Abstract
Background/Aim: Rhupus syndrome, an overlap of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), is a rare condition characterized by heterogeneous clinical manifestations and difficult management. Conventional therapies, including glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), immunosuppressants, and biologics, are often limited by drug intolerance and steroid-related complications. Molecular hydrogen (H2) has emerged as a potential adjuvant therapy due to its antioxidant and immunomodulatory properties. This report aimed to evaluate the clinical efficacy of H2 as an adjunct to rituximab in a patient with refractory Rhupus and multiple drug intolerances.
Case Report: We report a 47-year-old male with a 27-year history of rheumatoid arthritis, who subsequently developed systemic lupus erythematosus, fulfilling criteria for Rhupus syndrome. His disease course was complicated by multiple drug intolerances, including adverse reactions to methotrexate, sulfasalazine, hydroxychloroquine, azathioprine, leflunomide, and rituximab at standard dosing. Despite reduced-dose rituximab and mycophenolic acid, disease activity persisted and lupus nephritis was confirmed. In October 2023, oral molecular hydrogen capsule therapy was initiated as adjuvant treatment, resulting in significant clinical improvement, which was paralleled by characteristic changes in T- and B-cell subsets, normalization of anti-dsDNA antibody, erythrocyte sedimentation rate (ESR), and complement levels, and successful discontinuation of prednisone. Hydrogen therapy was well tolerated without major adverse effects. The patient developed avascular necrosis from prior corticosteroid use but recovered well after hip arthroplasty in January 2025. Disease control was sustained with mycophenolic acid and continued hydrogen therapy.
Conclusion: This case suggests molecular hydrogen therapy as a potential adjuvant for refractory Rhupus with multiple drug intolerances, showing immune modulation, reduced inflammation, steroid withdrawal, and sustained control with low-dose rituximab. Further studies are needed to confirm its efficacy and standardize its use.
Introduction
Rhupus syndrome is an overlap condition of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The most widely accepted definition of rhupus is the simultaneous fulfillment of the diagnostic criteria for SLE [Systemic Lupus International Collaborating Clinics (SLICC) or American College of Rheumatology (ACR) classification criteria] and for RA [ACR or ACR/European League Against Rheumatism (EULAR) criteria] (1). However, the coexistence of RA and SLE is exceedingly rare, with the largest recent series reporting prevalences of 1.3% (2) and 1.4% (3). Due to its heterogeneous clinical manifestations and multisystem involvement, management remains highly challenging (2, 4). At present, there is no standardized classification, follow-up, or therapeutic guideline for rhupus (1). Current treatment approaches are mainly derived from a limited number of clinical trials, case reports, and retrospective cohort studies, with a lack of large randomized controlled trials. Thus, management largely relies on clinical experience and extrapolation from established treatment strategies for SLE and RA (2). Glucocorticoids are administered at diagnosis in most patients, with a mean daily dose ranging from 6.5 to 15 mg (2, 4-6). Conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, hydroxychloroquine, sulfasalazine, azathioprine, and leflunomide, are commonly administered in combination with glucocorticoids (2, 5, 7). Immunosuppressive agents, including mycophenolate mofetil, cyclophosphamide, and cyclosporine, are primarily reserved for patients with major organ involvement, particularly renal disease (8-11). Biologic agents applied in rhupus management include anti-tumor necrosis factor (anti-TNF) therapies (e.g., etanercept, adalimumab) (7, 12), abatacept (13), and rituximab (5, 14). However, studies have demonstrated that long-term glucocorticoid use significantly increases the risk of avascular necrosis (AVN) of the femoral head, as well as infections and cardiovascular complications (15, 16). Management becomes even more challenging when patients develop intolerance or adverse reactions to conventional therapies. Drug-induced leukopenia, pneumonitis, and other severe adverse events may necessitate discontinuation of effective treatments, thereby further limiting therapeutic options for these complex cases (17). Consequently, the search for novel adjuvant therapies with favorable safety profiles has become a critical component of disease management.
Molecular hydrogen (H2) has demonstrated potential as an adjuvant therapy in various autoimmune and inflammatory diseases, including RA, SLE, and cardiovascular disorders (18-22). In recent years, H2 has attracted attention as a promising therapeutic strategy owing to its unique antioxidant and immunomodulatory properties. H2 selectively scavenges highly cytotoxic hydroxyl radicals (•OH) and peroxynitrite (ONOO−), while also regulating key cellular signaling pathways, including activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to enhance antioxidant defenses, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) to reduce pro-inflammatory cytokine expression, and modulation of apoptosis through upregulation of B-cell lymphoma-2 (Bcl-2) and suppression of caspase-3 (23-26). Moreover, H2 can suppress NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, eliminate mitochondrial reactive oxygen species, and promote the restoration of immune homeostasis by enhancing regulatory T cell function, inhibiting pathogenic T helper 17 (Th17) responses, and improving B-cell subset balance (27-31). These multifaceted mechanisms suggest that H2 may not only alleviate symptoms of autoimmune diseases but also modify disease progression, thereby offering a novel avenue for personalized immunoregulatory therapy.
In this case report, we present a 47-year-old male with a 27-year history of RA who subsequently developed SLE (Rhupus). Despite continuous treatment, his disease progressively worsened and was further complicated by multiple drug intolerances, ultimately leading to avascular necrosis of the femoral head. We particularly highlight the role of molecular hydrogen therapy as an adjuvant to rituximab, with observed benefits including immune modulation, normalization of inflammatory markers, and successful discontinuation of corticosteroids. This study was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taiwan (IRB No. C202405129; July 31, 2024). All procedures complied with institutional guidelines and the ethical standards of the Declaration of Helsinki and its amendments.
Case Report
The patient was a 47-year-old male civil servant who was initially diagnosed with RA at Taipei Veterans General Hospital in 1997, at the age of 20. In June 2014, at age 37, he developed features consistent with SLE, including left auricular vasculitis and elevated anti–double-stranded DNA antibody levels (102 IU/ml), thereby establishing the diagnosis of Rhupus syndrome (1-3). He received extensive treatment (Figure 1) to stabilize his condition. In April 2017, treatment with sulfasalazine and hydroxychloroquine was initiated; however, these were discontinued due to nausea and visual disturbances. In June of the same year, he developed SLE-associated pneumonia of the left lower lobe requiring hospitalization, intravenous corticosteroids (15), blood transfusion, and intravenous albumin replacement, and subsequently suffered bilateral lower limb cellulitis. In September 2017, his SLE disease activity worsened, presenting with proteinuria and pancytopenia (WBC: 3,500/μl; Hb: 8.5 g/dl; PLT: 126,000/μl), accompanied by progressive weakness and anemia. Between 2017 and 2018, the patient received multiple courses of rituximab (500 mg) (5, 14), and in July 2017 commenced therapy with mycophenolic acid (Myfortic) (32, 33). Methotrexate (MTX) was added in January 2018, but was discontinued in August 2018 due to recurrent oral ulcers (12). Despite rituximab at 500 mg, his clinical symptoms continued to deteriorate, and in June 2018 a renal biopsy confirmed diffuse proliferative lupus nephritis (ISN/RPS class IV+V), with a National Institutes of Health (NIH) activity index of 11/24 and chronicity index of 1/12 (34, 35). In December 2018, the patient developed abdominal cramping during rituximab infusion at 500 mg, necessitating dose reduction to 100 mg. Although long-term maintenance at 100 mg was instituted due to this adverse reaction, it should be noted that the official U.S. prescribing information for rituximab recommends temporary interruption, slowing, or discontinuation of infusion in response to infusion reactions, but does not provide guidance for dose reduction. This adjustment therefore reflected a clinical judgment rather than a guideline-based strategy and warrants further discussion. During reduced-dose rituximab therapy, disease activity varied over time, while inflammatory markers showed a gradual decline yet stayed above normal limits (Table I).
The patient was diagnosed with rheumatoid arthritis (RA) in 1997 and systemic lupus erythematosus (SLE) in 2014, meeting criteria for Rhupus. He was treated with long-term steroids, rituximab (initially 500 mg, later reduced to 100 mg), and began molecular hydrogen therapy in October 2023. Key events included intolerance to sulfasalazine and hydroxychloroquine (July 2017), SLE progression (September 2017), biopsy-confirmed lupus nephritis (June 2018), and avascular necrosis (January 2025).
Serial laboratory data.
In October 2023, at the age of 46, the patient initiated oral molecular hydrogen capsule therapy (each capsule containing 170 mg hydrogen-enriched calcium, releasing approximately 1.7×1021 molecules of hydrogen, administered once daily) as an adjuvant treatment (HoHo Biotech Co., Ltd., Taipei, Taiwan, ROC). To evaluate immunological and serological changes before and after hydrogen therapy, peripheral whole blood was analyzed using flow cytometry and serological assays. Subsequent flow cytometric analyses were performed according to standard fluorescent labeling protocols, employing lyophilized reagent antibody kits (Beckman Coulter, Brea, CA, USA). The methodology, procedures, immunophenotypic analyses, and gating strategies were conducted as previously described (31, 36, 37). Results demonstrated significant alterations in T- and B-cell subsets. Specifically, eight distinct immune parameters showed characteristic temporal changes (29-31). The frequencies of effector memory (EM) T helper (Th) T-cell immunoglobulin and mucin domain 3 (Tim-3)+ (effector memory T helper cells expressing Tim-3), naïve Tc killer cell lectin-like receptor subfamily G member 1 (KLRG1)+, KLRG1+ central memory (CM) cytotoxic T cell, and plasmablasts fluctuated over time with transient peaks and subsequent declines (Figure 2). In contrast, naïve Fas cell surface death receptor (Fas)+ B cell, class non-switched memory B cells, regulatory B cells (Breg), and resting regulatory T cells (Treg) demonstrated patterns of initial reduction followed by gradual recovery (Figure 3).
Immunophenotypic changes were evaluated in effector memory Th cells expressing T-cell immunoglobulin and mucin domain 3 (Tim-3), naïve cytotoxic T cells (Tc) expressing killer cell lectin-like receptor subfamily G member 1 (KLRG1), central memory Tc expressing KLRG1, and plasmablasts before and after starting hydrogen capsule therapy in October 2023, with healthy controls (HC) shown for comparison. Whole-blood analyses were performed at multiple time points. (A) Effector memory Th cells (Tim-3+) show a transient rise followed by a decline post-therapy. (B) Naïve Tc cells (KLRG1+) exhibit a decreasing trend. (C) Central memory Tc cells (KLRG1+) decline after therapy. (D) Plasmablasts fluctuate, with intermittent increases during follow-up.
Immunophenotypic changes in naïve B cells expressing Fas cell surface death receptor (Fas), class non-switched memory B cells, B regulatory cells (Bregs), and resting regulatory T cells (Tregs) were evaluated before and after starting hydrogen capsule therapy in October 2023, with healthy controls (HC) shown for comparison. Whole-blood analyses were performed at multiple time points. (A) Naïve B cells (Fas+) increase after therapy. (B) Class non-switched memory B cells rise during later stages of therapy. (C) Bregs show a delayed increase following an initial decline. (D) Resting Tregs exhibit a recovery trend after hydrogen therapy.
During hydrogen therapy, in addition to the patient’s remarkable clinical improvement, laboratory findings also demonstrated normalization of inflammatory markers (Table I). Anti-dsDNA antibody levels, which remained as high as 332 IU/ml in April 2018, stabilized within the normal range following initiation of hydrogen capsule therapy in 2023. The erythrocyte sedimentation rate (ESR), elevated at 69 mm/h in April 2018, progressively declined and first fell below the upper limit of normal in July 2025 after hydrogen therapy. Complement levels also approached normalization, with C3 maintained between 93-124 mg/dl following treatment, and C4 rising from persistently below normal to the lower limit of the reference range. These findings suggest a strong association between hydrogen capsule therapy and reduced disease activity, with stabilization of laboratory indices at low variability. Notably, in December 2024 the patient successfully discontinued prednisone (38, 39), maintaining disease control with mycophenolic acid (Myfortic 360 mg twice daily) (38).
On April 29, 2024, the patient underwent ureteroscopic laser lithotripsy with placement of a left double-J stent for a mid-ureteral stone complicated by mild-to-moderate hydronephrosis, microscopic hematuria, acute kidney injury, and sepsis. The stent was removed on May 9, 2024. A second course of hydrogen therapy was administered from June to September, followed by a third course initiated in December, both of which yielded sustained clinical improvement without significant adverse effects (19, 25, 26). Although overall disease activity remained stable, the patient began to experience left hip pain in 2024. Imaging studies revealed avascular necrosis with collapse of the femoral head, presumed to be related to long-term corticosteroid exposure (15, 16). In January 2025, at the age of 48, he underwent total hip arthroplasty with good postoperative recovery. His current medications include colchicine, celecoxib, mycophenolic acid (Myfortic), pitavastatin, bisoprolol, warfarin, olmesartan, and ongoing hydrogen therapy (1-3, 19, 25, 26). This study adhered to the CARE reporting guidelines (2013 CARE Checklist).
Discussion
This case highlights a history of significant drug intolerances: MTX induced pneumonitis and recurrent oral ulcers; azathioprine and leflunomide caused leukopenia; sulfasalazine triggered nausea after three weeks of use; hydroxychloroquine led to visual disturbances; and standard-dose rituximab provoked abdominal pain. These multiple drug intolerances markedly restricted conventional therapeutic options. This case illustrates several noteworthy aspects of molecular hydrogen therapy as an adjuvant approach in the management of complex autoimmune overlap syndromes.
The immunological changes observed after hydrogen therapy provide valuable insights into its potential mechanisms of action. Distinct temporal patterns were identified in specific immune cell subsets, suggesting a modulatory effect on both innate and adaptive immunity. In the T-cell compartment, Tim-3 expression on effector memory T helper cells showed a transient increase followed by a decline after hydrogen therapy (19, 20). Tim-3 is a critical immune checkpoint molecule regulating T-cell activation and inflammation (29). Aberrant Tim-3 expression has been implicated in autoimmune pathogenesis, and its modulation may represent one mechanism through which hydrogen therapy influences disease activity (19, 20, 29). Furthermore, the decreased expression of KLRG1 within naïve and central memory cluster of differentiation 8 (CD8)+ cytotoxic T cells (Naïve Tc, CM Tc) indicates that hydrogen therapy may attenuate CD8+ T-cell exhaustion, thereby restoring long-term immune surveillance and contributing to the maintenance of immune homeostasis in autoimmune disease (19, 20, 40).
The increase in Breg and resting Treg is of particular importance, as these cell populations play critical roles in maintaining immune tolerance and suppressing pathological autoimmune responses (36, 37, 41, 42). Previous studies have demonstrated that both the frequency and function of these regulatory cells are diminished in RA and SLE (37). In this case, an initial decrease followed by a subsequent increase in Breg and resting Treg populations was observed following hydrogen therapy, suggesting that the enhancement of these regulatory subsets may contribute to the restoration of immune homeostasis and, consequently, to clinical improvement.
During the course of treatment, plasmablasts exhibited multiple peaks, indicating intermittent humoral immune activation under hydrogen therapy. However, this was not accompanied by clinical deterioration, possibly reflecting the effective suppression of excessive immune responses by regulatory mechanisms (36, 43, 44). The observed increase in Fas expression among naïve B cells may promote apoptosis of autoreactive B cells, thereby reducing the generation of pathogenic autoantibodies (37, 43, 44). Within memory and regulatory B-cell populations, class non-switched memory B cells increased during the later phase of treatment, which may help stabilize long-term immune memory and prevent exaggerated responses against self-antigens (37, 44, 45).
This case report further demonstrates that in a patient who required reduced-dose rituximab due to intolerance at standard dosing in 2018, the addition of oral hydrogen capsule therapy from 2023 onward was associated with notable changes, including concurrent improvement in immune cell subsets and clinical parameters, as well as successful discontinuation of corticosteroids. These findings support the hypothesis that hydrogen therapy may exert disease-modifying effects –rather than merely symptomatic relief– through multiple pathways, including the restoration of regulatory cell populations, attenuation of immune exhaustion markers, and promotion of apoptosis in autoreactive B cells (36, 37).
The clinical course of this patient underscores the challenges in managing Rhupus syndrome, particularly in the setting of multiple drug intolerances. Rituximab, a B-cell–depleting therapy, has demonstrated efficacy in both RA and SLE and is therefore considered an appropriate option for Rhupus (5, 14). However, due to intolerance at the standard dosage, the patient required dose reduction, which may have compromised therapeutic efficacy. In this context, the addition of hydrogen therapy likely provided complementary immunomodulatory effects, enabling disease control despite suboptimal rituximab dosing (19, 20, 24).
Despite improved disease control, the patient developed AVN, reflecting the cumulative damage associated with prior long-term corticosteroid exposure. AVN of the femoral head is a well-recognized complication of corticosteroid therapy, occurring in 5-40% of patients receiving long-term treatment (15, 16). In this case, the femoral head damage likely predated the initiation of hydrogen therapy and should be regarded as a consequence of previous management strategies rather than a failure of current therapy.
Achieving sustained disease control with successful corticosteroid withdrawal represents a major therapeutic accomplishment in this patient. Steroid-free remission is a critical treatment goal in autoimmune diseases, as it reduces the risk of further corticosteroid-related complications (15, 39). In this case, disease stability was achieved with low-dose rituximab in combination with hydrogen therapy after prior treatment failures, suggesting a potential synergistic effect that warrants further investigation (5, 14).
Conclusion
This case provides preliminary evidence that molecular hydrogen may serve as an effective adjuvant therapy for complex autoimmune diseases with limited treatment options. In a patient with multiple drug intolerances restricting conventional approaches, hydrogen therapy contributed to sustained disease stability. The accompanying immunological data offer insights into potential mechanisms and biomarkers for further study. However, controlled trials are needed to confirm these findings and define standardized protocols for hydrogen therapy in autoimmune conditions (19, 20, 24, 46).
Acknowledgements
This study was funded by the National Science and Technology Council, Taiwan (grants NSTC 112-2314-B-016-033, NSTC 113-2314-B-016-052, NSTC 114-2314-B-016-052-MY3) and Tri-Service General Hospital, Taiwan (grants TSGH-E-112218 and TSGH-E-113238).
Footnotes
Authors’ Contributions
HLT: 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.
Conflicts of Interest
The Authors declare no conflicts of interest or competing interests related to this study.
Artificial Intelligence (AI) Disclosure
During manuscript preparation, a large language model (Microsoft Copilot, by OpenAI) was used only for language editing and stylistic improvements in selected paragraphs. All research data generation, analysis, and interpretation were performed solely by the authors. No figures or visual data were created or modified using generative AI or machine learning-based tools.
- Received October 7, 2025.
- Revision received October 20, 2025.
- Accepted October 22, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
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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