title: Clinical utility of random anti-tumour necrosis factor drug testing and measurement of anti-drug antibodies on long-term treatment response in rheumatoid arthritis.
abstract: BACKGROUND
  Up to 40% of patients with rheumatoid arthritis treated with anti-tumour necrosis factor (TNF) drugs do not respond because of primary inefficacy or loss of response. Although one explanation is that immunogenicity leads to the development of anti-drug antibodies and low drug concentrations, the clinical usefulness of pharmacological monitoring is debated. Our aim was to assess whether the presence of anti-drug antibodies and non-trough drug concentrations could predict treatment response in patients with rheumatoid arthritis treated with anti-TNF drugs.
  
  
  METHODS
  331 patients were selected from a multicentre prospective cohort (160 treated with adalimumab, 171 etanercept). Serum samples were collected at 3, 6, and 12 months after treatment initiation. Anti-drug antibodies were measured with RIA, drug concentrations with ELISAs, and Disease Activity Score in 28 joints (DAS28) at each timepoint. Linear and logistic regression, generalised estimating equation (GEE), and receiver operating characteristic curves were used to test the association and predictive value of anti-drug antibodies and non-trough drug concentrations on treatment response (ΔDAS28).
  
  
  RESULTS
  835 serial samples were tested (414 adalimumab, 421 etanercept). Anti-adalimumab antibodies were detected in 31 (24·8%) of 125 patients who had completed 12 month follow-up and none of the etanercept patients. The presence of anti-drug antibodies was associated with lower adalimumab concentrations (Spearman r=-0·66, p=0·0041). At 3 months, anti-drug antibody formation and low adalimumab concentrations were significant predictors of poor treatment response at 12 months (area under curve [AUC] 0·68, 95% CI 0·54-0·81, and 0·66, 0·55-0·77, respectively; and both combined 0·71, 0·57-0·85). Adalimumab concentration was the most significant independent predictor of ΔDAS28 after adjustment for confounders (regression coefficient 0·12, 95% CI 0·06-0·18; p=0·003). High etanercept concentrations were associated with better treatment response (p=0·01), but low concentrations at 3 months were not a significant predictor of poor treatment response at 12 months (AUC 0·58, 95% CI 0·46-0·70). In the combined GEE model including adalimumab and etanercept, a body-mass index of 30 kg/m(2) or more was associated with low drug concentrations (regression coefficient 0·78, 95% CI 0·37-1·18; p<0·0001).
  
  
  CONCLUSIONS
  Pharmacological testing in anti-TNF initiated patients is clinically useful even in the absence of trough levels. At 3 months, presence of anti-drug antibodies and low adalimumab concentrations are a significant predictor for poor treatment response at 12 months. Strengths of this study include a large, prospective cohort and use of RIA to measure antibodies (less prone to drug interference). Although non-trough concentrations might have underestimated the frequency of antibodies, their presence still predicted response.
  
  
  BACKGROUND
  MJ is a MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the UK Medical Research Council (grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca, and the Medical Evaluation Unit. Arthritis Research UK (grant ref 20385).
authors: Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: meghna.jani@manchester.ac.uk.
authors: Meghna
authors: M
authors: Jani
authors: Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK.
authors: Hector
authors: H
authors: Chinoy
authors: The Dermatology Centre, University of Manchester, Manchester, UK.
authors: Richard B
authors: RB
authors: Warren
authors: The Dermatology Centre, University of Manchester, Manchester, UK.
authors: Christopher E M
authors: CE
authors: Griffiths
authors: Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK.
authors: Darren
authors: D
authors: Plant
authors: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK.
authors: Ann W
authors: AW
authors: Morgan
authors: School of Medicine & Medical Science, University College Dublin, Dublin, Ireland.
authors: Anthony G
authors: AG
authors: Wilson
authors: Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors: Kimme L
authors: KL
authors: Hyrich
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: John
authors: J
authors: Isaacs
authors: Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK.
authors: Anne
authors: A
authors: Barton