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.

Maintaining remission in patients with granulomatosis with polyangiitis or microscopic polyangiitis: the role of ANCA

“…Obvious targets to study more intensively concerning ANCA as a predictor of relapse are the avidity, glycosylation profile, or epitope specificity of ANCA [96][97][98][99]. In addition, biomarkers that are not (necessarily) related to ANCA may also be relevant, such as markers reflecting inflammation, injury, and repair [111]. Multiple studies have already shown an association of such a biomarker [111,112], but the number of included patients restrict the analysis to the predictive value of a single biomarker.…”

“…In addition, biomarkers that are not (necessarily) related to ANCA may also be relevant, such as markers reflecting inflammation, injury, and repair [111]. Multiple studies have already shown an association of such a biomarker [111,112], but the number of included patients restrict the analysis to the predictive value of a single biomarker. Future collaborations may increase the amount of included patients and will enable us to analyze the predictive value of a panel of biomarkers to better predict relapses.…”

ANCA-positive vasculitis: Clinical implications of ANCA types and titers

“…Monach et al, among others, have identified three biomarkers, CXCL13, MMP-3 and TIMP-1, which stand out due to their ability to distinguish active AAV better than other reference markers studied, including CRP and ESR. 20 Renal morphology of ANCA-negative patients with pauci-immune focal glomerulonephritis is indistinguishable from that of ANCA-positive patients according to Salama and Rees, raising the question of what the etiology of injury in the absence of these antibodies is. Thus, it seems highly likely that additional factors are required for AAV expression, leading to the need to analyze the role of newer described autoantibodies as well as their specificities for LAMP-2, plasminogen and moesin.…”

ANCA-associated Vasculitis: A Prothrombotic State Even in Remission?

“…At first glance, it might appear that investigating active AAV would be more fruitful, but since abnormalities related to leukocytes, endothelial cells, platelets, and coagulation proteins are all prominent in active AAV 4,11,12,13,14 , it is likely that multiple prothrombotic mechanisms are operating simultaneously. Thus, clinical remission provides an opportunity to identify prothrombotic abnormalities with the prospect of defining clear -and likely surprising -mechanisms.…”

“…This type of assay has been used in only 1 previous study of patients with vasculitis, which reported very high thrombin generation in children with active vasculitis, particularly those with clinically apparent thrombosis, but mostly normal levels in children with inactive vasculitis 12 . In the study by Hilhorst, et al, ETP was clearly higher on average among patients than controls (although there was some overlap), in spite of the fact that levels of the anticoagulant proteins tissue factor pathway inhibitor, protein C, and protein S were at least nominally higher among patients.…”