Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis
Authors: Hum Ryan M , Ho Pauline , Nair Nisha , Jani Meghna , Morgan Ann W , Isaacs John D , Wilson Anthony G , Hyrich Kimme L , Plant Darren , Barton Anne ,   the BRAGGSS Collaborators, Gaston H , Mulherin D , Price T , Sheeran T , Chalam V , Baskar S , Emery P , Morgan A , Buch M , Bingham S , O’Reilly S , Badcock L , Regan M , Ding T , Deighton C , Summers G , Raj N , Stevens R , Williams N , Isaacs J , Platt P , Walker D , Kay L , Griffiths B , Ng W -F , Peterson P , Lorenzi A , Foster H , Friswell M , Thompson B , Lee M , Griffiths I , Hassell A , Dawes P , Dowson C , Kamath S , Packham J , Shadforth M , Brownfield A , Williams R , Mukhtyar C , Harrison B , Snowden N , Naz S , Ledingham J , Hull R , McCrae F , Thomas A , Young Min S , Shaban R , Wong E , Kelly C , Heycock C , Hamilton J , Saravanan V , Wilson G , Bax D , Dunkley L , Akil M , Tattersall R , Kilding R , Till S , Boulton J , Tait T , Bukhari M , Halsey J , Ottewell L , Buckley C , Situnayake D , Carruthers D , Grindulis K , Khatack F , Elamanchi S , Raza K , Filer A , Jubb R , Abernathy R , Plant M , Pathare S , Clarke F , Tuck S , Fordham J , Paul A , Bridges M , Hakim A , O’Reilly D , Rajagopal V , Bhagat S , Edwards C , Prouse P , Moitra R , Shawe D , Bamji A , Klimiuk P , Bowden A , Mitchell W , Bruce I , Barton A , Gorodkin R , Ho P , Hyrich K , Dixon W , Rai A , Kitas G , Erb N , Klocke R , Douglas K , Pace A , Sandhu R , Whallett A , Birrell F , Allen M , Chaudhuri K , Chattopadhyay C , McHale J , Jones A , Gupta A , Pande I , Gaywood I , Lanyon P , Courtney P , Doherty M , Chinoy H , O’Neill T , Herrick A , Jones A , Cooper R , Bucknall R , Marguerie C , Rigby S , Dunn N , Green S , Al-Ansari A , Webber S , Hopkinson N , Dunne C , Quilty B , Szebenyi B , Green M , Quinn M , Isdale A , Brown A , Saleem B , Samanta A , Sheldon P , Hassan W , Francis J , Kinder A , Neame R , Moorthy A , Al-Allaf W , Taggart A , Fairburn K , McKenna F , Green M , Gough A , Lawson C , Piper M , Korendowych E , Jenkinson T , Sengupta R , Bhalla A , McHugh N , Bond D , Luqmani R , Bowness B , Wordsworth P , David J , Smith W , Mewar D , Tunn E , Nelson K , Kennedy T , Nixon J , Woolf A , Davis M , Hutchinson D , Endean A , Coady D , Wright D , Morley C , Raftery G , Bracewell C , Kidd L , Abbas I , Filer C , Kallarackal G 
Published: October 2022

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.