HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

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Prevalence of NUDT15 genetic variants and incidence of thiopurine-induced leukopenia in Inflammatory Bowel Disease: A systematic review and meta-analysis

BACKGROUND AND AIMS: Nudix hydrolase 15 (NUDT15) genetic variants confer an increased risk of thiopurine-induced leukopenia (TIL), however their global prevalence in Inflammatory Bowel Disease (IBD) patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients. METHODS: Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants, were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early (≤8 weeks) and late (>8 weeks) leukopenia, and relative risk of developing leukopenia. RESULTS: 20 studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C>T C/T diplotype was 13% (95% CI: 10-18%), *3/*3 c.415C>T T/T diplotype was 2% (95% CI: 1-2%), *1/*5 c.52G>A G/A diplotype was 2% (95% CI: 1-3%) and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% (95% CI: 4-12%). The pooled prevalence of *1/*3 was high in Japanese (20%, 95% CI: 16-24%) and Chinese patients (18%, 95% CI: 12-27%). The incidence of early leukopenia was 20% (95% CI: 16-26%) in *1/*3 patients, 99% (95% CI: 7-100%) in *3/*3 patients and 49% (95% CI: 29-69%) in *1/*6 patients. The incidence of late leukopenia was 36% (95% CI: 26-49%) in *1/*3 patients. CONCLUSIONS: NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations to guide thiopurine dosing and prevent myelotoxicity.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease.

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58). CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449