| Rheumatoid arthritis(RA)is an untreatable systemic autoimmune disease,and it is one of the major diseases causing labor force loss in our young and middle-aged population,which can lead to reduced quality of life and even disability in severe cases.As the standard treatment option for RA,MTX is widely used in RA patients because of its affordability,efficacy and safety,and has been extensively studied in clinical applications and basic pharmacology.However,up to 50% of RA patients still respond inadequately to MTX treatment or have reduced efficacy of retreatment after relapse,when alternative therapies are the only option and the optimal treatment period is also missed.The early stages of RA patients begin with joint swelling and there may be a three-month window of treatment.If treatment is administered during this period,there is less potential for cartilage damage and bone erosion and a greater likelihood of remission.Therefore,early and precisely sustained treatment may be a window of opportunity for treatment of RA,with great potential to improve the degree of disease activity in patients and increase the efficiency of RA attainment therapy.However,achieving personalized treatment of patients with MTX remains a great challenge at this time,as there are no reliable molecular markers to predict and screen for therapeutic response to MTX in the clinical setting.Therefore,the analysis and mining of useful biomarkers at the molecular level,which makes it possible to develop targeted therapies,may delay the disease and reduce the degree of disease activity in patients.The main research of this paper is as follows:(1)Eight patients and two healthy controls were randomly selected from the Department of Rheumatology and Immunology,Ningbo First Hospital,Ningbo,China.The diagnosis of RA met the diagnostic criteria of ACR/EULAR,and the efficacy of patients after MTX treatment was evaluated according to the DAS28-ESR classification method,and they were divided into four MTX effective(Responder)and four MTX ineffective(Non-responder).Highthroughput sequencing of the TCRB CDR3 region in 10 samples revealed that the TCR group library diversity was significantly higher in the Responder group than in the Non-responder group(P>0.05).TRBV6-6 gene differed significantly between the HC and Responder groups(P=0.028)and between the Responder and Non-responder groups(P=0.003).The RA patient group showed excessive clone amplification,and the Top5/10 clone accumulation frequency in the Responder group was significantly higher than that in the Non-responder group;no shared clones were found in the Responder and Non-responder groups for the time being.(2)Thirty-two patients with initial RA were randomly selected from the Department of Rheumatology and Immunology,Ningbo First Hospital,Ningbo,China,and were treated with MTX monotherapy for an average of three months,and were divided into 21 MTX effective(response group)and MTX ineffective patients(non-response group)by efficacy assessment.Tetra-primer ARMS-PCR was used to design specific primers for MTX metabolic pathway gene polymorphisms MTHFR C677 T,MTHFR A1298 C and MTRR A66 G sites to identify patient genotypes.Statistical association of genetic polymorphisms with clinical efficacy of MTX and disease activity of patients revealed smoking(P=0.037),alcohol consumption(P=0.016),and male(P=0.037)as influencing factors for non-response to MTX.Baseline ESR levels,TJC,SJC,and DAS28 were significantly reduced by MTX treatment in the response group(P<0.001).No correlation was observed between genotype and MTX efficacy and disease activity to predict MTX response. |
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