Linear IgA bullous dermatosis (LABD) is a rare subepidermal autoimmune blistering disease characterized by linear deposition of IgA along the basement membrane zone. Although most reported cases are ...idiopathic, there is a subset of patients with drug-induced LABD. Various drugs have been associated with the drug-induced form of the disease. This paper reviews the literature on drugs reported to elicit linear IgA dermatosis and its specific clinical presentation. In addition, a case report of a 77-year-old male patient with linear IgA dermatosis induced by vancomycin is described. The aim of this paper is to emphasize the need to include this differential diagnosis in cases of suspected adverse drug reactions, as well as to highlight the role of drugs in LABD.
A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most ...commonly used mouse model of psoriasis.
We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis.
Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR.
We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and TH17-skewing cytokines, resulting in a TH17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation.
In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/TH17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis.
Display omitted
Display omitted
Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully ...understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease.
We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases.
We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients.
NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE.
NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD.
Interface dermatitis is a characteristic histological pattern that occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct ...type of skin inflammation. Here we investigated the overlap of two different interface dermatitis positive skin diseases, lichen planus and lupus erythematosus. The shared transcriptome signature pointed toward a strong type I immune response, and biopsy-derived T cells were dominated by IFN-γ and tumor necrosis factor alpha (TNF-α) positive cells. The transcriptome of keratinocytes stimulated with IFN-γ and TNF-α correlated significantly with the shared gene regulations of lichen planus and lupus erythematosus. IFN-γ, TNF-α, or mixed supernatant of lesional T cells induced signs of keratinocyte cell death in three-dimensional skin equivalents. We detected a significantly enhanced epidermal expression of receptor-interacting-protein-kinase 3, a key regulator of necroptosis, in interface dermatitis. Phosphorylation of receptor-interacting-protein-kinase 3 and mixed lineage kinase domain like pseudokinase was induced in keratinocytes on stimulation with T-cell supernatant—an effect that was dependent on the presence of either IFN-γ or TNF-α in the T-cell supernatant. Small hairpin RNA knockdown of receptor-interacting-protein-kinase 3 prevented cell death of keratinocytes on stimulation with IFN-γ or TNF-α. In conclusion, type I immunity is associated with lichen planus and lupus erythematosus and induces keratinocyte necroptosis. These two mechanisms are potentially involved in interface dermatitis.
Histopathological differentiation of early Mycosis Fungoides (MF) from benign chronic inflammatory dermatoses remains difficult and often impossible, despite the inclusion of all available diagnostic ...parameters.
To identify the most impactful histological criteria for a predictive diagnostic model to discriminate MF from atopic dermatitis (AD).
In this multicenter study, two cohorts of patients with either unequivocal AD or MF were evaluated by two independent dermatopathologists. Based on 32 histological attributes, a hypothesis-free prediction model was developed and validated on an independent patient's cohort.
A reduced set of two histological features (presence of atypical lymphocytes in either epidermis or dermis) was trained. In an independent validation cohort, this model showed high predictive power (95% sensitivity and 100% specificity) to differentiate MF from AD and robustness against inter-individual investigator differences.
The study investigated a limited number of cases and the classifier is based on subjectively evaluated histological criteria.
Aiming at distinguishing early MF from AD, the proposed binary classifier performed well in an independent cohort and across observers. Combining this histological classifier with immunohistochemical and/or molecular techniques (such as clonality analysis or molecular classifiers) could further promote differentiation of early MF and AD.
Highly effective targeted therapies are available to treat noncommunicable chronic inflammatory skin diseases. In contrast, the exact diagnosis of noncommunicable chronic inflammatory skin diseases ...is complicated by its complex pathogenesis and clinical and histological overlap. Particularly, the differential diagnosis of psoriasis and eczema can be challenging in some cases, and molecular diagnostic tools need to be developed to support a gold standard diagnosis. The aim of this work was to develop a real-time PCR-based molecular classifier to distinguish psoriasis from eczema in formalin-fixed and paraffin-embedded-fixed skin samples and to evaluate the use of minimally invasive microbiopsies and tape strips for molecular diagnosis. In this study, we present a formalin-fixed and paraffin-embedded–based molecular classifier that determines the probability for psoriasis with a sensitivity/specificity of 92%/100%, respectively, and an area under the curve of 0.97, delivering comparable results to our previous published RNAprotect-based molecular classifier. The psoriasis probability, as well as levels of NOS2 expression, positively correlated with the disease hallmarks of psoriasis and negatively with eczema hallmarks. Furthermore, minimally invasive tape strips and microbiopsies were effectively used to differentiate psoriasis from eczema. In summary, the molecular classifier offers broad usage in pathology laboratories as well as outpatient settings and can support the differential diagnosis of noncommunicable chronic inflammatory skin diseases on a molecular level using formalin-fixed and paraffin-embedded tissue, microbiopsies, and tape strips.
Abstract
Highly specific and efficient drugs have been developed to treat noncommunicable chronic inflammatory skin diseases (ncISD). Due to their specificity, these drugs require precise diagnostics ...to attribute the most efficient treatment to each patient. Diagnosis is complicated by the complex pathogenesis of ncISD and their clinical and histological overlap. Especially, precise diagnosis of psoriasis and atopic eczema is difficult in special cases, and molecular tools need to be developed to support gold standard diagnosis. Psoriasis and eczema are among the most prevalent skin diseases worldwide with a combined incidence rate of at least 2%. Although more than a dozen of immune-modulating therapies, particularly monoclonal antibodies targeting specific cytokines or their receptors, have become available over the last decade allowing highly effective treatment, the ultimate breakthrough would include accurate diagnostic tools. Diagnosis of both diseases largely depends on a subjective visual exam and histopathological examination. Due to phenotypical overlaps of both diseases, up to 50% of cases with a palmoplantar localization are misdiagnosed. To close this diagnostic gap, a gene expression-based classifier using NOS2 and CCL27 has been proposed and its clinical validity examined and proven in various patient cohorts. This study aims to develop a real-time based molecular classifier (MC) to distinguish psoriasis from atopic eczema in formalin-fixed, paraffin-embedded (FFPE)-fixed skin samples for diagnostic measures and to evaluate the potential of minimally invasive microbiopsies and noninvasive tape strips or sampling disks for molecular diagnosis. The FFPE, micro-(Ø1mm) and macrobiopsies (Ø4–6 mm), and tape strips were collected from psoriasis and eczema lesions and analysed by real-time polymerase chain reaction (PCR) for the expression of NOS2 and CCL27. A molecular classifier (MC) was established using a linear regression model. We transferred the RNAprotect-based molecular classifier to FFPE samples and were able to produce comparable results. Whereas the RNAprotect based MC distinguished psoriasis from eczema with a sensitivity and specificity for psoriasis of 97.7% and 100%, respectively, and an AUC of 0.99, the FFPE-based classifier determined probabilities for psoriasis with a sensitivity and specificity and of 92% and 100%, respectively, and an AUC of 0.97. To test if microbiopsies are also adequate tissue samples for the MC, we analysed gene expression in 83 pairs of macro- and microbiopsies by real-time quantitative-PCR. Delta-CT values showed no significant difference between macro- and microbiopsies. The MC led to reliable results in the vast majority of samples (91.57%) independent of biopsy size, with a small increase of misclassification (4.98%). The FFPE-based molecular classifier (MC) precisely separates eczema from psoriasis and efficiently identifies subtypes of both diseases. The reliability of the two markers NOS2 and CCL27 has been shown in FFPE tissue facilitating a possible implementation of this molecular diagnostic aid in routine clinical pathological practice. We further show that the gene expression profile of RNA later fixed microbiopsies is comparable to standard 4–6 mm biopsies and that microbiopsies are equally suited for the MC. We demonstrate the potential of tape strips of inflamed epidermis for molecular diagnostics of ncISD. Due to the minimally invasive sampling procedure, tape stripping may be particularly useful for the testing of visible and sensitive skin areas and in children as well as for repetitive sampling procedures necessary to monitor treatment responses over time. In summary, the MC discriminates psoriasis from eczema producing meaningful results in a broad range of skin tissue derived from invasive to minimally invasive sampling techniques. Further efforts are required to simplify and shorten the labor- and cost-intensive procedures of RNA isolation and real-time PCR. One possible solution is a fully automated and closed system, which would allow the integration of molecular diagnostics into the routine patient management at the point of care.
Ixekizumab gegen die Acrodermatitis continua Pilz, Anna Caroline; Roenneberg, Sophie; Biedermann, Tilo ...
Journal der Deutschen Dermatologischen Gesellschaft,
07/2018, Letnik:
16, Številka:
7
Journal Article
PDF
