Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis

Paul A. Monach, Roscoe L. Warner, Gunnar Tomasson, Ulrich Specks, John H. Stone, Linna Ding, Fernando C. Fervenza, Barri J. Fessler, Gary S. Hoffman, David Iklé, Cees G M Kallenberg, Jeffrey Krischer, Carol A. Langford, Mark Mueller, Philip Seo, E. William St. Clair, Robert Spiera, Nadia Tchao, Steven R. Ytterberg, Kent J. JohnsonPeter A. Merkel

Research output: Contribution to journalArticle

Abstract

Objective To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG).3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC). Results All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low. Conclusions Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.

Original languageEnglish (US)
Pages (from-to)1342-1350
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume72
Issue number8
DOIs
StatePublished - Aug 2013

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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Antineutrophil Cytoplasmic Antibodies
Biomarkers
Blood Proteins
Repair
Inflammation
Wounds and Injuries
Vasculitis
Granulomatosis with Polyangiitis
Blood Sedimentation
Sedimentation
C-Reactive Protein
Area Under Curve
Matrix Metalloproteinase 3
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
ROC Curve
Screening
Needs Assessment
Proteins

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. / Monach, Paul A.; Warner, Roscoe L.; Tomasson, Gunnar; Specks, Ulrich; Stone, John H.; Ding, Linna; Fervenza, Fernando C.; Fessler, Barri J.; Hoffman, Gary S.; Iklé, David; Kallenberg, Cees G M; Krischer, Jeffrey; Langford, Carol A.; Mueller, Mark; Seo, Philip; St. Clair, E. William; Spiera, Robert; Tchao, Nadia; Ytterberg, Steven R.; Johnson, Kent J.; Merkel, Peter A.

In: Annals of the Rheumatic Diseases, Vol. 72, No. 8, 08.2013, p. 1342-1350.

Research output: Contribution to journalArticle

Monach, PA, Warner, RL, Tomasson, G, Specks, U, Stone, JH, Ding, L, Fervenza, FC, Fessler, BJ, Hoffman, GS, Iklé, D, Kallenberg, CGM, Krischer, J, Langford, CA, Mueller, M, Seo, P, St. Clair, EW, Spiera, R, Tchao, N, Ytterberg, SR, Johnson, KJ & Merkel, PA 2013, 'Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis', Annals of the Rheumatic Diseases, vol. 72, no. 8, pp. 1342-1350. https://doi.org/10.1136/annrheumdis-2012-201981
Monach, Paul A. ; Warner, Roscoe L. ; Tomasson, Gunnar ; Specks, Ulrich ; Stone, John H. ; Ding, Linna ; Fervenza, Fernando C. ; Fessler, Barri J. ; Hoffman, Gary S. ; Iklé, David ; Kallenberg, Cees G M ; Krischer, Jeffrey ; Langford, Carol A. ; Mueller, Mark ; Seo, Philip ; St. Clair, E. William ; Spiera, Robert ; Tchao, Nadia ; Ytterberg, Steven R. ; Johnson, Kent J. ; Merkel, Peter A. / Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. In: Annals of the Rheumatic Diseases. 2013 ; Vol. 72, No. 8. pp. 1342-1350.
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abstract = "Objective To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG).3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC). Results All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low. Conclusions Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.",
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T1 - Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis

AU - Monach, Paul A.

AU - Warner, Roscoe L.

AU - Tomasson, Gunnar

AU - Specks, Ulrich

AU - Stone, John H.

AU - Ding, Linna

AU - Fervenza, Fernando C.

AU - Fessler, Barri J.

AU - Hoffman, Gary S.

AU - Iklé, David

AU - Kallenberg, Cees G M

AU - Krischer, Jeffrey

AU - Langford, Carol A.

AU - Mueller, Mark

AU - Seo, Philip

AU - St. Clair, E. William

AU - Spiera, Robert

AU - Tchao, Nadia

AU - Ytterberg, Steven R.

AU - Johnson, Kent J.

AU - Merkel, Peter A.

PY - 2013/8

Y1 - 2013/8

N2 - Objective To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG).3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC). Results All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low. Conclusions Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.

AB - Objective To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG).3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC). Results All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low. Conclusions Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.

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