Henoch-Schönlein purpura:can we prevent nephritis and progression?

1. Henoch-Schönlein purpura:can we prevent nephritis and progression? A Oner and J-C Davin: experts Comments :R Bogdanovic ESPN Lyon 2008

2. Relation between biological IgA abnormalities and mesangial IgA deposits in isolated hematuria in childhood Davin, Foidart, Mahieu Clin Nephrol 1987. In HSP, predominant IgA deposits in mesangium and along capillary walls as well as in other organs. High frequence of IgA abnormalities in HSP vs C and NS

3. Normal control HSP and IgAN Terminal galactosyl residues binding to hepatocytes No more terminal galactosyl residue No IgA1 hepatic clearance

4. Effecter mechanisms of IgA deposits in HSPN MC activation by IgACC MC EC activation by IgACC, IL-8:Inflammation vWF:Thrombocyte aggregation EC Fibrosis Podocyte Crescents formation

5. To treat or not to treat? What patient ? dilemma: all kind of initial clinical symptoms can resolve spontaneously or lead to CRF

6. Risk of CRF in 78 patients with HSPN followed during 23.4 y (mean) Goldstein et al, Lancet 1992 Patients to treat

7. Long term outcome of HSPN (Goldstein et al, Lancet 1992)

8. ANY INITIAL RENAL PRESENTATION OR EVEN APPARENT COMPLETE HEALING CAN LEAD TO CHRONIC RENAL INSUFFICIENCY

9. Major prognostic factors • Initial clinical signs • Persisting proteinuria • Persisting renal insufficiency • Frequent relapsing macroscopic hematuria • Histology

10. Therapeutic use of histological findings > 50% Crescents, high activity index High chronicity index, low activity index Intensify immunosuppression Add ACE inhibitors, No immunosuppression,

11. Interpretation of non prospective randomized studies on HSPN • A/ Spontaneous complete recovery Bariety et al (1964),Vernier et al (1975): the natural history of this disease favors rapid recovery even following the appearance of the nephrotic syndrome, renal insufficiency, or gross haematuria during the first few months of illness • B/ Late deterioration by hyperfiltration after apparent complete recovery. • C/ Unpredictable evolution according to clinical symptoms • D/ No placebo group possible in some categories of patients because of high CRF risk

12. Effective treatments for HSPN (RCT)Cochrane Renal group 2008 • Anti-inflammatory • Steroids (no) • Plasma exchange (no) • Immunosuppressive • Steroids (no) • CCP,MMF,CsA (no) • Rituximab (no) • Plasma exchange (no) • Anti-coagulation • Anti-platelets aggregation (no) • Heparin (no) • Anti-MC proliferation • ACE inhibitors (no but well for IgAN) • Anti-hyperfiltration • ACE inhibitors (no but well for IgAN)

13. Historical series (no MPNS) NS Patients Number: 29 ESRF:11 (38%) Latest follow-up: ? Relation CRI and > 50% crescents MPNS series NS Patients Number:38 ESRF:4 (10%) Latest follow-up: 1-16 y Relation delayed treatment/ CRI Methylprednisolone pulse therapy in the treatment of severe forms of Schönlein Henoch purpura nephritisNiaudet and Habib Ped Nephrol 1997

14. Treating severe Henoch-Schönlein and IgA nephritis with plasmapheresis aloneShenoy, Ognjanovic, Coulthard 2007 -14 HSPN, 2 IgAN -Mean GFR at presentation: 56 ml/min/ 1.73m2 -Nephrotic syndrome -Plasmapheresis only -Mean follow up: 4 years

15. Case report Presentation: purpura, microhematuria, proteinuria, NS, joints pain, mild renal insufficiency Biopsy 1: diffuse endocapillary proliferation, 25 % crescents Biopsy 2: diffuse endocapillary proliferation, 25 % crescents Proteinuria MPNS followed by prednison MMF Plasmapheresis 3x / w Biopsy 2 Biopsy 1

16. Patient History CPP MPNS • Patient history • 6 year old girl • Palpable purpura 6 months ago • Abdominal pain, arthralgia • Proteinuria and hypoalbuminemia • Delayed treatment Pred ACE-I Proteinuria (g/L) Renal biopsy Pl. albumin (g/L) 25% glomeruli with crescents Mesangial proliferation Pl.creatinine (µmol/L Mesangial and subentothelial IgA deposits Apparent recovery CRF

17. What we actually do • no renal symptoms, • no treatment • Isolated hematuria, minimal proteinuria • No biopsy no treatment, excepted in repeated macroscopic hematuria. • In all other cases: renal biopsy • a/ < 50% crescents: MPNS followed by prednisone • Insufficient response: add immunosuppression, • Insufficient response: repeat biopsy: eventually PEs • b/ > 50% crescents: ID + immunosuppression • Insufficient response, repeat biopsy • Add PEs • c/ residual proteinuria: ACE inhibitors • Apparent recovery • Look for hyperfiltration and eventually ACE inhibitors

18. General Data 232 patients/y (1-18y)/16 millions Incidence 1-18y: 6.1/100,000 3-6 y: 14.9/100,000 IgA in skin biopsy (53%) Henoch Schonlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria.Aalberse J, Dolman K, Ramnath G, Peirera R, Davin JC Ann Rheum Dis 2007 how many of them have really HSP?

19. EULAR/PRES Endorsed Consensus Criteria for the Classification of Childhood Vasculatides under review by the ACR (Vienna 2005)Ann.Rheum. Dis. Online Dec 2005 Seza Ozen, Nicolino Ruperto Michael Dillon Arvind Bagga Karryl Barron Jean-Claude Davin Tomisaku Kawasaki Carol Lindsay Ross Petty Anne-Marie Prieur Angello Ravelli Patricia Woo EULAR/PRES Classification Criteria for HSP • At least one of the following 4 should be present: • Diffuse abdominal pain • Any biopsy showing predominant IgA deposition • Arthritis or arthralgia • Renal involvement (any hematuria and/or proteinuria) • In the presence of Palpable Purpura(mandatory criterion)

20. Message to take home • Treat excepted for mild symptoms • MPNS and not prednisone only • Do not delay treatment • Repeat biopsy if treatment failure • Adapt treatment according to histology and response • Follow at long term even when complete recovery • International multicenter RCT are needed