Background and Aims: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well... Show moreBackground and Aims: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors. Methods: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk. Results: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development. Conclusions: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome Show less
My project, Tracing Shumi: Politics and Aesthetics in Modern Japanese Literary Discourse and Fiction, traces the concept of shumi (趣味) in late 19th and early 20th century Japanese literary... Show moreMy project, Tracing Shumi: Politics and Aesthetics in Modern Japanese Literary Discourse and Fiction, traces the concept of shumi (趣味) in late 19th and early 20th century Japanese literary discourse and fiction. The word shumi was introduced in the 1880s as a translation word for the notion of 'taste'. However, my project aims to show how the word operated beyond a mere translation of an idea. Instead, I demonstrate how shumi was used to rhetorically frame the ways in which people were supposed to behave, sense, and consume and which actors and institutions benefited from such discursive frameworks. Yet at the same time, this dissertation argues that the language of shumi also undermined the very ideological structures it sought to engender. Ultimately, Tracing Shumi, sheds light on how modernity unfolds in the intersection of politics and aesthetics, beyond a limited imagination of politics entirely in terms of power and of aesthetics solely in terms of beauty, at a specific juncture in Japanese history. Show less
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
Beukel, M.D. van den; Stoelinga, A.E.C.; Meer, A.J. van der; Meulen, S. van der; Zhang, L.; Tushuizen, M.E.; ... ; Trouw, L.A. 2023
Background(Auto)immune mediated and cholestatic liver disease (AILD) includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Especially AIH... Show moreBackground(Auto)immune mediated and cholestatic liver disease (AILD) includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Especially AIH is characterized by the presence of autoantibodies and elevated serum immunoglobulins. In rheumatoid arthritis, autoantibodies against post-translational modifications (PTMs) such as citrullination (Cit) and carbamylation (CarP) are used as diagnostic and prognostic markers, respectively. We studied the presence of six anti-PTM antibodies in patients with the three AILDs and non-AILD. MethodsAntibodies against six PTMs (malondialdehyde-acetaldehyde adducts (MAA), advanced glycation end-products (AGE), CarP, acetylation (AL), Cit, and nitration (NT)) were tested in sera of patients with AILD (n = 106), non-AILD (n = 101) and compared with healthy controls (HC) (n = 100). Levels and positivity were correlated with clinical and biochemical features in a well-defined cohort of untreated AIH patients. ResultsAnti-PTM antibodies were more often detectable in sera from AILD patients compared with HCs (anti-MAA: 67.9% vs. 2.0%, anti-AGE: 36.8% vs. 4.0%, anti-CarP: 47.2% vs. 5.0% and anti-AL: 18.9% vs. 5.0%). In untreated AIH, time to complete biochemical response (CBR) was associated with anti-MAA, anti-AGE, anti-CarP and anti-AL antibodies. Significantly more patients with at least three anti-PTM antibodies attained CBR at 12 months of treatment (13 vs. 3 p = 0.01). ConclusionAnti-PTM antibodies are frequently present in AILD. The presence of anti-MAA, anti-AGE and anti-CarP antibodies correlates with the presence of AIH within this cohort. In AIH, harboring at least three anti-PTM antibody responses is positively associated with CBR. Determination of anti-PTM antibodies in liver disease may have diagnostic and prognostic value. 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
Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life... Show moreBackground & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. Methods: All PSC patients living in a geographically defined area covering similar to 50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. Results: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were (sic)12 169 and mean work productivity loss was 25%. Conclusions: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time. Show less
Background & AimsPrimary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life... Show moreBackground & AimsPrimary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss.MethodsAll PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time.ResultsA total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%.ConclusionsOur data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time. Show less
Biewenga, M.; Verhelst, X.P.D.M.J.; Baven-Pronk, M.A.M.C.; Putter, H.; Berg, A.P. van den; Nieuwkerk, K.C.M.J. van; ... ; Dutch Autoimmune Hepatitis Study G 2021
Background No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic... Show moreBackground No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. Methods The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. Results In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). Conclusions A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated. Show less
