Study On Association Of Infliximab Concentration,Antibodies To Infliximab And Polymorphism With Efficacy And Safety In Chinese Crohn's Disease Patients

Background and objective: Infliximab,the first anti-TNF-? monoclonal antibody for treatment of Crohn's disease(CD),neutralizes the biological activity of tumor necrosis factor(TNF)-? by inhibiting binding to its receptors and induces apoptosis of immune cells secreting TNF-?.Clinical trials showed its benefit,however some patient had no response.Infusion reaction and infections are major concerns of adverse events.Recents studies suggested infliximab trough level(IFX-TL)and antibodies to infliximab(ATI)could predict clinical efficacy.There is great individual difference in infliximab concentrations,clinical efficacy and genetic backgound.In order to provide evidence for optimizing the therapy,we studied the association of infliximab concentrations,antibodies to infliximab(ATI),genetic polymorphism of drug targets with efficacy and safety in Chinese CD patients.Method: A single-centered cohort study including 209 CD patients was conducted during 2015 January and 2016 December.Regimen: 5mg/kg at week 0,2,6 and every 8 weeks after Factors influencing efficacy and safety were analysed.Samples were collected 0.5h before the next administration and had infliximab concentration and ATI titres measured by ELISA.Correlation between infliximab concentration and ATI titres with clinical activity and adverse events was analysed.Single nucleotide polymorphisms(SNP)in TNF-?(-238,-308,-857),TNFRSF1A(rs767455,rs4149570),TNFRSF1B(rs1061622,rs1061624,rs3397),FASLG(rs763110)and CASP9 93 were genotyped by SNa Pshot assay.Single nucleotide polymorphism(SNP)and haplotypes were analysed for association with biological and clinical response and ADR incidence after 2 weeks and 30 weeks of therapy.All results were statistically evaluated with SPSS version 19.0.Student's t-test,one-way ANOVA,and non-parametreic tests were used to assess continuous variables.Differences in frequencies were compared by Chi-square or Fisher's exact test.Correlation were calculated with Pearson's or Spearman's correlation coefficient.Best cutoff value for IFX-TL and ATI titres was determined with receiver operating characteristic(ROC)curve.Logisitic regression analysis was used to analyzed the relationship between infliximab concentrations,ATI titres and clinical response.Haplotype analysis of genotype data was done using SHEsis online software.Results: 1.Changes from baseline in C-reaction protein(CRP)and erythrocyte sedimentation rate(ESR)level was significantly different(P<0.05).A total of 21.5%(45/209,50 cases)of patients were reported to have experienced adverse drug reactions(ADRs).Patients with concomitant use of azathioprine had higher biological remission rate(defined by CRP or ESR)(P<0.05),while those treated with intermittent therapy had lower biological remission rate(PESR=0.059).Concomitant use of steroids might increase the risk of infections [31.6%(6/19)vs 7.4%(14/ 190),P=0.004].2.Median IFX-TL in maintainance therapy was 1.23 ?g·ml-1[interquartile range(IQR): 0.90],positively correlated with?CRP(r=0.350,P=0.017).Median ATI titres was 5.36AU·ml-1(IQR: 47.68).ATI titres were decreasing in quartiles of infliximab concentration(P<0.001),and positively correlated with CRP level(r=0.366,P<0.001).34 of 104 cases(32.69%)were ATI positive,defined as ATI titres above 10AU·ml-1.Patients who had intermittent therapy of infliximab had higher incidence for ATI positive [30.3%(30/99)vs 80.0%(4/5),P=0.038].3.Cutoff value of IFX-TL above 0.72 ?g·ml-1[Specificity 81.8%,Sencitivity 70.0%,area under the curve 0.777] was associated with optimal induction,defined as CRP below 5mg/L.Multivariable logistic regression showed inadequante IFX-TL(<0.72 ?g·ml-1),ATI positive and abnormal pre-treatment CRP level as risk factors for loss of response [ORIFX=17.955(95%CI: 3.352-96.181,P=0.001),ORATI=7.045(95%CI: 1.571-31.598,P=0.011),ORCRP =1.033(95%CI: 0.995-1.071,P=0.088)].4.TNF-?-238 GG genotype was associated with clinical response at week 30(P=0.038).TNFRSF1 B rs1061624G-rs3397 C haplotype might be protective factors for clinical response[w2 0.442 vs 0.132,P=0.028,OR=5.21(95%CI: 1.08-25.01);w30 0.391 vs 0.091,P=0.048,OR=6.38(95%CI: 10.83-49.35)].Conclusion: Infliximab could reduce CRP and ESR level significantly.Infliximab trough level in maintainance therapy was 1.23?g·ml-1(IQR: 0.90)and positively correlated with ?CRP.Cutoff value above 0.72 ?g·ml-1 was associated with optimal response(defined as CRP below 5mg/L),which was lower than those from European and American but similar with Asian.Inadequante IFX-TL(<0.72 ?g·ml-1),ATI positive and abnormal pre-treatment CRP level were risk factors for loss of response.Median ATI titres was 5.36AU·ml-1(IQR: 47.68).ATI titres were decreasing in quartiles of infliximab concentration,and positively correlated with CRP level.TNF-?-238 GG genotype and TNFRSF1 B rs1061624G-rs3397 C haplotype might be protective factors for clinical response.This study suggested Chinese CD patients could predict clinical response and personalize the therapy by measuring IFX-TL,ATI titres and genetic polymorphism,therefore reduce unnecessary medical expense.