VASCULITIS

REVIEW

Vasculitis Clinicopathologic process characterized by

inflammation and necrosis of blood vessels

PATOGENESIS

classification

Vasculitis has been categorized by :- • predominant sizes of the blood vessels • presence or absence of antineutrophil

cytoplasmic antibodies (ANCA) • pattern of organ involvement• presence or absence of granulomas,

eosinophilic/ Lymphocytic infiltration

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

Small vessel vasculitis• Cutaneous leukocytoclastic vasculitis• Henoch–Schönlein purpura• Urticarial vasculitis• Wegener’s granulomatosis• Churg–Strauss syndrome• Microscopic polyangiitis (polyarteritis)• Essential cryoglobulinaemia• Vasculitis secondary to connective tissue disorders • Vasculitis secondary to viral infection• Eosinophilic vasculitis• Erythema elevatum diutinum• Rheumatoid nodules• Reactive leprosy• Septic vasculitis

Medium-sized vessel vasculitis• Polyarteritis nodosa

• Kawasaki disease

• Isolated CNS Vasculitis Large vessel vasculitis

• Giant cell arteritis

• Takayasu’s arteritis

Small vessel vasculitis

leukocytoclastic vasculitis

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 legs

Sites

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%

Aetiology idiopathic

• 50%

infection • 15–20%

collagen vascular disorders • 15–20%

medications • 10–15%

Malignancy • less than 5%

Histology:

Neutrophils enter the walls of small venules

small fragments of nuclear debris are present (nuclear dust).

Fibrin

Neutrophils and nuclear dust

Fibrin

Direct immunofluorescence

IgM, IgG, c3 within vascular walls

IgA in HSP

HENOCH-SCHÖNLEIN PURPURA

Henoch-Schönlein purpura

Tetrad• Palpable purpura • Arthritis/arthralgia • Abdominal pain • Renal disease

Less common manifestations• Orchitis, intussusception, pancreatitis,

neurological abnormalities, uveitis, carditis and pulmonary haemorrhage

Mostly in children

IgA. Deposits

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

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 or papular erythematous rash •Hemorrhagic lesions•Tender cutaneous or subcutaneous nodules

Skin lesions

WEGENER’S GRANULOMATOSIS

triad systemic small vessel vasculitis necrotizing granulomatous

inflammation of both the upper and lower respiratory tracts

glomerulonephritisusually associated with

ANCA

EPIDEMIOLOGY

Predominant age: • Mean age of onset in mid-40's

• has been described in all age groups

Predominant sex: • Male > Female (3:2)

Wegener’s granulomatosis

commonest initial manifestation• rhinorrhea

• severe sinusitis

• nasal mucosa ulcerations

• one or several nodules in the nose, larynx, trachea, or bronchi

Wegener’s granulomatosis Fever, weight loss and malaise occur The “strawberry gums” appearance

of hypertrophic gingivitis is characteristic

Nodules may appear in crops, especially along the extensor surface of the extremities

may later ulcerate

WEGENERS’ GRANULOMATOSIS

•strawberry gums•Lesion on anterior nares

Wegener’s granulomatosis

Focal necrotizing glomerulonephritis• 85%

Other organs frequently involved • joints• eyes • CNS

SIGNS & SYMPTOMS

• Pulmonary infiltrates (71%) • Sinusitis (67%) • Arthralgia/arthritis (44%) • Fever (34%) • Cough (34%) • Otitis (25%) • Rhinitis (22%)

SIGNS & SYMPTOMS

• Hemoptysis (18%) • Ocular inflammation (16%) • Weight loss (16%) • Skin rash (13%) • Epistaxis (11%) • Renal failure (11%) • Chest pain, anorexia, proptosis, dyspnea, oral

ulcers, hearing loss, headache (all < 10%)

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

A limited number of erythematous, purpuric, nonblanchable papules and nodules on the dorsa of fingers and hands; a few lesions have centralareas of infarction.

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

D/D from CSS

Features of CSS

• lack of upper respiratory involvement

• lack of severe glomerulonephritis• asthma • eosinophilia

c-ANCA

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

1/3

c-ANCA WG Sensitivity

• 66%

• 91% if only considering active disease Specificity

• 98%

Patients with WG who are negative for ANCA/anti-PR3 usually have positive P-ANCA/anti-MPO

non ANCA reactivity may well have localized WG and a better prognosis when compared with those who are ANCA-positive

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

• frequently seen in patients with other vasculitic syndromes

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/leucocytoclastic 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.

Complications Disease related

• Destructive nasal lesions with "saddle nose" deformity

• Deafness from refractory otitis

• Necrotic pulmonary nodules with hemoptysis

• Interstitial lung disease

Complications

• Renal failure

• Foot drop from peripheral nerve disease • Skin ulcers, digital and limb gangrene

from peripheral vascular involvement

Prognosis

• Without treatment, • almost uniformly fatal with 10% 2 year survival and mean survival of 5 months

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

MICROSCOPIC POLYANGIITIS

Microscopic polyangiitisMicroscopic polyarteritis nodosaMicroscopic polyarteritis

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

cANCA may be positive strongly associated with

• lung involvement • (primarily alveolar haemorrhage)

• crescentic glomerulonephritis

Microscopic polyangiitis

thought by some investigators to represent part of a clinical spectrum that includes Wegener's granulomatosis, since both are associated with the presence of ANCA and similar histologic changes outside the respiratory tract.

CRYOGLOBULINAEMIC VASCULITIS

Cryoglobulinaemic vasculitis  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.

most often due to hepatitis C virus infection. (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

VASCULITIS SECONDARY TO CONNECTIVE TISSUE DISORDERS

Vasculitis secondary to connective tissue disorders

lupus erythematosus rheumatoid arthritis relapsing polychondritis Behcet's disease

Vasculitis secondary to viral infection most commonly observed hepatitis

B and C may also be seen with

• HIV

• cytomegalovirus

• Epstein-Barr virus

• Parvovirus B19

Medium sized vessel vasculitis

Medium-sized vessel vasculitis• Polyarteritis nodosa

• Kawasaki disease

• Isolated CNS Vasculitis

POLYARTERITIS NODOSA

Polyarteritis nodosa

typically affects medium-sized muscular arteries

occasional involvement of small muscular arteries

Not typically associated with ANCA

Two major forms

systemic benign cutaneous

Organ involvement

PAN can affect virtually any organ, but has a striking tendency to spare the lungs

kidney, GI tract, skin, muscles, joints, genitourinary tract, peripheral and central nervous system, heart, testes, epididymis and ovaries

ETIOLOGY Idiopathic most cases HBV infection

• (particularly in patients with a history of intravenous drug abuse)

Other associations• Other viruses including HCV• SLE • IBD• hairy cell leukemia• Minocycline

Clinical features

• Fever • Weakness • Weight loss • Malaise • Myalgia • Arthralgia• Headache • Abdominal pain and vague discomfort

SIGNS & SYMPTOMS

• Renal - hypertension, hematuria (usually microscopic), proteinuria, progressive renal failure

• Musculoskeletal - myalgia, migratory arthralgia and arthritis

• Gastrointestinal - recurrent and severe pain, hepatomegaly, nausea, vomiting and bleeding

• CNS - seizures, CVA's, headache, papillitis, altered mental states

• Peripheral nervous system - mononeuritis multiplex (most often manifested as foot drop)

• Cardiac - pericarditis, CHF associated with hypertension and/or myocardial infarction

• Genitourinary - usually asymptomatic but may have testicular, epididymal, ovarian pain. Neurogenic bladder reported.

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

POLYARTERITIS NODOSAErythematous nodular lesion along vessels more prominent on lower limbs

livedo reticularis with or without ulceration

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

subcutaneous hemorrhages

LABS

• Abnormal urine sediment • High neutrophil count • Anemia of chronic disease • Elevated sedimentation rate • Hypergammaglobulinemia • Hepatitis B surface antigen positive in 30%

of cases

LAB finding

P-ANCA positive in 20% C-ANCA not associated with PAN

Arteriography and cross-sectional imaging alternative to biopsy for diagnosis is

conventional mesenteric or renal arteriography

multiple aneurysms and irregular constrictions in the larger vessels with occlusion of smaller penetrating arteries

Renal arteriogram

abrupt cutoffs of small arteries

microaneurysms

Conventional angiography of hepatitic, renal, splanchnic and splenic circulations

most reliable method of demonstrating the aneurysms, stenoses and abnormal vessels in PAN

However not specific to this disorder

Histopath

inflammatory necrotizing and obliterative panarteritis that attacks the small and medium-sized arteries

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.

Skin biopsy is usually not sufficient to establish the diagnosis of PAN

Tissue biopsy of affected muscle / nerve /kidney may confirm the presence of vasculitic lesions

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 recurrent skin, joint, and muscle

involvement without involvement of vital organs

Cutaneous findings similar to those described for the systemic form

Most patient respond well to aspirin, prednisone, methotrexate, alone or in combination

Cutaneous polyarteritis nodosa

Erythematous lesions on the leg

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 Isolated CNS vasculitis  affects medium and small arteries over a

diffuse area of the central nervous system, without symptomatic involvement of extracranial vessels.

Large vessel vasculitis

Large vessel vasculitis

Takayasu arteritis Giant cell arteritis (temporal arteritis)

Large vessel vasculitis Takayasu arteritis 

• primarily affects the aorta and its primary branches.

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

• Skin lesions- minority of cases• 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

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

cranial branches of the arteries originating from the aortic arch

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

Evaluation of vasculitis

Evaluation of vasculitis

clinical diagnosis histopathological confirmation assessment of the extent of the disease establish an underlying aetiology

Evaluation of vasculitis clinical diagnosis

• Purpura, livedo, cutaneous necrosis, and purple toe syndrome etc

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 • Nervous system. Central or peripheral, diffuse or

localized • Musculoskeletal. Non-erosive polyarthritis • Gastrointestinal. Abdominal pain, gastrointestinal

bleeding • Pulmonary. Pleural effusion, pleuritis • Cardiac. Pericardial effusion

establish an underlying aetiology

Medications infections Diseases associated with immune

complexes• connective tissue diseases• malignancy• inflammatory bowel disease

VASCULITISDiagnostic approach History  Physical examination Laboratory tests

History

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

• such as systemic lupus erythematosus

Physical examination

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

Findings suggestive of an underlying vasculitic process• palpable purpura• mononeuritis multiplex

Basic laboratory analysis Blood CP/ESR urinalysis CRP serum creatinine LFTs hepatitis serologies muscle enzyme chest x-ray ECG

Blood culture

(if pyrexial)

ASO titre ANA Complement ANCA Tissue biopsy IF studies

Other investigations (When indicated)

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

Remove triggering agent

Minimize stasis compression

stocking elevation of

dependent areas NSAIDs Antihistamines

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

Colchicine• 0.6 mg twice daily

Dapsone Azathioprine Methotrexate Biological agents

• Infliximab

• Rituximab

Treatment LCV

Symptomatic relief• Supportive therapy

• Antihistamines

• Non-steroidal anti-infl ammatory drugs

Skin lesions alone• Colchicine

• Dapsone

• Pentoxiphylline

Ulcerative skin lesions alone

• Thalidomide

• Methotrexate

• Prednisolone

Systemic disease• Prednisolone

• Azathioprine

• Cyclophosphamide

• Mycophenolate mofetil

• Ciclosporin

• Interferon-α (if hepatitis C-associated)

• Intravenous gammaglobulin

• Extracorporeal immunomodulation

• Infliximab

• Rituximab

HSP oral antihistamines systemic corticosteroids dapsone

• (100–200 mg once daily)

colchicine • (0.6 mg twice to three times daily)

hydroxychloroquine• (200 mg once to twice daily)

Dapsone plus pentoxifylline mycophenolate mofetil

• (2 g once daily)

PAN Treatment (as per severity)

Mild PAN• constitutional symptoms, arthritis, anemia, but

normal renal function, no gastrointestinal involvement, and no neurologic deficits) and those with isolated cutaneous disease

Moderate and severe PAN• renal insufficiency, or gastrointestinal, cardiac

or neurologic involvement

Mild PAN Prednisone

• 1 mg/kg per day (maximum 60 to 80 mg/day) for approximately four weeks.

• On significant improvement prednisone is tapered slowly for an overall course of approximately nine months.

• who do not respond to glucocorticoids alone, or who relapse as the dose of prednisone is tapered, treatment is as described below for severe PAN.

Moderate and severe Prednisone

• 1 mg/kg per day, maximum of 60 to 80 mg per day)

• The initial high dose is continued for two to four weeks, until significant improvement is observed.

• The dose should then be tapered slowly, for an overall course of approximately six months.

Oral cyclophosphamide, 1.5 to 2 mg per kg

unable to tolerate an oral regimen

(eg, due to gastrointestinal involvement) severe, life-threatening manifestations or worsening mononeuropathy multiplex

• Intravenous methylprednisolone be given initially for three days, followed by the oral prednisone regimen.

• Monthly intravenous infusions of cyclophosphamide (initial dose 600 to 750 milligrams/m(2) per month), rather than oral administration in this setting.

Other modalities

• plasmaphoresis. - conflicting• Renal transplantation

Patients with hepatitis B-associated PAN• combination of antiviral and immune

suppressing drugs

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 – 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.

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).

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