Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by debilitating symptoms including skin and visceral fibrosis, systemic skin hardening, Raynaud's phenomenon and other vascular dysfunctions, and immune abnormalities. The disease poses a significant medical challenge with no cure currently available. As such, SSc is designated as an intractable disease in Japan, with patients receiving government subsidies for medical expenses. Oxidative stress (OS) is implicated in the pathogenesis of SSc and the antioxidant combination Tweendee X®︎ (TwX) has shown promising results in mitigating OS-related conditions. HOCl-induced SSc-mice are known to exhibit similar skin and visceral fibrosis, vascular disorders, and autoimmunity observed in human. In a study done using these mice, Twx demonstrated a significant reduction in lung and skin fibrosis compared to untreated HOCl-induced SSc mice. TwX also significantly reduced advanced oxidized protein products (AOPP) in serum, Col-1 gene expression and the activation of B cells involved in autoimmunity. SSc is a disease state in which autoimmune abnormalities, fibrosis, and vascular disorders are intertwined, and therefore for a treatment to be effective it needs to address multiple issues. Thus the efficacy of TwX may stem from its strong antioxidant capacity to regulate OS, which cannot be achieved by a single antioxidant on its own. In other studies, targeting other OS-related conditions, TwX was safe and proved to be effective at prevent dementia in humans with mild cognitive impairment and to significantly improve cognitive impairment in Alzheimer's (AD) mouse models. TwX may offer a new approach to antioxidant treatment for SSc, to address multiple abnormalities that are characteristic of the disease.

Chronic graft-versus-host disease (cGvHD) occurs in 20-50% of recipients following allogeneic haematopoietic stem cell transplantation (allo-HSCT). Corticosteroids (CS) remain the first line treatment but have suboptimal efficacy and carry the risk of long-term side effects. New agents with a better safety profile and higher efficacy, ideally combining immunomodulatory and antifibrotic properties, are urgently needed. From 2016 to 2020, we conducted a phase 2 clinical trial with ATO in chronic GvHD (ClinicalTrials.gov ID NCT02966301 - GMED16-001). This study aimed to evaluate the efficacy and safety of a first-line combination of arsenic trioxide (ATO) and CS in adult patients with cGvHD who require systemic therapy after a first allo-HSCT for a haematological disease. In this prospective, national, multicenter, single-arm, open-label phase II study, conducted in 5 university hospital centers in France, ATO was initiated within 10 days of starting CS at 1 mg/kg/day. Patients received 11 infusions of ATO per 4-week cycle, at a dose of 0.15 mg/kg per infusion. Patients received 1 or 2 cycles of treatment depending on the clinical response and the assessment of the treating physician. The results were published in July 2022 in a paper entitled "High Response Rate and Corticosteroid Sparing with ATO-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation". The GMED16-001 study demonstrated convincing efficacy and safety characteristics of the intravenous drug (Trisenox^®/Arscimed^®): the first-line use of ATO in addition to corticosteroids was associated with a high clinical response rate and correlated with rapid corticosteroid (CS) sparing in moderate to severe cGvHD after allo-HSCT. We performed a post-hoc analysis of the data to determine the best schedule for treating cGvHD patients with ATO. Our post-hoc analysis leads us to the conclusion that two cycles of ATO, at 0.15 mg/kg/day, 5 days per week for 4 weeks each, separated by a 4-week therapy-free interval, appears to be the most promising treatment schedule.