Efficacy Research Of Dexamethasone And Rituximab For ITP Patients

Background:Primary immune thrombocytopenia is an autoantibodies-mediated bleeding disorder.The main manifestations of ITP vary from asymptomatic patients,petechiae and ecchymoses in skin and mucosa,or even viscera hemorrhage such as gastrointestinal hemorrhage,genitourinary tract hemorrhage and intracranial hemorrhage,sometimes posing a threat to life.The main characters are isolated thrombocytopenia in peripheral blood,increased megakaryocyte counts in bone marrow together with dysmaturity,shortened platelet lifespan,and appearance of platelet autoantibodies.Recent studies have shown that ITP is a very heterogeneous disorder.The main pathogenesis includes humoral immunity disturbance,platelet autoantibody generation,T helper(Th)cell and regulate T cell(Treg)dysfunctions and cytotoxic T cell hyperfunction.The major aim for treatment of ITP is to provide a safe platelet count,rather than a normal platelet count.Corticosteroids are the standard first-line therapy for ITP patients,with a response rate of 70?90%.However,sustained responses are lower and become between 30%and 80%on account of disease relapses during dose reduction or after corticosteroid withdrawal,.Patients who do not have a persistent response to corticosteroids usually should get the second-line treatment(such as splenectomy and rituximab).For patients with chronic ITP,splenectomy is considered as the standard second-line treatment.Splenectomy is a kind of invasive operation related with perioperative and postoperative complications,and there is no ways to forecast the responses of the operation.On account of the availability of new medical drugs and emerging evidence of long-term remissions,physicians become more unwilling to recommend the splenectomy and patients are more reluctant to accept splenectomy.There are many available second-line treatments,for instance,rituximab,thrombopoietic agents,immunosuppressive agents,cytotoxic agents,etc.Of these many medicines,the anti-CD20 antibody rituximab and thrombopoietic agents were more used.At present,there are still many problems during the course of treatment with rituximab for ITP,such as,are there any indicators that can predict the efficacy of rituximab?the exact curative effect of rituximab and its application?whether rituximab early intervention can delay or even avoid splenectomy?etc.By contrast,the therapeutic effect of high dose dexamethasone treatment on ITP is reported to be related to the type of platelet autoantibodies.To this end,the thesis carried out two aspects:1.Study between the efficacy of low dose rituximab or high dosedexamethasone on ITP and species of platelet autoantibody;2.The meta-analysis of the ITP remission rate of rituximab was used to provide the basis for ITP individualized treatment.PART ? Correlation Analysis of Platelet-Specific Autoantibodies to High Dose Dexamethasone or Low Dose Rituximab Efficacy in The Treatment of ITPPurposePlatelet specific autoantibody is a marker of ITP humoral immunity perturbance,and its correlation with therapeutic efficacy of ITP is not clear.This research was through the retrospective analysising 86 cases of small dose of RTX second-line treating ITP and looked for the relationsp of platelet specific autoantibodies,GP? b/?a and GP ? b/?,the relationship between the curative effect and platelet specific autoantibodies was found in 127 patients with high dose dexamethasone,to explore the curative effect of ITP first line and second-line treatments.Objects and MethodsThe study objects for low dose rituximab therapy(100mg weekly for 4weeks or 375mg/m2 once)were 86 cases of ITP patients and for high-dose dexamethasone therapy(40mg/d×4d,repeated once in inefficacy patients after half month)were 127 cases of ITP patients with glucocorticoid treatment failing.Modified monoclonal antibody-specific immobilization of platelet antigen(MAIPA)essay was used to check the anti-platelet GP ?b/?a and GP ? b/? antibodies.Retrospectively observed the patient response to the treatment of glucocorticoid and RTX,compared the differences of two drugs' efficacy of different kinds of platelet autoantibodies through statistical analysis.Response was defined as the platelet count ?30×109/L,and the platelet count at least more than two times of based number and no hemorrhage clinical symptoms.Results1.127 cases of patients in dexamethasone group,platelet autoantibodies totally positive rate was 70.1%(89/127),GP?b/?a antibody positive rate was 42.5%(54/127),GP ? b/? antibody positive rate was 46.5%(59/127).Response rate of GP? b/?a antibody positive group(38.9%,21/54)was inferior to GP ? b/?a antibody negative group(74.0%,54/73),the difference was statistically significant(P<0.05).There was no statistical difference(P>0.05)between GP ? b/? antibody positive group(61.0%,36/59)and GPIb? antibody negative group(57.4%,39/68).The patients'age(P>0.05,OR 0.956,95%CI 0.932?2.016),gender(P>0.05,OR 1.168,95%CI 0.526?4.982)and initial platelet number(P>0.05,OR 1.506,95%CI 0.986?2.259)showed no correlation with efficacy.There was no interaction between two antibodies(P>0.05,OR 1.286,95%CI 0.351?8.287).2.86 cases of patients in rituximab group,platelet autoantibodies totally positive rate was 58.1%(50/86),GP ? b/?a antibody positive rate was 41.9%(36/86),GP I b/? antibody positive rate was 36.0%(31/86).Response rate of GP ? b/?a antibody positive group(75.0%,27/36)was higher than GP ? b/?a antibody negative group(46.0%,23/50),the difference was statistically significant(P<0.05).There was no statistical difference(P>0.05)between GP ? b/? antibody positive group(54.8%,17/31)and GP ? b/? antibody negative group(60,0%,33/55).The patients' age(P>0.05,OR 0.996,95%CI 0.966?1.027),gender(P>0.05,OR 0.939,95%CI 0.351?2.516),initial platelet number(P>0.05,OR 1.030,95%CI 0.958?1.107)and RTX dose(P>0.05,OR 0.921,95%CI 0.348?2.433)showed no correlation with efficacy.There was no interaction between two antibodies(P>0.05,OR 1.552,95%CI 0.214?11.284).Conclusions1.GP? b/?a antibody was poor prognostic factor for dexamethasone treatment in ITP.2.GP? b/?a antibody was good prognostic factor for RTX treatment in ITP.3.There was no correlation between GP ? b/IX antibody and high-dose dexamethasone or RTX in ITP treatment.PART ? The Response Rate of Rituximab for ITP:a Meta-Analysis of Randomized Controlled TrialsPurposeUsing a meta-analysis system to assess the exact efficacy of lituximab in treating ITP and its position in chronic ITP treatment through database retrieval of a large number of literatures,in order to provide theoretical basis for clinical rational,safe and even early use of rituximab.Materials and MethodsRetrieve Medline(Pubmed),Embase,Cochrane Library,and Google academic search engine,according to the standard of inclusion and exclusion criteria,the data extraction is carried out in accordance with the standards.The main data includes treatment regimen,complete response rate(CR),overall response rate(OR).The quality of methodology is evaluated and explained according to the requirements and criteria of Cochrane Collaboration.The main research indicator is overall response rate(OR)of rituximab to treat ITP.OR included greater than 30×109/L(OR30)or 50×109/L(OR50).The secondary research indicator is complete response rate(CR),PLT is greater than 100×109/L(CR100)or 150×109/L(CR150).The control group was not able to carry out the control analysis because the control group in the collected clinical trial contained different treatment schemes.The classification method of adverse drug events is completely different,and the safety of ITP is not summarized.The I2 test and Q test were used to determine the heterogeneity of the research data.If heterogeneity exists,subgroup analysis and sensitivity analysis are performed to find the source of heterogeneity.The report bias was evaluated using funnel plot and Egger linear regression method.The analysis software is Meta-Analyst,and the Review Manager is used to detect the bias.ResultsWe preliminarily searched the database for 4077 literatures.After reading the literature title and the summary screening,we excluded 3956 articles,and 114 were excluded after reading the full text.In the end,seven literatures were included in the meta-analysis.The number of patients in each document ranged from 60 to 138,with a total of 716 cases.Four trials recorded OR30 rate,the mean rate achieved 67.7%(95%CI:0.60?0.74)in 171 patients,there was no heterogeneity after calculation(I2 = 0.0%,P=0.39).Four studies recorded OR50,the mean rate achieved 60.4%(95%CI:0.45?0.73)in 188 patients,there was moderate heterogeneity after calculation(I2 =42.5%,P=0.01),Li et al.'s article may lead to the heterogeneity.The heterogeneity descended(I2 = 37.4%,P = 0.08)when this study was excluded and a meta-analysis was performed for the other three studies.Six studies recorded CR100,the mean rate achieved 48.1%(95%CI:0.37?0.59)in 251 patients,there was mild heterogeneity after calculation(I2 = 39.6%,P = 0.01).By subgroup analysis for study designing sort,100 mg weekly rituximab articles might generate the heterogeneity.Though conducting a subgroup analysis according to study region,it was found that trials performed in the non Europe area produced major heterogeneity.To estimate the robustness of this meta-analysis,a sensitivity analysis was performed through excluding each study per iteration.The outcome uncovered that the excluding of each trial did not alter the total result.Two studies recorded CR150,the mean rate achieved 31.8%(95%CI:0.15?0.55)in 95 patients,there was moderate heterogeneity(I2 =44.0%,P = 0.03).In Zaja et al.'s article,rituximab associated with dexamethasone to cure ITP might have led to heterogeneity.For the analyzing of OR30,the funnel plot did not express significant asymmetry,in the Egger linear regression test,it manifested no distinct proof for publication bias among the trials(P= 0.029,95%CI:0.195?1.395).For the analyzing of OR50 and CR100,the funnel plots expressed good symmetry in the funnel plots,in the Egger linear regression tests,they manifested no proof of publication bias among the articles(OR50,P = 0.479,95%CI:-1.007?1.514;CR100,P= 0.379,95%CI:-0.552?1.162).For the analyzing of CR150,it manifested the publication bias.Only two trials in CR50 analysis was the main reason for the bias risk.ConclusionsThis meta-analysis revealed that rituximab possessed high response rate for the treatment of primary immune thrombocytopenia.Therefore,rituximab was a wonderful choice for ITP patients.In this meta-analysis adverse events were not analyzed for the limitation of the collected trials,however,all the seven studies manifested that there were few adverse events and rare serious adverse events of rituximab for ITP.In summary,it is rational and scientific to earlier use rituximab for patients with immune thrombocytopenia.