Livedoid vasculopathy L95.0

Eminently chronic, regularly recurring, thrombo-embolic occlusive disease of the cutaneous vascular plexus (see vasculopathy below), which clinically leads to a characteristic "livedo image" and, as a result of thrombotic vasculopathy of small and medium-sized skin vessels, to flashy, jagged, highly painful erosions or flat ulcers. Healing leaving flat, depigmented scars(atrophy blanche).

Brief clinical triad (LAU): Livedo racemosa, atrophieblanche, recurrent ulcers

Incidence: < 1/100,000 (meets the criteria of orphan disease).

Idiopathic courses of the disease are often described, genetic disposition is questionable.

Relationships to lupus erythematosus, polyarteritis nodosa, phospholipid antibody syndrome, coagulation disorders or hypercoagulability (factor V Leiden mutation, prothrombin gene mutation, protein C and protein S deficiency), hyperhomocysteinemia; venous insufficiency, chronic (CVI) are described.

Predominantly occurring in adolescents and younger adults (15-40 years). The disease predominantly (70-80%) affects the female sex.

Reticular, deep red, livid, flat indurated plaques and erythema, with formation of bizarre, mostly very painful (not the live image but the stabbing permanent pain leads to the doctor!), therapy-resistant flat ulcers in the ankle area, especially in the summer months (summer ulcerations), which heal with 0.3-1.0 cm large, flatly sunken, splatter-like whitish scars with red accentuated edge margin (vascular ectasia). Symmetrical appearance on the lower extremities is described but is not the rule.

Environmental analysis often reveals pathological coagulation parameters with porthrombotic properties such as: antiphospholipid antibodies and protein C deficiency.

Notice. The biopsy must be performed at an early stage. It must cover the lesional area sufficiently deeply and broadly (transition from healthy to diseased) so that the triggering vascular problem can be reliably assessed in the incision. Step cuts are mandatory!

Atrophic epithelium. In the middle and deep layers of the dermis, rather sparse, perivascular, lymphocytic infiltrate as well as dilated vessels, partly bulging with erythrocytes or filled with various old, hyaline thrombi (almost obligatory phenomenon). These fibrinoid effusions lead to hyalinization and infarction of the vessel wall, with subsequent focal necrobiosis and necrosis.

No signs of leukocytoclastic vasculitis!

Clinical differential diagnosis:

• Poly- (Peri-)arteriitis nodosa: 1.0 - 5.0 cm large, initially coarse, usually very pressure dolent, also spontaneously painful, reddish to livid coloured plaques or nodules (iceberg phenomenon) with a tendency to painful ulceration. Histologically, the process is located at the cutis-subcutaneous border with clear inflammatory symptoms! A live image like a flash can be part of the clinical symptomatology.
• Sneddon syndrome: Here the skin process is of systemic changes (occlusion of cerebral vessels with neurological failure symptoms). Systemic changes are always absent in livedovasculopathy! Phospholipid antibodies are detectable in more than 50% of patients!
• Embolia cutis medicamentosa: Acute event, minutes to a few hours after an i.m. Injection (anamnesis leads to a diagnosis of exclusion!), painful, hard infiltration with lightning-figure-like skin markings. Secondary: Development of deep ulcerations which heal with bizarrely shaped atrophic scars.
• Arteriosclerotic occlusive ulcers (see below hypertonic leg ulcer): Not infrequently grafting on the clinical picture of livedo racemosa (here underlying arteriolosclerosis), sudden (overnight) formation of haemorrhagic, jagged, very painful ulcers. Always evidence of peripheral AVK (exclusion of livedovasculopathy).
• Calciphylaxis: Localized, mostly symmetrical picture of the razemous livedo; this is accompanied by linear or also planar, 2.0 to 20 cm large, eminently painful, hard, red or even skin-coloured plaques or nodules. Mostly also painful ulcers of different sizes (histology is diagnostic, see below).
• Livedo reticularis (in Anglo-American usage called Livedo racemosa!): This functional disorder is best described by the term "Cutis marmorata". It is a cold-induced, large-meshed, livid marbling, which, depending on the form, disappears or appears after heating or cooling. Often peripheral acrocyanosis. The jagged "lightning figure-like" pattern of the livedo racemosa (exclusion phenomenon) is always missing. Pain is always missing (exclusion of livedovasculopathy).
• Cutis marmorata teleangiectatica congenita: Congenital clinical picture (exclusion criterion) with asymmetrically distributed Cutis marmorata with telangiectasia and phlebectasia; often conspicuously thin, translucent (atrophic) skin with clear vein pattern.
• Atrophie blanche: Always at the bottom of a chronic venous insufficiency (exclusion criterion). Spattered, slightly sunken, scarred areas with surrounding brown pigmentation. Mostly capillary ectasia detectable at the edges. Possible development of mostly small, rarely also the entire atrophy zone of superficial erosions or ulcers ( atrophy blanche ulcer). The clinical feature of these ulcers is a stabbing permanent pain that is not compatible with the size of the ulcer.

Histological differential diagnosis:

• Calciphylaxis: Thrombotic dermal and subcutaneous vessels with distinct basophilic calcifications in the lumen and walls (exclusion phenomenon).
• Dermatoliposclerosis (congestive dermatosis): Intralobular lipomembranous (membranocytic) fat necrosis and pronounced septal sclerosis. In advanced stages of dermatoliposclerosis, broad sclerosed septums with English wall-thickened capillaries and venules with PAS-positive perivascular fibrin sheaths, as well as macrophages and fibroblasts are found. In the dermis: Perivascular superficial and deep sclerosing dermatitis with wall thickened, glomeruli-like bulging vessels.
• Leucocytoclastic vasculitis: vascular wall necrosis with fibrinoid vascular wall swelling, neutrophil infiltration and perivascular nuclear dust.
• Thrombophlebitis migrans: Sclerosing endophlebitis (giant cell vasculitis) with complete or partial closure of the vascular lumina by thrombi. Frequent detection of giant cells...

Current treatment paradigms are based on a small evidence base, mainly on case reports and case series of low evidence (Micieli R et al. 2018). In a major review (Micieli R et al. 2018), the following ranking (by frequency of therapies mentioned) was established:

Anticoagulants were the most commonly used monotherapy and achieved a favorable response in 62 of 63 patients (98%) (Weishaupt C et al 2019).

Anabolic steroids, intravenous immunoglobulins (IVIG), and antiplatelet agents were the second, third, and fourth most commonly used therapies, respectively. The following is a priority list based on my own experience (author of this article)!

• IVIG: According to my own experience, which has been confirmed in the meantime, prompt and long-term improvements (especially in the almost always present severe pain symptoms!) can be achieved under repetitive (4 week intervals) immunoadsorption and/or IVIG alone (high-dose immunoglobulin therapy: 0.5-1.0g-2.0/kgKG divided into 3 consecutive days i.v.).
• Alternative: Heparin 2-3 times/day 5000-7500 IU s.c.
• Alternative: Enoxaparin (Clexane®) 1 mg/kg bw/day. Duration of therapy adapted to symptoms, usually for about 4 weeks.
• Alternative: Rivarobaxan (Xarelto®), initially 2 x 10 mg/day p.o. Symptom-adapted therapy with 1x10 mg/day p.o.
• Alternative prednisolone/azathioprine: If there is no convincing improvement of the disease with these therapy regimens, immunosuppressive therapy with prednisolone (e.g. Decortin H) 100 mg/day p.o. can be started. Reduce steroid dose depending on clinic, maintenance dose of 5-10 mg/day. Combination therapy with azathioprine (e.g. Imurek®) 100 mg/day p.o. is recommended.

Not very convincing and not recommended:

• Acetylsalicylic acid (e.g. ASS-ratiopharm) 2 times/day 500 mg p.o., also in combination with dipyridamole (e.g. Curantyl 3-5 times/day 1 drg. p.o.).
• Sulfasalazine (e.g. azulfidine): dose gradually up to 1000 mg p.o. 3 times/day.

• The disease fulfils the criteria of an "orphan disease". This must be taken into account in all therapeutic modalities. See below Orphan Diseases, see below. Orphan drugs.
• Randomised clinical trials are required to better establish these treatments in clinical practice.

• A 24-year-old, obese female patient has been suffering from extremely painful "open sores" on the ankle regions of both feet periodically since the age of 12, especially in the summer months. These would heal after a few weeks with scarring. Treatment over the years was antibiotic and immunosuppressive (azathioprine and glucocorticoids in medium doses), with no demonstrable improvement in the findings. Apart from that, symptomatic pain therapy with metamizole and aspirin was carried out. The presentation of the patient was pain-driven.
• Findings: On all ankles there are irregular, red-brown, only moderately indurated plaques up to 8x8 cm in size, which are interspersed with smaller (about 0.5-1.0 cm in size) whitish, bizarrely configured scarred depressions. These are accentuated reddened in their marginal area. In places, livedo patterns are detectable at the edges. There are also highly painful red erosions measuring 0.2-0.6 cm with and without crusts.
• Histology: In the middle and deep layers of the dermis sparse, perivascular, lymphocytic infiltrate as well as dilated vessels, partly bulging with erythrocytes, partly characterized by hyaline effusions (almost obligatory phenomenon). Clearly thickened vessel walls. No signs of leukocytoclastic vasculitis.
• Other findings: No evidence of AVK or CVI. Laboratory: completely o.B.
• Therapy: Consistent therapy with a low molecular weight heparin (Enoxaprin = Clexane; 1mg/kgKG/day s.c.). Significant reduction in pain within 10 days and healing of the erosions without complications under the usual indifferent wound management). No new erosive foci in the meantime. Enoxaprine therapy was discontinued after 4 weeks.

1. Brown-Falco O et al (1972) On azathioprine therapy of livedo racemosa with ulceration. Dermatologist 23: 136-138
2. Calamia KT et al (2002) Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation. J Am Acad Dermatol 46:133-137
3. Feldacker M, Hines EA, Kierland RR (1955) Livedo reticularis with summer ulcerations. Arch Derm Syph 72: 31-37
4. Fritsch P et al (1995) Livedo vasculititis. Dermatologist 46: 215-224
5. Goerge T (2010) Low-molecular-weight heparin therapy for the treatment of livedovasculopathy. Akt DErmatol 36: 484-487
6. Goerge T (2014) Vasculopathy and vasculitis. Act Dermatol 40: 519-522
7. Hairston BR et al (2006) Livedoid vasculopathy. Arch Dermatol 142: 1413-1418
8. Kerk N et al (2013) Livedoid vasculopathy - athrombotic disease. Vasa 42: 317-322
9. Kreuter A et al (2004) Pulsed intravenous immunoglobulin therapy in livedoid vasculitis.: an open trial evaluating 9 consecutive patients. J Am Acad Dermatol 51:574-579
10. Micieli R et al (2018) Treatment for livedoid vasculopathy: a systematic review. JAMA Dermatol 154:193-202.
11. Monshi B et al (2014) Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients. J Am Acad Dermatol 71:738-744
12. Muller CSL et al (2016) Diagnostic and histologic features of cutaneous vasculitides/vasculopathies. Act Dermatol 42: 286-301
13. O'Leary PA, Montgomery H, Brunsting LA (1944) Livedo reticularis: recurrent ulcerations of the ankles in the summer. Arch Dermat Syph 50: 213
14. Sams WM (1988) Livedo vasculitis. Therapy with pentoxifylline. Arch Dermatol 124: 684-687
15. Schanz S et al (2003) Intravenous immunoglobulin in livedo vasculitis: a new treatment option? J Am Acad Dermatol 49: 555-556

16. Weishaupt C et al.(2019) Characteristics, risk factors and treatment reality in livedoid vasculopathy - a multicentre analysis. J Eur Acad Dermatol Venereol 33:1784-1791.