SAT0189 Dynamics of circulating tnf during adalimumab treatment of rheumatoid arthritis using a novel drug-tolerant tnf assay
Authors: L. C. Berkhout, M. J. l'Ami, J. Ruwaard, M. H. Hart, P. Ooijevaar-de Heer, K. Bloem, M. T. Nurmohamed, R. F. van Vollenhoven, M. Boers, C. Smith, G. Wolbink, T. Rispens
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Tumor necrosis factor- (TNF) inhibitors are effective in the treatment of rheumatoid arthritis (RA); these include adalimumab, which binds TNF to form inactive complexes. Once in remission, a proportion of patients can successfully discontinue adalimumab treatment, indicating that blocking TNF is no longer necessary for disease control. We developed a novel assay that can quantify TNF in the presence of large amounts of TNF-inhibitor, i.e. a 'drug-tolerant' assay. <h3>Objectives:</h3> To investigate, for the first time, the relationship between TNF levels and disease course during adalimumab treatment. <h3>Methods:</h3> The new drug-tolerant competition enzyme-linked immunosorbent (ELISA) assay was used to quantify TNF levels on initiation and during 2 years of adalimumab treatment in 206 consecutive RA patients. The relationship between TNF levels and clinical response was evaluated. <h3>Results:</h3> Circulating TNF levels were close to the detection limit at baseline, but TNF levels increased on average &gt;50-fold upon adalimumab treatment (<b>figure 1A</b>; black lines show median (IQR)), and reached a stable level in time in the majority of patients (<b>figure 1B</b>; representatives of n=206), regardless of disease activity. During treatment, TNF was in complex with adalimumab, and recovered as inactive 3:1 adalimumab:TNF complexes. Low TNF levels at week four were associated with a higher frequency of anti-drug antibodies (ADAs) at subsequent time points (<b>figure 1C</b>) and significantly less methotrexate (MTX) use at baseline. Furthermore, week four TNF levels were significantly correlated with SDAI score, with significantly lower TNF levels in patients who did not reach remission (Spearman r = -0.18; p=0.015; <b>figure 1D</b>) <h3>Conclusions:</h3> TNF levels, mostly in complexed form, do not appear to decline in patients that reach remission, and may therefore not be predictive for treatment discontinuation. However, low complexed TNF levels in the early phase of treatment (wk 4) are strongly associated with ADA formation and can be used to identify non-responders in the early phase of treatment. <h3>Disclosure of Interest:</h3> L. Berkhout: None declared, M. l9Ami: None declared, J. Ruwaard: None declared, M. Hart: None declared, P. Ooijevaar-de Heer: None declared, K. Bloem: None declared, M. Nurmohamed Consultant for: Abbott, Roche, Pfizer, MSD, UCB, SOBI, BMS, Speakers bureau: Abbott, Roche, Pfizer, 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, C. Smith: None declared, G. Wolbink Grant/research support from: Pfizer, Speakers bureau: Pfizer, UCB, AbbVie, Biogen, BMS, T. Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, AbbVie, Regeneron