Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis

Ryan M Hum; Pauline Ho; Nisha Nair; Meghna Jani; Ann W Morgan; John D Isaacs; Anthony G Wilson; Kimme L Hyrich; Darren Plant; Anne Barton; BRAGGSS Collaborators

doi:10.1093/rheumatology/keac564

Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis

Rheumatology (Oxford). 2023 Jun 1;62(6):2090-2097. doi: 10.1093/rheumatology/keac564.

Authors

Ryan M Hum^{1

2

3}, Pauline Ho^{1

2

3}, Nisha Nair^{1

2}, Meghna Jani^{1

2}, Ann W Morgan⁴, John D Isaacs⁵, Anthony G Wilson⁶, Kimme L Hyrich^{1

2

3}, Darren Plant^{1

2}, Anne Barton^{1

2

3}; BRAGGSS Collaborators

Collaborators

BRAGGSS Collaborators:
H Gaston, D Mulherin, T Price, T Sheeran, V Chalam, S Baskar, P Emery, A Morgan, M Buch, S Bingham, S O'Reilly, L Badcock, M Regan, T Ding, C Deighton, G Summers, N Raj, R Stevens, N Williams, J Isaacs, P Platt, D Walker, L Kay, B Griffiths, W-F Ng, P Peterson, A Lorenzi, H Foster, M Friswell, B Thompson, M Lee, I Griffiths, A Hassell, P Dawes, C Dowson, S Kamath, J Packham, M Shadforth, A Brownfield, R Williams, C Mukhtyar, B Harrison, N Snowden, S Naz, J Ledingham, R Hull, F McCrae, A Thomas, S Young Min, R Shaban, E Wong, C Kelly, C Heycock, J Hamilton, V Saravanan, G Wilson, D Bax, L Dunkley, M Akil, R Tattersall, R Kilding, S Till, J Boulton, T Tait, M Bukhari, J Halsey, L Ottewell, C Buckley, D Situnayake, D Carruthers, K Grindulis, F Khatack, S Elamanchi, K Raza, A Filer, R Jubb, R Abernathy, M Plant, S Pathare, F Clarke, S Tuck, J Fordham, A Paul, M Bridges, A Hakim, D O'Reilly, V Rajagopal, S Bhagat, C Edwards, P Prouse, R Moitra, D Shawe, A Bamji, P Klimiuk, A Bowden, W Mitchell, I Bruce, A Barton, R Gorodkin, P Ho, K Hyrich, W Dixon, A Rai, G Kitas, N Erb, R Klocke, K Douglas, A Pace, R Sandhu, A Whallett, F Birrell, M Allen, K Chaudhuri, C Chattopadhyay, J McHale, A Jones, A Gupta, I Pande, I Gaywood, P Lanyon, P Courtney, M Doherty, H Chinoy, T O'Neill, A Herrick, A Jones, R Cooper, R Bucknall, C Marguerie, S Rigby, N Dunn, S Green, A Al-Ansari, S Webber, N Hopkinson, C Dunne, B Quilty, B Szebenyi, M Green, M Quinn, A Isdale, A Brown, B Saleem, A Samanta, P Sheldon, W Hassan, J Francis, A Kinder, R Neame, A Moorthy, W Al-Allaf, A Taggart, K Fairburn, F McKenna, M Green, A Gough, C Lawson, M Piper, E Korendowych, T Jenkinson, R Sengupta, A Bhalla, N McHugh, D Bond, R Luqmani, B Bowness, P Wordsworth, J David, W Smith, D Mewar, E Tunn, K Nelson, T Kennedy, J Nixon, A Woolf, M Davis, D Hutchinson, A Endean, D Coady, D Wright, C Morley, G Raftery, C Bracewell, L Kidd, I Abbas, C Filer, G Kallarackal

Affiliations

¹ Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
² National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, University of Manchester, Manchester, UK.
³ Kellgren Centre for Rheumatology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, University of Manchester, Manchester, UK.
⁴ NIHR Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds, UK.
⁵ Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK.
⁶ University College Dublin Centre for Arthritis Research, Conway Institute, University College Dublin, Dublin, Ireland.

Abstract

Objectives: Interventions aimed at increasing TNF-α inhibitor serum drug levels (SDLs) may improve treatment response; however, previous studies suggesting SDL cut-offs have not accounted for treatment adherence. The aim of this study was to establish the relationship between adalimumab/certolizumab SDLs and EULAR good vs non-/moderate response and to define SDL cut-offs associated with good response in fully adherent patients.

Methods: In a prospective observational study, 475 patients with RA were treated with certolizumab (n = 192) or adalimumab (n = 283). At baseline and 3, 6 and 12 months, patients had 28-joint DAS, self-reported treatment adherence and SDLs measured. Fully adherent patients were analysed as a subgroup. Follow-up data at 3, 6 and 12 months were analysed separately. Median SDLs were compared in good vs non-/moderate response patients and receiver operating characteristics (ROC) curves were used to establish cut-off SDLs.

Results: Fully adherent good responders had significantly higher median adalimumab/certolizumab SDLs compared with non-/moderate responders (P = 0.04 and P = 0.0005, respectively). ROC analysis reported 3 month non-trough adalimumab SDLs discriminated good vs non-/moderate response with an area under the curve (AUC) of 0.63 (95% CI 0.52, 0.75), with a cut-off of 7.5 mg/l being 39.1% specific and 80.9% sensitive. Similarly, 3 month non-trough certolizumab SDLs discriminated good vs non-/moderate response with an AUC of 0.65 (95% CI 0.51, 0.78), with a cut-off of 26.0 mg/l being 43.9% specific and 77.8% sensitive.

Conclusion: In fully adherent patients, higher SDLs are detected in good responders, suggesting that interventions to improve SDLs, such as encouraging adherence, could improve treatment response. The 3 month non-trough SDL cut-offs of 7.5 mg/l for adalimumab and 26.0 mg/l for certolizumab may be useful in clinical practice.

Keywords: RA; TNF-α; adalimumab; adherence; certolizumab; inhibitors; serum drug levels; therapeutic response.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adalimumab / therapeutic use
Antirheumatic Agents* / therapeutic use
Arthritis, Rheumatoid* / drug therapy
Certolizumab Pegol / therapeutic use
Humans
Treatment Outcome
Tumor Necrosis Factor-alpha

Substances

Adalimumab
Antirheumatic Agents
Certolizumab Pegol
Tumor Necrosis Factor-alpha

Abstract

Publication types

MeSH terms

Substances

Grants and funding