Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers
Objective To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab.Methods In three...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2024-02-01
|
| Series: | RMD Open |
| Online Access: | https://rmdopen.bmj.com/content/10/1/e003769.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849720634619199488 |
|---|---|
| author | Anne Gitte Loft Inge Juul Sørensen Mikkel Østergaard Susanne J Pedersen Morten Asser Karsdal Ole Rintek Madsen Anne-C Bay-Jensen Peder Frederiksen Signe Holm Nielsen Helena Port Frederik Christiansen Sengul Seven |
| author_facet | Anne Gitte Loft Inge Juul Sørensen Mikkel Østergaard Susanne J Pedersen Morten Asser Karsdal Ole Rintek Madsen Anne-C Bay-Jensen Peder Frederiksen Signe Holm Nielsen Helena Port Frederik Christiansen Sengul Seven |
| author_sort | Anne Gitte Loft |
| collection | DOAJ |
| description | Objective To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab.Methods In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering.Results Based on all three studies, we identified two orthogonal dimensions reflecting: (1) inflammation and neutrophil activity (driven by C1M and CPa9-HNE) and (2) collagen turnover (driven by PRO-C2). Three endotypes were identified: high inflammation endotype (Endotype1), low inflammation endotype (Endotype 2) and high collagen turnover endotype (Endotype3). Endotype1 showed higher disease activity (Ankylosing Spondylitis Disease Activity Score (ASDAS)) at baseline compared with Endotype2 and Endotype3 and higher percentage of patients responding to adalimumab based on ASDAS clinical improvement at week 24. Endotype3 showed higher percentage of patients with 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index response at week 24 compared with Endotype2.Conclusion These endotypes differ in their tissue remodelling profile and may in the future have utility for patient stratification and treatment tailoring. |
| format | Article |
| id | doaj-art-e93364d1901648c3841a9b940360238c |
| institution | DOAJ |
| issn | 2056-5933 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | RMD Open |
| spelling | doaj-art-e93364d1901648c3841a9b940360238c2025-08-20T03:11:52ZengBMJ Publishing GroupRMD Open2056-59332024-02-0110110.1136/rmdopen-2023-003769Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkersAnne Gitte Loft0Inge Juul Sørensen1Mikkel Østergaard2Susanne J Pedersen3Morten Asser Karsdal4Ole Rintek Madsen5Anne-C Bay-Jensen6Peder Frederiksen7Signe Holm Nielsen8Helena Port9Frederik Christiansen10Sengul Seven11Department of Clinical Medicine, Aarhus University, Aarhus, Denmark3 Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet, Copenhagen, DenmarkCopenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Glostrup, DenmarkCopenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Glostrup, DenmarkNordic Bioscience, Herlev, Denmark3 Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet, Copenhagen, DenmarkNordic Bioscience, Herlev, DenmarkNordic Bioscience, Herlev, DenmarkNordic Bioscience, Herlev, DenmarkDepartment of Clinical Medicine, Copenhagen University Hospital, Kobenhavn, DenmarkNordic Bioscience, Herlev, DenmarkCopenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, DenmarkObjective To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab.Methods In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering.Results Based on all three studies, we identified two orthogonal dimensions reflecting: (1) inflammation and neutrophil activity (driven by C1M and CPa9-HNE) and (2) collagen turnover (driven by PRO-C2). Three endotypes were identified: high inflammation endotype (Endotype1), low inflammation endotype (Endotype 2) and high collagen turnover endotype (Endotype3). Endotype1 showed higher disease activity (Ankylosing Spondylitis Disease Activity Score (ASDAS)) at baseline compared with Endotype2 and Endotype3 and higher percentage of patients responding to adalimumab based on ASDAS clinical improvement at week 24. Endotype3 showed higher percentage of patients with 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index response at week 24 compared with Endotype2.Conclusion These endotypes differ in their tissue remodelling profile and may in the future have utility for patient stratification and treatment tailoring.https://rmdopen.bmj.com/content/10/1/e003769.full |
| spellingShingle | Anne Gitte Loft Inge Juul Sørensen Mikkel Østergaard Susanne J Pedersen Morten Asser Karsdal Ole Rintek Madsen Anne-C Bay-Jensen Peder Frederiksen Signe Holm Nielsen Helena Port Frederik Christiansen Sengul Seven Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers RMD Open |
| title | Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers |
| title_full | Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers |
| title_fullStr | Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers |
| title_full_unstemmed | Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers |
| title_short | Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers |
| title_sort | identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood derived extracellular matrix biomarkers |
| url | https://rmdopen.bmj.com/content/10/1/e003769.full |
| work_keys_str_mv | AT annegitteloft identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT ingejuulsørensen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT mikkeløstergaard identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT susannejpedersen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT mortenasserkarsdal identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT olerintekmadsen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT annecbayjensen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT pederfrederiksen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT signeholmnielsen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT helenaport identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT frederikchristiansen identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers AT sengulseven identificationofpatientendotypesandadalimumabtreatmentrespondersinaxialspondyloarthritisusingbloodderivedextracellularmatrixbiomarkers |