| backgroundMTX is the first-line and anchor drug for RA treatment.The optimal therapeutic dose in the Western Hemisphere is about 20-25 mg/week.In East Asia,because of lower body weight,pharmacogenetics may be different,so the therapeutic dose will be reduced.Studies have suggested that the efficacy of MTX in treating RA is related to the concentration of MTX-PGs in red blood cells.We have observed that RA patients in this area can achieve therapeutic effects by taking MTX alone or in combination with other DMARDs at 10 mg-15mg/week.Therefore,assuming that there is a minimum effective starting dose in the10mg-15mg/week interval that can be used to treat RA patients in this region,By analyzing the relationship between oral MTX dose,MTX-PGs concentration in red blood cells,clinical efficacy and adverse reactions in RA patients in this region,Find the lowest effective starting MTX dose for RA treatment in this area to guide clinical treatment.Purpose1.Analyze the disease activity indicators of each MTX dose group(10mg/week,12.5mg/week,15mg/week)before and after treatment.2.Explore the clinical efficacy of each dose group after treatment.3.DAS28 analysis after treatment in each dose group4.Analyze the factors affecting the efficacy5.Explore the relationship between MTX dose(mg6/kg.w)and effective MTX-PGs concentration.6.Explore the relationship between MTX dose(mg/w)and MTX-PGs concentration.7.MTX-PGs concentration distribution corresponding to each dose of MTX in RA population8.The increase in MTX-PGs concentration after every 2.5mg/week increase in MTX9.Analysis of factors affecting the concentration of MTX-PGs10.The amount of MTX-PGs concentration attenuation after MTX is stopped for 2months.11.Explore the MTX-PGs concentration of each curative effect group(marked effect group,effective group,total effective group,ineffective group).12.The relationship between the total effective group MTX-PGs concentration and DAS28.13.Analyze specific adverse reactions and constituent ratios of each dose group.14.Analysis of overall adverse reactions in each dose group.Method1.Collect data1.1 Patient recruitmentUsing retrospective analysis and self-control study,Collection of RA patients treated with MTX in our center from November 2014 to June 2019.According to the inclusion and exclusion criteria,a total of 165 cases were included.According to the weekly oral MTX dose,it was divided into 67 people in the 10 mg group,66 people in the 12.5 mg group,and 32people in the 15 mg group.1.2 Collecting patient dataCollect baseline demographic data,other data before and after treatment(MTX stable dose time≥8weeks),other data including DAS28-ESR and related specific indicators,MTX dose,creatinine,bilirubin,AST,ALT,GGT,ALP,WBC,RBC,PLT,MTX-PGs concentrations,adverse reactions and side effects.2.MTX-PGs detection methodDetection of MTX-PGs concentration in red blood cells by high performance liquid chromatography-tandem mass spectrometry,Venous blood time was controlled on the 6th day after the 8th week of stable dose of MTX.3.Methods for determining clinical efficacyEfficacy was judged according to the EULAR response standard,which was further divided into a significantly effective group,an effective group,and an ineffective group.In the following statistics of this study,the significant group and the effective group were classified as the total effective group.4.Statistical methodsStatistical analysis uses SPSS 22.0 software,descriptive statistics of measurement data is expressed inor Md,Counting data is expressed by frequency or rate.The Kolmogorov-Smirnov test or Shapiro-Wilk test in descriptive statistics was used to test the distribution of measurement data.If the measurement data obey a normal distribution,ANOVA is used to compare the means;if the measurement data is a non-normal distribution,the Wilcoxon signed rank test of 2 related samples in the non-parametric test,and the Kruskal-Wallis H(K)Test and Mann-Whitney U test for comparison of 2 independent samples.The comparison of rates uses Chi-square test and Fisher’s exact test.Unconditional logistic regression was used to analyze the factors affecting clinical efficacy.Multiple linear regression analysis was used to analyze the factors affecting the concentration of MTX-PGs.The ROC curve and the area under the curve were used to analyze the relationship between the concentration of MTX-PGs and the efficacy of each dose group.All differences were statistically significant at P<0.05.Result1.Analysis of disease activity indicators before and after treatment in each dose group of MTXDAS28,SJC,TJC,and VAS in each dose group had statistically significant differences after treatment than before treatment(P<0.05);After treatment,there was no statistically significant difference in ESR and CRP in the 10 mg group and 15 mg group from before treatment(P>0.05).The efficacy-related indicators corresponding to the other dose groups were significantly lower after treatment than before treatment,and the difference was statistically significant(P<0.05).2.Explore the clinical efficacy of each dose group after treatmentThere were 81 effective cases out of 165 people,The total effective rates of each dose group(10mg group,12.5mg group,15mg group)were 37.31%(95%CI 25.73%～48.89%),57.58%(95%CI45.66%～69.50%),56.25%(95%CI39.06%～73.44%);84 cases were ineffective,of which 35 cases had DAS28≤3.2 before and after treatment,which belonged to continuous low disease activity.There were 116 patients showing total response(81 cases)and persistent low disease activity(35cases),accounting for 70.3%(95%CI63.33%-77.27%).The total effective rate of each dose group was at least partially different with statistical significance(χ~2=6.276,P<0.05);Pairwise comparison,the total effective rate of the 10 mg group was significantly lower than that of the 12.5 mg group,and the difference was statistically significant(χ~2=5.475,P<0.05),while the total effective rate of the 12.5 mg group and the 15 mg group was not statistically significant(χ~2=0.015,P>0.05).3.DAS28 analysis after treatment in each dose group.There were at least some significant differences in DAS28 after treatment in the three dose groups(P<0.05).Further pairwise comparisons suggest:After treatment,DAS28 was significantly lower in the 12.5 mg group than in the 10 mg group(P<0.05),and there was no significant difference between the 12.5 mg group and the 15 mg group(P>0.05).4 Analysis of factors that affect the efficacyUse forward stepwise regression method in maximum likelihood estimation in unconditional logistics regression to screen independent variables(total bilirubin,alkaline phosphatase,GGT,AST,ALT,ESR,CRP,RBC,WBC,PLT,albumin),DAS28,MTX-PGs concentration,MTX dose,height,age,endogenous creatinine clearance rate before treatment),Total bilirubin,alkaline phosphatase,GGT,AST,ALT,ESR,CRP,RBC,WBC,PLT,albumin,DAS28 before treatment,MTX-PGs concentration,MTX dose,height,age,endogenous creatinine clearance rate were not found The difference between total effective and ineffective was statistically significant(P>0.05).5.Relationship between MTX dose and effective MTX-PGs concentrationThis study found that The average effective MTX-PGs concentration of MTX for RA treatment is 110ng/ml,Therefore,analyze the relationship between the MTX dose and MTX-PGs concentration taken by the patient per kilogram per week,and establish a regression equation to obtain:Y=85.494+166.147X,where Y is the MTX-PGs concentration(ng/ml)and X is MTX dose(mg/kg.w);The model’s R~2=0.184,the model’s F=10.391,P=0.002<0.05,and the partial regression coefficient test P=0.002<0.05,which is statistically significant.Further analysis shows:when Y=110,X=0.147,Therefore,when RA patients in southwestern China take MTX at a dose of≥0.147mg/kg.w,it can be preliminarily considered that the clinically effective MTX-PGs concentration can be achieved.6.The relationship between the concentration of MTX and MTX-PGs in each dose groupThe concentrations of MTX-PGs in each dose group(10mg group,12.5mg group,15mg group)are:92.0(88.0,96.0)ng/ml,112.0(103.0,115.0)ng/ml,127.5(102.0,153.8)ng/ml.At least partial differences in the concentration of MTX-PGs in each dose group were statistically significant(χ~2=75.296,P<0.05);Pairwise comparison,the concentration of MTX-PGs in the 10 mg group was lower than that in the 12.5 mg group,the difference was statistically significant(Z=-8.534,P<0.05);The MTX-PGs concentration in the 12.5 mg group was lower than that in the 15 mg group,the difference was statistically significant(Z=-2.411,P<0.05),The concentration of MTX-PGs in the 10 mg group was lower than that in the 15 mg group,and the difference was statistically significant(Z=-5.494,P<0.05).The concentration of MTX-PGs in the 10mg group(normal distribution in actual statistics,the concentration is 92.5±7.0ng/ml)is lower than the effective MTX-PGs concentration reported in the literature(105.89±24.23ng/ml),the difference is statistically significant(t=-13.788,P=0.000<0.05).7.MTX-PGs concentration distribution corresponding to each dose of MTX in RA populationAnalyzed the concentration of MTX-PGs in 198 out of 165 people,In the RA population,the corresponding MTX-PGs concentrations when taking 10mg,12.5mg,and 15mg MTX weekly are:91.00(88.00,96.00)ng/ml,112.00(103.00,114.75)ng/ml,127.50(102.00,153.75))ng/ml.8.MTX-PGs concentration increase after every 2.5 mg/week increase in MTXMTX-PGs concentrations were recorded in 42 of 165 patients after an increase of 2.5mg/week,For every 2.5 mg/week increase in MTX,the increase in MTX-PGs concentration was 15(10.5,25.25)ng/ml.9.Factors affecting the concentration of MTX-PGsA multiple linear regression model was used to analyze the effects of age,MTX dose,height,weight,creatinine,total bilirubin,direct bilirubin,albumin,red blood cells,white blood cells,and platelets on the concentration of MTX-PGs.Use theα=0.099 level to test whether the variable is entered.The equation established by the stepwise entry method is Y=5.424+8.614X,where Y is the MTX-PGs concentration(ng/ml),X is the MTX dose(mg/week),R~2=0.549,and the mode’s analysis of variance:F=107.16,P=0.000<0.05,t=10.352 corresponding to the partial regression coefficient,P=0.000<0.05.The equation established by the full-variable model method is Y=-13.05+8.427X,where Y is the concentration of MTX-PGs(ng/ml),X is the dose of MTX(mg/week),the corresponding R~2=0.586,the model’s analysis of variance:F=10.015,P=0.000<0.05,t=8.959 corresponding to the partial regression coefficient,P=0.000<0.05.10.Changes in MTX-PGs concentration after 2 months of stopping MTXIn patients with effective MTX treatment,Explored the changes in the concentration of MTX-PGs in the red blood cells of RA patients treated with MTX stopped for 8 weeks and routine weekly pulsed for 8 weeks.A total of 4 patients were enrolled,and the results suggested that the average attenuation of MTX-PGs concentration after 8 weeks of drug withdrawal was 35.50±9.11ng/ml compared to before drug withdrawal.11.Explore the MTX-PGs concentration of each effect groupA total of 150 patients were included in the MTX-PGs concentration statistics.The concentration of MTX-PGs in each curative effect group(marked effect group,effective group,total effective and ineffective group)is:108.04±20.68ng/ml[median:104.00(93.75,117.25)ng/ml],110.0±19.8ng/ml[median:105.00(96.00,120.00)ng/ml],105.00(95.00,117.50)ng/ml,101.00(91.50,112.00)ng/ml.12.Relationship between MTX-PGs concentration and DAS28 in total effective groupA total of 73 MTX-PGs concentrations and correspondingΔDAS28 values in the total effective group were analyzed.We did not find a linear correlation betweenΔDAS28corresponding to MTX-PGs.13.Analysis of specific adverse reactions and composition ratios of each dose groupAdverse reactions occurred in 53 of 165 patients.There was no statistically significant difference in the rates of adverse reactions with different characteristics in patients taking different MTX doses(P=0.570>0.05).14.Analyze the total adverse reactions of each dose group.The total adverse reaction rate of each dose group was at least partially different with statistical significance(χ~2=6.272,P<0.05),Pairwise comparison:There was no significant difference in the total adverse reaction rate between the 10mg group and the 12.5m group(χ~2=2.879,P>0.05),and the difference between the 15mg group and the 12.5m group was statistically significant(χ~2=5.331,P<0.05).Conclusion1.From the dimensions of the relationship between the dose group and the clinical efficacy indicators(1)Among the 165 patients,70.3%of the 165 patients had effective treatment and DAS28≤3.2,and about 30%had poor response to MTX.(2)DAS28-ESR,SJC,TJC,and VAS in each dose group were all improved after treatment.(3)Comparison of the total effective rate of each dose group suggests that MTX12.5mg/week is the better starting dose.(4)The 12.5mg group among the three dose groups was the lowest dose that reduced DAS28 significantly.2.From the perspective of the relationship between dose group and MTX-PGs concentration(1)It was only found that the dose of MTX had an effect on the concentration of MTX-PGs.The concentration of MTX-PGs increased with the increase of the dose of MTX.When taking 10mg,12.5mg,and 15mg MTX weekly,the corresponding MTX-PGs concentration was as follows:92.0(88.0,96.0)ng/ml,112.0(103.0,115.0)ng/ml,127.5(102.0,153.8)ng/ml.For every 2.5 mg/week increase in MTX,the increase in MTX-PGs concentration is 15.00(10.50,25.25)ng/ml.(2)When RA patients in southwest China take MTX dose≥0.147mg/kg.w,clinically effective MTX-PGs concentration can be achieved.(3)The concentration of MTX-PGs decreased by about 35.50±9.11ng/ml two months after stopping MTX.(4)The overall MTX-PGs concentration in the 10mg group was lower than the effective MTX-PGs concentration reported in the literature(105.89±24.23ng/ml).3.From the perspective of the relationship between clinical efficacy and MTX-PGs concentration(1)The concentration of MTX-PGs in the markedly effective group,effective group,total effective and ineffective group is:108.04±20.68ng/ml[median expression:104.00(93.75,117.25)ng/ml],110.0±19.8ng/ml[The median is expressed as:105.00(96.00,120.00)ng/ml],105.00(95.00,117.50)ng/ml,101.00(91.50,112.00)ng/ml.(2)There is no linear correlation between the concentration of MTX-PGs and the correspondingΔDAS28.It cannot be considered that the higher the concentration of MTX-PGs,the more obvious the change of DAS28.4.Analysis of adverse reactions in each dose groupThere was no significant difference in the total adverse reaction rate between the MTX10mg group and the 12.5m group.The occurrence of adverse reactions with different characteristics was not significantly correlated with the dose of MTX. |
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