Small Vessel Vasculitis

Small Vessel Vasculitis 

Banff- Rocky Mountain 

Barry Kassen, MD, FRCPC,FACP 

Head, Division of Internal Medicine – UBC/VGH/SPH 

Acting Head, Division of Community Internal Medicine 

November, 2009


Objectives 

1. To understand small vessel vasculitis 

2. To understand an approach to therapy of small 

vessel vasculitis


Classification of Vasculitis 

1. Large vessel vasculitis 

2. Medium vessel vasculitis 

3. Small vessel vasculitis 

Plus: Antineutrophil Cytoplasmic Antibodies (ANCA)


Classification (continued) 

Large Vessel Vasculitis 

Takayasu’s 

Giant Cell Arteritis 

2. Medium Sized Vessel Vasculitis 

Polyarteritis Nodosa (PAN) 

Microscopic Polyarteritis (MPA) 

Kawasaki’s Disease 

Primary Central Nervous System Vasculitis 

3. Small Vessel Vasculitis 

Churg-Strauss Arteritis (CSA) 

Wegeners Granulomatosis (WG) 

Microscopic Polyarteritis (MPA) 

Henoch- Schonlein Purpura 

Essential Cryoglobulinemic Vasculitis 

Hypersensitivity Vasculitis 

Vasculitis Secondary to Connective Tissue Disorders 

Vasculitis Secondary to Viral Infections


Mimics and Secondary Causes of Vasculitis 

Mimics of vasculitis Secondary causes of vasculitis 

Atheroembolic disease Infections Tuberculosis 

Atheromatous vascular disease Hepatitis B 

Anti-phospholipid syndrome Hepatitis C 

Multiple myeloma HIV 

Infective endocarditis Parvovirus 

Other chronic infections Cystic fibrosis 

Para-neoplastic syndromes Malignancy Lymphoma 

Autoinflammatory syndromes Solid organ malignancy 

Hypersensitivity reactions Connective tissue disorders Rheumatoid arthritis 

Cocaine and amphetamine abuse Systemic lupus erythematosus 

Scleroderma 

Sjogren’s syndrome 

Drugs Penicillamine 

Propylthiouracil 

Hydralazine 

Minocycline 

Cocaine 

Environmental exposure Dusts 

Silica


A diagnostic pathway for vasculitis 

Components of a vasculitis diagnosis 

1. Compatible clinical phenotype 

2. Supported by specific serology (e.g. ANCA) or radiology (e.g. 

angiography) 

3. Confirmation by tissue biopsy 

4. Exclusion of mimics and secondary causes 

5. Observation over time to improve certainty of diagnosis 

(D. Jayne / Best Practice & Research Clinical Rheumatology 23 (2009) 445–453 447)


Clinical Spectrum of Antineutrophil 

Cytoplasmic Antibodies (ANCA) 

1982- discovered 

Two types of ANCA assays 

Indirect Immunofluorescence assay (IF) 

Enzyme Linked Immunosorbent assay (ELISA) 

Target antigens 

Proteinase 3 (PR3) 

Myeloperoxidase (MPO)


Immunofluorescence Patterns in Vasculitis 

Incubate patients serum with ethanol-fixed neutrophils (alcohol fixed 

buffy coat leukocytes) 

2 patterns seen visually 

#1 C- ANCA 

There is diffuse straining throughout the cytoplasm. (antigen is 

proteinase 3) 

#2 P-ANCA 

There is staining around the nucleus (antigen is myeloperoxidase) 

Caution: 

ANCA testing has no references for normal range 

Positive predictive value for vasculitis 25%-50% 

There are other antigens in the cytoplasm (lactoferrin, elestase, etc.) 

ANA positive may give “false positive”. (to P-ANCA)

C-ANCA

P- ANCA


Enzyme-Linked Immonoassays (ELISA) 

This test is more specific than I.F and so is performed following I.F. 

Antibodies to: 

• Proteinase 3 (PR3) 

• Myeloperoxidase (MPO) 

C-ANCA 

• Most cases antibody is to PR3 

P-ANCA 

• Most cases antibody to Myeloperoxidase (MPO) 

• ELISA has higher specificity and higher positive predicative 

values for vasculitis.


Disease Associations with ANCA 

Wegener’s Granulomatosis, microscopic polyarteritis, Churg-Strauss, renal-limited 

vasculitis, drug induced vasculitis syndromes. 

Classic drug association is propylthiouracil or methimazole. 

Nonvasculitis Rheumatic Disorders 

RA, SLE, Sjogren’s Syndrome, JRA, Scleroderma 

Autoimmune Gastrointesinal Disorders 

Ulcerative Colitis 

Crohn’s disease 

Cystic Fribrosis 

Others: Subacute bacterial endocarditis 

Infectious mononucleosis 

graft vs.. host 

autoimmune hepatitis 

etc.


ANCA 

Is a positive test a “True Positive” ? 

IF- positive predictive value for vasculitis- 45% 

ELISA- positive predictive value 83% 

IF plus ELISA-88% 

Does a negative ANCA exclude small vessel vasculitis? 

40% of limited Wegener’s are ANCA negative 

10% of severe Wegener’s are ANCA negative 

30% of MPA 

50% of CSS


Does a positive ANCA alleviate the need for 

confirmation of diagnosis by tissue biopsy? 

The Predictive value of ANCA testing depends heavily on the clinical 

situation. 

Multi-centered European Collaborative study (Kidney International 

1998). 

Comparison of vasculitis patients with controls who had other 

vasculitis, other glomerulopathies, etc and 740 healthy 

volunteers. 

Sensitivity and specificity of ANCA (IF/ELISA) varied for WG, 

MPA, and pauci-immune vasculitis. Therefore a biopsy is still 

required in ANCA positive patients to make a diagnosis of 

Primary Vasculitis.


Does a Rise in ANCA Predict a Disease Flare? 

WGET (Research group, 2005) 

180 patients followed by ANCA 3 monthly. 

No difference in median time to relapse, disease activity or organ 

involvement. 

Controversy, though, still exists. 

Does Persistently Negative ANCA Assure Disease 

quiescence? 

If initially positive then helpful for proof of remission.


Epidemiology of Small Vessel Vasculitis 

Is Systemic vasculitis becoming more common? 

Incidence of ANCA associated vasculitis in Norfolk, England 

1989-1993- incidence 20.3 case per million 

1999-2003- incidence 17.1 cases per million 

Incidence in Northern Germany 

1999-incidence 48 cases per million 

2002- incidence 42 cases per million


Pathogenesis of Vasculitis 

Do leukotriene inhibitors cause Churg-Strauss Syndrome? 

1998 Wechsler- 8 cases of glucocorticoid-dependant asthma treated with 

zafirlukast. 

Developed Eosinophilia, pulmonary infiltrates and cardiomyopathy. 

2003- Mayo Clinic Review (91 cases) of Churg-Strauss 

16 cases received leukotriene inhibitors before onset of disease. 

6 patients received leukotriene inhibitors during remission. 

4 years interval between onset of asthma and vasculitis in both groups (16/91; 

65/91) 

4/6 patients in remission received leukotrienes with no flare.


What is the significance of ANCA among patients with 

Churg-Strauss Vasculitis? 

Patients with this disease may be ANCA (MPO) positive or negative. 

• Retrospective analysis 93 patients (1989-2004) 

• 35 ANCA Positive 

small vessel vasculitis disease 

Manifest by: 

Purpura (25.7% vs. 6.9%) 

• Pulmonary hemorrhage (20.0% vs. 0%) 

• Mononeuritic multiplex (51.4% vs. 24.1%) 

• Renal involvement (51.4% vs. 12.1%) 

• ANCA Negative Patients 

Parenchymal lung disease 

Cardiac involvement 

Are there 2 phenotypes based on ANCA status? 

ANCA positive with vasculitic manifestation? 

• ANCA negative with eosinophil driven processes leading to cardiopulmonary manifestation?


Treatment of Vasculitis 

Are short courses of cyclophosphamide effective for the treatment of 

ANCA associated vasculitis (AAV)? 

CYCAZAREM (Cyclophosphamide or Azathioprine as a Remission for Vasculitis) 

NEJM 2003. 

• Patients WG or MPA 

• Induction therapy: (3 months) 

Cyclophosphamide 2 mg/kg p.o. 

Prednisone 1 mg/kg/p/o. 

• Post induction: (3 month-12 months) 

Cyclophosphamide 1.5 mg/kg p.o. 

Azathioprine 2 mg/kg (prednisone 10 mg daily) 

• 12 months to 10 months all patients switched to AZA 1.5 mg/kg plus 

prednisone 7.5 mg daily. 

• Relapse rate the same: 

Cyclophosphamide- 14% 

AZA – 16%


Is there a role for plasma exchange in the 

treatment of ANCA associated vasculitis? 

European union vasculitis study group (EUVAS) MEPEX Trial- 2007, 137 patients 

randomized to Methylprednisone IV or plasma exchange. 

Results: 

All patients had serum creatine greater than 500 micromoles 

Plasma exchange 7 over 2 weeks 

Methylprednisolone one gram daily x3 

Both groups received cyclophasphmade 2.5 mg/kg and prednisone 60 mg 

daily. 

35 died during the trial. 

23/35 died in the first 3months. 

71/137 had independent renal function.


Mepex Trial Results (cont’d) 

Plasma exchange was associated with a significantly higher likelihood of being 

alive and having independent renal function at 3 months. 

69% in plasma exchange gp 

49% in methylprednisone gp 

Plasma exchange was associated with a significant reduction in risk of progression 

to end stage renal disease at one year. 

19% vs. 43% 

Mortality rate high in both groups 35/137 (infection, pulmonary hemorrhage, CVS)


Are TNF inhibitors effective treatment of 

ANCA associated vasculitis? 

WGET (Wegener’s Granulomatosis etanercept trial) 

Design to see if etanercept, after induction therapy, would maintain 

remission ( in patients who were maintained on standard therapy) 

180 patients (follow up 27 months) 

50% patients who achieved remission 126/180 were able to 

maintain this. 

There was no difference in remission rate, flares or adverse events 

between groups. 

But, 6 etanercept patients developed malignancies (no control 

patients)


Do early generalized ANCA associated vasculitis 

patients treated with methotrexate fare as well as 

those treated with cyclophosphamide ? 

NORAM (Non-renal Alternative with Methotrexate trial), De Grout- 2005. 

100 patients with limited Wegener’s received either methotrexate or 

cyclophosphamide with glucocortoids. 

6 month remission rates 

MTX-89.8% 

CYC- 93.5% 

18 month relapse rates 

MTX 69.5% 

CYC 46.5% 

Higher does of prednisone in MTX group 8.8 vs. 6.2


Remission Maintenance in Vasculitis 

When should remission maintenance be stopped for patients with 

ANCA associated vasculitis? 

NIH longitudal study (1992) 

33% cured after first course of RX. 

CYCAZAREM 

WG is more likely than MPA to flare. 

Clinical trials in AAV 

Support use of lose dose prednisone to maintain remission.


Are patients with systemic vasculitis at risk of 

Venous thromboembolism? 

Venous obstruction (SVC or IVC occlusion) or Budd Chiari syndrome has 

been reported in Bechet’s disease. 

Superficial phlebitis…….. Buerger’s disease. 

Wegener’s Granulomatosis ……..venous thrombosis (Annals of Internal 

Med- 2005) is seven times greater than the incidence in patients with 

systemic lupus erythematosis.


References 

Small vessel and Nuclear Vessel Vasculitis- Seo/Johnston, Arthritis and Rheumatism Vol 57, No. 

8, Dec 15, 2007, p 1552-1559. 

The Diagnosis of Vasculitis, Jayne, Best Practice and Research Clinical Rheumatology 23 

(2009) 445-453. 

EULAR Recommendations for the management of primary small and medium vessel vasculitis, 

Ann Rheum Dis 2009; 68; 310-317. 

The Last Classification of Vasculitis- Kallenberg, Clinic Rev Allerg Immunol (2008) 35:5-10 

Uptodate- 2009, Rhuematoid Disease Clinics of North America, Vasculitis- 2001 

Azathoprine or Methotrexate Maintenance for ANCA- Associated Vasculitis-Pagnoux, NEJM 

2008; 359; 2790-2803

Small Vessel Vasculitis

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