Background/Purpose:  Patients with refractory rheumatoid arthritis (RA) have T-cell dysfunction that associates the activation of mTOR that is inhibited by rapamycin, which has been developed as a medication under the generic designation of sirolimus. Recently, we have reported that absolute number of peripheral regulatory T (Treg) cells reduced in RA patients. Since rapamycin has been reported to expand Tregs, in this study, we assessed safety, tolerance, and efficacy of sirolimus for RA treatment.

Methods:  We did a double-arm, open-label, and phase 1/2 trial of sirolimus in patients with RA at the Second Hospital of Shanxi Medical University (Taiyuan, Shanxi, China). Eligible participants (aged 18 to 65 years) fulfill the revised the 1987 ACR/EULAR criteria for the classification of RA and did not achieve remission with the conventional treatment over at least 2 years. We excluded patients with allergy or intolerance to sirolimus, with malignant disease or a history of malignancy, or with chronic or severe infection. Patients in control group (n=19) were given conventional glucocorticoids and DMARDs treatment. Patients in sirolimus group (n=38) were given not only conventional treatment, but also oral sirolimus at a starting dose of 0.5 mg on alternate days for 24 weeks. The demographic features, clinical manifestations and laboratory indicators were compared before and after the treatment. This trial is registered at Chinese Clinical Trial Registry, number ChiCTR-IPR-17010307.

Results:  There was no difference between sirolimus and control group in gender and age (P > 0.05). After 24 weeks of the sirolimus treatment, except C-reaction protein, there was a significant decrease in disease activity measures including DAS28, ESR, the number of tender joints and swollen joints (P < 0.001). Patients with sirolimus treatment had a significant increase in the number of Tregs and a lower DMARDs usage rate (P < 0.05). There was no difference in blood routine, liver and renal functions both before and after the treatment between two groups (P > 0.05).

Conclusion:  Sirolimus treatment selectively up-regulated Tregs and partly decreased the usage of DMARDs without over-treatment and evaluated side effect. The further study is required to increase the RA patients in sirolimus and conventional treatment groups.