anca vasculitis & anti gbm
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Dr Shrier presents a complete review on ANCA vasculitis and Anti GBM diseaseTRANSCRIPT
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