The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab

1130-0108/2023/115/11/608-614 • REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS REV ESP ENFERM DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 © Copyright 2023 y Creative Commons (CC-BY-NC-ND). Sociedad Española de Patología Digestiva (SEPD) y © Arán Ediciones S.L. The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab Pilar Navajas Hernández1, Pilar del Pino Bellido2, Laura Lorenzo González3, Concepción González Rodríguez4, Antonio Pérez Pérez4, Federico Argüelles Arias1,5 Departments of 1Gastroenterology and 4Biochemistry. Hospital Virgen Macarena. Seville, Spain. 2Hospital Juan Ramón Jiménez. Huelva, Spain. 3Hospital San Juan de Dios del Aljarafe. Seville, Spain. 5Gastroenterology Department. Universidad de Sevilla. Seville, Spain Received: 07/02/2023 · Accepted: 03/06/2023 Correspondence: Pilar Navajas Hernández. Department of Gastroenterology. Hospital Virgen Macarena. Av. Dr. Fedriani, 3. 41009 Seville, Spain. e-mail: [email protected] TRABAJO ORIGINAL Studies suggest that the presence of a genetic allele (HLA-DQA1*05) is implicated in a worse response and development of antibodies to certain biologic therapies, in particular anti-TNFs (the most commonly used drugs in inflammatory bowel disease). Newer drugs used more recently in IBD include Ustekinumab and Vedolizumab. There is no evidence that this genotype is associated with response to these drugs, which is why the aim of this study was to evaluate whether the presence of the HLA-DQA1*05 allele is associated with a reduced response to ustekinumab and vedolizumab. To do this, a retrospective study was performed, in which we concluded that the clinical response to these drugs was not affected by the presence of the HLA-DQA1*05 allele in both treatment groups in contrast to the anti-TNF drugs, HLA-DQA1*05 carrier status does not correlate with decreased response to ustekinumab or vedolizumab. Lay summary REV ESP ENFERM DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 609 The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab Conflict of interest: the authors declare no conflict of interest. Navajas Hernández P, del Pino Bellido P, Lorenzo González L, González Rodríguez C, Pérez Pérez A, Argüelles Arias F. The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab. Rev Esp Enferm Dig 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 ABSTRACT Background: the success of strategies with earlier anti-TNF drugs for the treatment of inflammatory bowel disease (IBD) have been shadowed by the development of anti-drug antibodies that reduce their effectiveness. The HLADQA1*05 allele has been shown to increase the risk of immunogenicity to anti-TNF drugs by approximately two-fold. The negative impact of this allele has not been fully investigated for newer biotherapies. Objective: whether the presence of the HLA-DQA1*05 allele is associated with a reduction of response to ustekinumab and vedolizumab was investigated. Material and methods: the impact of HLA-DQA1*05 on disease activity in 93 patients with IBD, treated with ustekinumab (n = 39) or vedolizumab (n = 54) was investigated in a retrospective cohort study. Treatment response and remission was assessed at 6 and 12 months for ustekinumab, and up to 18 and 24 months for vedolizumab, using Harvey-Bradshaw index (Crohn’s disease) and Mayo score (ulcerative colitis). Results: the HLA-DQA1*05 allele was found in 35.9 % and 38.9 % of patients treated with ustekinumab and vedolizumab, respectively. Clinical response was not affected by the presence of the HLA-DQA1*05 allele for both treatment groups. Conclusions: in contrast to anti-TNF drugs, HLA-DQA1*05 presence does not correlate with the decreased response to ustekinumab or vedolizumab. Keywords: HLA-DQA1*05 allele. Ustekinumab. Vedolizumab. Inflammatory bowel disease. INTRODUCTION Inflammatory bowel disease (IBD) comprises a group of disorders of variable etiologies, associated with an inordinate immune response resulting in the development of lesions. Interactions between genes, immune system, intestinal microbiota and the environment constitute the current pathophysiological basis that can explain the disease (1). Nowadays, there is a limited therapeutical arsenal for the treatment of IBD. Consequently, it is important to select the best drug for each patient. Currently, therapy selection is based on the severity of symptoms, specific features of the disease (subtype, location, complications), patient characteristics (age, comorbidities, and extraintestinal manifestations) and history of previous treatment (2). The advent of biological therapies has been a paradigm-shift in the course of IBD, demonstrating their efficacy to reduce intestinal damage caused by chronic inflammation. Within this group, the initial strategies identified tumor necrosis factor as the main target (anti-TNF therapies). Both infliximab and adalimumab are the most representative and widely used drugs for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC) (3). Unfortunately, one of the problems arising from the use of anti-TNF therapies is that their repeated administration may induce the formation of antibodies against the drug, leading to diminishing response and subsequent treatment failure. Reporter rates of immunogenicity are greater in patients treated with infliximab (a chimeric monoclonal antibody of mouse origin) than with adalimumab (a human monoclonal antibody). The combination of immunomodulators reduces the risk of immunogenicity, improving treatment results, but increases the risk of infection and hematological toxicity (4). It has been suggested that identifying patients who are at higher risk of immunogenicity could guide the choice of anti-TNF therapy and therefore, the use of preventive measures, such as combining treatment with an immunosuppressive drug. However, knowledge about the cellular and molecular mechanisms underlying the immunogenicity of biologics is limited. Retrospective studies have shown that one of the factors conferring immunogenic risk has a genetic basis. Specifically, the Personalising Anti-TNF Therapy in Crohn’s Disease (PANTS) study published in 2019 revealed that carrying one or more alleles of the HLADQA1*05 allele, specifically HLA-DQA1*05:01 and HLA-DQA1*05:05, confers at least double the risk of immunogenicity to anti-TNF drugs. This causes an increase in anti-drug antibody levels and a shortened bioavailability of the drug (5). The most striking evidence of this phenomenon was observed among carriers of this allele treated with infliximab monotherapy, 92 % of whom developed antibodies after one year. A lower risk was noted in patients under therapy with adalimumab administered in combination with an immunosuppressant. The use of combination therapy of anti-TNF factor with immunosuppressants has been associated with better outcomes in patients with IBD (6). Accordingly, it was suggested that patients treated with anti-TNF therapy who carry any of the mentioned HLA alleles should receive an immunomodulator agent. In those patients in whom the immunomodulator drug is contraindicated or not tolerated, infliximab should not be considered. In contrast, patients who do not carry the allele could receive either infliximab or adalimumab therapy (7). Unfortunately, the influence of the HLA-DQA1*05 allele on the effectiveness of newer biological therapies for IBD has not been fully investigated. Information on the relationship between this allele and immunogenicity against new biologic drugs, such as ustekinumab and vedolizumab, is scarce. The aim of the present study was to analyze if carriage of HLA-DQA1*05 allele affects clinical response to non-anti- TNF biologics, namely ustekinumab and vedolizumab, in patients with IBD. For this purpose, HLA-DQA1*05 carriage and clinical response of patients with IBD receiving treatment with ustekinumab and vedolizumab was retrospectively investigated. REV ESP ENFER DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 610 P. Navajas Hernández et al. PATIENTS AND METHODS Design and participants A total of 93 patients diagnosed with IBD who had been or were being treated with ustekinumab or vedolizumab until January 2022 were selected for a retrospective cohort study in our hospital. The inclusion criteria in both groups were all patients older than 18 years, with a diagnosis of IBD on treatment with ustekinumab and vedolizumab, from which further data were obtained (including a minimum study period of one year). The study was approved by the Ethics Committee of the Hospital Universitario Virgen Macarena (Seville, Spain) (COD_2379-N-20). All patients were informed of the purpose of the study as well as the procedures they were to undergo (blood tests) and signed the written informed consent. Medical treatment All patients had an indication for treatment with newer biological drugs following failure with other lines of treatment. The choice of drug was made based on comorbidities, patient preference in terms of the type of administration and medical judgment. Evaluations Information on demographic variables (gender, age) and smoking habits was collected. The initial diagnosis of IBD (ulcerative colitis or Crohn’s disease) and the different types according to the Montreal classification (8) were recorded. Disease activity was measured using specific scales for Crohn’s disease (Harvey-Bradshaw index) (9) and ulcerative colitis (Mayo activity index) (1). The presence of HLADQA1*05 (5) and analytical data such as C-reactive protein values (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin were measured. The variables treatment response (defined as improvement) and remission (defined as the disappearance of symptoms and analytical/endoscopic signs of the disease without steroid therapy) were assessed at 6 and 12 months with ustekinumab and up to 18 and 24 months with vedolizumab. The subsequent incorporation of ustekinumab into our Inflammatory Bowel Disease Unit compared to vedolizumab limited the follow-up time. Other variables of interest were the presence of complications, extraintestinal manifestations, adherence to treatment or the use of concomitant treatments. Method of analysis of HLADQ-A1*05 The analysis of HLA-DQA1*05 alleles was performed in the Autoimmunity Laboratory of the Hospital Universitario Virgen Macarena. A whole blood sample is collected from the patient and anticoagulated with ethylenediaminetetraacetic acid (EDTA) and kept refrigerated. For DNA extraction, the commercial MagCore® Genomic DNA Whole Blood kit is used, in which 40 µl of proteinase was added to 400 µl of whole blood in extraction tubes that were introduced into the MagCore® extruder, together with Cartrige Code 102 extraction cartridges (RBC Bioscience Corp, Taipei, Taiwan). The amplification technique was performed using the INNO-Li- PA® protocol for the amplification of HLA-DQA1 and HLADQB1 alleles (Fujirebio Iberia, Barcelona, Spain). Molecular typing of HLA-DQA1 alleles was performed by INNO-LiPA® HLA-DQA1 strip reverse hybridization, automated in the Au- to-LiPA™ 48 analyser (Fujirebio Iberia, Barcelona, Spain). One strip per patient was performed. The positive conjugate control and the two HLA-DQA1 control strips should be observed on each strip. The positive conjugate control reflects the final reaction of the conjugate added to reveal hybridization and precipitated substrate. The two HLA-DQA1 hybridization control strips show that an adequate amount of HLA-DQA1 amplified material was added for hybridization. This control strip is placed on the line marked when the strip is glued to the holder. All three control strips must always be positive, except for the negative control. Statistical analysis For the descriptive analysis, the absolute frequency (N) and relative frequency (%) were calculated for the qualitative variables, and the mean and standard deviation for quantitative variables. The Chi-squared test was calculated to determine whether there was a dependence between the qualitative variables. The Kaplan-Meier method was used to calculate the percentage of patients entering response and remission depending on the presence or absence of the studied allele. The log-rank test was used to compare the different survival distributions. A Cox multivariate analysis with the entire cohort was used to adjust for potential confounders such as age, sex, smoking, type of inflammatory disease, type of biologic, presence of HLA DQ-A1*05 and concomitant use of immunosuppressants. Statistical analysis was performed using the IBM SPSS Statistics 25 statistical package applying a significance level of 0.05. RESULTS A total of 93 patients were included in the study, most were females (57 %) and the average age was 43 ± 12.7 years. The diagnosis was Crohn’s disease for all of the patients in the ustekinumab group, and 29 (53.7 %) in the vedolizumab group. Baseline characteristics are described in tables 1 and 2. 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. As shown in tables 1 and 2, no significant demographic or phenotypic differences were found between HLA-DQA1*05 carriers versus non-carriers, in either treatment group. Furthermore, no significant difference was found in terms of extraintestinal manifestations, perianal disease and previous or concomitant treatments (Tables 1 and 2). According to the Kaplan-Meier method, in terms of response and remission variables, 50 % of ustekinumab-treat- ed patients with HLA-DQA1*05 were in remission one year after treatment initiation, compared to 56 % in those without the allele. REV ESP ENFERM DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 611 The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab Table 1. Characteristics of patients treated with ustekinumab, depending on the presence of HLA-DQA1*05 HLA-DQA1*05 carrier Yes No n = 14 (35.9%) n = 25 (64.1%) n % n % p value* Gender Men Women 6 8 42.9 57.1 13 12 52.0 48.0 0.416 Smoking No Ex-smoker Smoker 8 2 4 57.1 14.3 28.6 13 6 6 52.0 24.0 24.0 0.767 Age (Montreal, CD) A1 A2 A3 2 10 2 14.3 71.4 14.3 3 18 4 12.0 72.0 16.0 0.973 Location (Montreal, CD) L1 L2 L3 L4 7 0 7 0 50.0 0 50.0 0 9 5 10 1 36.0 20.0 40.0 4.0 0.262 Behavior (Montreal, CD) B1 B2 B3 8 2 4 57.1 14.3 28.6 12 9 4 48.0 36.0 16.0 0.311 Perianal disease 6 42.9 12 48.0 0.511 Extraintestinal manifestations 3 21.4 9 36 0.283 Concomitant corticosteroids 13 92.9 20 80.0 0.282 Concomitant azathiprione 8 57.1 17 68.0 0.368 Concomitant methotrexate 5 35.7 8 32.0 0.542 Previous anti-TNF treatment Infliximab Adalimumab Certolizumab 14 9 5 0 100 25 14 8 1 100 -† CD: Crohn’s disease. *p-value as determined by Chi-squared test. †p-value has not been calculated because “previous anti-TNF treatment” is a constant. Table 2. Characteristics of patients treated with vedolizumab, depending on the presence of HLA-DQA1*05 HLA-DQA1*05 appearance Yes n = 21 (38.9 %) No n = 33 (61.1 %) n % n % p value* Gender Men Women 10 11 47.6 52.4 11 22 33.3 66.7 0.222 Smoking No Ex-smoker Smoker 15 3 3 71.4 14.3 14.3 22 4 7 66.7 12.1 21.2 0.810 Disease Crohn’s disease (CD) Ulcerative colitis (UC) 6 15 28.6 71.4 23 10 69.7 30.3 0.004 (Continues on next page) REV ESP ENFER DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 612 P. Navajas Hernández et al. Fig. 1. Response and remission of patients treated with ustekinumab, depending on the presence of HLA-DQA1*05. Table 2 (cont.). Characteristics of patients treated with vedolizumab, depending on the presence of HLA-DQA1*05 HLA-DQA1*05 appearance Yes n = 21 (38.9 %) No n = 33 (61.1 %) n % n % p value* Age Montreal (CD, UC) A1 A2 A3 5 10 6 23.8 47.6 28.6 9 19 5 27.3 57.6 15.2 0.489 Location Montreal (CD) L1 L2 L3 1 1 4 16.7 16.7 66.7 5 10 8 21.7 43.5 34.8 0.345 Location Montreal (UC) E1 E2 E3 4 9 2 26.7 60.0 13.3 2 6 2 20.0 60.0 20.0 0.870 Behavior Montreal (CD) B1 B2 B3 3 2 1 50.0 33.3 16.7 10 6 7 43.5 26.1 30.4 0.793 Severity Montreal (UC) S1 S2 S3 6 7 2 40.0 46.7 13.3 1 5 4 10.0 50.0 40.0 0.156 Perianal disease 2 9.5 9 27.3 0.107 Extraintestinal manifestations 6 28.6 18 54.5 0.055 Concomitant corticosteroids 13 61.9 23 71.9 0.321 Concomitant azathioprine 3 14.3 4 12.1 0.563 Concomitant methotrexate 2 9.5 5 15.2 0.437 Previous anti-TNF treatment Infliximab Adalimumab Certolizumab Golimumab 19 10 7 1 1 90.5 28 17 11 1 0 84.8 0.437 CD: Crohn’s disease; UC: ulcerative colitis. *p-value as determined by Chi-squared test. REV ESP ENFERM DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 613 The HLA-DQA1*05 genotype does not influence the clinical response to ustekinumab and vedolizumab Fig. 2. Response and remission of patients treated with vedolizumab, depending on the presence of HLA-DQA1*05. No significant differences were found between carriers and non-carriers (response p = 0.325; remission p = 0.671) (Fig. 1). In patients treated with vedolizumab, numerically higher remission rates were observed at two 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) (Fig. 2). In a Cox multivariate analysis with the entire cohort, adjusting for potential confounders (age, sex, smoking, type of inflammatory disease, type of biologic, presence of HLA DQ-A1*05 and concomitant immunosuppressant use), patients receiving ustekinumab were more likely to achieve remission at 12 months follow-up (HR = 2.011; 95 % CI: 1.047-3.861, p = 0.036). No significant outcomes were found for the other features. The relationship between drug intensification and the presence of the allele was analyzed and no significant statistical differences were found. In the case of ustekinumab, 28.6 % of patients carrying ustekinumab intensified the drug compared to 36 % of non-carriers (p = 0.458). For patients on vedolizumab, 42.9 % of those carrying the allele intensified the drug versus 27.3 % of those who did not (p = 0.187). CRP, ESR and fecal calprotectin levels at three, six and 12 months were analyzed for ustekinumab. Statistically significant differences were only obtained for ESR at six months, with the median being higher in carriers (Me = 13) than in non-carriers (Me = 7) (p = 0.023). For vedolizumab, these same measurements were obtained at three, six, 12, 18 and 24 months, with statistically significant findings for CRP at three, six and 24 months, being higher in non-carriers (p < 0.05). DISCUSSION The present study investigated a possible relationship between the presence of the HLA-DQA1*05 allele with clinical response to ustekinumab or vedolizumab in patients with IBD. To the best of our knowledge, this is the first study that reports the absence of a relationship between response to ustekinumab or vedolizumab and the presence of the HLA-DQA1*05 allele in these patients. Similar findings have been published in some abstract articles only for ustekinumab (11,12). Previous studies (5,13,14) have reported that the risk of generating antibodies following treatment with infliximab and adalimumab is high and consequently, the loss of treatment efficacy during the first year is elevated. It is critical to identify factors that could induce antibody formation. These factors include monotherapy, especially with infliximab, the episodic treatment and the recently described association of the HLADQA1*05 allele with immunogenicity to anti-TNF drugs (13,14). In the study by Sazonovs et al. (5), authors performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a cohort of 1,240 biologic-naïve patients. The presence of the HLADQA1*05 allele increased the rate of immunogenicity in this group of patients, with the highest rate of immunogenicity being observed in HLA-DQA1*05-positive patients who were treated with infliximab monotherapy. The latter observation was extremely relevant since it was the first one that described a genome-wide significant association between HLADQA1*05 and the development of antibodies against anti-TNF agents. In a more recent study including 262 patients, Wilson et al. (14) concluded that HLA-DQA1*05 was independently associated with a higher risk of infliximab antibody formation in addition to a loss of response and treatment discontinuation. Another study established the risk of immunogenicity derived from HLADQA1*05, not only in anti-TNF but also in other biologics (tocilizumab, rituximab, among others), which would justify the need to study this effect in other biologics different from anti-TNF (15). In contrast with the earlier biological therapies, the risk of antibody formation against newer treatments is low (6.2 % for ustekinumab, 8.4 % for vedolizumab and 5.0 % for etrolizumab) for combination and monotherapy combined (16). REV ESP ENFER DIG 2023;115(11):608-614 DOI: 10.17235/reed.2023.9491/2023 614 P. Navajas Hernández et al. Thus, vedolizumab and ustekinumab provide us with alternatives for patients who have failed to respond to other anti-TNF agents (17). Our results indicate that the role of HLADQA1*05 presence could be less impactful in the clinical effectiveness of ustekinumab or vedolizumab in IBD. Determination of HLA-DQA1*05 could be an effective laboratory approach in guiding the selection of the most successful biologic therapy in IBD patients (19,20). Other predictors of response to these biologics have been studied, such as a lower Harvey-Bradshaw index score or female sex for ustekinumab (21,22) and patients naïve to anti-TNF or the initial use of azathioprine prior to the biologic for vedolizumab (23). Our study has some limitations, first the small sample size and the non-randomized design (retrospective study), which may affect the statistical power. To avoid baseline differences between groups, patients were carefully selected during the same period and by the same gastroenterologists to ensure that they shared similar characteristics. It should be considered that the study period coincided with that of the COVID-19 pandemic, which led to a decrease in the indication of new treatments. The follow-up time of our study was limited to 12 months in patients treated with ustekinumab and two years for those treated with vedolizumab, which may be insufficient to evaluate remission in the long-term scenario. Additional clinical studies with larger sample sizes and longer follow-up periods would be needed to corroborate these findings. Further investigative studies should also address how a deeper knowledge of the cellular and molecular properties of the bowel mucosa would help us to elucidate the mechanism associated with worse response to anti-TNF therapies associated with HLA-DQA1*05 status. Another limitation is that it was not possible to measure drug levels in the blood at the time of the study. It would be interesting to analyze their relationship with the presence of the genotype in future studies. In conclusion, in contrast to what has been described in the literature on the HLA-DQA1*05 and anti-TNF drugs relationship, our study provides evidence that the presence of this allele does not impact clinical effectiveness in IBD patients treated with ustekinumab or vedolizumab. CONCLUSION The presence of the allele HLA-DQA1*05 does not seem to predict a worse outcome in patients treated with ustekinumab or vedolizumab. REFERENCES 1. Colombel JF, Narula N, Peyrin-Biroulet L. Management strategies to improve outcomes of patients with inflammatory bowel diseases. Gastroenterology 2017;152:351-61 e5. DOI: 10.1053/j.gastro.2016.09.046 2. Jalan KN, Walker RJ, Sircus W, et al. Pseudopolyposis in ulcerative colitis. Lancet 1969;2:555-9. DOI: 10.1016/S0140-6736(69)90260-8 3. Levesque BG, Sandborn WJ, Ruel J, et al. Converging goals of treatment of inflammatory bowel disease from clinical trials and practice. Gastroenterology 2015;148:37-51 e1. DOI: 10.1053/j.gastro.2014.08.003 4. 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 prospecti- ve, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019;4:341-53. DOI: 10.1016/S2468-1253(19)30012-3 5. 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;158:189-99. DOI: 10.1053/j.gastro.2019.09.041 6. Targownik LE, Benchimol EI, Bernstein CN, et al. Combined biologic and immunomodulatory therapy is superior to monotherapy for decreasing the risk of inflammatory bowel disease-related complications. J Crohns Colitis 2020;14:1354-63. DOI: 10.1093/ecco-jcc/jjaa050 7. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383-95. DOI: 10.1056/NEJMoa0904492 8. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19(Suppl A):5A-36A. DOI: 10.1155/2005/269076 9. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet 1980;1:514. 10. Feuerstein JD, Cheifetz AS. Crohn disease: epidemiology, diagnosis, and management. Mayo Clin Proc 2017;92:1088-103. DOI: 10.1016/j.mayocp.2017.04.010 11. Colombel JF, Martín-Arranz MD; Brinkman B, el at. Impact of the HLA-DQA1*05 allele on ustekinumab loss of response, anti-drug antibodies, and concentration in patients with inflammatory bowel disease. Am J Gastroenterol 2022;117:S15. DOI: 10.14309/01.ajg.0000897736.01948.e9 12. Camps B, Rodríguez F, Rodríguez L, et al. El alelo HLADQ-A1*05 no se asocia con la pérdida de respuesta secundaria a ustekinumab en pacientes con enfermedad de Crohn. Gastroenterol Hepatol 2020;43(Espec Congr):89. 13. Powell Doherty RD, Liao H, Satsangi JJ, et al. Extended analysis identifies drug-specific association of 2 distinct HLA class II haplotypes for development of immunogenicity to adalimumab and infliximab. Gastroenterology 2020;159:784-7. DOI: 10.1053/j.gastro.2020.03.073 14. Wilson A, Peel C, Wang Q, et al. HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease. Aliment Pharmacol Ther 2020;51:356-63. DOI: 10.1111/ apt.15563 15. Hässler S, Bachelet D, Duhaze J, et al.; ABIRISK consortium. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: a prospective multicohort study of the ABIRISK consortium. PLoS Med 2020;17(10):e1003348. DOI: 10.1371/journal.pmed.1003348 16. Bots SJ, Parker CE, Brandse JF, et al. Anti-drug antibody formation against biologic agents in inflammatory bowel disease: a systematic review and meta-analysis. BioDrugs 2021;35:715-33. DOI: 10.1007/s40259-021-00507-5 17. Wilson A, Kim RB. Letter: genetic variation in the HLA-DQA1*05 allele predicts tumour necrosis factor-alpha antagonist immunogenicity - Does location matter? Aliment Pharmacol Ther 2021;53:1055-6. 18. Shim HH, Chan PW, Chuah SW, et al. A review of vedolizumab and ustekinumab for the treatment of inflammatory bowel diseases. JGH Open 2018;2:223- 34. DOI: 10.1002/jgh3.12065 19. Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol 2011;106:685-98. DOI: 10.1038/ ajg.2011.103 20. Kerur B, Fiedler K, Stahl M, et al. Utilization of antitumor necrosis factor biologics in very early onset inflammatory bowel disease: a multicenter retrospecti- ve cohort study from North America. J Pediatr Gastroenterol Nutr 2022;75:64- 9. DOI: 10.1097/MPG.0000000000003464 21. Barré A, Colombel J-F, Ungaro R, et al. Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease. Aliment Pharmacol Ther 2018;47(7):896-905. DOI: 10.1111/apt.14550 17 22. Lorenzo L, Valdés T, Vázquez JM, et al. Ustekinumab in Crohn’s disease: real-world outcomes and predictors of response. Rev Esp Enferm Dig 2022;114(5):272-9. 23. Bamias G, Kokkotis G, Gizis M, et al. Predictors of response to vedolizumab in patients with ulcerative colitis: results from the Greek VEDO-IBD Cohort Dig Dis Sci 2022;67(3):1007-17. DOI: 10.1007/s10620-021-06907-5