You are here

  • Home
  • Archive
  • Volume 10, Issue 4
  • Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial

Article Text

Article menu

Download PDFPDF

Treatments
Original research
Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial
  1. Johanna Elin Gehin1,
  2. Rolf Anton Klaasen1,
  3. Eirik Klami Kristianslund2,
  4. Ingrid Jyssum2,
  5. Joseph Sexton2,
  6. David John Warren1,
  7. Daniel Aletaha3,
  8. Espen Andre Haavardsholm2,4,
  9. Silje Watterdal Syversen2,4,
  10. Guro Løvik Goll2,4 and
  11. Nils Bolstad1
  1. 1Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
  2. 2Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
  3. 3Division of Rheumatology, Medical University of Vienna, Vienna, Austria
  4. 4Faculty of Medicine, University of Oslo, Oslo, Norway
  1. Correspondence to Dr Johanna Elin Gehin; johgeh{at}ous-hf.no

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.

  • Adalimumab
  • Rheumatoid Arthritis
  • Pharmacokinetics

Data availability statement

Data may be obtained from a third party and are not publicly available. Data are available from Sandoz upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2024-004888

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Low serum drug levels are associated with lack or loss of response to tumour necrosis factor inhibitors.

    • In order to individualise adalimumab therapy by therapeutic drug monitoring, the therapeutic range must be identified.

    WHAT THIS STUDY ADDS

    • In this study using longitudinal data from a randomised phase III trial, adalimumab trough levels ≥4.0 mg/L were associated with treatment response, as well as remission and low disease activity later in the disease course.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • The suggested cut-off can guide personalised dosing in clinical practice and clinical trials assessing the effectiveness of therapeutic drug monitoring of adalimumab in rheumatoid arthritis.

    Introduction

    Tumour necrosis factor inhibitors (TNFi) and other biological drugs have revolutionised treatment of rheumatoid arthritis (RA), and remission has become an achievable treatment goal.1 With the introduction of biosimilar medicinal products, and subsequent large cost reductions, access to TNFi has improved.2 3 However, some patients either do not respond adequately to treatment or lose treatment response over time, with the risk of irreversible joint damage and loss of physical function highly affecting quality of life.4–6 Previous studies have demonstrated large variations in drug exposure among patients on the same standard dose,7 8 and lack or loss of effect can be caused by insufficient drug exposure, which is often related to development of neutralising antidrug antibodies (ADAb).9 To ensure sustainable use of TNFi and other biological disease-modifying antirheumatic drugs (DMARDs), strategies to optimise their efficacy are needed. There is increasing evidence that personalised treatment by therapeutic drug monitoring (TDM), that is, dose adjustments guided by serum drug level and presence of neutralising ADAb, can improve treatment with TNFi.9 10 The Norwegian Drug Monitoring Trial demonstrated that a TDM-based treatment strategy was more effective than standard of care in sustaining disease control in maintenance treatment with the TNFi infliximab.11 As highlighted by the European Alliance of Associations for Rheumatology (EULAR) research agenda, prospective studies comparing TDM with usual care are needed for other TNFi as well.12 In order to develop TDM algorithms for use in clinical trials and every-day patient care, the therapeutic range must be identified for each biological drug.12

    The TNFi adalimumab, a fully human monoclonal antibody, is the most widely used biologic drug worldwide. Efficient strategies to optimise its use could improve quality of life and increase access to the drug for millions of patients. However, robust evidence for the therapeutic range is still lacking.12 13 Previous data suggest the lower limit of the therapeutic range for adalimumab in RA is close to 5 mg/L and indicate lack of additional benefit of serum levels above 12 mg/L,7 14–17 but robust evidence is lacking, particularly in the context of a randomised phase III trial.12 This study aims to provide such evidence by analysing longitudinal data from the randomised ADMYRA trial. Data from phase III studies represent a unique opportunity to corroborate the therapeutic ranges suggested in previous studies, enabling future randomised clinical trials to assess TDM-based strategies.

    The main aims of the present study were to identify the lower limit of a therapeutic range for adalimumab conducive to achieve early treatment response and remission later in the disease course, and to assess the consequences of ADAb formation on clinical efficacy in patients with RA.

    Methods

    Study design and population

    ADMYRA (NCT02744755) was a phase III randomised, double-blind, parallel-group, 48-week multicentre trial.18 The trial was conducted from March 2016 to September 2017 in 83 centres in 13 countries including patients with moderate-to-severe active RA with inadequate response to DMARDs, including methotrexate. Eligible patients were randomised 1:1 to receive either GP2017 (Hyrimoz; Sandoz GmbH., Austria) or reference adalimumab (Humira; AbbVie, USA, AbbVie) 40 mg subcutaneously every second week. At week 24 (end of study part 1), patients achieving improvement in 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP) >0.6 points from baseline, continued to part 2 of the study. In part 2 of the study (weeks 24–46), all patients received GP2017. All doses of study drugs were administered at the study site until week 24, and thereafter self-administered by the patients from week 24 to week 46. Blood samples for measurement of adalimumab levels and ADAb were collected as trough levels, that is, prior to administration of study drug, at weeks 2, 4, 12, 24, 36 and 48. The inclusion and exclusion criteria have been described previously.18 Patients were required to have active disease (DAS28-CRP≥3.2) despite treatment with methotrexate, stable dose of methotrexate and systemic glucocorticoids (doses <7.5 mg/daily) prior to baseline, and no prior exposure to adalimumab or other TNFi therapies. Treatment with other biological DMARDs were allowed until 6 months or 5 half-lives before baseline. The present study is a post hoc analysis of data from the ADMYRA study.18 The data were shared by Sandoz, but Sandoz had no role in analysis of data or interpretation of results. In this post hoc analysis, patients with at least one available adalimumab trough level measurement and clinical data recorded at weeks 12, 24 and/or 48 were included. Measurements of trough levels and ADAb from weeks 12, 24 and 48 were assessed in the present analyses. The researchers who conducted the present analyses were blinded regarding treatment with GP2017 or reference adalimumab. Thus, all analyses were performed for adalimumab overall and did not distinguish between GP2017 or reference adalimumab.

    Patient and public involvement

    Patient or public representatives were not involved in the study.

    Clinical disease activity and response measures

    Disease activity was classified according to the DAS28-erythrocyte sedimentation rate (ESR).19 Treatment response was defined by the EULAR response criteria.20 Remission and low disease activity (LDA) were defined as DAS28-ESR <2.6 and ≤3.2, accordingly.21

    Measurement of serum adalimumab levels and antidrug antibodies

    In the ADMYRA trial, adalimumab trough levels were measured using a Sandoz in-house validated ELISA.18 22 In brief, serum samples were incubated in microplate wells coated with TNFα and adalimumab/TNFα-complexes were subsequently determined using an enzyme-labelled secondary antibody. ADAb were assessed by a drug-tolerant electrochemiluminescence (ECLIA) bridging assay including acid dissociation steps. Thereafter, the neutralisation capacity of ADAb was tested with a competitive ligand-binding ELISA assay.

    Statistical analyses

    Correlations between baseline variables and week 12 adalimumab trough levels were assessed by univariable and multivariable linear regression analyses. Associations between adalimumab trough levels and disease activity/response were assessed by explorative concentration–effect analyses and were further evaluated by multivariate linear and logistic mixed models for repeated measures as well as separate models at each time point (weeks 12, 24 and 48). CRP was log-transformed due to skewed distribution. The multivariable models adjusted for age, gender and body weight. Differences in CRP levels in groups stratified by adalimumab trough level were also assessed by independent samples Mann-Whitney U test. Proportions of patients in remission/LDA by ADAb status were compared by χ2 tests. Baseline factors associated with ADAb were assessed by univariable and multivariable logistic regression analyses. Analyses were performed on complete data sets without imputation for missing data. Stratification of patients into groups by adalimumab trough level was tailored to achieve even numbers of patients in each group, with the exception of the <1.0 mg/L group, which was defined separately. Statistical analyses were performed using IBM SPSS Statistics, V.29 (IBM Corp) and Stata V.16 (StataCorp).

    Results

    Study population and baseline characteristics

    In the ADMYRA trial, a total of 353 patients were randomised, whereof 331 patients completed the initial 24-week part of the study and 325 patients entered the second part of the study. Of these, 303 patients completed 48 weeks follow-up.18 Adalimumab trough levels were recorded in 336, 330 and 302 patients, and ADAb were recorded in 337, 327 and 299 patients, at weeks 12, 24 and 48, respectively. Baseline characteristics of the study population are shown in online supplemental table S1. In brief, 295 (84%) patients were females, mean age was 51 years (SD 13), median CRP 6.0 mg/L (IQR 3.0–13.0) and mean baseline DAS28-ESR was 6.6 (SD 0.9). All patients received concomitant treatment with methotrexate at a median weekly dose of 15 mg (IQR 15–20). Of these, one patient received 7.5 mg/week, while all other patients received 10–25 mg/week (online supplemental figure S1). No patients increased their methotrexate dose during the study, while 10 patients decreased the methotrexate dose (by 2.5–15 mg/week). 193 (55 %) patients received concomitant oral glucocorticoids at baseline (median daily dose 5 mg (IQR 4.0–5.5), max dose 16.0 mg daily). The dose of oral glucocorticoids was stable during the study for most of these patients, except in 16 patients who had a dose alteration during the study (seven started treatment with oral glucocorticoids, five increased and four reduced the dose). As described previously, compliance with study treatment was high—75% of patients completed the study receiving all treatments and another 16% of patients missed only one dose in total.18

    Distribution of adalimumab trough levels

    Adalimumab trough levels assessed at weeks 12, 24 and 48 are shown in figure 1. Median 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. Out of the 42 patients with low (<1.0 mg/L) trough levels at week 12, one patient had paused treatment and 33 patients were ADAb positive. At week 24, 52 patients had low levels, whereof three patients had paused, one discontinued treatment and 46 were ADAb positive. At week 48, 50 patients had low levels, whereof one patient had paused, nine discontinued treatment and 41 were ADAb positive. Baseline factors associated with lower week 12 adalimumab trough levels were weight and CRP (online supplemental table S2). An association between baseline methotrexate dose and week 12 adalimumab trough levels could not be shown using these data (online supplemental figure S1).

    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.

    Adalimumab trough levels and association with disease activity

    In serial serum samples collected at weeks 12, 24 and 48, visual assessment of plots (figure 2A,B) indicate that adalimumab trough levels ≥3.9 mg/L were associated with a higher proportion of patients in DAS28-ESR remission and/or LDA (figure 2A) and lower median CRP levels (figure 2B) than trough levels <3.9 mg/L. In longitudinal analyses, the suggested cut-off 3.9 mg/L was supported by multivariable mixed effect regression analyses, that yielded OR 3.88 (95% CI 1.80, 8.38), p<0.001 for DAS28 remission and OR 3.38 (95% CI 1.86, 6.16), p<0.001 for DAS28 LDA in patients with adalimumab trough levels ≥3.9 mg/L versus <3.9 mg/L. Further, adalimumab trough levels ≥3.9 mg/L were negatively associated with log CRP (β −0.62 (95% CI −0.77 to –0.46), p<0.001).

    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.

    Adalimumab trough levels and early treatment response

    As depicted in figure 3A–C, among patients with week 12 adalimumab trough levels up to 7.7 mg/L, higher trough levels were associated with greater mean improvement in DAS28 from baseline (β 0.10 (95% CI 0.04, 0.17), p=0.003) (figure 3A), as well as higher proportions of patients achieving both EULAR good response (OR 1.27 (95% CI 1.11, 1.45), p<0.001) and DAS28 remission (OR 1.22 (95% CI 1.03, 1.43), p=0.02) and/or LDA (OR 1.27 (95% CI 1.11, 1.45), p<0.001) at week 12 (figure 3B,C). There was a trend towards greater reduction in CRP levels from baseline among patients with trough levels ≥1.0 mg/L, compared with <1.0 mg/L (figure 3D), but the difference was not statistically significant (β −0.28 (95% CI −3.98, 3.41), p=0.88).

    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.

    Adalimumab trough levels and later remission/LDA

    As shown in figure 4A,B and table 1, week 12 adalimumab trough levels ≥3.5 mg/L were associated with LDA at week 24 and remission and LDA at week 48. Further, week 24 trough levels ≥4.2 mg/L were associated with remission and LDA at week 48 (figure 4C and table 1).

    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.

    View this table:
    Table 1

    Remission/LDA at weeks 24 and 48 by adalimumab trough level

    Higher week 24 and week 48 adalimumab trough levels were associated with LDA at the concurrent time points (week 48 data shown in figure 4D); OR (per increase in adalimumab unit (mg/L)) 1.07 (95% CI 1.02, 1.12), p=0.003 at week 24 and OR 1.09 (95% CI 1.04, 1.14), p<0.001 at week 48. Week 48 adalimumab trough levels were associated with week 48 remission; OR 1.09 (95% CI 1.04, 1.14), p<0.001, but there was no statistically significant association between adalimumab trough levels and remission at week 24; OR 1.02 (95% CI 0.97, 1.08), p=0.37.

    Furthermore, the median CRP levels at weeks 24 and 48 were significantly lower among patients with week 12 adalimumab trough levels ≥3.5 mg/L, compared with <3.5 mg/L; median 2.5 mg/L (IQR 1.0–4.8) versus 7.0 mg/L (IQR 3.0–12.0), p<0.001 at week 24, and median 3.0 mg/L (IQR 1.0–5.0) versus 6.0 mg/L (IQR 2.3–11.8), p<0.001 at week 48. Week 24 data are shown in figure 5. This was supported by multivariable linear regression analyses showing a negative association between adalimumab trough levels ≥3.5 mg/L and log CRP; β −0.90 (95% CI −1.17 to –0.64), p<0.001 at week 24, and β −0.60 (95% CI −0.86 to –0.33), p<0.001 at week 48.

    Figure 5
    Figure 5

    Median (IQR) week 24 C reactive protein levels in groups of patients stratified by week 12 adalimumab trough level.

    Variation in adalimumab trough levels during follow-up

    To study the variation in serum trough levels over time, adalimumab trough levels were divided into categories (<4.0, 4.0–8.0 and >8.0 mg/L). As depicted in figure 6, most patients stayed within the same category during follow-up. The variation in trough level over time was largest among patients in the middle category (ie, 4.0–8.0 mg/L).

    Figure 6
    Figure 6

    Alluvial plot showing changes in adalimumab trough levels during the study; weeks 12, 24 and 48.

    Antidrug antibodies: influence on treatment response

    After 12 weeks of treatment, 50 patients (15%) had measurable ADAb by drug-tolerant ECLIA assay, whereof 47 were also ADAb positive in the neutralisation assay. Seven patients had transient ADAb (ie, negative at week 24). At weeks 24 and 48, 58 (17%) and 42 patients (14%) had ADAb. At week 12, only 3 out of 50 ADAb-positive patients (6%) were EULAR good responders, compared with 92 of 287 (32%) of ADAb negative (p<0.001). Early ADAb development was also associated with poorer long-term outcomes. The proportions of patients in remission and LDA at weeks 24 and 48 were significantly lower among ADAb-positive than ADAb-negative patients as per weeks 12 and 24 ADAb status (table 2). Among the ADAb-positive patients with concomitant adalimumab trough levels ≥1.0 mg/L, only a few were in remission/LDA. These are described in further detail in the online supplemental appendix.

    View this table:
    Table 2

    Proportion of patients in Remission or Low Disease Activity by ADAb status

    Baseline factors associated with ADAb during weeks 12–48 were CRP and negative rheumatoid factor (online supplemental table S3).

    Discussion

    This post hoc study of longitudinal data from a large, randomised phase III trial in patients with RA with active disease starting treatment with adalimumab indicates that a therapeutic adalimumab level of 4.0 mg/L would be suitable for implementation in clinical trials and clinical practice. This is based on results indicating a therapeutic threshold of 3.9 mg/L in longitudinal analyses as well as the relationship between week 12 trough levels ≥3.5 mg/L and LDA at week 24 and remission and LDA at week 48. The thresholds for drug levels were based on explorative concentration–effect analyses (depicted in figures 2–4) and were further evaluated by regression analyses. The results were consistent across analyses assessing clinical composite disease activity measures as well as CRP. Regarding treatment response at week 12, although no clear cut-off could be identified, higher trough levels were associated with improved treatment responses. ADAb were detected in 15% of patients at week 12. In patients with detectable ADAb at week 12, a lower proportion of patients achieved week 12 EULAR response and were in remission/LDA at weeks 12, 24 and 48, compared with patients without ADAb.

    The therapeutic threshold of 4.0 mg/L is in line with results from previous observational studies in different patient populations and using different methodology for serum drug measurements.7 14–17

    The results from our study, using high-quality longitudinal data from a randomised clinical trial, add independent evidence to corroborate previous findings. This is important, as it allows adoption of a therapeutic threshold in clinical practice and in clinical trials assessing the effect of TDM of adalimumab in patients with RA. Since a large proportion of patient are outside the suggested range when receiving the standard dose, TDM could be implemented to ensure suitable levels.

    In line with previous studies,7 8 our study revealed large variations in serum trough levels between individuals on the same standard dose, indicating a potential for individual dose optimisation to maximise therapeutic responses while reducing risk of side effects and unnecessary costs. The intraindividual variation was modest, and most patients had trough levels within the same category (low, middle, high) during the first year after treatment initiation. The upper limit of the therapeutic range could not be identified, but no clear benefit of serum levels above the suggested therapeutic threshold of 4.0 mg/L was shown. For most patients, it is likely beneficial to aim for serum levels above but close to 4.0 mg/L. However, we cannot exclude that some patients and clinical situations might benefit from higher levels. As illustrated in figure 3, some patients did not respond adequately to treatment despite drug levels above the therapeutic threshold. These patients were likely to have a primary treatment failure, that is, a mismatch between the target molecule of the drug and key disease mediators, and would likely benefit from switching treatment rather than increasing the dose of adalimumab. This illustrates the potential of TDM in guiding of treatment decisions.

    A drug-tolerant ECLIA assay was used to detect ADAb in this study. This could affect the proportion of patients with detectable ADAb, with the risk of also detecting ADAb of low clinical relevance.9 However, the proportion of patients with detectable ADAb after 12 weeks of treatment (15%) was comparable to a previous observational study that detected ADAb in 10% of patients using a drug sensitive assay.7 Due to different study populations and assays, the proportion of patients reported with detectable antiadalimumab antibodies range between 0% and 50% in RA.9 The observed negative clinical implications of ADAb, that is, lower proportion of patients who responded to treatment, was also in line with previous studies.23 24

    In contrast to previous studies,15 25 we were unable to find an association between methotrexate dose and adalimumab trough levels in our study. We believe that this was a result of the uniform use of relatively high methotrexate doses in this study compared with previous studies,15 25 as all except one patient were on a weekly dose of 10 mg or higher. Thus, it was not possible to study the effect of methotrexate use versus no use or different methotrexate doses on trough levels or ADAb formation in our study.

    Strengths of the current study include the use of high-quality data from a randomised clinical trial with a high retention rate. Bias due to lack of adherence to treatment was unlikely to be a concern in this trial, especially as treatment was administered by study personnel up to week 24 and compliance with study treatment was high among the patients who completed the study. Access to longitudinal trough levels and clinical data was another strength of our study. The use of an objective marker of inflammation, that is, CRP, in addition to conventional clinical disease activity measures was also a strength. On the other hand, the use of a study population with relatively stringent inclusion and exclusion criteria could limit the external validity of our results. The current study was not suited to study the effect of methotrexate and methotrexate dose on drug levels and ADAb formation.

    In conclusion, adalimumab levels above 4.0 mg/L were associated with better treatment response and remission and can be used as a lower therapeutic target level for TDM of adalimumab therapy. The clinical value of the therapeutic target level needs to be explored in a randomised clinical trial assessing the effectiveness and cost-effectiveness of TDM in treatment with adalimumab.

    Data availability statement

    Data may be obtained from a third party and are not publicly available. Data are available from Sandoz upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study protocols of the ADMYRA trial were approved by the Independent Ethics Committee or Institutional Review Board for each centre. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank Sandoz for providing the data from the ADMYRA phase III study for this study.

    References

    1. ↵
      1. Smolen JS,
      2. Landewé RBM,
      3. Bergstra SA, et al
      . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023;82:3–18. doi:10.1136/ard-2022-223356
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Kvien TK,
      2. Patel K,
      3. Strand V
      . The cost savings of biosimilars can help increase patient access and lift the financial burden of health care systems. Semin Arthritis Rheum 2022;52:151939. doi:10.1016/j.semarthrit.2021.11.009
      OpenUrl
    3. ↵
      1. Goll GL,
      2. Kvien TK
      . Improving patient access to biosimilar tumor necrosis factor inhibitors in immune-mediated inflammatory disease: lessons learned from Norway. Expert Opin Biol Ther 2023;23:1203–9. doi:10.1080/14712598.2023.2273938
      OpenUrl
    4. ↵
      1. Arora A,
      2. Mahajan A,
      3. Spurden D, et al
      . Long-Term Drug Survival of TNF Inhibitor Therapy in RA Patients: A Systematic Review of European National Drug Registers. Int J Rheumatol 2013;2013:764518. doi:10.1155/2013/764518
    5. ↵
      1. Movahedi M,
      2. Hepworth E,
      3. Mirza R, et al
      . Discontinuation of biologic therapy due to lack/loss of response and adverse events is similar between TNFi and non-TNFi class: Results from a real-world rheumatoid arthritis cohort. Semin Arthritis Rheum 2020;50:915–22. doi:10.1016/j.semarthrit.2020.06.020
      OpenUrl
    6. ↵
      1. van Mulligen E,
      2. Weel A,
      3. Kuijper TM, et al
      . The impact of a disease flare during tapering of DMARDs on the lives of rheumatoid arthritis patients. Semin Arthritis Rheum 2020;50:423–31. doi:10.1016/j.semarthrit.2020.02.011
      OpenUrl
    7. ↵
      1. Jyssum I,
      2. Gehin JE,
      3. Sexton J, et al
      . Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases. Rheumatology (Oxford) 2024;63:1746–55. doi:10.1093/rheumatology/kead525
      OpenUrl
    8. ↵
      1. l’Ami MJ,
      2. Krieckaert CL,
      3. Nurmohamed MT, et al
      . Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis 2018;77:484–7. doi:10.1136/annrheumdis-2017-211781
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Gehin JE,
      2. Goll GL,
      3. Brun MK, et al
      . Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs 2022;36:731–48. doi:10.1007/s40259-022-00559-1
      OpenUrlCrossRefPubMed
    10. ↵
      1. Syversen SW,
      2. Gehin JE,
      3. Goll GL, et al
      . Therapeutic Drug Monitoring: A Tool to Optimize Treatment of Inflammatory Joint Diseases. Arthritis Rheumatol 2024;76:667–9. doi:10.1002/art.42764
      OpenUrl
    11. ↵
      1. Syversen SW,
      2. Jørgensen KK,
      3. Goll GL, et al
      . Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA 2021;326:2375–84. doi:10.1001/jama.2021.21316
      OpenUrlCrossRefPubMed
    12. ↵
      1. Krieckaert CL,
      2. van Tubergen A,
      3. Gehin JE, et al
      . EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases. Ann Rheum Dis 2023;82:65–73. doi:10.1136/annrheumdis-2022-222155
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Krieckaert C,
      2. Hernández-Breijo B,
      3. Gehin JE, et al
      . Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: a systematic literature review informing EULAR points to consider. RMD Open 2022;8:e002216. doi:10.1136/rmdopen-2022-002216
    14. ↵
      1. Hum RM,
      2. Ho P,
      3. Nair N, et al
      . Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis. Rheumatology (Oxford) 2023;62:2090–7. doi:10.1093/rheumatology/keac564
      OpenUrl
    15. ↵
      1. Goss SL,
      2. Klein CE,
      3. Jin Z, et al
      . Methotrexate Dose in Patients With Early Rheumatoid Arthritis Impacts Methotrexate Polyglutamate Pharmacokinetics, Adalimumab Pharmacokinetics, and Efficacy: Pharmacokinetic and Exposure-response Analysis of the CONCERTO Trial. Clin Ther 2018;40:309–19. doi:10.1016/j.clinthera.2018.01.002
      OpenUrl
    16. ↵
      1. Chen D-Y,
      2. Chen Y-M,
      3. Hsieh T-Y, et al
      . Drug trough levels predict therapeutic responses to dose reduction of adalimumab for rheumatoid arthritis patients during 24 weeks of follow-up. Rheumatology (Sunnyvale) 2016;55:143–8. doi:10.1093/rheumatology/kev298
      OpenUrl
    17. ↵
      1. Pouw MF,
      2. Krieckaert CL,
      3. Nurmohamed MT, et al
      . Key findings towards optimising adalimumab treatment: the concentration-effect curve. Ann Rheum Dis 2015;74:513–8. doi:10.1136/annrheumdis-2013-204172
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Wiland P,
      2. Jeka S,
      3. Dokoupilová E, et al
      . Switching to Biosimilar SDZ-ADL in Patients with Moderate-to-Severe Active Rheumatoid Arthritis: 48-Week Efficacy, Safety and Immunogenicity Results From the Phase III, Randomized, Double-Blind ADMYRA Study. BioDrugs 2020;34:809–23. doi:10.1007/s40259-020-00447-6
      OpenUrl
    19. ↵
      1. Prevoo MLL,
      2. Van’T Hof MA,
      3. Kuper HH, et al
      . Modified disease activity scores that include twenty-eight-joint counts development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. doi:10.1002/art.1780380107
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. van Gestel AM,
      2. Haagsma CJ,
      3. van Riel PLCM
      . Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 1998;41:1845–50. doi:10.1002/1529-0131(199810)41:10<1845::AID-ART17>3.3.CO;2-B
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Fransen J,
      2. Creemers MC,
      3. Riel PL
      . Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatol (Sunnyvale) 2004;43:1252–5. doi:10.1093/rheumatology/keh297
      OpenUrl
    22. ↵
      1. Guerrieri D,
      2. Horvat M,
      3. Fan J, et al
      . Signal-to-noise ratio to assess magnitude, kinetics and impact on pharmacokinetics of the immune response to an adalimumab biosimilar. Bioanalysis 2024;16:33–48. doi:10.4155/bio-2023-0152
      OpenUrl
    23. ↵
      1. Thomas SS,
      2. Borazan N,
      3. Barroso N, et al
      . Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs 2015;29:241–58. doi:10.1007/s40259-015-0134-5
      OpenUrlCrossRefPubMed
    24. ↵
      1. Strand V,
      2. Balsa A,
      3. Al-Saleh J, et al
      . Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs 2017;31:299–316. doi:10.1007/s40259-017-0231-8
      OpenUrlCrossRef
    25. ↵
      1. Krieckaert CL,
      2. Nurmohamed MT,
      3. Wolbink GJ
      . Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012;71:1914–5. doi:10.1136/annrheumdis-2012-201544
      OpenUrlFREE Full Text

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • EAH, SWS, GLG and NB are joint senior authors.

    • X @siljews

    • Contributors Study design: JEG, RAK, EKK, IJ, EAH, SWS, GG and NB. Data analysis: JEG, RAK and JS. Manuscript preparation: JEG and RAK. Critical revision of the manuscript: RAK, EKK, IJ, JS, DJW, DA, EAH, SWS, GG and NB. All authors have approved the final manuscript. JEG is the guarantor of this work.

    • Funding This project has received funding from the European Union’s Horizon Europe research and innovation program under grant agreement No 101095052 for data analyses and manuscript preparation. The ADMYRA study was funded by Hexal AG, a Sandoz company. Sandoz provided the data from the ADMYRA study for the present analyses, and has reviewed the manuscript for accuracy and completeness, but had no influence on and did not provide funding for the data analysis or presentation of results.

    • Disclaimer Views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the granting authority can be held responsible for them.

    • 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.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.