Therapy,Vol. Vol.••, 28,2015, 2015,••–•• 248–253 Dermatologic Therapy, Printed in in the the United United States States · All Allrights rightsreserved reserved

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DERMATOLOGIC THERAPY ISSN ISSN 1396-0296 1396-0296

THERAPEUTIC HOTLINE: HOTLINE THERAPEUTIC SHORT PAPERS Livedoid vasculopathy and high levels of lipoprotein (a): response to danazol Paulo Ricardo Criado*, Danielle Priscilia de Souza Espinel†, Neusa Yuriko Sakai Valente†, Afsaneh Alavi‡ & Robert S. Kirsner§ *Dermatology, Dermatology Sao Paulo, Hospital das Clínicas da Faculdade de Medicina da USP, †Dermatology Department, São Paulo University, São Paulo, Brazil, ‡Medicine (Dermatology), University of Toronto, Toronto, Ontario, Canada and §Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida

ABSTRACT: Livedoid vasculopathy (LV) is a thrombo occlusive disorder presenting with recurrent painful ulcers of lower extremities. Association of LV with increased level of lipoprotein (a) (LP(a) ), a risk factor for cardiovascular disease, has been reported. Danazol has been used with success in the management of LV, but none of the previous studies looked at the correlation between response to the treatment and level of LP(a). The aim of this study was to demonstrate the efficacy of low-dose danazol in the treatment of LV and its effects on LP(a). We present four cases with LV who were successfully treated with low-dose danazol, assessing the clinical characteristics and laboratory tests including the level of LP(a). The average age of the patients was 45 years and the mean duration of the disease was 19 years. The treatment regime of danazol 200 mg daily led to complete healing of ulcers and reduction in pain and a 70% (ranging from 52 to 87%) reduction in the level of LP(a). The limitation of this study is “small sample size.” In our patients with LV, low-dose danazol led to clinical improvement along with significant reduction in the level of LP(a). KEYWORDS: pharmacology, skin signs of systemic disease, therapy-systemic

Introduction Livedoid vasculopathy (LV) is an occlusive cutaneous disease of the dermal vessels with scant inflammation on histopathology examination. LV is

Address correspondence and reprint requests to: Afsaneh Alavi, MD, dermatologist, Wound Care Centre, Women’s College Hospital (Main Building), 76 Grenville Street 10th floor. Toronto, ON M5S 1B2, Canada or email: [email protected].

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characterized by the presence of painful recurrent ulcerations of lower extremities, especially in the ankles and feet, livedo reticularis and ivory-white atrophic scars, called atrophie blanche (1). The main pathophysiologic mechanism considered is a vaso-occlusive phenomenon as a result of intraluminal thrombosis of the dermis venules (2). However, the etiopathogenesis is not completely established, and so many cases remain idiopathic. Disorders related to hypercoagulable states, impaired of fibrinolysis and/or autoimmune diseases are the conditions most frequently

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Danazol for livedoid vasculopathy

Criado et al.

associated with LV (1–3). Recently, some authors have reported an association between LV and high levels of lipoprotein (a) (LP(a) ) (3,4), that procoagulant and antifibrinolytic properties define it as an independent risk factor for cardiovascular diseases (5–7). The treatment of LV is still a challenge, despite several reports of success with various drugs. Some therapeutic modalities such as immunosuppressive (8), vasodilators (8), antiplatelet agents (8), pentoxifylline (9,10), anticoagulants (11–13), tissue plasminogen activator (14,15), hyperbaric oxygen therapy (16) and anabolic steroids (17–19) are often included in the therapeutic ladder. Danazol is a synthetic anabolic steroid with an androgenic activity, which has a fibrinolytic action and is used in the treatment of various diseases such as endometriosis, hypoplasminogenemia, protein C deficiency, hereditary angioedema, antithrombin III deficiency and thrombotic thrombocytopenic purpura (18). Its effect on the lipid profile, significantly reducing LP(a) serum levels, is described in the literature (20–22). Danazol has an attenuated anabolic and virilizing action, being extensively metabolized in the liver. The most commonly reported adverse effects are mild hirsutism, weight gain, hair loss and amenorrhea. However at low doses (3–5 mg/kg or 200 mg/ day), side effects are rare (18). The aim of this study was to demonstrate the efficacy of low-dose of danazol in the treatment of LV and its effects on LP(a).

Patients and methods A retrospective analysis of medical records of patients with a clinical and histopathologic diagnosis of LV, with high levels of LP(a) who received danazol between January 2012 to June 2014 was performed. Four patients were identified. All patients were women and received 200 mg daily danazol, with reduction to 100 mg/day after full remission. Topical cerium nitrate-silver sulfadiazine ointment was used to dress the ulcers in all patients. No associated serious medical illness was reported. The severity of the disease was evaluated before and after the treatment with danazol according to the severity score proposed by Monshi et al. (23), in total, six scores based on the presence of atrophie blanche (absent/present = 0/1), livedo reticularis (absent/present = 0/1), ulceration (intact skin/erosion/ulceration = 0–2) and pain (none/moderate/severe = 0–2). Remission was defined as complete disappearance of

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active lesions (purpura, ulcerations and pain). The patients of reproductive age were counseled regarding an effective contraception method during treatment along with pregnancy tests prior to treatment and on monthly basis. The diagnosis was confirmed in all cases by skin biopsy and clinico histologic correlation and basic blood work were performed before, during and after treatment. Some other laboratory tests such as antinuclear antibody, anti-neutrophil cytoplasmic antibody, C3 and C4, rheumatoid factor, viral serology for hepatitis c, hepatitis b, and HIV were also assessed. Thrombophilia screening was performed in all the patients including complete blood cell count, platelet count, prothrombin time, partial thromboplastin time, fibrinogen, antithrombin III activity, protein C, protein S, prothrombin gene mutation, factor V Leiden mutation, serum homocysteine levels, testing for lupus anticoagulants and the anticardiolipin antibodies immunoglobulin M (IgM) and immunoglobulin G (IgG). LP(a) was measured using the immunoturbidimetric technique and the values considered elevated were those above 30 mg/dL (24). All the patients had already received pentoxifylline and acetylsalicylic acid, of which only the pentoxifylline was maintained (400 mg, 8/8h), for ethical reasons.

Results The mean age of the patients was 45 years and the mean duration of the disease was 19 years (Table 1). All the patients initially presented with a similar clinical picture, with purpuric papules and plaques with and without ulcers of varying sizes, hyperpigmentation and atrophie blanche affecting the lower limbs bilaterally (Fig. 1). Livedo racemosa was observed only in Patient 2 (Fig. 1C,D). The mean time to pain relief was 1.5 weeks (from 2 to 1), the mean time to cessation of new lesions was 4 weeks (from 2 to 8) and the mean time to complete wound healing was 10.5 weeks (from 6 to 20). The duration of danazol treatment was on average 7.8 months. Patient 1 presented an irregular menstrual cycle with normalization soon after discontinuation of danazol. No side effect was observed in the other patients (Table 1). Laboratory tests revealed low levels of antithrombin III activity in Patient 2, no other laboratory parameters were observed in the other patients. All patients presented elevated levels of LP(a) (Table 1) with an average of 71 mg/dL (from 33 to 131 mg/dL) on pretreatment, and 18.7 mg/dL (from 9 to 33 mg/dL) post-treatment; the mean

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250

36/F

52/F

63/F

2

3

4

30

20

15

10

Prednisone/ enoxaparin/ pentoxifylline and ASA Antithrombin III Warfarin/ deficiency and pentoxifylline/ LP(a) elevation ASA; cyclosporine LP(a) elevation Enoxaparin/ pentoxifylline and ASA LP(a) elevation Corticosteroids/ metothrexate pentoxifylline and ASA

LP(a) elevation

Previous Treatments

8 5:1

6 5:1

2 Pentoxifylline hyperbaric oxygen therapy danazol/6 m

8 6:2

20 5:1

1

1

Case 1 = C3; Case 2 = IGM, C3; Case 3 =IGM, C3, Case 4 = C3 2

69:9

33:16

51:17

131:33

87

52

66

75

5:1

5:1

6:2

5:1

Score B/A LP(a) % of LP( a) Score B/A (pre-Rx)/ (Pre-Rx)/ reduction (pre-Rx)/ (post-Rx) Immunoflorescence (post-Rx) after danazol (post-Rx)

3

3

Pentoxifylline danazol/7 m

Pentoxifylline danazol/12 m

8

Tn TH

Pentoxifylline danazol/ 6m

Current treatments

ASA, acetylsalicylic acid; F, female; LP(a), lipoprotein (a); score (B), before danazol; score (A), after danazol; Tn, time to cessation of developing new lesions; TH, time to complete healing.

28/F

1

Disease’s Age/ duration Thrombophlic Case gender (in years) screening

Table 1. Demographic, clinical and laboratorial data of four patients with livedoid vasculopathy treated with danazol

Criado et al. Danazol for livedoid vasculopathy

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Danazol for livedoid vasculopathy

FIG. 1. Efficacy of danazol on livedoid vasculopathy. Case 1: (A) before treatment and (B) after treatment; Case 2 (C) before treatment and (D) after treatment; and Case 4 (E) before treatment and (F) after treatment.

FIG. 2. Histopathology with hyalinization of the walls of small vessels in dermis (A) and thrombus occluding the lumen vessels (B).

reduction in serum levels of LP(a) was 70% (from 52% to 87%). The Fig. 2 shows histopathologic findings. Direct immunofluorescence showed C3 deposition in the vessel walls in all patients and deposition of IgM in Patients 2 and 3.

Discussion LP(a) has obtained considerable clinical interest as the discovery of its strong association with cardiovascular diseases (5–7). LP(a) is a complex molecule consisting of a core of glycoprotein bound to apoB-100 (low-density lipoprotein, LDL) connected, covalently, by a disulfide bridge to a glycoprotein (apo (a)) (25). Apo (a) has a structure homologous to plasminogen, it is formed by a variable number of kringle IV type domains, the smaller the size, the higher the serum level of

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LP(a) and the greater the interference with the plasminogen activity. Additional effects on the coagulation and fibrinolysis system are the increased expression of the plasminogen activator tissue inhibitor type 1 (PAI-1), inactivation of the tissue factor pathway inhibitor and the fibrin binding. The atherogenic properties conferred on LP(a) by acting on monocytes chemotaxis, stimulating the proliferation of foam cells and smooth muscle cells and increasing endothelial adhesion molecules (26). Therefore, these actions give LP(a) a triple effect: pro-atherogenic, prothrombotic and antifibrinolytic. Elevated levels of LP(a) have already been reported in patients with LV (3,4). The use of danazol on LV has been reported in the literature (17–19). Hsiao et al. (18) reported seven patients with LV treated with 200 mg of danazol and observed a mean time to pain relief, mean time to

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cessation of new lesion formation and mean time to total healing of 3,2, 1,6 and 10,8 weeks, respectively. Despite the similarity of the results, the LP(a) was not measured. The analysis of anticoagulation and fibrinolysis proteins before and after danazol revealed no significant change. Danazol is an androgen-like steroid, a synthetic analog of 17-a-ethinyl testosterone that alters endothelial function during angiogenesis (27). As noted, several articles have shown its efficacy as an alternative for moderate and severe cases of LV. Danazol likely induces hepatic synthesis of several protease inhibitors such as the C1-esterase inhibitor, α-1 antitrypsin, proteins C and S, antithrombin III, and also proteins of the coagulation and fibrinolysis system such as plasminogen (26). At the same time it changes the lipid profile, increasing LDL and decreasing high-density lipoprotein and LP(a) (20–22). Because of these effects danazol, has been used in patients with antithrombin III deficiency (28), proteins C and S deficiencies (17), hereditary angioedema (29,30) and hypoplasminogenemia (17). Menstrual irregularities and weight gain have been the main side effects observed in patients using low-dose danazol and are related to its androgenic action (28–30). Amenorrhea occurs in most women treated with danazol, but menstruation usually normalizes 2–3 months after suspension, similar to that observed in Patient 1. Although there are no controlled studies in humans, danazol may cause fetal harm such as spontaneous abortion and birth defects when used in pregnant women (31). Danazol is contraindicated in cases of renal, hepatic or cardiac dysfunction, as well as in abnormal genital bleeding (29). To evaluate the effect of danazol on lipid profile and LP(a), Crook et al. (20), analyzed the lipid profile of 26 premenopausal women with endometriosis using 600 mg/day of danazol compared with a control group and observed a decrease of 78.6% in LP(a) in the treated group; results similar to those seen in our patients. Hartgens et al. (22) also examined the effect of anabolic steroids on healthy male athletes versus a control group and found an 84% reduction in the levels of LP(a). The pathophysiology of LV remains idiopathic in about 50% of patients (1) although the finding of high levels of LP(a) in our patients may be another pro-coagulant/antifibrinolytic factor in the pathophysiology of LV. Agirbasil et al. (32) observed the reduction in fibrinolysis in patients with LV, through the

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increased stability of PAI-1. The investigators suggested that a possible cofactor or mutation could explain this instability. This cofactor could be high levels of LP(a), which were not investigated in their patients. The reduction in serum levels of LP(a) occurred in our patients and correlated with the clinical response. Despite previously described, this is the first study to observe the effect of danazol on LP(a) and clinical response in patients with LV in parallel. Moreover, our report suggests that although the pro-fibrinolytic and anticoagulant effect of danazol is not fully understood, the reduction of LP(a) with its already well-established profibrinolytic actions may play a major role. However, controlled studies evaluating the role of LP(a) in LV and the mechanisms of action of danazol are required.

Funding source None.

Conflict of interest No relevant conflict of interest to this article.

References 1. Criado PR, Rivitti EA, Sotto MN, de Carvalho JF. Livedoid vasculopathy as a coagulation disorder. Autoimmun Rev 2011: 10 (6): 353–360. 2. Criado PR, Rivitti EA, Sotto MN, et al. Livedoid vasculopathy: an intringuing cutaneous disease. An Bras Dermatol 2011: 86: 961–977. 3. Vasconcelos R, Criado PR, Belda W Jr. Livedoid vasculopathy secondary to high levels of lipoprotein (a). Br J Dermatol 2011: 164: 1107–1124. 4. Goerge T, Weishaupt C, Metze D, et al. Livedoid vasculopathy in a pediatric patient with elevated lipoprotein(a) levels: prompt response to continuous lowmolecular-weight heparin. Arch Dermatol 2010: 146 (8): 927–928. 5. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009: 302 (4): 412–423. 6. Ariyo AA, Thach C, Tracy R, Cardiovascular Health Study Investigators. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003: 349 (22): 2108– 2154. 7. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Genetic evidence that lipoprotein(a) associates with atherosclerosis stenosis rather than venous thrombosis. Arterioscler Thromb Vasc Biol 2012: 32: 1732–1741. 8. Callen JP. Livedoid vasculopathy: what it is and how the patient should be evaluated and treated. Arch Dermatol 2006: 142: 1481–1482.

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Criado et al. 9. Sams WM Jr. Livedo vasculitis. Therapy with pentoxifylline. Arch Dermatol 1988: 124: 684–687. 10. Sauer GC. Pentoxifylline (Trental) therapy for the vasculitis of atrophie blanche. Arch Dermatol 1986: 122: 380–381. 11. Hairston BR, Davis MD, Gibson LE, Drage LA. Treatment of livedoid vasculopathy with low molecular-weight heparin: report of 2 cases. Arch Dermatol 2003: 139: 987–990. 12. Browing CE, Callen JP. Warfarin therapy for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia. Arch Dermatol 2006: 142: 75–78. 13. Nakamura S, Kishibe M, Nishi K, et al. Livedoid vasculopathy; favorable clinical response with low dose warfarin. Eur J Dermatol 2011: 21: 1011–1012. 14. Deng A, Gocke CD, Hess J, Heyman M, Paltiel M, Gaspari A. Livedoid vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity (4G/4G) treated successfully with tissue plasminogen activator. Arch Dermatol 2006: 142: 1466–1469. 15. Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992: 67: 923–933. 16. Yang CH, Ho HC, Chan YS, Liou LB, Hong HS, Yang LC. Intractable livedoid vasculopathy successfully treated with hyperbaric oxygen. Br J Dermatol 2003: 149 (3): 647–652. 17. Hsiao GH, Chiu HC. Livedoid vasculitis. Response to lowdose danazol. Arch Dermatol 1996: 132 (7): 749–751. 18. Hsiao GH, Chiu HC. Low dose danazol in the treatment of livedoid vasculitis. Dermatology 1997: 194: 251–255. 19. Wakelin SH, Ellis JP, Black MM. Livedoid vasculitis with anticardiolipin antibodies: improvement with danazol. Br J Dermatol 1998: 139 (5): 935–937. 20. Crook D, Sidhu M, Seed M, O’Donnell M, Stevenson JC. Lipoprotein a levels are reduced by danazol, an anabolic steroid. Atherosclerosis 1992: 92 (1): 41–47. 21. Shepherd J. Danazol and plasma lipoprotein metabolism. Int J Gynaecol Obstet 1995: 50 (Suppl. 1): s23–s26. 22. Hartgens F, Rietjens G, Keizer HA, Kuipers H, Wolffenbuttell BHR. Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a). Br J Sports Med 2004: 38: 253–259.

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Danazol for livedoid vasculopathy 23. Monshi B, Posch C, Vujic I, et al. Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients. J Am Acad Dermatol 2014: 71: 738– 744. 24. Molinari EA, Pichler PF, Grilhofer H, Kostner GM. Immunoturbidimetric determination of lipoprotein(a): improvement in the measurement of turbid and triglyceride-rich samples. Clin Chim Acta 1995: 235 (1): 59–69. 25. Wang JJ, Gong JB, Li HQ, et al. Lipoprotein(a) complexes with beta2-glycoprotein-I in patients with coronary artery disease. J Atheroscler Thromb 2012: 19: 81–89. 26. Spence JD, Koschinsky M. Mechanism of lipoprotein(a) pathogenicity: protrombotic, proaterosclerotic, or both? Arterioscler Thrombvasc Biol 2012: 32: 1550–1551. 27. Thomas GW, Rael LT, Bar-Or R, et al. Biphasic effect of danazol on human vascular endothelial cell permeability and f-actin cytoskeleton dynamics. Biochem Biophys Res Commun 2012: 421: 707–712. 28. Fairfax AJ, Ibbotson RM. Effect of danazol on the biochemical abnormality of inherited antithrombin III deficiency. Thorax 1985: 40: 646–650. 29. Fust G, Farkas H, Csuka D, Varga L, Bork K. Long-term efficacy of danazol treatment in hereditary angioedema. Eur J Clin Invest 2011: 41: 256–262. 30. Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, Rusicke E, Heller C, Klingebiel T. C1- inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion 2009: 49: 1987–1995. 31. Marti-Carvajal AJ, Pena-Marti GE, Comunian-Carrasco G. Medical treatments for idiopathic thrombocytopenic purpura during pregnancy. Cochrane Database Syst Rev 2009: (4): CD007722. 32. Agirbasil M, Eren M, Eren F, et al. Enhanced functional stability of plasminogen activator inhibitor-1 in patients with livedoid vasculopathy. J Thromb Thrombolysis 2011: 32: 59–63.

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Livedoid vasculopathy and high levels of lipoprotein (a): response to danazol.

Livedoid vasculopathy (LV) is a thrombo occlusive disorder presenting with recurrent painful ulcers of lower extremities. Association of LV with incre...
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