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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis and Anti-Glomerular Basement Membrane Antibody Glomerulonephritis,[object Object],Peter Bryan Schrier, M.D.,[object Object],Hofstra North Shore LIJ School of Medicine,[object Object]
Today’s Discussion,[object Object],Introduction to Vasculitis Classification,[object Object],Specifically small vessel vasculitis and ANCA vasculitis,[object Object],What are ANCA’s, anyway?,[object Object],Introduction to ANCAs and ANCA-associated vasculitis,[object Object],Wegener’s Granulomatosis,[object Object],With brief MPA discussion,[object Object],Churg-Strauss Syndrome,[object Object],Anti-GBM antibody syndrome/Goodpasture’s Disease,[object Object]
Introduction to Vasculitis Classification,[object Object]
Clinical Classification of Systemic Vasculitis,[object Object]
Anca vasculitis & anti gbm
Anca vasculitis & anti gbm
What are ANCA’s, anyway?,[object Object],Introduction to ANCAs and ANCA-associated vasulitis,[object Object]
What are ANCAs?,[object Object],Anti-neutrophil cytoplasmic antibodies,[object Object],Antibodies against myeloperoxidase (MPO-ANCA) and Proteinase 3 (PR3-ANCA),[object Object],MPO & PR3 are found in the azurophilic granules of neutrophils and the lysosomes of monocytes.,[object Object],ANCAs are autoantibodies ,[object Object],Therefore ANCA-associated vasculitis is an autoimmune disease,[object Object],John H. Stone, MD, MPH,[object Object]
ANCA testing,[object Object],2 methods,[object Object],Immunofluorescence,[object Object],Uses alcohol-fixed buffy coat leukocytes,[object Object],More sensitive,[object Object],ELISA,[object Object],Uses purified specific antigens (MPO and PR3),[object Object],If Pt’s blood has antibodies to the antigens, result +,[object Object],More specific,[object Object],John H. Stone, MD, MPH,[object Object]
Immunofluorescence,[object Object],Cytoplasmic or Perinuclear patterns,[object Object],Cytoplasmic immunofluorescence pattern (C-ANCA),[object Object],Most often associated with anti-proteinase 3,[object Object],Can occur with MPO,[object Object],Perinuclear immunofluorescence pattern (P-ANCA),[object Object],Almost always associated with myeloperxidase,[object Object],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,[object Object]
ANCA testing,[object Object],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,[object Object],Any of the ANCA-associated vasculitides can be associated with either type of ANCA or no ANCAs at all.,[object Object],Other autoimmune disease can be ANCA positive, at least on immunofluorescence,[object Object]
ANCA in Vasculitis and other Autoimmune Diseases,[object Object]
Anca vasculitis & anti gbm
ANCA in Vasculitis and other Autoimmune Diseases,[object Object]
What to do?,[object Object]
Pathophysiology of ANCA-Associated Vasculitis,[object Object]
Pathophysiology of ANCA-Associated Vasculitis,[object Object],Journal of Leukocyte Biology. 2003;74:3-15.,[object Object]
Pathophysiology of ANCA-Associated Vasculitis,[object Object]
Clinical Classification of Systemic Vasculitis,[object Object]
Wegener’s Granulomatosis,[object Object],Vasculitis of small and medium sized arteries,[object Object],Systemic necrotizing angiitis,[object Object],Necrotizing granulomatous inflamation of the respiratory tract,[object Object],Necrotizing glomerulonephritis,[object Object],Peak age 35-50 yrs.,[object Object],Male: Female 1.5:1,[object Object],90% European descent,[object Object]
Clinical Presentation,[object Object],(Including RPGN),[object Object]
Saddle Nose Deformity,[object Object]
Diagnostic Criteria for Wegener’s Granulomatosis (ACR),[object Object],British Journal of Rheumatology 1997;36:453–458,[object Object]
Diagnostic Criteria for Wegener’s Granulomatosis (CHCC),[object Object],British Journal of Rheumatology 1997;36:453–458,[object Object]
Proposed Pathogenesis,[object Object],PR3-ANCA (anti-proteinase-3)    activation of primed neutrophils,[object Object],Production of reactive oxygen species,[object Object],Realease of lytic enzymes from lysosomes,[object Object],Elastases,[object Object],Proteinase-3 (PR3) after all degrades proteins!,[object Object],Leads to tissue injury,[object Object],Kallenberg CGM. Pathogenesis of PR3-ANCA associated vasculitis. J Autoimmun. February-March 2008;30:29-36,[object Object]
Proposed Pathogenesis,[object Object],Genetic Associations,[object Object],Specific alleles of Cytotoxic T-lymphocyte antigen 4 (CTLA-4),[object Object],Specific alleles of Fcγ IIIb receptor on neutrophils, monocytes, and macrophages,[object Object],A defective alpha-1 antitrypsin allele,[object Object],Environmental Associations,[object Object],Northern latitudes,[object Object],Farming,[object Object],Environmental allergies and drug allergies,[object Object],Silica or solvent exposure,[object Object],Nasal staphlococcus aureus > associated with relapses,[object Object],Bactrim has been shown to decrease relapse,[object Object]
Diagnosis for the Nephrologist,[object Object],Routine Labs,[object Object],Elevated BUN & creatinine,[object Object],Anemia- normocytic,[object Object],Leukocytosis,[object Object],Neutrophil predominant,[object Object],NO eosinophilia,[object Object],Rheumatologic non-specific,[object Object],Erythrocyte Sedimentation Rate,[object Object],C-reactive Protein,[object Object],Rheumatoid Factor,[object Object],Anti-nuclear Antibodies,[object Object]
Diagnosis for the Nephrologist,[object Object],Urinalysis with microscopic examination,[object Object],Hematuria/ Red cell casts,[object Object],Proteinuria,[object Object],“active urinary sediment”,[object Object],Serologic Studies,[object Object],ANCA,[object Object],Most often C-ANCA but can be P-ANCA or ANCA negative,[object Object],Confirm with ELIZA for anti-PR3,[object Object],Imaging,[object Object],Chest Xray or CT,[object Object],BIOPSY!!!,[object Object]
Imaging,[object Object]
Biopsy,[object Object]
Biopsy,[object Object],Z. Xu, MD.,[object Object]
Treatment- Induction,[object Object],Cytotoxics,[object Object],Cyclophosphamide- Oral vs. Intravenous X 3-6 months,[object Object],Same rate of inducing remission,[object Object],Oral has fewer relapses, but more side effects (leukopenia, infection),[object Object],Rituximab ,[object Object], For patients who refuse cyclophosphamide because of risks (e.g. fertility) or have other contraindications,[object Object],For cyclophsophamide-resistant patients,[object Object],Methotrexate for non-organ-threatening disease,[object Object],Nephrol Dial Transplant. 2001;16(10):2018-27,[object Object],Ann Intern Med. 2009;150(10):670-80,[object Object]
Treatment- Induction,[object Object],Glucocorticoid,[object Object],Pulse vs. standard dose,[object Object],Daily oral glucocorticoid taper over 4-6 months,[object Object],Alternate day glucocorticoids is no longer done,[object Object],Plasma exchange (controversial),[object Object],Severe renal dysfunction (creat >5.7/ pt requiring HD),[object Object],Diffuse alveolar hemorrhage,[object Object],PCP prophylaxis with trimethoprim/ sulfamethoxazole during induction with cytotoxics,[object Object],Use atovaquone for methotrexate,[object Object]
Treatment- Maintenance,[object Object],Birmingham Vasculitis Activity Score adjusted for Wegener’s should be used to assess remission and replapse,[object Object],Azathioprine vs. Methotrexate  X 12-18 months,[object Object],Azathioprine for GFR<50 ml/min,[object Object],Azathioprine after induction with Methotrexate,[object Object],Methotrexate only if induction was with Cyclophosphamide,[object Object],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,[object Object]
Microscopic Polyangiitis,[object Object],Most common ANCA vasculitis,[object Object],Median age ~ 50s,[object Object],Vasculitis of small and medium sized arteries,[object Object],Renal lesions same as with Wegener’s, but most often renal-limited,[object Object],No granulomas,[object Object],More often MPO-ANCA, but can be PR3-ANCA and, rarely, ANCA negative.,[object Object]
Clinical Presentation,[object Object]
Microscopic Polyangiitis,[object Object],May be on the same disease spectrum as Wegener’s Granulomatosis,[object Object],Treatment is the same as for Wegener’s, based on the Birmingham Vasculitis Activity Score,[object Object]
Churg-Strauss Syndrome,[object Object],Allergic Granulomatosis and angiitis,[object Object],Vasculitis of small and medium sized arteries,[object Object],Necrotizing vasculitis,[object Object],Builds over years until full presentation as it progresses through the following phases:,[object Object],Prodromal Phase- teens-20s,[object Object],Allergic rhinitis,[object Object],Asthma,[object Object],Eosinophilic phase,[object Object],Vasculitic phase as early as 20s-30s, but mean age is 50s,[object Object],Curr Opin Rheumatol. 2010;22(1):21-8,[object Object]
Clinical Presentation,[object Object],Causes 50% deaths from CSS,[object Object]
Cutaneous Involvement,[object Object]
Diagnostic Criteria for Churg-Strauss (ACR),[object Object],British Journal of Rheumatology 1997;36:453–458,[object Object]
Diagnostic Criteria for Churg-Struass (CHCC),[object Object],British Journal of Rheumatology 1997;36:453–458,[object Object]
Proposed Pathogenesis,[object Object]
Diagnosis for the Nephrologist,[object Object],Routine Labs,[object Object],Elevated BUN & creatinine,[object Object],Eosinophilia (>10%),[object Object],Anemia,[object Object],Rheumatologic,[object Object],Erythrocyte Sedimentation Rate,[object Object],C-reactive Protein,[object Object],Rheumatoid Factor,[object Object],Urinalysis with microscopic examination,[object Object],Hematuria/ Red cell casts,[object Object],Proteinuria,[object Object],active urinary sediment,[object Object]
Diagnosis for the Nephrologist,[object Object],Serologic Studies,[object Object],ANCA,[object Object],Often P-ANCA but can be C-ANCA or ANCA negative,[object Object],Confirm with ELIZA for anti-MPO,[object Object],Elevated IgE levels,[object Object],Hypergammaglobulinemia,[object Object],Elevated eosinophilic cationic protein (ECP),[object Object],Bronchioalveolar Lavage (BAL) with eosinophilia,[object Object],Imaging,[object Object],Chest Xray or CT,[object Object],BIOPSY!!!,[object Object]
Imaging,[object Object]
Biopsy,[object Object],Eosinophilic infiltrates,[object Object],Prominent necrosis,[object Object],Giant cell vasculitis of small arteries and veins,[object Object],Interstitial and perivascular necrotizing granulomas,[object Object],Eosinophilic leukocytoclastic angiits,[object Object]
Biopsy,[object Object]
Treatment- Assess Disease Severity,[object Object],Five Factors Score,[object Object],Cardiac involvement,[object Object],Gastrointestinal involvement,[object Object],Renal involvement (creatinine > 1.58mg/dl),[object Object],Proteinuria (>1g/24h),[object Object],Central nervous system involvement,[object Object],Birmingham Vasculitis Activity Score also used on occasion,[object Object],These help assess disease severity and determine aggressiveness of initial treatment,[object Object]
Treatment- Induction,[object Object],Glucocorticoids,[object Object],Pulse vs. standard dose depending on severity,[object Object],Daily oral glucocorticoids tapered symptoms and eosinophilia improve over 12-18 months,[object Object],Are often continued for other reasons (e.g. severe asthma),[object Object],Cyclophosphamide,[object Object],Only in severe cases (although renal involvement is usually enough to qualify as as severe case),[object Object],Daily oral vs. monthly IV,[object Object],Daily oral with slightly more side effects,[object Object],Monthly IV with slightly more relapse,[object Object],Usually achieve remission within 6 months,[object Object]
Treatment,[object Object],Maintenance,[object Object],Azathioprine vs. Methotrexate  X 12-18 months,[object Object],Azathioprine preferred over methotrexate,[object Object],Methotrexate pneumonitis complicates matters,[object Object],Second line- for relapses or refractory cases,[object Object],Mycofenolate Mofetil,[object Object],Intravenous Immunoglobulin (IVIG),[object Object],Hydroxyurea,[object Object],Interferon-alpha,[object Object],Rituximab (though may cause bronchospasm),[object Object]
Drug-Induced ANCA Vasculitis,[object Object],Propylthiouracil (PTU),[object Object],Accumulates in neutrophils and binds to MPO,[object Object],Alters the MPO antigen  ?  autoantibodies,[object Object],Usually resolves with d/c PTU,[object Object],Hydralazine,[object Object],Drug-induced SLE and Drug-induced ANCA vasculitis,[object Object],Requires d/c hydralazine and corticosteroids + cyclophosphamide,[object Object],Minocycline,[object Object],P-ANCA, but against antigens other than MPO,[object Object],Others: Sulfonamides, Penicilliamine, allopurinol,[object Object],John H. Stone, MD, MPH,[object Object]
Anti-Glomerular Basement Membrane Antibody Syndrome,[object Object]
Anti- GBM,[object Object],Acute or Rapidly Progressive Glomerulonephritis,[object Object],Circulating autoimmune antibodies against the glomerular basement membrane,[object Object],Nomenclature,[object Object],When renal-limited, the disease is called Anti-GBM Antibody Syndrome,[object Object],When pulmonary hemorrhage is also present, the disease is called Goodpasture’s disease (after the doctor who first described it),[object Object],Sometimes any pulmonary renal syndrome with pulmonary hemorrhage is called Goodpasture’s Syndrome,[object Object]
Anti-GBM,[object Object],Anti-GBM disease is rare; approximately 1 per million,[object Object],Found in all age groups,[object Object],Tends to present as Goodpasture’s disease in younger patients (age<30) and as anti-GBM antibody syndrome in older patients (age>50),[object Object],Prognosis is overall poor,[object Object],It is especially poor if renal function is poor,[object Object],Once recovery is successful, it rarely relapses,[object Object]
Pathogenesis,[object Object]
Pathogenesis,[object Object]
Pathogenesis,[object Object],Pharmaceutical Research, Vol. 25, No. 12, December 2008 (# 2008),[object Object]
Possible Associations,[object Object],HLA-DR15 haplotype (especially DRB 1*1501 allele),[object Object],Found in 80% of patients with anti-GBM disease,[object Object],This may have something to do with T-cell recognition of an epitope that is usually degraded by endosomal proteases before T-cell maturation,[object Object],It is possible that T-cells then sensitize B-cells to produce anti-GBM antibodies,[object Object],Regulatory CD25+ T-cells attenuate the glomerular injury,[object Object],Pulmonary hemorrhage usually requires initial insult to the lung to expose the NC1 domain of the type 3 collagen,[object Object],e.g. cigarette smoke, respiratory infection, etc.,[object Object]
Clinical Presenation,[object Object],Rapidly Progressive Glomerulonephritis,[object Object],+- Pulmonary hemorrhage,[object Object],Increased DLCO,[object Object],No systemic complaints (malaise, fever/chills, weight loss,etc.),[object Object]
Diagnosis,[object Object],Routine Labs,[object Object],Eleavated BUN & creatinine,[object Object],Rapidly Progressive rise in creatinine over time,[object Object],Urinalysis with microscopic examination,[object Object],Hematuria/ Red cell casts,[object Object],Proteinuria,[object Object],active urinary sediment,[object Object],Serologies,[object Object],Anti-GBM antibody (though this is not always reliable),[object Object],ANCAs are positive in up to 1/3 of patients,[object Object],Usually P-ANCA,[object Object]
Biopsy,[object Object]
Biopsy,[object Object],http://www.kidneypathology.com,[object Object]
Treatment,[object Object],Outcome best correlated with % crescents,[object Object],>75% crescents almost always indicates nearly 0% chance of renal recovery,[object Object],Initial management,[object Object],Plasmapharesis/exchange X 2-3 weeks,[object Object],Pulse glucocorticoids followed by standard dose PO,[object Object],Cyclophosphamide (PO vs IV),[object Object],Duration of treatment ,[object Object],3-4 months if serological conversion to anti-GBM negative,[object Object],Longer if anti-GBM remains positive (~ 6-9 months),[object Object],If still anti-GBM positive after 3 months, Azathioprine may be substituted for cyclophosphamide,[object Object]
Treatment,[object Object],Patient’s requiring aggressive treatment:,[object Object],Concurrent ANCA vasculitis (or just positive ANCAs!),[object Object],Systemic vasculitic symptoms (rash, arthralgia, etc),[object Object],Pulmonary hemorrhage,[object Object],Maintenance,[object Object],Prednisone X 6-9 mo vs. 1 mo. taper to off,[object Object],+-Azathioprine X 6-9 months,[object Object],If true remission (serological and symptomatic), pt’s usually do not relapse, and treatment can usually be discontinued,[object Object]
Today’s Discussion,[object Object],Introduction to Vasculitis Classification,[object Object],Specfically small vessel vasculitis and ANCA vasculitis,[object Object],What are ANCA’s, anyway?,[object Object],Introduction to ANCAs and ANCA-associated vasulitis,[object Object],Wegener’s Granulomatosis,[object Object],With brief MPA discussion,[object Object],Churg-Strauss Syndrome,[object Object],Anti-GBM antibody syndrome/Goodpasture’s Disease,[object Object]

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Anca vasculitis & anti gbm

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Editor's Notes

  1. ANCA produce tissue damage by activating cytokine-primed neutrophils and monocytesThese activated neutrophils adhere to endothelial cells, releasing proteolytic granule contents and proinflammatory cytokines
  2. The release of inflammatory cytokines causes the downstream release of reactive oxygen species and oxidative damage, which further activates the endothelium causing more inflammation…In short, ANCAs activate neutrophil
  3. Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis.
  4. Lung biopsy specimen from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation
  5. CYCLOPS trial - Pulse IV vs. daily PO
  6. MEPEX trial –Plasmapharesis vs IV methylprednisolone BOTH WITH PO prednisone and cyclophosphamide (not the best trial)
  7. CYCAZAREM- Azathioprine vs. Cycophosphamide in maintenance. Same efficacy, MANY fewer complications. So we use Azathioprine. Another study compared MTX &amp; AZA. Same relapse rate. Same side effect rate, just different side effects.
  8. Pathogenetic model proposed for Churg–Strauss syndrome, based on available experimental evidence. Hypothetical allergens or antigens may be uptaken by antigen-presenting cells and presented to CD4+ T cells, leading to T-cell activation and expansion. Antigen-presenting cells (which can be of different cell types, for example, dendritic cells, monocyte macrophages, and eosinophils) have a restricted HLA repertoire and often express HLA-DRB4. Once activated, CD4+ T cells secrete IFN-γ, which promotes granulomatous inflammation, and also drive eosinophil activation and expansion through the secretion of IL-4, IL-5, and IL-13, or by means of the CD95–CD95L pathway. Eosinophils mediate tissue damage mainly by secreting granule proteins such as ECP and MBP. Endothelial cells may also contribute to tissue infiltration by eosinophils by releasing eotaxin-3, a chemokine with strong chemotactic activity on eosinophils. B cells are also likely to play a pathogenetic role: activated on antigen encountering and &apos;helped&apos; by T-helper 2 cytokines such as IL-4 and IL-13, they may become mature plasma cells and then produce different autoantibodies, including ANCA, which may in turn mediate vasculitis. ANCA, anti-neutrophil cytoplasmic antibodies; CD95L, CD95 ligand; ECP, eosinophilic cationic protein; IFN-γ, interferon-γ; IL(-4, -5, -13), interleukin(-4, -5, -13); MBP, major basic protein; TCR, T-cell receptor.
  9. The most common radiological manifestations consist of transient, patchy, nonsegmental areas of consolidation without predilection for any lung zone.[24-26] The areas of consolidation can be symmetric or asymmetric and may have a peripheral distribution similar to that seen in chronic eosinophilic pneumonia[25,26] (Fig. 5). Less common manifestations include small or large nodules, unilateral or bilateral pleural effusions, and hilar lymphadenopathy.
  10. Skin &amp; Kidney
  11. Type IV collagen
  12. Alpha 3, alpha 4, alpha 5 form a triple helical molecule (the promotor) which then dimerize to form a Hexamer of type IV collagen.
  13. Fig 1  A hypothetical structure of α3 chain type IV collagen. Linear structure of human α3 chain type IV collagen composed of three distinct domains: a cysteine rich N-terminal 7S domain, a central triple helical domain with multiple small interruptions and a globular C-terminal non-collagenous (NC1) domain.
  14. Crescentic glomerulonephritis (RPGN)