Study On The Relationship Between TNF-Related Gene Polymorphism,Blood Concentration And Efficacy And Safety Of Infliximab In Patients With Crohn’s Disease

Objective: Infliximab can effectively induce and maintain the clinical remission of Crohn’s disease,but there are significant individual differences in its clinical efficacy.About 50% ～ 54% of Crohn’s disease patients have secondary loss of response during one year of continuous infliximab treatment.The specific reason is unknown.Therefore,it is very important for infliximab maintenance therapy to know whether patients have a potential risk of secondary unresponse.Studies have shown that the clinical efficacy of infliximab may be related to genetic factors,and related studies mainly focus on TNFrelated gene polymorphism.However,at present,there are different conclusions on the relationship between TNF-related gene polymorphism and the efficacy of infliximab in patients with Crohn’s disease,and there are few domestic studies.The purpose of this study was to analyze the efficacy and safety of infliximab in the treatment of Crohn’s disease,and to explore the independent influencing factors of infliximab in patients with Crohn’s disease treated with infliximab and the correlation between steady-state valley concentration of infliximab,TNF-related gene polymorphism and clinical efficacy in patients with Crohn’s disease.In order to find the potential genetic factors to predict the efficacy of infliximab and clearly predict the critical value of valley concentration in the treatment of infliximab,so as to provide clinical basis for optimizing the treatment of patients with Crohn’s disease.Methods:(1)Patients with Crohn’s disease who were treated with infliximab for the first time were included,and the efficacy was evaluated with the help of Crohn’s disease activity index.The efficacy and safety were evaluated by comparing the inflammation index,nutrition index,Crohn’s disease activity index score,liver and kidney function index and adverse reaction events before the third treatment and the sixth treatment;(2)The clinical data of patients with Crohn’s disease in maintenance stage treated with infliximab were included.According to the clinical response of infliximab,the patients were divided into continuous response group and secondary response group.The genotypes of TNF-α-238 rs361525,TNF-α-308 rs1800629,TNFRSF1 B rs1061622,TNFRSF1 B rs1061624,TNFRSF1 B rs3397 and FASLG843 rs763110 were detected by fluorescence staining in situ hybridization and universal fluorescence probe,and the differences of TNF related genotypes were analyzed.Screening of independent risk factors for secondary failure in infliximab therapy and evaluation of its diagnostic efficacy;(3)The clinical data of patients with Crohn’s disease treated with infliximab for more than 5 times were included.The steady-state valley concentration of infliximab was detected by enzyme-linked immunosorbent assay.TNF-α-238 rs361525,TNF-α-308rs1800629,TNFRSF1 B rs1061622,TNFRSF1 B rs1061624,TNFRSF1 B rs3397 and FASLG843 rs763110 were detected by fluorescence staining in situ hybridization and general fluorescent probe technique.Crohn’s disease activity index score was used to evaluate the curative effect.To analyze the correlation between the steady-state valley concentration level of infliximab,TNF-related gene polymorphism and clinical efficacy,to clearly predict the valley concentration threshold of infliximab treatment and evaluate its diagnostic efficacy.Results:(1)CRP,ESR and CDAI of patients with Crohn’s disease were significantly improved after treatment with infliximab.The clinical remission rate of patients with Crohn’s disease after treatment was higher than that before treatment.Abnormal liver biochemical indexes were the highest incidence of adverse reactions;(2)The incidence of secondary loss of response in patients with Crohn’s disease is as high as 37.7%.Univariate analysis showed that the percentage of patients with history of perianal surgery,the level of CRP before the first IFX treatment and the level of CRP before the fourth IFX treatment in the secondary loss response group were significantly higher than those in the continuous response group.There was no significant association between TNF-α-238rs361525,TNF-α-308 rs1800629,TNFRSF1 B rs1061622,TNFRSF1 B rs1061624,TNFRSF1 B rs3397 and FASLG843 rs763110 gene polymorphisms between the two groups.Logistic multivariate analysis showed that the history of perianal surgery(P<0.048)and the level of CRP before the fourth IFX treatment(P<0.001)were independent risk factors for secondary loss of response to infliximab treatment.The combination of the two variables predicted that the diagnostic efficacy of infliximab in the treatment of secondary loss of response was better than that of single variable.Conclusion:(1)Infliximab is effective and safe in the treatment of Crohn’s disease.the efficacy,laboratory indexes and adverse events related to liver and renal function should be closely monitored to avoid secondary failure and serious adverse reactions.in order to improve the safety and effectiveness of clinical medication;(2)The valley concentration of infliximab≥1.68g/ml can be used as an effective predictor of clinical treatment in patients with Crohn’s disease in maintenance stage.At the same time,more attention should be paid to the patients with Crohn’s disease with CRP≥2.50mg/L and a history of perianal surgery before the fourth IFX treatment,the risk of secondary failure during treatment is higher,and their clinical response should be closely monitored.The polymorphisms of TNF-α-238 rs361525,TNF-α-308 rs1800629,TNFRSF1 B rs1061622,TNFRSF1 B rs1061624,TNFRSF1 B rs3397 and FASLG843 rs763110 have no significant effect on the serum concentration and clinical efficacy of infliximab in the treatment of Crohn’s disease,so it can not be used as a predictor of secondary failure of infliximab in patients with Crohn’s disease in southern Anhui.At the same time,this study also has some limitations,for example,due to the small sample size in a single-center study,it is necessary to further combine multicenter,expand the sample size to conduct prospective studies and increase other genetic and related factors that may affect the secondary failure response and valley concentration of infliximab in the treatment of infliximab,so as to provide more clinical evidence for optimizing the drug administration regimen for patients with Crohn’s disease;(3)There was no significant difference in the valley concentration and clinical response rate of infliximab in patients with Crohn’s disease among different TNF-related genotypes.The valley concentration of infliximab in patients with effective clinical treatment was significantly higher than that in patients with ineffective treatment [(1.8±0.3)vs,P<0.001].The steady-state valley concentration of infliximab ≥ 1.68g/ml in patients with Crohn’s disease could predict the efficacy of clinical treatment.