and Effector Lymphocytes
CHIN LIU, JENG-WEI LU, CHUN-HSIEN WU, YI-JUNG HO, SHAN-WEN LUI, TING-YU HSIEH, KUANG-YIH WANG, FENG-CHENG LIU
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