Background/Purpose: Therapeutic drug monitoring (TDM) would be important if there was evidence to support the utility of measured drug concentrations in making changes to dose in order to improve drug efficacy and/or reduce toxicity. To determine the influence from variables, including patient characteristics and disease activity, on adalimumab concentrations and to assess the relationships between adalimumab concentrations, the presence of anti-drug antibodies (ADAs) and disease activity in RA.

Methods: 156 people with RA, receiving adalimumab for at least 4 months were recruited. Disease activity assessed by DAS28 with responders defined as DAS28≤3.2. Serum and plasma obtained for measurement of adalimumab concentrations and ADAs, and a panel of cytokines in a sub-group.

Results: Univariate analysis revealed a negative correlation between weight, DAS28, SJC28, TJC28, CRP, pain VAS, fatigue VAS, physicians global, duration of morning stiffness, and adalimumab concentrations. NZ Europeans, those on methotrexate, those without ADAs, and those with DAS28≤3.2 had higher adalimumab concentrations. Multivariate analysis, which included the presence of ADAs, revealed CRP (p< 0.001), weight (p< 0.004) and ethnicity (p< 0.001) were all independently negatively associated with adalimumab concentrations. There was a negative correlation between IL-6 and adalimumab concentrations (r=-0.038; p< 0.01). There was a negative correlation between adalimumab concentration and DAS28 (r=-0.37; p< 0.0001). Adalimumab concentrations were higher in those with DAS28 ≤3.2 compared to those with DAS28 >3.2 (median (IQR) 10.8 (6.4-20.8) mg/l vs.7.1 (1.5-12.6) mg/l; p < 0.001). Anti-drug antibodies were measured in the 45 participants with an adalimumab concentration < 5mg/l. 23/45 (51%) had HMSA titer >2 indicating the presence of anti-drug antibodies and of these 8/23 (34.8%) had an anti-drug antibody/adalimumab ratio ≥8AU, consistent with these being neutralizing antibodies. Adalimumab concentrations were lower in those with anti-drug antibody ratios ≥8AU compared to those with anti-drug antibody ratios < 8AU (mean (95%CI) 0.43 (0.00-1.06) vs. 1.84 (1.39-2.37) p=0.001). Adalimumab concentrations were lower in those 23 with HMSA titer >2 compared to those without ADA (mean (95%CI) 1.01 (0.00-1.56) vs. 2.47 (1.75-3.38) p=0.002).

Conclusion: Adalimumab concentration correlates negatively with markers of inflammatory disease activity in RA. Adalimumab concentration in the range 5 to 7 mg/l detected in serum are associated with better inflammatory disease control. Very low drug concentrations (< 5mg/l) are associated with the detection of anti-drug antibodies. These associations are consistent with the hypothesis that achieving an adequate serum adalimumab concentration is important for disease control and that the presence of ADA may be one mechanisms important in drug resistance.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/relationship-between-adalimumab-concentrations-plasma-cytokines-anti-drug-antibodies-and-disease-activity-in-rheumatoid-arthritis/