Effect Of Low-dose IL-2 Combined With Rapamycin In The Treatment Of Refractory Systemic Lupus Erythematosus

Objective:1.To compare the difference between refractory SLE patients and healthy controls(HC);2.To compare the changes of absolute value of peripheral blood lymphocytes and their ratio to Treg cells between patients with refractory SLE and healthy control group,and the correlation with SLEDAI score,course of disease,erythrocyte sedimentation rate and complement(C3,C4);3.To compare the changes of absolute value of peripheral blood lymphocytes and their ratio to Treg cells,SLEDAI score,erythrocyte sedimentation rate,complement(C3,C4),glucocorticoid and immunosuppressive agent dose in patients with refractory SLE treated with low dose IL-2 combined with rapamycin during follow-up.Methods:A total of 180 patients were enrolled in this study,110 patients with refractory SLE(93.64 % female,mean age 34.24±15.95)and 70 healthy controls(93.02 % female,mean age 39.30±13.28)matched by age and sex.110 patients with refractory SLE were diagnosed in accordance with the classification standard of SLE(schedule 1)revised by American college of rheumatology(ACR)in 1997.All patients were from the outpatient department of rheumatology and inpatient department of rheumatology,second hospital of Shanxi medical university from December 2015 to January 2018.Sixty-six of the 110 refractory SLE patients(93.94 % female,mean age 33.10±11.60)were treated with low-dose IL-2(1 million units/week,subcutaneous injection)combined with rapamycin(0.5mg/day,oral)on the basis of standard treatment(including glucocorticoids,immunosuppressants,biologics or combinations),and the rest were treated with standard treatment regimen.Peripheral blood lymphocytes of the subjects were extracted and their expression in refractory SLE group and healthy control group was analyzed,and their correlation with SLEDAI score,erythrocyte sedimentation rate and complement was analyzed.The changes of absolute value of peripheral blood lymphocytes and their ratio to Treg cells,SLEDAI score,erythrocyte sedimentation rate,complement(C3,C4),glucocorticoids and immunosuppressive agents in 66 patients with refractory SLE were analyzed during the follow-up period(pre-treatment,6 weeks,12 weeks,24 weeks).All the data were analyzed by SPSS 20.0.Results:1.Firstly,there was no significant difference in sex composition ratio and age between refractory SLE group and healthy control group.2.Compared the peripheral blood lymphocytes of healthy people and refractory SLE patients,Treg cells in refractory SLE group were lower than those in HC group(P <0.001).Th17 cells in refractory SLE group had no statistical difference compared with HC group(P > 0.05),and Th17/Treg ratio was higher than HC group(P < 0.001).CD8+T cells in refractory SLE group were not significantly different from HC group(P >0.05),and CD8 +T/Treg ratio was higher than HC group(P <0.001).Th1 cells in refractory SLE group were not significantly different from HC group(P > 0.05),and Th1/Treg ratio was higher than HC group(P = 0.002).There was no significant difference in Th2 cells between refractory SLE group and HC group(P > 0.05),and Th2/Treg ratio was higher than HC group(P < 0.001).B cells in refractory SLE group were lower than those in HC group(P < 0.001),and B/Treg ratio was not significantly different from HC group(P > 0.05).NK cells in refractory SLE group were lower than those in HC group(P < 0.001),and NK/Treg ratio was not significantly different from HC group(P > 0.05).3.That correlation of B,NK,CD8+T,Th1,Th2,Th17 and Treg cells with ESR,SLEDAI score,complement C3,complement C4 and other activity index in peripheral blood lymphocytes of patient with refractory SLE was analyzed.It was found that B,NK,CD8+T,Th1,Th2,Th17 and Treg cells were not correlated with disease duration,SLEDAI score,ESR,C3,C4.4.Treg cells were increased at 6,12 and 24 weeks after the treatment of low-dose IL-2 combined with rapamycin in patients with refractory SLE(P = 0.001,P = 0.003,P< 0.001).Th17 cells after treatment had no difference compared with those before treatment(P > 0.05).Th17/Treg ratio at 24 weeks after treatment was lower than that before treatment(P = 0.002),and Th17/Treg ratio at 24 weeks after treatment was lower than that at 6 weeks after treatment(P = 0.005).CD8+T cells increased at 6,12,24 weeks after treatment and before treatment(P < 0.001,P < 0.001,P < 0.001).The ratio of CD8+T/Treg after treatment was not different from that before treatment(P > 0.05).There was no difference in Th1 cells and Th1/Treg ratio between before and after treatment(P > 0.05,P > 0.05).There was no difference in Th2 cells after treatment compared with that before treatment(P > 0.05),and the Th2 /Treg ratio at 6,12 and 24 weeks after treatment was lower than that before treatment(P = 0.034,P = 0.006,P <0.001).There was no difference in B cells and B/Treg ratio between the two groups after treatment and before treatment(P > 0.05,P > 0.05).NK cells increased at 6,12 and 24 weeks after treatment(P = 0.001,P < 0.001,P = 0.004),and NK/Treg ratio was no difference after treatment(P > 0.05).The dosage of glucocorticoids in the 24 th week after treatment was lower than that before treatment(P < 0.05).The amount of DMARDS in 24 weeks after treatment was lower than that before treatment(P < 0.05).Conclusion:1.The decrease of Treg cells and Th17 / Treg cell imbalance may play an important role in the occurrence and development of refractory SLE.2.Low-dose IL-2 combined with rapamycin treatment can promote the proliferation of various lymphocyte subsets.In particular,it can significantly increase the number of Treg cells in peripheral blood,so that the ratio of each subgroup and Treg cells tends tobalance.3.The balance of Th17/Treg cell favors the decrement of glucocorticoids and DMARDs and suggests a good prognosis.