small vessel vasculitis
TRANSCRIPT
Small Vessel Small Vessel VasculitisVasculitis
By: Iyad JaberBy: Iyad Jaber
Iashvili Children’s HospitalIashvili Children’s Hospital
Tbilisi, Georgia Tbilisi, Georgia
Wegener’s Wegener’s GranulamatosisGranulamatosis
WG WG Also known as Granulomatosis with Polyangitis Also known as Granulomatosis with Polyangitis
WG EpidemiologyWG Epidemiology The prevalence of WG in the United States is estimated to be 3 cases per
100,000 people. The incidence and prevalence of WG in the United Kingdom is estimated at
10.2 cases and 250 cases per million population, respectively. Race-, sex-, and age-related demographics WG is more common in individuals of northern European descent
(approximately 90%); it occurs less commonly in blacks. In European populations, WG is slightly more common in men, with a male-
to-female ratio of 1.5:1 . Women are more likely to have limited disease. The onset of WG may occur at any age, although patients typically present at
age 35-55 years. WG is rare in childhood.
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 urine Microhematuria (>5 red blood cells per high power field) or red cell casts in urine
sediment sediment
Granulomatous inflammation on biopsyGranulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery Histologic 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)
At least 2 out of these 4 should be present to describe the pt. as having the WG. At least 2 out of these 4 should be present to describe the pt. as having the WG.
Wegnere’s Granulomatosis (WG) Wegnere’s Granulomatosis (WG) Classical Symptoms Classical 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 TractUpper Respiratory TractEarEar
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.
Upper Respiratory TractUpper Respiratory Tract NoseNose
Nasal crusting Nasal crusting Frequent Frequent
nosebleeds nosebleeds Erosion and Erosion and
perforation of the perforation of the nasal septum.nasal septum. The bridge The bridge
of the nose can collapse resulting in a of the nose can collapse resulting in a
““saddle–nose deformitysaddle–nose deformity”.”.
Upper Respiratory TractUpper Respiratory Tract Sinuses/TracheaSinuses/Trachea
SinusesSinuses Chronic sinus Chronic sinus
inflammationinflammation
TracheaTrachea subglottic stenosissubglottic stenosis
LungsLungs NodulesNodules (which may (which may
cavitate) cavitate)
Alveolar opacities Alveolar opacities Pleural opacities Pleural opacities Diffuse hazy Diffuse hazy
opacitiesopacities (which may reflect (which may reflect alveolar hemorrhage) alveolar hemorrhage)
KidneyKidney Glomerulonephritis w/ associated hematuria Glomerulonephritis w/ associated hematuria
and proteinuriaand proteinuria Can lead to renal failure if not treated Can lead to renal failure if not treated
aggressively aggressively Renal masses (rare)Renal masses (rare) Active urine sediment: red blood cell castsActive urine sediment: red blood cell casts
RBC castsRBC casts
SkinSkin ““palpable purpura” most palpable purpura” most
commoncommon
Raynaud’s phenomenonRaynaud’s phenomenon—due to inadequate —due to inadequate blood flow to fingers and blood flow to fingers and toestoes
UlcersUlcers
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, and tingling, shooting pains in the extremities, and sometimes to weakness in a foot, hand, arm, or leg sometimes to weakness in a foot, hand, arm, or leg
Meninges Meninges 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
WG PathogenesisWG PathogenesisRisk 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 protein tyrosine single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22)phosphatase (PTPN22)
AAT deficiencyAAT deficiency Environmental—inhalational? Environmental—inhalational?
SilicaSilica lead lead mercurymercury
PathogenesisPathogenesisANCAANCA
ANCAs may be not only markers for Wegener's ANCAs may be not only markers for Wegener's granulomatosis and related disorders, but they granulomatosis 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-primed Adding ANCAs to these cytokine-primed neutrophils causes them to generate oxygen neutrophils causes them to generate oxygen radicals and release enzymes capable of radicals and release enzymes capable of damaging blood vessels. damaging blood vessels.
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
Nasal or oral inflammationNasal or oral inflammation Development of painful or painless oral ulcers or purulent or bloody nasal Development 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, or Chest 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 casts Microhematuria (>5 red blood cells per high power field) or red cell casts
in urine sediment in urine sediment
Granulomatous inflammation on biopsyGranulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall Histologic 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 ClassificationDiagnosisDiagnosis
DiagnosisDiagnosis
Biopsy specimens showing the triad of vasculitis, granulomata, Biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis and large areas of necrosis SinusesSinuses NoseNose Skin-Skin---leukocytoclastic vasculitis with little or no complement and leukocytoclastic vasculitis with little or no complement and
immunoglobulin on immunofluorescence immunoglobulin 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 inflammation vasculitis 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
Antineutrophil cytoplasmic Antineutrophil cytoplasmic antibodies antibodies
ANCAANCA
~90% of Wegener's cases are ANCA+~90% of Wegener's cases are ANCA+ In limited disease, up to 40% may be ANCA negativIn limited disease, up to 40% may be ANCA negativ
80 - 90 % PR3-ANCA 80 - 90 % PR3-ANCA
Remaining MPO-ANCARemaining MPO-ANCA
WG TreatmentWG Treatment
Monthly IV cyclophosphamideMonthly IV cyclophosphamide -- -- less toxic but less less 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 rate effective 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
WG Treatment ..newWG Treatment ..new
RituximabRituximab 11 refractory patients all responded with 11 refractory patients all responded with
remission and decrease in ANCA titers (8/11 remission and decrease in ANCA titers (8/11 became ANCA negative)became ANCA negative) Arthritis Rheum. 2005 Jan;52(1):262-8Arthritis Rheum. 2005 Jan;52(1):262-8
TreatmentTreatment
However, 50% in remission relapse However, 50% in remission relapse
cyclophosphamide is very toxiccyclophosphamide 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)
Churg-Strauss Churg-Strauss SyndromeSyndrome
CSSCSSalso referred to as allergic angiitis and
granulomatosis
Churg-Strauss syndrome is an uncommon disease with an estimated annual incidence of 1–3 per million. The disease can occur at any age with the possible exception of infants. The mean age of onset is 48 years, with a female-to-male ratio of 1.2:1.
CSS EpidemiologyCSS Epidemiology
Pathology and Pathogenesis
The necrotizing vasculitis of Churg-Strauss syndrome involves small and medium-sized muscular arteries, capillaries, veins, and venules.
A characteristic histo-pathologic feature of Churg-Strauss syndrome is granulomatous reactions.
These are usually associated with infiltration of the tissues with eosinophils.
strong association with asthma and its clinico-pathologic manifestations, including eosinophilia, granuloma, and vasculitis, point to aberrant immunologic phenomena.
EEosinophils InfiltrationInfiltration
Clinical Manifestations OOften exhibit nonspecific manifestations:
Fever,
Malaise,
Anorexia,
and weight loss. The pulmonary finding similar to the asthmatic attacks with The pulmonary finding similar to the asthmatic attacks with
pulmonary infiltration.pulmonary infiltration. Mononeuritis multiplex is the second most common
manifestation. Allergic rhinitis and sinusitis develop in up to 61% of patients
and present on the early course. HHeart disease occurs in 14% of patients and is an important
cause of mortality.(CHF or Heart attack)
Skin lesions occur in 51% of patients and include purpura in addition to cutaneous and subcutaneous nodules.
The renal disease in Churg-Strauss syndrome is less common and generally less severe.
Transient pulmonary infiltrates in a Transient pulmonary infiltrates in a patient with Churg-Strauss syndrome patient with Churg-Strauss syndrome
The skin rashes of Churg-Strauss The skin rashes of Churg-Strauss syndromesyndrome
Laboratory Manifestations
The characteristic laboratory finding in virtually all patients is striking eosinophilia.
Evidence of inflammation as evidenced by: elevated ESR, fibrinogen, or globulins
Approximately 48% of patients with Churg-Strauss syndrome have circulating ANCA that is usually antimyeloperoxidase.
ANCA Negative CSSANCA Negative CSS
Clinical patterns: Clinical patterns: PericarditisPericarditis LivedoLivedo Symetrical polyneuropathySymetrical polyneuropathy pleuritispleuritis
Eosinophil rich tissue infiltratesEosinophil rich tissue infiltrates IL-10 genetic polymorphismsIL-10 genetic polymorphisms
Clinical Criteria for CSSClinical Criteria for CSS Lanham’s criteria (all of the following)Lanham’s criteria (all of the following)
AsthmaAsthma Peak eosinophilia >1.5 x 10Peak eosinophilia >1.5 x 1099 cells/L cells/L Systemic vasculitis, two or > extrapulmonary sitesSystemic vasculitis, two or > extrapulmonary sites
American College of Rheumatology (4 of the American College of Rheumatology (4 of the following in the setting of vasculitis)following in the setting of vasculitis) AsthmaAsthma Peak eosinophilia >10% total WBCPeak eosinophilia >10% total WBC Peripheral neuropathy attributed to vasculitisPeripheral neuropathy attributed to vasculitis Transient pulmonary infiltratesTransient pulmonary infiltrates Paranasal sinus diseaseParanasal sinus disease Biopsy showing blood vessels with extravasular eosinophils Biopsy showing blood vessels with extravasular eosinophils
Clinical Criteria for CSSClinical Criteria for CSS(continued)(continued)
Chapel Hill Consensus ConferenceChapel Hill Consensus Conference AsthmaAsthma Peripheral Eosinophilia Peripheral Eosinophilia Eosinophil-rich granulomatous inflammation Eosinophil-rich granulomatous inflammation
involving the respiratory tractinvolving the respiratory tract Necrotizing vasculitis affecting small to medium Necrotizing vasculitis affecting small to medium
vessels vessels
TreatmentTreatment
Glucocorticoids (oral prednisone 40-60 mg/dayoral prednisone 40-60 mg/day)) alone appear to be effective in many patients.
In glucocorticoid failure or in patients who present with fulminant multisystem disease, the treatment of choice is a combined regimen of daily cyclophosphamide and prednisone.
High doses of intravenous steroids High doses of intravenous steroids (usually (usually methylprednisolone) maybe useful for those who methylprednisolone) maybe useful for those who failed in the above 2 lines.failed in the above 2 lines.
Factors associated with poor Factors associated with poor prognosis in CSSprognosis in CSS
Factor 5 score (French Vasculitis Study Group)Factor 5 score (French Vasculitis Study Group) Elevated Serum Creatinine (> 1.58mg/dl)Elevated Serum Creatinine (> 1.58mg/dl) ProteinuriaProteinuria Severe GI tract involvementSevere GI tract involvement CardiomyopathyCardiomyopathy Central Nervous System involvementCentral Nervous System involvement
No factors present = five year mortality 12%No factors present = five year mortality 12%1 factor= five year mortality of 25%1 factor= five year mortality of 25%> 2 factors= five year mortality of 46%> 2 factors= five year mortality of 46%
Microscopic Polyangiitis Microscopic Polyangiitis
MPAMPAAlso known as Hypersensitivity VasculitisAlso known as Hypersensitivity Vasculitis
MPA Epidemiology MPA Epidemiology
Incidence of MPA is 1: 100,000 per yearIncidence of MPA is 1: 100,000 per year a slight predominance in men and a mean age at a slight predominance in men and a mean age at
onset of approximately 50 yearsonset of approximately 50 years 11 % of pts develop alveolar hemorrhage 11 % of pts develop alveolar hemorrhage 90% of pts develop Necrotizing 90% of pts develop Necrotizing
Glomerulonephritis Glomerulonephritis
The Chapel Hill International Consensus CriteriaThe Chapel Hill International Consensus Criteria
a necrotizing vasculitis (with few or no deposits) a necrotizing vasculitis (with few or no deposits) affecting small vessels (i.e., capillaries, venules, or affecting small vessels (i.e., capillaries, venules, or arterioles)arterioles)
It was noted that MPA is frequently associated with It was noted that MPA is frequently associated with necrotizing glomerulonephritis and pulmonary necrotizing glomerulonephritis and pulmonary capillaritiscapillaritis
MPA Clinical FeaturesMPA Clinical Features
Clinical FeatureClinical Feature PercentagePercentage
Constitutional symptoms Constitutional symptoms 76-79 %76-79 %
FeverFever 50-72 %50-72 %
Renal DiseaseRenal Disease 100 %100 %
ArthralgiaArthralgia 28-65 %28-65 %
PurpuraPurpura 40-44 %40-44 %
Pulmonary DiseasePulmonary Disease 50 %50 %
Neurologic DiseaseNeurologic Disease 28 %28 %
ENTENT 32 %32 %
MPA signs and symptomsMPA signs and symptoms Fever Malaise, fatigue, flulike syndrome Myalgia Weight loss Hemoptysis Dyspnea Cough Gastrointestinal bleeding Abdominal pain CNS involvement Arthralgias Myalgia
MPA Pulmonary DiseaseMPA Pulmonary Disease
Lung involvement is common in MPA and is present in more Lung involvement is common in MPA and is present in more than half of reported cases in most seriesthan half of reported cases in most series
Diffuse alveolar hemorrhage (DAH) is the most serious form of Diffuse alveolar hemorrhage (DAH) is the most serious form of lung involvement and has been reported in 12 to 29 percent of lung involvement and has been reported in 12 to 29 percent of patients patients
The clinical manifestations range from mild dyspnea and anemia The clinical manifestations range from mild dyspnea and anemia without any hemoptysis to massive hemorrhage and bleeding without any hemoptysis to massive hemorrhage and bleeding with profound hypoxia with acute onset in most patientswith profound hypoxia with acute onset in most patients
The radiographic features of DAH are nonspecific, The radiographic features of DAH are nonspecific, demonstrating patchy or diffuse alveolar infiltrationdemonstrating patchy or diffuse alveolar infiltration
The characteristic histopathology of MPA is that of pulmonary The characteristic histopathology of MPA is that of pulmonary capillaritis capillaritis
MPA: image showing capillaritis and alveolar hemorrhage with a butterfly appearance.
MPA Renal DiseaseMPA Renal Disease
The renal lesion of MPA is that of necrotizing The renal lesion of MPA is that of necrotizing glomerulonephritisglomerulonephritis
Glomerulonephritis (focal and segmental to severe diffuse and crescentic)
It is indistinguishable from the renal lesion of It is indistinguishable from the renal lesion of WGWG
Elevated erythrocyte sedimentation rate (ESR) Renal testsElevated serum BUN and creatinine (70%) Abnormal urine sediment Proteinuria (80%) Hematuria (67%) Leukocyturia (44%) Erythrocyte casts ANCA positive (80%) Perinuclear ANCA related to myeloperoxidase ANCA (60%) Cytoplasmic ANCA related to proteinase-3 ANCA (40%)
MPA Dx workupMPA Dx workup
Treatment Treatment
CyclophosphamideCyclophosphamide Methotrexate Methotrexate CyclosporineCyclosporine PrednisonePrednisone AzathioprineAzathioprine Rituximab Rituximab (Remission induction, remission maintenance, (Remission induction, remission maintenance,
relapse treatment) relapse treatment)
Thank you ! Thank you !