ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: L2

Proteome-Wide Analysis and CXCL4 As a Pathogenic Biomarker in Systemic Sclerosis

Timothy Radstake1, Lenny van Bon2, Alsya Affandi1, Jasper Broen3, Romy Christmann4, Lukasz Stawski5, Giuseppina Farina6, Allison Mathes7, Marta Cossu8, MArk Wenink9, Roger Hesselstrand10, Tore Saxne11, Dirk Wuttge10, John D. Reveille12, Shervin Assassi12, Maureen D. Mayes13, Wim B van den Berg14, Vanessa Smith15, Filip De Keyser15, Claudio Lunardi16, Piet L.C. Van Riel17, Madelon C. Vonk18, Lorenzo Beretta19, Maria Trojanowska20 and Robert Lafyatis4, 1Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 2Rheumatology and Clinical Immunology, University Medical Center Utrecht/Radboud University Nijmegen Medical Center, Utrecht/Nijmegen, Netherlands, 3Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 4Rheumatology, Boston University School of Medicine, Boston, MA, 5Rheumatology, Boston Medical Center, Boston, MA, 6Arthritis center, Boston University, Boston, MA, 7rheumatology, Boston Medical Center, boston, MA, 8Rheumatology and Clinical Immunology, University Medical Center Utrecht, utrecht, Netherlands, 9rheumatology and Clinical Immunology, university Medical Center Utrecht, utrecht, Netherlands, 10Rheumatology, Lund University, Lund, Sweden, 11Section of Rheumatology, Deparment of Clinical Sciences, Lund, Lund University, Lund, Sweden, 12Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 13University of Texas Health Science Center at Houston, Houston, TX, 14Experimental Rheumatology, Radboud university medical center, Nijmegen, Netherlands, 15Department of Rheumatology, Ghent University Hospital, Ghent, Belgium, 16Department of Medicine, Università degli Studi di Verona, Verona, Italy, 17Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 18Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 19Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 20Arthritis Center, Boston University, Boston, MA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: ACR Late-Breaking Abstract Oral Session

Session Type: Late-Breaking Abstracts

Background/Purpose:

We hypothesized that plasmacytoid dendritic cells are implicated in the pathogenesis of systemic sclerosis via mechanisms beyond previously suggested type I interferon production.

Methods:

We isolated plasmacytoid dendritic cells from healthy persons and from systemic sclerosis patients with distinct clinical phenotypes, exploited proteome-wide analysis and validated these observations in five large systemic sclerosis cohorts and compared results to those in patients with systemic lupus erythematosus (SLE), ankylosing spondylitis and hepatic fibrosis. We correlated plasma CXCL4 levels with systemic sclerosis features. We also studied the direct effects of CXCL4 in vitro and in vivo.

Results:

Proteome-wide analysis and validation demonstrated that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in the circulation and the skin. CXCL4 was significantly higher in systemic sclerosis patients (25624 ± 2652 pg/ml) compared to controls (92.5 ± 77.9 pg/ml) and to patients with systemic lupus erythematosus (1346 ± 1011 pg/ml), ankylosing spondylitis (1368 ± 1162 pg/ml) and liver fibrosis (1668 ± 1263 pg/ml). CXCL4 levels correlated with skin and lung fibrosis, and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted systemic sclerosis disease progression and the risk for systemic sclerosis development. In vitro, CXCL4 downregulated Fli-1 expression, induced markers of endothelial cell activation and potentiated TLR responses. In vivo, CXCL4 induced influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis.

Conclusion:

CXCL4 is elevated in systemic sclerosis patients, correlates with the presence and progression of complications such as lung fibrosis and pulmonary arterial hypertension and recapitulates pathogenic halmarks seen in SSc. As such, CXCL4 is a novel marker for prognosis and a candidate for therapeutic targetting.

Of Note; This paper is conditionally accepted for publication in the New England Journal of Medicine

Disclosure:

T. Radstake,
None;

L. van Bon,
None;

A. Affandi,
None;

J. Broen,
None;

R. Christmann,
None;

L. Stawski,
None;

G. Farina,
None;

A. Mathes,
None;

M. Cossu,
None;

M. Wenink,
None;

R. Hesselstrand,
None;

T. Saxne,
None;

D. Wuttge,
None;

J. D. Reveille,
None;

S. Assassi,
None;

M. D. Mayes,
None;

W. B. van den Berg,
None;

V. Smith,
None;

F. De Keyser,
None;

C. Lunardi,
None;

P. L. C. Van Riel,
None;

M. C. Vonk,

Actelion Pharmaceuticals US,

5;

L. Beretta,
None;

M. Trojanowska,
None;

R. Lafyatis,
None.

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