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Cutaneous Manifestationsof Antiphospholipid AntibodySyndrome

Sari Weinstein, MDa, Warren Piette, MDa,b,*aDivision of Dermatology, John H. Stroger, Jr. Hospital of Cook County,1900 West Polk Street, Room 519, Chicago, IL 60612, USAbDepartment of Dermatology, Rush University Medical Center,Annex Building, Suite 220, 707 S. Wood, Chicago, IL 60612, USA

Although no skin finding is pathognomonic for antiphospholipid anti-body syndrome (APS), many cutaneous findings can be helpful in sug-gesting this diagnostic possibility. The cutaneous syndromes that

should prompt consideration of APS are the focus of this article.

LIVEDO RETICULARIS AND RACEMOSALivedo reticularis is the most frequently associated cutaneous manifestation in

patients who have APS, observed as the presenting sign in up to 40% ofpatients and seen in up to 70% of patients who have systemic lupus erythema-tosus (SLE) and APS [1]. In patients who have SLE, the finding of moderate-to-extensive livedo reticularis probably warrants testing for antiphospholipidantibodies (aPLs). In a recent consensus statement on the updated classificationcriteria for APS, Miyakis and colleagues [2] defined livedo reticularis as thepersistent, not reversible with rewarming, violaceous, red or blue, reticularor mottled pattern of the skin of the trunk, arms, or legs. It may consist of reg-ular, unbroken circles (regular livedo reticularis), or irregular, broken circles

(livedo racemosa). The livedo patterns were further classified, depending onthe width of branching pattern (greater or less than 10 mm), into fine and largelivedo reticularis and fine and large livedo racemosa. Although the terms arefrequently used interchangeably, compared with livedo reticularis, livedo race-mosa is a coarser and more irregular pattern, is more often irregularly distrib-uted, and may be more generalized (Fig. 1). Some investigators believe theracemosa variant to be a major clinical feature of APS, strongly associatedwith the arterial subset of APS, which includes cerebrovascular events, arterial

*Corresponding author. Division of Dermatology, John H. Stroger, Jr. Hospital of CookCounty, 1900 West Polk Street, Room 519, Chicago, IL 60612. E-mail address: [email protected] (W. Piette).

0889-8588/08/$ see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.hoc.2007.10.011 hemonc.theclinics.com

Hematol Oncol Clin N Am 22 (2008) 6777

HEMATOLOGY/ONCOLOGY CLINICSOF NORTH AMERICA
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thrombosis, systemic hypertension, heart valve abnormalities, Raynauds phe-nomenon, and pregnancy morbidity, and consider it an independent, additive,thrombotic risk factor [1,3]. Livedo reticularis has been observed less fre-quently in those who have only venous thrombosis.

An impairment of blood flow and lowered oxygen tension at the peripheryof skin segments is responsible for the mottling observed clinically. The cuta-neous blood supply is arranged in inverted cones supplied by a central arteriolearising perpendicularly from vessels in the fascia. This arteriole is responsiblefor the blood supply to a 1- to 4-cmdiameter zone on the skin surface. The

netlike pattern results from cyanotic discoloration at the junctions betweencones, where deoxygenated blood accumulates. The ring size of the reticulatepattern depends on the body site and is usually smallest on the palms and larg-est on the trunk or thighs.

The pathophysiology of livedo is not well characterized, but the relationshipwith arterial thrombosis suggests a possible role for the endothelial cell. Thevasoconstriction of livedo racemosa may be induced by an interaction of anaPL with the endothelial cell or other cellular element of vessels, altering theirfunction [1,4]. Many autoantibodies associated with APS are directed against

phospholipid-protein complexes expressed on, or bound to, the surface ofendothelial cells. When bound, these cells may become prothrombotic, leadingto the production of procoagulant substances such as tissue factor, plasminogenactivator inhibitor 1, and endothelin 1; the increased expression of theseprocoagulants may be responsible, in part, for the hypercoagulability andthromboses observed in APS.

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

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Unfortunately, livedo reticularis is a nonspecific cutaneous finding. In neo-nates, generalized livedo reticularis is an expected finding, termed cutis mar-morata. Physiologic livedo reticularis in adults is common, triggered by coldand reversed by warming. Associations of nonphysiologic livedo reticulariswith systemic diseases or medications are many; one recent review cited justshort of 100 conditions [5].

IDIOPATHIC LIVEDO RETICULARIS WITH CEREBROVASCULARACCIDENTS (SNEDDONS SYNDROME)In 1965, Sneddon reported the association of livedo reticularis or racemosawith cerebrovascular accidents [6]. Sneddons syndrome is a rare, but poten-tially severe, condition typically affecting young or middle-aged women, withthe first cerebrovascular accident typically occurring before 45 years of age.Livedo of either type, typically on the trunk and buttocks but also on the extrem-ities and face, may precede the onset of stroke by years. Although the relationshipbetween APS and Sneddons syndrome is not clear, the prevalence of aPLs inSneddons syndrome has ranged from 0% to 85%, and most authorities suggestthat 40% to 50% of patients who have Sneddons are antibody positive [1].

Skin biopsies are often nondiagnostic in Sneddons syndrome. Multiple deeppunch biopsies from the center and the violaceous areas are required to in-crease sensitivity. According to Zelger and colleagues [4], small-to-medium

sized arteries at the dermal-subcutis boundary are involved in a stage-specificpattern. Initial lesions are characterized by the attachment of lymphohistiocyticcells and the detachment of endothelial cells (endotheliitis). Early-phase lesionsdisplay partial or complete occlusion of vascular lumens by a plug of lympho-histiocytic cells and fibrin. Intermediate-phase lesions show replacement of plugby proliferating subendothelial cells and dilated capillaries in the adventitia ofthe occluded vessel. Late-phase lesions show fibrosis 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 smallartery disease primarily affecting the brain and skin vessels [7].

No treatment has consistently been effective for livedo. In patients who haveSneddons or APS, chronic anticoagulation may be warranted, even though thelivedo may worsen on anticoagulant or antiplatelet therapy. In light of thehigher association of arterial occlusion in patients who have livedo racemosa,patients should reduce other risk factors, including smoking and use of estro-gen-containing oral contraceptives. Low-dose aspirin is frequently prescribed,although its efficacy is unproven [8]. Further study is needed on the potential

benefit of clopidogrel, statins, and angiotensin-converting enzyme inhibitors.

ATROPHIE BLANCHE AND LIVEDOID VASCULOPATHYAtrophie blanche is a term that has been used for several different conditions,leading to some confusion in the literature. Originally described as atrophieblanche en plaque by Milian in 1929, synonyms for this disease include livedo

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The pathogenesis of livedoid vasculopathy and atrophie blanche is unknownbut it is believed to involve some altered local or systemic control of coagula-tion [11]. Many studies support a vaso-occlusive pathogenesis, and elevatedfibrinopeptide A levels, defective release of vascular plasminogen activator,and decreased thrombomodulin expression have been described [9]. Livedoidvasculopathy is observed in patients who have procoagulant proclivities,including factor V Leiden, hyperhomocysteinemia, altered fibrinolysis or plate-let activation, and aPLs [11]. However, control patients are seldom included inthese reports, so it is unclear whether multiple screenings simply increase thediscovery of incidental abnormalities.

Treatment of idiopathic atrophie blanche usually begins with aspirin, otherantiplatelet agents, or pentoxifylline (Trental). When these fail, treatment is dif-ficult. 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 efficacy [12].

Atrophie blanchelike lesions are seen in lupus patients, typically in associa-tion with aPLs, so the presence of such lesions should always prompt an APSworkup in these patients. They are also seen in nonlupus patients who haveAPS, so a workup should be considered in patients with typical atrophieblanche lesions who are older, male, or who have lesions in sites other thanperimalleolar areas.

No consensus exists regarding the treatment of livedoid vasculopathy in thesetting of APS, although treatment to prevent further thromboses is probablyindicated. Anecdotal success has been reported with antiplatelet, anticoagulant,and fibrinolytic therapies, including tissue plasminogen activator [11,13].Hydroxychloroquine appears to be helpful in some lupus patients who haveatrophie blanchetype lesions (personal observation), and appeared to reducethe 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, vaso-occlusive disorder that predominately affects the skin initially, followed bythe gastrointestinal tract and central nervous system. Affected men outnumberwomen three to one [15]. Visceral lesions may result in fatal bowel and cerebralinfarctions. Some cases of only cutaneous involvement have been reported.Mucous membranes, particularly the conjunctiva, may be involved. Skinlesions begin as crops of 2- to 5-mm pale rose or yellowish-gray firm papuleson the trunk and extremities that evolve over 2 to 4 weeks with the develop-ment of a central depression and ultimately a porcelain white scar, often

with a rim of telangiectasias. The end-stage appearance is very similar to thatof atrophie blanche. It is unclear from the literature how many patients withbenign Degos disease, or skin-limited disease have been tested for aPLs.Degos-like lesions can be a cutaneous presentation of APS [16]. Patients whohave 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-shapedzone of dermal infarction whose base is in contact with the overlying epidermisand apex is adjacent to a thrombosed vessel in the deep dermis. However, theclassic histopathology occurs in only a minority of biopsies, and additional fea-tures must be sought, such as lymphocytic vasculitis; dermal mucin deposition;perineural and intraneural lymphocytic infiltrates; perivascular and periadnex-al lymphocytic infiltrates; atrophy and compact hyperkeratosis of the epider-mis; dermalepidermal interface changes, including vacuolar change andnecrotic basal keratinocytes; and sclerosing panniculitis [17]. The dermismay show frank necrosis or edema, mucin deposition, and slight sclerosis [18].

The pathogenesis of Degos disease is unclear; the three main theories areviral, autoimmune, and coagulation abnormality. Raised circulating levels offibrinogen and cryoprofibrin, and increased platelet aggregation and adhesive-ness, 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 definitive treatmentexists [15]. It is unknown how often responsive cases are associated with aPLs.

CATASTROPHIC ANTIPHOSPHOLIPID SYNDROMEThe catastrophic APS, also known as CAPS, is a quickly progressing, often

lethal manifestation first defined in 1992; in 2003, it also became known asAshersons syndrome. Most often encountered in patients who have APS with-out lupus (49.9%), but also commonly in patients who have SLE and lupus-like disease (45%), this condition is characterized by rapid onset, resultingin multiple organ dysfunction; small-vessel occlusive disease with thromboticmicroangiopathy; fulminant tissue necrosis, particularly in the gastrointestinaltract; and evidence of the systemic inflammatory response syndrome. Dissem-inated intravascular coagulation is also present in many patients [19].

The clinical appearance is similar to that of purpura fulminans, with wide-

spread hemorrhagic infarction of the skin and intravascular thrombosis.Retiform (branching, stellate) purpura or eschar, usually noninflammatory, isa typical cutaneous lesion of most cutaneous microvascular occlusionsyndromes, and APS and CAPS are no exception (Fig. 3) [11,18,20]. Theorgans involved clinically are renal (70%), pulmonary (66%), brain (60%),heart (52%), and skin (47%). It may arise in patients already diagnosed withAPS and undergoing treatment, or in patients never before identified. Triggersidentified in nearly two thirds of patients include infections; trauma, includingminor surgical procedures such as biopsies; obstetric-related complications;

anticoagulation withdrawal; neoplasia; and drugs. Treatment includes intrave-nous gamma globulins, plasma exchanges, high-dose intravenous steroids,fibrinolytic agents, and fresh-frozen plasma. The use of rituximab in patientswith severe thrombocytopenia has also been successful [19]. A review of 250patients with CAPS has been organized by the Europhospholipid Group andis available at http://www.med.ub.es/mimmun/forum/caps.htm [21]. Some

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cases of CAPS have been called symmetric peripheral gangrene, but this acralpresentation is not unique to APS.

PAPULAR AND PLAQUE OCCLUSIVE LESIONSCutaneous necrosis is another common manifestation of APS and may be sec-ond 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 APSand were the presenting sign in close to 4%. Lesions in Fig. 3 are typical of thispresentation. The most commonly involved sites are the upper and lowerextremities and helices of ears, cheeks, trunk, and forehead [22]; lesions maybe widespread. The onset is often acute, with painful purpura [3]. Retiform(branching, stellate) lesions are typical of this presentation [11,18,20]. Occasion-ally, some lesions may have peripheral erythema, and necrotic bullae may form

in affected areas. Pathology reveals diffuse, noninflammatory thrombosis ofdermal vessels without evidence of vasculitis [3,23]. Many investigators regardwidespread necrosis as a major thrombotic event, warranting long-term antico-agulation with an international normalized ratio higher than three, with orwithout low-dose aspirin [23].

Cutaneous digital gangrene, with preceding ischemic symptoms, has alsobeen observed in up to 7.5% of patients with APS, and requires full anticoagu-lation [16,22].

Subungual splinter hemorrhages have been reported, appearing concurrently

with thrombotic events or lupus flares [16].Many nonspecific skin lesions, including red macules, purpura, small red or

cyanotic lesions on the hands and feet, localized necrosis, ecchymoses, andpainful skin nodules are also observed; these may be readily mischaracterizedclinically as vasculitis if a biopsy is not taken. These pseudovasculitis lesionswere the presenting manifestations in 2.6% of subjects in a European cohort

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


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[22]. For such isolated lesions, combination therapy with low-dose aspirin anddipyridamole has been reported to be effective in some cases, but anticoagula-tion is usually prescribed.

ANETODERMAPrimary anetoderma is a rare skin disease of unknown cause characterized byloss of elastic fibers in the skin. Also known as macular atrophy, it was firstdescribed by Jadassohn in 1892. Lesions typically appear on the upper trunkand proximal extremities, presenting as multiple round, well-circumscribed,finely wrinkled patches or papules of slack skin that appear sunken, atrophied,or flaccid and demonstrate inward herniation or loss of substance on palpation

(Figs. 4 and 5). Histopathologic examination of lesions should confirmdecreased-to-absent elastic fibers in the upper and middle dermis, but requiresspecial stains, usually Verhoeff-van Gieson elastin stain. Elastophagocytosismay be present [24].

Anetoderma is an uncommon syndrome that is most often idiopathic(primary) or develops at sites of inflammation (secondary) from many derma-toses, most commonly acne and varicella [25]. For more than 20 years, aneto-derma has been reported in patients with connective tissue disease, especiallySLE. The association of anetoderma and APS was first described by Hodak

and colleagues [26] and Disdier and colleagues [27] in the early 1990s; sincethen, nearly two dozen reports have described patients presenting with bothconditions. 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, andflaccid.


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areata; primary hypothyroidism with antithyroid antibodies; multiple sclerosis;and primary Addisons disease) and infections (HIV, syphilis, tuberculosis, andLyme disease) [25]. It is still unclear what role, if any, aPLs play in the patho-genesis of anetoderma. However, several investigators suggest that the pres-ence of anetoderma may warrant a workup for autoimmune disease and, in

particular, APS [28].Its association with so many immunologic abnormalities suggests an immu-

nologic mechanism for the elastolysis observed. One hypothesis is an increasedrelease or activation of elastase by inflammatory cells; others suggest loss ofelastic fibers due to phagocytosis by macrophages, or reduced synthesis of elas-tic fibers; another theory suggests that microthrombosis in dermal vessels leadsto local ischemia followed by degeneration of elastic fibers [29,30]. Someinvestigators propose a possible common epitope between elastic fibers andphospholipids (possibly beta-2GP1) as an explanation for an autoimmune-

mediated process [31]. Recently, an abnormal balance between tissue metallo-proteinases and tissue inhibitors has been demonstrated in anetodermic skin;the investigators suggest hypoxia reoxygenation in the skin may trigger a localimbalance of metalloproteinases and their inhibitors, leading to elastic tissuedestruction.

Treatment of anetoderma is difficult. Multiple modalities have been attemp-ted without consistent success, including topical and intralesional corticoste-roids, penicillin G sodium, dapsone, colchicine, phenytoin, salicylates,hydroxychloroquine, and vitamin E [24,30].

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pholipid syndrome. J Rheumatol 2006;33(12):237982.[2] Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the

classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost2005;4:295306.

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


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[3] Frances C, Niang S, Laffitte E, et al. Dermatologic manifestations of the antiphospholipidsyndrome. 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 Dermatol2005;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 anti-

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[9] Acland KM, Darvay A, Wakelin SH, et al. Livedoid vasculitis: a manifestation of the anti-phospholipid syndrome? Br J Dermatol 1999;140(1):1315.

[10] Hairston B, Davis M, Pittelkow M, et al. Livedoid vasculopathy: further evidence for procoa-gulant 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 Derma-

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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 Derma-

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emphasis on histopathology as papules chronologically evolve. Am J Dermatopathol2001;23(2):11623.

[18] Robson K, Piette W. The presentation and differential diagnosis of cutaneous vascular occlu-sion syndromes. Adv Dermatol 1999;15(6):15382.

[19] Asherson RA, Frances C, Iaccarino L, et al. The antiphospholipid antibody syndrome: diag-nosis, 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 antiphos-pholipid (Ashersons) syndrome. Immunobiology 2005;210(10):72733.

[22] Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologicmanifestations and patterns of disease expression in a cohort of 1,000 patients. ArthritisRheum 2002;46(4):101927.

[23] Rossini J, Roverano S, Graf C, et al. Widespread cutaneous necrosis associated with anti-phospholipid 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-oldwoman. Arch Dermatol 2007;143:10914.

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[26] Hodak E, Shamai-Lubovitz O, David M, et al. Immunologic abnormalities associated withprimary anetoderma. Arch Dermatol 1992;128(6):799803.

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