Meghna Jani1, Hector Chinoy2, Richard B Warren3, Christopher E M Griffiths3, Darren Plant2, Ann W Morgan4, Anthony G Wilson5, Kimme L Hyrich6, John Isaacs7, Anne Barton2. 1. Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: meghna.jani@manchester.ac.uk. 2. 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. 3. The Dermatology Centre, University of Manchester, Manchester, UK. 4. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK. 5. School of Medicine & Medical Science, University College Dublin, Dublin, Ireland. 6. Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. 7. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: 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).
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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: 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: J Braun; H M Lorenz; U Müller-Ladner; M Schneider; H Schulze-Koops; Ch Specker; A Strangfeld; U Wagner; T Dörner Journal: Z Rheumatol Date: 2018-02 Impact factor: 1.372