Part II: Cutaneous manifestations of peripheral vascular disease.

In this Part 2 of a 2-part continuing medical education series, we review the epidemiology of peripheral vascular disease, its association with cutaneous symptoms, and the diagnosis and evaluation of cutaneous features of vascular disorders. As peripheral vascular disease becomes more prevalent globally, it is essential for dermatologists to become competent at accurately recognizing and diagnosing cutaneous manifestations and directing individuals to receive appropriate care and treatment.

A comprehensive narrative review of the cutaneous manifestations associated with COVID-19.

The systemic and respiratory clinical manifestations of coronavirus disease 2019 (COVID-19) include fever, coughing, sneezing, sore throat, rhinitis, dyspnea, chest pain, malaise, fatigue, anorexia and headache. Moreover, cutaneous manifestations have been reported in 0.2% to 20.4% of cases. Early diagnosis of COVID-19 leads to a better prognosis; knowledge of its cutaneous manifestations is one way that may help fulfil this goal. In this review, PubMed and Medline were searched with the terms "dermatology", "skin" and "cutaneous", each in combination with "SARS-CoV-2" or "COVID-19". All articles, including original articles, case reports, case series and review articles published from the emergence of the disease to the time of submission, were included. In this comprehensive narrative review, we tried to provide an analysis of the cutaneous manifestations associated with COVID-19, including maculopapular rash, urticaria, Chilblain-like, vesicular lesions, livedo reticularis and petechiae in asymptomatic/symptomatic COVID-19 patients that might be the first complication of infection after respiratory symptoms. Immune dysregulation, cytokine storms, side effects of antiviral drugs, environmental conditions and high-dose intravenous immunoglobulin (IVIG) therapy might be involved in the pathogenesis of the cutaneous manifestations in COVID-19 patients. Therefore, knowledge of cutaneous COVID-19 manifestations might be vital in achieving a quick diagnosis in some COVID-19 patients, which would help control the pandemic. Further research is very much warranted to clarify this issue.

Risk of livedo with antiphospholipid antibodies in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Livedo is a well-known skin condition in patients with systemic lupus erythematosus (SLE) which correspond to small vessels involvement. The influence of antiphospholipid antibodies (aPL) on the occurrence of livedo is controversial. The aim of our study was to estimate the risk of livedo associated with aPL in patients with SLE. METHODS: We conducted a systematic review and meta-analysis of the literature from 1977 to 2021 to estimate the risk of livedo in SLE patients according to different aPL profiles. Data sources were PubMed, Embase, Cochrane Library, hand search, and reference lists of studies. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcome (livedo). Two independent investigators assessed study eligibility, quality, and extracted patient characteristics from each study as well as exposure (aPL) and outcome (livedo). Risk estimates were pooled using random effects models and sensitivity analyses. For all stages of the meta-analysis, we followed the PRISMA guidelines. PROSPERO registration number: CRD42015027377. RESULTS: Of the 2,355 articles identified, 27 were included with a total of 4,810 SLE patients. The frequency of livedo was 25.5% in aPL-positive patients and 13.3% in aPL-negative patients. The overall Odds Ratio (OR) for livedo in aPL-positive patients compared to aPL-negative patients was 2.91 (95% CI; 2.17-3.90). The risk of livedo was significantly increased for most of aPL subtypes, including lupus anticoagulant (LA) (OR = 4.45 [95% CI; 2.21-8.94]), IgG anticardiolipin (OR = 3.95 [95% CI; 2.34-6.65]), and IgG anti-ß2-glycoprotein 1 (OR = 3.49 [95% CI; 1.68-7.27]). CONCLUSIONS: We demonstrated in this meta-analysis an excess risk of livedo in aPL-positive SLE patients compared to aPL-negative patients. For daily practice, in patients with SLE, livedo associated with aPL could correspond to a peculiar group of patients with small vessel disease. Livedo could be a good candidate for inclusion in future classification criteria for antiphospholipid syndrome.

Transient breast livedo reticularis-like exanthem in an adolescent with COVID-19.

Livedo reticularis-like eruptions have been described in different viral infections. In patients with COVID-19, livedo reticularis-like rashes are usually mild, typically present in a symmetric distribution and mostly involve the lower limbs. A case of livedo reticularis located exclusively on the breasts of a girl with mild systemic symptoms of COVID-19 is presented. Coagulation studies were normal and findings disappeared within 1 week.

COVID-19 Skin Manifestations in Skin of Colour.

Coronavirus disease (COVID-19) skin manifestations have been increasingly reported in medical literature. Recent discussions have identified a lack of images of skin of color (SOC) patients with COVID-19 related skin findings despite people with skin of color being disproportionately affected with the disease. There have been calls to prioritize the identification of COVID-19 skin manifestations in patients with SOC and disseminate these findings. The objective of this article is to review the existing literature on COVID-19 skin manifestations and, where possible, discuss how they may present differently in patients with SOC. Further research is needed to allow primary care physicians and dermatologists to be aware of and easily identify patients with cutaneous findings that may be secondary to COVID-19. Patients presenting with idiopathic dermatologic manifestations should be considered for COVID-19 testing and follow public health guidelines for self-isolation.

Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review.

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

Raynaud's phenomenon and related vasospastic disorders.

Raynaud's phenomenon, which is characterized by episodic digital pallor, cyanosis and rubor upon exposure to cold environment or to stress, is relatively common, although the prevalence depends on the climate. Still, it is under-diagnosed, under-treated, and often confused with other conditions. Primary Raynaud's phenomenon (i.e., Raynaud disease) must be distinguished from secondary Raynaud's phenomenon (i.e., Raynaud syndrome) as long-term morbidity and outcomes differ vastly between the two conditions. Additionally, the practitioner must differentiate between Raynaud's phenomenon and related vascular disorders, such as acrocyanosis, pernio, and livedo reticularis. In this article, we review differences between the conditions and suggest an approach to diagnosis and treatment strategy for these disorders.

Investigating the spectrum of dermatologic manifestations in COVID-19 infection in severely ill patients: A series of four cases.

COVID-19, an infectious disease caused by the novel coronavirus, was initially identified in Wuhan, China, in December 2019. By March 2020, it was declared a pandemic by the World Health Organization. Although most findings have been reported in the lungs, primarily due to catastrophic respiratory decline, other organs, including the skin, are affected. Recent reports have been published describing the clinical spectrum of COVID-19-related lesions. In addition, recent case series have described a subset of these lesions having underlying thrombotic microangiopathy with increased complement activation characterized by increased C4d deposition within the blood vessel walls. Herein, we describe a series of COVID-19-related cutaneous manifestations found at autopsy examination and their underlying histopathologic findings. Although the clinical manifestations seen in these lesions vary widely, the underlying etiology of thrombotic microangiopathy remains consistent and reproducible.

Livedoid cutaneous metastasis of signet-ring cell gastric carcinoma.

Cutaneous metastasis of gastric cancer is extremely rare. Nodular forms are more common and inflammatory forms are exceptionally encountered. Herein, we report a case of inflammatory cutaneous metastasis of signet-ring cell gastric cancer (poorly cohesive gastric carcinoma with signet-ring cell component) masquerading as livedo reticularis. To our knowledge, such a clinical presentation of cutaneous metastasis has not been reported for gastric cancer. It is imperative to preserve a high index of clinical suspicion for diagnosing cutaneous metastases. Our case highlights the importance of obtaining a skin biopsy in patients with a known history of internal malignancy. Bizarre, newly erupting, evolving, persistent, or treatment-refractory dermatologic lesions (such as nodules, ulcers, erythematous, reticular, or livedoid patches) might be clues for an underlying internal malignancy and require prompt histopathological sampling. Personal medical history, histopathological examination, and immunohistochemical profiling are equally important in distinguishing primary cutaneous carcinomas from secondary metastatic deposits. Early recognition of a cutaneous metastasis might enable appropriate staging and timely intervention, thereby prolonging survival.

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 in neurological diseases: an update on the differential diagnoses.

Livedo is a net-like violaceous skin pattern. It can be classified as physiological or pathological. The physiological livedo reticularis usually appears in cold conditions, whereas the pathological and irregular livedo, which persists in warm temperatures, is often labeled as 'livedo racemosa'. Some neurological pathologies are associated with livedo, most commonly those with an inflammatory component or those derived from systemic disorders. The present review summarizes the most important central and peripheral neurological diseases in pediatric and adult age groups associated with livedo, providing physicians with an overview of the clinical presentation, etiology, diagnosis and management of these conditions.

[Recognize rare diseases on the skin]. / Seltene Erkrankungen an der Haut erkennen.

The correct interpretation of skin manifestations can facilitate the diagnosis of many rare systemic diseases. Such manifestations can be due to autoimmune diseases (e.g. dermatomyositis, systemic lupus erythematosus, systemic sclerosis and sarcoidosis) and metabolic diseases (e.g. Anderson-Fabry disease and porphyria cutanea tarda). Other cutaneous symptoms are of great importance because they are possible warning signs of occult diseases of internal organs. This is true for example for some diseases from the group of neutrophilic dermatoses, such as Sweet's syndrome and pyoderma gangraenosum.

Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency.

Deficiency of adenosine deaminase type 2 (DADA2) is a rare form of autoinflammatory disorder with limited reported cases. In this paper, we have presented the clinico-immunological, radiological and genetic characteristics of five surviving and three deceased childhood-onset DADA2 patients. We aimed to compare surviving and deceased patients in terms of clinical features and treatment modalities. Moreover, we have evaluated the causes of death in our DADA2 subjects together with the previously reported cases. Demographic features, clinical characteristics, imaging findings, mutations and pharmacological treatments of DADA2 subjects were noted from patient records of pediatric and adult rheumatology clinics in a retrospective and longitudinal nature. Eight patients from seven families were enrolled. While five of them were surviving, three of them had died due to various reasons. Median age of the patients at disease onset and diagnosis was 7 years (range 0.5-13 years) and 14 years (range 5-27 years), respectively. The main clinical manifestations were cutaneous findings (7/8), recurrent low-grade fever (6/8), neurological involvement (6/8) and gastrointestinal involvement (5/8). All patients had increased acute phase reactants at presentation and also during the disease flares. Until the diagnosis of DADA2 was confirmed, five patients have been followed-up with the diagnosis of PAN: two patients both with PAN and FMF, and one patient with CAPS and vasculitis. Demographic, clinical, neurological features and genetic mutations did not differ in surviving and deceased DADA2 patients. Deceased and surviving subjects differed in terms of treatment modalities after the diagnosis of DADA2. Anti-TNF alpha treatment has been initiated in five surviving patients as soon as the diagnosis of DADA2 was established. However, three patients who have died were not able to use sufficient doses of anti-TNF alpha treatment; in one case due to reluctance of patient and in two cases due to establishment of the definite diagnosis by genetic analysis at the same time with the last fatal DADA2 episode. Despite limited number of patients, this case series for the first time compares the phenotypic, genotypic and medication differences between surviving and deceased DADA2 patients. Anti-TNF alpha treatment seems to be efficient and lifesaving in DADA2 patients.

[Cutaneous polyarteritis nodosa].

Cutaneous polyarteritis nodosa is a rare disease that affects vessels of the deep skin and the subcutaneous tissue. Its etiopathology remains unknown. It predominantly affects skin, and the main cutaneous symptoms are subcutaneous nodules, livedo reticularis, and ulcerations that are mainly located on legs. Cutaneous polyarteritis nodosa can also cause extracutaneous symptoms (fever, malaise, myalgias, arthralgias, neuropathy). It is a chronic benign disease with a relapsing course. Diagnostic criteria for this disease were recently proposed and both clinical and typical histological features must be present to confirm the diagnosis. Treatment of cutaneous polyarteritis nodosa depends on the severity of the disease and the frequency of relapses. Mild forms limited to skin lesions should be treated with nonsteroidal anti-inflammatory drugs, colchicine and locally applied glucocorticosteroids. Cases that are refractory to the treatment, that recur with extracutaneous symptoms may require applying more aggressive approach (glucocorticosteroids orally, hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil or intravenous immunoglobulins). The prognosis in cutaneous polyarteritis nodosa is favorable and the disease rarely turns into a systemic form.

Adverse reaction after hyaluronan injection for minimally invasive papilla volume augmentation. A report on two cases.

OBJECTIVES: To report two cases of adverse reaction after mucosal hyaluronan (HY) injection around implant-supported crowns, with the aim to augment the missing interdental papilla. MATERIAL AND METHODS: Two patients with single, non-neighbouring, implants in the anterior maxilla, who were treated within the frames of a randomized controlled clinical trial testing the effectiveness of HY gel injection to reconstruct missing papilla volume at single implants, presented an adverse reaction. Injection of HY was performed bilaterally using a 3-step technique: (i) creation of a reservoir in the mucosa directly above the mucogingival junction, (ii) injection into the attached gingiva/mucosa below the missing papilla, and (iii) injection 2-3 mm apically to the papilla tip. The whole-injection session was repeated once after approximately 4 weeks. RESULTS: Both patients presented with swelling and extreme tenderness with a burning sensation on the lip next to the injection area, after the second injection session. In one of the cases, a net-like skin discoloration (livedo reticularis) was also noted. The symptoms lasted for up to 7 days, and in both cases, symptoms resolved without any signs of skin or mucosal necrosis or any permanent damage. CONCLUSION: Most likely, water attraction over time by the highly hygroscopic HY, exerted progressively an external vascular compression and at least partial occlusion of neighbouring blood vessels. An infection or an allergic reaction seems unlikely, since all symptoms gradually disappeared within a week irrespective use of antimicrobials, while an allergic reaction most likely would not have been restricted to one side.

Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.

OBJECTIVE: To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. RESULTS: Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. CONCLUSION: This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.

Livedo Reticularis: A Presenting Sign of Escherichia Coli Sepsis in a Newborn.

UNLABELLED: Livedo reticularis is a red cutaneous netlike pattern that is caused by abnormalities of the microvascularization and can be associated with many other potential systemic etiologies. We describe a case of a newborn that presented with livedo reticularis on his first day of life without any obvious systemic signs. The livedo reticularis was associated with Escherichia Coli K1 meningitis as revealed by laboratory tests. Clinical infectious signs developed a few hours later. Despite appropriate antibiotics therapy, he died on his second day because of sepsis and disseminated intravascular coagulation. Cerebrospinal fluid culture, blood culture, and culture of samples from trachea showed the presence of Escherichia Coli serotype K1 with many virulence determinants. CONCLUSION: In newborn, livedo reticularis must not be considered as physiological, but as a potential sign of unknown severe bacterial infection. Thus, the presence of livedo reticularis must require urgent laboratory tests.

Efficacy of intravenous immunoglobulins in livedoid vasculopathy: long-term follow-up of 11 patients.

BACKGROUND: Evidence for the efficacy of various therapies of livedoid vasculopathy (LV) is limited. OBJECTIVE: We sought to determine efficacy and tolerability of 2 g/kg of intravenous immunoglobulins (IVIG) every 4 weeks in patients with LV. METHODS: This was a long-term follow-up study of 11 patients with LV treated with 2 g/kg of IVIG assessing the clinical characteristics, disease course, and quality of life. RESULTS: The treatment regimen led to complete remission of ulcerations and pain in 17 of 29 disease episodes (59%) after 3 cycles and in 25 of 29 episodes (86%) after 6 cycles. Two disease episodes showed remission after 7 and 8 cycles, resulting in a total number of remissions of 27 (93%). Subscore analysis showed resolution of pain in 80% after 2 IVIG cycles. Disease severity and quality of life were significantly improved after 6 cycles. Median duration of remissions was 26.7 months after initial and 7.5 months after subsequent disease episodes. LIMITATIONS: This was a retrospective study that did not include the comparison of IVIG efficacy and its impact on quality of life with treatment options. CONCLUSIONS: In our patients with LV, high-dose IVIG led to fast and complete resolution of pain and ulcerations and to substantial improvement in quality of life.

Lesson of the month 1: sudden onset postural livedo reticularis, cyanotic toes and multiorgan failure.

Cholesterol embolisation syndrome (CES) is a rare but serious disease with high mortality caused by the formation of an embolus made up of cholesterol crystals from atherosclerotic plaques. Its clinical presentation is usually initially insidious and it often remains unrecognised because of its non-specific clinical presentation, which can cause delays in treatment and high mortality. The most common physical symptoms are cutaneous. We present a lethal case of CES to increase the awareness about this serious condition.

Painful, Tender, Localized, Idiopathic Livedo Reticularis.

Livedo reticularis (LR) is a unique cutaneous condition characterized by a reddish-blue to purple, net-like cyanosis of the skin, often associated with disturbances in cutaneous blood flow. This case report discusses a 30-year-old woman with a history of Hashimoto thyroiditis, vitamin D deficiency, migraines, and goiter who presents with painful, localized LR on her right flank. Despite her extensive medical history, there were no significant findings in her laboratory and imaging studies, including a normal epidermis in skin biopsies. The LR in this case is distinguished by its persistence and the presence of pain, a symptom not commonly associated with LR. Various treatments, including 5% lidocaine ointment, oral analgesics, and gabapentin, were considered, but her symptoms remained stable over 13 months. This case exemplifies the complexity of LR, particularly when presenting with atypical symptoms like pain. It highlights the need for further research into the pathophysiology and treatment of LR, especially in cases deviating from the typical symptomatology, and suggests the potential value of a multi-disciplinary approach to management.