Background: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which... Show moreBackground: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Method:s: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Show less
Background Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2-4 weeks.... Show moreBackground Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2-4 weeks. The safety and efficacy of both strategies have been unexplored. Methods We established a cohort of 900 AIH patients from 12 centres in 7 European countries. There were 631 patients who used AZA as part of the therapeutic regimen. We distinguished two groups: patients with early AZA (<2 weeks) or delayed AZA initiation (>= 2 weeks). Primary outcome was discontinuation of AZA in the first year of treatment. Cox regression and propensity score matching was performed to determine difference in outcomes between groups. Results Patients with early AZA initiation had significantly lower transaminases and bilirubin at baseline. Discontinuation rates of AZA did not differ between early and delayed starters (16.6% vs 14.2%), which did not reach statistical significance (hazard ratio 0.97, 95% confidence interval 0.61-1.55,P = .90). Stratification according to baseline disease activity or propensity score matching did not alter the results. Main reason for AZA discontinuation was intolerance to treatment (14.0% vs 13.2%,P = .78) with nausea and vomiting as main side effects. AIH remission rates were comparable among groups. Conclusion The discontinuation rate of AZA in AIH treatment is similar to 15% in the first year of treatment. Early or delayed AZA initiation does not differ in remission and discontinuation rates in AIH induction therapy. Our data suggest that either strategy may be used as part of AIH treatment. Show less
Pape, S.; Gevers, T.J.G.; Vrolijk, J.M.; Hoek, B. van; Bouma, G.; Nieuwkerk, C.M.J. van; ... ; Heneghan, M.A. 2020
BACKGROUND & AIMS: Changes in serum levels of transaminases immediately after initiation of treatment for autoimmune hepatitis (AIH) might be associated with biochemical markers of remission... Show moreBACKGROUND & AIMS: Changes in serum levels of transaminases immediately after initiation of treatment for autoimmune hepatitis (AIH) might be associated with biochemical markers of remission and liver-related events. We assessed the outcomes of patients with vs without rapid response to treatment of AIH in a large international cohort.METHODS: We performed a retrospective cohort study, collecting data from 2 independent cohorts of adults with AIH from 12 centers in 7 countries in Europe. We collected information on patient demographics; serologic, histologic, and biochemical analyses; and treatment. We used a receiver operating characteristic curve and Youden index to calculate the optimal percentage decrease in level of aspartate aminotransferase (AST) after 8 weeks of treatment that associated with normalization of transaminase levels after 26 weeks of treatment with predniso(lo)ne (primary outcome) in the first (discovery) cohort (n = 370). We evaluated the results in the second (validation) cohort (n = 370). Secondary outcomes were liver-related death or transplantation. We performed univariate and multivariable logistic and Cox regression with correction for confounders.RESULTS: A significant decrease in level of AST after 8 weeks of treatment was significantly associated with normalization of transaminase levels at 26 and 52 weeks (P <.001); a decrease of more than 80% in level of AST was associated with optimal normalization. In both cohorts, rapid responders (>= 80% decrease in level of AST after 8 weeks) were more likely to achieve normalization of transaminases at 26 and 52 weeks when compared to non-rapid responders. Rapid responders in the discovery cohort had lower risk of liver-related death or transplantation (adjusted hazard ratio 0.18; 95% CI 0.05-0.63; P =.007), although this was not confirmed in the validation cohort. Results from measurement of alanine aminotransferase did not differ significantly from those of AST for the primary outcome. Slow responders (without normalization of transaminases after 1 year) had the highest risk of liver transplantation or liver-related death.CONCLUSIONS: In a retrospective study of patients with AIH, we found that a rapid response to treatment, based on level of AST after 8 weeks, associates with normalization of transaminase levels in the following year. Patients with a rapid response also have a lower risk of liver-related death or transplantation than patients without this rapid response. Show less
Pape, S.; Gevers, T.J.G.; Belias, M.; Mustafajev, I.F.; Vrolijk, J.M.; Hoek, B. van; ... ; Drenth, J.P.H. 2019
