Circulating markers of vascular injury and angiogenesis in antineutrophil cytoplasmic antibody-associated vasculitis

Abstract

Objective To identify biomarkers that distinguish between active ANCA-associated vasculitis (AAV) and remission in a manner superior or complementary to established markers of systemic inflammation. Methods Markers of vascular injury and angiogenesis were measured before and after treatment in a large clinical trial in AAV. 163 subjects enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Serum levels of E-selectin, ICAM-3, MMP1, MMP3, MMP9, P-selectin, thrombomodulin, and VEGF were measured at study screening (time of active disease) and at month 6. ESR and CRP levels had been measured at the time of the clinical visit. The primary outcome was the difference in marker level between screening and month 6 among patients in remission (BVAS/WG score of 0) at month 6. Results All subjects had severe active vasculitis (mean BVAS/WG score 8.6 +/− 3.2 SD) at screening. Among the 123 subjects clinically in remission at month 6, levels of all markers except E-selectin showed significant declines. MMP3 levels were also higher among the 23 subjects with active disease at month 6 than among the 123 subjects in remission. MMP3 levels correlated weakly with ESR and CRP. Conclusion Many markers of vascular injury and angiogenesis are elevated in severe active AAV and decline with treatment, but MMP3 appears to distinguish active AAV from remission better than the other markers studied. Further study of MMP3 is warranted to determine its clinical utility in combination with conventional markers of inflammation and ANCA titers.

Decreased CD5+ B Cells in Active ANCA Vasculitis and Relapse after Rituximab

“…PR3-ANCA (compared with MPO-ANCA), lung disease, upper respiratory tract disease, a clinical diagnosis of granulomatosis with polyangiitis (compared with microscopic polyangiitis or renal limited disease), cardiovascular involvement, and a lack of renal impairment (creatinine ,200 mmol/L) have been reported as risk factors for relapse (19)(20)(21). Nevertheless, no clinical or serologic measure is currently available that allows effective disease monitoring and distinguishes patients in long-term stable remission from those at imminent risk of relapse (22)(23)(24)(25)(26). Such a tool would allow physicians to better tailor the duration and intensity of immunosuppressive therapy based on the individual patient's needs.…”

Relation between Asymptomatic Proteinase 3 Antibodies and Future Granulomatosis with Polyangiitis

“…However, future genetic and epigenetic analysis may define a subpopulation at increased risk for disease (33,34). Polymorphisms in the PR3 promoter region, Fc-g IIa and IIIa receptors, CD-18, C3, C4, IL-10, and the a-1 antitrypsin genes were found to be associated with GPA (3,(33)(34)(35). PR3-ANCA vasculitis was specifically shown to be associated with HLA-DP, SERPINA1, and PRTN3 (33).…”

“…Subclinical PR3-ANCA trends described in our study could provide diagnostic synergy with future high-risk genomes, epigenetic profiles, or proteomes. Evaluation of the prediagnostic serum levels of cPR3-ANCA, matrix metalloproteinases (e.g., matrix metalloproteinase-3), CD8+ T cell transcript signatures, fibrinogen, and lysosomalassociated membrane protein 2 would help to even better define the subclinical pathophysiology of GPA (1,35). In addition, further evaluation of potential IgG subclass switching of PR3-ANCA would also have potential diagnostic value (36).…”

Elevated Expression of Pentraxin 3 in Anti-neutrophil Cytoplasmic Antibody-associated Glomerulonephritis with Normal Serum C-reactive Protein

“…Previous reports have suggested that some other biomarkers of vasculitis may be more reliable than CRP, such as soluble CD40 ligand, P-selectin, monocyte chemoattractant protein 1, B cell-attracting chemokine 1, matrix metalloproteinase-3, tissue inhibitor of metalloproteinases-1, or PTX3 (8)(9)(10)(11)(12). CRP is a systemic inflammatory marker protein that is induced by interleukin-6 and is produced in the liver, whereas PTX3 is induced by interleukin-1 or tumor necrotic factor-α and is produced in cells such as macrophages and endothelial cells (8,9).…”