30June2020

Y-ECCO Literature Review: Samantha Baillie

Samantha Baillie

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HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for Inflammatory Bowel Disease

Wilson A, Peel C, Wang Q, Pananos A, Kim R

Alimentary Pharmacology and Therapeutics 2020;51:356–63. doi: 10.1111/apt.15563.


Samantha Baillie
© Samantha Baillie

Introduction

The anti-TNF monoclonal antibody infliximab offers an effective treatment for patients with Inflammatory Bowel Disease (IBD) refractory to conventional immunomodulator therapies. Successful biologic therapy can lead to clinical and endoscopic remission as well as reduced hospitalisation and requirement for surgery [1].

Unfortunately, as a large protein and chimeric antibody, infliximab is immunogenic and this frequently leads to formation of anti-drug antibodies (ADA), with subsequent secondary loss of response (LOR), drug discontinuation and adverse reactions [2]. Identifying patients at increased risk of developing antibodies prior to treatment may establish which individuals require closer drug level monitoring, concomitant immunomodulator therapy and observation for adverse events.

Previous work by Sazonovs et al. identified the first genetic locus to be robustly associated with immunogenicity to anti-TNF therapies [3]. The HLADQA1*05 allele variant rs2097432, carried by approximately 40% of Europeans, significantly increased the rate of formation of infliximab ADA. In the study reviewed here, Wilson et al. aimed to independently identify whether presence of the variant allele was associated with increased risk of ADA formation, LOR, drug discontinuation and adverse events.

Methods

This retrospective cohort study was carried out in a single centre (Personalized Medicine Clinic at Western University, London, Canada) between March 2013 and November 2018. Infliximab‐exposed patients aged 18 years or older and with a histopathological diagnosis of Crohn’s Disease (CD) or Ulcerative Colitis (UC) were included.

Data were collected from medical records, including age, sex, weight, smoking history, IBD diagnosis, other medical history, duration of IBD, IBD medication exposure, infliximab dose and frequency, date of initiation, response and presence or absence of infliximab ADAs. Data were also collected with regard to the patients’ IBD history, including disease phenotype, disease activity at the time of infliximab initiation [using clinical scoring indices, the Harvey‐Bradshaw Index (HBI) or the partial Mayo score], hospitalisations and history of and time to surgical resection. All participants were tested for the HLADQA1*05 rs2097432 allele variant.

The primary endpoint was the risk of infliximab ADA formation. Secondary outcomes included the risk of LOR to infliximab (defined as HBI ≥3 points or partial Mayo score ≥3 points after week 14 of infliximab dosing despite an initial response to infliximab induction therapy, with a 3‐point reduction in the HBI or partial Mayo score), the risk of infliximab discontinuation and the risk of infliximab‐related adverse drug events.

Key findings

A total of 1114 participants were screened, with exclusion of 225 non-IBD individuals, 598 with no infliximab exposure, 17 with no therapeutic drug monitoring available, 7 with prior non-infliximab anti-TNF therapy and 5 with interruptions to infliximab dosage. Two hundred and sixty-two participants remained (CD, n=152; UC, n=110) with 40% HLADQA1*05A>G variant carriers. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR=7.29, 95% confidence interval (CI) = 2.97–17.191, p=1.46×10−5) independent of age, sex, weight, dose and co‐immunosuppression with an immunomodulator. Variant carriers had an increased risk of infliximab LOR (adjusted HR=2.34, 95% CI=1.41–3.88, p=0.001) and discontinuation (adjusted HR=2.27, 95% CI=1.46–3.43, p=2.53×10−4) but not infliximab‐associated adverse drug events. Seventy-nine percent of participants with ADA carried at least one variant allele.

Additional findings were that participants with ADA were older (mean age = 44.32 vs 39.02 years, p=0.04) and weighed less (70.38±21.14 vs 78.52±17.12 kg, p=0.002) compared to those without ADA.

Conclusion

This study demonstrated that the rs2097432 genetic variation in the HLADQA1*05 region is associated with infliximab ADA formation and that carriers are more likely to lose response and discontinue infliximab. Variant carriers had a sixfold risk of antibody formation and a twofold risk of LOR or drug discontinuation, even after adjusting for factors such as age, sex, weight, dose and co‐immunosuppression. Interestingly, this study also suggested that combination therapy with an immunomodulator reduces the risk of developing ADA in variant carriers, although statistical significance was not reached.

Although infliximab‐associated adverse drug events such as infection, rash or infusion reaction were not associated with HLADQA1*05 variant carrier status, the study team noted that there was a low number of reported events overall, 11/262, of which seven were not typical reactions expected of ADA formation.

Limitations of this study include the retrospective design and the small sample size. Additionally, five patients were excluded from the study due to interruptions in drug dosing, which raises the question of whether interruptions may be related to adverse events. Furthermore, the study used clinical scoring tools alone to determine LOR, without endoscopic assessment for failure of mucosal healing.

Of note, the genome-wide study identifying the HLADQA1*05 region as a variant associated with ADA formation included patients of European descent only [3]. While 79% of patients with ADA had the HLADQA1*05 variant, the remaining 21% developed antibodies despite not carrying this specific genetic variant. It may be that the participants represent a more ethnically diverse population with alternative uninvestigated genetic variants. The benefit of pre-treatment allele testing would need to take into account the local population, and similar genome-wide studies in other patient groups need to be performed.

This study demonstrates the clinical relevance of the HLADQA1*05 genetic variant as a potential predictor of ADA formation which could be used to aid the delivery of patient-tailored care. The association between the HLADQA1*05 region genetic variant and ADA was established prior to this study; however, ADA themselves may be transient and not clinically relevant [2]. This study added clinical relevance by identifying the relationship between the genetic variant allele and altered clinical outcomes, including LOR and drug discontinuation.

The ability to identify patients at higher risk of developing ADA would allow for tailored management, whether that be through alternative therapy, closer therapeutic drug monitoring or use of concomitant immunomodulators.

References

  1. Kennedy N, Heap G, Green H, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4:341–53.
  2. Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108:962–71.
  3. Sazonovs A, Kennedy N, Moutsianas L, et al. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's disease. Gastroenterology. 2020;158:189–99.

 

Samantha Baillie is a gastroenterology trainee at Lewisham Hospital, London, UK. She has an interest in personalised therapy in Inflammatory Bowel Disease to improve clinical outcomes.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Y-ECCO, Volume 15, Issue 2