VASCULITIS

REVIEW

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 -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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus arteritis

Proposed working classification of vasculitis

Small vessel vasculitis

Cutaneous small vessel vasculitis - not further classified HenochSchnlein purpura Essential mixed cryoglobulinaemia Waldenstrms hypergammaglobulinaemic purpura Associated with collagen vascular disease Urticarial vasculitis Erythema elevatum diutinum Eosinophilic vasculitis Rheumatoid nodules Reactive leprosy Septic vasculitis

Cont, Larger vessel vasculitis Polyarteritis nodosa Microscopic polyarteritis Cutaneous form Systemic form Granulomatous vasculitis Wegeners granulomatosis Allergic granulomatosis of Churg and Strauss Lymphomatoid granulomatosis Giant cell arteritis Temporal arteritis Takayasus arteritis Larger vessel vasculitis with collagen vascular disease Nodular vasculitis

Chapel Hill Consensus Conference classification

Small vessel vasculitis Cutaneous leukocytoclastic vasculitis HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus 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

Sites ankles and lower legs

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

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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus arteritis

Henoch-Schnlein purpura
Tetrad Mostly in children IgA. Deposits

Palpable purpura
Abdominal pain

Arthritis/ arthralgia

Renal disease

Typical sites

HSP

Course & Prognosis

majority of patients fully recover within several weeks or months

chronic
510% of patients

Renal involvement
Common 4050% Haematuria, Proteinuria progress to end-stage renal disease 13% 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-Schnlein purpura
evidence for streptococcal Infection 30%

Less common manifestations

Orchitis (1020% of boys), intussusception, pancreatitis, neurological abnormalities, uveitis, carditis and pulmonary haemorrhage

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 Sjgrens 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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus arteritis

WEGENERS GRANULOMATOSIS

triad
Glomerulonephritis

Granulomatous inflammation

of upper & lower resp tract

ANCA association

Systemic small vessel vasculitis

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 Wegeners gramulomatosis

WEGENERS GRANULOMATOSIS

strawberry gums Lesion on anterior nares

A large ulcer on the palate covered by a dense, adherent, necrotic mass

similar lesions occur in the sinuses and tracheobronchial tree.

strawberry gums

Upper Respiratory
rhinorrhea severe sinusitis nasal mucosa ulcerations Epistaxis Otitis

Renal
hematuria red cell and other casts proteinuria Renal biopsy
crescentic glomerulonephritis

Respiratory
Cough, Hemoptysis Pulmonary infiltrates

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

Mostly P-ANCA or atypical ANCA

infections
malaria, HIV

connective tissue disorders

SLE, rheumatoid arthritis

GIT
IBD, chronic autoimmune liver and biliary tract disease

some apparently healthy individuals.

 Perinuclear

staining (p-ANCA)

nonspecific
No link with disease activity

frequently seen in patients with other vasculitic syndromes SLE

ANCA

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

C-ANCA
cytoplasmic staining

P-ANCA
perinuclear and/or nuclear staining

Atypical ANCA (a-ANCA)

various patterns
Immunoglobulin IgG mostly IgM / IgA rarely

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

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

Wegeners 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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus arteritis

Churg-Strauss arteritis

( allergic granulomatosis )

classically involves the arteries of the lung and skin Skin lesions Clinical signs: Palpable purpura
allergic rhinitis asthma eosinophilia systemic vasculitis
Macular/papular erythematous rash Hemorrhagic lesions Tender cutaneous /subcutaneous nodules livedo reticularis new-onset Raynauds

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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus arteritis

Microscopic polyangiitis
Syn: 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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus 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(8090%)

SLE Myeloproliferative disorders chronic infections

Cryoglobulinaemic vasculitis
Palpable

purpura

Polyarteritis-like dermal nodules Raynauds 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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus 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 nodosa cutaneous 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
510-mm nodules may be tender, pulsatile or secondarily ulcerated

Other cutaneous feature

Livedo digital

reticularis

with or without ulceration

gangrene

punched-out ulcers

purpura,

urticaria, subcutaneous hemorrhages

POLYARTERITIS NODOSA
Erythematous 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 Cogans syndrome

Vasculitis
Mostly at branch points of medium sized arteries nodose swellings

microaneurysms

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
microaneurysms

abrupt cutoffs of small arteries

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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus 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 HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus 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

Giant cell arteritis (temporal arteritis)

ACR classification criteria

Age 50 years at time of disease onset Localized headache of new onset Tenderness or decreased pulse of the temporal artery ESR greater than 50 Biopsy (that includes an artery) necrotizing arteritis with predominance of mononuclear cells or granulomatous process with multinucleated giant cells
Prednisolone 4060 mg daily should be started as soon as the diagnosis is suspected

Chapel Hill Consensus Conference classification

Small vessel vasculitis Cutaneous leukocytoclastic vasculitis HenochSchnlein purpura Wegeners granulomatosis ChurgStrauss syndrome Microscopic polyangiitis Essential cryoglobulinaemia

Medium-sized vessel vasculitis

Classic polyarteritis nodosa Kawasaki disease

Large vessel vasculitis

Giant cell arteritis Takayasus arteritis

Takayasu arteritis

(Pulseless disease)

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

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 criteria

Age 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 branches or 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 clinical diagnosis H/P Confirmation

Find underlying cause

Find extent of disease

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

Physical exam

Investigations

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
usually self-limiting

Oral Steroids
3080 mg once daily tapered over 23 weeks

General measures
Remove triggering agent Minimize stasis compression stocking elevation of dependent areas

Colchicine
0.6 mg twice daily

Dapsone Other modalities

Azathioprine Cyclophosphamide Ciclosporin Methotrexate Biological agents

Symptomatic
NSAIDs Antihistamines

Infliximab Rituximab

HSP

frequently self-limiting Supporting treatment mostly

oral antihistamines systemic corticosteroids

1 mg/kg/day for 2 weeks tapering over a further 2 weeks effective in abdominal pain arthritis, mild nephritis

mycophenolate mofetil
2 g once daily

Renal disease

high-dose corticosteroids
either alone or with cyclophosphamide

dapsone
100200 mg once daily

Pulse steroid therapy

Followed by oral steroid and immunosuppressants

shorten the duration of HSP Improves skin lesions

colchicine
0.6 mg twice to three times daily

hydroxychloroquine
200 mg once to twice daily

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)

PAN

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

Wegeners granulomatosis

TREATMENT

Prednisone
given initially in high doses (60-100 mg/day). After initial 2-4 weeks may be tapered to alternateday regimen. Then gradually discontinued over 2-6 months in most patients, depending on clinical course.

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- 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