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La Revue de Medecine Interne Dec 2022Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND... (Review)
Review
Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND are classified based upon the localization of neutrophils within the skin and clinical features. Recent findings suggest that ND are due to two main mechanisms: i) a polyclonal hereditary activation of the innate immune system (polygenic or monogenic); or ii) a clonal somatic activation of myeloid cells such as encountered in myelodysplastic syndrome or VEXAS syndrome. ND belong to internal medicine as a great number of patients with ND suffer from an underlying condition (such as hematological malignancy, inflammatory bowel disease, auto-immune and auto-inflammatory diseases). ND are diagnoses of exclusion and physicians should always consider differential diagnoses, particularly skin infections. Here, we review the pathophysiology and classification of the main ND (i.e., subcorneal pustular dermatosis (Sneddon-Wilkinson Disease) and Intercellular IgA dermatoses, aseptic pustulosis of the folds, Sweet syndrome, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, erythema elevatum diutinum, neutrophilic urticarial dermatosis and neutrophilic panniculitis), their clinical and histopathological features, and we highlight the investigations that are useful to identify ND-associated diseases and to exclude the differential diagnoses.
Topics: Humans; Sweet Syndrome; Pyoderma Gangrenosum; Skin Diseases, Vesiculobullous; Vasculitis, Leukocytoclastic, Cutaneous; Neutrophils
PubMed: 35870984
DOI: 10.1016/j.revmed.2022.06.007 -
The New England Journal of Medicine Dec 2020Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory...
BACKGROUND
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.
METHODS
We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.
RESULTS
We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.
CONCLUSIONS
Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Topics: Age of Onset; Aged; Aged, 80 and over; Autoimmune Diseases; Cytokines; Exome; Genetic Diseases, X-Linked; Genotype; Giant Cell Arteritis; Humans; Immunoblotting; Inflammation; Male; Middle Aged; Multiple Myeloma; Mutation, Missense; Myelodysplastic Syndromes; Polyarteritis Nodosa; Polychondritis, Relapsing; Sequence Analysis, DNA; Sweet Syndrome; Syndrome; Ubiquitin-Activating Enzymes
PubMed: 33108101
DOI: 10.1056/NEJMoa2026834 -
American Journal of Clinical Dermatology May 2022Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is an inflammatory, non-infectious skin reaction characterized clinically by tender, erythematous... (Review)
Review
Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is an inflammatory, non-infectious skin reaction characterized clinically by tender, erythematous papules/plaques/pustules/nodules commonly appearing on the upper limbs, trunk, and head and neck; histologically, SS is characterized by dense neutrophilic infiltrate in the dermis. SS is accompanied by fever; an elevation of inflammatory markers (e.g., erythrocyte sedimentation rate, C reactive protein) in serum may also be observed. Although most cases of SS are idiopathic, SS also occurs in the setting of malignancy or following administration of an associated drug. SS has also been reported in association with pregnancy and a burgeoning list of infectious (most commonly upper respiratory tract infections) and inflammatory diseases; likewise, the litany of possible iatrogenic triggers has also grown. Over the past several years, a wider spectrum of SS presentation has been realized, with several reports highlighting novel clinical and histological variants. Corticosteroids continue to be efficacious first-line therapy for the majority of patients with SS, although novel steroid-sparing agents have been recently added to the therapeutic armamentarium against refractory SS. New mechanisms of SS induction have also been recognized, although the precise etiology of SS still remains elusive. Here, we catalogue the various clinical and histological presentations of SS, summarize recently reported disease associations and iatrogenic triggers, and review treatment options. We also attempt to frame the findings of this review in the context of established and emerging paradigms of SS pathogenesis.
Topics: Adrenal Cortex Hormones; Humans; Iatrogenic Disease; Neck; Skin; Sweet Syndrome
PubMed: 35157247
DOI: 10.1007/s40257-022-00673-4 -
Dermatology (Basel, Switzerland) 2023Sweet syndrome (SS), the prototypical neutrophilic dermatosis, is characterized by abrupt onset of tender plaques and nodules, classically accompanied by fever and... (Review)
Review
Sweet syndrome (SS), the prototypical neutrophilic dermatosis, is characterized by abrupt onset of tender plaques and nodules, classically accompanied by fever and leukocytosis. While management mainly relies on systemic corticosteroids, inadequate response can be seen in some patients that necessitates exploring other treatment options. Early diagnosis of malignancy-associated SS (MA-SS) along with detection of concomitant malignancy is crucial for improving patients' outcomes. Data regarding various clinical manifestations, extracutaneous associations, treatment, and outcomes are poorly characterized in the literature. We aimed to review all published case reports and case series to portray clinical features of SS including extracutaneous manifestations. We also describe reported treatment options and their outcomes to draw attention toward unmet therapeutic needs in the management of SS. In addition, for clinical and practical purposes, we attempted to delineate the distinction between MA-SS and nonmalignant subtypes of SS.
Topics: Humans; Sweet Syndrome; Leukocytosis; Fever; Adrenal Cortex Hormones; Neoplasms
PubMed: 37019090
DOI: 10.1159/000530519 -
Journal of the American Academy of... Dec 2023In 2020, Beck et al described a novel adult autoinflammatory syndrome entitled VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic), a newly-discovered... (Review)
Review
In 2020, Beck et al described a novel adult autoinflammatory syndrome entitled VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic), a newly-discovered disorder that connected previously unrelated inflammatory syndromes and a prototype for a new class of hematoinflammatory diseases. Eighty-nine percent of published cases have documented skin involvement, but despite the high incidence and diagnostic accessibility of skin manifestations, there has been little focus on the dermatological features of VEXAS syndrome thus far. A PubMed search of all published case reports of VEXAS syndrome to date was performed, with inclusion of all cases confirmed by genetic sequencing, and this review summarizes the reported dermatological signs. There have already been 141 confirmed published cases since original publication, 126 of which had documented cutaneous signs. A wide range of skin presentations are reported, including Sweet-like urticated and tender erythematous nodules, cartilaginous involvement with chondritis, cutaneous vasculitis, and periorbital angiodema. Many patients had been diagnosed with Sweet syndrome, relapsing polychondritis, polyarteritis nodosa, or erythema nodosum. Hallmarks of skin histopathology are a neutrophilic dermatosis with coexisting or exclusive leukocytoclastic vasculitis. The new classification therefore helps link previously disparate inflammatory skin conditions into a unifying pathophysiological pathway.
Topics: Adult; Humans; Vacuoles; Dermatologists; Skin; Dermatitis; Mutation
PubMed: 35121074
DOI: 10.1016/j.jaad.2022.01.042 -
Reumatologia Clinica Jan 2024VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene... (Review)
Review
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.
Topics: Adult; Humans; Myelodysplastic Syndromes; Glucocorticoids; Immunosuppressive Agents; Mutation; Skin Diseases, Genetic
PubMed: 38160120
DOI: 10.1016/j.reumae.2023.12.004 -
Archives of Pathology & Laboratory... Apr 2024Myelodysplasia cutis is an emerging concept in cutaneous neoplasia. Many of these cases were previously included under the umbrella of histiocytoid Sweet syndrome.... (Review)
Review
CONTEXT.—
Myelodysplasia cutis is an emerging concept in cutaneous neoplasia. Many of these cases were previously included under the umbrella of histiocytoid Sweet syndrome. However, with the advent of next-generation sequencing, cutaneous involvement by myelodysplastic syndrome is being increasingly recognized.
OBJECTIVE.—
To review histiocytoid Sweet syndrome and myelodysplasia cutis and discuss our current understanding of these entities. Additionally, to discuss how next-generation sequencing can be applied in the evaluation of cutaneous infiltrates of immature histiocytoid cells.
DATA SOURCES.—
The English-language literature from 2005 to 2023 on the topic of histiocytoid Sweet syndrome and myelodysplasia cutis was reviewed.
CONCLUSIONS.—
Biopsy specimens showing infiltrates of histiocytoid, immature myeloid cells may represent cutaneous involvement by myelodysplastic syndrome. Close clinical correlation is recommended in these cases. Recent studies suggest that next-generation sequencing is useful in separating myelodysplasia cutis from true histiocytoid Sweet syndrome. This distinction has important implications for patients.
Topics: Humans; Myelodysplastic Syndromes; Skin; Skin Neoplasms; Sweet Syndrome
PubMed: 37787422
DOI: 10.5858/arpa.2023-0132-RA -
The Medical Clinics of North America May 2022Malignancy is the second leading cause of death in the United States, following heart disease. In most cancers, early detection is one of the most important factors in... (Review)
Review
Malignancy is the second leading cause of death in the United States, following heart disease. In most cancers, early detection is one of the most important factors in determining prognosis. As clinicians it is therefore important to be aware of potential clues of underlying malignancy on physical examination. Given the wide range of malignancies, and the heterogeneous nature of their presentations, this article is by no means exhaustive. Instead, it discusses in depth some of the more frequently encountered physical examination findings that may suggest malignancy. Specifically, it covers lymphadenopathy, cutaneous findings related to various cancers, and malignancy related thrombosis.
Topics: Early Detection of Cancer; Humans; Neoplasms; Prognosis; United States
PubMed: 35491062
DOI: 10.1016/j.mcna.2021.12.006 -
Dermatologic Clinics Apr 2024Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis that is poorly understood. It was first described by Kieffer and colleagues as an urticarial... (Review)
Review
Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis that is poorly understood. It was first described by Kieffer and colleagues as an urticarial eruption that is histopathologically characterized by a perivascular and interstitial neutrophilic infiltrate with intense leukocytoclasia and without vasculitis or dermal edema. NUD clinically presents as a chronic or recurrent eruption that consists of nonpruritic macules, papules, or plaques that are pink to reddish and that resolve within 24 hours without residual pigmentation. NUD is often associated with systemic diseases such as Schnitzler syndrome, lupus erythematosus, adult-onset Still's disease, and cryopyrin-associated periodic syndromes.
Topics: Adult; Humans; Skin; Urticaria; Schnitzler Syndrome; Lupus Erythematosus, Systemic; Still's Disease, Adult-Onset; Exanthema
PubMed: 38423683
DOI: 10.1016/j.det.2023.08.009