New Therapies in ANCA- -Associated Associated New Therapies in ANCA Renal Vasculitis Renal Vasculitis Mayo Clinic Day Mayo Clinic Day International Renal Meeting International Renal Meeting Cagliari, Italy , Italy Cagliari May 2, 2011 May 2, 2011 Ulrich Specks, MD Ulrich Specks, MD Professor of Medicine Professor of Medicine Division of Pulmonary and Critical Care Medicine, Division of Pulmonary and Critical Care Medicine, Thoracic Diseases Research Unit, Thoracic Diseases Research Unit, Mayo Clinic, Rochester, MN, USA Mayo Clinic, Rochester, MN, USA 3030715-
Disclosures Disclosures � Off-label use of drugs: All references to medications discussed in this presentation with the exception of rituximab constitute off-label applications. � Speaker Relationships with Industry: Speaker bureau: none Consulting: Dynavax, Sanofi-Aventis Other: Genentech has provided drug and funding to NIAID for the conduct of the RAVE trial. 3030715-
Agenda Agenda � How to categorize patients for treatment purposes � Discuss rationale for targeting B cells in AAV � Randomized controlled trial results � What to do for relapsing patients longterm � I will not cover: � Churg-Strauss syndrome � Plasma exchange for AAV 3030715-
Necrotizing Granulomatous Necrotizing Granulomatous Inflammation Inflammation � of Wegener � s Granulomatosis of Wegener s Granulomatosis Limited Disease = Localized Limited Disease = Localized to Early Systemic Dz Dz to Early Systemic 3030715-
Small Vessel Vasculitis Small Vessel Vasculitis & Capillaritis & Capillaritis Common to MPA and WG Common to MPA and WG Severe disease Severe disease 3030715-
Small Vessel Vasculitis & Capillaritis Common Small Vessel Vasculitis & Capillaritis Common to MPA and WG to MPA and WG Pauci Pauci- -immune immune Scleritis Scleritis Palpable purpura Focal segmental Focal segmental Palpable purpura Necrotizing GN Leukocytoclastic vasculitis Leukocytoclastic vasculitis Necrotizing GN Multiple Mononeuritis Multiple Mononeuritis Sensori- -neural HL neural HL Sensori Severe disease = generalized disease Severe disease = generalized disease 3030715-
1.0 0.9 Proportion surviving 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 Months Adapted by Salama from Walton, Br Med J 1958 3030715-
Remission Induction with Pred + CYC Remission Induction with Pred + CYC � Median survival: 21.7 years (CI 15.6-27.9) � Predictors of survival: age >50, lung, kidney � Complete remission in 53 - 93%* � Relapse > 5 years: 50 - 75% � Overall mortality during observation: 14% 12-13% due to WG or treatment for WG Hoffman et al. Ann Intern Med 1992; 116:488- Hoffman et al. Ann Intern Med 1992; 116:488 -498 498 Reinhold- -Keller et al. Arthritis Rheum. 2000; 43:1021 Keller et al. Arthritis Rheum. 2000; 43:1021- -1032 1032 Reinhold *Jayne et al. NEJM 2003; 349:36- -44 44 *Jayne et al. NEJM 2003; 349:36 3030715-
CYC: The Good / The Bad The Bad CYC: The Good / � 91% marked � � 42% permanent morbidity � 91% marked 42% permanent morbidity improvement improvement � 46% serious infections � 46% serious infections � 43% hemorrhagic cystitis � 43% hemorrhagic cystitis ↑ risk bladder CA fold ↑ � 33 � 75% complete � � 33- -fold risk bladder CA 75% complete ↑ risk lymphoma fold ↑ � 11 � 11- -fold risk lymphoma remission remission � 57% infertility � 57% infertility � Steroid � Steroid- -induced damage induced damage � � Cushingoid habitus, weight gain, Cushingoid habitus, weight gain, hypertension, cataracts, fractures hypertension, cataracts, fractures Hoffman 1992 Hoffman 1992 3030715-
Question 1 Question 1 25 y/o y/o male C male C- -ANCA/PR3 ANCA/PR3- -ANCA positive with acute ANCA positive with acute 25 onset of malaise, arthralgias, pulmonary mass lesion, onset of malaise, arthralgias, pulmonary mass lesion, RBC casts on urine micro, creatinine of 2.8 mg/dL, RBC casts on urine micro, creatinine of 2.8 mg/dL, ESR of 78 mm/hr should be treated with: ESR of 78 mm/hr should be treated with: A. Prednisone, methotrexate, TMP/SMX, folic acid A. Prednisone, methotrexate, TMP/SMX, folic acid B. Prednisone, cyclophosphamide, TMP/SMX B. Prednisone, cyclophosphamide, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX D. Prednisone, cyclophosphamide, etanercept D. Prednisone, cyclophosphamide, etanercept E. Prednisone, rituximab, TMP/SMX E. Prednisone, rituximab, TMP/SMX 3030715-1
Answer to Question 1 Answer to Question 1 25 y/o y/o male C male C- -ANCA/PR3 ANCA/PR3- -ANCA positive with acute ANCA positive with acute 25 onset of malaise, arthralgias, pulmonary mass lesion, onset of malaise, arthralgias, pulmonary mass lesion, RBC casts on urine micro, creatinine of 2.8 mg/dL, RBC casts on urine micro, creatinine of 2.8 mg/dL, ESR of 78 mm/hr should be treated with: ESR of 78 mm/hr should be treated with: A. Prednisone, methotrexate, TMP/SMX, folic acid A. Prednisone, methotrexate, TMP/SMX, folic acid B. Prednisone, cyclophosphamide, TMP/SMX B. Prednisone, cyclophosphamide, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX D. Prednisone, cyclophosphamide, etanercept D. Prednisone, cyclophosphamide, etanercept E. Prednisone, rituximab, TMP/SMX E. Prednisone, rituximab, TMP/SMX 3030715-1
Question 2 Question 2 25 y/o y/o male P male P- -ANCA/MPO ANCA/MPO- -ANCA positive presenting ANCA positive presenting 25 with fatigue, purpura, RBC casts on urine micro, with fatigue, purpura, RBC casts on urine micro, creatinine of 2.8 mg/dL, ESR of 78 mm/hr should be creatinine of 2.8 mg/dL, ESR of 78 mm/hr should be treated with: treated with: A. Prednisone, methotrexate, TMP/SMX, folic acid A. Prednisone, methotrexate, TMP/SMX, folic acid B. Prednisone, cyclophosphamide, TMP/SMX B. Prednisone, cyclophosphamide, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX D. Prednisone, cyclophosphamide, etanercept D. Prednisone, cyclophosphamide, etanercept E. Prednisone, rituximab, TMP/SMX E. Prednisone, rituximab, TMP/SMX 3030715-1
Answer to Question 2 Answer to Question 2 25 y/o y/o male P male P- -ANCA/MPO ANCA/MPO- -ANCA positive presenting ANCA positive presenting 25 with fatigue, purpura, RBC casts on urine micro, with fatigue, purpura, RBC casts on urine micro, creatinine of 2.8 mg/dL, ESR of 78 mm/hr should be creatinine of 2.8 mg/dL, ESR of 78 mm/hr should be treated with: treated with: A. Prednisone, methotrexate, TMP/SMX, folic acid A. Prednisone, methotrexate, TMP/SMX, folic acid B. Prednisone, cyclophosphamide, TMP/SMX B. Prednisone, cyclophosphamide, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX C. Prednisone, mycophenolate mofetil, TMP/SMX D. Prednisone, cyclophosphamide, etanercept D. Prednisone, cyclophosphamide, etanercept E. Prednisone, rituximab, TMP/SMX E. Prednisone, rituximab, TMP/SMX 3030715-1
The ANCA Type Matters ! The ANCA Type Matters ! � ANCA-type: PR3-ANCA conveys � worse mortality (RR 3.78) Hogan 1996 � higher relapse rate Jayne 2003; Booth 2003 � more rapid renal function loss Franssen 1995 3030715-1
MMF versus versus CYC (iv) for Remission Induction CYC (iv) for Remission Induction MMF of AAV with Moderate Renal Involvement of AAV with Moderate Renal Involvement Hu et al. Hu et al. Nephol Nephol Dial Transplant 2008; 23:1307 Dial Transplant 2008; 23:1307- -12 12 � Prospective, randomized controlled, open label trial. � N=35, severe disease, 28 MPO-ANCA, 2 PR3-ANCA. � Active renal disease, serum creatinine < 500 µ mol/L. � GCS: methyl-prednisolone 0.5 g/d x 3 followed by oral prednisone 0.6-0.8 mg/kg x 4 weeks, tapered by 5 mg per week to 10 mg/d. � N=18 randomized to 1.5 to 2.0 g of MMF x 6 months. � N=17 randomized to i.v. CYC (0.75-1.0 g/m 2 once monthly). 3030715-1
MMF vs CYC (IV) for Remission Induction MMF vs CYC (IV) for Remission Induction of AAV with Moderate Renal Involvement of AAV with Moderate Renal Involvement 25 CYC CYC 20 MMF MMF 15 BVAS score BVAS score 10 5 0 0 3 6 Months Months Hu et al: et al: Nephrol Nephrol Dial Transplant 23:1307, 2008 Dial Transplant 23:1307, 2008 Hu 3030715-1
MMF vs CYC (IV) for Remission Induction of MMF vs CYC (IV) for Remission Induction of AAV with Moderate Renal Involvement AAV with Moderate Renal Involvement 4.5 MMF MMF 4.0 CYC CYC 3.5 3.0 Scr 2.5 Scr (mg/dL) (mg/dL) 2.0 1.5 1.0 0.5 0.0 0 3 6 Follow- -up (mo) up (mo) Follow Hu et al: et al: Nephrol Nephrol Dial Transplant 23:1307, 2008 Dial Transplant 23:1307, 2008 Hu 3030715-1
MMF vs CYC (IV) for Remission Induction of MMF vs CYC (IV) for Remission Induction of AAV with Moderate Renal Involvement AAV with Moderate Renal Involvement MMF CYC P MMF CYC P Remission 77.8% 47.1% Remission 77.8% 47.1% Intention to treat anal Intention to treat anal Remission 77.8% 61.5% Remission 77.8% 61.5% (lost to follow- -up up (0) (4) (lost to follow (0) (4) excluded) excluded) BVAS at 6 mo 0.2 2.6 <0.05 BVAS at 6 mo 0.2 2.6 <0.05 (± ±0.89) 0.89) (± ±1.7) 1.7) ( ( Adverse events 22.2% 35.3% NS Adverse events 22.2% 35.3% NS Hu et al: et al: Nephol Nephol Dial Transplant 23:1307, 2008 Dial Transplant 23:1307, 2008 Hu 3030715-1
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