Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial

l’Ami, M.; Krieckaert, C.; Nurmohamed, Michael T.; Vollenhoven, Ronald F. van; Rispens, Theo; Boers, Maarten; Wolbink, Gertjan

doi:10.1136/annrheumdis-2017-211781

Cited by 63 publications

(61 citation statements)

References 18 publications

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“…A recent systematic review found very limited and low‐quality information on potential markers for successful dose reduction or discontinuation of biologic agents in RA . Some studies with adalimumab have suggested that a higher trough level of adalimumab may be a good marker for reducing the dose; however, in our study, we did not determine drug serum levels .…”

Section: Discussionmentioning

confidence: 72%

Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis in Clinical Remission: A Randomized, Open‐Label Trial

Sanmarti

Veale

Martı́n-Mola

et al. 2019

Arthritis & Rheumatology

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Objective. To evaluate the efficacy and safety of increasing the dose interval of subcutaneous tocilizumab (TCZ-SC) in patients with rheumatoid arthritis (RA) who are in clinical remission.Methods. RA patients with active disease and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or to a biologic agent were entered into a single-arm treatment phase with 162 mg of TCZ-SC administered once weekly (TCZ-SC 162 mg qw) as monotherapy or in combination with a csDMARD for 24 weeks. Patients who achieved clinical remission at weeks 20 and 24 were randomized to continue with the same regimen or to switch to 162 mg TCZ-SC administered every 2 weeks (TCZ-SC 162 mg q2w) for 24 weeks (open-label). Patients with a Disease Activity Score in 28 joints (DAS28) of <2.6 were considered to be in clinical remission.Results. In total, 179 (45%) of 401 patients in the single-arm phase achieved clinical remission and were randomized to continue to receive TCZ-SC 162 mg qw (n = 89) or to switch to TCZ-SC 162 mg q2w (n = 90) for 24 weeks. At week 48, significantly more patients treated with TCZ-SC 162 mg qw remained in clinical remission compared to patients who received TCZ-SC 162 mg q2w (90% versus 73%; P = 0.004). The results of other efficacy measures revealed greater efficacy with TCZ-SC 162 mg qw, but none of the efficacy outcomes in this group were significantly different from those in patients treated with TCZ-SC 162 mg q2w, except for the mean change from baseline in the DAS28 score at week 48 (mean change −4.07 points [SD 1.29] versus −3.65 points [SD 1.35]; P = 0.034). Tolerability and safety parameters were similar between the treatment groups.Conclusion. Increasing the dose interval of TCZ-SC in patients with RA was associated with a lower likelihood of maintaining remission after 24 weeks and was not associated with better tolerability. However, most patients were able to sustain remission with a half-dose of TCZ-SC, and therefore this strategy deserves further investigation.

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Section: Discussionmentioning

confidence: 72%

Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis in Clinical Remission: A Randomized, Open‐Label Trial

Sanmarti

Veale

Martı́n-Mola

et al. 2019

Arthritis & Rheumatology

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“…In this case, the assay analyte will not be detectable and the complex should first be dissociated to make the analyte accessible for detection. L'Ami et al showed that quantitation of the therapeutic anti-TNF-α antibody, adalimumab, can be used to determine dosing intervals and to individualize disease control in patients with rheumatoid arthritis [20]. We integrated an acidification step into the ELISA assay, and in this way increased tolerability towards high concentrations of drug and/or ADA.…”

Section: Discussionmentioning

confidence: 99%

“…and simultaneously increase therapeutic effectiveness [19]. L'Ami et al showed that quantitation of the therapeutic anti-TNF-α antibody, adalimumab, can be used to determine dosing intervals and to individualize disease control in patients with rheumatoid arthritis [20]. This approach requires reliable drug quantitation, even in the presence of nADA.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity assay development and validation for biological therapy as exemplified by ustekinumab

Poor

Ulshöfer

Gabriel

et al. 2019

Clinical and Experimental Immunology

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Introduction of biotherapeutics has been a major milestone in the treatment of different chronic diseases. Nevertheless, the immune system can recognize the administered biological as non-self and respond with generation of anti-drug antibodies (ADA), including neutralizing ADA (nADA). Immunogenic responses may result in altered drug dynamics and kinetics leading to changes in safety and efficacy. However, there are several challenges with standard techniques for immunogenicity testing. Ustekinumab (UST), used in different inflammatory diseases, is a therapeutic antibody directed against the shared p40 subunit of interleukin (IL)-12 and IL-23, interfering in the pathogenically crucial T helper type 1 (Th1)/Th17 pathway. We established and validated different approaches for detection and quantitation of UST, UST-specific ADA and nADA. Addressing the obstacle of complex formation of UST with nADA, we developed an acidification assay to approach the total amount of nADA. Validated methods were based on surface plasmon resonance spectroscopy (SPR), enzyme-linked immunosorbent assay (ELISA) and a cell-based approach to characterize neutralizing capacity of nADA. Parameters assessed were determination and quantitation limits, linearity, range, precision, accuracy and selectivity. Quantitation of ADA and UST was feasible at lower concentrations using ELISA, whereas SPR showed a wider linear range for determination of ADA and UST. Accuracy, precision and linearity for quantitation were comparable using ELISA, SPR and the cell-based approach. All validated parameters fulfill the requirements of regulatory agencies. A combination of the testing approaches could address the increasing demand of precision medicine as it can be suitable for capturing the whole spectrum of immunogenicity and is transferable to other biologicals.

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“…We have read the recent paper of l‘Ami et al titled ‘Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial’ with interest 1. The topic of dose tapering is an important one and we welcome all research efforts in this field, especially controlled trials.…”

mentioning

confidence: 99%

Comment on l’Ami et al titled ’Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial'

Broeder

Bemt

2017

Ann Rheum Dis

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Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial

Abstract: NTR3509; Results.

Cited by 63 publications

References 18 publications

Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis in Clinical Remission: A Randomized, Open‐Label Trial

Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis in Clinical Remission: A Randomized, Open‐Label Trial

Immunogenicity assay development and validation for biological therapy as exemplified by ustekinumab

Comment on l’Ami et al titled ’Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial'

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