New Therapies in ANCA- -Associated Associated New Therapies in - - PowerPoint PPT Presentation

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New Therapies in ANCA New Therapies in ANCA-

• Associated

Associated Renal Vasculitis Renal Vasculitis

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

Mayo Clinic Day Mayo Clinic Day International Renal Meeting International Renal Meeting Cagliari Cagliari, Italy , Italy May 2, 2011 May 2, 2011

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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.

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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

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Necrotizing Granulomatous Necrotizing Granulomatous Inflammation Inflammation

• f Wegener
• f Wegener
• s Granulomatosis

s Granulomatosis

Limited Disease = Localized Limited Disease = Localized to Early Systemic to Early Systemic Dz Dz

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Small Vessel Vasculitis Small Vessel Vasculitis & Capillaritis & Capillaritis Common to MPA and WG Common to MPA and WG Severe disease Severe disease

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Small Vessel Vasculitis & Capillaritis Common Small Vessel Vasculitis & Capillaritis Common to MPA and WG to MPA and WG

Severe disease = generalized disease Severe disease = generalized disease

Scleritis Scleritis Palpable purpura Palpable purpura Leukocytoclastic vasculitis Leukocytoclastic vasculitis Pauci Pauci-

• immune

immune Focal segmental Focal segmental Necrotizing GN Necrotizing GN Multiple Mononeuritis Multiple Mononeuritis Sensori Sensori-

• neural HL

neural HL

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Adapted by Salama from Walton, Br Med J 1958

10 20 30 40 50 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Months Proportion surviving

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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 Reinhold-

• Keller et al. Arthritis Rheum. 2000; 43:1021

Keller et al. Arthritis Rheum. 2000; 43:1021-

• 1032

1032 *Jayne et al. NEJM 2003; 349:36 *Jayne et al. NEJM 2003; 349:36-

• 44

44

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CYC: The Good / CYC: The Good / The Bad The Bad

• 91% marked

91% marked improvement improvement

• 75% complete

75% complete remission remission

• 42% permanent morbidity

42% permanent morbidity

• 46% serious infections

46% serious infections

• 43% hemorrhagic cystitis

43% hemorrhagic cystitis

• 33

33-

• fold

fold ↑ ↑ risk bladder CA risk bladder CA

• 11

11-

• fold

fold ↑ ↑ risk lymphoma risk lymphoma

• 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

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Question 1 Question 1

25 25 y/o y/o male C male C-

• ANCA/PR3

ANCA/PR3-

• ANCA positive with acute

ANCA positive with acute

• nset of malaise, arthralgias, pulmonary mass lesion,
• nset 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

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Answer to Question 1 Answer to Question 1

25 25 y/o y/o male C male C-

• ANCA/PR3

ANCA/PR3-

• ANCA positive with acute

ANCA positive with acute

• nset of malaise, arthralgias, pulmonary mass lesion,
• nset 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

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Question 2 Question 2

25 25 y/o y/o male P male P-

• ANCA/MPO

ANCA/MPO-

• ANCA positive presenting

ANCA positive presenting 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

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Answer to Question 2 Answer to Question 2

25 25 y/o y/o male P male P-

• ANCA/MPO

ANCA/MPO-

• ANCA positive presenting

ANCA positive presenting 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

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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

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MMF MMF versus versus CYC (iv) for Remission Induction CYC (iv) for Remission Induction

• f AAV with Moderate Renal Involvement
• f AAV with Moderate Renal Involvement

Hu Hu et al. 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 µmol/L. GCS: methyl-prednisolone 0.5 g/d x 3 followed by

• ral 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/m2 once

monthly).

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5 10 15 20 25 Hu Hu et al: et al: Nephrol Nephrol Dial Transplant 23:1307, 2008 Dial Transplant 23:1307, 2008

BVAS BVASscore

score

Months Months

3 6

CYC CYC MMF MMF

MMF vs CYC (IV) for Remission Induction MMF vs CYC (IV) for Remission Induction

• f AAV with Moderate Renal Involvement
• f AAV with Moderate Renal Involvement

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Hu Hu et al: et al: Nephrol Nephrol Dial Transplant 23:1307, 2008 Dial Transplant 23:1307, 2008

Scr Scr (mg/dL) (mg/dL) Follow Follow-

• up (mo)

up (mo)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 3 6

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 MMF CYC CYC

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Hu Hu et al: et al: Nephol Nephol Dial Transplant 23:1307, 2008 Dial Transplant 23:1307, 2008

MMF MMF CYC CYC P P Remission Remission 77.8% 77.8% 47.1% 47.1% Intention to treat anal Intention to treat anal Remission Remission 77.8% 77.8% 61.5% 61.5% (lost to follow (lost to follow-

• up

up (0) (0) (4) (4) excluded) excluded) BVAS at 6 mo BVAS at 6 mo 0.2 0.2 2.6 2.6 <0.05 <0.05 ( (± ±0.89) 0.89) ( (± ±1.7) 1.7) Adverse events Adverse events 22.2% 22.2% 35.3% 35.3% NS NS

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

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MMF for Remission Induction & Maintenance in MPA with Mild to Moderate Renal Dysfunction

Prospective Pilot Trial in 17 Patients

Silva et al. JASN 2010

MMF for Remission Induction MMF for Remission Induction & & Maintenance in Maintenance in MPA with Mild to Moderate Renal Dysfunction MPA with Mild to Moderate Renal Dysfunction

Prospective Pilot Trial in 17 Patients Prospective Pilot Trial in 17 Patients

Silva et al. JASN 2010 Silva et al. JASN 2010

• F. Silva, U. Specks, N. Leung, S. Kalra, M. Hogan,

F.C. Fervenza. Mayo Nephrology Collaborative Group Divisions of Nephrology and Pulmonary Medicine, Mayo Clinic, Rochester, MN.

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MMF for MPA with Mild Renal Involvement MMF for MPA with Mild Renal Involvement Inclusion Criteria Inclusion Criteria

Silva et al. JASN 2010 Silva et al. JASN 2010 epub epub (in press) (in press)

• Microscopic Polyangiitis1
• New diagnosis or relapse
• Positive p-ANCA/MPO-ANCA
• Active mild to moderate renal involvement

Renal biopsy or hematuria

(dysmorphic RBCs, RBC casts)

Serum creatinine ≤ 3.0mg/dl

• Microscopic Polyangiitis1
• New diagnosis or relapse
• Positive p-ANCA/MPO-ANCA
• Active mild to moderate renal involvement

Renal biopsy or hematuria

(dysmorphic RBCs, RBC casts)

Serum creatinine ≤ 3.0mg/dl

• 1. Chapel Hill Consensus Definition

Arthritis Rheum. 37 (2) : 187-1992, 1994.

• 1. Chapel Hill Consensus Definition

Arthritis Rheum. 37 (2) : 187-1992, 1994.

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MMF for MPA with Mild Renal Involvement MMF for MPA with Mild Renal Involvement

Effect on Disease Activity Effect on Disease Activity

20 40 60 80 100 2 4 8 12 24 36 48 60 72 Time (weeks) Cases (%) Remission Active Relapse Intolerance

Silva et al. JASN 2010 Silva et al. JASN 2010 epub epub (in press) (in press)

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Challenges of the 1990 Challenges of the 1990

• s

s

• Do all patients need CYC?

Do all patients need CYC?

• NIH cohort studies and NORAM trial

NIH cohort studies and NORAM trial

• Can we get by with shorter courses of CYC?

Can we get by with shorter courses of CYC?

• NIH cohort

NIH cohort studies and CYCAZAREM trial studies and CYCAZAREM trial

• Can CYC be applied in a safer fashion?

Can CYC be applied in a safer fashion?

• CYCLOPS trial

CYCLOPS trial

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Question 3 Question 3

5 months later this 25 5 months later this 25 y/o y/o male C male C-

• ANCA/PR3

ANCA/PR3-

• ANCA

ANCA positive is in remission after induction with positive is in remission after induction with prednisone, prednisone, cyclophosphamide, TMP/SMX. Creat is 1.3 mg/dl. cyclophosphamide, TMP/SMX. Creat is 1.3 mg/dl. What is your choice of remission maintenance agent? What is your choice of remission maintenance agent?

• A. Methotrexate 20 mg once per week, TMP/SMX
• A. Methotrexate 20 mg once per week, TMP/SMX
• B. Azathioprine 150 mg/d, TMP/SMX
• B. Azathioprine 150 mg/d, TMP/SMX
• C. Mycophenolate mofetil 1g twice daily, TMP/SMX
• C. Mycophenolate mofetil 1g twice daily, TMP/SMX

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Answer to Question 3 Answer to Question 3

5 months later this 25 5 months later this 25 y/o y/o male C male C-

• ANCA/PR3

ANCA/PR3-

• ANCA

ANCA positive is in remission after induction with positive is in remission after induction with prednisone, cyclophosphamide, TMP/SMX. Creat is prednisone, cyclophosphamide, TMP/SMX. Creat is 1.3 mg/dl. 1.3 mg/dl. What is your choice of remission maintenance What is your choice of remission maintenance agent? agent?

• A. Methotrexate 20 mg once per week, TMP/SMX
• A. Methotrexate 20 mg once per week, TMP/SMX
• B. Azathioprine 150 mg/d, TMP/SMX
• B. Azathioprine 150 mg/d, TMP/SMX
• C. Mycophenolate mofetil 1g twice daily, TMP/SMX
• C. Mycophenolate mofetil 1g twice daily, TMP/SMX

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20 40 60 80 100 6 12 18 24 30 36 Pagnoux Pagnoux et al: NEJM 359:2790, 2007 et al: NEJM 359:2790, 2007

Relapse Relapse-

• free survival (%)

free survival (%) Months since randomization Months since randomization

• No. at risk
• No. at risk

Azathioprine Azathioprine 63 63 57 57 54 54 43 43 25 25 14 14 9 9 Methotrexate Methotrexate 63 63 58 58 53 53 44 44 30 30 22 22 11 11

Time to First Relapse Time to First Relapse

P=0.78 P=0.78 Azathioprine Azathioprine Methotrexate Methotrexate

AZA vs MTX for Remission Maintenance AZA vs MTX for Remission Maintenance

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0.0 0.2 0.4 0.6 0.8 1.0 1 2 3 4 Hiemstra Hiemstra: JAMA, 2010 : JAMA, 2010

Proportion Proportion

• No. at risk
• No. at risk

Azathioprine Azathioprine 80 80 72 72 57 57 46 46 6 6 Mycophenolate Mycophenolate 76 76 60 60 47 47 37 37 4 4 mofetil mofetil

First Major Relapse First Major Relapse

Azathioprine Azathioprine Mycophenolate mofetil Mycophenolate mofetil

MMF vs AZA for Remission Maintenance MMF vs AZA for Remission Maintenance

Years Years

HR 2.14 (95% CI 0.99 HR 2.14 (95% CI 0.99-

• 4.64)

4.64) P=0.054 P=0.054

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Hiemstra Hiemstra et al: JAMA, 2010 et al: JAMA, 2010

MMF vs AZA for Remission Maintenance MMF vs AZA for Remission Maintenance

0.0 0.2 0.4 0.6 0.8 1.0 1 2 3 4

Proportion Proportion

• No. at risk
• No. at risk

Azathioprine Azathioprine 80 80 72 72 57 57 46 46 6 6 Mycophenolate Mycophenolate 76 76 60 60 47 47 37 37 4 4 mofetil mofetil

First Relapse First Relapse

Azathioprine Azathioprine Mycophenolate mofetil Mycophenolate mofetil

Years Years

HR 1.69 (95% CI 1.06 HR 1.69 (95% CI 1.06-

• 2.70)

2.70) P=0.03 P=0.03

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Question 4 Question 4

25 25 y/o y/o woman C woman C-

• ANCA/PR3

ANCA/PR3-

• ANCA positive with acute

ANCA positive with acute

• nset of malaise, arthralgias, pulmonary mass lesion,
• nset 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

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Answer to Question 4 Answer to Question 4

25 25 y/o y/o woman C woman C-

• ANCA/PR3

ANCA/PR3-

• ANCA positive with acute

ANCA positive with acute

• nset of malaise, arthralgias, pulmonary mass lesion,
• nset 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

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Question 5 Question 5

27 27 y/o y/o man, C man, C-

• ANCA/PR3

ANCA/PR3-

• ANCA positive, has been in

ANCA positive, has been in remission on azathioprine for a year, now presents remission on azathioprine for a year, now presents with fatigue, R scleritis, RBC casts on urine micro, with fatigue, R scleritis, RBC casts on urine micro, creatinine of 3.5 mg/dL; he should get: creatinine of 3.5 mg/dL; he should get:

• 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

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Answer to Question 5 Answer to Question 5

27 27 y/o y/o man, C man, C-

• ANCA/PR3

ANCA/PR3-

• ANCA positive, has been in

ANCA positive, has been in remission on azathioprine for a year, now presents remission on azathioprine for a year, now presents with fatigue, R scleritis, RBC casts on urine micro, with fatigue, R scleritis, RBC casts on urine micro, creatinine of 3.5 mg/dL; he should get: creatinine of 3.5 mg/dL; he should get:

• 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

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Wegener Wegener

• s Granulomatosis Etanercept Trial

s Granulomatosis Etanercept Trial

WGET WGET Design Design

WGET Research Group: Controlled WGET Research Group: Controlled Clin Clin Trials 23:450, 2002 Trials 23:450, 2002

Etanercept Etanercept Placebo Placebo Rz Rz 1:1 1:1 180 Patients 180 Patients Clinic Clinic Rz Rz 1:1 1:1 Etanercept Etanercept Placebo Placebo Limited Limited Dz Dz Severe Severe Dz Dz Pred/MTX Pred/MTX Pred/CYC Pred/CYC

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• No difference in time to

No difference in time to remission remission

• No difference in frequency

No difference in frequency

• f remission
• f remission
• No difference in duration of

No difference in duration of remission remission

• No difference in severity or

No difference in severity or frequency of flares frequency of flares

• No difference in severity or

No difference in severity or frequency of adverse frequency of adverse events events

• Except: 6 vs 0

Except: 6 vs 0 malignancies in the malignancies in the treatment arm (P=0.01) treatment arm (P=0.01)

NEJM 352:351, 2005 NEJM 352:351, 2005

Cumulative probability Cumulative probability sustained remission sustained remission Months Months

0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25 30 35 40

Control Control Etanercept Etanercept P=0.39 P=0.39

Primary WGET Results Primary WGET Results

Etanercept is Not Effective for WG in Addition to Etanercept is Not Effective for WG in Addition to Standard Therapy Standard Therapy

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Primary WGET Results Primary WGET Results

Efficacy of Standard Therapy Efficacy of Standard Therapy

• Remission (BVAS/WG = 0) achieved (anytime)

Remission (BVAS/WG = 0) achieved (anytime) 91% 91%

• Newly diagnosed :

Newly diagnosed : 92% 92%

• Existing disease:

Existing disease: 90.5% 90.5% No difference in limited (MTX) No difference in limited (MTX) versus versus severe (CYC) disease severe (CYC) disease

• Sustained remission (BVAS/WG = 0 x 6 months):

Sustained remission (BVAS/WG = 0 x 6 months): 72% 72%

• Remission achieved and maintained throughout

Remission achieved and maintained throughout remainder of trial (median follow remainder of trial (median follow-

• up 22 months):

up 22 months): 49.4% 49.4%

• Suffered at least 1 severe adverse events (including

Suffered at least 1 severe adverse events (including life life-

• threatening or death:

threatening or death: 57% 57%

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Role of B Lymphocytes in Wegener s Granulomatosis

• Efficacy of CYC attributed to profound effect

Efficacy of CYC attributed to profound effect

• n B lymphocytes
• n B lymphocytes

Cupps Cupps et al: J et al: J Immunol Immunol 128:2453, 1982 128:2453, 1982

• Correlation between frequency of activated

Correlation between frequency of activated peripheral blood B cells (but not T cells) and peripheral blood B cells (but not T cells) and Disease activity of WG (BVAS) Disease activity of WG (BVAS) Disease extent (generalized vs limited) Disease extent (generalized vs limited)

Popa Popa et al: J Allergy et al: J Allergy Clin Clin Immunol Immunol 103:885, 1999 103:885, 1999

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• Precursors of (auto)

Precursors of (auto) antibody antibody-

• secreting

secreting plasma cells plasma cells

• Regulation of immune

Regulation of immune responses responses

• Modify immunoglobulin

Modify immunoglobulin production production

• Cytokine production

Cytokine production

• Expression of

Expression of costimulatory molecules costimulatory molecules

• Antigen presentation

Antigen presentation

• Differentiation &

Differentiation & regulation of T cells regulation of T cells and dendritic cells and dendritic cells

Salama Salama A and Pusey C: A and Pusey C: Nature Nature Clin Clin Prac Prac 2:221, 2006 2:221, 2006

Functions of B Lymphocytes Functions of B Lymphocytes

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Rituximab vs Cyclophosphamide for Induction Rituximab vs Cyclophosphamide for Induction

• f Remission in ANCA
• f Remission in ANCA-
• Associated Vasculitis

Associated Vasculitis A Randomized Controlled Trial (RAVE) A Randomized Controlled Trial (RAVE)

Stone JH, Merkel PA, Stone JH, Merkel PA, Spiera Spiera R, R, Seo Seo P, Langford CA, Hoffman GS, P, Langford CA, Hoffman GS, Kallenberg Kallenberg CGM, St. Clair EW, CGM, St. Clair EW, Turkiewicz Turkiewicz A, A, Tchao Tchao NK, Webber L, Ding L, NK, Webber L, Ding L, Sejismundo Sejismundo L, L, Mieras Mieras K, K, Weitzenkamp Weitzenkamp D, D, Ikle Ikle D, D, Seyfert Seyfert-

• Margolis V, Mueller M,

Margolis V, Mueller M, Brunetta Brunetta P, Allen NB, P, Allen NB, Fervenza Fervenza FC, FC, Geetha Geetha D, Keogh KA, D, Keogh KA, Kissin Kissin EY, EY, Monach Monach PA, PA, Peikert Peikert T, T, Stegeman Stegeman C, C, Ytterberg Ytterberg SR, and SR, and Specks U Specks U for the RAVE for the RAVE-

• ITN Research Group

ITN Research Group

ACR 2009 Annual Meeting ACR 2009 Annual Meeting Philadelphia, PA Philadelphia, PA Plenary Session I: Discovery 2009 Plenary Session I: Discovery 2009 Sunday, October 18, 2009 Sunday, October 18, 2009

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RAVE Trial Hypotheses RAVE Trial Hypotheses

• Rituximab is as effective as conventional

Rituximab is as effective as conventional therapy (cyclophosphamide) for the induction therapy (cyclophosphamide) for the induction

• f remission in severe ANCA
• f remission in severe ANCA-
• associated

associated vasculitis vasculitis

• Rituximab offers other substantial advantages

Rituximab offers other substantial advantages

• ver standard therapy
• ver standard therapy
• B cell depletion by anti

B cell depletion by anti-

• CD20 therapy induces

CD20 therapy induces stable remissions by re stable remissions by re-

• establishing tolerance

establishing tolerance to ANCA target antigens to ANCA target antigens

NEJM 2010; 363:221 NEJM 2010; 363:221-

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RAVE Trial Design RAVE Trial Design

Non-inferiority Trial

Assumptions: Percentage of patients with severe AAV achieving remission without therapy by 6 months = 0%. Percentage of patients in both treatment groups who achieved disease remissions off prednisone at 6 months would be 70%.1 Agreement with FDA: A lower non-inferiority limit (∆) of 20% on the difference between the rituximab and cyclophosphamide treatment arms. Patients enrolled with MPA < 50%.

1 Based on WGET Results

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Primary Outcome Measure Primary Outcome Measure

• Percentage of patients who have achieved

Percentage of patients who have achieved clinical remission (BVAS/WG = 0) clinical remission (BVAS/WG = 0) and and completed the steroid taper by 6 months completed the steroid taper by 6 months ( (

• complete remission

complete remission

• )

)

• Longer

Longer-

• term follow

term follow-

• up (to 18 months)

up (to 18 months) to gauge duration of rituximab to gauge duration of rituximab-

• induced

induced remissions and effects of B cell depletion remissions and effects of B cell depletion

• n immune tolerance
• n immune tolerance

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Secondary Outcome Measures Secondary Outcome Measures

• Remission on <10 mg prednisone

Remission on <10 mg prednisone

• Safety

Safety

• Restoration of tolerance

Restoration of tolerance

• Duration of remission

Duration of remission

• Longitudinal (cumulative) disease activity

Longitudinal (cumulative) disease activity

• Damage

Damage

• Quality of life (SF

Quality of life (SF-

• 36)

36)

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Important Important Inclusion Inclusion Criteria Criteria

• Active severe AAV (WG or MPA)

Active severe AAV (WG or MPA)

• According to Chapel Hill definitions

According to Chapel Hill definitions

• Maximum number of MPA <50%

Maximum number of MPA <50%

• BVAS/WG

BVAS/WG ≥ ≥3 3

• At least 1

At least 1

• major

major

• BVAS/WG or deemed

BVAS/WG or deemed severe enough to require CYC severe enough to require CYC

• PR3

PR3-

• ANCA or MPO

ANCA or MPO-

• ANCA positive at

ANCA positive at screening screening

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Important Important Exclusion Exclusion Criteria Criteria

• Disease severity

Disease severity

• Limited disease, not requiring CYC

Limited disease, not requiring CYC

• Too severe

Too severe

• disease

disease Mechanical ventilation because of alveolar Mechanical ventilation because of alveolar hemorrhage hemorrhage Serum creatinine >4.0 mg/dL Serum creatinine >4.0 mg/dL

• CYC use within 4 months prior to enrollment

CYC use within 4 months prior to enrollment

• History of CYC toxicity or unresponsiveness

History of CYC toxicity or unresponsiveness

• Any previous RTX use

Any previous RTX use

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Study Design Study Design

Severe Severe WG or MPA WG or MPA PR3 PR3-

• or MPO
• r MPO-
• ANCA

ANCA positive positive n=200 n=200 Pred RTX infusions (375 mg/m2 x 4) CYC-placebo for 3-6 mo Pred RTX-placebo infusions CYC (2 mg/kg po) for 3-6 mo AZA-placebo for 15-12 mo AZA for 15-12 mo 1-3 g IV methylprednisolone

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Baseline Characteristics Baseline Characteristics

Treatment Assignment was Stratified by ANCA Treatment Assignment was Stratified by ANCA-

• Type and Center

Type and Center

Rituximab Rituximab Cyclophosphamide Cyclophosphamide n=99 n=99 n=98 n=98 ANCA type (%) ANCA type (%) PR3 PR3-

• ANCA

ANCA 66.7 66.7 66.3 66.3 MPO MPO-

• ANCA

ANCA 32.3 32.3 33.7 33.7

NEJM 2010; 363:221 NEJM 2010; 363:221-

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98 available for analysis

98 allocated to CYC/placebo

• 24 with microscopic polyangiitis
• 74 with Wegener

s granulomatosis Evaluated for endpoint 81 completed 6 mo as randomized 17 people with 20 early outcomes 2 early treatment failures 7 blinded crossovers 2 on best medical judgment 2 deaths 4 withdrawals, defined as failures

99 allocated to rituximab/placebo

• 24 with microscopic polyangiitis
• 74 with Wegener

s granulomatosis

• 1 not specified

Evaluated for endpoint 84 completed 6 mo as randomized 15 people with 22 early outcomes 7 early treatment failures 6 blinded crossovers 7 on best medical judgment 1 death 1 withdrawal, defined as failure

Randomize 1:1 RTX RTX 99 available for analysis

197 197 participants enrolled participants enrolled

CYC CYC

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Primary Efficacy Endpoint Analysis Primary Efficacy Endpoint Analysis

Complete Remission at 6 Months Complete Remission at 6 Months

RTX RTX CYC CYC Difference Difference n=99 n=99 n=98 n=98 (%) (%) P P Yes Yes 63 63 (63.6%) (63.6%) 52 52 (53.1%) (53.1%) 10.6 10.6 0.089 0.089 95% CI (%) 95% CI (%) 54.1, 73.2 54.1, 73.2 43.1, 63.0 43.1, 63.0

ITT analysis, worst case imputation ITT analysis, worst case imputation

BVAS/WG = 0 BVAS/WG = 0 and and prednisone = prednisone = 0 mg 0 mg

BVAS/WG = 0 Pred = 0 mg

Treatment effect

• 40%

40%

• 30%

30%

• 20%

20%

• 10%

10% 0% 0% 10% 10% 20% 20% 30% 30% Noninferiority margin P<0.0001 Superiority boundary P=0.089

• 3.2%

10.6% 24.3%

( )

NEJM 2010; 363:221 NEJM 2010; 363:221-

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10 20 30 40 50 60 70 80 30 60 90 120 150 180 Rituximab Rituximab Cyclophosphamide Cyclophosphamide

Prednisone in RAVE Prednisone in RAVE

Glucocorticoid Glucocorticoid dose (mg) dose (mg) Study day Study day Permitted dose range Permitted dose range

Patients remaining in assigned treatment arm throughout 6 months Patients remaining in assigned treatment arm throughout 6 months NEJM 2010; 363:221 NEJM 2010; 363:221-

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Secondary Efficacy Endpoint Analysis Secondary Efficacy Endpoint Analysis

Remission at 6 Months Remission at 6 Months

RTX RTX CYC CYC Difference Difference n=99 n=99 n=98 n=98 (%) (%) P P Yes Yes 70 70 (70.7%) (70.7%) 61 61 (62.2%) (62.2%) 8.5 8.5 0.103 0.103 95% CI (%) 95% CI (%) 61.8, 79.7 61.8, 79.7 52.6, 71.8 52.6, 71.8

BVAS/WG = 0 BVAS/WG = 0 and and prednisone prednisone <10 mg <10 mg

ITT analysis, worst case imputation ITT analysis, worst case imputation

Treatment effect

Noninferiority margin P<0.0001 Superiority boundary P=0.103

• 4.7%

8.5% 21.7%

( )

BVAS/WG = 0 Pred <10 mg

• 40%

40%

• 30%

30%

• 20%

20%

• 10%

10% 0% 0% 10% 10% 20% 20% 30% 30%

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Major Renal Disease Subset Major Renal Disease Subset

RTX RTX CYC CYC n=99 n=99 n=98 n=98 >1 major BVAS/WG item >1 major BVAS/WG item 49 (49.5%) 49 (49.5%) 50 (51.0%) 50 (51.0%) Creatinine clearance Creatinine clearance 53 mL/min 53 mL/min 69 mL/min 69 mL/min Achieved primary outcome Achieved primary outcome 61% 61% 62% 62% BVAS/WG = 0, Pred <10 mg BVAS/WG = 0, Pred <10 mg 67% 67% 70% 70% Increase in creatinine Increase in creatinine +11 mL/min +11 mL/min + 10 mL/min + 10 mL/min clearance clearance

P=0.04 P=0.04

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Alveolar Hemorrhage Subset Alveolar Hemorrhage Subset

RTX RTX CYC CYC n=99 n=99 n=98 n=98 Alveolar hemorrhage at BL Alveolar hemorrhage at BL 27 (27.3%) 27 (27.3%) 23 (23.5%) 23 (23.5%) Achieved primary outcome Achieved primary outcome 59.3% 59.3% 47.8% 47.8% BVAS/WG = 0, Pred <10 mg BVAS/WG = 0, Pred <10 mg 70.4% 70.4% 60.9% 60.9% Early treatment failure Early treatment failure 3 3 1 1 Crossover Crossover 2 2 1 1 Death by 6 months Death by 6 months 1 1 NEJM 2010; 363:221 NEJM 2010; 363:221-

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Treatment Response by Treatment Response by Disease Status at Baseline Disease Status at Baseline

10 20 30 40 50 60 70 80 New disease Severe flare

% %

n=96 n=96 n=101 n=101

P=0.67 P=0.67 P=0.013 P=0.013 Rituximab Rituximab Cyclophosphamide Cyclophosphamide 60.4% 60.4% 64.6% 64.6% 66.7% 66.7% 42.0% 42.0%

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Treatment Response by Disease Type Treatment Response by Disease Type

10 20 30 40 50 60 70 80 MPA WG

% %

n=48 n=48 n=148 n=148

P=0.76 P=0.76 P=0.14 P=0.14 Rituximab Rituximab Cyclophosphamide Cyclophosphamide 66.7% 66.7% 62.5% 62.5% 63.0% 63.0% 50.0% 50.0%

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Treatment Response by ANCA Treatment Response by ANCA-

• Type

Type

10 20 30 40 50 60 70 80 MPO-ANCA PR3-ANCA

% %

n=66 n=66 n=131 n=131

P=0.80 P=0.80 P=0.04 P=0.04 Rituximab Rituximab Cyclophosphamide Cyclophosphamide 60.6% 60.6% 63.6% 63.6% 65.2% 65.2% 47.7% 47.7%

Exploratory Analysis Exploratory Analysis

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No No Difference Between Treatment Arms Difference Between Treatment Arms by 6 Months by 6 Months

• Time to achieving remission

(first BVAS/WG = 0)

• Severe or limited disease flares
• Overall adverse events & rate
• Serious adverse events & rate
• Selected adverse events & rate

NEJM 2010; 363:221 NEJM 2010; 363:221-

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Selected Adverse Events (Safety Sample) Selected Adverse Events (Safety Sample)

Secondary Endpoint Secondary Endpoint

RTX RTX CYC CYC n=99 n=99 n=98 n=98 P P Total number of events Total number of events 35 35 44 44 Participants with Participants with ≥ ≥1 event (no.) 1 event (no.) 19 (19.2%) 19 (19.2%) 32 (32.7%) 32 (32.7%) 0.03 0.03 Participant months (no.) Participant months (no.) 569.3 569.3 561.3 561.3 Rate of selected adverse events Rate of selected adverse events 0.061 0.061 0.078 0.078 0.29 0.29

Death (all causes) Death (all causes) 1 1 2 2 Grade Grade ≥ ≥2 leukopenia 2 leukopenia 5 5 16 16 Grade Grade ≥ ≥3 infections 3 infections 2 2 3 3 Hemorrhagic cystitis Hemorrhagic cystitis 1 1 1 1 Malignancy Malignancy 1 1 2 2 Venous thromboembolic events Venous thromboembolic events 6 6 9 9 Hospitalization ( Hospitalization (Dz Dz or Rx complication)

• r Rx complication)

12 12 7 7 Infusion reaction precluding further Rx Infusion reaction precluding further Rx 1 1

NEJM 2010; 363:221 NEJM 2010; 363:221-

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RAVE Primary Results Summary RAVE Primary Results Summary

• Demographic characteristics, disease phenotype

Demographic characteristics, disease phenotype and disease activity of patients were distributed and disease activity of patients were distributed equally across both treatment arms equally across both treatment arms

• Rituximab is not inferior to cyclophosphamide for

Rituximab is not inferior to cyclophosphamide for remission induction in patients with severe AAV remission induction in patients with severe AAV

• There was no difference in treatment response

There was no difference in treatment response to rituximab or cyclophosphamide in patients to rituximab or cyclophosphamide in patients with: with:

• Major renal disease

Major renal disease

• Alveolar hemorrhage

Alveolar hemorrhage

NEJM 2010; 363:221 NEJM 2010; 363:221-

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RAVE Primary Results Summary RAVE Primary Results Summary

• The treatment response to

The treatment response to rituximab rituximab was was superior superior to cyclophosphamide in patients who to cyclophosphamide in patients who entered the trial with a entered the trial with a severe disease flare severe disease flare

• There was no difference in severe or limited

There was no difference in severe or limited disease flares by 6 months disease flares by 6 months

• There was no difference in severe adverse

There was no difference in severe adverse events rate by 6 months events rate by 6 months

• Fewer patients in the rituximab arm had

Fewer patients in the rituximab arm had ≥ ≥1 1 of

• f

the protocol the protocol-

• selected

selected AEs AEs by 6 months by 6 months

NEJM 2010; 363:221 NEJM 2010; 363:221-

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RAVE Conclusions RAVE Conclusions

• Rituximab represents the first proven alternative

Rituximab represents the first proven alternative to cyclophosphamide for remission induction in to cyclophosphamide for remission induction in severe ANCA severe ANCA-

• associated vasculitis

associated vasculitis

• This is of particular importance for patients

This is of particular importance for patients

• who present with a

who present with a severe disease flare severe disease flare who want to who want to preserve their fertility preserve their fertility

NEJM 2010; 363:221 NEJM 2010; 363:221-

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FDA extended the label of RTX for WG and MPA based on the RAVE trial results.

3030715-6

Another Randomized Controlled Trial: Another Randomized Controlled Trial: RITUXVAS RITUXVAS

• Randomized (3:1), controlled, open-label
• 44 patients (older than in RAVE)
• All ANCA-positive, all new diagnosis
• All had severe renal disease (more severe than

in RAVE)

• Comparing:

RTX plus two infusions of CYC (N=33) Intravenous CYC for 6 months,

followed by oral AZA (N=11)

• Everybody remained on ~10 mg of prednisone
• Primary endpoint: sustained remission at 12 mo

NEJM 2010; 363:211 NEJM 2010; 363:211-

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Main RITUXVAS Results Main RITUXVAS Results

No difference between treatment arms of: No difference between treatment arms of:

• Mortality high: 18% in each arm
• Sustained remission at 12 months:

RTX 76% vs CYC 82% (ITT analysis) RTX 93% vs CYC 90% (of survivors)

• Time to remission: RTX - 90 days vs CYC - 94 days
• Relapse rate
• Time to relapse
• Improvement of renal function
• Adverse events rate

NEJM 2010; 363:211 NEJM 2010; 363:211-

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Conclusion: over 12 months one course of RTX achieves the same results as 6 months of CYC followed by AZA.

3030715-6

• R. Cartin-Ceba, J. Golbin, K.A. Keogh, T. Peikert,

F.C.Fervenza, S.R. Ytterberg, and U. Specks.

RITUXIMAB FOR RITUXIMAB FOR REMISSION INDUCTION AND REMISSION INDUCTION AND MAINTENANCE MAINTENANCE IN ANCA IN ANCA-

• ASSOCIATED VASCULITIS:

ASSOCIATED VASCULITIS: A SINGLE A SINGLE-

• CENTER TEN

CENTER TEN-

• YEAR

YEAR EXPERIENCE EXPERIENCE

ACR 2010 ACR 2010

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Objectives Objectives

• To evaluate the efficacy and safety of rituximab

for remission induction and long-term maintenance in patients with chronically relapsing AAV

• Determine the effect of repeated courses of RTX
• n:

Duration of B cell depletion ANCA levels Severity of clinical relapses Adverse events Immunoglobulin levels

3030715-6

Methods Methods

• Single-center observational study.
• All patients with AAV treated with

2 courses of RTX between January 2000 and May 2010.

• Four weekly infusions at 375 mg/m2 were used

for remission induction and maintenance.

• More recently, 1g x 2 was used for remission

maintenance in 9 patients.

• Once RTX was started all other

immunosuppressive drugs were discontinued.

• All patients followed the same GC taper.

ACR 2010 ACR 2010

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637 AAV patients from 01/2000-5/2010 108 patients received

• 1 courses of RTX

Excluded: 54 RAVE trial participants 475 no RTX therapy 55 patients received only

• ne RTX course

53 patients received

• 2 courses of RTX and

were included in the analysis

ACR 2010 ACR 2010

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Baseline Characteristics Baseline Characteristics

Age (years) median (IQR) Age (years) median (IQR) 46 (30 46 (30-

• 61)

61) Female gender, n (%) Female gender, n (%) 28 (53) 28 (53) Time from diagnosis (years), median (IQR) Time from diagnosis (years), median (IQR) 10 (8 10 (8-

• 14)

14) Follow up period since first RTX (years), Follow up period since first RTX (years), median (IQR) median (IQR) 4.4 (2.7 4.4 (2.7-

• 6.2)

6.2) PR3 PR3-

• ANCA, n (%)

ANCA, n (%) 52 (98) 52 (98) Relapse on CYC, n (%) Relapse on CYC, n (%) 42 (79) 42 (79) Serious side effects of CYC, n (%) Serious side effects of CYC, n (%) 9 (17) 9 (17) CyC CyC contraindicated, n (%) contraindicated, n (%) 2 (4) 2 (4) ACR 2010 ACR 2010

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Rituximab treatment characteristics Rituximab treatment characteristics

Total RTX courses 233 (209 courses 375 mg/m2 X 4, 24 courses 1g X 2) RTX courses per patient, median (IQR) 4 (3-5) Preemptive RTX courses, N=148 per patient, median (IQR) 2 (1-3) Therapy of relapse, N=85 per patient, median (IQR) 1 (1-2) Median time to repletion of B cells in months (IQR; range) 8.5 (6-11; 5-22) Time to repletion of B cells: 375 mg/m2 X 4: months, median (IQR) 1000 mg X 2: months, median (IQR) 7.6 (7-9) 8.6 (7-9)

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Representative patient with relapsing WG Representative patient with relapsing WG

8 8 6 6

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Results Results -

• Efficacy

Efficacy

• Remission (BVAS=0) achieved in all patients

Remission (BVAS=0) achieved in all patients treated for relapses with RTX and GCS. treated for relapses with RTX and GCS.

• All relapses

All relapses

• after reconstitution of B cells

after reconstitution of B cells

• accompanied or preceded by rise in ANCA*

accompanied or preceded by rise in ANCA*

• All patients treated preemptively had documented

All patients treated preemptively had documented B cell reconstitution and rise in ANCA levels from B cell reconstitution and rise in ANCA levels from nadir. nadir.

• No rise of ANCA levels was observed in the

No rise of ANCA levels was observed in the absence of B cells. absence of B cells.

• No differences were found with the two different

No differences were found with the two different dosing regimens when used preemptively. dosing regimens when used preemptively.

ACR 2010 ACR 2010

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Results Results -

• Safety

Safety

Adverse events and infections Adverse events and infections

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Conclusions from Mayo Clinic Cohort Study Conclusions from Mayo Clinic Cohort Study

• RTX is effective and safe for induction and

RTX is effective and safe for induction and maintenance of remission in patients with maintenance of remission in patients with relapsing GPA (WG). relapsing GPA (WG).

• B cell depletion is effective at maintaining

B cell depletion is effective at maintaining remission in these patients, supporting a crucial remission in these patients, supporting a crucial pathogenic role for B cells in the disease. pathogenic role for B cells in the disease.

• Prolonged B cell depletion is well tolerated and

Prolonged B cell depletion is well tolerated and associated with a low risk of infection. associated with a low risk of infection.

Pneumocystis Pneumocystis jerovecii jerovecii pneumonia prophylaxis advised! pneumonia prophylaxis advised!

• Timing of retreatment can be individualized

Timing of retreatment can be individualized based on B cell counts and ANCA levels in these based on B cell counts and ANCA levels in these patients. patients.

ACR 2010 ACR 2010

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The King is Dead! Long Live the Queen! The King is Dead! Long Live the Queen!

Does Anybody Still Need Cyclophosphamide in 2011? Does Anybody Still Need Cyclophosphamide in 2011?

For remission induction in limited WG - NO For remission maintenance - NO For MPO-ANCA positive MPA with mild renal disease - PROBABLY

NOT (MMF instead - to be proven in a RCT)

For patients with severe WG or MPA, RTX is as effective (not inferior)

as CYC maybe with an edge - NO

Young patients wanting to preserve fertility - Definitely NO For remission induction in severe disease flares - NO For patients who failed CYC or have contraindications for CYC, RTX

has become the de facto standard of care.

Patients who fail rituximab or don

t tolerate it - maybe some

CAUTION: Rituximab is an immunosuppressive agent! Infection risk seems similar to that of carefully monitored CYC followed by AZA