Henoch-Schoenlein Purpura / IgA Vasculitis: past and present

Transcription

1 Henoch-Schoenlein Purpura / IgA Vasculitis: past and present S.Marinaki Nephrology Department and Renal Transplant Unit University of Athens,Laiko General Hospital Athens,Greece 4 th -8 th October 2017 Sarajevo, Bosnia and Herzegovina S.Marinaki

2 IgAV / Henoch-Schoenlein purpura 1 st description : 1802 Heberden Ηeberden W.Commentari di morborium-historia e cutatione.london,payne: Schoenlein: association of purpiric rash and arthritis Schoenlein JL.Allgemeine und spezielle Pathologie und Therapie.Etlinger:Wuerzburg, Ηenoch: addition of renal and GI involvement Henoch E.Neunter Abschnitt. Die haemorragische Purpura.Hirschwald,1874 S.Marinaki

3 Jennette JC et al.arthritis & Rheumatism 2013;65 (1):1-11

4 IgAV: Immune-complex small vessel vasculitis Jennette JC et al.arthritis & Rheumatism 2013;65 (1):1-11

5 Revised Classification: IgAV ΙgA vasculitis (IgAV) has replaced the term Henoch-Schoenlein purpura Basis: pathophysiological mechanism Circulation and tissue deposition of abnormal IgA1 ΙgAV: systemic vasculitis or single-organ involvement ΙgAV with isolated cutaneous vasculitis Renal-limited IgAV = ΙgAN Patients with initial single-organ involvement systemic manifestations Jennette JC et al.arthritis & Rheumatism 2013;65 (1):1-11

6 IgA vasculitis (IgAV) Classic triad Palpable purpura Arthralgia/arthritis GI manifestations Renal involvement is frequent: 45-50% of adult patients with IgAV The most important determinant of outcome

7 Εpidemiology of IgAV Children The most common vasculitis in childhood Annual incidence cases per children Most common in children : 4 to 7 years Predominance in boys Peak incidence in autumn and winter Adults Yang YH et al.autoimmunity Reviews 2014;13: Less frequent Annual incidence: / population No seasonal variation in incidence. Male predominance / M:F ratio of 5:1 Gardner-Medwin JM et al. Lancet 2002;360(9341):

8 Pathogenesis of IgAV Extrinsic factors, in the presence of a specific genetic background lead to initiation of the pathogenetic mechanism in IgAV Children The clinical presentation is often preceded by a respiratory infection Possible implication of viruses and bacteria as a trigger Group-A, β- hemolytic streptococcus in 20-50% of children with IgAV Trapani S et al.semin Arthritis Rheum 2005; 35:

9 Adults Pathogenesis of IgAV Association between IgAV and malignancy Retrospective study n= 200 pts with AASV n=129 pts with IgAV RR of malignancy: 6.02 in AASV and 5.25 in IgAV Retrospective study, n=250 pts Mortality rate of 26% at 15 years Leading cause of death: malignancy 30% of pts Pankhurst T et al. Rheumatology (Oxford )2004;43(12): Solid tumors, mostly lung and GI carcinomas Pillebout E et al. J Am Soc Nephrol 2002;13: IgAV Association with hematologic malignancies (lymphoma and IgA myeloma) Secondary to infections, vaccines and medications Rigante D et al.autoimmun Rev 2013;12:

10 Salvadori M et al.world J Nephrol 2015;6(4): S.Marinaki

11 Pathogenesis of IgAN / IgAV Nephritis Deposition of IC in the mesangium (2 routes:circulation and deposition or in situ formation of IC) Μesangial cells Proliferation and secretion of inflammatory mediators Complement activation/ros Podocyte damage Entering of inflammatory mediators into urinary space Injury of the glomerular filtration barrier Glomerular damage PTEC injury Tubular atrophy Interstitial fibrosis (IFTA) Wyatt RJ et al.n Engl J Med 2013;368: S.Marinaki

12 Differential diagnosis of IgAV

13 Skin biopsy in the differential diagnosis of IgAV Skin biopsy : LCV (leukocytoclastic vasculitis) + IF: prominent IgA deposition

14 Diagnostic criteria for IgAV

15 Clinical manifestations of IgAV Palpable purpura Classic triad Purpura Arthralgia/arthritis GI involvement Symmetric, predominantly at the lower extremities, at pressure sites Children: spontaneous resolution after 2-3 weeks / relapse in about 1/3 of pts Adults: in about 30% of pts, presentation with more severe forms including blisters, hemorragic and necrotic lesions Pillebout et al. Presse Med 2008;37(12): S.Marinaki

16 Clinical manifestations of IgAV Purpura

17 Clinical manifestations of IgAV Purpura

18 Clinical manifestations of IgAV Joint involvement Affects about 75% of pts Joint pain, most often of the knees and ankles, impairing walking Overt arthritis is less common Gastrointestinal involvement In 50-75% of pts Presenting symptom colicky abdominal pain 2 to 10 days after the onset of rash In 10-20% of pts abdominal symptoms may precede the onset of purpura Occult GI bleeding is common Gross bleeding (melanotic or hemorragic stools) < 10% of pts Most frequently involved sites : duodenum and small intestine Severe GI complications : intususseption and perforation in 1-5% of pts Esaki M et al.gastrointest Endosc 2002;56:920-3 S.Marinaki

19 Clinical manifestations of IgAV Renal involvement Frequency: 45-85% in adults, 25-54% in children Microscopic hematuria and subnephrotic proteinuria: 80% Μacroscopic hematuria: not common Αrterial hypertension: 30% Impaired renal function at presentation: 30% Νephritic or nephrotic syndrome:10-20% Pillebout E et al. Presse Med 2008;37(12): Differences in renal involvement between children and adults Children: self-limiting disease, good prognosis, relapses are uncommon Adults: more severe initial presentation, relapses in 20-30%, worse outcome Blanco R et al.arthritis Rheum 1997;40(5): S.Marinaki

20 Implication of renal biopsy in adults Rarity of the disease Differential diagnosis from other small-vessel vasculitides Severely impaired renal function at presentation Prognosis / Therapeutic decisions

21 Renal Histology Renal IgAV=IgAN

22 Histological Classification of IgAN Oxford Classification 2009 (IgAN) IgAN with egfr>30ml/min, exclusion of crescentic IgAN Histologic features prognostic indicators of renal outcome (ΜΕST) 1. Μesangial hypercellularity (Μ) 2. Εndocapillary proliferation (Ε) 3. Segmental glomerulosclerosis or adhesion (S) 4. Tubular atrophy and interstitial fibrosis (Τ) Cattran DC et al.kidney Int 2009;76: S.Marinaki

23 Histological Classification of IgAV Pillebout E et al. Presse Med 2008;37:1773-8

24 Study Retrospective Multicenter Italy Coppo etal Retrospective Spain Blanco etal Retrospective Finland Rauta et al Retrospective Multicenter France Pillebout et al Number of patients 95 Adults 57 Children 116 Children 46 Adults 38 Adults 250 Adults Follow up (years) 1.8 Outcome of IgAV nephritis 5 CKD ESRD Death Recovery Prognostic indicators 16% 7% 32% 31% 94% 89% GFR Proteinuria>1g/d ay Arterial hypertension 6 19% 8% Proteinuria>1g/d ay 15 38% 11% 26% Proteinuria>1g/d ay Initial GFR<50ml/min

25 Outcome and prognosis of IgAV nephritis Worse renal outcome in adults Progression to ESRD: 3-5% in children Adulthood IgAV nephritis more frequent and with more severe initial presentation Progression of CKD not uncommon / 25-30% of patients reach ESRD Negative prognostic indicators Proteinuria > 1g/day Impaired renal function at presentation Pillebout E et al. J Am Soc Nephrol 2002;13: S.Marinaki

26 Therapy of extrarenal manifestations of IgAV Skin involvement Steroids are ineffective in shortening the course or the severity of skin lesions and as prevention of relapses Colchicine ( 1mg/day,) Dapsone Leukotriene receptor antagonist (Montelukast) Small series of patients (predominantly children) Satisfactory results but limited efficacy in preventing relapses Gastrointestinal and joint involvement Steroids are effective and are considered first line treatment as monotherapy Pyne D et al.rheumatology (Oxford) 2001;40(12):430-1

27 Therapy of IgAV nephritis There are no RCT s neither in children nor in adults All existing recommendations are grade D, or not graded IgAV nephritis in adults should be treated the same as in children (weak evidence, level of recommendation 2D) Recommendations in children refer to the recommendations for IgAN It is suggested to treat IgAV with renal involvement the same as IgAN KDIGO,Kidney International Supplements 2012;2: S.Marinaki

28 Immunosuppressive therapy in IgAV nephritis Prospective, open-label trial France CESAR STUDY n=54 adults with severe, proliferative IgAV nephritis Exclusion of pts with RPGN Randomization Steroid monotherapy vs steroids + cyclophosphamide Follow up: 12 months No additional benefit in renal outcome in the steroid plus cyclophosphamide group Pillebout E et al. Kidney Int 2010;78(5): S.Marinaki

29 Therapy of IgAV nephritis = Therapy of IgAN 4 patient groups 1. Patients at low risk for progression the silent majority 2. Patients with micro-macroscopic hematuria, proteinuria<3.5 and>1g/24hr ±AH+ preserved renal function at presentation the typical IgAN patient 3. Patients with severely impaired renal function at presentation point of no return 4. Rare manifestations of IgAN / IgAV Νephrotic syndrome Rapid deterioration of renal function Floege J and Eitner F.J Am Soc Nephrol 2011;22: S.Marinaki

30 1. Patients at low risk for progression the silent majority Diagnosis : incidentically Presentation with isolated microscopic hematuria Need for long-term follow-up >10 years Difficult to achieve in otherwise healthy individuals (!) Risk of progression to ESRD ~ 15-20% after > 20 years Floege J and Eitner F.J Am Soc Nephrol 2011;22: S.Marinaki

31 2. Patients with micro-macroscopic hematuria, proteinuria<3.5 and>1g/24hr ±AH+ preserved renal function at presentation the typical IgAN patient General supportive measures Persistent proteinuria >1g/day Six-month course of high-dose steroid monotherapy S.Marinaki

32 Monotherapy with corticosteroids Study (RCT) Pozzi, Italy Katafuchi, Japan Hogg, USA Lv, China Corticosteroid regimen IV MP 1g/day x 3 days (month 1,3 and 5) + per os prednisone 0,5 mg/kg every other day Duration: 6 mo per os prednisolone 20 mg/day Gradual tapering to 5 mg/day at 18 months per os prednisone 60 mg/m 2 every other day for 3 months 40 mg/m 2 for 9 mo 30 mg/m 2 for 12 mo per os prednisone 0,8-1 mg/kg /day for 2 months Then tapering by 5-10 mg/2 weeks Duration: 6-8 mo RAAS blockade 14% at baseline and during follow-up 2% at baseline and during follow-up Enalapril in hypertensive patients Cilazapril Outcome 10-year renal survival 97% in the steroid group vs. 50% in the control group No improvement in kidney survival No difference between the 2 groups in 2 years Significantly fewer patients with a 50 % increase in scr in the steroid group Control group Supportive treatment Dipyridamole Supportive treatment Supportive treatment

33 Immunosupressive Therapy Study Ballardie, United Kingdom,2002 Pozzi, Italy,2010 Stop-IgAN trial Eitner and Floege, Germany, 2015 Combination per os prednisone 40 mg/day (10 mg/day by 2 years) + per os CYC 1,5 mg/kg/day (3 months) THEN per os Aza 1,5 mg/kg/day (2-6 years) MP (Pozzi regimen) + per os Aza 1,5 mg/kg/day (6 months) Steroids (GFR>50ml/min or Steroids + IS (CYC/Aza) GFR30-50ml/min Control group Supportive treatment (no immunosuppression) Corticosteroid monotherapy (Pozzi) Optimized supportive treatment RAAS blockade Inconsistent 50% of patients at baseline Optimized in all patients Outcome Significant improvement of renal survival at 5 years (72% vs. 6%) No additional benefit from the addition of Aza in 5 years No additional benefit after follow up of 3 years in the Steroid ± IS group

34 3. Patients with severely impaired renal function at presentation point of no return Definition? Creatinine > mg/dl or egfr<30-20ml/min Optimization of supportive treatment is mandatory Immunosuppression has no indication and may be even harmful Hou FF et al. N Engl J Med 2006;354: S.Marinaki

35 4. Rare manifestations of IgAN / IgAV Νephrotic syndrome Rapid deterioration of renal function Overt nephrotic syndrome (podocytopathy) Therapy as for minimal change disease (MCD) Rapid deterioration of renal function Repeat biopsy within 5-10 days Differentiation between rapidly progressive GN ( RPGN ) and acute tubular injury (ATI ) due to tubular obliteration by red cell casts Floege J and Eitner F.J Am Soc Nephrol 2011;22: S.Marinaki

36 Rare manifestations of IgAN / IgAV Rapidly progressive glomerulonephritis (RPGN) (Suggestion, level 2D of recommendation) Treatment as for ANCA-associated vasculitis CyC + MP (±PLEX) KDIGO,Kidney International Suppl 2012;2: Severe histolical features with crescents ± fibrinoid necrosis, not defined as RPGN (crescents in < 50% of glomeruli)? Positive outcomes in small case-series with IS Tumlin JA et al.nephrol Dial Transplant 2003; 18: Tang Z et al. Am J Nephrol 2002; 22: Pankhurst T et al.nephron Clin Pract 2009; 112: c16 c24 S.Marinaki

37 In summary IgAV in adults represents a rare entity which should always be included in the differential diagnosis of a patient presenting with nephritic features and skin rash. Though our understanding of IgAV has improved over the last years, several questions about the pathogenetic mechanisms, the genetic predisposition, the determinants of outcome and the optimal therapeutic approach still remain unanswered.

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