title: Understanding disease activity in children with IgA vasculitis
Creators: name: Marro, Julien
Publisher: name: University of Liverpool Repository
Year: 2022

description: Introduction IgA vasculitis (IgAV, formerly Henoch Schönlein purpura – HSP) is the most common vasculitis encountered by paediatricians. Despite an excellent outcome in the vast majority of children, a small subgroup will suffer from a prolonged disease course and renal involvement (IgAV nephritis – IgAVN) remains a concern with 1-2% developing chronic kidney disease 5. An improved understanding of the disease pathophysiology alongside standardisation of care is required to improve disease outcomes. Aim The aim of this thesis was to improve the understanding of disease activity in paediatric IgAV. Material and methods Initially, this thesis retrospectively described the clinical characteristics and factors associated with children with recurrent/persisting disease and a systematic literature review was performed to identify definitions of recurrent and persisting IgAV in order to propose standardised definitions. Subsequently, this thesis used enzyme-linked immunoassays (ELISA) on a cohort of 47 children with IgAV and 12 healthy controls (HCs) to identify differences in the urinary concentrations of immunoglobulin A (IgA) and complement C5a. Finally, proteome profilers array kits were used to evaluate the variations in the urinary proteome between patients with and without nephritis by semi-quantitatively assessing 124 key proteins of inflammation in children with IgAV and HCs. Results A total of 13 children were included in the case series: (9 recurrent, 4 persisting). Joint involvement was the main reason prompting referral, the median time from initial presentation to diagnosis was 18.4 months (range [5.3-150.8]) and to treatment with disease-modifying anti-rheumatic drugs was 24.1 months [1.8-95.4]. The systematic literature review identified 40 studies, allowing a proposed definition of recurrent IgAV (‘a new onset of typical purpura alongside any other characteristic signs of IgAV -as per EULAR/PRINTO/PReS- at a time 4 weeks after the complete resolution of previous symptoms’) and persisting IgAV (‘typical purpura alongside any other characteristic signs of IgAV -as per EULAR/PRINTO/PReS- lasting over 4 weeks’). The ELISA data revealed that urinary concentrations of IgA and C5a were statistically significantly increased in patients with nephritis -IgAVN group- (IgA-205.0μg/mmol [51.8-850.1]; C5a-66.4ng/mmol [12.5-345.1]) compared to patients without nephritis -IgAVwoN group- (IgA-p=0.006; C5a-p=0.006) and HCs (IgA-p&lt;0.001; C5a-p=0.001). Both markers were individually excellent at 9 distinguishing IgAV patients with and without nephritis (IgA–AUC=0.811, p=0.002; C5a–AUC=0.826, p=0.001). The proteome profilers identified 20 urinary proteins that were significantly increased in IgAVN compared to IgAVwoN. The largest fold-changes were reported for B-cell activating factor, Cripto-1, sex-hormone binding globulin, angiotensinogen and apolipoprotein A1. The urinary levels of complement components C5/C5a and factor D were also statistically significantly increased in IgAVN. Conclusion This thesis investigated some aspects of complex disease activity in paediatric IgAV. Initially, in children with a recurrent and/or prolonged disease course, then the discovery of urinary markers of kidney inflammation provided novel insight into the pathophysiology of IgAVN and potential therapeutic targets. Further large longitudinal studies, randomised clinical trials and standardised clinical guidelines are urgently needed to improve outcomes in this disease.