Rheumatoid arthritis (RA) is an autoimmune-inflammatory disease in which the severity of disease and pain are associated with inflammation and oxidative stress. Patients with RA have elevated serum levels of inflammatory cytokines and altered expression of immune factors, including nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB), peroxisome proliferator-activated receptor-gamma (PPAR-γ), forkhead box P3 (FoxP3), T-box transcription factor TBX (T-bet), GATA binding protein 3 (GATA-3), and RAR-related orphan receptor γt (RORγt). Ginger (Zingiber officinale, Zingiberaceae) rhizome is used in traditional medicine to treat pain and stiffness in osteoarthritis and has demonstrated antioxidant and anti-inflammatory effects. According to the authors, there is limited information regarding the efficacy of ginger for the treatment of RA. Further, they state that there are no studies evaluating the effect of ginger on inflammation and immune markers. Hence, the purpose of this randomized, double-blind, placebo-controlled clinical trial was to evaluate the effect of ginger on NF-κB, PPAR-γ, FoxP3, T-bet, GATA-3, and RORγt gene expression and disease activity in patients with RA.
Patients (n = 70, aged 19-69 years) with active RA according to the American College of Rheumatology (ACR) criteria, and referred to the Rheumatology Research Center, Shariati Hospital; Tehran, Iran participated in this 25-month study (study initiation and conclusion dates not reported). Included patients had disease duration ≥ two years, were treated with disease-modifying anti-rheumatic drugs (DMARDs; methotrexate, hydroxychloroquine, and prednisolone <10 mg/day), and were not treated with non-steroidal anti-inflammatory drugs (NSAIDs). Excluded patients had a history of myocardial infarction, hyperlipidemia, abnormal renal or hepatic function; were taking vitamins, mineral supplements, thyroid hormones, antihypertensive drugs, contraceptives, diuretics, or β-blockers; used alcohol; or were smokers, pregnant, or lactating. Patients were instructed to maintain their usual diet, exercise, and medical therapies.
For 12 weeks, patients received either 1500 mg/day ginger rhizome powder (Research Center for Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran) or placebo containing fried wheat (Triticum spp., Poaceae) seed powder that was stored in a box with ginger for two weeks to imbue it with ginger aroma. The chemical profile of the ginger supplement was not reported. The rhizome powder was not chemically analyzed to determine its composition. Patients completed a 24-hour dietary intake diary for three consecutive days before and after the intervention. At baseline and study end, the following parameters were assessed: anthropometric measures; physical activity (evaluated with the validated International Physical Activity Questionnaire), gene expression of NF-κB, PPAR-γ, FoxP3, T-bet, GATA-3, and RORγt; and Disease Activity Score of 28 joints (DAS28) with erythrocyte sedimentation rate (ESR, a measure of inflammation severity). The combined clinical DAS28 score and laboratory ESR assessment (DAS28-ESR) is widely used as a measure of RA disease activity.
Sixty-three patients completed the study; three patients in the ginger group and four patients in the placebo group were excluded from the analysis due to protocol violations (lack of compliance and change in medication). Anthropometric measures, dietary intake, physical activity, and medications were not significantly different between groups at baseline. At the end of the study, there was no significant change in these variables compared to baseline in either group.
Compared with placebo, the ginger group had a significant increase in FoxP3 expression (P = 0.02) and a significant decrease in T-bet (P = 0.04) and RORγt (P = 0.02) expression. The ginger group had a significant increase in PPAR-γ expression compared with baseline (P = 0.04) but not compared to the placebo group (P = 0.12). There were no significant changes in NF-κB and GATA-3 expression in either group; however, there was a trend towards a decrease in NF-κB expression and an increase in GATA-3 expression in the ginger group (P = 0.06 for both). The ginger group had a significant decrease in the DAS28-ESR score compared with baseline (P = 0.001) and placebo (P = 0.003). The authors do not discuss adverse effects (AEs); however, the study flow chart shows that one patient in the ginger group and two patients in the placebo group did not take all of their capsules due to heartburn.
The authors conclude that 1500 mg/day ginger for 12 weeks can improve disease symptoms (as evidenced by the DAS28-ESR score improvement) in patients with RA via increased expression of the immunomodulatory FoxP3 and decreased expression of the pro-inflammatory T-bet and RORγt genes. Limitations of the study are the chemical profile of the ginger supplement was not reported, the small sample size, relatively short study duration, transcription factor protein levels were not measured, other RA inflammation markers were not evaluated, and blinding efficacy was not assessed. Based on these promising findings and the limited number of other studies in this area, “further studies are suggested to investigate the effect of ginger consumption on autoimmunity, inflammation, and clinical manifestations in RA patients,” the authors write. The authors declare no conflicts of interest.
Peer Reviewer’s Comment
This is an exploratory study showing a trend of effectiveness that oral ginger rhizome powder may improve clinical symptoms and serum biomarkers of inflammation. The results should now be proven in a definitive study in which the study hypothesis is backed at best by a power of 90%. The expected results should then be of clinical relevance.
Presently, no data are available on the relationship between the change of biomarkers and clinically relevant improvement. The future study should, therefore, be used to obtain further information on the correlation between clinical improvement and improvement of biomarkers of inflammation in order to see if biomarkers can be used as surrogates to prove effectiveness.
Aryaeian N, Shahram F, Mahmoudi M, et al. The effect of ginger supplementation on some immunity and inflammation intermediate genes expression in patients with active rheumatoid arthritis. Gene. May 25, 2019;698:179-185. doi: 10.1016/j.gene.2019.01.048.