Henoch Schonlein Purpura A proposed pathway for follow-up Watson L 1,2, Richardson A 1, Holt R.C.L 1, Jones C.A 1, Beresford M.W 2. Departments of Paediatric Nephrology 1 and Rheumatology 2, Alder Hey Children’s NHS Foundation Trust Hospital & Institute of Translational Medicine, University of Liverpool, UK

Henoch Schonlein Purpura Small vessel vasculitis IgA complex, C3 deposition Arterioles, Capillaries, Venules Inflammatory neutrophils, monocytes Typically presents with rash Scrotal involvement Abdominal pain, bleeding, intussusception Non-erosive arthritis, arthralgia Renal involvement Rarely neurological, lung

Diagnosis More common preschool; 90% <10 years old EULAR classification criteria 1 Purpura/petechiae rash Plus any one of; Abdominal involvement, Renal involvement, Joint involvement (arthritis/arthralgia), Histological evidence of IgA deposits. 1. Ozen, 2010

Commonest childhood vasculitis Incidence cases per 100,000 child population 2 (SSNS 3 cases per 100,000; IDDM 207 cases per 100,000) Average North West DGH; Catchment population of 60,000 children 3 ≈ 6-12 cases of HSP diagnosed by a DGH/year Rare for GP population Average GP 2000 patients, 18% (274) children; 1 case for approx. every 36 GP’s Henoch Schonlein Purpura 2. Gardner-Medwin et al, 2002, 3.

HSP nephritis (HSPN) Seen in up to 40% – Asymptomatic & only long term consequence – Requires active screening Long term outcome of HSPN – Unselected cohorts risk of renal impairment 1% Risk rises if nephritic or nephrotic 1 Up to 20% nephrotic range proteinuria – Cohorts with established HSPN 15-20% ESRF 2,3 – Accounts for 1.7% all UK ESRF 4 1.Mir et al 2007, 2. Shenoy et al, 2007, 3. Butani et al, 2007, 4. UK Renal Registry 2005

Screening for HSPN Screening varies 1 – Within a centre, region, national & international Centre 1: Paediatrician led follow up Centre 2: GP led follow up ‘uncomplicated cases’ Screening imposes financial burden, parental anxiety Variations also in renal referral process and biopsy indications 1.Weiss P et al J Ped 2009

HSP diagnosis Diagnosis; EULAR criteria Screening for nephritis No renal involvement Renal involvement Resolved renal involvement Persistent/r esolve 20% ESRF HSPN Diagnosis; Renal biopsy ISKDC classification

Evidence-based treatment of HSPN Systematic review of RCTs: no difference Early corticosteroids V’s placebo, total n=379 1 Cyclophosphamide V’s supportive, n=56 Cyclosporin V’s methylprednisolone RCT, n=24 2 Other studies Cyclophosphamide + methylprednisolone, n=12 3 Azathioprine + steroids, n=21 4 Cochrane: Few RCTs 5 – Sparse data, no proven benefit of treatment Challenges: self resolving, high risk groups, no standardised care 1. Tizard et al, unpublished, personal communication; Dudley 2007, Huber 2004, Mollica 2004, Ronkainen Jauhola et al, Flynn et al, Bergstein et al, Chartapisak W et al. 2009

HSP diagnosis Diagnosis; EULAR criteria Screening for nephritis No renal involvement Renal involvement Resolved renal involvement HSPN 20% ESRF Persistent/r esolve Diagnosis; Renal biopsy ISKDC classification ? ? ?

HSP screening at Alder Hey Designed in 2004, multi-disciplinary Paediatric nurse led Urine dipstick, blood pressure Parent education Hand held records Triaged according to urinalysis (day 7) – Intensive (8 visits over 12 months) – Standard (5 visits) Total of 12 months monitoring

Aims Primary To describe renal involvement in an unselected cohort of children with HSP Secondary To revise our nurse led HSP monitoring pathway

Primary outcome Primary outcome; Need to exit the nurse led pathway for a medical review Exit criteria (excluding patients from nurse led monitoring) Hypertension Urine albumin:creatinine ratio (UACR) > 200mg/mmol Serum albumin <30g/l eGFR < 80 ml/min/1.73m 2 Macroscopic haematuria >28 days 12 months completed monitoring with urine abnormalities

Investigations Presence of proteinuria Presence of exit criteria

HSP coding: Identified n=176 Standard FU: No proteinuria n=80 Intensive FU: Proteinuria n=22 Excluded: Other diagnosis n=11 No care pathway n=61 HSP & sufficient data n=104 46% renal involvement at diagnosis DNA n=2 Day 7: allocation n=102 Developed proteinuria n=13 Moved area n=2 Standard FU (n=65): Outcome n=1 renal; n=64 normal Intensive FU (n=35): Outcome n=8 renal; n=27 normal Outcome Discharged n=91; renal n=9 Month 12: outcome n=100

Results

Older patients more likely to develop HSPN P<0.01

Outcome Primary outcome; 9 patients required review – 2 patients early review (<3 months) – 7 patients referred after 12 months monitoring All patients who developed proteinuria were <6m from diagnosis Proteinuria triggered medical review prior to other criteria Follow up; – 2 patients early review; grade 3b HSPN, 1 resolved – 7 patients late review; monitored+/- ACEi, 4 under FU

Day 7 Urinalysis: Predicting outcome Proteinuria: Poor predictor Confidence Interval – Positive predictive ratio 32% (15 to 55%) – Sensitivity 78% (45 to 94%) Absence of proteinuria: Good predictor of normal outcome – Negative predictive ratio 97% (90 to 99%) – Specificity 84% (75 to 90%)

Revised HSP Monitoring Pathway Updated our current practice – ‘The Alder Hey HSP Monitoring Pathway’ 6 month monitoring period Paediatric led – Availability of BP cuffs, paediatric phlebotomists, easy referral for paediatric advice, parental anxiety Stratified according to day 7 urinalysis All urine testing undertaken by trained nurses Revised exit criteria

The Alder Hey HSP pathway Standard monitoring 1 month review 3 month review 6 month review Discharge Intensive monitoring Day 14 review 1 month review 2 month review 3 month review 4 month review 6 month review Refer for medical review Presentation & diagnosis Day 7 review

Exit criteria

Robust peer review

Future strategies Universal follow up – Clinical improvements; standardise care, equity, improved awareness – Research opportunities; describe ‘at risk’ patients, early intervention, facilitate RCTs Regional standardisation

National interest Adoption; NW centres, Scottish region, Evelina Hospital UK support to adopt pathway – Welsh Paediatric Society – British Association of General Paediatrics – Scottish Paediatric Network (SPARN) – Paediatric Nephrology CSG (Prof Saleem) – Paediatric Rheumatology CSG (Prof Beresford) – General Paediatric CSG (Dr Powell)

HSP diagnosis Diagnosis; EULAR criteria Screening for nephritis No renal involvement Renal involvement Resolved renal involvement HSPN 20% ESRF Persistent/r esolve Diagnosis; Renal biopsy ISKDC classification ? ? ? National screening Reliable data Characterise ‘at risk’ patients Develop renal biopsy indications Evidence based management

Phased development (3-years) Phase 1: Universal screening, HSP registry Pathway revalidation Phase 2: HSPN Working Group, HSPN registry Data biopsy indications & management Phase 3: Standardise HSPN management, Renal biopsy indications & consensus management Randomised controlled trials

Conclusions All HSP patients require 6m renal screening – Renal involvement common – Majority will have a normal renal outcome – High risk groups - proteinuria, older, non-Caucasian – Evidence based renal monitoring Universal monitoring with phased development

Acknowledgements Patients, families: Alder Hey patients and families Authors: Professor Michael Beresford Dr. Caroline Jones Dr. Richard Holt Dr. Amanda Richardson Original HSP pathway committee: Dr. Gavin Cleary Dr. Briar Stewart Dr. Dave Casson Elvina White Pauline Stone Clinicians: Dr. Henry Morgan Dr. Brian Judd Dr. Eileen Baildam Dr. Liza McCann Ward D2 staff