A208 HLA-DQA1*05 GENOTYPE PREDICTS ANTI-DRUG ANTIBODY FORMATION AND LOSS OF RESPONSE DURING INFLIXIMAB THERAPY FOR INFLAMMATORY BOWEL DISEASE
Bibliographic record
Abstract
Abstract Background The underlying mechanism for immunogenicity in anti-TNFa-exposed patients with inflammatory bowel disease is poorly understood. Anti-drug antibodies are a leading contributor to infliximab loss of response and adverse drug events. Currently, it is not feasible to identify patients at risk of antibody formation prior to initiating infliximab. The genetic variation HLADQA1*05(rs2097432) has been linked to infliximab antibody formation in a cohort of patients with Crohn’s disease. Aims Due to the wide variation in the frequency of HLADQA1* 05 across ethnic groups, we aim to independently evaluate the association between HLADQA1*05and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events, in a Canadian inflammatory bowel disease cohort. Methods In a retrospective cohort study, infliximab-exposed patients with inflammatory bowel disease (n=262) were screened for the genetic variation, HLADQA1*05A>G(rs2097432). The risk of infliximab anti-drug antibody formation, infliximab loss of response, adverse events, and discontinuation were assessed in wild type (GG) and variant-carrying (AG or AA) individuals. Results Forty percent of all participants were HLADQA1*05A>Gvariant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>Gvariant carriers in an IBD population (adjusted HR=7.29, 95%CI=2.97–17.191, p=1.46x10-5) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (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=2.53x10-4) though not with infliximab-associated adverse drug events. Conclusions HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. As a result, we propose that pre-emptive genetic screening for the HLADQA1* 05A>Gvariant would be useful in order to predict individuals at risk of developing immunogenicity. There may be a role for genotype-guided application of combination therapy in inflammatory bowel disease. Funding Agencies NoneWolfe Medical Research Chair in Pharmacogenomics (MOP-89753 to RBK), the Academic Medical Organization of Southwestern Ontario (INN18-005 to RBK and AW; S17-004 to AW), and Lawson Health Research Institute (IRF-05-19 to AW)
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".