8 Skin Manifestations of Antiphospholipid 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 reticularis 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 thrombotic 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 immunoglobulins, the presence of IgA anticardiolipin antibodies (aCL) has been reported as an independent predictive factor for skin lesions (skin ulcers, chilblain lupus, and vasculitis) [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 anastomoTable 8.1. The skin and antiphospholipid syndrome. ● ● ● ● ● ● ● ● ● ●

Livedo reticularis Sneddon’s syndrome Skin ulcers Necrotizing vasculitis Livedoid vasculitis Cutaneous gangrene Superficial thrombophlebitis Pseudovasculitic lesions: Nodules, papules, pustules, palmar–plantar erythema Subungual bleeding Anetoderma

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Table 8.2. Livedo reticularis and associated diseases. ● ● ● ● ● ● ●

Antiphospholipid syndrome Systemic lupus erythematosus (with or without aPL) Systemic vasculitis (polyarteritis nodosa, cryoglobulinemia) Pseudovasculitic syndromes (cholesterol embolization) Overlapping syndromes Scleroderma Infectious diseases (syphilis, tuberculosis)

sis between the two cones where diminished blood flow is associated with the dilatation of venules and capillaries. Therefore, the alteration in arterial blood flow caused by the livedo may result from: ● ● ●

Blood inflow obstruction Blood hyperviscosity 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 relationship 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 complete network (Fig. 8.1).

Figure 8.1. Livedo reticularis of the gluteal region and both thighs of a patient with SLE and APS.

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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 syndrome 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 noninflammatory 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).

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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.

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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 histological 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 attributed 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 phenomenon, cryoglobulinemia, macroglobulinemia, venous vascular pathology, and diabetes [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 hyperpigmentation. 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.

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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.

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Figure 8.6. Digital necrosis with gangrene of the fingers of a patient with SLE and APS.

Some patients (3%) develop extensive superficial skin necrosis generally involving 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-toblack linear lesions, which persist after ungual compression. They are not exclusively associated with the APS because ungual trauma can be seen in healthy subjects as well as patients with infectious endocarditis. They are caused by thrombotic or embolic phenomena. It is worth pointing out that the presence of these

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Figure 8.7. SLE along with APS presenting with papuloerythematosus skin lesion (irregular borders) on the lower limb.

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 mechanism 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 endarterial 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

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Figure 8.8. Biopsy of skin with non-inflammatory vascular thrombosis (venular) of a patient with SLE and APS.

observed. Based on skin involvement, the following histopathologic pattern is observed [36]: ●

●

Gangrenous lesion Vascular thrombosis Dermal hemorrhage Obliterating endarteritis Epidermal necrosis Ulcerous lesion Vascular thrombosis Capillary proliferation Obliterating endarteritis Dermal hemorrhage Deposit of hemosiderin

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Livedo reticularis Center of the reticular pattern (apparently normal skin): Normal biopsy Obliterating endarteritis in deep arterioles of the dermis or hypodermis Tissue of the reticulate (involved segment of the skin): Hyperplasia of dermal vessels

Wherever the site of biopsy in livedo reticularis, thrombosis is rare except in the case of catastrophic APS or in the presence of ulcers and necrosis.

Association of Skin Lesions with Different Organ Involvement It should be remembered that 41% of patients with APS begin their disease with skin manifestations and that 40% of patients will develop multisystem thrombotic phenomena during the course of the disease. The association of livedo reticularis with cerebrovascular involvement has already been pointed out (Sneddon’s syndrome). The presence of multiple subungual hemorrhages might coincide with thrombotic events of other organs such as the brain, skin, adrenal glands, kidney, etc.

Entities Associated with APS Different pathologic entities have been described to occur in association with APS. It should be underscored that patients affected with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) are susceptible to thrombosis during the active stage of the disease in relation to aPL. Up to 10% of patients will develop ischemic lesions of the central nervous system and embolic events, including peripheral necrosis [37, 38]. Skin lesions observed in this life-threatening syndrome are livedo reticularis, acrocyanosis, extensive skin necrosis, palmar erythema, and gangrene [39].

Treatment It is hard to predict if the patient who only has a skin lesion will later develop an extra cutaneous thrombotic event. However, it is worth remembering that 40% of patients that begin with skin lesions will eventually undergo systemic involvement. Hence, it is important to consider extensive skin necrosis and digital ischemia as major thrombotic events; in these cases, patients should receive long-term anticoagulant treatment [40–42]. The approach to minor skin manifestations is less clear. It is yet to be defined whether platelet antiaggregation is enough or whether it will be necessary to attempt the use of more aggressive treatments. Alternative treatments should be developed for patients resistant to standard approaches [43]. Thrombolytic agents in low dose have been proposed in patients with skin lesions where the thrombotic events account for the clinical picture (i.e.,

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livedoid vasculitis). Thrombolytic agents not only accomplish the patency of involved arteries but also play a significant role by increasing microcirculation. Some patients have been treated with streptokinase or urokinase with or without heparin with varying degree of responses. The intravenous infusion of recombinant tissue plasminogen activator at a dose of 20 mg/day diluted in saline solution during 8 hours for 10 days resulted in the healing of ulcer lesions [44]. Unwanted effects such as bleeding that might threaten the patient’s life should be considered. This therapeutic modality should be selected when all the other alternatives have failed. It is critical to test coagulation status prior to and during infusion; treatment should be withdrawn as soon as minimum bleeding is noticed [44, 45]. Although anecdotal, the efficacy of sildenafil, a phosphodiesterase inhibitor, in the treatment of non-healing ulcers has also been reported [46].

Conclusion aPL are strongly related to thrombotic events. It is the most common acquired coagulation defect among the ones accountable for procoagulant states. Skin involvement might be the first manifestation of APS (41%) and over one third of these patients will develop multisystem thrombotic events during the course of the disease. Therefore, a close monitoring of these patients is warranted.

References 1. Battagliotti CA. Sindrome de anticuerpos antifosfolipidicos. In: Battagliotti CA, Greca A, et al, eds. Temas relacionados de terapeutica clinica. Rosario: UNR Editora; 1996:328–334. 2. Alegre VA, Gastineau DA, Winkelmann RK. Skin lesions associated with circulating lupus anticoagulant. Br J Dermatol 1989;120:419–429. 3. Gibson GE, Su WP, Pittelkow MR. Antiphospholipid syndrome and the skin. J Am Acad Dermatol 1997;36:970–982. 4. Tajima C, Suzuki Y, Mizushima Y, Ichikawa Y. Clinical significance of immunoglobulin A antiphospholipid antibodies: possible association with skin manifestations and small vessel vasculitis. J Rheumatol 1998;25:1730–1736. 5. Eng AM. Cutaneous expressions of antiphospholipid syndromes. Semin Thromb Hemost 1994;20:71–78. 6. Naldi L, Locati F, Marchesi L, et al. Cutaneous manifestations associated with antiphospholipid antibodies in patients with suspected primary antiphospholipid syndrome: a case-control study. Ann Rheum Dis 1993;52:219–222. 7. Asherson RA, Mayou SC, Merry P, Black MM, Hughes GR. The spectrum of livedo reticularis and anticardiolipin antibodies. Br J Dermatol 1989;120:215–221. 8. Weinstein C, Miller MH, Axtens R, Buchanan R, Littlejohn GO. Livedo reticularis associated with increased titers of anticardiolipin antibodies in systemic lupus erythematosus. Arch Dermatol 1987;123:596–600. 9. Niang S, Frances C, Barete S, et al. Dermatologic manifestations of the antiphospholipid syndrome [abstract]. Arthritis Rheum 2003;48:S879. 10. Sneddon IB. Cerebro-vascular lesions and livedo reticularis. Br J Dermatol 1965;77:180–185. 11. Martinez Hernandez PL, Lopez Guzman A, Espinosa Arranz E, Monereo Alonso A, Arnalich Fernandez F. Sindrome de Sneddon: valor diagnostico de los anticuerpos antifosfolipidicos. Rev Clin Esp 1991;189:272–274. 12. Tourbah A, Piette JC, Iba-Zizen MT, Lyon-Caen O, Godeau P, Frances C. The natural course of cerebral lesions in Sneddon syndrome. Arch Neurol 1997;54:53–60. 13. Stephens CJ. Sneddon’s syndrome. Clin Exp Rheumatol 1992;10:489–492.

Skin Manifestations of Antiphospholipid Syndrome

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14. Macario F, Macario MC, Ferro A, Goncalves F, Campos M, Marques A. Sneddon’s syndrome: a vascular systemic disease with kidney involvement? Nephron 1997;75:94–97. 15. Ohtani H, Imai H, Yasuda T, et al. A combination of livedo racemosa, occlusion of cerebral blood vessels, and nephropathy: kidney involvement in Sneddon’s syndrome. Am J Kidney Dis 1995;26:511–515. 16. Grattan CE, Burton JL. Antiphospholipid syndrome and cutaneous vasoocclusive disorders. Semin Dermatol 1991;10:152–159. 17. Reyes E, Alarcon-Segovia D. Leg ulcers in the primary antiphospholipid syndrome. Report of a case with a peculiar proliferative small vessel vasculopathy. Clin Exp Rheumatol 1991;9:63–66. 18. Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. A report of two cases and a review of the literature. J Am Acad Dermatol 1986;15:211–219. 19. Schmid MH, Hary C, Marstaller B, Konz B, Wendtner CM. Pyoderma gangrenosum associated with the secondary antiphospholipid syndrome. Eur J Dermatol 1998;8:45–47. 20. Chacek S, MacGregor-Gooch J, Halabe-Cherem J, Nellen-Hummel H, Quinones-Galvan A. Pyoderma gangrenosum and extensive caval thrombosis associated with the antiphospholipid syndrome – a case report. Angiology 1998;49:157–160. 21. Bard JW, Winkelmann RK. Livedo vasculitis. Segmental hyalinizing vasculitis of the dermis. Arch Dermatol 1967;96:489–499. 22. Leroux B, Baron E, Garrido G, Alonso A, Bergero A, Fernandez-Bussy R. Vasculitis livedoide: nuestra experiencia. Dermatol Argent 1998;2:121–126. 23. Winkelmann RK, Schroeter AL, Kierland RR, Ryan TM. Clinical studies of livedoid vasculitis: (segmental hyalinizing vasculitis). Mayo Clin Proc 1974;49:746–750. 24. Kern AB. Atrophie blanche. Report of two patients treated with aspirin and dipyridamole. J Am Acad Dermatol 1982;6:1048–1053. 25. Stephansson EA, Niemi KM, Jouhikainen T, Vaarala O, Palosuo T. Lupus anticoagulant and the skin. A longterm follow-up study of SLE patients with special reference to histopathological findings. Acta Derm Venereol 1991;71:416–422. 26. Hassan ML, Di Fabio NA, Martinez Aquino E, Schroh R, Kien C, Magnin PH. Vasculitis livedoide. Estudio clinico, histopatologico y laboratorial de 10 casos. Rev Arg Dermatol 1987;68:311–319. 27. Hughes GR. The Prosser-White oration 1983. Connective tissue disease and the skin. Clin Exp Dermatol 1984;9:535–544. 28. Paira S, Roverano S, Zunino A, Oliva ME, Bertolaccini ML. Extensive cutaneous necrosis associated with anticardiolipin antibodies. J Rheumatol 1999;26:1197–1200. 29. Dodd HJ, Sarkany I, O’Shaughnessy D. Widespread cutaneous necrosis associated with the lupus anticoagulant. Clin Exp Dermatol 1985;10:581–586. 30. Asherson RA, Jacobelli S, Rosenberg H, McKee P, Hughes GR. Skin nodules and macules resembling vasculitis in the antiphospholipid syndrome – a report of two cases. Clin Exp Dermatol 1992;17:266–269. 31. Frances C, Piette JC, Saada V, et al. Multiple subungual splinter hemorrhages in the antiphospholipid syndrome: a report of five cases and review of the literature. Lupus 1994;3:123–128. 32. Frances C, Piette JC. Antiphospholipid antibody syndrome (Hughes’ syndrome). Dermatol Ther 2001;14:117–125. 33. Hodak E, Feuerman H, Molad Y, Monselise Y, David M. Primary anetoderma: a cutaneous sign of antiphospholipid antibodies. Lupus 2003;12:564–568. 34. Disdier P, Harle JR, Andrac L, et al. Primary anetoderma associated with the antiphospholipid syndrome. J Am Acad Dermatol 1994;30:133–134. 35. Stephansson EA, Niemi KM. Antiphospholipid antibodies and anetoderma: are they associated? Dermatology 1995;191:204–209. 36. Alegre VA, Winkelmann RK. Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatol 1988;19:117–124. 37. Martinovic Z, Perisic K, Pejnovic N, Lukacevic S, Rabrenovic L, Petrovic M. Antiphospholipid antibodies in inflammatory bowel diseases. Vojnosanit Pregl 1998;55:47–49. 38. Mevorach D, Goldberg Y, Gomori JM, Rachmilewitz D. Antiphospholipid syndrome manifested by ischemic stroke in a patient with Crohn’s disease. J Clin Gastroenterol 1996;22:141–143. 39. Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998;77:195–207. 40. Lockshin MD. Which patients with antiphospholipid antibody should be treated and how? Rheum Dis Clin North Am 1993;19:235–247. 41. Derksen RH, de Groot PG, Kater L, Nieuwenhuis HK. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulant treatment. Ann Rheum Dis 1993;52:689–692.

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42. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993–997. 43. Curwin J, Jang IK, Fuster V. Expanded use of thrombolytic therapy. Mayo Clin Proc 1992;67:1004–1005. 44. Gertner E, Lie JT. Systemic therapy with fibrinolytic agents and heparin for recalcitrant nonhealing cutaneous ulcer in the antiphospholipid syndrome. J Rheumatol 1994;21:2159–2161. 45. Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992;67:923–933. 46. Gertner E. Treatment with sildenafil for the healing of refractory skin ulcerations in the antiphospholipid syndrome. Lupus 2003;12:133–135.