| Objective:To explore the effects of disease-modifying anti-rheumatic drugs(DMARDs)and low-dose rapamycin on the absolute counting of lymphocyte subtypes;and to evaluate the efficacy and safety of low-dose rapamycin combination therapy for patients with active rheumatoid arthritis(RA).Methods:Total 62 patients with active RA were randomly divided into rapamycin group(n =42)and the control group(n =20).Conventional treatments were used in both control group and rapamycin group.Patients in the rapamycin group were additionally received rapamycin orally at a dose of 0.5mg on alternate days for 12 weeks.In the study,the disease activity measures such as the 28-joint Disease Activity Score,tender joint count(TJC),swollen joint count(SJC),erythrocyte sedimentation rate(ESR)and C-reactive protein(CRP)were recorded and compared between rapamycin group and the control group.The laboratory assessments such as complete blood counts,liver and kidney function tests were examined on week 0,3,6 and 12.All the peripheral lymphocyte subpopulations and the CD4+T subgroups were measured by FCM before and after the treatment.The incidence and severity of all adverse events were recorded.Results:No significant difference observed in age(50.3±10.6 vs.51.8±8.7)years old and gender(female percentage 80.9% vs.85.0%)compared between rapamycin group and the control group(P > 0.05).Before the treatment,there were no significant differences in the numbers of CD4+T cell subsets between rapamycin group and control group(P > 0.05).After treatment,there was a significant difference in Tregs [29(17.4,40)vs.15.9(13.2,29.7),P = 0.042] and Th17 cells [7.3(5,10.5)vs.3.5(3.0,5.4),P = 0.011] between rapamycin group and the control group.Patients treated with conventional immunosuppressants alone had a significant decrease of pro-inflammatory Th17 cells at week 12.Meantime,the level of anti-inflammatory Tregs was also significantly reduced from 35.0(22.7,42.4)/?l at week 0 to 15.9(13.2,29.7)/?l at week 12(P<0.05).In contrast,the number of Tregs was not decreased at the end of this study in Patients who received rapamycin combination therapy(P > 0.05).Before the treatment,there were no differences in other disease activity measures(P > 0.05),except the TJC of patients in rapamycin group was 6.22±5.21,which was higher than that of conventional treated patients(3.61±2.77,P<0.05)..After treatments,all the disease activity measures of all these patients were significantly decreased(P < 0.05)and all the disease activity measures in both rapamycin group and control group were comparable at the end of this study.Further,patients in rapamycin group had lower usage rate of DMARDs which required controlling disease activity compared with control group patients.The number of Tregs and Th17 in the rapamycin group was significantly higher than those of the control group(P<0.05).There were no differences in blood routine,serum Alanine transaminase(ALT),aspartate aminortransferase(AST),Blood urea nitrogen(BUN),serum creatinine(Scr)between two groups before the treatment(P > 0.05).After the treatment,these measurements were also comparable in these two groups(P > 0.05)).Except one patient developed limb oedema after one weeks of treatment with rapamycin and thereby withdrew from the study,no thrombocytopenia,mucositis,or proteinuria was observed.Conclusion:Low-dose rapamycin immunoregulatory therapy selectively up-regulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without over-treatment and evaluable side effect.Further study is required using a large sample of RA patients treated with rapamycin for longer period. |
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