Vasculitis Review

VASCULITISREVIEW

Vasculitis Clinicopathologic process characterized by

inflammation and necrosis of blood vessels

PATOGENESIS

Causes of Vasculitis Infections Drugs diseases associated with immune

complexes • connective tissue diseases• inflammatory bowel disease• malignancy

Idiopathic

INFECTIONS Virus

• hepatitis B, hepatitis C, HIV, CMV, parvovirus B19

Bacteria• Examples

• group A β-haemolytic streptococci– HSP

• Superantigen of S.aureus– Kawasaki disease (TSST-1), WG

Fungai

classification

classification Small vessel vasculitis Medium-sized vessel vasculitis Large vessel vasculitis

•Small vessels •capillaries, arterioles, venules

•medium- sized vessels •such as visceral vasculature, including renal, coronary or hepatic arteries

• large vessels •aorta and its great vessels

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Proposed working classification of vasculitis

Small vessel vasculitis•Cutaneous small vessel vasculitis - not further classified•Henoch–Schönlein purpura•Essential mixed cryoglobulinaemia•Waldenström’s hypergammaglobulinaemic purpura•Associated with collagen vascular disease•Urticarial vasculitis•Erythema elevatum diutinum•Eosinophilic vasculitis•Rheumatoid nodules•Reactive leprosy•Septic vasculitis

Larger vessel vasculitisPolyarteritis nodosa

Microscopic polyarteritisCutaneous form Systemic form

Granulomatous vasculitis• Wegener’s granulomatosis• Allergic granulomatosis of Churg and Strauss• Lymphomatoid granulomatosisGiant cell arteritis• Temporal arteritis• Takayasu’s arteritisLarger vessel vasculitis with collagen vascular diseaseNodular vasculitis

Cont,

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

leukocytoclastic vasculitis skin vasculitis with palpable purpura is

typically a major finding

Biopsy of these lesions reveals inflammation of the small blood vessels, most prominent in the postcapillary venules

Clinical features palpable purpura

• macular in the early stages• may progress to papules, nodules, vesicles,

plaques, bullae or pustules• secondary findings - ulceration, necrosis and

post-inflammatory hyperpigmentation oedema

livedo reticularis urticaria

ankles and lower legsSites

symptoms

often asymptomatic pruritus pain burning

systemic symptoms relatively uncommon fever, arthralgia, myalgia and anorexia. presence of symptoms affecting other organ

systems should raise the suspicion of other vasculitides such as:- • HSP• mixed cryoglobulinaemia• Small vessel vasculitis associated with PAN or

with WG.

Course resolve within several weeks or

a few months recurrent disease at intervals up

to years• 10%

Histology:

Neutrophils • enter the walls of small venules

Nuclear dust • small fragments of nuclear debris are

present Fibrin

Neutrophils and nuclear dust

Fibrin

Direct immunofluorescence

IgM, IgG, c3 within vascular walls

IgA in HSP

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Henoch-Schönlein purpuraIgA. Deposits Mostly in children

Tetrad

Typical sites

HSP Course & Prognosis

• majority of patients fully recover within several weeks or months

chronic • 5–10% of patients

Renal involvement • Common 40–50%• Haematuria, Proteinuria• progress to end-stage renal disease 1–3%• major factor determining the long-term

morbidity and mortality

IgA- pivotal part in HSP

Serum IgA • 50% with active disease

IgA immune complexes Deposition of IgA

• in blood vessel walls• renal mesangium

Henoch-Schönlein purpura

Less common manifestations• Orchitis (10–20% of boys), intussusception,

pancreatitis, neurological abnormalities, uveitis, carditis and pulmonary haemorrhage

evidence for streptococcal Infection 30%

Urticarial vasculitis

Lesions differ from those of simple urticaria• lesions persist for more than 24 h• often demonstrate purpura• symptoms of burning (rather than itch)

• Biopsy- vasculitis• post-inflammatory pigmentation

lesions persisting for more than 24 h

Associations of urticarial vasculitis

connective tissue diseases • SLE • Sjögren’s syndrome

Other diseases• hepatitis B or C• IgM or IgA gammopathies• serum sickness • colonic cancer

Drug ingestion Physical stimuli

• Exercise, UV light ,cold

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

WEGENER’S GRANULOMATOSIS

triad

ANCA association

cutaneous manifestations palpable purpura

• most common cutaneous manifestation Oral ulcers

• second most common other skin lesions

• subcutaneous nodules, papules, vesicles, petechiae, ulcers or pyoderma gangrenosum like lesions.

A pyoderma gangrenosum-like irregular ulceration jagged and undermined borders is often the first manifestation of Wegener’s gramulomatosis

WEGENERS’ GRANULOMATOSIS

•strawberry gums•Lesion on anterior nares

A large ulcer on the palate covered by a dense, adherent, necrotic masssimilar lesions occur in the sinuses and tracheobronchialtree.

strawberry gums

Upper Respiratory• rhinorrhea • severe sinusitis• nasal mucosa

ulcerations• Epistaxis• Otitis

Respiratory • Cough, Hemoptysis• Pulmonary infiltrates

Renal • hematuria• red cell and other

casts • proteinuria• Renal biopsy

• crescentic glomerulonephritis

General• Fever, Weight loss• Arthralgia/arthritis

"saddle nose" deformity

Investigations C-ANCA 80 %

chest X-ray Renal biopsy Other

• elevated ESR and CRP, anaemia, leukocytosis and positive rheumatoid factor

c-ANCA

WG• 80 %

MPA 1/3 CSS 20% necrotizing and crescentic GN 1/3

ANCA Positive infections

• malaria, HIV connective tissue disorders

• SLE, rheumatoid arthritis GIT

• IBD, chronic autoimmune liver and biliary tract disease

some apparently healthy individuals.

Mostly P-ANCA or atypical ANCA

Perinuclear staining (p-ANCA) • nonspecific• No link with disease activity• frequently seen in patients with other

vasculitic syndromes • SLE

ANCA C-ANCA

• cytoplasmic staining P-ANCA

• perinuclear and/or nuclear staining Atypical ANCA (a-ANCA)

• various patterns

classified, according to their IIF pattern on ethanol-fixed neutrophils

Immunoglobulin•IgG mostly•IgM / IgA rarely

C-ANCA patternheavy staining in the cytoplasm while the multilobulated nuclei (clear zones) are nonreactive

P-ANCA patternStaining is limited to the perinuclear region and the cytoplasm is nonreactive

Wegener’s granulomatosis Histologically

the cutaneous lesions may demonstrate a leukocytoclastic vasculitis with or without granulomatous inflammation

WEGENERS’ GRANULOMATOSIS

•Perivascular lymphocytic infiltrate•Necrotizing leukocytoclastic small vessel vasculitis •granulomatous inflammation

ACR criteria Nasal or oral inflammation

• oral ulcers • purulent or bloody nasal discharge

Abnormal chest radiograph • nodules• fixed infiltrates• cavities.

Abnormal urinary sediment • microscopic hematuria • red cell casts

Granulomatous inflammation on biopsy of an artery or perivascular area.

Prognosis• Without treatment

• almost uniformly fatal • 2 year survival - 10%• mean survival of 5 months

• With aggressive treatment,• survival improved to 75-90% at 5

years

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Churg-Strauss arteritis ( allergic granulomatosis )

classically involves the arteries of the lung and skin

Clinical signs:• allergic rhinitis • asthma• eosinophilia• systemic vasculitis

•Palpable purpura•Macular/papular erythematous rash •Hemorrhagic lesions•Tender cutaneous /subcutaneous nodules•livedo reticularis•new-onset Raynaud’s

Skin lesions

D/D WG/CSS Features of CSS

• lack of upper respiratory involvement • lack of severe glomerulonephritis• asthma • Eosinophilia• involvement of the GIT, spleen and heart, in

contrast with the strong association with renal disease in patients with WG.

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Microscopic polyangiitisSyn: Microscopic polyarteritis nodosa

Microscopic polyarteritis

systemic vasculitis affecting blood vessels ranging in size from capillaries to medium-sized arteries

strongly associated with :-• lung involvement

• (primarily alveolar haemorrhage) • necrotizing glomerulonephritis

P-ANCA commonly positive cANCA may be positive palpable purpura

absence of granulomatous inflammation or asthma suggests MPA instead of CSS or WG

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Cryoglobulinaemic vasculitis

Small and medium sized vessels are affected• mainly in skin and kidneys  

presence of cryoglobulins• serum proteins that precipitate in the cold and

dissolve upon rewarming. • Cryoglobulins typically are composed of a

mixture of immunoglobulins and complement components.

Causes hepatitis C virus

• most commonly(80–90%) SLE Myeloproliferative disorders chronic infections

Cryoglobulinaemic vasculitis Palpable purpura Polyarteritis-like dermal nodules Raynaud’s phenomenon cold aggravation of the

vasculitis lesions Livedo acrocyanosis bullae necrosis ulceration

Glomerulonephritis Arthralgia migratory myalgia

Diagnosis• Cryoproteins• antibodies to HCV• Low complement• ANA• RA factor• Band on electrophoresis

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Polyarteritis nodosa Typically affects medium-sized

arteries• occasional involvement of small arteries

Association with HBV No glomerulonephritis No lung parenchymal involvement Not typically associated with ANCA

Polyarteritis nodosacutaneous manifestations 40% of patients usually a subcutaneous nodule or

group of nodules along the course of a blood vessel.

Typically seen around the knee, anterior lower leg and dorsum of the foot• 5–10-mm nodules may be tender, pulsatile or

secondarily ulcerated

Livedo reticularis –with or without ulceration

digital gangrene ‘punched-out’ ulcers purpura, urticaria,

subcutaneous hemorrhages

Other cutaneous feature

POLYARTERITIS NODOSAErythematous nodular lesion along vessels more prominent on lower limbs

Systemic features Constitutional

– fever, weight loss, arthralgia and malaise

kidneys • infarctions and ischaemic• nephropathy lead to hypertension and renal failure

heart • angina, myocardial infarction

gut • ischaemia, bleeding, perforation • infarction, presenting as abdominal pain

Misc• Orchitis• mononeuritis multiplex

ETIOLOGY Idiopathic most cases HBV infection

• particularly in patients with a history of intravenous drug abuse

Other viruses • hepatitis C, parvovirus B19, HIV,VZV

Other associations• streptococcal infection, SLE, IBD, malignancies,

particularly hairy cell leukemia, Minocycline, familial Mediterranean fever and Cogan’s syndrome

Vasculitis Mostly at branch points of medium sized arteries

microaneurysms

nodose swellings

may rupture

luminal thrombosis and obliteration

distal tissue ischaemia and necrosis

Investigations HbsAg P-ANCA 20% Routine investigation

• CRP / ESR (useful for monitoring disease activity)• leukocytosis with neutrophilia, thrombocytosis• haematuria, proteinuria

Tissue biopsy• Skin, affected muscle or nerve

Angiography• hepatic, renal, splanchnic and splenic circulations • most reliable method of demonstrating the aneurysms,

stenoses and abnormal vessels

Renal arteriogram

abrupt cutoffs of small arteries

microaneurysms

Histopathology inflammatory necrotizing and

obliterative panarteritis that attacks the small and medium-sized arteries• Infiltrate neutrophil-rich initially• subsequently mononuclear cells are

predominant

No granulomas

Left panel: Involvement of a single small artery in the subcutis by a necrotizing vasculitis which is neutrophilic rich at its inception and then evolves into a predominance of mononuclear cells. Right panel: Inflammatory infiltrate in the adventitia with marked necrosis and fibrin deposition of the vascular wall.

•diffuse inflammation of the adventitia • marked thickening of the inner layers by loose connective tissue (arrows). •The lumen (L) is significantly narrowed.

Prognosis

• Expected course of untreated polyarteritis nodosa is poor

• Untreated--5 year survival rate 13% • Steroid treatment may increase

percentage survival rate to 50-80%• Renal and GI signs most serious

prognostic factors

major causes of death

Renal failure mesenteric, cardiac, or cerebral

infarction

ACR criteria Otherwise unexplained

weight loss > 4 kg Livedo reticularis Testicular pain or tenderness Myalgias

• excluding that of the shoulder and hip girdle, weakness, or polyneuropathy

Mononeuropathy or polyneuropathy

New onset diastolic blood pressure

Elevated blood urea or creatinine

Evidence of hepatitis B virus infection

Characteristic arteriographic abnormalities

biopsy of small- or medium-sized artery containing polys

Cutaneous polyarteritis nodosa absence of visceral involvement Cutaneous findings

• similar to those described for the systemic form

Diagnosis of exclusion Treatment

• aspirin, prednisone,. Penicillin.

Cutaneous polyarteritis nodosa

Erythematous lesions on the leg

Cutaneous polyarteritis nodosa

Nodules and ulceration Livedo of legs

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Kawasaki disease

Kawasaki disease   arteritis of large, medium, and small arteries,

particularly the coronary arteries. usually occurs in children often associated with a mucocutaneous lymph

node syndrome exanthem it causes is not vasculitic. Treatment

• intravenous immunoglobulin (IVIG) and aspirin 

skin lesions Polymorphic skin lesions

• urticarial• morbilliform• maculopapular• erythema-multiforme-like patterns• pustules on knees or buttocks• scarlatina-like erythroderma

Swollen Hands and feet Palmoplantar erythema

• subsequent desquamation.

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Giant cell arteritis (temporal arteritis)• inflammation most prominently involves the

cranial branches of the arteries originating from the aortic arch

•painfull arteritis•location: temporal•Headache,swelling, •may progress and affect eye•Over 50 years•Polymyalgia Rheumatica

ACR classification criteriaGiant cell arteritis (temporal arteritis)

Age ≥ 50 years at time of disease onset Localized headache of new onset Tenderness or decreased pulse of the temporal artery ESR greater than 50Biopsy (that includes an artery)

necrotizing arteritis with predominance of mononuclear cells or granulomatous process with multinucleated giant cells

Prednisolone 40–60 mg daily should be started as soon as the diagnosis is suspected

Chapel Hill Consensus Conference classification Small vessel vasculitis

Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia

Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Takayasu arteritis 

• primarily affects the aorta and its primary branches.

• extremities become cool, and pain develops with use (arm or leg claudication).

• Skin lesions- 1/3• resembling erythema nodosum or pyoderma

gangrenosum found over the legs• vasculitis of small vessels on biopsy

(Pulseless disease)

Hypertension is a common presenting feature

– Renal artery stenosis,– increased arterial stiffness and – increased sensitivity of the carotid sinus

reflex

blood pressure should be recorded in all four limbs

ACR classification criteriaAge at disease onset ≤ 40 years Claudication of the extremities Decreased pulsation of one or both brachial arteries Difference of systolic blood pressure at least 10 mmHg in between the arms Bruit

over one or both subclavian arteries or abdominal aorta

Arteriographic narrowing or occlusion entire aorta/its primary branchesor large arteries in the proximal upper or lower extremities,

at least three of the six criteria

Takayasu arteritis

Evaluation of vasculitis

Evaluation of vasculitis Aims & Objective

Evaluation of vasculitis clinical diagnosis

• Purpura, livedo, cutaneous necrosis, and purple toe syndrome etc• smaller vessel involvement

– palpable purpura • in dependent areas, typically the ankles

and lower legs• Medium vessel vasculitis

– Nodules raise suspicion– Livedo reticularis – multiple sites of peripheral gangrene

histopathological confirmation• Punch biopsy• Deeper elliptical Incisional biopsy

- should be performed for suspected larger vessel vasculitides

assessment of the extent of the disease General. Myalgia, arthralgia, fever Renal. Proteinuria, haematuria Gastrointestinal. Abdominal pain,

gastrointestinal bleeding Pulmonary. Pleural effusion, pleuritis Nervous system. Central or peripheral, diffuse or

localized Musculoskeletal. Non-erosive polyarthritis Cardiac. Pericardial effusion

establish an underlying aetiology

Medications Infections Diseases associated with immune

complexes• connective tissue diseases• malignancy• inflammatory bowel disease

VASCULITIS Diagnostic approach

History

Drugs H/O Hepatitis B or C H/O underlying disease

• SLE H/O Systemic complaints

Physical examination

to determine • extent of vascular lesions• distribution of affected organs• `presence of additional disease

Basic laboratory analysis Blood CP/ESR urinalysis CRP serum creatinine LFTs hepatitis serologies Tissue biopsy IF studies chest x-ray

Blood culture(if pyrexial)

ASO titre ANA Complement ANCA ECG

Other investigations (When indicated)

muscle enzyme Cryoglobulins PFTs CSF CNS imaging biopsies of artery, kidney, lung or nerve Electromyography Arteriography

• aortic arch or visceral vessels

baseline tests for possible corticosteroid or immunosuppressive therapy

Glucose G-6-PD status (dapsone)

TREATMENT

Treatment LCCV

General measures• Remove triggering

agent• Minimize stasis• compression stocking • elevation of dependent

areas Symptomatic

• NSAIDs• Antihistamines

Oral Steroids• 30–80 mg once daily • tapered over 2–3 weeks

Colchicine• 0.6 mg twice daily

Dapsone Other modalities

• Azathioprine• Cyclophosphamide • Ciclosporin • Methotrexate• Biological agents

– Infliximab – Rituximab

•usually self-limiting

oral antihistamines systemic corticosteroids

• 1 mg/kg/day for 2 weeks• tapering over a further 2 weeks• effective in abdominal pain

arthritis, mild nephritis dapsone

• 100–200 mg once daily• shorten the duration of HSP• Improves skin lesions

colchicine • 0.6 mg twice to three times daily

hydroxychloroquine• 200 mg once to twice daily

mycophenolate mofetil • 2 g once daily

Renal disease high-dose corticosteroids

• either alone or with cyclophosphamide

Pulse steroid therapy• Followed by oral steroid and

immunosuppressants

HSPfrequently self-limitingSupporting treatment mostly

Urticarial vasculitis Systemic corticosteroids Dapsone Colchicine Antihistamines

• control of angio-oedema urticaria-like lesions in addition to above modalities

Mild• Prednisolone alone (1mg/kg per day)

Moderate/Severe• Prenisolone plus Cyclophophmide (1.5 to 2 mg per kg)

Life threatening/Intolerance to oral• Intravenous methylprednisolone be given initially for

three days, followed by the oral prednisone• 12 pulses of cyclophosphamide every 2 weeks for the first

three pulses and thereafter monthly PAN with HBV

• combination of antiviral and immune suppressing drugs

PAN

TREATMENT

Prednisone – • given initially in high doses (60-100 mg/day). • After initial 2-4 weeks may be tapered to alternate-

day regimen. • Then gradually discontinued over 2-6 months in

most patients, depending on clinical course.

Wegener’s granulomatosis

TREATMENT Cyclophosphamide – orally In stable patient

– may be started at 2 mg/kg/day orally.– Dosage may need to be adjusted, based on patient

response and toxicity (usually bone marrow suppression).

IV in critically ill patient• initially at a dose of 4 mg/kg/day IV for 2-3 days,

then continued at 2 mg/kg/day orally.

Cryoglobulinaemic vasculitis Treatment of underlying cause Treatment of HCV-associated

• Pegylated interferon-α with ribavirin• usual initial choice

• immunosuppressive agents • avoided, or relatively non-aggressive therapy can be

used (low-dose corticosteroids or Colchicine)• Place in glomerulonephritis

• Rituximab• Plasmapheresis