Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis and Anti-Glomerular Basement

Membrane Antibody Glomerulonephritis

Peter Bryan Schrier, M.D.

Hofstra North Shore LIJ School of Medicine

Today’s Discussion

Introduction to Vasculitis Classification Specifically small vessel vasculitis and ANCA

vasculitis

What are ANCA’s, anyway? Introduction to ANCAs and ANCA-associated

vasculitis

Wegener’s Granulomatosis With brief MPA discussion

Churg-Strauss Syndrome

Anti-GBM antibody syndrome/Goodpasture’s Disease

Introduction to Vasculitis

Classification

Clinical Classification of Systemic Vasculitis

What are ANCA’s, anyway?

Introduction to ANCAs and ANCA-associated vasulitis

What are ANCAs? Anti-neutrophil cytoplasmic antibodies

Antibodies against myeloperoxidase (MPO-ANCA) and Proteinase 3 (PR3-ANCA)

MPO & PR3 are found in the azurophilic granules of neutrophils and the lysosomes of monocytes.

ANCAs are autoantibodies Therefore ANCA-associated vasculitis is an

autoimmune disease

John H. Stone, MD, MPH

ANCA testing 2 methods

Immunofluorescence Uses alcohol-fixed buffy coat leukocytes More sensitive

ELISA Uses purified specific antigens (MPO and PR3) If Pt’s blood has antibodies to the antigens,

result + More specific

John H. Stone, MD, MPH

Immunofluorescence

Cytoplasmic or Perinuclear patterns Cytoplasmic immunofluorescence pattern (C-

ANCA) Most often associated with anti-proteinase 3 Can occur with MPO

Perinuclear immunofluorescence pattern (P-ANCA) Almost always associated with myeloperxidase Perinuclear pattern is due to an artifact of

ethanol fixation of anti-MPO leading to positively charged granules that are attracted to the negatively charged nucleus

ANCA testing Although particular ANCAs are linked with

particular diseases, it is possible to be ANCA + without manifesting a disease syndrome, and it is possible to manifest a traditional ANCA-associated vasculitis without + ANCAs

Any of the ANCA-associated vasculitides can be associated with either type of ANCA or no ANCAs at all.

Other autoimmune disease can be ANCA positive, at least on immunofluorescence

ANCA in Vasculitis and other Autoimmune

Diseases

ANCA in Vasculitis and other Autoimmune

Diseases

What to do?

Pathophysiology of ANCA-Associated

Vasculitis

Pathophysiology of ANCA-Associated

Vasculitis

Journal of Leukocyte Biology. 2003;74:3-15.

Pathophysiology of ANCA-Associated

Vasculitis

Clinical Classification of Systemic Vasculitis

Wegener’s Granulomatosis

Vasculitis of small and medium sized arteries

Systemic necrotizing angiitis

Necrotizing granulomatous inflamation of the respiratory tract

Necrotizing glomerulonephritis

Peak age 35-50 yrs.

Male: Female 1.5:1

90% European descent

Clinical Presentation

(Including RPGN)

Saddle Nose Deformity

Diagnostic Criteria for Wegener’s Granulomatosis

(ACR)

British Journal of Rheumatology 1997;36:453–458

Diagnostic Criteria for Wegener’s Granulomatosis

(CHCC)

British Journal of Rheumatology 1997;36:453–458

Proposed Pathogenesis

PR3-ANCA (anti-proteinase-3) activation of primed neutrophils Production of reactive oxygen species Realease of lytic enzymes from lysosomes

Elastases Proteinase-3 (PR3) after all degrades proteins!

Leads to tissue injury

Kallenberg CGM. Pathogenesis of PR3-ANCA associated vasculitis. J Autoimmun. February-March 2008;30:29-36

Proposed Pathogenesis

Genetic Associations Specific alleles of Cytotoxic T-lymphocyte antigen 4

(CTLA-4) Specific alleles of Fcγ IIIb receptor on neutrophils,

monocytes, and macrophages A defective alpha-1 antitrypsin allele

Environmental Associations Northern latitudes Farming Environmental allergies and drug allergies Silica or solvent exposure Nasal staphlococcus aureus > associated with relapses

Bactrim has been shown to decrease relapse

Diagnosis for the Nephrologist

Routine Labs Elevated BUN & creatinine Anemia- normocytic Leukocytosis

Neutrophil predominant NO eosinophilia

Rheumatologic non-specific Erythrocyte Sedimentation Rate C-reactive Protein Rheumatoid Factor Anti-nuclear Antibodies

Diagnosis for the Nephrologist

Urinalysis with microscopic examination Hematuria/ Red cell casts Proteinuria “active urinary sediment”

Serologic Studies ANCA

Most often C-ANCA but can be P-ANCA or ANCA negative

Confirm with ELIZA for anti-PR3

Imaging Chest Xray or CT

BIOPSY!!!

Imaging

Biopsy

Biopsy

Z. Xu, MD.

Treatment- Induction

Cytotoxics Cyclophosphamide- Oral vs. Intravenous X 3-6

months Same rate of inducing remission Oral has fewer relapses, but more side effects

(leukopenia, infection) Rituximab

For patients who refuse cyclophosphamide because of risks (e.g. fertility) or have other contraindications

For cyclophsophamide-resistant patients Methotrexate for non-organ-threatening

disease

Ann Intern Med. 2009;150(10):670-80

Nephrol Dial Transplant. 2001;16(10):2018-27

Treatment- Induction

Glucocorticoid Pulse vs. standard dose Daily oral glucocorticoid taper over 4-6 months Alternate day glucocorticoids is no longer done

Plasma exchange (controversial) Severe renal dysfunction (creat >5.7/ pt requiring

HD) Diffuse alveolar hemorrhage

PCP prophylaxis with trimethoprim/ sulfamethoxazole during induction with cytotoxics Use atovaquone for methotrexate

Treatment- Maintenance

Birmingham Vasculitis Activity Score adjusted for Wegener’s should be used to assess remission and replapse

Azathioprine vs. Methotrexate X 12-18 months Azathioprine for GFR<50 ml/min Azathioprine after induction with Methotrexate Methotrexate only if induction was with

Cyclophosphamide

Mycofenolate Mofetil or Rituximab may be used if azathioprine and methotrexate are not tolerated/contraindicated or if there are relapses while on MTX or AZA

Microscopic Polyangiitis

Most common ANCA vasculitis

Median age ~ 50s

Vasculitis of small and medium sized arteries

Renal lesions same as with Wegener’s, but most often renal-limited

No granulomas

More often MPO-ANCA, but can be PR3-ANCA and, rarely, ANCA negative.

Clinical Presentation

Microscopic Polyangiitis

May be on the same disease spectrum as Wegener’s Granulomatosis

Treatment is the same as for Wegener’s, based on the Birmingham Vasculitis Activity Score

Churg-Strauss Syndrome

Allergic Granulomatosis and angiitis

Vasculitis of small and medium sized arteries

Necrotizing vasculitis

Builds over years until full presentation as it progresses through the following phases: Prodromal Phase- teens-20s

Allergic rhinitis Asthma

Eosinophilic phase Vasculitic phase as early as 20s-30s, but mean age

is 50s

Curr Opin Rheumatol. 2010;22(1):21-8

Clinical Presentation

Causes 50% deaths from CSS

Cutaneous Involvement

Diagnostic Criteria for Churg-

Strauss (ACR)

British Journal of Rheumatology 1997;36:453–458

Diagnostic Criteria for Churg-

Struass (CHCC)

British Journal of Rheumatology 1997;36:453–458

Proposed Pathogenesis

Diagnosis for the Nephrologist

Routine Labs Elevated BUN & creatinine Eosinophilia (>10%) Anemia

Rheumatologic Erythrocyte Sedimentation Rate C-reactive Protein Rheumatoid Factor

Urinalysis with microscopic examination Hematuria/ Red cell casts Proteinuria active urinary sediment

Diagnosis for the Nephrologist

Serologic Studies ANCA

Often P-ANCA but can be C-ANCA or ANCA negative Confirm with ELIZA for anti-MPO

Elevated IgE levels Hypergammaglobulinemia Elevated eosinophilic cationic protein (ECP)

Bronchioalveolar Lavage (BAL) with eosinophilia

Imaging Chest Xray or CT

BIOPSY!!!

Imaging

Biopsy Eosinophilic infiltrates

Prominent necrosis

Giant cell vasculitis of small arteries and veins

Interstitial and perivascular necrotizing granulomas

Eosinophilic leukocytoclastic angiits

Biopsy

Treatment- Assess Disease Severity

Five Factors Score Cardiac involvement Gastrointestinal involvement Renal involvement (creatinine > 1.58mg/dl) Proteinuria (>1g/24h) Central nervous system involvement

Birmingham Vasculitis Activity Score also used on occasion

These help assess disease severity and determine aggressiveness of initial treatment

Treatment- Induction

Glucocorticoids Pulse vs. standard dose depending on severity Daily oral glucocorticoids tapered symptoms and

eosinophilia improve over 12-18 months Are often continued for other reasons (e.g. severe

asthma)

Cyclophosphamide Only in severe cases (although renal involvement is

usually enough to qualify as as severe case) Daily oral vs. monthly IV

Daily oral with slightly more side effects Monthly IV with slightly more relapse

Usually achieve remission within 6 months

Treatment Maintenance

Azathioprine vs. Methotrexate X 12-18 months Azathioprine preferred over methotrexate

Methotrexate pneumonitis complicates matters

Second line- for relapses or refractory cases Mycofenolate Mofetil Intravenous Immunoglobulin (IVIG) Hydroxyurea Interferon-alpha Rituximab (though may cause bronchospasm)

Drug-Induced ANCA Vasculitis

Propylthiouracil (PTU) Accumulates in neutrophils and binds to MPO Alters the MPO antigen ? autoantibodies Usually resolves with d/c PTU

Hydralazine Drug-induced SLE and Drug-induced ANCA vasculitis Requires d/c hydralazine and corticosteroids +

cyclophosphamide

Minocycline P-ANCA, but against antigens other than MPO

Others: Sulfonamides, Penicilliamine, allopurinol

John H. Stone, MD, MPH

Anti-Glomerular Basement Membrane Antibody Syndrome

Anti- GBM Acute or Rapidly Progressive Glomerulonephritis

Circulating autoimmune antibodies against the glomerular basement membrane

Nomenclature When renal-limited, the disease is called Anti-GBM

Antibody Syndrome When pulmonary hemorrhage is also present, the

disease is called Goodpasture’s disease (after the doctor who first described it)

Sometimes any pulmonary renal syndrome with pulmonary hemorrhage is called Goodpasture’s Syndrome

Anti-GBM Anti-GBM disease is rare; approximately 1

per million

Found in all age groups Tends to present as Goodpasture’s disease in

younger patients (age<30) and as anti-GBM antibody syndrome in older patients (age>50)

Prognosis is overall poor It is especially poor if renal function is poor

Once recovery is successful, it rarely relapses

Pathogenesis

Pathogenesis

Pathogenesis

Pharmaceutical Research, Vol. 25, No. 12, December 2008 (# 2008)

Possible Associations

HLA-DR15 haplotype (especially DRB 1*1501 allele) Found in 80% of patients with anti-GBM disease This may have something to do with T-cell recognition

of an epitope that is usually degraded by endosomal proteases before T-cell maturation

It is possible that T-cells then sensitize B-cells to produce anti-GBM antibodies Regulatory CD25+ T-cells attenuate the glomerular

injury

Pulmonary hemorrhage usually requires initial insult to the lung to expose the NC1 domain of the type 3 collagen e.g. cigarette smoke, respiratory infection, etc.

Clinical Presenation

Rapidly Progressive Glomerulonephritis

+- Pulmonary hemorrhage

Increased DLCO

No systemic complaints (malaise, fever/chills, weight loss,etc.)

Diagnosis Routine Labs

Eleavated BUN & creatinine Rapidly Progressive rise in creatinine over time

Urinalysis with microscopic examination Hematuria/ Red cell casts Proteinuria active urinary sediment

Serologies Anti-GBM antibody (though this is not always

reliable) ANCAs are positive in up to 1/3 of patients

Usually P-ANCA

Biopsy

Biopsy

http://www.kidneypathology.com

Treatment Outcome best correlated with % crescents

>75% crescents almost always indicates nearly 0% chance of renal recovery

Initial management Plasmapharesis/exchange X 2-3 weeks Pulse glucocorticoids followed by standard dose PO Cyclophosphamide (PO vs IV)

Duration of treatment 3-4 months if serological conversion to anti-GBM

negative Longer if anti-GBM remains positive (~ 6-9 months)

If still anti-GBM positive after 3 months, Azathioprine may be substituted for cyclophosphamide

Treatment Patient’s requiring aggressive treatment:

Concurrent ANCA vasculitis (or just positive ANCAs!)

Systemic vasculitic symptoms (rash, arthralgia, etc)

Pulmonary hemorrhage

Maintenance Prednisone X 6-9 mo vs. 1 mo. taper to off +-Azathioprine X 6-9 months If true remission (serological and

symptomatic), pt’s usually do not relapse, and treatment can usually be discontinued

Today’s Discussion

Introduction to Vasculitis Classification Specfically small vessel vasculitis and ANCA

vasculitis

What are ANCA’s, anyway? Introduction to ANCAs and ANCA-associated

vasulitis

Wegener’s Granulomatosis With brief MPA discussion

Churg-Strauss Syndrome

Anti-GBM antibody syndrome/Goodpasture’s Disease