| Objective:To provide evidence-based risk or protective factors,we tried to explore factors about the relapse and disability related to Relapsing Remitting Multiple Sclerosis(RRMS).Meanwhile,we also explored the regulation of "Zheng-Zhi-Fang" for treating the relapse and disability,in order to provide some ideas of traditional Chinese medicine for multiple sclerosis.Methods:This research was divided into five parts.By literature review,retrospective cases and biomarkers study,we explored factors related to the relapse and disability.At the same time,the regulation of "Zheng-Zhi-Fang" was studied by telephone interviews and complex network analysis.The details were as follows:1.Literatures about factors associated with relapses were searched and screened systematically,and the meta-analysis was used to systematically evaluate literatures.Heterogeneity was analyzed by subgroup analysis,sensitivity analysis,and publication bias.So as to objectively summarize factors.2.The relapse and disability of retrospective cases,including 32 RRMS patients,were analysised by logistic regression analysis method.It was adjusted by age,sex,course of the disease,comorbidities,repeated symptoms,disease modifying treatment,residual symptoms,relapsing symptoms,focal location,lipids and other factors.3.For patients in the stage of relapse and remission,miRNA(miR-155,miR-146a,miR-326,miR-223,miR-21)and neurofilament light chain(NfL),which were related to immune inflammation and disease activity,were detected by RT-PCR and SimoA,in order to explore biomarkers related to the relapse.4.We investigated 50 RRMS patients by the telephone interview,and this part studied how to use the traditional Chinese medicine to influence the relapse rate and disability.It was analysised by logistic regression analysis method,and it also was adjusted by age,course of the disease,BMI,gender,disease modifying treatment,repeated symptoms,residual symptoms,the first symptom,causes,comorbidity,smoking,drinking alcohol,etc.Finally,the regulation of "Zheng-Zhi" had been explained.5.We chose the effective prescription for the relapse or disability in the RRMS patients in remission stage.We used python programme to generate matrix list of Chinese herbs,and used Gephi software to do complex network analysis,and selected Fruchterman Reingold to map complex network,and then done clustering analysis for the core of herbs.Finally,the regulation of "Zheng-Zhi-Fang" had been explained by exploring the effective prescription.Results:1.44 literatures were selected in this study.Included literatures involves infection,pregnancy,stress,vaccine,vitamin D,comorbidities,gene,smoking,obesity,age,lipid,gender,salt,temperature and degree of disability.Results of meta analysis showed that the virms or bacteria infections,postpartum,stress,low vitamin D level,comorbidity,and genes were risk factors associated with relapses.During pregnancy period was the protective factor.The conclusions of infection(RR=2.07),pregnancy period(RRF=0.56)and postpartum period(RR=1.43)were reliable.2.Regarding the relapse rate as dependent variable,univariate analysis showed duration,damp-heat syndrome and liver-kidney Yin deficiency syndrome may influence the relapse rate.The regression analysis showed only the duration entered the equation.It indicated the lower duration may lead the higher relapse rate.The lower duration was the risk factor for relapses(OR=1.692).Regarding the degree of disability at relapse stage as dependent variable,the results of univariate analysis showed that the degree of disability may be affected by comorbidities,history of allergy,residual symptoms,residual walking difficultly,residual dyspraxia,focal location(brain,periventricular).The results of regression analysis showed that both comorbidities and residual walking difficultly were risk factors for the degree of disability(OR=22.73、43.82).3.The results of RT-PCR showed that the level of miR-21 in the relapse group was lower than the remission group,and the difference was statistically significant(P<0.05).The level of miR-155,miR-146a,miR-326 and miR-223 in the relapse group were lower than that the remission group,but the difference were not statistically significant.The level of NfL in the relapse group was higher than the remission group,but the difference was not statistically significant.From 3 prospective cases in the relapse period,3 months and 6 months after relapse,it was found that 2 patients in the relapse period showed a significant downward trend in the recovery process.4.The univariate analysis showed that the relapse rate might be influenced by repeated symptoms,repeated sensory disturbance,causes of relapse and monthly utilization rate of traditional Chinese medicine.The results of regression analysis only showed that there was a strong correlation between repeated symptoms and higher relapse rate.(OR=13.51)Taking disability degree as dependent variable,it was found that seven factors in univariate analysis,including monthly utilization rate of traditional Chinese medicine,duration,disease modifying treatment,residual symptoms,repeated sensory disturbance,motor disturbance and sensory disturbance at first onset.The results of regression analysis showed that motor disturbance at first onset and residual symptoms were risk factors of disability(OR=112.73,10.91).While the monthly utilization rate of traditional Chinese medicine was the protective factor of disability(OR=0.03).5.According to the effect for relapse and disability,152effective prescriptions were selected.Through complex network analysis,the results showed 162 nodes,3883 edges,and the average degree was 47.94.The core nodes were radix rehmanniae,radix curcumae,fructus corni,poria cocos,siegesbeckiae,rhizoma anemarrhenae,fructus ligustri lucidi,yam rhizome,clematis root,radix scutellariae,radix glycyrrhizae,rhizoma zedoariae,stone calamus,medicinal indianmulberry root,bighead atractylodes rhizome,radix paeoniae alba,cistanche,etc.Rehmannia is one of the most important node,the degree is 139.In the matrix list,3884 herb pairs were generated,among which the highest weight was rehmannia and dogwood,followed by rehmannia and poria,dogwood and poria.Through cluster analysis,the main treatment methods were reinforcing liver and kidney,and combined clearing heat and dampness,dispelling toxins and dredging.Conclusion:1.Factors related to the relapse and disability of RRMSThis research found that the virus or bacteria infection,postpartum period,lower disease duration were risk factors for relapses,while during pregnancy period was the protective factor.Comorbidities were risk factor for disability at relapse stage.In view of the above factors,we should have the awareness of preventing infection.During the risk period of infection,we should adopt anti-infective therapy and pay attention to patients.In pregnancy stage,the risk of relapses and the difficulty of treatment should not be ignored.In clinical work,we should pay attention to the early initiation of preventing relapses and the treatment of comorbidities.For the miR-21 and NfL,it will probably be the potential sensitivity biomarker related to relapses,laying the foundation for larger sample size research in the future.2.The "Zheng-Zhi-Fang" of TCM in prevention and treatment of relapse and disability for RRMSWe took the disability and relapses as the "Zheng",TCM treatment as the "Zhi",and core herbs group and pairs as the "Fang".This study preliminarily explained the"Zheng-Zhi" rule from the time dimension.Patients who used TCM more than one week per month can reduce the risk of disability compared with patients who use less than one week,and the higher utilization rate of TCM could effectively alleviate the disability.At the same time,"Zheng-Zhi-Fang" had been preliminary explained.In response to the effective prescription for relapses and disability,the core herbs based on rehmannia were discovered,and the main treatment methods were reinforcing liver and kidney,and combined clearing heat and dampness,dispelling toxins and dredging.It is the deficiency origin and excess in superficiality in MS,with liver and kidney deficiency as the origin,and turbidity toxin as the superficiality.Innovation:Little domestic research were about to factors related to relapse and disability in RRMS,and little sysmatic reviews were about to all factors.This study was to explore the factors related to relapse and disability by literature review,case study,biomarkers.This was the first meta analysis of overall factors,and we tried to explore the related factors in Chinese RRMS patients.At the same time,this study focused on "Zheng-Zhi-Fang",taking relapse and disability as the point,and tried to explore the unilization of traditional Chinese medicine and the regulation of herbs by telephone interviews and complex network analysis.Finally,the idea of "Yin-Zheng-Zhi-Fang" was preliminarily discussed by integrating the evidence-based factors of this study and the treatment with traditional Chinese medicine. |
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