9a1c wg mitchell-7-5-06
TRANSCRIPT
Wegener’s Wegener’s GranulomatosGranulomatos
isisKelly MitchellKelly Mitchell
July 5, 2006 July 5, 2006
Morning ReportMorning Report
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
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
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
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%
Classic SymptomsClassic Symptoms
Upper respiratory tract Upper respiratory tract sinuses sinuses NoseNose earsears tracheatrachea
LungsLungs KidneysKidneys
EyeEye ScleritisScleritis
UveitisUveitis
Orbital Orbital pseudotumor pseudotumor /proptosis/proptosis
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.
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”.
Upper Respiratory Upper Respiratory TractTract
Sinuses/TracheaSinuses/Trachea SinusesSinuses Chronic sinus Chronic sinus
inflammationinflammation TracheaTrachea
subglottic stenosissubglottic stenosis
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)
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
RBC castsRBC casts
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
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
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
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
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.
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
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
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
Antineutrophil cytoplasmic Antineutrophil cytoplasmic antibodies antibodies
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
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
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
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)
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
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
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?