THU0184 SIROLIMUS SELECTIVELY INCREASES CIRCULATING TREG CELL NUMBERS AND RESTORES THE TH17/TREG BALANCE IN RHEUMATOID ARTHRITIS PATIENTS WITH DAS28 ≤ 3.2 WHO PREVIOUSLY RECEIVED CONVENTIONAL DMARDS
Authors: Hong-Qing Niu, LI Zhao-Hua, Wen-Peng Zhao, Xiang-Cong Zhao, Chen Zhang, Jing Luo, Chong Gao, Caihong Wang, LI Xiao-Feng
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Many immunosuppressants used to treat rheumatoid arthritis (RA) were designed to broadly suppress T cell function, including that of regulatory T cells (Tregs). Patients with inactive RA also show a reduced frequency of peripheral Tregs <sup>[1]</sup>. Tregs are essential for maintaining effective immune tolerance and a homeostatic balance of Th17/Treg. Accordingly, there has been increasing interest in developing Treg-friendly regimens to minimize or eliminate the immunosuppression of conventional medications for RA. mTOR signaling negatively controls the development and function of Tregs. Rapamycin, an mTOR inhibitor, could expand Tregs (CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>) in patients with active systemic lupus erythematosus <sup>[2]</sup> and active RA <sup>[3]</sup>; however, the response of Tregs to rapamycin in RA patients with DAS28 ≤ 3.2 is still unclear. <h3>Objectives</h3> To investigate the effects of rapamycin, under the generic name sirolimus, on Tregs in RA patients with DAS28 ≤ 3.2 who previously received conventional DMARDs. <h3>Methods</h3> Fifty-five RA patients and 60 healthy controls were enrolled in this study. All patients had previously received conventional DMARDs and had a low DAS28 score (≤ 3.2). Peripheral blood samples and clinical information were obtained at baseline and following 6 and 12 weeks of sirolimus treatment, or after 12 weeks of conventional treatment. The circulating levels of lymphocyte subpopulations were assessed by flow cytometry. <h3>Results</h3> Thirty-five patients received sirolimus and 20 patients continued treatment with conventional DMARDs. None of the baseline clinical characteristics differed significantly between the two groups. The absolute counts and proportions of CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Tregs were significantly lower in all RA patients with DAS28 ≤ 3.2 as compared with those in healthy controls. By contrast, the difference in circulating Th17 cell numbers was not significant. Sirolimus administration resulted in significant elevations in circulating Treg cell numbers and significant reductions in the Th17/Treg cell ratio, whereas the circulating level of Tregs and the Th17/Treg cell ratio in patients under conventional treatment both showed a tendency of reduction (Figure 1). Furthermore, a greater proportion of patients under sirolimus treatment achieved DAS28-based remission at 12 weeks. <h3>Conclusion</h3> Sirolimus can favorably expand Tregs in RA patients with DAS28 ≤ 3.2, consequently restoring a healthy balance of Th17/Treg cells, which might improve the likelihood of long-term and sustained clinical remission and reduce the probability of disease flare-ups in RA. These findings provide valuable insights that might potentially lead to changes in clinical practice for the routine treatment of RA. <h3>References</h3> [1] Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int, 2012, 32(9): 2731-2736. [2] Lai ZW, Kelly R, Winans T, et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet, 2018, 391(10126): 1186-1196. [3] Wang J, Zhang SX, Hu FY, et al. Sirolimus treatment in patients with refractory rheumatoid arthritis: a double-arm, open-label, phase 1/2 trial. Arthritis Rheumatol, 2018, 70 (Suppl 9): 2018 ACR/ARHP Annual Meeting Abstract Supplement. <h3>Disclosure of Interests</h3> None declared