Dataset Information

Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis.

ABSTRACT:

Background

The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept (ETN) dose maintenance, reduction or withdrawal on patients with rheumatoid arthritis (RA) who had already achieved stable low disease activity (LDA) on ETN 50 mg+methotrexate (MTX).

Methods

Patients with RA (n=91) and stable LDA with ETN 50 mg once weekly (QW)+MTX were included. After 8 weeks with unchanged treatment, 73 patients were randomised in a double-blind design to ETN 50 mg QW+MTX (ETN50), ETN 25 mg QW+MTX (ETN25) or placebo QW+MTX (PBO) for 48 weeks. Patients who flared were declared failures and treated with open-label ETN50 until week 48. The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks.

Results

The proportion of non-failure patients was significantly lower with ETN50 (52%; p=0.007) and ETN25 (44%; p=0.044) versus PBO (13%). Median time to failure was significantly shorter with PBO (6 weeks) compared with ETN50 (48 weeks; p=0.001) and ETN25 (36 weeks; p<0.001). The majority of patients who flared regained LDA with open-label ETN50 quickly. Adverse events were consistent with the known side effect profiles of these medications.

Conclusions

In patients with established RA who have achieved stable LDA on ETN50+MTX, continuing both is superior to PBO+MTX. Reduced dose ETN was also more effective than PBO in maintaining a favourable response, suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA.

Trial registration number

NCT00858780.

SUBMITTER: van Vollenhoven RF

PROVIDER: S-EPMC4717401 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis.

van Vollenhoven Ronald F RF Østergaard Mikkel M Leirisalo-Repo Marjatta M Uhlig Till T Jansson Marita M Larsson Esbjörn E Brock Fiona F Franck-Larsson Karin K

Annals of the rheumatic diseases 20150414 1

<h4>Background</h4>The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept (ETN) dose maintenance, reduction or withdrawal on patients with rheumatoid arthritis (RA) who had already achieved stable low disease activity (LDA) on ETN 50 mg+methotrexate (MTX).<h4>Methods</h4>Patients with RA (n=91) and stable LDA with ETN 50 mg once wee ...[more]

PMID: 25873634

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Project description:IntroductionThe therapy of rheumatoid arthritis (RA) was advanced by biological agents, yet costly. This study aims to identify the effective threshold dose of etanercept (ENT) and cost-effectiveness in methotrexate (MTX)-resistant RA in real world.MethodsEligible patients had an inadequate response (DAS28-ESR > 3.2) to initial MTX monotherapy, and subsequently received etanercept. The effective cut-off value of cumulative dose was identified to maintain remission response (DAS28-ESR < 2.6) at month 24 by using restricted cubic splines. Remission rate, low disease activity (LDA) rate, glucocorticoid exposure, safety, and cost-effectiveness were compared between the saturated and non-saturated dose groups divided by the cut-off dose.ResultsSeventy-eight (14.2%) of 549 enrolled patients were eligible, and 72 patients completed follow-up. The 2-year cumulative cut-off dose that maintained remission response at 24 months was 1975 mg. And the recommended threshold dosing strategy of etanercept was twice weekly (BIW) for the first 6 months, every week (QW) for the next 6 months, and every 2 weeks (Q2W) and every month (QM) for the second year. Greater net changes in DAS28-ESR score were observed in the ENT saturated dose group than in the non-saturated dose group (average change 0.569, 95%CI 0.236-0.901, p = 0.001). The proportion of patients achieving remission (27.8% vs 72.2%, p < 0.001) and LDA (58.3% vs 83.3%, p = 0.020) in the non-saturated group was both significantly lower than that in the saturated group at 24 months. The incremental cost-effectiveness ratio of the saturated group referred to the non-saturated group was 5791.2 $/QALY.ConclusionsIn refractory RA patients, the effective cumulative cut-off dose of etanercept for sustained remission at 24 months was calculated as 1975 mg, and receiving saturated dose was more effective and cost-effective than with non-saturated dose. Key Points • The effective cumulative cut-off dose of etanercept for sustained remission at 24 months in RA patients is calculated as 1975 mg. • Receiving saturated dose of etanercept is more effective and cost-effective than with non-saturated dose in refractory RA patients.

Project description:ObjectivePatients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination.MethodsOf the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24-week open-label period. These 253 patients then entered a 48-week, double-blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease-worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run-in period. The primary end point was the proportion of patients in whom SDAI-defined remission was maintained without disease-worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease-worsening, and the proportion of patients in whom SDAI-defined remission was recaptured after initiation of rescue therapy.ResultsBaseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI-defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI-defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease-worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI-defined remission was recaptured in 70-80% in each treatment group. No new safety signals were reported.ConclusionThe efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI-defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision-making when withdrawal of therapy is being considered to reduce treatment burden in patients with well-controlled RA.

Project description:ObjectivesEtanercept biosimilars show comparable efficacy to their originators among biologic-naïve patients with RA in randomized controlled trials. Nationwide guidelines have obligated prescribing of etanercept biosimilars from 2016, resulting in significant cost savings. This analysis aimed to compare the effectiveness of etanercept originator vs etanercept biosimilar amongst biologic-naïve RA patients treated in routine clinical practice in the UK.MethodsBiologic-naïve RA patients starting etanercept in the British Society for Rheumatology Biologics Register in Rhematoid Arthritis (BSRBR-RA) cohort study from 2010 were included. Data collected at start of therapy includes patient demographics and disease activity. Follow-up data includes changes in disease activity and anti-rheumatic therapy. Six- and 12-month primary outcomes include DAS for 28-joints (DAS28) remission, EULAR response and minimal clinically important difference in function. Etanercept drug survival was assessed using Kaplan-Meier and Cox regression, including reasons for treatment withdrawal. Multiple imputation accounted for missing data. Propensity-decile adjustment was used to account for confounding by indication.ResultsA total of 1806 biologic-naïve RA patients started etanercept: 1009 originator, 797 biosimilar. At 6 and 12 months, the proportion of patients achieving DAS28 remission and EULAR response were similar between treatments. During follow-up, 19% of originator patients switched onto etanercept biosimilar. Patients were censored at time of switch. Patients on originator were no more likely to stop therapy vs biosimilar; 71% of originator and 76% of biosimilar patients remained on therapy at 1 year.ConclusionsIn one of the largest analyses of patients with RA, biologic-naïve RA patients treated with etanercept originator showed similar outcomes vs biosimilar using real-world data. Drug survival, and disease activity after 6 and 12 months of therapy, was similar between cohorts.

Project description:BackgroundBiologic disease-modifying antirheumatic drugs (bDMARDs) are important options for managing rheumatoid arthritis (RA). Once patients achieve disease control, clinicians may consider dose reduction or withdrawal of the bDMARD. Results from published studies indicate that some patients will maintain remission; however, others will flare. We analyzed data from three etanercept down-titration studies in patients with RA to determine what extent of remission provides the greatest predictability of maintaining remission following dose reduction or discontinuation.MethodsPatients with moderate to severe RA from the PRESERVE, PRIZE, and Treat-to-Target (T2T) randomized controlled trials were included. We determined the proportion of patients achieving remission with etanercept at the last time point in the induction period, and sustained remission (last two time points), according to the Disease Activity Score 28-joints (DAS28), the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean criteria, and the clinical disease activity index (CDAI). We also calculated the proportion achieving DAS28 deep remission (DAS28 ≤ 1.98), sustained deep remission (last two time points), and low disease activity (LDA), and LDA according to the CDAI. Then, we evaluated whether they maintained remission or LDA following etanercept dose reduction or withdrawal.ResultsPatients achieving sustained and/or deep remission were more likely than patients achieving remission or LDA to maintain remission/LDA after etanercept dose reduction or withdrawal. In PRESERVE, the proportions of patients with DAS28 sustained deep remission, deep remission, sustained remission, remission, and LDA who maintained remission following etanercept dose reduction were 81%, 67%, 58%, 56%, and 36%, respectively, P < 0.001 for trend. In PRESERVE, this trend was significant when etanercept was discontinued and when ACR/EULAR Boolean and CDAI remission criteria were used. Although some sample sizes were small, the PRIZE and T2T studies also demonstrated response trends according to ACR/EULAR Boolean and CDAI remission criteria, and T2T demonstrated response trends according to DAS28.ConclusionsThese results suggest that patients achieving disease control according to a stringent definition, such as sustained ACR/EULAR Boolean or CDAI remission, or a new definition of sustained deep remission by DAS28, have a higher probability of remaining in remission or LDA following etanercept dose reduction or withdrawal.Trial registrationPRESERVE: ClinicalTrials.gov identifier: NCT00565409 , registered 30 November 2007; PRIZE: ClinicalTrials.gov identifier: NCT00913458 , registered 4 June 2009; T2T: ClinicalTrials.gov identifier: NCT01578850 , registered 17 April 2012.

Project description:Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA.An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n?=?36) or no response (n?=?36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients.Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P?=?1.39 × 10(-8) and cg26401028, P?=?1.69 × 10(-8) ). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P?=?2.63 × 10(-7) and P?=?1.05 × 10(-6) , respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P?=?0.03; n?=?56) and in the independent replication cohort (P?=?0.003; n?=?1,204).We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed.

Dataset Information

Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis.

Background

Methods

Results

Conclusions

Trial registration number

Publications

Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis.

Similar Datasets

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