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 year­old 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 3­month was also considered as result of a prothrombotic con­ course and a 6­month 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. Follow­up 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 non­inflammatory thrombosis of the upper In initial phases, reduced blood flow results in ery­ and mid­dermal venulae [5]. Given its heterogeneous thematous­violaceous streaks with net­like 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