Vasculitis: A Review of Pathogenesis, Diagnosis and Treatment ISNH July 12, 2010

Joanne M. Bargman MD FRCPC Staff Nephrologist and Professor of Medicine University Health Network and University of Toronto

Mr. P.

1999: 53 yo construction worker

dyspnea, cough, purulent nasal discharge,

anorexia, wt. loss and fever X 3 months 10 days PTA had nasal polyps removed, complicated by nosebleed +++ FD: elevated creatinine to ER

Mr. P.

O/E mildly hypoxic, BP 160/100

elevated JVP, bibasilar crackles Urinalysis: blood, protein, pigmented casts

Labs: Hb 9.8 g/dl, WC 36K, plts 522K

K+ 6.1, creatinine 10.4 mg/dl pANCA +; cANCA CXR: diffuse bilateral interstitial infiltrates failed diuresis line inserted for urgent
hemodialysis

Mr P: Renal Biopsy

How Would You Treat This Patient?

1. 2. 3. 4. 5.

High-dose corticosteroid plus monthly pulsed cyclophosphamide High-dose corticosteroid plus daily oral cyclophosphamide High-dose corticosteroid alone and monitor closely High-dose corticosteroid plus mycophenolate mofetil (MMF) High-dose corticosteroid, cyclophosphamide and adjunctive plasmapheresis

Course in Hospital

pulsed with solumedrol, started on daily oral cyclophosphamide P ANCA positive, C ANCA negative able to come off hemodialysis discharged Jan 2000: creatinine 3.0 mg/dl

Prednisone 25 mg tid, cyclophosphamide 200 mg od

Jan 2001: pred/CTX stopped, creatinine stable at 1.9 mg/dl May 2010: creatinine 1.9 mg/dl, ANCA neg

Outline

ANCA-associated vasculitis

description pathogenesis treatment

summary

The Syndrome of Rapidly Progressive Glomerulonephritis (RPGN)

Differential Diagnosis Immune complex-associated (primary or secondary)

Lupus nephritis Membranoproliferative GN Acute post-infectious GN IgA nephropathy / Henoch-Schonlein nephritis idiopathic immune complex crescentic nephritis

The Syndrome of Rapidly Progressive Glomerulonephritis (RPGN)

Differential Diagnosis (contd) pauci-immune

ANCA-associated glomerulonephritis

crescentic nephritis associated with anti-GBM antibody

The Syndrome of Rapidly Progressive Glomerulonephritis (RPGN)

Differential Diagnosis other diseases that have fooled me cholesterol embolic disease thrombotic microangiopathy acute interstitial nephritis acute tubular necrosis in a patient with GN

Distribution of Different Types of Crescentic GN by Age (Jennette 2003)

80 70 60 50 40 30 20 10 0 1-20 yo 21-60 yo > 60 yo pauci-im I.C. anti-GBM other cresc

ANCA-Associated Disease

With evidence of systemic vasculitis:

microscopic polyangiitis Wegeners granulomatosis Churg-Strauss vasculitis Renal-limited vasculitis

Without evidence of systemic vasculitis:

You Can Smell Vasculitis

Request from FD: Very pleasant 61 y lady. Flu shot in October. Saw me Nov 4 for abd pain: U/A trace of blood, abdo U/S normal. Seen again Nov 11 with decreased energy since September, with chronic cough. CXR shows consolidation L base. Nov 27 still c/o decreased energy. Dec 8 bloodwork shows creatinine 1.9 mg/dl, Hb 8.3, ESR 72.

The Renal Lesion

focal necrotizing glomerulonephritis crescents VERY RARE to see small vessel vasculitis or granulomatous angiitis on renal biopsy therefore, usually cannot differentiate between microscopic polyangiitis and Wegeners on usual kidney biopsy

The Vasculitidies: Clinical Characteristics and Distinctions

Microscopic polyangiitis

constitutional symptoms, anemia,

lung,neurologic, skin

Wegeners granulomatosis

ENT, lung, granulomatous angiitis

Churg-Strauss vasculitis

eosinophilia, asthma, granulomatous

inflammation

Etiology of Pulmonary-Renal Syndrome (Niles et al 1996)

%

60 50 40 30 20 10 0 ANCA GBM etiology

the most common cause of pulmonary- renal syndrome is ANCA-associated vasculitis

both

Microscopic polyangiitis Wegeners Granulomatosis

Types of ANCA

Directed against myeloperoxidase (MPO)

perinuclear IF: pANCA

Directed against PR3 antigen

cytoplasmic IF: cANCA

Immunofluorescence: Perinuclear ANCA (pANCA)

Immunofluorescence: Cytoplasmic ANCA (cANCA)

Types of ANCA (contd)

Anti PR3 most commonly found in Wegeners Granulomatosis Anti MPO most commonly found in the rest Anti MPO has also been detected in other, non-vasculitic diseases some pauci-immune vasculitic diseases are ANCA-negative

Types of ANCA vasculitis

Drug-associated ANCA vasculitis propylthiouracil pimagedine minocycline methimazole

Clinical Features

Anti PR3 (cANCA)-associated vasculitis

male predominance nodular, cavitating lung disease more frequent eye involvement more active, aggressive renal disease

Clinical Features

Anti MPO (PANCA)-associated vasculitis

female predominance diffuse, patchy lung disease more chronic renal lesions (not-soRPGN)

Time to Doubling Serum Creatinine: PR3 vs MPO ANCA (Franssen et al, 1995)
% doubling 70 s. creat 60
50 40 30 20 10 0 < 2 wks 2 to 12 wks 3-6 months > 6 months PR3 MPO

EB

63 year old woman Previous history of myocarditis Presents with SOB, rising creatinine, active urine sediment, anemia, ANCA + Biopsy: focal necrotizing glomerulitis Rx prednisone and cyclophosphamide X 3 months, then prednisone and MMF

EB(2)

excellent response to therapy creatinine settles at 1.3 mg/dl , Hb 13.6 2 years later: shortness of breath

Hb unchanged 13.7 albumin 3.9 g/dl

Outline

ANCA-associated vasculitis

description pathogenesis treatment

summary

Pathogenesis of ANCA-Associated Vasculitis

MPO and PR3 reside in azurophilic granules and lysosomes of neutrophils and monocytes How do antibodies to MPO/PR3

reach their target inside the cell? cause disease in the absence of immune
complex formation?

Pathogenesis of ANCA-Associated Vasculitis

MPO or PR3

ANCAs

Neutrophil priming (TNF? Other?)

Activated PMN -respiratory burst -release of O2 radicals and lytic enzymes -adherence to endothelial cells

Experimental Evidence that ANCAs are Sufficient to Cause Disease (Xiao et al, 2002)

Mouse MPO
immunization

MPO-knockout mice

Spleen cells and/or purified IgG anti-MPO Rag2-/- mice

(no functioning B or T lymphocytes)

Experimental Evidence that ANCAs are Sufficient to Cause Disease (Xiao et al, 2002)
Splenocytes or MPO IgG from immunized MPO-knockout mice Rag2-/Systemic necrotizing vasculitis -crescentic GN -granulomatous inflammation -pulmonary hemorrhage

Pathogenesis: Activation Phase

(Bosch JAMA 2007)

Pathogenesis: Effector Phase

(Bosch JAMA 2007)

Outline

ANCA-associated vasculitis

description pathogenesis treatment

summary

Treatment of ANCA-Associated Vasculitis

Principles of Treatment early diagnosis is important

saves the kidneys saves the patient

think of the diagnosis

rapidly falling hemoglobin an important clue multi-system symptomatology

Treatment of ANCA-Associated Vasculitis

Principles of Treatment (contd)

sensitivity and specificity of ANCA depends on clinical setting (pre-test probability) dont wait for the renal biopsy (and you may not have to do a renal biopsy!) warn patient about severity of disease and side effects of therapy document this warning in the patient record

Treatment of ANCA-Associated Vasculitis

What we know: corticosteroids and cyclophosphamide have changed the natural history of this previously-fatal illness

Treatment of ANCA-Associated Vasculitis

What we dont know (or arent too sure about):

incremental benefit of pulse corticosteroid vs daily oral prednisone at the start of treatment the role of plasmapheresis pulse cyclophosphamide vs daily oral cyclophosphamide cyclophosphamide-reducing regimens preventing relapses

How Would You Treat This Patient?

1. 2. 3. 4. 5.

High-dose corticosteroid plus monthly pulsed cyclophosphamide High-dose corticosteroid plus daily oral cyclophosphamide High-dose corticosteroid alone and monitor closely High-dose corticosteroid plus mycophenolate mofetil (MMF) High-dose corticosteroid, cyclophosphamide and adjunctive plasmapheresis

Plasmapheresis for ANCA-Associated Vasculitis: Studies to Date

studies in the 1980s conflicting, anecdotal In 1990s, 2 randomized, controlled trials: Canadian Apheresis group: patients with idiopathic crescentic GN Hammersmith Hospital: patients with focal necrotizing GN No benefit for plasmapheresis in the groups as a whole

Outcome of Patients Who Were DialysisDependent in the Studies

% able 100 to come 90 80 off 70 dialysis 60
50 40 30 20 10 0 Canadian Hammersmith PLEX no PLEX

Why Doesnt Plasmapheresis Help More Dramatically?

ANCA-associated vasculitis responds well to conventional immunosuppression (75-100% remission rate) so it is hard to show additional benefit of plasmapheresis only in subgroup of severe renal impairment has adjunctive therapy with plasmapheresis been suggested to be helpful

The Role of Plasmapheresis/Plasma Exchange

theoretical benefit to removal of ANCAs if they are pathogenic to the disease most studies of PLEX/PE in non-renal vasculitis have not demonstrated benefit Pusey et al (1991) demonstrated greater chance of recovery of dialysis-dependent renal failure with addition of PE

incremental benefit similar to using pulse compared to oral prednisone

Jayne J Am Soc Neph 2007

The MEPEX Trial

137 patients biopsy-proven renal vasculitis ANCA positive

43% PR3 (cANCA) 52% MPO (pANCA) 5% ANCA negative

serum creatinine > 6.0 mg/dl

MEPEX: Treatment Protocol

Both groups

oral prednisone 1 mg/kg, tapered to .25 mg/kg

by week 10, 15 mg/day by 3 months and 10 mg/day from 5 to 12 months oral CTX 2.5 mg/kg (2.0 mg/kg if > 60) for 3 months oral CTX 1.5 mg/kg for the next 3 months then changed at 6 months to AZA 2 mg/kg thereafter

MEPEX: Treatment Protocol

Study Treatment

IV methyprednisolone 1000 mg daily X 3;

Or plasma exchange

60 ml/kg BW replacement with 5% albumin 7 sessions in the first 14 days

The MEPEX Trial

Jayne J Am Soc Neph 2007

At 3 months: renal recovery in 49% of MP group and 69% of PLEX group (p=0.02) difference in renal recovery established by 2 months

Jayne J Am Soc Neph 2007

The MEPEX Trial

no difference in overall survival in either group by 12 months risk reduction of ESRD was 24% at 12 m in PLEX group the development of ESRD was a strong predictor of death

MEPEX Trial: Final Thoughts

took years to be published benefit of PLEX established by 2 months, no further improvement why not give PLEX and IV methylprednisolone?

One of the Many Problems with Treatment of ANCA-Associated Vasculitis: Mr. R.

1989

20 year old man presented with progressive hemoptysis and severe hypoxia unresponsive to antibiotics open lung biopsy: granulomatous angiitis c/w Wegeners Granulomatosis renal function normal, trace blood and protein Rx cyclophosphamide 2 mg/kg BW daily and prednisone treated for 18 months and D/Ced

One of the Many Problems with ANCAAssociated Vasculitis (contd)

1991-1995

continued ANCA PR3 positivity cough with streaky hemoptysis bloody nasal discharge intolerant of Septra red eye: membranous conjuctivitis Worsening of red eye: scleritis

1996

no response to topical corticosteroids eye doctor recommended re-starting systemic rx

One of the Many Problems with ANCAAssociated Vasculitis (contd)

May 1996

pt refused prednisone restarted cyclophosphamide 100mg/od bronchoscopy: inflammatory tracheobronchitis c/w Wegeners gross hematuria cytoscopy: transitional cell CA

June 1997

resection and intravesical BCG cyclophosphamide discontinued

One of the Many Problems with ANCAAssociated Vasculitis (contd)

1998

subglottic stenosis with marked inflammation

c/w Wegeners, worsening stridor (airway 5 mm) restarted high dose prednisone

January 1999

methotrexate 15 mg weekly

One of the Many Problems with ANCAAssociated Vasculitis (contd)

Current status 2010

markedly overweight diabetic hypertensive PR3 ANCA remains strongly positive occasional bloody nasal discharge continues on methotrexate weekly

One of the Many Problems with ANCAAssociated Vasculitis (contd)

signicant relapse rate, especially with Wegeners (>50% over 8 yrs) chronic cyclophosphamide therapy is associated with

urothelial cancer myelodysplastic syndromes up to and including leukemia 10-fold risk of lymphoma gonadal toxicity

Regimens to Reduce Exposure to Cyclophosphamide (CTX)

treatment with prednisone and methotrexate in Wegeners pulse CTX instead of daily oral CTX treatment with prednisone and CTX for 3 to 6 months, then conversion to a different drug

azathioprine methotrexate mycophenolate mofetil

Regimens to Reduce Exposure to Cyclophosphamide (CTX)

pulse vs daily oral CTX in new Wegeners (Guillevin 1997)

27 pts IV CTX 0.7 g/m2 q3wk until remission, then at increasing intervals for 2 yrs 23 pts oral CTX 2 mg/kg/d X 1y, then tapered by 25% q4months

Pulse vs daily oral CTX in new Wegeners (Guillevin 1997)

PR

death

(actuarial)

Regimens to Reduce Exposure to Cyclophosphamide (CTX)

Pulse vs daily oral CTX in ANCAassociated vasculitis (Haubitz 1998) 47 pts,( > 50% had pANCA disease)

25 received CTX 2mg/kg/day 22 received 0.75g/m2 q4weeks

Rx continued for at least 1 year

Pulse vs daily oral CTX in ANCA-associated vasculitis (Haubitz 1998)

CTX: Daily Oral vs Pulse Therapy

bottom line appears to be that daily oral CTX, compared to pulse CTX, is associated with

higher remission rate lower relapse rate (Wegeners) more infectious complications more gonadal toxicity (by FSH levels)

CYCLOPS Study: Pulse versus Daily Oral Cyclophosphamide (de Groot 2009)

ANCA positive vasculitis with renal involvement Serum creatinine > 150 but less than 500 umol per l

CYCLOPS Study: Pulse versus Daily Oral Cyclophosphamide (de Groot 2009)

Regimen:

Prednisone 1 mg per kg tapering to 12.5 mg by month 3 and 5 mg at month18, AND

IV CTX 15 mg per kg q2weeks X3, q3weeks after

OR

daily oral CTX

CTX doses reduced in elderly and creat 300+

CYCLOPS Study Pt Characteristics

CYCLOPS continued

Treated until remission + 3 more months CTX then switched to azathioprine

CYCLOPS: Time to Remission and eGFR

CYCLOPS: Cumulative Dose of CTX

daily oral CTX group received 15.9 g (11-22.5) versus pulse group received 8.2 g (5.9510.55) no difference in total prednisone dose twice as many relapses in pulse group compared to daily oral, but not statistically significant

Regimens to Reduce Exposure to Cyclophosphamide (CTX)

CTX vs AZA as remission maintenance therapy in ANCA-associated vasculitis (Jayne et al, 2003)

155 pts ANCA+ vasculitis (most Wegeners) with mean GFR ~ 50 ml/min After induction of remission, randomized to

continued CTX (1.5 mg/kg) for 12 mos total, or change to azathioprine (2 mg/kg)

18 month total followup

Regimens to Reduce Exposure to Cyclophosphamide (CTX)

CTX vs AZA as remission maintenance therapy in ANCA-associated vasculitis (Jayne et al, 2003) no difference in relapse rate CTX (14%) vs AZA (15%) only predictor of relapse was microscopic polyangiitis (8%) vs Wegeners (18%) no difference in serious adverse events

AZA vs MTX for Maintenance Therapy

Pagnoux et al 2008

patients with ANCA vasculitis after remission (prednisone and pulse CTX)

azathioprine 2 mg/kg
OR methotrexate 0.3 mg/kg up to 25 mg/week X 12 months, then withdrawal over 3 months

(continued)

AZA vs MTX Maintenance Therapy

no difference between AZA or MTX but... by 20 months: 35% relapse most after withdrawing the drugs!

Regimens to Reduce Exposure to Cyclophosphamide (CTX)

Remission therapy with MMF in ANCAassociated vasculitis (Nowack 1999)

9 WG and 2 PA pts remission induction with corticosteroids and CTX (3 IV) CTX changed to MMF 2 g/day followed for 15 months only 1 relapse (WG)

Other Regimens to Reduce Exposure to Cyclophosphamide (CTX)

Anecdotal reports using

Cyclosporin Rabbit anti-thymocyte globulin Anti CD4 Anti CD20 Anti CD52 TMP/SMX Etanercept (TNF antagonist)

Treatment of Antineutrophil Cytoplasmic AntibodyAssociated Vasculitis: A Systematic Review (Bosch JAMA 2007)

2 meta-analyses, 20 RCTs, 62 uncontrolled trials with > 10 patients EUVAS definitions of disease

Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Systematic Review (Bosch JAMA 2007)

Generalized Organ-Threatening Disease, including serum creatinine < 5.7 mg/dl Induction: daily oral CTX + prednisone remains gold standard intravenous CTX less toxic but may (or may not) have more relapses Maintenance: continue CTX pulse or switch to AZA, MMF or leflunomide

Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Systematic Review (Bosch JAMA 2007)

Severe Renal Vasculitis and Immediately LifeThreatening Disease pulse cyclophosphamide (no trials) intravenous methylprednisolone (no trials) plasma exchange (MEPEX)

A New Frontier: Induction with MMF?

Hu Neph Dial Transplant 2008 MMF vs pulse CTX for induction 35 patients, mostly pANCA

MMF: 2 g/day CTX: 0.75-1.0 g/m2 monthly X 6

4 pts in CTX group lost to F/U (?)

Induction Therapy With MMF vs Pulse Cyclophosphamide (contd)

at 6 months, vasculitis activity scores better in MMF group 8/18 pts in MMF and 2/17 in CTX group recovered renal function

Outline

the syndrome of rapidly progressive glomerulonephritis ANCA-associated vasculitis

description pathogenesis treatment (prevention of progression)

summary

Summary (I)

in adulthood, the syndrome of rapidly progressive glomerulonephritis is most often the result of a pauci-immune crescentic nephritis the commonest correlate of this lesion is with ANCA positivity and vasculitis

Summary (II)

evidence is growing that ANCAs are pathogenically linked to vasculitis, with the neutrophil being the vector of damage successful treatment mandates early diagnosis and intensive immunotherapy there is increasing recognition that cylclophosphamide -sparing regimens are needed to reduce complications of the therapy itself