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Cutaneous
Vasculitis Update:
Tables 1 - 6
Review
article text
Table 1. Names and definitions of vasculitides
adopted by the Chapel Hill Consensus Conference (CHCC) and America
College of Rheumatology (ACR) on the nomenclature of systemic vasculitis.
| |
Chapel Hill Consensus conference (CHCC) Criteria |
American College of Rheumatology (ACR) Criteria |
| Large-vessel vasculitis |
|
|
| Giant cell (temporal) arteritis (GCA) |
Granulomatous arteritis of the aorta and its
major branches, with a predilection for the extracranial braches
of the carotid artery. Often involves the temporal artery. Usually
occurs in patients older than 50 and often associated with polymalygia
rheumatica. |
1. Age > 50year at onset
2. New type of headache
3. Abnormal temporal artery on examination
4. Elevated erythrocyte sedimention rate
5. Temporal artery biopsy shows vasculitis
Sensitivity 93.5%, specificity 91.2% for 3 criteria
|
| Takayasu arteritis |
Granulomatous inflammation of the aorta and
its major branches. Usually occurs in patients younger than
50. |
1. Age < 40year at onset
2. Limb claudication
3. Decreased brachial artery pulses
4. Blood pressure >10mg Hg difference between arms
5. Bruits
6. Abnormal arteriogram
Sensitivity 90.5%, specificity 97.8% for 3 criteria |
| Medium-sized vessel vasculitis |
|
|
| Polyartertis nodosa (PAN) |
Necrotizing inflammation of medium sized or small arteries
without glumerulonephritis or vasculitis in arterioles, capillaries
or venules. |
1. Weight loss > 4kg
2. Livedo reticularis
3. Testicular pain or tenderness
4. Myalgias, myopathy or tenderness
5. Neuropathy
6. Hypertension (diastolic > 90mg Hg)
7. Renal impairment (elevated BUN or creatinine)
8. Hepatitis B virus
9. Abnormal arteriography
10. Biopsy of artery showing neutrophils
Sensitivity of 82.2%, specificity 86.6% for 3 criteria
|
| Kawasaki disease |
Arteritis involving large, medium-sized, and small arteries,
and associated with mucocutaneous lymph node syndrome. Coronary
arteries are often involved. Aorta and veins may be involved.
Usually occurs in children. |
|
| Small-vessel vasculitis |
|
|
| Wegener granulomatosis (WG) |
Granulomatous inflammation involving the respiratory tract,
and necrotizing vasculitis affecting small to medium-sized vessels
(eg, capillaries, venules, arterioles, and arteries). Necrotizing
glomerulonephritis is common. |
1. Nasal or oral inflammation
2. Chest x-ray showing nodules, infiltrates, or cavities
3. Microscopic hematuria or red cell casts in urine
4. granulomatous inflammation on biopsy
Sensitivity of 88.2%, specificity 92% for 2 criteria
|
| Churg-Strauss syndrome (CSS) |
Eosinophil-rich and granulomatous inflammation involving respiratory
tract, and necrotizing vasculitis affecting small to medium-sized
vessels, and associated with asthma and eosinophilia.
|
1. Asthma
2. Eosinophilia (>10%)
3. Neuropathy
4. Pulmonary infiltrates (non-fixed)
5. extravascular eosinophils on biopsy
Sensitivity 85%, specificity 99.7% for 4 criteria
|
| Microscopic polyangiits (MPA) |
Necrotizing vasculitis, with few or no immune deposits, affecting
small vessels (capillaries, venules and arterioles). Necrotizing
arteritis involving small and medium sized vessels may be present.
Necrotizing glomerulonephritis is very common. Pulmonary capillaritis
often occurs. |
|
| Henoch-Shönlein purpura (HSP) |
Vasculitis, with IgA dominant immune deposits, affecting
small vessels (capillaries, venules and arterioles). Typically
involves skin, gut, and glomeruli and is associated with arthralgias
or arthritis.
|
1. Palpable purpura
2. Age at onset < 20yr
3. Bowel angina
4. Vessel wall neutrophils on biopsy
Sensitivity 87%, specificity 88% for 2 criteria
|
| (Essential) cryoglobulinemic vasculitis (CV) |
Vasculitis, with cryoglobulin immune deposits, affecting small
vessels (ie, capillaries, venules, or arterioles), and associated
with cryoglobulins in the serum. Skin and glomeruli are often
involved. |
|
| Cutaneous leukocytoclastic vasculitis (CLA) (a.k.a. hypersensitivity
vasculitis) |
Isolated cutaneous leukocytoclastic angiitis without systemic
vasculitis or glomerulonephritis |
1. Age > 16yr at onset
2. Medications that may have precipitated event
3. Palpable purpura
4. Cutaneous eruption
5. Positive biopsy results
Sensitivity of 71%, specificity 83.9% for 3 criteria |
From Jennette et al (30) and
ACR (18-25)
Table 2. Histologic diagnostic criteria for
cutaneous vasculitis.
| Histologic signs of acute (active) vasculitis |
| *Disruption and/or destruction of vessel wall by inflammatory
infiltrate |
| *Infiltration of muscular vessel walls by inflammatory cells |
| (Muscular vessels are not the site of diapedesis) |
| *Intramural and/or intraluminal fibrin deposition (“fibrinoid
necrosis”) |
| *Nuclear dust, perivascular (leukocytoclasia) |
| Endothelial swelling, sloughing or necrosis |
| Secondary changes of active vasculitis (suggestive of,
but not diagnostic of vasculitis) |
| RBC extravasation (petechiae, purpura, hematoma) |
| Eccrine gland necrosis (or regeneration with basal cell hyperplasia) |
| Ulceration |
| Necrosis/infarction |
| Histologic sequellae of vasculitis (chronic signs) |
†Lamination (onion-skinning) of vessel wall constituents
(concentric proliferation of pericytes and smooth muscle cells) |
†Lumenal obliteration (endarteritis obliterans)
(Intimal or medial proliferation of cellular elements leading
to luminal occlusion) |
| Segmental or complete loss of elastic lamina in medium and
large vessels |
| Reactive angioendotheliomatosis |
| Neo-vascularization of the adventitia |
Changes adjacent to vasculitis indicative of subtype
or etiology
|
Lamellar or storiform fibrosis
Erythema elevatum dinutinum, granuloma faciale or inflammatory
pseudotumor |
Palisading (necrotizing) granulomatous dermatitis (“Winkelmann
granuloma”)
“Red” extravascular granuloma (eosinophils, flame
figures)
Churg Strauss syndrome
“Blue” extravascular granuloma (neutrophils, nuclear
dust) Wegener’s granulomatosus, rheumatoid vasculitis |
Vacuolar interface dermatitis (sometimes dermal mucin deposition)
Connective tissue disease, e.g. lupus erythematosus, dermatomyositis |
“Pustular” dermatosis with intraepidermal or subepidermal
neutrophilic abscesses
Infectious trigger |
*: required for diagnosis of vasculitis. †: other
types of vessel injury can cause same pattern.
Table 3. Factors associated with vasculitis
| Disease state or associated factor |
Specific entity or agent |
| Gene polymorphisms |
MHC, ICAM-1, IL-Ra, eNOS |
| Chronic infection |
Bacteria (Neisseria sp, Staphylococcus aureus, Streptococcus
sp, Mycobacteria sp), rickettsia (Rocky Mountain Spotted fever),
virus (Hepatitis viruses A, B, & C, Hantavirus, herpesviridae,
parvovirus B19, and human immunodeficiency virus), fungus, protozoa
(malaria), helminthic infections (gnathostomiasis, schistosomiasis) |
| Drugs |
Insulin, antibiotics (penicillin, sulfonamides, chloramphenicol,
streptomycin), anticonvulsants (hydantion), diuretics (thiazides,
furosemide), analgesics (aminosalicylic acid, phenylbutazone),
phenothiazines, vitamins, quinine, streptokinase, tamoxifen,
oral contraceptives, serum (sickness), propylthoiuracil, potassium
iodide, granulocyte colony stimulating factor (GCSF), leukotriene
inhibitors (montelukast), interferons (IFN-???), nicotine patches |
| Vaccines (336-341) |
Anti-influenza, anthrax, hepatitis B |
| Chemicals, environmental agents, external factors |
Insecticides, petroleum products, particulate silca (quartz,
granite, sandstone, and grain dust), solvents, farm work, drug
abuse (cocaine), radiocontrast media, protein A column pheresis,
arthropod assaults, prolonged exercise, coronary artery bypass
surgery, coral ulcers
|
| Allergy |
Food allergens (milk proteins, gluten), drug allergy, atopy,
hyposensitization antigen |
| Connective tissue diseases |
Systemic lupus erytthematosus, rheumatoid arthtitis, Sjögren’s
syndrome, mixed connective tissue disease, scleroderma, dermatomyositis/mysositis,
relapsing polychondritis, ankylosing spondylitis, primary biliary
cirrhosis, adult Still’s disease
|
| Other systemic inflammatory diseases |
Behçet’s disease, sarcoidosis, inflammatory bowel
disease |
| Chronic disease |
Cryoglobulinemia, hyperglobulinemic states, cystic fibrosis,
bowel-bypass syndrome, alpha-1 anti-trypsin deficiency, St.
Jude aortic valve replacement, diabetes mellitus, chronic hepatitis
(viral, alcoholic), endocarditis, Wiskott-Aldrich syndrome,
Hemolytic anemia
|
| Immunodeficiency states |
Primary combined immunodeficiency, acquired immunodeficiency
syndrome (AIDS) |
| Cancer, lymphroliferative disorders |
Hodgkin’s disease, mycosis fungoides, chronic lymphocytic
leukemia, B and T cell lymphomas, myeloma, adult T cell lymphoma/leukemia,
Waldenström’s macroglobulinemia, angioimmunoblasttic
lymphadenopathy, Hairy cell leukemia |
| Cancer, solid tumors/carcinomas |
Lung, colon, renal, breast, prostate, head and neck squamous
cell carcinoma, nasopharyngeal carcinoma, Barrett’s esophagus
|
From (7, 13, 30, 31, 34, 44, 61-77,
88, 89). eNOS: endothelial nitric oxide synthetase. MHC:
major histocompatibility complex.
Table 4. Frequency of etiologic factors and
associated diseases in patients presenting with cutaneous vasculitis
along with incidence
| |
Frequency*
mean%, range |
Incidence‡
median rate, range (regions studied) |
| Idiopathic vasculitis (CLA)§ |
39.0%, 3-72% |
15.4/106- 29.7/106 (Norwich, England/Lugo, Spain)† |
| Henoch-Schönlein purpura (HSP) |
10.1%, 0-88% |
13.0/106- 14.3/106 (Norwich, England/Lugo, Spain) |
| Primary systemic vasculitis |
4.4%, 0-13% |
19.8/106 (Norwich, England) |
| Wegener’s Granulomatosis (WG) |
1.1%, 0-6% |
4.9/106 (Lugo, Spain), 0.5/106- 15.0/106 (Bath/Bristol, England/Northern
Norway) |
| Polyarteritis nodosa (PAN) |
2.5%, 0-10% |
7.0/106 (Olmsted County, Minnesota), 2.0/106-77/106 (Michigan/Alaska) |
| Churg-Strauss syndrome (CSS) |
0.6%, 0-8% |
2.4/106 (Norwich, England), 1.1/106- 4.0106 (Lugo, Spain/Olmsted
county, Minnesota) |
| Giant cell arteritis (GCA) |
0.1%, 0-2% |
10.2/105 (Lugo, Spain), 0.1-27/105 (Japan/northern India/Iceland) |
| Microscopic polyangiitis (MPA) |
=1%¶ |
8.0/106 (Norwich, England), 0.5/106-24/106 (Leicester, England/Kuwait) |
Connective tissue disease (CTD)
|
11.7%, 0-44% |
|
| Systemic lupus erythematosus (SLE) |
3.5%, 0-19% |
5.3/106 (Lugo, Spain) |
| Rheumatoid arthritis (RA) |
5.2%, 0-20% |
7.9/106 (Norwich, England 2004), 6.0/106- 12.5/106 (Norwich,
England 1994/Lugo, Spain) |
| Sjögren syndrome (SS) |
1.3%, 0-25% |
|
| Other systemic disorders |
2%, 0-15% |
4.8/106 (Lugo, Spain) |
| Behçets disease (BD) |
0.6%, 0-3% |
|
| Sarcoidosis |
0.2%, 0-2% |
|
| Inflammatory Bowel disease |
0.7%, 0-8% |
|
| Cryoglobulinemic vasculitis (CV) |
2.9%, 0-28% |
|
| Infections (mostly upper respiratory tract) |
22.5%, 0-62% |
|
| Viral hepatitis |
3.1%, 0-22% |
|
| Strepococcus sp |
2.1%, 0-28% |
|
| Septicemia/severe bacterial infections |
1.2%, 0-11% |
|
Drugs
|
20.1%, 0-69% |
|
| Malignancy |
4.3%, 0-16% |
|
*: Pooled data (n=2061) from studies (13,
31, 34, 44, 61-85) examining for triggering factors and/or
associated conditions in patients, mostly adults, presenting with
cutaneous vasculitis. §: many of these case would be termed
hypersensitivity vasculitis per ACR or cutaneous leukocytoclastic
angiitis (CLA) per CHCC criteria. ‡: rates and ranges derived
from Gonzalez-Gay & Garcia-Porrua (87),
Watts & Scott (86) and Watts et all (100).
Rates are dependent on period and population studied. †: per
criteria of ACR for hypersensitivity vasculitis. ¶: From Watts
et al (75); cases of MPA would have fallen
under the diagnosis of PAN per ACR criteria.
Table 5. Pathogenic mechanisms implicated in
cutaneous vasculitis.
| Pathogenic mechanism* |
Vasculitic syndrome |
Vasculitis pattern |
In situ blood vessel |
Serologic studies |
References |
| Direct infection |
Rickettsial infections |
Lymphocytic small vessel |
Intra-endothelial Rickettsia species, T cells |
IgG to Rickttsia species |
(138, 255-257) |
| Type I Anaphylactic |
Eosinophilic vasculitis |
Eosinophilic small vessel |
MBP, ICAM, dec mast cells/tryptase |
inc Eos, inc MBP inc Neut, inc ESR, dec C |
(146, 147) |
| |
Churg Strauss Syndrome (CSS) |
Eosin-/neutrophilic mostly small and medium |
ECP, inc Eos, ExGr with eosinophilic necrosis |
inc Eos, inc IgE
inc p-ANCA, inc ESR, incIFN-?, inc IL-2 |
(145, 258-260) |
| Type II Cytotoxic-cytolytic antibody |
Wegener’s granulomatosis (WG) |
Neutrophilic mostly small and medium |
ExGr with basophilic necrosis |
cANCA,inc ESR, inc WBC, inc CRP, inc IFN-?, inc IL-2 |
(151, 258, 261-263) |
| |
Microscopic polyangiitis , |
Neutrophilic mostly small and medium |
(MPA) No ExGr |
pANCA |
(144, 151, 264) |
| Type III Immune complex |
Henoch-Schönlein Purpura (HSP) |
Neutrophilic small vessel |
IgA IC, MAC |
inc IgA |
(189) |
| |
Cutaneous leukocytoclastic angiitis (CLA/LCV/hypersensitivity
vasculitis) |
Neutrophilic small vessel |
IC, MAC, NE, ICAM-1, E-selectin, VLA |
dec C inc IL-2, inc Il-2r, inc IL-8,inc VEGF |
(86, 88, 170-172, 179, 265) |
| |
Cryoglobulinemic vasculitis (CV) |
Neutrophilic mostly small and medium |
IgG-mRF immune deposits |
dec C, Hepatitis C virus, inc Cryocrit |
(266) |
| |
Polyarteritis nodosa (PAN) |
Neutrophilic medium |
IC, MAC, E-selectin, ICAM |
dec C, Hepatitis B virus, incIFN-?, inc IL-2 |
(174, 188, 258, 267) |
| Type IV Delayed hypersensitivity |
Giant cell arteritis (GCA) |
Granulomatous medium vessel |
inc CD3+/CD4+? inc activated CD68+, IL-1b, VEGF, PDGF, IL-2,
IFN- |
dec CD3+/CD8+?? inc activated CD68+, Il-1?, TNF?, IL-6 |
(193) |
| |
Chronic graft-vs.-host disease |
Lymphocytic small vessel** |
dec microvessel density? |
CD8+, GMP-17 inc vWF |
(204, 205, 211) |
| |
Sneddon’s Syndrome |
Lymphocytic medium vessel**/endarteritis obliterans |
T-cells,incSMC, inc collagen |
AECA |
(47, 268, 269 |
Adapted from Schmitt and Gross (354) and Jennette (355).
*:Coombs and Gell classification (115). **: endothelialitis. ANCA:
antineutrophil cytoplasmic antibodies; pANCA perinuclear and cANCA-cytoplasmic.
AECA: antiendothelial antibodies. C?: complement consumption. CRP:
C-reactive protein. EBV: Epstein-Barr virus. ECP: eosinophilic cationic
protein. Eos: eosinophils. ESR: erythrocyte sedimentation rate.
ExGr: extravascular grnaulomas. GMP-17: granule membrane protein
17, marker of activated effector cytotoxic T cells. IC: immune complexes.
MAC: membrane attack complex, C5b-9. MBP: major basic protein. MRF:
monoclonal rheumatoid factor. Neut: neutrophils. NE: neutrophil
elastase. SMC: smooth muscle cells. VEGF: vascular endothelial growth
factor. VLA: very late activation antigen. vWF: von Willibrand factor
Table 6. Clinical assessment and laboratory
work up for extracutaneous (systemic) vasculitis and associated
disorders.
| Signs and symptoms of vasculitis |
Ancillary studies |
| Systemic (generalized) disease |
Malaise, myalgia, arthralgia/arthritis, headache,
fever, weight loss |
Skin biopsy (3 specimens)
1) 4-6mm punch or excisional biopsy extending to the subcutis
for routine histologic examination
2) 4mm punch for direct immunoflouesence
3) 4mm punch biopsy for tissue culture and sensitivity
Laboratory studies
1) Routine blood tests for full blood count, erythrocyte sedimentation
rate, aminotransferases, alkaline phospatase, albumin, bilirubin,
creatinine, blood urea nitrogen, serum electrolytes and urine
analysis
2) Tests for ANCA, antinuclear antibodies (ANA), rheumatoid
factor, antidouble-stranded DNA, cryoglobulins, preciptins
(Ro, La, RNP, Sm), and complement studeis(CH50, C3, C4)
3) Thrombophilia tests for anticardiolipin antibody, lupus
anticoaguolant (activated partial thromboplastin time, Russell
viper venom test), thrombin time, prothrombin time, antigenic
and functional antithrombin III, protein C, protein S, factor
V Leiden mutation, and serum homocysteine levels
4) Paraproteinemia screens including serum protein electrophoresis,
serum protein immunofixation, serum immunoglobulins and random
urine protein immunofixation
5) Viral serologic screens for human immunodeficiency virus
and hepatitis B and C
6) ECG, Chest X-ray |
| Mucous membranes and eyes |
Oral or genital ulcers, proptosis, conjunctivitis, episcleritis,
visual disturbances, uveitis, retinal exudates/hemorrhages |
| Ear, nose and throat disease |
Nasal obstruction, bloody nasal discharge, crusting, sinus
involvement, new deafness, hoarseness/stridor, subglottic stenosis
|
| Respiratory disease |
Persistent cough, dyspnea, wheeze, hemoptysis, pulmonary hemorrhage,
noudles, cavities, infiltrates, pleurisy, pleural effusion,
respiratory failure |
| Genitourinary disease |
Hypertension >95mgHg diastolic, proteinuria >0.2g/24hr,
hematuria >10 red blood cells/ml, renal impairment/failure,
rise in creatinine > 30% or fall in creatinine clearance
> 25% |
| Neurologic disease |
Organic confusion/dementia, seizures (not hypertensive), stroke,
cord lesion, sensory peripheral neuropathy, cranial nerve palsy,
motor mononeuritis multiplex |
| Gastrointestinal disease |
Severe abdominal pain, bloody diarrhea, intestinal perforation/infarction,
acute pancreatitis |
Adapted from Luqmani et al (223) and
Mimoune D et al (46).
Review article text
References
Figures 1-10
Figures 11-20
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