Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay

Many biopharmaceuticals (BPs) are known to be immunogenic in the clinic, which can result in modified pharmacokinetics, reduced efficacy, allergic reactions and anaphylaxis. During recent years, several technologies to predict immunogenicity have been introduced, but the predictive value is still considered low. Thus, there is an unmet medical need for optimization of such technologies. The generation of T cell dependent high affinity anti-drug antibodies plays a key role in clinical immunogenicity. This study aimed at developing and evaluating a novel in vitro T cell:PBMC assay for prediction of the immunogenicity potential of BPs. To this end, we assessed the ability of infliximab (anti-TNF-α), rituximab (anti-CD20), adalimumab (anti-TNF-α) and natalizumab (anti-α4-integrin), all showing immunogenicity in the clinic, to induce a CD4+ T cells response. Keyhole limpet hemocyanin (KLH) and cytomegalovirus pp65 protein (CMV) were included as neo-antigen and recall antigen positive controls, respectively. By analyzing 26 healthy donors having HLA-DRB1 alleles matching the European population, we calculated the frequency of responding donors, the magnitude of the response, and the frequency of BP-specific T cells, as measured by 3[H]-thymidine incorporation and ELISpot IL-2 secretion. KLH and CMV demonstrated a strong T cell response in all the donors analyzed. The frequency of responding donors to the BPs was 4% for infliximab, 8% for adalimumab, 19% for rituximab and 27% for natalizumab, which is compared to and discussed with their respective observed clinical immunogenicity. This study further complements predictive immunogenicity testing by quantifying the in vitro CD4+ T cell responses to different BPs. Even though the data generated using this modified method does not directly translate to the clinical situation, a high sensitivity and immunogenic potential of most BPs is demonstrated

T Cell Response to Infliximab in Exposed Patients: A Longitudinal Analysis

This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression in vitro. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA– patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio

Monocyte NOTCH2 expression predicts interferon-beta immunogenicity in multiple sclerosis patients

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β–treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration

Response to biologic drugs in patients with rheumatoid arthritis and antidrug antibodies

IMPORTANCE There are conflicting data on the association of antidrug antibodies with response tobiologic disease–modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA).OBJECTIVE To analyze the association of antidrug antibodies with response to treatment for RA.DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Riskof Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patientswith RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and theUK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD.Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018,and data were analyzed in June 2022.EXPOSURES Patients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti–tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximabaccording to the choice of the treating physician.MAIN OUTCOMES AND MEASURES The primary outcome was the association of antidrug antibodypositivity with EULAR (European Alliance of Associations for Rheumatology; formerly, EuropeanLeague Against Rheumatism) response to treatment at month 12 assessed through univariate logisticregression. The secondary end points were the EULAR response at month 6 and at visits from month6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibodyserum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (MesoScale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum wasmeasured using enzyme-linked immunosorbent assay.RESULTS Of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%])were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treatedwith anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab.There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI,0.09-0.38; P all the visits starting at month 6 using generalized estimating equation models confirmed the inverseassociation between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65;P P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factorwere independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody–negative vs antidrugantibody–positive status (mean difference, −9.6 [95% CI, −12.4 to −6.9] mg/L; P concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) andadalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vsresponders. Methotrexate comedication at baseline was inversely associated with antidrugantibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).CONCLUSIONS AND RELEVANCE Results of this prospective cohort study suggest an associationbetween antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrugantibodies could be considered in the treatment of these patients, particularly nonresponders tobiologic RA drugs.Pathophysiology and treatment of rheumatic disease

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: Recommendations of the innovative medicines initiative ABIRISK consortium

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies, and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry, and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk, and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices, and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium (Anti-Biopharmaceutical [BP] Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu), was formed by leading clinicians, academic scientists, and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation, and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp). This article is protected by copyright. All rights reserved

Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A

International audienceReplacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach. Data Availability Statement: ABIRISK does not own the data analyzed in this study, which were collected in the context of other past and current projects by both ABIRISK partners and non-ABIRISK research groups in the different centers and provided to ABIRISK exclusively for the purpose of the performed analyses upon official request and ethical approval. For this reason access to the minimal dataset underlying the findings cannot be made publicly available, but can be obtained by interested researchers upon request to the ABIRISK steering committee by submissio

Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS

BackgroundUpon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon beta (IFN beta) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon beta preparations.MethodsWe analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.ResultsBinding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFN beta -1a s.c.- (odds ratio (OR)=3.55 (95% confidence interval=2.81-4.48), p=2.1x10(-26)) and rs28366299 in IFN beta -1b s.c.-treated patients (OR=3.56 (2.69-4.72), p=6.6x10(-19)). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFN beta -1a s.c. (OR=2.88 (2.29-3.61), p=7.4x10(-20)) while DR3-DQ2 was protective (OR=0.37 (0.27-0.52), p=3.7x10(-09)). The haplotype DR4-DQ3 was the major risk haplotype for IFN beta -1b s.c. (OR=7.35 (4.33-12.47), p=1.5x10(-13)). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFN beta -1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC=0.91 (0.85-0.95), sensitivity=0.78, and specificity=0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR =73.9 (11.8-463.6, p=4.4x10(-6)) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71-0.92), sensitivity=0.80, specificity=0.76, with an OR=13.8 (3.0-63.3, p=7.5x10(-4)).ConclusionsWe identified several HLA-associated genetic risk factors for ADA against interferon beta, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds

Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis

International audienceOBJECTIVES:To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients.METHODS:The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data.RESULTS:ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3).CONCLUSIONS:The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: a prospective multicohort study of the ABIRISK consortium

BackgroundBiopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.Methods and findingsThe European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 x 10(-5) for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.ConclusionIn our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity.Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.Author summaryWhy was this study done?Biopharmaceutical products such as monoclonal antibodies are widely used to treat autoimmune diseases.Biopharmaceutical products may induce the development of antidrug antibodies, which often lead to therapy failure.Patient-related factors that influence the development of antidrug antibodies need to be characterized.What did the researchers do and find?We set up a European multicohort prospective study on 4 autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis) treated with 8 different biopharmaceutical products.We collected demographic and clinical data and tested antidrug antibodies in longitudinal serum samples from 560 patients. For 457 patients who gave consent, we also collected genetic data.We identified antibiotics and immunosuppressants as negatively associated risk factors and heavy smoking, infections during the study, the allele and a minor variant in the chemokine gene associated with increased protein expression as risk factors of antidrug antibody development.What do these findings mean?Our findings suggest that the combination of immunosuppressant and biopharmaceutical therapy could be associated with decreased risk of antidrug antibody occurrence, which has implications for rheumatoid arthritis and inflammatory bowel diseases, for which immunosuppressants are often, but not always, given together with biopharmaceuticals.Patients heterozygotes or homozygotes for the HLA-DQA1*05 allele may have an increased risk of antidrug antibody occurrence associated with biopharmaceutical therapy.The small study size warrants a validation through independent studies, in particular for the genetic findings