Abstract Background Anti-tumor necrosis factor alpha drugs (anti-TNFα) are effective in inflammatory bowel disease (IBD) but loss of response (LOR) is common. HLA-DQA1*05 allele has been associated with immunogenicity and treatment failure. We aimed to assess whether HLA-DQA1*05 is an independent predictor of primary non-response (PNR), LOR and immunogenicity in IBD patients treated with anti-TNFα under proactive therapeutic drug monitoring (PTDM). Methods We conducted a prospective, multicentre cohort study in Zaragoza, Spain. Adults with Crohn’s disease (CD) or ulcerative colitis (UC) initiating infliximab (IFX) or adalimumab (ADA) between January 2021 and September 2023 were enrolled and followed for at least 54 weeks. PTDM with predefined trough-level assessments was performed at weeks 6,14,30, and 54. HLA-DQA1*05 carriage was determined. Logistic regression models were used to estimate adjusted odds ratios and 95% confidence intervals for PNR, clinical remission at week 54, and documented immunogenicity. Cox proportional hazards models were applied to estimate adjusted hazard ratios and 95% confidence intervals for LOR. Results Of 146 screened patients, 116 were included (88 with CD and 28 with UC; mean age 42 ± 15.9 years; 53% male). HLA-DQA1*05 was present in 46.6% of patients. PNR occurred in 14.6% of patients, and LOR occurred in 27.0% of initial responders. Immunogenicity was observed in 13.9% of patients, occurring more frequently with infliximab than adalimumab (38.2% vs. 3.7%). Clinical remission at week 54 was achieved in 62.1% of patients and was associated with early biological remission and sustained therapeutic drug levels. Carriage of HLA-DQA1*05 was the only independent risk factor for LOR despite PTDM (adjusted HR 3.43; 95% CI 1.39–8.47) but was not independently associated with PNR or immunogenicity. Low drug concentrations at week 6 independently predicted PNR (OR 9.76; 95% CI 2.50–51.0), immunogenicity (OR 9.70; 95% CI 1.98–70), and clinical remission at week 54 (OR 0.39; 95% CI 0.15–0.95). Concomitant use of immunomodulators was associated with a lower risk of PNR (OR 0.15; 95% CI 0.02–0.74) and immunogenicity (OR 0.21; 95% CI 0.03–0.96). Conclusion HLA-DQA1*05 carriage triples the risk of LOR to anti-TNFα therapy despite PTDM. Early sub-therapeutic drug levels (week 6) remain the main driver of PNR and immunogenicity, whereas combination therapy confers a protective effect. These findings support the use of genotyping and early drug-level optimization to individualize anti-TNF strategies in IBD. References: 1. Sazonovs A, Kennedy NA, 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(1):189-199. doi:10.1053/j.gastro.2019.09.04 2. Kennedy NA, Heap GA, Green HD, 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(5):341-353. doi:10.1016/S2468-1253(19)30012-3. 3. Ungar B, Levy I, Yavne Y, et al. Optimizing anti-TNF-α therapy: serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2016;14(4):550-557.e2. doi:10.1016/j.cgh.2015.10.025 4. Fuentes-Valenzuela E, García-Alonso FJ, Maroto-Martín C, et al. Influence of HLA-DQA1*05 genotype in adults with inflammatory bowel disease and anti-TNF treatment with proactive therapeutic drug monitoring: a retrospective cohort study. Inflamm Bowel Dis. 2023;29(10):1586-1593. doi:10.1093/ibd/izad046 Conflict of interest: Ms. Lopez, Julia: J.López De-La-Cruz has served as speaker or has received education funding from Ferring, Gilead, Faes Farma,Janssen, Takeda, and Abbvie. Louro, Javier: No conflict of interest Gargallo-Puyuelo, Carla: XXX
Lopez et al. (Thu,) studied this question.