BackgroundAutoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of... Show moreBackgroundAutoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH.MethodsThe TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness.DiscussionThis is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines.Trial registrationClinicalTrials.gov NCT05221411. Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021. Show less
Snijders, R.J.A.L.M.; Stoelinga, A.E.C.; Gevers, T.J.G.; Pape, S.; Biewenga, M.; Verdonk, R.C.; ... ; Dutch Autoimmune Hepatitis Working 2022
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
Calcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF)... Show moreCalcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about acute rejection. Therapeutic drug monitoring (TDM) may be advantageous when a CNI or MMF is withdrawn. The impact of late concentration-controlled CNI withdrawal with MMF on renal function, the incidence of acute rejection and markers of cardiovascular disease was evaluated in a randomised trial. In 158 stable renal transplant recipients on a CNI-based regimen with prednisone and MMF either the CNI or MMF was withdrawn. A total of 119 patients participated in the cardiovascular substudy. Late concentration-controlled CNI withdrawal resulted in improved renal function, especially in patients with an estimated glomerular filtration rate of less than 50 ml/min/1.73 m2, with a low acute rejection rate. The progression of left ventricular diastolic dysfunction was prevented by CNI elimination. CNI withdrawal decreased ambulatory blood pressures, but had no specific impact on carotid IMT. In conclusion, late CNI withdrawal with TDM of MMF may result in improved outcome by beneficial effects on renal function and cardiovascular risk, with a low risk of rejection in the majority of stable renal transplant recipients. Show less
After using C0-monitoring as the tool for therapeutic drug monitoring of cyclosporine for many years, studies suggested that C2-monitoring might be better. After switching 31 liver transplant... Show moreAfter using C0-monitoring as the tool for therapeutic drug monitoring of cyclosporine for many years, studies suggested that C2-monitoring might be better. After switching 31 liver transplant patients using cyclosporine from C0 via C2 to flexible limited sampling models (LSM), combinations of blood sampling time points 0+2h (r_=0.94); 0+1+2h (r_=0.94); 0+1+3h (r_=0.92); 0+2+3h (r_=0.92) and 0+1+2+3h (r_=0.96) showed excellent correlation with AUC0-12h with acceptable precision and bias. When evaluating the LSM0+1+2+3h model in the 18 months after introduction there was no significant change in average cyclosporine dose and creatinine clearance, compared to previous C2-monitoring. Especially LSM0+2h was optimal in terms of accuracy, ease-of-use and intrapatient variability. When optimizing tacrolimus monitoring after calculating limited sampling formulas (LSF) and LSM single and multiple-point combinations showed good correlations with AUC0-12h. The best single point calculation in terms of estimating systemic tacrolimus exposure using LSM were LSM 4h (r_=0.97) and LSM 6h (r_=0.97). During the study of the pharmacokinetic behaviour of MMF we found a wide range in MPA clearance in the population (8.08__57.47 L/h). Looking at possible sources of this variability in MPA clearance we divided our group, based on clinical selection, into two groups (with and without calcineurin inhibitors). These groups were used for further development of LSM for monitoring MPA. The combination 0-_-1-2h showed very good correlations with trapezoidal AUC0-12h for both models, with acceptable bias and precision. Show less
