Safety And Efficacy Of Tocilizumab Versus Azathioprine In Highly Relapsing Neuromyelitis Optica Spectrum Disorder

ObjectivesThis study is a randomized controlled study of the IL-6 receptor blocker tocilizumab(TCZ)and the purine antagonist azathioprine(AZA)in the treatment of patients with highly relapsing optic neuromyelitis spectrum disease(NMOSD)Objective to observe the efficacy and safety of two drugs in the treatment of patients with highly relapsing NMOSD.Look for drugs that are more effective in preventing relapses in remissionResults1.We included a total of 77 patients and were randomly divided into two groups:39 cases in the tocilizumab group and 38 cases in the azathioprine group.There were 35 women in the tocilizumab group and 33 patients in the azathioprine group.The average age of the patients was 49.3 ± 13.2 years in the tocilizumab group and 46.3 ± 13.4 years in the azathioprine group.The average course of disease at randomization was 5.7 ±2.8 years in the tocilizumab group and 6.5 ± 3.1 years in the azathioprine group.The average number of attacks in the 24 months before randomization was 1.71 ± 0.60 times in the tocilizumab group and 1.68±0.68 times in the azathioprine group.The median baseline EDSS scores were 5.0(4.0,6.0)and 4.75(4.0,5.5),respectively,and were at moderate to severe levels.32(82.1%)patients in the tocilizumab group had positive serum AQP4-IgG,and 32(84.2%)had positive serum AQP4-IgG in the azathioprine group.19 patients(48.7%)were accompanied by other autoimmune diseases in the tocilizumab group and 12 patients(31.6%)in the azathioprine group There was no statistical difference in the patient’s baseline level2.The primary endpoint event was the first relapse,5(12.8%)relapses in the tocilizumab group,and 17(44.7%)relapses in the azathioprine group(HR 0.2356[95%CI0.1016-0.5462];p=0.0019),according to Intention-To-Treat(ITT),the relative risk of recurrence in the tocilizumab group to the azathioprine group decreased by 76.44%throughout the study.Following study protocol analysis(Per-Protocol,PP),when tocilizumab and azathioprine were used as a single agent,32(88.9%)of the 36 patients in the tocilizumab group did not relapse.In the azathioprine group,21 out of 32(65.6%)patients had no recurrence(HR 0.2812[95%CI 0.1013-0.7802];p=0.02).As a single agent,tocilizumab reduced the risk of recurrence by 71.88%3.4(10.3%)in the tocilizumab group achieved a 12-week confirmed disability progression;11(28.9%)in the azathioprine group,(HR 0.3064[95%CI 0.1109-0.8461];p=0.0306)The relative risk of the tocilizumab group was reduced by 69.36%compared with the azathioprine group4.The median level of EDSS score in tocilizumab group decreased from 5.0(4.0,6.0)to 4.5(3.5,5.5),p=0.0028;the EDSS score of azathioprine group was 4.75(4.0,5.5)before treatment,After treatment,it was 4.5(3.8,5.5),p=0.1611.The EDSS score of tocilizumab group decreased significantly5.After 60 weeks of treatment,the titer of AQP4 antibody remained unchanged after azathioprine treatment.However,after tocilizumab treatment,the AQP4 antibody titer was significantly reduced.The AQP4-IgG titer of the tocilizumab group decreased by 50%on average.6.Observed by the investigator and reported by the patient,a total of 692 adverse events were recorded,of which 37(94.8%)patients in the tocilizumab group had a total of 321 cases,and 35(92.1%)patients in the azathioprine group with 371 cases.The main adverse events were liver toxicity(33.3%)13/39 tocilizumab vs(52.6%)20/38 azathioprine;upper respiratory tract infection(33.3%)13/39 tocilizumab vs(50%)19/38 azathioprine;urinary tract infection(38.5%)15/39 tocilizumab vs(34.2%)13/38 azathioprine;anemia(28.2%)11/39 tocilizumab vs(39.5%)15/38 azathioprine;leukopenia(10.3%)4/39 tocilizumab vs(39.5%)15/38 azathioprine;nausea(12.8%)5/39 tocilizumab vs(47.4%)18/38 azathioprine;and fatigue(23.1%)9/39 tocilizumab vs(34.2%)13/38 azathioprine.Among the adverse events considered by the investigators to be related to treatment,the most common in the tocilizumab group was elevated liver enzymes,followed by urinary tract infections and upper respiratory tract infections.The most common group of azathioprine is elevated liver enzymes,followed by anemia and leukopenia.There were no grade 4 or higher adverse events in the tocilizumab group compared with 2(5.3%)of the azathioprine group,and 1(2.6%)died of intracranial infection with Listeria monocytogenes causing cerebral edema and cerebral hernia.Two(5.1%)people in the tocilizumab group withdrew from the study due to adverse events,one of whom was cerebral hemorrhage at the basal ganglia.2(5.3%)of the azathioprine group withdrew from the study due to serious adverse eventsConcusionCompared with azathioprine(AZA),tocilizumab(TCZ)can effectively reduce the risk of relapse by 76.44%in the treatment of patients with highly relapsing neuromyelitis optica spectrum disorder(NMOSD).As a single medication,it can reduce the risk of relapse by 72.48%.At the same time,tocilizumab can effectively alleviate the progress of disability.Compared with azathioprine,the risk of 12-week confirmed disability progression reduced by 69.36%.At the same time,the EDSS score of the tocilizumab group decreased from the baseline level,and the AQP4-IgG titer decreased by 50%from the baseline level,while the azathioprine group showed no significant change.Therefore,tocilizumab is superior to azathioprine in efficacy.But both have certain adverse events.This study provides new evidence for modified therapy in NMOSD patients during remission.