Inflammatory and vaso-occlusive ulcers: Part I - clinical presentation and diagnosis.

In this CME, we review two specific categories of ulcers: inflammatory (where inflammation is the primary pathologic process leading to ulceration) and vaso-occlusive (where occlusion is the primary process). Inflammatory ulcers include pyoderma gangrenosum and vasculitides, whereas livedoid vasculopathy, calciphylaxis and Martorell ulcers are vaso-occlusive ulcers. Determining the causes of ulcers in these conditions may require laboratory evaluation, biopsy and imaging.

Inflammatory and vaso-occlusive ulcers: Part II - Management.

In the second part of this CME, we present an approach for the management of inflammatory and vaso-occlusive ulcers and highlight the need for further research in this field. The three overarching principles for management are etiology-specific treatment, ulcer care, and consideration of patient comorbidities and risk factors for poor healing. Both etiology-specific treatment and management of patient comorbidities and risk factors often require collaboration with providers from other specialties. Ulcer care is governed by TIME, or tissue debridement, infection control, management of moisture imbalance and epithelial edge advancement. As wound healing is a dynamic process, management should be adapted to changes in the status of the ulcer.

Lymphocytic vasculitis in livedoid vasculopathy: A report of 137 cases.

BACKGROUND: Livedoid vasculopathy (LV) is characterized by fibrin deposition and thrombosis in the small vessels of the superficial dermis. It is widely recognized as an occlusive disease, which is primarily treated with anticoagulation therapy. METHODS: We retrospectively analyzed the clinical and histopathological characteristics of patients diagnosed with LV at a tertiary dermatology department to explore the characteristics of lymphocytic vasculitis in LV. The frequency of vasculitis and the types of vessels involved were examined based on the diameters and elastic fiber distribution of the involved vessels. In addition, the immunophenotypes of infiltrating lymphocytes were analyzed. RESULTS: In a large retrospective series including 358 LV cases, we identified 137 (38.3%) cases of lymphocytic vasculitis. Among them, 48 cases involved medium-sized vessels, including arterioles and venules, whereas 89 cases involved only small vessels. In addition, 12 cases displayed a segmental distribution of vasculitis. The infiltrating lymphocytes were mainly T cells, with dominant cells stained positive for CD4. CONCLUSIONS: Lymphocytic vasculitis forms part of the histological spectrum of LV, affecting both medium-sized and small vessels. It is possible that the occlusion of small vessels may represent a phenomenon secondary to lymphocytic vasculitis.

Occlusive cutaneous vasculopathies as cause of chronic ulcers.

The term occluding vasculopathies covers a large number of different conditions. These often manifest as skin ulcers. Occluding vasculopathies should be considered in the differential diagnosis of leg ulcers. The term "occlusive vasculopathies" encompasses pathophysiologically related entities that share structural or thrombotic obliteration of small cutaneous vessels. In this article, we will focus on livedoid vasculopathy with and without antiphospholipid syndrome and calciphylaxis with differentiation from hypertonic leg ulcer as the most relevant differential diagnoses of leg ulcer. The term also includes vascular occlusion, for example due to oxalate or cholesterol embolism, and septic vasculopathy. This often leads to acral ulceration and is therefore not a differential diagnosis with classic leg ulcers. It will not be discussed in this article. Occlusive vasculopathy may be suspected in the presence of the typical livedo racemosa or (non-inflammatory) retiform purpura as a sign of reduced cutaneous perfusion in the wound area. Inflammatory dermatoses, especially vasculitides, must be differentiated. This is achieved by histopathological evaluation of a tissue sample of sufficient size and depth taken at the appropriate time. In addition, specific laboratory parameters, particularly coagulation parameters, can support the diagnosis.

Endothelial dysfunction, thrombophilia, and nailfold capillaroscopic features in livedoid vasculopathy.

BACKGROUND: Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease. OBJECTIVES: This study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology. METHODS: This case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients. RESULTS: Plasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05-2.79] ng/ml vs. 1.89 [1.43-2.33] ng/ml, p = 0.007; 1.15 [0.88-1.4] ng/ml vs. 0.76 [0.56-0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26-18.26] vs. 19.80 % [16.47-24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-ß2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %). CONCLUSIONS: In conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.

The simultaneous occurrence of livedoid vasculopathy and lymphocytic thrombophilic arteritis in six cases.

Lymphocytic thrombophilic arteritis and livedoid vasculopathy may both present with livedo racemosa and ulceration. We present 6 cases with features of both conditions, raising the possibility that they are either closely linked or are part of a spectrum of the same condition.

Livedoid vasculopathy and peripheral neuropathy: A retrospective cohort study of 55 Chinese patients and literature review.

Livedoid vasculopathy (LV) is a thrombo-occlusive vascular disease with an uncertain aetiology. In addition to cutaneous manifestations, LV patients may develop peripheral neuropathy. This study aimed to examine features of peripheral neuropathy in Chinese LV patients. We retrospectively reviewed and analysed the clinical data of 55 LV patients treated at Peking Union Medical College Hospital and conducted a literature review of peripheral neuropathy in LV patients. The incidence of peripheral neuropathy in our cohort was 12.73%. Among the seven patients with neuropathy, five were women and two were men. Median age at enrollment and disease onset in these patients was 27.29 and 22.57 years, respectively. Mean time from the appearance of cutaneous manifestations to the development of neurological symptoms was 38.67 months. Peripheral neuropathy was generally refractory to treatment, asymmetric in the distal extremities, and slowly progressive. The main symptom was numbness; hypoesthesia and neuromuscular manifestations occurred occasionally. The proportion of patients reporting seasonal worsening of symptoms was significantly higher in LV patients with peripheral neuropathy than in LV patients without neuropathy (P < .05). Peripheral neuropathy is a potential complication of LV. LV patients with peripheral neuropathy require long-term follow-up.

Livedoid vasculopathy: A review with focus on terminology and pathogenesis.

Livedoid vasculopathy (LV) is a rare thrombotic vasculopathy of the dermis characterized by painful, relapsing ulcers over the lower extremities. Diagnosis is challenging due to the overlap in clinical appearance and nomenclature with other skin disorders. Treatment selection is complicated by poor understanding of the pathogenesis of LV and lack of robust clinical trials evaluating therapy efficacy. The terminology and pathophysiology of LV are reviewed here, along with its epidemiology, clinical and histologic features, and treatment options. A diagnostic pathway is suggested to guide providers in evaluating for comorbidities, referring to appropriate specialists, and choosing from the available classes of therapy.

Platelet count and plateletcrit: Potential haematological biomarkers for livedoid vasculopathy?

BACKGROUND: The pathogenesis of livedoid vasculopathy (LV) remains unknown. Although platelet activation occurs in LV, little research has been conducted on LV platelet morphology parameters. The purpose of this study was to investigate whether platelet morphology changes in LV and its clinical significance. METHODS: Twenty-seven LV patients and 21 cutaneous small vessel vasculitis (CSVV) patients, all at the active stage, were included. Platelet parameters in active- and stable-stage LV and CSVV patients were compared. Correlations between these platelet parameters and LV composite clinical scores were analysed. RESULTS: LV patients' mean age was 25.48 years (range: 9-62 years), and 81.48% (22/27) were women and 18.52% (5/27) were men. The platelet counts and plateletcrit (PCT) levels were significantly elevated in LV patients compared with CSVV patients and in active-stage LV patients compared with stable-stage LV patients after treatment. LV patient composite clinical scores that reflected disease severity and activity were positively correlated with the platelet count and PCT levels. CONCLUSION: Altered platelet morphology was detected in LV patients. Platelet count and PCT might be haematological biomarkers for early prediction of LV activity and relapses and for differential identification between LV and CSVV.

Cutaneous involvement by T-cell prolymphocytic leukemia presenting as livedoid vasculopathy.

T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive neoplasm derived from post-thymic T-cells. Patients are typically middle aged with a slight male predominance who present with a high white blood cell count, hepatosplenomegaly, lymphadenopathy, and other symptoms typically associated with leukemia. Although cutaneous involvement has been reported in up to 30% of cases of T-PLL, to our knowledge, none have presented with a presentation resembling livedoid vasculopathy. In the correct clinical context, an underlying hematolymphoid neoplasm should be included in the differential diagnosis of a patient presenting with livedoid vasculopathy.

Rivaroxaban for treatment of livedoid vasculopathy: A systematic review.

Rivaroxaban is a direct inhibitor of activated coagulation factor X and competitively targets factor Xa via reversible binding. We conducted a systematic review of the efficacy and safety of rivaroxaban for treatment of livedoid vasculopathy (LV) by searching the PubMed, Cochrane and Embase databases. A total of 22 articles and 1 registered clinical trial were identified in the search of which 13 were included. The studies included 73 LV patients receiving rivaroxaban therapy (10-20 mg per day). Overall, 60 patients (82.2%) had responses to therapy, achieving remission of both pain and ulceration. Few adverse effects were observed. Thus, the consensus of the clinical evidence is that rivaroxaban is a well-tolerated and effective treatment for LV. However, this still needs to be confirmed by large prospective and/or case control studies.

Livedoid vasculopathy: Clinical course and long-term outcome in Asian patients with a review of the literature.

Livedoid vasculopathy (LV) is an uncommon, chronic, and recurrent thrombo-occlusive vascular disorder. Data specific to LV in Thai population remains scarce. This study aimed to evaluate the clinical course and treatment outcomes of LV in Thai patients, and to perform a literature review for studies that reported on anticoagulant treatment in LV. Seventy-four patients with a mean age of 37.6 ± 14.7 years were included. The female to male ratio was 5.2:1, and the median follow-up was 10.5 months. Most patients had primary LV disorder. Forty-eight patients were improved with treatments, with a median duration of 11.4 months. Combination treatments were commonly used, including anti-inflammatories, antiplatelets, and immunosuppressants. Add-on therapy with anticoagulant or psoralen plus ultraviolet-A (PUVA) led to disease improvement in a majority of the patients treated. Kaplan-Meier analysis demonstrated that 38.5%, 53.7%, and 57.9% would have disease improvement at 1, 2, and 3 years, respectively. Of 39 studies (n = 219) that reported on anticoagulant treatment in LV, anticoagulant drug was used as monotherapy in 104 patients. The mean duration of anticoagulant treatment was 7.2 ± 3.8 months, which led to disease improvement in 97 patients (93.3%). Bleeding side effect was found in 9 patients (8.7%). The highest incidence of LV was found among females aged 30 to 40 years. Combination therapy with anti-inflammatory drugs, antiplatelet drugs, and immunosuppressants led to disease improvement. The observed efficacy of add-on PUVA or anticoagulant is promising and should be further investigated. Further studies are needed to guide the development of an LV management guideline.

Intravenous Immunoglobulin Therapy in Livedoid Vasculopathy: Retrospective Observation of Clinical Outcome and Patient's Activity Level.

BACKGROUND: Livedoid vasculopathy (LV) is a rare disease characterized by livedo racemosa, atrophie blanche, ulcerations, and severe pain. Low molecular weight heparins and rivaroxaban can be used in LV-patients. In addition, intravenous immunoglobulins (IVIG) have been described as treatment-option. OBJECTIVES: Objective was to investigate the therapeutic effect of IVIG on ulcer, pain and restrictions in daily life. METHODS: Thirty-two LV-patients who received IVIG at the Department of Dermatology Tübingen between 01/2014 and 06/2019 were identified. Twenty-five of these patients were available for further follow up and were included in the study. Patients were interviewed using a questionnaire focusing on the course of the disease, symptoms, and subjective response to IVIG-treatment. RESULTS: Twenty-five patients were included in the study (mean follow up: 28.9 months). Patients received an average of 6.8 cycles (range 1-45) of IVIG during the observed period.Significant improvements were seen regarding skin findings, pain, and limitation of daily activities. Complete remission of symptoms was observed in 68% of patients. Good tolerability of IVIG was shown in 92%. CONCLUSIONS: A good therapy response regarding ulceration, pain, and daily life restrictions with good tolerability was demonstrated for IVIG (2 g/kg bodyweight over 5 days).

Retiform purpura: Workup and therapeutic considerations in select conditions.

In this article we focus on updates in select etiologies of retiform purpura. These causes of retiform purpura, in addition to bacterial or fungal sepsis, disseminated intravascular coagulation, purpura fulminans, and catastrophic antiphospholipid syndrome, are important diagnoses with potential for morbidity and mortality. Important aspects in the pathophysiology, patient demographics and risk factors, updates in the diagnostic workup, histopathology, and treatment of these specific conditions are discussed.

Intravenous immunoglobulin in resistant livedoid vasculopathy: Analysis of a case series.

We report a retrospective analysis the efficacy of high-dose intravenous immunoglobulins on 9 patients with Livedoid vasculopathy for whom resistant to immunosuppressants plus anticoagulants or could not be prescribed. Intravenous immunoglobulins were used 2 g/kg per month in these patients. The treatment induced stabilization of the disease and all patients demonstrated improvement with IVIg. Complete and partial clinical response was achieved in 6 and 3 patients respectively.

A 75-year-old woman with primary antiphospholipid syndrome presenting with livedoid vasculopathy.

The clinical presentation of primary antiphospholipid syndrome (PAPS) can vary, often mimicking many other medical conditions. Therefore, it is difficult to diagnose at the first presentation because of the absence of classical symptoms. We described an unusual presentation of PAPS mimicking livedoid vasculopathy (LV), where the only diagnostic clue at the initial presentation was skin lesions in both lower legs. A 75-year-old Han Chinese woman presented with features mimicking LV, without clinically significant antiphospholipid syndrome (APS). After many relevant laboratory examinations and histopathological examination, the patient was finally diagnosed as having PAPS. LV should not be treated as an independent disease, but as a skin manifestation. A high degree of suspicion of APS is needed in patients presenting or diagnosed with LV. Early interventions are necessary to prevent and reduce the risk of thrombosis. This case presents a rare clinical manifestation and provides significant information on PAPS.

[Diagnosis and treatment of vasculitic ulcerations]. / Diagnostik und Behandlung vaskulitischer Ulzerationen.

Vasculitis is a rare cause of skin ulceration. Depending on the size of the affected vessel, the patient's comorbidities and the pathophysiology present, different clinical morphologies can be seen, which can often give preliminary indications of the type of underlying vasculitis. There may be systemic or cutaneous manifestations; thus, a targeted diagnostic workup should be initiated at an early stage. Treatment should be interdisciplinary if there is systemic participation. Vasculopathies (e.g., livedoid vasculopathy), in which occlusion of the vascular lumen is the main pathophysiological feature, should be delimitated from vasculitis. If vasculitic or vasculopathic ulceration is present, stage-appropriate wound management is recommended.

Three cases of lymphocytic thrombophilic arteritis presenting with an annular eruption.

We describe three patients who presented with a striking erythematous non-blanching annular eruption and features of lymphocytic thrombophilic arteritis (LTA), with a prominent lymphocytic vasculitis involving deep dermal vessels. Lymphocytic inflammation was also evident in the superficial vessels and one patient had small superficial ulcers over the ankle area resembling livedoid vasculopathy (LV). Multiple biopsies demonstrated a persistent absence of neutrophils in the infiltrate consistent with a lymphocytic process. In addition to highlighting the annular morphology as a novel presentation of LTA, these cases suggest a possible relationship between LV and LTA and support the notion that they are distinct from neutrophilic vasculitides such as cutaneous polyarteritis nodosa.

Analysis of serum levels and cutaneous expression of lipoprotein (a) in 38 patients with livedoid vasculopathy.

BACKGROUND: Coagulation disorders contribute to the development of livedoid vasculopathy (LV). Elevated plasma levels of lipoprotein(a) [Lp(a)] are an independent risk factor for the development of cardiovascular disease and associated with hypercoagulable states. Increased serum Lp(a) levels have been reported in patients with LV and may have an important role in the pathogenesis of LV. OBJECTIVES: To investigate Lp(a) expression in skin lesions and circulating serum Lp(a) levels in patients with LV. METHODS: Skin biopsy samples from 38 patients (27 women and 11 men) with active lesions diagnosed as LV and 9 samples of normal skin (5 women and 4 men) from control patients without LV were evaluated for skin expression of Lp(a) by immunohistochemistry. Plasma levels of Lp(a) were analyzed by immunoturbidimetry. RESULTS: We found that lesional skin in patients with LV expressed 10-fold higher Lp(a) immunostaining than controls. High plasma levels of Lp(a) were observed in LV patients. We did not find a correlation (P = .02) between expression of Lp(a) in the skin and plasma levels of Lp(a) in patients with LV. CONCLUSIONS: Increased Lp(a) expression in lesional skin of LV patients suggests the role of Lp(a) in the thrombo-occlusive vasculopathy observed in this disease.