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Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis
  1. Paul A Monach1,
  2. Roscoe L Warner2,
  3. Gunnar Tomasson1,
  4. Ulrich Specks3,
  5. John H Stone4,
  6. Linna Ding5,
  7. Fernando C Fervenza6,
  8. Barri J Fessler7,
  9. Gary S Hoffman8,
  10. David Iklé9,
  11. Cees GM Kallenberg10,
  12. Jeffrey Krischer11,
  13. Carol A Langford8,
  14. Mark Mueller12,
  15. Philip Seo13,
  16. E William St. Clair14,
  17. Robert Spiera15,
  18. Nadia Tchao16,
  19. Steven R Ytterberg17,
  20. Kent J Johnson2,
  21. Peter A Merkel1,18
  1. 1Vasculitis Center, Section of Rheumatology, and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA
  2. 2Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  4. 4Rheumatology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  5. 5National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  6. 6Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  7. 7Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, Alabama, USA
  8. 8Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, Ohio, USA
  9. 9Rho, Chapel Hill, North Carolina, USA
  10. 10Department of Rheumatology and Clinical Immunology, University Medical Center, Groningen, The Netherlands
  11. 11Department of Pediatrics, University of South Florida College of Medicine, Tampa, Florida, USA
  12. 12Immune Tolerance Network, Bethesda, Maryland, USA
  13. 13Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
  14. 14Division of Rheumatology and Immunology, Duke University, Durham, North Carolina, USA
  15. 15Rheumatology Division, Hospital for Special Surgery, New York, New York, USA
  16. 16Immune Tolerance Network, San Francisco, California, USA
  17. 17Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  18. 18Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Professor Peter A Merkel, Division of Rheumatology, University of Pennsylvania, 8th Floor Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104, USA; pmerkel{at}upenn.edu

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.

  • Autoimmune Diseases
  • Chemokines
  • Cytokines

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