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Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.

ABSTRACT: 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.

SUBMITTER: Plant D

PROVIDER: S-EPMC4914881 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.

Plant Darren D Webster Amy A Nair Nisha N Oliver James J Smith Samantha L SL Eyre Steven S Hyrich Kimme L KL Wilson Anthony G AG Morgan Ann W AW Isaacs John D JD Worthington Jane J Barton Anne A

Arthritis & rheumatology (Hoboken, N.J.) 20160421 6

<h4>Objective</h4>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.<h4>Methods</h4>An epigenome-wide assoc ...[more]

PMID: 26814849

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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:ObjectiveWe undertook this study to estimate changes in cell-specific DNA methylation (DNAm) associated with methotrexate (MTX) response using whole blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment.MethodsPatients included in this study were from the Rheumatoid Arthritis Medication Study (n = 66) and the University of California San Francisco Rheumatoid Arthritis study (n = 11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. Disease Activity Scores in 28 joints using the C-reactive protein level were collected at baseline and after 3-6 months of treatment with MTX. Methylation profiles were generated using the Illumina Infinium HumanMethylation450 and MethylationEPIC v1.0 BeadChip arrays using DNA from whole blood. MTX response was defined using the EULAR response criteria (responders showed good/moderate response; nonresponders showed no response). Differentially methylated positions were identified using the Limma software package and Tensor Composition Analysis, which is a method for identifying cell-specific differential DNAm at the CpG level from tissue-level ("bulk") data. Differentially methylated regions were identified using Comb-p software.ResultsWe found evidence of differential global methylation between treatment response groups. Further, we found patterns of cell-specific differential global methylation associated with MTX response. After correction for multiple testing, 1 differentially methylated position was associated with differential DNAm between responders and nonresponders at baseline in CD4+ T cells, CD8+ T cells, and natural killer cells. Thirty-nine cell-specific differentially methylated regions associated with MTX treatment response were identified. There were no significant findings in analyses of whole blood samples.ConclusionWe identified cell-specific changes in DNAm that were associated with MTX treatment response in RA patients. Future studies of DNAm and MTX treatment response should include measurements of DNAm from sorted cells.

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:Although several randomized clinical trials have confirmed that there is no difference in efficacy between etanercept and its biosimilar versions in the treatment of rheumatoid arthritis (RA), limited real-world evidence is available. We conducted a cohort study to compare the effectiveness and treatment persistence between the reference etanercept (ETN) and the biosimilar GP2015 in RA patients in a real-life setting. Adults with a diagnosis of RA who initiated treatment with ETN or GP2015, between January 2007 and December 2019, were included. The follow-up period was 52 weeks. The primary outcome was the mean of change in the DAS28-CRP values and the adjusted mean difference from baseline to 52 weeks between ETN and GP2015. Other effectiveness endpoints assessed were the rate of patients who achieved remission or low disease activity (LDA) at week 52, who showed a reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 and rate of good responder patients (those meeting both effectiveness measures) at week 52. Treatment effectiveness over time (baseline, 26 and 52 weeks) was compared between the ETN and GP2015 groups using mixed effects models. Treatment persistence (probability of maintaining the same treatment over time) was also evaluated and shown using Kaplan-Meier survival curves. A total of 115 RA patients were included (ETN, n = 90; GP2015, n = 25). No differences were observed in the primary outcome: DAS28-CRP score decreased from baseline to week 52 [5.1 to 2.7 (mean of change -2.37) in ETN group and 5.0 to 2.2 (mean of change -2.84) in GP2015 group, p-value = 0.372] and the adjusted mean difference was -0.37 (-1.03 to 0.29). No differences were also observed in the other effectiveness endpoints assessed among patients treated with ETN or GP2015: rate of patients who achieved remission (54.1% vs. 66.7%, p-value = 0.303) and LDA (71.6% vs. 80.9%, p-value = 0.391) at week 52, reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 (75.6% vs. 80.9%, p-value = 0.613) and rate of good responder patients (58.1% vs. 76.1%, p-value = 0.202). Drug survival was 82% and 80% for ETN and GP2015, respectively (log-rank p-value = 0.804). Etanercept and its biosimilar GP2015 show similar effectiveness and treatment persistence in RA patients in a real-life setting.

Dataset Information

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.

Publications

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.

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