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Aysin Bakkaloglu, M.D. Hacettepe University Faculty of Medicine Pediatric Nephrology and Rheumatology Ankara, TURKIYE ESPN 2008 Lyon, FRANCE TREATING DIFFICULT.

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Presentation on theme: "Aysin Bakkaloglu, M.D. Hacettepe University Faculty of Medicine Pediatric Nephrology and Rheumatology Ankara, TURKIYE ESPN 2008 Lyon, FRANCE TREATING DIFFICULT."— Presentation transcript:

1 Aysin Bakkaloglu, M.D. Hacettepe University Faculty of Medicine Pediatric Nephrology and Rheumatology Ankara, TURKIYE ESPN 2008 Lyon, FRANCE TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS

2 Plan of the talk Treatment of difficult patients of renal vasculitis –ANCA associated vasculitis - Wegener granulamatosis - Microscopic polyangiitis –Classic polyarteritis nodosa –Takayasu arteritis

3 ANCA ASSOCIATED VASCULITIS Wegeners granulomatosis Microscopic polyangiitis Renal limited vasculitis Churg-Strauss syndrome Histologic similarities Potential contribution of ANCA to their pathogenesis Similar responses to immunosuppressive therapy Nat Clin Rheumatol 2006; 2:

4 GOALS of TREATMENT in ANCA ASSOCIATED VASCULITIS Patient survival Induce remission of active state Reduce disease relapse Minimize therapeutic toxicity –Least toxic and most effective therapy –Prevent and monitor toxicity

5 CHALLENGES in TREATING ANCA ASSOCIATED VASCULITIS Rarety of ANCA associated vasculitis in children High morbidity and mortality Definitions of –disease stages –activity stages –outcome measures Duration of treatment

6 CASE 1

7 12 year old girl Weakness, periumblical abdominal pain Loss of appetite Nausea, vomiting Pallor Decreased urine output with hematuria Besbas N et al. Pediatr Nephrol 2003;18:

8 Laboratory Tests Hb : 7.8 g/dl WBC : 7300 /mm 3 Platelet : 240 x10 3 /mm 3 CRP : 10.2 mg/dl ESR: 120 mm/hr BUN: 51 mg/dl Cre : 5.84 mg/dl T. prot: 7.3 g/dl Alb: 3.2 g/dl Urinary pH: 6.5 density: 1020 protein: RBC / hpf Urinary protein: 87.5 mg/m 2 /hr GFR: 18 ml/min/ 1.73 m 2 ANA: Negative Anti ds-DNA: Negative ANCA: –p-ANCA: strong positive (IFA) –MPO-ANCA: 250 EU/ml (ELISA) Anti-GBM: positive Besbas N et al. Pediatr Nephrol 2003;18:

9 Renal Biopsy Besbas N et al. Pediatr Nephrol 2003;18:

10 1 mo2 mo3 mo4 mo5 mo6 mo9 mo12 mo15 mo18 mo21 mo24 mo 0.5 mg/kg/d prednisone MPZ 2 mg/kg/d cyclophosphamide 2 mg/kg/d azathiopurine Plasma exchange MMF Etanercept Rituximab Etanercept Rituximab Serum creatinine (mg/dl)

11 Nine years after successful renal transplantation –Cre: 0.98 mg/dl –GFR: 112 ml/min/1.73 m 2

12 CASE 2

13 Necrotic tissue (soft palate, digits and uvula) Arthritis Myalgia Limitation of motion URTI Hoarseness, swollen edematous tongue, speech abnormality, wt loss URTI Hoarseness, swollen edematous tongue, speech abnormality, wt loss Fatigue, worsening of the symptoms and myalgia Glossitis, iv penicilin Fever Subcutaneous nodules (fingertips, nose) Generalized maculopapular rash Necrotic lesions (right foot sole) Generalized edema Fever Subcutaneous nodules (fingertips, nose) Generalized maculopapular rash Necrotic lesions (right foot sole) Generalized edema Ceftriaxone and clindamicin iv Iloprost, Pentoxiphyllin Amlodipine, Captopril Piperacillin-Tazobactam, Vancomycin, Rifampicin, Fluconazole Iloprost, Pentoxiphyllin Amlodipine, Captopril Piperacillin-Tazobactam, Vancomycin, Rifampicin, Fluconazole days year old, girl

14 Physical Examination BP: 130/60 mmHg Pulse: 92 /min BW: 40 kg (75p) Height: 146 cm (50-75p) BP: 130/60 mmHg Pulse: 92 /min BW: 40 kg (75p) Height: 146 cm (50-75p) Maculopapular rash Edema (pretibial and dorsum of hand) Tongue atrophy and tissue loss Necrotic lesions

15 Laboratory Tests Hb : 7.4 g/dl WBC : /mm 3 Platelet: 550x10 3 /mm 3 CRP : 14.9 mg/dl ESR: 90 mm/hr BUN: 8 mg/dl T. prot: 6.17 g/dl Alb: 2.39 g/dl Urinary ph: 6.5 density:1020 protein: -, 1-2 RBC IgA : 158 mg/dl (68-378) IgM : 144 mg/dl (50-250) IgG : 2050 mg/dl ( ) ANA: Negative Anti-DNA: Negative c-ANCA: Mild staining at IIF Negative for MPO, PR3 Thrombotic panel including ACLs all (-) MEFV: V726A/-

16 Paranasal CT

17 Necrotizing Vasculitis

18 Oral prednisone (2 mg/kg/day) Oral cyclophosphamide (2 mg/kg/day) Oral prednisone (2 mg/kg/day) Oral cyclophosphamide (2 mg/kg/day) days 15 Pulse steroid 17 Plasma exchange 19 Plasma exchange 21 Plasma exchange 23 Plasma exchange 25 Plasma exchange Plasma exchange Hematuria, proteinuria, dyspnea 14

19 Classification of a child as WG: 3 of the following six should be present: 1. Abnormal urinalysis* 2. Granulomatous inflammation on biopsy* 3. Nasal-sinus inflammation* 4. Subglottic, tracheal or endobronchial stenosis 5. Abnormal chest x-ray or CT* 6. PR3 ANCA or C-ANCA staining Classification of a child as C-PAN: Biopsy showing small and/or mid-size artery necrotizing vasculitis and/or angiographic abnormalities +2 out of the following 7 criteria 1. Skin involvement* 2. Myalgia or muscle tenderness* 3. Systemic hypertension 4. Mononeuropathy or polyneuropathy 5. Abnormal urinalysis and/or impaired renal function* 6. Testicular pain or tenderness 7. Signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or CNS)* EULAR/PRES Criteria. Ann Rheum Dis; 2006

20 Prednisolone –oral 2 mg/kg –IV 15 mg/kg/dose CYC –Oral 2 mg/kg –500 mg/m 2 Cre (> 500 mmol/l ) Vital organ involvement plasma exchange AZA: 1-2 mg/kg/d CS: 0.25 mg/kg/alternate day Risk factors for ERSD and relapse: Upper or lower respiratory tract disease Proteinase-3 ANCA seropositivity Severe kidney disease Female sex 3-6 months 12 months or longer Bakkaloglu A et al. Arch Dis Clin 2001; 85: Besbas N et al. Pediatr Nephrol 2000; 14:

21 INDUCTION THERAPY Prednisone ( 1-2 mg/kg/day) ± MP ( 3 pulses) Cyclophosphamide ( 2 mg/kg/day) or iv pulses mo. NORAM: MTX vs CYC MEPEX: PE vs MP CYCLOPS: CYC iv vs oral WEGET: Etanercept vs placebo SOLUTION: ATG Maintenance therapy NORAM: MTX vs CYC CYCAZAREM: AZA vs CYC IMPROVE: AZA vs MMF REMAIN: AZA, 24 mo vs 48 mo

22 Rituximab (RITUXVAS): –Several, uncontrolled studies (refractory) Many reports observed disease remissions in relapsing and refractory patients with ANCA associated or other vasculitides Leflunomide Deoxypergualin Anti CD52: –Predominantly leads to T-lymphocyte depletion –Its use has been complicated by a high frequency of infection Anti-thymocyte globulin (ATG): –Should be reserved for severe refractory WG Recent Alternative Therapies

23 CASE 3

24 3 year old girl Poor appetite, fatigue, weight loss for one month Over the past five days –Severe and frequent vomiting –Subsequently developed drowsiness and unconsciousness –High blood pressure –Subarachnoid hemorrhage Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7):

25 Physical examination Body temperature: 36.6 C Pulse rate: 104 /min Respiratory rate: 20 /min Blood pressure: –180/110 mm Hg (left arm) –175/105 mm Hg (right arm) She was unconscious Mydriasis Diminished light reaction in the right eye Right third nerve and left six nerve palsies Left hemiparesis Deep tendon reflexes were all diminished Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7):

26 Laboratory Tests Hb : 9.9 g/dl WBC : /mm 3 Platelet: 675x10 3 /mm 3 CRP : 10.2 mg/dl ESR: 60 mm/hr BUN: 8 mg/dl Cre: 0.5 mg/dl Urinary pH: 6.5 density: 1011 protein: protein-, 1-2 WBC /hpf IgA : 168 mg/dl (68-378) IgM : 1220 mg/dl (50-250) IgG : 1450 mg/dl ( ) ANA: Negative Anti-DNA: Negative ANCA: Negative HBsAg : Negative Anti-HCV: Negative

27 CT/MRI Topaloglu R et al. Pediatr Nephrol 2005; 20:

28 Angiography Topaloglu R et al. Pediatr Nephrol 2005; 20:

29 CLASSIC POLYARTERITIS NODOSA Hypertensive emergency Subarachnoidal hemorrhage Angiography: Diffuse aneurysmal changes Steroid intravenous, followed by p.o. route Cyclophosphamide 2 mg/kg, p.o., 6 mo. Azathiopurine (12 mo.) MMF (12 mo.) Low dose steroid (alternate day continuing)

30 CASE 4

31 12 year old girl Abdominal pain, myalgia Nausea Fever Rash on extremities Recurrent abdominal pain and fever- FMF? Blood pressure: 150/90 mmHg

32 Laboratory Tests Hb : 11.7 g/dl WBC : /mm 3 Platelet: 558 x10 3 /mm 3 CRP : 18 mg/dl ESR: 55 mm/hr BUN: 12 mg/dl Cre : 0.6 mg/dl Urinary pH: 6.5 density: 1018 protein: RBC/hpf IgA : 184 mg/dl (68-378) IgM : 770 mg/dl (50-250) IgG : 1850 mg/dl ( ) ANA: Negative Anti-DNA: Negative ANCA: –c-ANCA: positive (IFA) PR-3 ANCA : positive (ELISA) HBsAg : Positive HBV DNA: 330 pg/ml (0-5) MEFV: M694 V/-

33

34 Renal Angiography

35 Liver biopsy-Chronic hepatit B infection grade 1 – Lamuvidine therapy (1 year) Polyarteritis nodosa –1 mg/kg/day oral prednisone –4 months later steroids tapered and stopped FMF –More inflammation, more vasculitis among FMF patients –Increased MEFV mutations among vasculitis patients –0.03 mg/kg colchicum dispert 8 years follow up, BP (normal), renal function test (normal) Medicine (Baltimore). 2005; 84: 1-11.

36 CASE 5

37 9 month old girl Fever and irritability Mother-carrier for HBs Ag Blood pressure: 180/100 mmHg ESH: 70 mm/hr Urinalysis: protein +++ Angiogram: Renal and mesenteric microaneurysms HBs Ag (+) HBe Ag (+) HBV DNA > 2000 pg/ml Duzova A et al. Eur J Pediatr 2001; 160:

38 HBV DNA pg/ml HBs Ag HBe Ag Antihypertensive drugs Prednisolone (2 mg/kg) Cyclophosphamide (2 mg/kg) Interferon >2000 >2000 >2000 > Months Blood pressure (mmHg) Diastolic BP Systolic BP * Figure 1: Time course of blood pressure, treatment and virological parameters 5x10 6 U/m 2 10x10 6 U/m 2 Duzova A et al. Eur J Pediatr 2001; 160: *: anaemia and leukocytopenia

39 CASE 6 & 7

40 Patient 6 Age at diagnosis: 12 y Headache BP: 150/100 mm Hg ESR: 44 mm/hr ppd: positive Urinalysis: Proteinuria Angiography RRA: Normal LRA: Stenosis Entire thoracic and abdominal artery involvement, presence of aneurysms

41

42 Medical treatment –Prednisolone (bolus, po) –CYC (po) –MTX (po/sc) –Anti-hypertensive CCB Alpha-blocker Beta-blocker Anti-tbc treatment Surgical treatment –Left nephrectomy Duration of follow up: 10 years Low dose steroid TREATMENT

43 Patient 7 Age at diagnosis: 16 y Arthralgia MEFV : E148Q/- FMF? 4 years Headache BP: 180/100 mm Hg ESR: 16 mm/hr Angiography RRA: stenosis at the origin LRA: stenosis at the origin Involvement of SMA and suprarenal abdominal aorta

44

45 TREATMENT Medical treatment –Prednisone (po) –MTX (po) –Anti-hypertensive CCB Beta blocker Surgical treatment Thoraco-abdominal by pass, left aorta renal by pass Right aorta renal by pass Duration of follow up: 1 year Low dose steroid and MTX

46

47 Takayasu Arteritis Mainstay of the treatment is to attenuate inflammatory process and control HTN Corticosteroids: Therapy is continued until patients achieve remission Cyclophosphamide (1-2 mg/kg/d) Azathioprine (1-2 mg/kg) Methotrexate (0.3 mg/kg/wk) Anti-TNF Ozen S et al. J Pediatr 2007; 150: Hoffman et al. Arthritis Rheum 2004; 50:

48 Summary Vasculitis should be excluded in any patient with renal or extrarenal symptoms and: –Elevated acute phase reactants –Constitutional symptoms –Organ involvement Diagnosis is typically delayed 3 mo.; and the absence of extra-renal disease is associated with a longer delay. Longterm outcomes are closely related to the severity of organ dysfunction at diagnosis ANCA testing enables earlier identification. In last 3 decades: MP+CYC therapy enables 75-90% remission at 6 mo. A variety of treatment options now available for AAV. Balance should be made between disease suppression and treatment toxicity.


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