EXTENDED REPORT Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up Eva L Kneepkens, 1 James Cheng-Chung Wei, 2 Michael T Nurmohamed, 1,3 Kai-Jieh Yeo, 2 C Y Chen, 2 Irene E van der Horst-Bruinsma, 1,3 Desiree van der Kleij, 4 Theo Rispens, 5 Gertjan Wolbink, 1,5 Charlotte L M Krieckaert 1 Handling editor Tore K Kvien ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2013-204185). 1 Department of Rheumatology, Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands 2 Departments of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan 3 Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands 4 Laboratory for Monoclonal Therapeutics, Sanquin Diagnostic Services, Amsterdam, The Netherlands 5 Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands Correspondence to Dr Eva-Linda Kneepkens, Department of Rheumatology, Jan van Breemen Research Institute | Reade, Dr Jan van Breemenstraat 2, Amsterdam 1056 AB, The Netherlands; e.kneepkens@reade.nl Received 27 June 2013 Revised 3 September 2013 Accepted 5 November 2013 To cite: Kneepkens EL, Wei JC-C, Nurmohamed MT, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/ annrheumdis-2013-204185 ABSTRACT Background Immunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases. Objectives To study the relationship between clinical response, adalimumab levels and antidrug antibodies (ADAb) in ankylosing spondylitis (AS). Methods Observational cohort study of 115 consecutive AS patients treated with adalimumab in the Netherlands (n=85) and Taiwan (n=30), monitored during 24 weeks. Adalimumab levels and ADAb titres were determined using an ELISA and an antigen binding test (ABT), respectively, designed by Sanquin Research, Amsterdam. Response to adalimumab treatment was defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) response, and disease activity was measured using the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (CRP) (ASDAS). Results At baseline, median BASDAI (IQR) was 6.4 (4.5–7.6) and mean ASDAS (SD) was 3.5 (1.0). After 24 weeks, 49 (42.6%) patients were BASDAI50 responders and mean ASDAS (SD) for responders was 1.5 (1.0) vs 2.6 (1.0) for non-responders ( p<0.001). Thirty-one (27.0%) patients had detectable ADAb. After 24 weeks, adalimumab levels (mg/L) (IQR) were significantly higher in ADAb-negative patients than in ADAb-positive patients (12.7 (8.2–18.0) vs 1.2 (0.0– 2.0), (p<0.001)). A significant association was demonstrated between adalimumab levels and ASDAS ( p=0.02; RC -1.1; 95% CI -2.0 to -0.2). Eleven (9.6%) patients had no detectable adalimumab levels and high detectable ADAb titres (>100 AU/mL). In these patients, CRP and erythrocyte sedimentation rate remained elevated during treatment. Conclusions Adalimumab levels are related to clinical response in AS patients measured with ASDAS and are influenced by ADAb detectable with an ABT. INTRODUCTION Approximately 40% of ankylosing spondylitis (AS) patients do not respond to tumour necrosis factor (TNF) inhibitors. 1 Part of the non-response cannot be explained; however, an important reason for non-response is low drug levels as a result of the development of antidrug antibodies (ADAb). Previous studies of adalimumab treatment in AS patients showed percentages of detectable ADAb around 30% during 6–12 months of follow-up, leading to low or undetectable adalimumab levels and assessment of spondyloarthritis (ASAS) non- response. 23 A diminished treatment response asso- ciated with ADAb development has been described for rheumatoid arthritis (RA) to a larger extent. 4–8 These studies, from three different medical centres, observed different proportions of patients that developed ADAb. In patients with AS, the fre- quency of ADAb might be higher compared with patients with RA due to the lack of concomitant disease modifying antirheumatic drugs (DMARDs) (particularly methotrexate) in the treatment of AS. In RA, methotrexate has been shown to reduce the percentage of detectable ADAb. 9 10 Currently, there is no firm evidence to support a significant benefit of methotrexate monotherapy in the treatment of AS. 11 Several randomised controlled trials (RCTs) have studied the beneficial effect of methotrexate in addition to infliximab in AS patients; however, a significant difference in disease activity or inflixi- mab levels could not be demonstrated by these trials. 12–15 Previous studies showed that serum drug levels may vary widely between patients, but despite these observed variations, 245 pharmacokinetics of TNF inhibitors is currently not taken into account when treating AS patients. Considering the high costs of TNF inhibitors, there is a need to optimise TNF inhibitor treatment by identifying causes for non-response and preventing overtreatment in responders. The aim of this study was to investigate the relationship between clinical response, adalimu- mab levels and ADAb in AS in order to explore the utility of drug level and ADAb testing for the opti- misation of adalimumab treatment in AS patients. PATIENTS AND METHODS Study design and patients This prospective observational cohort study con- sisted of 126 consecutive adult patients with AS (according to the 1984 modified New York Criteria 16 ) who received adalimumab therapy at the department of Rheumatology of the Jan van Breemen Research Institute | Reade, Amsterdam, and Chung Shan Medical University Hospital, Taichung. All patients had failed to respond to at least two non-steroid anti-inflammatory drugs (NSAIDs) in the maximal tolerable dosage or had contraindications for the use of NSAIDs before Kneepkens EL, et al. Ann Rheum Dis 2013;0:1–6. doi:10.1136/annrheumdis-2013-204185 1 Clinical and epidemiological research ARD Online First, published on December 10, 2013 as 10.1136/annrheumdis-2013-204185 Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd (& EULAR) under licence. group.bmj.com on December 16, 2013 - Published by ard.bmj.com Downloaded from