Hematol Oncol Clin N Am 22 (2008) 6777

HEMATOLOGY/ONCOLOGY CLINICS
OF NORTH AMERICA

Cutaneous Manifestations of Antiphospholipid Antibody Syndrome

Sari Weinstein, MDa, Warren Piette, MDa,b,*
a

Division of Dermatology, John H. Stroger, Jr. Hospital of Cook County, 1900 West Polk Street, Room 519, Chicago, IL 60612, USA b Department of Dermatology, Rush University Medical Center, Annex Building, Suite 220, 707 S. Wood, Chicago, IL 60612, USA

lthough no skin nding is pathognomonic for antiphospholipid antibody syndrome (APS), many cutaneous ndings can be helpful in suggesting this diagnostic possibility. The cutaneous syndromes that should prompt consideration of APS are the focus of this article. LIVEDO RETICULARIS AND RACEMOSA Livedo reticularis is the most frequently associated cutaneous manifestation in patients who have APS, observed as the presenting sign in up to 40% of patients and seen in up to 70% of patients who have systemic lupus erythematosus (SLE) and APS [1]. In patients who have SLE, the nding of moderateto-extensive livedo reticularis probably warrants testing for antiphospholipid antibodies (aPLs). In a recent consensus statement on the updated classication criteria for APS, Miyakis and colleagues [2] dened livedo reticularis as the persistent, not reversible with rewarming, violaceous, red or blue, reticular or mottled pattern of the skin of the trunk, arms, or legs. It may consist of regular, unbroken circles (regular livedo reticularis), or irregular, broken circles (livedo racemosa). The livedo patterns were further classied, depending on the width of branching pattern (greater or less than 10 mm), into ne and large livedo reticularis and ne and large livedo racemosa. Although the terms are frequently used interchangeably, compared with livedo reticularis, livedo racemosa is a coarser and more irregular pattern, is more often irregularly distributed, and may be more generalized (Fig. 1). Some investigators believe the racemosa variant to be a major clinical feature of APS, strongly associated with the arterial subset of APS, which includes cerebrovascular events, arterial

*Corresponding author. Division of Dermatology, John H. Stroger, Jr. Hospital of Cook County, 1900 West Polk Street, Room 519, Chicago, IL 60612. E-mail address: wpiette@ cchil.org (W. Piette). 0889-8588/08/$ see front matter doi:10.1016/j.hoc.2007.10.011 2008 Elsevier Inc. All rights reserved. hemonc.theclinics.com

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Fig. 1. Livedo. Sneddons syndrome with widespread livedo. Although focal areas have a mostly regular reticulate pattern (eg, knee), most areas have a less regular, coarse pattern of racemosa.

thrombosis, systemic hypertension, heart valve abnormalities, Raynauds phenomenon, and pregnancy morbidity, and consider it an independent, additive, thrombotic risk factor [1,3]. Livedo reticularis has been observed less frequently in those who have only venous thrombosis. An impairment of blood ow and lowered oxygen tension at the periphery of skin segments is responsible for the mottling observed clinically. The cutaneous blood supply is arranged in inverted cones supplied by a central arteriole arising perpendicularly from vessels in the fascia. This arteriole is responsible for the blood supply to a 1- to 4-cmdiameter zone on the skin surface. The netlike pattern results from cyanotic discoloration at the junctions between cones, where deoxygenated blood accumulates. The ring size of the reticulate pattern depends on the body site and is usually smallest on the palms and largest on the trunk or thighs. The pathophysiology of livedo is not well characterized, but the relationship with arterial thrombosis suggests a possible role for the endothelial cell. The vasoconstriction of livedo racemosa may be induced by an interaction of an aPL with the endothelial cell or other cellular element of vessels, altering their function [1,4]. Many autoantibodies associated with APS are directed against phospholipid-protein complexes expressed on, or bound to, the surface of endothelial cells. When bound, these cells may become prothrombotic, leading to the production of procoagulant substances such as tissue factor, plasminogen activator inhibitor 1, and endothelin 1; the increased expression of these procoagulants may be responsible, in part, for the hypercoagulability and thromboses observed in APS.

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Unfortunately, livedo reticularis is a nonspecic cutaneous nding. In neonates, generalized livedo reticularis is an expected nding, termed cutis marmorata. Physiologic livedo reticularis in adults is common, triggered by cold and reversed by warming. Associations of nonphysiologic livedo reticularis with systemic diseases or medications are many; one recent review cited just short of 100 conditions [5]. IDIOPATHIC LIVEDO RETICULARIS WITH CEREBROVASCULAR ACCIDENTS (SNEDDONS SYNDROME) In 1965, Sneddon reported the association of livedo reticularis or racemosa with cerebrovascular accidents [6]. Sneddons syndrome is a rare, but potentially severe, condition typically affecting young or middle-aged women, with the rst cerebrovascular accident typically occurring before 45 years of age. Livedo of either type, typically on the trunk and buttocks but also on the extremities and face, may precede the onset of stroke by years. Although the relationship between APS and Sneddons syndrome is not clear, the prevalence of aPLs in Sneddons syndrome has ranged from 0% to 85%, and most authorities suggest that 40% to 50% of patients who have Sneddons are antibody positive [1]. Skin biopsies are often nondiagnostic in Sneddons syndrome. Multiple deep punch biopsies from the center and the violaceous areas are required to increase sensitivity. According to Zelger and colleagues [4], small-to-medium sized arteries at the dermal-subcutis boundary are involved in a stage-specic pattern. Initial lesions are characterized by the attachment of lymphohistiocytic cells and the detachment of endothelial cells (endotheliitis). Early-phase lesions display partial or complete occlusion of vascular lumens by a plug of lymphohistiocytic cells and brin. Intermediate-phase lesions show replacement of plug by proliferating subendothelial cells and dilated capillaries in the adventitia of the occluded vessel. Late-phase lesions show brosis and shrinkage of vessels [1]. True vasculitis is not a feature. Sneddons syndrome may have two distinct causes, one aPL related with preferential arteriolar involvement, the other a primary nonaPL-related small artery disease primarily affecting the brain and skin vessels [7]. No treatment has consistently been effective for livedo. In patients who have Sneddons or APS, chronic anticoagulation may be warranted, even though the livedo may worsen on anticoagulant or antiplatelet therapy. In light of the higher association of arterial occlusion in patients who have livedo racemosa, patients should reduce other risk factors, including smoking and use of estrogen-containing oral contraceptives. Low-dose aspirin is frequently prescribed, although its efcacy is unproven [8]. Further study is needed on the potential benet of clopidogrel, statins, and angiotensin-converting enzyme inhibitors. ATROPHIE BLANCHE AND LIVEDOID VASCULOPATHY Atrophie blanche is a term that has been used for several different conditions, leading to some confusion in the literature. Originally described as atrophie blanche en plaque by Milian in 1929, synonyms for this disease include livedo

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reticularis with summer ulcerations; segmental hyalinizing vasculitis; livedo vasculitis; livedoid vasculitis; hypersensitivity-type vasculitis; and painful purpuric ulcers with reticular pattern of the lower extremities (PURPLE) [911]. The disease is often chronic, with seasonal exacerbations. Idiopathic atrophie blanche (or white atrophy) is most often seen in young to middle-aged women, typically presenting as disproportionately painful lesions around the malleoli that rapidly progress to punched-out ulcers roughly 3 to 8 mm in diameter (Fig. 2). Within a few days to weeks, the ulcer margin is surrounded by punctate telangiectasias. These ulcers can be persistent but usually heal eventually with a porcelain white scar surrounded by telangiectasias. When presenting in this location, in women, and in this age group, without any systemic ndings, aPLs are seldom associated. The term atrophie blanche has also been applied to the white macules, typically less than 1 cm in diameter, that may be seen on the legs of individuals who have prominent varicosities. Because these lesions typically develop without an antecedent ulcer or pain, do not have surrounding telangiectasias, and do not appear to be associated with any coagulopathy, the term pseudo atrophie blanche might be better applied to these sorts of lesions. Livedoid vasculopathy is a more extensive variant of atrophie blanche in which individual punctuate ulcers link with reticulate erythema or purpura to form areas several cm in diameter. The epidemiology for idiopathic and secondary forms is identical to that of atrophie blanche. The histopathology of atrophie blanche and livedoid vasculopathy shows brin deposition within the walls and lumens of affected supercial dermal vessels, often with hyalinization of vessel walls. Thrombus within the lumen and red cell extravasation may be present, but the absence of a perivascular inltrate or leukocytoclasia argues against a true vasculitis. Late-stage lesions may show epidermal atrophy with thickened hyalinized vessels [9].

Fig. 2. Atrophie blanche. Two lesions of atrophie blanche near the ankle. One has healed with white scar. Expected telangiectasias are not prominent in this patient.

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The pathogenesis of livedoid vasculopathy and atrophie blanche is unknown but it is believed to involve some altered local or systemic control of coagulation [11]. Many studies support a vaso-occlusive pathogenesis, and elevated brinopeptide A levels, defective release of vascular plasminogen activator, and decreased thrombomodulin expression have been described [9]. Livedoid vasculopathy is observed in patients who have procoagulant proclivities, including factor V Leiden, hyperhomocysteinemia, altered brinolysis or platelet activation, and aPLs [11]. However, control patients are seldom included in these reports, so it is unclear whether multiple screenings simply increase the discovery of incidental abnormalities. Treatment of idiopathic atrophie blanche usually begins with aspirin, other antiplatelet agents, or pentoxifylline (Trental). When these fail, treatment is difcult. Minimally androgenic anabolic steroids have occasionally been helpful. A regimen of phenformin and anabolic steroid has been used successfully, but metformin does not appear to have similar efcacy [12]. Atrophie blanchelike lesions are seen in lupus patients, typically in association with aPLs, so the presence of such lesions should always prompt an APS workup in these patients. They are also seen in nonlupus patients who have APS, so a workup should be considered in patients with typical atrophie blanche lesions who are older, male, or who have lesions in sites other than perimalleolar areas. No consensus exists regarding the treatment of livedoid vasculopathy in the setting of APS, although treatment to prevent further thromboses is probably indicated. Anecdotal success has been reported with antiplatelet, anticoagulant, and brinolytic therapies, including tissue plasminogen activator [11,13]. Hydroxychloroquine appears to be helpful in some lupus patients who have atrophie blanchetype lesions (personal observation), and appeared to reduce the risk of thrombosis in a large lupus cohort [14]. MALIGNANT ATROPHIC PAPULOSIS (DEGOS DISEASE) Malignant atrophic papulosis, also known as Degos disease, is a rare, vasoocclusive disorder that predominately affects the skin initially, followed by the gastrointestinal tract and central nervous system. Affected men outnumber women three to one [15]. Visceral lesions may result in fatal bowel and cerebral infarctions. Some cases of only cutaneous involvement have been reported. Mucous membranes, particularly the conjunctiva, may be involved. Skin lesions begin as crops of 2- to 5-mm pale rose or yellowish-gray rm papules on the trunk and extremities that evolve over 2 to 4 weeks with the development of a central depression and ultimately a porcelain white scar, often with a rim of telangiectasias. The end-stage appearance is very similar to that of atrophie blanche. It is unclear from the literature how many patients with benign Degos disease, or skin-limited disease have been tested for aPLs. Degos-like lesions can be a cutaneous presentation of APS [16]. Patients who have such lesions, especially without visceral or central nervous system disease, should probably be investigated for the presence of aPLs.

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Histologically, the classic description is that of an inverted, wedge-shaped zone of dermal infarction whose base is in contact with the overlying epidermis and apex is adjacent to a thrombosed vessel in the deep dermis. However, the classic histopathology occurs in only a minority of biopsies, and additional features must be sought, such as lymphocytic vasculitis; dermal mucin deposition; perineural and intraneural lymphocytic inltrates; perivascular and periadnexal lymphocytic inltrates; atrophy and compact hyperkeratosis of the epidermis; dermalepidermal interface changes, including vacuolar change and necrotic basal keratinocytes; and sclerosing panniculitis [17]. The dermis may show frank necrosis or edema, mucin deposition, and slight sclerosis [18]. The pathogenesis of Degos disease is unclear; the three main theories are viral, autoimmune, and coagulation abnormality. Raised circulating levels of brinogen and cryoprobrin, and increased platelet aggregation and adhesiveness, have been reported in patients with Degos disease [15]. Case reports have shown variable responses to antiplatelet therapy (aspirin, dipyridamole, and heparin), systemic corticosteroids, cyclophosphamide, azathioprine, phenformin, and ethylestrenol, and thus, no denitive treatment exists [15]. It is unknown how often responsive cases are associated with aPLs. CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME The catastrophic APS, also known as CAPS, is a quickly progressing, often lethal manifestation rst dened in 1992; in 2003, it also became known as Ashersons syndrome. Most often encountered in patients who have APS without lupus (49.9%), but also commonly in patients who have SLE and lupuslike disease (45%), this condition is characterized by rapid onset, resulting in multiple organ dysfunction; small-vessel occlusive disease with thrombotic microangiopathy; fulminant tissue necrosis, particularly in the gastrointestinal tract; and evidence of the systemic inammatory response syndrome. Disseminated intravascular coagulation is also present in many patients [19]. The clinical appearance is similar to that of purpura fulminans, with widespread hemorrhagic infarction of the skin and intravascular thrombosis. Retiform (branching, stellate) purpura or eschar, usually noninammatory, is a typical cutaneous lesion of most cutaneous microvascular occlusion syndromes, and APS and CAPS are no exception (Fig. 3) [11,18,20]. The organs involved clinically are renal (70%), pulmonary (66%), brain (60%), heart (52%), and skin (47%). It may arise in patients already diagnosed with APS and undergoing treatment, or in patients never before identied. Triggers identied in nearly two thirds of patients include infections; trauma, including minor surgical procedures such as biopsies; obstetric-related complications; anticoagulation withdrawal; neoplasia; and drugs. Treatment includes intravenous gamma globulins, plasma exchanges, high-dose intravenous steroids, brinolytic agents, and fresh-frozen plasma. The use of rituximab in patients with severe thrombocytopenia has also been successful [19]. A review of 250 patients with CAPS has been organized by the Europhospholipid Group and is available at http://www.med.ub.es/mimmun/forum/caps.htm [21]. Some

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Fig. 3. Retiform. Purpura lesion is mostly nonblanchable. The retiform branching pattern is typical of most cutaneous microvascular occlusive lesions.

cases of CAPS have been called symmetric peripheral gangrene, but this acral presentation is not unique to APS. PAPULAR AND PLAQUE OCCLUSIVE LESIONS Cutaneous necrosis is another common manifestation of APS and may be second only to livedo reticularis in frequency. In the Cervera and colleagues [22] series, necrotic skin ulcerations were observed in 5.5% of patients who had APS and were the presenting sign in close to 4%. Lesions in Fig. 3 are typical of this presentation. The most commonly involved sites are the upper and lower extremities and helices of ears, cheeks, trunk, and forehead [22]; lesions may be widespread. The onset is often acute, with painful purpura [3]. Retiform (branching, stellate) lesions are typical of this presentation [11,18,20]. Occasionally, some lesions may have peripheral erythema, and necrotic bullae may form in affected areas. Pathology reveals diffuse, noninammatory thrombosis of dermal vessels without evidence of vasculitis [3,23]. Many investigators regard widespread necrosis as a major thrombotic event, warranting long-term anticoagulation with an international normalized ratio higher than three, with or without low-dose aspirin [23]. Cutaneous digital gangrene, with preceding ischemic symptoms, has also been observed in up to 7.5% of patients with APS, and requires full anticoagulation [16,22]. Subungual splinter hemorrhages have been reported, appearing concurrently with thrombotic events or lupus ares [16]. Many nonspecic skin lesions, including red macules, purpura, small red or cyanotic lesions on the hands and feet, localized necrosis, ecchymoses, and painful skin nodules are also observed; these may be readily mischaracterized clinically as vasculitis if a biopsy is not taken. These pseudovasculitis lesions were the presenting manifestations in 2.6% of subjects in a European cohort

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[22]. For such isolated lesions, combination therapy with low-dose aspirin and dipyridamole has been reported to be effective in some cases, but anticoagulation is usually prescribed. ANETODERMA Primary anetoderma is a rare skin disease of unknown cause characterized by loss of elastic bers in the skin. Also known as macular atrophy, it was rst described by Jadassohn in 1892. Lesions typically appear on the upper trunk and proximal extremities, presenting as multiple round, well-circumscribed, nely wrinkled patches or papules of slack skin that appear sunken, atrophied, or accid and demonstrate inward herniation or loss of substance on palpation (Figs. 4 and 5). Histopathologic examination of lesions should conrm decreased-to-absent elastic bers in the upper and middle dermis, but requires special stains, usually Verhoeff-van Gieson elastin stain. Elastophagocytosis may be present [24]. Anetoderma is an uncommon syndrome that is most often idiopathic (primary) or develops at sites of inammation (secondary) from many dermatoses, most commonly acne and varicella [25]. For more than 20 years, anetoderma has been reported in patients with connective tissue disease, especially SLE. The association of anetoderma and APS was rst described by Hodak and colleagues [26] and Disdier and colleagues [27] in the early 1990s; since then, nearly two dozen reports have described patients presenting with both conditions. Other systemic associations include multiple autoimmune diseases (SLE; discoid lupus; lupus profundus; systemic sclerosis; vitiligo; alopecia

Fig. 4. Anetoderma. Clustered lesions on midback. Lesions are typically pale, soft, and accid.

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Fig. 5. Anetoderma. Close-up anetoderma on ear lobe.

areata; primary hypothyroidism with antithyroid antibodies; multiple sclerosis; and primary Addisons disease) and infections (HIV, syphilis, tuberculosis, and Lyme disease) [25]. It is still unclear what role, if any, aPLs play in the pathogenesis of anetoderma. However, several investigators suggest that the presence of anetoderma may warrant a workup for autoimmune disease and, in particular, APS [28]. Its association with so many immunologic abnormalities suggests an immunologic mechanism for the elastolysis observed. One hypothesis is an increased release or activation of elastase by inammatory cells; others suggest loss of elastic bers due to phagocytosis by macrophages, or reduced synthesis of elastic bers; another theory suggests that microthrombosis in dermal vessels leads to local ischemia followed by degeneration of elastic bers [29,30]. Some investigators propose a possible common epitope between elastic bers and phospholipids (possibly beta-2GP1) as an explanation for an autoimmunemediated process [31]. Recently, an abnormal balance between tissue metalloproteinases and tissue inhibitors has been demonstrated in anetodermic skin; the investigators suggest hypoxia reoxygenation in the skin may trigger a local imbalance of metalloproteinases and their inhibitors, leading to elastic tissue destruction. Treatment of anetoderma is difcult. Multiple modalities have been attempted without consistent success, including topical and intralesional corticosteroids, penicillin G sodium, dapsone, colchicine, phenytoin, salicylates, hydroxychloroquine, and vitamin E [24,30]. References
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[3] Frances C, Niang S, Laftte E, et al. Dermatologic manifestations of the antiphospholipid syndrome. Arthritis Rheum 2005;52:178590. [4] Zelger B, Sepp N, Stockhammer G, et al. Sneddons syndrome: long-term follow-up of 21 patients. Arch Dermatol 1993;129:43747. [5] Gibbs M, English J, Zirwas M. Livedo reticularis: an update. J Am Acad Dermatol 2005;52(6):100919. [6] Sneddon I. Cerebro-vascular lesions and livedo reticularis. Br J Dermatol 1965;77:1805. [7] Frances C, Piette JC. The mystery of Sneddon syndrome: relationship with antiphospholipid syndrome and systemic lupus erythematosus. J Autoimmun 2000;15(2):13943. [8] Erkan D, Harrison MJ, Levy R, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 2007;56(7):238391. [9] Acland KM, Darvay A, Wakelin SH, et al. Livedoid vasculitis: a manifestation of the antiphospholipid syndrome? Br J Dermatol 1999;140(1):1315. [10] Hairston B, Davis M, Pittelkow M, et al. Livedoid vasculopathy: further evidence for procoagulant pathogenesis. Arch Dermatol 2006;142:14138. [11] Piette W. Cutaneous manifestations of microvascular occlusion syndromes. In: Bolognia J, Jorrizo J, Rapini R, editors. Dermatology. 1st edition. London: Mosby; 2003. p. 2003. [12] Shornick J, Nicholes B, Bergstresser P, et al. Idiopathic atrophie blanche. J Am Acad Dermatol 1983;8(6):7928. [13] Klein K, Pittelkow M. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992;67:92333. [14] Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 1996;5(Suppl 1):S1622. [15] Katz S, Mudd L, Roenigk H. Malignant atrophic papulosis (Degos disease) involving three generations of a family. J Am Acad Dermatol 1997;37:4804. [16] Gibson G, Su W, Pittelkow M. Antiphospholipid syndrome and the skin. J Am Acad Dermatol 1997;36:97082. [17] Harvell J, Williford P, White W. Benign cutaneous Degos disease: a case report with emphasis on histopathology as papules chronologically evolve. Am J Dermatopathol 2001;23(2):11623. [18] Robson K, Piette W. The presentation and differential diagnosis of cutaneous vascular occlusion syndromes. Adv Dermatol 1999;15(6):15382. [19] Asherson RA, Frances C, Iaccarino L, et al. The antiphospholipid antibody syndrome: diagnosis, skin manifestations, and current therapy. Clin Exp Rheumatol 2006;24(Suppl 40): S4651. [20] Piette W. Purpura and coagulation. In: Bolognia J, Jorrizo J, Rapini R, editors. Dermatology. 1st edition. London: Mosby; 2003. p. 35563. [21] Asherson R. Multiorgan failure and antiphospholipid antibodies: the catastrophic antiphospholipid (Ashersons) syndrome. Immunobiology 2005;210(10):72733. [22] Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46(4):101927. [23] Rossini J, Roverano S, Graf C, et al. Widespread cutaneous necrosis associated with antiphospholipid antibodies: report of four cases. J Clin Rheumatol 2002;8(6):32631. [24] Pascual J, Gimenez E, Sivera F, et al. Atrophic macules and papules in a 24-year-old woman. Arch Dermatol 2007;143:10914. [25] Sparsa A, Piette JC, Weschsler B, et al. Anetoderma and its prothrombotic abnormalities. J Am Acad Dermatol 2003;49(6):100812. [26] Hodak E, Shamai-Lubovitz O, David M, et al. Immunologic abnormalities associated with primary anetoderma. Arch Dermatol 1992;128(6):799803. [27] Disdier P, Harle J, Andrac L, et al. Primary anetoderma associated with the antiphospholipid syndrome. J Am Acad Dermatol 1994;30:1334.

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[28] de Souza E, Christofoletti P, Cintra M. Anetoderma associated with primary antiphospholipid syndrome. J Am Acad Dermatol 2007;56(5):8812. [29] Venhoff N, Miehle N, Juttner E, et al. Clinical images: anetoderma in systemic lupus erythematosus with antiphospholipid antibodies. Arthritis Rheum 2005;52(7):36580. [30] Bilen N, Bayramgurler D, Sikar A, et al. Anetoderma associated with antiphospholipid syndrome and systemic lupus erythematosus. Lupus 2003;12(9):7146. [31] Romani J, Perez F, Llobet M, et al. Anetoderma associated with the antiphospholipid antibodies: case report and review of the literature. J Eur Acad Dermatol Venereol 2001;15(2):1758.