Effect Of Plasma Concentration And Anti-drug Antibodies Of Yisaipu On Clinical Efficacy In Patients With Ankylosing Spondylitis And Predictors Of Early Clinical Response

Background:At present,tumor necrosis factor(TNF)inhibitors as well as their biosimilar for the treatment of ankylosing spondylitis(AS)are growing rapidly.While enriching the choice of therapeutic schedules,the scientific evaluation of the efficacy of these biosimilar is also very important.Clinical studies have shown that blood concentration and anti-drug antibodies(ADA)can affect clinical efficacy of TNF inhibitors treatment and low level of blood concentration and the production of ADA are the important reasons of poor clinical efficacy.In addition,it needs at least 3 months of full dose treatment to determine whether the treatment of TNF inhibitor is effective.If we could predict the response of TNF inhibitor before the treatment,we might choose a more effective treatment plan for AS patients.However,there are few reports on the effective blood concentration of TNF inhibitor biosimilars,especially on the production of ADA and the predictors of clinical efficacy,and the research conclusions of those problems are conducive to optimize the clinical application of TNF inhibitor biosimilars,and have a certain significance to guide the clinicians.Yisaipu(recombinant human TNF receptor II: IgG Fc fusion protein for injection;Sunshine Guojian Pharmaceutical Co.,Ltd.,Shanghai,China)has been widely used in the treatment of Chinese patients with active AS.As a biosimilar of etanercept,there was no significant difference in pharmacokinetics,pharmacodynamics,immunogenicity,efficacy and safety between yisaipu and etanercept.However,the prediction of the efficacy of yisaipu,the effective blood concentration of yisaipu,as well as whether anti-yisaipu antibodies affects yisaipu levels and clinical efficacy has not yet been reported in any studies.Therefore,this study chose yisaipu as a representative biosimilar.Objective:(1)To investigate the effective yisaipu level in the treatment of active ankylosing spondylitis.(2)To investigate the production of anti-yisaipu antibody and its influence on yisaipu levels and clinical efficacy in patients with AS.(3)To investigate the relationship between inflammatory cytokines and disease activity in patients with AS and baseline predictors of clinical response after 12 weeks of yisaipu treatment.Thus provide the basis for estimation of clinical efficacy and adjustment of medication regimens during yisaipu treatment and achieve precision medicine in different patients with AS.Methods:This study enrolled 60 patients with AS who were treated with yisaipu.All the patients were diagnosed according to the 1984 modified New York Criteria for AS.Serum and clinical data were collected at baseline and treatment week 4,12,and 24.Another 21 individuals were selected as health control group.Yisaipu and ADA levels were measured using an enzyme-linked immunosorbent assay(ELISA)while the IL-1?,IL-6,IL-17 A and TNF-? levels were measured using cytometric bead array(CBA).At baseline,we compared the differences of inflammatory cytokines between AS patients and healthy controls,as well as the correlation between inflammatory cytokines and disease activity.We detected the yisaipu and ADA levels at treatment week 4,12 and 24.Observe the relationship between the yisaipu levels and the improvement of the clinical data.Meanwhile,we divided the patients into two groups according to whether they achieved moderate or inactive disease activity(AS Disease Activity Score-C-reactive protein,ASDAS-CRP <2.1)at each time point,compare the difference of yisaipu levels between patients with different disease activity and calculated the cut-off values of effective yisaipu levels at each time point by receiver operating characteristic(ROC)curve.Then we discussed the difference of clinical data between patients whose yisaipu levels were above and below the cut-off value.We also divided the patients into two groups at each time point based on whether they were ADA-positive.Furthermore,we discussed the difference of yisaipu levels,TNF-? levels and ASAS 20 remission rates between two groups.After 12 weeks of treatment,patients were divided into two groups.The patients who achieved ASAS 40,ASAS partial remission,or ASAS 5/6 were classified as good responders,and those who did not achieve ASAS 40 were classified as non/poor responders.We compared the baseline clinical data of these two groups.The ROC curve was used to analyze the cut off values of baseline predictors,and binary logistic regression was used to investigate the association between baseline predictors and clinical response.The patients were divided into different groups according to whether the baseline predictors reached cut off values.The differences of clinical data and the percentage of patients who reached good responders between different groups were compared at 12 weeks of treatment.Results:At baseline,the IL-1?,IL-6,IL-17 A,and TNF-? levels of patients with AS were significantly higher than those of healthy controls.The TNF-?,IL-1? and IL-6 levels were positively correlated with disease activity.After 24 weeks of yisaipu treatment,the desease activity and inflammatory cytokines were significantly decreased than those at baseline.Compared with baseline,the yisaipu level increased from 0?g/m L to 2.24±1.32 ?g/m L within 4 weeks.Yisaipu levels are associated with improvement in Bath AS Disease Activity Index(BASDAI)?ASDAS-CRP and CRP.Higher yisaipu levels are associated with greater improvement of these clinical data.We found that patients with ASDAS-CRP ?2.1 exhibited significantly lower yisaipu levels than those with ASDAS-CRP <2.1.The cut-off values of yisaipu level of patients who achieved ASDAS-CRP <2.1 at week 4,12,and 24 were 2.32,2.12,and 2.36 ?g/m L,respectively.Patients with yisaipu levels above the cut off value had lower BASDAI scores,and TNF-? levels.We found that patients developed ADA at different time points and some of the ADA-positive patients reverted to a negative status following the treatment.At treatment week 4,there were 18 patients with ADA(median 1.60ng/ml,quartile 0.61-3.35);at treatment week 12,there were 19 patients with ADA(median1.34ng/ml,quartile 0.72-2.68);at treatment week 24,there were 13 patients with ADA(median 2.24ng/ml,quartile 0.96-3.25).In this study,the average duration of ADA was 9.38 weeks.ADA had no effect on the ASAS 20 remission rates,but patients with ADA had lower yisaipu levels and higher TNF-? levels.After 12 weeks of treatment,only 21 patients(35.00%)failed to achieve ASAS 40 remission.We then compared the baseline characters between good responders and non/poor responders,and found that good responders had lower baseline IL-6 level and ESR than non/poor responders.Further,we analyzed the IL-6 level and ESR as baseline predictors of clinical response with the ROC curve to identify the cut off value,sensitivity,and specificity.The cut off value of IL-6 level and ESR was 9.05 pg/m L and 47.00 mm/h,respectively.Binary logistic regression found that baseline high IL-6 level and high ESR had an adverse relationship with clinical response,and the combination of IL-6 level and ESR could predict clinical response more effectively.Therefore,patients might achieve ASAS 40,ASAS partial remission,or ASAS 5/6 after 12 weeks of yisaipu treatment when their baseline IL-6 level is <9.05 pg/m L and ESR is <47.00 mm/h.In addition,patients with baseline IL-6 level and ESR both below the cut off value had lower disease activity and higher ASAS 40 rate at 12 weeks of yisaipu treatment.Conclusions:(1)There is a close relationship between the yisaipu level and the clinical effect.The blood concentration of yisaipu should reach the e ffective level to achieve clinical efficacy.The cut-off values of yisaipu level of patients who achieved ASDAS-CRP <2.1 at week 4,12,and 24 were 2.32,2.12,and 2.36 ?g/m L,respectively.(2)Compared with other TNF inhibitors,anti-yisaipu antibodies,with lower positive rate and shorter duration,can reduce the yisaipu levels of AS patients,but has no significant effect on ASAS 20 remission rate.(3)The combination of baseline IL-6 level and ESR can predict the clinical response of 12 weeks of yisaipu treatment in patients with AS.(4)Detecting the baseline IL-6 level and ESR,and monitoring yisaipu and anti-yisaipu antibody levels might facilitate the estimation of treatment efficacy and adjustment of medication regimens during yisaipu therapy to achieve precision medicine in different patients with AS.