Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases

Abstract

Objectives: To explore associations between serum adalimumab level, treatment response and drug survival in order to identify optimal drug levels for therapeutic drug monitoring of adalimumab. Also, to assess the occurrence and risk factors of anti-drug antibody (ADAb) formation.

Methods: Non-trough adalimumab and ADAb levels were measured by automated fluorescence assays in serum collected after 3 months of adalimumab treatment in patients with RA, PsA or axial SpA (axSpA) included in the observational NOR-DMARD study. Treatment response was evaluated after 3 months and drug survival was evaluated during long-term follow-up.

Results: In 340 patients (97 RA, 69 PsA, 174 axSpA), the median adalimumab level was 7.3 mg/l (interquartile range 4.0-10.3). A total of 33 (10%) patients developed ADAbs. Findings were comparable across diagnoses. In RA and PsA, adalimumab levels ≥6.0 mg/l were associated with treatment response [odds ratio (OR) 2.2 (95% CI 1.0, 4.4)] and improved drug survival [hazard ratio 0.49 (95% CI 0.27, 0.80)]. In axSpA, a therapeutic level could not be identified, but higher adalimumab levels were associated with response. Factors associated with ADAb formation were previous bDMARD use, no methotrexate comedication and the use of adalimumab originator compared with GP2017.

Conclusion: Higher adalimumab levels were associated with a better response and improved drug survival for all diagnoses, with a suggested lower threshold of 6.0 mg/l for RA/PsA. This finding, the large variability in drug levels among patients receiving standard adalimumab dose and the high proportion of patients developing ADAbs encourages further investigations into the potential role of therapeutic drug monitoring of adalimumab.

Keywords: TNF inhibitors; adalimumab; anti-drug antibodies; inflammatory joint disease; serum drug level.

Figure 1.

Serum adalimumab levels by diagnosis, treatment response and remission/inactive disease at 3 months. Violin plot showing the probability density of the data at different values, smoothed by a kernel density estimator. Each data point is a participant, the solid orange line shows the group median and red dots are participants with ADAb formation. (A) Adalimumab levels for all participants and by diagnosis. (B and C) Adalimumab levels by (B) response to treatment (EULAR good and moderate response and ASDAS major and clinically important improvement) and (C) DAS28 remission/ASDAS inactive disease at 3 months. *Mann-Whitney U test

Figure 2.

Treatment response, remission and drug survival in RA and PsA patients. (A and B) Drug-level range is divided into groups with ≈21 patients in each. Percent distribution of (A) EULAR response and (B) DAS28 remission in RA/PsA patients at 3 months according to adalimumab level. (C) Kaplan–Meier curve for 1.5 years drug survival stratified by adalimumab level at 3 months. Comparing RA/PsA patients with adalimumab ≥6 mg/l vs <6 mg/l, there was a significant difference in the survival estimates; P = 0.0003 (logrank)

Figure 3.

Treatment response, inactive disease and drug survival in axSpA patients. (A and B) Drug-level range is divided into groups with ≈22 patients in each. Percent distribution of (A) ASDAS improvement and (B) ASDAS inactive disease in axSpA patients at 3 months according to adalimumab level. (C) Kaplan–Meier curve for 1.5 years drug survival stratified by adalimumab level at 3 months. There was no significant difference in the survival estimates; P = 0.082 (logrank)

Figure 4.

Serum drug level and drug survival by originator and GP2017 adalimumab. (A) Violin plot showing the probability density of the data at different values, smoothed by a kernel density estimator. Each data point is a participant and the solid orange line shows the group median. Red dots are participants with ADAb formation. (B) Kaplan–Meier curve for 1.5 years drug survival stratified by originator and GP2017 adalimumab. There was no significant difference in the survival estimates; P = 0.16 (logrank)