Clinical Approach to Cutaneous Vasculitis

Ko-Ron Chen; J. Andrew Carlson

Disclosures

Am J Clin Dermatol. 2008;9(2):71-92. 

In This Article

Diagnosis

The type of cutaneous lesions closely correlates with the size of the vessel affected by vasculitis ( Table II ). Biopsies that show sparse superficial perivascular neutrophilic infiltrates associated with nuclear debris and extravasated red blood cells are found in urticarial papules and plaques, which last longer than 24 hours, burn rather than itch, and resolve with residual pigmentation. Small, predominately superficial vessel involvement results in purpuric macules, infiltrated erythema, whereas deeper dermal, small-vessel vasculitis correlates with palpable purpura, vesiculobullous lesions, and superficial ulcers (figures 2 and 3). Deep, punched-out ulcers, nodules, pitted scars, or livedo racemosa are associated with arterial muscular-vessel involvement, which will be located at the dermal-subcutis interface or within the subcutis (figure 4).[1,4] As the clinical manifestations of vasculitis are protean, and diagnosis is based on a constellation of clinical, histologic, imaging, and laboratory features, it is not surprising that non-vasculitis disorders can mimic vasculitis (figure 5). Cutaneous pseudovasculitis represents a heterogeneous collection of disorders that are capable of simulating cutaneous vasculitis and can be broadly classified into diseases that produce hemorrhage (petechiae, purpura, and ecchymoses) or vessel occlusion with resultant livedo, cyanosis, ulcers, digital necrosis, and/or gangrene ( Table III ).[8] The diagnosis of a pseudovasculitic disorder requires a high index of suspicion and should always be part of the differential diagnosis of vasculitis. A skin biopsy is a crucial step in differentiating pseudovasculitis from authentic vasculitis; the absence of histologic evidence of vasculitis, particularly after multiple biopsies, should direct evaluation and diagnosis towards a pseudovasculitis (figure 5).

Cutaneous vasculitis. Most examples of cutaneous vasculitis are the result of vascular immune complex deposits, which lead to a neutrophilic small-vessel (leukocytoclastic) vasculitis (a) manifesting as palpable purpura (b). Immune complexes can also arise in the setting of infection, producing secondary leukocytoclastic vasculitis. This patient had a history of ventricular septal defect that was complicated by streptococcal septicemia and was associated with IgA and IgM vascular immunoglobulin deposition (c). Infections have been associated with the development of IgA vascular immune complexes.[33]

Severe cutaneous leukocytoclastic angiitis. Pan-dermal small- and/or muscular-vessel vasculitis leads to severe cutaneous vasculitis characterized by multiple superficial ulcerations and infiltrated erythema. Extensive compromise of the vascular bed (superficial and deep venular plexus and arterioles) explains the presence of ulcerations in this patient with severe cutaneous leukocytoclastic angiitis.

Multiple painful, erythematous nodules in polyarteritis nodosa. Biopsy demonstration of muscular-vessel vasculitis (arteritis) is the key to diagnosis. The involved vessel is typically at the dermal-subcutis junction where arteries bifurcate.

Livedo reticularis. Livedo reticularis (a) is due to an arterial occlusion from a cholesterol embolus and can be caused by arteritis (b) or non-arteritis-related luminal occlusion due to emboli (cholesterol embolus) [c] or thrombi. A deep punch or excisional biopsy is required to differentiate between these two causes of livedo.

Biopsy: Timing, Technique, and Choice of Lesions

Selection of clinical lesions and type of pathologic assessment has great impact on the diagnostic yield of cutaneous biopsies.[4] A biopsy extending to the subcutis taken from the most tender, reddish, or purpuric lesional skin is the key to obtaining a significant diagnostic result and serial sections are often required to identify the main vasculitic lesions. First, the optimal time for a skin biopsy is < 48 hours after the appearance of a vasculitic lesion. If the biopsy is poorly timed, the pathologic features of vasculitis may be absent - a fact that must be considered when interpreting a negative biopsy from a patient whose clinical findings suggest vasculitis. A punch biopsy of a lesion at the appropriate stage will enable histologic confirmation of most small-vessel vasculitic syndromes. Purpuric lesions obtained in the first 24 hours are characterized by fibrin deposits within the vessel wall accompanied by neutrophilic infiltration of the wall and surrounding hemorrhage and nuclear debris. After 24 hours, neutrophils begin to be replaced by lymphocytes and macrophages. Thus, a biopsy of lesions > 48 hours old, regardless of the underlying form of vasculitis, may show lymphocyte-rich infiltrates. Secondly, the choice of a shave, punch, or excisional biopsy will affect which vessels are examined as the type of vessel is dependent on the location within the skin and the subcutis, i.e. the deeper the location, the larger the vessel. Therefore, if a medium vessel vasculitis such as PAN is suspected, the biopsy must include the subcutaneous fat where medium-sized vessels are situated. An incisional biopsy is required for cases affecting larger vessels (nodular vasculitis and GCA) [figure 1]. In the case of livedo racemosa, a deep biopsy extending to the subcutis should be taken from the center of the circular livedo segment (the 'white' center, not the 'red' periphery) because this is where the stenosed vessel responsible for the cyanotic periphery is located. When a muscular-vessel vasculitis is suspected, level sections thoroughly sampling the biopsy are often required (figure 6). Thirdly, biopsies should be obtained from non-ulcerated sites, or if not possible, from the edge of a superficial ulcer. In the case of deep ulcers, biopsy of the subcutis including the central ulcerated area increases diagnostic yield and recognition of a muscular vessel vasculitis (e.g. PAN).[35] Lastly, omission of a biopsy for DIF studies wastes an opportunity to collect potentially valuable information and often leads to misdiagnosis. It is best to take two biopsies, one for light microscopy and one for a DIF examination, rather than split one specimen, which can produce crush artifacts rendering the specimen uninterpretable. In fact, multiple biopsies and extending the biopsy depth to the subcutis and fascia can significantly increase the diagnostic yield for vasculitis.[4] Similar to hematoxylin and eosin evaluation, the presence of diagnostic immunofluorescence patterns is inversely related to the age of the lesion biopsied. 100% of biopsies will harbor immunoglobulins within the first 48 hours, 70% will be positive at 48-72 hours, and after 72 hours immunoglobulins will not be detected; however, complement can still be detected in >50% of vasculitic lesions after 72 hours.[36]

Muscular-vessel vasculitis. This is a segmental process and serial sections are therefore often required for diagnosis. In this example, the first/initial section (a) was negative and identification of arteritis at the dermo-subcutaneous junction was obtained by performing serial (level) sections (b).

Clinical and Laboratory Work-up

In addition to biopsy confirmation and histologic classification (e.g. neutrophilic small, small and muscular, muscular vessel-only vasculitis), DIF evaluation is a critical component of diagnosis. The absence of immune complexes (ICs), so-called pauci-immune vasculitis, is the expected finding in WG, CSS, and MPA with or without medium-sized vessel involvement. Deposition of IgG, IgM, and/or C3 in or around the vessels characterizes IC-mediated vasculitis such as cryoglobulinemic vasculitis (CV), CTD vasculitis, and CLA. Predominant IgA vascular deposits are requisite for diagnosis of HSP and can be a clue to the presence of certain underlying disorders where there is immune dysregulation or enhanced susceptibility to IC entrapment.[33] Basement membrane zone or keratinocyte nuclear (in vivo anti-nuclear antibodies [ANA]) immunoreactants, mostly IgG, can be found in CTD vasculitis such as LV. In the evaluation of urticarial vasculitis (UV), the finding of basement membrane zone fluorescence may be seen in patients with hypocomplementemic states and who have CTD. In addition, IgM deposition in blood vessels may be readily seen in cases of vasculitis with a circulating rheumatoid factor (RF) or with monoclonal production of IgM as found in CV; IgA is absent in these cases.[37]

After histologic and DIF evaluation, in order to establish the diagnosis of a specific vasculitis syndrome, the cutaneous vasculitis patient must be evaluated for the presence and extent of systemic disease, identifying any treatable etiology such as drug, infection, malignancy, or coexisting systemic disease, and treating such conditions.[1,4] These steps will include a careful clinical history determining whether this is an acute or chronic condition and searching for triggers such as drugs or infections or symptoms indicative of pre-existing or concomitant disease, physical examination, chest x-ray, and routine laboratory tests (blood and urine).[1,4] If specific symptoms or signs of systemic disease such as mononeuritis or micro-hematuria are evident, further studies should be considered to arrive at a diagnosis of an ANCA-positive systemic vasculitis or secondary systemic vasculitis.[1,4] Clinical examination helps to determine the size of the vessel involvement, which can also narrow the differential diagnosis ( Table I and Table II ). For patients suspected of having chronic or systemic vasculitis, the following laboratory studies are recommended: complete blood cell count with differential, blood urea nitrogen/creatinine, liver function panel, urinalysis, stool guaiac, hepatitis B and C virus serologies, cryoglobulins, antiphospholipid antibodies, immunoglobulins (IgG, IgA, and IgM), complement levels (CH50, C3, C4), ANCA, ANA, and RF.[1,4,38] Additional tests to consider are blood cultures and echocardiography if the patient has a high fever and/or has a heart murmur, and anti-streptolysin O titers in children or in adults with a history of cardiac septal defect.[39]

ANCA testing has been established as a useful tool for the diagnosis of small-vessel vasculitides. ANCA-associated vasculitides include WG, MPA, CSS, and some drug-related vasculitis, but ANCA can be also found in patients with inflammatory bowel disease, CTD, and other chronic inflammatory diseases, some of whom may have vasculitis. Positive ANCA patterns should be separated into perinuclear pattern of ANCA (p-ANCA) and cytoplasmic ANCA (c-ANCA). p-ANCA may be seen with myeloperoxidase (MPO) antibodies as well as others (e.g. LF-lactoferrin, CG-cathepsin) and is found in MPA and CSS. c-ANCA are mostly anti-proteinase-3 (PR-3), which is strongly associated with WG. However, not all primary systemic vasculitis is ANCA positive[40] and the early stage of WG can be ANCA negative.[41] Conversely, the presence of ANCA is not diagnostic of systemic vasculitis as up to 60% of patients with cutaneous LCV can have a positive ANCA and disease limited to their skin, and ANCA are found at low levels in many systemic inflammatory and pulmonary disorders that mimic vasculitis.[36] In the latter group, atypical indirect immunofluorescent patterns (i.e. both cytoplasmic and perinuclear) are present and antibodies to PR-3 and MPO are rare by antigen-specific ELISA testing.

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