Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone: A Placebo-controlled Clinical Trial

Jacob Sode, Sophine B Krintel, Anting Liu Carlsen, Merete L Hetland, Julia S Johansen, Kim Hørslev-Petersen, Kristian Stengaard-Pedersen, Torkell Ellingsen, Mark Burton, Peter Junker, Mikkel Østergaard, Niels H H Heegaard

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647).

METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.

RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively.

CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.

Original languageEnglish
JournalJournal of Rheumatology
Volume45
Issue number1
Pages (from-to)53-61
ISSN0315-162X
DOIs
Publication statusPublished - Jan 2018

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Controlled Clinical Trials
MicroRNAs
Methotrexate
Placebos
ROC Curve
Antirheumatic Agents
Rheumatology
Plasma Cells
Adalimumab
Rheumatic Diseases
Reverse Transcriptase Polymerase Chain Reaction
Joints
Research Personnel

Keywords

  • Biological markers
  • Plasma micro-RNA
  • Rheumatoid arthritis

Cite this

Sode, Jacob ; Krintel, Sophine B ; Carlsen, Anting Liu ; Hetland, Merete L ; Johansen, Julia S ; Hørslev-Petersen, Kim ; Stengaard-Pedersen, Kristian ; Ellingsen, Torkell ; Burton, Mark ; Junker, Peter ; Østergaard, Mikkel ; Heegaard, Niels H H. / Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone : A Placebo-controlled Clinical Trial. In: Journal of Rheumatology. 2018 ; Vol. 45, No. 1. pp. 53-61.
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title = "Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone: A Placebo-controlled Clinical Trial",
abstract = "OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647).METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63{\%} and 82{\%} area under the ROC curves, respectively.CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.",
keywords = "Biological markers, Plasma micro-RNA, Rheumatoid arthritis",
author = "Jacob Sode and Krintel, {Sophine B} and Carlsen, {Anting Liu} and Hetland, {Merete L} and Johansen, {Julia S} and Kim H{\o}rslev-Petersen and Kristian Stengaard-Pedersen and Torkell Ellingsen and Mark Burton and Peter Junker and Mikkel {\O}stergaard and Heegaard, {Niels H H}",
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Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone : A Placebo-controlled Clinical Trial. / Sode, Jacob; Krintel, Sophine B; Carlsen, Anting Liu; Hetland, Merete L; Johansen, Julia S; Hørslev-Petersen, Kim; Stengaard-Pedersen, Kristian; Ellingsen, Torkell; Burton, Mark; Junker, Peter; Østergaard, Mikkel; Heegaard, Niels H H.

In: Journal of Rheumatology, Vol. 45, No. 1, 01.2018, p. 53-61.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone

T2 - A Placebo-controlled Clinical Trial

AU - Sode, Jacob

AU - Krintel, Sophine B

AU - Carlsen, Anting Liu

AU - Hetland, Merete L

AU - Johansen, Julia S

AU - Hørslev-Petersen, Kim

AU - Stengaard-Pedersen, Kristian

AU - Ellingsen, Torkell

AU - Burton, Mark

AU - Junker, Peter

AU - Østergaard, Mikkel

AU - Heegaard, Niels H H

PY - 2018/1

Y1 - 2018/1

N2 - OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647).METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively.CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.

AB - OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647).METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively.CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.

KW - Biological markers

KW - Plasma micro-RNA

KW - Rheumatoid arthritis

U2 - 10.3899/jrheum.170266

DO - 10.3899/jrheum.170266

M3 - Journal article

C2 - 29142030

VL - 45

SP - 53

EP - 61

JO - Journal of Rheumatology

JF - Journal of Rheumatology

SN - 0315-162X

IS - 1

ER -