Systemic Review Of Effects And Safety Of Tacrolimus In Treatment Of Rheumatoid Arthritis

Objective: To evaluate the efficacy and safety of tacrolimus(TAC)in the treatment of rheumatoid arthritis(RA).Method: We searched the Pubmed,Embase,Cochrane Library,CBM,Wangfang database and CNKI(all up to December,2020)to discover and select the randomized controlled trials(RCTs)and Quasi-randomized controlled trial(quosi-RCT)investigating TAC for treatment of RA.The included comparisons were TAC versus placebo,blank or other active agents.The primary outcomes were ACR(American College of Rheumatology)20/50/70.The secondary outcomes included Disease Activity Score Using 28-Joint Count(DAS28),duration of morning stiffness,grip strength,swollen joint counts(SJCs),tender joint counts(TJCs),erythrocyte sedimentation rate(ESR),C-reactive protein(CRP),Modified Health Assessment Questionnaire(M-HAQ),pain visual analog scale(VAS,100 mm),patient’s global assessment of disease activity(Pt GA)VAS,physician’s global assessment of disease activity(PGA)VAS.Safety outcomes included adverse events and withdrawals because of adverse reaction,etc.Two reviewers independently identified the included trials,evaluated risk of bias and extracted the data.We used the Review manager software 5.3 to analyze the data.The effects size for dichotomous data were expressed as relative risk(RR)and 95% confidence interval(CI)and mean difference(MD)and 95% CI for continuous data.Result: A total of 14 RCTs(n=1842)were included in this study,all were RA patients who were inadequate response to conventional synthetic DMARDs(cs DMARDs)(cs DMARDs-IR).3 RCTs(n=934)compared TAC with placebo.All reported the primary outcomes,showing that TAC was superior to placebo group in ACR20 and ACR50,pooled RRs(95% CI)were 2.23(1.64,3.03)and 2.76(1.27,5.96).However,there was no significant difference in ACR70 and the RR was 5.13(0.61,43.41).In the secondary outcomes,patients gained benefit from TAC in CRP,ESR,SJC,TJC,pain VAS,Pt GA VAS and PGA VAS.There were no significant increases in overall adverse reactions and withdrawals due to adverse reactions,but the incidence of higher serum creatinine level(≥ 40% from the baseline)found in TAC group with the RR 2.65(1.70,4.14).Subgroup analysis showed that patients in both higher dose(3-5 mg/d)and lower dose(1-2 mg/d)TAC group could benefit in both the primary and secondary outcomes mentioned above.We further compared higher dose TACwith lower dose group and found that the higher dose group did better in ACR20(RRwas 1.56,95% CI1.22 to 2.01)as well as ESR,SJC and TJC.However,higher serum creatinine was more frequent(RR was 2.19,95% CI 1.13 to 4.25).One RCT(n=144)compared TAC(2 mg/d)with blank controlbut did not report any primary outcome.In terms of secondary outcomes of SJC,TJC,grip strength and morning stiffness time,the TAC group was better than blank control group.Nine RCTs(n=700)compared TAC with cs DMARDs,including cyclophosphamide(CTX),leflunomide(LEF)and iguratimod(IT).They did not report any primary outcome indicators.Seven RCTs compared TAC(1-2 mg/d)with CTX(0.4-1.0 g/d).These were non-blind studieswith higher bias risks.Meta-analysis showed that TAC was superior in DAS28,CRP,ESR,SJC,TJC,morning stiffness time and pain VAS and no significant difference in adverse reactions between the intervention groups.One randomized,double-blind,multicenter RCT(n=74)compared TAC(1.5-3 mg/d)with LEF(10-20 mg/d).The results showed that TAC was better in TJC(MD was-2.89,95% CI-5.27 to-0.51).There was no significant difference in DAS28.The adverse reactions were fewer in TAC than in LEF group(RRwas 0.80,95% CI 0.66 to 0.97).One non-blind RCT(n=156)compared TAC(2 mg/d)with IT(50mg/d),showing that there was trivial difference(significant statistically but insignificant clinically)in SJC,TJC,pain VAS and incidence of adverse events.TAC group had a longer morning stiffness time,MD was 8.40(5.87,10.93)min and could be of clinical significance.One non-blind RCT(n=84)compared TAC(5mg/d)with infliximab(3 mg/kg/q2w),showing that TAC was inferior in DAS28,morning stiffness time,SJC,TJC and ESR,but there was no significant difference in the incidence of adverse reactions,although this study have high risks of biases in terms of implementation bias and measurement bias.Conclusion: Compared with placebo,TAC might significantly increase the success rates of ACR20 and ACR50 in cs DMARD-IR RA patients and the patients might gain significant benefitin terms of CRP,ESR,SJC,TJC,pain VAS,Pt GA VAS and PGA VAS.There was no significant increase in overall adverse reactions and withdrawal due to adverse reactions,but higher serum creatinine was more frequent.The patients might benefit from both higher dose(3-5 mg/d)and lower dose(1-2 mg/d)TAC in both primary and secondary outcomesmentioned above.Higher dose TAC may have better efficacy than lower dose TAC but greater nephrotoxicity.TAC might be superior to CTX in DAS28,CRP,ESR,SJC,TJC,morning stiffness time and pain VAS,but similar in adverse reactions.Comparison of TAC with LEF or IT showed no significant difference.TAC was inferior to infliximab in DAS28,ESR,TJC,SJC and morning stiffness time.In summary,TAC could be an important choice for second-line treatment of RA and attentionshould be paid to renal adverse reactions.