How many patients carry the HLA-B*39:01 allele?

Assuming a population-wide carriage frequency of 2.3% for HLA-B*39:01 among Caucasians, an adverse event frequency of 1 in 120 patients, and an odds ratio similar to that observed in this study (43.6), the authors estimate that as few as 6 patients carrying the HLA-B*39:01 allele would need to avoid treatment with infliximab to prevent one DILI case.

What is the common indication of infliximab use?

Cases with unknown indication of infliximab use were primarily matched to controls with Crohn’s disease, as this is the most common disease among infliximab users available in BioVU.

How many controls were included in this study?

In order to achieve sufficient power (80%) to detect meaningful HLA associations in this study, the authors sought to include at least three matched controls per DILI case [12].

How many cases were tested for HLA haplotype associations?

Given the fairly low number of alleles tested for causal associations (N=76), as well as known HLA haplotype associations within homogenous ethnicities [13,19,20], no corrections for multiple comparisons were employed in this study and p-values below 0.05 were considered significant.

What was the significance threshold for GWAS associations?

Secondary to HLA associations, GWAS associations were also explored using PLINK and a genotypic Fisher’s Exact Test with a genome-wide significance threshold of 5.0 x 10-8.

What was the average age at the initiation of treatment for cases?

Average body mass index (BMI) was 27.1 (range: 17-41) for cases and 24.6 (range: 17.2-48.7) for controls, while the average age at the initiation of treatment for cases was 37 years (range: 12-60) in cases and 34 years (range: 11-70) in controls.

Why were there more cases with underlying Crohn’s disease?

There were significantly more controls with underlying Crohn’s disease (P=0.02), and significantly more cases with unknown indication of use (P=0.04), which was due to matching unknown indications in cases with Crohn’s disease controls.

How many patients would be screened for this HLA before infliximab?

If patients were screened for this HLA prior to infliximab therapy, the authors would expect to avoid one DILI case for every 267 patients tested.

Open AccessJournal Article10.1038/S41397-020-0159-0

HLA associations with infliximab-induced liver injury

Christopher D. Bruno, +8 more

- 06 Feb 2020

- Pharmacogenomics Journal

- Vol. 20, Iss: 5, pp 681-686

TL;DR: A strong association with HLA-B*39:01 was identified as a potentially causal risk factor for infliximab-induced DILI, and future work should aim to validate this finding and explore possible mechanisms through which the biologic interacts with this particular allele.

Abstract: Biomarkers that are able to identify patients at risk of drug-induced liver injury (DILI) after treatment with infliximab could be important in increasing the safety of infliximab use. We performed a genetic analysis to identify possible human leukocyte antigen (HLA) associations with DILI in European Caucasian users of infliximab in a retrospective study of 16 infliximab-DILI patients and 60 matched controls. In infliximab-associated liver injury, multiple potentially causal individual HLA associations were observed, as well as possible haplotypes. The strongest associated HLA allele was HLA-B*39:01 (P = 0.001; odds ratio [OR] 43.6; 95% confidence interval [CI] 2.8-infinity), which always appeared with another associated allele C*12:03 (P = 0.032; OR 6.1; 95% CI 0.9–47.4). Other associations were observed with HLAs DQB1*02:01 (P = 0.007; OR 5.7; 95% CI 1.4–24.8), DRB1*03:01 (P = 0.012; OR 4.9; 95% CI 1.2–20.5), and B*08:01 (P = 0.048; OR 3.4; 95% CI 0.9–13.2), which also appeared together whenever present in cases. Additional associations were found with HLA-DPB1*10:01 (P = 0.042; OR 20.9; 95% CI 0.7–infinity) and HLA-DRB1*04:04 (P = 0.042; OR 20.9; 95% CI 0.7–infinity). A strong association with HLA-B*39:01 was identified as a potentially causal risk factor for infliximab-induced DILI. Future work should aim to validate this finding and explore possible mechanisms through which the biologic interacts with this particular allele.

1. What tests were used to determine differences in clinical characteristics between cases and controls?

Differences in clinical characteristics between cases and controls were tested in R using Fisher’s Exact Test for discrete variables and the WilcoxonMann-Whitney test with normal approximation for continuous variables.

2. What were the primary indications for infliximab use among cases?

Primary indications for infliximab use among cases included Crohn’s disease (44%), psoriatic arthritis (13%), ulcerative colitis (6%), ankylosing spondylitis (6%), erythroderma (6%), sarcoidosis (6%), juvenile idiopathic arthritis (6%), or unknown (13%).

3. How many controls were included in the study?

Genotyping for genome-wide genotyping association studies (GWAS) of cases and controls was performed by Vanderbilt Technologies for Advanced Genomics (VANTAGE, Nashville, Tennessee) using the Illumina Human MEGA Ex Vanderbilt platform (N=18 cases, N=60 controls).

4. How many cases were matched to controls?

In addition to GWAS genotyping, direct HLA typing was possible for a total of 71 samples (N=11 cases, N=60 controls) by the Institute for Immunology & Infectious Diseases (iiiD, Perth, Australia).

Table 3: Significant HLA Allele Associations

Table 2: Mean (standard deviation) of DILI Latency and Clinically Relevant Lab Values

Table 1: Clinical Characteristics of Cases and Controls

Table 5: Population Impact Measures for Top HLA Associations

Table 4: Population Frequencies of Significant HLA Alleles

Citations

Journal Article•10.1016/j.jhep.2021.08.024

Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment

01 Jan 2022

- Journal of Hepatology

TL;DR: In this article , a study of 36 patients with infliximab-induced drug-induced liver injury, approximately half of patients were treated with steroids and the results suggest that patients receiving steroids recover more quickly.

...read moreread less

Journal Article•10.1016/J.JHEP.2021.08.024

Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment.

Helgi Björnsson, +3 more

- 03 Sep 2021

- Journal of Hepatology

TL;DR: In this paper, the authors found that approximately half of patients with infliximab-induced liver injury had slow improvement in ALT despite cessation of therapy and were treated with corticosteroids.

...read moreread less

•Journal Article•10.5501/wjv.v12.i2.100

Immune-mediated liver injury following COVID-19 vaccination

Georgios Schinas, +5 more

- 25 Mar 2023

- World journal of virology

TL;DR: In this paper , a review of available data associated with immune-mediated liver injury associated with COVID-19 vaccination and elucidate potential mechanisms underlying its pathogenesis is presented, while patterns of molecular mimicry between the spike (S) protein and prominent liver antigens may account for the autoimmune presentation.

...read moreread less

Journal Article•10.1016/J.YAMP.2020.07.010

Pharmacogenomics of Drug-Induced Liver Injury

Ann K. Daly

- 01 Nov 2020

Journal Article•10.1016/j.mcna.2022.12.008

Drug-Induced Liver Injury due to Biologics and Immune Check Point Inhibitors.

Fernando Bessone, +1 more

- 01 Feb 2023

- Medical Clinics of North America

TL;DR: The most widely used biologics are the tumor necrosis factor-α (TNF-α) receptor antagonists: infliximab, adalimumab, and etanercept as mentioned in this paper .

...read moreread less

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HLA associations with infliximab-induced liver injury

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Most frequently asked questions

1. What tests were used to determine differences in clinical characteristics between cases and controls?

2. What were the primary indications for infliximab use among cases?

3. How many controls were included in the study?

4. How many cases were matched to controls?

5. How many patients carry the HLA-B*39:01 allele?

6. What is the common indication of infliximab use?

7. How many controls were included in this study?

8. How many cases were tested for HLA haplotype associations?

9. What was the significance threshold for GWAS associations?

10. What was the average age at the initiation of treatment for cases?

11. Why were there more cases with underlying Crohn’s disease?

12. How many patients would be screened for this HLA before infliximab?

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Citations

Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment

Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment.

Immune-mediated liver injury following COVID-19 vaccination

Pharmacogenomics of Drug-Induced Liver Injury

Drug-Induced Liver Injury due to Biologics and Immune Check Point Inhibitors.

References

R: A language and environment for statistical computing.

PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses

A global reference for human genetic variation.

Principal components analysis corrects for stratification in genome-wide association studies

A global reference for human genetic variation

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