The Clinical Efficacy And Safety Of Tacroliums To Treat Refractory Moderate And Severe Rheumatoid Arthritis Patients For 6 Months

ObjectiveRheumatoid arthritis(RA)is a chronic autoimmune disease characterized by proliferative synovitis and joint damage caused by abnormal activation of immunocompetent cells,suah as T cells,B cells and monocyte-macrophages.The main therapeutic goal of RA is to control inflammatory responses as early as possible to achieve disease remission or low disease activity,and to reduce the structure and joint damage by the use of conventional chemical DMARDs(conventional synthetic DMARDs,csDMARDs)or biological DMARDs(bDMARDs),but there are still a considerable number of RA patients who are resistance or intolerance to csDMARDs,and difficult to achieve compliance therapy.In clinical practice,these refractory rheumatoid arthritis(RRA),including those accompany with extra-articular manifestations,require novel drug strategy to control the condition.T cell dysfunction plays a major role in the pathogenesis of RA.The abnormal activation of T cell triggers B cells to synthesize antibodies,which cause the activation of monocyte-macrophage and produce cytokines.It is widely involved in the pathophysiological process of RA.Tacrolimus(TAC),also known as FK506,is a macrolide calcineurin inhibitor isolated from Streptomyces,inhibit the activation of T cells,synthesis and secretion of cytokine by binding to specific proteins in T cells.In our country,TAC was used to prevent allograft rejection after liver and kidney transplantation.Over the past few decades,several studies from Japan have confirmed the effectiveness and safety of TAC in the treatment of RA and listed it as a second-line csDMARDs drug.But other countries have less reported the results of TAC on RA patients who are intolerant or resistant to csDMARDs.The aim of this study was to assess the long-term safety and efficacy of tacrolimus(TAC)combination with oral methotrexate(MTX)and/or prednisolone on RRA who with poor response or intolerance to DMARDs.Methods116 with moderate and severe RRA patients who had poor response to csDMARDs(no-response,NR)or intolerant csDMARDs(not-tolerance,NT)in Qilu Hospital of Shandong University.Treatment with TAC monotherapy(TAC),or TAC combined with MTX(T+M),or TAC combined with hormone(T+P)therapy for 24weeks.During the observation period,the initial dosage of TAC was 2mg/days,the dose was reduced gradually after disease controlled in12 weeks.MTX 7.5mg-15mg,once a week;the maximum dose prednisolone starting 10-15mg/days,the dose reduced after disease controlled.All the patients met the criterion of the AmericanCollege of Rheumatology(ACR)diagnostic criteria in 1987.Their gender,age,thecourse of disease,erythrocyte sedimentation rate(ESR),C-reactive protein(CRP),the painfu(T28)and swellen(SW28)number of 28 joints' were recorded at each follow-up.Each patient should fill in the Health Assessment Questionnaire(HAQ)survey,and the disease activity index:the DAS28-ESR score,the simplified disease activity index(SDAI),the clinical disease activity index(CDAI)and the improvement of ACR20 were calculated.The dose of TAC and concomitant drugs and adverse reactions were recorded.In the course of follow-up,we divided the patients into four subgroups:moderate group(M)and severe group(S),Tac monotherapy group(TAC)and Tac combined with MTX group(T+M),previous poor response to DMARDs(NR)and previous intolerance to DMARDs(NT),with prednisolone group(T+P)and unused prednisolone group(T+0).69 patients fulfilled the 24 weeks observation(59.48%).Disease activity index were compared using paired t test,Student's t test,General linear model repeated measurements,correlation.Results69 RRA patients were treated with TAC for 24 weeks.During the observation period the disease activity,function and inflammation index of all patients were significantly decreased(p<0.01),such as DAS28-ESR,SDAI,CDAI.All subgroups obtained a significant decrease in disease activity at 3 weeks,12 weeks,and 24 weeks(P<0.01).ACR20 response rate of 3 weeks,12weeks and 24weeks were 47.83%,60.87%and 62.32%.The disease activity,joint function and inflammation index were significantly decreased in patients with TAC at weeks 3.The activity of the disease continued to decrease at 12 weeks and 24 weeks(p<0.05),but the decrease trend was slower than that of 3 weeks.There was a significant difference in the decrease of disease activity between the M and S groups(p<0.01).The baseline activity of S group was obviousiy higher than that of M group,while the disease activity and function of S group decreased significantly faster than M group at weeks 3,12,24.There was no statistical difference between other subgroups.The total adverse reaction rate of TAC was 13.04%/times in all 24 weeks procession,and most patients were well tolerated to TAC.The most common adverse reactions are infection,hyperglycemia,hypertension,liver and kidney dysfunction,diarrhea.Two patients withdraw due to severe infection,one of them had the basic disease of pulmonary fibrosis.Adverse reactions offen occurred in the NT group,T + P group,and a variety of adverse reactions easy to occur simultaneously or occurred in the same patient.ConclusionWhen the traditional DMARDs treatment fails or intolerant,and biological agents are not appropriate or can not be used,TAC treatment of patients is a good choice to RRA.Our data confirm that TAC monotherapy or combined with MTX,hormone has a significant effect on RRA,can quickly and permanently improve the disease activity of RRA.The incidence of adverse reactions is low and can be tolerated.Therefore,TAC is an effective and safe treatment option for RRA patients.In the future.TAC can be combined with other csDMARDs or bDMARDs for RRA patients.