SAT0185 Certolizumab pegol serum levels ≥20 mg/l are associated with improvement in das28 in rheumatoid arthritis patients. data from the nor-dmard study
Johanna Elin GehinSilje Watterdal SyversenD. J. WarrenGuro Løvik GollJ. SextonEldri Kveine StrandTore K KvienNils BolstadE. Lie
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Abstract:
Background:
Measurement of serum drug levels can help clinicians tailor treatment with TNF-inhibitors. An association between certolizumab pegol (CP) serum levels and treatment response in rheumatoid arthritis (RA) patients (pts) has previously been demonstrated in a prospective observational study (1). These results need to be confirmed in other studies, with particular focus on finding an optimal therapeutic serum level for CP.Objectives:
To examine the association between serum CP drug levels and treatment response in RA pts and to identify a therapeutic target level.Methods:
Patients with a clinical diagnosis of RA starting standard treatment with CP included in the NOR-DMARD registry with biobank sample at 3 months follow-up, were included in the present analyses. Serum drug levels (non-trough) were analysed with an in-house immunofluorometric assay automated on the AutoDELFIA immunoassay platform. We studied association between serum CP level and &x25B3;DAS28 and EULAR good/moderate response at 3 months by multivariable linear and logistic regression analyses, respectively, adjusting for age, sex and prior bDMARD (Y/N).Results:
In 91 included patients, median serum drug level at 3 months follow up was 34.7 mg/L (17.6–44.6). Response data were available in 81/91 patients. Serum CP level ≥20 mg/L was associated with greater improvement in DAS28 at 3 months (β=0.89 (95% CI 0.03–1.74), P=0.04. 44.4 % of pts with CP level <20 mg/L achieved EULAR response after 3 months treatment, while 73.5 % of pts with CP level 20–40 mg/L and 55.2 % with ≥40 mg/L were responders. However, the difference in EULAR response between pts with CP level ≥20 vs. <20 mg/L did not reach statistical significance (OR 1.5 (95% CI 0.5–5.1), P=0.48).Conclusions:
Certolizumab serum levels ≥20 mg/L were associated with DAS28 improvement, but not significantly with EULAR response after 3 months treatment in RA pts. We suggest 20 mg/L as a lower target limit for non-trough CP samples in RA-patients. No additional benefit of having a certolizumab level over 40 mg/L was observed.Reference
[1]Jani M, et al. AnnRheum Dis2017;76(1):208–13.Disclosure of Interest:
J. E. Gehin Consultant for: Roche, S. Syversen Consultant for: Roche, D. Warren: None declared, G. Goll Consultant for: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, J. Sexton: None declared, E. Strand Consultant for: Pfizer, T. Kvien Consultant for: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Epirus, Hospira, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, UCB, N. Bolstad Consultant for: Pfizer, Orion Pharma, Napp pharmaceuticals, Takeda, Roche, E. Lie: None declaredKeywords:
Certolizumab pegol
Therapeutic Drug Monitoring
Biological therapy (infliximab and adalimumab) in inflammatory bowel diseases is based on the IgG1 anti-TNF monoclonal antibodies with potent anti-inflammatory effects whose main mechanism of action is thought to be the induction of inflammatory cell apoptosis. Unquestionably, which arises from the most recent studies and meta-analysis, anti-TNF angents are an effective therapy primarily for the treatment of Crohn's disease, but also ulcerative colitis, in different clinical situations. Infliximab has the most extensive clinical trial data, but other biological agents, such as adalimumab and certolizumab pegol appear to have similar benefits. In terms of future research, more long-term data are needed for both certolizumab pegol in Crohn's disease and adalimumab in ulcerative colitis. Important role in the application of biological therapy is assessing its effectiveness and cost-benefit relationships that are estimated by regular follow-up. In the absence of response (primary and secondary) therapeutical options are dose increase, giving the drug in shorter intervals and substitution with other biological drug.
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Anti-tumour necrosis factor (TNF) agents are recommended as second-line therapy for patients with axial spondyloarthropathies. This analysis reviewed data on studies investigating the efficacy and tolerability of anti-TNF agents in patients with non-radiographic axial spondyloarthritis (nr-axSpA) who had failed first-line non-steroidal anti-inflammatory (NSAID) treatment. Efficacy data from RCTs were used to calculate the number needed to treat (NNT) for individual anti-TNFs and then the cost per responder was determined to provide an indication of the value of each therapy. A systematic literature review and analysis of search results over the period January 2008 to September 2014 identified four randomised placebo-controlled trials that were included in the analysis. Adalimumab, etanercept and certolizumab pegol were all effective and well tolerated in patients with nr-axSpA. A patient was more likely to reach ASAS20 or ASAS40 when treated with etanercept or adalimumab, the NNT was lowest for adalimumab, and the risk of adverse events was higher with certolizumab pegol 200 mg every 2 weeks. The cost per responder (NNT) was lowest for adalimumab, followed closely by certolizumab 400 mg every 4 weeks, intermediate for certolizumab 200 mg every 2 weeks and highest for etanercept. Although all anti-TNF agents were associated with clinical improvement in patients with nr-axSpA, adalimumab presented a better cost per responder than etanercept and certolizumab pegol.
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Our aim was to identify and compare the effectiveness of antitumor necrosis factor biologics when used as initial agents and when used in succession for the treatment of moderate to severe Crohn's disease (CD).Studies directly comparing the efficacy of biologics are lacking. When one biologic loses efficacy, patients are often treated with an alternate biologic. The effectiveness of this strategy has not been thoroughly investigated.This is a retrospective cohort study from a database of 153 patients with CD treated with infliximab, adalimumab, or certolizumab pegol. Response rates determined by physician global assessment were compared between biologics when given as initial agents and after failure of 1 or 2 prior biologics.There were no significant differences in response between infliximab (64.5%), adalimumab (60.0%), and certolizumab pegol (66.7%) when given as initial biologics. As second-line or third-line agents after prior biologic failure, there was a trend toward increased response with infliximab (83.3%) versus adalimumab (52.7%) and certolizumab pegol (59.4%); however, this did not meet statistical significance. After failure or loss of response of 2 previous biologics, use of a third biologic was still effective with a response rate of 54.2%.All 3 biologics have similar efficacy in the treatment of CD when given as initial agents. Infliximab has a trend toward increased response after prior biologic failure; however, this did not meet statistical significance. Even after loss of response or failure of 2 previous biologics, trial of a third alternate biologic is an effective strategy.
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The introduction of biological tumor necrosis factor (TNF)-α inhibitors has transformed the paradigm for the treatment of inflammatory bowel disease (IBD), i.e. Crohn's disease and ulcerative colitis. The specific TNF inhibitors currently approved for patients with IBD are infliximab, adalimumab and certolizumab pegol for Crohn's disease refractory to conventional treatment and infliximab, adalimumab, and golimumab for ulcerative colitis. Additionally, many patients with IBD have extraintestinal manifestations, and biological TNF inhibitors have also been shown to be of therapeutic benefit for these patients. The present chapter highlights these indications.
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Abstract Background Clinical application of therapeutic drug monitoring (TDM) to optimise anti‐TNF therapies in patients with IBD depends upon target ranges. Aims To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab. Methods A systematic review was performed, and relevant literature was summarised and critically examined. Results Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area‐under‐receiver‐operator‐curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end‐points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8‐5.7 µg/mL are reported depending upon end‐points used, with consistent AUROC 0.68‐0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9‐11.8 µg/mL (AUROC 0.66‐0.83) in some studies, but no cut‐off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design. Conclusions Evidence for exposure‐response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.
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Biological agents for the treatment of rheumatic diseases have made a major breakthrough over the past decade.Since the discovery of adalimumab,a tumor necrosis factor(TNF)-α inhibitor,the rheumatoid arthritis therapy has been made significant progress.This article reviews related progress in the treatment of rheumatoid arthritis with adalimumab.
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Abstract Background The therapeutic landscape for inflammatory bowel disease (IBD) has expanded in recent years. The anti-TNF drug adalimumab remains one of the most commonly prescribed treatments. However, rates of loss of response to adalimumab are significant. Therapeutic Drug Monitoring (TDM) has emerged as a tool to prevent loss of response to treatment but there is no consensus on the optimum TDM testing strategy., 2 testing strategies are commonly used - proactive TDM (pTDM), performed during sustained clinical response and reactive TDM (rTDM), performed following loss of response. The aim of this work was to compare adalimumab drug levels (DL) and drug survival (DS) for patients exposed to pTDM compared to rTDM testing strategies. Methods Data for patients with IBD, treated with adalimumab, and exposed to TDM, was extracted from the Scottish Biologic TDM database. Patients were assigned to pTDM or rTDM groups based on the indication of their first TDM test. Prescribing information was extracted from the NHS Scotland Safe Haven homecare prescribing database. Homecare delivery dates were used to infer start and end dates of adalimumab treatment. Where adalimumab start date was before, 2017, a start date of, 1/1/2017 was used to coincide with the introduction of the Scottish TDM service. The study period was, 1/1/2017 to, 1/3/2020 giving a maximum duration of drug exposure of, 38 months. The most recent drug level was used for each patient to reflect the impact of the TDM strategy employed. SPSS was used to perform statistical analysis. Results 367 patients were included for analysis, 190 males and, 177 females, 262 with Crohn’s disease and, 105 with Ulcerative Colitis., 314 patients were assigned to the pTDM group, and, 53 to the rTDM group. The mean DL across both groups was, 9.5 mcg/ml, with no significant difference seen between pTDM and rTDM groups (p=0.642). Median DS in the pTDM group was, 21 months versus, 15.6 months in the rTDM group. 277 patients (75.5%) remained on treatment at the end of the study, 244 (77.7%) in the pTDM group, versus, 33 (62.3%) in the rTDM group. DS was significantly higher in the pTDM group compared to the rTDM (p=0.004) group (Fig., 1), with divergence of the survival curve seen after, 6 months. Conclusion pTDM has been clearly favoured by clinicians from the outset of the TDM service. Whilst our data shows that DLs do not vary significantly between TDM groups, importantly, the DS with adalimumab is longer with pTDM as part of routine clinical care, when compared to rTDM. Further evaluation of clinical outcomes including steroid prescription, hospital admissions and surgery rates in the context of pTDM and rTDM strategies is therefore warranted, and in progress.
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Background: Therapeutic drug monitoring (TDM) measuring drug trough levels (TL) and antidrug antibodies (ADA) may aid the therapeutic decision in patients with inflammatory bowel disease (IBD) who loose response to anti-TNF therapy. Our aim was to evaluate the frequency and predictive factors of loss of response to adalimumab therapy and the role of the therapeutic drug monitoring to predict the loss of response in adalimumab treated IBD patients. Methods: 112 IBD patients (with 214 TDM measurements, CD/UC 84/28, male/female 50/62, mean age CD/UC: 36/35 years, mean duration of adalimumab therapy CD/UC: 157.8/70.1 weeks) were enrolled in this consecutive cohort from two referral IBD centres in Hungary. Demographic data were comprehensively collected and a harmonized monitoring strategy was applied. Previous and current therapy, laboratory data and clinical activity at the time of the TL and ADA measurement were recorded. Patients were evaluated either at the time of suspected LOR or during follow-up. TDM measurements were done by commercial ELISA (LISA TRACKER, Theradiag, France). Results: Among 112 IBD patients, LOR/drug persistence was 25.9%/74.1%.The probability of ADA positivity and low TL (<4.0 μg/mL) was 12.1% and 17.8% in the first year and 17.3% and 29.5% and in the second year after start of adalimumab therapy in Kaplan-Meier analysis. Dose intensification was needed in 29.5% during the study period. There was an association between female gender, ADA positivity and LOR (female gender: p<0.001, OR: 7.770 CI95%: 2.483–24.315, ADA positivity: p=0.007 OR: 3.616 CI95%: 1.374–9.518)), while no other parameters, including TL was associated with LOR or dose intensification. Table 1. ADA and TL status in IBD patients treated with adalimumab Conclusions: Our results suggest that ADA development, low TL and need for dose intensification are frequent during adalimumab therapy and support the use of routine TDM assessment in IBD patients. Female gender, and ADA positivity were predictors of loss of response.
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Concomitant
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To compare the cost of treating rheumatoid arthritis, psoriasis and Crohn’s disease with adalimumab compared with selective immunosuppressive cytokines blockers and inhibitors of tumor necrosis factor-alpha. We conducted a through systemic review of the literature and compared data from adalimumab with etanercept, abatacept, infliximab, tocilizumab, certolizumab pegol and golimumab in treating rheumatoid arthritis, with etanercept, infliximab, and ustekinumab in the treatment of plaque psoriasis, and with infliximab and certolizumab pegol in the treatment of Crohn’s disease. A cost minimization analysis was then considered appropriate under the perspective of a private health care provider in Mexico and a time horizon of five years. The costs of medication and application (2014) were considered. It has been assumed that patients have a weight of 70 kg based on the National Health and Nutrition Survey 2012 and a discount rate of 5% was applied. Adalimumab proved to be less expensive in the base case against considered alternatives. The total discounted cost of using adalimumab for 5 years for rheumatoid arthritis was $ 1,030,807.61 (followed by abatacept -$1,032,233.83- and certolizumab -$1,093,401.30-); in the case of psoriasis was $ 1,047,883.48 (followed by ustekinumab -$1,210,738.82- and etanercept -$1,237,387.15-); for Crohn’s disease was $ 1,072,947.28 (followed by infliximab -$1,353,574.18- and certolizumab -$2,091,555.72-). Treatment with adalimumab incurs lower costs compared with etanercept, abatacept, infliximab, tocilizumab, certolizumab pegol and golimumab in treating rheumatoid arthritis; etanercept, infliximab, and ustekinumab in the treatment of psoriasis and certolizumab pegol and infliximab in treating Crohn’s disease. Further budget impact and probabilistic sensitivity analyses could provide additional information about these alternatives.
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