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
Sites
 palpable purpura 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%
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 Mostly in children
• Palpable purpura
• Arthritis/arthralgia IgA. Deposits
• Abdominal pain
• Renal disease
 Less common manifestations
• Orchitis, 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
 Churg-Strauss arteritis 
( allergic granulomatosis )
 classically involves the arteries of the lung and
skin
 Clinical signs:
• allergic rhinitis
• asthma
• eosinophilia Skin lesions
• systemic vasculitis •Palpable purpura
•macular or papular erythematous
rash
•Hemorrhagic lesions
•Tender cutaneous or subcutaneous
nodules
 WEGENER’S
GRANULOMATOSIS
 triad
 systemic small vessel vasculitis
 necrotizing granulomatous
inflammation of both the upper
and lower respiratory tracts
 glomerulonephritis
usually 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 mass
similar lesions occur in the sinuses and tracheobronchial
tree.
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%

non ANCA reactivity may well have localized WG and a

better prognosis when compared with those who are ANCA-
positive
Patients with WG who are negative for ANCA/anti-PR3
usually have positive P-ANCA/anti-MPO
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
• frequently seen in patients with other
vasculitic syndromes
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
 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 involveme nt
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 polyangiitis
Microscopic polyarteritis nodosa
Microscopic 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  most often due to
cryoglobulins hepatitis C virus
• serum proteins that infection. (80–90%)
precipitate in the cold  SLE
and dissolve upon  Myeloproliferative
rewarming. disorders
• Cryoglobulins typically  chronic infections
are composed of a
mixture of
immunoglobulins and
complement
components.
 Cryoglobulinaemic vasculitis
 Glomerulonephritis
 Palpable purpura  Arthralgia
 Polyarteritis-like dermal nodules migratory myalgia
 Raynaud’s phenomenon
 cold aggravation of the  Diagnosis
vasculitis lesions
 Cryoproteins
 Livedo
 antibodies to HCV
 acrocyanosis,
 bullae
 necrosis
 ulceration
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 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
 5–10-mm nodules may be tender,
pulsatile or secondarily ulcerated
POLYARTERITIS NODOSA
Erythematous
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

microaneurysms

abrupt cutoffs of small arteries

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.
•diffuseinflammation 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  New onset diastolic
unexplained weight blood pressure
loss > 4 kg  Elevated blood urea
 Livedo reticularis or creatinine
 Testicular pain or  Evidence of hepatitis
tenderness B virus infection
 Myalgias (excluding  Characteristic
that of the shoulder arteriographic
and hip girdle), abnormalities
weakness, or  biopsy of small- or
polyneuropathy medium-sized artery
 Mononeuropathy or containing polys
polyneuropathy
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
 VASCULITIS
Diagnostic 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  Blood culture
 urinalysis (if pyrexial)
 CRP  ASO titre
 serum creatinine  ANA
 LFTs  Complement
 hepatitis serologies  ANCA
 muscle enzyme  Tissue biopsy
 chest x-ray  IF studies
 ECG
 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
 Oral Steroids
• 30–80 mg once daily,
 Remove triggering • tapered over 2–3 weeks
agent  Colchicine
 Minimize stasis • 0.6 mg twice daily
 compression  Dapsone
stocking  Azathioprine
 elevation of  Methotrexate
dependent areas  Biological agents
 NSAIDs • Infliximab
 Antihistamines • Rituximab
Treatment
LCV
 Systemic disease
 Symptomatic relief • Prednisolone
• Supportive therapy • Azathioprine
• Antihistamines • Cyclophosphamide
• Non-steroidal anti-infl
ammatory drugs
• Mycophenolate mofetil
• Ciclosporin
 Skin lesions alone
• Colchicine • Interferon-α (if hepatitis
• Dapsone C-associated)
• Pentoxiphylline • Intravenous
gammaglobulin
 Ulcerative skin lesions
• Extracorporeal
alone
immunomodulation
• Thalidomide
• Methotrexate • Infliximab
• Prednisolone • 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
 Wegener’s granulomatosis

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.
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