harold c. schott chair director, center for vasculitis

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

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

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

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

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 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

Often presents acutely

Constitutional features

Gastrointestinal tract

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

ischemia, infarction

angina, MI

Biopsy

DiagnosisPolyarteritis Nodosa

Necrotizing inflammation of medium or small arteriesabundant neutrophils and fibrinoid changes

Diagnosis

Arteriogram

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

• 80% estimated 5 year survival with treatment• Relapses occur in 15-30%

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

affected in 95% of patients

Granulomatosis with polyangiitis (Wegener’s)

affected in 85%

Pulmonary nodulesinfiltrates

Cavitary lesions Pulmonary hemorrhage

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:

Organ triad:sinus lung kidney

Multisystem disease

Can also affect:

jointeyeskinnerveother sites

• 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)

MyeloperoxidaseProteinase -3

cANCA cytoplasmic staining

pANCAperinuclear staining

TargetAntigens

In Vasculitis

Indirect Immunofluorescence

(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

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

• 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)

For severe disease:

For non-severe disease:Prednisone + methotrexate

Prednisone + rituximab (Stone et al. NEJM 2010; Specks et al. NEJM 2013)

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

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

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

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)

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:

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

KidneyMesangial proliferationSegmental, crescentic glomerulonephritis

(+) IgA often IgG, C3Prognostic utility

• 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

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

Palpable purpura

Arthritis

Neuropathy

Glomerulonephritis

occurs in 10-50%proteinuria, hematuriararely rapidly progressive

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

Biopsies

DiagnosisDiagnosis

Kidney

Membranoproliferative glomerulonephritisAcellular intraluminal protein (cryoglobulins), (+) immunofluorescence

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

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

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

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 216-445-6056langfoc@ccf.org

Highlight important aspects of vasculitic disease that may appear on Allergy Board exams or in Allergy clinical practice

This summary is not all encompassing:Recognize

Vasculitis - Conclusion

Other rare forms of vasculitis The vasculitides are complex diseases

harold c. schott chair director, center for vasculitis

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