Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2024 Jan 10;10(1):e003769.
doi: 10.1136/rmdopen-2023-003769.

Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers

Helena Port  1   2 , Frederik Christiansen  2 , Signe Holm Nielsen  2 , Peder Frederiksen  2 , Anne-C Bay-Jensen  2 , Morten Asser Karsdal  2 , Sengul Seven  3 , Inge Juul Sørensen  4   5 , Anne Gitte Loft  6 , Ole Rintek Madsen  4   3   5 , Mikkel Ostergaard  4   3   5 , Susanne J Pedersen  3   5
Affiliations
Randomized Controlled Trial

Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers

Helena Port et al. RMD Open. .

Abstract

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.

Keywords: Adalimumab; Chondrocytes; Spondylitis, Ankylosing.

PubMed Disclaimer

Conflict of interest statement

Competing interests: MØ: research grants from AbbVie, BMS, Merck, Novartis and UCB, and speaker and/or consultancy fees from AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB. SJP: speaker’s bureau MSD, Pfizer, AbbVie, UCB, Novartis. Consulting fees and/or honoraria: AbbVie, UCB, Novartis. Grant/research support: AbbVie, MSD and Novartis. HP: none. Frederik Christiansen: Employed at Nordic Bioscience A/S. SHN: employed and shareholder of Nordic Bioscience A/S. PF: none. A-CB-J: employed and shareholder of Nordic Bioscience A/S. MK Shareholder of: employed and shareholder of Nordic Bioscience A/S. SS: None. IJS: none. AGL: speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, and UCB. Research grant from Novartis. ORM: none.

Figures

Figure 1
Figure 1
Principal component analysis biplot of individuals and principal component dimensions. Ellipses represent 80% of the patients within the cluster, which are differentiated by colour. Cluster 1, 2 and 3 correspond to Endotype1, 2 and 3, respectively.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Advances in Extracellular Matrix-Associated Diagnostics and Therapeutics.
    Karsdal M, Cox TR, Parker AL, Willumsen N, Sand JMB, Jenkins G, Hansen HH, Oldenburger A, Geillinger-Kaestle KE, Larsen AT, Black D, Genovese F, Eckersley A, Heinz A, Nyström A, Holm Nielsen S, Bennink L, Johannsson L, Bay-Jensen AC, Orange DE, Friedman S, Røpke M, Fiore V, Schuppan D, Rieder F, Simona B, Borthwick L, Skarsfeldt M, Wennbo H, Thakker P, Stoffel R, Clarke GW, Kalluri R, Ruane D, Zannad F, Mortensen JH, Sinkeviciute D, Sundberg F, Coseno M, Thudium C, Croft AP, Khanna D, Cooreman M, Broermann A, Leeming DJ, Mobasheri A, Ricard-Blum S. Karsdal M, et al. J Clin Med. 2025 Mar 10;14(6):1856. doi: 10.3390/jcm14061856. J Clin Med. 2025. PMID: 40142664 Free PMC article. Review.

References

    1. Sieper J, Poddubnyy D. Axial Spondyloarthritis. Lancet 2017;390:73–84. 10.1016/S0140-6736(16)31591-4 - DOI - PubMed
    1. Port H, Nielsen SH, Madsen SF, et al. . Extracellular matrix protein turnover markers are associated with axial Spondyloarthritis—a comparison with postpartum women and other non-axial Spondyloarthritis controls with or without back pain. Arthritis Res Ther 2022;24:152. 10.1186/s13075-022-02839-1 - DOI - PMC - PubMed
    1. Bay-Jensen AC, Leeming DJ, Kleyer A, et al. . Ankylosing Spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: A cross-sectional study. Rheumatol Int 2012;32:3565–72. 10.1007/s00296-011-2237-8 - DOI - PubMed
    1. Mortensen JH, Guo X, De Los Reyes M, et al. . The VICM biomarker is released from activated Macrophages and inhibited by anti-GM-CSFRα-mAb treatment in rheumatoid arthritis patients. Clin Exp Rheumatol 2019;37:73–80. - PubMed
    1. Mortensen JH, Sinkeviciute D, Manon-Jensen T, et al. . A specific Calprotectin Neo-EPITOPE (Cpa9-HNE) in serum from inflammatory bowel disease patients is associated with neutrophil activity and endoscopic severity. J Crohns Colitis 2022;16:1447–60. 10.1093/ecco-jcc/jjac047 - DOI - PMC - PubMed

Publication types