AB0421 Rapamycin reduces disease activity through restoring regulatory t cell numbers in patients with active refractory rheumatoid arthritis

Abstract

BackgroundCD4+CD25+Foxp3+ T regulatory (Treg) cells play a key role in peripheral tolerance. Rapamycin was approved by the FDA to preserve renal allografts and to be efficacious in patients with several autoimmune diseases [1].ObjectivesTo investigate the status of Treg cells in active refractory rheumatoid arthritis (RA) and the effects of rapamycin on patients with RA.MethodsForty-five active refractory RA patients were enrolled. Rapamycin was used at a dose of 0.5 mg every 2 days [the preliminary, open-label clinical trial of rapamycin (Clinical Trials.gov number: ChiCTR-IPR-17010307)]. Clinical improvement and immunological assessments were performed before 1st rapamycin dose and 12 weeks post treatment. Blood samples were obtained from RA patients and 75 healthy volunteers for estimation of CD4+ T cell subsets.ResultsTwo patients dropped out due to non-compliance. As compared to healthy controls (median of Treg cells: 33.32 cell/ul), the absolute counts of circulating Treg cells were significantly decreased in patients with active refractory RA (median: 27.17 cell/ul; P=0.046). While the median ratios of Th17/Treg cells in patients with active refractory RA (median: 0.26) were significantly higher than those of healthy volunteers (median: 0.19; P=0.029). No difference in the absolute counts of circulating Th17 cells and Th1 cells was observed between patients with active refractory RA and healthy subjects. Rapamycin treatment led to clinical improvement with the median post-treatment DAS28-ESR decreasing when compared to baseline (from 4.19 to 3.78) in active refractory RA patients. Sixteen patients (16/43 patients, 37.21%) achieved an EULAR moderate response and 6 patients (6/43 patients, 13.95%) reached good response at week 12. Rapamycin administration resulted in an increase in the absolute counts of Treg cells in active refractory RA patients, from a median of 27.17 cell/ul (at week 0) to 37.57 cell/ul (at week 12) (P=0.041). The ratios of Th17/Treg cells shows a reduction from a median of 0.26 at baseline to 0.20 at week 12, but the difference is not significant (P =0.376). No significant difference was observed in the absolute counts of circulating Th17 and Th1 cells after rapamycin treatment. Interestingly, we observed that Treg cells increased before the complete remission of the disease (DAS28 score <2.6) in patients with active refractory RA. At week 12, the mean dose of prednisone which refractory RA patients were receiving decreased from 11.98 mg/d to 8.31 mg/d, with a dose reduced by ≥30% than that at baseline. The categories of DMARDs use were also reduced (P<0.05). No serious adverse events was observed during the 12-week period of rapamycin treatment.ConclusionsReduced absolute number of Treg cells was found in the patients with active refractory RA, indicating an imbalance between Th17 and Treg cells. Rapamycin elicits rapid improvement of disease activity via restoring circulating Treg cells numbers in patients with active refractory RA.References Perl A. Activation of mTOR (mechanistic tar...