S100A12 Serum Levels and PMN Counts Are Elevated in Childhood Systemic Vasculitides Especially Involving Proteinase 3 Specific Anti-neutrophil Cytoplasmic Antibodies

Abstract

Objectives: Chronic primary systemic vasculitidies (CPV) are a collection of rare diseases involving inflammation in blood vessels, often in multiple organs. CPV can affect adults and children and may be life- or organ-threatening. Treatments for adult CPV, although effective, have known severe potential toxicities; safety and efficacy of these drugs in pediatric patients is not fully understood. There is an unmet need for biologic measures to assess the level of disease activity and, in turn, inform treatment choices for stopping, starting, or modifying therapy. This observational study determines if S100 calcium-binding protein A12 (S100A12) and common inflammatory indicators are sensitive markers of disease activity in children and adolescents with CPV that could be used to inform a minimal effective dose of therapy.Methods: Clinical data and sera were collected from 56 participants with CPV at study visits from diagnosis to remission. Serum concentrations of S100A12, C-reactive protein (CRP) and hemoglobin (Hb) as well as whole blood cell counts and erythrocyte sedimentation rate (ESR) were measured. Disease activity was inferred by physician's global assessment (PGA) and the pediatric vasculitis activity score (PVAS).Results: Serum concentrations of standard markers of inflammation (ESR, CRP, Hb, absolute blood neutrophil count), and S100A12 track with clinically assessed disease activity. These measures—particularly neutrophil counts and sera concentrations of S100A12–had the most significant correlation with clinical scores of disease activity in those children with vasculitis that is associated with anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3.Conclusions: S100A12 and neutrophil counts should be considered in the assessment of disease activity in children with CPV particularly the most common forms of the disease that involve proteinase 3 ANCA.Key messages:- In children with chronic primary systemic vasculitis (CPV), classical measures of inflammation are not formally considered in scoring of disease activity.- Inflammatory markers—specifically S100A12 and neutrophil count—track preferentially with the most common forms of childhood CPV which affect small to medium sized vessels and involve anti neutrophil cytoplasmic antibodies (ANCA) against proteinase-3.

Different Disease Endotypes in Phenotypically Similar Vasculitides Affecting Small-to-Medium Sized Blood Vessels

“…Patients described in this study were enrolled in the Pediatric Vasculitis Initiative (PedVas) ( 17 , 18 ) and included children (18 yrs of age and younger) and adults with small-to-medium sized blood vessel vasculitis. Two pediatric cohorts were used for this study: Cohort 1 contained a total of 30 patients that contributed samples at diagnosis ( n = 25) or relapse ( n = 5); at the time of sample and data collection, disease activity was high (indicated by PVAS; see clinical data description) and this cohort was used for initial transcriptomic discovery.…”

Gene–Dose Effect of MEFV Gain-of-Function Mutations Determines ex vivo Neutrophil Activation in Familial Mediterranean Fever

“…Cytokines or cytokine receptor antagonists (IL-1β, IL-6, IL-8, IL-10, IL-18, IL-1Ra, and TNFα), neutrophilic granula proteins (Proteinase 3, MPO), and chemokines [MCP-1, MIP-1α (CCL-3), MIP-1β (CCL-4), and MIP-3α (CCL-20)] in culture supernatants (SNs) were quantified by multiplexed bead array assays (ProcartaPlex, Thermo Fisher, Waltham, MA, USA; R&D Systems, Minneapolis, MN, USA) according to the manufacturers' instructions. S100A12 was detected by a combination of in-house monoclonal anti-S100A12 antibodies (19) translated to the MagPlex microsphere platform (Luminex, Hertogenbosch, The Netherlands) (20). Data acquisition was performed on a MagPix instrument (Merck Millipore) using xPONENT v4.2 software (Luminex).…”

Adenosine deaminase 2 activity negatively correlates with age during childhood

“…2a). Concentrations of C-reactive protein (CRP), a known biomarker of inflammation [26], were within the normal range (< 5 μg/ml [27]) for 94/100 healthy participants aged 0-2 yrs (n = 16; youngest being 5 months of age), 3-5 yrs (n = 19), 6-8 yrs (n = 18), 9-11 yrs (n = 16), 12-14 yrs (n = 13), 15-18 yrs (n = 12). Samples from 6 individuals with elevated CRP (suggestive of underlying inflammatory processes) were excluded from further analysis ( Supplementary Figure 3, Additional file 1).…”