VASCULITIS AND UPDATES

VASCULITIDES AND UPDATES
BY- DR. NEKTAANAND
GUIDE- DR. V.R PAWAR

• DEFINITION: Vasculitis is a clinicopathological
process characterized by inflammation of and damage
to blood vessels. The vessel lumen is usually
compromised, and this is associated with ischemia of
the tissues supplied by the involved vessel.

PATHOPHYSIOLOGYAND PATHOGENESIS
• Immune complex formation
• ANCA mediated
• T lymphocyte mediated granuloma formation
• Immunopathogenic mechanisms that occur in response to certain antigenic
stimuli.

CHAPEL HILL CLASSIFICATION
Large vessels Aorta and its major branches and the
analogous veins.
1-GIANT CELL ARTERITIS/ TEMPORAL
ARTERITIS,
2-TAKAYASU ARTERITIS.
Medium vessels : The main visceral arteries , veins and
their initial branches.
1-POLYARTERITIS NODOSA
2- KAWASAKI DISEASE
Small vessels Intraparenchymal arteries, arterioles,
capillaries, venules, and veins.
ANCA POSITIVE -1-MICROSCOPIC
POLYANGIITIS
2-WEGENERS GRANULOMATOSIS (GPA)
3-CHURG STRAUSS SYNDROME (EGPA)
ANCA NEGATIVE -1-HENOCH
SCHONLEIN PURPURA
2-CRYOGLOBULINAMIC VASCULITIS

Classification of Vasculitis according to the 2012 Revised International Chapel Hill Consensus
Conference on the Nomenclature of Systemic Vasculitides
(Primary angitis of central nervous system)

TYPES OF VASCULITIS CATEGORISED ON THE BASIS OF PROPOSED PATHOGENIC
MECHANISM
• DIRECT INFECTION OF VESSEL
• Bacterial vasculitis
• Mycobacterial vasculitis
• Syphilitic vasculitis
• Rickettsial vasculitis
• Fungal vasculitis
• Viral vasculitis
• IMMUNOLOGIC INJURY
• Immune complex mediated vasculitis
• Henoch-Schonlein purpura
• Cryoglobinemic vasculitis
• Lupus vasculitis
• Rheumatoid vasculitis
• Serum sickness vasculitis
• Induced by whole serum
• Induced by heterologous protein
• Infection induced immune complex vasculitis
• Viral
• Bacterial

• Paraneoplastic vasculitis
• Bechet’s disease
• Some drug- induced vasculitides(sulfonamides
• Direct antibody attack mediated vasculitis
• Goodpasture’s syndrome(mediated by antiendothelial antibodies)
• Kawasaki disease
• Antineutrophil cytoplasmic autoantibody- mediated vasculitis
• Wegener’s granulomatosis
• Microscopic polyangiitis
• Churg-strauss syndrome
• Some drug induced vasculitis(thiouracil)
• Cell mediated vasculitis
• Allograft cellular vascular rejection
• Unknown
• Giant cell arteritis
• Takayasu arteritis
• Polyarteritis
• Bechet's disease

LARGE VESSEL VASCULITIS
• GIANT CELLARTERITIS or TEMPORALARTERITIS:-
 Age > 50
 New onset headache, Jaw claudication.
 Sudden onset of – blindness
 Associated with polymyalgia rheumatic.
 Abnormal artery biopsy (mononuclear cell infiltrate, granulomatous inflammation,
usually multinucleated giant cells)
 Temporal artery abnormality (tender or decreased pulse)
Temporal artery biopsy - Since involvement of the vessel may be segmental,
positive yield is increased by obtaining a biopsy segment of 3–5 cm together
with serial sectioning of biopsy specimens

A- The temporal artery of a patient with classic giant cell arteritis shows a thickened, nodular
vessel on the surface of the head
B-H & E stain -temporal artery showing giant cells at the degenerated internal elastic lamina.
C-Elastic tissue stain showing focal destruction of internal elastic lamina.

DIFFERENTIAL DIAGNOSIS
• Takayasu Arteritis
• Infection related vasculitis
• Polyarteritis nodosa

TAKAYASU ARTERITIS= PULSELESS DISEASE= AORTIC
ARCH SYNDROME
• Onset before age of 40yrs
• Constitutional features
• Reovascular hypertension
• Decreased brachial artery pulse
• Decreased blood pressure(SBP difference >10 mmhg)
• Angiographic evidence of narrowing or occlusion of aorta or its primary branches
or large limb arteritis.

MICROSCOPY
A. Aortic arch angiogram showing narrowing of brachiocephalic, carotid, and subclavian arteries
B. Histologic appearance in active Takayasu aortitis- destruction and fibrosis of the arterial media associated with
mononuclear infiltrates and inflammatory giant cells

TAKAYASU ARTERITIS IS CATEGORISED AS-
TYPE 1- involvement of localized to aortic arch and its branches
TYPE 2- thoracic, descending, abdominal arteries
TYPE 3- combined of 1 and 2
TYPE 4- pulmonary artery
• Atherosclerosis
• Thromboangisis obliterans
• Syphilitic aortitis
• Giant cell arteritis

MEDIUM VESSEL VASCULITIS
• 1. POLYARTERITIS NODOSA-
• Necrotizing inflammation of medium or small sized artery.
• Systemic vasculitis involving renal and visceral vessels except pulmonary vessels.
• All patients should be screened for hepatitis B.
• Men > women ,age-20-60yrs
• C/F- fever, malaise, weight loss,weakness,myalgia
• Antibodies against myeloperoxidase or proteinase-3 (ANCA) are rarely found in
patients with PAN.

• Polyarteritis nodosa may present segmentally, and multiple stages of
inflammation (acute, chronic, and healed lesions) may be encountered
within the same patient.
• Classic Polyarteritis nodosa - segmental transmural necrotizing
inflammation

MICROSCOPY
Polyarteritis nodosa -Necrosis and fibrin are
present in the tunica media (arrows) of a
pancreatic artery surrounded by inflammatory
cells.
Polyarteritis nodosa- segmental fibrinoid
necrosis and thrombotic occlusion of the lumen
of this small artery.

• Kawasaki disease
• Chrug’s strauss syndrome
• Takayasu arteritis
• Burger’s disease
• Arterioscleosis

• 2. KAWASAKI DISEASE-
• C – Conjunctivitis (non purulent)
• R - Rash
• A – Adenopathy ( Cervical Lymphadenopathy)
• S – Strawberry tongue
• H – Hand (Palmar erythema & swelling)
• Burn (fever lasting at least 5 days or more)
• Illness of infancy and childhood (80% of patients are 4 years old or
younger)

• It predominantly involve small and medium sized arteritis,
especially the coronary arteritis, so mc cause of myocardial
infraction in children.
• Area of necrosis with more leukocytes seen under
microscope.

SMALL VESSEL VASCULITIS
GRANULOMATOSIS WITH POLYANGIITIS (WEGENER'S)-
• The histopathologic hallmarks of granulomatosis with polyangiitis (Wegener's) are
necrotizing vasculitis of small arteries and veins together with granuloma
formation, which may be either intravascular or extravascular.
• Focal necrotizing, often crescentic, glomerulonephritis
• Necrotizing granulomas of the upper respiratory tract (ear, nose, sinuses, throat) or
the lower respiratory tract (lung) or both.
• Necrotizing or granulomatous vasculitis affecting small to medium-sized vessels
most prominent in the lungs and upper airways
• Associated with PR-3 ANCA, earlier known as C-ANCA.

Granulomas with geographic patterns of central necrosis surrounded
by zone of proliferating fibroblasts with giant cells & leukocyte
infilterates
MICROSCOPY

• Churg- Strauss syndrome
• Lymphomatoid granulomatosis

MICROSCOPIC POLYANGIITIS-
• Also called as hypersensitivity or leukocytoclastic vasculitis
• It is necrotizing vasculitis with few or no immune complexes affecting
small vessels (capillaries, venules, or arterioles). Associated with
MPO- ANCA.
• Glomerulonephritis is very common in microscopic polyangiitis, and
pulmonary capillaritis often occurs. The absence of granulomatous
inflammation in microscopic polyangiitis is said to differentiate it from
Wegener's.
• The mean age of onset is 57 years of age, and males are slightly more
frequently affected than females.
• Granulomatous inflammation is absent

• Wegener's vasculitis

MPA GPA PAN
BLOOD VESSEL SIZE Small to Medium Small to Medium Medium
BLOOD VESSEL TYPE Arterioles to venules, And sometimes
Arteries and veins
Arterioles to venules, And sometimes
Arteries and veins
Muscular Arteries
GRANULOMATOUS INFLAMMATION NO YES NO
LUNG SYMPTOMS YES1 YES1 NO
GLOMERULONEPHRITIS YES YES NO
RENAL HYPERTENSION NO NO YES
ANCA-POSITIVITY 75% 65-90% NO
MPA GPA PAN

CHURG-STRAUSS SYNDROME-
• Churg-Strauss syndrome, also referred to as eosinophilic granulomatosis with polyangitis , Also
called allergic granulomatosis and angiitis
• It is characterized by asthma, peripheral and tissue eosinophilia, extravascular granuloma
formation, and vasculitis of multiple organ systems.
• The mean age of onset is 48 years, with a female-to-male ratio of 1.2:1.
• ANCAs (mostly MPO-ANCAs) are present
• Churg- Strauss syndrome is a multisystem diseases with cutaneous involvement (palpable
purpura), gastrointestinal tract bleeding, and renal disease (primarily as focal and segmental
glomerulosclerosis).
• Myocardial involvement- cardiomyopathy

MICROSCOPY
Churg-Strauss syndrome: depicted is a necrotic
vasculitis with a notable eosinophilic infiltrate and
fibrosis.

• Eosinophilic pneumonia

IgA VASCULITIS -HENOCH-SCHÖNLEIN PURPURA
• It is a small-vessel vasculitis characterized by palpable purpura (most
commonly distributed over the buttocks and lower extremities),
arthralgia, gastrointestinal signs and symptoms, and
glomerulonephritis.
• Henoch-Schönlein purpura is usually seen in children; most patients
range in age from 4 to 7years however, the disease may also be seen in
infants and adults. .
• The male-to-female ratio is 1.5:1.

• Cryoglobinemic vasculitis
• Drug induced vasculitis
• Infectious vasculitis- Neisseria

CRYOGLOBULINAMIC VASCULITIS-
• Usually systemic disease in which deposits of IgG or IgM immune complexes
cause glomerulonephritis (focal, diffuse), cutaneous vasculitis (skin rash) and
synovitis (arthritis)
• Defined by presence of serum cryoglobulins, which are immunoglobulin complexes
that precipitate at 4°C and become soluble again at 30°C
• Type I: cryoglobulins is single monoclonal immunoglobulin class, usually due to
myeloma, Waldenström macroglobulinemia or other lymphoma
• Type II: mixture of 2+ immunoglobulins, one a monoclonal antibody against
polyclonal IgG; usually IgG-IgM, in which IgM is monoclonal and has rheumatoid
factor activity
• Type III: both immunoglobulin components are usually polyclonal IgG and IgM

CLINICAL FEATURES
• Cryoglobulinemia may be associated with a systemic vasculitis,
associated with HCV infection
• Meltzer’s triad (purpura, arthralgia, weakness) occurs in <40% of
patients
• neuropathy, and glomerulonephritis.
• Although this can be observed in association with a variety of
underlying disorders including multiple myeloma,lymphoproliferative
disorders, connective tissue diseases, infection, and liver disease, in
many instances it appeared to be idiopathic.

MICROSCOPY
Amorphous pink cryoglobulin deposited throughout the vessel wall & in the lumen –
thrombus like appearance –H & E . Bright red on PAS stain

• Henoch- scholein purpura
• Drug induced vasculitis
• Infectious vasculitis

Thromboangiitis Obliterans:-
(Buerger`s Disease)
• Characterized by segmental, thrombosing inflammatory process
affecting intermediate and small arteries and sometimes veins
• Upper & lower extremities vessels are commonly involved
• Occurs - heavy cigarette smokers usually before age 35
• Early manifestations include cold induced Raynaud phenomenon
,intermittent claudication, instep claudication, and venous
inflammation.
• The vascular insufficiency of Burger disease tends to be accompanied
by severe pain—even at rest—undoubtedly due to the neural
involvement.

MICROSCOPY
Thromboangiitis obliterans (Burgers disease). The lumen is
occluded by a thrombus containing abscesses , and the vessel
wall is infiltrated with leukocytes

Bechet's Disease:-
• Neutrophilic vasculitis that classically presents as
a clinical triad of recurrent oral aphthous ulcers,
genital ulcers, and uveitis
• There is an association with certain HLA-B51 and a
cross-reactive immune response to certain
microorganisms is implicated.
• DIFFERENTIAL DIAGNOSIS:-
• Neutrophilic dermatitis
• Sweet’s syndrome
• Leulocytoclastic arteritis

MICROSCOPY
Histology of ulcers
revealing neutrophilic
infiltrate and vasculitis

Systemic lupus erythematosus :-
• Cutaneous vasculitis is common feature
• Mimicking the ANCA-associated vasculitis, is extremely rare but
associated with a particularly poor prognosis.
• Patients have typical autoantibodies associated with lupus including
ANA, DNA binding hypocomplementemia, and sometimes Ro and La
antibodies
• Clinical features include peripheral neuropathy, particularly
mononeuritis multiplex
• Rapidly progressive glomerulonephritis may also sometimes be
associated with systemic vasculitis

Systemic rheumatoid vasculitis
• Vasculitis has been known to be associated with RA for many
years.
• Recent studies have suggested that this complication is
becoming increasingly rare
• Extra articular manifestations such as nodules and pulmonary
fibrosis. The commonest findings are nail fold or nail bed
infarcts
• Vasculitis has very rarely been described as the presenting
feature of rheumatoid arthritis.
Nailfold vasculitis in a patient
with rheumatoid arthritis.

Infectious vasculitis
• Bacterial vasculitis
• Mycobacterial vasculitis
• Syphilitic vasculitis
• Rickettsial vasculitis
• Fungal vasculitis
• Viral vasculitis

Histologic section of the ascending aorta
showing adventitial and medial chronic
inflammatory infiltrate.
Higher magnification from the adventitia
demonstrating obliterans and perivascular
cuffing by lymphocytes and plasma cells.
Aortic aneurysm
Syphilitic vasculitis

• Considerable progress has been made in understanding the pathogenesis of
vasculitis, and consequently promising biomarker discoveries.
• It should be remembered that primary outcome measures in clinical trials of
vasculitis .
• These particular monogenic forms of vasculitis have significant therapeutic
implications, and demonstrate that an understanding of the molecular basis of
vasculitis can identify new therapeutic pathways, new biomarkers and new
treatments.
UPDATES IN VASCULITIS

What is a biomarker, and what is it a biomarker of?
• A biomarker is defined as any characteristic that is objectively measured and
evaluated as an indicator of normal biological processes, pathogenic processes,
or pharmacological responses to a therapeutic intervention .
• biomarkers and/or new genetic tests could help include: diagnostic tests to
robustly identify important clinical phenotypes of vasculitis (for epidemiological
studies and/or clinical trials), e.g. identifying novel genetic diagnostic tests for
monogenic vasculitides and granulomatosis with polyangiitis (GPA).
• Monogenic vasculitides includes- DADA2, CANDLE and SAVI

ANCA-associated vasculitides-AAV
• granulomatosis with polyangiitis (GPA), most commonly associated
with proteinase 3 (PR3)-ANCA, although myeloperoxidase (MPO)-
ANCAs are present in a minority;
• microscopic polyangiitis (MPA), typically associated with MPO-
ANCA;
• single organ disease,
• renal-limited vasculitis (again mainly associated with MPO-ANCA);
and
• eosinophilic granulomatous polyangiitis (EGPA) [5]. As most
children with EGPA are in fact ANCA-negative

ANCA as a diagnostic biomarker
• Cases of “ANCA-negative” AAV are acknowledged, in ANCA testing methodology (including
using both indirect immunofluorescence and enzyme-linked immunosorbent assay for screening).
• It is increasingly recognized that such “ANCA-negative” AAV patients have a broad differential
diagnosis that may include entities such as chronic granulomatous disease, IgG4 disease,
monogenic granulomatous diseases including Blau syndrome, or other immune-mediated
renal pathology.
• Pediatric patients with vasculitis (particularly single organ disease)who were initially ANCA
negative, and who subsequently became ANCA positive, suggesting that the negative predictive
value of ANCA testing for patients with single organ disease at first testing might be suboptimal.
Thus, the diagnostic utility of ANCA as a biomarker for AAV is largely irrefutable , and when
positive are especially useful for those with atypical presentations and/or single organ disease.
• The fact that ANCA positivity is usually a requirement for enrolment into clinical trials involving
patients with AAV, and is included in paediatric classification criteria and adult definitions of AAV,
may amplify the notion that a decreasing number of patients are ANCA negative.

ANCA as a biomarker of disease activity
That an increase in the PR3-ANCA titre was not a very sensitive or specific
predictor of subsequent relapse in general, they did observe some association
between an increase in PR3-ANCA level and risk of subsequent relapse that was
dependent on specific factors.

Other biomarkers and miscellaneous vasculitides: endothelial injury and repair
concept
• Endothelial activation and injury are central to the pathogenesis, with increased
endothelial cell adhesion molecule expression, and a switch to a prothrombotic
endothelial phenotype, both of which contribute to the vascular pathology of
vasculitis .
Two important biomarkers of endothelial injury are –
• endothelial micro particles (EMPs),
• circulating detached mature endothelial cells (CECs).
Von Will brand factor (VWF), a plasma protein synthesized primarily by
megakaryocytes and endothelial cells, mediates platelet aggregation and adhesion .
Levels increase in response to endothelial injury or activation, and have been
described as a biomarker of disease activity in many vasculitides including KD,
HSP and AAV.

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