Background The molecular target rapamycin (mTOR) signaling can regulate between effector and regulatory T cell lineage commitment . Rapamycin, the inhibitor of mTOR, has appeared to be a new therapy for several autoimmune diseases, such as systemic lupus erythematosus .
Objectives To evaluate whether rapamycin is beneficial in patients with Rheumatoid Arthritis (RA), and compared with Methotrexate in efficiency and safety.
Methods Fifty-eight DMARDs-naive RA patients were enrolled, thirty-eight were treated with Rapamycin (0.5 mg every 2 days, combined with IL-2 50WIU per day for 5 days), the others with Methotrexate (10mg per week) taken as control. Clinical improvement and immunological assessments were performed at baseline, 1 and 12 weeks. Treatment group assessed CD4+ T cell subsets by flow cytometry at baseline, 1 and 12 weeks.
Results We enrolled 58 patients. At baseline, patients had a mean DAS28 of 3.34 (0.81). Rapamycin group and Methotrexate group included 38 and 20 patients, respectively, with no significant differences in baseline characteristics. At 1 week, the mean DAS28 after Rapamycin treatment (2.43 [0.77]) and Methotrexate (2.25 [0.86]) was not significantly different (P=0.43). Same as ESR (24.74 [24.53], 21.76 [24.27], P=0.66). The dose of glucocorticoid during hospitalization of rapamycin treatment group (720.8 [554.3]) was lower than Methotrexate (1202.3 [943.1], P=0.042). The length of hospital stay of Rapamycin (14.5 [3.9]) was lower than Methotrexate (21.0 [3.8], P<0.001). Rapamycin administration resulted in an increase in the absolute counts of Treg cells from a median of 36.82 cell/ul (at week 0) to 99.80 cell/ul (at week 1) (P<0.001). The ratios of Th17/Treg cells showed a reduction from a median of 0.16 to 0.09, and the difference was significant (P=0.047). At 12 week, 5 patients treated with Rapamycin dropped out because of non-compliance. the mean DAS28 was not significantly different (2.36 [0.97], 2.16 [0.86], P=0.51). The same as the daily dose of glucocorticoid (10.21 [32.3], 9.16 [40.1], P=0.804). The absolute counts of Treg cells increased from a median of 36.82 cell/ul (at baseline) to 43.26 cell/ul after Rapamycin administration (P=0.028). The ratios of Th17/Treg had no significant difference from a median of 0.16 at baseline to 0.12 at week 12 (P=0.937). Liver enzyme elevations occurred on 2 patients after Methotrexate therapy for 1 week. However, there were no serious adverse events observed during the 12-week period of rapamycin treatment.
Conclusions Rapamycin combined with the low-dose IL-2 appears to be a safe and effective therapy for RA, by a rapid increase of circulating Treg cells and a correction of the ratio of Th17/Treg cells, which has gotten a same response compared with Methotrexate.
Zheng Y. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.[J]. Immunity, 2009, 30(6):832–844.
Fernandez D, Bonilla E, Mirza N, et al. Rapamycin Reduces Disease Activity and Normalizes T Cell Activation–Induced Calcium Fluxing in Patients With Systemic Lupus Erythematosus[J]. Arthritis & Rheumatology, 2006, 54(9):2983–2988.
Disclosure of Interest None declared