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

ABSTRACT: 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.

SUBMITTER: Hassler S

PROVIDER: S-EPMC7598520 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Hässler Signe S Bachelet Delphine D Duhaze Julianne J Szely Natacha N Gleizes Aude A Hacein-Bey Abina Salima S Aktas Orhan O Auer Michael M Avouac Jerôme J Birchler Mary M Bouhnik Yoram Y Brocq Olivier O Buck-Martin Dorothea D Cadiot Guillaume G Carbonnel Franck F Chowers Yehuda Y Comabella Manuel M Derfuss Tobias T De Vries Niek N Donnellan Naoimh N Doukani Abiba A Guger Michael M Hartung Hans-Peter HP Kubala Havrdova Eva E Hemmer Bernhard B Huizinga Tom T Ingenhoven Kathleen K Hyldgaard-Jensen Poul Erik PE Jury Elizabeth C EC Khalil Michael M Kieseier Bernd B Laurén Anna A Lindberg Raija R Loercher Amy A Maggi Enrico E Manson Jessica J Mauri Claudia C Mohand Oumoussa Badreddine B Montalban Xavier X Nachury Maria M Nytrova Petra P Richez Christophe C Ryner Malin M Sellebjerg Finn F Sievers Claudia C Sikkema Dan D Soubrier Martin M Tourdot Sophie S Trang Caroline C Vultaggio Alessandra A Warnke Clemens C Spindeldreher Sebastian S Dönnes Pierre P Hickling Timothy P TP Hincelin Mery Agnès A Allez Matthieu M Deisenhammer Florian F Fogdell-Hahn Anna A Mariette Xavier X Pallardy Marc M Broët Philippe P

PLoS medicine 20201030 10

<h4>Background</h4>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.<h4>Methods and findings</h4>The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multi ...[more]

PMID: 33125391

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Project description:Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies. In this context, we propose a novel test statistic for selecting loci of interest harbored by the X chromosome that are associated with time-to-event data taking into account skewed X-inactivation (XCI-S). The proposed statistic relies on a semi-parametric additive hazard model and is straightforward to implement. Results from the simulation study show that the test provides higher power gains than the score tests from the Cox model (under XCI process or its escape) and the Xu et al.'s XCI-S likelihood ratio test. We applied the test to the data from the real-world observational multicohort study set-up by the IMI-funded ABIRISK consortium for identifying X chromosome susceptibility loci for drug immunogenicity in patients with autoimmune diseases treated by biotherapies. The test allowed us to select two single nucleotide polymorphisms (SNPs) with high linkage disequilibrium (rs5991366 and rs5991394) located in the cytoband Xp22.2 that would have been overlooked by the Cox score tests and the Xu et al.'s XCI-S likelihood ratio test. Both SNPs showed a similar protective effect for drug immunogenicity without any occurrence of ADA positivity for the homozygous females and hemizygous males for the alternative allele. To our knowledge, this is the first study to investigate the association between X chromosome loci and the occurrence of anti-drug antibodies. We think that more X-Chromosome GWAS should be performed and that the test is well-suited for identifying X-Chromosome SNPs, while taking into account all patterns of the skewed X-Chromosome inactivation process.

Project description:BackgroundSeveral lifestyle factors are associated with an increased risk of colorectal cancer (CRC). Although lifestyle factors co-occur, in most previous studies these factors have been studied focusing upon a single risk factor or assuming independent effects between risk factors.AimTo examine the pairwise effects and interactions of smoking, alcohol consumption, physical inactivity, and body mass index (BMI) with risk of subsequent colorectal cancer (CRC).Methods and resultsWe used METCA cohort data (pooled data from seven population-based Finnish health behavior survey studies during years 1972-2015) consisting of 171 063 women and men. Participants' smoking, alcohol consumption, physical inactivity and BMI measures were gathered, and participants were categorized into those exposed and those not exposed. The incidence of CRC was modeled by Poisson regression with main and interaction effects of key lifestyle factors. The cohort members were followed-up through register linkage to the Finnish Cancer Registry for first primary CRC case until the end of 2015. Follow-up time was 1715, 690 person years. The highest pairwise CRC risk was among male smokers who had overweight (BMI ≥ 25 kg/m2 ) (HR 1.75, 95% CI 1.36-2.26) and women who had overweight and consumed alcohol (HR 1.45, 95% CI 1.14-1.85). Overall, among men the association of lifestyle factors and CRC risk was stronger than among women. In men, both having overweight and being a smoker combined with any other adverse lifestyle factor increased CRC risk. Among women, elevated CRC risks were observed for those who were physically inactive and who consumed alcohol or had overweight. No statistically significant interactions were detected between pairs of lifestyle factors.ConclusionsThis study strengthens the evidence of overweight, smoking, and alcohol consumption as CRC risk factors. Substantial protective benefits in CRC risk can be achieved by preventing smoking, maintaining BMI to <25 kg/m2 and not consuming alcohol.

Project description:BackgroundLifestyle factors influence the risk of morbidity and mortality, but the extent to which they are associated with employees' absence from work due to illness is unclear. We examined the relative contributions of smoking, alcohol consumption, high body-mass index, and low physical activity to diagnosis-specific sickness absence.MethodsWe did a multicohort study with individual-level data of participants of four cohorts from the UK, France, and Finland. Participants' responses to a lifestyle survey were linked to records of sickness absence episodes, typically lasting longer than 9 days; for each diagnostic category, the outcome was the total number of sickness absence days per year. We estimated the associations between lifestyle factors and sickness absence by calculating rate ratios for the number of sickness absence days per year and combining cohort-specific estimates with meta-analysis. The criteria for assessing the evidence included the strength of association, consistency across cohorts, robustness to adjustments and multiple testing, and impact assessment by use of population attributable fractions (PAF), with both internal lifestyle factor prevalence estimates and those obtained from European populations (PAFexternal).FindingsFor 74 296 participants, during 446 478 person-years at risk, the most common diagnoses for sickness absence were musculoskeletal diseases (70·9 days per 10 person-years), depressive disorders (26·5 days per 10 person-years), and external causes (such as injuries and poisonings; 12·8 days per 10 person-years). Being overweight (rate ratio [adjusted for age, sex, socioeconomic status, and chronic disease at baseline] 1·30, 95% CI 1·21-1·40; PAFexternal 8·9%) and low physical activity (1·23, 1·14-1·34; 7·8%) were associated with absences due to musculoskeletal diseases; heavy episodic drinking (1·90, 1·41-2·56; 15·2%), smoking (1·70, 1·42-2·03; 11·8%), low physical activity (1·67, 1·42-1·96; 19·8%), and obesity (1·38, 1·11-1·71; 5·6%) were associated with absences due to depressive disorders; heavy episodic drinking (1·64, 1·33-2·03; 11·3%), obesity (1·48, 1·27-1·72; 6·6%), smoking (1·35, 1·20-1·53; 6·3%), and being overweight (1·20, 1·08-1·33; 6·2%) were associated with absences due to external causes; obesity (1·82, 1·40-2·36; 11·0%) and smoking (1·60, 1·30-1·98; 10·3%) were associated with absences due to circulatory diseases; low physical activity (1·37, 1·25-1·49; 12·0%) and smoking (1·27, 1·16-1·40; 4·9%) were associated with absences due to respiratory diseases; and obesity (1·67, 1·34-2·07; 9·7%) was associated with absences due to digestive diseases.InterpretationLifestyle factors are associated with sickness absence due to several diseases, but observational data cannot determine the nature of these associations. Future studies should investigate the cost-effectiveness of lifestyle interventions aimed at reducing sickness absence and the use of information on lifestyle for identifying groups at risk.FundingNordForsk, British Medical Research Council, Academy of Finland, Helsinki Institute of Life Sciences, and Economic and Social Research Council.

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Dataset Information

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

Publications

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

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