Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration.We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04).MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.
Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). There is a relationship between adalimumab concentration and clinical response but it has never been quantified individually.
Objectives
To describe the individual relationship between adalimumab concentration and disease activity in RA patients and to select an adalimumab target concentration necessary to reach either a low disease activity or clinical remission.
Methods
We measured adalimumab concentration in 127 samples from 30 RA patients who received 40 mg subcutaneously every other week. Disease activity score (DAS 28) were available at baseline, and at weeks 6, 12, 24 and 52. The relationship between adalimumab concentrations and DAS 28 was described by pharmacokinetic-pharmacodynamic (PK-PD) modelling using a direct inhibitory model.
Results
Median adalimumab concentrations increased over all the year whereas median DAS 28 decreased. At steady state, median adalimumab concentration [min-max] was 7.8 mg/L [1.8-15.0] and median DAS 28 was 2.9 [0.8-6.3]. The concentration-response relationship of adalimumab was well described by the direct inhibitory model. For a typical patient, adalimumab concentration required to decrease baseline DAS28 by 2 was 11.8 mg/L. The relationship between baseline DAS 28 and adalimumab concentration at steady state is displayed in figure 1. It shows that, if baseline DAS 28 is 6, the steady state adalimumab concentration necessary to achieve a low disease activity is 10 mg/L with 25%>75% confidence interval of 5-20 mg/L. To achieve remission, the required adalimumab concentration is 15 mg/L [8-30 mg/L].
Image/graph
Conclusions
This is the first study describing the individual concentration-effect relationship of adalimumab in RA. This model can be used to select the target concentration of adalimumab when therapeutic drug monitoring is applied.
Acknowledgements
Pr. Christian Marcelli. CHU Caen, Pr. René-Marc Flipo. CHU Lille, Pr. Patrice Fardellone. CHU Amiens
Immunogenicity of anti TNF monoclonal antibodies leads to poor or secondary loss of response. Methotrexate reduces anti-drug antibodies (ADA) to adalimumab at week 26 in spondyloarthritis (SpA).1
Objectives:
Herein we sought to examine adalimumab long term persistence in aDA positive versus aDA negative SpA patients.
Methods:
The CoMARIS study (Combination of Methotrexate and adalimumab to Reduce Immunization in patients with axial SpA) is a 26-week prospective, randomised, open-labelled, multicentre study in which patients received adalimumab 40 mg subcutaneously (s.c.) every other week either in combination with MTX 10 mg s.c. For 26 weeks or without MTX. In a post hoc analysis, we reviewed the charts of patients to assess adalimumab persistence. A Cox model analysis was performed to test the following covariates: MTX combination or not, sex, presence of aDA at week 26.
Results:
Data from 104 patients (54 without MTX and 50 with MTX) were reviewed, and time of adalimumab discontinuation was collected. The median time of follow-up was 210.57 weeks. ADA positivity at week 26 was the only covariate associated with adalimumab persistence. The median retention rate of adalimumab in aDA positive patients was 56.9 weeks, as compared with 98.6 weeks in those without aDA (log rank: p=0.015). In the Cox model analysis, the presence of aDA at week 26 increased the risk of adalimumab discontinuation by 1.78 [IC 95%=1.11-2.85], p=0.016.
Conclusion:
Immunogenicity is a key factor that contributes to adalimumab discontinuation in SpA. MTX at initiation may therefore be considered in combination to adalimumab in SpA patients.
References
[1] Ducourau E, et al. Methotrexate reduces adalimumab immunogenicity in patients with spondyloarthritis: a randomized clinical trial. EULAR17-1527.
Acknowledgement:
This work was promoted by the Regional University Hospital Center of Tours and supported by grants from the French Ministry for Health and Sport within the framework of the Programme Hospitalier de Recherche Clinique 2011.
Disclosure of interests:
Marine Samain: None declared, Emilie Ducourau Speakers bureau: BMS and abbvie, theo Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, abbvie, Regeneron, Emmanuelle Dernis: None declared, Fabienne Le Guilchard: None declared, Lucia andras: None declared, aleth Perdriger: None declared, Eric Lespessailles Grant/research support from: Grants/research support from amgen, Eli Lily, MSD, UCB., Consultant for: Consultant for amgen, Expanscience, Eli Lilly, MSD, UCB., antoine Martin: None declared, Grégoire Cormier: None declared, Thomas armingeat: None declared, Valerie Devauchelle-Pensec Grant/research support from: Roche-Chugai, Speakers bureau: MSD, BMS, UCB, Roche, Elisabeth Gervais Speakers bureau: abbvie, BMS, MSD, Pfizer, Roche, UCB, Novartis, Benoit Le Goff Speakers bureau: abbvie, BMS, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB, Novartis, annick de Vries: None declared, Eric Piver: None declared, Gilles Paintaud Grant/research support from: Novartis, Roche Pharma, Sanofi-Genzyme, Chugai, Pfizer and Shire, Céline Desvignes: None declared, David Ternant Speakers bureau: Sanofi, amgen, Hervé Watier: None declared, Philippe Goupille Grant/research support from: Financial compensation received from MSD on a pro-rota basis for participation in Scientific Committee meetings and functions for this study, Speakers bureau: abbvie, Biogaran, BMS, Hospira, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB, Denis Mulleman Speakers bureau: Pfizer, Novartis, Grifols
Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA), but the response is highly variable between patients. Good responders have significantly higher adalimumab serum concentrations than non-responders.1 In a recent issue of the Annals , Pouw et al 2 have proposed a therapeutic cut-off concentration for adalimumab that is predictive of clinical response at a population level but, as for other TNF-α antagonists, no individualised target concentration has been defined to adjust the dose in RA.3
In a post hoc analysis we measured adalimumab concentrations in 127 samples from 30 patients with RA who received 40 mg adalimumab subcutaneously every other week.4 Concomitantly to blood sampling, disease activity score in 28 joints (DAS28) was recorded at baseline and at 6 weeks, 12 weeks, 24 weeks and 52 weeks after treatment initiation. Then, we studied the relationship between adalimumab concentration and DAS28 with a direct Emax inhibition pharmacokinetic-pharmacodynamic model, using Monolix V.3.1 (INRIA, Saclay, France). Emax models are often used to describe the concentration-response relationship, where the ‘quantity’ of response is monotonically related to drug concentration.5 With such a model, the relationship reaches an asymptote for high adalimumab concentrations when DAS28 reaches its minimal value. Estimated baseline DAS28 and adalimumab IC50, that is, adalimumab concentration leading to 50% decrease of baseline DAS28, were 5.7 (coefficient of variation=10%) and 11.8 mg/L (coefficient of variation=75%), respectively. Therefore, for a patient with a median baseline DAS28=5.7, with an adalimumab concentration of 11.8 mg/L, the baseline DAS28 would be decreased twofold (figure 1). The adalimumab target concentration necessary to achieve a …
Biologic Disease Modifying Anti-Rheumatic Drugs (bDMARD) tapering is possible in rheumatoid arthritis (RA) patients in sustained remission. However, only minimal data are available on progressive tapering of non-TNF bDMARD such as tocilizumab (TCZ) or abatacept (ABA).
Objectives:
The TOLEDO (Towards the Lowest Efficacious Dose) trial aimed to assess the impact on disease activity of progressive spacing of TCZ or ABA in RA patients in sustained remission compared to their maintenance at full dose.
Methods:
In this multicenter open-label non-inferiority randomized controlled trial, patients fulfilling ACR-EULAR 2010 criteria for RA were included if they were 1) treated with ABA or TCZ for ≥ 1 year (monotherapy or in combination with csDMARD, corticosteroid allowed at a dose ≤ 5 mg/day), 2) in DAS28VS remission (DAS28 <2.6) for ≥ 6 months and 3) with no X-ray damage progression in the year before inclusion. They were randomized into 2 arms: TCZ or ABA maintenance at full dose or DAS28-driven progressive injection spacing arm adapted in which bDMARD IV or SC injections were progressively spaced out every 3 months according to a predetermined 4-step algorithm up to bDMARD discontinuation at step 4. Spacing was reversed to the previous interval in case of relapse. The primary outcome was the evolution of disease activity according to DAS44 during the 2-year follow-up, which was analyzed with a linear mixed-effect model. Relapse and durable relapse rates (respectively defined as DAS28 > 3.2, and DAS28 >3.2 not recovered at the following visit despite bDMARD escalation at previous step) were also compared between the 2 arms. Analysis were done per protocol (PP) according to a non-inferiority hypothesis (non-inferiority margin at 0.25 for DAS44 and 0.07 for relapse rates).
Results:
117 patients were randomized in Spacing arm and 116 in Maintenance arm (90 and 112 respectively for PP analysis). 165 (72.4%) patients were treated with TCZ and 63 (27.6%) with ABA. At the end of the follow-up in the Spacing arm, 12.4% of patients were able to discontinue their bDMARD (step 4), 38.9% had tapered them (step 1 to 3) and 23.9% needed to go back to initial step (step 0). In terms of disease activity, the non-inferiority of the Spacing strategy in terms of disease activity (DAS44) was not demonstrated for the whole population and the ABA subgroups: slope difference of 11% (95% CI: -9%, 32%) and 37% (95% CI: -4%, 77%) respectively. However, it was satisfied for the TCZ subgroup: slope difference 3% (95% CI: -21%, 27%) (Figure 1). Relapses (Figure 2) were more frequent in the Spacing arm: +45% (95% CI: 32%, 57%), +48% (95% CI: 24%, 71%) and +43% (95%CI: 29%, 58%) in the whole population, ABA and TCZ subgroups respectively. Durable relapses were more frequent in the Spacing arm: +10% (95%CI: 0%, 19%), 16% (95%CI: -5%, 37%) and 7% (95%CI: -3%, 16%) in the whole population, ABA and TCZ subgroups respectively, compared with Maintenance arm.
Conclusion:
The TOLEDO trial generally failed to demonstrate the non-inferiority of the proposed tapering strategy in comparison to maintenance at full dose. However, the non-inferiority was satisfied in terms of disease activity for the TCZ subgroup.
Disclosure of Interests:
Joanna KEDRA: None declared, Philippe Dieudé: None declared, Hubert MAROTTE: None declared, Alexandre Lafourcade: None declared, Emilie Ducourau Speakers bureau: BMS and Abbvie, Thierry Schaeverbeke: None declared, Aleth Perdriger: None declared, Martin SOUBRIER: None declared, Jacques Morel: None declared, Arnaud Constantin: None declared, Emmanuelle Dernis: None declared, Valérie Royant: None declared, Jean-Hugues Salmon Speakers bureau: Janssen Novartis, Thao Pham Speakers bureau: Lilly, Novartis, Jacques-Eric Gottenberg Grant/research support from: Bristol-Myers Squibb, Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Lilly, Pfizer, Sanofi-Genzyme, UCB Pharma, Consultant for: Bristol-Myers Squibb, Eli Lilly, UCB, Sanofi-Genzyme, Pfizer, Edouard Pertuiset: None declared, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Valerie Devauchelle-Pensec Grant/research support from: Roche-Chugai, Speakers bureau: MSD, BMS, UCB, Roche, Philippe Gaudin Speakers bureau: Roche, Chugai, BMS, Abbvie, Servier, Pfizer, MSD, UCB, ESAOTE, Genévrier, Janssen, Novartis, Lilly, Biogen, Amge, Gregoire CORMIER: None declared, Philippe Goupille: None declared, Xavier Mariette Grant/research support from: Servier, Consultant for: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, UCB Pharma, Francis Berenbaum: None declared, Didier Alcaix: None declared, SID AHMED ROUIDI: None declared, Jean-Marie Berthelot: None declared, Agnès Monnier: None declared, Christine Piroth: None declared, Frederic Lioté Grant/research support from: institutional grants from Grunenthal, Ipsen Pharma/Menarini, Novartis, SOBI for the European Crystal Network Workshops, Consultant for: Grunenthal, Novartis, Vincent Goeb: None declared, Cecile Gaujoux-Viala Consultant for: Speaking and/or consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Merck-Serono, Medac, Nordic Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi and UCB Pharma., Speakers bureau: Speaking and/or consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Merck-Serono, Medac, Nordic Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi and UCB Pharma., Isabelle CHARY VALCKENAERE: None declared, David Hajage: None declared, Florence Tubach Grant/research support from: Financial compensation received from MSD on a pro-rota basis for participation in Scientific Committee meetings and functions for this study, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant for: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, Sanofi Genzyme, SOBI, UCB
Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). Subcutaneous injections of adalimumab lead to highly variable trough concentrations between patients [1] that may partly explain the variability of response. To date, adalimumab pharmacokinetics (PK) after subcutaneous route has never been described.
Objectives
The goal of this study is to analyse the quantitative influence of individual factors on adalimumab PK in RA patients.
Methods
One hundred and twenty seven samples from 30 RA patients were used to measure adalimumab concentration [in a post-hoc analysis]. All patients received adalimumab 40 mg subcutaneously every other week. CRP levels and RA disease activity score (DAS28) were available at baseline, weeks 6, 12, 24 and 52. Adalimumab PK was described using a single compartment model with first-order absorption and elimination rates. A population approach was used. Sex, age, body weight, corticosteroid use and CRP levels were tested as covariates on each pharmacokinetic parameter.
Results
The following pharmacokinetic parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd/F) = 12.4 L (75%), apparent clearance (CL/F) = 0.31 L/day (17%) and first-order absorption constant (ka) = 0.41 day-1. Apparent clearance increased with body weight and was higher in men. Age, CRP levels, and concomitant treatment with corticosteroid had no effect on pharmacokinetic parameters. Adalimumab concentrations reached steady state after 20 weeks in men and 28 weeks in women.
Conclusions
Men eliminate adalimumab faster than women and the rate of elimination increases with weight in RA. Monitoring of serum adalimumab concentrations may be useful to avoid underexposure and treatment failure. Time to steady state was long and raises the question of a loading dose of adalimumab at initiation.
References
Bartelds GM et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007; 66(7):921-926.
