PLoS Medicine (Oct 2020)

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

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

DOI
https://doi.org/10.1371/journal.pmed.1003348
Journal volume & issue
Vol. 17, no. 10
p. e1003348

Abstract

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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 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.