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Wegener’s Wegener’s Granulomatosi Granulomatosi s s Kelly Mitchell Kelly Mitchell July 5, 2006 July 5, 2006 Morning Report Morning Report

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Page 1: Endoscopic Laser surgery For Subglottic Stenosis in Wegerners Granulomatosis  Endoscopic Laser surgery For Subglottic Stenosis in Wegerners Granulomatosis

Wegener’s Wegener’s GranulomatosGranulomatos

isisKelly MitchellKelly Mitchell

July 5, 2006 July 5, 2006

Morning ReportMorning Report

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History of Wegener’sHistory of Wegener’s In 1931, two patients died from In 1931, two patients died from

prolonged sepsis with inflammation of prolonged sepsis with inflammation of blood vessels scattered throughout the blood vessels scattered throughout the body. body.

In 1936, Wegener first described a In 1936, Wegener first described a distinct syndrome in three patients distinct syndrome in three patients found to have necrotizing granulomas found to have necrotizing granulomas involving the upper and lower involving the upper and lower respiratory tract. respiratory tract.

In 1954, seven more patients described, In 1954, seven more patients described, resulting in definate criteria resulting in definate criteria

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The ControversyThe Controversy

Wegener’s vs PR3-ANCA vasculitisWegener’s vs PR3-ANCA vasculitis Lancet, 22 April 2006Lancet, 22 April 2006 Suggestion that using Wegener’s name Suggestion that using Wegener’s name

“needs balanced discussion within the “needs balanced discussion within the scientific community”scientific community”

Reiter's syndrome-Reiter's syndrome- reactive arthritis reactive arthritis

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The Problem with The Problem with ChangingChanging

Multiple ANCA+ diseases:Multiple ANCA+ diseases: microscopic polyangiitis (MPA)microscopic polyangiitis (MPA) "renal-limited" vasculitis "renal-limited" vasculitis (pauci-immune (pauci-immune

glomerulonephritis without evidence of extrarenal disease)glomerulonephritis without evidence of extrarenal disease) Churg-Strauss syndrome (CSS)Churg-Strauss syndrome (CSS) Drug-induced vasculitisDrug-induced vasculitis Goodpasture’sGoodpasture’s Rheumatic disordersRheumatic disorders Autoimmune GI disordersAutoimmune GI disorders CFCF

Diagnostic Criteria primarily clinicalDiagnostic Criteria primarily clinical

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Criteria for ClassificationCriteria for Classification Nasal or oral inflammationNasal or oral inflammation

Development of painful or painless oral ulcers or purulent or Development of painful or painless oral ulcers or purulent or bloody nasal dischargebloody nasal discharge

Abnormal chest radiographAbnormal chest radiograph Chest radiograph showing the presence of nodules, fixed Chest radiograph showing the presence of nodules, fixed

infiltrates, or cavitiesinfiltrates, or cavities

Abnormal Urinary sedimentAbnormal Urinary sediment Microhematuria (>5 red blood cells per high power field) or red Microhematuria (>5 red blood cells per high power field) or red

cell casts in urine sediment cell casts in urine sediment

Granulomatous inflammation on biopsyGranulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within Histologic changes showing granulomatous inflammation within

the wall of an artery or in the perivascular or extravascular area the wall of an artery or in the perivascular or extravascular area (artery or arteriole)(artery or arteriole)

* For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least 2 of * For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%specificity of 92.0%

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Classic SymptomsClassic Symptoms

Upper respiratory tract Upper respiratory tract sinuses sinuses NoseNose earsears tracheatrachea

LungsLungs KidneysKidneys

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EyeEye ScleritisScleritis

UveitisUveitis

Orbital Orbital pseudotumor pseudotumor /proptosis/proptosis

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Upper Respiratory Upper Respiratory TractTract

EarEar Ear infections that are slow Ear infections that are slow

to resolve.to resolve. Recurrent otitis media. Recurrent otitis media. Decrease in hearing.Decrease in hearing.

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Upper Respiratory Upper Respiratory TractTract

NoseNose Nasal crusting Nasal crusting Frequent Frequent

nosebleeds nosebleeds Erosion and Erosion and

perforation of perforation of the nasal the nasal septum.septum. The bridge of The bridge of the nose can collapse resulting the nose can collapse resulting

in a “saddle–nose deformity”.in a “saddle–nose deformity”.

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Upper Respiratory Upper Respiratory TractTract

Sinuses/TracheaSinuses/Trachea SinusesSinuses Chronic sinus Chronic sinus

inflammationinflammation TracheaTrachea

subglottic stenosissubglottic stenosis

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LungsLungs NodulesNodules (which (which

may cavitate) may cavitate)

Alveolar Alveolar opacities opacities

Pleural Pleural opacities opacities

Diffuse hazy Diffuse hazy opacitiesopacities (which may (which may reflect alveolar hemorrhage) reflect alveolar hemorrhage)

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KidneyKidney Glomerulonephritis w/ associated Glomerulonephritis w/ associated

hematuria and proteinuriahematuria and proteinuria Can lead to renal failure if not Can lead to renal failure if not

treated aggressively treated aggressively Renal masses (rare)Renal masses (rare) Active urine sediment: red blood cell Active urine sediment: red blood cell

castscasts

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RBC castsRBC casts

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SkinSkin ““palpable purpura” palpable purpura”

most commonmost common

Raynaud’s Raynaud’s phenomenon—due phenomenon—due to inadequate to inadequate blood flow to blood flow to fingers and toesfingers and toes

UlcersUlcers

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MiscellaneousMiscellaneous JointsJoints

Arthritis can occur, with joint swelling and Arthritis can occur, with joint swelling and painpain

NervesNervesPeripheral nerve involvement leads to Peripheral nerve involvement leads to numbness, tingling, shooting pains in the numbness, tingling, shooting pains in the extremities, and sometimes to weakness in a extremities, and sometimes to weakness in a foot, hand, arm, or leg foot, hand, arm, or leg

Meninges Meninges Prostate glandProstate gland Genito–urinary tractGenito–urinary tract Constitutional symptoms of fatigue, low–Constitutional symptoms of fatigue, low–

grade fever, and weight lossgrade fever, and weight loss

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Incidence of symptomsIncidence of symptoms

SymptomSymptom At OnsetAt Onset TotalTotal ENT ENT 75%75% 95%95% Lung Lung 50 50 8585 Joints Joints 30 30 7070 Fever Fever 25 25 5050 Kidney Kidney 20 20 7575 Cough Cough 20 20 5050 Eye Eye 15 15 5050 Skin Skin 15 15 4545 Weight Loss Weight Loss 10 10 3535 Nervous System (Central/Peripheral) 0 Nervous System (Central/Peripheral) 0 10/15 10/15

One-third of patients may be without symptoms at onset of One-third of patients may be without symptoms at onset of diseasedisease

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PathogenesisPathogenesisRisk factors and inciting eventsRisk factors and inciting events

Exact events obscureExact events obscure Infectious—staph?Infectious—staph? Genetic Genetic

single nucleotide polymorphism in a gene encoding a single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22)protein tyrosine phosphatase (PTPN22)

AAT deficiencyAAT deficiency Environmental—inhalational? Environmental—inhalational?

SilicaSilica lead lead mercurymercury

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PathogenesisPathogenesisANCAANCA

ANCAs may be not only markers for ANCAs may be not only markers for Wegener's granulomatosis and related Wegener's granulomatosis and related disorders, but they may also be actors in disorders, but they may also be actors in pathogenesispathogenesis

Neutrophils exposed to cytokines such as Neutrophils exposed to cytokines such as TNF, express PR3 & MPO (the targets TNF, express PR3 & MPO (the targets for ANCAs)for ANCAs)

Adding ANCAs to these cytokine-primed Adding ANCAs to these cytokine-primed neutrophils causes them to generate neutrophils causes them to generate oxygen radicals and release enzymes oxygen radicals and release enzymes capable of damaging blood vessels. capable of damaging blood vessels.

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PathogenesisPathogenesis

““Priming” of NeutrophilsPriming” of Neutrophils Exposing PR3 and MPO epitopesExposing PR3 and MPO epitopes

ANCA bindingANCA binding Degranulation/ROS Degranulation/ROS

production/neutrophil-endothelial production/neutrophil-endothelial cell interactioncell interaction

Increased ANCA = Increased Increased ANCA = Increased degranulation ratedegranulation rate

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Nasal or oral inflammationNasal or oral inflammation Development of painful or painless oral ulcers or Development of painful or painless oral ulcers or

purulent or bloody nasal dischargepurulent or bloody nasal discharge

Abnormal chest radiographAbnormal chest radiograph Chest radiograph showing the presence of nodules, fixed Chest radiograph showing the presence of nodules, fixed

infiltrates, or cavitiesinfiltrates, or cavities

Abnormal urinary sedimentAbnormal urinary sediment Microhematuria (>5 red blood cells per high power Microhematuria (>5 red blood cells per high power

field) or red cell casts in urine sediment field) or red cell casts in urine sediment

Granulomatous inflammation on Granulomatous inflammation on biopsybiopsy Histologic changes showing granulomatous Histologic changes showing granulomatous

inflammation within the wall of an artery or in the inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)perivascular or extravascular area (artery or arteriole)

Criteria for ClassificationCriteria for ClassificationDiagnosisDiagnosis

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DiagnosisDiagnosis

Biopsy specimens showing the triad of vasculitis, Biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis granulomata, and large areas of necrosis SinusesSinuses NoseNose Skin-Skin---leukocytoclastic vasculitis with little or no complement leukocytoclastic vasculitis with little or no complement

and immunoglobulin on immunofluorescence and immunoglobulin on immunofluorescence Kidney-Kidney---segmental necrotizing glomerulonephritis that is segmental necrotizing glomerulonephritis that is

usually pauci-immune on immunofluorescence / EMusually pauci-immune on immunofluorescence / EM Lung--Lung--vasculitis and granulomatous inflammation vasculitis and granulomatous inflammation (Only large sections of lung tissue obtained via (Only large sections of lung tissue obtained via

thoracoscopic or open lung biopsy are likely to show all thoracoscopic or open lung biopsy are likely to show all of the histologic features) of the histologic features)

Seropositivity for C-ANCAsSeropositivity for C-ANCAs

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Antineutrophil cytoplasmic Antineutrophil cytoplasmic antibodies antibodies

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ANCAANCA

~90% of Wegener's cases are ~90% of Wegener's cases are ANCA+ANCA+ In limited dz, up to 40% may be ANCA In limited dz, up to 40% may be ANCA

negneg

80 - 90 % PR3-ANCA 80 - 90 % PR3-ANCA

Remaining MPO-ANCARemaining MPO-ANCA

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Is ANCA sufficient?Is ANCA sufficient?

Concensus is that tissue dx is Concensus is that tissue dx is necessarynecessary

Rarely may initiate tx w/o biopsyRarely may initiate tx w/o biopsy

Should attempt to confirm w/ biopsy Should attempt to confirm w/ biopsy when ablewhen able

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TreatmentTreatmentTraditionalTraditional

PrednisonePrednisone (initiated at 1 mg/kg (initiated at 1 mg/kg daily for 1 to 2 months. then daily for 1 to 2 months. then tapered) tapered)

CyclophosphamideCyclophosphamide (2mg/kg daily (2mg/kg daily for at least 12 months)for at least 12 months)

>90% improve and 75% remit >90% improve and 75% remit

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TreatmentTreatment

However, 50% in remission relapse However, 50% in remission relapse

AND daily cyclophos is very toxicAND daily cyclophos is very toxic pancytopenia, pancytopenia, infection, infection, hemorrhagic cystitishemorrhagic cystitis bladder cancer (increased 33-fold)bladder cancer (increased 33-fold) lymphoma (increased 11-fold) lymphoma (increased 11-fold)

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TreatmentTreatment Monthly IV cyclophosphamideMonthly IV cyclophosphamide -- -- less toxic less toxic

but less effectivebut less effective

Weekly methotrexateWeekly methotrexate -- -- maintains remissionmaintains remission

Trimethoprim-sulfamethoxazoleTrimethoprim-sulfamethoxazole -- -- controversial (?effective for disease limited to the respiratory tract), controversial (?effective for disease limited to the respiratory tract), reduces the relapse rate reduces the relapse rate

SteroidsSteroids —prednisone vs solumedrol —prednisone vs solumedrol PlasmapheresisPlasmapheresis --unproven, awaiting MEPEX trialunproven, awaiting MEPEX trial

Recommended for anti-GBM+, pulm hemmorhage, renal failureRecommended for anti-GBM+, pulm hemmorhage, renal failure IVIGIVIG— — recommended in the setting of infection during PLEXrecommended in the setting of infection during PLEX

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VasculiditiesVasculidities Large vessel vasculitis Large vessel vasculitis

Takayasu arteritis Takayasu arteritis Giant cell arteritis Giant cell arteritis

Medium sized vessel vasculitis Medium sized vessel vasculitis Polyarteritis nodosa Polyarteritis nodosa Isolated central nervous system vasculitis Isolated central nervous system vasculitis

Small vessel vasculitis Small vessel vasculitis Churg-Strauss arteritis Churg-Strauss arteritis Wegener's granulomatosis Wegener's granulomatosis Microscopic polyarteritis Microscopic polyarteritis Henoch-Schönlein purpuraHenoch-Schönlein purpura Essential cryoglobulinemic vasculitisEssential cryoglobulinemic vasculitis Hypersensitivity vasculitis Hypersensitivity vasculitis Vasculitis secondary to connective tissue disorders -- Vasculitis secondary to connective tissue disorders --

SLE, rheumatoid arthritis, relapsing polychondritis, SLE, rheumatoid arthritis, relapsing polychondritis, Behcet's diseaseBehcet's disease

Vasculitis secondary to viral infection —hepatitis B and Vasculitis secondary to viral infection —hepatitis B and C, HIV, CMV, EBV, Parvo B19C, HIV, CMV, EBV, Parvo B19

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What, then, is the role of What, then, is the role of ANCA?ANCA?

Is a positive test result a "true-positive"? Is a positive test result a "true-positive"? Does a negative ANCA assay exclude an Does a negative ANCA assay exclude an

"ANCA-associated" vasculitis? "ANCA-associated" vasculitis? Is the presence of a positive ANCA assay in Is the presence of a positive ANCA assay in

and of itself sufficient to establish the and of itself sufficient to establish the diagnosis (ie, does it preclude the need for diagnosis (ie, does it preclude the need for biopsy?) biopsy?)

Does an increase in ANCA titer predict a Does an increase in ANCA titer predict a disease flare? disease flare?

Does a persistently negative ANCA ensure Does a persistently negative ANCA ensure disease quiescence? disease quiescence?