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


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))


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 ???


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.


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


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


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)


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


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


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

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Vasculitic Syndromes - an overview