CASE REPORTS Ref: Ro J Rheumatol. 2021;30(1) DOI: 10.37897/RJR.2021.1.4

LIVEdoid vasculopathy – benefit of intravenous immunoglobulin in a refractory case Stefan Cristian Dinescu1, Andreea Lili Barbulescu2, Paulina Lucia Ciurea1, Roxana Mihaela Dumitrascu3, Beatrice Andreea Chisalau3, Cristina Dorina Parvanescu3, Sineta Cristina Firulescu4, Florentin Ananu Vreju1 1 Department of Rheumatology, University of Medicine and Pharmacy, Craiova, Romania 2 Department of Pharmacology, University of Medicine and Pharmacy, Craiova, Romania 3Doctoral School, University of Medicine and Pharmacy, Craiova, Romania 4 Department of Rheumatology, Emergency County Hospital, Craiova, Romania

Abstract 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.

Keywords: thrombosis, purpura, ulcer, intravenous immunoglobulins

INTRODUCTION cal form with no identifiable predisposing condition, which proved responsive only to intravenous immu­ Livedoid vasculopathy (LV) is a rare vascular dis­ noglobulin. ease which typically manifests as recurrent ulcerative lesions on the lower extremities. Although the under­ lying pathogenesis is not well defined, most cases are CASE PRESENTATION linked to a procoagulant state. Associated conditions We report the case of a 41 year-old female patient include inherited and acquired thrombophilias, can­ with a long standing history of livedoid vasculopathy cer or autoimmune diseases. Relation to the latter and of approximately 10 years. Although no relevant dis­ also the evidence of therapeutic response to immuno­ ease history was reported before her diagnosis, her suppressive drugs supports the potential role of auto­ family history was significant, with autoimmunity on immunity [1]. Onset of the disease usually occurs her mother’s side in the form of autoimmune thyroid­ between 15 and 50 years with an estimated incidence itis and autoimmune hepatitis, while her father had of 1:100,000 and a female predominance of 3:1 [2]. been diagnosed with Hodgkin lymphoma. The chronic course marked by recurrent exacerba­ At onset, the disease manifested with features of tions leads to porcelain white scars known as atro­ livedo reticularis, purpuric macules and papules lo­ phie blanche. Numerous disease mimickers imply a cated on the lower leg, around the ankle and on the particularly challenging differential diagnosis which dorsa of the foot. Cutaneous lesions were symmetri­ usually relies on histpathological examination. This cal, accompanied by slight edema. After 5 months, case report highlights an atypical and refractory clini­ skin ulcers started to emerge, that caused some pain

Corresponding author: Received: 11.02.2021 Accepted: 25.02.2021 Andreea Lili Barbulescu E-mail: [email protected]

Romanian Journal of Rheumatology – Volume XXX, No. 1, 2021 21 22 Romanian Journal of Rheumatology – Volume XXX, No. 1, 2021

FIGURE 1. (A) cutaneous lesions 1 year after disease onset; note the presence of multiple ulcerations with perilesional inflammation, located around the ankle, some of which have merged to form larger reticulated and slow healing ulcers; (B) ulcer formations covered by hematic crusts persist 1 year into the treatment with corticosteroid, anti-platelet drugs and vasodilators and had a major aesthetic impact (Figure 1A). Dis­ and hidroxicloroquine were added, but could not pro­ ease course was marked by recurrent exacerbations vide significant improvement (Figure 1B). Over the with new ulcers developing, while scarring in re­ next five years, the patient went through various solved lesions lead to the typical atrophie blanche treatment trials which included aspirin, colchicine, features. cilostazol and dapsone. Initial investigations took into account the family With no apparent benefit from the aforementioned background for autoimmunity and the clinical fea­ therapies and poor healing of ulcerative lesions, a tures of purpuric rash, which raised the suspicion of new approach was considered using intravenous im­ a systemic vasculitis. Antinuclear antibody panel munoglobulin (IVIG) administered once per month. test, along with antineutrophil cytoplasmic antibod­ Currently, the patient has completed a total of nine ies were negative. Development of necrotic ulcers cycles of IVIG, which were divided into a 3-month was also considered as result of a prothrombotic con­ course and a 6-month course during the past 2 years. dition. Screening for inherited and acquired throm­ A significant improvement of skin lesions was ob­ bophilia was negative and included: protein C and S tained after the first IVIG course, with persistent deficiency, prothrombin mutation and factor V Leid­ healing and absence of new ulcer formation through­ en, antithrombin III deficiency, cryoglobulinemia out the second course (Figure 2). and homocysteinemia. Antiphospholipid syndrome Maintenance therapy includes: dapsone, diosmi­ was also excluded. The only serum abnormality num, soludexide, aspirin and colchicine. Follow-up which could hint to a possible autoimmune disease investigations provided no additional information re­ was a constant C3 hypocomplementemia. garding a prothrombotic state, malignancy or autoim­ Skin biopsy was necessary at this point given the munity, except a constant C3 hypocomplementemia. scarcity of serum markers and also the diagnostic The patient never developed other features sugges­ ambiguity based solely on clinical features. Histo­ tive of a connective tissue disease. pathological examination of the skin sample showed multiple thrombi formation in dermal vessels, with DISCUSSIONS fibrin deposits inside the lumen and vessel wall. Few Livedoid vasculopathy remains an unusual diag­ necrotic areas were present in the epidermis. More nosis due to its rare occurrence and lack of familiarity importantly, perivascular inflammation and leukocy­ among practitioners. The earliest report by Millman toclasia were absent. As a result, a diagnosis of live­ in 1929 [1], described this entity as atrophie blanche. doid vasculopathy could be established. The actual term of “livedoid vasculopathy” was first Initial therapy targeted the vascular insufficiency introduced by Bard and Winkelmann [3]. Other terms using pentoxifilin, soludexide and diosminum. After used to designate LV include: livedo/livedoid vascu­ diagnosis of LV was confirmed, oral corticosteroids litis, segmental hyalinizing vasculitis, livedo reticu­ Romanian Journal of Rheumatology – Volume XXX, No. 1, 2021 23

FIGURE 2. (A) clinical outcome after first 3 cycles of IVIG; note the significant improvement in number and size of ulcers; (B) classic porcelain-white atrophic scarring and residual hyperpigmentation, with no new ulcer formations, throughout the second course of IVIG laris with summer ulcerations or PURPLE (painful antibodies. Some authors have considered LV also as purpuric ulcers with reticular pattern on the lower a potential manifestation of seronegative antiphos­ extremities) [4]. pholipid syndrome in SLE patients with recurrent Current knowledge on pathogenesis and evidence thrombosis [7]. of specific histopathology features helped to distin­ A triad of clinical features is present in most pa­ guish it from vasculitis, as it was considered in earlier tients and consist of livedo racemosa (less frequently reports. LV is defined as a vasooclusive syndrome, livedo reticularis), ulcerations and atrophie blanche. caused by non-inflammatory thrombosis of the upper In initial phases, reduced blood flow results in ery­ and mid-dermal venulae [5]. Given its heterogeneous thematous-violaceous streaks with net-like pattern. ethiopathogenic background, it should be viewed as a Purpuric macules and papules develop symmetrically cutaneous manifestation of a prothrombotic disease. on the lower limbs, and can be accompanied by pain Main disorders associated with LV include thrombo­ and pruritus [1]. These evolve into hemorrhagic ves­ philias, autoimmune diseases and neoplasia [1]. icles which become small ulcers when ruptured and However, up to 20% of cases remain idiopathic [5]. tend to merge in larger reticulated ulcerations. After a This was also the case for our patient, in which all period of several months, the lesions slowly heal and initial and subsequent tests could not link the LV di­ turn into irreversible white porcelain scars called agnosis to predisposing disease state. atrophie blanche or capilaritis alba [2]. The scars may The underlying prothrombotic mechanism de­ feature peripheral telangiectasia. Lesions in different pends on the predisposing condition and falls into stages of evolution can coexist. LV does not develop one of the three categories of Virchow’s triad: en­ systemic involvement; this is rather related to an as­ dothelial damage, stasis of the blood and hypercoag­ sociated autoimmune disease. Mononeuritis multi­ ulability state [4]. Diseases associated with endothe­ plex caused by vasa nervorum thrombosis may lead lial damage include: systemic lupus erythematous to paresthesia or hyperesthesia in some patients [4]. (SLE), systemic scleroderma, mixed connective tis­ LV has a chronic course with recurrent exacerbations. sue disease, rheumatoid arthritis, polyarteritis nodosa Accurate diagnosis has a 5-year delay on average and hyperhomocysteinemia [4,6]. Hyperviscosity which prevents early treatment in many patients [2]. syndrome can be linked to cryoglobulinemia, heavy Misdiagnosis leads to irreversible skin lesions and chain disease or chronic myelogenous leukemia [4]. psychological scarring. A histopathology examina­ Hypercoagulability related to thrombophilia is a pos­ tion is essential, taking into account the wide differ­ sible cause of LV and requires screening for coagula­ ential diagnosis. Adequate skin sample should be ob­ tion factor deficiencies (protein C, S, antithrombin) tained from erythematous-purpuric lesions, while or mutations (factor V Leiden and prothrombin). LV avoiding ulcerated areas [4]. Characteristic histo­ can be found in conjunction with antiphospholipid pathological features are fibrin deposits in the vascu­ 24 Romanian Journal of Rheumatology – Volume XXX, No. 1, 2021

lar lumen of upper and mid-dermal capillaries, seg­ most commonly used class in monotherapy. Anti­ mental hyalinization of vessel wall, and lack of platelet drugs found effective in LV treatment in­ leukocytoclasia. Based on histopathology, LV can be clude: aspirin, dipyridamole and pentoxiphylline. clearly differentiated from an immune-mediated ne­ Anabolic steroids such as danazol proved beneficial crotizing vasculitis. Perivascular infiltration is ab­ through the interference with hepatic production of sent or minimal and predominantly lymphocytic. coagulation factors. By contrast, glucocorticoids Neutrophils are found around ulcerated areas. Tissue have low success rates and this is due to the pau­ samples must include the dermo-hypodermal junc­ ci-immune nature of this disease [5]. Treatment with tion. This is important for the differentiation from IVIG has provided encouraging results in individual polyarteritis nodosa which can imitate LV clinically, cases and some large group studies. Kreuter et al. but develops vessel occlusion in the deep dermis. studied low dose IVIG (0.5 g/kg) in 9 patients and Other, features of LV include: hyalinized fibrin rings, obtained significant regression of skin lesions in each epidermis necrosis due to ischemia and extravasation case [9]. In a study by Monshi et al. on 11 patients of red blood cells in the superficial dermis which treated with 2g/kg IVIG, complete remission was ob­ leads to cutaneous hemosiderosis [5]. Hyalinization tained in some cases after only 3 cycles, although the of the dermis, epidermis atrophy and teleangiectazia vast majority of flares (89%) required 6 cycles [10]. of upper dermis are changes seen in late stages. In our experience, significant improvement was ob­ Changes seen in direct immunofluorescence do not served after first 3 cycles, while persistent remission provide any specific information in regard to diagno­ was obtained following the second 6 cycle course. sis; these include deposition of fibrin, immunoglobu­ lin, and complement [4]. CONCLUSIONS Management of LV patients is non-standardized, dependent on personal experience and evidence from Livedoid vasculopathy is a chronic cutaneous case reports and case series. Main goals of therapy manifestation due to microvascular thrombosis, are improvement of skin lesions, pain relief and pre­ which can develop in the setting of various connec­ vention of recurrence. Recommendations include tive tissue diseases. Rheumatologists need to be smoking cessation, compression stockings, use of aware of this entity that is often misdiagnosed and anticoagulants and antiplatelet drugs, anabolic ster­ becomes challenging when appropriate treatment is oids, vasodilators, tissue plasminogen activator, delayed. Slow healing ulcerations with periodic ex­ psoralens plus ultraviolet A (PUVA), IVIG or hyper­ acerbations and development of irreversible scars baric oxygen [6]. Micieli et al. published in a system­ significantly impacts patient’s quality of life. There is atic review treatment data from 339 LV patients [8]. a need for high quality evidence from control studies Anticoagulants showed high efficiency and were the regarding optimal treatment.

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