The incidence of chronic graft-versus-host-disease is rising year by year, which has become the leading cause of non-transplantation related death and has become the most difficult complication of allogeneic hematopoietic stem cell transplantation to deal with. Inflammation and fibrosis play dominant roles in the pathogenesis of chronic graft-versus-host-disease. Studies have shown that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on chronic graft-versus-host-disease. Here, we report a patient with severe chronic graft-versus-host-disease successfully treated by drinking hydrogen rich water which may be a safe and effective method for chronic graft-versus-host-disease.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely used in many hematological diseases. Chronic graft-versus-host disease (cGVHD) is one of the most common complications of allo-HSCT which has become the leading cause of non-transplantation related death (Martin et al., 2010). With the increase application of allo-HSCT in elderly patients, the wide application of peripheral blood stem cells as a graft and improvement of the early survival rate after transplantation, the incidence of cGVHD is rising year by year (Anasetti et al., 2012). cGVHD is a kind of disease similar to systemic lupus erythematosus (SLE) and scleroderma (Lee et al., 2003).
It is widely accepted that imbalance of inflammatory factors (such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, IL-6, IL-10, IL-12, interferon (INF)-gamma, transforming growth factor (TGF)-beta, etc.) and fibrosis occupy the dominant position in the mechanism of cGVHD (Flowers and Martin, 2015).
In 2007, Ohsawa et al. (2007) discovered that hydrogen gas has antioxidant properties. Since then, hydrogen gas has come to the forefront of therapeutic medical gas research. Recent basic and clinical research (Fukuda et al., 2007; Cai et al., 2008; Nagata et al., 2009; Sun et al., 2009) proved that hydrogen could down-regulate cytokines, including chemokine (C-C motif) ligand 2 (CCL2), IL-1β, IL-6, IL-12, TNF-α, etc. In 2011, Terasaki et al. (2011) also demonstrated that hydrogen has anti-fibrosis effect. Since 2009, hydrogen was applied on the field of organ transplantation including intestinal transplantation, lung transplantation, renal transplantation and heart transplantation. It was demonstrated that hydrogen could protect allograft function in those models (Buchholz et al., 2008; Nakao et al., 2009; Cardinal et al., 2010; Kawamura et al., 2010, 2011; Chuai et al., 2012). We also reported the therapeutic effects of hydrogen gas on acute graft-versus-host disease (Qian and Shen, 2013; Qian et al., 2013). We reasoned that hydrogen may have therapeutic effects on cGVHD.
A 54-year-old Chinese man in our outpatient clinic was diagnosed with myelodysplastic syndromes French-American-British (FAB) subtype refractory anemia with excess blasts-2 (RAEB-2) based on bone marrow morphology and developed cGVHD 3 years after allo-HSCT. He was diagnosed to have cGVHD. Clinical characters are shown in Table 1 according to National Institutes of Health (NIH) standards (Jagasia et al., 2015). He was given treatment of prednisone and tacrolimus, but the symptoms were not controlled. When he came to our outpatient clinic, he was still treated with oral 10 mg prednisone daily and 0.5 mg tacrolimus. We added hydrogen-rich water (500 mL three times per day, 0.6 mM) which was prepared as we previously described (Qian et al., 2013). Prednisone and tacrolimus were tapered in three months. After 3 and 6 months, the patient's clinic characters were evaluated again as shown in Table 1. The patient is still alive until this report with good life quality.
The incidence of cGVHD is rising year by year, and there is no ideal treatment, cGVHD has become the most intractable complications after allo-HSCT, which greatly reduces the patient's life quality and survival rate. In the past three decades, glucocorticoids (e.g., prednisone, prednisolone, dexamethasone), calcineurin inhibitors (e.g., tacrolimus, cyclosporin) and other immunosuppressive agents still play critical roles in cGVHD. cGVHD is often with long course, and side effects of these drugs are always too severe to be tolerated (Flowers and Martin, 2015). Hydrogen, however, has few side effects, making it able to be used safely for a long term. Further studies with large sample size are needed to verify whether hydrogen results in a significant improvement in patient outcomes.