DIAGNOSING

CUTANEOUS
VASCULITIS
By: Dr. Donna Braham
Objectives
• Classify Vasculitis
• Know when to consider Vasculitis
• Rule out mimickers of Vasculitis
• Diagnose cutaneous small vessel vasculitis – In particular
Henoch–Schönlein Purpura, Essential Cryoglobulinemic
vasculitis and Cutaneous Leukocytoclastic angiitis
Vasculitis
• Specific pattern of inflammation of the blood vessel wall
and it can occur in any size vessel and in any organ
system of the body.

• Cutaneous vasculitis may be:

• (1) a skin-limited disease
• (2) a primary cutaneous vasculitis with secondary systemic
involvement
• (3) a cutaneous manifestation of a systemic vasculitis
Cutaneous Vasculature
• Small vessels (Superficial and
mid dermis of the skin):
• Arterioles
• Capillaries
• Postcapillary venules

• Medium-sized vessels (Deep

dermis or subcutis):
• Small arteries
• Veins

• Large vessels include the

aorta and named arteries.
Chapel Hill Consensus Conference on the
Nomenclature of Systemic Vasculitis
• Small Vessel Vasculitis • Medium-sized Vessel
• Granulomatosis with
Vasculitis
Polyangiitis (GPA) -Wegener’s
Granulomatosis • Polyarteritis Nodosa
• Eosinophilic Granulomatosis • Kawasaki Disease
with polyangiitis (EGPA) -
Churg-Strauss Syndrome
• Microscopic Polyangiitis (MPA) • Large-sized Vessel
• Henoch-Schonlein purpura
(HSP)
Vasculitis
• Essential Cryoglobulinemic • Giant cell (temporal)
vasculitis arteritis
• Cutaneous Leukocytoclastic • Takayasu arteritis
angiitis (CSVV)
Epidemiology
• The incidence of biopsy-proven cutaneous vasculitis of all
types is 15–60 patients per million per year.
• Cutaneous vasculitis occurs in all age groups
• mean age in adults, 47 years; mean age in children, 7 years
• Much more common in adults than in children
• Slight female predominance
• The majority of children have Henoch–Schönlein purpura
which is associated with pesticide and drugs.
• All are more common in whites compared with other
populations
• Genetic and environmental factors, including infection,
drugs, and silica play a role
Pathogenesis
1. Immune complex-mediated inflammation
• Polyarteritis nodosa,
• Cryoglobulinaemia
• Henoch-Schönlein purpura

2. Autoantibody-mediated inflammation (ANCA)

• Wegener's granulomatosis
• Churg-Strauss syndrome
• Microscopic polyangiitis
• Necrotizing glomerulonephritis

3. Cell-mediated inflammation
• GCA
Immune complex-mediated vasculitis
• Circulating antigens (e.g. infectious
agents, medications, neoplasms)
induce antibody formation.
• Binding of antibodies to circulating
antigens creates immune
complexes.
• Immune complex deposition within
postcapillary venules activates
complement and subsequently
leads to an increase in adhesion
molecule expression on the
endothelium.
• Complement split products (C3a
and C5a) induce mast cell
degranulation and neutrophil
chemotaxis.
Immune complex-mediated vasculitis
• Mast cell degranulation leads to increased vascular
dilation and permeability, enhancing immune complex
deposition and leukocyte tethering to endothelium
• Neutrophils release proteolytic enzymes (such as
collagenases and elastases) and free oxygen radicals that
damage the vessel wall.
• In addition, formation of the membrane attack complex
(C5–C9) on the endothelium leads to the activation of the
clotting cascade and the release of cytokines and growth
factors with ensuing thrombosis, inflammation and
angiogenesis.
Autoantibody-mediated inflammation -Anti-
neutrophillic cytoplasmic autoantibodies
• The autoantibodies activate
neutrophils

• The activated neutrophils are

then primed by cytokines to
show MPO and PR3 on their
surfaces

• They then adhere to the

endothelial walls of blood
vessels and release oxygen
radicals and enzymes that
damage the surrounding
tissues
Clinical Presentation
• Vary from a benign loco-regionally restricted process to systemic
necrotising vasculitis leading to life-threatening conditions.
• Constitutional symptoms (the B-symptoms)
• Fatigue, weight loss, night sweats and low grade fever
• Systemic symptoms develop in 5–25% of patients with CSVV
• Arthralgias and arthritis 15–65%
• Genitourinary 3–7%
• Gastrointestinal involvement 3–5%
• In general, signs or symptoms of gastrointestinal, renal or
neurologic involvement should increase the clinical suspicion for a
systemic vasculitis.
• In one study, the presence of paresthesias or fever and the
absence of painful lesions were identified as risk factors for an
associated systemic disease
Think Vasculitis if?
• Unexplained systemic illness

• Symptoms of organ system ischaemia

• Nephritic syndrome
Cutaneous Small Vessel Vasculitis
• The skin lesions of CSVV usually appear 7–10 days after the
triggering event.

• In systemic vasculitic syndromes, signs of systemic

involvement often precede the appearance of associated
cutaneous lesions.

• The lesions favor dependent sites, as well as areas under

tight-fitting clothing, reflecting the influence of hydrostatic
pressure and stasis on the pathophysiology.

• In general, the lesions are asymptomatic, but they may itch,

burn or sting.
Cutaneous Small Vessel Vasculitis
• Palpable or macular
purpura
• Urticarial papules
• Pustules
• Vesicles
• Petechiae
• targetoid lesions
Small and medium-sized
(“mixed”)
• Cryoglobulinemia -Types II and • Petechiae
III
• Palpable purpura

• ANCA-associated • Livedo racemosa

• Microscopic polyangiitis
• Wegener’s granulomatosis
• Retiform purpura
• Churg–Strauss syndrome

• Ulcers

• Secondary causes
• Subcutaneous nodules
• Infections
• Inflammatory disorders (e.g. AI-
CTD) • Digital necrosis
Medium-sized Vessel
• Polyarteritis nodosa • Livedo racemosa
(PAN)
• Classic (systemic) PAN • Retiform purpura
• Cutaneous PAN

• Ulcers

• Subcutaneous nodules

• Digital necrosis
Large Vessel
• Temporal Arteritis
• Early – erythematous or cyanotic skin, alopecia, purpura, tender
nodules on frontotemporal scalp
• Late – Ulceration and/or gangrene of frontotemporal scalp or
tongue
• Takayasu’s arteritis
• Erythematous subcutaneous nodules +/− ulceration, pyoderma
gangrenosum-like lesions on the extremities (lower > upper)
• May have evidence of small and/or medium-sized vessel vasculitis
Mimics of vasculitis
• Infections

• Embolic disorders

• Malignancy

• Drugs
Conditions that may cause secondary vasculitis

• Idiopathic 50%

• Infections 15–20%

• Connective tissue diseases 15–20%

• Drugs 10–15%

• Neoplasms 2–5%

• Genetic disorders Rare

• Immunodeficiency syndromes
• Familial Mediterranean fever and other periodic fever syndromes
Infection
1. Bacterial
• Beta-hemolytic streptococci, especially group A
• Mycobacterium leprae
• Neisseria meningococcus (in chronic meningococcemia)
• Mycobacterium tuberculosis
• Atypical mycobacteria

2. Septic vasculitis
3. Infective endocarditis
4. Viral
• Upper respiratory tract infection
• Hepatitis C > B ≫ A, including vaccines
• HIV
• Parvovirus B19
Inflammatory disorders
1. Autoimmune connective tissue diseases
• Rheumatoid arthritis
• SLE
• Sjögren’s syndrome

2. Inflammatory bowel disease

3. Behçet’s disease
4. Hypergammaglobulinemic purpura of Waldenström
5. Seronegative spondyloarthropathies
6. Sarcoidosis
7. Cystic fibrosis
8. Primary biliary cirrhosis
9. Bowel-associated dermatosis–arthritis syndrome
10. Gluten enteropathy (adult HSP)
Drug-exposure
• Uncommon
• ACE inhibitors
• Common • TNF-α inhibitors
• Allopurinol • Beta-blockers
• Cocaine adulterated with levamisole
• Bortezomib • COX-2 inhibitors
• Cephalosporins, esp. cefaclor • Furosemide
• Interferons
• D-penicillamine • Leukotriene inhibitors
• Macrolide antibiotics
• G-CSF
• Quinine
• Hydralazine • Retinoids
• Sirolimus
• Methotrexate • Sulfonylureas
• Minocycline • Vancomycin
• Warfarin
• NSAIDs • Rare
• Oral contraceptives • Amiodarone
• Aspirin
• Penicillins • Atypical antipsychotics
• Gabapentin
• Phenytoin
• Insulin
• Propylthiouracil/other antithyroid agents • Leflunomide
• Mefloquine
• Quinidine • Metformin
• Quinolones • Methamphetamine
• 3,4-methylenedioxymethamphetamine
• Serum (e.g. ATG) • Phenothiazines
• Streptokinase • Radiographic contrast media
• Rituximab
• Sulfonamides • SSRIs
• Tocolytics (e.g. ritodrine, terbutaline)
• Thiazides
• Vitamins
• Food/drug additives
• SSKI
Neoplasms
• Plasma cell dyscrasias
• Monoclonal gammopathies
• Multiple myeloma
• Myelodysplasia
• Myeloproliferative disorders
• Lymphoproliferative disorders
• Hairy cell leukemia
• Solid organ carcinomas (adults with IgA-positive
vasculitis)
Skin Biopsy
• Within the first 24 to 48 hours of appearance
• > 48 to 72 hours may have a predominantly mononuclear
rather than neutrophilic infiltrate
• Perilesional skin for direct immunofluorescence (DIF)
• ~80% of cases of CSVV DIF demonstrates deposition of C3,
IgM, IgA and/or IgG in a granular pattern within the vessel walls
• Immunoglobulin deposition is highest (up to 100%) in skin
lesions present for ≤48 hours.
• 30% of samples obtained 48–72 hours after lesion onset, DIF
will be negative for immunoglobulins, and only C3 will be
detected in lesions present for >72 hours.
• In ANCA-positive vasculitis, the DIF of lesional skin is usually
negative.
Histology
• Leukocytoclastic vasculitis
• Transmural infiltration of the walls of
postcapillary venules by neutrophils
• Fibrinoid necrosis of the damaged
vessel walls
• Leukocytoclasia (degranulation and
fragmentation of neutrophils, leading
to the production of nuclear dust)
• Extravasated erythrocytes, and signs
of endothelial cell damage

• Neovascularization of the
adventitia, in the form of small
capillaries, is commonly seen in
older lesions of medium-sized
vessel vasculitis
Prognosis
• Depends upon the severity of systemic involvement
• ~ 90% spontaneous resolution of cutaneous lesions within
several weeks or a few months
• 10% will have chronic or recurrent disease at intervals of
months to years
• Average duration of disease activity is 28 months
• The presence of arthralgias or cryoglobulinemia and an
absence of fever may portend chronicity
• Autoimmune connective tissue disease or neoplasm, will
also affect prognosis
Treatment
• First-line therapy • Third-line therapy
• Discontinue incriminated
• Azathioprine (2
drugs
• Supportive care
mg/kg/day)
• Treat underlying infections,
• Methotrexate
neoplasms • IVIg
• NSAIDs • Cyclosporine
• Antihistamines
• Cyclophosphamide
• Second-line therapy
• Plasmopharesis
• Colchicine (0.6 mg bid–tid)
• Dapsone (50–200 mg/day)
• Corticosteroids
• Hydroxychloroquine
Henoch–Schönlein Purpura
• CSVV with vascular IgA deposition
• Most commonly occurs in children <10 years of age
• 1 to 2 weeks following an upper respiratory tract infection
• 20–50% of HSP patients have positive antistreptolysin O titers, no
causal role for group A β-hemolytic streptococci has been
demonstrated.
• Genetic polymorphisms may predispose to more severe
disease
• HLA-B35 positivity may predispose to renal disease
• Absence of ICAM-1 469 K/E variant have less severe
gastrointestinal involvement
• May be associated with an underlying malignancy in adults
HSP Classic Tetrad
1. Purpura (100%)
• Intermittent palpable purpura
• Symmetrically distributed on the buttocks and lower extremities, but may also involve the trunk, upper extremities and
face

2. Arthritis and arthralgias (75%)

• Knees and ankles

3. Abdominal pain and/or melena (50–75%)

• May precede the purpura
• Colicky abdominal pain (65%)
• Gastrointestinal bleeding (30%)
• Vomiting

4. Hematuria (40–50%)
• Microscopic hematuria (40%)
• Proteinuria (25%)
• Nephritis is clinically evident within 3 months
• 1–3% of children will develop long-term renal impairment
• Orchitis is a rare form of involvement in young boys.
Fever ~ 20% of adults and 40% of children
Prognosis
• Individual lesions usually regress within 10 to 14 days
• Complete resolution of skin involvement over a period of
several weeks to months
• Recurrences of skin disease are observed in 5–10% of
patients
• Poor prognostic factors include:
• Renal failure at the time of onset
• Nephrotic syndrome
• Hypertension
• Decreased factor XIII activity
Adult HSP
• Necrotic skin lesions are present in 60% of adults while
cutaneous necrosis is observed in <5% of children
• 30% will develop chronic renal insufficiency
• Purpura above the waist
• Fever
• Elevated ESR
• 60–90% of patients with neoplasm-associated IgA
vasculitis will have cancer of a solid organ - lung
Diagnosis
• Leukocytoclastic vasculitis of the small dermal blood vessels
• DIF demonstrates perivascular IgA, C3 and fibrin deposits, IgA ANCA may be
present in some patients
• 80% of all adults with CSVV may demonstrate some vascular IgA deposition and
IgA deposition can be seen in other diseases (e.g. drug hypersensitivity), a
diagnosis of HSP is supported by IgA predominance in the correct clinical setting

EULAR/PReS:
• Palpable purpura and at least one of the following must be present:
• arthritis (acute, any joint) or arthralgia
• diffuse abdominal pain
• any biopsy demonstrating predominant IgA deposition
• renal involvement (hematuria and/or proteinuria)

• Evidence of medium-sized vessel disease or widespread lesions (including the

face) may indicate an underlying IgA paraproteinemia
Treatment
• First-Line – Supportive care
• Second-Line therapy
• Dapsone
• Colchicine
• Corticosteroids
• Azathioprine ± Corticosteroids
• Cyclophosphamide ± Corticosteroids
• Cyclosporine ± Corticosteroids
• Antihistamines
• Third-Line therapy
• IVIg
• Rituximab
• Mycophenolate mofetil
• Corticosteroids + tacrolimus
• Aminocaproic acid
• Plasmapharesis
• Factor XIII
Cryoglobulinemic Vasculitis
• Cryoglobulins are cold-precipitable immunoglobulins that
can be divided into three subtypes, all of which have
cutaneous manifestations
• Palpable purpura, typically on the lower extremities
• Myalgias and arthralgias (70%)
• Associated with mixed serum cryoglobulins (IgM and IgG),
most commonly in the setting of HCV infection
• Peripheral neuropathy (Sensory – 40%)
• Glomerulonephritis (Membranoproliferative -25%)
• GI or Hepatitis (30%) – Viral or autoimmune hepatitis
CLASSIFICATION OF CRYOGLOBULINS
Subtype Molecular Associations Pathophysiol Clinical
composition ogy manifestatio
ns
I Monoclonal IgM Plasma cell Vascular Raynaud’s
> IgG dyscrasias, occlusion phenomenon,
lymphoproliferat retiform
ive disorders purpura,
gangrene,
acrocyanosis
II Monoclonal IgM HCV, HIV, Vasculitis Palpable
(>IgG) against autoimmune purpura,
polyclonal IgG connective arthralgias,
tissue diseases, peripheral
lymphoproliferat neuropathy,
ive disorders glomerulonephri
tis
III Polyclonal IgM
against
polyclonal IgG
Diagnosis
• Tests for cryoglobulins can be falsely negative and need to be assayed during
clinical flares on more than one occasion
• The blood sample should be kept at 37°C while being transported to the
laboratory.
• 70% of patients have circulating RF activity
• 20% have antinuclear antibodies
• 15% of patients with mixed cryoglobulinemia have a monoclonal gammopathy
as detected by serum protein electrophoresis and/or immunofixation
electrophoresis
• HBV, HCV and HIV serologies should be evaluated =/- viral load
• complement levels (C4 levels) - do not necessarily correlate with the severity
of the disease

• Pathology
• DIF, granular deposits consisting predominantly of IgM and C3 in a vascular
pattern are observed in the papillary dermis
Treatment
• Directed toward any underlying disease
• All patients with HCV-associated mixed cryoglobulinemia should be
treated with interferon-α plus ribavirin
• Resolution of the cutaneous (100%), renal (50%), and neurologic (25–75%)
manifestations
• Interferon-α alone may improve the cutaneous vasculitis (50–100%), but is less
effective in reversing the neurologic or renal involvement
• In rare cases, interferon may trigger or worsen the peripheral neuropathy.

• Second-line therapy
• Corticosteroid + Cyclophosphamide

• Third-line therapy
• IVIg
• Rituximab (± ribavirin, IFN)
• Plasmaphoresis
Summary
• Think Vasculitis if: Unexplained systemic illness,
Symptoms of organ system ischaemia, Nephritic
syndrome
• Biopsy early lesions (24-48hrs) and send perilesional skin
for Direct immunofluorescence
• Always consider mimickers of Vasculitis first - Infections,
embolic disorders, malignancy and drugs
• Search for Secondary causes of CSVV – Infections,
connective tissue diseases, drugs, neoplasms, rarely
genetic disorders
• Clinical Tetrad of HSP – palpable purpura,
arthritis/arthralgia, abdominal pain and hematuria
References
• Jennette JC, Falk RJ. Small‐vessel vasculitis. N Engl J
Med 1997;337:1512–23.
• Curr Rheumatol Rep. 2005 Aug;7(4):270-5
• Lupus (1998) 7, 280± 284 Pathogenesis of vasculitis
• Bolognia Dermatology 3rd Ed. By Jean Bolognia
• EULAR Textbook on Rheumatic Diseases, Johannes
Bijlsma
• Major categories of non ‐infectious vasculitis

• Large vessel vasculitis

• Giant cell arteritis
• Takayasu arteritis
• Medium‐sized vessel vasculitis
• Polyarteritis nodosa
• Kawasaki disease
• Small vessel vasculitis
• ANCA‐associated small vessel vasculitis
•     MPA
•     WG
•     CSS
•     Drug‐induced ANCA‐associated vasculitis
• Immune complex small vessel vasculitis
•     Henoch–Schönlein purpura
•     Cryoglobulinaemic vasculitis
•     Lupus vasculitis
•     Rheumatoid vasculitis
•     Sjögren's syndrome vasculitis
•     Hypocomplementaemic urticarial vasculitis
•     Behcet's disease
•     Goodpasture's syndrome
•     Serum sickness vasculitis
•     Drug‐induced immune complex vasculitis
•     Infection‐induced immune complex vasculitis
• Paraneoplastic small vessel vasculitis
•     Lymphoproliferative neoplasm ‐induced vasculitis
•     Myeloproliferative neoplasm ‐induced vasculitis
•     Carcinoma‐induced vasculitis
• Inflammatory bowel disease vasculitis
Pathogenesis
• CSVV - mediated by immune complexes that form in the
presence of antigen excess.
• Immune complex deposition in postcapillary venules
activates complement, which, in turn, induces mast cell
degranulation and neutrophil chemotaxis. Neutrophils
release proteolytic enzymes and free oxygen radicals,
leading to damage of the vessel wall (Fig. 24.1A).
Increased adhesiveness between inflammatory cells and
the endothelium, due to enhanced expression of adhesion
molecules (e.g. selectins, LFA-1), also plays a role in the
pathogenesis of cutaneous vasculitis
General clinical Signs or presenting disorders Type of vasculitis
Feature
Constitutional symptoms Low grade fever, fatigue, malaise, anorexia, GCA, GPA, MPA, eGPA, PAN, less commonly
weight loss other vasculitis.

Polymyalgia rheumatica Proximal muscle pain with morning stiffness GCA

Myalgias Diffuse PAN , GPA, MPA, eGPA

Non-destructive oligoarthritis Joint swelling, warmth, painful range of motion, PAN, MPA, eGPA, GPA, hypersensitive vasculitis
migratory

Skin lesions Livedo reticularis, necrotic lesions, ulcers, Any medium-vessel vasculitis
nodules, digital tip infarcts

Palpable purpura, urticaria-like Any small-vessel vasculitis

ENT symptoms Sinusitis, otitis, hearing loss GPA, eGPA, MPA

Cranial symptoms Headache GCA, TAK, GPA

Multiple mononeuropathy (mononeuritis multiplex) Injury to two or more separate peripheral nerves PAN, eGPA and GPA MPA,
(e.g. drop foot, wrist drop)

Renal Renal artery involvement PAN, TAK

Involvement

Glomerulonephritis MPA, GPA, cryoglobulinaemia, Henoch-Schönlein

purpura
• Eosinophilia and elevated IgE in the blood and tissues (in
situ) are characteristically associated with allergic angiitis
and granulomatosis eg. Churg–Strauss syndrome’; CSS
Pathogenesis of Vasculitis
Anti-neutrophillic cytoplasmic autoantibodies
• Primarily directed against intracellular neutrophilic proteins
(e.g. proteinase-3, myeloperoxidase), which can translocate
to the neutrophil’s cell surface following primary activation by
cytokines such as tumor necrosis factor (TNF)-α.
• Binding to the surface of neutrophils results in neutrophil-
mediated vessel damage.
• Because the vessel damage in ANCA-positive vasculitides is
directly mediated by neutrophils rather than by immune
complex deposition, they are referred to as “pauci-immune”
vasculitides.
• Formation of ANCA may be related to an impairment in
neutrophil apoptosis which results in a prolonged opportunity
for autoantibody development
• In medium-sized vessel vasculitis, the affected blood vessels reside within the
reticular dermis or subcutis. As a result, the latter typically presents with livedo
racemosa, retiform purpura, ulcers, subcutaneous nodules and/or digital
necrosis. In general, the presence of ulcers or necrosis suggests deeper
arterial involvement. The combination of palpable purpura (or other signs of
CSVV) plus signs of medium-sized vessel disease points to a “mixed” pattern
of vasculitis (see Table 24.1), as is seen in ANCA-associated vasculitides,
mixed cryoglobulinemia, or autoimmune connective tissue disease-associated
vasculitis. Since polyarteritis nodosa affects only medium-sized vessels, it
rarely presents with cutaneous signs of small vessel involvement.

• Arthralgias and arthritis as well as constitutional symptoms such as fever,

weight loss and malaise can be manifestations of vasculitis of any size
vessel2. For patients with systemic involvement, presenting symptoms and
signs (e.g. abdominal pain, paresthesias, hematuria) will vary according to the
affected organs.
Small Vessel (Cutaneous small vessel vasculitis)

• Henoch–Schönlein purpura
• Acute hemorrhagic edema of infancy
• Urticarial vasculitis
• Erythema elevatum diutinum
• Secondary causes of CSVV:
• Drug exposure
• Infections
• Malignancies, most often hematologic