This document summarizes Wegener's granulomatosis (WG), a rare disease characterized by inflammation of blood vessels. In the 1930s it was first described by Friedrich Wegener based on patients exhibiting necrotizing granulomas in the respiratory tract and inflammation of blood vessels throughout the body. Diagnosis is based on clinical criteria including nasal or oral inflammation, lung abnormalities on chest imaging, kidney involvement, and granulomatous changes on biopsy. Pathogenesis involves antineutrophil cytoplasmic antibodies (ANCA) that activate neutrophils, causing tissue damage. WG commonly affects the upper respiratory tract, lungs and kidneys. Treatment involves immunosuppressive medications like glucocorticoids and cyclophosphamide

1. Wegener’sWegener’s
GranulomatosisGranulomatosis
Kelly MitchellKelly Mitchell
July 5, 2006July 5, 2006
Morning ReportMorning Report

2. History of Wegener’sHistory of Wegener’s
 In 1931, two patients died from prolongedIn 1931, two patients died from prolonged
sepsis with inflammation of blood vesselssepsis with inflammation of blood vessels
scattered throughout the body.scattered throughout the body.
 In 1936, Wegener first described a distinctIn 1936, Wegener first described a distinct
syndrome in three patients found to havesyndrome in three patients found to have
necrotizing granulomas involving the upper andnecrotizing granulomas involving the upper and
lower respiratory tract.lower respiratory tract.
 In 1954, seven more patients described, resultingIn 1954, seven more patients described, resulting
in definate criteriain definate criteria

3. 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 “needsSuggestion that using Wegener’s name “needs
balanced discussion within the scientific community”balanced discussion within the scientific community”
 Reiter's syndrome-Reiter's syndrome- reactive arthritisreactive arthritis

4. The Problem with ChangingThe Problem with Changing
 Multiple ANCA+ diseases:Multiple ANCA+ diseases:
 microscopic polyangiitis (MPA)microscopic polyangiitis (MPA)
 "renal-limited" vasculitis"renal-limited" vasculitis (pauci-immune glomerulonephritis without(pauci-immune glomerulonephritis without
evidence of extrarenal disease)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

5. Criteria for ClassificationCriteria for Classification
 Nasal or oral inflammationNasal or oral inflammation
 Development of painful or painless oral ulcers or purulent or bloody nasal dischargeDevelopment of painful or painless oral ulcers or purulent or bloody nasal discharge
 Abnormal chest radiographAbnormal chest radiograph
 Chest radiograph showing the presence of nodules, fixed infiltrates, or cavitiesChest radiograph showing the presence of nodules, fixed infiltrates, or cavities
 Abnormal Urinary sedimentAbnormal Urinary sediment
 Microhematuria (>5 red blood cells per high power field) or red cell casts in urineMicrohematuria (>5 red blood cells per high power field) or red cell casts in urine
sedimentsediment
 Granulomatous inflammation on biopsyGranulomatous inflammation on biopsy
 Histologic changes showing granulomatous inflammation within the wall of an arteryHistologic changes showing granulomatous inflammation within the wall of an artery
or in the perivascular or extravascular area (artery or arteriole)or in the perivascular or extravascular area (artery or arteriole)
* 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* 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 specificity of 92.0%presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%

6. Classic SymptomsClassic Symptoms
 Upper respiratory tractUpper respiratory tract
 sinusessinuses
 NoseNose
 earsears
 tracheatrachea
 LungsLungs
 KidneysKidneys

7. EyeEye
 ScleritisScleritis
 UveitisUveitis
 OrbitalOrbital
pseudotumorpseudotumor
/proptosis/proptosis

8. Upper Respiratory TractUpper Respiratory Tract
EarEar
 Ear infections that are slow to resolve.Ear infections that are slow to resolve.
 Recurrent otitis media.Recurrent otitis media.
 Decrease in hearing.Decrease in hearing.

9. Upper Respiratory TractUpper Respiratory Tract
NoseNose
 Nasal crustingNasal crusting
 FrequentFrequent
nosebleedsnosebleeds
 Erosion andErosion and
perforation of theperforation of the
nasal septum.nasal septum. The bridgeThe bridge
of the nose can collapse resulting in aof the nose can collapse resulting in a
“saddle–nose deformity”.“saddle–nose deformity”.

10. Upper Respiratory TractUpper Respiratory Tract
Sinuses/TracheaSinuses/Trachea
 SinusesSinuses
 Chronic sinusChronic sinus
inflammationinflammation
 TracheaTrachea
 subglottic stenosissubglottic stenosis

11. LungsLungs
 NodulesNodules (which may(which may
cavitate)cavitate)
 Alveolar opacitiesAlveolar opacities
 Pleural opacitiesPleural opacities
 Diffuse hazyDiffuse hazy
opacitiesopacities (which may reflect(which may reflect
alveolar hemorrhage)alveolar hemorrhage)

12. KidneyKidney
 Glomerulonephritis w/ associated hematuriaGlomerulonephritis w/ associated hematuria
and proteinuriaand proteinuria
 Can lead to renal failure if not treatedCan lead to renal failure if not treated
aggressivelyaggressively
 Renal masses (rare)Renal masses (rare)
 Active urine sediment: red blood cell castsActive urine sediment: red blood cell casts

13. RBC castsRBC casts

14. SkinSkin
 ““palpable purpura” mostpalpable purpura” most
commoncommon
 Raynaud’s phenomenonRaynaud’s phenomenon
—due to inadequate—due to inadequate
blood flow to fingers andblood flow to fingers and
toestoes
 UlcersUlcers

15. MiscellaneousMiscellaneous
 JointsJoints
Arthritis can occur, with joint swelling and painArthritis can occur, with joint swelling and pain
 NervesNerves
Peripheral nerve involvement leads to numbness,Peripheral nerve involvement leads to numbness,
tingling, shooting pains in the extremities, andtingling, shooting pains in the extremities, and
sometimes to weakness in a foot, hand, arm, or legsometimes to weakness in a foot, hand, arm, or leg
 MeningesMeninges
 Prostate glandProstate gland
 Genito–urinary tractGenito–urinary tract
 Constitutional symptoms of fatigue, low–grade fever,Constitutional symptoms of fatigue, low–grade fever,
and weight lossand weight loss

16. Incidence of symptomsIncidence of symptoms
SymptomSymptom At OnsetAt Onset TotalTotal
 ENTENT 75%75% 95%95%
 LungLung 5050 8585
 JointsJoints 3030 7070
 FeverFever 2525 5050
 KidneyKidney 2020 7575
 CoughCough 2020 5050
 EyeEye 1515 5050
 SkinSkin 1515 4545
 Weight LossWeight Loss 1010 3535
 Nervous System (Central/Peripheral) 0Nervous System (Central/Peripheral) 0 10/1510/15
One-third of patients may be without symptoms at onset of diseaseOne-third of patients may be without symptoms at onset of disease

17. PathogenesisPathogenesis
Risk factors and inciting eventsRisk factors and inciting events
 Exact events obscureExact events obscure
 Infectious—staph?Infectious—staph?
 GeneticGenetic
 single nucleotide polymorphism in a gene encoding a protein tyrosinesingle nucleotide polymorphism in a gene encoding a protein tyrosine
phosphatase (PTPN22)phosphatase (PTPN22)
 AAT deficiencyAAT deficiency
 Environmental—inhalational?Environmental—inhalational?
 SilicaSilica
 leadlead
 mercurymercury

18. PathogenesisPathogenesis
ANCAANCA
 ANCAs may be not only markers for Wegener'sANCAs may be not only markers for Wegener's
granulomatosis and related disorders, but theygranulomatosis and related disorders, but they
may also be actors in pathogenesismay also be actors in pathogenesis
 Neutrophils exposed to cytokines such as TNF,Neutrophils exposed to cytokines such as TNF,
express PR3 & MPO (the targets for ANCAs)express PR3 & MPO (the targets for ANCAs)
 Adding ANCAs to these cytokine-primedAdding ANCAs to these cytokine-primed
neutrophils causes them to generate oxygenneutrophils causes them to generate oxygen
radicals and release enzymes capable ofradicals and release enzymes capable of
damaging blood vessels.damaging blood vessels.

19. PathogenesisPathogenesis
 ““Priming” of NeutrophilsPriming” of Neutrophils
 Exposing PR3 and MPO epitopesExposing PR3 and MPO epitopes
 ANCA bindingANCA binding
 Degranulation/ROS production/neutrophil-Degranulation/ROS production/neutrophil-
endothelial cell interactionendothelial cell interaction
 Increased ANCA = Increased degranulation rateIncreased ANCA = Increased degranulation rate

20.  Nasal or oral inflammationNasal or oral inflammation
 Development of painful or painless oral ulcers or purulent or bloody nasalDevelopment of painful or painless oral ulcers or purulent or bloody nasal
dischargedischarge
 Abnormal chest radiographAbnormal chest radiograph
 Chest radiograph showing the presence of nodules, fixed infiltrates, orChest radiograph showing the presence of nodules, fixed infiltrates, or
cavitiescavities
 Abnormal urinary sedimentAbnormal urinary sediment
 Microhematuria (>5 red blood cells per high power field) or red cell castsMicrohematuria (>5 red blood cells per high power field) or red cell casts
in urine sedimentin urine sediment
 Granulomatous inflammation on biopsyGranulomatous inflammation on biopsy
 Histologic changes showing granulomatous inflammation within the wallHistologic changes showing granulomatous inflammation within the wall
of an artery or in the perivascular or extravascular area (artery or arteriole)of an artery or in the perivascular or extravascular area (artery or arteriole)
Criteria for ClassificationCriteria for Classification
DiagnosisDiagnosis

21. DiagnosisDiagnosis
 Biopsy specimens showing the triad of vasculitis, granulomata,Biopsy specimens showing the triad of vasculitis, granulomata,
and large areas of necrosisand large areas of necrosis
 SinusesSinuses
 NoseNose
 Skin-Skin---leukocytoclastic vasculitis with little or no complement andleukocytoclastic vasculitis with little or no complement and
immunoglobulin on immunofluorescenceimmunoglobulin on immunofluorescence
 Kidney-Kidney---segmental necrotizing glomerulonephritis that is usually pauci-segmental necrotizing glomerulonephritis that is usually pauci-
immune on immunofluorescence / EMimmune on immunofluorescence / EM
 Lung--Lung--vasculitis and granulomatous inflammationvasculitis and granulomatous inflammation
(Only large sections of lung tissue obtained via thoracoscopic or open(Only large sections of lung tissue obtained via thoracoscopic or open
lung biopsy are likely to show all of the histologic features)lung biopsy are likely to show all of the histologic features)
 Seropositivity for C-ANCAsSeropositivity for C-ANCAs

23. Antineutrophil cytoplasmicAntineutrophil cytoplasmic
antibodiesantibodies

24. ANCAANCA
 ~90% of Wegener's cases are ANCA+~90% of Wegener's cases are ANCA+
 In limited dz, up to 40% may be ANCA negIn limited dz, up to 40% may be ANCA neg
 80 - 90 % PR3-ANCA80 - 90 % PR3-ANCA
 Remaining MPO-ANCARemaining MPO-ANCA

25. Is ANCA sufficient?Is ANCA sufficient?
 Concensus is that tissue dx is necessaryConcensus is that tissue dx is necessary
 Rarely may initiate tx w/o biopsyRarely may initiate tx w/o biopsy
 Should attempt to confirm w/ biopsy when ableShould attempt to confirm w/ biopsy when able

26. TreatmentTreatment
TraditionalTraditional
 PrednisonePrednisone (initiated at 1 mg/kg daily for 1 to(initiated at 1 mg/kg daily for 1 to
2 months. then tapered)2 months. then tapered)
 CyclophosphamideCyclophosphamide (2mg/kg daily for at least(2mg/kg daily for at least
12 months)12 months)
 >90% improve and 75% remit>90% improve and 75% remit

27. TreatmentTreatment
However, 50% in remission relapseHowever, 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)

28. TreatmentTreatment
 Monthly IV cyclophosphamideMonthly IV cyclophosphamide ---- less toxic but lessless toxic but less
effectiveeffective
 Weekly methotrexateWeekly methotrexate ---- maintains remissionmaintains remission
 Trimethoprim-sulfamethoxazoleTrimethoprim-sulfamethoxazole ---- controversial (?controversial (?
effective for disease limited to the respiratory tract), reduces the relapse rateeffective for disease limited to the respiratory tract), 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

31. VasculiditiesVasculidities
 Large vessel vasculitisLarge vessel vasculitis
 Takayasu arteritisTakayasu arteritis
 Giant cell arteritisGiant cell arteritis
 Medium sized vessel vasculitisMedium sized vessel vasculitis
 Polyarteritis nodosaPolyarteritis nodosa
 Isolated central nervous system vasculitisIsolated central nervous system vasculitis
 Small vessel vasculitisSmall vessel vasculitis
 Churg-Strauss arteritisChurg-Strauss arteritis
 Wegener's granulomatosisWegener's granulomatosis
 Microscopic polyarteritisMicroscopic polyarteritis
 Henoch-Schönlein purpuraHenoch-Schönlein purpura
 Essential cryoglobulinemic vasculitisEssential cryoglobulinemic vasculitis
 Hypersensitivity vasculitisHypersensitivity vasculitis
 Vasculitis secondary to connective tissue disorders -- SLE, rheumatoidVasculitis secondary to connective tissue disorders -- SLE, rheumatoid
arthritis, relapsing polychondritis, Behcet's diseasearthritis, relapsing polychondritis, Behcet's disease
 Vasculitis secondary to viral infection —hepatitis B and C, HIV, CMV,Vasculitis secondary to viral infection —hepatitis B and C, HIV, CMV,
EBV, Parvo B19EBV, Parvo B19

32. What, then, is the role of ANCA?What, then, is the role of ANCA?
 Is a positive test result a "true-positive"?Is a positive test result a "true-positive"?
 Does a negative ANCA assay exclude an "ANCA-Does a negative ANCA assay exclude an "ANCA-
associated" vasculitis?associated" vasculitis?
 Is the presence of a positive ANCA assay in and ofIs the presence of a positive ANCA assay in and of
itself sufficient to establish the diagnosis (ie, does ititself sufficient to establish the diagnosis (ie, does it
preclude the need for biopsy?)preclude the need for biopsy?)
 Does an increase in ANCA titer predict a disease flare?Does an increase in ANCA titer predict a disease flare?
 Does a persistently negative ANCA ensure diseaseDoes a persistently negative ANCA ensure disease
quiescence?quiescence?