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)
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
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

mean%, range
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%  
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).

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