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. 2025 Jun 27;39(4):2186–2195. doi: 10.21873/invivo.14014

Molecular Hydrogen Therapy in Rheumatoid Arthritis: A Case Report on the Amelioration of Methotrexate-induced Myelosuppression and Immune Modulation

TING-HAO TU 1, JENG-WEI LU 2,3,4, YI-JUNG HO 5,6, SHAN-WEN LUI 7, TING-YU HSIEH 8, KUANG-YIH WANG 9, FENG-CHENG LIU 9
PMCID: PMC12223656  PMID: 40579028

Abstract

Background/Aim

Rheumatoid arthritis (RA) is a chronic autoimmune disease with systemic manifestations. Methotrexate (MTX) remains a cornerstone of RA treatment, offering significant therapeutic benefits; however, it is also associated with adverse effects, particularly myelosuppression. Molecular hydrogen, recognized for its anti-inflammatory and antioxidant properties, has demonstrated potential in mitigating oxidative stress and modulating immune responses in RA. This study aimed to evaluate the efficacy of molecular hydrogen therapy in alleviating MTX-induced myelosuppression while preserving its immunoregulatory effects in a patient with RA.

Case Report

We present the case of a 66-year-old Taiwanese female diagnosed with RA according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. The patient presented to the emergency department on August 30, 2024, with oral ulcers, sore throat, weakness, and diarrhea. Clinical assessment revealed hypotension, tachycardia, pancytopenia, hepatic insufficiency, and acute kidney injury. Outpatient medications were discontinued, and molecular hydrogen therapy was initiated. The patient exhibited marked clinical improvement, with normalization of laboratory parameters. Flow cytometry analysis demonstrated a progressive increase in the percentages of PD-1+ subsets of Th and Tc cells, as well as memory and activated regulatory T (Treg) cells. In contrast, B regulatory (Breg) cell levels remained unchanged. No adverse events were observed during the course of hydrogen therapy.

Conclusion

This is the first case report to highlight severe MTX-induced myelosuppression in an RA patient and to demonstrate the potential of molecular hydrogen therapy in modulating immune markers.

Keywords: Rheumatoid arthritis, hydrogen therapy, Th cell PD-1+ subsets, Tc cell PD-1+ subsets, Treg cell, Breg cell

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, hyperplasia, and progressive joint destruction, often leading to cartilage and bone deformities. In addition to musculoskeletal symptoms, RA presents with systemic manifestations, including cardiovascular, pulmonary, dermatological, and psychological disorder (1). The etiology of RA is multifactorial, involving genetic predisposition, aging, sex, and environmental triggers such as smoking, air pollution, silica exposure, and periodontal disease (1,2). The underlying pathogenesis is driven by dysregulated immune responses involving autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies (1). Although RA remains incurable, disease-modifying antirheumatic drugs (DMARDs) play a crucial role in managing symptoms and preventing disease progression (2,3). Methotrexate (MTX), a conventional synthetic DMARD (csDMARD), has been the first-line treatment for RA since the 1980s. Its mechanisms of action are multifaceted, including folate antagonism, adenosine signaling, modulation of cytokine profiles, and induction of reactive oxygen species (ROS) (2,4). Approximately 25%-40% of patients experience significant symptom improvement with MTX monotherapy, and nearly half of those with early RA achieve low disease activity or remission when MTX is combined with glucocorticoids (3). In cases of inadequate response, step-up therapy may involve the addition of another csDMARD, a biologic DMARD (bDMARD), or a targeted synthetic DMARD (tsDMARD) (5). Despite its efficacy, MTX is associated with various adverse effects, including nausea, stomatitis, hepatotoxicity, and myelosuppression (2-4). Up to 25% of patients discontinue MTX due to hematologic complications, with pancytopenia being a severe and unpredictable toxicity that can occur even at low doses (7.5-25 mg weekly) (6,7). MTX disrupts hematopoiesis by inhibiting cell maturation, leading to cytopenia across all blood cell lineages (7). Additionally, non-traumatic oral ulcers are a well-documented side effect, even in patients receiving low-dose MTX therapy (8).

Although the precise mechanisms underlying the anti-inflammatory and immunosuppressive effects of MTX remain incompletely understood, its role in reactive oxygen species (ROS) generation is well established. ROS contribute to cytostasis in monocytes and cytotoxic T (Tc) cells, playing a crucial role in MTX-mediated immunosuppression (9). The antagonism of polyamines, which possess oxygen-scavenging properties, may further contribute to ROS generation (10). Additionally, MTX enhances apoptosis in transformed T cells by inhibiting the recycling of oxidized dihydrobiopterin to tetrahydrobiopterin, leading to reduced levels of this essential cofactor and potentially increasing superoxide production (10). While ROS exert modulatory effects on cellular function at low concentrations, excessive oxidative stress is a key driver of MTX-induced toxicity (11). In animal models, oxidative stress has been implicated in MTX-induced intestinal damage, and co-administration of antioxidants has been shown to attenuate ROS generation and mitigate adverse effects (10,11).

Molecular hydrogen, known for its anti-inflammatory, antioxidant, and antiapoptotic properties, has been investigated as a potential therapeutic agent for various inflammatory diseases, including coronavirus disease 2019 (COVID-19), spinal cord injury (SCI), and RA (12-14). Preclinical and clinical studies have explored multiple administration methods, such as inhalation, hydrogen-rich water consumption, hydrogen saline injection, and encapsulation with coral calcium (12,15). As a selective scavenger of hydroxyl radicals, molecular hydrogen has demonstrated significant potential in reducing oxidative stress, thereby mitigating atherosclerosis and enhancing RA treatment outcomes when used alongside conventional therapy (13). Studies suggest that molecular hydrogen activates antioxidant mechanisms and suppresses key inflammatory pathways, including mitogen activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which contribute to RA pathogenesis (13,16). Furthermore, several reports indicate that molecular hydrogen therapy may improve immune markers in autoimmune diseases, supporting its potential as an adjunctive treatment strategy (17-19).

This article presents a case study of a 66-year-old female with RA undergoing long-term MTX therapy, who was admitted with myelosuppression and oral ulcers. Hydrogen therapy was initiated as an adjuvant treatment to evaluate its potential in mitigating MTX-related adverse effects while preserving its immunoregulatory functions. This study was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (IRB: B202105106, approval date: 18 July 2023), and conducted in accordance with relevant ethical guidelines. Written informed consent was obtained from all participants (No. B202105106-42). The study adhered to institutional ethical standards, the 1964 Helsinki Declaration, and its subsequent amendments or comparable ethical guidelines.

Case Report

This case involves a 66-year-old Taiwanese female who was referred from the rehabilitation outpatient department due to a one-year history of pain in the proximal interphalangeal and metacarpophalangeal joints of both hands. She tested positive for rheumatoid factor and was diagnosed with RA in March 2020, based on the 2010 American College of Rheumatology/European League Against Rheumatism criteria (score: 10). The patient had been under regular follow-up at the Rheumatology and Immunology outpatient department, receiving MTX 15 mg weekly, prednisolone 5 mg three times daily, leflunomide 20 mg daily, sulfasalazine 500 mg twice daily, and tocilizumab 162 mg weekly (Figure 1). On August 30, 2024, she presented to the emergency department with a three-day history of oral ulcers on the lips and upper hard palate (Figure 2A and Figure 3), sore throat, weakness, and watery diarrhea. On admission, her vital signs indicated hypotension (79/57 mmHg) and tachycardia (128 bpm). Laboratory findings revealed pancytopenia (white blood cell count: 2,020/μl; absolute neutrophil count: 531/μl; hemoglobin: 8.4 g/dl; platelet count: 20,000/μl), normal inflammatory markers (C-reactive protein: <0.1 mg/dl; erythrocyte sedimentation rate: 2 mm/h), hepatic insufficiency (alanine transaminase: 61 U/l), and acute kidney injury (AKI) with an elevated creatinine level of 1.2 mg/dl (baseline creatinine on August 1, 2024: 0.7 mg/dl) (Figure 4). Stool examination showed no white or red blood cells, while urine analysis revealed pyuria (white blood cells: 10-20/HPF), hyaline casts, and renal tubular epithelial cells (2-5/HPF). Peripheral blood MTX concentration was measured at <0.04 μmol/l. Chest X-ray and electrocardiography showed no significant abnormalities. The patient was initially managed with a two-unit platelet transfusion and an intravenous injection of methylprednisolone (80 mg) and was subsequently admitted for further evaluation. A tentative diagnosis of MTX-induced adverse effects was made.

Figure 1.

Figure 1

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Timeline of disease-modifying anti-rheumatic drugs (DMARDs), steroids, and other medical interventions for rheumatoid arthritis and methotrexate-induced myelosuppression. On August 10, 2023, the oral dose of prednisolone was reduced from 5 mg three times daily to 5 mg twice daily. On September 3, 2024, molecular hydrogen therapy was initiated at a dose of one capsule per day. On September 5, 2024, intravenous ceftazidime administration was switched to oral levofloxacin. On September 12, 2024, sulfasalazine 500 mg twice daily and prednisolone 5 mg twice daily were administered.

Figure 2.

Figure 2

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Morphological changes of mucosal lesions on the lips. (A) On August 31, 2024, the patient presented with a linear ulcer on the upper and lower lips, accompanied by hemorrhagic crusting. (B) By November 7, 2024, both the upper and lower lips showed complete resolution, with no evidence of ulcers or crusting.

Figure 3.

Figure 3

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Morphological changes of the mucosal lesion on the upper hard palate. A single, non-healing ulcer with an irregular, mildly raised border was observed on the left upper hard palate upon admission.

Figure 4.

Figure 4

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Line graphs depicting the levels of white blood cell count, absolute neutrophil count (ANC), hemoglobin, platelet count, creatinine, and alanine transaminase (ALT). (A-D) A marked decrease in these parameters is observed upon the patient’s admission. Following medical intervention, these values return to baseline levels within one month, indicating an improvement in pancytopenia. (E-F) Elevated levels of creatinine and ALT were noted in August 2024, indicating deteriorating renal and hepatic function. These values decreased to the normal range during hospitalization, with renal and hepatic function remaining stable in the subsequent month.

During hospitalization, MTX, sulfasalazine, leflunomide, and tocilizumab were discontinued. The patient received subcutaneous filgrastim (300 mg) and intravenous methylprednisolone (80 mg) for two days, along with supportive care and symptom management. Complete blood count, hepatic function, and renal function were closely monitored. On September 2, 2024, intravenous methylprednisolone was transitioned to oral prednisolone (5 mg twice daily). Molecular hydrogen therapy was initiated on September 3, 2024, with the administration of one hydrogen capsule daily (Figure 1). Each capsule contained 170 mg of hydrogen-rich coral calcium, delivering approximately 1.7×1021 molecules of hydrogen. On September 4, 2024, a gastroscopy was performed to evaluate anemia, revealing a gastric ulcer and superficial gastritis. Laboratory parameters, including creatinine, alanine transaminase, and complete blood count, gradually normalized (Figure 4). The patient was discharged on September 7, 2024, with stable vital signs and significant improvement in hepatic insufficiency, acute kidney injury, and pancytopenia. However, ulcers on the lips and upper hard palate persisted. By November 7, 2024, these ulcers showed notable improvement (Figure 2B). Fatigue severity was assessed using the Brief Fatigue Inventory-Taiwanese (BFI-T) before and after molecular hydrogen therapy. The evaluation demonstrated a marked reduction in fatigue levels, from severe (score: 8.1) to mild (score: 3.0)

No adverse events were observed during the administration of hydrogen capsules. To evaluate immune cell dynamics before and after hydrogen therapy, whole-blood analysis was performed using flow cytometry. Blood samples were processed using standard fluorescent dye preparation methods and fluorescent antibody reagent kits with dried reagents (Beckman Coulter, Brea, CA, USA). Immunophenotypic analysis, including cell gating, was conducted following established protocol (19-22). Our immunophenotypic assessment revealed a consistent increase in the percentage of regulatory B (Breg) cells following hydrogen therapy (Figure 5). Similarly, the proportions of memory regulatory T (Treg) cells and activated Treg cells demonstrated an upward trend post-treatment (Figure 6). Additionally, a notable increase in the percentage of both PD-1+ T helper (Th) cell subsets and PD-1+ cytotoxic T (Tc) cell subsets was observed after hydrogen therapy (Figure 7). This study adheres to the CARE reporting guidelines (2013 CARE Checklist).

Figure 5.

Figure 5

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Immunophenotypic changes in regulatory B (Breg) cells before and after the administration of molecular hydrogen therapy, initiated on September 3, 2024. Whole-blood analysis was performed fourteen times, covering both pre-therapy (up to March 5, 2020) and post-therapy (from September 3, 2024, to October 1, 2024) periods. The percentage trend of Breg cells remained consistent following the administration of molecular hydrogen therapy. HC: Initiation of molecular hydrogen capsules therapy.

Figure 6.

Figure 6

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Immunophenotypic changes in memory regulatory T (Treg) cells and activated Treg cells before and after the initiation of molecular hydrogen therapy on September 3, 2024. Whole-blood analysis was performed fourteen times, covering both pre-therapy (up to March 5, 2020) and post-therapy (from September 3, 2024, to October 1, 2024) periods. The percentage trends of memory Treg cells and activated Treg cells demonstrate an upward trajectory following the administration of molecular hydrogen therapy. HC: Initiation of molecular hydrogen capsules therapy.

Figure 7.

Figure 7

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Immunophenotypic changes in T helper (Th) cell subsets and cytotoxic T (Tc) cell subsets before and after the initiation of molecular hydrogen therapy on September 3, 2024. Whole-blood analysis was conducted fourteen times, covering both pre-therapy (up to March 5, 2020) and post-therapy (from September 3, 2024, to October 1, 2024) periods. (A to D) The percentage changes in Th cell PD-1+ subsets, including Naïve Th PD-1+, central memory (CM) Th PD-1+, effector Th PD-1+, and effector memory (EM) Th PD-1+, show an upward trend following the administration of molecular hydrogen therapy. (E to H) The percentage changes in Tc cell PD-1+ subsets, including Naïve Tc PD-1+, central memory (CM) Tc PD-1+, effector Tc PD-1+, and effector memory (EM) Tc PD-1+, also demonstrate an increasing trend after molecular hydrogen therapy. HC: Initiation of molecular hydrogen capsules therapy.

Discussion

This case report is the first to highlight the immunoregulatory effects of molecular hydrogen therapy in a patient with RA experiencing severe MTX-induced adverse effects. MTX, a widely used csDMARD, is generally well tolerated; however, it can lead to serious complications, including myelosuppression and hepatotoxicity. We report the case of a 66-year-old female with long-standing RA who developed severe pancytopenia and hepatic insufficiency, most likely attributable to MTX toxicity. Prompt recognition and timely intervention resulted in significant clinical improvement and resolution of pancytopenia. Additionally, the development of AKI in this patient was likely exacerbated by dehydration, which impaired MTX elimination and intensified its toxicity.

Breg cells play a crucial role in modulating immune responses and preventing autoimmunity by suppressing Th1 and Th17 cells while promoting Treg cell function (23). Previous studies have demonstrated an inverse correlation between Breg cell frequency and disease severity, suggesting their potential role in mitigating RA disease activity (24,25). In our case, the percentage of Breg cells did not show significant fluctuations before or after hydrogen therapy, indicating that the patient did not experience a notable RA flare-up. This finding suggests that her myelosuppression and oral ulcers were more likely attributable to MTX toxicity rather than disease progression.

In contrast to Breg cells, the role of Treg cells in the peripheral blood of patients with RA as a potential biomarker of disease activity remains a subject of debate (20). However, several studies have reported a significant increase in Treg cell frequencies in the peripheral blood of patients undergoing MTX treatment (26). Treg cells, a subset of CD4+ T cells, are characterized by the expression of the master transcription factor Forkhead box protein 3 (Foxp3), which is essential for maintaining the suppressive function of these cells (27). MTX treatment has been shown to enhance the expression of Foxp3 and CTLA-4 proteins, effectively restoring the previously impaired suppressive activity of Treg cells. This effect is believed to be mediated through a reduction in the expression of the DNA methyltransferase 1 (DNMT1) gene, leading to a significant decrease in methylation levels at the FOXP3 upstream enhancer region and the NFAT binding site within the CTLA-4 promoter. As a result, this demethylation process promotes transcriptional activity and enhances the expression of these key proteins (28). In our study, however, the therapeutic effect of MTX was not apparent during the period when adverse effects were observed, as no significant increase in the percentages of memory Treg cells and activated Treg cells was detected. In contrast, the percentages of both memory and activated Treg cells significantly increased following the initiation of molecular hydrogen therapy. These findings suggest that molecular hydrogen therapy may have the potential to modulate the percentage of Treg cells and restore their suppressive function, potentially offering a therapeutic benefit in patients experiencing MTX-induced toxicity.

The programmed cell death 1 (PD-1) receptor, along with its ligands PD-L1 and PD-L2, forms a critical inhibitory pathway that plays a key role in maintaining immune tolerance and homeostasis. This pathway also acts as a negative regulator in the pathogenesis and progression of RA (29,30). Studies have shown a significant reduction in PD-1 expression on both CD4+ and CD8+ T cells in RA patients compared to healthy controls. This decreased PD-1 expression is associated with higher disease activity, as the sustained activation of T cells, without its negative regulatory effect, may lead to uncontrolled and dysregulated inflammatory responses (30,31). The findings of our study suggest that MTX loses its efficacy in controlling disease activity, as evidenced by the instability observed in the percentage of PD-1+ T cells. Specifically, our data reveal a reduction in PD-1+ T cells that corresponds with the patient’s development of myelosuppression, indicating that MTX toxicity negatively affected both the proportion of PD-1+ T cells and their immunosuppressive function. Considering that ROS generated by MTX can induce cytostasis in T cells, molecular hydrogen therapy was introduced to mitigate the oxidative damage caused by ROS. The results indicate that the percentage of PD-1+ T cells returned to baseline levels following treatment. These findings suggest that molecular hydrogen therapy may mitigate ROS-induced oxidative damage to immune cells, thereby restoring their functionality and proportion in peripheral blood. However, further large-scale studies with long-term follow-up are required to confirm the efficacy of molecular hydrogen therapy and to establish practical guidelines for its use in patients with RA experiencing MTX-induced adverse effects.

Conclusion

This case study highlights the potential for severe myelosuppression as a complication of long-term MTX therapy in patients with RA and demonstrates the potential efficacy of molecular hydrogen therapy in managing such complications. The therapeutic promise of molecular hydrogen is particularly significant, given its antioxidant mechanisms and its ability to modulate immune markers. However, further research with larger sample sizes and extended follow-up periods is essential to confirm its clinical efficacy.

Conflicts of Interest

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

Authors’ Contributions

THT: Conceptualization, methodology, writing - original draft, writing review and editing. JWL: Conceptualization, methodology, writing - original draft, writing review and editing. YJH: Conceptualization, methodology, project administration, 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 Undergraduate Research Fellowship, Ministry of Science and Technology (MOST 111-2314-B-016-026), the National Science and Technology Council (NSTC 112-2314-B-016-033), and Tri-Service General Hospital (TSGH-E-111215; TSGH-E-112218) in Taiwan.

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.

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