title: Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.
  
  
  METHODS
  A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.
  
  
  RESULTS
  Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody-positive patients received lower median dosages of methotrexate compared with antidrug antibody-negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m(2) and poor adherence were associated with lower drug levels.
  
  
  CONCLUSIONS
  Pharmacologic testing in anti-tumor necrosis factor-treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
authors.affiliation: Meghna Jani, MBChB, MSc, MRCP: Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Meghna
authors.initials: M
authors.lastname: Jani
authors.affiliation: Hector Chinoy, MBBS, PhD, MRCP, MSc, BMedSci: Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, and NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Hector
authors.initials: H
authors.lastname: Chinoy
authors.affiliation: Richard B. Warren, BSc, MBChB, PhD, MRCP, Christopher E. M. Griffiths, BSc, MBBS, MD, FRCP, FRCPath, FMedSci: The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Warren
authors.affiliation: Richard B. Warren, BSc, MBChB, PhD, MRCP, Christopher E. M. Griffiths, BSc, MBBS, MD, FRCP, FRCPath, FMedSci: The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Christopher E M
authors.initials: CE
authors.lastname: Griffiths
authors.affiliation: Darren Plant, PhD, Anne Barton, MBChB, PhD, FRCP: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, and NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.affiliation: Bo Fu, PhD: Centre for Biostatistics, Institute of Population Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.affiliation: University of Leeds, Leeds, UK.
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.affiliation: University of Sheffield, Sheffield, UK.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, and NIHR Newcastle Biomedical Research Centre, Newcastle-upon-Tyne, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.affiliation: Kimme L. Hyrich, MD, PhD, FRCPC: Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
authors.forename: KimmeL
authors.initials: K
authors.lastname: Hyrich
authors.affiliation: Darren Plant, PhD, Anne Barton, MBChB, PhD, FRCP: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, and NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000276:immunology / Q000627:therapeutic use*; D012460:Sulfasalazine / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D006886:Hydroxychloroquine; D000068879:Adalimumab; D000068800:Etanercept; D008727:Methotrexate