James Oliver1, Nisha Nair1, Anne Barton1,2, Darren Plant3,4, Gisela Orozco1, Samantha Smith1, Kimme L Hyrich2,5, Ann Morgan6, John Isaacs7,8, Anthony G Wilson9. 1. Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK. 2. NIHR Manchester BRC, Manchester University Foundation Trust, Manchester, UK. 3. Versus Arthritis Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK. darren.plant@manchester.ac.uk. 4. NIHR Manchester BRC, Manchester University Foundation Trust, Manchester, UK. darren.plant@manchester.ac.uk. 5. Versus Arthritis Centre for Epidemiology, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK. 6. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK. 7. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. 8. National Institute for Health Research Newcastle Biomedical Research Centre at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK. 9. UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland.
Abstract
BACKGROUND: Despite the success of TNF-inhibitor therapy in rheumatoid arthritis treatment, up to 40% of patients fail to respond adequately. This study aimed to identify transcriptome-based biomarkers of adalimumab response in rheumatoid arthritis (RA) to aid timely switching in non-responder patients and provide a better mechanistic understanding of the pathways involved in response/non-response. METHODS: The Affymetrix Human Transcriptome Array 2.0 (HTA) was used to measure the transcriptome in whole blood at pre-treatment and at 3 months in EULAR good- and non-responders to adalimumab therapy. Differential expression of transcripts was analysed at the transcript level using multiple linear regression. Differentially expressed genes were validated in independent samples using OpenArray™ RT-qPCR. RESULTS: In total, 813 transcripts were differentially expressed between pre-treatment and 3 months in adalimumab good-responders. No significant differential expression was observed between good- and non-responders at either time-point and no significant changes were observed in non-responders between time-points. OpenArray™ RT-qPCR was performed for 104 differentially expressed transcripts in good-responders, selected based on magnitude of effect or p value or based on prior association with RA or the immune system, validating differential expression for 17 transcripts. CONCLUSIONS: An early transcriptome signature of DAS28 response to adalimumab has been identified and replicated in independent datasets. Whilst treat-to-target approaches encourage early switching in non-responsive patients, registry evidence suggests that this does not always occur. The results herein could guide the development of a blood test to distinguish responders from non-responders at 3 months and support clinical decisions to switch non-responsive patients to an alternative therapy.
BACKGROUND: Despite the success of TNF-inhibitor therapy in rheumatoid arthritis treatment, up to 40% of patients fail to respond adequately. This study aimed to identify transcriptome-based biomarkers of adalimumab response in rheumatoid arthritis (RA) to aid timely switching in non-responder patients and provide a better mechanistic understanding of the pathways involved in response/non-response. METHODS: The Affymetrix Human Transcriptome Array 2.0 (HTA) was used to measure the transcriptome in whole blood at pre-treatment and at 3 months in EULAR good- and non-responders to adalimumab therapy. Differential expression of transcripts was analysed at the transcript level using multiple linear regression. Differentially expressed genes were validated in independent samples using OpenArray™ RT-qPCR. RESULTS: In total, 813 transcripts were differentially expressed between pre-treatment and 3 months in adalimumab good-responders. No significant differential expression was observed between good- and non-responders at either time-point and no significant changes were observed in non-responders between time-points. OpenArray™ RT-qPCR was performed for 104 differentially expressed transcripts in good-responders, selected based on magnitude of effect or p value or based on prior association with RA or the immune system, validating differential expression for 17 transcripts. CONCLUSIONS: An early transcriptome signature of DAS28 response to adalimumab has been identified and replicated in independent datasets. Whilst treat-to-target approaches encourage early switching in non-responsive patients, registry evidence suggests that this does not always occur. The results herein could guide the development of a blood test to distinguish responders from non-responders at 3 months and support clinical decisions to switch non-responsive patients to an alternative therapy.
Authors: James Oliver; Nisha Nair; Anne Barton; Darren Plant; Gisela Orozco; Samantha Smith; Kimme L Hyrich; Ann Morgan; John Isaacs; Anthony G Wilson Journal: Arthritis Res Ther Date: 2021-05-08 Impact factor: 5.156
Authors: Melanie J Millier; Niamh C Fanning; Christopher Frampton; Lisa K Stamp; Paul A Hessian Journal: Arthritis Res Ther Date: 2022-02-26 Impact factor: 5.156