ANCA--VASCULITIS

DR VIKRANT
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
 SYSTEMIC
VASCULITIS
NOMENCLATURE
 SYSTEMIC
VASCULITIS
NOMENCLATURE
FREQUENCY OF ANCA
POSITIVITY IN
DIFFERENT CONDITIONS
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
• DISEASE CATEGORISATION
• INDUCTION REMISSION : TRIALS AND SOC
• MAINTENANCE REMISSION : TRIALS AND SOC
• TREATMENT FOR REFRACTORY AND RELAPSE AAV
• NEWER APPROACHES
• UNMET NEEDS
•
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
ROLE OF COMPLEMENT
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
 ASSESSMENT OF DISEASE SEVERITY.

Localized Upper and/or lower respiratory tract disease without any

other Systemic involvement or constitutional symptom
Early systemic, Any, without organ-threatening or life-threatening disease

Generalized Renal or other organ threatening disease, serum

creatinine (5.6 mg/dl)
Severe Renal or other vital organ failure, serum creatinine(5.6
mg/dl)
Refractory Progressive disease unresponsive to glucocorticoids and
Cyclophosphamide
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
CYCLOPS TRIAL

NORAM TRIAL

RAVE TRIAL

RITUXVAS TRIAL

MEPEX TRIAL

PEXIVAS TRIAL
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
 CYCLOSPHAMIDE
PREDNISOLONE
AGENTS RITUXIMAB
USED IN
INDUCTION PLASMAPHERESIS
MMF
MTX
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
MTX GOOD ONLY FOR LOCALISED DISEASE WITH CREATININE OF 1.

EQUAL REMISSION RATES THOUGH LONGER TIME TAKEN

HIGHER RELAPSE RATE SO BETTER BE USED ONLY FOR LOCALISED DISEASE

C/I WHEN eGFR < 50

 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
 Rituximab in ANCA-associated Vasculitis (RAVE) trial

RAVE trial, was the first multicenter, randomized, double-blind, controlled trial
assessing the non-inferiority of RTX versus the standard of care (CYC) for remission
induction in patients with severe AAV and GC weaning at 6 months.

The patients met the following criteria:

severe GPA or MPA, newly diagnosed or relapsing disease, older than 15 years old, with
active disease defined as a BVAS/WG equal to or above 3, ANCA-PR3+ or ANCA-
MPO+.
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED

3. DOSES OF AGENTS USED

4. ORAL OR IV CYC

5. EARLY DISEASE : MTX OR CYC

6. PLACE OF RTX

7. PLACE OF PEx
PLASMA EXCHANGE MAY BE OF BENEFIT IN 3
CONDITIONS

LIFE THREATENING PULMONARY DIALYSIS REQUIRING RENAL CONCURRENT ANTI GBM

HEMORRHAGE FAILURE AT THE TIME OF DISEASE
PRESENTATION
 PEXIVAS TRIAL
• NO DIFFERENCE IN PRIMARY ENDPOINTS WITH OR
WITHOUT PE

• SUBGROUP ANALYSIS FAILED TO SHOW BENEFIT IN

PATIENTS WITH PULMONARY HEMORRHAGE.

• THIS MIGHT LIMIT USE OF PE IN AAV + ANTI GBM

DISEASE PAIENTS WHEN CONFIRMED

• NO DIFFERENCE IN EFFICACY WITH BOTH STEROID

GROUP BUT A LOW INFECTION RATE WITH LDCS.
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
• DISEASE CATEGORISATION
• INDUCTION REMISSION : TRIALS AND SOC
• MAINTENANCE REMISSION : TRIALS AND SOC
• TREATMENT FOR REFRACTORY AND RELAPSE AAV
• NEWER APPROACHES
• UNMET NEEDS
•
 Induction therapy

Localized CS+MTX

Early systemic CS+MTX or CYC

Generalized CS+CYC

Severe CS+CYC+PE

Refractory DESOXYPERGUALIN ,
MMF ,
ATG or
RTX
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
• DISEASE CATEGORISATION
• INDUCTION REMISSION : TRIALS AND SOC
• MAINTENANCE REMISSION : TRIALS AND SOC
• TREATMENT FOR REFRACTORY AND RELAPSE AAV
• NEWER APPROACHES
• UNMET NEEDS
•
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 IMPORTANT TRIALS IN
MAINTENANCE
1. CYCAZAREM

2. WEGENT

3. IMPROVE

4. MAINRITSAN ½

5. RITAZAREM

6. REMAIN TRIAL
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 PREDNISOLONE

CYCLOPHOSPHAMIDE

AGENTS USED .AZATHIOPRINE

IN
.RITUXIMAB
MAINTENANCE
MMF

MTX
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 WEGENT TRIAL
( AZA OR MTX)
REMISSION WITH CYC AND CS

AFTER REMISSION RANDOMISED TO AZA OR MTX

BASELINE CREATININE WAS 2 AT INDUCTION AND 1.5 AT

RANDOMISATION

BOTH HAVE SIMILAR EFFICACY / RELAPSE/ADVERSE

EFECTS.
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 QUESTIONS TO ANSWER

1. VARIOUS IMPORTANT TRIALS

2. AGENTS USED
3. DOSES OF AGENTS USED
4. AZA OR CYC
5. AZA OR MTX
6. AZA OR MMF
7. AZA OR RTX
8. HOW LONG???
 REMAIN TRIAL

AZA AND CS TILL 48M BETTER THAN 24M IN RELAPSE PREVENTION

LESS RELAPSE AND BETTER RENAL SURVIVAL IN 48M ARM

HOWEVER ONLY 35% IN WITHDRAWL GROUP HAD RELAPSE WHICH

MEANS 2/3RD DID NOT REQUIRE CONTINUATION

THEREFORE- PROLONG COURSE SHOULD BE USED IN PATIENTS

WITH HIGHER RISK FOR RELAPSE.
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
 Maintenance therapy

Localized LDS + AZA or LEF or MTX

Early systemic LDS + AZA

Generalized LDS + AZA OR MMF

Severe LDS + AZA OR MMF

Refractory No consensus
 Induction therapy Maintenance therapy

Localized CS+MTX LDS + AZA or LEF or MTX

Early systemic CS+MTX or CYP LDS + AZA

Generalized CS+CYP LDS + AZA OR MMF

Severe CS+CYP+PE LDS + AZA OR MMF

Refractory DESOXYPERGUALIN , No consensus

MMF ,
ATG or
RTX
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
• DISEASE CATEGORISATION
• INDUCTION REMISSION : TRIALS AND SOC
• MAINTENANCE REMISSION : TRIALS AND SOC
• TREATMENT FOR REFRACTORY AND RELAPSE AAV
• NEWER APPROACHES
• UNMET NEEDS
•
 REFRACTORY DISEASE

UNRESPONSIVENESS TO STANDARD INDUCTION WITH

CYC AND CS, THE PERSISTENCE OF RENAL AND OR
SYSTEMIC MANIFESTATIONS OF VASCULITIS.

RENAL RESISTANCE IS DEFINED AS PRESENCE OF

HEMATURIA,RBC CAST AND DECLINING RENAL
FUCNTIONS

RESISTANCE IS OBSERVED TO BE AROUND 20%.

 TREATMENT OPTIONS OF
REFRACTORY VASCULITIS

1. IVIG- INHIBITS ANCA BINDING TO Ag / NEUTROPHIL STIMULATION

2. 15-DEOXYPERGUALIN- INHITS T CELLS MATURATION
3. ATG-
4. HSCT
5. RTX
 RELAPSE

RECURRENCE OF S/S OF VASCULITIS IN ANY ORGAN

AFTER PARTIAL OR CR

ANTI-PR3/CARDIOVASCULAR INVOLVEMENT : ASSO

WITH INCREASED RELAPSE

NASAL CARRIAGE OF S.AUREUS ASSO WITH

INCREASED RELAPSE
 TREATMENT OF RELAPSES

PROTOCOL USED IS SIMILAR TO INDUCTION

CYC+CS AND OR PE(WHEN NECESSARY)

IF HIGH CUMULATIVE DOSE OF CYC BEFORE THEN USE

RTX

IF NO MAINTENANCE USED BEFORE THEN INSTITUTE

AZA/MMF WITH OR WITHOUT CS

RELAPSE WHILE ON MAINTENANCE THERAPY-TRY

IVIG
 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
TNF ALPHA BLOCKERS: INFLIXIMAB / ADALIMUMAB /

ETANERCEPT (WGET)

AVACOPAN : C5a INHIBITOR ( ADVOCATE TRIAL)

 OUTLINE OF PRESENTATION
• CLASSIFICATION AND NOMENCLATURE
• DEFINITION
• PATHOPHYSIOLOGY
• APPROACH TO TREATMENT
DISEASE CATEGORISATION
INDUCTION REMISSION : TRIALS AND SOC
MAINTENANCE REMISSION : TRIALS AND SOC
TREATMENT FOR REFRACTORY AND RELAPSE AAV
NEWER APPROACHES
UNMET NEEDS
SHOULD PR3 AND MPO ANCA BE TREATED DIFFERENTLY

OPPORTUNITIES FOR REMISSION INDUCTION

IMPROVE MORTALITY
MINIMIZE TOXICITY, PARTICULARLY CS
MINIMIZE TISSUE DAMAGE, PARTICULARLY RENAL
ROLE OF Pex
NOVEL DRUGS

OPPORTUNITIES FOR REMISSION MAINTENANCE

INDIVIDUALISED TREATMENT
IDENTIFY BIOMARKERS FOR RELAPSE
TARGETTING DRUGS SPECIFIC TO AT RISK POPULATION
TARGET THE DEFECT AT THE ROOT OF RELAPSE RISK
NOVEL DRUGS
NEWLY PROPOSED APPROACH
THANKYOU..
 ASSESSMENT OF DISEASE SEVERITY.

Localized Upper and/or lower respiratory tract disease without any

other Systemic involvement or constitutional symptom
Early systemic, Any, without organ-threatening or life-threatening disease

Generalized Renal or other organ threatening disease, serum

creatinine (5.6 mg/dl)
Severe Renal or other vital organ failure, serum creatinine(5.6
mg/dl)
Refractory Progressive disease unresponsive to glucocorticoids and
Cyclophosphamide
 Induction therapy Maintenance therapy

Localized CS+MTX LDS + AZA or LEF or MTX

Early systemic CS+MTX or CYP LDS + AZA

Generalized CS+CYP LDS + AZA OR MMF

Severe CS+CYP+PE LDS + AZA OR MMF

Refractory DESOXYPERGUALIN , No consensus

MMF ,
ATG or
RTX