TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS

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

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 • Histologic similarities • Potential contribution of ANCA to theirpathogenesis • Similar responses toimmunosuppressive therapy • Wegener’s granulomatosis • Microscopic polyangiitis • Renal limited vasculitis • Churg-Strauss syndrome Nat Clin Rheumatol 2006; 2: 661-670

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: 696-699

8. Hb : 7.8 g/dl WBC : 7300 /mm3 Platelet : 240 x103 /mm3 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 : 1020protein : 4+ 7-8 RBC / hpf Urinary protein : 87.5 mg/m2/hr GFR : 18 ml/min/ 1.73 m2 ANA : Negative Anti ds-DNA : Negative ANCA: p-ANCA: strong positive (IFA) MPO-ANCA: 250 EU/ml (ELISA) Anti-GBM: positive Laboratory Tests Besbas N et al. Pediatr Nephrol 2003;18: 696-699

9. Renal Biopsy Besbas N et al. Pediatr Nephrol 2003;18: 696-699

10. Serum creatinine (mg/dl) Plasma exchange MPZ 0.5 mg/kg/d prednisone 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 9 mo 12 mo 15 mo 18 mo 21 mo 24 mo 2 mg/kg/d cyclophosphamide 2 mg/kg/d azathiopurine Etanercept Rituximab MMF

11. Nine years after successful renal transplantation • Cre: 0.98 mg/dl • GFR: 112 ml/min/1.73 m2

12. CASE 2

13. Fever • Subcutaneous nodules (fingertips, nose) • Generalized maculopapular rash • Necrotic lesions (right foot sole) • Generalized edema 10 year old, girl • URTI • Hoarseness, swollen edematous tongue, speech abnormality, • wt loss Glossitis, iv penicilin • Necrotic tissue (soft palate, digits and uvula) • Arthritis • Myalgia • Limitation of motion days 4 0 2 6 Fatigue, worsening of the symptoms and myalgia Ceftriaxone and clindamicin iv Iloprost, Pentoxiphyllin Amlodipine, Captopril Piperacillin-Tazobactam, Vancomycin, Rifampicin, Fluconazole

14. 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 Physical Examination

15. Hb : 7.4 g/dl WBC : 20100 /mm3 Platelet: 550x103 /mm3 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 (650-1600) ANA : Negative Anti-DNA : Negative c-ANCA : Mild staining at IIFNegative for MPO, PR3 Thrombotic panel including ACLs all (-) MEFV : V726A/- Laboratory Tests

16. Paranasal CT

17. Necrotizing Vasculitis

18. Oral prednisone (2 mg/kg/day) Oral cyclophosphamide (2 mg/kg/day) Hematuria, proteinuria, dyspnea Plasma exchange Plasma exchange Plasma exchange Plasma exchange Plasma exchange Plasma exchange Pulse steroid 15 17 19 21 23 25 32 60 14 days

19. 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)* 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 EULAR/PRES Criteria. Ann Rheum Dis; 2006

20. Cre ­ (> 500 mmol/l ) plasma exchange Vital organ involvement • Prednisolone • oral 2 mg/kg • IV 15 mg/kg/dose • CYC • Oral 2 mg/kg • 500 mg/m2 3-6 months • 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 12 months or longer Bakkaloglu A et al. Arch Dis Clin 2001; 85: 427-430. Besbas N et al. Pediatr Nephrol 2000; 14: 325-327.

21. INDUCTION THERAPY NORAM: MTX vs CYC MEPEX: PE vs MP CYCLOPS: CYC iv vs oral WEGET: Etanercept vs placebo SOLUTION: ATG Prednisone ( 1-2 mg/kg/day) ± MP ( 3 pulses) Cyclophosphamide ( 2 mg/kg/day) or iv pulses 3 - 6 mo. NORAM: MTX vs CYC CYCAZAREM: AZA vs CYC IMPROVE: AZA vs MMF REMAIN: AZA, 24 mo vs 48 mo Maintenance therapy

22. Recent Alternative Therapies • 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

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): 1011-5.

25. 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 Physical examination Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7): 1011-5.

26. Hb : 9.9 g/dl WBC : 22100/mm3 Platelet: 675x103 /mm3 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 (650-1600) ANA : Negative Anti-DNA : Negative ANCA : Negative HBsAg : Negative Anti-HCV: Negative Laboratory Tests

27. CT/MRI Topaloglu R et al. Pediatr Nephrol 2005; 20: 1011-1015.

28. Angiography Topaloglu R et al. Pediatr Nephrol 2005; 20: 1011-1015.

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. Hb : 11.7 g/dl WBC : 12400 /mm3 Platelet: 558 x103 /mm3 CRP : 18 mg/dl ESR : 55 mm/hr BUN : 12 mg/dl Cre : 0.6 mg/dl Urinary pH: 6.5 density: 1018 protein: +++ 10-15 RBC/hpf IgA : 184 mg/dl (68-378) IgM : 770 mg/dl (50-250) IgG : 1850 mg/dl (650-1600) 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/- Laboratory Tests

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: 519-520

38. >2000 >2000 >2000 >2000 714 HBV DNA pg/ml HBs Ag HBe Ag Antihypertensive drugs Prednisolone (2 mg/kg) Cyclophosphamide (2 mg/kg) Interferon + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + *: anaemia and leukocytopenia * 5x106 U/m2 10x106 U/m2 200 180 160 140 120 Blood pressure (mmHg) 100 80 60 Diastolic BP 40 Systolic BP 0 2 4 6 8 16 18 20 22 30 Figure 1: Time course of blood pressure, treatment and virological parameters Months Duzova A et al. Eur J Pediatr 2001; 160: 519-520

39. CASE 6 & 7

40. 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 Patient 6

42. TREATMENT • 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

43. 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 Patient 7

45. 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 TREATMENT

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: 72-76 Hoffman et al. Arthritis Rheum 2004; 50: 2296-2304

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.