Sa1677 HLA-DRB1*0301 and HLA-DRB1*0401 Modify the Presentation and Outcome in Autoimmune Hepatitis Type-1

Gerven, Nicole M. van; Boer, Ynto S. de; Zwiers, Antonie; Verwer, Bart J.; Drenth, Joost P.H.; Hoek, B. van; Erpecum, Karel J. van; Beuers, Ulrich; Buuren, Henk R. van; Ouden, Jannie W. den; Verdonk, Robert C.; Koek, Ger H.; Brouwer, Johannes T.; Guichelaar, Maureen M. J.; Vrolijk, Jan Maarten; Coenraad, Minneke J.; Kraal, Georg; Mulder, Chris J.; Nieuwkerk, C. van; Verspaget, Hein W.; Bloemena, Elisabeth; Kumar, Vinod; Zhernakova, Alexandra; Wijmenga, Cisca; Franke, Lude; Bouma, Gerd

doi:10.1016/s0016-5085(15)33445-4

Cited by 12 publications

(13 citation statements)

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“…TPMT*3A was the only TPMT mutation identified and was found in six patients (three responders to standard therapy and three patients with failure of standard therapy). Eighty-three per cent of the patients in our cohort had the genotypes HLA-DRB1 *03 or *04, which are reported to be associated with the diagnosis, severity and treatment response of AIH [10,14]. However, we found no difference in the frequency of these genotypes between the two AIH groups.…”

Section: Treatment Regimenscontrasting

confidence: 61%

“…Genetic factors may also affect treatment response. In AIH, this has been shown for the HLA-DRB1*0301 allele [13,14]. With regard to genes related to the standard treatment of AIH, it is known that pharmacogenetic variants can be associated with an altered sensitivity to immunosuppressive treatment, including glucocorticoids [15], but only few studies have ever reported this to affect the treatment response in diseases [16][17][18].…”

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confidence: 99%

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Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment

Eriksen

Kreutzfeldt

Grønbæk

et al. 2017

Basic Clin Pharma Tox

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The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants. Fifty-six consecutive patients with AIH [41 female and 15 male; median age 42 years (12-76)] were retrospectively stratified according to being responders to standard therapy (n = 33) or patients with failure of standard therapy (n = 23). Their blood DNA was exome-captured and sequenced. Genomic variants were filtered and compared between the groups using Ingenuity Variant Analysis (3.1.20150407). The exome sequencing and data processing revealed glucocorticoid receptor signalling to be the most prominently affected pathway among the patients with failure of standard therapy (highly significant). Standard treatment failure was not associated with thiopurine S-methyltransferase variants or the HLA-DRB1*03 genotype. In conclusion, enrichment of variants related to glucocorticoid receptor signalling was a particular genomic trait of the AIH patients in whom standard treatment failed and alternative immunosuppression was required. If confirmed, a future application of this finding may be to identify prospective cases of failure of standard treatment already at diagnosis.

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Section: Treatment Regimenscontrasting

confidence: 61%

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confidence: 99%

Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment

Eriksen

Kreutzfeldt

Grønbæk

et al. 2017

Basic Clin Pharma Tox

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“…Not quite unexpectedly in view of previously identified associations with HLA-DR3 and DR4, a highly significant association was found with chromosome 6 harbouring the HLA genes. This association could be pinned down to and confirmed associations with the alleles encoding the HLA-DR3 and DR4 proteins in a hypothesis-free way [12] . Of relevance, several other loci in the genome were identified that are most likely involved in the susceptibility to the disease, including the SH2B1 locus.…”

Section: Theoretical Considerationsmentioning

confidence: 58%

Treatment Withdrawal in Autoimmune Hepatitis

Bouma

Nieuwkerk²

2015

Dig Dis

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Background: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disorder of unknown aetiology, which when left untreated can lead to liver cirrhosis and hepatic failure. Current treatment strategies include long-term treatment with corticosteroids and/or azathioprine. Most patients respond well to immunosuppressive therapy and treatment usually results in an asymptomatic course of AIH in remission. Nevertheless, both drugs are associated with serious side effects that can sometimes be severe and may necessitate drug withdrawal. Whether or not treatment in patients who are in longstanding remission can be discontinued is unknown. Key Messages: Available data rely on retrospective data sets and are not conclusive. Some studies indicate that a sustained remission after treatment withdrawal is feasible, whereas other studies have found relapse rates in up to 90% of patients, even in patients with established histological remission. Patients who relapse after drug withdrawal have a high probability for a re-relapse to occur. Life-long maintenance therapy should be strongly considered in these patients, since patients who have multiple relapses are more likely to progress to cirrhosis, liver transplantation and death from liver failure. Conclusion: For a majority of patients, AIH is a lifelong disease requiring permanent treatment. Patients in longstanding clinical remission on monotherapy, with complete normalisation of aminotransferases and IgG could be offered one attempt of drug withdrawal. The risk of disease progression after a single relapse appears low, while a patient's realization that infinite maintenance therapy is mandatory may improve drug adherence.

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“…The presence of HLA-DR3 is associated with a lower remission rate, a higher relapse frequency and a frequent requirement for liver transplantation [55]. Further, patients carrying DRB1*03:01 develop a more pronounced hypergammaglobulinaemia [56] and are associated with a significantly higher risk for adverse treatment outcome with subsequent requirement for liver transplantation or resulting in death from acute liver failure [42,57]. In contrast, individuals with HLA-DR4 are associated with a more favourable clinical outcome characterized by a higher rate of complete remission and a lower frequency of cirrhosis [58].…”

Section: Genetic Predispositionmentioning

confidence: 99%

Pathogens and autoimmune hepatitis

Christen

Hintermann

2018

Clinical and Experimental Immunology

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Autoimmune hepatitis (AIH) is a severe form of hepatitis resulting in the autoimmune-mediated destruction of the liver parenchyma. Whereas many of the immunopathogenic events have been elucidated and some of the drivers of the disease have been identified, little is known about the aetiology of the disease. There are certain risk factors, such as particular human leucocyte antigen (HLA) haplotypes, that enhance the susceptibility for AIH or influence the severity of the disease. However, as for many other autoimmune diseases, the mere presence of such risk factors does not warrant the occurrence of the disease. Not all individuals carrying risk factors develop AIH, and not all patients with AIH are carriers of high-risk alleles. Thus, additional environmental factors need to be considered as triggers for AIH. Environmental factors include diet, sunlight exposure, stress, medication and hygiene, as well as pathogen infections and vaccinations. This review discusses if pathogens should be considered as triggers for the initiation and/or propagation of AIH.

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Sa1677 HLA-DRB10301 and HLA-DRB10401 Modify the Presentation and Outcome in Autoimmune Hepatitis Type-1

Cited by 12 publications

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Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment

Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment

Treatment Withdrawal in Autoimmune Hepatitis

Pathogens and autoimmune hepatitis

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