Analysis Of Risk Factors For Infliximab Loss Of Response In Patients With Inflammatory Bowel Disease

Objectives: To analyze the related risk factors of primary loss of response(PLOR)and secondary loss of response(SLOR)in patients with inflammatory bowel disease(IBD)treated with infliximab(IFX),and to explore the adjusted therapy after loss of response(LOR)to IFX.Methods: 78 patients hospitalized with IBD and treated with IFX from January2013 to January 2021 were retrospectively selected.There were 40(51.3%)patients with UC and 38(48.7%)patients with CD,49(62.8%)patients were males and 29(37.2%)patients were females.Age of diagnosis of the disease was between 18 and 68 years old with an average age of 34 years.IFX was administered with a dose of 5 mg/kg intravenously at week 0,2 and 6 as an induction remission therapy,followed by maintenance therapy with the same dose every 8 weeks,the total treatment time was≥14weeks.According to the modified Mayo score and Best CDAI score,patients with ulcerative colitis(UC)and Crohn’s disease(CD)were evaluated for their condition and efficacy before each IFX infusion.According to the response,78 patients were divided into response group of 54 cases(69.2%)and loss of response group of 24 cases(30.8%),among the latter 2 cases were PLOR(2.6%)and 22 cases were SLOR(28.2%).The patient’s general medical history data was collected and level of C-reactive protein(CRP),albumin,interleukin-6(IL-6),interleukin-8(IL-8)and other indexes at the 0th and 14 th week of IFX infusion was measured,and the IFX trough levels(IFX-TLs)and anti-IFX antibodies(ATI)were detected.The adjusted therapy in patients with LOR to IFX was also analyzed.Results:1.After 14.3(8.1-19.4)months of IFX therapy,the PLOR and SLOR rate were 2.6%and 28.2%,respectively,and the cumulative LOR rate was 30.8%.2.Among the baseline parameters,the level of IL-6 in the loss of response group was 44.79pg/L(26.68-94.40pg/L),which was higher than that in the response group[42.95(12.60-44.79pg/L)],a statistically significant difference between the two groups(P=0.011);the level of IL-8 in the loss of response group was 552.30pg/L(291.75-863.00pg/L),which was higher than that in the response group[496pg/L(158.25-552.39pg/L)],also a statistically significant difference between the two groups(P=0.019).Among the parameters at 14 th week,the CRP level in the loss of response group was 8.07mg/L(3.16-23.20mg/L),which was higher than that in the response group[3.26mg/L(3.13-3.72mg/L)],and the difference between the two groups was also statistically significant(P = 0.004).3.ATI had a significant negative correlation with the trough level of IFX(P=0.019,r=-0.457).The IFX-TLs in the response group was 1.3μg/m L(0.15μg/m L-9.6μg/m L),which was higher than the IFX-TLs in the loss of response group[0.4μg/m L(0.39μg/m L-0.5μg/m L)](P=0.054).When IFX-TLs was grouped by the predicting failure threshold of 0.5ug/ml,the percentage of patients with high IFX-TLs(63.6%)in the response group was higher than that in the loss of response group(13.3%),and there was a statistically significant difference between the groups(P=0.014).There was a statistical difference in the number of ATI positive(ATI>30ng/m L)patients between the response group and the loss of response group,and the ATI positive rate in the loss of response group was significantly higher than that in the response group(53.5% vs 0%,P = 0.007).4.The risk factors for LOR to IFX were high level of IL-6(P=0.027,OR=1.020,95%CI 1.002～1.039)and high level of CRP at 14 th week(P=0.002,OR=1.100,95%CI1.035～1.170).When level of IL-6 was greater than 56.1pg/L,SLOR could be predicted with a sensitivity of 40.9% and a specificity of 92.6%(AUC=0.678,95% CI0.542-0.813,P=0.016);when CRP level at 14 th week was greater than 4.71mg/L,SLOR could be predicted with a sensitivity of 63.6% and a specificity of 77.8%(AUC=0.68,95% CI 0.535-0.828,P=0.014).5.91.7% of patients with LOR adjusted their therapeutic protocol.All the patients with PLOR underwent colectomy.In patients with LOR to IFX who had adjusted therapy for more than 12 weeks,the cumulative frequency of various adjusting measures was as the followings: adding immunosuppressant in 69.2%,intensifying treatment(shortening the interval between doses)in 38.5%,adding short-course of intravenous hormone in 23.1%,undergoing GMA in 15.4%,adding other biological agents in 15.4%,undergoing fecal bacteria transplantation in 7.7%,and performing colon resection in 15.4%.Conclusions: The high level of IL-6 and CRP in the 14 th week of IFX therapy in IBD patients are the risk factors for LOR.Low blood IFX concentration and high anti-infliximab antibody are associated with LOR.IL-6>56.1pg/L and CRP>4.71mg/L at the 14 th week could predict the occurrence of SLOR.Combining immunosuppressive agents and IFX intensive therapy after LOR are effective ways to regain response in patients with IBD.