title: Methods of measuring disease activity in paediatric IgA vasculitis
Creators: name: Williams, Chloe
name: Toner, Aileen
name: Dowsett, Tom
name: Murphy, Jared
Publisher: name: University of Liverpool Repository
Year: 2022

description: Introduction: IgA vasculitis (IgAV, Henoch-Schönlein purpura, HSP) is the most common vasculitis of childhood and currently contributes to 1-2% of all chronic kidney disease (CKD) stage 5. New methods of measuring disease activity are required to improve the standard of care given. The aim of this thesis is to evaluate methods of measuring disease activity in IgAV using urine biomarkers and a disease-specific scoring tool. Methods: Firstly, a systematic literature review was performed using 4 search engines and a search term strategy with predefined inclusion and exclusion criteria. Promising biomarkers were divided in terms of traditional or novel and described using statistical significance and area under the curve (AUC) values. Secondly, a specific disease activity scoring tool (the IgA-VAS) was developed and preliminarily validated in a cohort of paediatric patients with IgAV. Test validity, concurrent validity and inter-rater agreement were assessed retrospectively. A randomly selected subgroup were also scored using a visual analogue scale. Results: The systematic review identified 13 eligible studies. A total of 2,446 paediatric patients were included: healthy controls (n=761), children with IgAV-N (n=1,236) and children with IgAV without nephritis (IgAV-noN, n=449). 51% were male, median age 7.9 years. The traditional markers, 24-hour protein quantity and urine protein:creatinine ratio were deemed acceptable for assessing severity of nephritis (AUC &lt;0.8). Urinary albumin concentration (Malb) performed well (AUC 0.81-0.98). The most promising novel urinary biomarkers in predicting presence of nephritis were kidney injury molecule-1 (KIM-1) (AUC 0.93), monocyte chemotactic protein-1 (MCP-1) (AUC 0.83), N-acetyl--glucosaminidase (NAG) (0.76-0.96), and angiotensinogen (AGT) (AUC not available). Urinary KIM-1, MCP-1, and NAG appeared to correlate with disease severity. The IgA-VAS consists of 40 manifestations, each with a score from 0-10, divided into 5 domains: cutaneous, gastrointestinal, musculoskeletal, renal and other. For preliminary validation, retrospective scoring was performed in a single tertiary centre over a 5-year period. 153 children met the inclusion criteria: 54% were male with a median age of 5.7 years (range 0.6-16.7). Median total scores for the IgA-VAS were 7/125 (range 2-31) and 5/125 (range 2-29) for rater 1 and rater 2 respectively. Median PVAS scores were 6/63 (range 2-25) and 5/63 (range 2-20). Correlation between all overlapping domains of the two tools was strong (all r&gt;0.5, p&lt;0.001). Inter-rater reliability overall was low for both tools (0.131 and 0.225, p&lt;0.001). For the IgA-VAS, interrater reliability was low for the cutaneous, renal, and other domains (0.332, 0.237, 0.288 p&lt;0.001) and high for the gastrointestinal and musculoskeletal domains (0.543 and 0.667, p&lt;0.001). The general, cutaneous, and renal subsystems in the PVAS had a low inter-rater reliability (0.347, 0.213, 0.304, p&lt;0.001) and was better for the abdominal domain (0.579, p&lt;0.001). The IgA-VAS moderately 7 correlated with the visual analogue scale for both raters (r=0.482, r=0.362, p&lt;0.05), however the PVAS strongly correlated with rater 1 (r=0.504, p=0.004) and moderately correlated with rater 2 (r=0.372, p=0.043). Conclusion: Future studies should focus on multicentre prospective studies for biomarker discovery and validation of the IgA-VAS in a large cohort of paediatric patients.