Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.

Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands.

BACKGROUND AND AIMS: Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). METHODS: Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. RESULTS: The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. CONCLUSION: This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.

Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission.

BACKGROUND & AIMS: Current treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse. METHODS: A total of 131 patients (out of a cohort including 844 patients) from 7 academic and 14 regional centres in the Netherlands were identified in whom treatment was tapered after at least 2 years of clinical and biochemical remission. Relapse was defined as alanine-aminotransferase levels (ALT) three times above the upper limit of normal and loss of remission as a rising ALT necessitating the reinstitution of drug treatment. RESULTS: During follow-up, 61 (47%) patients relapsed and 56 (42%) had a loss of remission. In these 117 patients, 60 patients had fully discontinued medication whereas 57 patients were still on a withdrawal scheme. One year after drug withdrawal, 59% of the patients required retreatment, increasing to 73% and 81% after 2 and 3 years, respectively. Previous combination therapy of corticosteroids and azathioprine, a concomitant autoimmune disease and younger age at time of drug withdrawal were associated with an increased risk of relapse. Subsequent attempts for discontinuation after initial failure in 32 patients inevitably resulted in a new relapse. CONCLUSIONS: This retrospective analysis indicates that loss of remission or relapse occurs in virtually all patients with AIH in long-term remission when immunosuppressive therapy is discontinued. These findings indicate a reluctant attitude towards discontinuation of immunosuppressive treatment in AIH patients.

Cytotoxic T lymphocyte antigen-4 +49A/G polymorphism does not affect susceptibility to autoimmune hepatitis.

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNP) in the Cytotoxic T lymphocyte antigen-4 gene (CTLA-4) have been associated with several autoimmune diseases including autoimmune Hepatitis (AIH). In this chronic idiopathic inflammatory liver disease, conflicting results have been reported on the association with a SNP at position +49 in the CTLA-4 gene in small patient cohorts. Here, we established the role of this SNP in a sufficiently large cohort of AIH patients. METHODS: The study population consisted of 672 AIH patients derived from academic and regional hospitals in the Netherlands and was compared with 500 controls selected from the 'Genome of the Netherlands' project cohort. Genotype frequencies were assessed by PCR for patients and by whole genome sequencing for controls. RESULTS: No significant differences in allele frequencies were found between patients and controls (G Allele: 40% vs 39%, P = 0.7). Similarly, no significant differences in genotype frequencies between patients and controls were found. Finally, there was no relation between disease activity and the G allele or AG and GG genotypes. CONCLUSION: The Cytotoxic T Lymphocyte Antigen-4 +49 A/G polymorphism does not represent a major susceptibility risk allele for AIH in Caucasians and is not associated with disease severity at presentation.

Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial.

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 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. METHODS: 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. TRIAL REGISTRATION: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.

Seroprevalence of Hepatitis E Virus in Autoimmune Hepatitis Patients in the Netherlands.

BACKGROUND AND AIMS: In recent years chronic courses of hepatitis E virus (HEV) infection have been described in immunosuppressed individuals. This may implicate a potential role for HEV in the development of autoimmune diseases, including autoimmune hepatitis (AIH). Here we investigated the prevalence of HEV-antibodies in AIH patients in an endemic Central European country. METHODS: HEV-specific immunoglobulin G (IgG) and HEV RNA were determined in 354 and 377 AIH patients, respectively. Clinical characteristics and disease outcome parameters were retrospectively collected. RESULTS: No HEV viraemic patients were identified in this cohort. A total of 106 AIH patients (29.9%) tested positive for anti-HEV IgG, and this figure was slightly higher compared to the prevalence in a reference cohort including 5,329 healthy Dutch blood donors (26.7%; P>0.05). CONCLUSION: This is the largest study on the association between HEV infection and AIH. Apparently silent HEV infection is present in a significant proportion of AIH patients, yet appears not to have significant clinical repercussions in this immune compromised group of patients. Nevertheless, since acute hepatitis E may present with histological and biochemical features of AIH, the possibility of a (concomitant) HEV infection should be considered in this category of patients.