Syndrome
Carlos A. Battagliotti
Several skin manifestations have been described in patients with antiphospholipid syndrome (APS) (Table 8.1) [1–3]. The most frequent skin lesions are livedo reticu- laris and skin ulcers.
Vascular occlusion is generally the first and most frequent manifestation observed in patients with antiphospholipid antibodies (aPL), accounting for 41% of the cases. Forty percent of these patients present with other multisystem throm- botic phenomena during the course of the disease, underscoring the significance of skin lesions as a diagnostic marker and predictor of systemic involvement.
In spite of the association of skin lesions with different isotypes of immunoglobu- lins, the presence of IgA anticardiolipin antibodies (aCL) has been reported as an independent predictive factor for skin lesions (skin ulcers, chilblain lupus, and vas- culitis) [4].
Livedo Reticularis
Livedo reticularis is the most common skin manifestation in patients with APS, characterized by a dark purple reticular pattern usually involving the upper and lower limbs [3, 5].
The skin normally receives its blood supply through a vascular system arranged in the form of cones with their base towards the skin surface. Each cone is supplied by an arteriole. The pattern of livedo reticularis corresponds to areas of anastomo-
86 Table 8.1. The skin and antiphospholipid syndrome.
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Livedo reticularis
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Sneddon’s syndrome
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Skin ulcers
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Necrotizing vasculitis
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Livedoid vasculitis
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Cutaneous gangrene
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Superficial thrombophlebitis
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Pseudovasculitic lesions: Nodules, papules, pustules, palmar–plantar erythema
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Subungual bleeding
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Anetoderma
sis between the two cones where diminished blood flow is associated with the dilata- tion of venules and capillaries. Therefore, the alteration in arterial blood flow caused by the livedo may result from:
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Blood inflow obstruction
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Blood hyperviscosity
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Blood outflow obstruction
Livedo may be observed in normal subjects, especially women, after exposure to cold, displaying a symmetrical and regular mottled pattern. However, the relation- ship with a large number of pathological conditions (Table 8.2) is very important. A detailed examination of the features of the reticular pattern, including location, extension, symmetry, and regularity, and the presence of associated skin lesions will contribute to the differential diagnosis [3, 6–8].
The pattern of involvement associated with APS is generally disseminated, with incomplete circular segments, non-infiltrated, persistent, or irregular with wide ramifications (livedo racemosa). Some patients present a fine, regular, and com- plete network (Fig. 8.1).
Skin Manifestations of Antiphospholipid Syndrome 87
Table 8.2. Livedo reticularis and associated diseases.
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Antiphospholipid syndrome
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Systemic lupus erythematosus (with or without aPL)
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Systemic vasculitis (polyarteritis nodosa, cryoglobulinemia)
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Pseudovasculitic syndromes (cholesterol embolization)
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Overlapping syndromes
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Scleroderma
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Infectious diseases (syphilis, tuberculosis)
Figure 8.1. Livedo reticularis of the gluteal region and
both thighs of a patient with SLE and APS.
In a recent study, the presence of livedo reticularis was associated with arterial but no venous events, suggesting that livedo reticularis could be consider as a marker of the arterial APS subset [9].
Sneddon’s Syndrome
In 1965, Sneddon described the association between livedo reticularis and stroke [10]. Later on, the presence of aPL in some of the patients that carry the syndrome suggests that a subset of patients might have APS [11–13].
Although there are differences in the terminology used for the Sneddon syn- drome livedo, its features are very clear. The skin lesions are extensive, patchy, persistent, and do not disappear with skin heating. Usually, this is the pattern observed in patients with a prior condition that accounts for the vascular lesion (secondary Sneddon’s syndrome), such as autoimmune or thrombophilic diseases.
Beyond the initial description, there are numerous reports of cardiac and renal involvement and development of hypertension, as well as gynecological and obstetrical complications [14, 15]. There are no laboratory tests that contribute to a definite diagnosis; however, 35% of patients with Sneddon’s syndrome have anti-endothelial cell antibody as opposed to patients with stroke and no livedo reticularis. Prognosis is variable, mainly depending on the extension and progression of brain lesions that might lead to a severe and definite mental deterioration.
The pathological study of livedo reticularis shows endothelitis and obliterating endarteritis without necrotizing vasculitis [13]. In some cases the characteristics of APS overlap so that in all patients affected with livedo reticularis with non- inflammatory small vessel thrombosis in their biopsy, the measurement of aPL is mandatory.
Skin Ulcers
Lower limb ulcers are one of the most frequent skin manifestations in patients with APS [2]. They have been observed in 20% to 30% of patients. The prevalence of skin ulcers is very high when associated with aCL in systemic lupus erythematosus (SLE) [3, 5].
Although characteristics are variable, ulcers are painful, small (0.5–3.0 cm in diameter), with stellate, oval, or irregular borders surrounded by a purple-brownish and recurrent purple halo. They are generally located in the ankles, legs, and feet.
Healing is difficult; when accomplished it results in a white scar with a pigmented halo [16, 17] (Fig. 8.2).
Giant ulcers and cases resembling gangrenous pyoderma have been reported [18–20], although in the latter case, the characteristic undercut of the borders of pyoderma are absent. Post-phlebitic ulcers are seldom seen though an increased prevalence of aPL has been described in elderly patients with venous ulcers (Figs.
8.2 and 8.3).
Skin Manifestations of Antiphospholipid Syndrome 89
Figure 8.2. Patient with primary APS that presents necrotic ulcers on the leg and necrosis of the toes.
Figure 8.3. Primary APS with giant skin ulcer on the left leg refractory to anticoagulant and fibrinolytic treatment.
Necrotizing Vasculitis and Livedoid Vasculitis
Generally, no inflammatory changes are observed in the biopsies taken from skin lesions of patients suffering from APS. The association with vasculitis might reflect the coexistence of two diseases, most commonly SLE.
In 1967, Bard and Winkelmann described a group of patients with chronic and recurrent livedoid-like lesions circumscribed to the lower limbs and with histologi- cal images of hyalinizating segmentary vasculitis of the dermis vessels related to thrombotic occlusion and lymphocytic infiltration [21]. This disorder was termed livedoid vasculitis or segmentary hyalinizing vasculitis. These cases presented with livedo lesions, purpura with a trend towards ulceration that became covered with dark crusts, and inflammatory borders. After weeks or months they healed, forming porcelain-white star-like scars, atrophic with telangiectasis and hyperpigmented borders. These latter lesions have been termed white atrophy and some authors consider it as a disorder per se. The term was coined by Milian in 1929, who attrib- uted its formation to a previous ulceration with a probable syphilitic or tuberculous etiology. There is consensus in that there are different stages in the evolution of the same process that leads to livedoid vasculitis. Other authors believe that “white atrophy” is the end stage of different disorders that result in a stellate porcelain-like star [22–24].
Livedoid vasculitis predominates in young women with characteristic lesions on the lower limbs; it recurs with seasonal exacerbations. Its presentation might be primary or idiopathic. However, it is sometimes related to SLE, Sjögren’s syndrome, APS, polyarteritis nodosa, rheumatoid arthritis, scleroderma, Raynaud’s phenome- non, cryoglobulinemia, macroglobulinemia, venous vascular pathology, and dia- betes [23, 25].
Controversy exists as to the pathogenesis but possible suggested mechanisms include imbalance of the coagulation and fibrinolysis system and alteration of platelet function.
Skin lesions typically found are erythematosus plaques, petechial purpura, livedo, painful ulcers of different sizes, white atrophy, telangiectases, and hyperpigmenta- tion. In some patients, direct immunofluorescence of skin vessels reveals IgG, IgM, IgA, fibrin, and, to a lesser degree, deposits of complement [26].
Histological characteristics of livedoid vasculitis overlap with the vascular changes seen in the APS. Segmental hyalinization and non-inflammatory occlusion of the dermal arterioles leading to skin ulceration is observed.
Cutaneous Gangrene and Necrosis
Digital gangrene is a well-recognized manifestation in patients with APS [2, 3, 27].
The process starts with erythematosus macules, cyanosis, or pseudocellulitis ending in necrosis. In patients with SLE or other autoimmune diseases, aPL quite often coexists with other pathogenic factors such as cryoglobulins, antiendothelial cell antibodies, or hepatitis viruses. Patients who are smokers, hypertensive, or are on oral contraceptives have an increased risk of necrosis (Figs 8.4, 8.5, and 8.6).
Angiographic images show occlusion or severe stenosis of middle- and large-size
vessels.
Skin Manifestations of Antiphospholipid Syndrome 91
Figure 8.4. Evolution to gangrene with distal necrosis of the left foot toes in the patient carrier of primary APS shown in Figure 8.3.
Figure 8.5. Cure by spontaneous amputation of the left foot toes affected with gangrene in a patient with
primary APS.
Some patients (3%) develop extensive superficial skin necrosis generally involv- ing the limbs, head, and buttocks [28]. The onset is sudden, with an extensive and painful purpuric lesion followed by a necrotic plaque with purpuric and active edges and bullous lesions. The thrombozing microangiitis seen in examined tissues is characteristic [2, 29].
Superficial Thrombophlebitis
Thrombotic episodes in the deep veins of the lower limbs are common. Similar mechanisms might lead to the involvement of the superficial venous territory [3].
Pseudo-vasculitic Lesions: Nodules, Papules, Pustules, Palmo–Plantar Erythema
A wide variety of skin lesions might be included under the term pseudo-vasculitic, erythematosus macules, painful nodules, and purpura, among others. APS accounts for the microthrombosis observed in skin vessels [3, 30] (Figs. 8.7 and 8.8).
Subungual Hemorrhages
Chipe-like subungual hemorrhages are longitudinally distributed, small reddish-to- black linear lesions, which persist after ungual compression. They are not exclu- sively associated with the APS because ungual trauma can be seen in healthy subjects as well as patients with infectious endocarditis. They are caused by throm- botic or embolic phenomena. It is worth pointing out that the presence of these
Figure 8.6. Digital necrosis with gangrene of the fingers of a patient with SLE and APS.
lesions in several fingers is related to an underlying pathological process [3, 5].
Their sudden onset on multiple fingers is usually concomitant to other thrombotic event [31, 32].
Anetoderma
Anetoderma is a rare elastolytic disorder characterized by a limited area of slack skin associated with loss of substance on examination and a loss of elastic tissue in the histopathology [33]. Although its cause is unknown, an immunological mecha- nism has been suggested as playing an important role in this elatolytic disease.
Some reports suggest that anetoderma may be the presenting sign of autoimmune disorders [34, 35], particularly in those with aPL [25, 35].
What Do Skin Lesion Biopsies of Patients with APS Show?
The main histopathological picture is non-inflammatory thrombosis in small- and medium-sized arteries and/or veins of the dermis and hypodermis [3, 36]. A pattern that might be associated or be the only one observed is that of obliterating endarter- ial occlusion, characterized by narrowing of the vessel lumen with endothelial cell proliferation and fibrohyalinization of the vessel wall. The absence of vasculitis is characteristic. Lymphocytic or lymphoplasmocytic infiltrating isolates might be
Skin Manifestations of Antiphospholipid Syndrome 93
Figure 8.7. SLE along with APS presenting with
papuloerythematosus skin lesion (irregular borders)
on the lower limb.
observed. Based on skin involvement, the following histopathologic pattern is observed [36]:
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Gangrenous lesion Vascular thrombosis Dermal hemorrhage Obliterating endarteritis Epidermal necrosis
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Ulcerous lesion Vascular thrombosis Capillary proliferation Obliterating endarteritis Dermal hemorrhage Deposit of hemosiderin
Figure 8.8. Biopsy of skin with non-inflammatory vascular thrombosis (venular) of a patient with SLE and APS.
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