Molecular hydrogen therapy in musculoskeletal conditions: An evidence-based review and critical analysis

Table 2 Clinical trials investigating hydrogen therapy in rheumatoid arthritis

Ref.	Year	Study design	Participants (number, conditions, characteristics)	Intervention (method, dose, duration)	Primary outcomes (measured)	Secondary outcomes (measured)	Statistical significance	Main conclusions	Limitations
Ishibashi et al[39]	2012	Small pilot study, open-label, no placebo control	20 RA patients	Hydrogen-rich water (duration 4 weeks)	Disease activity, oxidative stress markers	Significant decrease in disease activity and oxidative stress markers		Suggests potential benefits but requires further validation	Open-label, small sample size, lack of placebo control
Ishibashi et al[18]	2014	Randomized, double-blind, placebo-controlled pilot study	24 RA patients	Intravenous infusion of 500 mL of 1 ppm H2-saline daily for 5 days	DAS28	IL-6, TNF-α, MMP-3, urinary 8-OHdG	DAS28: Significant decrease in H2 group (P < 0.05); IL-6: Significant decrease in H2 group (P < 0.05); MMP-3: Significant decrease in H2 group (P < 0.05); 8-OHdG: Significant decrease in H2 group (P < 0.05); TNF-α: No remarkable change	H2 infusion safely and effectively reduced RA disease activity	Small sample size (n = 24); short duration (5-day infusion, 4-week follow-up); generalizability limited
Shen et al[38]	2022	Clinical trial (NCT05196295)	15 autoimmune patients (14 RA, 1 SLE; average age 54 years, 80% female)	Oral hydrogen-rich coral calcium: Low (1 capsule/day), medium (3 capsules/day), high (6 capsules/day) for 1 month	Safety (adverse effects)	DAS28, BFI-T, CRP, ESR, CBC, urinary biomarkers	Safety: No adverse effects reported; DAS28: Significant decrease overall (P = 0.02), pronounced in high dose (P = 0.01); BFI-T: Significant decrease overall (P = 0.0002), pronounced in high/medium doses; CRP/ESR: Trend of decrease, not statistically significant; WBC: Neutrophils: Significant decrease; monocytes: Significant increase	No adverse effects; potential therapeutic effects addressed for future studies	Small sample size (n = 15); short duration (1 month); no separate RA treatment control group; need for more calcium biomarkers; need for longer studies (≥3 months)

RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; DAS28: Disease Activity Score 28; IL: Interleukin; TNF: Tumor necrosis factor; MMP-3: Matrix metalloproteinase-3; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; BFI-T: Brief Fatigue Inventory-Taiwan; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; CBC: Complete blood count; WBC: White blood count.