title: Key findings towards optimising adalimumab treatment: the concentration-effect curve.
abstract: OBJECTIVE
  To determine a concentration-effect curve of adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for adalimumab concentrations.
  
  
  METHODS
  In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg adalimumab subcutaneously every other week. The relationship between adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration-effect curve. A receiver-operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration-effect curve and a concentration table.
  
  
  RESULTS
  Clinical efficacy improved with increasing adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5-8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on adalimumab monotherapy had a median adalimumab level of 4.1 μg/mL (IQR 1.3-7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3-10.6, p<0.001).
  
  
  CONCLUSIONS
  Adalimumab trough levels in a range of 5-8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.
authors: Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands.
authors: Mieke F
authors: MF
authors: Pouw
authors: Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands.
authors: Charlotte L
authors: CL
authors: Krieckaert
authors: Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands.
authors: Michael T
authors: MT
authors: Nurmohamed
authors: Biologicals Laboratory, Sanquin Diagnostic Services, Sanquin, Amsterdam, The Netherlands.
authors: Desiree
authors: D
authors: van der Kleij
authors: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands.
authors: Lucien
authors: L
authors: Aarden
authors: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands.
authors: Theo
authors: T
authors: Rispens
authors: Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands.
authors: Gertjan
authors: G
authors: Wolbink
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000097:blood / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D011446:Prospective Studies; D012372:ROC Curve; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000068879:Adalimumab; D011241:Prednisone; D008727:Methotrexate
keywords: Anti-TNF; Pharmacokinetics; Rheumatoid Arthritis