THU0211 Six months after treatment discontinuation tnf is still in complex with adalimumab
Authors: M.J. l’Ami, L.C. Berkhout, M.T. Nurmohamed, R.F. van Vollenhoven, M. Boers, J. Ruwaard, F. Hooijberg, T. Rispens, G. Wolbink
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Many patients with rheumatoid arthritis (RA) are successfully treated with tumour necrosis factor inhibitors (TNFi). We recently developed a novel assay that can quantify TNF in the presence of large amounts of TNFi, i.e. a 'drug-tolerant' assay. We showed in RA patients that TNF levels increased and stabilised during adalimumab treatment due to complex forming between TNF and adalimumab. In the presence of adalimumab, all TNF was in complex and biologically inactive. Once in remission, some patients can discontinue the TNFi for a prolonged period. It is unclear how long adalimumab levels are detectable and TNF complexes are formed after the last adalimumab administration. <h3>Objectives</h3> To investigate adalimumab levels and complexed TNF levels 6 months after the last adalimumab administration. <h3>Methods</h3> TNF and adalimumab levels were measured using a novel drug-tolerant competition enzyme-linked immunosorbent assay (ELISA), and a regular ELISA, respectively, in 11 consecutive RA patients with stable low disease activity (disease activity score of 28 joints&lt;3.2) who discontinued adalimumab for 6 months (prior dose: 40 mg every 2 weeks). Blood samples were drawn prior to adalimumab discontinuation and 3 and 6 months thereafter. <h3>Results</h3> After the last adalimumab administration, mean adalimumab level decreased from 5.5 (SD 2.9) to 0.55 (0.52) and 0.11 (0.13) μg/mL at 3 and 6 months after treatment discontinuation, respectively (<b>figure 1A</b>). In contrast, complexed TNF levels remained stable for prolonged periods of time: in 8 patients TNF levels at 3 months were indistinguishable from levels seen at baseline, on standard-dose adalimumab (<b>figure 1B</b>). After 6 months, TNF still remained stable in patients with adalimumab concentrations above 0.1 µg/mL (n=4). Overall, mean TNF levels decreased from median 381 (inner quartiles 16; 707) to 290<sup>2; 755</sup> and 83<sup>2; 532</sup> pg/mL at 3 and 6 months after treatment discontinuation, respectively. In 5 patients, TNF levels decreased significantly. In those patients, adalimumab levels dropped to, or below the detection limit. <h3>Conclusions</h3> This is the first study showing that TNF is still in complex with adalimumab in the majority of patients 6 months after the last administration. Therefore, one may wonder at which point in time a patient has truly discontinued adalimumab treatment. <h3>Disclosure of Interest</h3> M. l'Ami: None declared, L. Berkhout: None declared, M. Nurmohamed Grant/research support from: Pfizer, AbbVie, Roche, BMS, MSD, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Sanofi, and Celgene, Speakers bureau: Pfizer, AbbVie, Roche, BMS, MSD, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Sanofi, and Celgene, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, UCB, Consultant for: AbbVie, AstraZeneca, Biotest, BMS, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, UCB, M. Boers: None declared, J. Ruwaard: None declared, F. Hooijberg: None declared, T. Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, AbbVie and Regeneron, G. Wolbink Speakers bureau: Pfizer, UCB, AbbVie, Biogen, BMS