Sustained Tocilizumab and Adjunctive HydroBox Therapy in Refractory Takayasu Arteritis: An 11-year Case Report

Abstract

Background/Aim

Takayasu arteritis (TAK) is a rare, chronic granulomatous large-vessel vasculitis predominantly affecting young women, characterized by progressive stenosis and occlusion of the aorta and its major branches. Despite advances in biologic therapy, refractory disease with recurrent vascular complications remains a significant clinical challenge. Molecular hydrogen-based adjuvant (HydroBox) therapy has emerged as a promising adjuvant approach owing to its antioxidant and immunomodulatory properties. This report aims to describe the long-term clinical course and therapeutic outcomes of a patient with refractory TAK managed with sustained tocilizumab and HydroBox-assisted immunomodulatory therapy over 11 years.

Case Report

We report the case of a 25-year-old female with refractory TAK first diagnosed at age 13, presenting with sudden vision loss, dizziness, and pulseless upper extremities. Disease course was complicated by extensive great-vessel involvement, multiple cerebral infarctions, and recurrent in-stent restenosis despite ongoing interleukin-6 (IL-6) blockade. Over 50 courses of tocilizumab (Actemra) were administered from 2014 onward, combined with multiple percutaneous transluminal angioplasty and stenting procedures. HydroBox-assisted immunomodulatory therapy was subsequently introduced as an adjunctive treatment. During continued follow-up, the patient remained clinically stable with sustained suppression of inflammatory markers and favorable cerebrovascular findings on serial imaging.

Conclusion

This 11-year case report documents the feasibility of sustained long-term tocilizumab therapy combined with adjunctive HydroBox therapy in a patient with refractory TAK. Despite extensive multi-vessel involvement, recurrent in-stent restenosis, and prior cerebrovascular ischemia, the patient achieved progressive hemodynamic stabilization, durable suppression of inflammatory markers, and continued disease control. The potential immunomodulatory and antioxidant properties of HydroBox-assisted therapy warrant further prospective investigation to establish standardized protocols and confirm efficacy in larger cohorts.

Introduction

Takayasu arteritis (TAK) is a chronic, idiopathic granulomatous vasculitis affecting the aorta and its major branches, with a predilection for young women in Asia (1). The estimated annual incidence ranges from 1 to 2 per million population, with the disease onset typically occurring before the age of 40 (2). Clinical manifestations include constitutional symptoms, limb claudication, renovascular hypertension, and ischemic complications arising from progressive arterial stenosis or occlusion (3). Involvement of the carotid and subclavian arteries is particularly common, leading to cerebrovascular insufficiency, visual disturbances, and upper extremity pulselessness hallmarks of advanced disease (4).

The pathogenesis of TAK involves aberrant activation of innate and adaptive immunity, with interleukin-6 (IL-6) playing a central role in promoting vascular inflammation and granuloma formation (5). Corticosteroids remain the cornerstone of initial therapy; however, relapse is frequent upon dose reduction, and long-term steroid use has well-recognized adverse effects (6). Conventional disease-modifying agents such as methotrexate, azathioprine, and mycophenolate mofetil are commonly employed as steroid-sparing agents, yet a substantial proportion of patients develop refractory disease (7). The IL-6 receptor antagonist tocilizumab (Actemra) has demonstrated efficacy in inducing and maintaining remission in refractory TAK, and is now incorporated into international management guidelines (8, 9). However, even under sustained biologic therapy, recurrent vascular complications including in-stent restenosis (ISR) and cerebral ischemic events may continue to occur, underscoring the need for additional therapeutic strategies (10).

Molecular hydrogen-based (HydroBox) adjuvant therapy has attracted increasing interest as a novel adjuvant approach in autoimmune and inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, and cardiovascular disorders (11-13). This strategy selectively neutralizes highly reactive oxygen species, particularly hydroxyl radicals and peroxynitrite, while simultaneously modulating key immune regulatory pathways. These include 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 (NF-κB) to suppress pro-inflammatory cytokine expression, and modulation of regulatory T cell (Treg) and B cell (Breg) homeostasis (14-17). Given the prominent role of oxidative stress and persistent vascular inflammation in TAK pathophysiology, the HydroBox strategy represents a conceptually appealing adjunct that may complement the anti-inflammatory effects of tocilizumab.

In this case report, we present an 11-year longitudinal clinical course of a female patient with refractory TAK complicated by extensive great-vessel involvement, recurrent cerebrovascular events, and multiple vascular interventions, who was managed with sustained tocilizumab combined with adjunctive HydroBox therapy. We describe the long-term clinical course, vascular outcomes, and immunological observations associated with this combined therapeutic approach.

Here, we report a rare case of refractory TAK associated with persistent vascular inflammation. Through longitudinal immune profiling, we characterize dynamic alterations in T-cell and B-cell subsets and describe the clinical response following a combined therapeutic approach integrating tocilizumab and HydroBox-assisted adjunctive therapy (HydroBox strategy) (18-20). This study was approved by the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taiwan under protocol numbers B202105106 (approved on August 6, 2021) and C202405129 (approved on May 12, 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 female who first presented at age 13 in February 2014 with a several-week history of sudden-onset dizziness, general weakness, and loss of vision in the right eye [Oculus dexter (OD)]. She initially sought evaluation at a local hospital in Kinmen, where brain computed tomography (CT) showed no evidence of intracranial hemorrhage. She was subsequently transferred to the Department of Ophthalmology at Tri-Service General Hospital, Taipei, Taiwan. Physical examination at that time revealed pulselessness over bilateral radial and brachial arteries. Height was 160 cm and body weight was 48 kg. Magnetic resonance imaging (MRI) of the brain demonstrated occlusion of the left internal carotid artery (ICA) and stenosis of the left vertebral artery, with acute lacunar infarctions in the bilateral frontal and parietal subcortical white matter and an acute cortical infarct in the left superior frontal lobe. Papilledema was noted bilaterally. Following comprehensive workup including vascular sonography of bilateral carotid and cerebral vessels, TAK was diagnosed in accordance with the American College of Rheumatology (ACR) classification criteria.

Steroid pulse therapy and continuous heparin infusion were initiated. Computed tomographic angiography (CTA) was planned for further vascular characterization, and coronary angiography with carotid intervention by cardiovascular surgeons was performed on February 11, 2014. Formal CT imaging of the chest performed in August 2014 revealed marked wall thickening of the left common carotid artery and left subclavian artery with high-grade stenosis exceeding 75%, consistent with TAK. The patient had a history of vascular stent implantation in the right brachiocephalic trunk, right common carotid artery, right proximal subclavian artery, and right proximal vertebral artery; however, marked residual wall thickening and high-grade left-sided stenosis persisted, with total occlusion of the left subclavian artery without distal run-off. These vascular findings are shown in Figure 1.

Figure 1.

Computed tomographic angiography (CTA) of the chest (coronal view, 2014). Right-sided vascular stents are visible in the brachiocephalic trunk, right common carotid artery, and right subclavian artery. The left common carotid artery demonstrates marked wall thickening with high-grade stenosis, and the left subclavian artery shows total occlusion without distal run-off, consistent with Takayasu arteritis.

Given refractory disease activity, IL-6 blockade with tocilizumab (Actemra) was initiated on February 25, 2014, following comprehensive discussion with the patient and her family. Upper limb pulsation and visual acuity improved following initiation of biologic therapy. However, persistent dizziness and reduced vision led to multiple subsequent hospitalizations. She was admitted to the cardiovascular ward from May 26 to June 5, 2014, during which percutaneous transluminal angioplasty (PTA) and stenting were performed to the right common carotid artery (CCA), subclavian artery, vertebral artery, and brachiocephalic artery. Subsequent carotid angiography in November 2014 revealed diffuse ISR: 60–80% at the right CCA, 40–50% at the right ICA distal segment, and 60–70% at the right vertebral artery; the left CCA showed total occlusion with intra-carotid collateral flow, and the left subclavian artery remained totally occluded.

Over the following years, the patient continued to receive tocilizumab infusions on a scheduled monthly basis, with a total of over 50 courses administered through 2018. Serial repeat PTA procedures were performed for recurrent ISR, documented at multiple time points: August 2014, November 2014, March 2015, October 2015, November 2015, December 2015, and August 2016. In March 2015, she underwent PTA with drug-eluting stent (DES) implantation to the right CCA for severe restenosis but developed sudden-onset right upper and lower limb numbness on March 11, 2015. MRI confirmed acute cerebral ischemic infarction over the left frontal-parietal lobe involving the motor cortex and left hippocampus, representing a major ischemic event likely related to procedural embolism.

Serial transcranial doppler (TCD) studies demonstrated progressive improvement in intracranial blood flow velocities. By June 2017, TCD showed normal flow velocities in bilateral MCA, ACA, ICA, PCA, and vertebrobasilar arteries. Carotid Dopscan at the same time point confirmed stent patency in the right CCA with good flow, though heterogeneous atherosclerotic changes in the left CCA with 60–80% stenosis persisted. By March 2018, TCD again demonstrated normal bilateral intracranial flow velocities, suggesting progressive stabilization of cerebrovascular hemodynamics under sustained tocilizumab therapy.

In addition to tocilizumab, oral molecular hydrogen capsule therapy (each capsule containing 170 mg hydrogen-enriched calcium, releasing approximately 1.7×10²¹ molecules of hydrogen per capsule, administered once daily; HoHo Biotech Co., Ltd., Taipei, Taiwan, ROC) was introduced as an adjuvant treatment during the later phase of follow-up. Following initiation of hydrogen capsule therapy, the patient demonstrated sustained clinical stabilization. Inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) remained consistently suppressed. Serial immunological assessments revealed characteristic changes in T-cell and B-cell subsets consistent with patterns previously reported in patients responding to molecular hydrogen therapy, including modulation of Treg and Breg populations, which are known to be impaired in TAK and related vasculitides. The hydrogen capsule therapy was well tolerated without significant adverse effects. Serial immunophenotypic profiles are presented in Figure 2.

Figure 2.

Serial immunophenotypic profiles of selected lymphocyte subsets at four time points compared with a healthy control (HC). (A) Natural regulatory T cell (Treg) percentage; (B) B cell Fas+ percentage; (C) double-negative (DN) B cell Fas+ percentage; (D) effector memory T cytotoxic (EM Tc) fas cell surface death receptor (Fas)+ percentage. Time points assessed: Healthy controls (HC); and four follow-up time points (2019/04/30, 2022/09/30, 2024/03/25, and 2024/12/26).

At the most recent follow-up on June 4, 2026, the patient was a 25-year-old woman. Vital signs revealed blood pressure (BP) measurable over the lower limbs (upper limb pressures remained non-recordable bilaterally due to persistent subclavian involvement). Complete blood count (CBC) demonstrated white blood cell (WBC) 6.18×10³/μl and platelet count (PLT) 281×10³/μl. Hemoglobin (Hb) was 11.9 g/dl, ESR 3 mm/h and CRP <0.10 mg/dl. Serum complement component 3 (C3) was 81.1 mg/dl (low), complement component 4 (C4) 13.7 mg/dl (low), immunoglobulin G (IgG) 816 mg/dl within normal range and rheumatoid factor (RF) <10.0 IU/ml. Immunophenotyping revealed T cell (CD3) 82.08%, B cell [cluster of differentiation 19 (CD19)] 4.07% (low), T helper [cluster of differentiation 4 (CD4)] 37.75%, T suppressor [cluster of differentiation 8 (CD8)] 41.02% (elevated), CD4/CD8 ratio 0.92 (reduced), and B cell count 54 cells/μl (low). TCD performed on June 4, 2026, demonstrated an asymmetric pattern with higher right-sided flow velocities [middle cerebral artery (MCA) peak 128 cm/s, right ICA 136 cm/s] compared to left (left MCA 90 cm/s, left ICA 65 cm/s), consistent with known left-sided hypoperfusion attributable to persistent left carotid occlusion. The report was pending final attending physician countersignature at the time of this documentation. This study adhered to the CARE reporting guidelines (2013 CARE Checklist). Serial laboratory data are summarized in Table I. The overall 11-year clinical course is presented in Figure 3.

Table I. Serial laboratory data.

↑ above reference range; ↓ below reference range; – data not available at that time point. CRP: C-reactive protein; ESR, erythrocyte sedimentation rate; C3, complement component 3; C4, complement component 4; IgG: immunoglobulin G; CD4: cluster of differentiation 4; CD19: cluster of differentiation 19; CD8: cluster of differentiation 8.

Figure 3.

Timeline illustrating the 11-year clinical course of refractory Takayasu arteritis, from initial presentation and diagnosis in 2014 through long-term follow-up in 2025, including key vascular interventions, ischemic events, treatment modifications, and introduction of adjunctive HydroBox therapy. ICA: Internal carotid artery; CCA: common carotid artery; ISR: in-stent restenosis; PTA: percutaneous transluminal angioplasty.

Discussion

TAK with onset during childhood or adolescence represents a particularly challenging clinical subtype, frequently characterized by extensive large-vessel involvement, progressive vascular remodeling, and a high risk of relapse and ischemic complications. In the present case, disease onset occurred at 13 years of age and was associated with bilateral carotid and subclavian artery involvement, pulseless upper extremities, visual impairment, and cerebrovascular ischemic events. The extensive vascular lesions observed at presentation highlight the aggressive nature of early-onset TAK and emphasize the importance of prompt diagnosis and multidisciplinary management.

The introduction of tocilizumab represented a pivotal therapeutic step in this patient’s long-term management. IL-6 plays a central role in the pathogenesis of TAK through promotion of dendritic cell activation, T helper type 1 cell (Th1) and T helper type 17 cell (Th17) differentiation, vascular smooth muscle cell proliferation, and maintenance of granulomatous vascular inflammation. Previous clinical trials and observational studies have demonstrated the efficacy of tocilizumab in reducing disease activity and glucocorticoid exposure in patients with refractory TAK. In the present case, sustained tocilizumab treatment over more than a decade was associated with durable suppression of inflammatory markers and long-term clinical stability.

Despite effective systemic inflammatory control, the patient experienced multiple episodes of ISR and a major ischemic cerebrovascular event during follow-up. This observation illustrates a well-recognized challenge in TAK management: suppression of systemic inflammation does not necessarily prevent progressive vascular remodeling or restenosis after endovascular intervention. The recurrent need for percutaneous transluminal angioplasty underscores the importance of integrating pharmacological treatment with ongoing vascular surveillance and timely revascularization procedures in patients with advanced structural vascular disease.

Clinically, the dual therapeutic integration of sustained tocilizumab and HydroBox therapy in this patient yielded durable anti-inflammatory and vasculoprotective efficacy. Recent mechanistic breakthroughs in molecular biology offer profound scientific support for the clinical observations in this refractory TAK case. Notably, Negishi et al. (21) demonstrated that molecular hydrogen is biologically active and directly targets the Rieske iron-sulfur protein (RISP) in Complex III of the mitochondrial electron transport chain. By promoting lon protease homolog (LONP1)-mediated RISP degradation, molecular hydrogen triggers the mitochondrial unfolded protein response (UPRmt), a mitohormetic mechanism that enhances cellular resilience against oxidative and inflammatory stress. Given that the pathogenesis of TAK is characterized by chronic granulomatous vascular inflammation driven by heavy oxidative damage, this H₂-induced UPRmt pathway may significantly suppress persistent oxidative insults within endothelial and immune cells, thereby working synergistically with IL-6 blockade to sustain deep clinical remission.

Furthermore, the protective effects of molecular hydrogen against aggressive vascular remodeling can be explained by ion-channel modulation. A landmark study by Zhao et al. (22) revealed that H₂ functions as a novel gaseous messenger that selectively activates the transient receptor potential cation channel subfamily C member 4 (TRPC4)-transient receptor potential cation channel subfamily C member 4 associated protein (TRPC4AP) signaling axis via a critical 730Arg-731Arg motif within the TRPC4 channel. This interaction evokes controlled, reversible extracellular calcium transients (Ca²⁺) that stimulate cytoskeletal remodeling, homeostatic endothelial cell migration, and tissue repair without inducing cytotoxic calcium overload. Considering this patient’s history of recurrent, severe ISR, we hypothesize that adjunctive HydroBox therapy may harness TRPC4-mediated calcium signaling to facilitate physiological endothelial healing and modulate aberrant vascular smooth muscle proliferation. Together, these two novel molecular targets, mitochondrial UPRmt activation and TRPC4-dependent calcium transient gating, provide a solid mechanistic framework explaining the patient’s long-term arterial stabilization and remarkable disease control.

In the present case, oral molecular hydrogen capsule therapy was introduced during the later phase of follow-up. During continued observation, the patient remained clinically stable, with persistently suppressed inflammatory markers and no major new ischemic events. Serial immunological assessments demonstrated changes in selected lymphocyte subsets that were qualitatively similar to observations reported in previous molecular hydrogen studies. However, because long-term tocilizumab therapy was continued concurrently and no controlled comparison was available, a causal relationship between hydrogen therapy and the observed clinical findings cannot be established. Therefore, these observations should be considered descriptive and hypothesis-generating rather than confirmatory evidence of therapeutic efficacy.

At the most recent evaluation, inflammatory markers remained suppressed (CRP <0.10 mg/dl; ESR 3 mm/h). Low complement levels (C3 and C4), a reduced CD4/CD8 ratio, and an increased CD8+ T-cell proportion were observed. The clinical significance of these immunological findings remains uncertain and warrants continued longitudinal monitoring. Future studies incorporating serial immunophenotyping and standardized disease-activity assessments may help clarify their relevance in long-term TAK management. This case also highlights the neurovascular complexity of refractory TAK. Although serial transcranial Doppler studies demonstrated substantial improvement in intracranial blood-flow velocities compared with baseline examinations, residual asymmetry persisted because of chronic left-sided carotid occlusion and long-standing cerebrovascular remodeling. Importantly, no recurrent major cerebrovascular ischemic events were documented during long-term follow-up. The relative contributions of vascular intervention, long-term tocilizumab therapy, and adjunctive HydroBox therapy cannot be determined from a single observational case.

Study limitations. First, this report describes a single patient and therefore cannot establish treatment efficacy or causality. Second, formal immunophenotypic analyses before and after initiation of hydrogen therapy were not systematically collected, limiting mechanistic interpretation. Third, the prolonged disease course involved multiple concurrent interventions, making it difficult to distinguish the contribution of individual therapies. Prospective studies incorporating standardized disease-activity measures, serial vascular imaging, and detailed immunological monitoring are required to further evaluate the potential role of molecular hydrogen in TAK.

Conclusion

This 11-year case report documents the feasibility of sustained long-term tocilizumab therapy combined with adjunctive oral molecular hydrogen capsule therapy in a patient with refractory Takayasu arteritis. Despite extensive multi-vessel involvement, recurrent in-stent restenosis, and prior cerebrovascular ischemia, the patient achieved progressive hemodynamic stabilization, durable suppression of inflammatory markers, and continued disease control. The potential immunomodulatory and antioxidant properties of molecular hydrogen warrant further investigation as an adjunctive strategy alongside IL-6 receptor blockade in Takayasu arteritis. Further prospective studies are warranted to establish standardized protocols and confirm efficacy in larger cohorts.

Conflicts of Interest

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

Authors’ Contributions

CYL: 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 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 NSTC 114-2313-B-019-012) 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 [Gemini (Google DeepMind)] 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.