Background In the past two decades TNF inhibitors have proved especially effective in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. However, despite a high responder rate there is a substantial number of patients showing a primary therapy failure or loss of efficacy after initial response. The presence of anti-drug antibodies and serum drug levels are considered as variables that influence therapy outcome.
Objectives It was the aim of the study to analyse the clinical relevance of anti-drug antibodies and drug levels in the course of a long term treatment of rheumatoid arthritis (RA) patients with etanercept (ETN).
Methods In this retrospective analysis, 508 serum samples from 104 RA patients (86 female/18 male, mean age 51.1±11.5 years (mean±SD), mean disease duration 10.8±8.3 years) were obtained after 6, 12, 24, 36, and 48 months of treatment with ETN, and selected for determination of anti-ETN antibodies and drug levels. If available, serum samples obtained at least 2 weeks after discontinuation of ETN treatment (due to side effects, non-response, remission or surgery) were used for analysis to exclude any interference of high drug levels with the anti-drug antibody assay. For the determination of anti-ETN and ETN levels, Promonitor® - assays (Proteomika, Spain) were used according to the manufacturer's instructions.
Results Mean baseline disease activity (DAS28) of 5.77±1.19 decreased to 3.69±1.35, 3.43±1.27, 3.39±1.27 and 3.16±1.19 after 6, 12, 24, and 48 months of ETN treatment. No anti-ETN antibodies were found at any time point, neither in the course of treatment nor in samples from 72 of these patients obtained at least two weeks after discontinuation of ETN treatment (mean 51±3.9 months, range 18–120 months).
Mean ETN serum levels for all patients were 3.58±0.17μg/ml, 4.33±0.24μg/ml, 4.22±0.29μg/ml, 4.21±0.27, and 4.66±0.42μg/ml after 6, 12, 24, 36, and 48 months, respectively.
In the course of treatment ETN levels remained stable in most patients, mean levels (calculated from up to 5 single values) between individual patients ranged between 0.9 and 9.91μg/ml. ETN serum levels were not associated with patient related variables such as age, disease duration, rheumatoid factor, ACPA reactivity, creatinine or estimated glomerular filtration rate. There was a slight trend that a higher body weight is associated with lower ETN levels without reaching statistical significance.
In the lower quartile of patients with mean ETN level ≤2.5μg/ml, the DAS28 decreased from 5.52±1.34 to 3.73±0.96 (-1.79, 3.81±1.62 (-1.71), and 3.54±1.54 (-1.98) after 6, 24, and 48 months. A stronger DAS28 improvement was found in the upper quartile >5.07μg/ml from 6.01±1.19 to 3.68±1.57 (-2.33), 3.19±1.14 (-2.82), and 3.08±0.88 (-2,93), respectively.
Conclusions Our study confirms the lack of anti-drug antibodies in a large cohort of RA patients in the course of a long-term treatment with ETN.
ETN drug levels are characterized by a wide inter-individual variability with limited prognostic value for therapy outcome. Our findings do not explain the treatment failure in some patients indicating that other factors/mechanisms determine the lack or loss of efficacy.
Disclosure of Interest S. Drynda Grant/research support from: Supported by a Research Grant of Pfizer Pharma GmbH, Germany, J. Kekow: None declared