Second-line Drug Selection For Adult Autoimmune Hepatitis:A Systematic Review And Meta-analysis

Background: Autoimmune hepatitis(AIH)is a predominant condition with immune mediated destruction of liver parenchyma and can occur in all ages and mainly in women.Autoimmune hepatitis is characterized by autoantibodies,hypergammaglobulinemia,and interface hepatitis on histological examination.The clinical presentation may be acute,acute severe(fulminant),or asymptomatic.According to epidemiological investigations in recent years,the incidence of autoimmune hepatitis has increased obviously.It can gradually result in cirrhosis,liver failure,and death.Immunosuppressive therapy is essential for autoimmune hepatitis and can significantly improve survival.Standard first-line therapy involves corticosteroids alone or in combination with azathioprine,which is effective in 80 percent of patients.However,a significant proportion of patients may not achieve complete biochemical response with these options or can not tolerate the drugs due to severe side effects.Objective: Mycophenolate mofetil(MMF),cyclosporine,tacrolimus,and budesonide are second-line alternatives in AIH treatment,which have been described in patients who are ineffective or intolerant to standard therapy.We systematically reviewed these research literatures and conducted a meta-analysis of their efficacy and safety as second-line drugs for adult AIH patients.Methods: Databases EMBASE,Pubmed?Cochrane and Web Of Science were searched to carry out a systematic review and meta-analysis.The keywords used were ‘Hepatitis,Autoimmune' and descriptor terms(MeSH).These terms were linked with each immunosuppressant of interest,including "Prednisone" [Mesh] ?“Azathioprine”[MesH] ? "Tacrolimus" [Mesh] ? "Mycophenolatemofetil" [Mesh] ? "Cyclophosphamide" [Mesh] ? "Cyclosporine" [Mesh] ? "Budesonide" [Mesh] ? "Methotrexate" [Mesh]? "Cyclophosphamide" [Mesh].The date of the last search was June 2018.We calculated the pooled response rate and adverse events rate,with the corresponding 95% confidence interval(CI).All calculations were performed using the Open Meta-Analyst statistical software.Response rate was compared between subgroups(intolerance or nonresponse to standard of care)when data was available,and was expressed with risk ratio(RR)and 95% confidence interval(CI).We selected the research model based on the I~2 calculated by Meta-Analyst.If the study was homogeneity(I~2<50%),we choose the fixed effect model to analysis,and if not,we chose the random effects model.Results: Twenty studies on the second-line drug therapy for adult patients with autoimmune hepatitis(10 in MMF,2 in cyclosporine,3 in tacrolimus,and 5 in budesonide)were finally included,which were all retrospective study and involved 557 cases.Pooled response rate of MMF(341 cases)was 0.587(95%CI 0.476-0.690;I~2 =0.377).Pooled response rate of tacrolimus(94 cases)was 0.759(95%CI 0.431-0.929;I~2 = 0.291).Pooled response rate of cyclosporine(26 cases)was 0.653(95%CI 0.455-0.809;I~2 = 0.000).Pooled response rate of budesonide(96 cases)was 0.573(95%CI 0.372-0.751;I~2 =0.347).Five studies of MMF(n =341)could be divided into two groups according to intolerance or nonresponse to standard therapy.Risk ratio(RR)was 1.720(95%CI 0.969-3.054;P=0.072),I~2 =0.732.Pooled adverse events rate of MMF was 0.193(95%CI 0.127-0.283,I~2 =0.359),which is the lowest.Pooled adverse events rate of budesonide was 0.330(95%CI 0.240-0.434,I~2 =0.000).Pooled adverse events rate of tacrolimus was 0.406(95%CI 0.083-0.838,I~2 =0.465).Pooled adverse events rate of cyclosporine was 0.484(95%CI 0.294-0.678,I~2 =0.230).Because of the small study number,no additional sensitivity analyses could be performed.Conclusion: Among second-line drug for adult autoimmune hepatitis patients who were intolerant or non-responsive to standard treatment,the highest response rate was tacrolimus,while the response of MMF,cyclosporine and budesonide were similar.The incidence of adverse reactions of MMF was the lowest,the incidence of adverse reactions of tacrolimus was higher,and that of cyclosporine was the highest.At present,MMF and tacrolimus as second-line drugs for adult AIH patients are both better choices.As for patients who do not respond to first-line treatment,the efficacy of tacrolimus is better than MMF.