Genome Variant Identifies Anti-Drug Antibodies for Crohn's Disease

Alekseis Sazonovs

The allele HLA-DQA1*05 could be a useful biomarker in predicting anti-drug antibodies for Crohn’s disease patients.

A team, led by Alekseis Sazonovs, Wellcome Sanger Institute, performed a genome-wide association study to identify variants linked to the time of development of anti-drug antibodies of 1240 biologic-naïve patients with Crohn’s disease starting anti-tumor necrosis factor (anti-TNF) drugs such as infliximab or adalimumab.

“In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents,” the authors wrote. “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.”

In the multicenter, prospective observation cohort, investigators identified the treatment failure rates of infliximab, the biosimilar CT-P13, and adalimumab.

Patients were initially studied for 12 months or until drug withdrawal.

In the first year, study visits were scheduled at first dose, post-induction weeks 12-14, weeks 30 and 54, and at treatment failure.

Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay and significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.

Anti-TNF has become the most widely used biologic drug to treat immunemediated diseases. However, repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies could facilitate the selection of therapy and use of preventative strategies.

Immunogenicity is more common in patients treated with infliximab, a murine-human chimeric monoclonal antibody than adalimumab, a fully human monoclonal antibody.

Immunogenicity is a major cause of low anti-TNF drug level, infusion reactions, and non-remission in patients with Crohn’s disease.

Combination immunomodulatory therapy decreases the risk of immunogenicity to both adalimumab and infliximab. Infliximab also improves treatment outcomes.

However, patients are still commonly treated with anti-TNF monotherapy due to concerns about the increased risk of adverse drug reactions, opportunistic infections, and malignancies linked to combination therapy with immunomodulatory.

The HLA-DQA1*05 allele, which significantly increases the rate of immunogenicity (HR, 1.90; 95% CI, 1.60—2.25; P =5.88 × 10¹³), is carried by approximately 40% of Europeans.

“The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05,” the authors wrote. “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.”

In the replication cohort, the investigators confirmed the findings of the previous study (HR, 2.00; 95% CI, 1.35—2.98; P = 6.60 × 10^-4).

The 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), as well as for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37–2.22) or in combination with an immunomodulatory (HR, 2.01; 95% CI, 1.57–2.58).

The study, “HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease,” was published online in Gastroenterology.