Dataset Information

High discontinuation rate of azathioprine in autoimmune hepatitis, independent of time of treatment initiation.

ABSTRACT: 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. 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 ~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.

SUBMITTER: Pape S

PROVIDER: S-EPMC7496382 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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High discontinuation rate of azathioprine in autoimmune hepatitis, independent of time of treatment initiation.

Pape Simon S Gevers Tom J G TJG Vrolijk Jan Maarten JM van Hoek Bart B Bouma Gerd G van Nieuwkerk Carin M J CMJ Taubert Richard R Jaeckel Elmar E Manns Michael P MP Papp Maria M Sipeki Nora N Stickel Felix F Efe Cumali C Ozaslan Ersan E Purnak Tugrul T Nevens Frederik F Kessener Dominik J N DJN Kahraman Alisan A Wedemeyer Heiner H Hartl Johannes J Schramm Christoph C Lohse Ansgar W AW Heneghan Michael A MA Drenth Joost P H JPH

Liver international : official journal of the International Association for the Study of the Liver 20200611 9

<h4>Background</h4>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.<h4>Methods</h4>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 we ...[more]

PMID: 32410363

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Project description:BackgroundThiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries.ObjectiveTo test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing.DesignRetrospective cohort study.SettingTwo tertiary care centers.PatientsThiopurine users with White or Black race.MeasurementsAzathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count.ResultsThe rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype (n = 101) and 1.34 per 100 person-years among those with the TT or TC genotype (n = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P = 0.013).LimitationsUnmeasured confounding; data limited to tertiary centers.ConclusionPatients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race.Primary funding sourceNational Institutes of Health.

Project description:Background & aimsAssociation studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.MethodsWe performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.ResultsA total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.ConclusionsOur study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.Impact and implicationsThis study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

Dataset Information

High discontinuation rate of azathioprine in autoimmune hepatitis, independent of time of treatment initiation.

Publications

High discontinuation rate of azathioprine in autoimmune hepatitis, independent of time of treatment initiation.

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