Vasculitic Syndromes - an overview
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Transcript of Vasculitic Syndromes - an overview
Small- Vessel VasculitidesSmall- Vessel Vasculitides
Learning ObjectivesLearning Objectives
Review the 4 types of hypersensitivity reactionsReview the 4 types of hypersensitivity reactions
Understand the ANCA testUnderstand the ANCA test
Differentiate then consolidate the different ANCA Differentiate then consolidate the different ANCA diseases and Pulmonary-Renal syndromesdiseases and Pulmonary-Renal syndromes
Do some questionsDo some questions
Vasculitis:Vasculitis:
A clinicopathologic process characterized by A clinicopathologic process characterized by inflammation of and damage to blood vessels, inflammation of and damage to blood vessels, often resulting in complete or partial occlusion often resulting in complete or partial occlusion of the involved vessels, with resulting ischemic of the involved vessels, with resulting ischemic damage to the supplied organ/tissue.damage to the supplied organ/tissue.
Vasculitis may be a primary or secondary Vasculitis may be a primary or secondary manifestation of a disease processmanifestation of a disease process
May affect a single, or multiple organsMay affect a single, or multiple organs
EtiologyEtiology
Several have been proposed, however, there is Several have been proposed, however, there is no uniform consensusno uniform consensus
For now, let’s focus on immune complex For now, let’s focus on immune complex deposition – a process similar to serum deposition – a process similar to serum sicknesssickness
EtiologyEtiology
Ag-Ab complexes deposit in blood vessel walls Ag-Ab complexes deposit in blood vessel walls whose integrity have already been whose integrity have already been compromised by vasogenic amines (histamine, compromised by vasogenic amines (histamine, leukotrienes, bradykinin) released from leukotrienes, bradykinin) released from activated platelets and mast cellsactivated platelets and mast cells
Complement components (primarily the Complement components (primarily the classical pathway) are activated and recruit classical pathway) are activated and recruit PMN’sPMN’s
EtiologyEtiology
Exactly why only certain immune complexes Exactly why only certain immune complexes cause vasculitis and why only certain blood cause vasculitis and why only certain blood vessels are affected remains in large part a vessels are affected remains in large part a mysterymystery
Hypersensitivity ReactionsHypersensitivity Reactions
Type I – immediate HSType I – immediate HS ““classic” allergyclassic” allergy Prior sensitizationPrior sensitization IgE mediatedIgE mediated Massive degranulationMassive degranulation Early and late responsesEarly and late responses
Type 2 – cytotoxic HSType 2 – cytotoxic HS IgG binds to target tissueIgG binds to target tissue C’ activationC’ activation Direct cytotoxic actionDirect cytotoxic action
AIHAAIHA ITPITP Goodpasture’sGoodpasture’s Myasthenia GravisMyasthenia Gravis
Hypersensitivity ReactionsHypersensitivity Reactions
Type 3 – IC HSType 3 – IC HS ““serum sickness”serum sickness” Ab form complex with Ab form complex with
circulating Ag circulating Ag Deposition results in C’ Deposition results in C’
activationactivation
Leukocytoclastic vasculitis Leukocytoclastic vasculitis is hallmark manifestationis hallmark manifestation
Arthus reactionArthus reaction
Type 4 – cell-mediated HSType 4 – cell-mediated HS Delayed-type HSDelayed-type HS Previously sensitized T-cells Previously sensitized T-cells
are requiredare required
Mantoux testMantoux test Contact dermatitisContact dermatitis Allograft rejectionAllograft rejection
ANCA ANCA
AAnti-nti-NNeutrophil eutrophil CCytoplasmic ytoplasmic AAntibodiesntibodies
Ab directed against proteins in the cytoplasmic Ab directed against proteins in the cytoplasmic granules of PMN’s and monocytesgranules of PMN’s and monocytes
Wegener’s GranulomatosisWegener’s Granulomatosis Microscopic PolyangiitisMicroscopic Polyangiitis Churg-StraussChurg-Strauss Crescentic/necrotizing GNCrescentic/necrotizing GN
c-ANCAc-ANCA
Serum from patients bind to Serum from patients bind to ccytoplasmic granules and ytoplasmic granules and show a granular appearance on immunofluorescenceshow a granular appearance on immunofluorescence
Proteinase-3 (Proteinase-3 (PR-3PR-3) is the major antigen) is the major antigen Serine proteaseSerine protease Present in azurophilic granulesPresent in azurophilic granules
Most labs reflexively send a confirmatory test for PR-3 Most labs reflexively send a confirmatory test for PR-3 when this pattern is seen, or have eliminated the when this pattern is seen, or have eliminated the immunofluorescence aspect entirelyimmunofluorescence aspect entirely
p-ANCAp-ANCA
Localized, Localized, pperi-nuclear staining pattern on PMN’seri-nuclear staining pattern on PMN’s
Myeloperoxidase (Myeloperoxidase (MPOMPO) is the major target Ag) is the major target Ag ElastaseElastase Cathepsin GCathepsin G LactoferrinLactoferrin LysozymeLysozyme Permeability-increasing proteinPermeability-increasing protein
Only MPO has been convincingly associated with Only MPO has been convincingly associated with vasculitis, the others may be seen in other ANCA+ vasculitis, the others may be seen in other ANCA+ diseases (IBD, drugs, endocarditis)diseases (IBD, drugs, endocarditis)
Proposed Mechanism of Proposed Mechanism of DiseaseDisease
PR-3 and MPO are mobilized to surface of PMN’s and PR-3 and MPO are mobilized to surface of PMN’s and monocytes when activated by TNF-monocytes when activated by TNF-αα or IL-1 or IL-1
Now can react with circulating ANCANow can react with circulating ANCA
PMN’s degranulate and induce inflammation locallyPMN’s degranulate and induce inflammation locally
How the ANCA are generated in the first place is less How the ANCA are generated in the first place is less clearclear
Wegener’sWegener’s
SystemicSystemic diseasedisease
GranulomatousGranulomatous vasculitis of vasculitis of upper and lower upper and lower respiratory tractrespiratory tract with associated with associated GNGN, variable degrees , variable degrees of disseminated vasculitisof disseminated vasculitis
Involves Involves small arteries and veinssmall arteries and veins
Prevalence: 3 per 100,000Prevalence: 3 per 100,000 Extremely rare in blacksExtremely rare in blacks Equal M:F ratioEqual M:F ratio Mean age of onset is 40Mean age of onset is 40
Wegener’sWegener’s
Multiple b/l Multiple b/l nodular cavitary infiltratesnodular cavitary infiltrates Lung biopsy: classic Lung biopsy: classic granulomatous necrotizing vasculitisgranulomatous necrotizing vasculitis
Nasal ulcers, sinus disease, septal perforation, saddle-Nasal ulcers, sinus disease, septal perforation, saddle-bridge deformity, tracheal stenosisbridge deformity, tracheal stenosis Nasal biopsy: usually reveals the same, not as sensitiveNasal biopsy: usually reveals the same, not as sensitive
FSGS FSGS RPGN RPGN Kidney biopsy: Kidney biopsy: rarelyrarely shows granulomas or immune complex shows granulomas or immune complex
deposition (focal, segmental, necrotizing deposition (focal, segmental, necrotizing pauci-immune GNpauci-immune GN))
Wegener’sWegener’s
Peripheral WBC tests indicate an unbalanced TPeripheral WBC tests indicate an unbalanced THH1 1 cytokine patterncytokine pattern
90% are 90% are PR-3 PR-3 positive (positive (c-ANCAc-ANCA) during active disease) during active disease A few pt’s will be MPO positive rather than PR-3A few pt’s will be MPO positive rather than PR-3
BUT…BUT…You must establish tissue diagnosis!! Aim for lungs.You must establish tissue diagnosis!! Aim for lungs.
Must differentiate from other rare diseases such as angiocentric immunoproliferative diseases and lymphomatoid granulomatosis
Wegener’s RxWegener’s Rx
Previously, uniformly fatal in matter of weeks to monthsPreviously, uniformly fatal in matter of weeks to months
CyclophosphamideCyclophosphamide (2mg/kg/day) (2mg/kg/day) Maintain WBC >3000 & PMN >1500Maintain WBC >3000 & PMN >1500 6-12 months!!6-12 months!!
GlucocorticoidsGlucocorticoids 1mg/kg/day, taper at 1 month and off at 6 months1mg/kg/day, taper at 1 month and off at 6 months
Remission rate: 75%Remission rate: 75% 90% have marked improvement90% have marked improvement Plasmapheresis in refractory/progressive casesPlasmapheresis in refractory/progressive cases
Microscopic PolyangiitisMicroscopic Polyangiitis
Disease entity characterized by a necrotizing vasculitis Disease entity characterized by a necrotizing vasculitis with few or no immune complexes, affecting small with few or no immune complexes, affecting small vessels (arterioles, capillaries, venules)vessels (arterioles, capillaries, venules)
First coined in ???First coined in ???
Microscopic PolyangiitisMicroscopic Polyangiitis
Disease entity characterized by a necrotizing vasculitis Disease entity characterized by a necrotizing vasculitis with few or no immune complexes, affecting small with few or no immune complexes, affecting small vessels (arterioles, capillaries, venules)vessels (arterioles, capillaries, venules)
First coined in 1992, by the Chapel Hill Consensus First coined in 1992, by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Conference on the Nomenclature of Systemic VasculitidesVasculitides
Incidence is uncertain due to previous lumping together Incidence is uncertain due to previous lumping together with PAN. Etiology unknown.with PAN. Etiology unknown.
Microscopic PolyangiitisMicroscopic Polyangiitis
Pauci-immunePauci-immune GNGN is very common (79%) is very common (79%) renal biopsy is identical to that in Wegener’srenal biopsy is identical to that in Wegener’s
Pulmonary infiltrates and hemorrhage may occur as a Pulmonary infiltrates and hemorrhage may occur as a result of capillaritis, but biopsies result of capillaritis, but biopsies lack granulomaslack granulomas Upper airway disease and pulm nodules/cavities absentUpper airway disease and pulm nodules/cavities absent
Immunohistochemical staining lacks IC deposition, Immunohistochemical staining lacks IC deposition, suggesting that IC complex formation is not part of the suggesting that IC complex formation is not part of the pathogenesispathogenesis
Microscopic PolyangiitisMicroscopic Polyangiitis
75% of patients are c-ANCA+75% of patients are c-ANCA+
Treatment is identical to Wegener’sTreatment is identical to Wegener’s, and distinguishing , and distinguishing between the two is somewhat academicbetween the two is somewhat academic
5-yr survival is 74%5-yr survival is 74%
Churg-Strauss SyndromeChurg-Strauss Syndrome
Incidence: ~1 per 1,000,000Incidence: ~1 per 1,000,000 Occurs at any age, but mean is 48yrsOccurs at any age, but mean is 48yrs
Clinical TetradClinical Tetrad AsthmaAsthma EosinophiliaEosinophilia (blood and peripheral) (blood and peripheral) Extravascular Extravascular granulomagranuloma VasculitisVasculitis affecting mutiple organs affecting mutiple organs
Involves Involves small and medium-sized arteries, small and medium-sized arteries, capillaries, and veinscapillaries, and veins
Churg-Strauss SyndromeChurg-Strauss Syndrome
Granulomatous inflammation with eosinophilic Granulomatous inflammation with eosinophilic infiltration of involved organsinfiltration of involved organs LungLung KidneyKidney Skin Skin HeartHeart
Presents as Presents as systemic syndromesystemic syndrome (fever, malaise, (fever, malaise, anorexia, weight loss) with anorexia, weight loss) with severe asthma attackssevere asthma attacks (may (may be precipitated by initiation of leukotriene inhibitors)be precipitated by initiation of leukotriene inhibitors)
Churg-Strauss SyndromeChurg-Strauss Syndrome
p-ANCA sensitivity: 48%p-ANCA sensitivity: 48%
TreatmentTreatment GlucocorticoidsGlucocorticoids titrated to control asthma titrated to control asthma Add Add cyclophosphamidecyclophosphamide as second line as in Wegener’s as second line as in Wegener’s
Goodpasture’s SyndromeGoodpasture’s Syndrome
A specific subset of A specific subset of anti-GBM diseaseanti-GBM disease in which in which pulmonary hemorrhage occurspulmonary hemorrhage occurs Target: noncollagenous domain of Target: noncollagenous domain of αα3 chain of 3 chain of Type IV Type IV
collagencollagen
Typically seen in Typically seen in young malesyoung males (5-40y/o) (5-40y/o)
Type II HS reaction - inflammation and tissue Type II HS reaction - inflammation and tissue destruction mediated by direct Ab binding and destruction mediated by direct Ab binding and secondary activation of classical C’ pathway or direct secondary activation of classical C’ pathway or direct activation of cytotoxic T-cells or phagocytesactivation of cytotoxic T-cells or phagocytes
Goodpasture’s SyndromeGoodpasture’s Syndrome
KidneyKidney RPGN and crescentic GN are most commonRPGN and crescentic GN are most common
Pulmonary hemorrhage (50-60% of all pt’s), quite rare Pulmonary hemorrhage (50-60% of all pt’s), quite rare in patients >50y/oin patients >50y/o
NOTNOT associated with ANCA positivity associated with ANCA positivity
Goodpasture’s SyndromeGoodpasture’s Syndrome
Gold standard diagnostic test?Gold standard diagnostic test? Renal biopsy with immunohistochemical stainingRenal biopsy with immunohistochemical staining
Circulating anti-GBM antibodies (IgG) is 90-95% sensitiveCirculating anti-GBM antibodies (IgG) is 90-95% sensitive Levels directly correlate with severity, organ survival, and relapseLevels directly correlate with severity, organ survival, and relapse
TreatmentTreatment PlasmapheresisPlasmapheresis daily until titers undetectable (1-2 weeks!) daily until titers undetectable (1-2 weeks!) PrednisonePrednisone 1mg/kg/day 1mg/kg/day CyclophosphamideCyclophosphamide or azathioprine or azathioprine