harold c. schott chair director, center for vasculitis
TRANSCRIPT
Vasculitis
Carol A. Langford, MD, MHS
Harold C. Schott ChairDirector, Center for Vasculitis Care and Research
Department of Rheumatic and Immunologic Diseases Cleveland Clinic
• Research Grant : Genentech, Bristol-Myers Squibb
• At this time, only one therapeutic agent is approved for the treatment of vasculitis (GPA and MPA).
• Unlabeled uses of other therapeutic agents are identified and discussed.
Disclosure
Educational ObjectivesVasculitis
• Identify forms of vasculitis that are commonlyencountered by the allergist/immunologist
• Describe clinical manifestations of vasculitis thatcould present to the allergist/immunologist
• Explain the diagnostic approach to vasculitis
• Recognize therapeutic options used in vasculitis
Upon completion of this session, participants should be able to:
Vasculitis
Why is vasculitis important to the allergist/immunologist ?
• Vasculitis is an immunologically mediated process
• Presence of symptoms that may be referred to an allergist
(sinus disease and asthma are seen in certain forms of vasculitis)
• In some communities, vasculitis patients managed by allergists
• Included in Board examinations
inflammation
blood vessel damage
compromise of vessel lumen attenuation of vessel wall
organ ischemia aneurysm formationhemorrhage
Vasculitis = Inflammationof the Blood Vessel
Presenting Features of Vasculitis
Systemic symptoms:As evidenced by histology: vasculitis is an inflammatory process
fever, night sweatsfatigue, malaiseanorexia, weight lossarthralgias, myalgias
Organ specific symptoms / signs of tissue injuryInfluenced by:
degree of collateral circulationunderlying health of organthe size of blood vessel that is affected
Large Vessel
Example Clinical Consequence
AortaSubclavian arteryOphthalmic artery
stenosis, aneurysmarm claudicationblindness
Digital arteryMesenteric arteryEpineural arteries
blue ischemic digitbowel infarctionmononeuritis (foot drop)
SkinKidneyLung
palpable purpuraglomerulonephritispulmonary hemorrhage
Wide range of severity Wide range of presentations
Medium Vessel
Small Vessel
Vein
V
enul
e C
apill
ary
Arte
riole
Arte
ries
A
orta
Takayasu arteritisGiant cell arteritisKawasaki diseasePolyarteritis nodosaGranulomatosis with polyangiitis (Wegener’s)Microscopic polyangiitis Eosinophilic granulomatosis with
polyangiitis (Churg-Strauss)IgA Vasculitis (Henoch-Schönlein)Cutaneous vasculitis
Vasculitis is not a specific disease Blood vessel inflammation can be seen in a variety of settings
Primary Vasculitides Secondary VasculitidesVasculitis occurring secondary
to an underlying disease or exposure
Unique disease entities without a currently identified underlying
cause where vasculitis forms the pathological basis of tissue injury
Jennette JC et al. Arthritis Rheum. 2013; 65:1-11
MedicationsInfectionMalignancyTransplantCryoglobulinemiaConnective tissue disease
- Rheumatoid arthritis- SLE- Sjögren’s syndrome- Myositis
Vein
V
enul
e C
apill
ary
Arte
riole
Arte
ries
A
orta Large Vessel
Giant cell arteritis Takayasu arteritis
Medium VesselPolyarteritis nodosaKawasaki disease
Small VesselGranulomatosis with polyangiitis (Wegener’s)Microscopic polyangiitisEGPA (Churg-Strauss)IgA vasculitis (Henoch-Schönlein)
How are the vasculitic diseasesdistinguished from each other ?
How Do Forms of Primary Vasculitis Differ ?
Vessel size: large, medium, small vessel
Epidemiology: age, sex, ethnicity, frequency
Clinical Manifestations: symptoms, signspatterns of organ involvement
Diagnosis: biopsyarteriographyclinical features + laboratory abnormalities
Treatment and Outcome: supportive careprednisoneother immunosuppressive therapiesother therapies
Granulomatous large vessel vasculitis
Preferentially affects the extracranial branches of the carotid artery
The most common form of systemic vasculitis
Occurs over the age of 50
2:1 Female:Male
Giant Cell Arteritis DiagnosisEpidemiology(Also called temporal arteritis)
Symptoms:FeverFatigueHeadacheScalp tenderness Jaw / tongue claudicationPolymyalgia rheumatica (40-50%)
(pain along hip and shoulder girdle)
SignsNodular, tender temporal artery with diminished or absent pulsation
Most dreaded complication:Visual loss due to optic nerve ischemia from arteritis of ocular vessels
Giant Cell Arteritis Clinical Manifestations
Clinical Manifestations
Giant Cell Arteritis Diagnosis
Suggested by:Compatible age, symptoms, signsElevated erythrocyte sedimentation rate (ESR)
Diagnosed by: temporal artery biopsy
Panmural mononuclear infiltrationDisruption internal elastic laminaGiant cells
Diagnosis
TreatmentOutcome
Prednisone 40-60 mg dailyBegin immediately while biopsy is being arranged Reduces symptoms and prevents visual lossMost patients require treatment for > 2 years
• Acute mortality (stroke, MI) - very uncommon May be late mortality from thoracic aortic aneurysms
• Relapse requiring an increase in steroid dose occurs in ~75%
• Prednisone-related toxicity occurs in 35-86% of patients
TreatmentOutcome
Aspirin 81 mg dailyReduces cranial ischemic complications (strokes, vision loss)Use with prednisone in all patients without contraindications
Giant Cell Arteritis
Kawasaki Disease
Disease of children – 80% occur prior to age 5 years
Vasculitis of large, medium, and small arteries
Primary cause of acquired heart disease (from coronary arteritis)
in children from the USA and Japan
DiagnosisEpidemiology
Acute febrile illnessFollowed within 1-3 days by:
rashconjunctival injectioncervical adenopathyextremity changes oral mucosal changes
Courtesy of Karyl Barron MD
Clinical Manifestations
Clinical Manifestations
Kawasaki Disease
Primary complication - Coronary artery aneurysms
appear 1-4 weeks after fever onsetdevelop in 15-25% of untreated patients
Courtesy of Karyl Barron MD
Clinical Manifestations
Clinical Manifestations
Kawasaki Disease
Diagnosis
rashconjunctival injectioncervical adenopathyextremity changes oral mucosal changes
Diagnosis is clinical
Based on Fever + 5 features
DiagnosisKawasaki Disease
Intravenous immunoglobulin (IVIg) 2 g/kg as a single dose - reduces risk of aneurysms
Aspirin – given concurrently
• 1-2% acute mortality – risk is of late mortality from aneurysms
• Relapses are uncommon (3-5%)
TreatmentOutcomeTreatmentOutcome
Kawasaki Disease
Polyarteritis Nodosa
First form of vasculitis describedHas since gone through changes in nomenclature
Polyarteritis Nodosa
Polyarteritis Nodosa Microscopic Polyangiitis
Small vesselsPulmonary hemorrhage
GlomerulonephritisANCA associatedFrequent relapses
Not hepatitis associated
Medium vesselsNo lung involvement
No glomerular involvementNot associated with ANCA
Relapses uncommonPAN-like disease with Hep B
1994 – Chapel Hill Consensus Conference
DiagnosisEpidemiology
Often presents acutely
Polyarteritis Nodosa
Constitutional features
Nerve
Renal
Gastrointestinal tract
Heart
Digital infarction
hypertension, infarction(not a glomerulonephritis)
pain, infarction, perforation, bleeding
mononeuritis multiplex (ie: foot / wrist drop)CNS disease
fever, weight loss, arthralgias, night sweats
Clinical Manifestations
Clinical Manifestations
ischemia, infarction
angina, MI
Biopsy
DiagnosisPolyarteritis Nodosa
Necrotizing inflammation of medium or small arteriesabundant neutrophils and fibrinoid changes
Diagnosis
Arteriogram
Renal
microaneurysms stenoses, beading
DiagnosisPolyarteritis Nodosa Diagnosis
Mesenteric
PAN-like vasculitis associated with Hepatitis B anti-viral therapy plays an important role immunosuppressive therapy only as necessary to control vasculitis
PAN - Non-Hepatitis AssociatedBased on severity
Prednisone + daily cyclophosphamide for life-threatening diseasePrednisone alone may be considered for non-severe disease
Polyarteritis Nodosa
• 80% estimated 5 year survival with treatment• Relapses occur in 15-30%
TreatmentOutcomeTreatmentOutcome
Granulomatosis with polyangiitis (Wegener’s)(Formerly called Wegener’s granulomatosis)
Adults age 40-60 yearscan be seen in all ages
Women = Men
Uncommon – affects 3 in 100,000
Vasculitis affecting the small to medium vesselsGranulomatous inflammation of the respiratory tract
DiagnosisEpidemiology
Sinus
affected in 95% of patients
Clinical Manifestations
Clinical Manifestations
Granulomatosis with polyangiitis (Wegener’s)
affected in 85%
Pulmonary nodulesinfiltrates
Cavitary lesions Pulmonary hemorrhage
Lung
Clinical Manifestations
Clinical Manifestations
Granulomatosis with polyangiitis (Wegener’s)
Kidney - 80% affected during disease course20% have glomerulonephritis at diagnosis
typically asymptomatic can be rapidly progressivemay lead to renal failure
ProteinuriaHematuria
Red blood cell casts
Detected by urinalysis:
Clinical Manifestations
Clinical Manifestations
Granulomatosis with polyangiitis (Wegener’s)
Organ triad:sinus lung kidney
Clinical Manifestations
Clinical Manifestations
Multisystem disease
Can also affect:
jointeyeskinnerveother sites
Granulomatosis with polyangiitis (Wegener’s)
• 1982 Davies et al.Detected serum IgG antibodies that stained neutrophil cytoplasm in 8 patients with segmental necrotizing glomerulonephritis
• 1985 Van der Woude et al.Demonstrated the association between cytoplasmic staining autoantibodiesand active granulomatosis with polyangiitis (Wegener’s)
Antineutrophil Cytoplasmic Antibodies (ANCA)
Antineutrophil Cytoplasmic Antibodies (ANCA)
MyeloperoxidaseProteinase -3
cANCA cytoplasmic staining
pANCAperinuclear staining
TargetAntigens
In Vasculitis
Indirect Immunofluorescence
ELISA
(target antigen-specific)
proteinase 3myeloperoxidase
cANCA pANCA
Methods of ANCA Testing
Load Antigen
Add SerumAntibody
Add Antibody Enzyme Conjugate
Add EnzymeSubstrate
Measure OpticalDensity
A (+) ANCA done by immunofluorescence should be confirmed
by antigen-specific (PR3, MPO) ELISA
GPA (Wegener’s)Microscopic polyangiitisEGPA (Churg-Strauss)Idiopathic crescentic GN
Inflammatory bowel diseaseOther autoimmune diseasesInfectionDrugs
positive pANCA by IIFpositive anti-MPO by ELISA
positive pANCA by IIFnegative anti-MPO by ELISApANCA
GPA (Wegener’s) Microscopic polyangiitis EGPA (Churg-Strauss)
Case reports of associations
positive cANCA by IIFpositive anti-PR3 ELISA
positive cANCA by IIFnegative anti-PR3 ELISA
cANCA
Can (+) ANCA diagnose granulomatosis with polyangiitis (Wegener’s) ?
Usually no – biopsy still required in most people
Do high ANCA levels indicate active vasculitis ?
Key Issues Regarding ANCA
Clinical Applications
Pathophysiology
Are ANCA pathogenic or an epiphenomenon ?
Unclear some in vitro and in vivo data support pathogenicitythere are also important contradictions in human disease
Levels are higher overall in people with active disease but are not reliable in assessing disease activity in the individual patient
NecrosisGranulomatous inflammationSmall vessel vasculitis
focal, segmental, crescentic, necrotizing GNfew to no immune complexes (Pauci-immune glomerulonephritis)
cANCA (anti-PR3) - found in 75-90% of patients
Diagnosis
Sinus and Lung biopsies
Kidney biopsy
Diagnosis
Can suggest GPA Should generally not be used for diagnosis
Granulomatosis with polyangiitis (Wegener’s)
• Untreated disease – median survival time 5 monthsMortality from pulmonary or renal failure
• 80% survival with treatment• Relapse occurs in 50%
Prednisone + cyclophosphamide (CYC)Give CYC for 3-6 months then transition to a less toxic medication (usually azathioprine or methotrexate)
TreatmentOutcomeTreatmentOutcome
For severe disease:
For non-severe disease:Prednisone + methotrexate
Prednisone + rituximab (Stone et al. NEJM 2010; Specks et al. NEJM 2013)
OR
Granulomatosis with polyangiitis (Wegener’s)
Separated from PAN in 1994
Vasculitis of small vessels with few to no immune deposits Frequently affects the glomerulus and pulmonary capillaries
Many similarities to granulomatosis with polyangiitis (Wegener’s)• small vessel disease• high frequency of ANCA• pulmonary hemorrhage and glomerulonephritis• differs in lacking granulomatous inflammation
DiagnosisEpidemiologyMicroscopic Polyangiitis
Microscopic Polyangiitis Clinical Manifestations
Clinical Manifestations
pulmonary – alveolar hemorrhage renal – glomerulonephritis
Other prominent sites of involvementnerveskin
Small vessel vasculitis
focal, segmental, crescentic, necrotizing GNfew to no immune complexes (Pauci-immune Glomerulonephritis)
pANCA (anti-MPO) - found in 50-80% of patients
Diagnosis
Lung biopsies
Kidney biopsy
Diagnosis
Can suggest MPA Should generally not be used for diagnosis
Microscopic Polyangiitis
• Like GPA (Wegener’s) - poor outcome if untreatedMortality from pulmonary or renal failure
• 75% 5-year survival with treatment• Relapse occurs in at least 35%
TreatmentOutcomeTreatmentOutcomeMicroscopic Polyangiitis
Prednisone + cyclophosphamide (CYC)Give CYC for 3-6 months then transition to a less toxic medication (usually azathioprine or methotrexate)
For severe disease:
For non-severe disease:Prednisone + methotrexate
Prednisone + rituximab (anti-CD20)OR
Vasculitis of small to medium-sized vessels
Eosinophilic and granulomatous inflammation of the respiratory tract
Eosinophilic GranulomatosisWith Polyangiitis (Churg-Strauss)
Uncommon – affects 3 people per million
Men = Women
DiagnosisEpidemiology
Prodromal phase: asthma, allergic rhinitis
Eosinophilic phase: peripheral eosinophiliaeosinophilic tissue infiltrates
Thought of as having 3 phases(Helpful conceptually but - not seen in all patients
- often do not occur in sequence)
Vasculitic phase: nerveskinlungGI tractheart
Clinical Manifestations
Clinical Manifestations
Eosinophilic GranulomatosisWith Polyangiitis (Churg-Strauss)
Biopsy:
Diagnosis
Eosinophilic tissue infiltratesExtravascular “allergic granuloma”Small vessel vasculitis
ANCA associated in ~40% of patientsusually pANCA (anti-MPO)
Diagnosis often based on clinical features: asthma, hypereosinophilia, clinical manifestations consistent with vasculitis
Often difficult to demonstrate
DiagnosisEosinophilic GranulomatosisWith Polyangiitis (Churg-Strauss)
Prednisone alone: can be used in many instances
Severe disease: prednisone + cyclophosphamide
• Vasculitic relapses occur in 26%• Asthma relapses are common - may limit ability to taper prednisone
Cardiac involvement main cause of patient mortality
• Prognosis influenced by factors of severe disease (GI, renal, cardiac, CNS)
TreatmentOutcomeTreatmentOutcome
Eosinophilic GranulomatosisWith Polyangiitis (Churg-Strauss)
Affects predominantly children75% occur before the age of 8 years
2/3 of patients report an antecedent respiratory infection
Small vessel vasculitis
Immune complex - IgA deposits
IgA Vasculitis (Henoch-Schönlein) DiagnosisEpidemiology
• palpable purpura
• arthritis
• glomerulonephritis
• GI involvement (intussusception)
4 cardinal manifestations:
Clinical Manifestations
Clinical Manifestations
From: Churg and Churg. Systemic Vasculitis
IgA Vasculitis (Henoch-Schönlein)
Diagnosis established by the pattern of clinical manifestations
Biopsies (usually not required)
SkinLeukocytoclastic small vessel vasculitis
(+) IgA deposits
DiagnosisDiagnosis
From: Churg and Churg. Systemic Vasculitis
KidneyMesangial proliferationSegmental, crescentic glomerulonephritis
(+) IgA often IgG, C3Prognostic utility
IgA Vasculitis (Henoch-Schönlein)
• 1-3% disease related mortality• Relapses occur in 40%, usually within first 3 months• ESRD – 2-5% in children, may be up to 13% in adults• adults may have more severe disease
Treatment rarely required - typically self-limited
Prednisonemay reduce arthritis, abdominal discomfort, risk of intussusception
Prednisone + cytotoxic therapyconsider for active glomerulonephritis with renal function loss
TreatmentOutcomeTreatmentOutcome
IgA Vasculitis (Henoch-Schönlein)
Cryoglobulinemic Vasculitis
Small vessel vasculitis with cryoglobulin immune deposits
Cryoglobulin – cold-precipitable monoclonal or polyclonal immunoglobulin
Can occur in conjunction with a variety of disease processesPlasma cell or lymphoid neoplasms (myeloma)Chronic infectionConnective tissue diseases
Majority of cases of cryoglobulinemic vasculitis related to HCV
DiagnosisEpidemiology
Cryoglobulinemic Vasculitis
Palpable purpura
Arthritis
Neuropathy
Glomerulonephritis
occurs in 10-50%proteinuria, hematuriararely rapidly progressive
Clinical Manifestations
Clinical Manifestations
DiagnosisCryoglobulinemic Vasculitis
(+) cryoglobulins - are difficult to measure(+) rheumatoid factor(+) hepatitis C (if negative search for other causes)Hypocomplementemia
Laboratories:
Diagnosis
Diagnosis is usually clinical combining:- compatible clinical findings- laboratory features supportive of cryoglobulinemia- when possible an underlying cause
BiopsiesMay be useful in selected settings
Cryoglobulinemic Vasculitis
Biopsies
Skin
From: Churg and Churg. Systemic Vasculitis
DiagnosisDiagnosis
Kidney
Membranoproliferative glomerulonephritisAcellular intraluminal protein (cryoglobulins), (+) immunofluorescence
Cryoglobulinemic Vasculitis
Treat underlying processHepatitis C-associated – anti-viral therapy
Immunosuppressive therapyanecdotal experience only – may increase hepatitis C viremia
Plasmapheresis brief responses but not a long-term option
• improvement in vasculitis is associated with clearance of viremia• Relapse typically occurs with return of viremia
TreatmentOutcomeTreatmentOutcome
For HCV-associated cryoglobulinemic vasculitis:
Rituximab (anti-CD20)targets clonal/oligoclonal B cells producing pathogenic RFbenefit demonstrated from multiple trials
Small vessel vasculitis of the skin - most common vasculitic manifestation
Leukocytoclasis: nuclear disruptionManifests clinically: palpable purpura
Cutaneous Vasculitis
> 70% occur in the setting of an underlying process:medicationinfectionmalignancyconnective tissue diseaseheralding feature of a primary systemic vasculitis
When no cause found: idiopathic cutaneous vasculitis
Treatment: Treat/remove underlying disease/exposure when presentIdiopathic: use least toxic yet effective regimen
Cutaneous Vasculitis
Consists of two key elements:• Clinical manifestations of urticaria• Histology: leukocytoclastic vasculitis, largely involving postcapillary venules
Skin lesions differ from common urticaria:• Wheals may have a central dark or red appearance• Lesions last > 24 hours • Often resolve with residual hyperpigmentation• Typically painful with a burning/stinging sensation• Pruritis less common than true urticaria
Can be associated with systemic features• Musculoskeletal (arthralgias, arthritis)• Pulmonary (COPD)• Renal• GI
Urticarial Vasculitis
Leukocytoclastic vasculitis
~80% will have (+) immunofluorescence: immunoglobulin, complement or fibrin
- around blood vessels- basement membrane zone of dermal-epidermal junction
Urticarial VasculitisHistology
Not specific for urticarial vasculitis and can be seen in SLE
From: Churg and Churg. Systemic Vasculitis
Most cases are idiopathic
Can be secondary to:• Monoclonal gammopathy• Neoplasia• Ultraviolet light sensitivity• Repeated cold exposure
Normocomplementemic urticarial vasculitis (NUV)
Hypocomplementemic urticarial vasculitis (HUV)
Most are secondary to:• Systemic lupus erythematosus• Sjögren’s syndrome• Serum sickness reaction• Neoplasia
HUVS
Complement – CH50, C3, C4, C1qTo conclusively state as normal - values should be repeated on2-3 occasions over several months of observation during both activity and quiescence
Urticarial Vasculitis
Urticarial VasculitisLaboratory Studies and Investigations
• Complement (CH50, C3, C4, C1q)• CBC with differential• Urinalysis• Chemistries• Hepatitis B and C serologies• ANA, anti-DNA, ENA• ANCA• RF and anti-CCP• SPEP• Cryoglobulins
Obtain in patients with a compatible clinical and histologic picture to detect hypocomplementemia and systemic features:
Consider other investigations as appropriate:• chest imaging• Skeletal radiographs in patients with joint pain• PFTs (to look for COPD)
• Urticarial vasculitis is the dominant feature• Angioedema occurs in 50% and can be the presenting feature• Moderate to severe COPD occurs in 50%• Ocular inflammation (uveitis) occurs in 30%• Can get glomerulonephritis• Many features resemble SLE (some propose it is a subset of SLE)
Labs• C3, C4 can be undetectable to low normal• C1q low in all patients when disease is active• Anti-C1q antibodies (C1q precipitins) detectable in all patients• Anti-DNA and anti-Sm are uncommon
Specific autoimmune disorder that involves > 6 months of urticaria with hypocomplementenia in the presence of systemic findings
Clinical features
Urticarial VasculitisHypocomplementemic Urticarial Vasculitis Syndrome (HUVS)
• Urticaria for more than 6 months • Hypocomplementemia
Major criteria (both must be present)
Minor criteria (must have 2 or more)
• Venulitis of the dermis (established via biopsy) • Arthralgia or arthritis • Mild glomerulonephritis • Uveitis or episcleritis • Recurrent abdominal pain • Positive C1q precipitin test with a suppressed C1q level
Urticarial VasculitisHypocomplementemic Urticarial Vasculitis Syndrome (HUVS)
Diagnostic criteria (Schwartz et al. Mayo Clin Proc 1982;57:231)
Treat underlying disease if one is present
For cutaneous lesions, variable efficacy:• Prednisone• Hydroxychoroquine• Dapsone• Colchicine
For severe systemic disease:• Systemic immunosuppression may be required
For HUVS• Treatment as above for cutaneous or systemic disease • Some series have shown stabilization with cyclosporin• COPD often presents significant challenges
Urticarial VasculitisTreatment
Concise references:Primer on Allergic and Immunologic Diseases Harrison’s Textbook of Internal Medicine
Detailed references: Hoffman et al. Inflammatory Diseases
of Blood Vessels 2nd Ed, 2012.
For more information on vasculitis:
Questions regarding a vasculitis patient
Carol A. Langford, MD MHS [email protected]
Highlight important aspects of vasculitic disease that may appear on Allergy Board exams or in Allergy clinical practice
Goal
This summary is not all encompassing:Recognize
Vasculitis - Conclusion
Other rare forms of vasculitis The vasculitides are complex diseases