PROF. S. RAJESWARI M.D., D.MDirector & Head,Institute Of RheumatologyMadras Medical College & RGGGHChennai, Tamil Nadu, India

State Of Art : AAV Management

ANCA VASCULITIS

Small Vessel Vasculitis

Clinical phenotypes

GPA – ENT (granulomatous) EGPA MPA GPA/MPA overlap

(Multiorgan L,K,PAH,RPGN)

ANCA TESTING AND APPLICATIONS

IIF followed by ELISA IIF : cANCA vs pANCA

Hinderance with ANA Subjective

ELISA : anti PR3 & MPO New generation ELISA Multiplex ELISA Positive predictive value

C ANCA + anti-PR3 – 90% active GPA P ANCA + anti-MPO – MPA and EGPA Atypical ANCA• Multiple antigens drugs, cocaine• LAMP2 Serial ANCA – individualised

ANCA – cornerstone for AAV diagnosisAppropriate clinical setting supporting pathology

Future

ANCA TESTING

Anti-PR3 positivity • High mortality (RR >3)• Independent risk factor - relapse• Faster decline in renal function in Renal AAV

BIOPSY

Kidney Biopsy (in Renal involvement) high yield 80% - Segmental necrotising pauci-immune GN Prognostic Sclerosis + tubular atrophy – ESRDPulmonary – 85% AAV To differentiate between GPA & MPA• GPA - nodules, cavities• MPA - pulmonary Infiltrates, DAH Lung Bx -• Thoracoscopic• Open lung• Trans bronchial o For diagnosis and exclusion of infections / malignancyo Negative transbronchial specimen should not exclude AAV diagnosis BAL - DAH, infections / malignancy

IDEAL RX

• History• Co-morbidities• Severity• Pattern

TREATMENT PRINCIPLES

SEVERE (Life/Organ threatening) LIMITED (Non organ/life threatening )

1. RPGN2. DAH3. Mesenteric ischemia4. Scleritis5. CNS involvement

1. Mild renal2. Mild pulmonary

Aggressive treatment Mild treatment

TREATMENT PRINCIPLES

5-FFS (activity & severity)1. Age > 652. Absent ENT disease 3. Cardiac4. GI ischemia5. Renal insufficiency

Removed from original FFS: Proteinuria, CNS

STEROIDS

TREATMENT

INDUCTION MAINTENANCE ACTIVE/RELAPSING

Corticosteroids Tapering dose Corticosteroids corticosteroids or

STOP

CYCLOPHOSPHAMIDE• Oral CYC – 2mg/kg/d

• Toxicity – cumulative dose 168 mg/ kg • Hemorrhagic cystitis, malignancy, infertility – 50%

• IV CYC – 15mg/kg every 2 to 3 weeks• ↓Cumulative dose• 1/3 leucopenia

Rx mode - individualized

CYCLOPS oral/IV IV CYC – ↑ relapse

RITUXIMAB - B-CELL TARGETED THERAPY

RTX non inferior to CYC Dose : 375 mg/m2/week – 4 weeks Induction & Remission High dose steroids – tapered by 6 months

RITUXIMAB 2011 FDA approved Rx in MPA & GPA

B-CELL TARGETED THERAPY

RAVE

Single dose RTX-375mg/m2 vs

CYC + placebo followed by AZA

RITUXIVAS

New AAV + renal RTX + IV CYC vs IV CYC Alone

Non-Inferior to Cyclophosphamide

RITUXIMAB• Induction : 1g every 6 months• End. Pt: - ↓ relapse - Longer remissionON GOINGRTX: 2 regimens1. Reconstitution of B lymphocytes and rising ANCAs2. Fixed interval retreatment every 6 months INDIVIDUALISEDRTX - GPAGRANULOMATOUS OTOLARYNGOLOGIC DISEASE

SEVERE RENAL ± ALVEOLAR HEMORRHAGE

S.Creatinine > 5.7mg %• Plasma Exchange (7) + Methyl Prednisolone (1g x 3)• Survival: (69% P.E+M.P) (49% M.P alone)

DAH ± RENAL• Plasma Exchange + G.C

MEPEX

PEXIVAS

LIMITED DISEASE

• MTX 15-25mg / wk vs CYC (oral) (Induction Of Remission)

Primary End point6 months – MTX - 90% - Longer time to act – relapse CYC - 94% 18months – MTX – relapse ↑ 6 yrs – MTX – relapse ↓

NORAM

MAINTENANCE THERAPY – CYC VS AZA

• Newly diagnosed patientsInduction : Oral CYCMaintenance : ↓ Oral CYC OR AZA switch (at 12 months)Primary End point – relapse – 18 months

CYCAZAREM

Nil significant

MAINTENANCE THERAPY (AZA vs MTX)

• Induction : IV CYC• Maintenance : AZA/MTX – (precautions) - 12 months

Nil significant

WEGENT

MAINTENANCE THERAPY (MMF vs AZA)

• Induction : CYC• Maintenance : MMF (2g/day) / AZA (2mg/kg/d)

36 months

IMPROVE

MMF: Relapse ↑ (hence for refractory)

MAINTENANCE THERAPY (MTX vs LEF)

• Induction : CYC• Maintenance : LEF (30mg/d) vs MTX

LEF associated with ↑ adverse events

MTX associated with ↑ relapse

STAPHYLOCOCCAL PROPHYLAXIS(MILD LOCALISED U.AIRWAY)

TMP – SMX – 800 mg /160 mg twice daily vs placebo Primary End point – 24mths – TMP/SMX - Remission

COMORBIDITES• Thrombo-embolism 20 fold ↑ (DVT & PTE screening)

• Accelerated atherosclerosis• CVA & MI 2 to 4 fold ↑ in the first 5 yrs• HTN 40% AAV• DM 10% AAV

• Malignancy• Oral CYC – Bladder (5% at 10 years)• Non melanoma, lymphoma, leukemia.

DAMAGESEQUELAE OF AAV

Disease activity Treatment toxicity(ACTIVITY) (DAMAGE)

CAUTION:Active diseaseAvoid accrual of permanent damage

FOLLOW UP• CLINICAL INVESTIGATIONS

•Urine •Lab tests - basic

RELAPSE

55% First few years Maintenance – 2 years Mortality – 1st year – a) infection 48% b) Vasculitis

ETANERCEPT Induction: ETN Vs PLACEBO (WGET) Maintenance MTX – limited CYC – severe Flares common in ETN & PLACEBO

BEWARE: SOLID MALIGNANCIES WITH ETN with prior CYCLO!

EGPA

C/F Asthma Eosinophilia ENT Eosinophilic lung Infiltrates Vasculitis –

Glomerulonephritis,peripheral neuropathy, Purpura ↓ compared to GPA

Biopsy• Kidney• Nerve – epineural

vasculitis & eosinophilia – (50%)

FUTURE – TARGETS• Innate/Adaptive immunity• B-cell survival factors• T-cell co-stimulation• Molecular mechanisms• ECULIZUMAB (C5a inhibitor)

• MEPOLIZUMAB – IL-5 antagonist (safe & steroid sparing)

LEVEL OF EVIDENCE AND STRENGTH OF RECOMMENDATION

STATEMENT I

• Treatment at centres of expertise• Individual assessment by specialists

Level of evidence 3Grade of recommendation CStrength of Voting 100%

STATEMENT II

• Positive biopsy : strongly supportive of vasculitis

• Needed in

• Establishing diagnosis at baseline and during relapse

Level of evidence 3Grade of recommendation CStrength of Voting 81%

• Pauci Immune GN eg GPA 91.5%• ENT – Biopsy 68.4%• Transbronchial lung biopsy in GPA 12% in EGPA 66.7%

• Open lung biopsies higher yield !!!• Renal Biopsy (preferably USG guided) Risk of bleeding

higher in PLEX !!

STATEMENT II - BIOPSY

STATEMENT III - INDUCTION OF REMISSION - AAV

• New onset organ threatening vasculitis• Life threatening vasculitis

Cyclophosphamide

GPA/MPA

EGPA

LOE IA 3GOR A CSOV 100

%88%

Steroids+

Cyclophosphamide or

Rituximab

Rituximab

GPA EGPA

LOE IB 3GOR A CSOV 82% 59%

STATEMENT III – PROPHYLAXIS THERAPY

• Pneumocystis jiroveci, with either

• TMP 400/SM2 80mg/day

• Inhaled pentamidine – monthly

• Dapsone

• Atovaquone

STATEMENT III – TAPERING STEROIDS

• Steroids tapered to 7.5mg – 10mg by 3 months

STATEMENT IV – INDUCTION OF REMISSION

MTX MMFLOE IB 1BGOR B CSOV 77% 65%

• Non organ threatening vasculitis

Steroids+

MTX 20-25mg/wkor MMF

METHOTREXATE

INDICATED CONTRAINDICATED

Nasal and paranasal sinuses without bone / cartilage inv./olfactory deafness

Renal involvement

Skin without ulceration Retro-orbital disease

Myositis Cardiac involvement

Non cavitating pulm.nodules/Infiltrates without hemoptysis

Acute onset mononeuritis multiplex

CYC/RTX – NA or CI or patient’s choice Alveolar hemorrhage

Mesenteric ischemia

Meningeal

STATEMENT V – RELAPSE

• Relapse of life or organ threatening vasculitis

Cyclophosphamide

GPA/MPA

EGPA

LOE IA 3GOR A CSOV 88% 88%

Steroids+

Cyclophosphamide or

Rituximab

Rituximab

GPA EGPA

LOE IB 4GOR A DSOV 94% 100%

WHAT TO DO IN NON SEVERE RELAPSES?

a) Double dose of steroids

b) Temporarily ↑ the dose of steroids

c) Start pulse again

d) ↓ Immunosuppression

WHAT SHOULD BE THE MODE OF IMMUNOSUPPRESSION IN NON SEVERE RELAPSE?

a) Only steroids

b) Intensification of immunosuppression

c) Modification of immunosuppression

d) Both b and c

IF SERUM CREATININE > 5.7 MG%, DAH, RPGN ???

a) Pulse steroid

b) Pulse CYC

c) To add PLEX

d) AZA

STATEMENT VII - PLEX

• Plasma exchange considered if

• Serum creatinine > 5.7 mg% in RPGN

• Severe diffuse alveolar hemorrhage

• Prevents ESRD – 3mths

PLEX RPGN DAHLOE IB 3GOR B CSOV 77% 88%

STATEMENT VIII- REMISSION MAINTENANCEWITH WHAT AND HOW LONG ?? GPA/MPA

AZA RTX MTX MMFLOE 1B 1B 1B 1BGOR A A A ASOV 94% 59% 53% 53%

Low dose steroids+

AZA / RTX / MTX / MMF

EGPA AZALOE 3

GOR CSOV 77%

At least 2 yearsMore for PR3 positive AAV

STATEMENT IX – AAV REFRACTORY TO REMISSION INDUCTION

• EULAR definition:

• Unchanged or ↑ disease activity in acute AAV after 4 weeks of

standard therapy in acute AAV

• Lack of response: < 50% in BVAS after 6wks of treatment

• Chronic persistent disease: One major or 3 minor items of BVAS

after 12 wks of treatment

• Re evaluation – infection/malignancy/damage

Steroids +Cyclophosphami

de

Steroids +Rituximab

Switch therapy

STATEMENT IX – AAV REFRACTORY TO REMISSION INDUCTION

Switching therapy

LOE 3

GOR CSOV 71%

STATEMENT IX

• Topical mupirocin in nasal carriers of Staphylococcus aureus

• Anti-MPO positive renal disease

• Worst prognosis

• Tubulo-interstitial inflammation

• CD3+ T-cell tubulitis

• Tubular atrophy

• Poor outcome with sclerosis

• Anti –PR3 positive CVS and lung disease relapse

RITUXIMAB IN REFRACTORY AAV

1. Refractory Renal disease2. Refractory retro orbital disease3. Anti-PR3 +ve AAV

Steroids +IV

Cyclophosphamide

Steroids +Oral

CyclophosphamideSwitch therapy

if Rituximab NA

? IVIg

• Pre-infusion IgA screening• Used in

• Remission failure• Persistent low activity

STATEMENT X – CHANGE IN TREATMENT (CLINICAL ASSESSMENT vs ANCA)

• Structured clinical assessment better than ANCA !!• However, predictors of high relapse

Persistent ANCA titers 4 fold in titers

ANCA negative becoming positive

Clinical assessment

LOE 4

GOR DSOV 100%

• Each visit Urine analysis• 1-3 months Inflammatory markers Renal function CBC LFT Blood sugar

STATEMENT X – CLINICAL ASSESSMENT AND FOLLOW UP

STATEMENT XI – UNEXPLAINED HEMATURIA & CYC

• Persistent unexplained hematuria vs CYC exposure• Urology opinion• MESNA – bladder protective

Clinical assessment

LOE 2B

GOR CSOV 100%

STATEMENT XII –SERUM IgG

• after RTX & CYC

• with infections

• Recommended to check IgG levels

• Prior to each course of RTX

• Recurrent infections

Hypo gamma globulinemia

LOE 3

GOR CSOV 65%

VACCINATIONS

• Influenza vaccine

• Pneumococcal

• Herpes zoster ?? (follow local guidelines)

STATEMENT XIII – CARDIOVASCULAR RISK ASSESSMENT AND OTHER COMORBIDITIES

• CVS – risk factors• FFS >5 at 7yrs of Rx (1/3)• CKD - Follow KDIGO guidelines

CVS risk assessment

LOE 2B

GOR BSOV 53%

STATEMENT XIV - COUNSELING

• Bewildering Confusing Fearful

M Yates et al. Ann Rheum Dis doi:10.1136/annrheumdis-2016-209133

ALGORITHM FOR THE MANAGEMENT OF AAV

POINTS TO PONDER• AAV – Systemic disease• Potent fatal damage• Organ Loss• Life affected

• Social• Personal• Educational

• Life Long disease• Depression

HOLISTIC APPROACH

CASE VIGNETTES

CASE 1• 30 yr / FClinical features:• Scleromalacia perforans• Right Jugular foramen syndrome• Right LMN facial nerve palsy• Right lower cranial nerve palsy

(9,10,11,12 cranial nerve)• Nail bed infarcts

• B/L Otomastoiditis; Right modified radical mastoidectomy done

• Jugular venous thrombosis; Right facial nerve decompression done

• Left maxillary sinusitis, Left nasal cavity mucosal hypertrophy

• HPE: S/o granulomatous inflammation• MRI Brain: multiple deep white matter

infarcts. S/o vasculitis• c-ANCA pattern (IIF) and ANCA (E) –

anti-PR3 +• Treatment:

• CYC Remission Relapse RTX

CASE 2• 30 yr/ F• Left eye proptosis & visual loss• Left maxillary sinusitis• Past H/o B/L CSOM• Frontal granuloma• Anti - PR3 positive• IIF - cANCA positive• Nil renal • Treatment: Pulse iv CYC

RTX i /v/o Refractory AAV

CASE 2Baseline After 6 months

CASE 2Baseline After 6 months

CASE 3

MPA or MPA /GPA overlap• Sclero kerato-uveitis• Systemic hypertension• Pauci-immune Crescentric

glomerulonephritis• Lung infiltrates• ANCA : MPO + PR3 –• Treatment – CYC by EUVAS protocol

CASE 4• 17 year old boy• Known asthmatic since childhood• Multiple erythaematous macules and • nodules over extremities• Generalized lymphadenopathy• Left maxillary sinusitis• Eosinophilia in blood • Raised IgE levels (>2500 IU/mL)• ANCA and ANA negative• Bilateral reticulo nodular opacities

CASE 5Lymph node biopsy - Eosinophilia Skin biopsy – Perivascular neutrophil

infiltration

CASE 5

Fleeting opacities

• Treatment• Steroids • Rituximab tried but developed anaphylaxis• Given CYC infusion• Stable till 2 infusions• Developed mesenteric ischemia• High dose steroids & IVIg• Developed transverse sinus thrombosis and peripheral neuropathy• PLEX done• Succumbed

TO SUM UP• History & Clinical assessment• Importance of ANCA testing• Principles of induction and remission maintenance• Variety of drugs ( Steroids MTX/CYC/RTX AZA/MMF/RTX)• Other modalities: PLEX• Co-morbidities • Vaccination• Treatment should be individualized

ANCA Associated Vasculitis

Angry Aggressive Vasculitis

AAV

THAN Q