title: Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis.
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.
authors.affiliation: Vasculitis Center, Section of Rheumatology, and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.forename: Roscoe L
authors.initials: RL
authors.lastname: Warner
authors.forename: Gunnar
authors.initials: G
authors.lastname: Tomasson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.forename: Linna
authors.initials: L
authors.lastname: Ding
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Fervenza
authors.forename: Barri J
authors.initials: BJ
authors.lastname: Fessler
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.forename: David
authors.initials: D
authors.lastname: Iklé
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Krischer
authors.forename: Carol A
authors.initials: CA
authors.lastname: Langford
authors.forename: Mark
authors.initials: M
authors.lastname: Mueller
authors.forename: Philip
authors.initials: P
authors.lastname: Seo
authors.forename: E William
authors.initials: EW
authors.lastname: St Clair
authors.forename: Robert
authors.initials: R
authors.lastname: Spiera
authors.forename: Nadia
authors.initials: N
authors.lastname: Tchao
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ytterberg
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Johnson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
mesh_terms: D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood* / Q000188:drug therapy / Q000473:pathology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000032:analysis; D054382:Chemokine CXCL13 / Q000097:blood; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006304:Health Status; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D008875:Middle Aged; D011506:Proteins / Q000378:metabolism*; D012372:ROC Curve; D012074:Remission Induction; D000069283:Rituximab; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015415:Biomarkers; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D018925:Chemokines; D016207:Cytokines; D007155:Immunologic Factors; D011506:Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D000069283:Rituximab; D002097:C-Reactive Protein; D019278:Matrix Metalloproteinase 3