Effect Of Metformin On Regulatory T Cell Counts And Th17/Treg Balance In Rheumatoid Arthritis Patients With Low To Moderate Disease Activity

Background:Regulatory T cell(Treg)reduction,an imbalance between helper T cell 17(Th17)and Treg might play an important role in the pathogenesis of Rheumatoid Arthritis(RA).Metformin induces immune tolerance and restores Th17/Treg homeostasis by promoting Treg proliferation.However,the counts of Treg,Th17/Treg and other lymphocytes in RA patients with low to moderate disease activity have been rarely reported.In addition,the changes in Treg and Th17/Treg after metformin treatment in these patients remain unknown.Here,we investigated the changes of Treg,Th17/Treg and other lymphocytes in RA patients with low to moderate disease activity before and after metformin intervention,and explored the prospect of metformin in RA.Objective:1.To analyze the lymphocyte counts in RA patients with low to moderate disease activity.2.To investigate the changes of Treg and Th17/Treg ratio in RA patients with low to moderate disease activity after treatment with metformin for 0,12,24 weeks,and evaluate the clinical efficacy and safety.Methods:Record the number of swollen joints and tender joints in RA patients according to the RA diagnostic criteria established by ACR/EULAR in 2010,VAS score and clinical data were collected,we also extracted their peripheral blood for ESR testing and lymphocyte subsets were detected by flow cytometry,then calculated the DAS28 score.A case group of 60 RA patients with 2.6≤DAS28≤5.1 who had not used glucocorticoids or immunosuppressive drugs in the past one month were included,and 30 healthy people with gender and age matched in the control group.The RA group was divided into two groups randomly.One group received 24 weeks of metformin combination therapy,and the other group received conventional DMARDs.Once the12 w and 24 w treatment was completed,we detect ESR and lymphocyte subsets,calculate the DAS28 score.Independent samples t-test,Wilcoxon rank-sum test,Generalized estimation equation and Chi-square test were applied for statistical analysis.Results:1.Treg in the RA group were significantly lower(P = 0.006)than those in the healthy control group,while Th17/Treg ratio were significantly higher(P<0.001),there is no statistical difference to the expression of Th17 and other lymphocyte cells between RA patients and healthy controls.2.After 12 weeks of treatment,Treg in metformin group were significantly higher(P=0.008),Th17 were slightly elevated,and Th17/Treg ratio was decreased,but there was no statistical significance;Treg and Th17 in conventional group were slightly decreased,and Th17/Treg ratio was slightly elevated,but there was no statistical significance.After 24 weeks of treatment,Treg in metformin group increased(P = 0.025)to normal and were higher(P = 0.001)than conventional group,Th17 were slightly elevated,and Th17/Treg ratio was decreased to normal,but there was no statistical significance;Treg and Th17 in conventional group were slightly decreased,and Th17/Treg ratio was slightly elevated,but there was no statistical significance.At 24 weeks,Treg,Th17 in metformin group were higher than those at week 12,and Th17/Treg ratio was lower,but they were not statistically significant;Treg,Th17 in conventional group were all lower than those at week 12,and Th17/Treg ratio was higher,but they were not statistically significant.12 and 24 weeks of treatment,ESR,DAS28 and CDAI score decreased significantly(P<0.001),while two groups without statistical difference.After 24 weeks of metformin treatment,the number of patients who use DMARDs were decreased,but there was not significantly changed.Conclusion:1.RA patients with low to moderate disease activity have reduced Treg cell counts and elevated Th17/Treg;2.Metformin maintains Th17/Treg balance by increasing the number of Treg in RA patients with low to moderate disease activity,thereby promoting clinical remission and having good safety.