White : Diseases of the Skin - Purpura, Vasculitis, Neutrophilic Dermatoses and Related Disorders

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Gary M. White & Neil H. Cox

Diseases of the Skin

14	Purpura,Vasculities,NeutrophilicDermatoses,and Related Disorders

APPROACH TO VASCULITIS

The list of possible investigations in a patient with suspected vasculitis is potentially huge, given the large number of causes. Some suggestions for a logical approach are provided here and in Tables 14.3 and 14.4. This section is written from a dermatologic perspective, and the approach would be different in, for example, a patient suspected of having fever due to occult systemic vasculitis. Most vasculitis presenting due to cutaneous lesions is of small-vessel vasculitis type, in which about half will have no identifiable cause.

The main factors to consider in the approach to suspected vasculitis are as follows.

•	Consideration of features that may indicate a serious vasculitis (either a serious cause or likely serious consequences).
•	Which tests are required to reach a diagnosis.
•	What treatment is necessary, and additional tests that may be necessary as a therapeutic baseline.
•	Is it seriousfi

Table 14.3 DOES THE PATIENT HAVE A SERIOUS VASCULITIS ? QUESTIONS TO ASK

Is the patient otherwise wellfi	General malaise, fever, or organ-specific systemic symptoms should be considered; these may indicate either a systemic cause (such as infections) or may occur as a consequence of systemic vasculitis. Is the patient taking any new drugs for a medical conditionfi
Is there evidence of occult internal involvementfi	In particular, it is important to perform urinalysis for evidence of hematuria or proteinuria; also, to consider cardiac murmurs that may be associated with subacute bacterial endocarditis.
Does the morphology of lesions suggest an occlusive or larger-vessel disease processfi	For example, retiform non-inflammatory lesions, livedo, acral infarcts or cyanosis, larger nodules, broad areas of purpura or necrosis.
Does the pattern suggest an infective causefi	For example, predominance of pustular lesions. Also note the presence of fever, as discussed above.
Does the body site of lesions cause concernfi	Is the pattern consistent with a cutaneous small-vessel vasculitis (CSVV)fi This usually affects the lower half of the body primarily, especially the lower legs; more widespread lesions suggest a more severe process. Conjunctival or fundal involvement suggests the possibility of subacute bacterial endocarditis.
Does the skin damage of individual lesions warrant systemic therapyfi	Small lesions of CSVV may not require aggressive therapy, whereas larger necrotic lesions may require active treatment.

Table 14.4 SOME INVESTIGATIONS TO DETERMINE THE CAUSE OF CUTANEOUS VASCULITIS

Investigation	Details
Basic bloods	Complete blood count; electrolytes, and renal and hepatic function; inflammatory markers (erythrocyte sedimentation rate, C-reactive protein)
Urinalysis	Plus 24-h urinary protein excretion if positive dipstick test
Skin biopsy	Of a fresh lesion, with direct immunofluorescence studies: confirms vasculitis and helps to distinguish vessel wall damage versus occlusive patterns
Autoantibodies	Antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), antiphospholipid, with or without others if connective tissue disorder suspected
Immunology tests	Complement levels (may be low in urticarial vasculitis or lupus erythematosus)
Infection screen	Depends on the situation; always required if there is fever or systemic malaise (may include blood cultures, throat swab, cerebrospinal fluid culture, viral serology, etc.)
Other blood tests	Cryoglobulins or electrophoresis, protein C, and protein S
Other investigations for systemic disease	Depends on history, clinical findings, and likely cause, for example chest X-ray, nasal or respiratory tract biopsy (Wegener granulomatosis), nerve conduction studies or biopsy and/or angiography (polyarteritis), etc.

An important first step, as it dictates the urgency of referral or investigation, is to consider whether there are features of concern regarding significant systemic involvement, infective causes, or a need for systemic therapy. The most common clinically identifiable internal involvements in vasculitides are fever (which may indicate an infective cause or may be a consequence of internal vasculitis), arthralgia, and nephritis (hematuria and proteinuria). The questions listed in Table 14.3 may help.

PRACTICE POINTS

•	Always consider infection as a cause of vasculitic lesions: treatment with immunosuppressive agents may be detrimental.
•	Remember that fever, malaise, and other systemic symptoms may reflect either the cause or the effect of a systemic vasculitis.
•	Always test for proteinuria and hematuria, even in the absence of any systemic symptoms.
•	Drug-induced vasculitis accounts for a significant minority of cases of cutaneous small-vessel vasculitis.

Investigations to determine a cause

Investigations in any vasculitis with palpable purpura are directed toward both identifying a cause, and determining the presence and extent of internal organ involvement (see Table 14.3). Some suggested initial investigations to identify a cause of vasculitis are provided in Table 14.4.

As a general approach, it is reasonable to test full blood count, urinalysis, renal function, liver enzymes, and erythrocyte sedimentation rate (ESR) in all patients. Skin biopsy (discussed later) is also extremely helpful, especially if fresh lesions are present (Fig.14.10). Tests for immunologic abnormalities (ANA, ANCA, rheumatoid factor, and other autoantibodies), complement levels, and cryoglobulins; tests for underlying infections or malignancy; and other organ-specific tests may be required, depending on the clinical severity and progression. For example, they are generally not necessary in a patient with a reasonably definite drug cause for cutaneous vasculitis and mild arthralgia, but some or all of these would be indicated for a patient with severe vasculitis or recurrent unexplained episodes.

Figure 14.10 Vasculitis with mixed age of lesions; the red lesions are fresh and are more useful for histologic diagnosis than the older lesions represented by brown hemosiderin staining. Note the Koebner-like reaction of lesions along lines of scratch, in this instance probably just reflecting erythrocyte leakage from the trauma to small vessels. (From Lawrence CM, Cox NH. Physical Signs in Dermatology, 2nd edn. London: Mosby, 2002.)

Skin biopsy is a critical investigation in determining likely diagnostic territory and thus directing further investigations, and should always be performed in a patient who has ongoing new vasculitic lesions or who is unwell. It may not be necessary in, for example, an uncomplicated case of likely drug-induced vasculitis in an otherwise well patient in whom no fresh lesions are developing. When sending a skin biopsy, it is important to perform direct immunofluorescence, as a positive result confirms an immune-mediated process; positivity for IgA is specific for HSP. Note that immune deposits in the skin are destroyed within 12–24h, so a fresh lesion must be biopsied for this evaluation to be meaningful. Potentially useful results from skin biopsy might include the following.

•	Usually able to distinguish primary vessel wall damage from occlusion with secondary vasculitis.
•	May be specific features, for example segmental changes in deeper skin arteries due to polyarteritis, eosinophilic infiltrate of Churg–Strauss syndrome, etc.
•	Positive direct immunofluorescence confirms immunologic basis, for example IgA-positive in HSP.
•	If occlusive, may be able to distinguish the type of occlusion, for example platelet (‘white thrombi'), cryoglobulin, crystal (e.g. cholesterol emboli), and fungi (a particular risk if the lesions are necrotic and in an immunosuppressed patient).
•	Consider sending additional biopsy samples, depending on the clinical situation, for example frozen tissue for histology (if cholesterol emboli are suspected) and tissue for culture (endocarditis, systemically unwell, or immunosuppressed patient).

PRACTICE POINTS

•	Skin biopsy is crucial in investigation of cutaneous vasculitis.
•	Direct immunofluorescence should be included; it is crucial that this requires biopsy of fresh lesions.
•	Consider additional biopsy samples, depending on the clinical situation, for example frozen tissue for histology (suspected cholesterol emboli) and tissue for culture (necrotic lesions in immunosuppressed patient).
•	Make sure the biopsy includes deep dermis and some fat, so that larger vessels can be evaluated.

Investigations as a therapeutic baseline

Treatments for vasculitis are considered in more detail later. Some patients with mild small-vessel vasculitis may require only rest, without any active intervention. However, some patients will require significant immunosuppressive or other drug therapy. It is therefore helpful to consider likely treatment, and to perform relevant baseline tests, as part of the initial work-up.

Many of the tests to determine a cause double as baselines for therapy with corticosteroids, dapsone, or immunosuppressive agents. Additionally, it may be appropriate to measure glucose and blood pressure (corticosteroids), glucose-6-phosphate dehydrogenase level (dapsone), thiopurine methyltransferase level (azathioprine), etc.; see Chapter 4 for more details of individual agents.