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Clinical Trial
. 2024 Nov 13;10(4):e004888.
doi: 10.1136/rmdopen-2024-004888.

Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial

Johanna Elin Gehin  1 , Rolf Anton Klaasen  2 , Eirik Klami Kristianslund  3 , Ingrid Jyssum  3 , Joseph Sexton  3 , David John Warren  2 , Daniel Aletaha  4 , Espen Andre Haavardsholm  3   5 , Silje Watterdal Syversen  3   5 , Guro Løvik Goll  3   5 , Nils Bolstad  2
Affiliations
Clinical Trial

Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial

Johanna Elin Gehin et al. RMD Open. .

Abstract

Objectives: The objectives of this study are to identify a therapeutic serum level for adalimumab associated with remission and low disease activity in patients with rheumatoid arthritis.

Methods: Associations between serum adalimumab trough levels and disease activity were examined using longitudinal data from a 48-week randomised phase III trial including patients with tumour necrosis factor inhibitor-naïve rheumatoid arthritis with active disease starting adalimumab treatment. Disease activity was classified according to 28-joint Disease Activity Score (DAS28)-erythrocyte sedimentation rate and C reactive protein (CRP) levels.

Results: Adalimumab trough levels were recorded longitudinally for 336, 330 and 302 patients at weeks 12, 24 and 48, respectively. All patients received concomitant methotrexate. Median adalimumab trough levels were 6.4 mg/L (IQR 3.4-9.5) at week 12, 7.5 mg/L (IQR 3.5-10.9) at week 24 and 7.6 mg/L (IQR 3.6-12.0) at week 48. In serial serum samples from weeks 12, 24 and 48, trough levels ≥3.9 mg/L were associated with DAS28 remission (OR 3.88 (95% CI 1.80, 8.38), p<0.001) and lower CRP levels (p<0.001). Week 12 trough levels ≥3.5 mg/L were associated with DAS28 low disease activity at week 24 (OR 2.62 (1.50, 4.56), p<0.001) and remission at week 48 (OR 1.99 (1.02, 3.88), p=0.04), as well as lower CRP levels at both time points (p<0.001).

Conclusion: Adalimumab trough levels above 4.0 mg/L were associated with remission/low disease activity throughout the first year of adalimumab therapy and can be considered a lower target level for therapeutic drug monitoring of adalimumab therapy.

Keywords: Adalimumab; Pharmacokinetics; Rheumatoid Arthritis.

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Conflict of interest statement

Competing interests: JG and RAK reports funding from the European Union’s Horizon Europe research and innovation program under grant agreement No 101095052. DA reports research grants from Lilly and Galapagos and consulting fees from Abbvie, Gilead, J&J, Lilly, MSD, Novartis and Sandoz. EAH reports funding from The Norwegian Regional Health Authorities (inter-regional KLINBEFORSK grants) and The Norwegian Research Council (grant number 328657), speakers' bureaus from Pfizer and UCB; and advisory board participation for Pfizer and AbbVie. SWS reports advisory board participation for AstraZeneca. GG reports personal fees from AbbVie, UCB, Janssen and Novartis. All other authors declare no competing interests.

Figures

Figure 1
Figure 1. Distribution of adalimumab trough levels at weeks 12, 24 and 48. Red dots represent patients with detectable antidrug antibodies. Two observations of antidrug antibody positivity with concurrent high adalimumab trough levels (28.7 mg/L at week 24 and 33.2 mg/L at week 48) were removed from the plot as these were considered erroneous due to clear deviations from the other observations in the same two patients.
Figure 2
Figure 2. Disease activity in patients stratified by adalimumab trough level in combined data from weeks 12, 24 and 48. (A) Proportion of patients with DAS28-ESR remission/low disease activity. (B) Median (IQR) C reactive protein levels. Patients were stratified into groups to include even numbers of observations in each (62–65 in A, and 51–63 in B). The <1.0 mg/L group included 139 observations in A and 138 in B. DAS28, 28-joint Disease Activity Score; ESR, erythrocyte sedimentation rate; LDA, low disease activity.
Figure 3
Figure 3. Treatment response and disease activity states at 12 weeks by adalimumab trough level. (A) Improvement in DAS28-ESR from baseline (unadjusted means (95% CI)). (B) European Alliance of Associations for Rheumatology (EULAR) good, moderate, none responders at 12 weeks. (C) Proportion of patients in DAS28-ESR Remission/Low Disease Activity. (D) Median (IQR) change from baseline in C reactive protein levels. Patients are stratified into equal groups with ~42 patients (41–42) in each (the <1.0 mg/L group was defined separately). DAS28, 28-joint Disease Activity Score; ESR, erythrocyte sedimentation rate; CRP, C reactive protein.
Figure 4
Figure 4. Proportion of patients in DAS28-ESR Remission/Low disease activity in patients stratified by adalimumab trough level. (A) Week 24 DAS28-ESR state, by week 12 adalimumab trough level. (B) Week 48 DAS28-ESR state, by week 12 adalimumab trough level. (C) Week 48 DAS28-ESR state, by week 24 adalimumab trough level. (D) Week 48 DAS28-ESR state, by week 48 adalimumab trough level. Patients were stratified into groups to achieve even numbers in each (the <1.0 mg/L group was defined separately); week 12: ~42 patients (41–42) in each. Week 24: <1.0 mg/L group 51 patients, all other groups ~40 patients (37–42) in each. Week 48: <1.0 mg/L group 44 patients, all other groups ~37 patients (35–38) in each. DAS28, 28-joint Disease Activity Score; ESR, erythrocyte sedimentation rate; LDA, low disease activity.
Figure 5
Figure 5. Median (IQR) week 24 C reactive protein levels in groups of patients stratified by week 12 adalimumab trough level.
Figure 6
Figure 6. Alluvial plot showing changes in adalimumab trough levels during the study; weeks 12, 24 and 48.
See this image and copyright information in PMC

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