HLA-DQA1*05 Genotype Does Not Influence Clinical Response to Ustekinumab, Vedolizumab

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No significant demographic or phenotypic differences were found between HLA-DQA1*05 carriers versus non-carriers, in either treatment group.

This study investigated the impact of the HLA-DQA1*05 allele on response to ustekinumab (Stelara; Janssen) and vedolizumab (Entyvio; Takeda) in patients with inflammatory bowel disease (IBD). This investigation was prompted by previous studies showing a correlation between presence of the HLA-DQA1*05 allele and IBD treatment failure in patients receiving the TNF-alpha inhibitors infliximab or adalimumab. Patients possessing the HLA-DQA1*05 allele were more likely to develop anti-drug antibodies and fail TNF-alphas, requiring a therapy change to a different IBD therapeutic drug class. With biologics being the current cornerstone of IBD therapy, it is important to understand the pharmacogenomic implications of these medications.

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Ustekinumab and vedolizumab are becoming more commonly used to induce and maintain remission in IBD. The 2021 American Gastroenterological Association’s (AGA) guideline for the outpatient management of moderate to severe Crohn disease recommends ustekinumab and vedolizumab be considered as first line treatment options, as well as the TNF alpha inhibitors. A similar recommendation is given in the 2020 AGA guideline for the outpatient management of moderate to severe ulcerative colitis. No prior studies have looked at the potential pharmacogenomic implications of ustekinumab and vedolizumab.

This study looked specifically at whether an association exists between the presence of the HLA-DQA1*05 allele and treatment response to ustekinumab and vedolizumab in patients being treated for either Crohn’s disease or ulcerative colitis.

The researchers designed a single-site, retrospective cohort study with 93 patients diagnosed with IBD being treated with ustekinumab or vedolizumab. The inclusion criteria in both groups were all patients older than 18 years, with a diagnosis of IBD and being treated with ustekinumab and vedolizumab.

Disease activity was measured using specific scales for Crohn disease [Harvey-Bradshaw index and ulcerative colitis (Mayo activity index)]. The presence of HLA-DQA1*05 and labs including C-reactive protein values (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin were measured. Variable treatment response was defined as none-to-moderate improvement in symptoms and objective laboratory and endoscopic signs, while remission was defined as disappearance of symptoms and both laboratory and endoscopic signs of the disease without the use of steroid therapy. Treatment response was assessed at 6 and 12 months for patients treated with ustekinumab and at 18 and 24 months for patients treated with vedolizumab.

Among the 93 patients in the study, the HLA-DQA1*05 allele was detected in 35.9% (n=14) of patients treated with ustekinumab and 38.9% (n=21) of those treated with vedolizumab. No significant demographic or phenotypic differences were found between HLA-DQA1*05 carriers versus non-carriers, in either treatment group.

Another important finding was that no significant difference was observed in terms of extraintestinal IBD manifestations, perianal disease, and previous or current concomitant treatments. In terms of response and remission variables, 50% of ustekinumab-treated patients with HLA-DQA1*05 were in remission one year after treatment initiation, whereas remission occurred in 56% of patients without the allele. No significant difference in ustekinumab treatment response was found between HLA-DQA1*05 carriers and non-carriers (response p=0.325; remission p=0.671). In patients treated with vedolizumab, higher remission rates were observed at 2 years in HLA-DQA1*05 carriers (44.4%) compared to non-carriers (30.3%). However, this difference was not statistically significant (response p=0.166; remission p=0.494).

The presence of the allele HLA-DQA1*05 does not appear to predispose patients to treatment failure when treated with ustekinumab or vedolizumab. No negative correlation was observed as previous studies have shown with the association of HLA-DQA1*05 allele carriers and TNF-alpha inhibitor treatment failure.

The study did have a number of limitations as it was retrospective in design, not randomized, no statistical power calculation was performed, and the HLA assay only looked for the presence of 2 different alleles meaning an association between ustekinumab and vedolizumab treatment response and other HLAs was not analyzed. While a larger scale, prospective, powered trial is needed, ustekinumab and vedolizumab appear to be effective treatment options for patients with IBD carrying the HLA-DQA1*05 allele. This study highlights the importance of further investigating and understanding the critical role of how HLAs can impact immunogenicity and response to medications.

Reference

Navajas Hernández Pilar, del Pino Bellido Pilar, Lorenzo González Laura, González Rodríguez Concepción, Pérez Pérez Antonio, Argüelles Arias Federico. The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab. Rev Esp Enferm Dig 2023. doi: 10.17235/reed.2023.9491/2023.

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