Hassler, Signe, Bachelet, Delphine, Duhaze, Julianne, Szely, Natacha, Gleizes, Aude, Abina, Salima Hacein-Bey, Aktas, Orhan, Auer, Michael, Avouac, Jerome ORCID: 0000-0002-2463-218X, Birchler, Mary, Bouhnik, Yoram, Brocq, Olivier, Buck-Martin, Dorothea, Cadiot, Guillaume, Carbonnel, Franck, Chowers, Yehuda, Comabella, Manuel, Derfuss, Tobias, De Vries, Niek, Donnellan, Naoimh, Doukani, Abiba, Guger, Michael, Hartung, Hans-Peter, Havrdova, Eva Kubala, Hemmer, Bernhard, Huizinga, Tom, Ingenhoven, Kathleen, Hyldgaard-Jensen, Poul Erik, Jury, Elizabeth C., Khalil, Michael, Kieseier, Bernd, Lauren, Anna, Lindberg, Raija, Loercher, Amy, Maggi, Enrico, Manson, Jessica, Mauri, Claudia, Oumoussa, Badreddine Mohand, Montalban, Xavier ORCID: 0000-0002-0098-9918, Nachury, Maria, Nytrova, Petra, Richez, Christophe, Ryner, Malin, Sellebjerg, Finn ORCID: 0000-0002-1333-9623, Sievers, Claudia, Sikkema, Dan, Soubrier, Martin, Tourdot, Sophie, Trang, Caroline, Vultaggio, Alessandra, Warnke, Clemens, Spindeldreher, Sebastian, Donnes, Pierre, Hickling, Timothy P., Mery, Agnes Hincelin, Allez, Matthieu, Deisenhammer, Florian, Fogdell-Hahn, Anna, Mariette, Xavier, Pallardy, Marc and Broet, Philippe (2020). Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium. PLos Med., 17 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1549-1676

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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 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. 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. Author summary Why 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hassler, SigneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bachelet, DelphineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duhaze, JulianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szely, NatachaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gleizes, AudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abina, Salima Hacein-BeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aktas, OrhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auer, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Avouac, JeromeUNSPECIFIEDorcid.org/0000-0002-2463-218XUNSPECIFIED
Birchler, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouhnik, YoramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brocq, OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buck-Martin, DorotheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cadiot, GuillaumeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carbonnel, FranckUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chowers, YehudaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Comabella, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Derfuss, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Vries, NiekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donnellan, NaoimhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doukani, AbibaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guger, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartung, Hans-PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Havrdova, Eva KubalaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemmer, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huizinga, TomUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ingenhoven, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hyldgaard-Jensen, Poul ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jury, Elizabeth C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khalil, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kieseier, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauren, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindberg, RaijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loercher, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maggi, EnricoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manson, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauri, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oumoussa, Badreddine MohandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montalban, XavierUNSPECIFIEDorcid.org/0000-0002-0098-9918UNSPECIFIED
Nachury, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nytrova, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richez, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryner, MalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sellebjerg, FinnUNSPECIFIEDorcid.org/0000-0002-1333-9623UNSPECIFIED
Sievers, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sikkema, DanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soubrier, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tourdot, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trang, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vultaggio, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warnke, ClemensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spindeldreher, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donnes, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hickling, Timothy P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mery, Agnes HincelinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allez, MatthieuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deisenhammer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fogdell-Hahn, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mariette, XavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallardy, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broet, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-316187
DOI: 10.1371/journal.pmed.1003348
Journal or Publication Title: PLos Med.
Volume: 17
Number: 10
Date: 2020
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1549-1676
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MODIFYING ANTIRHEUMATIC DRUG; NEUTRALIZING ANTIBODIES; INFLAMMATORY DISEASES; RHEUMATOID-ARTHRITIS; INTERFERON-BETA; GUT MICROBIOTA; RECOMMENDATIONS; METHOTREXATE; TOCILIZUMAB; MONOTHERAPYMultiple languages
Medicine, General & InternalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31618

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