small vessel vasculitis

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 !