Background/Purpose: Immunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases.

Objectives: To study the relation between clinical response, adalimumab levels and anti-drug antibodies (ADA) in ankylosing spondylitis (AS) patients.

Methods: Prospective observational cohort study of 115 consecutive AS patients treated with adalimumab in the Netherlands (n=85) and Taiwan (n=30), monitored during a maximum of 24 weeks. Adalimumab levels and ADA titres were determined retrospectively using an enzyme linked immunosorbent assay (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 (50% improvement or an absolute improvement of 2 points on a BASDAI, scale 0-10) and disease activity was measured using the AS Disease Activity Score, including CRP (ASDAS).

Results: Of 115 patients 78 (67.8%) were male and 95 (82.6%) were HLA-B27 positive. At baseline median BASDAI (IQR) was 6.4 (4.5-7.6) and mean ASDAS (SD) was 3.5 (1.0). After 24 weeks of follow-up 49 (42.6%) patients were BASDAI responders (last observation carried forward). Mean ASDAS (SD) for responders was 1.5 (1.0) vs. 2.6 (1.0) for non-responders (p<0.001). Nine patients dropped out: 8 patients due to treatment failure or adverse events and 1 due to loss of follow-up. Thirty-one (27.0%) patients had detectable ADA. Median ESR levels (mm/hour) were significantly different between patients with or without ADA (respectively, 35.5(13.0-52.5) vs.19.0 (7.0-34.0), p=0.008). After 24 weeks, median adalimumab level (mg/L) (IQR) was significantly higher for ADA negative than for ADA positive patients (12,7 (8.2-18.0) vs. 1.2 (0.0-2.0),  p<0.001). At 24 weeks the percentage of detectable ADA was higher in patients from Taiwan 12 (40.0%) vs. Dutch patients, 19 (22.4%) (p=0.06). General estimate equation analysis demonstrated a significant association between adalimumab levels and ASDAS (p=0.02; RC -1.1; 95% CI -2.0 to -0.2). For BASDAI response no significant association with adalimumab levels was found. Eleven (9.6%) patients had no detectable adalimumab levels and high detectable ADA titres (>100 AU/mL). In these patients CRP and ESR remained elevated, although BASDAI decreased during 24 weeks of follow-up.

Conclusion: Adalimumab levels are related to clinical response in AS patients and are influenced by ADA detectable with an ABT. Therefore therapeutic drug monitoring should be investigated further as a possible tool to optimise treatment. 

Fig. 1. Median CRP levels (mg/L) for AS patients divided in 3 groups: no detectable ADA titres with normal drug levels (> 5 mg/L); intermediate detectable ADA titres with low drug levels (< 5 mg/L) and high detectable ADA titres with low drug levels (< 5 mg/L) during 24 weeks of follow-up.