title: High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort.
abstract: OBJECTIVE
  To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels.
  
  
  METHODS
  This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels.
  
  
  RESULTS
  ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=-0.037, 95% CI -0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI -0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations.
  
  
  CONCLUSIONS
  This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level.
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.|Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
authors.forename: Meghna
authors.identifier: http://orcid.org/0000-0002-1487-277X
authors.initials: M
authors.lastname: Jani
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University and National Institute of Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and National Institute of Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.affiliation: University College of Dublin School of Medicine and Medical Science, Dublin, Ireland.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.affiliation: National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, UK.
authors.forename: Darren
authors.identifier: http://orcid.org/0000-0003-1395-9344
authors.initials: D
authors.lastname: Plant
authors.affiliation: Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.|National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, UK.
authors.forename: Kimme L
authors.identifier: http://orcid.org/0000-0001-8242-9262
authors.initials: KL
authors.lastname: Hyrich
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.|National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, UK.
authors.forename: Hector
authors.initials: H
authors.lastname: Chinoy
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.|National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, UK.
authors.forename: Anne
authors.identifier: http://orcid.org/0000-0003-3316-2527
authors.initials: A
authors.lastname: Barton
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000097:blood / Q000276:immunology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D000068582:Certolizumab Pegol / Q000008:administration & dosage / Q000097:blood / Q000276:immunology* / Q000627:therapeutic use; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D018501:Antirheumatic Agents; D000068582:Certolizumab Pegol
keywords: Anti-TNF; DMARDs (biologic); Rheumatoid Arthritis; TNF-alpha; Treatment