Livedo of the Forearm in the Aftermath of Forearm Erysipelas

Livedo is an ischemic dermopathy caused by vasculopathies or prothrombotic states, and characterized by the violaceous lace-like mottling of the skin. We report on a patient who developed livedo reticularis – livedo racemosa overlap syndrome as a late sequel of erysipelas, the livedo being restricted to the limb segment affected earlier by erysipelas and devoid of systemic vasculopathy. Though erysipelas and livedo are common disorders, we could not find in the literature reports of an occurrence like that observed in this patient. In this case a favorable prognosis of livedo could be predicted. In a different context, livedo may be the alarming signal of an undiagnosed systemic disease.

The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

LIVEDO RETICULARIS: CLINICAL SIGNIFICANCE AND TREATMENT

Livedo reticularis (LR) is a hyperpigmented discoloration of the skin characterized by a violet, reticulated cyanotic pattern, and is more common on the extremities and trunk. LR is in the form of intact circular networks. If the circular reticulated appearance is distorted and shows an irregular fracture pattern, it is defined as livedo racemosa (LRC). LR is a benign, primary disease that affects young and middle-aged women. LRC, on the other hand, is a secondary disease, pathological and permanent. In LR, the vivid cone discoloration is symmetrical, reversible, and uniform. In LRC, the vivid cone discoloration is irreversible, and fractured. Although it has been stated as a concept that the pathological livedoid form is LCR, there is no clear distinction between LR and LRC in clinical studies and generally 'livedo reticularis' is used to describe both. Our study includes eight patients diagnosed with livedo reticularis between January 2013 and May 2021. One of our patients was male and the other was female. Their ages ranged from 25 to 70 years and the mean age was 45.5±16.7 years. Although the main complaints were coldness, numbness and pain, aesthetic anxiety was prominent in all patients. On physical examination, violet-colored fishing net-like appearances were noted on the lower extremities of all patients. It was accompanied by venous insufficiency in six of the patients. As a result of the treatment we applied, there was improvement in venous insufficiency. However, as a result of the vasodilator treatment we applied for cosmological purposes, there was no obvious improvement in the reticulated appearances. Because of the risk of developing neurovascular and cardiovascular complications several years after the onset of livedoid vasculopathy, it is important to monitor these patients. Considering that LR may be seen before pulmonary symptoms during the COVID-19 pandemic period, necessary tests should be performed to rule out the diagnosis of COVID-19 in these cases.

Therapeutic Perspectives in Sneddon’s Syndrome

Sneddon’s syndrome is a rare but severe progressive chronic disease, characterized by multiple discoloration skin patches called Livedo racemosa and recurrent cerebrovascular events. It mainly affects women aged around 40. Considering the two main forms, antiphospholipid (APS) positive and negative, the available treatments are directed at either one of them. The idiopathic form (APS negative) is associated with a more severe prognosis as chronic oral anticoagulant therapy (COA) is more difficult to manage. One therapeutic perspective in controlling disease progression in these patients is by understanding the protein Z deficiency in these patients as a deciding factor in the success of the COA therapy.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients

Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.

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.

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).

Livedo racemosa bei primärem Antiphospholipidsyndrom

ZusammenfassungDas Antiphospholipidsyndrom umfasst als Kardinalsymptome rezidivierende arteriovenöse thrombembolische Ereignisse, vermehrte Aborte oder Schwangerschaftskomplikationen und das Vorliegen von Antiphospholipid-Antikörpern. In ca. 20 % der Fälle liegt eine Livedo racemosa als kutane Manifestation vor. Die Therapie besteht in der Prophylaxe weiterer Thromboembolien.Wir berichten über einen Patienten mit Multiorganbeteiligung (Livedo racemosa, Milz-, Pankreas-, Darm- und fraglich Niereninfarkte) bei Nachweis von ß2-Glykoprotein-I-IgG-Antikörper.

Cutaneous Manifestations in COVID-19: Report on 31 Cases from Five Countries

The increasingly frequent cutaneous manifestations of coronavirus disease (COVID-19) remain to pose a problem to clinicians. Herein, we aimed to describe the clinical and pathological findings of skin lesions in patients with COVID-19. The case series, which was based on the International Dermatological Registry circulated to dermatologists worldwide, was conducted across organizations and societies belonging to five different countries. We documented 31 patients with dermatologic manifestations associated with COVID-19, including maculopapular rashes (16.10%), urticarial lesions (26.80%), pseudochilblains (22.60%), petechiae/purpura (6.50%), distal ischaemia and necrosis (6.50%), livedo racemosa (12.90%), and others (9.70%). Twenty-six cases (83.90%) were qRT-PCR-confirmed COVID-19 cases, two (6.50%) were serologically confirmed, while two others (9.7%) were suspected cases owing to previous contact with COVID-19-positive patients. Therefore, our findings indicate that a febrile rash or even a rash in an afebrile state in the early stages of the disease may be the only clinical manifestation of COVID-19. In the future, we recommend close monitoring of all patients with skin lesions not attributable to other causal factors; in the diagnostic perspective, clinicians should aim to confirm if the skin lesions are associated with COVID-19.