LIVEdoId VascuLopathy – bEnEfIt of IntraVEnous ImmunogLobuLIn In a rEfractory casE

Livedoid vasculopathy is a rare vascular disease which typically manifests as recurrent ulcerative lesions on the lower extremities. It is classified as a vasculopathy, not a true vasculitis, and defined as a vasooclusive syndrome, caused by non-inflammatory thrombosis of the upper and mid-dermal venulae. Main disorders associated with LV include thrombophilias, autoimmune diseases and neoplasia. A triad of clinical features is present in most patients and consist of livedo racemosa (less frequently livedo reticularis), ulcerations and atrophie blanche. Management generally relies on antiplatelet drugs, anticoagulants, vasodilators and fibrinolytic therapy. Some benefit has been observed with intravenous immunoglobulin, colchicine, hyperbaric oxygen, while glucocorticoids are efficient to a lesser extent. This case report highlights a refractory clinical form with no identifiable predisposing condition, which proved responsive only to intravenous immunoglobulin.


INTRODUCTION
Livedoid vasculopathy (LV) is a rare vascular dis ease which typically manifests as recurrent ulcerative lesions on the lower extremities. Although the under lying pathogenesis is not well defined, most cases are linked to a procoagulant state. Associated conditions include inherited and acquired thrombophilias, can cer or autoimmune diseases. Relation to the latter and also the evidence of therapeutic response to immuno suppressive drugs supports the potential role of auto immunity [1]. Onset of the disease usually occurs between 15 and 50 years with an estimated incidence of 1:100,000 and a female predominance of 3:1 [2]. The chronic course marked by recurrent exacerba tions leads to porcelain white scars known as atro phie blanche. Numerous disease mimickers imply a particularly challenging differential diagnosis which usually relies on histpathological examination. This case report highlights an atypical and refractory clini cal form with no identifiable predisposing condition, which proved responsive only to intravenous immu noglobulin.

CASE PRESENTATION
We report the case of a 41 yearold female patient with a long standing history of livedoid vasculopathy of approximately 10 years. Although no relevant dis ease history was reported before her diagnosis, her family history was significant, with autoimmunity on her mother's side in the form of autoimmune thyroid itis and autoimmune hepatitis, while her father had been diagnosed with Hodgkin lymphoma.
At onset, the disease manifested with features of livedo reticularis, purpuric macules and papules lo cated on the lower leg, around the ankle and on the dorsa of the foot. Cutaneous lesions were symmetri cal, accompanied by slight edema. After 5 months, skin ulcers started to emerge, that caused some pain and had a major aesthetic impact ( Figure 1A). Dis ease course was marked by recurrent exacerbations with new ulcers developing, while scarring in re solved lesions lead to the typical atrophie blanche features.
Initial investigations took into account the family background for autoimmunity and the clinical fea tures of purpuric rash, which raised the suspicion of a systemic vasculitis. Antinuclear antibody panel test, along with antineutrophil cytoplasmic antibod ies were negative. Development of necrotic ulcers was also considered as result of a prothrombotic con dition. Screening for inherited and acquired throm bophilia was negative and included: protein C and S deficiency, prothrombin mutation and factor V Leid en, antithrombin III deficiency, cryoglobulinemia and homocysteinemia. Antiphospholipid syndrome was also excluded. The only serum abnormality which could hint to a possible autoimmune disease was a constant C3 hypocomplementemia.
Skin biopsy was necessary at this point given the scarcity of serum markers and also the diagnostic ambiguity based solely on clinical features. Histo pathological examination of the skin sample showed multiple thrombi formation in dermal vessels, with fibrin deposits inside the lumen and vessel wall. Few necrotic areas were present in the epidermis. More importantly, perivascular inflammation and leukocy toclasia were absent. As a result, a diagnosis of live doid vasculopathy could be established.
Initial therapy targeted the vascular insufficiency using pentoxifilin, soludexide and diosminum. After diagnosis of LV was confirmed, oral corticosteroids and hidroxicloroquine were added, but could not pro vide significant improvement ( Figure 1B). Over the next five years, the patient went through various treatment trials which included aspirin, colchicine, cilostazol and dapsone.
With no apparent benefit from the aforementioned therapies and poor healing of ulcerative lesions, a new approach was considered using intravenous im munoglobulin (IVIG) administered once per month. Currently, the patient has completed a total of nine cycles of IVIG, which were divided into a 3month course and a 6month course during the past 2 years. A significant improvement of skin lesions was ob tained after the first IVIG course, with persistent healing and absence of new ulcer formation through out the second course ( Figure 2).
Maintenance therapy includes: dapsone, diosmi num, soludexide, aspirin and colchicine. Followup investigations provided no additional information re garding a prothrombotic state, malignancy or autoim munity, except a constant C3 hypocomplementemia. The patient never developed other features sugges tive of a connective tissue disease.

DISCUSSIONS
Livedoid vasculopathy remains an unusual diag nosis due to its rare occurrence and lack of familiarity among practitioners. The earliest report by Millman in 1929 [1], described this entity as atrophie blanche. The actual term of "livedoid vasculopathy" was first introduced by Bard and Winkelmann [3]. Other terms used to designate LV include: livedo/livedoid vascu litis, segmental hyalinizing vasculitis, livedo reticu Current knowledge on pathogenesis and evidence of specific histopathology features helped to distin guish it from vasculitis, as it was considered in earlier reports. LV is defined as a vasooclusive syndrome, caused by noninflammatory thrombosis of the upper and middermal venulae [5]. Given its heterogeneous ethiopathogenic background, it should be viewed as a cutaneous manifestation of a prothrombotic disease. Main disorders associated with LV include thrombo philias, autoimmune diseases and neoplasia [1]. However, up to 20% of cases remain idiopathic [5]. This was also the case for our patient, in which all initial and subsequent tests could not link the LV di agnosis to predisposing disease state.
The underlying prothrombotic mechanism de pends on the predisposing condition and falls into one of the three categories of Virchow's triad: en dothelial damage, stasis of the blood and hypercoag ulability state [4]. Diseases associated with endothe lial damage include: systemic lupus erythematous (SLE), systemic scleroderma, mixed connective tis sue disease, rheumatoid arthritis, polyarteritis nodosa and hyperhomocysteinemia [4,6]. Hyperviscosity syndrome can be linked to cryoglobulinemia, heavy chain disease or chronic myelogenous leukemia [4]. Hypercoagulability related to thrombophilia is a pos sible cause of LV and requires screening for coagula tion factor deficiencies (protein C, S, antithrombin) or mutations (factor V Leiden and prothrombin). LV can be found in conjunction with antiphospholipid antibodies. Some authors have considered LV also as a potential manifestation of seronegative antiphos pholipid syndrome in SLE patients with recurrent thrombosis [7].
A triad of clinical features is present in most pa tients and consist of livedo racemosa (less frequently livedo reticularis), ulcerations and atrophie blanche. In initial phases, reduced blood flow results in ery thematousviolaceous streaks with netlike pattern. Purpuric macules and papules develop symmetrically on the lower limbs, and can be accompanied by pain and pruritus [1]. These evolve into hemorrhagic ves icles which become small ulcers when ruptured and tend to merge in larger reticulated ulcerations. After a period of several months, the lesions slowly heal and turn into irreversible white porcelain scars called atrophie blanche or capilaritis alba [2]. The scars may feature peripheral telangiectasia. Lesions in different stages of evolution can coexist. LV does not develop systemic involvement; this is rather related to an as sociated autoimmune disease. Mononeuritis multi plex caused by vasa nervorum thrombosis may lead to paresthesia or hyperesthesia in some patients [4]. LV has a chronic course with recurrent exacerbations.
Accurate diagnosis has a 5year delay on average which prevents early treatment in many patients [2]. Misdiagnosis leads to irreversible skin lesions and psychological scarring. A histopathology examina tion is essential, taking into account the wide differ ential diagnosis. Adequate skin sample should be ob tained from erythematouspurpuric lesions, while avoiding ulcerated areas [4]. Characteristic histo pathological features are fibrin deposits in the vascu lar lumen of upper and middermal capillaries, seg mental hyalinization of vessel wall, and lack of leukocytoclasia. Based on histopathology, LV can be clearly differentiated from an immunemediated ne crotizing vasculitis. Perivascular infiltration is ab sent or minimal and predominantly lymphocytic. Neutrophils are found around ulcerated areas. Tissue samples must include the dermohypodermal junc tion. This is important for the differentiation from polyarteritis nodosa which can imitate LV clinically, but develops vessel occlusion in the deep dermis. Other, features of LV include: hyalinized fibrin rings, epidermis necrosis due to ischemia and extravasation of red blood cells in the superficial dermis which leads to cutaneous hemosiderosis [5]. Hyalinization of the dermis, epidermis atrophy and teleangiectazia of upper dermis are changes seen in late stages. Changes seen in direct immunofluorescence do not provide any specific information in regard to diagno sis; these include deposition of fibrin, immunoglobu lin, and complement [4].
Management of LV patients is nonstandardized, dependent on personal experience and evidence from case reports and case series. Main goals of therapy are improvement of skin lesions, pain relief and pre vention of recurrence. Recommendations include smoking cessation, compression stockings, use of anticoagulants and antiplatelet drugs, anabolic ster oids, vasodilators, tissue plasminogen activator, psoralens plus ultraviolet A (PUVA), IVIG or hyper baric oxygen [6]. Micieli et al. published in a system atic review treatment data from 339 LV patients [8]. Anticoagulants showed high efficiency and were the most commonly used class in monotherapy. Anti platelet drugs found effective in LV treatment in clude: aspirin, dipyridamole and pentoxiphylline. Anabolic steroids such as danazol proved beneficial through the interference with hepatic production of coagulation factors. By contrast, glucocorticoids have low success rates and this is due to the pau ciimmune nature of this disease [5]. Treatment with IVIG has provided encouraging results in individual cases and some large group studies. Kreuter et al. studied low dose IVIG (0.5 g/kg) in 9 patients and obtained significant regression of skin lesions in each case [9]. In a study by Monshi et al. on 11 patients treated with 2g/kg IVIG, complete remission was ob tained in some cases after only 3 cycles, although the vast majority of flares (89%) required 6 cycles [10]. In our experience, significant improvement was ob served after first 3 cycles, while persistent remission was obtained following the second 6 cycle course.

CONCLUSIONS
Livedoid vasculopathy is a chronic cutaneous manifestation due to microvascular thrombosis, which can develop in the setting of various connec tive tissue diseases. Rheumatologists need to be aware of this entity that is often misdiagnosed and becomes challenging when appropriate treatment is delayed. Slow healing ulcerations with periodic ex acerbations and development of irreversible scars significantly impacts patient's quality of life. There is a need for high quality evidence from control studies regarding optimal treatment.