Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
NCPC New Preparation Branch Factory, North China Pharmaceutical Co., Ltd., 115 Hainan Road, Shijiazhuang, Hebei, China.
J Immunol Res. 2019 Nov 3;2019:7684352. doi: 10.1155/2019/7684352. eCollection 2019.
We have reported previously the insufficient absolute number or functional defects of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA), challenging conventional unspecific immunosuppressive therapy. Sirolimus, a mTOR inhibitor, is reported to allow growth of functional Tregs; here, we investigated the efficacy of low-dose sirolimus combined with conventional immunosuppressants (sirolimus immunoregulation therapy) for RA treatment with lower side effects and better tolerance.
In this nonblinded and parallel-group trial, we randomly assigned 62 patients to receive conventional glucocorticoids and immunosuppressants with or without sirolimus at a dosage of 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups and CD4T subsets were compared before and after the treatment.
Finally, 37 patients in the sirolimus group and 18 in the conventional treated group completed the 6-month study. By 24 weeks, the patients with sirolimus experienced significant reduction in disease activity indicators including DAS28, ESR, and the number of tender joints and swollen joints ( < 0.001). Notably, they had a higher level of Tregs as compared with those with conventional therapy alone ( < 0.05), indicating that sirolimus could partly restore the reduced Tregs. Concomitantly, their usage of immunosuppressants for controlling disease activity was decreased as compared with the conventional group with no difference in blood routine, and liver and renal functions both before and after the treatment of sirolimus and between the two groups ( > 0.05).
Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect. Further study is required using a large sample of RA patients treated with sirolimus for a longer period. This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=17245).
我们之前曾报道过类风湿关节炎（RA）患者调节性 T 细胞（Treg）数量不足或功能缺陷，这对常规非特异性免疫抑制治疗提出了挑战。雷帕霉素是一种 mTOR 抑制剂，据报道它可以促进功能性 Treg 的生长；在这里，我们研究了低剂量雷帕霉素联合常规免疫抑制剂（雷帕霉素免疫调节疗法）治疗 RA 的疗效，以期降低副作用和提高耐受性。
在这项非盲、平行组试验中，我们将 62 例患者随机分为两组，以 2:1 的比例接受常规糖皮质激素和免疫抑制剂治疗，其中 31 例患者隔日接受 0.5mg 雷帕霉素治疗，共 24 周。比较治疗前后患者的人口统计学特征、临床表现和实验室指标，包括外周血淋巴细胞亚群和 CD4T 亚群。
最终，雷帕霉素组 37 例和常规治疗组 18 例患者完成了 6 个月的研究。24 周时，雷帕霉素组患者的疾病活动指标，包括 DAS28、ESR 和压痛关节数和肿胀关节数均显著降低（<0.001）。值得注意的是，与单独接受常规治疗的患者相比，他们的 Treg 水平更高（<0.05），表明雷帕霉素可以部分恢复减少的 Treg。同时，与常规组相比，雷帕霉素组控制疾病活动的免疫抑制剂使用量减少，且治疗前后血常规、肝肾功能两组间均无差异（>0.05）。
低剂量雷帕霉素免疫调节治疗可选择性上调 Treg，部分替代免疫抑制剂控制疾病活动，且无过度治疗和可评估的副作用。需要进一步研究使用大样本 RA 患者接受雷帕霉素治疗更长时间。本试验在中国临床试验注册中心（http://www.chictr.org.cn/showproj.aspx?proj=17245）注册。
