Clinical Approach to Cutaneous Vasculitis

Ko-Ron Chen; J. Andrew Carlson

Am J Clin Dermatol. 2008;9(2):71-92.

Treatment

In general, treatment of cutaneous vasculitis should include avoidance of triggers (excessive standing, infection, drugs) and the induction of therapy that follows a ladder from safe and cheap (e.g. support hose and antihistamines) for non-ulcerative, purpuric lesions to expensive and dangerous (e.g. pulses of cyclophosphamide) treatments for severe systemic disease with ulcers and infarcts ( Table VI ).^{[1,4,6,7,8,38,83]}

In most instances, cutaneous vasculitis represents a self-limited condition and will be relieved by leg elevation, avoidance of standing, and therapy with NSAIDs. There is minimal evidence for the benefit of many therapeutic modalities in this setting. Identification of the cause of vasculitis (e.g. infection, drug, or CTD) and its treatment is the first and most effective means of managing a patient with vasculitis. In addition, patients should also be given basic instructions on self-care, including diminishing factors known to exacerbate vasculitis such as excessive standing, avoidance of cold exposure, and wearing tight fitting clothing, and to rest with the legs elevated and to keep warm. Symptomatic relief of pruritus or burning in most cases can be achieved with NSAIDs, acetylsalicylic acid (aspirin), or antihistamines. These therapies, however, have not been shown to alter the course of disease or to prevent recurrence. In patients who show significant symptomatic disease, recurrent vasculitis, progression of disease to nodular, ulcerative, or vesiculobullous vasculitis, or who develop systemic involvement, more aggressive therapy will be required.

For mild, limited cutaneous vasculitis that is persistent, recurrent, and/or symptomatic, use of colchicine or dapsone, alone or together, has been shown to lead to prompt and complete resolution of cutaneous vasculitis in case reports and case series.^[1,38] For moderate-to-severe skin disease, prednisone is considered standard therapy for single episodic moderate-to-severe CLA. For persistent/resistant CLA, prednisone monotherapy is not recommended because of its significant serious adverse effects, and instead is used as an adjunctive, low-dose therapy with other corticosteroid-sparing agents such as methotrexate or azathioprine.

Standard therapy for systemic vasculitis with internal organ involvement is a combination of prednisone and cyclophosphamide that leads to a 1-year survival rate of >80%; 5-year survival rates are significantly lower due to disease relapse and treatment related-morbidity, mostly due to immunosuppressive effects.^[1,6,83] Once remission has been induced by cyclophosphamide (3-6 months), a switch to a maintenance regimen with methotrexate or azathioprine (maintenance therapy) is recommended to avoid the adverse complications of cyclophosphamide therapy. Mycophenolate mofetil or leflunomide are used in patients intolerant of, or who show a lack of efficacy from, methotrexate or azathioprine. Maintenance therapy should continue for at least 24 months following successful induction of remission.

For both refractory systemic and cutaneous vasculitis, intravenous immunoglobulin and plasmapheresis have been shown to be effective in case reports and case series.^[1,38]As the pathogenic mechanisms for most vasculitic syndromes are still being defined, targeted therapy interrupting the vasculitis sequence has not been widely implemented in the treatment of vasculitis to date with the exception of tumor necrosis factor-a blockade and B-cell lymphocyte depletion. To date, infliximab has shown the most promise in the treatment of vasculitis, as demonstrated in open-label trials of ANCA-positive systemic vasculitis, Behçet disease, CV, RV, and CPAN. Depletion of B cells by rituximab has shown great promise in open-label studies of CV, WG, and ANCA-associated systemic vasculitis. Lastly, other promising therapies for patients with recalcitrant digital ischemia are vascular dilators such as the endothelin receptor antagonists bosentan and prostacyclin analogs such as iloprost.^[87]

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Table I. Classification of Cutaneous Vasculitis by Histologic Findings and Laboratory Studies (Reproduced From Carlson and Chen, ^[2] With Permission)
Small-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cutaneous idiopathic leukocytoclastic angiitis (IgM/IgG), leukocytoclastic vasculitis secondary to infections or drugs (IgM/IgG) [also known as hypersensitivity vasculitis, allergic vasculitis], Henoch-Schönlein purpura (IgA), acute infantile hemorrhagic edema (IgA), urticarial vasculitis (IgM/IgG), infective endocarditis (IgM/IgG/IgA), chronic localized fibrosing vasculitis: erythema elevatum diutinum (IgA), granuloma faciale (IgM/IgG), inflammatory pseudotumors
Incidental vasculitis (DIF-): Sweet syndrome, pustular vasculitis of the dorsa of the hands, pyoderma gangrenosum
Eosinophilic
Eosinophilic vasculitis, primary or secondary to connective tissue disease or parasites
Some cases of Churg-Strauss syndrome
Granulomatous
Post-herpetic eruptions
Necrobiosis lipoidica (some lesions)
Lymphocytic
Rickettsial and viral infections
Lichenoid dermatitides, some cases, e.g. pityriasis lichenoides, graft vs host disease, perniosis
Rare drug reactions and arthropod assaults
Mixed, predominately small- and medium-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cryoglobulinemic vasculitis (IgM/IgG), hepatitis B- and C-related vasculitis (IgM/IgG), connective tissue disease vasculitis (e.g. lupus, rheumatoid arthritis, Sjögren syndrome) [IgM/IgG]
ANCA-associated/pauci-immune (DIF-): Wegener granulomatosis, microscopic polyangiitis (microscopic polyarteritis nodosa), Churg-Strauss syndrome, drug-induced ANCA vasculitis
Miscellaneous/other: Behçet disease, septic vasculitis, inflammatory bowel disease, malignancy-associated vasculitis
Eosinophilic
Churg-Strauss syndrome
Lymphocytic
Degos disease
Rickettsial and viral infections
Collagen tissue disease vasculitis (e.g. Sjögren syndrome, lupus vasculitis)
Behçet disease
Muscular (medium)-vessel vasculitis
Neutrophilic
Polyarteritis nodosa, classic and cutaneous
Nodular vasculitis (erythema induratum)
Eosinophilic
Juvenile temporal arteritis
Granulomatous
Giant cell (temporal) arteritis
Takayasu arteritis
Post-herpetic eruptions
Nodular vasculitis (erythema induratum)
Lymphocytic
Sneddon syndrome
Degos disease
Beurger disease (thromboangiitis obliterans)
Superficial thrombophlebitis (Mondor disease, sclerosing lymphangiitis)
Kawasaki disease

ANCA = anti-neutrophil cytoplasmic antibody; DIF+ = direct immunofluorescence examination of skin lesions shows vessel-wall immune complexes and/or complement deposition; DIF- = direct immunofluorescence examination of skin lesions reveals no vessel-wall immune complexes and/or complement deposition.

Clinical Manifestations of Vasculitis Based on Vessel Size Affected (Adapted From Carlson et al., ^[1] With Permission; © Elsevier 2006)
Large^a	Medium^b	Small^c
Limb claudication	Subcutaneous nodules	Purpura
Asymmetric blood pressure	Ulcers (deep)	Infiltrated erythema
Absence of pulses	Livedo reticularis	Urticaria
Aortic dilation	Pitted palmar/digital scars	Vesiculobullous lesions
Bruits	Digital gangrene	Ulcers (superficial)
Constitutional symptoms^d	Mononeuritis	Splinter hemorrhages
	Aneurysms	Scleritis, episcleritis, uveitis
	Infarct	Palisaded neutrophilic granulomatous dermatitis^e
	Erythematous nodules	Glomerulonephritis
	Hypertension (renal artery)	Gastric colic
	Constitutional symptoms^d	Pulmonary hemorrhage
		Constitutional symptoms^d

^a Large vessels (aorta and its branches) are not found in the skin. However, large-vessel vasculitic syndromes, giant cell arteritis, and Takayasu arteritis can rarely involve muscular arteries and small vessels of the skin.^[3]
^b In the skin, medium vessels are the small arteries or small veins (diameter <800 µm, four to eight medial muscular layers without distinct tunica adventitia) found in the subcutis or dermal-subcutis junction.
^c Small vessels include arterioles, post-capillary venules, and capillaries found in both the dermis and subcutis.
^d Fever, weight loss, malaise, arthralgia, and arthritis are common to vasculitic syndromes of all vessel sizes.
^e Also known as extravascular necrotizing granuloma. Small-vessel neutrophilic vasculitis is frequently seen in the vicinity of granulomas and necrosis.

Mimickers of Vasculitis (Pseudovasculitis) ^a [Adapted From Grau ^[34] and Carlson and Chen ^[8]]
Relative frequency	Pseudovasculitic disorder	Mechanism
Common	Antiphospholipid antibody syndrome	Thrombosis
	Cholesterol embolization	Embolus
	Septic vasculitis (vasculopathy)^b	Infection and embolus
	Infective endocarditis^b	Infection and embolus
	Pigmented purpuric dermatitis	Hemorrhage
	Solar purpura	Hemorrhage
	Purpura fulminans	Thrombosis
	Warfarin necrosis	Thrombosis
	Livedo vasculopathy	Thrombosis
Less frequent than vasculitis	Hypothenar hammer syndrome (fibromuscular dysplasia)	Vascular trauma
	Scurvy	Hemorrhage
	Thrombotic thrombocytopenic purpura	Thrombosis
Rare	Amyloidosis	Vessel-wall pathology
	Calciphylaxis	Vessel-wall pathology
	Cardiac myxoma	Embolus
	Ergotamine and cocaine abuse	Vasospasm
	Angiotropic B-cell lymphoma	Intravascular proliferation/embolus

^a Signs indicating the possibility of pseudovasculitis: atherosclerosis, significant disease; non-confirmatory biopsies for vasculitis; cardiac murmur; livedo reticularis; absence of inflammatory markers (e.g. normal erythrocyte sedimentation rate); abnormal eating habits (e.g. chronic alcoholism); and isolated vascular lesions on imaging studies.
^b Can also present as an authentic vasculitis with immune complex deposition.

Classification of Cutaneous Vasculitis by Histologic Findings and Laboratory Studies (Reproduced From Carlson and Chen, ^[2] With Permission)
Small-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cutaneous idiopathic leukocytoclastic angiitis (IgM/IgG), leukocytoclastic vasculitis secondary to infections or drugs (IgM/IgG) [also known as hypersensitivity vasculitis, allergic vasculitis], Henoch-Schönlein purpura (IgA), acute infantile hemorrhagic edema (IgA), urticarial vasculitis (IgM/IgG), infective endocarditis (IgM/IgG/IgA), chronic localized fibrosing vasculitis: erythema elevatum diutinum (IgA), granuloma faciale (IgM/IgG), inflammatory pseudotumors
Incidental vasculitis (DIF-): Sweet syndrome, pustular vasculitis of the dorsa of the hands, pyoderma gangrenosum
Eosinophilic
Eosinophilic vasculitis, primary or secondary to connective tissue disease or parasites
Some cases of Churg-Strauss syndrome
Granulomatous
Post-herpetic eruptions
Necrobiosis lipoidica (some lesions)
Lymphocytic
Rickettsial and viral infections
Lichenoid dermatitides, some cases, e.g. pityriasis lichenoides, graft vs host disease, perniosis
Rare drug reactions and arthropod assaults
Mixed, predominately small- and medium-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cryoglobulinemic vasculitis (IgM/IgG), hepatitis B- and C-related vasculitis (IgM/IgG), connective tissue disease vasculitis (e.g. lupus, rheumatoid arthritis, Sjögren syndrome) [IgM/IgG]
ANCA-associated/pauci-immune (DIF-): Wegener granulomatosis, microscopic polyangiitis (microscopic polyarteritis nodosa), Churg-Strauss syndrome, drug-induced ANCA vasculitis
Miscellaneous/other: Behçet disease, septic vasculitis, inflammatory bowel disease, malignancy-associated vasculitis
Eosinophilic
Churg-Strauss syndrome
Lymphocytic
Degos disease
Rickettsial and viral infections
Collagen tissue disease vasculitis (e.g. Sjögren syndrome, lupus vasculitis)
Behçet disease
Muscular (medium)-vessel vasculitis
Neutrophilic
Polyarteritis nodosa, classic and cutaneous
Nodular vasculitis (erythema induratum)
Eosinophilic
Juvenile temporal arteritis
Granulomatous
Giant cell (temporal) arteritis
Takayasu arteritis
Post-herpetic eruptions
Nodular vasculitis (erythema induratum)
Lymphocytic
Sneddon syndrome
Degos disease
Beurger disease (thromboangiitis obliterans)
Superficial thrombophlebitis (Mondor disease, sclerosing lymphangiitis)
Kawasaki disease

Classification of Cutaneous Vasculitis by Histologic Findings and Laboratory Studies (Reproduced From Carlson and Chen, ^[2] With Permission)
Small-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cutaneous idiopathic leukocytoclastic angiitis (IgM/IgG), leukocytoclastic vasculitis secondary to infections or drugs (IgM/IgG) [also known as hypersensitivity vasculitis, allergic vasculitis], Henoch-Schönlein purpura (IgA), acute infantile hemorrhagic edema (IgA), urticarial vasculitis (IgM/IgG), infective endocarditis (IgM/IgG/IgA), chronic localized fibrosing vasculitis: erythema elevatum diutinum (IgA), granuloma faciale (IgM/IgG), inflammatory pseudotumors
Incidental vasculitis (DIF-): Sweet syndrome, pustular vasculitis of the dorsa of the hands, pyoderma gangrenosum
Eosinophilic
Eosinophilic vasculitis, primary or secondary to connective tissue disease or parasites
Some cases of Churg-Strauss syndrome
Granulomatous
Post-herpetic eruptions
Necrobiosis lipoidica (some lesions)
Lymphocytic
Rickettsial and viral infections
Lichenoid dermatitides, some cases, e.g. pityriasis lichenoides, graft vs host disease, perniosis
Rare drug reactions and arthropod assaults
Mixed, predominately small- and medium-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cryoglobulinemic vasculitis (IgM/IgG), hepatitis B- and C-related vasculitis (IgM/IgG), connective tissue disease vasculitis (e.g. lupus, rheumatoid arthritis, Sjögren syndrome) [IgM/IgG]
ANCA-associated/pauci-immune (DIF-): Wegener granulomatosis, microscopic polyangiitis (microscopic polyarteritis nodosa), Churg-Strauss syndrome, drug-induced ANCA vasculitis
Miscellaneous/other: Behçet disease, septic vasculitis, inflammatory bowel disease, malignancy-associated vasculitis
Eosinophilic
Churg-Strauss syndrome
Lymphocytic
Degos disease
Rickettsial and viral infections
Collagen tissue disease vasculitis (e.g. Sjögren syndrome, lupus vasculitis)
Behçet disease
Muscular (medium)-vessel vasculitis
Neutrophilic
Polyarteritis nodosa, classic and cutaneous
Nodular vasculitis (erythema induratum)
Eosinophilic
Juvenile temporal arteritis
Granulomatous
Giant cell (temporal) arteritis
Takayasu arteritis
Post-herpetic eruptions
Nodular vasculitis (erythema induratum)
Lymphocytic
Sneddon syndrome
Degos disease
Beurger disease (thromboangiitis obliterans)
Superficial thrombophlebitis (Mondor disease, sclerosing lymphangiitis)
Kawasaki disease

Overlap of the Range of Clinicopathologic Findings Found in Cutaneous and Systemic Vasculitic Syndromes (Reproduced From Carlson and Chen, ^[2] With Permission From Lippincott Williams and Wilkins)
Affected organs	CLA (%)	HSP (%)	UV^a (%)	CV (%)	PAN (%)	CSS (%)	MPA (%)	WG (%)	GCA (%)	LV (%)	RV (%)
Skin disease	100	100	100	90	28-60	50-78	50-65	40-50	<50^b	90	80-90
DIF+ (C3 or Ig), vessels	82-100	87-93 (IgA)	50, 30-100^a	83, 67-100	≤60^c	0	0	54, 25-75	-	≈53	≈79 (IgM)
BMZ	0	0	34, 1-96	-	20	-	-	Rare	-	≈60	-
ANCA (any type, IIF)	Rare	IgA ANCA	-	10	10-27	40-75	≈75	90, 65-100	Rare	11-31	32, 16-43
PR-3/c-ANCA	-	-	-	1	8	3-35	10-50	75-90	-	0	0
MPO/p-ANCA	-	-	-	2	11	38-59	50-80	5-20	-	31	<2
Systemic symptoms^d	6-23	<10	7	100	31-76	72-100	41-79	27-51	40-50	50-100	45-72
Upper respiratory tract symptoms	-	<5	<5	<5	<5	50-75	0	95	9	Rare	-
Lung disease	-	<5	10	<5	<5	≤100	≤70	≤85	-	12% (1.4 OR)	9-34
asthma	-	-	7	-	-	90-100	0	0	-	Rare	-
x-ray findings	-	-	3	-	-	40-50	15-70	70-85	-	-	-
alveolar hemorrhage	-	Rare	-	-	-	7	10-50	5-15	-	-	-
Genitourinary manifestations	3-7	40-50	<5	30-55	60-80^e	≤40	≤90	≤80	-	16-38	6-25
glomerulonephritis	-	12	3	-	0	10-40	75-90	70-80	-	-	-
lower tract disease	-	Rare	-	-	5-10	<2	<5	<2	-	-	-
Gastrointestinal manifestations	3-5	35-65	15	<40	14-53	30-40	30	<5	-	18	4-10
Nervous system manifestations	-	10	<5	40-80	≤72	≤80	≤70	≤50	≤15	12-21	36-45
central	-	-	Rare	Rare	3-28	5-30	10-15	5-10	3-15	(2.1 OR)	-
peripheral	-	-	<5	≤80	38-72	70-80	60-70	40-50	-	5	-
Cardiac disease	-	Rare	Rare	<40	5-30	10-40	10-15	10-25	-	15% (3.1 OR)	6-34
Ocular disease	-	Rare	4	40	<5	<5	<5	50-60	14-16		4-25
Arthralgia/arthritis	14-65	75	33	70	50-75	40-50	40-60	60-70	15-39	62-67	100

^a For patients with hypocomplementemic UV, the frequency of DIF+ results and extracutaneous symptoms is significantly elevated.^[45]
^b Scalp/artery tenderness, scalp necrosis, scalp cords or artery swelling, decreased or absent temporal artery pulses.
^c DIF evaluation of cases of cutaneous PAN.^[47]
^d Symptoms of weight loss, anorexia, malaise, fever, fatigue, and/or weakness.
^e Renal involvement in PAN affects arteries and results in nephrogenic hypertension.
ANCA = anti-neutrophil cytoplasmic antibody; BMZ = basement membrane zone; c-ANCA = cytoplasmic ANCA; CLA = cutaneous leukocytoclastic angiitis; CSS = Churg-Strauss syndrome; CV = cryoglobulinemic vasculitis; DIF = direct immunofluorescence; GCA = giant cell (temporal) arteritis; HSP = Henoch-Schönlein purpura; IIF = indirect immunofluorescence; LV = lupus vasculitis; MPA = microscopic polyangiitis; MPO = myeloperoxidase; OR = odds ratio of likelihood that patient with LV will have disease affecting that organ compared with systemic lupus erythematosus patient with vasculitis^[46]; PAN = polyarteritis nodosa; p-ANCA = perinuclear pattern of ANCA; PR-3 = anti-proteinase-3; RV = rheumatoid vasculitis; UV = urticarial vasculitis; WG = Wegener granulomatosis; - indicates no data.

Clinical, Pathologic, and Laboratory Findings in Patients With Cutaneous Vasculitis Indicating a High Probability of Systemic Disease (Adapted From Russell and Gibson ^[7])
Findings	Suspected systemic vasculitis syndrome
Clinical signs or symptoms
High fever	Infection, systemic inflammatory disorders
Paresthesia, foot drop	CSS, PAN, RV
Abdominal pain	HSP, CSS, MPA, PAN, RV, LV, BD
Frank arthritis	RV, infection, PAN, systemic inflammatory disorder
Hypertension	PAN
Purpura above waist, upper extremities	HSP, MPA, WG, CSS
>1 type of vasculitic lesion^a	HSP, MPA, WG, CSS, RV, LV, BD
Punctate palmar lesions	LV
Laboratory evaluation
ESR >40 mm/h	Infection, hematologic malignancies, systemic inflammatory disorders
Elevated RF, cryoglobulins, and low complement	CV
Chest x-ray: infiltrates or cavities	WG (fixed infiltrates), CSS (non-fixed infiltrates), MPA, malignancy
Hematuria and/or proteinuria and/or abnormal creatinine	Dermal-renal vasculitis syndrome: WG, MPA, HSP, SLE, CV, infective endocarditis
Hypocomplementemia	UV associated with SLE, RV, CV, infective endocarditis
Abnormal blood count	Infection, hematologic malignancy, systemic inflammatory disorders
c-ANCA (PR-3)	WG
p-ANCA (MPO)	MPA, CSS
Eosinophilia, elevated IgE, elevated RF	CSS
Histologic examination
Deep dermal and/or subcutaneous small- and/or muscular-vessel vasculitis	Systemic vasculitis syndrome (WG, CSS, MPA, CV, BD, RV, LV, septic vasculitis), malignancy-associated
Palisaded neutrophilic (extravascular) granulomatous dermatitis	WG, CSS, LV, RV
Tissue neutrophilia	SLE, infection
Tissue eosinophilia	CSS and drug-induced vasculitis
Direct immunofluorescence
Isolated or predominant IgA vascular deposits	HSP
Lupus band (IgG, IgM, and/or C3 at the BMZ)	LV, UV associated with SLE

^a Purpura plus ulcers, nodules, bullae, and/or livedo reticularis.
BD = Behçet disease; BMZ = basement membrane zone; c-ANCA = cytoplasmic anti-neutrophil cytoplasmic antibody; CSS = Churg-Strauss syndrome; CV = cryoglobulinemic vasculitis; ESR = erythrocyte sedimentation rate; HSP = Henoch-Schönlein purpura; LV = lupus vasculitis; MPA = microscopic polyangiitis; MPO = myeloperoxidase; PAN = polyarteritis nodosa; p-ANCA = perinuclear pattern of anti-neutrophil cytoplasmic antibody; PR-3 = anti-proteinase-3; RF = rheumatoid factor; RV = rheumatoid vasculitis; SLE = systemic lupus erythematosus; UV = urticarial vasculitis; WG = Wegener granulomatosis.

Therapeutic Ladder for Treatment of Cutaneous Vasculitis (Modified From Carlson et al., ^[1] With Permission; © Elsevier 2006)
Category	Findings	Treatment (disease) [level of evidence]^a
General measures	Most cases of cutaneous vasculitis will represent a self-limited, short-lived (<3 weeks), single episode of purpura of the lower extremities	Confirm diagnosis by biopsy (all vasculitic syndromes) Exclude systemic disease Determine whether triggers or causative disease exist and remove or treat, respectively [IV] Rest, avoid standing [none] Leg elevation [none] Avoid cold exposure and tight fitting clothing [none] Support hose [none] Antihistamines, aspirin (acetylsalicylic acid), or NSAIDs for symptomatic relief [III]
Mild, limited skin disease	Persistent or recurrent disease and/or symptomatic disease (burning and pruritus)	Dapsone and/or colchicines (CLA, HSP, BD, UV) Dapsone: start at 25-50 mg/day, titrate [V] Colchicines: 0.5-0.6 mg two to three times a day [for V; against effect IV] Other agents: pentoxifylline: 400 mg three times a day (BD, CPAN) [V]
Moderate-to-severe skin disease	Extensive and/or recurrent skin disease with persistent lesions, development of vesicles, ulcers and or nodules, and/or intractable symptoms	Methotrexate, azathioprine, and/or prednisone (GCA, CPAN, CLA, RV, LV) Methotrexate: 5-20 mg/week [V] Azathioprine: maximum dose dependent on TPMT levels, TPMT <5 U, no azathioprine; 5-13.7 U, 0.5 mg/kg; 13.7-19 U, 1.5 mg/kg; >19 U, 2.5 mg/kg [IV] Prednisone: 15-80 mg/day orally or 1-1.5 mg/kg/day [III] Other agents Hydroxchloroquine: 400 mg three times a day (HUV, LV) [V] Cyclosporine (ciclosporin): 2.5-5 mg/kg/day orally, divided twice a day [V] Cyclophosphamide: 100 mg/day to 2 g/kg/day orally [V]
Systemic vasculitis present	Skin and other organ disease with risk of death or permanent organ damage, serum creatinine >150 µmol/L (severe >500 µmol/L)	Prednisone ± cyclophosphamide or azathioprine or cyclosporine or mycophenolate mofetil (CSS, MPA, PAN, WG, HSP) [Ia] Intravenous methylprednisolone 1 g/day for 3 days, then prednisone: 1-1.5 mg/kg/day orally [I] Azathioprine: maximum dose dependent on TPMT levels, TPMT <5 U, no azathioprine; 5-13.7 U, 0.5 mg/kg; 13.7-19 U, 1.5 mg/kg; >19 U, 2.5 mg/kg [Ia] Cyclophosphamide: 100 mg/day to 2 g/kg/day orally [Ia] or as 12 pulses^[85,86](CSS, MPA, PAN) [Ib] Cyclosporine: 2.5-5 mg/kg/day orally, divided twice a day (II) Mycophenolate mofetil: 2 g/day orally (HUV, WG, MPA) [Ib]
Maintenance therapy	No evidence of active systemic vasculitis (remission)	Withdrawal of cyclophosphamide, with substitution of azathioprine or methotrexate for ≈24 months or more (ANCA-positive patients should continue immunosuppression for up to 5 years^[6]) [Ib/IIb]
Relapsing vasculitis	Moderate skin/minor systemic disease	Prednisone (increased dosage), followed by gradual taper and methotrexate or azathioprine (WG) [III]
	Severe systemic disease	Cyclophosphamide and prednisone [III] or plasmapheresis [V]
Novel therapy	Treatment resistance/refractory vasculitis	TNF inhibitors: etanercept/infliximab (BD, WG, PAN) [against Ib/for III]
	Specific underlying disease	Intravenous immunoglobulin 200-1000 mg/kg/day (BD, CLA, WG, MPA) [Ib] Plasmapheresis (CV, WG, CSS, MPA, PAN) [IV] Rituximab (CV, WG, HUV) [III] Leflunomide (WG, RV) [III] Vascular dilators, bosentan, iloprost (PAN) [V]

^a Levels of evidence based on Sunderkotter et al.^[9] and taken from reviews by Sunderkotter et al.,^[9] Fiorentino,^[38] Russell and Weenig,^[84] and Bosch et al.^[83]
ANCA = anti-neutrophil cytoplasmic antibody; BD = Behçet disease; CSS = Churg-Strauss syndrome; CLA = cutaneous leukocytoclastic angiitis; CPAN = cutaneous PAN; CV = cryoglobulinemic vasculitis; GCA = giant cell arteritis; HSP = Henoch-Schönlein purpura; HUV = hypocomplementemic UV; LV = lupus vasculitis; MPA = microscopic polyangiitis; PAN = polyarteritis nodosa; RV = rheumatoid vasculitis; TNF = tumor necrosis factor; TPMT = thiopurine methyltransferase; U = units; UV = urticarial vasculitis; WG = Wegener granulomatosis.

Mimickers of Vasculitis (Pseudovasculitis) ^a [Adapted From Grau ^[34] and Carlson and Chen ^[8]]
Relative frequency	Pseudovasculitic disorder	Mechanism
Common	Antiphospholipid antibody syndrome	Thrombosis
	Cholesterol embolization	Embolus
	Septic vasculitis (vasculopathy)^b	Infection and embolus
	Infective endocarditis^b	Infection and embolus
	Pigmented purpuric dermatitis	Hemorrhage
	Solar purpura	Hemorrhage
	Purpura fulminans	Thrombosis
	Warfarin necrosis	Thrombosis
	Livedo vasculopathy	Thrombosis
Less frequent than vasculitis	Hypothenar hammer syndrome (fibromuscular dysplasia)	Vascular trauma
	Scurvy	Hemorrhage
	Thrombotic thrombocytopenic purpura	Thrombosis
Rare	Amyloidosis	Vessel-wall pathology
	Calciphylaxis	Vessel-wall pathology
	Cardiac myxoma	Embolus
	Ergotamine and cocaine abuse	Vasospasm
	Angiotropic B-cell lymphoma	Intravascular proliferation/embolus

Therapeutic Ladder for Treatment of Cutaneous Vasculitis (Modified From Carlson et al., ^[1] With Permission; © Elsevier 2006)
Category	Findings	Treatment (disease) [level of evidence]^a
General measures	Most cases of cutaneous vasculitis will represent a self-limited, short-lived (<3 weeks), single episode of purpura of the lower extremities	Confirm diagnosis by biopsy (all vasculitic syndromes) Exclude systemic disease Determine whether triggers or causative disease exist and remove or treat, respectively [IV] Rest, avoid standing [none] Leg elevation [none] Avoid cold exposure and tight fitting clothing [none] Support hose [none] Antihistamines, aspirin (acetylsalicylic acid), or NSAIDs for symptomatic relief [III]
Mild, limited skin disease	Persistent or recurrent disease and/or symptomatic disease (burning and pruritus)	Dapsone and/or colchicines (CLA, HSP, BD, UV) Dapsone: start at 25-50 mg/day, titrate [V] Colchicines: 0.5-0.6 mg two to three times a day [for V; against effect IV] Other agents: pentoxifylline: 400 mg three times a day (BD, CPAN) [V]
Moderate-to-severe skin disease	Extensive and/or recurrent skin disease with persistent lesions, development of vesicles, ulcers and or nodules, and/or intractable symptoms	Methotrexate, azathioprine, and/or prednisone (GCA, CPAN, CLA, RV, LV) Methotrexate: 5-20 mg/week [V] Azathioprine: maximum dose dependent on TPMT levels, TPMT <5 U, no azathioprine; 5-13.7 U, 0.5 mg/kg; 13.7-19 U, 1.5 mg/kg; >19 U, 2.5 mg/kg [IV] Prednisone: 15-80 mg/day orally or 1-1.5 mg/kg/day [III] Other agents Hydroxchloroquine: 400 mg three times a day (HUV, LV) [V] Cyclosporine (ciclosporin): 2.5-5 mg/kg/day orally, divided twice a day [V] Cyclophosphamide: 100 mg/day to 2 g/kg/day orally [V]
Systemic vasculitis present	Skin and other organ disease with risk of death or permanent organ damage, serum creatinine >150 µmol/L (severe >500 µmol/L)	Prednisone ± cyclophosphamide or azathioprine or cyclosporine or mycophenolate mofetil (CSS, MPA, PAN, WG, HSP) [Ia] Intravenous methylprednisolone 1 g/day for 3 days, then prednisone: 1-1.5 mg/kg/day orally [I] Azathioprine: maximum dose dependent on TPMT levels, TPMT <5 U, no azathioprine; 5-13.7 U, 0.5 mg/kg; 13.7-19 U, 1.5 mg/kg; >19 U, 2.5 mg/kg [Ia] Cyclophosphamide: 100 mg/day to 2 g/kg/day orally [Ia] or as 12 pulses^[85,86](CSS, MPA, PAN) [Ib] Cyclosporine: 2.5-5 mg/kg/day orally, divided twice a day (II) Mycophenolate mofetil: 2 g/day orally (HUV, WG, MPA) [Ib]
Maintenance therapy	No evidence of active systemic vasculitis (remission)	Withdrawal of cyclophosphamide, with substitution of azathioprine or methotrexate for ≈24 months or more (ANCA-positive patients should continue immunosuppression for up to 5 years^[6]) [Ib/IIb]
Relapsing vasculitis	Moderate skin/minor systemic disease	Prednisone (increased dosage), followed by gradual taper and methotrexate or azathioprine (WG) [III]
	Severe systemic disease	Cyclophosphamide and prednisone [III] or plasmapheresis [V]
Novel therapy	Treatment resistance/refractory vasculitis	TNF inhibitors: etanercept/infliximab (BD, WG, PAN) [against Ib/for III]
	Specific underlying disease	Intravenous immunoglobulin 200-1000 mg/kg/day (BD, CLA, WG, MPA) [Ib] Plasmapheresis (CV, WG, CSS, MPA, PAN) [IV] Rituximab (CV, WG, HUV) [III] Leflunomide (WG, RV) [III] Vascular dilators, bosentan, iloprost (PAN) [V]

Mimickers of Vasculitis (Pseudovasculitis) ^a [Adapted From Grau ^[34] and Carlson and Chen ^[8]]
Relative frequency	Pseudovasculitic disorder	Mechanism
Common	Antiphospholipid antibody syndrome	Thrombosis
	Cholesterol embolization	Embolus
	Septic vasculitis (vasculopathy)^b	Infection and embolus
	Infective endocarditis^b	Infection and embolus
	Pigmented purpuric dermatitis	Hemorrhage
	Solar purpura	Hemorrhage
	Purpura fulminans	Thrombosis
	Warfarin necrosis	Thrombosis
	Livedo vasculopathy	Thrombosis
Less frequent than vasculitis	Hypothenar hammer syndrome (fibromuscular dysplasia)	Vascular trauma
	Scurvy	Hemorrhage
	Thrombotic thrombocytopenic purpura	Thrombosis
Rare	Amyloidosis	Vessel-wall pathology
	Calciphylaxis	Vessel-wall pathology
	Cardiac myxoma	Embolus
	Ergotamine and cocaine abuse	Vasospasm
	Angiotropic B-cell lymphoma	Intravascular proliferation/embolus

Classification of Cutaneous Vasculitis by Histologic Findings and Laboratory Studies (Reproduced From Carlson and Chen, ^[2] With Permission)
Small-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cutaneous idiopathic leukocytoclastic angiitis (IgM/IgG), leukocytoclastic vasculitis secondary to infections or drugs (IgM/IgG) [also known as hypersensitivity vasculitis, allergic vasculitis], Henoch-Schönlein purpura (IgA), acute infantile hemorrhagic edema (IgA), urticarial vasculitis (IgM/IgG), infective endocarditis (IgM/IgG/IgA), chronic localized fibrosing vasculitis: erythema elevatum diutinum (IgA), granuloma faciale (IgM/IgG), inflammatory pseudotumors
Incidental vasculitis (DIF-): Sweet syndrome, pustular vasculitis of the dorsa of the hands, pyoderma gangrenosum
Eosinophilic
Eosinophilic vasculitis, primary or secondary to connective tissue disease or parasites
Some cases of Churg-Strauss syndrome
Granulomatous
Post-herpetic eruptions
Necrobiosis lipoidica (some lesions)
Lymphocytic
Rickettsial and viral infections
Lichenoid dermatitides, some cases, e.g. pityriasis lichenoides, graft vs host disease, perniosis
Rare drug reactions and arthropod assaults
Mixed, predominately small- and medium-vessel vasculitis
Neutrophilic
Immune-complex mediated (DIF+): cryoglobulinemic vasculitis (IgM/IgG), hepatitis B- and C-related vasculitis (IgM/IgG), connective tissue disease vasculitis (e.g. lupus, rheumatoid arthritis, Sjögren syndrome) [IgM/IgG]
ANCA-associated/pauci-immune (DIF-): Wegener granulomatosis, microscopic polyangiitis (microscopic polyarteritis nodosa), Churg-Strauss syndrome, drug-induced ANCA vasculitis
Miscellaneous/other: Behçet disease, septic vasculitis, inflammatory bowel disease, malignancy-associated vasculitis
Eosinophilic
Churg-Strauss syndrome
Lymphocytic
Degos disease
Rickettsial and viral infections
Collagen tissue disease vasculitis (e.g. Sjögren syndrome, lupus vasculitis)
Behçet disease
Muscular (medium)-vessel vasculitis
Neutrophilic
Polyarteritis nodosa, classic and cutaneous
Nodular vasculitis (erythema induratum)
Eosinophilic
Juvenile temporal arteritis
Granulomatous
Giant cell (temporal) arteritis
Takayasu arteritis
Post-herpetic eruptions
Nodular vasculitis (erythema induratum)
Lymphocytic
Sneddon syndrome
Degos disease
Beurger disease (thromboangiitis obliterans)
Superficial thrombophlebitis (Mondor disease, sclerosing lymphangiitis)
Kawasaki disease

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Clinical Approach to Cutaneous Vasculitis

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