Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Mucosal Fixed Drug Eruption with Oral, Conjunctival, Nasal, and Anal Lesions: A Case Report.

is missing (Short communication).

Current Perspective Regarding the Immunopathogenesis of Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS/DRESS).

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe type of adverse drug eruption associated with multiorgan involvement and the reactivation of human herpesvirus 6, which arises after prolonged exposure to certain drugs. Typically, two waves of disease activity occur during the course of DIHS/DRESS; however, some patients experience multiple waves of exacerbation and remission of the disease. Severe complications, some of which are related to cytomegalovirus reactivation, can be fatal. DIHS/DRESS is distinct from other drug reactions, as it involves herpes virus reactivation and can lead to the subsequent development of autoimmune diseases. The association between herpesviruses and DIHS/DRESS is now well established, and DIHS/DRESS is considered to arise as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune responses and antiviral immune responses, each of which may be mediated by distinct types of immune cells. It appears that both CD4 and CD8 T cells are involved in the pathogenesis of DIHS/DRESS but play distinct roles. CD4 T cells mainly initiate drug allergies in response to drug antigens, and then herpesvirus-specific CD8 T cells that target virus-infected cells emerge, resulting in tissue damage. Regulatory T-cell dynamics are also suggested to contribute to the diverse symptoms of DIHS/DRESS. However, the pathomechanisms of this complex disease remain largely unknown. In particular, how viral infections contribute to the pathogenesis of DIHS/DRESS and why autoimmune sequelae arise in DIHS/DRESS are yet to be elucidated. This review describes the clinical features of DIHS/DRESS, including the associated complications and sequelae, and discusses recent advances in our understanding of the immunopathogenic mechanisms of DIHS/DRESS.

Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus.

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis. SLE was chemically induced into IRF7-deficient mice, and glomerulonephritis with deposits of IgG and lipogranulomas were observed after 10 mo. However, these mice failed to produce anti-dsDNA, ssDNA, ribonucleoprotein, and Sm autoantibodies. Following the chemical induction, IRF7-deficient mice expressed substantially lower levels of IFN-stimulated genes than did wild-type mice, but NF-κB target genes were equally upregulated in both strains. Therefore, the type I IFN pathway seems critical for the autoantibody production, but the NF-κB activation is sufficient for the development of glomerulonephritis in this model. Our study thus demonstrates a specific requirement for IRF7 in autoantibody production and uncovers a new layer of complexity in the pathogenesis of SLE.

Clinical and immunologic features of recurrent herpes zoster (HZ).

BACKGROUND: Recurrent herpes zoster (HZ) is thought to be rare, but there have been few large-scale studies of recurrent HZ. OBJECTIVE: We conducted a large-scale prospective cohort study to characterize recurrent HZ. METHODS: We examined 12,522 participants aged 50 years or older in Shozu County and followed them up for 3 years. We compared the incidence of HZ and postherpetic neuralgia, severity of skin lesions and acute pain, cell-mediated immunity, and varicella-zoster virus-specific antibody titer between primary and recurrent HZ. RESULTS: A total of 401 participants developed HZ: 341 with primary HZ and 60 with recurrent HZ. Skin lesions and acute pain were significantly milder and the incidence of postherpetic neuralgia was lower in patients aged 50 to 79 years with recurrent HZ than in those with primary HZ. Varicella-zoster virus skin test induced a stronger reaction in patients aged 50 to 79 years with recurrent HZ than in those with primary HZ. LIMITATIONS: Information on previous HZ episodes was self-reported by participants, so it could not be confirmed that they actually had a history of HZ. CONCLUSION: Recurrent HZ was associated with milder clinical symptoms than primary HZ, probably because of stronger varicella-zoster virus-specific cell-mediated immunity in the patients with recurrence.

Interferon regulatory factor 8 integrates T-cell receptor and cytokine-signaling pathways and drives effector differentiation of CD8 T cells.

We recently demonstrated that differentiation of cytotoxic T cells requires cooperation between T-cell receptor (TCR)/costimulation and γc-cytokines. Here we demonstrate that the transcription factor IFN regulatory factor 8 (IRF8) is expressed in CD8 T cells by the combination of these two signals. More importantly, depletion of IRF8 in these cells abrogated the differentiation of naive CD8 T cells into effector cells in an experimental graft-vs.-host disease mouse model. We also show that IRF8 seems to not operate upstream of other critical factors such as T-bet and eomesodermin, which have been implicated in effector maturation. Collectively, our work shows that IRF8 integrates the TCR/costimulation and γc-cytokine-signaling pathways and mediates the transition of naive CD8 T cells to effector cells, thus identifying IRF8 as one of the molecular regulators of CD8 T-cell differentiation.

Type I IFN Derived from Ly6Chi Monocytes Suppresses Type 2 Inflammation in a Murine Model of Atopic Dermatitis.

The roles of innate immune cells, including eosinophils, basophils, and group 2 innate lymphoid cells, in atopic dermatitis (AD) have been well-documented, whereas that of monocytes, another component of the innate immunity, remains rather poorly understood, thus necessitating the topic of this study. In addition, cytokines and cellular pathways needed for the resolution of type 2 inflammation in AD need further investigation. Using a murine AD model, we report here that (i) Ly6Chi monocytes were rapidly recruited to the AD lesion in a CCR2-dependent manner, blockade of which exacerbated AD; (ii) type I IFN production is profoundly involved in this suppression because the blockade of it by genetic depletion or antibody neutralization exacerbated AD; and (iii) Ly6Chi monocytes operate through the production of type I IFN because Ly6Chi monocytes from Irf7-null mice, which lack type I IFN production, failed to rescue Ccr2-/- mice from severe AD upon adoptive transfer. In addition, in vitro studies demonstrated type I IFN suppressed basophil expansion from bone marrow progenitor cells and survival of mature basophils. Collectively, our work suggests that Ly6Chi monocytes are the first and dominant inflammatory cells reaching AD lesions that negatively regulate type 2 inflammation through the production of type I IFN.

Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Current Knowledge of the Molecular Pathogenesis of Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease, which can be limited to the skin or associated with systemic lupus erythematosus (SLE). Gene expression analysis has revealed that both the innate and adaptive immune pathways are activated in CLE. Ultraviolet (UV) light, the predominant environmental factor associated with CLE, induces apoptosis in keratinocytes, and the endogenous nucleic acids released from the apoptotic cells are recognized via pattern recognition receptors, including Toll-like receptors. This leads to the production of type I interferon, a major contributor to the pathogenesis of CLE, by plasmacytoid dendritic cells. UV irradiation can also induce the externalization of autoantigens, such as SS-A/Ro, exposing them to circulating autoantibodies. T-helper 1 cells have been reported to play important roles in the adaptive immune response to CLE. Other environmental factors associated with CLE include drugs and cigarette smoke. Genetic factors also confer a predisposition to the development of CLE, and many susceptibility genes have been identified. Monogenetic forms of CLE also exist. This article aims to review current knowledge about the pathogenesis of CLE. A better understanding of the environmental, genetic, and immunoregulatory factors that drive CLE may provide important insights for the treatment of CLE.

Drug-Induced Hypersensitivity Syndrome/Drug Reaction With Eosinophilia and Systemic Symptoms: Predictive Score and Outcomes.

BACKGROUND: We previously developed a drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) severity (DDS) score that may predict DIHS/DRESS-associated complications (DACs), including myocarditis, gastrointestinal bleeding, and autoimmune diseases. OBJECTIVE: To externally confirm the predictive accuracy of the DDS score, clarify its ability to identify patients at high risk of DACs and fatal outcome, and determine which treatments might reduce or increase the risk. METHODS: We conducted a nationwide multicenter retrospective study in which we followed 48 patients with DIHS/DRESS at 5 university hospitals in Japan for 1 year after onset. Patients were divided into mild, moderate, and severe DIHS/DRESS groups depending on their early DDS score. RESULTS: Eight cases had DACs in the severe group (n = 17); no DACs were observed in the mild group (n = 12). Receiver-operating characteristic curve analysis showed that a cutoff DDS score of ≥4.0 and ≤2.0 could differentiate patients who would and would not develop DACs, respectively. In the moderate-to-severe disease groups, DACs occurred only in patients who received corticosteroids and not in those who received supportive care. None of the patients who received early treatment for cytomegalovirus developed DACs. Autoimmune DACs were significantly more common in patients who received pulse corticosteroid therapy. Four deaths occurred within the 1-year follow-up; all were in patients with infectious DACs who received systemic corticosteroids. CONCLUSION: Our scoring system allows early identification of patients at increased risk for DACs. Risk factors for DACs include systemic or pulse corticosteroid therapy.

Pathogenesis of Paradoxical Reactions Associated with Targeted Biologic Agents for Inflammatory Skin Diseases.

Targeted biologic agents have dramatically changed the therapeutic landscape for immune-mediated inflammatory diseases, particularly in rheumatology and dermatology. Their introduction has resulted in a paradigm shift, i.e., they produce significant clinical improvements in most patients with such diseases. Nevertheless, a variety of adverse reactions associated with these agents have been observed, including so-called paradoxical reactions (PRs), which are a new class of adverse events. PRs involve the de novo development or worsening of immune-mediated inflammatory disease during treatment with a targeted biologic agent that is commonly used to treat the idiopathic counterpart of the drug-induced reaction. In addition, the efficacy of biologic agents targeting individual cytokines and the existence of PRs to them have provided proof that cytokines are key drivers of various immune-mediated inflammatory diseases and helped researchers elucidate the molecular pathways underlying the pathophysiology of these diseases. Here, a comprehensive review of the targeted biologic agents used to treat immune-mediated inflammatory diseases, particularly psoriasis and atopic dermatitis, is provided, with a specific focus on biologic agents that inhibit cytokine signaling involving tumor necrosis factor-α, interleukin (IL)-12/23 (p40), IL-17A (and the IL-17 receptor [R]), IL-23 (p19), and the IL-4Rα, and their associated PRs. The characteristic clinical manifestations and potential immunological mechanisms of the PRs induced by these biologic agents are also reviewed.