Predicting Response to Anti-TNF Requires Deep Dive Into HLA-DQA1*05 Gene Variants

By Marilynn Larkin

May 26, 2020

NEW YORK (Reuters Health) - Although a recent study implicated HLA-DQA1*05 in the development of antibodies against anti-TNF therapies in Crohn's disease, a new analysis of specific variants of the gene reveals different therapy-specific responses.

"We demonstrate that it is not possible to predict a specific patient's risk to develop anti-drug antibodies on the carriage of the DQA1*05 gene variant family alone," Dr. Nicola Ternette of the University of Oxford told Reuters Health on behalf of the authors.

"Our reanalysis of the PANTS (Personalising Anti-TNF Therapy in Crohn's Disease) study cohort (https://bit.ly/2XpwYxB) clearly demonstrates that there is no increased risk for the development of anti-adalimumab antibodies for carriers of the HLA-DQA1*05:01 variant and its extended haplotype," she noted, "while this haplotype did predispose the carrier to an increased risk for the development of anti-infliximab antibodies."

By contrast, the HLA-DQA1*05:05 extended haplotype was associated with the development of anti-drug antibodies for both adalimumab and infliximab, she said.

Dr. Ternette and colleagues hypothesized that due to the different molecular composition of adalimumab and infliximab, their antigenic presentation and resulting potential to induce immunogenicity would differ

They studied gene variants in 1,240 biologic-naïve patients with Crohn's disease who started therapy with either infliximab or adalimumab using 4D resolution to visualize individual HLA-DOA1*05 variants. The goal was to assess the significance of each variant with respect to immunogenicity related to treatment.

Immunogenicity was defined as an anti-drug antibody concentration of > 10 AU/mL, irrespective of the drug level, at any time point across the initial 12-month study and two year follow-up. Anti-drug antibodies were measured in serum samples at each patient visit.

As reported in Gastroenterology, and noted by Dr. Ternette, Cox regression analyses of the drug-specific cohorts demonstrated that alleles HLA-DQA1*05:01, HLA-DQB1*02:01, and HLA-DRB1*03:01 were not associated with adalimumab immunogenicity (hazard ratio = 1.071).

Conversely, alleles HLA-DQA1*05:05, HLA-DQB1*03:01, and HLA-DRB1*11:01 were all significantly associated with development of adalimumab immunogenicity (HR=2.164).

By contrast, HLA-DQA1*05:01, HLA-DQB1*02:01, and HLA-DRB1*03:01 was highly significantly associated with infliximab immunogenicity (HR=1.928), whereas associations with HLA-DQA1*05:05, HLA-DQB1*03:01, and HLA-DRB1*11:01 were less significant (HR=1.406).

The authors also observed additional associations of immunogenicity for each drug in the variant of the HLA-DRB1 gene: HLA-DRB1*03:01 (infliximab, HR=2.008 and adalimumab, HR=2.912).

Dr. Ternette said, "Genetic testing to predict immunogenicity is not yet available for clinical practice, but may be possible in time. Based on our findings, it is evident that only high-resolution (4D) sequencing of the HLA gene region could lead to accurate patient stratification in the future."

"It is too early to utilize these observations in the clinic until the causality of this association is understood in more detail, and these results are further confirmed in larger cohort studies," she added.

Dr. Garrett Lawlor, Associate Director, Inflammatory Bowel Diseases Program at Columbia University Medical Center in New York City, commented in an email to Reuters Health, "This will over time have important clinical implications as more data grow in the literature around it."

"If we could simply do a blood test to look for these genetic markers, we could understand what patients are likely to respond to a given drug, before we even start the drug," he said. "This will impact efficacy (we only give the drug to patients for whom it will work), cost (patients will not be given an expensive drug if we already know they will not respond to it), and safety (patients will not be exposed to a potentially harmful drug). This is the basis of precision medicine."

"This study will be replicated in other cohorts of patients worldwide to validate the data," he added, "and it will be interesting to see if the same variants are noted in patients of different ethnicities."

SOURCE: https://bit.ly/3bQGkHH Gastroenterology, online April 7, 2020.

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