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INTRAVASCULAR OCCLUSIVE CAUSES OF VASCULITIS - LIKE LESIONS

Several varied disorders may cause intravascular occlusion, which mimics vasculitis. Indeed, many of these disorders cause inflammation and a secondary vasculitis. The features include varying degrees of livedo (Fig.14.30); dusky, necrotic, or ulcerated extremities (Fig.14.31); large acute necrotic lesions; and internal organ involvement. The relevant disorders include the following.

Figure 14.30 Examples of livedo.(a) Patchy faint livedo in a patient with positive antinuclear antibody but no clear clinical diagnosis. (b) Vasculitis with a prominent livedo patterning on the leg. (c) Typical chicken wire appearance of livedo. This was a fixed lesion that occurred in a patient who had a renal transplant operation, with no subsequent livedo elsewhere, and was felt to represent a gluteal artery occlusion. (d) Vasculitic ulcer with adjacent livedo. See also Fig. 18.53. (Panel d courtesy of Dr. G. Dawn.)

Figure 14.31 Acral changes of hyperviscosity syndrome. (a) A dusky blue toe. This is a common feature in occlusive types of vasculitis. (b) A purpuric fingertip lesion due to occlusive vasculitis. This patient had lesions of several fingers and toes of both hands and feet, with no cause demonstrated despite extensive investigation. Treatment with aspirin prevented further fresh lesions.

Livedo

Livedo reticularis and livedo racemosa are descriptive terms applied to a net-like or ‘chicken wire' reticulate patterning of vascular lesions (Figs 14.30 and 14.32). The terms overlap in common usage; some view them as identical, others use livedo racemosa when the network pattern is broader and more clearly defined. These terms have been applied to a confluent physiologic pattern (seen best in babies and young women, and capable of blanching with pressure), a rare congenital abnormality (cutis marmorata telangiectatica, Fig.19.17), and a more patchy ‘broken livedo' pattern that occurs in some vasculitides and vasoocclusive disorders (when it may be associated with necrosis and ulceration). This last patchy and potentially necrosing pattern is indicative of several potential underlying vascular disease processes, including the following.

Figure 14.32 (a) Cryoglobulinemia presenting as a livedo pattern on the leg with exacerbations over many years. Hepatitis screen was negative, and lesions occurred over many years despite a series of immunosuppressive therapies. (b) Cryoglobulinemia presenting with rather retiform purpuric lesions on the knees. By contrast to the retiform purpura that occurs in Henoch–Schönlein purpura, these cryoglobulin lesions have no urticated or inflammatory component.

Cryoglobulinemia and other cold-precipitating proteins

Cryoglobulinemia

Cryoglobulins are cold-precipitating proteins in the circulation, which fall into three classes.

The most common disorder is that due to type II or type III mixed cryoglobulinemia, which is now recognized to occur secondary to hepatitis C infection in about 50% of cases (conversely, about 2% of patients with hepatitis C infection will develop cryoglobulins). Other cases occur secondary to connective tissue disorders, hematologic malignancies, and other infections or causes of chronic antigenemia.

    The clinical features of this disorder are purpuric vasculitis due to intravascular occlusion, arthralgia, and systemic vasculitis causing nephritis, neuropathy, hepatitis, and pneumonitis. The cutaneous lesions (Fig. 14.32) typically affect acral sites and may cause livedo, purpuric lesions, ulceration, duskiness of digits (‘purple toe' or ‘blue toe' syndrome), or gangrene.

    Treatment includes preventive measures such as avoiding peripheral cooling, non-specific therapies such as high-dose systemic steroids, and a variety of immunosuppressive and cytotoxic therapies (such as azathioprine, cyclophosphamide, chlorambucil, fludarabine, and 2-chloro-deoxyadenosine). Plasmapheresis may be used to reduce circulating levels of cryoglobulin. Interferon and ribavirin is probably the treatment of choice for patients with underlying hepatitis C infection. Immunosuppressive agents and chemotherapy may be required for underlying connective tissue disease or lymphoma.

Cryofibrinogenemia

This is a rare disorder that may be secondary to hematologic and other malignancies or may occur in isolation (Fig. 14.33). The cutaneous features are the same as in cryoglobulinemia.

    Treatments are similar to those for cryoglobulinemia, but fibrinolytic therapy with stanozolol can also be extremely effective.

Figure 14.33Idiopathic cryofibrinogenemia, demonstrating a dusky blue color with some infarction of the periungual skin. This responded to stanozolol and low-dose prednisolone.

Embolic occlusion

Etiology and pathogenesis

Embolic vasculitis may have several causes, including the following.

Figure 14.34 Infective emboli causing fingertip pustules. These should be cleaned and pierced to obtain bacteriology cultures of the pus content.

Clinical

The features vary to some extent, depending on the cause, but include livedo, infarcts, purpuric lesions, ulcers, and blisters. Endocarditis (see earlier) and cholesterol emboli (below) are the commonest causes. Cardiac myxoma may cause fever, malaise, and cardiac murmurs. Fat emboli occur in the context of a recent fracture, and may also affect other organs, such as lungs.

Cholesterol emboli

Cholesterol emboli most typically arise from the lower aorta or femoral vessels, and hence affect one or both legs. They may be dislodged during arteriography or arterial surgery, or after cardiopulmonary resuscitation, and should be strongly suspected in cases of apparently unilateral foot vasculitis. However, this condition causes most diagnostic difficulty when there are spontaneous recurrent episodes of embolization or episodes affecting both lower legs. The process may occur after use of anticoagulants or thrombolytic therapy.

    The cutaneous signs include livedo reticularis, purpuric rash, decreased perfusion manifest as a dusky extremity or extremities or as gangrene, and ulcers or infarction (Fig.14.35). Myalgia and renal involvement (hypertension; hematuria or proteinuria, or renal failure) may occur, as may involvement of the brain (stroke), eyes (acute loss of vision), or gastrointestinal tract (abdominal pain, diarrhea, and gastrointestinal blood loss). The majority of patients have palpable distal pulses.

    The characteristic pathologic lesion is the presence of cholesterol clefts, seen as needle-shaped defects in arteriolar walls in the histologic specimen (the cholesterol dissolves out during standard tissue processing). In acute lesions, the clefts are surrounded by inflammation, and there may be associated eosinophilia, hypocomplementemia, elevated ESR, and occasionally a positive ANCA; all these may suggest immunologic vasculitides such as polyarteritis nodosa.

    If minor, supportive treatment may be all that is needed. Otherwise, surgery may be needed.

Figure 14.35 Cholesterol emboli. Embolic fragments of larger vessels lodge in the extremities, causing decreased blood flow, pain, a livedo pattern, and necrosis. Angiography or other manipulation of the vessels may precipitate this condition, as may antithrombotic and anticoagulant drugs of various types.

Antiphospholipid syndrome

Etiology and pathogenesis

The antiphospholipid syndrome (APS) is a constellation of features that occur due to anticardiolipin antibodies or the lupus anticoagulant, together known as antiphospholipid antibodies (aPL). These are a heterogeneous group of antibodies, which may explain the wide range of clinical manifestations; indeed, some individuals with positive antibody tests never develop any clinical disease. The two antibody systems are distinct but often coexist.

    The APS may occur as a primary disorder or associated with a huge range of conditions (Table 14.6), of which the main one is lupus erythematosus.

Clinical

Clinical manifestations are due to arterial and venous thromboses in various organs, and probably direct effects on phospholipids in other tissues, such as placenta and brain. Features include the following.

    Full laboratory evaluation is relatively specialized, but prolongation of the kaolin partial thromboplastin time (KPTT) or dilute Russell viper venom time (dRVVT) are readily available screening tests. Different types of aPL can be measured (anticardiolipin antibody and lupus anticoagulant), and other antibodies may also be markers for this condition (such as the type M5 antimitochondrial antibody).

Figure 14.36 Antiphospholipid syndrome. The clinical presentations of this disorder are protean and include those shown here. (a) Broad bands of livedo around the knees in a patient with anticardiolipin antibodies; physiologic livedo has a finer patterning and less obvious lesions.(b) Digital infarcts, a non-specific feature of several vascular occlusion disorders.

Differential diagnosis

This includes other causes of livedo, vascular occlusion, and vasculitis.

Treatment

Treatment of APS remains a contentious issue, as even high-titer antibodies do not necessarily lead to clinical disease; in such cases, the dangers of aggressive anticoagulation may outweigh the potential benefits. In patients anticoagulated with heparin, the doses required to achieve benefit may be higher than usual. Even on treatment, catastrophic APS (which may be provoked by infection) can still occur, and stopping anticoagulants may lead to thrombotic episodes. Aspirin is commonly used, warfarin or long-term subcutaneous heparin is appropriate for treatment of thrombosis but more debatable for long-term prophylaxis, and oral steroids are probably beneficial in pregnancy but less appropriate in the long term. Plasmapheresis and immunosuppressive agents may be useful in some cases, and hydroxychloroquine has been shown to reduce the risk of thromboses in patients with SLE and anticardiolipin antibodies.

Vascular coagulopathies

Sneddon syndrome, Degos disease, and idiopathic livedoid vasculopathy, all disorders that may cause livedo reticularis, are difficult to classify on an etiologic basis. Antiphospholipid antibodies are demonstrable in some cases, but not all. They are best considered to involve abnormal thrombotic mechanisms at the microvascular level.

Sneddon syndrome

This eponymous name was applied to patients with generalized reticular livedo associated with cerebrovascular accidents. It appears to have a variety of pathogenetic mechanisms. About 20% of patients will be found to have aPL (discussed earlier). A further 30% have antiendothelial cell antibodies, alone or with aPL.

    Patients are typically young women. Widespread livedo (Fig. 14.37) is the characteristic cutaneous feature, which may be accompanied by digital ischemia or infarction. Neurologic features include cerebrovascular accidents, but also peripheral nerve problems such as mononeuritis multiplex. Hypertension may also occur.

    This condition is relatively refractory to therapy, and tends not to respond to steroids or immunosuppressive agents, as there is no inflammatory vasculitis. Anticoagulants, antifibrinolytic agents, and antiplatelet agents are all used (see section on idiopathic livedoid vasculopathy, later in this chapter), as well as vasodilators (see Raynaud phenomenon, Ch.  13).

Figure 14.37 Sneddon syndrome. Livedo on the legs in a patient with previous mononeuritis multiplex. The lesions respond poorly to treatment, because there is no significant inflammatory component that can be potentially modified.

Malignant atrophic papulosis (Degos disease)

This is a rare disorder in which non-inflammatory thrombosis of dermal vessels causes characteristic small papules that progress to form ivory-white atrophic scars (Fig. 14.38). Classically, the lesions are associated with internal involvement of gastrointestinal tract or nervous system, causing gastrointestinal infarction and bleeding, or cerebrovascular accidents. However, it is likely that ‘less exciting' cases limited to the skin are relatively underreported.

    Treatment with fibrinolytic agents may be helpful, but generally the response is poor. Morphologically similar lesions may occur in other disorders, such as dermatomyositis.

Figure 14.38 Degos disease (malignant atrophic papulosis) showing a typical porcelain-white atrophic area due to an endarteritis. This is not a neoplastic disorder, but gastrointestinal involvement may be lethal, hence the use of the term malignant.

Idiopathic livedoid vasculopathy

The etiology of this disorder is unknown, but it is probably due to intravascular thrombotic occlusion (of several etiologies) with secondary vasculitic features, rather than to a primary vessel wall inflammation. Some patients clearly have venous stasis disease, in which case the livedo change with white scarring is often termed atrophie blanche (although this term is purely a description, and applies equally to any cause of livedoid vasculopathy; Fig 14.39a).

    The typical features are livedo racemosa, ulceration, and necrosis (Fig. 14.39b). Pain is a prominent feature, and may be seasonal (livedo reticularis with summer or winter ulcerations). White, stellate scars occur at sites of previous ulceration.

    Treatment is difficult. Antiinflammatory and immunosuppressive agents are relatively unhelpful. Various combinations of fibrinolytic, anticoagulant, and antiplatelet agents are used, including aspirin, dipyridamole, oxpentifylline, and heparin. Danazol appears to be a particularly useful fibrinolytic agent in this disorder, but does have androgenic side effects, such as amenorrhea in women.

Figure 14.39 Idiopathic livedoid vasculopathy showing (a) an atrophie blanche pattern of white scar with punctuate vessels, and (b) a more livedoid pattern with ulceration.

Disseminated intravascular coagulation (DIC)

This disorder typically occurs in a patient who is profoundly ill. The normal inhibition of clotting mechanisms leads to intravascular coagulation associated with consumption of platelets and clotting factors. Associated or underlying diseases include gram-negative sepsis and shock. Patients with defects in protein C or S are predisposed.

    Widespread areas of necrosis are seen. The distal extremities are usually affected first, but the condition, if unchecked, will spread centrally (Figs 14.40 and 14.41).

    Treatment usually needs to occur in an intensive care unit setting. Pressors, fluid support, administration of fresh frozen plasma, fibrinogen, and platelets, as well as treatment of any underlying condition, are needed. Activated protein C (APC), a natural anticoagulant, is showing benefit in treating patients with DIC, but mortality remains high.

Figure 14.40 (a,b) Disseminated intravascular coagulation causing a livedo patterning of necrotic areas. (Panel b courtesy of Dr. G. Dawn.)

Figure 14.41 (a,b) Disseminated intravascular coagulation: a more severe case with confluence of lesions, widespread vascular occlusion, and necrotic areas of skin. Death is common in severe cases; amputation or permanent deformity of limbs may occur in survivors if the pattern is mainly acral, as shown here. (Courtesy of O. Dale Collins III.)

PRACTICE POINTS

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.