Severe autoimmune hemolytic anemia following immunotherapy with checkpoint inhibitors in two patients with metastatic melanoma: a case report.

Introduction: Over the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening. Case report: Herein, we report two patients on immune checkpoint inhibitors for metastatic melanoma who developed AIHA with symptoms of dyspnea and fatigue. In the first patient, symptoms alleviated after discontinuation of combined anti CTLA-4 and anti-PD-1 therapy, initiation of corticosteroids and application of a single red blood cell transfusion. Due to subsequent progress of melanoma, combinational anti-PD-1 and tyrosine kinase inhibitor therapy was initiated based on multidisciplinary tumor board decision. After two months, she again developed the described hematological and clinical signs of AIHA leading to cessation of anti-PD-1 therapy and initiation of corticosteroids, which again resulted in an alleviation of her symptoms. Due to further progression, the patient received dacarbazine for several months before she decided to stop any therapy other than palliative supportive care. In the second patient, discontinuation of anti-PD-1 therapy and initiation of corticosteroids entailed a complete alleviation of his symptoms. After refusing chemotherapy due to subsequent melanoma progression, he received radiotherapy of bone metastases and is currently enrolled in a clinical trial. The patient did not develop AIHA ever since. Conclusion: Hematologic immune-related adverse events due to treatment with immune checkpoint inhibitors are rare but can have life-threatening consequences. If dyspnea and other clinical symptoms are present, AIHA should be considered as a potential cause and treated promptly in a multidisciplinary setting. An expanded comprehension of risk factors and pathogenesis of AIHA is needed to identify high-risk patients beforehand, leading to more effective predictive and reactive treatment approaches.

Current Concepts on Pathogenic Mechanisms and Histopathology in Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune disease that may be limited to the skin or can be associated with systemic lupus erythematosus (SLE). CLE occurs in several morphologic subtypes ranging from isolated, disc-shaped plaques to disseminated skin lesions. The typical histopathologic pattern of skin lesions is named interface dermatitis and characterized by a lymphocytic infiltrate and necroptotic keratinocytes at the dermo-epidermal junction. Other histopathologic patterns primarily involve the dermis or subcutis, depending on the subtype. One critical mechanism in CLE is the chronic reactivation of innate and adaptive immune pathways. An important step in this process is the recognition of endogenous nucleic acids released from dying cells by various pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and other cytosolic receptors. Crucial cells in CLE pathogenesis comprise plasmacytoid dendritic cells (pDCs) as major producers of type I IFN, T cells exerting cytotoxic effects, and B cells, previously believed to contribute via secretion of autoantibodies. However, B cells are increasingly considered to have additional functions, supported by studies finding them to occur in highest numbers in chronic discoid lupus erythematosus (CDLE), a subtype in which autoantibodies are often absent. More precise knowledge of how CLE subtypes differ pathophysiologically may allow a tailored pharmacotherapy in the future, taking into account the specific molecular signature in relation to the morphologic subtype.

Bullous Pemphigoid in Patients Receiving Immune-Checkpoint Inhibitors and Psoriatic Patients-Focus on Clinical and Histopathological Variation.

BACKGROUND: The most common autoimmune blistering disease, bullous pemphigoid (BP), shows an increased prevalence in psoriatic patients and oncologic patients undergoing immune-checkpoint blockade (ICB). Even though the same autoantigens (BP180/BP230) are detectable, it remains obscure whether clinical or histopathological differences exist between these different groups of BP patients. In this study, we strived to analyze this matter based on own data and previously published reports. METHODS: We performed an institutional chart review from 2010-2020 to identify BP patients with psoriasis (n = 6) or underlying ICB (n = 4) and matched them with idiopathic cases of BP (n = 33). We compared clinical characteristics, subtypes, and dermatopathological determinants (e.g., tissue eosinophilia/neutrophilia, papillary edema, lymphocytic infiltration) among the groups. RESULTS: ICB-associated BP affects men more often and might show mucosal involvement more frequently. We found no statistically significant dermatopathological differences among the groups. CONCLUSIONS: Clinicians should be aware of an increased risk of BP in patients with psoriasis and oncologic patients receiving ICB; atypical pruritic skin lesions should prompt a workup including a skin biopsy for histopathology and direct immunofluorescence in these patients. Larger studies might be necessary to detect slight dermatopathological variation.

Annular plaques mimicking Rowell's syndrome in the course of coronavirus disease 2019 mRNA vaccines: An overlooked phenomenon?

Effective vaccines for prevention of severe course and lethal outcome of coronavirus disease 2019 have been developed and approved in regulatory rolling and fast-track procedures; they are now widely distributed worldwide. Data about cutaneous side-effects of the new mRNA-type vaccines is scant, however. We herein report two similar cases of cutaneous adverse drug reactions (ADR) mimicking Rowell's syndrome that occurred after the first dose of BNT162b2 and mRNA-1273, respectively. Both patients achieved prompt clinical improvement with a short pulse of oral prednisolone and non-steroidal inflammatory drugs. We suspect this phenomenon to occur in a timeframe of 7-14 days after vaccination due to an interferon-γ-driven shift towards type I immunity in susceptible individuals. As rheumatic patients were excluded from phase III clinical trials and as most countries prioritized the elderly population to receive the vaccinations first, cutaneous ADR might become more frequent once the younger part of the population is vaccinated over the course of 2021. Atypical cutaneous ADR might be misinterpreted or overlooked by non-dermatologists. Further studies are required to determine the best suitable vaccine types for individual groups of patients.

Targeted Therapies in Autoimmune Skin Diseases.

Unlike the established anti-inflammatory drugs with a broad range, new-targeted therapeutic approaches have emerged in the management of autoimmune skin diseases to increase efficacy and decrease adverse reactions on the basis of an improved molecular understanding of pathogenesis. Most inflammatory dermatoses are driven by misled immune responses physiologically directed at exogenous pathogens, that is, type 1 immunity against viral pathogens, type 2 immunity against parasites, and type 3 immunity against fungi and bacteria. Pathogenic hallmarks of these major immune reaction patterns are characterized within this article, and a comprehensive overview of current clinical trials evaluating targeted therapeutics for respective dermatoses is outlined.

The Initial Stage of Neutrophilic Dermatosis of the Dorsal Hands: A Case Report and Discussion of Differential Diagnoses.

Neutrophilic dermatosis of the dorsal hands (NDDH) is considered a localized variant of acute febrile neutrophilic dermatosis. It is a rare condition and presents with erythematous tender nodules and plaques on the extensor sides of the hands. Forty percent of NDDH cases occur in association with an underlying disease, with hematologic disorders being the most frequent type. Here, we describe the case of a 77-year-old male patient who presented with acute tumid, erythematous lesions of the fingers. As part of this report, we discuss possible differential diagnoses of NDDH and seek to raise awareness of this rare condition, as misdiagnoses often lead to a delay in adequate treatment and thus more dramatic disease courses.

Single-Center Clinico-Pathological Case Study of 19 Patients with Cutaneous Adverse Reactions Following COVID-19 Vaccines.

(1) Background: Coronavirus disease 2019 (COVID-19) vaccines are currently employed on a population-wide scale in most countries worldwide. Data about unusual cutaneous adverse drug reactions (ADR) are scant, though. (2) Methods: We retrospectively analyzed moderate to severe vaccine-related ADR in the Department of Dermatology and Allergy of the University Hospital Bonn between May to June 2021 and analyzed related skin biopsies. (3) Results: As a specialized dermatological academic center, we encountered a total of n = 19 clinically and pathologically heterogeneous cutaneous ADR with a female predominance. Delayed cutaneous ADR occurred as late as 30 days after vaccination. The majority of ADR were mild, though a few patients required systemic treatment (antihistamines, glucocorticosteroids). (4) Conclusions: The clinico-pathological spectrum of cutaneous side effects with COVID-19 vaccines is wide; however, the benefits outweigh the risks by far. More dermatopathological studies on cutaneous ADR not limited to COVID-19 vaccines are desirable to enable a better understanding of underlying pathophysiological mechanisms.

Cutaneous Adverse Reactions to COVID-19 Vaccines: Insights from an Immuno-Dermatological Perspective.

(1) Background: Numerous vaccines are under preclinical and clinical development for prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19). In light of high efficacy rates and satisfactory safety profiles, some agents have already reached approval and are now distributed worldwide, with varying availability. Real-world data on cutaneous adverse drug reactions (ADRs) remain limited. (2) Methods: We performed a literature research concerning cutaneous ADRs to different COVID-19 vaccines, and incorporated our own experiences. (3) Results: Injection site reactions are the most frequent side effects arising from all vaccine types. Moreover, delayed cutaneous ADRs may occur after several days, either as a primary manifestation or as a flare of a pre-existing inflammatory dermatosis. Cutaneous ADRs may be divided according to their cytokine profile, based on the preponderance of specific T-cell subsets (i.e., Th1, Th2, Th17/22, Tregs). Specific cutaneous ADRs mimic immunogenic reactions to the natural infection with SARS-CoV-2, which is associated with an abundance of type I interferons. (4) Conclusions: Further studies are required in order to determine the best suitable vaccine type for individual groups of patients, including patients suffering from chronic inflammatory dermatoses.

Grzybowski's Generalized Eruptive Keratoacanthomas in a Patient with Terminal Kidney Disease-An Unmet Medical Need Equally Ameliorated by Topical Imiquimod Cream and Lapacho Tea Wraps: A Case Report.

INTRODUCTION: Development of singular keratoacanthoma (KA) is generally considered a benign condition as it has a tendency to regress spontaneously in spite of histological similarity to squamous cell carcinoma. Most KAs undergo excision to rule out differential diagnoses. Several alternative treatment modalities (keratinolytic, ablative, immunomodulating, antiproliferative, or targeted therapy) have been described in the past with varying success, underlining the therapeutic challenges associated with large or multiple lesions. Isomorphic response (Koebner phenomenon) may limit the efficacy of ablative options, and comorbidity may limit the use of systemic treatments. Less aggressive topical immunomodulatory treatment options represent an alternative with varying therapeutic success. CASE REPORT: Here, we describe the clinical course of a 51-year-old male patient with terminal kidney disease who suffered from the rare benign pruritic condition of Grzybowski's generalized eruptive keratoacanthomas (GEKA) and experienced a significant reduction of lesions and symptoms upon topical therapy with imiquimod 5% cream and lapacho tea dressings alike. CONCLUSIONS: Very little is known about the potential antiinflammatory or antiproliferative effects on the epidermis of the popular phytotherapeutic agent lapacho tea. More studies are warranted considering both the etiology and treatment of GEKA and topical use of phytotherapeutics in dermatology in general. Management of large or multiple KAs remains challenging.

Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases-Implications for Therapeutic Approaches.

B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL).

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions.

Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN) -driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1-/- -mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1-/- -mouse model and appears to be a promising therapeutic approach for CLE patients.

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis-Translation of Pathogenic Fundamentals Into an In Vitro Model.

Interface dermatitis is a histopathological pattern mirroring a distinct cytotoxic immune response shared by a number of clinically diverse inflammatory skin diseases amongst which lichen planus and cutaneous lupus erythematosus are considered prototypic. Interface dermatitis is characterized by pronounced cytotoxic immune cell infiltration and necroptotic keratinocytes at the dermoepidermal junction. The initial inflammatory reaction is established by cytotoxic immune cells that express CXC chemokine receptor 3 and lesional keratinocytes that produce corresponding ligands, CXC motif ligands 9/10/11, recruiting the effector cells to the site of inflammation. During the resulting anti-epithelial attack, endogenous immune complexes and nucleic acids are released from perishing keratinocytes, which are then perceived by the innate immune system as danger signals. Keratinocytes express a distinct signature of pattern recognition receptors and binding of endogenous nucleic acid motifs to these receptors results in interferon-mediated immune responses and further enhancement of CXC chemokine receptor 3 ligand production. In this perspective article, we will discuss the role of innate nucleic acid sensing as a common mechanism in the perpetuation of clinically heterogeneous diseases featuring interface dermatitis based on own data and a review of the literature. Furthermore, we will introduce a keratinocyte-specific in vitro model of interface dermatitis as follows: Stimulation of human keratinocytes with endogenous nucleic acids alone and in combination with interferon gamma leads to pronounced production of distinct cytokines, which are essential in the pathogenesis of interface dermatitis. This experimental approach bears the capability to investigate potential therapeutics in this group of diseases with unmet medical need.

Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type I IFN-associated inflammation. Keratinocytes are known to determine the interface dermatitis pattern in CLE by production of proinflammatory cytokines in the lower epidermis. These cytokines drive a cytotoxic anti-epithelial immune response resulting in keratinocytic cell death and release of endogenous nucleic acids. We hypothesized that these endogenous nucleic acids (RNA and DNA motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen recognition receptors. Gene expression analyses showed an excessive activation of innate immune response pathways with strong expression of IFN-regulated cytokines in CLE skin lesions. Cultured keratinocytes produce large amounts of these cytokines in response to stimulation of PRR with endogenous nucleic acids. UV stimulation enhances the immunogenicity of endogenous nucleic acids and induces CLE-like skin lesions in knockout mice lacking the cytosolic DNase TREX1. Our results provide evidence for a pathogenetic role of endogenous nucleic acids in CLE. They are released within the cytotoxic inflammation along the dermo-epidermal junction and have the capacity to drive the CLE-typical inflammation. UV irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8-hydroxyguanosine). These findings explain the photosensitivity of patients with lupus and identify pathways of the innate immune system as targets for future therapies.

Spleen tyrosine kinase (SYK) is a potential target for the treatment of cutaneous lupus erythematosus patients.

Spleen tyrosine kinase (SYK) is a protein kinase involved in cell proliferation and the regulation of inflammatory pathways. Due to the increasing evidence that kinase inhibitors have potential as specific anti-inflammatory drugs, we have investigated the potential for SYK inhibition as a therapeutic target in autoimmune diseases, particularly cutaneous lupus erythematosus (CLE). Skin samples of patients with different CLE subtypes and appropriate controls were analysed for the expression of SYK and SYK-associated pro-inflammatory mediators via gene expression analysis and immunohistochemistry. The functional role of SYK in keratinocytes was investigated in vitro, using LE-typical pro-inflammatory stimuli and a selective inhibitor of SYK. SYK-associated genes are strongly upregulated in CLE skin lesions. Importantly, phosphorylated SYK (pSYK) is strongly expressed by several immune cell types and also keratinocytes in CLE skin. In vitro, immunostimulatory nucleic acids are capable of inducing SYK phosphorylation in keratinocytes leading to the induction of pro-inflammatory cytokines, while small-molecule SYK inhibition decreases the expression of these proteins. The results demonstrate that pSYK is expressed by immune cells and keratinocytes in skin lesions of CLE patients. LE-typical stimuli induce the expression of pSYK in vitro. Small-molecule SYK inhibition leads to a reduction of pSYK expression and downregulation of pro-inflammatory cytokines in keratinocytes. We therefore believe that pSYK provides a potential future drug target for the treatment of patients who suffer from CLE and related skin disorders. Specifically, our study reveals evidence supporting the use of topical SYK inhibitors in treating lupus.