Jacob Sode1,2, Sophine B Krintel3,4, Anting Liu Carlsen3,4, Merete L Hetland3,4, Julia S Johansen3,4, Kim Hørslev-Petersen3,4, Kristian Stengaard-Pedersen3,4, Torkell Ellingsen3,4, Mark Burton3,4, Peter Junker3,4, Mikkel Østergaard3,4, Niels H H Heegaard3,4. 1. From the Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen; Department of Rheumatology, Frederiksberg Hospital, Frederiksberg; Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense; Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup; Department of Medicine and Oncology, Herlev and Gentofte Hospital, Herlev; Faculty of Health Sciences, University of Copenhagen, Copenhagen; Department of Rheumatology, King Christian 10th Hospital for Rheumatic Diseases, Gråsten; Department of Rheumatology, Aarhus University Hospital, Aarhus; Department of Rheumatology, Odense University Hospital, Odense; Department of Clinical Genetics, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. Jacob.Sode@gmail.com. 2. J. Sode, PhD, MD, Department of Autoimmunology and Biomarkers, Statens Serum Institut, Department of Rheumatology, Frederiksberg Hospital, and Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark; S.B. Krintel, PhD, MD, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics; A.L. Carlsen, PhD, Department of Autoimmunology and Biomarkers, Statens Serum Institut; M.L. Hetland, Professor, DMSc, PhD, MD, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, and The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics; J.S. Johansen, Professor, DMSc, MD, Department of Medicine and Oncology, Herlev and Gentofte Hospital, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen; K. Hørslev-Petersen, Professor, DMSc, MD, Department of Rheumatology, King Christian 10th Hospital for Rheumatic Diseases; K. Stengaard-Pedersen, Professor, DMSc, MD, Department of Rheumatology, Aarhus University Hospital; T. Ellingsen, Professor, PhD, MD, Department of Rheumatology, Odense University Hospital; M. Burton, PhD, Department of Clinical Genetics, Odense University Hospital; P. Junker, External Associate Professor, DMSc, MD, Department of Rheumatology C, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark; M. Østergaard, Professor, DMSc, PhD, MD, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen; N.H. Heegaard, Professor, DMSc, DSc, MD, Department of Autoimmunology and Biomarkers, Statens Serum Institut, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital. Jacob.Sode@gmail.com. 3. From the Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen; Department of Rheumatology, Frederiksberg Hospital, Frederiksberg; Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense; Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup; Department of Medicine and Oncology, Herlev and Gentofte Hospital, Herlev; Faculty of Health Sciences, University of Copenhagen, Copenhagen; Department of Rheumatology, King Christian 10th Hospital for Rheumatic Diseases, Gråsten; Department of Rheumatology, Aarhus University Hospital, Aarhus; Department of Rheumatology, Odense University Hospital, Odense; Department of Clinical Genetics, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. 4. J. Sode, PhD, MD, Department of Autoimmunology and Biomarkers, Statens Serum Institut, Department of Rheumatology, Frederiksberg Hospital, and Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark; S.B. Krintel, PhD, MD, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics; A.L. Carlsen, PhD, Department of Autoimmunology and Biomarkers, Statens Serum Institut; M.L. Hetland, Professor, DMSc, PhD, MD, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, and The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics; J.S. Johansen, Professor, DMSc, MD, Department of Medicine and Oncology, Herlev and Gentofte Hospital, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen; K. Hørslev-Petersen, Professor, DMSc, MD, Department of Rheumatology, King Christian 10th Hospital for Rheumatic Diseases; K. Stengaard-Pedersen, Professor, DMSc, MD, Department of Rheumatology, Aarhus University Hospital; T. Ellingsen, Professor, PhD, MD, Department of Rheumatology, Odense University Hospital; M. Burton, PhD, Department of Clinical Genetics, Odense University Hospital; P. Junker, External Associate Professor, DMSc, MD, Department of Rheumatology C, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark; M. Østergaard, Professor, DMSc, PhD, MD, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen; N.H. Heegaard, Professor, DMSc, DSc, MD, Department of Autoimmunology and Biomarkers, Statens Serum Institut, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital.
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) orplacebo (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 withMTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.
RCT Entities:
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.