Anetoderma and its prothrombotic abnormalities

Anetoderma and its prothrombotic abnormalities Agnes Sparsa, MD, Jean Charles Piette, MD, Bertrand Wechsler, MD, Zahir Amoura, MD, and Camille France`s, MD Paris, France Background: Anetoderma is characterized by circumscribed areas of flaccid skin due to the loss of elastic tissue in the dermis. It may be primary or secondary to various dermatoses. The primary form has been reported in association with autoimmune diseases and recently with antiphospholipid antibodies. Its etiology remains unknown. Objectives: To analyze clinical and laboratory data from a series of patients with anetoderma referred in our university reference center for connective tissue disorders. Patients and methods: All the consecutive patients with histologically confirmed anetoderma followed in our clinic from 1996 to 2001 were enrolled in this study. Laboratory investigations included the screening for prothrombotic abnormalities and classical immunological investigations for systemic lupus erythematosus. Clinical and laboratory data were analyzed retrospectively. Results: Anetoderma was primary in 9 cases and secondary to lupus profundus in 2 cases. Prothrombotic abnormalities were detected in 10 patients (9/9 with primary and 1/2 with secondary anetoderma). Antiphospholipid antibodies were detected in 9 patients. Only 4 patients fulfilled criteria for definite antiphospholipid syndrome which was primary for 3 and associated with systemic lupus erythematosus in the other. Conclusion: Patients with anetoderma should be evaluated for the possible presence of a prothrombotic state and warned of its potential risks when present.. (J Am Acad Dermatol 2003;49:1008-12.)

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netoderma, was initially described by Jadassohn in 1892.1 It is a rare disorder characterized by circumscribed areas of flaccid skin due to the loss of elastic tissue in the dermis.2 Anetoderma may be primary or secondary to various dermatoses. When primary, it is frequently observed in patients with autoimmune diseases and especially with antiphospholipid antibodies (aPL).3,4 The aim of this study was to analyze clinical and laboratory From the Department of Internal Medecine, University Hospital Pitie´. Funding sources: None. Conflicts of interests: None identified. Accepted for publication April 2, 2003. Reprint requests: Camille France˘s, Department of Internal Medecine, University Hospital Pitie´, 83, Boulevard de l’Hoˆpital, 75651 Paris Cedex 13, France. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1016/S0190-9622(03)02110-8

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data in a series of patients with anetoderma referred to us from our University Reference Center for Connective Tissue Disorders (CTD).

PATIENTS AND METHODS All patients with anetoderma followed in our clinic from 1996 to 2001 were included in this study. The diagnosis of anetoderma was suggested clinically by the presence of circumscribed areas of wrinkled, atrophic or slack skin. Histological proof of focal loss of normal elastic fibers within the dermis was always required. Deep skin biopsies were obtained surgically. Numerous serial sections of the biopsied tissues were examined. Laboratory investigations included standard biochemistry, blood cell counts, homocysteine blood levels (N ⱕ20 mol/l), functional and immunological levels of antithrombin III protein, biological activityand antigen levels of protein C and protein S, genomic analysis of factor V Q506R/G and prothrombin 20210G/A mutations. All patients were tested on at least 4 occasions for lupus

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anticoagulant (LA) and anticardiolipin antibodies (aCL). LA was usually screened by activated partial thromboplastin time and diluted thromboplastin time, and confirmed both by mixing studies and demonstration of phospholipid dependence. IgG and IgM aCL were measured by a solid-phase immunoassay with commercial ELISA kits (Biomedical Diagnostics SA, France). Results were considered positive when ⬎3 SD above the mean of normal controls on at least 2 occasions. Positive aCL results were divided into low (15-25 UGPL or UMPL), medium (26-80 UGPL or UMPL) or high (⬎80 UGPL or UMPL). Only medium or high values were taken into account. Biological false-positive serologic tests for syphilis (BFP-STS) were defined as a positive VDRL and a negative TPHA or FTA-ABS test. Anti-␤ 2 glycoprotein1 (␤2GP1) antibodies were detected with an ELISA using purified rabbit ␤2 GP1 (Behring) and non-irradiated plates. Results were considered positive when ⬎3 SD above the mean of normal controls. Antinuclear antibodies (ANA) were detected by immunofluorescence on rat liver tissue sections or Hep2 cells and considered positive when the titer was ⱖ1/100. Extractable nuclear antigens (ENA) were detected with an ELISA using various purified antigens. Anti-double-stranded DNA antibodies (aDNA) were measured by Farr assay and/or by Crithidia fluorescence. Patients’clinical and laboratory data were analyzed retrospectively. The underlying autoimmune diseases were diagnosed when the following criteria were present: systemic lupus erythematosus (SLE) according to the American College of Rheumatology revised criteria;5 antiphospholipid syndrome (APS) according to the preliminary criteria for the classification of definite APS;6 primary APS according to our strict exclusion criteria to rule out a possible SLE.7

RESULTS Eleven patients (7 females, 4 males) with anetoderma were followed from 1996 to 2001. Their mean age was 28.5 years (range: 16-43 years) at the time skin lesions were diagnosed. Anetoderma was considered to be primary for 9 patients who had not noticed previous lupus erythematous or other inflammatory skin lesions in the anetoderma-involved sites. In contrast, secondary anetoderma developed in 2 patients on sites of histologically proven lupus profundus. Patients with primary anetoderma had numerous lesions (⬎10) located on the upper portion of the chest and arms (Fig 1, A). The 2 patients with secondary anetoderma had fewer (⬍5), but larger le-

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Fig 1. A, Numerous herniated non-inflammatory lesions of primary anetoderma occurring in a patient with underlying APS and SLE. B, Herniated lesions of anetoderma secondary to lupus profundus.

sions that were present only on the upper portion of the arms (Fig 1, B). Their preceeding lupus profundus had been diagnosed based on the presence of hyaline necrosis of the fat which contained lymphocytic aggregates. Direct immunofluorescence assays for Ig deposits and complements were negative for both. No microthromboses could be detected in any biopsies of the anetoderma. All the patients with primary anetoderma had at least 1 prothrombotic abnormality (Table 1). Indeed, aPL were detected in 8 patients: only aCL (n⫽3), LA ⫹ aCL (n⫽2), LA ⫹ ␤2GP1 antibodies ⫹ BFP-STS (n⫽1), LA ⫹ aCL ⫹ ␤2GP1 antibodies (n⫽1), LA ⫹ heterozygous protein C deficiency (n⫽1). The last patient had a heterozygous protein S deficiency with biological activity and antigen level decreased (34%). Four patients satisfied the criteria for the classification of definite APS. APS was primary for 3 of them and associated with SLE in the other. Previous thrombotic events were arterial in 3 patients, and arterial and venous in the other. One woman had experienced recurrent fetal losses. Two other patients met the criteria for SLE, with LA detected in their sera; however, they had not had at least 1 clinical event required for the diagnosis of APS. The two patients with protein C or protein S deficiency had no history of a previous thrombotic event.

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Table I. Summary of clinical and biological data of patients with primary anetoderma Patients

Manifestations of SLE

Age (years)/sex

Thrombotic events

1 2

18/M 26/F

None Livedoid vasculitis

None None

3

34/F

None

4

24/F

Fetal losses, distal necrosis, strokes Strokes, livedoid vasculitis

5

16/M

None

6

18/F

7

28/F

Liver arterial occlusion None

8

28/M

9

35/F

Deep venous thrombosis, tibial arterial occlusion, strokes None

Evans’ syndrome, nephritis, pericarditis, pneumonitis None

None Acute LE, arthralgias, hair loss, Raynaud’s phenomenon None

Acute LE, arthralgias

Prothrombotic abnormalities

Immunological abnormalities

CTD

aCL heterozygous protein S deficiency (34%) aCL, LA

ANA (1/160) None

None None

ANA (1/320)

Primary APS

aCL

ANA (1/160)

APS ⫹ SLE

heterozygous protein C deficiency (40%), LA LA, aCL

None

None

None

Primary APS

LA, ␤2GP1 BFP-STS

ANA (1/640) aDNA

SLE

LA, ACL, ␤2GP1

None

Primary APS

aCL

ANA (1/160) nDNA

SLE

aCL, Anticardiolipin antibodies; ␤2GP1, anti-␤2 glycoprotein 1 antibodies; aDNA, anti-native deoxyribonucleic acid antibodies; ANA, antinuclear antibodies; APS, antiphospholipid syndrome; BFP-STS, biological false-positive test for syphilis; CTD, connective tissue disease; LA, lupus anticoagulant; LE, lupus erythematosus; SLE, systemic lupus erythematosus.

Both patients with secondary anetoderma had ANA without anti-DNA antibodies. One of them also had BFP-STS as the only sign of aPL presence associated with asymptomatic Libman-Sacks endocarditis. No abnormal homocysteine level, or factor II or V mutation was detected in any of these patients.

DISCUSSION Primary and secondary anetoderma are rare cutaneous elastolytic disorders, whose etiopathogenesis has not yet been clearly established. True secondary anetoderma, with the pouched lesions developing on the sites of inflammation, can occur after many dermatoses. The most common causes today are probably acne and varicella. Anetoderma can also appear with various inflammatory dermatoses, such as syphilis, sarcoidosis, tuberculosis, leprosy, Lyme disease, mastocytosis, nodular prurigo, or granuloma annulare, and with cutaneous tumors, such as xanthomas, pilomatrixomas, or cutaneous T-

or B-cell lymphomas.8,9 Anetoderma is rarely secondary to lupus profundus. Indeed, among the more than 50 cases of lupus profundus followed in our department, we observed only 2 such cases. One of them had asymptomatic Libman-Sacks endocarditis associated with the presence of BFP-STS.10 The role of aPL in the occurrence of secondary anetoderma could not be excluded but their prevalence has never been evaluated in this condition. Primary anetoderma was formerly classified according to the clinical aspect of the initial lesions. The Jadassohn-Pellizari form was characterized by an inflammatory onset of lesions, whereas the Schweninger-Buzzi form had no inflammatory stage. As the non-inflammatory clinical form does not exclude the presence of a histological dermis infiltrate,11 this classification is actually outdated. Patients with primary anetoderma did not recall any inflammatory stage preceeding the appearance of their lesions. No abnormal inflammatory infiltrate in the dermis or

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microthromboses were found at the time of biopsy. Thus, it is impossible to know whether these never occurred or were no longer seen due to the time lapse between onset of skin lesions and their being biopsied. Hence, the exact length of this time lapse could not be evaluated because some patients did not even notice the onset of skin lesions which were discovered by the physicians. They probably existed for many months or years and were thus too mature to still harbor microthromboses. Nevertheless, an ischemic process is strongly suggested by the presence of prothrombotic abnormalities in all of the patients with primary anetoderma. The relationship between heterozygous protein C or protein S deficiency and anetoderma may be coincidental, as no other case has been described previously in the literature. Futhermore, these heterozygous genetic disorders are frequently asymptomatic or predisposed only to venous thromboembolism.12 In contrast, the relationship between aPL and anetoderma cannot be considered coincidental. For many years, anetoderma was reported to occur in patients with CTD, especially SLE.11 In 1991, Stephansson et al pointed out the association of LA with anetoderma. Five of 33 SLE patients with LA had anetoderma containing histological microthromboses.13 Since that time, a review of the literature identified more than 20 reported patients with anetoderma and aPL,9 but these patients have no peculiar clinical or laboratory features. Anetoderma has been observed during the course of human immunodeficiency virus disease.14 When present, APS may be primary or associated with SLE. An ischemic process was also suggested for anetoderma that developed in preterm infants on the contact areas of electrocardiogram or encephalogram electrodes.15 Thus, various local inflammatory and non-inflammatory processes, e.g. anoxia, may trigger the mechanisms which lead to the degradation of elastic fibers. Increased production of progelatinase A and B, and activation of progelatinase A were observed in 3 patients’ anetodermic lesions.16 More recently, an abnormal balance between metalloproteinases and their tissue inhibitors was demonstrated in 5 samples of anetodermic skin compared with skin samples from healthy donors.17 Enhanced expressions of some metalloproteinases in various tissues (brain, vessel, heart, eye), may be induced by hypoxia-reoxygenation18-20 without changing those of their inhibitors.21 So, it is conceivable that hypoxia-reoxygenation in the skin may also trigger a local imbalance of metalloproteinases and their inhibitors leading to the destruction of elastic tissue.

CONCLUSION The high prevalence of prothrombotic abnormalities in this series of patients with anetoderma is unusual and probably reflected a selection bias of patients referred to our reference center for CTD. However, patients with anetoderma should be evaluated for the possible presence of a prothrombotic state and warned about its potential risks when present. REFERENCES 1. Jadassohn J. Ueber eire eigenartige form von [prime] atrophia maculosa cutis. Arch Dermatol Syph 1892;11:342-58. 2. Venencie PY, Winkelmann RK, Moore BA. Anetoderma. Clinical findings, associations and long-term follow-up evaluations. Arch Dermatol 1984;120:1032-9. 3. Disdier P, Harle´ JR, Andrac L, Verrot D, Bolla G, San Marco M, et al. Primary anetoderma associated with the antiphospholipid syndrome. J Am Acad Dermatol 1994;30:133-4. 4. France˘s C, Piette JC. Cutaneous manifestations of Hughes syndrome occurring in the context of lupus erythematosus. Lupus 1997;6:139-44. 5. Tan EM, Cohen AS, Fries J, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-77. 6. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Report of an international workshop. Arthritis Rheum 1999;42:1309-11. 7. Piette JC, Weschler B, France˘s C, Papo T, Godeau P. Exclusion criteria for primary antiphospholipid syndrome. J Rheumatol 1993;20:1802-4. 8. Montilla C, Alarcon-Segovia D. Anetoderma in systemic lupus erythematosus; relationship to antiphospholipid antibodies. Lupus 2000;9:545-7. 9. Romani J, Perez F, Llobet M, Planaguma M, Pujol RM. Anetoderma associated with antiphsopholipid antibodies: case report and review of the literature. J Eur Acad Dermatol Venereol 2000; 15:175-8. 10. Nesher G, Hany J, Rosenmann D, Abraham AS. Valvular dysfunction in antiphospholipid syndrome: prevalence, clinical features and treatment. Semin Arthritis Rheum 1997;27:27-35. 11. Venencie PY, Winkelmann RK. Histopathologic findings in anetoderma. Arch Dermatol 1984;120:1040-4. 12. Rao AK, Kaplan R, Sheth S. Inherited thrombophilic states. Semin Thromb Hemost 1998;24(suppl 1):3-12. 13. Stephansson EA, Niemi KM, Jouhikainen T, Vaarala O, Palosuo T. Lupus anticoagulant and the skin. A long term follow-up study of SLE patients with special reference to histopathological findings. Acta Derm Venereol (Stockh) 1991;71:416-22. 14. Lindstrom J, Smith KJ, Skelton HG, Redfield R, Alving BM, Wagner KF, et al. Increased anticardiolipin antibodies associated with the development of anetoderma in HIV-disease. Int J Dermatol 1995;34:408-15. 15. Prizant TL, Lucky AW, Frieden IJ, Burton PS, Suarez SM. Spontaneous atrophic patches in extremely premature infants: anetoderma of prematurity. Arch Dermatol 1996;132:671-74. 16. Venencie PY, Bonnefoy A, Gogly B, Groult N, Kut C, Pellat B, et al. Increased expression of gelatinase A and B by skin explants from patients with anetoderma. Br J Dermatol 1997;137:517-25.

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counts for acute myocardial ischemia and reperfusion injury. Circulation 2002;106:1543-9. 20. Ben-Yosef Y, Lahat N, Shapiro S, Bitterman H, Miller A. Regulation of endothelial matrix metalloproteinase-2 by hypoxia/ reoxygenation. Circ Res 2002;90:784-91. 21. Zhang X, Sakamoto T, Hata Y, Kubota T, Hisatomi T, Murata T, et al. Expression of matrix metalloproteinases and their inhibitors in experimental retinal ischemia-reperfusion injury in rats. Exp Eye Res 2002;74:577-84.