Molecular Hydrogen as an Adjuvant Therapy in Comorbid Sjögren’s Syndrome, SLE, and ILD: A Case Report on Immune Modulation and Fatigue Reduction

Abstract

Background/Aim

Systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) are chronic autoimmune diseases that often coexist. They share features such as systemic inflammation and multi-organ involvement and typically require long-term immunosuppressive treatment. However, long-term use of immunosuppressants can cause serious side effects, highlighting the need for adjunct therapies. Molecular hydrogen (H₂) therapy shows anti-inflammatory, antioxidant, and immunomodulatory properties, with potential benefits in liver, lung, and metabolic diseases. This case report examines a patient with overlapping SLE, SS, and interstitial lung disease (ILD), evaluating the effects of molecular hydrogen therapy on fatigue, immune modulation, and cardiac function.

Case Report

We present the case of a 69-year-old female diagnosed with Sjögren’s syndrome, SLE, and ILD. The patient exhibited chronic symptoms, including xerostomia, xerophthalmia, and respiratory distress, for which she had been receiving corticosteroids and immunomodulatory therapy. Given the persistent disease burden and concerns regarding long-term immunosuppressive therapy, molecular hydrogen therapy was introduced as an adjunctive treatment. Over several months, the patient experienced notable clinical improvements, including resolution of xerostomia, insomnia, dyspnea, chest pain, and dizziness. These symptomatic improvements correlated with favorable immunological shifts in T and B cell subsets, enhanced pulmonary imaging findings, and a reduction in inflammatory markers. Additionally, the patient reported a significant decrease in fatigue, allowing corticosteroid tapering and less reliance on nighttime oxygen. Ongoing hydrogen therapy with high-dose vitamin C maintained disease stability and improved quality of life.

Conclusion

This case highlights the potential of molecular hydrogen (H₂) therapy as a safe, effective adjunct in managing overlapping Sjögren’s syndrome, SLE, and ILD. H₂ therapy improved immune profiles and stabilized symptoms in a patient unresponsive to standard treatments.

Introduction

Autoimmune diseases such as Sjögren’s syndrome and systemic lupus erythematosus (SLE) are characterized by dysregulated immune responses, leading to chronic inflammation and progressive tissue damage (1,2). While conventional therapies primarily rely on broad immunosuppression, there is increasing interest in adjunctive treatments that offer more selective immunomodulation with fewer adverse effects (3). Molecular hydrogen (H₂) has gained attention as a potential adjunctive therapy for inflammatory and autoimmune diseases due to its antioxidant, anti-inflammatory, and immunomodulatory properties (4,5). Although emerging evidence suggests clinical benefits of H₂ therapy in inflammatory conditions (6-8), its effects on specific immune cell populations over time remain poorly characterized. A deeper understanding of the temporal dynamics of lymphocyte subsets during H₂ therapy could elucidate its mechanisms of action and inform the optimization of treatment strategies.

Lymphocyte surface markers play a pivotal role in immune regulation and homeostasis. Fas (CD95), a key death receptor, mediates activation-induced cell death and peripheral tolerance, with aberrant expression linked to the pathogenesis of autoimmune diseases (9). Similarly, programmed death-1 (PD-1) functions as an inhibitory receptor that modulates T cell activation and maintains immune tolerance, with dysregulated expression contributing to autoimmunity (10). Dynamic changes in these markers may serve as critical indicators of immune modulation and could provide mechanistic insights into the therapeutic effects of novel interventions.

Moreover, the chronic nature of Sjögren’s syndrome and SLE often results in persistent fatigue, significantly impairing quality of life. To assess chronic fatigue, the Taiwan Brief Fatigue Inventory (BFI-T) has been employed to quantify fatigue severity in daily activities, with scores ranging from 0 (no fatigue) to 10 (most severe fatigue). Originally developed for use in Taiwanese patients with cancer, chronic illnesses, and long-term fatigue (11), the BFI-T serves as both a monitoring tool for disease activity and an outcome measure for evaluating therapeutic interventions, including immunomodulatory and H₂ therapies. Further research is warranted to explore the broader applicability of BFI-T across diverse treatment modalities, facilitating a more individualized approach to fatigue management in chronic autoimmune diseases.

In this case, H₂ therapy was administered using hydrogen capsules (PURE HYDROGEN) obtained from HoHo Biotech Co., Ltd. (Taipei, Taiwan, ROC). Each capsule contained 170 mg of hydrogen-enriched calcium, capable of releasing approximately 1.7×10²¹ hydrogen molecules-equivalent to the hydrogen content found in 24 cups (200 ml per cup) of water with a hydrogen concentration of 1,200 ppb (0.6 mM). This case report provides a comprehensive longitudinal analysis of immune cell dynamics in a 69-year-old patient with overlapping Sjögren’s syndrome, SLE, and ILD who received adjunctive H₂ therapy alongside conventional treatment. Detailed immunophenotyping revealed distinct trajectory patterns in various lymphocyte subsets, which correlated with clinical improvement, highlighting the potential role of H₂ therapy in immune modulation, fatigue reduction, and pulmonary function enhancement. This is the first report to characterize immune cell dynamics during H₂ therapy, offering novel insights into its potential immunomodulatory mechanisms and therapeutic applications in autoimmune disease management.

This study was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taiwan (IRB approval number: B202105106; approval date: July 18, 2023) and was conducted in accordance with all applicable ethical guidelines. Written informed consent was obtained from the patient for the publication of this case report. The study adhered to the ethical standards of the institution and complied with the principles outlined in the 1964 Declaration of Helsinki and its subsequent amendments or equivalent ethical standards.

Case Report

The current report presents the case of a 69-year-old female patient with a medical history of Sjögren’s syndrome and SLE, complicated by ILD, refractory hypertension, recurrent urinary tract infections, restless leg syndrome, chronic insomnia, and osteoporosis [bone mineral density (BMD): -2.64]. Additional comorbidities included cervical spine disease with C4-C6 disc narrowing and osteophyte formation, as well as left S1 disc herniation with associated neuropathy.

At the age of 43, the patient underwent a salivary gland biopsy due to persistent xerostomia. Serological analysis revealed markedly elevated levels of anti-Ro antibody (1889) and anti-La antibody (1041), leading to a diagnosis of Sjögren’s syndrome. She was subsequently treated with corticosteroids and Myfortic (mycophenolic acid). At the age of 51, she was diagnosed with stage II invasive ductal carcinoma of the left breast. During chemotherapy, abnormally elevated antinuclear antibody (ANA) titers (1:640) were detected, leading to the confirmation of SLE. At the age of 60, imaging studies revealed fibrotic lung nodules and bronchiectasis, resulting in a diagnosis of ILD, accompanied by progressive respiratory impairment that significantly compromised her daily activities. Despite adherence to conventional treatments, including corticosteroid injections, immunosuppressive therapy, and dietary modifications, the patient showed only modest improvements in inflammatory markers, sleep quality, and respiratory function.

In December 2021, the patient commenced molecular hydrogen capsule therapy as an adjunctive treatment, taking one hydrogen capsule daily in combination with high-dose vitamin C supplementation. After several months, biochemical markers demonstrated substantial improvement, along with enhanced sleep quality, increased physical strength, disease stability, and improved appetite. Imaging studies, including chest X-ray and computed tomography (CT) scans, showed no further progression of pulmonary fibrosis or bronchiectasis, indicating effective disease control of ILD (Figure 1).

Figure 1.

The patient was diagnosed with interstitial lung disease (ILD) in 2015 and began hydrogen therapy in 2021. Since the initiation of therapy, the progression of pulmonary fibrosis and bronchiectasis was controlled, with no rapid deterioration observed on chest X-ray assessments.

Cardiovascular assessment using artificial intelligence (AI)-based electrocardiogram (EKG) analysis estimated the cardiac age to be 58.3 years for this patient, notably lower than her chronological age of 69, further indicating an overall improvement in her health status. Additionally, a quality-of-life evaluation using the Brief Fatigue Inventory-Taiwan version (BFI-T) revealed a significant reduction in fatigue and insomnia, along with an overall improvement in quality of life (Figure 2). Following hydrogen therapy, immunological changes were observed, including: a) Increased CD95+ T cells (Figure 3); b) Decreased TIM-3+ cytotoxic T cells (Tc) (Figure 4); c) Reduction in B cell subpopulations (DN/SM/naïve B cell PD-1, plasmablast) (Figure 5). Clinically, the patient’s condition remained stable, with no adverse effects reported, suggesting that hydrogen therapy may exert immunomodulatory effects.

Figure 2.

Timeline illustrating the progression of immune-related diseases and corresponding medication treatments for this patient.

Figure 3.

Immunophenotypic changes in T cells following molecular hydrogen therapy. Whole blood analysis was conducted before and after hydrogen therapy, with the Health Control (HC) group shown for comparison (far left). Panels (A, B, C) demonstrate that the percentages of central memory (CM) helper T cells (Th) Fas+, central memory (CM) cytotoxic T cells (Tc) Fas+, and effector memory (EM) cytotoxic T cells (Tc) Fas+ exhibit increasing trends after hydrogen therapy, eventually returning to levels comparable to those in the Health Control (HC) group.

Figure 4.

Immunophenotypic changes in T cells following molecular hydrogen therapy. Whole blood analysis was conducted before and after hydrogen therapy, with the Health Control (HC) group shown for comparison (far left). Panels (A, B, C) demonstrate that the percentages of central memory (CM) cytotoxic T cells (Tc) Tim-3+, effector memory (EM) cytotoxic T cells (Tc) Tim-3+, and naïve cytotoxic T cells (Tc) Tim-3+ exhibit decreasing trends after hydrogen therapy, eventually returning to levels comparable to those in the Health Control (HC) group.

Figure 5.

Immunophenotypic changes in B cells following molecular hydrogen therapy. Whole blood analysis was conducted before and after molecular hydrogen therapy, with the Health Control (HC) group shown for comparison (far left). Panels (A, B, C, D) demonstrate that double-negative (DN) B cells PD-1+, switched memory (SM) B cells PD-1+, naïve B cells PD-1+, and plasmablasts significantly decrease after molecular hydrogen therapy.

Discussion

This case underscores the potential of hydrogen therapy as an adjunctive treatment for patients with autoimmune clustering. Given the complexity of managing individuals with multiple immune comorbidities, the risk of drug interactions and cumulative side effects is markedly increased. The successful reduction in steroid use through hydrogen therapy helped maintain disease stability while mitigating the risks associated with osteoporosis, hypertension, diabetes, and infections (12). The patient, diagnosed with SLE, Sjögren’s syndrome, and ILD, exhibited notable biochemical improvements, enhanced quality of life, and reduced autoimmune activity following hydrogen therapy. These findings highlight the multifaceted therapeutic effects of hydrogen in modulating oxidative stress, reducing inflammation, and regulating immune responses.

Molecular hydrogen (H₂) exerts therapeutic effects through antioxidant, anti-inflammatory, anti-apoptotic, and gene-regulatory mechanisms (13). At therapeutic concentrations, H₂ is non-toxic, making it suitable for long-term use (14). Current research suggests that H₂ therapy holds potential for the treatment of various diseases, including stroke, myocardial ischemia-reperfusion injury, chronic kidney disease, diabetes, and chronic obstructive pulmonary disease (COPD) (15-17). A key mechanism of H₂ action is the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, which promotes the transcription of antioxidant enzymes and mitigates oxidative stress. This process involves the interaction of H₂ with hydroxyl radicals (•OH) and heme proteins (PrP-Fe), leading to the release and activation of NRF2, thereby providing antioxidative and cytoprotective effects (18).

Hydrogen capsules are formulated by stabilizing hydrogen on coral calcium, ensuring sustained release and antioxidant properties (17-21). In patients with pulmonary fibrosis-associated interstitial lung disease (PF-ILD) complicated by pneumonia, H₂ therapy has been shown to reduce lung 8-hydroxy-2’-deoxyguanosine-positive cells and suppress the elevation of tumor necrosis factor-alpha (TNF-α), BAX BCL2-associated X protein (BAX), transforming growth factor-beta (TGF-β), interleukin-6 (IL-6), and soluble collagen levels, demonstrating its immunomodulatory potential (22). Overall, hydrogen capsules exhibit antioxidative, anti-inflammatory, and lipid-regulating properties, offering potential therapeutic benefits for liver health, pulmonary diseases, and metabolic syndrome.

Flow cytometry and serological testing were employed for whole blood analysis to assess changes in immune cell populations, electrocardiogram (ECG)-predicted cardiac age, and fatigue levels before and after hydrogen therapy. Blood samples were processed using standard fluorescence dye protocols and immunophenotyping with fluorescent antibody reagent kits (Beckman Coulter, Brea, CA, USA). The analysis revealed that following hydrogen therapy, there was an increase in CD95⁺ T cells, a decrease in TIM-3⁺ cytotoxic T (Tc) cells, and a reduction in the PD-1⁺ B cell subset (Figure 3, Figure 4, and Figure 5). Additionally, ECG-predicted cardiac age was 58.3 years, notably lower than the chronological age of 69 years for this patient. Fatigue levels improved significantly, as evidenced by a reduction in the Brief Fatigue Inventory-Total (BFI-T) score, which decreased from 51 to 18, reflecting a substantial reduction in fatigue and a marked enhancement in quality of life.

Furthermore, no adverse effects were observed throughout the treatment period, further reinforcing the safety profile of molecular hydrogen therapy. Given its non-invasive nature and convenient oral administration, H₂ therapy represents a promising long-term management option for patients with multiple immune comorbidities. However, this case highlights the need for larger-scale randomized controlled trials to confirm these findings and establish standardized dosing protocols.

Conclusion

Molecular hydrogen therapy appears to be a safe and effective adjunctive treatment for patients with multiple autoimmune comorbidities, particularly those with an inadequate response to conventional therapies. By modulating immune-inflammatory responses and oxidative stress, H₂ may improve treatment outcomes, reduce the required dosage of conventional medications, and enhance quality of life. This case report further supports its therapeutic potential; however, further research is necessary to establish a causal relationship between this therapy and its effects, elucidate its mechanisms of action, and investigate its role in autoimmune diseases and associated pulmonary complications.

Conflicts of Interest

The Authors declare that they have no conflicts of interest or competing interests related to this study.

Authors’ Contributions

YHT: Conceptualization, methodology, writing original draft, writing review and editing. JWL: Conceptualization, methodology, writing original draft, writing review and editing. JIT: Conceptualization, methodology, writing review and editing. YJL: Conceptualization, methodology, project administration, writing, review and editing. HFH: Conceptualization, methodology, writing, review and editing. FAC: 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.

Acknowledgements

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

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.